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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY




    ENVIRONMENTAL HEALTH CRITERIA 146





    1,3-Dichloropropene, 1,2-Dichloropropane
    and Mixtures



    This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    World Health Orgnization
    Geneva, 1993

          The International Programme on Chemical Safety (IPCS) is a joint
    venture of the United Nations Environment Programme, the International
    Labour Organisation, and the World Health Organization.  The main
    objective of the IPCS is to carry out and disseminate evaluations of
    the effects of chemicals on human health and the quality of the
    environment.  Supporting activities include the development of
    epidemiological, experimental laboratory, and risk-assessment methods
    that could produce internationally comparable results, and the
    development of manpower in the field of toxicology.  Other activities
    carried out by the IPCS include the development of know-how for coping
    with chemical accidents, coordination of laboratory testing and
    epidemiological studies, and promotion of research on the mechanisms
    of the biological action of chemicals.

    WHO Library Cataloguing in Publication Data

    1,3-Dichloropropene, 1,2-dichloropropane and mixtures.

    (Environmental health criteria: 146)

    1. Environmental exposure    2. Hydrocarbons, Chlorinated - adverse
    effects  3. Hydrocarbons, Chlorinated - poisoning    4. Hydrocarbons,
    Chlorinated - toxicity   5. Occupational exposure    I.Series

          ISBN 92 4 157146 2         (NLM Classification QV 633)
          ISSN 0250-8634

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    to reproduce or translate its publications, in part or in full.
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    (c) World Health Organization 1993

          Publications of the World Health Organization enjoy copyright
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    that are not mentioned.  Errors and omissions excepted, the names of
    proprietary products are distinguished by initial capital letters.

    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR 1,3-DICHLOROPROPENE,
    1,2-DICHLOROPROPANE, AND MIXTURES

    PART A.   1,3-DICHLOROPROPENE

    PART B.   1,2-DICHLOROPROPANE

    PART C.   MIXTURES OF DICHLOROPROPENES AND DICHLOROPROPANE

    REFERENCES

    RESUME ET EVALUATION, CONCLUSIONS, ET RECOMMANDATIONS

    RESUMEN Y EVALUACION, CONCLUSIONES, Y RECOMENDACIONES
    
    WHO TASK GROUP ON ENVIRONMENTAL HEALTH
    CRITERIA FOR 1,3-DICHLOROPROPENE,
    1,2-DICHLOROPROPANE, AND MIXTURES

     Members

    Dr V. Benes, Department of Toxicology and Reference Laboratory,
         Institute of Hygiene & Epidemiology, Prague, Czechoslovakia

    Dr R. Drew, Key Centre for Toxicology, Department of Applied
         Biology, Royal Melbourne Institute for Technology, Melbourne,
         Victoria, Australia  (Chairman)

    Dr S.K. Kashyap, National Institute of Occupational Health,
         Ahmedabad, India

    Dr J.I. Kundiev, Research Institute of Labour Hygiene & Occupational
         Diseases, Kiev, Ukraine  (Vice-Chairman)

    Dr K. Mitsumori, Division of Pathology, Biological Safety Research
         Center, National Institute of Hygienic Sciences, Tokyo, Japan

    Dr Richard F. Shore, Ecotoxicology and Pollution Section, Institute
         of Terrestrial Ecology, Monks Wood Experimental Station, Abbots
         Ripton, Huntingdon, United Kingdom 

    Dr G.J. van Esch, Oranje, Bilthoven, Netherlands  (Rapporteur)

    Dr E.A.H. van Heemstra-Lequin, Laren, Netherlands  (Joint
          Rapporteur)

    Dr S. Wong, Bureau of Chemical Hazards, Environmental Health
         Directorate, Department of National Health and Welfare,
         Tunney's Pasture, Ottawa, Ontario, Canada 

     Observers

    Dr D.E. Owen, Shell Internationale Petroleum Maatschappij BV, The
         Hague, Netherlands

     Members from the Host Institution

    Dr W.H. Gross, Fraunhofer Institute of Toxicology & Aerosol
         Research, Hanover, Germany

    Dr J.R. Kielhorn, Fraunhofer Institute of Toxicology & Aerosol
         Research, Hanover, Germany

    Dr C.M. Melber, Fraunhofer Institute of Toxicology & Aerosol
         Research, Hanover, Germany

     Secretariat

    Dr R.F. Hertel, Fraunhofer Institute of Toxicology & Aerosol
         Research, Hanover, Germany

    Dr K.W. Jager, International Programme on Chemical Safety, World
         Health Organization, Geneva, Switzerland  (Secretary)

    Mme C. Partensky, Unit of Carcinogen Identification and Evaluation,
         International Agency for Research on Cancer  (IARC), Lyon,
         France

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

         Every effort has been made to present information in the
    criteria monographs as accurately as possible without unduly
    delaying their publication. In the interest of all users of the
    Environmental Health Criteria monographs, readers are kindly
    requested to communicate any errors that may have occurred to the
    Director of the International Programme on Chemical Safety, World
    Health Organization, Geneva, Switzerland, in order that they may be
    included in corrigenda.



                                  * * * 


         A detailed data profile and a legal file can be obtained from
    the International Register of Potentially Toxic Chemicals, Palais
    des Nations, 1211 Geneva 10, Switzerland (Telephone No. 7988400 or
    7985850).



                                   * * * 


     Note: The proprietary information contained in this monograph
    cannot replace documentation for registration purposes, because the
    latter has to be closely linked to the source, the manufacturing
    route, and the purity/impurities of the substance to be registered.
    The data should be used in accordance with paragraphs 82-84 and
    recommendations paragraph 90 of the Second FAO Government
    Consultation (1982).

    ENVIRONMENTAL HEALTH CRITERIA FOR
    1,3-DICHLOROPROPENE, 1,2-DICHLOROPROPANE, AND MIXTURES

         The meeting of the WHO Task Group on Environmental Health
    Criteria for 1,3-dichloropropene, 1,2-dichloropropane, and mixtures,
    which was held at the Fraunhofer Institute of Toxicology and Aerosol
    Research, Hanover, Germany, from 16 to 20 September 1990, was
    sponsored by the German Ministry of the Environment. Dr R.F. Hertel
    welcomed the participants on behalf of the host institute. Dr K.W.
    Jager, IPCS, welcomed the participants on behalf of Dr M. Mercier,
    Director of the IPCS, and the three IPCS cooperating organizations
    (UNEP/ILO/WHO). The Group reviewed and revised the draft criteria
    monograph and made an evaluation of the risks for human health and
    the environment from exposure to 1,3-dichloropropene, 1,2-
    dichloropropane, and mixtures of dichloropropenes and
    dichloropropane. 

         Dr E.A.H. van Heemstra-Lequin and Dr G.J. van Esch of the
    Netherlands cooperated in the preparation of the first draft of the
    EHC monograph. Dr van Esch prepared the second draft, incorporating
    the comments received following circulation of the first draft to
    the IPCS contact points for Environmental Health Criteria
    monographs.

         Dr K.W. Jager of the IPCS Central Unit was responsible for the
    scientific content of the monographs, and Mrs M.O. Head of Oxford
    for the editing.

         The fact that Shell and Dow Chemical made their proprietary
    toxicological information on their products available to the IPCS
    and the Task Group is gratefully acknowledged. This allowed the Task
    Group to make their evaluation on a more complete data base.

         The efforts of all who helped in the preparation and
    finalization of the publications are gratefully acknowledged. 

                                    * * *

         Partial financial support for the publication of this criteria
    monograph was kindly provided by the United States Department of
    Health and Human Services, through a contract from the National
    Institute of Environmental Health Sciences, Research Triangle Park,
    North Carolina, USA - a WHO Collaborating Centre for Environmental
    Health Effects.

    PART A

    ENVIRONMENTAL HEALTH CRITERIA FOR 1,3-DICHLOROPROPENE

    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR 1,3-DICHLOROPROPENE

    1.   SUMMARY AND EVALUATION, CONCLUSIONS, AND RECOMMENDATIONS

         1.1   Summary and evaluation
               1.1.1   Use, environmental fate, and environmental levels
               1.1.2   Kinetics and metabolism
               1.1.3   Effects on organisms in the environment
               1.1.4   Effects on experimental animals and  in vitro
                       test systems
               1.1.5   Effects on human beings
         1.2   Conclusions
         1.3   Recommendations

    2.   IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

         2.1   Identity
         2.2   Physical and chemical properties
         2.3   Conversion factors
         2.4   Analytical methods
               2.4.1   Sampling
               2.4.2   Determination of residues in crops and soil
               2.4.3   Determination of residues in water
               2.4.4   Determination of residues in air
               2.4.5   Determination of residues in food
               2.4.6   Determination of 3-chloroallyl alcohol
               2.4.7   Determination of mercapturic acids in urine

    3.   SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1   Natural occurrence
         3.2   Man-made sources
               3.2.1   Production levels and processes
               3.2.2   Use
               3.2.3   Sources of pollution

    4.   ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         4.1   Transport and distribution between media
               4.1.1   Air
               4.1.2   Water
               4.1.3   Soil
                       4.1.3.1   Hydrolysis
                       4.1.3.2   Volatilization
                       4.1.3.3   Uptake in crops
                       4.1.3.4   Movement in soil
                       4.1.3.5   Loss under field conditions
                       4.1.3.6   Results of supervised field trials
         4.2   Bioconcentration

         4.3   Abiotic degradation
               4.3.1   Photodegradation
         4.4   Biodegradation and biotransformation
               4.4.1   Miscellaneous

    5.   ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1   Air
         5.2   Water
         5.3   Crops
         5.4   Occupational exposure

    6.   KINETICS AND METABOLISM

         6.1   Absorption, distribution, and elimination
               6.1.1   Oral
                       6.1.1.1   Rat
                       6.1.1.2   Mouse
               6.1.2   Inhalation
                       6.1.2.1   Rat
         6.2   Influence on tissue levels of glutathione
               6.2.1   Oral
               6.2.2   Inhalation
         6.3   Biotransformation
               6.3.1   Rat
               6.3.2   Humans
         6.4   Reaction with macromolecules
               6.4.1   Mouse
               6.4.2   Rat
         6.5   Appraisal

    7.   EFFECTS ON ORGANISMS IN THE ENVIRONMENT

         7.1   Acute toxicity
               7.1.1   Microorganisms
               7.1.2   Algae
               7.1.3   Invertebrates
               7.1.4   Honey bees
               7.1.5   Fish
               7.1.6   Birds
         7.2   Short-term/long-term toxicity
               7.2.1   Invertebrates
               7.2.2   Fish
               7.2.3   Field studies
               7.2.4   Phytotoxicity

    8.   EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

         8.1   Single exposures
               8.1.1   Oral

               8.1.2   Inhalation
               8.1.3   Dermal
         8.2   Short-term exposures
               8.2.1   Oral
               8.2.2   Inhalation
                       8.2.2.1   Mouse
                       8.2.2.2   Rat
                       8.2.2.3   Other animal species
         8.3   Skin and eye irritation, sensitization
               8.3.1   Skin irritation
               8.3.2   Eye irritation
                       8.3.2.1    In vitro studies
               8.3.3   Sensitization
         8.4   Long-term exposure
         8.5   Reproduction, embryotoxicity, and teratogenicity
               8.5.1   Reproduction
                       8.5.1.1   Inhalation (rat)
                       8.5.1.2   Intraperitoneal (mouse)
               8.5.2   Teratogenicity
                       8.5.2.1   Inhalation (rat)
                       8.5.2.2   Inhalation (rabbit)
         8.6   Mutagenicity and related end-points
               8.6.1    In vitro studies
                       8.6.1.1   Microorganisms
                       8.6.1.2   Effects of glutathione on bacterial
                                 mutagenesis
                       8.6.1.3   Mammalian cells
                       8.6.1.4   DNA damage
                       8.6.1.5   Chromosomal effects
               8.6.2    In vivo studies
               8.6.3   Appraisal
         8.7   Carcinogenicity
               8.7.1   Oral
                       8.7.1.1   Mouse
                       8.7.1.2   Rat
               8.7.2   Inhalation
                       8.7.2.1   Mouse
                       8.7.2.2   Rat
               8.7.3   Appraisal
               8.7.4   Dermal and subcutaneous (mouse)
         8.8   Factors modifying toxicity, toxicity of metabolites, mode
               of action
               8.8.1   Toxicity of metabolites,  cis- and  trans-
                       1,3-dichloropropene oxide
                       8.8.1.1   Mutagenicity
                       8.8.1.2   Carcinogenicity
               8.8.2   Role of oxidation
               8.8.3   Role of glutathione
               8.8.4   Effect on liver enzyme activity

    9.   EFFECTS ON HUMANS

         9.1   General population
               9.1.1   Acute toxicity - poisoning incidents
               9.1.2   Controlled human studies
         9.2   Occupational exposure
               9.2.1   General
               9.2.2   Acute toxicity - poisoning incidents
               9.2.3   Effects of short- and long-term exposure

    10.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    1.  SUMMARY AND EVALUATION, CONCLUSIONS, AND RECOMMENDATIONS

    1.1  Summary and evaluation

    1.1.1  Use, environmental fate, and environmental levels

         "1,3-Dichloropropene" was introduced in 1956 as part of a
    mixture, containing 1,3-dichloropropenes, 1,2-dichloropropane, and
    other halogenated hydrocarbons, and has been widely used in
    agriculture as a pre-plant soil fumigant for the control of
    nematodes in vegetables, potatoes, and tobacco. Application is
    primarily by soil injection. The commercial formulation of 1,3-
    dichloropropene is a mixture of  cis- and  trans-isomers (in
    approximately equal proportions), which is a colourless to amber
    liquid with a penetrating, irritating, chloroform-like odour. The
    vapour pressure is 3.7 kPa at 20 °C. The technical product has a
    purity of 92% and may contain a number of impurities, such as 1,2-
    dichloropropane. The log P octanol/water partition coefficient is
    1.98.

         In air, decomposition of 1,3-dichloropropene is mainly by
    reaction with free radicals and ozone. The half-lives of the  cis-
    and  trans-isomers in the reaction with free radicals are 12 and
    7 h, respectively, and in the reaction with ozone, 52 and 12 days,
    respectively. Direct photo-transformation seems to be insignificant,
    but may be enhanced in the presence of atmospheric particles. 

         In water, 1,3-dichloropropene is likely to disappear rapidly,
    because of its relatively low water solubility and high volatility;
    half-lives of less than 5 h have been reported. 

         The distribution of 1,3-dichloropropene in soil compartments is
    dependent on the vapour pressure, diffusion coefficient,
    temperature, and moisture content of the soil. The persistence of
    1,3-dichloropropene in soil is influenced by volatilization,
    chemical and biological transformation, photochemical
    transformation, and organism uptake. Volatilization and diffusion in
    the vapour phase are the most significant mechanisms for
    environmental dispersion and dilution.

         Transformation of 1,3-dichloropropene is initially by
    hydrolysis to 3-chloroallyl alcohol and then by microbial
    transformation to 3-chloroacrolein and 3-chloroacrylic acid. In a
    laboratory study, the half-lives for the hydrolysis of the  cis-
    and  trans-isomers of 1,3-dichloropropene at 15 °C and 29 °C were
    11.0 and 2.0 days, respectively, for the  cis-isomer and 13.0 and
    2.0 days for the  trans-isomer. In soil with a pH of 7 and a
    temperature of 25 °C, the half-life for hydrolysis for both isomers
    was 4.6 days. Because of its relatively rapid disappearance from
    soil, residues are unlikely to accumulate when the fumigant is
    applied at the recommended rate and frequency.

         1,3-Dichloropropene is potentially mobile in soil, especially
    in open-textured, sandy soil with a low moisture content. Downward
    movement is enhanced by deep cultivation of soils with low porosity.
    1,3-Dichloropropene has been detected in "upper groundwater" (up to
    2 m below the surface), but not in deep groundwater, which is more
    likely to be used for drinking-water. 

         1,3-Dichloropropene can be taken up by crops. However,
    significant residues are unlikely to occur in edible crops, because
    these are not normally planted until most of the fumigant has
    dissipated.

         Bioaccumulation of 1,3-dichloropropene is unlikely, because of
    its relatively high water solubility (> 1 g/kg), low log P octanol
    water partition coefficient, and rapid elimination from mammals and
    other organisms.

    1.1.2  Kinetics and metabolism

         1,3-Dichloropropene administered orally to rodents is rapidly
    eliminated. The major route of elimination is in the urine where 81%
    of the  cis-isomer and 56% of the  trans-isomer are eliminated
    within 24 h of dosing. The half-life of elimination in the urine is
    5-6 h. Faecal elimination is minor. Expired carbon dioxide accounts
    for 4 and 24% of the elimination of the  cis- and  trans-isomers
    of 1,3-dichloropropene, respectively. Tissue concentrations after
    oral administration are low; the highest residual concentrations are
    found in the stomach wall, followed by lower amounts in the kidneys,
    liver, and bladder.

         Unchanged 1,3-dichloropropene is not found in the urine. The
     cis- and  trans-isomers are substrates for hepatic glutathione-
     S-alkyl transferase, forming mercapturic acids, which are excreted
    in the urine. The  trans-isomer is conjugated 4-5 times more slowly
    than the  cis-isomer. The principal urinary metabolite in rats and
    mice is  N-acetyl- S-(3-chloroprop-2-enyl)L-cysteine; this
    compound can be used for biological monitoring in humans. A second,
    minor metabolic pathway has been identified for the  cis-isomer
    that involves mono-oxygenation to  cis-1,3-dichloropropene oxide,
    which can also be conjugated with glutathione. The high proportion
    of the  trans-isomer that occurs in expired air results from an
    alternative metabolic pathway to conjugation that has a higher
    specificity for the  trans- than for the  cis-isomer.

         Inhalation exposure of rats to 1,3-dichloropropene did not lead
    to increases in blood concentrations proportional with dose. At a
    dose of 408.6 mg/m3 (90 ppm), respiratory frequency and
    respiratory minute volume were decreased and saturation of
    metabolism occurred at 1362 mg/m3 (300 ppm).  Cis- and  trans-
    isomers were rapidly eliminated from the blood, the half-life of

    elimination being 3-6 min at concentrations below 1362 mg/m3 but
    considerably longer (33-43 min) at higher concentrations. 

    1.1.3  Effects on organisms in the environment

         The EC50 values for growth (96 h) for the freshwater alga,
     Selenastrum capricornutum, and the estuarine diatom,  Skeletoneria
     costatum, are 4.95 mg/litre and 1 mg/litre, respectively. The
    acute toxicity (96-h LC50) of 1,3-dichloropropene for fish is of
    the order of 1-7.9 mg/litre. In an embryo-larval test on Fathead
    minnow, the maximum no-effect level was 0.24 mg/litre. These data
    and the fact that 1,3-dichloropropene is unlikely to persist in
    water, indicate that the hazard for fish lies in acute toxic
    effects, with little potential for additional effects resulting from
    long-term exposure.

         1,3-dichloropropene at dose levels of 30-60 mg/kg can reduce
    the abundance of fungi and the rate of microbial enzyme activity,
    but the effect is not usually long lasting (< 7 days) and does not
    occur in all soil types. In some studies, there was a significant
    increase in microbial numbers following application. 

         1,3-Dichloropropene is phytotoxic, however, its toxicity for
    Honey bees is low. Using a dusting technique, the 48-h LD50 was
    6.6 µg/bee. Birds are relatively non-sensitive to 1,3-
    dichloropropene. LC50s (8-day) of > 10 g/kg were reported for
    Mallard duck and Bobwhite quail.

    1.1.4  Effects on experimental animals and in vitro test systems

         The acute oral toxicity of 1,3-dichloropropene in animals is
    moderate to high. The LD50 values reported in rats ranged between
    127 and 713 mg/kg body weight. The oral LD50 values in rats for
    the  cis- and  trans-isomers were 85 and 94 mg/kg body weight,
    respectively.

         Acute dermal exposure is moderately toxic. Dermal LD50s of
    423 mg/kg body weight and 504 mg/kg body weight have been reported
    for the rat and the rabbit, respectively. The LD50 values for the
     cis- and  trans-isomers were 1090 and 1575 mg/kg body weight,
    respectively.

         Inhalation exposure (4 h) of rats indicated LC50s of 3310
    mg/m3 (729 ppm) for 1,3-dichloropropene; 3042-3514 mg/m3 for the
     cis-isomer, and 4880-5403 mg/m3 for the  trans-isomer.

         Acute intoxication showed central nervous and respiratory
    system involvement.

         Severe reactions were seen in rabbit skin and eye irritation
    tests, but recovery occurred in 14-21 days. The results of skin
    sensitization tests on guinea-pigs were positive. 

         Several short-term inhalation toxicity studies have been
    conducted on mice, rats, guinea-pigs, rabbits, and dogs. In mice,
    the nasal mucosa and urinary bladder were the target organs.
    Degeneration of the olfactory epithelium and hyperplasia of the
    respiratory epithelium were observed. Moderate hyperplasia of the
    transitional epithelium in the urinary bladder was found. A no-
    observed-effect level (NOEL) of 136 mg/m3 (30 ppm) in mice can be
    estimated.

         Similar degenerative changes of the olfactory epithelium and
    hyperplasia have been demonstrated in rats. The reported NOEL value
    for 1,3-dichloropropene from a well-designed study was 45.4 mg/m3;
    a NOEL of 136 mg/m3 has been reported for the  cis-isomer.

         A 90-day oral study on rats indicated a NOEL of 3 mg/kg body
    weight. The only observed effect at the next higher dose level of 10
    mg/kg body weight was an increase in relative kidney weight in the
    male.

         In a 2-generation, 2-litter, inhalation study on rats, doses of
    up to 408.6 mg/m3 (90 ppm) did not show adverse effects on the
    reproduction parameters examined. However, the highest dose level of
    408.6 mg/m3 induced maternal toxicity, as evidenced by decreased
    growth and histopathological changes in the nasal mucosa. A NOEL of
    136.2 mg/m3 (30 ppm) was established for maternal toxicity.

         Inhalation teratogenicity studies on rats and rabbits did not
    indicate teratogenic potential for 1,3-dichloropropene at exposure
    levels up to 1362 mg/m3, but embryotoxicity (reduction in litter
    size and increase in resorption rates) was seen in the rat. Maternal
    toxicity was observed in both rats and rabbits at dose levels of
    544.8 mg/m3 (120 ppm) or more.

         In most of the studies,  cis- and  trans-1,3-dichloropropene
    and mixtures were mutagenic in bacteria with, and without, metabolic
    activation. Pure 1,3-dichloropropene and pure  cis-1,3-
    dichloropropene were found to be negative in bacteria. Glutathione
    was shown to prevent the mutagenic activity of 1,3-dichloropropene
    in bacteria.  Cis-1,3-dichloropropene was negative in a gene
    mutation assay with V79 Chinese hamster cells as well as in the
    Chinese hamster ovary HPRT test.

          Cis- and  trans-1,3-dichloropropene induced unscheduled DNA
    synthesis in HeLa S3 cells. In rat hepatocytes, 1,3-
    dichloropropene did not elicit significant DNA repair. 1,3-
    Dichloropropene was positive in the  Bacillus subtilis strain H17
    microsome rec-assay with metabolic activation.

         In Chinese hamster ovary cells,  cis- and  trans-1,3-
    dichloropropene induced chromosome damage in the presence of
    metabolic activation but, in another study, 1,3-dichloropropene was
    positive without metabolic activation.  Cis-1,3-dichloropropene did
    not induce chromosomal damage in rat liver cells, but induced sister
    chromatid exchange in Chinese hamster ovary cells with, and without,
    metabolic activation and in Chinese hamster V79 cells without
    activation.

         1,3-Dichloropropene was negative in a bone marrow micronucleus
    test on mice and in a sex-linked, recessive lethal assay on
     Drosophila melanogaster.

         Carcinogenicity studies were carried out on mice and rats.
    Technical 1,3-dichloropropene (containing 1% epichlorhydrin) was
    administered by gavage for 2 years. In mice, a significant increase
    in epithelial hyperplasia and transitional cell carcinomas in the
    urinary bladder, an increase in lung tumours, a slight increase in
    tumours of the liver, and an increase in epithelial hyperplasia and
    squamous cell papillomas or carcinomas in the forestomach were
    found. In rats, increases in the incidence of neoplastic nodules in
    the liver and of squamous cell papillomas or carcinomas of the
    forestomach were observed.

         The carcinogenicity in mice and rats of 1,3-dichloropropene
    (without epichlorohydrin) was investigated in 2-year inhalation
    studies. In mice, increased incidences of hyperplasia of the urinary
    bladder, the forestomach, and the nasal mucosa were observed. There
    was an increase in the incidence of benign lung tumours. Some toxic
    changes in the olfactory mucosa of the nasal cavity were also seen
    in rats, but no increase in tumour incidence. 

         Epichlorohydrin was shown to produce forestomach tumours in a
    gavage study and nasal cavity tumours in an inhalation study on
    rats; a carcinogenic effect on the urinary bladder cannot be
    excluded for 1,3-dichloropropene administered orally to mice. 

    Mode of Action

         Given that the major metabolic route of elimination of 1,3-
    dichloropropene is via conjugation with glutathione, it is to be
    expected that situations that affect tissue glutathione (non-protein
    sulfhydryl) concentrations may modify the effects of the compound.
    1,3-Dichloropropene itself depletes the glutathione content of a
    variety of tissues, especially those that are the initial points of
    entry into the body, i.e., predominantly the forestomach and liver
    following gavage administration, and the nasal tissue after
    inhalation exposure. Decreases in nasal epithelium and forestomach
    glutathione occurred in mice after inhalation of 1,3-dichloropropene
    concentrations exceeding 22.7 mg/m3 (5 ppm) and 113.5 mg/m3 (25
    ppm), respectively.

         The toxicity of 1,3-dichloropropene in animals occurs at
    exposures that deplete glutathione and prior reduction of tissue
    glutathione exacerbates it. Long-term inhalation of concentrations
    higher than 90.8 mg/m3 (20 ppm) results in degeneration and
    hyperplasia of nasal and stomach epithelia in mice, and long-term
    inhalation at 272.4 mg/m3 (60 ppm) causes degeneration of nasal
    tissue in rats.

         The protective role of glutathione has been further highlighted
    by studies demonstrating that covalent binding of 14C-1,3-
    dichloropropene to mouse forestomach increased as the non-protein
    sulfhydryl content decreased. Similarly, in  in vitro test systems,
    the genotoxicity of 1,3-dichloropropene and its minor oxidative
    (cytochrome P-450) metabolite (1,3-dichloropropene oxide) was
    markedly ameliorated by glutathione. 

    1.1.5  Effects on human beings

         The exposure of the general population through air, water, or
    food is unlikely.

         Studies have shown that occupational exposures are generally
    below 4.54 mg/m3 (1 ppm), but higher levels have also been
    reported (up to 18.3 mg/m3 during filling or nozzle changing).
    Occupational exposure is likely to be through inhalation and via the
    skin. Irritation of the eyes and the upper respiratory mucosa
    appears promptly after exposure. Inhalation of air containing
    concentrations of > 6810 mg/m3 (> 1500 ppm) resulted in serious
    signs and symptoms of poisoning; lower exposures resulted in
    depression of the central nervous system and irritation of the
    respiratory system. Dermal exposure caused severe skin irritation. 

         Some liver and kidney function changes were reported in a group
    of 1,3-dichloroprepene applicators at the end of the application
    season. However, the cause-effect relationship has been contested.

         Some poisoning incidents have occurred in which persons were
    hospitalized with signs and symptoms of irritation of the mucous
    membrane, chest discomfort, headache, nausea, vomiting, dizziness,
    and, occasionally, loss of consciousness and decreased libido. Three
    cases of haematological malignancies have been attributed to an
    earlier accidental overexposure to 1,3-dichloropropene, but the
    cause-effect relationship remains uncertain.

         The fertility status of workers employed in the production of
    chlorinated three-carbon compounds was compared with a control
    group. There was no indication of an association between decreased
    fertility and exposure.

    1.2  Conclusions

    General population: In view of the low or non-existent exposure to
    1,3-dichloropropene, the risk to the general population is
    negligible.

    Occupational exposure: Filling operations and field applications
    may lead to operator exposure exceeding the maximum allowable
    concentration, when appropriate safety precautions have not been
    taken.

    Environment: Provided that 1,3-dichloropropene is used at the
    recommended rate, it is unlikely to attain levels of environmental
    significance and is unlikely to have adverse effects on populations
    of terrestrial and aquatic organisms.

    1.3  Recommendations

    *    Filling operations and field applications of 1,3-
         dichloropropene should only be conducted taking appropriate
         safety precautions, in order to ensure that exposure levels do
         not exceed the maximum allowable concentrations of 1,3-
         dichloropropene.

    *    Studies should be conducted to investigate the metabolic fate
         of  trans-1,3-dichloropropene in mammals and the potential
         role that oxidative metabolites of this isomer may have in
         mediating 1,3-dichloropropene toxicity.

    *    Glutathione transferase mediates the protective effect of
         glutathione against the toxicity of 1,3-dichloropropene. It is
         recommended that studies should be carried out to compare the
         relative enzyme kinetics of human glutathione  S-transferase
         from various tissues with enzyme activity from comparable
         animal tissues.

    *    The available data on the protective role of glutathione should
         be consolidated and published in the open literature. 

    *    Part of the genotoxicity of dichloropropene is mediated by
         oxidative metabolism. It is recommended that studies be
         undertaken to identify the responsible cytochrome P-450
         isoenzyme and compare its activity with human P-450 isoenzymes.

    *    The confounding role of epichlorohydrin in oral gavage
         carcinogenicity studies should be clarified. 

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1  Identity

     Primary constituents

    Chemical structure

    CHEMICAL STRUCTURE 01

    Chemical formula              C3H4Cl2

    Relative molecular mass       110.98

    Chemical name                 1,3-dichloropropene; (IUPAC);
                                  dichloro-1,3-propene; (F-ISO); 
                                  1,3-dichloro-1-propene; (CA).

    Common synonyms               gamma-chloroallylchloride,
                                  1,3-dichloropropylene

    Trade name                    TELONE II(R), D-D 92

    CAS registry number           542-75-6 ( cis- and  trans-isomers)
                                   cis-isomer: 10061-01-5
                                   trans-isomer: 10061-02-6

    RTECS registry number         UC8310000

    EINECS number                 208-826-5

         The commercial product is a mixture of  cis- and  trans-
    isomers and is more than 92% pure. In the past, 1% epichlorohydrin
    was added as a stabilizer, but nowadays an epoxidized vegetable oil
    is used.

         Other names are: Dedisol C, Nematox II, D-D 95, Telone 2000
    (Hayes, 1982; Worthing & Hance, 1991).

    2.2  Physical and chemical properties

    Freezing point                - 85 °Ca ( cis-isomer)

    Boiling point                 103.8-105.2 °C ( cis-isomer)a
                                  111.0-112.0 °C ( trans-isomer)b
                                  108.0 °C (1,3-dichloropropene)

    Vapour pressure at 25 °C      4850 Pa ( cis-isomer)a
                                  3560 Pa ( trans-isomer)b
                                  3.7 kPa (20 °C) (1,3-dichloropropene)

    Relative density (D 23/4)     1.221 kg/litre ( cis-isomer)a
                     (D 20/4)     1.214 kg/litre ( trans-isomer)b
    Water solubility              2.45 ( cis-isomer)a
    (at 20 °C, in g/litre)        2.49 ( trans-isomer)b 
                                  2.0 (1,3-dichloropropene)

    Flash point                   28.5 °C ( cis-isomer)a
                                  28.0 °C ( trans-isomer)b
                                  25.0 °C (1,3-dichloropropene)

    Self-ignition                 555 °C ( cis-isomer)a
                                  534 °C ( trans-isomer)b

    Log P octanol/water           1.82 at 20 °C ( cis-isomer)a
    partition coefficient         2.22 at 25 °C ( trans-isomer)b
                                  1.4-2.0 (1,3-dichloropropene)

    K(OM/Vc                       14 ( cis-isomer)
                                  15 ( trans-isomer)

    K (OM/V)c                     14 ( cis-isomer)

                                  15 ( trans-isomer)

                      

    a    purity 98.1%;
    b    purity 96.7%;
    c    K(OM/V) = µg adsorbed per g of organic matter (soil)
                           µg dissolved per ml water phase

    From: Leistra (1970), Krijgsheld & van der Gen (1986), Bennett &
    Ridge (1989), Schuurman (1989), van Hooidonk (1989), O'Connor
    (1990a).

         Neither the  cis- nor the  trans-isomer produces gas in
    contact with water, and they are not highly flammable in contact
    with diatomite.

         1.3-Dichloropropene is a colourless to amber coloured liquid
    with a penetrating, irritating, chloroform-like odour. The technical
    product is > 92% pure. The physical properties of a  cis/trans
    mixture depend on the ratio of the isomers (Yang, 1986). 

         Saturated atmosphere: 167 980 mg/m3 (37 000 ppm) at 25 °C.
    Explosive limit: 195 220 mg/m3 (43 000 ppm) (80 °C). Miscible with
    acetone, benzene, carbon tetrachloride, heptane, and methanol
    (Sittig, 1980; Hayes, 1982; Worthing & Hance, 1991). 

         Van Hooidonk (1989) and O'Connor (1990a) described methods to
    determine the water- and/or fat solubility of  cis- and  trans-
    1,3-dichloropropene using gas chromatography and ECD and/or FID
    detection.

         Details on ultraviolet/visible, infrared, and nuclear magnetic
    resonance spectra are given by O'Connor (1990a). 

    2.3  Conversion factors

         1 ppm (91.2% 1,3-dichloropropene) = 4.54 mg/m3 at 25 °C at 1
    atm (Krijgsheld & Van der Gen, 1986; Breslin et al., 1987). 

    2.4  Analytical methods

         Methods have been developed for the determination of 1,3-
    dichloropropene ( cis- and  trans-isomers) and of 1,2-
    dichloropropane in air, soil, water, and crops, and the degradation
    product 3-chloroallyl alcohol ( cis- and  trans-isomers) in soil
    and crops (see Tables 1 and 2). Current methods are based on gas
    chromatography (GC).

    2.4.1  Sampling

         In the case of crops and soil, the need for special care in the
    handling of samples and extracts has been stressed, because of the
    high volatility of 1,3-dichloropropene.

         To minimize loss of residue by volatilization, soil samples
    should be deep frozen as soon as possible after sampling, and
    shipped to the laboratory for analysis in sealed containers with a
    minimum of delay (Rexilius & Schmidt, 1982). The period of storage
    of deep frozen samples in the laboratory should also be kept as
    short as possible (Wallace, 1979). At -20 °C, Hermann & Matsuyama
    (1982) found a slow decline in the contents of all components of
    "MIX D/D", indicating a maximum acceptable storage period of 2
    months. No loss occurred in 4 months at a temperature of -80 °C.


        Table 1.  Methods of analysis for 1,3-dichloropropene and 1,2-dichloropropane in food and biological media
                                                                                                                                             
    Sample  Extraction           Clean-up                     Detection and         Recovery          Limit of           Reference
                                                              quantitation                          determination
                                                                                                                                             

    Crops,  steam distillation   absorption chromatography    gas chromatography       -a            0.01 mg/kg          Rexilius & Schmidt
    Soil    and diethyl ether    on acidic alumina            with ECD and FID                  (1,3-dichloropropene)    (1982); Shell (1985);
            extraction                                                                                0.1 mg/kg          Wallace (1974)
                                                                                                (1,2-dichloropropane)

            trapped in                    -                   gas chromatography       -a                 -              Shell (1980)
            ethyl acetate                                     with ECD

    Water   steam distillation   absorption chromatography    gas chromatography       -a            0.001 mg/kg         Shell (1985)
            and diethyl ether    on acidic alumina            with ECD                          (1,2-dichloropropane)
            extraction

    Air           -              absorption on Tenax GC,      gas chromatography       -a                -a              Leiber & Berk (1984)
                                 desorption with isooctane    with ECD

    Air           -              absorption on charcoal,      gas chromatography     90-100%         0.005 mg/m3         Van Sittert et al.
                                 desorption with              with FID                                                   (1977); Sherren &
                                 carbon disulfide                                                                        Woodbridge (1987a,b)

    Air           -              absorption on charcoal,      gas chromatography       85%             23 ngb            Albrecht et al.
                                 desorption with              with ECD                                                   (1986)
                                 methanol/benzene

    Blood   hexane                     -                      gas chromatography       90%          cis and trans        Kastl & Hermann
                                                              with 63Ni-ECD or                  1,3-dichloropropene,     (1983)
                                                              GS-MS (SIM)                         5.3-5.9 ng/litre

                                                                                                                                             

    a   Data on recovery and/or limit of determination not given.
    b   Given as mass/tube.

    Table 2.  Methods of analysis for 3-chloroallyl alcohol in food and biological media
                                                                                                                                              
    Sample  Extraction           Clean-up                     Detection and         Recovery          Limit of           Reference
                                                              quantitation                          determination
                                                                                                                                              

    Crop,   diethyl ether        derivatization with 3,5-     gas chromatography        -         crops: 0.05 mg/kg      Rexilius & Schmidt
    Soil                         dinitrobenzoyl chloride      with ECD                            soil: 0.02 mg/kg       (1982)
                                 and pyridine, absorption                                                                Wallace (1974)
                                 chromatography on acidic
                                 alumina

    Crop,   steam-distillation,  esterification with          capillary gas-            -                 -              Shell (1978)
    Soil,   hexane extraction    trifluoroacetic              chromatography            -                 -
    Water   with diethyl ether   anhydride                    with ECD                  -        water: 0.002 mg/kg      Shell (1985)

                                                                                                                                              
    

        Crop samples should be deep frozen as soon as possible after
    sampling, and water samples should be chilled or deep frozen; both
    should be shipped and stored under the same precautions as soil
    (Wallace, 1976b; Rexilius & Schmidt, 1982).

    2.4.2  Determination of residues in crops and soil

        A combined method for the determination and confirmation of 1,3-
    dichloropropene, 1,2-dichloropropane, and chloroallyl alcohol (3-
    CAA) in crops and soil has been developed (Wallace, 1974; Shell,
    1976). After steam distillation and extraction and clean up, the
    determination of residues is carried out using gas chromatography
    (electron capture (ECD) and flame ionization (FID)). The chloroallyl
    alcohol is derivatized, followed by a clean up and determination
    using ECD. Confirmation of the identity of residues is carried out
    by combined gas chromatography-mass spectrometry (GC-MS).

        With this method, the lower limit of determination in most crop
    and soil samples is 0.01 mg/kg for 1,3-dichloropropene and 0.1 mg/kg
    for 1,2-dichloropropane. For 3-chloroallyl alcohol, the lower limit
    of determination is 0.05 mg/kg for crops and 0.02 mg/kg for soil
    (Wallace, 1974; Rexilius & Schmidt, 1982; Shell, 1985).

        Alternative methods are described by Shell (1980) in which 1,3-
    dichloropropene and 1,2-dichloropropane are trapped in ethyl acetate
    and directly determined, without clean up by capillary GC with ECD.
    The 3-chloroallyl alcohol residues are steam-distilled without acid
    or alkali and "free residues" are washed with hexane, and extracted
    into diethyl ether. The alcohol residues are then esterified by
    trifluoroacetic anhydride and determined with capillary GC with ECD
    (Shell, 1978).

        Shell (1984) described a method based on the previously
    mentioned techniques of extraction and preparation of extracts;
    however, in both crops and soil, residues are determined by
    capillary GC with a Hall electrolytic conductivity detector (HECD).
    In addition, residues of 3-chloroallyl alcohol are determined
    without derivatization. The lower limit of determination is 0.01
    mg/kg.

    2.4.3  Determination of residues in water

        The methods described in section 2.4.2 can be adapted for the
    determination of residues of 1,3-dichloropropene, 1,2-
    dichloropropane, and 3-chloroallyl alcohol in water (Wallace, 1974).
    The alternative methods mentioned under section 2.4.2 also include
    procedures for water analysis (Wallace, 1974; Shell, 1978) (see
    Table 1).

        A laboratory analytical method (US EPA method 524.2), developed
    to monitor drinking-water, involves a standard inert (helium) gas
    purge extraction, isolation on a solid-phase trap (gas
    chromatography with a fused silica capillary column (FSCC) coated
    with a film of cyanopropylphenyl-dimethylpolysiloxane polymer),
    thermal desorption, and gas chromatography and identification and
    measurement with a low-cost, bench-top ion trap detector (ITD),
    which functions as a mass spectrometer. At a concentration of 0.2
    µg/litre, the total mean measurement accuracy was 99% for  trans-
    1,3-dichloropropene ( cis-isomer not measured) and 103% for 1,2-
    dichloropropane (Eichelberger et al., 1990).

        Telliard (1990) described broad-range methods for the
    determination of pollutants in waste water. US EPA method 1624 is
    used to determine purgeable organic compounds by calibrated isotope
    dilution or internal standard GC-MS and by reverse search of a GS-MS
    run for the analytes. The first technique can be used to determine
    1,2-dichloropropane and the second, 1,3-dichloropropene.

    2.4.4  Determination of residues in air

        Methods based on the use of solid absorbent traps or direct gas
    sampling procedures in conjunction with GC analysis have been
    described for the determination of 1,3-dichloropropenes and 1,2-
    dichloropropane in air.

        Leiber & Berk (1984) used Tenax-GC as an absorbent to monitor
    concentrations of chlorinated aliphatic hydrocarbons in workspace
    air. Isooctane, containing 1,3,5-tribromobenzene as internal
    standard, was used for the desorption of the hydrocarbons.
    Recoveries of 1,3-dichloropropenes were in the range of 1.8-18
    mg/m3. A similar method was used by Van Sittert et al. (1977) and
    Albrecht et al. (1986), but, in this case, the trapping medium was
    activated charcoal. It appears that charcoal had a better trapping
    capacity than Tenax-GC (Brown & Purnell, 1979) for 1,3-
    dichloropropenes. Trapped vapours were desorbed using carbon
    disulfide (recovery 90-100%) (van Sittert et al., 1977; HSE, 1990)
    or 1% v/v methanol-benzene mixture (mean recovery 85%) (Albrecht et
    al., 1986). Van Sittert et al. (1977) could determine 0.05 mg/m3
    of the  cis- and  trans-isomers of 1,3-dichloropropene in air.

        All authors warned that care should be taken in the handling of
    trapped samples.

        Parker et al. (1982) used charcoal filters to determine 1,3-
    dichloropropene and 1,2-dichloropropane levels in air. 

        Others have used more direct gas sampling procedures. Air from
    the head space above soil and water in sealed containers has been
    sampled and directly determined by GC with ECD or FID. Gas samples
    were trapped by injecting the air into an organic solvent, such as

    xylene or hexane, before GC analysis (Williams, 1968; Leistra, 1970;
    Abdalla, 1974; Abdalla et al., 1974; McKenry & Thomason, 1974; van
    Dijk, 1980).

    2.4.5  Determination of residues in food

        Reinert et al. (1983) described a dynamic heated headspace
    analysis of organic compounds including 1,2-dichloropropane in fish
    and shellfish tissue samples. The method included solvent (carbon
    disulfide) desorption of activated carbon adsorbent and
    determination with capillary column gas chromatography with a flame
    ionization detector. Recoveries were rather low (approximately 40-
    70%). Hiatt (1983) described a vacuum distillation apparatus and a
    procedure developed for the analysis of fish tissue. The volatile
    compounds were distilled from the sample and characterized by gas
    chromatography/mass spectrometry using fused silica capillary column
    (FSCC).

        A method was described by Daft (1989) to determine fumigants and
    related chemicals in fatty and non-fatty foods. The method started
    with liquid extraction with isooctane, when necessary with co-
    extraction with a mixture of acetone/NaCl in 25% phosphoric acid and
    isooctane. The isooctane extracts were analysed using gas
    chromatography. Excess fat was removed by micro-Florisil columns.
    The determination was done by ECD and HECD (Hall electroconductivity
    detection). Overall mean recovery was 73% from fatty foods and 78%
    from non-fatty foods; the recovery from both sample types after
    further Florisil chromatography was 55%.

    2.4.6  Determination of 3-chloroallyl alcohol

        In Table 2, analytical methods are described to determine 3-
    chloroallyl alcohol in food and biological media.

    2.4.7  Determination of mercapturic acids in urine

        In Table 3, methods are described to determine metabolites of
    1,3-dichloropropene in urine.

        Van Welie et al. (1989) used an analytical method to determine
     N-acetyl- S-( cis- and  trans)-3-chloroprop-2-enyl-L-cysteine
    ( cis- and  trans-DCP-MA) in urine, based on capillary gas
    chromatography with sulfur-selective detection. An internal standard
     N-acetyl- S-(benzyl)-L-cysteine and hydrochloric acid (resulting
    in a pH 1-2) were added to urine samples. The samples were extracted
    with ethyl acetate and the latter evaporated; the residues were
    methylated and determined using gas chromatography-flame photometric
    detection (GC-FPD). GC-MS was used for identification. The limits of
    determination were 0.107 mg/litre for  cis-DCP-MA and 0.115
    mg/litre for  trans-DCP-MA.


    
    Table 3.  Methods of analysis for metabolites of 1,3-dichloropropene in urine
                                                                                                                                              
    Sample   Extraction       Clean-up                 Detection and                    Recovery          Limit of                Reference
             derivatization   derivatization           quantitation                                       determination
                                                                                                                                              

    N-acetyl-S[cis-chloroprop-2-enyl]cysteine

    Urine    ether            derivatization with      gas chromatography with              -                   -                 Osterloh et
    (human)                   diazomethane etherate    electron impact ionization                                                 al. (1984)
                                                       silicone membrane 
                                                       separator, mass spectrometry

    Urine    ethyl acetate    derivatization with      gas chromatography with          cis-isomer and    for cis- and            van Welie 
    (human)                   diazomethane etherate    fused silica WCOT columns,       trans-isomer      trans-isomer range      et al. (1989)
                                                       sulfur-selective detection       105%              107-115 ng/ml

    Urine    ethyl acetate    derivatization with      gas chromatography with          cis-isomer        for the different       Onkenhout et
    (rat)                     diazomethane             nitrogen selective detection     66-83%            methods and for         al. (1986)
                                                       or negative chemical             trans-isomer      cis- and trans-isomer
                                                       ionization/mass spectrometry     56-85%            range 20-550 ng/ml

                                                                                                                                              
    

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

        As far as is known, 1,3-dichloropropene does not occur
    naturally.

    3.2  Man-made sources

    3.2.1  Production levels and processes

        1,3-Dichloropropene is produced by the high-temperature
    chlorination of propylene or from 1,3-dichloro-2-propanol by
    dehydration with POCl3 or with P2O5 in benzene. 

        1,3-Dichloropropene is a by-product in the synthesis of allyl
    chloride; 1,2-dichloropropane and to a lesser extent, 2,3-
    dichloropropene are also formed. In some commercial products,
    marketed for soil fumigation (mix D/D, Telone), 1,3-dichloropropene
    is the major and active ingredient (50-80% of total), but 1,2-
    dichloropropane (20-40%) and 2,3-dichloropropene (5-6.5%) are also
    present (Krijgsheld & Van der Gen, 1986). 

        Before 1978, about 25 000 tonnes of 1,3-dichloropropene were
    produced annually in the USA (Flessel et al., 1978). In Italy, 2187
    tonnes were produced in 1972 (De Lorenzo et al., 1977). Over 1285
    tonnes of 1,3-dichloropropene-containing pesticides were used in
    California in 1971 (Yang, 1986), while in the period 1970-77, the
    amount applied was approximately 1.8-2.7 million kg. In 1981, over
    7.2 million kg of 1,2-dichloropropane- and 1,3-dichloropropene-
    containing fumigants were used in California (California State Water
    Resources Control Board, 1983). 

        The estimated production in Europe in 1979 was 6-7
    kilotonnes/year.

        1,2-Dichloropropane, present as an impurity in the fumigant,
    does not add to the desired biological effects, but may, on the
    contrary, have unwanted ecotoxicological consequences. Therefore,
    there has been a more recent development to stop the use of the
    "impure" fumigant and to move to a purer preparation of 1,3-
    dichloropropene (> 90%) (Krijgsheld & Van der Gen, 1986).

    3.2.2  Use

        1,3-Dichloropropene, the main ingredient of Telone II, was
    introduced in 1956 as a commercial preplant soil fumigant for the
    control of nematodes in crops, such as vegetables, potatoes, and
    tobacco. It is applied from a tractor-drawn, high pressure injection

    system into the soil. The soil is treated prior to the planting of
    crops (De Lorenzo et al., 1977; Hayes, 1982; Maddy et al., 1982).

        1,3-Dichloropropene is effective against soil nematodes
    including root-knot, meadow, sting and dagger, spiral and sugar beet
    nematodes. The rates of application are determined according to the
    crop to be grown and the soil conditions, but generally lie within
    the range of 75-200 kg/ha (occasional maximum of 700 kg/ha)
    (Krijgsheld & van der Gen, 1986; Shell, IPM, 1990). 

    3.2.3  Sources of pollution

        1,3-Dichloropropene is used extensively as a soil fumigant for
    the treatment of agricultural land. After application, part of the
    chemical will evaporate and escape from the soil. Although
    significant biodegradation and abiotic decomposition will occur in
    the soil, there is a limited risk of leaching down to groundwater
    level (see section 4.1.3). The 1,3-dichloropropene that is used for
    fumigation is contaminated with 1,2-dichloropropane and 2,3-
    dichloropropene. At application rates of "MIX D/D" ranging from 200
    to 400 kg/ha, this may mean an input of 40-160 kg of 1,2-
    dichloropropane and 10-25 kg of 2,3-dichloropropene per hectare of
    land (Krijgsheld & van der Gen, 1986). The potential for groundwater
    contamination has been reduced by reducing the 1,2-dichloropropane
    content of the products used in agriculture. 

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

        As with other fumigants, the performance of 1,3-dichloropropene
    as a nematocide is dependent on a number of important factors
    influencing the movement of soil fumigants, e.g., the chemical and
    adsorptive characteristics of the toxicant (vapour pressure,
    solubility, diffusion coefficient, the distribution of the fumigant
    through air, water, and solid phases of the soil) and physical
    factors, such as temperature, moisture, organic matter, soil
    texture, and soil profile variability (Munnecke & van Gundy, 1979;
    NTP, 1985; Yang, 1986).

        Dichloropropenes can enter the aquatic environment as discharges
    from industrial effluents, through run off from agricultural land,
    and from municipal effluents. 

        The stability and mobility of 1,3-dichloropropene and 1,2-
    dichloropropane in air, soil, and groundwater are influenced by
    several processes, as shown in Fig. 1.

    4.1  Transport and distribution between media

        (See also section 4.1 of 1,2-dichloropropane and subsections). 

    4.1.1  Air

        Tuazon et al. (1984) calculated that, at a daytime OH-radical
    concentration of 2 x 106/cm3 (8 x 10-8 ppm) in the
    troposphere, the half-lives of  cis- and  trans-1,3-
    dichloropropene would be 12 and 7 h, respectively. The half-life for
    1,2-dichloropropane is > 313 days for a 24-h average OH-radical
    concentration of 1 x 106/cm3. For the reaction with ozone at a
    background level in the troposphere of 80 µg/m3 (0.04 ppm), the
    half-lives of  cis- and  trans-1,3 dichloropropene, were
    calculated to be 52 and 12 days. Direct phototransformation seems to
    be insignificant compared with the two other reactions, but may be
    enhanced in the presence of atmospheric particulates.

    4.1.2  Water

        Since the chloropropenes have a relatively low water solubility
    and high volatility, they will have a tendency to disappear rapidly
    from an aqueous medium. The half-life of evaporation of a chemical
    from a certain body of water will increase with the depth of the
    water and continuous evaporation will become increasingly dependent
    on sufficient agitation in the water. Evaporation can be expected to
    contribute significantly to the disappearance from the aquatic
    environment (Krijgsheld & van der Gen, 1986). 

    FIGURE 01

        Dilling et al. (1975) determined the rate of evaporation of 1,3-
    dichloropropene ( cis- and  trans-) from water at the 1 mg/litre
    level under ambient conditions. The time required for the compound
    to be reduced by 50% was 31 min and by 90%, 98 min. 

        Yon et al. (1991) determined that the half-life of evaporation
    of 1,3-dichloropropene ( cis- and  trans-isomers) from water was
    less than 5 h.

    4.1.3  Soil

        The persistence of 1,3-dichloropropene depends on chemical
    degradation, volatilization, microbial transformation, photochemical
    transformation, type of soil, water content of soil, and uptake into
    organisms. Thomason & McKenry (1974) studied the quantitative as
    well as the qualitative aspects of the movement and fate of 1,3-
    dichloropropene under various conditions in different types of soil.

        Since 1,3-dichloropropene is used as soil fumigant, some
    information is available on the distribution of the compound in
    soil. The adsorption of 1,3-DCP on soil was found to be proportional
    to the organic matter content of the soil. The K(om/v)sa for  cis-
    and  trans-1,3-dichloropropene were estimated to be 14 and 15,
    respectively, independent of ambient temperature (Leistra, 1970).
    Similar soil/water distribution coefficients (23 and 26), based on
    organic carbon content, were reported by Kenaga (1980).

        McKenry & Thomason (1974) demonstrated that high soil moisture
    was a major limiting factor in the total diffusion when soil
    moisture in the field approached field capacity. In contrast,
    Munnecke & van Gundy (1979) stated that soil moisture was a very
    important factor in that gaseous compounds are most effective in
    killing organisms when they are in a moist environment.

        Environmental transformation of 1,3-dichloropropene results from
    microbial action, with the exception of the initial hydrolysis of
     cis- and  trans-1,3-dichloropropene to 3-chloroallyl alcohol
    (Castro & Belser, 1966; Belser & Castro, 1971). The pathway for the
    transformation of 1,3-dichloropropene is given in Fig. 2. 

                      

    a See section 2.2.

    4.1.3.1  Hydrolysis

         Cis- and  trans-1,3-dichloropropene can be hydrolysed in soil
    to 3-chloroallyl alcohol (see Fig. 2). Hydrolysis rates for 1,3-
    dichloropropenes range from 1 to 3.4% per day, depending on
    temperature and moisture content. Hydrolysis rates also vary with
    soil type (particle size) because of differences in chemical
    diffusion rate and sorption capacity (California State Water
    Resources Control Board, 1983).

        Using [14C]-radiolabelled 1.3-dichloropropene in sterile
    buffered water at pH 5, 7, or 9 and temperatures of 10, 20, or 30
    °C, McCall (1987) found that the rate of hydrolysis was independent
    of pH at each temperature, and that the half-lives at temperatures
    of 30, 20, and 10 °C were 3.1, 11.3, and 51 days, respectively. One
    hydrolysis product, formed during the course of the study, was
    identified as 3-chloroallyl alcohol. The alcohol appeared to be
    stable to further hydrolytic conversion and was formed in the same
     cis-:trans-ratio as the initial 1,3-dichloropropene.

        The hydrolysis of  cis-1,3-dichloropropene (98.1%) was studied
    by O'Connor (1990b). The degradation reactions at all pH values were
    shown to follow pseudo first-order behaviour in the EEC-test,
    independent of the concentration. The degradation rate constants and
    environmental half-lives for  cis-1,3-dichloropropene at 25 °C at
    pH 4, pH 7, and pH 9 (extrapolated by measuring degradation at
    temperatures of 50, 60, and 70 °C, using Arrhenius relationships)
    were 100 h, 54.5 h, and 38 h, respectively. (Remark: although the
    rate of hydrolysis of  cis-1,3-dichloropropene did show some slight
    pH dependence, the author stated that this was probably within
    experimental error). It is hypothesized that the degradation
    proceeds via a resonance stabilized carbonium ion intermediate,
    resulting in the formation of a mixture of 3-chloroallyl alcohol and
    propenal (see Fig. 3). 

        Connors et al. (1990) studied the hydrolysis of 1,3-
    dichloropropene into 3-chloroallyl alcohol, under laboratory
    conditions. A 1.0 µg/litre  cis- and  trans-1,3-dichloropropene
    solution was prepared in a pH 5.5 or pH 7.0 buffer. The half-lives
    for the  cis- and  trans-isomers at 15 and 29 °C (pH 5.5) were
    11.0, 2.0 and 13.0, 2.0 days, respectively. At pH 7.0 and 25 °C, the
    value was 4.6 days for both isomers.

    FIGURE 02

    FIGURE 03

        Determination of the rate of hydrolysis of 1,3-dichloropropene
    at 25 °C in 50% aqueous ethanol indicated a half-time of 4 days for
    both the  cis- and  trans-isomers and appeared independent of the
    concentration in the range of 10-1000 mg/litre. Only small
    differences were observed in disappearance rates at pH levels of 5.5
    and 7.5. The effect of temperature was clearly demonstrated: at 29
    °C, the half-life for  cis-1,3-dichloropropene was 1.5-2.0 days,
    while, at 2 °C, the half-life was estimated to be 91-100 days
    (Krijgsheld & Van der Gen, 1986).

        The rates of transformation of the  cis- and  trans-isomers in
    soil layers of 0.1-0.2 m and 0.4-0.5 m in a bulb field in the
    Netherlands were determined in the laboratory. The initial contents
    of added 1,3-dichloropropene were approximately 12 and 62 mg/kg.
    Incubation took place at 15 °C. The half transformation time was
    about 4 days for both isomers. After 2 weeks, only small amounts
    (1%) of the initial amount were left. The transformation was slower
    in soil with the higher initial content (62 mg/kg) than in soil with
    12 mg/kg. The half-life was approximately 19 days for both isomers.
    Only small amounts were left after one month (Van der Pas & Leistra,
    1987).

        The behaviour of technical grade 1,3-dichloropropene in the soil
    from 4 fields (soil containing 13.2-24.6% of organic matter) was
    studied in the laboratory. The transformation rates of  cis- and
     trans-1,3-dichloropropene were measured in soil samples taken from
    the ploughed layer of the fields. Pure 1,3-dichloropropene was added
    at 35 µlitre/kg moist soil. The transformation in soil from one of
    the fields could be approximated with first- order kinetics during
    the whole incubation period of 21 days. The half-lives of the  cis-
    and  trans-isomers at 10 °C were 17 and 20 days, respectively. In
    soil from the 3 other fields, transformation of 1,3-dichloropropene
    with approximate first-order kinetics in the initial period of 7-14
    days was followed by a period of accelerated transformation. The
    concentration dropped below the limit of determination (0.1 mg/kg
    dry soil), 14-21 days after the start of the incubation. Presumably,
    soil microorganisms adapted their enzymes, resulting in an increased
    rate of transformation (Van den Berg & Leistra, 1989).

        In 6 loamy soils, transformation was gradual and pseudo first-
    order for 3-6 days, and then, very rapid. There was no difference
    between the transformation of the  cis- and  trans-isomers of 1,3-
    dichloropropene in these soils. When the initial content in dry soil
    was 62-80 mg/kg, less than 0.2% remained after a week (temperature
    15 °C). The greatly accelerated transformation that occurred after a
    short time lag suggests that the soils contained microorganisms that
    could transform 1,3-dichloropropene effectively (Smelt et al.,
    1989).

        Rapid transformation was found in 6 loamy soils from fields
    fumigated once or twice previously, as well as from fields never
    treated; after 7 days, less than 0.2% of the applied dose (3.7, 18,
    or 92 mg 1,3-dichloropropene/kg) remained. The incubation
    temperature was 15 °C. However, with an initial content of 470
    mg/kg, the transformation was suppressed with a half-life of 33
    days. In another loamy soil, which showed no accelerated
    transformation pattern, the pseudo half-lives increased from 4.3 to
    36 days, when initial content of 1,3-dichloropropene was raised from
    3.7 to 470 mg/kg (Smelt et al., 1989).

    4.1.3.2  Volatilization

        Volatilization and diffusion in the vapour phase are the most
    significant mechanisms for the environmental dispersal and dilution
    of 1,3-dichloropropene and 1,2-dichloropropane. Volatilization rates
    from soil surfaces depend on water solubility and vapour density as
    well as on soil properties, such as temperature and moisture
    content, the depth of application, and surface wind velocity.
    Estimates of volatilization of  cis-1,3-dichloropropene from soil
    have ranged from 20 to 75%. 

        D-D 92 was applied to sandy clay loam soil in a polyethylene
    tunnel and the air in the tunnel was monitored continuously for 1,3-
    dichloropropene for 4 weeks. The temperature in the tunnel was 18-29
    °C. D-D 92 was injected by hand at a dose rate of 225 kg/ha, at a
    depth of 15 cm. About 45% of the applied D-D 92 was volatilized as
    1,3-dichloropropene in the first week, increasing to 54% after 4
    weeks. No more than 5% was found as 1,3-dichloropropene or 3-
    chloroallyl alcohol in the soil at the end of the 4-week period
    (Sherren & Woodbridge, 1987c). 

    4.1.3.3  Uptake in crops

        Residues in edible crops arising from the use of "MIX D/D" or
    1,3-dichloropropene have only been detected in small amounts (<
    0.02 mg/kg). The most obvious reason for this is the fact that crops
    are not normally planted until most of the product has been
    eliminated. Under certain conditions, where low concentrations of
    1,3-dichloropropene persist for long periods of time, plants will
    absorb measurable quantities. Uptake has been shown to occur in
    potato tubers in sandy loam soil treated with 14C-1,2-
    dichloropropane and 14C-1,3-dichloropropene 6 months prior to
    planting (application rate 290 litre/ha). The total radioactivity
    (expressed as 1,3-dichloropropene equivalents) in the tubers was 7
    µg/kg (Roberts & Stoydin, 1976).

        Tomatoes, bush beans, and carrots absorbed 14C-1,3-
    dichloropropene from vermiculite culture solution and sand. During
    24 h, the compound was absorbed and translocated through the plants.

    3-Chloroallyl alcohol was also readily absorbed, but to a lesser
    extent than dichloropropene. Comparison of the metabolism of 1,3-
    dichloropropene and 3-chloroallyl alcohol showed rapid reversion to
    the general carbon pool, the half-lives for 1,3-dichloropropene and
    3-chloroallyl alcohol being 1.5 and 4.4 h, respectively (Berry et
    al., 1980).

    4.1.3.4  Movement in soil

        Vapour diffusion is usually the most important mode of downward
    movement for "MIX D/D". McKenry & Thomason (1974) injected either
    Telone or "MIX D/D" into a series of soils at 11 different sites in
    California. The moisture levels, temperatures, cultivation, and soil
    profiles at the sites varied. The movement was studied during 13 and
    69 days. The application rates ranged from 600 up to 2300 kg/ha. It
    was concluded that: 

    *   There was a substantial and downward movement of all the
        components.

    *   Downward movement was greatest in open-textured soils that were
        sufficiently moist but not saturated; the fumigant was
        detectable at a depth of a few metres.

    *   Downward movement was encouraged by deep cultivation in soils
        with horizons of low porosity.

        In the United Kingdom, however, Wallace (1979) found only traces
    of fumigant in the 40-60 cm layer, after an injection at a depth of
    18 cm. Wallace (1976a) had found comparable results in soil in
    Germany. In the European studies, the diffusion was slower, because
    the applications were made in late autumn; soils were wetter,
    colder, and heavier in texture. Thus, results from studies carried
    out under different agronomic and climatic conditions are not
    necessarily comparable.

        The vertical and horizontal movements of 1,3-dichloropropene
    were studied in a tree-nursery region in the north of the Federal
    Republic of Germany. Sounding pipes were used to collect water
    samples down to a depth of 4 m using the percussion-boring method.
    Further borings were set to a depth of 3 m on days 10-91 after
    application of a formulation containing  cis- and  trans-1,3-
    dichloropropene, methylisothiocyanate and 1,2-dichloropropane at 50
    ml/m2. Soil cores were analysed. 1,3-Dichloropropene showed a
    rather high mobility in the soil, as it could be detected at a depth
    of 4 m in all soil layers on the fourth day of application. In
    samples of the near-surface groundwater, collected 140 days after
    application, a concentration of 1.36 µg 1,3-dichloropropene per
    litre was found. Ten to 25 m from the treated area, 1,3-
    dichloropropene was also found in groundwater after 59 and 140 days
    (Rexilius & Schmidt, 1982).

    4.1.3.5  Loss under field conditions

        Williams (1968) studied the loss of 1,3-dichloropropene under
    field conditions in sandy loam and peat soils in Canada. The
    application rates were approximately 1000 and 2000 litre "Mix
    D/D"/ha, respectively. Eight months later, samples were collected
    and residues determined (Table 4).

        In studies in the Federal Republic of Germany, Netherlands, and
    the United Kingdom, only very low residues (1%) of the amount
    originally applied remained after 3 months in the soil (Wallace,
    1976a,b; Wallace, 1979).

        A comparative trial was carried out in the United Kingdom in
    which "MIX D/D" and 1,3-dichloropropene were injected, at a depth of
    15 cm, in clay loam at concentrations of 410 and 240 litre/ha,
    respectively (Table 5, see also section 4.3.2 of "MIX D/D"). Samples
    of soil were taken at depths of 0-20 cm, 20-40 cm, and 40-60 cm, at
    6 intervals up to 9´ months after application. As part of normal
    recommended agricultural practice, the soil was ploughed 5 weeks
    after treatment. Soil samples were analysed for residues of  cis-
    and  trans-1,3-dichloropropene, 1,2-dichloropropane, and  cis- and
     trans-3-chloroallyl alcohol. There was no significant difference
    between the residues of the 1,3-dichloropropene or the 3-chloroallyl
    alcohol resulting from the 2 treatments. As expected, no 1,2-
    dichloropropane residues were detected in soil samples treated with
    1,3-dichloropropene. Residues of the  cis- and  trans-1,3-
    dichloropropenes and  cis- and  trans-3-chloroallyl alcohols were
    detected in all samples up to 9´ months after treatment and down to
    the 20-40 cm soil layer. Before the soil was ploughed, the
    concentrations of these substances showed little change, and they
    were present in all 3 layers, but, after ploughing, the
    concentrations decreased gradually (Wallace, 1979).

    Table 4. Recovery of  cis- and  trans-1,3-dichloropropene from
    sandy loam or peat soils, 8 months after application of 1000 or 2000
    litre "MIX D/D"/ha, respectively
                                                                     
    Soil           Depth in cm           Residue in mg/kg soil
                                      cis-1,3-             trans-1,3-
                                   dichloropropene     dichloropropene
                                                                     

    Peat              0-10               1.4                 3.2
                      10-20              1.8                 4.8

    Sandy loam        0-10                -                   -
                      10-20              0.3                 0.4

                                                                     
    From: Williams (1968)


        Table 5. Residues from the plot treated with 1,3-dichloropropene at 240 litre/haa
                                                                                                                   
                                                            Concentration in soil (mg/kg)
                                                                                                                   
    Interval since   Soil depth        1,3-dichloropropenes     1,2-dichloropropane         3-chloroallyl alcohol
    application         (cm)                                                                                       
    (days)                           cis-isomer    trans-isomer                             cis-isomer      trans-isomer
                                                                                                                   

    3                    0-20          2.02          2.54               < 0.1               1.01             1.01
                        20-40          5.98          7.32                 0.2               3.16             3.34
                        40-60          0.14          0.15               < 0.1              1.57b            1.88b

    10                   0-20          6.29          7.66                 0.1               1.23             1.23
                        20-40          1.79          2.10               < 0.1               1.09             1.14
                        40-60          0.52          0.55               < 0.1              3.01b            3.24b

    23                   0-20          6.10          6.10                 0.2               2.39             2.39
                        20-40          3.26          3.20                 0.2               1.32             1.32
                        40-60          0.09          0.08               < 0.1               0.04             0.04

                                                                                                                   

    34                                            NORMAL CULTIVATION (ploughing of the soil)

                                                                                                                   

    40                   0-20          0.95          1.10               < 0.1               0.45             0.45
                        20-40          0.97          0.90               < 0.1               0.62             0.62
                        40-60          0.06          0.04               < 0.1             < 0.02           < 0.02

    67                   0-20          0.28          0.36               < 0.1               0.70             0.70
                        20-40          0.04          0.05               < 0.1               0.32             0.26
                        40-60          0.11          0.09               < 0.1               0.05             0.04

                                                                                                                   

    Table 5 (contd)
                                                                                                                   
                                                            Concentration in soil (mg/kg)
                                                                                                                   
    Interval since   Soil depth        1,3-dichloropropenes     1,2-dichloropropane         3-chloroallyl alcohol
    application         (cm)                                                                                       
    (days)                          cis-isomer   trans-isomer                            cis-isomer     trans-isomer
                                                                                                                   

    At harvest           0-20          0.08          0.06               < 0.1               0.20             0.20
    9´ months           20-40         0.02c         0.02c               < 0.1               0.04             0.03
                        40-60        < 0.01        < 0.01               < 0.1             < 0.02           < 0.02

                                                                                                                   

    Pre-treatment        0-20        < 0.01        < 0.01               < 0.1             < 0.02           < 0.02
                        20-40        < 0.01        < 0.01               < 0.1             < 0.02           < 0.02
                        40-60        < 0.01        < 0.01               < 0.1             < 0.02           < 0.02

                                                                                                                   

    a    From: Wallace (1979).
         Note: All residues are on a dry weight basis.
    b    Anomalous results.
    c    Results confirmed by GC/MS.
    

         1,3-Dichloropropene (D-D 95 and Telone II, containing > 92%),
    at concentrations of 240, 280, and 290 litre/ha, was injected into
    the soil of 3 bulb fields in the Netherlands in the summer. Nine
    points were sampled per field and the samples were taken at various
    times down to a depth of 3 m. Within a month, the concentrations
    decreased to less than 0.2 mg/kg and continued to decline gradually
    with time (Van der Pas & Leistra, 1987). 

         In 2 fields in the Netherlands (soil containing 15.7-24.6% of
    organic matter), the spread of the fumigant (application rate 150
    litre/ha) through the soil was measured. Only low fumigant
    concentrations (about 0.1-0.4 mg/kg) were measured at a depth of 0.3
    m. Around the depth of injection (0.15-0.2 m), the ratio of  cis-
    and  trans-isomers changed with time in favour of the  trans-
    isomer. Cumulative emissions into the air over a period of 3 weeks
    were calculated to range from 10 to 20% of the dosage of the  cis-
    isomer, and 4 to 15% of the  trans-isomer (Van den Berg & Leistra,
    1989).

    4.1.3.6  Results of supervised field trials

         A field study was undertaken in France in 1988, in which D-D 92
    was applied to the soil prior to planting vines, and the air in the
    vicinity of the treated area was monitored for 1,3-dichloropropene.
    D-D 92 was applied at approximately 600 kg/ha at a depth of 30-40
    cm. The air levels were monitored for 10 days. No samples contained
    1,2-dichloropropane at levels above the limit of determination of
    0.02 mg/m3. The highest 1,3-dichloropropene concentration found
    during the first 24 h (perimeter of the field) was 2.1 mg/m3 and
    this declined to 0.02-0.04 mg/m3 after 10 days. Air concentrations
    also decreased with increasing distance, downwind (Sherren, 1990).

    4.2  Bioconcentration

         No data are available on bioconcentration.

    4.3  Abiotic degradation

    4.3.1  Photodegradation

         Li (1979) obtained results comparable with those of Tuazon et
    al. (1984) working with ozone, by irradiation of vapour of  cis- 
    and  trans-1,3-dichloropropene with a GE-RS sunlamp (see section
    4.1.1). The main reaction product was 3-chloropropionyl chloride
    with smaller quantities of 3-chloropropionic acid, CO2, and
    phosgene. In this process, the initial reaction was epoxidation of
    the double bond. There is evidence of the importance of a surface
    reaction in the atmosphere, adsorption on to particulate matter
    seems to be necessary for an appreciable direct phototransformation
    to occur. Vapour phase photolysis of 1,3-dichloropropene was not

    detected after prolonged simulated sunlight irradiation in a
    reaction chamber. Photolysis occurred on the photoreactor surface
    walls suggesting surface-catalysing reactions. The reaction products
    suggest that 12-13% was totally degraded to CO2 after 5 days of
    irradiation. Over 20% was transformed to phosgene.

         No data on the photolytic decomposition of the chloropropenes
    in water are available. Nevertheless, UVR of these chemicals in
    methanol, in a frozen state, or as inclusion in adamantine matrices,
    may cause the production of allyl radicals, by cleavage of the
    allylic C-Cl bond (Krijgsheld & van der Gen, 1986). 

    4.4  Biodegradation and biotransformation

         Several studies have been performed on the persistence of 1,3-
    DCP in soil, after application as a fumigant. Biodegradation by soil
    microorganisms does occur, depending on soil type, temperature, and
    moisture content. The rate of disappearance ranges from a half-life
    of 3 days to one of 37 days, without any consistent correlation with
    organic matter content of the soil, or with pH. In sterile soils,
    the effect of temperature was minimal (Van Dijk, 1974; Tabak et al.,
    1981; California State Water Resources Control Board, 1983). In
    general, the rates of disappearance of the  cis- and  trans-
    isomers are similar and tend to increase with moisture content and
    temperature, conditions that may increase, not only biodegradation,
    but also loss by volatilization or chemical hydrolysis. Although
    between 15 and 80% decomposition of field applications of 1,3-
    dichloropropene has been shown, the large amount that can be
    absorbed (80-90%) can result in soil residues existing months after
    application is completed (Van Dijk, 1974; Roberts & Stoydin, 1976;
    Sittig, 1980; Krijgsheld & van der Gen, 1986).

         In biodegradability studies using a synthetic medium that
    contained 5 mg of yeast extract/litre and was inoculated with waste
    water, loss of 1,3-dichloropropene was determined after 7 days of
    incubation. Significant degradation was observed at 5 and 10 mg of
    1,3-dichloropropene/litre and gradual adaptation was shown in
    subcultures. The original culture degraded about 50% of the 1,3-
    dichloropropene in 7 days, while the third subculture was able to
    degrade approximately 85% at both substrate concentrations, in the
    same period of time (Tabak et al., 1981). 

         Battersby (1990a) determined the "ready biodegradability" of
     trans-1,3-dichloropropene (95.4%  trans- and 0.3%  cis-isomer)
    using the closed bottle procedure. The substance was not degraded in
    this system with a negligible proportion of the theoretical oxygen
    demand being consumed during the 28-day incubation period.

         The EEC-activated sludge respiration inhibition test was used
    to determine the effect of a  cis- (51.2-52.2%) +  trans- (43.9-
    44.1%) mixture of 1,3-dichloropropene containing 0.33% of 1,2-
    dichloropropane on the respiration rate of activated sludge. The
    EC50 for this mixture was 188 mg/litre (Battersby, 1990b). 

         The EEC-activated sludge respiration inhibition test was also
    used to determine the effect of  cis-1,3-dichloropropene (94.5-
    97.5%  cis-, 1.5%  trans-isomer and 0.25% 1,2-dichloropropane) on
    the respiration rate of activated sludge. The EC50 for the  cis-
    1,3-dichloropropene was 279 mg/litre (Battersby, 1990c). 

         Biodehalogenation by soil organisms has been demonstrated for
    1,3-dichloropropene. The fumigant appeared to be chemically
    hydrolysed to 3-chloroallyl alcohol and then converted to 3-
    chloroacrylic acid. The chlorine is removed and the intermediate
    products are converted to carbon dioxide and water. The rate of
    disappearance of 1,3-dichloropropene at 15-20 °C was 2-3.5% per day
    in sandy soil and up to 25% per day in clay soils. The chloroallyl
    alcohol disappeared at rates of 20-60% per day at 15 °C (Van Dijk,
    1974). Leistra et al. (1991) incubated 1,3-dichloropropene and its
    transformation product 3-chloroallyl alcohol in water-saturated
    subsoil material at 10 °C. The times for 50% and 95% transformation
    ranged from 15 to 47 days and from 27 to 79 days, respectively, for
    1,3-dichloropropene. The corresponding 50% and 95% transformation
    times for 3 chloroallyl alcohol were 0.8-4.2 and 4.0-6.5 days,
    respectively.

         Chemical hydrolysis is the first step in the transformation of
    1,3-dichloropropene. Further transformation is thought to result
    from microbial action; 3-chloroacrolein and 3-chloroacrylic acid
    have been isolated from the metabolism of 3-chloroallyl alcohol by
     Pseudomonas species (see Fig. 4) (Belser & Castro, 1971; Roberts &
    Stoydin, 1976).

         Soil culture studies using media enriched with 1,3-
    dichloropropenes, 1,2-dichloropropane, and "Mix D/D" at
    concentrations of up to 100 mg/kg, produced abundant growth of all
    microorganisms tested, indicating the use of the fumigants as carbon
    sources. Several of these organisms  (Rhizobium leguminosarum,
     Bacillus subtilis, Arthrobacter globiformis, and  Pseudomonas
     fluorescens) produced greater amounts of amino acids (Altman &
    Lawlor, 1966; Altman, 1969). The  cis- and  trans-isomers of 1,3-
    dichloropropene have undergone biodehalogenation by a  Pseudomonas
    sp. isolated from the soil.  Cis- and  trans-1,3-dichloropropene
    can be chemically hydrolysed in moist soils to the corresponding 3-
    chloroallyl alcohols, which can be metabolized to carbon dioxide and
    water by  Pseudomonas sp. (Fig. 4).

    FIGURE 04

         The degradation of Telone II (92% 1,3-dichloropropene  cis- 
    and  trans-isomers; 2% 1,2-dichloropropane and 5% mixture of
    propenes and hexenes, and 1% epichlorohydrin) in soil was studied
    using 14C-1,3-dichloropropene in Fuquay loamy sand samples
    collected from a field in Florida. The samples were collected
    before, and one, and two weeks, and 2 years following application at
    a rate of 15 kg/ha, at depths of 0-36 cm or 36-65 cm. After 28 days
    incubation of 14C-1,3-dichloropropene in the soil, it was degraded
    into 14CO2 (44%), water-soluble metabolites (probably 3-
    chloroallyl alcohol), bound residues, and possibly some microbial
    mass. Little or no difference was observed in the degradation of
    14C-1,3-dichloropropene in soil samples collected one week prior
    to the field application of Telone II, or two weeks and two years
    after application. A mixed bacteria culture isolated from the soil
    in the presence of a carbon source, completely degraded 14C-1,3-
    dichloropropene into 14CO2, water-soluble products and microbial
    mass (Ou, 1989).

    4.4.1  Miscellaneous

         Laboratory experiments were conducted to determine the effects
    of 1,3-dichloropropene on the activity of invertase in a sandy soil.
    The rates of application were 30 and 60 mg/kg. No inhibition was
    found. The same dose levels were used to test the influence of the
    compound on amylase in sandy soil. After 3 days, stimulation of the
    formation of glucose from the added starch was seen, especially at
    the lowest dose level. Microbial respiration was also tested in
    sandy loam. The treatment did not significantly decrease oxygen
    consumption (Tu, 1988).

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Air

         Telone II, at a rate of 293 litre/ha, was applied, at a depth
    of 0.45 m, simultaneously with pineapple crown planting. Each row of
    pineapple was covered with black polyethylene film at the time of
    planting. Air samples were taken inside the cover and at ground
    level, 10, 20, 22, 27, and 30 days after fumigation. The
    concentration inside the cover remained steady, at least until day
    9; thereafter, a decrease was noticed and, after 22 days, the
    substance was no longer detectable. At ground level, the
    concentration fell gradually and was non-detectable after 30 days
    (Albrecht & Chenchin, 1985).

         A small-scale, field study was undertaken in 1986, when air
    concentrations of 1,3-dichloropropene were measured in the vicinity
    of ground treated with D-D 92 (93.8%), by hand injector at a dose
    rate of 330 kg/ha. The air was monitored for 2 weeks. The
    concentration of 1,3-dichloropropene varied between 0.004 and 0.88
    mg/m3 during the first week. Levels of 1,3-dichloropropene in the
    second week were below the limit of determination (0.002 mg/m3)
    (Sherren & Woodbridge, 1987a). 

    5.2  Water

         An investigation of 1,3-dichloropropene in well-water in
    California was carried out by Maddy et al. (1982). Fifty-four wells
    were selected in locations of high nematocide use. No samples showed
    levels above the limit of determination of 0.1 µg/litre. In a
    survey, 72 water samples from wells in California were analysed for
    1,3-dichloropropene, but no samples contained levels above 1
    µg/litre (limit of determination) (Peoples et al., 1980).

         Connors et al. (1990) analysed potable water samples collected
    in 8 homes in 3 communities in Connecticut and did not find 1,3-
    dichloropropene (< 0.1 µg/litre).

         Dowty et al. (1975) conducted a survey on drinking-water in New
    Orleans, they found 1,3-dichloropropene, but did not give actual
    levels or frequency of occurrence.

         No 1,3-dichloropropene (limit of determination 1 µg/litre) was
    found in 30 Canadian potable water facilities (Otson et al., 1982). 

         Apparently, chlorination of organic materials in water may lead
    to traces of 1,3-dichloropropene (< 1 µg/litre). Therefore, this
    process may be responsible for the observed presence of the
    substance in tap water (Otson et al., 1982; Krijgsheld & Van der
    Gen, 1986).

         1,3-Dichloropropene has been identified in the waste water from
    a textile plant. A level of 2 µg  cis-isomer/litre was measured in
    the influent of the waste water treatment plant, while higher
    concentrations of  cis-1,3-dichloropropene (e.g., 6 µg/litre) were
    found in the effluent, together with the  trans-isomer (0.9-4
    µg/litre). Similarly, no 1,3-dichloropropene was detected in the
    influent of a municipal waste treatment plant, but, after "super-
    chlorination", a mean concentration of approximately 10 µg/litre
    could be detected in the liquid sludge (Krijgsheld & Van der Gen,
    1986).

         Hallberg (1989) reported studies on the presence of pesticides
    in groundwater in different States of the USA. 1,3-Dichloropropene
    was found only in Oregon, but no concentration(s) were reported.

         Van Beek et al. (1988) examined 33 groundwater wells up to a
    depth of 50 m in the northern Netherlands for the presence of 1,3-
    dichloropropene. In this area, "MIX D/D" had been used on a large
    scale as a nematocide in potato growing since 1967. 1,2-
    Dichloropropane was present in the groundwater, but no 1,3-
    dichloropropene (> 0.1 µg/litre) was found in 45 samples from these
    wells.

         Samples of upper groundwater (from 1-2 m below the water level)
    below 4 sandy soils were analysed in the Netherlands, for 2.5 years
    in 8 sampling rounds. 1,3-Dichloropropene was detected in the
    groundwater in 6/34 samples at concentrations in the range of 
    < 0.1-80 µg/litre. These observations were made below fields with
    potato, maize, and bulb flower crops, all on low-humic to moderately
    humic sandy soils (Loch & Verdam, 1989). 

         Lagas et al. (1989) analysed groundwater (up to 6 m depth) in 5
    areas (4 of which are described by Loch & Verdam, 1989), and found
    1,3-dichloropropene levels above the limit of detection (0.1
    µg/litre) in 2 out of 22 samples (range: < 0.1-0.2 µg/litre) taken
    from underneath potato crops and in 1 out of 8 samples (< 0.1-2.5
    µg/litre) from below maize and bulb crops. 

         On 5 sites in a polder in the Netherlands, samples of surface
    water were taken monthly in 1987-88 and analysed. The area is
    situated next to the dunes (where groundwater is being pumped up for
    the preparation of drinking-water), and is extensively used for
    bulb-culture. The maximum concentration found for 1,3-
    dichloropropenes ( cis- and  trans-) was 2.5 µg/litre (Greve et
    al.,  1989).

         In the Netherlands and the Federal Republic of Germany, 1,3-
    dichloropropene was found in areas with extensive agriculture and
    horticulture. 1,3-Dichloropropene was found in the upper groundwater
    (depth 1-5 m) and the average levels ranged from 0.6 to 2530

    µg/litre (maximum level 8620 µg/litre). In bores for irrigation (11-
    24 m depth), an average of 0.23 (< 0.02-0.89) µg/litre was found
    (Leistra & Boesten, 1989).

         Ahlsdorf et al. (1989) determined the presence of 1,3-
    dichloropropene in the upper groundwater of an area used for potato
    growing, which was treated with this nematocide (about 140 kg/ha) in
    1984. Very low levels of 1,3-dichloropropene (1-4 µg/litre) were
    found in soil with a high organic matter content, but concentrations
    of up to 8620 µg/litre were found in the groundwater of a clay
    podsol soil containing a high sand content, after one month.

         1,3-Dichloropropene was detected in irrigation wells that were
    close to a piece of land that was treated with the chemical (10-25 m
    distance) in Schleswig Holstein (Germany). In the well water,
    concentrations of 1,3-dichloropropene varied between 0.06 and 0.89
    µg/litre (Rexilius & Schmidt, 1982). 

    5.3  Crops

         Residues in edible crop commodities, arising from the use of
    1,3-dichloropropene or "MIX D/D", are reported to be generally below
    the limit of detection. The obvious reason for this, is the fact
    that crops are not normally planted until most of the product
    applied has dissipated. Another reason is that any 1,3-
    dichloropropene or "MIX D/D" taken up by the plant, would have to
    survive the whole crop cycle to be detected in the harvest
    commodity. 

         Supervised trials with "MIX D/D", with 23 crops in 8 countries
    showed that residues in edible crop commodities were below the
    limits of determination (< 0.01 mg/kg), for 1,3-dichloropropene,
    1,2-dichloropropane, and 3-chloroallyl alcohol. 

    5.4  Occupational exposure

         Albrecht (1987) carried out a survey to assess the exposure of
    72 workers on a Hawaiian pineapple farm (attendants, crown
    unloaders, (truck) drivers, irrigation workers, supervisors, mulch
    coverers, and planters). Exposures were predominantly below 4.54
    mg/m3 (1 ppm). The concentrations in these workers ranged between
    0.032 and 4.626 mg/m3 (0.007-1.019 ppm). 

         Brouwer et al. (1991a) studied the inhalation of  cis- and
     trans-1,3-dichloropropene in 12 commercial applicators in the
    Netherlands. The time-weighted average (TWA) concentrations of 1,3-
    dichloropropene ranged from 1.9 to 18.9 mg/m3. Short-term exposure
    levels during tank-loading and repair ranged up to 30 mg/m3. No
    correlation was observed between exposure and total area injected
    with 1,3-dichloropropene. Emission of 1,3-dichloropropene vapour

    from the soil or from spilled liquid dripping from the nozzles on to
    the soil may contribute to exposure.

         An employee air-monitoring study to determine the amount of
    Telone II to which personnel would be exposed, removing soil core
    samples in the immediate area of the drilling, was carried out. The
    concentration in the air was between 0.0982 and 1.79 mg/m3 on the
    first day, and between 0.202 and 3.056 mg/m3 on second day. The
    time-weighted averages from personal monitoring on days one and two
    were 0.65 and 0.90 mg/m3, respectively. The time-weighted averages
    from air monitoring on days one and two were 0.39 and 0.59 mg/m3
    (Fong & Maykoski, 1985). 

         A study on a single operator during a one-day application was
    carried out in the Federal Republic of Germany in 1986. Short-term
    inhalation exposures to 1,3-dichloropropene were observed during the
    filling operation (5.6-16.3 mg/m3) and during nozzle changing
    (18.3 mg/m3). The overall exposure during 11 h exceeded the
    recommended TWA value (Eadsforth et al., 1987). 

         An air monitoring study on exposure to 1,3-dichloropropene
    during the application of "Mix D/D" (not less than 50%) and D-D 92
    (not less than 92%) was carried out at different locations near
    Nimes in France in 1988. The 8-h time-weighted average (TWA) air
    concentrations of total 1,3-dichloropropene for the applicator on
    the 2 days of application were 11.3 and 13.2 mg/m3, respectively,
    and for the tractor driver on the second day, 14.4 mg/m3.
    Relatively high, short-term inhalation exposures of the applicator
    were measured during filling operations; the concentrations varied
    between 6.4 and 83.5 mg/m3. These short-term exposures were found
    to contribute significantly to the overall time-weighted average
    exposures over the working period (Rocchi & van Sittert, 1989).

         Albrecht & Chenchin (1985) found measurable concentrations of
    1,3-dichloropropene in the range of 2.4-18.5 mg/m3 during a 8-h
    shift in 8 out of 15 workers, planting pineapple crowns by hand,
    simultaneously with 1,3-dichloropropene (Telone II) treatment of the
    soil at 293 litre/ha.

    6.  KINETICS AND METABOLISM

    6.1  Absorption, distribution, and elimination

    6.1.1  Oral

    6.1.1.1  Rat

         Groups of 6 adult male and 6 female Carworth Farm E rats
    received, by stomach tube, 2.5-2.7 mg  cis-1,3-dichloro-[2-
    14C]propene or  trans-1,3-dichloro-[2-14C]propene in 0.5 ml
    arachis oil per rat, and excretion was followed. After 4 days, the
    animals were killed and the radioactivity measured in skin and
    carcasses. The excretion of radioactivity was very rapid, 80-90% was
    eliminated in the faeces, urine, and expired air in the first 24 h.
    The urine was the major route of elimination, i.e., 80.7 and 56.5%
    (average of males and females) of the dose for  cis- and  trans-
    1,3-dichloropropene, respectively. Only 2.6 and 2.2% of the 2
    isomers, respectively, were eliminated in the faeces in 4 days,
    while 3.9 and 23.5%, respectively, were eliminated as 14CO2 in 4
    days in the expired air. Levels of the other volatile compounds in
    air were only 1-3% of the dose. Up to 1% of the dose in the skin and
    carcass was found. The difference in the amount of labelled CO2 in
    expired air and urine indicated a difference in the kinetics of the
    2 isomers (Hutson et al., 1971).

         Groups of 8 adult Fischer 344 rats/sex were given non
    radiolabelled 1,3-dichloropropene at 5 mg/kg body weight, in corn
    oil, by gavage, for 14 consecutive days, prior to a single dose of 5
    mg 14C-1,3-dichloropropene/kg body weight (actual 4.5 mg)
    (uniformly labelled) (96.3%; 53.3%  cis- and 43.0%  trans-),
    administered to 5 out of the 8 rats on day 15. The remaining 3
    rats/sex were sacrificed. The distribution of radioactivity found in
    the tissues (4-6%) of repeatedly dosed rats, 48 h after dosing, was
    similar to that of single dosed animals. There was no sex difference
    in the distribution of the radioactivity. In addition to the
    repeatedly dosed rats, 2 rats of each sex, which had not been
    previously dosed, received a single gavage dose of 5 mg 14C-1,3-
    dichloropropene/kg body weight. The urine was the major route of
    elimination of the radioactivity derived from 14C-1,3-
    dichloropropene, which ranged from 60 to 65% of the administered
    dose in 48 h in the rats with repeated doses and a single dose.
    Elimination of 1,3-dichloropropene as 14CO2 was approximately
    (average) 26% of the administrated radioactivity with about 4-5% of
    the dose eliminated in the faeces, for all groups (Waechter & Kastl,
    1988).

         In another study, the fate of 14C- cis- and 14C- trans-
    1,3-dichloropropene (97%; 62%  cis and 38%  trans) was determined
    after a single oral dose of 1 or 50 mg/kg body weight to male

    Fischer 344 rats (3 animals per dose level). Urine, faeces, expired
    air, tissues, and remaining carcasses were analysed after 48 h.
    Urine was the major route of excretion, 51-61% of the administered
    dose being excreted over 48 h. In the carcass, 6% of the dose was
    found at the end of 48 h. On the basis of interval excretion data,
    half-lives for urinary excretion ranged from 5 to 6 h. Faeces and
    expired CO2 accounted for roughly 18% and 6%, respectively. The
    tissue concentrations of 14C activity were highest in the stomach
    wall, followed in decreasing order by kidneys, liver, bladder, skin,
    and fat (Dietz et al., 1984a,b, 1985). 

    6.1.1.2  Mouse

         The fate of 14C- cis- and 14C- trans-1,3-dichloropropene
    (97%; 62%  cis and 38%  trans) was studied after oral dosing of
    male B6C3F1 mice with 1 or 100 mg/kg body weight (3
    animals/dose level). Urine, faeces, expired air, tissues, and
    remaining carcasses were analysed after 48 h. Urine was the major
    route of excretion, with 63 and 79%, respectively, of the
    administered doses (1 and 100 mg/kg body weight) being excreted over
    48 h. Half-lives for urinary excretion ranged from 5 to 6 h. Faeces
    and expired CO2 accounted for 15 and 14% of the 14C-
    radioactivity, respectively. In the carcass, 2% was found. The
    tissue concentrations of 14C-activity were highest in the stomach
    wall, followed in decreasing order by kidneys, liver, bladder, fat,
    and skin (Dietz et al.,  1984a,b, 1985).

    6.1.2  Inhalation

    6.1.2.1  Rat

         Stott & Kastl (1985, 1986) studied the pharmacokinetics of the
    uptake of vapours of technical grade 1,3-dichloropropene (49.3%
     cis- and 42.8%  trans-isomer) and the disappearance of  cis- and
     trans-1,3-dichloropropene from the blood in groups of 3-6 male
    Fischer 344 rats exposed to actual concentrations of 136, 409, 1362,
    and 4086 mg/m3 for 3 h.

         The uptake of 1,3-dichloropropene did not increase
    proportionately with increasing exposure concentration due to an
    exposure level-related decrease in the respiration rate and
    respiration min/volume of rats exposed to > 409 mg 1,3-
    dichloropropene/m3 and the saturation of metabolism of 1,3-
    dichloropropene in rats exposed to > 1362 mg/m3. Absorption of
    inhaled 1,3-dichloropropene occurred via the lungs, primarily in the
    lower respiratory tract (approximately 50% of total inhaled), with a
    small amount via the nasal mucosa (11-16%).

         Following exposure to < 1362 mg/m3, both isomers were
    rapidly eliminated from the blood, with a half-life of 3-6 min.

    There was no interaction in the kinetics of both isomers. In
    addition, data obtained on rats exposed to 1362 mg/m3 revealed
    that this rapid elimination phase was followed by a slower
    elimination phase having a half-life of 33-43 min. These data
    demonstrated that a combination of saturable metabolism and
    chemically-induced changes in respiration control 1,3-
    dichloropropene uptake and body-burden in rats. However, only
    decreases in respiration appear to influence vapour uptake. 

         Fisher & Kilgore (1988a) studied the excretion of the
    mercapturic acid of  cis-dichloropropene in Sprague-Dawley rats. In
    a nose-only exposure system, groups of 3 rats were exposed for 1 h
    to Telone II (94%) at average concentrations of 0, 181.6, 485.8,
    1289.4, 1806.9, or 3582.1 mg/m3. Urine samples (24 h) were
    collected and analysed for the mercapturic derivative of  cis-
    dichloropropene. At the lower exposure levels (< 1289.4 mg/m3),
    urinary excretion of the mercapturic acid derivative increased with
    exposure level. With exposure to 1806.9 or 3582.1 mg/m3, no
    further increase was found, suggesting saturation of the metabolic
    process.

    6.2  Influence on tissue levels of glutathione

    6.2.1  Oral

         Oral administration of 1,3-dichloropropene to rats or mice
    resulted in significant, dose-related reductions in the levels of
    non-protein sulfhydryls (NPS) (indicator of tissue glutathione
    concentration) in the forestomach and to a lesser extent in the
    glandular stomach and liver (Dietz et al., 1984b, 1985, see also
    section 6.4).

    6.2.2  Inhalation

         Shortly after inhalation exposure of rats to  cis-1,3-
    dichloropropene, kidney and liver NPS contents were reduced in a
    dose-related manner, but returned to control values 18 h after
    exposure. Lung NPS levels were not affected (Stott & Kastl, 1986,
    see section 6.1.2.1; Nitschke & Lomax, 1990, see section 8.2.2.2). 

         Male Sprague-Dawley rats (200-250 g) were exposed through
    inhalation to 1,3-dichloropropene (Telone II, 94%) concentrations of
    0, 9.1, 22.7, 150, 1384.7, 3504.9, 4335.7, or 7790.6 mg/m3 to
    assess the relationship between 1,3-dichloropropene exposure
    concentration and tissue levels of reduced glutathione (GSH).
    Animals were exposed for 1 h in a dynamic, nose-only system. GSH
    contents were measured in the heart, kidneys, liver, lung, nasal
    mucosa, and testes, 2 h after 1,3-dichloropropene exposure. A
    decrease in nasal GSH, first seen at 22.7 mg/m3, followed an
    exposure concentration-dependent curve. Exposure to concentrations

    above 150 mg/m3 reduced the level of liver GSH. Lung GSH remained
    relatively constant at 75% of control concentrations up to 4335.7
    mg/m3. Significantly decreased GSH levels were observed in the
    heart, liver, lung, and testes at 7790.6 mg/m3. Kidney GSH content
    was not significantly decreased. Unchanged 1,3-dichloropropene was
    not present in the blood of animals 2 h after exposure to 4335.7
    mg/m3 or less. Serum lactic dehydrogenase activity was affected
    only at 7790.6 mg/m3. Lung weight, measured 2 and 6 h after
    exposure, did not differ from controls for any exposure level
    (Fisher & Kilgore, 1988b). 

         Four male Sprague-Dawley rats (200-250 g) were exposed to
    Telone II (94%) for 1 h, in a dynamic, nose-only exposure system.
    The actual 1,3-dichloropropene concentration was 354.1 ± 49.9, 703.7
    ± 408.6, and 1834.2 ± 113.5 mg/m3 (relative concentrations of
     cis- and  trans-isomers were approximately 62 and 38%,
    respectively). The GSH conjugation of 1,3-dichloropropene (GSCP) in
    the blood of rats following exposure showed that there was no
    significant difference between the regression line expressed as
    either monophasic or biphasic decay at any exposure concentration.
    Moreover, no differences were found in the regression lines between
    the exposure concentrations. The elimination half-time of GSCP was
    approximately 17 h following exposure to 354.1, 703.7, or 1834.2
    mg/m3, and, thus, was not dose-dependent. This fits a one-
    compartment model (Fischer & Kilgore, 1989).

    6.3  Biotransformation

    6.3.1  Rat

         In urine from rats and mice treated orally with 14C-
    dichloropropene, no unchanged parent compound, but 2 major and 2
    minor metabolites were found. The predominant metabolite was  N-
    acetyl- S-(3-chloroprop-2-enyl) cysteine with its sulfoxide or
    sulfone. These data indicate that conjugation with glutathione is a
    major route of 1,3-dichloropropene metabolism in the rat (Dietz et
    al., 1984a,b, 1985) (see Fig. 4 and section 6.1.1). 

         Although the spontaneous reaction of  cis-1,3-dichloropropene
    with glutathione is slow in the rat, the rapid urinary excretion is
    due to hepatic glutathione transferase, which catalyses its
    conjugation with glutathione. The transferase is present in the rat
    liver cytosol fraction and little microsomally mediated metabolism
    occurs. The  cis-isomer is a better substrate than the  trans-
    isomer for glutathione transferase. The conjugation then follows a
    classic mercapturic acid pathway (Boyland & Chasseaud, 1969). The
    conjugated product  N-acetyl- S-(3-chloroprop-2-enyl) cysteine and
    its sulfoxide are excreted in the urine of rats and mice (Climie et
    al., 1979; Dietz et al., 1984b; van Sittert, 1984, 1989). 

         It has been shown that a minor metabolic pathway of the  cis-
    1,3-dichloropropene is mono-oxygenase catalysed oxygenation, leading
    to the possible formation of the metabolite  cis-1,3-
    dichloropropene-oxide (II in Fig. 5) (Van Sittert, 1989). 

         Rats administered 25-450 µg  cis- and  trans-1,3-
    dichloropropene/kg body weight, intraperitoneally, showed excretion
    of  N-acetyl- S-( cis- and  trans-3-chloroprop-2-enyl)-L-
    cysteine for 55%  (cis-) and 45%  (trans-) of the dose within 24 h
    (Onkenhout et al., 1986).

         In the study of Waechter & Kastl (1988) (see section 6.1.1.1),
    in which rats were administered daily doses of 5 mg of non-labelled
    1,3-dichloropropene/kg body weight followed by a single dose of 5 mg
    14-C (uniformly) labelled 1,3-dichloropropene, or a single dose of
    5 mg/kg body weight, the major urinary metabolites were the
    mercapturic acid of 1,3-dichloropropene (1,3-D-MA) and its
    sulfoxide. The repeatedly dosed rats excreted slightly higher
    percentages of the dose as mercapturic acids than the single dosed
    rats (28.5% vs 22.7% for males and 25.5% vs 14.3% for females). The
    isomeric ratio of the 2,3-D-MA was approximately 80%  cis- and 20%
     trans- for all groups.

    6.3.2  Humans

         Van Welie et al. (1989, 1991) determined the relationship
    between respiratory occupational exposure to  cis- and  trans-1,3-
    dichloropropene and urinary excretion of 2 mercapturic acid
    metabolites,  N-acetyl- S-( cis- and  trans-)-3-chloroprop-2-
    enyl)-L-cysteine ( cis- and  trans-DCP-MA) by 12, 1,3-
    dichloropropene applicators in the Netherlands. Urinary excretion of
    these mercapturic acids followed first-order elimination kinetics.
    Urinary half-lives of elimination were 5.0 ± 1.2 h for the  cis-
    mercapturic acid and 4.7 ± 1.3 h for the transform. These values
    were not statistically significantly different. A clear correlation
    was observed between the 8-h time-weighted average (TWA) exposure to
     cis- and  trans-1,3-dichloropropene and complete cumulative
    urinary excretion of  cis- and  trans-DCP-MA. The  cis-DCP-MA
    yielded 3 times more mercapturic acid (45%) than the  trans- form
    (14%), probably because of differences in kinetics. It was concluded
    that the uptake of  cis- and  trans-1,3-dichloropropene, their
    metabolism to the corresponding mercapturic acids, and urinary
    excretion was a rapid process.

    FIGURE 05

         In California, applicators of 1,3-dichloropropene were also
    studied for personal air exposure and urinary excretion of
    mercapturic acid metabolites. The amount excreted was correlated
    with the product of the duration of exposure x TWA. The highest
    urinary metabolite concentration occurred during the application
    period, indicating rapid excretion. Skin absorption of vapour was
    not a significant route of exposure (Osterloh et al., 1984, 1989,
    see also section 9.2.1).

         Air and biological monitoring of 6 operators exposed to "Mix
    DD" soil fumigant during filling operations in the Netherlands was
    carried out in 1985-86. There was rapid metabolism and elimination:
    the half-lives of mercapturic acid excretion were 4-5 h, with a
    return to background levels after 24 h. It was calculated that,
    under linear, non-saturation conditions, approximately 23% of the
    inhalation dose of the  cis-isomer and 10% of the  trans-isomer
    are excreted in the urine as mercapturic acids (Eadsforth, 1987).

    6.4  Reaction with macromolecules

    6.4.1  Mouse

         The non-protein sulfhydryl (NPS) content, e.g., GSH, and
    covalent binding to macromolecules were determined in the tissues of
    male B6C3F1 mice. Single oral doses of 0, 1, 5, 25, 50, or 100
    mg 1,3-dichloropropene 97% ( cis- 62% : trans-isomer 38%)/kg body
    weight were given for NPS studies and 0, 1, 50, or 100 mg 14C-1,3-
    dichloropropene/kg body weight for binding studies. Non-glandular
    forestomach, glandular stomach, liver, kidneys, and bladder were
    analysed, 2 h after dosing. Although NPS depletion and dose-related
    increases in macromolecular binding were noted in several tissues of
    rats, these effects were more pronounced in the non-glandular
    stomach than in any other tissue (including glandular stomach,
    liver, kidneys, and bladder). The no-observed-effect level (NOEL)
    for NPS depletion in rat non-glandular stomach was 1 mg/kg body
    weight. NPS levels in non-glandular forestomach were significantly
    decreased at doses of 25 mg or higher and, in the liver, at 100
    mg/kg body weight. Binding in the non-glandular forestomach was
    greatest at dose levels that caused the most depletion of tissue
    NPS. Limited binding occurred in the liver, kidneys, and bladder
    (Dietz et al.,  1984b, 1985).

    6.4.2  Rat

         Groups of 3-9 male Fischer 344 rats (200-260 g) were
    administered 50 mg  cis-1,3-dichloropropene (94.1%  cis- and 2.5%
     trans-) or 50 mg  trans-1,3-dichloropropene (97.3%  trans- and
    0.8  cis-)/kg body weight, by gavage. The rats were sacrificed at
    various intervals after dosing, to determine the tissue non-protein
    sulfhydryls (NPS) in the liver, kidneys, forestomach, glandular

    stomach, and bladder. Blood samples were also taken to determine the
    presence of unchanged 1,3-dichloropropene.  Cis-1,3-dichloropropene
    was only detected in the blood (6.58 µg/litre) 15 min after dosing,
    the blood levels of  trans-1,3-dichloropropene were 11.72 and 8.38
    µg/litre, respectively, 15 and 45 min after dosing. A statistically
    significant decrease in the non-protein sulfhydryl contents of the
    liver, kidneys, forestomach, and glandular stomach was found. This
    depletion reached a maximum, approximately 2-h after dosing. No
    depletion was noted in the bladder. It is not possible to
    distinguish the effects of  cis- and  trans-1,3-dichloropropene on
    NPS, as the results for the individual isomers were not reported.
    The results indicated that orally administered 1,3-dichloropropene
    produces a rapid and significant depletion of tissue non-protein
    sulfhydryls in the rat (Dietz et al., 1982).

         The non-protein sulfhydryl (NPS) contents and covalent binding
    to macromolecules were determined in the tissues of male Fischer 344
    rats. Single, oral doses of 0, 1, 5, 25, 50, or 100 mg 1,3-
    dichloropropene 97% ( cis-62% and  trans-isomer 38%) were given
    for NPS studies and 0, 1, 50, or 100 mg 14C-1,3-dichloropropene/kg
    body weight for binding studies. NPS levels in non- glandular
    forestomach were significantly decreased with doses of 25 mg/kg body
    weight or more. Binding in the non-glandular forestomach was
    greatest at dose levels that caused a significant depletion of
    tissue NPS. Limited binding was noted in the liver, kidneys, and
    bladder (Dietz et al., 1984b, 1985). 

    6.5  Appraisal

         Mice, rats and humans metabolize 1,3-dichloropropene
    predominantly by conjugation with reduced glutathione (GSH). The
    glutathione conjugate is further metabolized to the corresponding
    mercapturic acid, which is then excreted in the urine. Consistent
    with the function of GSH as a detoxication mechanism, the
    genotoxicity of 1,3-dichloropropene was decreased in  Salmonella
     typhimurium when the concentration of GSH was increased to a
    mammalian physiological concentration (see sections 8.6.1.2, 8.9.2).

         The levels of GSH (measured as non-protein sulfhydryl content)
    were decreased at locations consistent with the route of exposure,
    i.e., predominantly in the forestomach and to a lesser extent in the
    glandular stomach and liver, following oral administration, and in
    the nasal tissue after inhalation exposure. For oral exposure, the
    extent of covalent binding of 1,3-dichloropropene to macromolecules
    was correlated with the decrease in non-protein sulfhydryl content.
    It is anticipated that toxic effects of 1,3-dichloropropene will
    occur at doses that deplete tissue sulfhydryls and will be
    manifested in the organs described above (forestomach, liver, and
    nasal tissue). 

    7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

         The United States Environmental Protection Agency published a
    Health and Environmental Effects Profile for 1,3-Dichloropropene in
    1985 (US EPA, 1985).

    7.1  Acute toxicity

    7.1.1  Microorganisms

         The major effect of 1,3-dichloropropene on soil microorganisms
    is on nitrogen transformation. The oxidation of ammonium from soil
    organic nitrogen is reduced by 1,3-dichloropropene; soil ammonium
    levels were significantly greater and soil nitrate levels were
    significantly lower in soils treated with 1,3-dichloropropene
    compared with untreated controls (Tu, 1973; Elliot et al., 1974,
    1977).

         In a series of studies, the effects of 1,3-dichloropropene at
    30 or 60 mg/kg soil were evaluated, in parallel, under laboratory
    conditions. In general, neither dose affected soil microorganisms or
    function appreciably. The effects of 1,3-dichloropropene on soil
    microorganisms and enzyme activity were not consistent in 3 soil
    types (sandy-, clay-, and organic soils). The numbers of fungi, 2
    days after fumigation, were significantly reduced in clay and sandy
    soils, but not in organic soil, but recovered after 7 days. 1,3-
    Dichloropropene either increased or decreased the number of non-
    symbiotic nitrogen fixers and enzyme activity in different soils
    (Tu, 1978, 1979, 1981a,b).

         Moje et al. (1957) studied the individual components of "MIX
    D/D" in old citrus soil and found that the toxicity was mainly due
    to its 1,3-dichloropropene content, in particular that of the  cis-
    isomer (see also section 7.1.1 of "MIX D/D"). Results were as
    tabulated on the next page.

         1,3-Dichloropropene was converted by the methanotrophic
    bacterium  Methylosinus trichosporium OB3b, grown in aerobic
    continuous cultures. The substance was added at a concentration of
    0.2 mmol/litre. After 24 h, 85% of the substance added was degraded
    (Oldenhuis et al., 1989).

         In field experiments with continuous potato cropping, it was
    found that sustained annual applications of 1,3-dichloropropene led
    to insufficient control of  Globodera rostochiensis. In the
    laboratory, 1,3-dichloropropene rapidly disappeared from these
    soils. This did not occur when the soil was sterilized. A bacterium
    was isolated from these soils, which was found to decompose 1,3-
    dichloropropene using it as a carbon and energy source. The

    bacterium was  Pseudomonas sp. Repeated application of 1,3-
    dichloropropene led to accelerated degradation of the substance
    (Lebbink et al., 1989).

                                              Reduction in
                                                                    
    Compound                        Fungi             Bacteria and
                                                      actinomycetes
                                                                    

     Cis-1,3-dichloropropene     85-95% reduction    85-100% reduction
                                at 25 mg/kg soil    at 250 mg/kg soil

     Trans-1,3-dichloropropene   100% reduction      100% reduction at
                                at 250 mg/kg soil   1000 mg/kg soil

                                                                    

    7.1.2  Algae

         The 96-h EC50 value for growth, based on the concentration of
    chlorophyll a and also on cell numbers of the freshwater green algae
     Selenastrum capricornutum in a static system, was 4.95 mg/litre
    for 1,3-dichloropropene. The estuarine diatome,  Skeletonema
     costatum, showed a 96-h EC50 value for growth, based on the
    concentration of chlorophyll a in culture, of 1 mg/litre (Leblanc,
    1984). The EC50 calculated from cell numbers was 1.04 mg/litre (US
    EPA, 1980). The compound is moderately toxic for marine algae.

         The toxicity of  cis-, trans- and a mixture of  cis- and
     trans-1,3-dichloropropenes for  Selenastrum capricornutum was
    determined in a sealed 72-h growth inhibition test. The 72-h EC50
    values (percentage reduction in area under the growth curve),
    expressed in terms of the mean measured concentration in the test
    media, were;  cis-isomer 2.8 mg/litre;  trans-isomer 11 mg/litre;
    and the mixture 8.2 mg/litre. The EC50 (percentage reduction in
    mean specific growth rate), (24-48 h) and EC50 (24-72 h) values
    determined by analysis of average specific growth rates were:  cis-
    isomer 4.6 and 3.1 mg/litre;  trans-isomer 6.6 and 7.5 mg/litre;
    and, for the mixture, 11 and 3.6 mg/litre, respectively (Girling,
    1989a,b,c).

         Rapid evaporation and sensitivity to hydrolysis are features of
    the chloropropenes that may interfere with proper determination of
    toxic concentrations of these chemicals for aquatic species, using
    the standard techniques. Significant loss of the test substance may
    have occurred during experiments carried out at temperatures above
    20 °C and under "static" conditions, i.e., lasting for several days
    without refreshing the medium. Determination of the actual
    concentrations has seldom been carried out, and it is suspected that

    several of the data reported for the chloropropenes present an
    underestimation of the toxic potential of these chemicals for
    aquatic organisms. On the other hand, the products of hydrolysis of
    the chloropropenes, for instance, chloroallyl alcohols are
    themselves toxic (Krijgsheld & Van der Gen, 1986).

    7.1.3  Invertebrates

         The acute toxicity of 1,3-dichloropropene for non-target
    aquatic crustacea is summarized in Tables 6 and 7. 

        Table 6. Acute toxicity of 1,3-dichloropropene for non-target aquatic crustacea
                                                                                        

    Species             Temperature      48-h LC50       96-h LC50      Reference
                           (°C)         (mg/litre)      (mg/litre)
                                                                                        

    Water flea              21            0.090a             -          Mayer &
    (Daphnia magna)                                                     Ellersieck (1986)

    Mysid shrimp                             -             0.79         US EPA (1980);
    (Mysidopsis bahia)                                                  Leblanc (1984)

                                                                                        

    a    48-h EC50 6 mg/litre (US EPA, 1980; Leblanc, 1980) in a static system.
    
         Leblanc (1980) calculated a no discernable effect concentration
    of 0.41 mg/litre for 1,3-dichloropropene in  Daphnia magna, under
    static conditions. However, the result was based on nominal
    concentrations and was higher than the 48-h LC50 given by Mayer &
    Ellersieck (1986).

    7.1.4  Honey bees

         1,3-Dichloropropene has been tested on worker Honey bees  (Apis
     mellifera) using a dusting technique. The 48-h LD50 was 6.6
    µg/bee and 1,3-dichloropropene was rated as "relatively non-toxic"
    for Honey bees (Atkins et al., 1973). 

        Table 7. Acute toxicity of  cis- and/or  trans-1,3-dichloropropenes in  Daphnia magna
                                                                                        
    Substance           Age      System      Temperature    48-h EC50     Reference
                                                (°C)       (mg/litre)
                                                                                        

    Cis-1,3 DCP        24 h      statica        18-22          1.4        Girling (1989a)
    (96%)

    Trans-1,3 DCP      24 h      staticb        18-22          3.1        Girling (1989c)
    (95.4% trans +
    0.3% cis)

    Cis- + trans-      24 h      staticc        18-23          3.1        Girling (1989b)
    mixture
    (51-52% cis +
    44% trans)
                                                                                        

    a    pH 7.6-8.4; total hardness 176 mg/litre; dissolved oxygen 8.8-9.8 mg/litre.
    b    pH 7.8-8.1; total hardness 170 mg/litre; dissolved oxygen 8.6-9.2 mg/litre.
    c    pH 7.9-8.3; total hardness 179 mg/litre; dissolved oxygen 8.6-9.9 mg/litre.
    
    7.1.5  Fish

         The data summarized in Tables 8 and 9, suggest that 1,3-
    dichloropropene is moderately toxic for fish. 

         Heitmuller et al. (1981) exposed sheepshead minnows to 1,3-
    dichloropropene under static conditions. They calculated a no-
    observed-effect concentration of 1.2 mg/litre, but this was based on
    nominal concentrations.

    7.1.6  Birds

         Worthing & Hance (1991) reported an LC50 (8-day) for Mallard
    duck and Bobwhite quail of > 10 000 mg/kg diet. 

    7.2  Short-term/long-term toxicity

    7.2.1  Invertebrates

         No data are available.


        Table 8.  Acute toxicity of 1,3-dichloropropene for fish
                                                                                                                                
    Species                     Type of test     Size (g, mm)     Temperature     96-h LC50       References
                                                                     (°C)        (mg/litre)
                                                                                                                                

    Fathead minnow                 static            0.9 g            18             4.1          Mayer & Ellersieck (1986)
    (Pimephales promelas)                                                        (3.39-4.97)

    Largemouth bass                static            1.0 g            18            3.65a         Mayer & Ellersieck (1986)
    (Micropterus salmoides)                                                      (3.52-3.78)

    Walleye                        static            1.3 g            18            1.08          Mayer & Ellersieck (1986)
    (Stizostedion vitreum)                                                       (0.99-1.18)

    Golden orfe                       -              2.8 g            20             9b           Reiff (1978); Krijgsheld & Van
    (Idus idus melanotus)                                                          (8-11)         der Gen (1986)

    Sheepshead minnow              static           8-15 mm          25-31         1.8c,d         US EPA (1980); Heitmuller
    (Cyprinodon variegatus)                                                       (0.7-4.5)       et al. (1981); Leblanc (1984)

    Rainbow trout                     -                -               -             3.9          Worthing & Hance (1991)
    (Salmo gairdneri)

    Bluegill                       static         0.32-1.2 g         21-23         6.1c,d         Buccafusco et al. (1981)
    (Lepomis macrochirus)                                                         (5.1-6.8)       US EPA (1980); Leblanc (1984)

    Guppy                        semi-static           -              22            0.5e          Krijgsheld & Van der Gen (1986)
    (Poecilia reticulata)

    Goldfish                       static            1.0 g            18            < 7.5         Mayer & Ellersieck (1986)
    (Carasius auratus)

                                                                                                                                

    Table 8 (continued)

    a   Tested in hard water, 272 mg CaCO3/litre.
    b   Tested in dechlorinated water, 260 mg CaCO3/litre.
    c   Tested in well water, 32-48 mg/litre CaCO3, pH 6.5-7.9, oxygen concentration 9.7 mg/litre reduced
        at the beginning to 0.3 mg/litre after 96-h exposure.
    d   Nominal concentrations.
    e   14-day test.
    

        Table 9. Acute toxicity of  cis- and/or  trans-1,3-dichloropropenes 
             in rainbow trout  (Salmo gairdneri)
                                                                                             
    Substance         Mean size     System       Temperature     96-h LC50     Reference
                       (cm, g)                      (°C)        (mg/litre)
                                                                                             

    Cis-1,3 DCP        4.7 cm        semi-          13-17           1.6        Girling (1989a)
    (96%)              (1.1 g)       statica

    Trans-1,3 DCP      4.0 cm        semi-          15-17           4.5        Girling (1989c)
    (95.4% trans +    (0.67 g)       staticb
    0.3% cis)

    Cis- + trans-      4.2 cm        semi-          13-17           2.0        Girling (1989b)
    mixture           (0.68 g)       staticc
    (51-52% cis +
    44% trans)

                                                                                             

    a    pH 7-7.8; total hardness, 226-258 mg/litre as CaCO3: dissolved oxygen, 6.4-10.2 mg/litre.
    b    pH 7.2-7.8; total hardness, 234-264 mg/litre as CaCO3: dissolved oxygen, 8.2-9.9 mg/litre.
    c    pH 7.5-8.3; total hardness, 251-284 mg/litre as CaCO3: dissolved oxygen, 8.1-10.2 mg/litre.
    
    7.2.2  Fish

         Embryo-larval tests have been conducted on Fathead minnows
     (Pimephales promelas) exposed to 1,3-dichloropropene. The maximum
    no-effect concentration was 0.24 mg/litre (no details are available)
    (US EPA, 1980).

    7.2.3  Field studies

         See section 7.3.2 of "Mixtures of dichloropropenes and
    dichloropropane" for effects of "MIX D/D" on worms. 

    7.2.4  Phytotoxicity

         1,3-Dichloropropene is highly phytotoxic.

    8.  EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS

         The United States Environmental Protection Agency, published a
    Health and Environmental Effects Profile for 1,3-dichloropropene in
    1985 (US EPA, 1985).

         In two other documents of the US EPA, health risk assessment
    information is given, on the basis of a comprehensive review of the
    toxicity data (US EPA, 1990, 1991).

    8.1  Single exposures

    8.1.1  Oral

         The acute oral LD50s for mice and rats are summarized in
    Table 10.

         The following signs of toxicity were observed after oral
    administration: hunched posture, lethargy, pilo-erection, decreased
    respiratory rate, ptosis, diarrhoea, diuresis, ataxia, tip-toe gait,
    red/brown staining around the snout, tremors, emaciation, and pallor
    of the extremities. Haemorrhages and congestion were found in the
    lungs and gastrointestinal tract. The livers showed patchy areas of
    pallor (Jones & Collier, 1986a; Jeffrey et al., 1987; Gardner,
    1989a,b,c).

    8.1.2  Inhalation

         The acute inhalation LC50s for 1,3-dichloropropene are
    summarized in Table 11.

         During the exposure and observation periods, the following
    symptoms were observed: partial closing of the eyes, pilo-erection
    salivation, lacrimation, lethargy, diarrhoea, reduction in
    respiratory rate, irregular respiratory movements (lung congestion
    was observed in dead animals) and hunched posture, brown staining of
    fur and fur loss, and reddening of ears, tail, and feet.
    Pathological signs were cardiopulmonary failure, acute tubular
    necrosis in the kidneys, and local effects on the respiratory tract.

         It was suggested that the irritating properties of the vapour
    might serve as a warning of its presence in air. Signs of
    intoxication included hypoactivity, anorexia, and chromodacryorrhoea
    (Coombs & Carter, 1976b).


        Table 10. Acute oral toxicity (LD50) of 1,3-dichloropropene
                                                                                                   
    Species             Concentration                 LD50 (mg/kg body         Reference
                        of substance                  weight, with 95%
                                                     confidence limits)
                                                                                                   

    Mouse (CD 1)        undiluted                            215               Coombs & Carter
                                                                               (1976b)

    Mouse               92% (in corn oil)              640 (582-704)a          Toyoshima et al.
     (JCL:ICR)                                         640 (547-749)b          (1978a)

    Rat                 94.5-97.5% cis-, 1.5%                85                Jeffrey et al.
     (Fischer 344)      trans-, 0.25%                                          (1987); Gardner
                        1,2-dichloropropane,                                   (1989b)
                        undiluted

    Rat                 96.7%, trans-,                       94                Gardner (1989c)
     (Fischer 344)      undiluted                           117a
                                                             78b

    Rat (CD)            undiluted                       127 (112-141)          Coombs & Carter 
                                                                               (1976b)

    Rat (not            92% (in corn oil)                   470b               Torkelson & Oyen
     specified)                                             713a               (1977)

    Rat (Sprague-       97.2%                          130 (110-170)a          Jones & Collier
     Dawley)                                        between 110 and 250b       (1986a)

    Rat                 D-D 95, undiluted                    57                Gardner (1989a)
     (Fischer 344)      (cis + trans 1 : 1)

    Rat                 92% (in corn oil)              560 (452-695)a          Toyoshima et al. 
     (Wistar)                                          510 (480-726)b          (1978b)

                                                                                                   

    Table 10 (contd)
                                                                                                   
    Species             Concentration                 LD50 (mg/kg body         Reference
                        of substance                  weight, with 95%
                                                     confidence limits)
                                                                                                   

    Rat                 97.5%                               300a               Jeffrey et al. (1987)
     (Fischer 344)                                          224b

                                                                                                   

    a    Male.
    b    Female.

    Table 11. The acute inhalation toxicity LC50 for 1,3-dichloropropene (4-h exposure)
                                                                                          

    Species             Concentration                LC50 (mg/m3)         Reference
                        of substance

                                                                                          

    Rat                 51% cis-, 43.4%                 3309.7            Blair (1977)
     (Wistar)           trans-isomer, 1% 
                        epichlorohydrin

    Rat                 Telone II                     2.70-3.07c          Cracknell et al.
     (Wistar)           (98.4%)                                           (1987)

    Rat                 95.6% cis- and                  3041.8a           Nitschke et
     (Fischer 344)      1.5% trans-isomer               3377.8b           al. (1990)

    Rat                 Telone II (97.5%;         > 3881.7-< 4698.9a      Streeter et al.
     (Fischer 344)      52.6% cis- and                  4014.2b           (1987) 
                        44.9% trans-isomer)

    Rat                 95.4% trans- and                4880.5b           Collins (1989)
     (Crb:CD(SD)Br)     0.3% cis-isomer                 5402.6a

                                                                                          

    a    male.
    b    female.
    c    mg/litre.
    

         A 2-h exposure to 1,3-dichloropropene at 4540 mg/m3 was
    lethal to rats, whereas guinea-pigs died following a single 7-h
    exposure to 1816 mg/m3 (Torkelson & Oyen, 1977). 

         One female and 3 male Rhesus monkeys (4-5 kg) were exposed to
    Telone II at 0, 113.5, 227, 454, 908, or 2724 mg/m3 for a single
    behavioural session of 1 h, with a 1-week recovery period after
    exposure. Data were obtained on all monkeys for each of the 5
    atmospheric concentrations. At concentrations ranging up to 908
    mg/m3, there were no significant indications of toxicity or
    alterations in behaviour (the monkeys were trained to perform on a
    dual component FRFR (Fixed Ratio followed by a Fixed Ratio) chained
    schedule, with light stimulation). Only slight eye irritation was
    observed in all monkeys at concentrations exceeding 454 mg/m3
    (Rosenblum & Talley, 1979).

    8.1.3  Dermal

         The acute dermal and subcutaneous LD50s are summarized in
    Table 12.

         After dermal application, the signs of intoxication were:
    diarrhoea, lethargy, hunched posture, decreased respiratory rate,
    with lacrimation, salivation, ataxia or abasia, loss of righting
    reflex, diarrhoea, diuresis, and red/brown staining around the eyes,
    snout or mouth. The lungs and gastrointestinal tract showed
    haemorrhages and irritation. Signs of skin irritation manifested by
    oedema, eschar formation, or subcutaneous haemorrhage were apparent
    (Jones & Collier, 1986b).

         One 24-h application of undiluted 1,3-dichloropropene to
    intact, occluded New Zealand white rabbit skin caused extremely
    severe eschar, resulting in black necrotic tissue. The skin had
    hardened and was cracking after 7 days. The animals used for dermal
    LD50 estimation with 1,3-dichloropropene showed lethargy and
    hypothermia at dose levels above 300 mg/kg body weight (Coombs &
    Carter, 1976b).

    8.2  Short-term exposures

    8.2.1  Oral

         Albino rats derived from the Wistar strain, were used in a 90-
    day test. Groups of 10 male and 10 female rats received doses (by
    gavage) of 0, 1, 3, 10, or 30 mg 1,3-dichloropropene (40%  cis- and
    28%  trans-isomer)/kg body weight on 6 days/week. General 


        Table 12. Acute dermal and subcutaneous LD50s for 1,3-dichloropropene
                                                                                                     
    Species          Route          Concentration             LD50 (g/kg body         Reference
                                    of substance             weight, with 95%
                                                            confidence limits)
                                                                                                     

    Mouse            dermal         92% (in corn oil)             > 1.211             Toyoshima et al.
     (JCL:ICR)                                                                        (1978a)

    Rat              dermal         92% (in corn oil)             > 1.211             Toyoshima et al.
     (Wistar)                                                                         (1978b)

    Rat (CD)         dermal         undiluted                      0.423              Coombs & Carter
                                                               (0.336-0.555)          (1976b)

    Rat (Sprague-    dermal         97.2%                     1.0 (0.8-1.3)a          Jones & Collier
     Dawley)                                               between 1.3 and 2.0b       (1986b)

    Rat              dermal         96.7%, trans-isomer            1.575              Gardner (1989c)
     (Fischer 344)                  undiluted

    Rat              dermal         94.5-97.5%                     1.09               Gardner (1989b)
     (Fischer 344)                  cis-, 1.5%
                                    trans-, 0.25%
                                    1,2-dichloropropane
                                    undiluted

    Rabbit (not      dermal         92%                            0.504              Torkelson & Oyen
     specified)                     undiluted                   (0.22-1.15)           (1977) 

    Mouse            subcutaneous   92% (in corn oil)       0.33 (0.29-0.376)a        Toyoshima et
     (JCL:ICR)                                              0.345 (0.30-0.40)b        al. (1978a) 

                                                                                                     

    Table 12. (contd)
                                                                                                     
    Species          Route          Concentration             LD50 (g/kg body         Reference
                                    of substance             weight, with 95%
                                                            confidence limits)
                                                                                                     

    Rat              subcutaneous   92% (in corn oil)       0.40 (0.345-0.464)a       Toyoshima et
     (Wistar)                                              0.366 (0.305-0.439)b       al. (1978b)

                                                                                                     

    a    Male.
    b    Female.
    

    condition, behaviour, and survival were not affected at any dose
    level. No distinct differences in haematological indices, serum
    enzyme activities, or urinalysis were observed. The relative kidney
    weights were significantly increased in the 30-mg group in both
    sexes and also in the males receiving 10 mg/kg. The relative liver
    weights of females at 30 mg/kg were significantly increased. Gross
    and microscopic examination did not reveal any abnormalities in the
    main organs. The 3 mg/kg body weight dose was without effect (Til et
    al., 1973).

    8.2.2  Inhalation

    8.2.2.1  Mouse

         CD-1 Albino mice, 10/sex per group were exposed to production
    grade Telone II (whole-body exposure) at 0, 45.4, 136.2, or 408.6
    mg/m3 for 6 h/day, 5 days/week, for 90 days. No significant
    differences in lesions were found between the control and treated
    groups upon gross and histological examination, except that there
    were compound-related effects on the nasal turbinates. These effects
    were decreased height of the nasal epithelial cells resulting from a
    loss of cytoplasm, and disorganization of the nuclei. Necrotic cells
    were only observed among the females exposed to 408.6 mg/m3. No
    alterations were found in the mice exposed to 136.2 mg/m3 (Coate &
    Voelker, 1979a,b). 

         Groups of 10 male and 10 female B6C3F1 mice were exposed
    (whole body) by inhalation to technical grade 1,3-dichloropropene
    90.9% ( cis 48.6% and  trans 42.3%) containing 2.4% 1,2-
    dichloropropane, 5.5% mixed isomers of chlorohexane, chlorohexene,
    and trichloropropene, and epichlorohydrin 1.2% (as stabilizer). The
    actual exposures were to levels of 0, 45.4, 136, 409, or 681 mg/m3
    for 6 h/day, 5 days/week for 13 weeks. Extensive haematological,
    clinical-chemical, and urinalysis studies, and histopathological
    examination of organs and tissues were performed. 

         A treatment-related depression in body weight was seen at doses
    of 409 and 681 mg/m3. In animals exposed to 681 mg/m3, transient
    brown discoloration of the fur with a strong mercaptan odour in the
    coats and urine was found. The poor growth rate was reflected in a
    decrease or increase in the relative weights of a number of organs,
    but without histological alterations. An exposure-related decrease
    in BUN levels was observed in male mice exposed to 409 and 681
    mg/m3. Furthermore, alanine transaminase levels were increased in
    mice exposed to 681 mg/m3. No other changes were found. The
    primary target tissues of inhaled 1,3-dichloropropenes were the
    nasal mucosa and urinary bladder. The changes in the nasal mucosa
    including slight degeneration of the olfactory epithelium and slight
    hyperplasia of respiratory epithelium in animals exposed to 409 and
    681 mg/m3 were dose-related. The animals also had small focal

    areas of nasal metaplasia, a condition in which the damaged sensory
    olfactory epithelium is replaced by ciliated respiratory epithelium
    (only in animals exposed to 681 mg/m3).

         The urinary bladders of female mice exposed to 409 and 681
    mg/m3 (7/10 and 6/10, respectively) had areas of moderate
    hyperplasia of the transitional epithelium (7-10 layers thick in
    contrast with 2-3 layers in control mice). Submucosal aggregates of
    lymphoid cells in the bladder, not associated with hyperplasia and
    not treatment-related, were found in female mice exposed to
    concentrations of 136 mg/m3 or more. No treatment-related effects
    were found in mice exposed to 45.4 mg/m3 (Stott et al.,  1984,
    1988).

    8.2.2.2  Rat

         Fischer 344 rats, 10/sex per group, were exposed to 0, 45.4,
    136, or 409 mg/m3 of production grade Telone II, for 6 h/day, 5
    days/week for 90 days. No significant differences in lesions were
    found between the control and treated groups on gross or
    histological examination, except that compound-related effects on
    the nasal turbinates were found. These effects included decreased
    height of the nasal epithelial cells resulting from a loss of
    cytoplasm, and a disorganization of the nuclei. Necrotic cells were
    observed in all of the male and female rats exposed to 409 mg/m3
    and in 6/10 of the female rats exposed to 136 mg/m3. No
    alterations were found in the animals with 45.4 mg/m3 (Coate &
    Voelker, 1979a,b).

         Groups of 5 male rats were exposed to atmospheres containing
    concentrations of 1,3  cis-/trans-dichloropropene (92%) of 0 or
    13.6 mg/m3 for 0.5, 1, 2, or 4 h/day, 5 days/week for 6 months.
    The only effect in all the exposed groups was a slight, apparently
    reversible change, seen microscopically in the kidneys of male rats
    (Torkelson & Oyen, 1977).

         Groups of 24 male and 24 female rats were exposed repeatedly to
    air containing 0, 4.54, or 13.6 mg 1,3-dichloropropene/m3 for 7
    h/day, 5 days/week for 6 months. Changes attributable to 1,3-
    dichloropropene were limited to cloudy swellings in the renal
    tubular epithelium of male rats in the 13.6 mg/m3 group. Female
    rats in this group showed an increased liver to body weight ratio,
    though no histopathological changes were observed. A recovery group
    of male and female rats was maintained for 3 months following the 6-
    month exposure to 4.54 or 13.6 mg/m3. No changes were observed in
    the renal epithelium following this recovery period (Torkelson &
    Oyen, 1977).

         In a well-designed study (Stott et al., 1984, 1988), groups of
    10 male and 10 female Fischer 344 rats were exposed through

    inhalation to technical grade 1,3-dichloropropene 90.9% (for
    composition see section 8.2.2.1) in actual concentrations of 0,
    45.4, 136, 409, or 681 mg/m3, for 6 h/day, 5 days/week for 13
    weeks. Haematological, clinical-chemical studies, urinalysis, and
    histopathological studies of organs and tissues were carried out. 

         In the rats exposed to 681 mg/m3, transient brown
    discoloration of the fur with a strong mercaptan odour in the coats
    and urine was found. The body weights of rats exposed to 409 or 681
    mg/m3 were decreased in an exposure-related manner. The relative
    weights of the testes were increased and thymus weights decreased.
    Rats exposed to 409 and 681 mg/m3 had slightly lower levels of
    serum proteins. No other treatment-related changes in clinical-
    chemical or haematological parameters were found. 

         The primary target tissues of inhaled 1,3-dichloropropenes were
    the nasal mucosa in male and female rats and the uteri in females.
    The effects consisted of dose-related degenerative effects on the
    nasal olfactory epithelium or mild hyperplasia of the respiratory
    epithelium or both, in all animals exposed to 409 and 681 mg/m3,
    and 2 of the 10 male animals in the 136 mg/m3 group. 

         The uteri of 7 out of 10 female rats exposed to 681 mg/m3
    were not developed as completely as those of control animals,
    suggesting hypoplasia of the uterine tissues. The only other change
    noted histologically was the atrophic appearance of the mesenteric
    adipose tissue in the rats exposed to 681 mg/m3. No treatment-
    related effects were observed in rats of either sex exposed to 45.4
    mg 1,3-dichloropropenes/m3 (Stott et al., 1984, 1988). 

         In a study to investigate the effects of 1,3-dichloropropene on
    tissue sulfhydryl levels, groups of 15 male and 15 female Fischer
    344 rats were exposed to vapours of  cis-1,3-dichloropropene (94.3-
    95.6%  cis-, 1.5%  trans-1,3-dichloropropene and 0.2% 1,2-
    dichloropropane) at 0, 45.4, 272.4, or 681.0 mg/m3 for 6 h/day, 5
    days/week for 9 exposures. Whole-body exposures occurred under
    dynamic air-flow conditions. On the day after the last exposure, 5
    males and 5 females/dose level were necropsied. Major organs were
    weighed and selected tissues were evaluated histopathologically.
    Groups of 5 animals/sex per dose level were used to determine the
    non-protein sulfhydryl (NPS) contents of the liver, kidneys, and
    lung, 1 and 18 h following the last exposure.

         Rats exposed to 681 mg/m3 lost weight, but not those exposed
    to 272.4 mg/m3. There were concentration-related decreases in
    liver, kidney, and lung NPS levels in male rats, when measured after
    1 h. After 18 h, the NPS levels were higher than those of the
    controls and there were no associated gross or histopathological
    changes in these organs. The NPS measurements for females were
    unremarkable. Histopathological examination revealed changes of

    moderate severity in the respiratory and olfactory mucosa in the
    nasal cavity of males and females exposed to 681 mg/m3. There were
    no changes in the animals exposed to 272.4 mg/m3 (Nitschke &
    Lomax, 1990).

         Groups of 10 male and 10 female Fischer 344 rats (6 weeks old)
    were exposed to  cis-1,3-dichloropropene at 0, 45.4, 136, or 409
    mg/m3 for 6 h/day, 5 days/week for 13 weeks. The test material was
    reported to consist of 94.3% (95.6%)  cis-1,3-dichloropropene, 1.5%
     trans-1,3-dichloropropene and 0.2% 1,2- dichloropropane. Whole-
    body exposures occurred under dynamic conditions. No exposure-
    related effects were noted in haematology or clinical chemistry. At
    409 mg/m3, body weights of male rats were significantly decreased
    compared with controls throughout the 13-week exposure period; body
    weights of female rats were significantly decreased during the first
    6 weeks, but were comparable with those of the controls at the end
    of the study. As a result of the decreased body weight in male rats,
    the relative liver, kidney, lung, and testes weights were
    significantly elevated in comparison with control values. The
    relative liver weight in females was also increased. These organ
    weight changes were not accompanied by gross or histopathological
    changes. Exposure-related changes only occurred in the nasal
    cavities of the rats of both sexes exposed to 409 mg/m3 and
    consisted of multifocal bilateral degeneration of olfactory
    epithelium and slight bilateral multifocal hyperplasia of
    respiratory epithelium. No effects were noted in rats exposed to
    45.4 or 136 mg/m3. The NOEL was considered to be 136 mg  cis-1,3-
    dichloropropene/m3 (Nitschke et al., 1991).

    8.2.2.3  Other animal species

         Groups of 12 male and 12 female guinea-pigs, 3 male and 3
    female rabbits and 2 dogs were exposed repeatedly to air containing
    0, 4.54, or 13.6 mg 1,3-dichloropropene/m3 for 7 h/day, 5
    days/week for 6 months. No changes resulting from 1,3-
    dichloropropene exposure were observed in guinea-pigs, rabbits, or
    dogs (Torkelson & Oyen, 1977).

    8.3  Skin and eye irritation, sensitization

    8.3.1  Skin irritation

         1,3-Dichloropropene is extremely irritating to the skin
    (Worthing & Hance, 1991).

         Telone II (52.63%  cis- and 44.91%  trans-1,3,-
    dichloropropene), 0.5 ml, was applied for 4 h to the back (clipped
    free of fur) of 2 male and 4 female New Zealand White rabbits. After
    4 h, the wrapping and gauze patch and any residual test substance
    were removed. Dermal irritation characterized as slight to moderate

    erythema and moderate to severe oedema was observed at the site of
    application immediately following the 4 h exposure period.
    Subsequent observations revealed slight to moderate erythema,
    oedema, and exfoliation. These changes were still present in some of
    the animals after 14 days (Jeffrey, 1987a). 

         In a 4-h rabbit skin irritancy test, undiluted  cis-1,3-
    dichloropropene (94.5-97.5%  cis-, 1.5%  trans-1,3-dichloropropene
    and 0.25% 1,2-dichloropropane) caused well defined erythema and
    moderate oedema shortly after removal of the semi-occlusive
    dressings in New Zealand White rabbits (3-5 months of age). After
    removal of the dressings, the skin was washed after 4 h. Resolution
    of the irritancy reaction was first apparent on the day after
    treatment and was complete within 14 days (Gardner, 1989b). 

         In another 4-h rabbit skin irritancy test, 0.5 ml of undiluted
     trans-1,3-dichloropropene (96.7%) caused irritation not exceeding
    well-defined erythema and slight oedema. New Zealand White rabbits
    (3-5 months of age) were used. After the 4-h exposure, the dressings
    were removed and the skin washed. Resolution of the irritation was
    first apparent 72 h after treatment and was complete by day 21
    (Gardner, 1989c).

    8.3.2  Eye irritation

         1,3-Dichloropropene is a severe eye irritant (Worthing & Hance,
    1991).

         Aliquots of 0.1 ml Telone II (52.63%  cis- and 44.91%  trans-
    1,3-dichloropropene) were instilled into the conjunctival sac of one
    eye of 4 male and 2 female New Zealand White rabbits. The eyes of
    all rabbits remained unwashed. Slight to marked redness and slight
    to moderate chemosis were found after the treatment. The treated
    eyes had a slight to marked amount of discharge as well as reddening
    of the iris. In one animal, opacity was found which resolved as did
    all the other changes within 14 days following treatment (Jeffrey,
    1987b).

         In the rabbit eye irritancy test, 0.1 ml  trans-1,3-
    dichloropropene (96.7%) caused moderate to severe conjunctival
    irritation and minor irritation changes of the cornea (opacities),
    chemosis, and iridial responses within 24 h following instillation
    into the eye. Resolution of the irritant effects of  trans-1,3-
    dichloropropene was advanced 7 days after treatment and complete one
    week later. There was an initial pain response (Gardner, 1989c). 

         Ten male and 10 female Sprague-Dawley rats  (Spartan substrain)
    were exposed to an aerosol (mean size 2.96 µm; 99% of particles were
    6 µm or less in diameter) in a glass chamber for 1 h at a nominal
    concentration of 5.2 mg/litre of air. Five male and 5 female animals

    were maintained under ambient conditions as controls. Slight
    transitory eye irritation was observed during the exposure (Yakel &
    Kociba, 1977).

    8.3.2.1  In vitro studies

         The corneal thickness of isolated eye preparations subjected to
    application of  cis-1,3-dichloropropene (94.5-97.5%  cis-, 1.5%
     trans-1,3-dichloropropene and 0.25% 1,2-dichloropropane) increased
    by more than 20% within 3 h. The isolated rabbit eye test described
    by Price & Andrews (1985) was used. Corneal uptake of fluorescein
    was demonstrated at the conclusion of the test. The results
    indicated that application of  cis-1,3-dichloropropene to the eye
     in vivo would cause significant tissue damage (Gardner, 1989b).

    8.3.3  Sensitization

         1,3-Dichloropropene was applied in corn oil in a 5% v/v
    concentration 3 times topically to the skin of guinea-pigs followed
    by a 1% concentration as a challenge following the method of Buehler
    (1965). A positive reaction was obtained in 5 out of 20 guinea-pigs
    of the "P" strain. The reaction was considered to be mild to
    moderate skin sensitization (Coombs & Carter 1976b). 

         Ten male, Hartley albion guinea-pigs received 3 dermal
    applications on the back of 0.4 ml of 0.1% (v/v) Telone II (52.63%
     cis- and 44.91%  trans-1,3-dichloropropene) in mineral oil;
    another group received only the vehicle during the induction phase
    of the study. The dermal sensitization potential was tested using
    the modified Buehler method. A positive control group received 2
    applications of 10% epoxy resin and a third application of 5% epoxy
    resin. All groups were challenged dermally 2 weeks after the last
    induction application. The control group did not show any signs of
    sensitization, while 5 out of the 10 animals of the positive control
    group revealed slight erythema. Nine out of 10 guinea-pigs
    challenged with 0.1% Telone II revealed slight to moderate erythema.
    Telone II was considered a potential skin sensitizer at the
    concentrations tested (Jeffrey, 1987c).

         In the guinea-pig maximization test of Magnusson & Kligman, all
    20 test animals showed positive responses, 24 and 48 h after removal
    of the challenge patches. Guinea-pigs of the Dunkin-Hartley strain
    (5-9 weeks of age) were used in this study. In a study by Gardner
    (1989b), 0.1%  cis-1,3-dichloropropene (94.5-97.5%  cis-, 1.5%
     trans-1,3-dichloropropene and 0.25% 1,2-dichloropropane) was
    injected intradermally; topical induction was carried out using a 5%
    solution in corn oil, and the topical challenge using 2.5% in corn
    oil.

         In the guinea-pig maximization test of Magnussen & Kligman, 16
    out of 20 test animals showed positive responses 24 and/or 48 h
    after removal of the challenge patches. Guinea-pigs of the Dunkin-
    Hartley strain (age 5-9 weeks) were used. Intradermal injection,
    carried out at concentrations of 0.05%  trans-1,3-dichloropropene
    (96.7%) or more resulted in red areas with defined edges. The
    concentration selected (10%) for topical induction did give slight
    irritation, but the concentration for the topical challenge of 5%
    was without effect. The solvent was corn oil (Gardner, 1989c).

    8.4  Long-term exposure

         See section 8.7 (Carcinogenicity).

    8.5  Reproduction, embryotoxicity, and teratogenicity

    8.5.1  Reproduction

    8.5.1.1  Inhalation (rat)

         Groups of 30 male and 30 female Fischer 344 rats (6 weeks of
    age) were exposed to Telone II (1,3-dichloropropene containing 2%
    epoxidized soybean oil) at 0, 45.4, 136, or 409 mg/m3 (first 7
    days of study: 0, 22.7, 90.8, or 272.4 mg/m3) for 6 h/day, 5
    days/week during the premating period and for 7 days/week during
    breeding, gestation, and lactation, for 2 generations. The Telone II
    used had a purity of 92% and the remainder of the test material
    comprised chlorinated and unchlorinated alkanes and alkenes as well
    as approximately 2.0% epoxidized soybean oil. Following 10 weeks of
    exposure, the adult rats (F0) were mated twice to produce the
    F1a and F1b litters. After weaning, 30 pups/sex per exposure
    from the F1b litters were selected and, after 12 weeks, used to
    produce the F2a and F2b litters. 

         All litters were examined on the day of parturition, the
    following indices of fertility being recorded: gestation length,
    litter size, pup survival indices, number of live pups on days 1 up
    to 28 postpartum, sex and weight of litters, lactation and
    individual body weights, and any visible physical abnormalities.
    Gross necropsy was carried out on adult rats F0 and F1 and
    weanling F1b and F2b rats and histopathological studies on adult
    rats. Inhalation of up to 409 mg/m3 for 2 generations did not
    adversely affect reproduction or neonatal growth or survival.
    Exposure to 409 mg/m3 resulted, however, in parental toxicity
    (F0, F1), as indicated by decreases in body weight and
    histopathological effects in the nasal mucosa (slight, focal
    hyperplasia of the respiratory mucosal epithelium and/or focal
    degenerative changes in the olfactory epithelium). No adverse
    effects were observed in the parents in the 136 mg/m3 group. The
    reproductive no-effect level was 409 mg/m3 (Breslin et al., 1987,
    1989). 

    8.5.1.2  Intraperitoneal (mouse)

         1,3-Dichloropropene (Telone II) in corn oil was injected
    intraperitoneally in B6C3F1 male mice (4 per group) at dose
    levels ranging from 10 mg up to 600 mg/kg body weight, daily for 5
    days, to study sperm morphology, epididymal sperm counts, and testes
    weights. Testicular toxicity was assessed at day 35. No animals
    survived at dose levels of 150 mg/kg body weight or more. No effects
    on the testes were found at dose levels up to 75 mg/kg body weight
    (Osterloh et al., 1983).

    8.5.2  Teratogenicity

    8.5.2.1  Inhalation (rat)

         In a range-finding study, groups of 7 or 8 female Fischer 344
    rats were exposed to Telone II (92.1%; 47.7%  cis- and 42.4%
     trans-1,3-dichloropropene, impurities, and 1.8% epichlorohydrin)
    at 0, 230, 680, or 1360 mg/m3 for 6 h/day on days 6-15 of
    gestation. 

         Consumption of food and drinking-water was decreased during the
    period of exposure in rats exposed to 680 or 1360 mg/m3 and the
    rats showed a significant decrease in body weight gain. Rats were
    sacrificed on day 16 and examined. During exposure, nasal exudate
    and red crusty material around the eyes were observed. In the group
    exposed to 1360 mg/m3, a significant decrease in litter size and
    significant increase in resorption were seen, while in the groups
    exposed to 230 and 680 mg/m3, the same changes were observed, but
    were not statistically significant (Kloes et al., 1983).

         Groups of 30 Fischer 344 rats were exposed, via inhalation, to
    1,3-dichloropropene 90.1% (47.7%  cis- and 42.4%  trans-isomer) at
    0, 91, 272, or 545 mg/m3 air for 6 h/day on days 6-15 of
    gestation. Food consumption and maternal body weight gain were
    depressed in all treated groups in a dose-related manner. A decrease
    in water consumption was found in rats at the highest dose-level. No
    consistent or dose-related effects on reproductive performance were
    found. The number of implantations, resorptions, litter size, fetal
    weights, and fetal lengths were comparable with the controls. A
    slight, but statistically significant, dose-related increase in the
    incidence of delayed ossification of the vertebral centra was found
    in rats, but considered of little toxicological significance in the
    light of the maternal toxicity observed. The authors stated that
    there was no evidence of a teratogenic or embryotoxic response at
    exposure levels up to and including 545 mg/m3 (John et al., 1983;
    Hanley et al., 1987). 

    8.5.2.2  Inhalation (rabbit)

         In a range-finding study, groups of 7 New Zealand White rabbits
    were exposed to Telone II (92.1%, 47.7%  cis- and 42.4%  trans-
    1,3-dichloropropene, impurities and 1.8% epichlorohydrin) at 0, 230,
    680 or 1360 mg/m3 for 6 h/day on days 6-18 of gestation. The
    rabbits were sacrificed on day 19 and examined. Six out of 7 rabbits
    exposed to 1360 mg/m3 showed signs of toxicity, such as rear limb
    ataxia, decreased or absence of righting reflex, and flaccid hind
    limb muscles; these animals died or were sacrificed. Histologically,
    no effects were detected in the brains of these animals. Maternal
    body weight was statistically significantly decreased during
    exposure in the 680 mg/m3 group, but weights in the 230 mg/m3
    group were comparable with those of the controls. There were no
    differences in the reproductive parameters between the groups
    exposed to 230 and 680 mg/m3 and the controls. No teratological
    effects were found (Kloes et al.,  1983).

         Groups of 25-31 inseminated New Zealand white rabbits were
    exposed to 1,3-dichloropropene 90.1% (47.7%  cis- and 42.4%  trans-
    isomer) at 0, 91, 272, or 545 mg/m3 air for 6 h/day on days 6-18
    of gestation. Decreased weight gain was observed among rabbits at
    272 and 545 mg/m3, but no pronounced maternal toxicity was
    observed. No evidence of teratogenic or embryotoxic responses was
    observed (John et al., 1983; Hanley et al., 1987). 

    8.6  Mutagenicity and related end-points

    8.6.1  In vitro studies

    8.6.1.1  Microorganisms

          Cis- and  trans-1,3-dichloropropene or a mixture were tested
    for their mutagenic activity in  Salmonella typhimurium and in
     Saccharomyces cerevisiae, with and without metabolic activation.
    Most of the studies showed a positive effect, especially with
     Salmonella typhimurium TA100 and TA1535, with, and without,
    metabolic activation. With TA98 and TA1537, positive and negative
    effects were found.  Saccharomyces cerevisiae was positive. The
    results are summarized in Table 13. Samples of highly purified 1,3-
    dichloropropene or  cis-1,3-dichloropropene, however, were not
    mutagenic to  Salmonella typhimurium TA100, indicating that trace
    impurities, such as 1,3-dichloropropene oxide, were the cause of the
    activity (Talcott & King, 1984; Watson et al., 1987, see section
    8.8.2).

         There was a difference in mutagenicity (expressed as rev/µmol)
    between the  cis and  trans isomers of 1,3-dichloropropene in
     Salmonella typhimurium TA100, with, and without, metabolic
    activation. The  cis-isomer induced a greater number of revertants,

    with, and without, S9 mix, than the  trans-isomer and also showed
    stronger alkylating properties in the NBP-test. Furthermore, a
    longer preincubation time invariably led to higher mutagenic
    activity, and an increase in protein added to the activating system
    increased the efficiency of the metabolic activation (Neudecker et
    al., 1980, Neudecker & Henschler, 1986).

          Salmonella typhimurium TA100 was used to test for the
    mutagenicity of  cis- and  trans-3-chloroallyl alcohol (99%),
    with, and without, metabolic activation. No mutagenicity was
    observed without S9 mix, over a range of 0.01-1000 µg/plate.
    However, a positive effect was obtained with S9 mix and  cis-3-
    chloroallyl alcohol (in high concentration) (Connors et al., 1990). 

         Von der Hude et al. (1988) used the SOS chromotest with
     Escherichia coli PQ 37, to examine 1,3-dichloropropene (in DMSO)
    at concentrations of 0, 1.0, 3.3 or 10.0 mmol/litre, without S9. In
    this strain, the structural gene for beta-galactosidase lacZ is
    placed under the control of the SOS-gene sfiA. The expression of
    this gene, induced by DNA-damage, is measured indirectly by
    determination of the beta-galactosidase activity. The test was
    positive with concentrations of 1.0 mmol/litre or more. 

    8.6.1.2  Effects of glutathione on bacterial mutagenesis

         The addition of glutathione (GSH), at physiological
    concentrations, to  in vitro bacterial test systems of  Salmonella
     typhimurium TA100 has shown a clear protective effect, i.e., a
    virtual elimination of the mutagenic response of 1,3-dichloropropene
    (Brooks et al., 1978; Climie et al., 1979; Creedy & Hutson, 1982;
    Wright & Creedy, 1982; Creedy, 1983; Creedy et al., 1984; Brooks &
    Wiggins, 1990). This protective effect occurs in either the presence
    or the absence of S9 for both the  (cis)- and  (trans)-isomers.
    Protection, in the presence of S9, is consistent with the operation
    of glutathione transferase enzyme occurring in the added S9
    fraction. This enzyme is also present in mammalian cells, and as the
    metabolic studies have shown, it plays a key role in the rapid
    detoxification of  cis-1,3-dichloropropene in mammalian tissue
    (Climie et al., 1979; Brooks & Wiggins, 1991). 

         Even in the absence of S9, this protection by GSH still exists
    against the mutagenic action of 1,3-dichloropropene. Thus, it is
    likely that an additional mechanism for protection exists that
    probably reflects a reaction between the mutagenic component(s) and
    GSH. This additional mechanism may also play an important role in
    the detoxification of 1,3-dichloropropene via a spontaneous
    nucleophilic substitution reaction between the chloromethyl carbon
    of 1,3-dichloropropene and the sulfur atom of glutathione. 


        Table 13.  Mutagenicity tests with 1,3-dichloropropenes (1,3-DCP) on microorganisms
                                                                                                                                          
    Substance            Organism/strain                  Dose          Type of         Metabolic      Result    Reference
                                                                         test          activation
                                                                                                                                          

                          Salmonella typhimurium
    Cis-1,3-DCP          TA1535, TA1537, TA1538          0.1-1.0       top agar        S9 mix/none        +      Neudecker et al. (1977)
    (99.9%)                                               µg/ml                                                  Kier et al. (1986)

    Cis-1,3-DCP          TA98, TA100, TA1535           20-2000 µg        plate         S9 mix/none        +      Brooks et al. (1978)
    (> 99%)
                         TA1538                        20-2000 µg        plate         S9 mix/none        -      Brooks et al. (1978)

    Cis-1,3-DCP          TA100, TA1535                78-1250 µg/ml        *           S9 mix/none        +      Brooks & Wiggins (1990)
    (96.3% + trans-
    1,3-DCP 1.5%, +      TA98, TA1537, TA1538         78-1250 µg/ml        *           S9 mix/none        -      Brooks & Wiggins (1990)
    1,2-DCP 0.25%)
    Cis-1,3-DCP          TA100, TA1535, TA1978          20-100 µg        plate         S9 mix/none        +      DeLorenzo et al. (1977)
                                                                                                                 Kier et al. (1986)

    Trans-1,3-DCP        TA1535, TA1537, TA1538       0.1-1.0 µg/ml    top agar        S9 mix/none        +      Neudecker et al. (1977)
    (97.5%)                                                                                                      Kier et al. (1986)

    Trans-1,3-DCP        TA100, TA1535, TA1978          20-100 µg        plate         S9 mix/none        +      DeLorenzo et al. (1977)
                                                                                                                 Kier et al. (1986)

    Trans-1,3-DCP        TA100, TA1535                39-1250 µg/ml        *           S9 mix/none        +      Brooks & Wiggins (1989a)
    (98% + cis-
    1,3-DCP 0.3%)        TA98, TA1537, TA1538         39-1250 µg/ml        *           S9 mix/none        -      Brooks & Wiggins (1989a)

    1,3-DCP (51.3%       TA100, TA1535                 20-2000 µg        plate         S9 mix/none        +      Brooks et al. (1978)
    cis, 43.7% 
    trans, 0.6%          TA98, TA1538                  20-2000 µg        plate         S9 mix/none        ±      Brooks et al. (1978)
    epichlorohydrin)

                                                                                                                                          

    Table 13 (contd)
                                                                                                                                          
    Substance            Organism/strain                  Dose          Type of         Metabolic      Result    Reference
                                                                         test          activation
                                                                                                                                          

    1,3-DCP ***          TA100, TA1535                 3-333 µg/ml       plate         S9 mix/none        +      Haworth et al. (1983)
                         TA98, TA1537                  3-333 µg/ml       plate         S9 mix/none        -      Haworth et al. (1983)

    1,3-DCP ***          TA100, TA1535                 1000 µg/ml          *           S9 mix/none        +      Priston et al. (1983)
                         TA98, TA1537                  1000 µg/ml          *           S9 mix/none        -      Priston et al. (1983)

    1,3-DCP ***          TA100                         0.1-10 µmol       plate         S9 mix/none        +      Stolzenberg & Hine (1980)

    1,3-DCP ***          TA98                            100 µg           **              none            +      Vithayathil et al. (1983)

                          Saccharomyces cerevisiae
    1,3-DCP ***          JD1                          1000 or 5000      liquid         S9 mix/none        +      Priston et al. (1983)
                                                          µg/ml
                                                         culture

                          Escherichia coli
    Cis-1,3-DCP          WP2 UVRA pKM 101             78-1250 µg/ml        *           S9 mix/none        +      Brooks & Wiggins (1990)
    (96.3% + trans-
    1,3-DCP 1.5% +
    1,2-DCP 0.25%)

    Trans-1,3-DCP        WP2 UVRA pKM 101             39-1250 µg/ml        *              none            -      Brooks & Wiggins (1989a)
    (98% + cis-1,3-                                                                      S9 mix           +
    DCP 0.3%)

                                                                                                                                          

    *   Assays were performed by the pre-incubation method in sealed containers.
    **  Salmonella/microsome multiple indicator test.
    *** Details of composition not given.
    

         These 2 mechanisms with GSH afford complete protection against
    the mutagenic activity of the  trans-isomer in bacterial test
    systems, in the presence and absence of S9 (Hutson & Stoydin, 1977;
    Creedy & Hutson, 1982; Wright & Creedy, 1982). 

         In the presence of Aroclor-induced rat liver S-9 fraction and a
    rat liver microsomal mono-oxygenase system,  cis-1,3-
    dichloropropene (I) is apparently metabolized to a mutagenic
    metabolite,  cis-1-chloro-3-chloromethyloxirane (II), which is not
    as effectively deactivated by glutathione as the parent compound.
     Cis-dichloropropeneoxide was shown not to be stable in aqueous
    medium, 2-chloroacroleine (III) was the product of hydrolysis,
    another direct-acting mutagen for  Salmonella typhimurium TA100
    (Hutson, 1984) (see Fig. 5). Glutathione transferase systems afford
    efficient protection against this bioactivated product of 1,3-
    dichloropropene. The protective action of glutathione-linked systems
    against the mutagenicity observed in  S. typhimurium has also been
    shown to occur  in vivo.

    8.6.1.3  Mammalian cells

         In a gene mutation assay, V79 Chinese hamster cells were
    exposed to  cis-1,3-dichloropropene (99.9%) in DMSO at dose levels
    of 2.5 to 20 µg/ml. No indication for an increased mutation
    frequency at the HGPRT locus was found in these cells (Meyer, 1980).

         Telone II (48.9%  cis- and 43.2%  trans-1,3-dichloropropene)
    was tested in the Chinese hamster ovary cell/HGPRT mutagenicity
    assay, with the cell line designated as CHO-K1-BH4, with, and
    without, metabolic activation. Three tests were carried out without
    activation. The first test with 50, 100, 150, 200, and 250
    mmol/litre, showed an increase in mutation frequency at the 200 and
    250 mmol/litre dose levels. However, the biological significance is
    doubtful because of the extreme toxicity at these high dose levels.
    In a repeat of this study using the same concentrations, no increase
    in mutation frequency was found. The results of a third study using
    concentrations of 50, 100, 125, 150, and 200 mmol/litre were also
    negative. The fourth test was with activation, with dose levels of
    50, 100, 125, 150, and 200 mmol/litre. The relative survival ranged
    from 98% at 50 mmol/litre to 14% at 200 mmol/litre. No increase in
    mutation frequency was observed. The results indicated that Telone
    II was not mutagenic in the CHO/HGPRT assay, with, or without,
    metabolic activation (Mendrala, 1986).

    8.6.1.4  DNA damage

          Cis- and  trans-1,3-dichloropropene were tested for their
    ability to induce unscheduled DNA synthesis (UDS) in Hela S3
    cells. The lowest dose, 10-4 mol/litre was the dose at which UDS
    occurred, the dose-response curves being rather shallow (Schiffmann
    et al., 1983).

         Telone II (49.5%  cis- and 42.6%  trans-1,3-dichloropropene)
    was evaluated in the rat hepatocyte unscheduled DNA synthesis assay
    at concentrations from 1 x 10-6 up to 3 x 10-3 mol/litre. In an
    initial and a repeat assay, toxic effects on the hepatocyte cultures
    (indicated as detachment of the cells and/or a granular appearance)
    occurred at 1 x 10-5 mol/litre and at 1 x 10-4 mol/litre or
    more, respectively. In both tests, Telone II failed to elicit
    significant DNA repair in the primary cultures of rat hepatocytes,
    over the wide range of concentrations tested, suggesting an apparent
    lack of genetic activity (Mendrala, 1985).

         The liquid  Bacillus subtilis strain H17 (arg-, trp-, recE+)
    microsome rec-assay was used to evaluate the DNA-damaging effect of
    1,3-dichloropropene with, and without, S9 mix. The concentrations of
    1,3-dichloropropene used with, and without, S9 mix were for
    CR50Rec+/CR50Rec-, 7.62 x 10 / 2.49 x 10 and 4.79 x 102/1.01 x
    103 mg/litre. With S9 mix, there was a strong DNA-damaging effect,
    but, without S9 mix, a reverse effect was observed (Matsui et al.,
    1989).

    8.6.1.5  Chromosomal effects

         Rat liver (RL1) cells were exposed to culture medium
    containing  cis-1,3-dichloropropene (99.9%) in DMSO, at
    concentrations of 2.5, 5.0, or 10 µg/ml. No indication was found
    that the compound induced chromosome damage in the liver cells
    (Meyer, 1980).

         The clastogenic potential of  trans-1,3-dichloropropene (95.4%
     trans-isomer and 0.3%  cis-isomer) was assessed from assays
    designed to monitor chromosome damage in CHO cells. Cultures were
    grown in incubated medium containing the test compound, for either 3
    h in the presence of S9-mix (concentration 0, 0.5, 2.5 or 5.0 µg/ml)
    or 24 h in the absence of S9 mix (concentration 0, 3, 15 or 30
    µg/ml). Methyl methane sulfonate and cyclophosphamide were used as
    positive controls. Metaphase cells were used for the analysis of
    chromosome aberrations after 8, 12, and 24 h, in the case of
    cultures with S9 mix, and, after 24 h, in the case of the cultures
    without S9 mix. At the 24-h sample time, it was concluded that
     trans-1,3-dichloropropene induced chromosome damage (gaps, breaks,
    and exchange figures) in the presence of S9 mix, but no effect was
    seen in its absence (Brooks & Wiggins, 1989b).

         Loveday et al. (1989) tested 1,3-dichloropropene (97.1%) for
    its ability to induce chromosomal aberrations in cultured CHO cells.
    In the first study, without S9, 49.1 µg/ml produced a strong
    positive response, i.e., 16% of cells with aberrations (large number
    of gaps). No metaphase cells were seen at the 98.0 µg/ml dose level.
    In a repeat study, these results could not be confirmed with 50, 75,
    and 100 µg/ml. All 3 doses produced 50% decreases in cell

    confluency. When the compound was tested with S9 mix, no chromosomal
    aberrations were found at 50 µg/ml, the highest dose at which
    metaphase cells could be found.

         Brooks & Wiggins (1991) assessed the mutagenic activity of
     cis-1,3-dichloropropene (94.5-97.5%  cis-isomer, 1.5%  trans-
    isomer, 0.25% 1,2-dichloropropane), in Chinese hamster ovary cells.
    The cultures were grown in medium containing the test substance for
    either 3 h in the presence of S9 mix or 24 h in the absence of S9
    mix. Metaphase cells were prepared for analysis for chromosome
    aberrations, 24 h following initiation of exposure with, and
    without, S9 mix. From the data obtained at the 24-h sample time, it
    was concluded that  cis-1,3-dichloropropene at 1, 5, or 10 µg/ml
    induced chromosome damage (gaps, breaks, and exchange figures) in
    the presence of S9 mix. No increase in metaphase chromosome damage
    was found with doses of up to 10 µg/ml in the absence of S9 mix.

         Loveday et al. (1989) tested 1,3-dichloropropene (97.1%) for
    its ability to induce Sister Chromatid Exchanges (SCEs), in cultured
    Chinese hamster ovary cells. The test was carried out with, and
    without, rat liver S9 fraction. DMSO was used as the solvent. 1,3-
    Dichloropropene induced SCEs without S9 at a dose level of 29.9
    µg/ml. A positive response was also found with S9. 

         Von der Hude et al. (1987) used the Sister Chromatid Exchange
    (SCE) test  in vitro in Chinese hamster V79 cells without S9 mix,
    to evaluate the effect of 1,3-dichloropropene (80%). The
    concentrations tested were 0 (DMSO), and 0.1 up to 0.8 mmol/litre.
    The 0.8 mmol/litre dose was toxic to the cells. A dose-related
    increase in the number of SCEs was found. Negative results were
    obtained with S9, at dose levels of 0.1-3.3 mmol/litre. 

    8.6.2   In vivo studies

         Telone II (49.5%  cis- and 42.6%  trans-1,3-dichloropropene)
    was evaluated in a mouse bone marrow micronucleus test to detect
    chromosomal aberrations and spindle malfunction. The substance
    (dissolved in corn oil) was administered to CD-1 (ICR) BR mice by
    single oral gavage at dose levels of 0 (corn oil), 38, 115, or 380
    mg/kg body weight. Groups of animals were sacrificed at intervals of
    24 and 48 h. A positive control group received cyclophosphamide at a
    dose of 120 mg/kg. There were no significant increases in the
    frequencies of micronucleated polychromatic erythrocytes in the
    Telone II groups compared with the controls. Positive results were
    obtained with the positive control group. Telone II was considered
    negative in the mouse bone marrow micronucleus test (Gollapudi et
    al., 1985). 

         Valencia et al. (1985) tested 1,3-dichloropropene (95.5%) for
    mutagenicity in  Drosophila melanogaster. The compound was tested
    for the induction of sex-linked recessive lethals (SLRLs) by feeding

    the substance in a 5% aqueous sucrose solution. The dose level fed
    was 0 or 5750 mg/litre. The mortality rate was 33% and sterility
    10%. 1,3-Dichloropropene induced an increased number of SLRLs, but
    no reciprocal translocations were induced. 

         The results of both dominant lethal and host-mediated assays
    carried out with "MIX D/D" were negative (see "Mixtures of
    dichloropropenes and dichloropropane", section 8.6.2). 

    8.6.3  Appraisal

         1,3-Dichloropropene ( cis- and  trans-isomer) showed
    mutagenic activity in  Salmonella typhimurium, especially in
    strains TA100 and TA1535 with, and without, metabolic activation.
    There is a difference in mutagenic potential between the  cis- and
     trans-isomers in TA100 with, and without, activation. The  cis-
    isomer induces a greater number of revertants than the  trans-
    isomer. 

         1,3-Dichloropropene does not possess a genotoxic potential in a
    variety of non-bacterial studies. Gene mutation has not been
    detected in  in vitro assays using the eukaryotic cell lines of
    either V79 or CHO (HGRPT locus) (Meyer, 1980; Mendrala, 1986).
    Chromosomal damage has not been observed  in vitro with rat liver
    cell cultures or in an  in vivo mouse micronucleus study using
    single oral doses of up to 380 mg/kg (Gollapudi et al., 1985).
    Interaction with DNA was not observed, even at cytotoxic doses, in
    an  in vitro rat liver unscheduled DNA synthesis study (Mendrala,
    1985). However, Schiffmann et al. (1983) found liver unscheduled DNA
    synthesis in Hela S3 cells.

    8.7  Carcinogenicity

    8.7.1  Oral

    8.7.1.1  Mouse

         A carcinogenicity study was carried out on groups of 50 male
    and 50 female (4-6 weeks old) B6C3F1 mice at dose levels of 0,
    50, or 100 mg (stabilized technical grade 1,3-dichloropropene)/kg
    body weight, administered in corn oil (5 ml/kg body weight), by
    gavage, 3 times per week for 104 weeks.

         The technical product contained 41.6%  cis- and 45.9%  trans-
    isomer of 1,3-dichloropropene, 2.5% 1,2-dichloropropane, 1.5%
    trichloropropene isomer, nine other impurities, (7.5%) and
    epichlorohydrin 1% (as stabilizer). The initial mean body weights of
    the treated mice were lower (6-22%) than those of the controls.
    These differences were caused by failure to fully randomize the
    distribution of the animals. No clinical signs were observed.

    However, the survival of vehicle control male mice was significantly
    lower than that in either dose group. Thirty-nine control male mice
    died with myocarditis, 25, between weeks 48 and 51. A slight
    increase in mortality was found in the female mice at a dose level
    of 100 mg/kg body weight. 

         The reduced survival of the control male mice did not allow for
    an adequate evaluation of carcinogenicity in males in this study.
    But, in both sexes, there was evidence for a 1,3-dichloropropene-
    related increase in transitional cell carcinomas of the urinary
    bladder (without the presence of calculi), liver tumours, squamous
    cell papillomas and/or carcinomas of the forestomach, and of
    alveolar/bronchiolar adenomas and carcinomas of the lung, at 50 or
    100 mg/kg body weight. In the female mice, an increase in basal cell
    or epithelial cell hyperplasia in the forestomach was also found
    (Table 14). It was stated that the presence of 1% epichlorohydrin, a
    direct acting mutagen and carcinogen (especially for the
    forestomach), may have influenced the development of forestomach
    lesions (Haseman et al., 1984; NTP, 1985; Yang, 1986; Yang et al.,
    1986).

    8.7.1.2  Rat

         A long-term carcinogenicity study was carried out on groups of
    52 F344/N rats of each sex (aged 6 weeks), at dose levels of 0, 25,
    or 50 mg stabilized technical grade 1,3-dichloropropene/kg body
    weight, administered in corn oil (5 ml/kg body weight), by gavage, 3
    times per week for 104 weeks.

         The technical product contained 41.6%  cis- and 45.9%  trans-
    isomer of 1,3-dichloropropene, 2.5% 1,2-dichloropropane, 1.5%
    trichloropropene isomer, 9 other impurities, (7.5%) and
    epichlorohydrin 1% (as stabilizer). Additional groups of 25 rats of
    each sex were assigned to each dose group. At 9, 16, 21, 24, and 27
    months of dosing, 5 rats/sex per group were killed and organs and
    tissues studied microscopically. Haematological and clinical-
    chemical studies were carried out on groups of 20 rats of each sex,
    11-13 times in the first 70 weeks of the study. The mean body weight
    of high-dose male rats was about 5% lower than those of the control
    and low-dose rats. No differences in body weight were observed in
    female animals. Mortality was comparable with the controls. The
    primary organs affected were the forestomach and liver. The
    incidences of non-neoplastic and neoplastic lesions are summarized
    in Table 15.


        Table 14.  Occurrence of microscopic lesions in mice in a 2-year gavage study of 1,3-dichloropropenea
                                                                                                                                 
    Lesions                                 Vehicle                         50 mg/kg                            100 mg/kg
                                            control                        body weight                         body weight
                                     male          female               male         female               male           female
                                                                                                                                 

    Urinary bladder
    Epithelial hyperplasia             b          2/50 (4%)          9/50 (18%)    15/50 (30%)         18/50 (36%)     19/48 (40%)
    Transitional cell carcinoma        b          0/50 (0%)           0/50 (0%)    8/50 (16%)           2/50 (4%)      21/48 (44%)

    Lung
    Alveolar/bronchiolar
    adenoma or carcinoma             1/50c        2/50 (4%)          13/50 (26%)    4/50 (8%)          12/50 (24%)     8/50 (16%)*

    Forestomach
    Epithelial hyperplasia             b          1/50 (2%)           0/50 (0%)     1/50 (2%)           4/50 (8%)     21/50 (42%)*
    Squamous cell papilloma            b          0/50 (0%)           2/50 (4%)     1/50 (2%)           3/50 (6%)d     4/50 (8%)*
    or carcinoma

    Liver
    Hepatocellular adenoma           5/50b        1/50 (2%)           7/50 (14%)   8/50 (16%)*         13/50 (26%)      3/50 (6%)
    or carcinoma

    Kidneys
    Hydronephrosis                     b          0/50 (0%)           0/50 (0%)     2/50 (4%)           0/50 (0%)      14/50 (28%)

                                                                                                                                 

    a    From: NTP (1985).
    b    Too many animals died during the study, but no epithelial hyperplasia or neoplasia were observed in these animals.
    c    As b but, a lung adenoma was found in one animal.
    d    Only squamous cell papilloma.
    *    P = < 0.05.

    Table 15.  Occurrence of microscopic lesions in rats in a 2-year gavage study of 1,3-dichloropropenea
                                                                                                                                 
    Lesions                                 Vehicle                           50 mg/kg                          100 mg/kg
                                            control                          body weight                       body weight
                                     male          female               male         female               male           female
                                                                                                                                 

    Forestomach

    Epithelial hyperplasia         2/52 (4%)      1/52 (2%)           5/52 (10%)    0/52 (0%)          13/52 (25%)c   16/52 (31%)c
    Squamous cell papilloma        1/52 (2%)      0/52 (0%)           1/52 (2%)    2/52 (4%)b          13/52 (25%)c     3/52 (6%)b
    or carcinoma

    Liver

    Neoplastic nodule              1/52 (2%)      6/52 (12%)          6/52 (12%)c   6/52 (12%)c       7/52 (13%)c     10/52 (19%)
    or carcinoma

                                                                                                                                 

    a    From: NTP (1985).
    b    Only squamous cell papilloma.
    c    P = ¾ 0.05
    

         Under the conditions of the study, 1,3-dichloropropene induced
    an increased incidence of squamous cell papillomas and carcinomas of
    the forestomach. In addition, a dose-related trend was observed in
    the incidence of neoplastic nodules in the livers of male rats. It
    was stated that the presence of 1% epichlorohydrin, a direct acting
    mutagen and carcinogen (especially for the forestomach), may have
    influenced the development of forestomach lesions (Haseman et al.,
    1984; NTP, 1985; Yang, 1986; Yang et al., 1986). 

         In the ancillary study, dose-related lesions were observed in
    the forestomach and liver. The development of the forestomach basal-
    cell hyperplasia and squamous-cell papilloma followed a time-
    dependent trend in high-dose males and females. Basal-cell
    hyperplasia was seen 9-16 months after dosing started. The neoplasms
    of the forestomach and liver were not seen until 24 months after
    dosing began.

    8.7.2  Inhalation

    8.7.2.1  Mouse

         Groups of 50 male and 50 female B6C3F1 mice (6-7 weeks of
    age) were exposed to 1,3-dichloropropene for 6 h/day, 5 days per
    week for up to 24 months. In addition, 2 ancillary groups, each with
    10 animals/sex per exposure level, were exposed to 1,3-
    dichloropropene for 6 or 12 months. The mice were exposed to 1,3-
    dichloropropane vapour at 0, 22.7, 90.8, or 272 mg/m3. The
    composition of the technical-grade 1,3-dichloropropene was 1,3-
    dichloropropene 92.1% ( cis-49.5% and  trans 42.6%); 1,2-
    dichloropropane 0.7%; and 5.2% mixtures of hexanes and hexadienes.
    Epoxidized soybean oil (approximately 2%) was added as stabilizing
    agent. Besides body weights, clinical-chemical parameters in the
    blood and urine and haematological parameters were determined for
    all animals terminated at 6 and 12 months and for 20 animals/sex per
    group at 24 months. At 6, 12, and 24 months, animals were sacrificed
    and the weight of 5 organs determined; a large number of organs and
    tissues were examined histopathologically.

         No significant differences in survival rates were observed
    between the groups. The body weights of male mice exposed to 272 mg
    1,3-dichloropropene/m3 were statistically significantly depressed
    in comparison with the controls. Examination of haematological and
    clinical-chemical parameters and urinalysis did not indicate any
    toxicity resulting from exposure to 1,3-dichloropropene for 6, 12,
    or 24 months.

         The mean relative liver weight of male animals exposed to 272
    mg/m3 showed a statistically significant decrease. Gross patho-
    logical examination of mice revealed morphological alterations
    involving the urinary bladder and lung, which were attributed to

    exposure to 1,3-dichloropropene. The bladder mucosal surface in
    females exposed to 272 mg/m3 for 12 months and 90.8 and 272
    mg/m3 for 24 months had a roughened appearance. In addition, a
    statistically significantly increased number of the females exposed
    to 90.8 and 272 mg/m3 showed inflammation and epithelial
    hyperplasia of the bladder mucosa, after 24 months. An increased
    number of male animals exposed to 272 mg/m3 also showed
    inflammation.

         Female mice exposed to 90.8 or 272 mg/m3 and males exposed to
    272 mg/m3 showed hypertrophy and hyperplasia of the nasal
    epithelium and degeneration of the olfactory epithelium. Additional
    microscopic changes, considered exposure-related, were hyperplasia
    and hyperkeratosis in the forestomach of 8/50 male mice following 24
    months exposure to 272 mg/m3. A statistically significant increase
    in the incidence of a benign tumour, bronchio-alveolar adenoma, was
    observed in male mice exposed to 272 mg 1,3-dichloropropene
    vapour/m3 for 24 months [22/50 (44%) vs 9/50 (18%) in controls].
    No statistically significant increase in tumour incidence was found
    in the groups exposed to 1,3-dichloropropene at 22.7 and 90.8
    mg/m3 (Table 16). The incidence of lung tumours in the males
    exposed to 272 mg/m3 was somewhat higher (7-32%) than the range of
    historical control values for this type of tumour in male
    B6C3F1 mice in 7 previous, long-term studies. The NOAEL in
    this study on mice for hypertrophy/hyperplasia of the nasal
    epithelium was 22.7 mg/m3 (Yano et al., 1985; Stott et al., 1987;
    Lomax et al., 1989). 

    8.7.2.2  Rat

         Groups of 50 male and 50 female Fischer 344 rats (7-9 weeks of
    age) were exposed to 1,3-dichloropropene for 6 h/day, 5 days/week
    for up to 24 months. In addition, 2 ancillary groups, each
    comprising 10 animals/sex per exposure level, were exposed to 1,3-
    dichloropropene for 6 or 12 months. The animals were exposed to 0,
    22.7, 90.8, or 272 mg/m3. The chemical composition of the test
    material was 92.1% 1,3-dichloropropene ( cis-49.5% and  trans-
    42.6%), 0.7% 1,2-dichloropropane, and mixtures of hexanes and
    hexadiens. Epoxidized soybean oil (approximately 2%) was present as
    stabilizer. Besides body weights of the animals, clinical-chemical
    parameters in the blood and urine and haematological parameters were
    determined for all animals terminated at 6 and 12 months and for 20
    animals/sex from each exposure group at 24 months.


        Table 16.  Incidence of various types of lesions observed in a mouse inhalation study with 1,3-dichloropropenea
                                                                                                                                         
                                                  Males (mg/m3)                                          Females (mg/m3)
                                  0           22.7          90.8           272            0           22.7          90.8           272
                                                                                                                                         

    Urinary bladder
    Hyperplasia mucosa        4/48 (9%)    7/48 (15%)    11/48 (23%)  37/47 (79%)b    1/47 (2%)     4/46 (9%)   21/48 (44%)b  44/45 (98%)b
    (simple or nodular)

    Lungs
    Bronchio-alveolar        9/50 (18%)    6/50 (12%)    13/50 (26%)  22/50 (44%)b    4/50 (8%)     3/50 (6%)     5/50 (6%)     3/50 (6%)
    adenoma

    Nasal tissues
    Degeneration of           1/50 (2%)       0/50        1/50 (2%)   48/50 (96%)b      0/50          0/50        1/50 (2%)   45/50 (90%)b
    olfactory epithelium

    Hyperplasia and          5/50 (10%)     1/50 (2%)     4/50 (8%)   48/50 (96%)b    4/50 (8%)     4/50 (8%)    28/50 (56%)  49/50 (98%)b
    hypertrophy of 
    respiratory epithelium

    Stomach
    Squamous papilloma        0/50 (0%)     3/50 (6%)     2/50 (4%)     0/50 (0%)     3/50 (6%)     2/50 (4%)     0/50 (0%)     3/50(6%)

                                                                                                                                         

    a    From: Lomax et al. (1989).
    b    Statistical difference from control mean identified by using Yate's kappa2 pairwise test, alpha = 0.05.
    

         At 6, 12, or 24 months, animals were sacrificed and the weight
    of 5 organs determined; a large number of organs and tissues were
    examined histopathologically. No significant influence on survival
    was observed. Mean body weights of both male and female rats exposed
    to 272 mg/m3 were statistically significantly decreased compared
    with mean control values. Examination of haematological and
    clinical-chemical parameters, urinalysis, and organ weights did not
    indicate any toxicity resulting from exposure to 1,3-dichloropropene
    for 6, 12, or 24 months.

         Gross pathological examination did not indicate any exposure-
    related effects after 6, 12, or 24 months. Exposure-related
    histological effects occurred in nasal tissues of rats exposed to
    272 mg/m3 for 24 months (Table 17), but not for 6 or 12 months.
    The microscopic changes were located in the olfactory mucosa, which
    covers the upper portions of the nasal cavity, nasal septum, and
    turbinates. The changes were characterized by unilateral or
    bilateral decreased thickness of olfactory epithelium and fibrosis
    of the submucosal tissues underlying eroded olfactory epithelium. At
    the lower dose levels, females did not show histopathological
    changes in the nasal tissue, while one male exposed to 22.7 mg/m3
    and one exposed to 90.8 mg/m3 showed decreased thickness of the
    olfactory epithelium. No effects were seen in the controls. No
    statistically significant increase in tumour incidence was found in
    exposed rats compared with controls (Lomax et al., 1987, 1989). 

    8.7.3  Appraisal

         Exposure to 1,3-dichloropropene, through inhalation, for up to
    24 months did not have any demonstrable effects on survival or
    spontaneous tumour development in male and female Fischer 344 rats.
    In mice, an increased incidence of bronchio-alveolar adenomas was
    found in the lungs of male mice, exposed to 272 mg/m3, but not at
    the lower dose level (90.8 mg/m3). The oral gavage study with 1,3-
    dichloropropene demonstrated an increased incidence of forestomach
    neoplasms in rats of both sexes at dose levels of 50 mg/kg body
    weight, administered 3 times/week for 24 months. Male rats treated
    with 25 or 50 mg/kg also had an increased incidence of neoplastic
    nodules in the liver. 

         In both the oral gavage and inhalation mouse bioassays with
    1,3-dichloropropene, a tumorigenic response was noted in tissues
    with which 1,3-dichloropropene had direct contact, i.e., the stomach
    and the lung. However, in the gavage study, tumours were also
    induced at sites distant from that at the primary "portal-of-entry"
    (lung and urinary bladder). This was not the case in the inhalation
    study, despite the fact that the dose of 1,3-dichloropropene
    received on a mg/kg body weight per day basis by mice exposed for 5
    days/week through inhalation was approximately 2-3 times higher than
    the dose levels administered orally 3 times/week in the NTP (1985). 

        Table 17. Microscopic changes in the nasal tissues of rats exposed to
              Telone II at 272 mg/m3a
                                                                                         
    Microscopic change            Vehicle control                 Overall incidence
                                 (male and female)             Male              Female
                                                                                         

    Decreased thickness of             0/100               20/50b (40%)       15/50b (31%)
    olfactory epithelium

    Erosion of olfactory               0/100               15/50b (30%)        6/50 (12%)
    epithelium

    Submucosal fibrosis                0/100                6/50b (12%)        2/50 (4%) 

                                                                                         

    a   From: Lomax et al. (1989).
    b   Statistical difference identified from control mean of
        Yate's kappa2 pairwise test, alpha = 0.05.
    
    The degeneration and subsequent hyperplasia of nasal and forestomach
    epithelium occurred only at concentrations that are known to deplete
    glutathione levels in these tissues. Tumorigenic effects occur at
    doses higher than those causing glutathione depletion and tissue
    damage. 

         The same mouse strain and similar test materials relative to
    1,3-dichloropropene were used in both bioassays, but there was a
    difference in the stabilizing agents in the test materials. The 1,3-
    dichloropropene used in the NTP study was stabilized with 1%
    epichlorohydrin, a carcinogen. It has been suggested that
    epichlorohydrin may have played a role in the tumorigenic response
    obtained in the gavage study because of the bolus nature of its
    administration. However, it is not known whether the increased
    incidence of tumours in the urinary bladder, lungs, forestomach, and
    liver in the mouse gavage study are attributable to the treatment
    with 1,3-dichloropropene or the effect of epichlorohydrin, since
    carcinogenicity studies of epichlorohydrin in mice have not been
    performed yet. In the inhalation study carried out by Lomax et al.
    (1989), the 1,3-dichloropropene was stabilized with the relatively
    nontoxic epoxidized soybean oil. The role of the stabilizing
    additive epichlorohydrin in generating the different tumours seen in
    the oral gavage studies on 1,3-dichloropropene is still uncertain.
    This question has to be further investigated before a more definite
    conclusion about the carcinogenic potential of 1,3-dichloropropene
    can be drawn. 

    8.7.4  Dermal and subcutaneous (mouse)

         Groups of 30 female Ha:ICR Swiss strain mice (6-8 weeks old)
    were treated with 0.2 ml acetone containing 41 or 122 mg purified
     cis-1,3 dichloropropene, applied to shaven skin 3 times weekly,
    for approximately 18 months. Control mice received acetone. In the
    group treated with 41 mg, no papillomas were found, but at the 122
    mg dose, 3 animals showed papillomas, and 2, carcinomas. No tumours
    were found at distant sites.  Cis-1,3-dichloropropene, applied once
    on the skin at a dose of 122 mg/mouse, was followed after 14 days by
    the application of 5 µg phorbol myristate acetate in 0.2 ml acetone,
    3 times weekly until the end of the study. No skin tumour-initiating
    activity was observed (van Duuren et al., 1979).

         A group of 30 female Ha:ICR Swiss mice were given weekly
    subcutaneous injections in the left flank of 0.05 ml trioctanoin
    containing 3 mg purified  cis-1,3-dichloropropene per injection.
    The study lasted 538 days. Control animals received only the
    vehicle. Six out of 30 mice showed local fibrosarcomas, whereas
    vehicle control animals did not. A positive control of 0.3 mg beta-
    propiolactone produced local sarcomas in 24 out of 30 mice during a
    378-day period (van Duuren et al., 1979).

         The relevance of the subcutaneous route for the assessment of
    carcinogenic properties remains questionable, especially when
    injections of an irritant material are made. It is probable that the
    persistent and physical properties rather than the chemical
    characteristics of  cis-1,3-dichloropropene are responsible for
    production of local sarcomas.

    8.8  Factors modifying toxicity, toxicity of metabolites, mode of
         action

    8.8.1  Toxicity of the metabolites,  cis- and  trans-1,3-
           dichloropropene oxide

         There is some evidence that a small proportion of  cis-1,3-
    dichloropropene is metabolized to  cis-1,3-dichloropropene oxide
    (Fig. 5; Hutson, 1984).

    8.8.1.1  Mutagenicity

          Cis- and  trans-1,3-dichloropropene oxide were tested for
    mutagenicity, in the absence of metabolic activation, in  Salmonella
     typhimurium TA1535 and  Escherichia coli WP2  uvr A, and for
    preferential inhibition of growth of DNA-repair-polymerase-deficient
     E. coli. Both oxides were potent mutagens and DNA modifiers. In
     Salmonella typhimurium TA1535, treated with 0.025 µmol/ml and in
     E. coli WP2  uvr A treated with 0.05 µmol/ml of bacterial
    suspension, a significant increase in revertant colonies was found.

    A gene mutation test with  E. coli (pol A1-/pol A1+) in the
    absence of metabolic activation, already showed an effect with
    0.0005 µmol/ml (Kline et al., 1982). 

         In the absence of an S9-fraction,  cis-dichloropropene oxide
    was strongly mutagenic towards  S. typhimurium TA100. The
    mutagenicity reached a maximum at 25 µg/plate. Above 300 µg/plate,
    marked cytotoxicity was observed. Glutathione (5 mmol/litre) caused
    a significant inhibitory effect on the mutagenicity and cytotoxicity
    of this epoxide, but did not offer complete protection. Inclusion of
    glutathione (5 mmol/litre) together with S9-fraction afforded
    complete protection over the range of concentrations of  cis-
    dichloropropene oxide up to 100 µg/plate (Hutson 1984; Watson et
    al., 1986a).

          Cis- and  trans-1,3-dichloropropene oxide were tested in a
    quantitative Syrian hamster embryo cell model. Both compounds at
    dose levels of 0.005, 0.01, or 0.02 mmol/litre ( cis-isomer) and
    0.01, 0.025, or 0.05 mmol/litre ( trans-isomer) induced
    morphological transformation of the Syrian hamster embryo cells
    (DiPaolo & Doniger, 1982).

    8.8.1.2  Carcinogenicity

         Female ICR/Ha Swiss mice (30 per group) were treated 3 times
    weekly, with  cis-1,3-dichloropropene oxide or  trans-1,3-
    dichloropropene oxide (containing 10-15% of  m-dichlorobenzene) on
    the skin. The dose level was 10 mg in 0.1 ml of acetone. The
    controls received only acetone. The median survival time was
    comparable with that of the controls (over 500 days). With  cis-
    dichloropropene oxide, 16/30 mice had local papillomas and 10/30
    squamous cell carcinomas of the skin; with  trans-dichloropropene
    oxide, this was 20/30 and 17/30, respectively. No tumours were found
    in the control animals (van Duuren et al., 1983).

         A study was also carried out on the same strain of mice using
    subcutaneous injections. Thirty female mice received 500 µg  cis-
    dichloropropene oxide or  trans-dichloropropene oxide in 0.05 ml
    tricaprylin once weekly. The median survival time was comparable to
    that of controls. With  cis-dichloropropene oxide, 4 animals had a
    local (fibro)sarcoma and one carcinoma, and, with  trans-
    dichloropropene oxide, 5 animals had fibrosarcomas. No tumours were
    found in the vehicle controls (van Duuren et al., 1983). 

    8.8.2  Role of oxidation

         When purified  cis-1,3-dichloropropene was heated for a few
    hours in an oxygen atmosphere, in either the light or dark, the non-
    mutagenic  cis-1,3-dichloropropene became strongly mutagenic.
    Heating under nitrogen was negative. Storage of  cis-1,3-

    dichloropropene at room temperature, in the presence of oxygen, for
    two months, made it mutagenic (Watson et al., 1987). Talcott & King
    (1984) demonstrated that purified samples of 1,3-dichloropropene
    were not mutagenic to  Salmonella typhimurium TA100. Four
    preparations of 1,3-dichloropropene were separated into different
    fractions and analysed for mutagenic activity. The fraction
    containing polar metabolites was found to be mutagenic. Its
    composition was too complex to characterize completely, but 2
    mutagens, epichlorohydrin and 1,3-dichloro-2-propanol, were
    identified.

         Watson et al. (1986 a,b; 1987) confirmed that the direct
    mutagenicity, inducing base-pair mutations, previously observed in
     Salmonella typhimurium TA100 treated with  cis-1,3-
    dichloropropene, was caused by trace impurities. These impurities
    resulted from the autooxidation of  cis- and  trans-1,3-
    dichloropropene and were identified as  cis- and  trans-
    dichloropropene oxides. The dichloropropene oxides made a
    significant contribution towards the intrinsic mutagenicity, when
    tested in  S. typhimurium TA100 (see section 8.8.1.1).

         The proposed formation of  cis- and  trans-dichloropropene
    oxides is shown in Fig. 6.

    FIGURE 06

         Autooxidation of  cis-1,3-dichloropropene occurs after radical
    initiation (5) to give the alkyl peroxy radical (6), which reacts
    with a second molecule of  cis-1,3-dichloropropene to give the free
    radical intermediate (7). Free rotation can occur in this molecule,
    prior to expulsion of the alkoxy radical (8), with concomitant
    formation of both  cis- and  trans-dichloropropene oxides (3) and
    (4). The alkoxy radical (8) may further abstract a proton or
    chlorine from  cis-1,3-dichloropropene, thus, continuing the chain
    reaction. Autooxidation reactions often proceed via several pathways
    and in the case of  cis-dichloropropene there are minor products,
    such as a 2-hydroxyperoxy intermediate, and unstable 1,2-dioxetanes
    leading to 1,3-dichloro-2-propanol and aldehydes, respectively.
     Trans-dichloropropene was considerably more resistant to
    autooxidations than  cis-dichloropropene (Watson et al.,  1987).

    8.8.3  Role of glutathione

         Glutathione (GSH) at physiological concentrations in  in vitro
    bacterial test systems of  Salmonella typhimurium TA100 has been
    shown to have a protective effect, i.e., a virtual elimination of
    the mutagenic response to 1,3-dichloropropene (Hutson & Stoydin,
    1977; DeLorenzo et al., 1977; Brooks et al., 1978; Climie et al., 
    1979; Wright & Creedy, 1982; Creedy & Hutson, 1982). 

         This protective effect occurs in either the absence or the
    presence of S9 for both the  cis- and  trans-isomer. In the
    absence of a rat liver fraction, the chemical reaction of  cis-1,3-
    dichloropropene with glutathione is slow, and, in the presence of
    the rat liver fraction, the reaction is rapid due to enzyme
    catalysis. The  trans-isomer (in the presence of the  cis
    compound) was degraded 4-5 times more slowly than the  cis-isomer
    (Hutson & Stoydin, 1977; Climie et al., 1979).

         This protective effect in the presence of S9 is consistent with
    the operation of a glutathione transferase enzyme occurring in the
    added S9 fraction. This enzyme, which conjugates  cis-1,3-
    dichloropropene with glutathione, is also present in mammalian cells
    and the metabolic studies have shown that it plays a key role in the
    rapid detoxification of  cis-1,3-dichloropropene in mammalian
    tissue (Climie et al., 1979; Brooks & Wiggins, 1991). 

         There is some evidence that the mutagenicity of these
    preparations is due to contaminants and that the protective action
    of glutathione is due to spontaneous conjugation reactions between
    these contaminants and glutathione. Pure  cis-dichloropropene did
    undergo metabolic activation catalysed by microsomal mono-oxygenase
    system from the rat liver. Thus, a small, but significant, dose-
    dependent increase in mutation was observed when  cis-
    dichloropropene was tested in  S. typhimurium TA100, in the
    presence of S9-liver fraction. When this S9 fraction was replaced by

    washed microsomes, which remove the glutathione activity, the
    mutagenic effect of  cis-1,3-dichloropropene was increased.
    Replacement of the glutathione  S-alkyl transferase(s) in the
    microsomal fraction from an S100 fraction, restored the glutathione-
    conjugating activity and afforded complete protection against  cis-
    1,3-dichloropropene.  Cis-dichloropropene undergoes rapid
    conjugation with glutathione in the presence of the mentioned
    transferase(s), which limits the availability of  cis-
    dichloropropene to undergo mono-oxygenase-catalysed bioactivation.
    These results also provide some evidence that these glutathione-
    linked conjugation systems also afford efficient protection against
    the mutagenic hazard posed by the bioactivation products of  cis-
    dichloropropene. Thus, the microbial mutagenicity of  cis-
    dichloropropene oxide was significantly reduced by glutathione (5
    mmol/litre) and this protective action was strongly enhanced in the
    presence of glutathione  S-alkyl transferases from the S100 (Fig.
    7).

    FIGURE 07

         It was concluded that the degree to which the genotoxic
    potential of  cis-dichloropropene or its autooxidation products is
    expressed  in vivo is likely to be lower than that found by
    microbial mutation assays.  Cis-dichloropropene is efficiently
    detoxified in mammals by the operation of a glutathione-dependent
     S-alkyl transferase (Watson et al., 1987).

    8.8.4  Effect on liver enzyme activity

         Miyaoka et al. (1990) studied the mechanism of 1,3-
    dichloropropene-induced hepatotoxicity in male mice of the ICR
    strain (6 weeks old). 1,3-Dichloropropene (300 mg/kg body weight),
    administered by gavage in corn oil, increased plasma GOT and GPT
    activities significantly, and centrilobular swelling occurred in the
    liver, 15 h after treatment. No such effect was found with 100 mg/kg
    body weight. Pretreatment of piperonylbutoxide (PIB, a cytochrome
    P450 inhibitor), at 200 mg/kg body weight i.p., significantly
    suppressed the elevation of plasma GOT and GPT activities caused by
    300 mg 1,3-dichloropropene/kg body weight, but increased the 1,3-
    dichloropropene concentration in the liver. The PIB pretreatment
    decreased the cytochrome P450 contents in liver microsomes, but
    prevented further reduction of cytochrome P450 after 1,3-
    dichloropropene treatment.

         With pretreatment with L-buthionine-S,R sulfoximine (a GSH
    depleting agent) at 1600 mg/kg body weight, plasma GOT activities
    increased significantly in animals receiving 100 mg 1,3-
    dichloropropene, whereas liver GSH contents and GST activity
    decreased. Cysteine administration, 2 h after 1,3-dichloropropene
    treatment, did not decrease the cytochrome P450 content, though it
    prevented the elevation of GOT and GPT activities and increased
    hepatic GSH concentration. The results suggest that 1,3-
    dichloropropene is biotransformed via cytochrome P450, and that the
    metabolites induce liver damage. GSH plays an important role in the
    detoxification of 1,3-dichloropropene (Miyaoka et al., 1990).

    9.  EFFECTS ON HUMANS

    9.1  General population

    9.1.1  Acute toxicity - poisoning incidents

         In a truck accident in California in 1975, about 4500 litres of
    1,3-dichloropropene (92%) was slowly spilled on to the highway. An
    estimated 80 persons were exposed to the vapour. Forty-six persons
    were examined at hospitals. The following symptoms were found in a
    small number of persons (4-6), headache, vomiting and nausea,
    dizziness, irritation of mucous membranes, and chest discomfort.
    Three persons lost consciousness at the scene of the accident. In 11
    out of 41 persons, slightly elevated SGOT and/or SGPT values were
    found. Twenty-eight patients were interviewed 1 or 2 weeks later.
    The most common symptoms were: headache (12), abdominal discomfort
    (6), chest discomfort (5), and malaise (5). Twenty-one patients were
    interviewed after 2 years; 10 patients complained of severe or
    unusual headache, 10 of chest pain or discomfort, and 13 of
    "personality changes" (fatigue, irritability, difficulty in
    concentrating, or decreased libido). The frequency of these long-
    persisting symptoms was not associated with the intensity of the
    exposure (Flessel et al., 1978). 

         Markovitz & Crosby (1984) reported 9 cases of acute poisoning
    following accidental over-exposure to 1,3-dichloropropene. The
    chemical spilled as the driver jack-knifed the container. Two of
    these cases died 6 years later, due to diffuse histocytic lymphoma.
    Authors have reported another case of myelo-monocytic leukaemia
    where the patient had been accidentally over-exposed to 1,3-
    dichloropropene (see section 9.2.2).

    9.1.2  Controlled human studies

         A smell detection test with 10 human volunteers was carried
    out. A level of 13.6 mg 1,3-dichloropropene/m3 air was detected by
    7 out of 10 volunteers. Some reported that the sense of smell
    diminished after a few minutes. Even a level of 4.54 mg/m3 was
    detected by these 7 persons, but it was noticeably fainter than 13.6
    mg/m3 (Torkelson & Oyen, 1977).

         In a study designed to determine the odour threshold of Telone
    II among 22 individuals, the lowest concentration at which odour was
    detected was 20 ± 14 mg/m3. This level is slightly above the US
    threshold limit value time-weighted average of 4.54 mg/m3, but
    below the short-term exposure limit of 45.4 mg/m3 (Rick & McCarty,
    1988).

    9.2  Occupational exposure

    9.2.1  General

         The most likely routes of human exposure to 1,3-dichloropropene
    are through inhalation and the skin. Irritation of the eyes and
    upper respiratory mucosa, accompanied by lacrimation, appear
    promptly after exposure to vapours (Gosselin et al., 1976). 

         Inhalation by humans of air containing concentrations greater
    than 6810 mg/m3 produces headaches, mucous membrane irritation,
    dizziness, nausea, vomiting, gasping, coughing, substernal pain, and
    respiratory distress (Gosselin et al., 1976; Flessel et al., 1978).
    Lower concentrations produce central nervous system depression and
    moderate irritation of the respiratory system.

         A 44-year-old male process operator at a pesticide plant had
    acute bullous dermatitis on both feet in 1988. Approximately one
    year later, an identical dermatitis developed. In both periods, he
    contaminated his shoes with a 1,3-dichloropropene formulation (D-D-
    95). In a patch test with 1,3-dichloropropene, even a concentration
    of 0.005% produced a positive reaction. Twenty volunteers did not
    react in this patch test at a concentration of 0.05% (Bousema et
    al., 1991).

         Maddy et al. (1990) summarized the pesticides that caused
    occupational illness/injury, reported by physicians in California
    during 1987. 1,3-Dichloropropene caused one case of systemic illness
    in that period. In the year 1986, 3 cases were mentioned, one with
    systemic effects, one with skin effects, and one with eye injury
    (Edmiston & Maddy, 1987).

         Fifteen applicators of 1,3-dichloropropene were studied for
    personal air exposure, urinary excretion of the metabolite, and
    excretion of the renal tubular enzyme  N-acetyl glucosaminidase
    (NAG). Each was studied for four, 6-8 h consecutive intervals
    following base-line determinations. The duration of exposure ranged
    from 120 to 697 min and the personal air concentrations ranged from
    0.3 to 9.4 mg/m3. The 24-h urinary excretion of the metabolite
    (average 2.6 mg, range: 0.5-9.2 mg) correlated well with the 1,3-
    dichloropropene air exposure product (minutes exposed x mg/m3).
    The mean excretion of NAG for all intervals was 2.6 mU/mg of
    creatinine (range: 1.0-7.7 mU/mg of creatinine); in 24 h, the mean
    was 4940 mU with a range of 278-8956 mU. Four of the 15 workers had
    an NAG activity of > 4 mU/mg creatinine in any of their urine
    collected after the base line. Nine workers showed increases in NAG
    excretion of more than 25% compared with the base line. The authors
    concluded that the elevated excretion of NAG indicated a possible
    subclinical nephrotoxic effect in the workers, though no complaints
    or cases of renal injury were reported (Osterloh et al., 1989).

    Stott et al. (1990) commented that the slight increase in NAG in the
    urine might be a result of the stimulation of exocytosis or an
    increase (induction) in the NAG activity in the kidneys, rather than
    an indication of nephrotoxicity. Taken together with the known
    metabolism and toxicity of 1,3-dichloropropene in laboratory
    animals, the findings by Osterloh et al. (1989) do not suggest any
    untoward effects in workers exposed occupationally to low levels of
    1,3-dichloropropene.

         Fourteen workers applying 1,3-dichloropropene were monitored at
    the start of the season, in July, and at the end of the season, in
    October, for liver function. The following parameters were measured;
    alanine aminotransferase, aspartate aminotransferase, alkaline
    phosphatase, lactic dehydrogenase, gamma-glutamyltrans-peptidase,
    and total bilirubin. Total bilirubin was significantly decreased at
    the end of the season. In combination with an increase in serum
    gamma-glutamyltranspeptidase activity this indicates moderate
    hepatic enzyme induction. The renal function was also studied by
    measuring creatinine and beta-2-microglobulin in serum and beta-2-
    microglobulin, albumin, alanine-aminopeptidase, beta-galactosidase,
    and retinol-binding protein in urine. The glomerular function
    parameters (increased albumin in urine and decreased creatinine in
    serum) changed significantly during the season. The tubular function
    (retinol-binding protein) also increased. On the basis of these
    data, a subclinical nephrotoxic effect cannot be excluded. Effects
    on the glutathione conjugation capacity were studied by measuring
    erythrocyte glutathione- S-transferase activity and blood
    glutathione concentration. Both parameters were significantly
    decreased (Brouwer et al., 1991b). The cause-effect relationship
    with 1,3-dichloropropene exposure has been questioned (Van Sittert
    et al., 1991).

    9.2.2  Acute toxicity - poisoning incidents

         A farmer in good health developed pain in the right ear, nasal
    mucosa, and pharynx after applying 1,3-dichloropropene to his fields
    from his tractor for 30 days. Hospital examination showed a red and
    painful external ear, hyperaemia, and superficial ulcerations of the
    nasal mucosa, and inflammation of the pharynx. The hose containing
    the 1,3-dichloropropene had a small leak, which had sprayed the
    chemical near the right side of his face. Over the following year,
    the man developed myelo-monocytic leukaemia. The man died of
    pneumonia 5 weeks after entering the hospital (Markovitz & Crosby,
    1984; NTP, 1985; Yang, 1986). The Task Group considers that the
    cause-effect relationship in this case is doubtful.

    9.2.3  Effects of short- and long-term exposure

         The fertility status of 63 males employed in the production of
    chlorinated three-carbon compounds were investigated in comparison
    with 63 non-exposed persons (at least 5 years without exposure).

    Data from reproductive medical history, hormone determination, and
    semen analysis were used. There were no indications for an
    association between lowered fertility by the standard fertility
    parameters, and exposure to allyl chloride, epichlorohydrin, and
    1,3-dichloropropene in the quantities occurring in the working
    environment. A possible source of bias in this study stems from the
    relatively low (64%) volunteer rate from the exposed group and the
    lack of an estimate of the individual variation (Venable et al.,
    1980). 

    10.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         1,3-Dichloropropene (technical grade) was considered by working
    groups of the International Agency for Research on Cancer (IARC) in
    1986 (IARC, 1986) and 1987 (IARC,1987). In the updating of 1987, it
    was evaluated as follows. "There is sufficient evidence for the
    carcinogenicity of 1,3-dichloropropene (technical-grade) in
    experimental animals. There is inadequate evidence for the
    carcinogenicity of 1,3-dichloropropene (technical-grade) in humans.
    The agent is possibly carcinogenic to humans (Group 2B)".

         Based on the results from 2-year gavage studies on rats and
    mice, using the linearized multistage model, the drinking-water
    concentration for an excess life-time cancer risk of 104, 105,
    or 106 is estimated to be 20, 2.0, or 0.2 µg/litre, respectively
    (WHO/EURO, 1990).

    PART B

    ENVIRONMENTAL HEALTH CRITERIA

    FOR

    1,2-DICHLOROPROPANE

    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR 1,2-DICHLOROPROPANE

    1.   SUMMARY AND EVALUATION, CONCLUSIONS AND RECOMMENDATIONS

         1.1   Summary and evaluation
               1.1.1   Use, environmental fate, and environmental levels
               1.1.2   Kinetics and metabolism
               1.1.3   Effects on organisms in the environment
               1.1.4   Effects on experimental animals and  in  vitro
                       test systems
               1.1.5   Effects on human beings
         1.2   Conclusions
         1.3   Recommendations

    2.   IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

         2.1   Identity
         2.2   Physical and chemical properties
         2.3   Conversion factors
         2.4   Analytical methods

    3.   SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1   Natural occurrence
         3.2   Man-made sources
         3.3   Uses

    4.   ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         4.1   Transport and distribution between media
               4.1.1   Air
               4.1.2   Soil
                       4.1.2.1   Volatilization
                       4.1.2.2   Uptake in crops
                       4.1.2.3   Movement in soil
         4.2   Biotransformation
         4.3   Bioconcentration

    5.   ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1   Environmental levels
               5.1.1   Air
               5.1.2   Water and soil
               5.1.3   Crops

    6.   KINETICS AND METABOLISM

         6.1   Absorption, distribution, and elimination
               6.1.1   Oral
               6.1.2   Inhalation
               6.1.3   Intraperitoneal
         6.2   Metabolic transformation

    7.   EFFECTS ON ORGANISMS IN THE ENVIRONMENT

         7.1   Aquatic organisms
               7.1.1   Algae
               7.1.2   Invertebrates
               7.1.3   Fish
                       7.1.3.1   Acute toxicity
                       7.1.3.2   Short-term/long-term toxicity
         7.2   Terrestrial organisms
               7.2.1   Earthworms
               7.2.2   Plants

    8.   EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

         8.1   Single exposures
         8.2   Short-term exposures
               8.2.1   Oral
                       8.2.1.1   Mouse
                       8.2.1.2   Rat
               8.2.2   Inhalation
                       8.2.2.1   Mouse
                       8.2.2.2   Rat
                       8.2.2.3   Rabbit
         8.3   Reproduction, embryotoxicity, and teratogenicity
               8.3.1   Reproduction
               8.3.2   Teratogenicity
                       8.3.2.1   Oral (rat)
                       8.3.2.2   Oral (rabbit)
         8.4   Mutagenicity and related end-points
               8.4.1    In vitro studies
                       8.4.1.1   Microorganisms
                       8.4.1.2   Mammalian cells
               8.4.2    In vivo studies
                       8.4.2.1    Drosophila melanogaster
                       8.4.2.2   Dominant lethal test
                       8.4.2.3   Miscellaneous
         8.5   Carcinogenicity
               8.5.1   Oral (mouse)
               8.5.2   Oral (rat)
         8.6   Factors modifying toxicity
         8.7   Special studies
               8.7.1   Liver

               8.7.2   Kidneys
               8.7.3   Central nervous system

    9.   EFFECTS ON HUMANS

         9.1   General population exposure
               9.1.1   Acute toxicity - poisoning incidents
         9.2   Occupational exposure

    10.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    1.  SUMMARY AND EVALUATION, CONCLUSIONS AND RECOMMENDATIONS

    1.1  Summary and evaluation

    1.1.1  Use, environmental fate, and environmental levels

         1,2-Dichloropropane is a liquid with a boiling point of 96.8 °C
    and a vapour pressure of 42 mmHg at 20 °C. The substance is soluble
    in water, ethanol, and ethyl ether. When heated, it emits highly
    toxic fumes of phosgene. The log P octanol/water partition
    coefficient is 2.28.

         This substance is used in furniture finish, dry cleaning fluid,
    and paint remover, gum processing, metal degreasing, oil processing,
    and as a rubber- and wax-making agent, and a chemical intermediate
    in the production of tetrachloroethylene and carbon tetrachloride.
    It is a component of the "MIX D/D", used as a pre-plant fumigant.

         Concentrations of 1,2-dichloropropane in city air have been
    measured at 1.2 µg/m3 (mean value), 0.021-0.040 µg/m3, and
    0.0065-1.4 µg/m3 in Philadelphia, Portland, and Japan,
    respectively. Decomposition in the atmosphere is slow; on the basis
    of reaction with hydroxyl radicals, the half-life of 1,2-
    dichloropropane was > 313 days. Phototransformation is likely to be
    the dominant process for the decomposition. Adsorption on to
    particulate matter is necessary for appreciable phototransformation.
    Volatilization is likely to be the major route of loss from water.

         In soil, the main routes of loss are volatilization and
    diffusion. 1,2-dichloropropane is persistent in soil. More than 98%
    of the 1,2-dichloropropane applied to loam soil was recovered 12-20
    weeks after treatment.

         Leaching of 1,2-dichloropropane occurs from soil and can
    contaminate upper and lower groundwater in areas where "MIX D/D" has
    been used as a soil fumigant. In well water and groundwater in the
    USA, concentrations of up to 440 µg/litre and 51 µg/litre,
    respectively, have been found. In the Netherlands, concentrations of
    up to 160 µg/litre have been measured in well water and 1,2-
    dichloropropane has been found to a depth of 13 m.

         1,2-Dichloropropane can be taken up by edible crops, but the
    residues detected have been low (< 0.01 mg/kg) and are unlikely to
    be biologically significant.

         Bioaccumulation of 1,2-dichloropropane is unlikely, because of
    its high water solubility (2.7 g/kg) and low log P octanol/water
    partition coefficient.

    1.1.2  Kinetics and metabolism

         1,2-Dichloropropane administered orally to rats is rapidly
    eliminated (80-90% within 24 h). There are no major differences in
    kinetics or elimination between males and females. Urine is the
    major route of elimination, up to half an oral dose being eliminated
    by this route within 24 h. Less than 10% is eliminated via the
    faeces. Approximately one-third is eliminated through expired air,
    both as carbon dioxide and as a mixture of volatile materials.
    Tissue concentrations are low, the highest concentration being found
    in the liver. Rapid elimination also occurs following the inhalation
    exposure of rats; 55-65% of a dose is eliminated in the urine and
    16-23% in expired air. The half-life of elimination from the blood
    is 24-30 min.

         Unchanged 1,2-dichloropropane is not found in urine. Three
    major urinary metabolites have been identified. These metabolites
    result from oxidative and conjugation pathways, which yield the
    mercapturates,  N-acetyl- S-(2-hydroxypropyl)-L-cysteine,  N-
    acetyl- S-(2-oxypropyl)-L-cysteine, and  N-acetyl- S-(1-carboxy-
    ethyl)-L-cysteine. 1,2-Dichloropropane can also be oxidized to
    lactate with resultant carbon dioxide or acetyl co-enzyme A
    production.

         Oral administration of 1,2-dichloropropane (2 ml/kg) to rats
    significantly depleted tissue glutathione contents. There was a
    correlation between tissue glutathione loss and expression of
    toxicity in the liver, kidneys, and red blood cells. Prior depletion
    of intracellular glutathione exacerbated 1,2-dichloropropane
    toxicity, whereas pretreatment with precursors for glutathione
    synthesis ameliorated the toxicity. These results demonstrate the
    protective effect of glutathione against 1,2-dichloropropane
    toxicity.

    1.1.3  Effects on organisms in the environment

         EC50 for freshwater algae have not been calculated because of
    difficulties with volatilization of the chemical from the test
    solution. The acute toxicity of 1,2-dichloropropane for aquatic
    invertebrates and fish is low to moderate; 48-h LC50 values for
    invertebrates range between 52 and > 100 mg/litre and 96-h LC50
    values for fish lie between 61 and 320 mg/litre. A short-term
    toxicity test on Fathead minnows demonstrated a maximum no-effect
    level of 82 mg/litre. A 32-day test on early life stage toxicity in
    the same species demonstrated that larval growth and survival were
    the most sensitive parameters. The estimated maximum acceptable
    toxicant concentration (MATC) was between 6 and 11 mg/litre. Growth
    inhibition was noted in Sheepshead minnows after 33 days at a 1,2-
    dichloropropane concentration of 164 mg/litre.

         1,2-Dichloropropane is phytotoxic.

         Contact tests on 4 species of earthworm showed an LC50 of 44-
    84 µg/cm2 (mean values) of filter paper. In artificial soil, the
    LC50 values were 3880-5300 mg/kg soil (dry weight). 

    1.1.4  Effects on experimental animals and in vitro test
           systems

         The acute oral toxicity of 1,2-dichloropropane in experimental
    animals is low. The oral LD50 for the rat is 1.9 g/kg body weight,
    and the dermal LD50 in rabbits is 8.75 ml/kg body weight.

         Short-term, oral toxicity studies of 1,2-dichloropropane in
    mice and rats showed growth inhibition, clinical toxic signs
    associated with central nervous system depression, and/or increased
    mortality at dose levels of 250 mg/kg body weight per day or higher.
    In rats given 250 mg/kg per day for 10 days, there were changes in
    serum enzymes indicative of slight hepatotoxicity with a NOEL of 100
    mg/kg per day.

         In a 13-week mouse inhalation study (highest dose 681 mg/m3),
    no adverse effects were observed. In a similar study on rats exposed
    to 68.1, 227, or 681 mg/m3, a decrease in body weight and minimal
    damage to nasal tissues occurred in the 2 highest dose groups.

         In a 2-generation reproduction study, rats exposed to 1,2-
    dichloropropane in drinking-water at 0.024, 0.1, 0.24% (equivalent
    to 33.6, 140 and 336 mg/kg body weight per day) resulted in lower
    maternal body weight gain and decreased water consumption at the mid
    and high dose levels. Neonatal body weights were lower at the high
    dose level. The NOAELs established for maternal and reproductive
    toxicity were 33.6 and 140 mg/kg body weight per day, respectively.

         Studies did not indicate any teratogenic activity of 1,2-
    dichloropropane at oral dose levels up to 125 mg/kg body weight in
    the rat and 150 mg/kg body weight in the rabbit. However, at these
    dose levels, 1,2-dichloropropane was maternally toxic and fetotoxic,
    as evidenced by central nervous system associated clinical signs,
    decreased maternal body weight gain, and delayed ossification of
    bones in the fetuses. The NOELs are 30 and 50 mg/kg body weight per
    day for the rat and rabbit, respectively. 

         1,2-Dichloropropane was mutagenic in bacteria in most studies
    with, and without, metabolic activation, but very high dose levels
    were used of up to 10 mg/plate. In Chinese hamster ovary cells, 1,2-
    dichloropropane caused chromosomal aberrations and sister chromatid
    exchange; in Chinese hamster V79 cells, it increased the sister
    chromatid exchange. In an  in vitro system with human lymphocytes,
    the tritiated thymidine uptake and cell viability in cultures grown

    with, and without, rat liver metabolizing system, were similar to
    those in control cultures. The results of a sex-linked recessive
    lethal test in  Drosophila melanogaster were negative. A dominant
    lethal test in rats, dosed for 14 weeks via drinking-water
    containing 1,2-dichloropropane, followed by 2 weeks of mating, was
    negative.

         In a carcinogenicity study on mice administered 125 or 250 mg
    1,2-dichloropropane/kg body weight by gavage, a dose-related
    increase in the incidence of liver adenomas was observed. The
    incidence of liver adenomas in treated groups was higher than that
    in the concurrent control group, but was within the historical
    control range.

         In rats administered dose levels of 125 and 250 mg/kg body
    weight (females) and 62 and 125 mg/kg body weight (males), by
    gavage, for 5 days per week over 113 weeks, a slight increase in the
    incidence of mammary gland adenocarcinomas exceeding the historical
    range was observed in high-dose females. 

    1.1.5  Effects on human beings

         Exposure of the general population to 1,2-dichloropropane via
    air and water is unlikely, except in areas where there is extensive
    use of 1,2-dichloropropane and "MIX D/D" in agriculture. Residues of
    1,2-dichloropropane in edible crops are generally below the limit of
    detection. In view of these low exposures to 1,2-dichloropropane,
    the risk to the general population is negligible.

         Several cases of acute poisoning have been reported due to
    accidental or intentional (suicide) over-exposure to 1,2-
    dichloropropane. Effects have been mainly on the central nervous
    system, liver, and kidneys. Haemolytic anaemia and disseminated
    intravascular coagulation have also been reported. In one case,
    delirium progressed to irreversible shock, cardiac failure, and
    death.

         Occupational exposures can be via both skin and inhalation.
    Several cases of dermatitis and skin sensitization have been
    reported in workers using solvent mixtures containing 1,2-
    dichloropropane.

    1.2  Conclusions

    *    General population: There is low or non-existent exposure of
         the general population to 1,2-dichloropropane from air and
         food. However, in certain areas, exposure may occur when
         groundwater is contaminated.

    *    Occupational exposure: With good work practices, hygienic
         measures, and safety precautions, the use of 1,2-
         dichloropropane is unlikely to present a risk for those
         occupationally exposed to it.

    *    Environment: 1,2-Dichloropropane is unlikely to attain levels
         of environmental significance when used at the recommended
         rate. It is unlikely to have adverse effects on populations of
         terrestrial and aquatic organisms.

    1.3  Recommendations

    *    Studies should be conducted to assess acute inhalation
         toxicity, eye and skin irritancy, and skin sensitization
         potential. 

    *    Appropriate safety precautions should be taken, when handling
         1,2-dichloropropane, in order to avoid exposures exceeding the
         maximum allowable concentration.

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL
        METHODS

    2.1  Identity

     Primary constituent

    Chemical structure                Cl
                                       '
                                  ClCH2CHCH3

    Chemical formula              C3H6Cl2

    Relative molecular mass       112.99

    Chemical name                 1,2-dichloropropane,
                                  dichloro-1,2-propane

    Common synonyms               propylene dichloride

    CAS registry number           78-87-5

    RTECS registry number         TX9625000

    EINECS number                 201-152-2

    2.2  Physical and chemical properties

         1,2-Dichloropropane is a liquid with a boiling point of 96.8
    °C. The vapour pressure is 42 mmHg at 20 °C (27.9 kPa at 19.6 °C).
    Its solubility is 2.7 g/kg water at 20 °C. It is soluble in ethanol
    and diethyl ether. The density is 1.1595 g/ml at 20 °C, and 1.437
    g/ml at 25 °C. It is flammable; the flash point is 21 °C (Cleveland
    open cup). When heated to decomposition, 1,2-dichloropropane emits
    highly toxic fumes of phosgene.

         The log P octanol/water partition coefficient is 2.28 (NTP,
    1983).

    2.3  Conversion factors

         1 ppm = 4.66 mg/m3

         1 mg/m3 = 0.214 ppm

    2.4  Analytical methods

         The analytical methods used are the same as those used for 1,3-
    dichloropropene.

         Boyd et al. (1981) developed a method to collect vapours of
    1,2-dichloropropane from air with solid sorbents (petroleum
    charcoal) in tandem with a personal sampling pump; desorption of the
    sorbed compound in acetone/cyclohexane and analysis of the extracts
    by gas chromatography. A Carbowax or Chromosorb column was used. The
    Hall electrolytic conductivity detector (in the halogen mode)
    offered better sensitivity than the electron-capture detector and
    the flame ionization detector. 

         An analytical method is described and issued in 1985 by NIOSH,
    method 1013, for the determination of 1,2-dichloropropane in air.
    The working range is 0.25-600 mg/m3. The limit of determination
    0.1 µg/sample (NIOSH, 1985).

         In method MDHS 28, a description is given for the determination
    of the time-weighted-average concentrations of chlorinated
    hydrocarbon solvent vapours in workplace atmospheres. The method is
    suitable for sampling over periods in the range of 10 min to 8 h.
    The method can also be used for the determination of personal
    exposure. The method is suitable for the measurement of airborne
    vapours containing concentrations in the range of approximately 1-
    1000 mg/m3 (about 0.2-200 ppm v/v) for samples of 10 litres of
    air. Charcoal is used as adsorbent and 15% (v/v) acetone in
    cyclohexane is recommended as a desorption solvent for 1,2-
    dichloropropane; determination takes place with a gas chromatograph
    fitted with a flame ionization detector (HSE, 1990).

         See section 2.4 of 1,3-dichloropropene.

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         1,2-Dichloropropane is not known to occur naturally.

    3.2  Man-made sources

         1,2-Dichloropropane is produced by the chlorination of
    propylene.

         The production of 1,2-dichloropropane in the USA in 1974 was 66
    million kg: in 1976, it was 32.2 million, and in 1980, 35 million kg
    (Fishbein, 1979).

         1,3-Dichloropropene, contaminated with 1,2-dichloropropane and
    2,3-dichloropropene, used for fumigation in the Netherlands at
    application rates ranging from 200 to 400 kg/ha, would mean an input
    of 40-160 kg of 1,2-dichloropropane and 10-25 kg of 2,3-
    dichloropropenes/ha (Krijgsheld & van der Gen, 1986). 1,2-
    Dichloropropane is more persistent in the environment than 1,3-
    dichloropropene and has a greater potential for contaminating
    groundwater, because of its slow chemical degradation. By reducing
    the 1,2-dichloropropane content of the products used in agriculture,
    the contamination of groundwater will decrease. 

    3.3  Uses

         1,2-Dichloropropane is a solvent for fats and oils. It has also
    been used as an insecticide fumigant on grain and soil and to
    control peach tree borers. Other uses are in gum processing, oil
    processing, and organic chemical synthesis, in rubber making, wax
    making, and the making of scouring compounds (Fishbein, 1979;
    Sittig, 1980; Baruffini et al., 1989). It is used in furniture
    finishing, dry cleaning fluid, paint remover, and metal degreasing,
    and is a chemical intermediate for the production of
    tetrachloroethylene and carbon tetrachloride (Fishbein, 1979). 

         It is a component of "MIX D/D" (Sittig, 1980; Worthing & Hance,
    1991).

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1  Transport and distribution between media

    4.1.1  Air

         Phototransformation is likely to be the dominant process for
    the decomposition of 1,2-dichloropropane, but vapour phase
    photolysis was not detected after prolonged simulated sunlight
    irradiation in a reaction chamber (California State Water Resources
    Control Board, 1983).

         Adsorption on to particulate matter seems to be necessary for
    appreciable direct phototransformation. The decomposition is rather
    slow in the atmosphere. It was calculated that, on the basis of
    reaction with hydroxyl radicals, the half-life of 1,2-
    dichloropropane was > 313 days for a 24-h average OH-radical
    concentration of 1 x 106 cm3 (Tuazon et al., 1984). 

         See also section 4.1.1 of 1,3-dichloropropene.

    4.1.2  Soil

         The persistence of 1,3-dichloropropene and 1,2-dichloropropane
    depends on chemical transformation, volatilization, microbial
    transformation, photochemical transformation, and uptake into
    organisms (see section 4.1.3.5 and Table 5 on 1,3-dichloropropene
    and section 4.3.2 and Table 23 on "MIX D/D"). The persistence and
    degradation depend on the type of soil and the temperature (Sittig,
    1980).

         Little or no chemical degradation of 1,2-dichloropropane has
    been observed in laboratory and field studies. More than 98% of 1,2-
    dichloropropane applied to a sandy loam soil and medium loam soil
    was recovered 12-20 weeks after treatment (Roberts & Stoydin, 1976).

    4.1.2.1  Volatilization

         See section 4.1.3.2 of 1,3-dichloropropene.

    4.1.2.2  Uptake in crops

         See section 4.1.3.3 of 1,3-dichloropropene.

    4.1.2.3  Movement in soil

         See section 4.1.3.4 of 1,3-dichloropropene. 

    4.2  Biotransformation

         In a well-run, waste-water treatment plant, Bi-Chem mutant
    bacteria can remove chlorinated aliphatic hydrocarbons, such as 1,2-
    dichloropropane (Straley et al., 1982).

         Oldenhuis et al. (1989) studied the conversion of 1,2-
    dichloropropane by the methanotrophic bacterium  Methylosinus
     trichosporium OB3b, grown in continuous cultures. 1,2-
    Dichloropropane was added at a concentration of 0.2 mmol/litre.
    After 24 h, complete degradation was found. 2,3-Dichloro-1-propanol
    was identified as a degradation product.

    4.3  Bioconcentration

         No data on bioconcentration are available. 

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Air

         The City of Philadelphia made an emission inventory of 99
    pollutants. In the periods 11 December 1983 to 31 March 1984 and 6
    February 1984 to 31 March 1984, the mean concentration of 1,2-
    dichloropropane observed in the air was 1.2 µg/m3 (Haemisegger et
    al., 1985; Sullivan et al., 1985). 

         In Portland, Oregon, the atmospheric gas-phase concentration of
    1,2-dichloropropane during rain events in the period February-April
    1984, ranged between 21 and 40 ng/m3 (Ligocki et al., 1985). 

         In Japan, ambient air levels of 1,2-dichloropropane were
    monitored in 13 cities in 1989. The substance was detected in 11 out
    of 36 samples at levels ranging from 0.0065 to 1.4 µg/m3 (Japan
    Environment Agency, 1991, letter from Sawamura, Ministry of Health
    and Welfare, Tokyo, Japan, to the IPCS).

    5.1.2  Water and soil

         It was reported from the USA that 1.4% of 945 wells contained a
    median level of 0.9 µg 1,2-dichloropropane/litre. In Maryland, 13
    out of 36 wells contained 1,2-dichloropropane at levels ranging from
    1 to 440 µg/litre. In California, 3 wells out of 64 were positive
    for 1,2-dichloropropane, in another study, 12 out of 95 wells were
    positive with levels ranging from 0.4 to 16 µg/litre. In the North
    Coast area, 18 out of 24 wells were positive, with 4 with levels
    above 10 µg/litre (California State Water Resources Control Board,
    1983).

         Hallberg (1989) also reported on the presence of 1,2-
    dichloropropane in groundwater in the USA; 1,2-dichloropropane was
    found in 7 States, with a maximum concentration of 51 µg/litre in
    Massachusetts. Connors et al. (1990) found levels of 0.7-19.0 µg
    1,2-dichloropropane/litre in potable water samples collected in 8
    homes in 3 communities in Connecticut.

         In 1984, micropollutants were analysed in well water in the
    northern part of the Netherlands in an area in which "MIX D/D" had
    been used for at least 20 years. 1,2-Dichloropropane was present in
    14 out of 26 wells at levels ranging from 0.1 up to 9.2 µg/litre
    water (Hoogsteen, 1986).

         Van Beek et al. (1988) studied the presence of 1,2-
    dichloropropane in well water in Noordbargeres in the potato growing
    area in the Northern Netherlands. Thirty-three wells were monitored

    and levels higher than 0.1 µg/litre were found in 17/45 samples. The
    highest concentration observed was 160 µg/litre. The 1,2-
    dichloropropane was found in well water up to a depth of 13 m. The
    average concentration of 1,2-dichloropropane (16 samples) found in
    Puttenveld in the northern Netherlands in a potato growing area, in
    the period 1985-86, was 1.1 µg/litre (range < 0.05-21.0 µg/litre)
    (Beugelink, 1987).

         In 1987-88, samples of surface water up to 1 m depth were taken
    monthly at 5 sites in a polder in the Netherlands and analysed. The
    area is situated next to the dunes (where groundwater is being
    pumped up for the preparation of drinking-water) and is extensively
    used for bulb culture. The maximum concentration of 1,2-
    dichloropropane found was 16.2 µg/litre (Greve et al., 1989).

         Lagas et al. (1989) analysed groundwater in 5 areas where
    potato, maize, and bulb crops were grown in the Netherlands. 1,2-
    Dichloropropane was found in 15 out of 22 samples of water collected
    to a depth of 6 m below potato crops in concentrations of < 0.1-200
    µg/litre and in 6 out of 8 samples below maize and bulb crops in
    concentrations of < 1-14 µg/litre. 

         Cotruvo (1985) reported the occurrence of 1,2-dichloropropane
    in 6 out of 466 samples of groundwater (source not specified) in the
    USA. The median and maximum concentrations were 0.9 µg/litre and 21
    µg/litre, respectively.

         In Japan, 1,2-dichloropropane levels in water and bottom
    sediment were monitored at 26 points (7 mouth of river, 4 lake, 8
    port and 7 bay areas) in 1989. The substance was detected in 20 out
    of 78 water samples with levels ranging from 0.00001 to 0.14
    µg/litre and in 9 out of 78 sediment samples with levels ranging
    from 0.16 to 10.0 µg/kg (Japan Environment Agency, 1991, letter from
    Sawamura, Ministry of Health and Welfare, Tokyo, Japan, to the
    IPCS).

    5.1.3  Crops

         Residues of 1,2-dichloropropane in edible crop commodities,
    arising from the use of 1,3-dichloropropene or "MIX D/D", are
    generally below the limit of detection. The obvious reason for this,
    is that crops are not normally planted until most of the product
    applied has been dissipated. Another reason is that any 1,2-
    dichloropropane taken up by the plant, would have to survive the
    whole crop cycle to be detected in the harvested commodity. 

         Supervised trials with "MIX D/D", in 23 crops in 8 countries
    showed that residues in edible crop commodities were below the
    limits of determination (< 0.01 mg/kg), for 1,3-dichloropropene,
    1,2-dichloropropane, and 3-chloroallyl alcohol.

    6.  KINETICS AND METABOLISM

    6.1  Absorption, distribution, and elimination

    6.1.1  Oral

         Adult male and female Carworth Farm E rats received 1,2-
    dichloro[1-14C]propane in 0.5 ml arachis oil, by stomach tube, and
    excretion was followed. After 4 days, the animals were killed and
    the radioactivity measured in the skin and carcass. The 24-h
    excretion of radioactivity was very rapid, 80-90% was eliminated in
    the faeces, urine, and expired air. The urine, the major route of
    excretion, contained 50.2% (average of male and female animals) of
    the administered dose. In expired air, 19.3% was found as labelled
    CO2 and 23.1% as other volatile radioactivity. Only 4.4% was
    detected in the faeces in first 24 h. The skin and carcass contained
    1.5 and 3.7% of the dose, respectively, on day 4 (Hutson et al.,
    1971).

         In Sprague-Dawley rats, dosed orally with 20 mg 1,2-
    dichloropropane/kg body weight per day for 4 consecutive days,
    unchanged 1,2-dichloropropane was found in expired air, but not in
    the urine (Jones & Gibson, 1980).

         14C-1,2-Dichloropropane (99.9%) was administered orally to
    groups of 4 Fischer 344 rats/sex in a single dose of 1 or 100 mg/kg
    body weight, followed by 1 mg/kg per day non-radiolabelled compound
    for 7 days, and a single 1 mg dose of 14C-1,2-dichloropropane/kg
    body weight on day 8. 14C-1,2-Dichloropropane was rapidly
    absorbed, metabolized, and excreted in both sexes. In all treated
    groups, the principal routes of elimination were via the urine (37-
    52%), expired air (31-36%) and faeces (5.5-7.9%); a total of 80-90%
    was eliminated in the first 24 h. The tissues and carcass contained
    7.1-10.6% of the dose. In general, the radioactivity was well
    distributed among the 13 organs and tissues analysed, 48 h after
    treatment. The liver contained the highest 14C-activity in all
    groups; from 0.229 to 0.416% of the dose/g wet weight. Peak
    concentrations were found in the blood 4 h after treatment. The
    quantities of volatile organic compounds found ranged from 0.14 to
    1.13% in the 1 mg/kg group and from 10 to 16% in the 100 mg/kg
    group; approximately 82% of the exhaled volatile organic compounds
    were in the form of 1,2-dichloropropane. Multiple exposure resulted
    in a statistically significant reduction in the amount of
    radioactivity eliminated in the urine, while the metabolism of 1,2-
    dichloropropane to CO2 was enhanced. At 100 mg/kg, there was a
    significant reduction of CO2 formation and enhancement of 14C
    elimination as volatile organic compounds (14.7-33.4%) compared with
    a single dose. No parent 1,2-dichloropropane was found in the urine,
    but 3 mercapturic acid metabolites of 1,2-dichloropropane were
    identified (Timchalk et al., 1989).

    6.1.2  Inhalation

         Groups of 4 Fischer 344 rats/sex were exposed to 14C-1,2-
    dichloropropane vapour for a 6-h period in head-only inhalation
    chambers at target concentrations of 23.3, 233, or 466 mg/m3. The
    14C-1,2-dichloropropane was rapidly absorbed, metabolized, and
    excreted. The urine contained between 55 and 65% of the dose, and
    expired air contained 16-23% of 14CO2. With increasing dose, a
    greater percentage of the recovered dose was eliminated as expired
    organic volatile compounds, i.e., 1.7, 2.1-3.4, and 6.3-6.7%,
    respectively. At 466 mg/m3, this increase was statistically
    significant. The faeces contained 6.3-9.7% of the dose and the
    tissues and carcass accounted for 5.8-10.0%. No sex difference was
    noted. Radioactivity was well distributed among all 13 organs when
    the tissues were analysed after 48 h. The liver and kidneys had the
    highest concentration ranging from 0.154 to 0.292% and from 0.098 to
    0.252% of the dose/g wet weight, respectively. Peak blood
    concentrations of 0.06, 0.92, and 3.87 µg/g blood for the 3 dose
    levels, respectively, were found at 4 h. Half-lives for elimination
    from blood were 24 and 30 min for females and males, respectively.
    No parent 1.2-dichloropropane was found in the urine, but 3
    mercapturic acid metabolites were identified (section 6.2) (Timchalk
    et al., 1989). 

    6.1.3  Intraperitoneal

         Groups of 5 male Wistar rats (200 g) were administered, i.p.,
    0, 10, 25, 50, 100, 250, or 500 mg 1,2-dichloropropane (97%)/kg body
    weight in 0.5 ml corn oil for 5 days (once daily) or for 4 weeks
    (five days/week). Urinary mercapturic acid excretion was monitored.
    A significant increase in mercapturic acid excretion was observed at
    all dose levels, with no further increase during the treatment: at
    lower doses, a return to baseline values occurred within 48 h of the
    end of the treatment. Mercapturic acid excretion at the end of weeks
    2, 3, and 4 was significantly lower than that observed at the end of
    the first week (Trevisan et al., 1989).

    6.2  Metabolic transformation

         1,2-Dichloropropane is metabolized to form a variety of
    metabolic products. Dichloropropane oxidation yielded the
    mercapturic acid,  N-acetyl- S-(2-hydroxypropyl)cysteine (Jones &
    Gibson, 1980). Three mercapturic acid metabolites were identified in
    the urine of Fischer 344 rats (110-140 g) administered 1,2-
    dichloropropane orally (100 mg/kg body weight) or by inhalation (466
    mg/m3 per 6 h). These compounds are  N-acetyl- S-(2-
    hydroxypropyl)-L-cysteine,  N-acetyl- S-(2-oxopropyl)-L-cysteine
    and  N-acetyl- S-(1-carboxyethyl)-L-cysteine. Fischer 344 rats
    were given a single oral dose of deuterium (D6)-labelled
    dichloropropane (105 mg/kg body weight) in a mechanistic study

    conducted to determine whether the conjugated metabolites are
    generated through a sulfonium ion intermediate. The results suggest
    that dichloropropane undergoes oxidation either prior to, or
    subsequent to, glutathione conjugation. There was no evidence to
    support the existence of a sulfonium intermediate in the formation
    of the 2-hydroxypropyl-mercapturic acid metabolite of
    dichloropropane (Fig. 8). Instead, this metabolite is thought to
    arise via the direct oxidation of 1,2-dichloropropane, either prior
    to, or following, conjugation with glutathione (Fig. 8) (Timchalk et
    al., 1989; Bartels & Timchalk, 1990).

    FIGURE 08

         Imberti et al. (1990) investigated the effects of a single dose
    of 1,2-dichloropropane of 2 ml/kg body weight (by gavage) on the
    intracellular glutathione (GSH) content of the liver, kidneys, and
    blood of male Wistar rats (180-250 g). 1,2-Dichloropropane,
    administered orally, caused a significant depletion of GSH within 24
    h of treatment, followed by a slow recovery, approaching normal
    levels after 96 h. The GSH depletion was associated with a marked
    increase in serum GOT, GPT, 5'-nucleotidase, gamma-glutamyl
    transpeptidase, alkaline phosphatase, urea, and creatinine, and a
    significant degree of haemolysis. The administration of L-
    buthionine-S,R sulfoximine (BSO) (0.5 g/kg body weight, i.p.), 4 h
    before 1,2-dichloropropane treatment, resulted in a significant
    increase in overall mortality. The administration of a GSH
    precursor,  N-acetylcysteine (NAC), i.p., at 250 mg/kg body weight,
    2 and 16 h after 1,2-dichloropropane treatment, prevented the loss
    of cellular GSH and reduced the extent of injury in the target
    tissues. There was a correlation between the depletion of liver GSH
    and the increases in GOT, GPT, and 5'-nucleotidase, between the
    depletion of GSH in the kidneys and the increase in serum urea and
    creatinine, and the depletion of GSH in blood and the occurrence of
    haemolysis.

         Both 1-chloro-2-hydroxypropane (II) and 1,2-epoxypropane (III)
    are proposed as intermediates in the metabolism to the mercapturic
    acid. 1,2-Epoxypropane can also be metabolized to propanediol (IV),
    which is further metabolized to pyruvate and enters the
    tricarboxylic acid cycle; carbon dioxide is released and expired.
    Epoxypropane may also be conjugated with glutathione (VI) and
    excreted in the urine. Jones & Gibson (1980) further proposed that
    the 1-chloro-2-hydroxypropane (II) may be metabolized to beta-
    chlorolactaldehyde (VII) and beta-chlorolactate (VIII) (Fig. 9).

    FIGURE 09

    7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    7.1  Aquatic organisms

    7.1.1  Algae

         The EC50 for CO2 uptake by marine algae  (Phaeodactylum
     tricornutum) was 50 mg/litre. 1,2-Dichloropropane was not found to
    exhibit any algistatic or algicidal effects in an acute toxicity
    study on  Selenastrum capricornutum, though the problems of losses
    of 1,2-dichloropropane from the test flasks, made it impossible to
    calculate EC values (Dynamic Corporation, 1991). 

         A general trend of decreasing algal population growth with
    increasing nominal concentrations of 1,2-dichloropropane was
    observed in an acute toxicity test on  Skeletonema costatum.
    Because the concentrations measured for each nominal value were
    variable, it was not appropriate to determine EC values. A NOEL of
    18 mg/litre was determined, though it was not possible to
    distinguish algistatic from algicidal effects (Dynamic Corporation,
    1991).

    7.1.2  Invertebrates

         The acute toxicity of 1,2-dichloropropane for non-target
    invertebrates is summarized in Table 18; 1,2-dichloropropane has a
    48-h LC50 of 50-100 mg/litre for these aquatic organisms. No
    discernible effects on  Daphnia magna were found at concentrations
    of less than 22 mg/litre (Leblanc, 1980). 

        Table 18. Acute toxicity of 1,2-dichloropropane in non-target
              aquatic insects and crustacea
                                                                             
    Species                  Temperature     48-h LC50     References
                                (°C)         mg/litre
                                                                             

    Barnacle nauplii              -             53         Pearson & McConnell
    (Elminius moderatus)                                   (1975)

    Brown shrimp                  -            > 100       Portmann & Wilson 
    (Crangon crangon)                                      (1971)

                                                                             
    
    7.1.3  Fish

    7.1.3.1  Acute toxicity

         The 96-h LC50 of 1,2-dichloropropane for freshwater and
    marine fish is 61-320 mg/litre (Table 19).

    7.1.3.2  Short-term/long-term toxicity

         Two embryo-larval tests have been conducted on Fathead minnow
     (Pimephales promelas) exposed to 1,2-dichloropropane. The maximum
    no-effect levels were 8.1 and 60 mg/litre, respectively (US EPA,
    1980).

         In the marine environment, growth inhibition was noted in the
    Sheepshead minnow  (Cyprinodon variegatus) after 33 days exposure
    to 164 mg 1,2-dichloropropane/litre (US EPA, 1980). 

         A 32-day test to study early life stage toxicity in Fathead
    minnows  (Pimephales promelas) demonstrated that larval growth and
    survival (28-day-old fish) were the most sensitive indicators of
    toxic effects. Embryo hatch and larval deformities at hatch were the
    least sensitive indicators of toxicity. The 1,2-dichloropropane
    (98%) was tested at dose levels of 0, 6, 11, 25, 51, and 110
    mg/litre (temperature of the water 25 °C, hardness 45 mg/litre as
    CaCO3, pH 7.4). The estimated maximum acceptable toxicant
    concentration (MATC) was between 6 and 11 mg/litre (Benoit et al.,
    1982).

    7.2  Terrestrial organisms

    7.2.1  Earthworms

         Neuhauser et al. (1985a,b; 1986) studied the toxicity of 1,2-
    dichloropropane for 4 species of earthworm  (Allolobophora
     tuberculata, Eisenia foetida, Eudrilus eugeniae and  Perionyx
     excavatus) using EEC earthworm artificial soil and a contact
    testing procedure (Edwards, 1983). The LC50 values and 95%
    confidence limits in the contact test were 84(65-110); 64(59-70);
    44(38-51); and 63(56-72) µg/cm2 of filter paper for the 4 species
    of earthworms, respectively. In the artificial soil test, the LC50
    values were 4272, 4240, 5300, and 3880 mg/kg dry weight artificial
    soil, respectively.

    7.2.2  Plants

         1,2-Dichloropropane is highly phytotoxic.


        Table 19.  Acute toxicity of 1,2-dichloropropane in fish
                                                                                                                  
    Species                       Size or age    Temperature          96-h LC50          References
                                                    (°C)              mg/litre
                                                                                                                  

    Guppy                         2-3 months        21-23         3.01 µmol/litref       Könemann (1981)
    (Poecilia reticulata)

    Bluegill sunfish               33-75 mm          23a                 320             Dawson et al. (1977)
    (Lepomis macrochirus)         0.32-1.2 g        21-23              280b,c            Buccafusco et al. (1981)
                                                                      (220-340)

    Fathead minnow                30-35 days        25d,e               140d             Wallbridge (1983)
    (Pimephales promelas)                                             (131-150)

    Tidewater silversides          40-100 mm         20a                 240             Dawson et al. (1977)
    (Menida beryllina

    Dab                            15-20 cm           -                  61              Pearson & McConnell (1975)
    (Pleuronectes limanda)

                                                                                                                  

    a    Hardness 55 mg/litre (as CaCO3), pH 7.6-7.9.
    b    Tested in well-water, 32-48 mg/litre CaCO3, pH 6.5-7.9, oxygen concentration at the beginning
         9.7 to 0.3 mg/litre after 96-h exposure.
    c    Static system (nominal concentrations).
    d    Flow-through system.
    e    Hardness 42-45 mg/litre (as CaCO3) pH 6.7-7.6.
    f    7-day LC50 (static system, renewal).
    

    8.  EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS

    8.1  Single exposures

         The acute oral LD50 for the rat has been reported to be 1.9
    (1.7-2.1) g/kg body weight and the dermal LD50 after a single skin
    exposure of rabbits was 8.75 (8.3-9.2) ml/kg body weight (Smyth et
    al., 1969; California State Water Resources Control Board, 1983).

    8.2  Short-term exposures

    8.2.1  Oral

    8.2.1.1  Mouse

         Groups of 5 male and 5 female B6C3F1 mice were
    administered (by gavage) 0, 125, 250, 500, 1000, or 2000 mg 1,2-
    dichloropropane (99.4%) per kg body weight, in corn oil. The doses
    were given for 14 consecutive days (range-finding study) followed by
    1 day of observation. All male mice in the 1000 and 2000 mg/kg
    groups and female mice in the 2000 mg/kg group died. Also 3 out of 5
    males receiving 500 mg/kg and 4 out of 5 females receiving 1000
    mg/kg died. No growth inhibition was seen in the surviving animals
    (NTP, 1986).

         Groups of 10 male and 10 female B6C3F1 mice were then
    administered 1,2-dichloropropane (99.4%) in corn oil, by gavage, 5
    days per week for 13 weeks, at doses of 0, 30, 60, 125, 250, or 500
    mg/kg body weight. Mortality was not significantly increased, and
    mean body weight changes were not dose-related. No compound-related
    histopathological changes were found at the highest dose level (NTP,
    1986).

    8.2.1.2  Rat

         Groups of 5 male and 5 female F344/N rats were administered
    1,2-dichloropropane (99.4%) at 0, 125, 250, 500, 1000, and 2000
    mg/kg body weight, in corn oil, by gavage, for 14 consecutive days
    (range-finding study) followed by 1 day of observation. All rats
    receiving the highest dose level died. Growth inhibition was seen in
    the surviving animals in the 1000 mg/kg group. At necropsy, renal
    medullae were red in the 2000 mg/kg group, not in lower dose levels
    (NTP, 1986).

         Groups of 10 male and 10 female F344/N rats were then
    administered 1,2-dichloropropane (99.4%) in corn oil, by gavage, 5
    days per week for 13 weeks at doses of 0, 60, 125, 250, 500, or 1000
    mg/kg body weight. All animals administered 1000 mg/kg and half of
    the males administered 500 mg/kg died. Growth inhibition was seen in
    the 500 mg/kg group. Centrilobular congestion of the liver occurred

    in the 1000 mg/kg group and 2 females of this group showed hepatic
    changes and centrilobular necrosis. Lower dose levels did not
    produce effects (NTP, 1986). 

         A 2-week study of 1,2-dichloropropane (99.9%) was conducted
    using groups of 10 Fischer 344 rats/sex to select doses for a
    subsequent 13-week study. Dose levels were 0 (corn oil), 300, or 500
    mg/kg body weight per day (by gavage) for 14 days. Data were
    obtained on body weight, clinical effects, body temperature,
    functional observational battery, motor activity, haematology,
    liver, kidney, and spleen weights, gross pathology and histological
    examination of the liver and kidneys. In both groups, transient
    clinical effects (tearing, blinking, and lethargy) were seen, and
    body weights were significantly decreased. The body temperatures of
    treated animals in both groups, recorded 1 h after dosing on day 13,
    were decreased by 0.3-0.5 °C. No effects on motor activity and
    haematology were noted. Liver and kidney weights were increased and
    spleen weight decreased. Histopathological changes (prominent
    nucleoli of hepatocytes in the centrilobular region, degeneration
    and necrosis of the liver cells) were found in the livers of animals
    in both the treated groups (Gorzinski & Johnson, 1989).

         In an oral toxicity study, adult male Sprague-Dawley rats were
    administered 0, 100, 250, 500, or 1000 mg 1,2-dichloropropane/kg
    body weight, in corn oil (by gavage), once a day, for up to 10
    consecutive days. Some rats were killed at each dose level 24 h
    after 1, 5, and 10 daily doses. After dosing, changes in body weight
    and clinical toxic signs were assessed. In addition, measurements of
    clinical chemistry parameters, urinary levels of glucose, alkaline
    and acid phosphatase and  N-acetyl glycosaminidase activities, and
    the histopathology of major organs, liver enzyme levels, as well as
    levels of non-protein sulfhydryls in the liver and kidneys were
    determined. Definite central nervous system depression and body
    weight loss, and increased renal nonprotein sulfhydryl (NPS) levels
    were seen at 250 mg/kg. Liver damage (both morphological and enzyme
    changes) was observed only at the 500 and 1000 mg/kg dose levels. In
    this study, "resistance" to 1,2-dichloropropane hepatotoxicity
    developed over the 10 consecutive days of exposure, as reflected by
    progressively lower serum enzyme levels and by decreases in the
    severity and incidence of toxic hepatitis and periportal
    vacuolization. Nucleolar enlargement in hepatocytes, however, was
    observed at all dose levels at both 5 and 10 days. There were a
    number of manifestations of haemolytic anaemia in various tissues,
    but no evidence of nephrotoxicity. On the basis of the parameters
    examined, a NOEL of 100 mg/kg body weight can be established
    (Bruckner et al., 1989).

         In a similar oral study, male Sprague-Dawley adult rats were
    treated with 0, 100, 250, 500, or 750 mg 1,2-dichloropropane/kg body
    weight, in corn oil, by gavage, 5 times weekly for up to 13 weeks.

    Over one-half of the animals in the 750 mg/kg group died within 10
    days. Histopathological changes included mild hepatitis and splenic
    haemosiderosis, adrenal medullary vacuolization and cortical
    lipidosis, testicular degeneration and a reduction in sperm, and an
    increased number of degenerated spermatogonia in the epididymis.
    Similar testicular and epididymal degenerative changes were observed
    in some animals in the 500 mg/kg group after 13 weeks of dosing.
    While no deaths occurred in the 100 or 250 mg/kg groups, more than
    50% in the 500 mg/kg group had died by 13 weeks. A dose-dependent
    decrease in body weight gain was observed. 1,2-Dichloropropane
    exhibited very limited hepatotoxic potential and no apparent
    nephrotoxic potential in this 13-week study (Bruckner et al., 1989).

    8.2.2  Inhalation

    8.2.2.1  Mouse

         B6C3F1 mice (aged 6-8 weeks) were exposed to target
    concentrations of 1,2-dichloropropane (99.9%) of 0, 69.9, 233, or
    699 mg/m3 for 6 h/day, 5 days/week, for 13 weeks. The mean actual
    concentrations were 0, 74.5, 233, or 694 mg/m3. There were no
    effects on haematology, gross pathology, and histopathology at
    concentrations as high as 699 mg/m3, in this study (Nitschke et
    al., 1988).

    8.2.2.2  Rat

         Fischer 344 rats (aged 6-8 weeks) were exposed to target
    concentrations of 0, 69.9, 233, or 699 mg 1,2-dichloropropane
    (99.9%)/m3 for 6 h/day, 5 days/week, for 13 weeks. The mean actual
    concentrations were 0, 74.5, 233, or 694 mg/m3. The body weights
    of rats exposed to 233 and 699 mg/m3 were significantly decreased.
    Minimal effects were observed microscopically in the nasal tissues
    of rats exposed to 233 and 699 mg/m3. A few rats exposed to 69.9
    mg/m3 also had slight thickening of a small portion of the
    respiratory nasal mucosa. No treatment-related effects were noted in
    haematology, clinical chemistry, or urinalysis, even at 699 mg/m3
    (Nitschke et al., 1988). A NOEL of 74.5 mg/m3 can be established.

    8.2.2.3  Rabbit

         New Zealand white rabbits (age 6-7 months) were exposed to 1,2-
    dichloropropane at 0, 699, 2330, or 4660 mg/m3 for 6 h/day, 5
    days/week, for 13 weeks. The mean actual concentrations were 0, 694,
    2204, or 4436 mg/m3. Minimal effects on nasal tissues were present
    in male rabbits only at the 4660 mg/m3 level. The primary effects,
    decreased red blood cell parameters (red cell blood count,
    haemoglobin, and packed cell volume), were observed in male rabbits
    exposed to 699 (minimal effects) - 4660 mg/m3, and in female
    rabbits exposed to 2330 and 4660 mg/m3 (Nitschke et al., 1988). No
    NOEL has been established. 

    8.3  Reproduction, embryotoxicity, and teratogenicity

    8.3.1  Reproduction

         Groups of 30 male and 30 female Sprague-Dawley rats each were
    provided with drinking-water containing 1,2-dichloropropane (99.9%)
    at concentrations of 0, 0.24, 1, or 2.4 g/litre (w/v) (equivalent to
    0, 33.6, 140, or 336 mg/kg body weight) over 2 generations. A
    concentration of 2.4 g/litre represented the maximum practicable
    attainable concentration, based on solubility. Adult rats were
    evaluated for body weights, water and feed consumption, reproductive
    performance, and gross pathological and histological changes. The
    litters were evaluated for size, neonatal growth, and survival.
    Decreases in water consumption reflective of rejection because of
    unpalatability, were observed at all levels tested in both sexes in
    the F0 and F1 generations. These decreases in water consumption
    resulted in significantly lower body weights in both generations
    administered 2.4 g/litre. These differences in water consumption and
    body weights were also evident among the females during gestation
    and/or lactation. The 0.24 g/litre dose level had a minor effect on
    water consumption and body weights, but no adverse effects on the
    animals. No treatment-related gross pathological changes were noted
    in any dose group and the histological changes were limited to
    increased hepatocellular granularity in both sexes in both
    generations at all dose levels.

         There were no histological changes in the reproductive tracts
    of either sex in either generation. Reproductive function, measured
    by fertility and litter size, was unaffected. The decreases in water
    consumption among females at 2.4 g 1,2-dichloropropane/litre
    resulted in significantly lower neonatal body weights and slightly
    increased neonatal mortality in their litters. These neonatal
    effects were considered secondary to the substantial decreases in
    maternal water consumption, rather than a direct effect of the
    substance. There were no neonatal effects at the 2 lower
    concentrations. The NOAEL for adults is 0.24 g/litre, and the
    reproductive NOAEL is 1 g/litre (equivalent to 140 mg/kg body
    weight) (Kirk et al.,  1990).

    8.3.2  Teratogenicity

    8.3.2.1  Oral (rat)

         Groups of 30 Sprague-Dawley rats were administered 1,2-
    dichloropropane (99.9%) in corn oil, by gavage, on gestation days 6-
    15 at dose levels of 0, 10, 30, or 125 mg/kg body weight per day.
    Parameters evaluated included maternal body weight and weight gain,
    feed and water consumption, fetal weights, and fetal morphology. The
    highest dose level produced transient decreases in respiration,
    movement, muscle tone and extensor thrust reflex, and increases in

    salivation and lacrimation, within 1 h of dosing on day 6 of
    gestation. A decrease in the frequency of these clinical symptoms
    occurred on the second day. In rats, 1,2-dichloropropane produced
    transient central nervous system depression and decreased maternal
    body weight gain and feed consumption at 125 mg/kg body weight.
    Fetal effects in rats were limited to a significant increase in the
    incidence of delayed ossification of the bones of the skull in the
    125 mg/kg group, secondary to maternal effects. A level of 30 mg/kg
    was considered the NOEL for maternal and fetal effects (Kirk et al.,
    1989; Hanley et al., 1990). 

    8.3.2.2  Oral (rabbit)

         Groups of 18 New Zealand white rabbits were administered 1,2-
    dichloropropane (99.9%) at dose levels of 0, 15, 50, or 150 mg/kg
    body weight per day on gestation days 7-19. On day 28 of gestation,
    Caesarean section was performed and the fetuses evaluated.
    Parameters evaluated included maternal body weight and weight gain,
    haematology, fetal body weights, and fetal morphology. In maternal
    rabbits, a dose of 150 mg/kg per day produced anorexia, significant
    decreases in weight gain, and anaemia, with microscopic examination
    revealing slight to moderate anisocytosis, poikilocytosis, and/or
    polychromasia, indicative of a regenerative anaemia. The only fetal
    effect in rabbits was a significant increase in the incidence of
    delayed ossification of the bones of the skull at the highest dose
    level, secondary to maternal effects. No effects were observed in
    the 15 and 50 mg/kg dose groups. The NOEL for both maternal and
    fetal effects was 50 mg/kg body weight (Hanley et al., 1989a).

    8.4  Mutagenicity and related end-points

    8.4.1  In vitro studies

    8.4.1.1  Microorganisms

         1,2-Dichloropropane was tested for its mutagenic activity in
     Salmonella typhimurium, Saccharomyces cerevisiae with, and without
    metabolic activation, and in  Aspergillus nidulans and
     Streptomyces coelicolor. Results in most studies on  S.
     typhimurium TA100 and TA1535 were positive, but negative results
    were obtained with TA98, TA1537, and TA1538,  S. cerevisiae, and
     S. coelicolor. In  Aspergillus nidulans, a forward mutation to 8-
    azaguanine resistance and methionine suppression was found with S9
    activation.

         The results are summarized in Table 20. 


        Table 20.  Mutagenicity tests with 1,2-dichloropropane on microorganisms
                                                                                                                                              
    Organism/strain                 Substance              Dose        Type of test      Metabolic activation   Result      Reference
                                                                                                                                              

    Salmonella typhimurium
    TA100, TA1535                    1,2-DCP             10-50 mg          plate              S9 mix/none          +        De Lorenzo et al.
    TA1978                                                                                    S9 mix/none          -        (1977)

    TA100                         1,2-DCP (65%           62.5-8000      suspension            S9 mix               +        Priston et al.
    TA1535                        1,2-DCP + 25%           µg/mld                              S9 mix/none          +        (1983)
                                 1,3-DCPropene)
    TA98, TA1537                                                                              S9 mix/none          -

    TA100                            1,2-DCP              1, 10,           plate              S9 mix/none          -        Stolzenberg & Hine
                                                         100 µmola                                                          (1980)

    TA100, TA1535                    1,2-DCP            1-10 µlitre        plate              S9 mix/none          +        Carere & Morpurgo
                                                                                                                            (1981)
    TA98, TA1537, TA1538                                                                      S9 mix/none          -

    TA100, TA1535                    1,2-DCP            0.33-10 mg         plate              S9 mix/none          +        Haworth et al. (1983)
                                                                                              (rat/hamster)
    TA98, TA1537                                                                              S9 mix/none          -
                                                                                              (rat/hamster)

    TA100, TA1535, TA1537         1,2-DCP (99%)         33-2000 µg         plate              S9 mix               -        NTP (1983)
                                                                                              S9 none             (+)
    TA98                                                                                      S9 mix/none          -
                                                                                              (rat/hamster)

    Saccharomyces cerevisiae

    JD1                           1,2-DCP (65%           62.5-8000           -                S9 mix               -        Priston et al.
                                  1,2-DCP + 25%           µg/mld                              S9 none             (+)       (1983)
                                 1,3-DC propene)

                                                                                                                                              

    Table 20 (contd)
                                                                                                                                              
    Organism/strain                 Substance              Dose        Type of test      Metabolic activation   Result      Reference
                                                                                                                                              


    Streptomyces coelicolarb         1,2-DCP           2-100 µlitre        plate              none                 -        Carere & Morpurgo
    A3                                                                                                                      (1981)

    Aspergillus nidulansc                             100-400 µlitre       plate              none                 +        Carere & Morpurgo
                                                                                                                            (1981)

    Aspergillus nidulans          1,2-DCP (99%)       154 mmol/litre                                               -        Crebelli et al.
                                                                                                                            (1984)

                                                                                                                                              

    a    The highest dose level, 100 µmol/plate gave complete inhibition of bacterial growth.
    b    Resistance to streptomycin.
    c    Resistance to 8-azaguanine.
    d    Concentrations of 1000 µg/ml and higher were cytotoxic.
    

         Crebelli et al. (1984) studied the induction of somatic
    segregation in  Aspergillus nidulans. Induction of haploidization,
    mitotic non-disjunction, and mitotic crossing-over was studied in
    heterozygous colonies exposed to 1,2-dichloropropane, 99%. No
    significant rise in frequency of any kind of segregated sectors was
    found. The concentration that was used was 154 mmol/litre. 

    8.4.1.2  Mammalian cells

         In cytogenetic studies using Chinese hamster ovary cells, 1,2-
    dichloropropane (99.4%) caused both chromosome aberrations and
    sister chromatid exchanges. Dose levels tested were 0.46-1.50 and
    0.113-1.13 mg/ml, respectively (Galloway et al., 1987). 

         Priston et al. (1983) also studied the ability of 1,2-
    dichloropropane (containing 65% 1,2-dichloropropane and 25% 1,3-
    dichloropropane) to induce chromosome damage using rat liver (RL4)
    cells, in concentrations of 5-20 µg/ml. An indication for a small
    increase in the frequency of chromatid gaps, chromatid and
    chromosome aberrations, was noticed, but only in the presence of
    cytotoxic effects. The Task Group considered this study inadequate.

         Von der Hude et al. (1987) used the Sister Chromatid Exchange
    test  in vitro in Chinese hamster V79 cells to evaluate the effect
    of 1,2-dichloropropane (99%). The concentrations tested were 0
    (DMSO), 1.0, 3.3, and 10.0 mmol/litre without S9 mix. A dose-related
    increase in SCEs was observed. With S9 mix and the same
    concentrations, the SCEs frequency was increased but was less than
    without S9 mix.

    8.4.2  In vivo studies

    8.4.2.1  Drosophila melanogaster

         Woodruff et al. (1985) tested 1,2-dichloropropane at 0 and 4200
    mg/litre by injection in germ cells and 0 and 33 552 mg/m3 by
    inhalation in  Drosophila melanogaster, using the sex-linked
    recessive lethal mutation for their mutagenicity. The results by
    injection and inhalation were negative.

    8.4.2.2  Dominant lethal test

         Groups of 30 male Sprague-Dawley rats were given 1,2-
    dichloropropane (99.9%) in the drinking-water at concentrations of
    0, 0.24, 1, or 2.4 g/litre, continuously, for a period of
    approximately 14 weeks, as part of a combined reproduction/ dominant
    lethal study (section 8.3.1). Exposed males (F0) were used for a
    dominant lethal test following completion of the breeding for the
    F1 litters of the reproduction study. They were mated with pairs
    of naive, untreated adult females for 2 successive periods of 1 week

    each. A separate, positive control group of 30 male rats was
    administered a single oral dose of 100 mg cyclophosphamide/kg body
    weight, 48 h prior to mating with untreated females. The uterine
    contents of the females were evaluated for evidence of dominant
    lethal effects as manifested by an increase in the resorption rate.
    Among 1,2-dichloropropane-treated males, concentration-related
    decreases in water consumption were noted at all levels and
    decreased body weights were noted in males given 1 or 2.4 g/litre in
    the water. Mating performance was unaffected in these animals.
    Resorption rates among these groups revealed that the weekly values
    for the females mated to treated males ranged from 2.2 to 8.1%, well
    within the historical control range. Resorption rates among the
    concurrent controls were low, ranging from 3.5 to 5.4%. The
    significant increases from the concurrent control values, identified
    during the first week of breeding in the resorption rates in the
    groups given 0.24 or 2.4 g/litre, were considered to be within the
    normal variation. Cyclophosphamide resulted in a 10-fold increase in
    the resorption rate. 1,2-Dichloropropane was not mutagenic in a
    dominant lethal assay in male Sprague-Dawley rats exposed
    continuously to concentrations of up to 2.4 g/litre in the drinking-
    water (Hanley et al., 1989b).

    8.4.2.3  Miscellaneous

         Perocco et al. (1983) studied the tritiated thymidine uptake
    and cell viability in human lymphocyte cultures grown with, or
    without, rat liver metabolizing system. Both the [3H]TdR uptake
    and the percentage of viable cells showed values very similar to
    control values. The 1,2-dichloropropane concentrations used ranged
    from 10-2 to 10-4 mmol/litre.

    8.5  Carcinogenicity

    8.5.1  Oral (mouse)

         Groups of 7 to 9-week-old hybrid B6C3F1 mice (50 males
    and 50 females) were administered 0, 125, or 250 mg 1,2-
    dichloropropane (99.4%)/kg body weight, in corn oil, by gavage, 5
    days/week for 113 weeks. No influence on growth was observed. The
    survival of the female animals at the highest dose level was
    significantly decreased. The incidence of non-neoplastic lesions
    showed lesions of the spleen (haemosiderosis and haematopoiesis were
    increased) in female mice at the highest dose level. 

         The incidences of neoplastic lesions are summarized in Table
    21.


        Table 21. The incidence of neoplastic lesions in a mouse study with 1,2-dichloropropanea
                                                                                                    
                                       Sex            Control          125 mg/kg        250 mg/kg
                                                                                                    

    Adenoma (liver)                    male           7/35 (20%)       9/33 (27%)       15/35 (43%)

    Carcinoma (liver)                  male           8/35 (23%)       10/33 (30%)      9/35 (26%)

    Adenoma and carcinoma (liver)      male           15/35 (43%)      18/33 (55%)      24/35 (69%)b

    Adenoma (liver)                    female         1/35 (3%)        5/29 (17%)       5/26 (19%)b

    Carcinoma (liver)                  female         1/35 (3%)        2/29 (7%)        2/26 (8%)

    Adenoma and carcinoma (liver)      female         2/35 (6%)        7/29 (24%)b      7/26 (27%)b

    Follicular cell adenoma and        female         1/34 (3%)        0/27 (0%)        5/24 (21%)b
    carcinoma (thyroid)

    Alveolar/bronchiolar adenoma       female         5/35 (14%)       0/29 (0%)        1/26 (4%)
    or carcinoma (lung)

    Squamous cell                      male           0/50 (0%)        1/48 (2%)        3/49 (6%)
    papillomas (forestomach)           female         0/50 (0%)        2/50 (4%)        2/50 (4%)c

                                                                                                    

    a    From: NTP (1986).
    b    P = < 0.05 - > 0.001.
    c    One high-dose female mouse had a squamous cell carcinoma.
    

         On the basis of the results of this study, the NTP concluded
    that 1,2-dichloropropane induces an increased incidence of liver
    tumours in male and female B6C3F1 mice (Haseman et al., 1984;
    NTP, 1986). However, the Task Group noted that the incidences of
    liver adenomas and carcinomas in the treated groups were within the
    historical ranges of this species (Haseman et al., 1985). The
    increased incidence of thyroid tumours is equivocal.


    8.5.2  Oral (rat)

         Groups of 50 male and 50 female F344/N rats (aged 7-9 weeks)
    were administered, by gavage, 0, 125 or 250 (female) and 0, 62, or
    125 mg (male) 1,2-dichloropropane (99.4%)/kg body weight, in corn
    oil, 5 days/week for 103 weeks. The highest dose level showed growth
    depression in both sexes. Survival of female rats at the high dose
    level was significantly lower. The incidence of non-neoplastic
    lesions was not significantly different from that in the controls,
    except for an increased incidence of foci of clear cell change and
    of necrosis in the liver in high-dose female rats.

         The incidences of neoplastic lesions are summarized in Table
    22. Apart from these tumours, squamous cell papillomas of the
    forestomach were found in 1 control male and 1 female rat. In high-
    dose females, there was an increased incidence of mammary gland
    adenocarcinomas, but not of mammary gland adenomas. Apart from these
    tumours, squamous cell papillomas of the fore-stomach were found in
    two high-dose females (not significantly increased compared to
    controls). There were no effects on tumour incidences in male rats
    (Haseman et al., 1984; NTP, 1986). 

    8.6  Factors modifying toxicity

         Weanling Wistar rats, fed for several weeks on low protein
    choline-deficient diets, were more susceptible to the effects of
    inhalation of 4660 mg 1,2-dichloropropane/m3 than rats on a
    control diet. This increased susceptibility could be corrected by
    dietary supplements of 1-methionine or 1-cysteine plus choline
    chloride (Heppel et al., 1946).

    8.7  Special studies

    8.7.1  Liver

         Groups of 5 male Wistar rats (200 g) were administered, i.p.,
    0, 10, 25, 50, 100, 250, or 500 mg 1,2-dichloropropane (97%)/kg body
    weight, in corn oil, for 5 days (once daily) or for 4 weeks (five
    days/week), or a single dose of 0, 50, 100, or 250 mg/kg body
    weight, to investigate the biochemical and histological liver
    changes. Reduced glutathione (GSH), glutathione- S-transferase,
    cytochrome P450, and protein contents were measured. A dose-

        Table 22. The incidence of neoplastic lesions in a rat study with 1,2-dichloropropanea
                                                                                              
                              Sex        Control        62 mg/kg male          125 mg/kg male 
                                                        125 mg/kg female       250 mg/kg female
                                                                                              

    Fibroadenoma             female      14/37 (38%)       20/43 (47%)            5/16 (31%)
     (mammary gland)

    Adenocarcinoma           female      1/37 (3%)         2/43 (5%)              4/16 (25%)b
     (mammary gland)

    Endometrial stromal      female      8/37 (22%)        14/42 (33%)            6/16 (38%)b
     polyps (uterine
     tumours)

    Liver tumours            male        3/50 (6%)         3/50 (6%)              2/50 (4%) 
                             female      0/50 (0%)         0/50 (0%)              0/50 (0%) 

    Islet cell adenoma       male        4/38 (11%)        1/42 (2%)              5/41 (12%)
     and carcinoma
     (pancreas)

                                                                                              

    a    From: NTP (1986).
    b    P = < 0.05.
    
    dependent decrease in liver-reduced glutathione was observed after a
    single injection and a dose-dependent increase after 4 weeks. The
    liver biochemical pattern after 4 weeks, characterized by a decrease
    of cytochrome P450 and by an increase in reduced glutathione and
    glutathione- S-transferase activity, suggests a hyperplastic
    evolution of the liver cells, probably a repair mechanism induced by
    the early depletion of glutathione. Histologically, the alterations
    confirm the regenerative nature (atypical mitosis and hyperplastic
    nodules) of the changes (Trevisan et al., 1989).

         The hepatotoxicity of 1,2-dichloropropane (97%) in adult male
    Wistar rats (5 per group) was studied following daily i.p. injection
    at dose-levels of 0, 50, 100, 250, or 500 mg/kg body weight per day,
    in corn oil, for 4 weeks. Biochemical changes in the liver were
    demonstrated. Significant findings included reduction of aminopyrine
    demethylase activity at 100 mg/kg or more, increased levels of
    reduced glutathione and glutathione- S-transferase activity at 50
    mg/kg or more, and decreased cytochrome P450 activity at 500 mg/kg.
    The activity of aniline hydroxylase was not affected. Duplicate
    groups of rats treated with 1,2-dichloropropane, but allowed a

    period of 4 weeks of recovery before being subjected to examination,
    showed that the induced biochemical changes in the liver were
    completely reversible (Trevisan et al., 1991).

         1,2-Dichloropropane toxicity is actually preferentially
    mediated by GSH depletion. This is suggested by the fact that GSH
    loss is correlated with an increase in the biochemical indices of
    liver and renal injury, and with the extent of haemolysis. 

         Pretreatment of 1,2-dichloropropane-intoxicated rats with
    buthionine-sulfoximine (BSO) (depleting GSH) markedly increased the
    overall mortality. Furthermore, the administration of the GSH
    precursor  N-acetyl-cysteine (NAC), preventing GSH depletion,
    reduced the damage in target tissues, as demonstrated by a smaller
    increase in some biochemical indices of cell injury and a smaller
    degree of haemolysis. A possible explanation for these findings is
    that, when the GSH level falls below a certain threshold value,
    irrespective of the causative agent, a series of common reactions is
    triggered, inducing peroxidation of membrane lipids, disturbances of
    Ca2 homeostasis, and DNA damage, which quickly lead to
    irreversible liver injury. Furthermore, it is also possible that
    electrophilic metabolites of 1,2-dichloropropane, formed in the
    absence of GSH, could directly attack a variety of cell
    macromolecules the function of which is essentially to ensure the
    physiological survival of the hepatocytes (Mitchell et al., 1973;
    Bellomo & Orrenius, 1985; Casini et al., 1987; Orrenius et al.,
    1989).

         Male Wistar rats were exposed (by gavage) to a single oral dose
    of 55 mg 1,2-dichloropropane/kg body weight in propylene glycol. The
    animals were killed 1-6 days after exposure. Glutathione (GSH),
    lipid peroxidation and protein of liver homogenate were measured.
    Reduction of hepatic GSH and total protein and enhanced hepatic
    lipid peroxidation still persisted 6 days after 1,2-dichloropropane
    administration (Di Nucci et al., 1988). 

         Groups of rats were treated orally, by gavage, with single
    doses of 1,2-dichloropropane ranging from 55 to 400 mg/kg body
    weight. 1,2-Dichloropropane was no longer detectable in the blood 24
    h after dosing at any dose level (Di Nucci et al., 1988). 

    8.7.2  Kidneys

         Renal failure caused by 1,2-dichloropropane has been reported
    by several authors who found an increase in serum creatinine and
    urea in intoxicated animals and humans and fatty degeneration or
    acute tubular damage in the kidney parenchyma (Heppel et al., 1946,
    Ponticelli et al., 1968; Pozzi et al., 1985; Imberti et al., 1987). 

         Imberti et al. (1990) suggested that, on the basis of the
    demonstration of 1,2-dichloropropane-induced depletion of kidney
    GSH, it may be postulated that the biochemical mechanisms involved
    in liver toxicity may also apply to the kidneys (Brezis et al.,
    1983). In addition, since most of the glutathione and cysteine
    conjugates of 1,2-dichloropropane are recovered in the urine, a
    direct toxicity of the conjugates to the kidneys seems to play an
    important role, as previously demonstrated for other conjugates
    (Stevens et al., 1988).

         It has been demonstrated that GSH plays an essential role in
    the maintenance of the physiological structure of the erythrocyte,
    preventing the formation of inter-protein or intra-protein
    disulfides within the membrane skeleton. Depletion of erythrocyte
    glutathione causes an increased fragility of this cell and
    subsequent haemolysis. The involvement of such a mechanism in 1,2-
    dichloropropane-induced haemolysis in intoxicated animals is
    supported by the demonstration of a concomitant loss in erythrocyte
    GSH and a correlation between these 2 phenomena (Imberti et al.,
    1990).

         Nephrotoxicity of 1,2-dichloropropane (97%) in adult male
    Wistar rats (5 per group) was studied following daily i.p. injection
    at dose levels of 0, 50, 100, 250, or 500 mg/kg body weight per day
    for 4 weeks. Biochemical and histopathological alterations of the
    kidneys were demonstrated. Kidney pathology involved a decrease in
    the activity of angiotensin-converting enzyme in the proximal tubule
    brush border and fraying of microvilli with epithelial coagulative
    necrosis. Duplicate groups of rats treated similarly with 1,2-
    dichloropropane, but allowed a period of 4 weeks of recovery before
    being subjected to examination, showed that the treatment-induced
    biochemical changes in the kidneys were completely reversible
    (Trevisan et al., 1988, 1991). 

    8.7.3  Central nervous system

         In the study of Gorzinski & Johnson (1989), in which Fischer
    344 rats were treated with 0, 300, or 500 mg 1,2-dichloropropane per
    kg body weight, by gavage, for 14 days, motor activity and a
    functional observational battery (unusual responses in behaviour,
    presence of convulsions, tremors, etc., and sensory function) were
    evaluated (section 8.2.1.2). No effects were seen on these
    parameters.

         Specific tests in groups of 15 Fischer 344 rats/sex given, by
    gavage, 0 (corn oil), 20, 65, or 200 mg 1,2-dichloropropane
    (99.9%)/kg body weight, 5 days/week for 13 weeks, included monthly
    evaluation of a functional observation battery, hind limb grip
    strength, and motor activity; a comprehensive neuropathology study
    was carried out at the end of the study. Clinical observations

    included measurement of body weight gain and body temperature. Body
    weights were decreased for male rats given 200 mg/kg body weight.
    The body temperature was within normal limits, except in the females
    given 200 mg/kg, which showed a slightly lower temperature. No
    functional effects were noted. No gross or histopathological effects
    on either the central or peripheral nervous system were observed
    (Johnson & Gorzinski, 1988).

    9.  EFFECTS ON HUMANS

    9.1  General population exposure

    9.1.1  Acute toxicity - poisoning incidents

         Ingestion of cleaning solvent (50 ml) containing 1,2-
    dichloropropane (other components not known) by a man produced coma
    followed by delirium, irreversible shock, cardiac failure, and
    death. Histopathologically, centri- and medio-lobular hepatic
    necrosis was found (Larcan et al., 1977).

         Two cases of disseminated intravascular coagulation syndrome
    (DIC) have been described in association with acute intoxication by
    1,2-dichloropropane. Effects on the central nervous system, liver,
    and kidney functions were also observed, but no details were given
    (Perbellini et al., 1985).

         Pozzi et al. (1985), from Italy, reported clinical observations
    on 3 other hospitalized persons with 1,2-dichloropropane poisoning.
    Two out of the 3 persons ingested the substance, while the third
    person was exposed through inhalation. The clinical symptoms were
    similar, despite different routes of exposure. All 3 suffered from
    acute renal and hepatic damage. Kidney biopsy, carried out on 1
    person, showed acute tubular necrosis. Haemolytic anaemia and
    disseminated intravascular coagulation were noted in all 3 patients,
    1 of whom died on the seventh day. The other patients recovered
    after treatment.

         Toxic hepatitis with portal hypertension has been described in
    a 49-year-old man, who ingested 1,2-dichloropropane in an attempted
    suicide (Thorel et al., 1986).

    9.2  Occupational exposure

         Baruffini et al. (1989) studied 10 cases of 1,2-dichloropropane
    dermatitis in the period 1985-88. Patients were painters or metal-
    workers in the engineering industry and they all had known contact
    with mixtures of solvents containing 10-40% 1,2-dichloropropane. On
    examination, the workers had itchy erythematous, oedematous,
    vesicular lesions on the fingers and dorsa of the hands. Two
    subjects also had scaling and fissuring of the palms. Cessation of
    exposure produced quick resolution of the dermatitis in all
    subjects. Patch tests were carried out. As controls, 120 subjects
    were similarly tested with 1,2-dichloropropane. All patients showed
    a positive response to concentrations of 2% 1,2-dichloropropane or
    more (allergic contact dermatitis). The results of the tests on the
    control subjects were negative. 

         Grzywa & Rudzki (1981) described cases of dermatitis in 2 women
    (47 and 55 years old), in a group of 60 persons, who had been
    exposed to Silform aerosols for 6 and 4 years, respectively. Silform
    aerosols contained 7.4, 11.0, or 12.7% 1,2-dichloropropane;
    methylsilicone oils, and Freon. The patch tests that were carried
    out were positive for 1,2-dichloropropane, but negative for
    methylsilicone oils.

    10.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         1,2-Dichloropropane was considered by working groups of the
    International Agency for Research on Cancer (IARC) in 1986 (IARC,
    1986) and in 1987 (IARC, 1987). In the updating of 1987, it was
    evaluated as follows: "There is limited evidence for the
    carcinogenicity of 1,2-dichloropropane in experimental animals.
    There are no data in humans. The agent is not classifiable as to its
    carcinogenicity to humans (Group 3)".

         WHO (in preparation) has proposed a provisional guideline value
    for drinking-water of 20 µg 1,2-dichloropropane/litre.

    PART C

    ENVIRONMENTAL HEALTH CRITERIA

    FOR

    MIXTURES OF DICHLOROPROPENES
    AND DICHLOROPROPANE

    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR MIXTURES OF DICHLOROPROPENES AND
    DICHLOROPROPANE

    1.   SUMMARY AND EVALUATION, CONCLUSIONS, AND RECOMMENDATIONS

         1.1   Summary and evaluation
               1.1.1   Use, environmental fate, and environmental levels
               1.1.2   Kinetics and metabolism
               1.1.3   Effects on organisms in the environment
               1.1.4   Effects on experimental animals and  in vitro
                       test systems
               1.1.5   Effects on humans
         1.2   Conclusions
         1.3   Recommendations

    2.   IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

         2.1   Identity
         2.2   Physical and chemical properties
         2.3   Analytical methods

    3.   SOURCES OF HUMAN AND ENVIRONMENTALEXPOSURE

         3.1   Natural occurrence
         3.2   Man-made sources
         3.3   Uses

    4.   ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         4.1   Air
         4.2   Water
         4.3   Soil
               4.3.1   Microbial transformation
               4.3.2   Loss under field conditions
               4.3.3   Soil function
         4.4   Bioconcentration

    5.   ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1   Groundwater
         5.2   Occupational exposure

    6.   KINETICS AND METABOLISM

    7.   EFFECTS ON ORGANISMS IN THE ENVIRONMENT

         7.1   Microorganisms
               7.1.1   Terrestrial microorganisms

                       7.1.1.1   Effects on nitrification
                       7.1.1.2   Recovery studies with microorganisms
         7.2   Aquatic organisms
               7.2.1   Invertebrates
               7.2.2   Fish
         7.3   Terrestrial organisms
               7.3.1   Birds
               7.3.2   Soil fauna
               7.3.3   Plants

    8.   EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

         8.1   Single exposures
               8.1.1   Oral
               8.1.2   Inhalation
               8.1.3   Dermal
         8.2   Short-term exposures
               8.2.1   Oral
                       8.2.1.1   Rat
                       8.2.1.2   Dog
               8.2.2   Inhalation
         8.3   Skin and eye irritation; sensitization
               8.3.1   Skin and eye irritation
               8.3.2   Sensitization
         8.4   Long-term exposures/carcinogenicity
               8.4.1   Oral
                       8.4.1.1   Rat
         8.5   Reproduction, embryotoxicity, and teratogenicity
               8.5.1   Reproduction
                       8.5.1.1   Oral
                       8.5.1.2   Inhalation
               8.5.2   Embryotoxicity and teratogenicity
                       8.5.2.1   Oral 
         8.6   Mutagenicity and related end-points
               8.6.1    In vitro studies (microorganisms)
               8.6.2    In vivo studies

    9.   EFFECTS ON HUMANS

         9.1   General population exposure
         9.2   Occupational exposure

    1.  SUMMARY AND EVALUATION, CONCLUSIONS AND RECOMMENDATIONS

    1.1  Summary and evaluation

    1.1.1  Use, environmental fate, and environmental levels

         The technical mixture of dichloropropenes and dichloropropane
    (abbreviated in this text to "MIX D/D") is a clear amber liquid with
    a pungent odour; it has a vapour pressure of 35 mmHg at 20 °C, and
    is soluble in halogenated solvents, esters, and ketones. 

         "MIX D/D" typically contains not less than 50% 1,3-
    dichloropropene (ratio of  cis- and  trans-isomers approximately
    1:1), the other main constituents being 1,2-dichloropropane and
    related compounds. It was widely used as a soil nematocide before
    planting.

         The environmental transport, distribution, and fate of the
    major constituents of "MIX D/D" in air, water, and soil is described
    in the sections 4 of the parts of this EHC monograph that deal with
    1,3-dichloropropene and 1,2-dichloropropane. 

         There is a significant potential for 1,2-dichloropropane
    derived from "MIX D/D" to leach from the soil and contaminate well
    water and groundwater. In an irrigation bore (68 m deep) in Western
    Europe, mean 1,2-dichloropropane concentrations at different depths
    ranged between 0.8 and 8.5 µg/litre, and the maximum concentration
    recorded was 165 µg/litre. 

         Significant uptake of the constituents of "MIX D/D" by crops is
    unlikely (see other parts of this EHC monograph). Bioaccumulation of
    the constituents of "MIX D/D" is also unlikely because of their low
    log P octanol/water partition coefficient and their relatively high
    water solubility. 

    1.1.2  Kinetics and metabolism

         No metabolic studies have been carried out on "MIX D/D". The
    two major components, 1,3-dichloropropene and 1,2-dichloropropane,
    are rapidly eliminated, primarily in the urine and, to a lesser
    extent, via expired air. The components of "MIX D/D" are metabolized
    by oxidative and conjunction pathways. The major urinary metabolites
    are mercapturic acids.

    1.1.3  Effects on organisms in the environment

         "MIX D/D" is moderately toxic for fish; 96-h LC50 values
    range between 1 and 6 mg/litre. The 1,3-dichloropropene is largely
    responsible for the toxicity of "MIX D/D".

         When used at recommended application rates, the main effects of
    "MIX D/D" are a transient (< 7 days) reduction in soil fungi and
    inhibition of the oxidation of ammonium ions to nitrate. "MIX D/D"
    is toxic for nitrifying bacteria. Soon after "MIX D/D" disappears
    from the soil, recolonization by bacteria takes place. In field
    trials, "MIX D/D" (applied at 600 litre/ha) killed soil
    invertebrates. Recolonization times ranged between 6 and 24 months.

         "MIX D/D" is highly phytotoxic.

    1.1.4  Effects on experimental animals and in vitro test
           systems

         The acute toxicity of "MIX D/D" for laboratory animals is
    moderate to high. The oral LD50 values in rats and mice range from
    132 to 300 mg/kg body weight. The dermal LD50 values for rats and
    rabbits are 779 and 2100 mg/kg body weight, respectively. The
    inhalation LC50 (4 h) for rats is approximately 4540 mg/m3.
    Acute exposure results in clinical signs associated with central
    nervous system depression. "MIX D/D" is a severe eye and skin
    irritant and it is a moderate dermal sensitizer. 

         The results of the available short-term toxicity studies in
    rats and dogs are inadequate to assess properly the toxicity
    potential of "MIX D/D", because the relatively low doses tested do
    not demonstrate any biologically significant effects. Several short-
    term inhalation (whole-body) studies have been conducted in rats.
    "MIX D/D" at levels up to 145 mg/m3 does not cause any toxic
    effects. At levels of 1362 mg/m3 or higher, toxic effects
    associated with central nervous system depression are evident. An
    exposure to 443 mg/m3 for 10 weeks leads to reduced body weight
    gain and increased absolute kidney weight.

         An oral teratology study in rats was inadequate for assessment
    of the teratological potential of "MIX D/D".

         In an inhalation rat study to investigate male and female
    fertility, no effects were found at dose levels up to 443 mg/m3
    for 10 weeks. Complete evaluation of reproductive effects of "MIX
    D/D" was not possible owing to inadequate protocol designs.

         "MIX D/D" is mutagenic in  Salmonella typhimurium strains
    TA100 and TA1535, as well as in  Escherichia coli WP2 HCR, without
    metabolic activation. There was no such effect in  Salmonella
    strains TA98, TA1537, and TA1538. 

         In a long-term study on rats fed diets containing up to 120 mg
    "MIX D/D" per kg (equivalent to 6 mg/kg body weight) for 2 years, no
    toxic or carcinogenic effects were seen. 

    1.1.5  Effects on humans

         "MIX D/D" is no longer widely used, and, thus, exposure of the
    general population via air, water, and food is unlikely. 

         The exposure of workers filling drums and of field applicators
    was generally below 4.5 mg 1,3-dichloropropene/m3 when recommended
    procedures were used; in other situations, levels up to 36.32
    mg/m3 have been measured.

         One case of acute fatal poisoning has been reported following
    accidental ingestion of "MIX D/D".

         Several cases of contact dermatitis and skin sensitization due
    to "MIX D/D" exposure have been reported.

    1.2  Conclusions

    -    General population. As "MIX D/D" is no longer widely used,
         the exposure of the general population to 1,3-dichloropropene
         via air, water, and food is negligible, but, in certain areas,
         exposure to 1,2-dichloropropane may occur when groundwater is
         contaminated.

    -    Occupational exposure. Filling operations and field
         applications of "MIX D/D" can lead to exposure of operators to
         1,3-dichloropropene that exceed maximum allowable
         concentrations, especially under warm climatic conditions.

    -    Environment. "MIX D/D" is unlikely to reach biologically
         significant levels in either the terrestrial or the aquatic
         environment when used at the recommended rate. Lasting adverse
         effects on organisms in the environment are unlikely to occur.

    1.3  Recommendations

    -    "MIX D/D" should not be used as a soil fumigant because of
         potential leaching to groundwater.

    -    Monitoring of residues in surface water and groundwater should
         be carried out in areas where "MIX D/D" has been used.

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL
        METHODS

    2.1  Identity

         The technical mixture of dichloropropenes and dichloropropane
    (abbreviated to "MIX D/D") contains not less than 50% of the  cis-
    and  trans-isomers (ratio approximately 1:1) of 1,3-dichloropropene
    and the other main constituent was 1,2-dichloropropane. Yang (1986)
    described a commercial "MIX D/D" containing 25%  cis-
    dichloropropene, 27% of  trans-dichloropropene, 29% 1,2-
    dichloropropane, and 19% other related chlorinated hydrocarbons. It
    may also contain 1% epichlorohydrin as a stabilizer. 

         CAS registry number: 8003-19-8.

         For the physical and chemical properties of the main
    constituents, see the sections 2.2 of the parts of this monograph
    dealing with 1,3-dichloropropene and 1,2-dichloropropane. 

         Major trade names are D-D mixture, Nemafene, Nemax, Vidden-D.

         Other formulations on the market are Ditrapex and Vortex
    (mixtures of 1,2-dichloropropane, 1,3-dichloropropene, and
    methylisothiocyanate), Ditrapex CP (the same mixture as Ditrapex,
    but also containing chloropicrin).

    2.2  Physical and chemical properties

         Technical "MIX D/D" is a clear amber liquid with a pungent
    odour. It has a vapour pressure of 4.6 kPa (20 °C) (35 mmHg at 20
    °C), flash distils over the range of 59-115 °C, and has a relative
    density of 1.17-1.22 g/cm3 at 20 °C; its flash point is 17.5 °C.
    Its solubility at room temperature is approximately 2 g/kg in water,
    but it is soluble at room temperature in hydrocarbon and halogenated
    solvents, esters, and ketones. The mixture is stable up to 500 °C
    (therefore stabilizers are not needed) but reacts with dilute
    organic bases, concentrated acids, halogens, and some metal salts.
    It is corrosive to some metals (e.g., aluminium, magnesium, and
    their alloys, and may remove lacquer from lacquer-lined containers.
    It is not corrosive to mild steel. 

    2.3  Analytical methods

         The same methods can be used as for 1,3-dichloropropene. 

         See section 2.4 of the part of this monograph that deals with
    1,3-dichloropropene.

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         "MIX D/D" does not occur naturally.

    3.2  Man-made sources

         "MIX D/D" is manufactured by high temperature chlorination of
    propene.

         For sources of pollution, see section 3.2.3 of the part of this
    monograph that deals with 1,3-dichloropropene and section 3.2 of
    1,2-dichloropropane.

    3.3  Uses

         "MIX D/D" is a preplant nematocide, effective against soil
    nematodes including root knot, meadow, sting and dagger, spiral, and
    sugar beet nematodes. It is usually applied by injection into the
    soil or through tractor-drawn hollow tines, to a depth of 15-20 cm
    at a rate of 150-400 litre/ha (occasionally to a maximum of 1000
    litre/ha), depending on soil type and the following crop. The soil
    surface is sealed by rolling. "MIX D/D" volatilizes and diffuses as
    a vapour and, thus, its effectiveness depends on how readily this
    can occur. Because the components of "MIX D/D" are highly
    phytotoxic, it is essential that, after an application of 220
    litre/ha or more, a period of not less than 14 days should elapse
    before planting or sowing (Shell, 1985). 

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1  Air

         (See section 4 of 1,3-dichloropropene and 1,2-dichloropropane).

    4.2  Water

         (See section 4 of 1,3-dichloropropene and 1,2-dichloropropane).

    4.3  Soil

         (See section 4 of 1,3-dichloropropene and 1,2-dichloropropane).

    4.3.1  Microbial transformation

         It has been demonstrated under  in vitro and  in vivo
    conditions that indigenous soil microflora can utilize C3
    chlorinated hydrocarbons. Four species,  Bacillus subtilis,
     Arthrobacter globiformis, Pseudomonas fluorescens, and  Rhizobium
     leguminosarum, were successfully grown on media including "MIX
    D/D" (Altman & Lawlor, 1966; Altman, 1969). 

         Toxicity tests were carried out with  Rhizobium phaseoli and
     Azotobacter beinjerinckii, both nitrogen-fixing bacteria, in
    cultures using unsterilized Hanford sandy loam. "MIX D/D" at
    concentrations ranging from 10 to 100 mg/kg and 100 to 1000 mg/kg
    caused growth inhibition in  Azotobacter beinjerinckii and
     Rhizobium phaseoli, respectively (Rader & Love, 1977a).

    4.3.2  Loss under field conditions

         A trial has been carried out in the United Kingdom in which
    "MIX D/D" was applied at 410 litre/ha (see section 4.1.3.5 of 1,3-
    dichloropropene). Samples of soil were taken at 3 depths: 0-20 cm,
    20-40 cm, and 40-60 cm, at 6 intervals up to 9´ months after
    application. The results are summarized in Table 23. Residues of
    1,3-dichloropropenes, 1,2-dichloropropane, and 3-chloroallyl
    alcohols were present in all 3 soil layers, especially before
    ploughing. They showed little change in the period before ploughing,
    but, thereafter, the concentrations decreased gradually (Wallace,
    1979).

    4.3.3  Soil function

         "MIX D/D" soil fumigant, 337 and 3370 kg active ingredient per
    ha, was used to evaluate the effect on nodulation of pinto bean
    plants in soil and on the growth of root nodule bacteria in culture.
    Unsterilized Hanford sandy loam was used. After 4 weeks' growing
    time, low and high doses of "MIX D/D" resulted in a reduction in


        Table 23. Residues from the plot treated with "Mix D/D" at 410 litre/ha
                                                                                                                        
                                                            Concentration in soil (mg/kg)
    Interval since      Soil depth         1,3-dichloropropenes        1,2-dichloropropane          3-chloroallyl
    application         (cm)                                                                       alcohols (days)
                                                                                                                        
                                       cis-isomer     trans-isomer                            cis-isomer    trans-isomer
                                                                                                                        

    3                      0-20           6.82            6.05                 8.7               2.02            1.98
                          20-40           6.83            7.08                 9.8               1.36            1.35
                          40-60           0.85            0.90                 1.4               0.24            0.24

    11                     0-20           3.50            3.50                 5.4               0.63            0.53
                          20-40           4.84            5.05                 6.5               1.86            2.11
                          40-60           0.35            0.35                 0.9               0.18            0.17

    24                     0-20           5.73            5.55                 9.4                1.0             1.0
                          20-40           6.07            6.21                12.5                2.0             2.0
                          40-60           0.70            0.63                 2.1               0.29            0.29

                                                                                                                        

    33                                         NORMAL CULTIVATION (ploughing of the soil)
                                                                                                                        

    40                     0-20           0.73            0.86                0.77               0.58            0.44
                          20-40           1.54            1.79                1.90               0.41            0.37
                          40-60           0.30            0.30                1.00               0.14            0.15

    73                     0-20           0.26            0.25                 0.2               0.16            0.11
                          20-40           0.64            0.62                 1.5               0.36            0.28
                          40-60           0.51            0.44                 2.9               0.22            0.19

    Table 23 (contd)
                                                                                                                        
                                                            Concentration in soil (mg/kg)
    Interval since      Soil depth         1,3-dichloropropenes        1,2-dichloropropane          3-chloroallyl
    application         (cm)                                                                       alcohols (days)
                                                                                                                        
                                       cis-isomer     trans-isomer                            cis-isomer    trans-isomer
                                                                                                                        

    At harvest             0-20           0.06            0.05                 0.1               0.16            0.08
    9´ months             20-40          0.03a           0.02a                 0.2               0.07            0.03
                          40-60         < 0.01          < 0.01                 0.2             < 0.02          < 0.02

                                                                                                                        

    Pre-                   0-20         < 0.01          < 0.01               < 0.1             < 0.02          < 0.02
    treatment             20-40         < 0.01          < 0.01               < 0.1             < 0.02          < 0.02
                          40-60         < 0.01          < 0.01               < 0.1             < 0.02          < 0.02

                                                                                                                        

    a    Results confirmed by GC/MS.
         From: Wallace (1979).
         Note: All residues are on a dry weight basis.
    

    root nodules of approximately 70 and 80%, respectively; the
    percentages of germination were about 90 and 50%, respectively
    (Rader & Love, 1977a).

         Unsterilized Oakdale loamy sand soil (81.6% sand, 11.2% silt
    and 1.06% organic carbon), treated with "MIX D/D" soil fumigant at
    337 and 1348 kg active ingredient/ha, in 1978, showed no decrease in
    soil phosphatase activity after 0, 4, and 8 weeks at an incubation
    temperature of 27 °C (Rader, 1979c). 

         The effects were studied of "MIX D/D" soil fumigant (337 and
    3370 kg/ha) on proteolytic enzyme activity in the treated soil. The
    soil proteases were assayed by the release of tyrosine from sodium
    caseinate in the treated soil, after incubation periods of 0, 4, 8,
    and 12 weeks, at 27 °C. No inhibitory effects were found (Rader,
    1979b).

         "MIX D/D", at a high dose of 100-1000 mg/kg, caused a temporary
    loss of cellulytic activity in  Trichoderma viride (Rader & Love,
    1977b).

         Laboratory studies were conducted to determine the effects of
    "MIX D/D" on the activities of invertase in a sandy soil. The rates
    of application were 150 and 300 mg/kg. No inhibition was found. The
    same dose levels were used to study the influence of "MIX D/D" on
    amylase activity in this soil. After 3 days, stimulation of glucose
    formation from the added starch was observed, especially at the
    lowest dose level. Microbial respiration was also studied. The
    treatments did not significantly decrease oxygen consumption (Tu,
    1988).

    4.4  Bioconcentration

         No data on bioconcentration are available.

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         Analyses have been made to determine whether residues of the
    active 1,3-dichloropropene isomers could be found in the edible
    parts of a number of crops, including potatoes, carrots, onions,
    cucurbits, rice, and sugar beet. At recommended rates and pre-
    planting intervals, residues of these propenes ( cis- and  trans-
    isomers) have not been detected (limit of determination 0.02 mg/kg)
    (see section 2.4 of 1,3-dichloropropene).

    5.1  Groundwater

         1,2-Dichloropropane levels of 0.8-8.5 µg/litre, with a maximum
    of 165 µg/litre, were reported in groundwater in the Netherlands
    from bores for irrigation at depths up to 68 m. These levels
    resulted from previous applications of "MIX D/D" (Leistra & Boesten,
    1989) (see section 5.1.2 of 1,2-dichloropropane).

    5.2  Occupational exposure

         Field studies were carried out in several locations in the
    Netherlands and in France to monitor personal exposure and
    environmental concentrations during application of "MIX D/D". In
    most of the 11 locations in the Netherlands, the time-weighted
    average of the exposure of the operators, as measured with personal
    sampler pumps during application, was of the order of 4.54 mg total
     cis- and  trans-1,3-dichloropropene per m3. When filling
    operations are carried out in the recommended way, personal
    exposures can be limited to a maximum of 4.54 mg/m3. Levels of the
    unsaturated components of "MIX D/D" in the air 1 m above the soil
    surface shortly after application were below 0.454 mg/m3.

         In most of the 9 locations in France, the time-weighted average
    exposure levels of the operators, as measured with personal sampler
    pumps, was of the order of 4.54-9.08 mg total  cis- and  trans-
    1,3-dichloropropene per m3. Peak exposures of up to 36.32 mg/m3
    were measured when the recommended safety precautions were
    insufficiently observed. Levels of the unsaturated components of
    "MIX D/D" in the air 1 m above the soil surface during application
    ranged from 1 to 6.4 mg/m3 (van Sittert et al., 1977; van Sittert,
    1978).

    6.  KINETICS AND METABOLISM

         See section 6 in the parts of this monograph that deal with
    both 1,3-dichloropropene and 1,2-dichloropropane. 

         No information is available on the kinetics and metabolism of
    other compounds, impurities, and stabilizers that may be present in
    "MIX D/D".

    7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    7.1  Microorganisms

         (See also relevant sections of 1,3-dichloropropene and 1,2-
    dichloropropane.)

    7.1.1  Terrestrial microorganisms

         The effects of "MIX D/D" on microorganisms and on soil function
    have been widely studied in Europe (Pochon et al., 1951; Bakker,
    1968; Sommer, 1970; Kämpfe, 1973; Lebbink & Kolenbrander, 1974), in
    Canada (Wensley, 1953; Elliot et al., 1972, 1974, 1977; Tu, 1972,
    1973, 1978, 1979, 1981a,b), in the USA (Thornton, 1951; Moje et al.,
    1957), and elsewhere (Dommergues, 1959; Mehta et al., 1963; Dubey et
    al., 1975; Ross & McNeilly, 1975). Main interest has been in the
    microorganisms involved in the nitrogen balance of the soil, as this
    bears strongly upon the yields of crops grown in treated soil.

         During the search for effective soil fumigants, the toxicity of
    "MIX D/D" for soil microorganisms has been investigated on 2 soil
    types, a sandy loam and a soil with high organic matter. At a dosage
    of 1200 mg/kg soil, the following reductions in soil microorganisms
    were found after 96 h: bacteria 90%, actinomycetes 99%, and fungi
    98%. The toxicity of the major components of "MIX D/D" for these
    same major groups of microorganisms has been studied in soil samples
    from old citrus plantations under laboratory conditions, and it was
    found that the toxicity of 1,2-dichloropropane for fungi and
    bacteria and actinomycetes was low to moderate (Moje et al., 1957). 

         The studies of Wensley (1953) and of Moje et al. (1957) are
    reasonably consistent and indicate that bacteria are more tolerant
    to "MIX D/D" than fungi, and, again, that the toxicity of "MIX D/D"
    is related mainly to its 1,3-dichloropropene content, in particular
    the  cis-isomer.

         Rader et al. (1978) studied the correlation between the numbers
    of soil microorganisms and the O2/CO2 exchange in treated soil.
    Unsterilized Hanford sandy loam (57.6% sand, 26.6% silt, 15.8% clay,
    and 0.7% organic carbon) was used and the soil had a moisture
    content of 6%. "MIX D/D" soil fumigant (dosages 336 and 2240 kg
    active ingredient/ha) caused a decrease in the populations of
    actinomycetes, bacteria, and fungi, and also reduced the oxygen
    utilization by soil microorganisms. 

    7.1.1.1  Effects on nitrification

         Kämpfe (1973) studied the inhibition by "MIX D/D" of
    nitrification in a black earth soil. Nitrogen (180 mg/kg, NH3 and
    NH3-water) and "MIX D/D" (80 mg/kg) were applied at different

    temperatures. The time of incubation was 30-120 days. At
    temperatures between 5 °C and 10 °C, nitrification of NH3 was
    severely inhibited for 90 days. After 120 days of incubation at 10
    °C, 70% of the nitrogen applied was retrieved as ammoniumion.

         The inhibition of ammonium nitrogen oxidation has led to the
    build-up of ammonium nitrogen in treated soil under both laboratory
    (Sommer, 1970) and field conditions (Thornton, 1951; Mehta et al.,
    1963; Elliot et al., 1974; Ross & McNeilly, 1975). 

         "MIX D/D" was extremely toxic to nitrifying bacteria in silty
    clay loam or loam soils. Doses of 200, 2000, and 20 000 mg "MIX
    D/D"/kg soil were tested. Inhibition of NH4+-oxidizing bacteria
    was found, but not of  Nitrobacter spp. Nitrogen mineralization was
    progressively depressed with increasing levels of "MIX D/D". At 200
    mg "MIX D/D"/kg soil, nitrate formation from ammonium nitrogen was
    very markedly reduced, while mineralization of nitrogen was only
    slightly reduced at 20 000 mg/kg soil (Dubey et al., 1975). These
    results are in agreement with the results of Bromley & Cook (1981).

         Bromley & Cook (1981) also studied the influence of "MIX D/D"
    on the nitrification processes in soil. Transient inhibition of
    nitrification (< 20 days) occurred in sandy clay treated with 200
    or 1000 mg "MIX D/D"/kg. Considerable (80% reduction compared with
    controls) and total inhibition occurred in soil treated with 2000
    and 10 000 mg "MIX D/D"/kg, respectively. There was no difference
    between the inhibitory effects of "MIX D/D" and those of a purified
    dichloropropene isomer mixture, indicating that the dichloropropenes
    were the active inhibitors in "MIX D/D". During inhibition of
    nitrification by "MIX D/D", ammonium accumulated but no significant
    nitrite accumulation was observed. This indicates that
    ammonification was unaffected and that inhibition of nitrification
    resulted from the specific inhibition of  Nitrosomonas spp.
    Overall, it was concluded that "MIX D/D" was not very active as a
    nitrification inhibitor, compared with commercially available
    inhibitors.

         Unsterilized Handford sandy loam was fumigated with "MIX D/D"
    soil fumigant. The soil was moistened to 75% moisture content, and
    was composed as follows: 0.7% organic carbon, 57.5% sand, 26.6%
    silt, and 15.8% clay. The activity of the nitrifying bacteria
    (oxidation of nitrite-nitrogen to nitrate-nitrogen) was monitored.
    After the treated soil had been incubated for 1-4 months at 27 °C,
    nitrite could not be detected. "MIX D/D" soil fumigant did reduce
    the oxidation of the ammonia to nitrite by  Nitrosomonas spp.,
    especially at a concentration four times normal field use. There was
    no effect on  Nitrobacter spp. (Rader, 1979a). 

         "MIX D/D" application kills a considerable part of the biomass.
    Lysis of the killed biomass provides the surviving microflora with a
    new and, to some extent, readily available substrate. The
    mineralization of this substrate, together with a small priming
    effect, gives an extra contribution to the inorganic nitrogen
    content of the soil (so-called "flush"). This contribution depends
    on the amount of biomass, which is related to the type of soil. The
    gain in nitrogen is approximately 5-10 kg N/ha. The nitrogen gain in
    spring, after autumn fumigation, can be attributed to a reduction in
    loss of nitrogen by diminished leaching and diminished
    denitrification of nitrate, and depends on the rate of
    mineralization, time of recovery of nitrification, weather
    conditions during the winter, and soil type (Lebbink & Kolenbrander,
    1974).

         In field trials, the influence of "MIX D/D" on nitrification
    was studied in loamy sand and black earth soils. Nitrogen
    application was 100 kg/ha; and the application of "MIX D/D" was
    between 37.1 and 46.6 kg/ha. When "MIX D/D" had been applied to the
    loamy sand, 61.5% of the September-applied nitrogen was retrieved in
    the top 20 cm in March of the following year. This percentage went
    up to 72 and 100%, respectively, when fertilizer was applied in
    October or November. On loamy sand, the yield obtained from the
    following crop was significantly increased. On black earth, "MIX
    D/D" application resulted in only a slight increase in crop yield
    (Kämpfe, 1973).

    7.1.1.2  Recovery studies with microorganisms

         "MIX D/D" was added to soil at 2 rates, approximately 10 and
    100 times the normal recommended treatment rates. A number of
    microbial assessments were made (see below). 

                                                                              
    Parameter                                  % reduction over control at:
                                            3000 litre/ha       30 000 litre/ha
                                                                              

    Evolution of carbon dioxide                   10                100
    Density of total bacteria                    nda                 98
    Density of proteolytic bacteria               44                 99
    Density of cellulolytic bacteria              30                100
    Mineralization of nitrogen                     9                 44
    Mineralization of asparagin                    0                 27

                                                                              

    a    Not determined.
         From: Dommergues (1959).
    
         Soon after the "MIX D/D" disappears from the soil,
    recolonization by bacteria takes place and the number of the
    different types of bacteria may be higher than before the "MIX D/D"
    treatment; this may lead to the production of higher levels of
    nitrogen/ha, perhaps because of a belated recovery of bacteriophages
    (Bakker, 1968).

         With "MIX D/D" (120 and 600 mg/kg), Tu (1972) found a decrease
    in bacterial and fungal populations in a loamy sand, but recovery to
    the same levels as the controls was rapid. In a series of studies by
    Tu (1978, 1979, 1981a,b), "MIX D/D" at 150 and 300 mg/kg soil, and
    1,3-dichloropropene at 30 and 60 mg/kg, were evaluated in parallel
    under laboratory conditions. In general, neither had much effect on
    either the numbers of soil microorganisms or their activity.
    Acetylene reduction, the population of non-symbiotic nitrogen-fixing
    organisms, and the viability of indigenous microorganisms were not
    affected. There was some stimulation of microbial numbers in some
    experiments. Soil enzyme activity was either not affected or only
    very slightly affected.

         Overall, the main effect of "MIX D/D" on soil microbial
    function, at normal usage levels, is to reduce the rate of turnover
    of ammonium. After autumn treatment, this is an advantage, as
    ammonium leaches from the soil less readily than nitrate and so is
    available in the spring for crop growth (Elliot et al., 1974). This
    effect, together with increased chlorine content, contributes to the
    yield increases beyond those expected from pest control alone, that
    are often noted following "MIX D/D" treatment (Goffart & Heiling,
    1958; Ennik et al., 1964; Bakker, 1968). 

    7.2  Aquatic organisms

    7.2.1  Invertebrates

         Varanka (1979) studied the toxicity of "MIX D/D" (50% 1,3-
    dichloropropene + 1,2-dichloropropane) for the larvae  (glochidia)
    of freshwater mussels ( Anodonta cygnea L.). The decrease of
    tryptamine-induced adductor muscle activity was used as an indicator
    of the effect of the pesticide. The presence of toxicants reduces
    the ability of the larval adductor muscle to contract when
    stimulated by tryptamine. In each experiment, 200-300 larvae
    originating from 4-5 adult mussels were used. The concentration of
    "MIX D/D" causing 50% reduction in adductor muscle activity, over a
    30-min exposure, was 18 mg/litre (20 ppm v/v). 

    7.2.2  Fish

         "MIX D/D" is moderately toxic for fish (Table 24). The toxicity
    is largely due to the 1,3-dichloropropene component, 1,2-
    dichloropropane being about two orders of magnitude less toxic than
    "MIX D/D" (see section 7.1.3 of 1,2-dichloropropane). 

         Harlequin fish  (Rasbora heteromorpha) were exposed in water
    containing 10 mg "MIX D/D"/litre. After 2 h, no deaths were found.
    The fish were then transferred to clean water and 3 days later there
    were still no deaths. In another study, 5 fish were exposed
    continuously in water containing 5 mg "MIX D/D"/litre. Three fish
    had died by 45 h, but no further deaths had occurred by 96 h (Reiff,
    1975).

         Application of "MIX D/D" (1000 litre/ha) to a vineyard in
    France caused contamination of a natural spring, which in turn led
    to contamination of fish-breeding basins and a pond. "MIX D/D" was
    detected in the spring water 20 days after the death of trout and
    carp. The concentrations in the spring and pond water ranged from
    0.4 to 2.4 mg/litre. Within 3 months, the concentration decreased to
    less than 0.1 mg/litre (Elgar et al., 1965). 

    7.3  Terrestrial organisms

    7.3.1  Birds

         No data were available.

    7.3.2  Soil fauna

         In one study in the United Kingdom, 99% of soil arthropods were
    killed following "MIX D/D" application. It took more than 2 years
    for the population to recover completely, although the chemical
    itself disappeared in about 4 weeks.  Collembola populations
    started to build up again after 6 months and exceeded 50% of the
    initial population after 10 months. Populations were not monitored
    beyond 10 months (Edwards & Lofty, 1969). 

         Studies on a light sandy soil in Belgium showed somewhat faster
    recolonization rates. In an unreplicated experiment, 10-11 months
    after the last of 5 successive yearly treatments of 600 litre "MIX
    D/D"/ha, it was found that populations of phytophagous nematodes,
    but not of saprophagous nematodes, were depressed. Earthworms,
    enchytraeid worms, mites, and  Collembola were present, mainly in 


        Table 24. Acute toxicity of "Mix D/D" to fish
                                                                                                      
    Species                         Size         Temperature       96-h LC50        References
                                                    (°C)          (mg/litre)
                                                                                                      
    Rainbow trout                   1.1 g            12              5.5a           Mayer & Ellersieck
    (Oncorhynchus mykiss)                                          (3.6-8.4)        (1986)
                                    1.1 g            12              1.97b
                                                                   (1.2-3.2)

    Cutthroat trout                 1.0 g            12              1-10           Mayer & Ellersieck
    (Salmo clarki)                                                                  (1986)

    Walleye                         1.3 g            18              0.98b          Mayer & Ellersieck
    (Stizostedion vitreum)                                                          (1986)

    Largemouth bass                 0.9 g            18              3.4b           Mayer & Ellersieck
    (Micropterus salmoides)                                                         (1986) 

    Bluegill sunfish                1.4 g            18              3.9b           Mayer & Ellersieck
    (Lepomis macrochirus)                                                           (1986)

    Channel catfish                 1.1 g            18              4.4b           Mayer & Ellersieck
    (Ictalurus punctatus)                                                           (1986)

    Harlequin fish                 2-3 cm          20-22c             4-5           Reiff (1975)
    (Rasbora heteromorpha)

    Carp                              -               -               6d            Reiff (1975)
    (Cyprimus carpio)
                                                                                                      

    a    Water hardness, 44 mg CaCO3/litre.
    b    Water hardness, 272 mg CaCO3/litre.
    c    Hard, chlorine-free water (260 mg CaCO3/litre).
    d    At 24 h.
    

    the top 5 cm of the soil. Populations of these groups were not
    significantly depressed relative to the untreated plot. Populations
    of earthworms and mites were significantly increased (van den Brande
    & Heungens, 1969). 

         In a replicated study, the influence of four, successive,
    yearly applications of "MIX D/D" (600 litre/ha) on the soil fauna
    was studied in a sandy soil in which begonias were grown. Again,
    recolonization was found between 6 and 12 months after treatment. Of
    the groups studied 12 months after the last treatment, there was
    little or no effect on the populations of Enchytraeidae,  Gamasina,
    Onychiuridae, Lumbricidae, and Acaridae. In the remaining 5 groups
    (of mites and  Collembola), the populations were also similar to
    those in untreated plots (Heungens & van Daele, 1974).

    7.3.3  Plants

         The components of "MIX D/D" are highly phytotoxic.

    8.  EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS

    8.1  Single exposures

    8.1.1  Oral

         The acute oral toxicity of "MIX D/D" (containing 51.5% of 1,3-
    dichloropropene) was moderate to high when it was administered to
    mice, rats, and dogs (Table 25). Signs of intoxication in rats and
    mice were hyperexcitability, followed by incoordination, depression,
    dyspnoea, and chromodacryorrhoea. Most of the surviving animals had
    recovered within 24 h of dosing (Hine et al., 1953; Coombs & Carter,
    1976a). 

    8.1.2  Inhalation

         Long-Evans rats were exposed for 4 h in atmospheres containing
    2043-81 720 mg "MIX D/D"/m3. The animals were observed for 10
    days. The LC50 was approximately 4540 mg/m3. The rats that died
    showed severe oedema of the lung, with haemorrhages. Congestion,
    cloudy swelling, and fatty degeneration of the liver were also
    observed (Hine et al., 1952, 1953).

    8.1.3  Dermal

         The acute toxicity of "MIX D/D" is low when it is applied in a
    single percutaneous dose to rats. Signs of intoxication included
    lethargy and chromodacryorrhoea that disappeared in survivors within
    4 days after dosing (Hine et al., 1953; Coombs & Carter, 1976a).

         Nineteen adult rabbits were treated with 1.2-4.8 g "MIX D/D"/kg
    body weight, on the skin, for 24 h. Inhalation of the vapour was not
    possible. A mucous nasal discharge was noted in one rabbit treated
    with 3 g "MIX D/D"/kg body weight. The skin showed extremely severe
    eschar with intense oedema, resulting in black necrotic tissue.
    Seven of the 10 animals receiving the three higher dose levels died
    in 8-48 h. The LD50 was 2.1 g/kg body weight (see Table 25) (Hine
    et al., 1952, 1953). 

    8.2  Short-term exposures

    8.2.1  Oral

    8.2.1.1  Rat

         Carworth Farm E-rats (12 of each sex per group) were dosed
    orally, by gavage, with emulsions of "MIX D/D" in corn oil at 0,
    0.0125, 0.025, 0.125, or 3.125 mg "MIX D/D"/kg body weight per day,
    for 3 months. The "MIX D/D" contained 55% 1,3-dichloropropenes, 26%
    1,2-dichloropropane, and 0.7% epichlorohydrin. There were no effects
    on general health, behaviour, growth rate, food intake, or blood 


        Table 25.  Acute toxicity of "Mix D/D"
                                                                                                                
    Species           Route           Vehicle             Sex        LD50 (mg/kg         References
                                                                    body weight)a
                                                                                                                

    Mouse             oral       propylene glycol        male            300             Hine et al. (1952, 1953)
    (Swiss)

    Mouse (CD-1)      oral           undiluted                      314 (276-365)        Coombs & Carter (1976a)

    Mouse (CF-1)      oral        3% D-D in DMSO                    234 (208-262)        Carter (1975)

    Rat               oral         suspension in                         140             Hine et al. (1952, 1953)
    (Long-Evans)                 propylene glycol

    Rat (CD)          oral           undiluted           male       227 (180-540)        Coombs & Carter (1976a)
                                                        female      132 (108-156)

    Dog               oral           undiluted                         > 230b            Carter (1975)

    Rat (CD)         dermal          undiluted                     779 (630-1103)        Coombs & Carter (1976a)

    Rabbit           dermal          undiluted           male     2100 (1540-2660)       Hine et al. (1952, 1953)

                                                                                                                

    a    With 95% confidence limits.
    b    Screening value from test with only 2 dogs/dose.  Apart from vomiting in dogs, no signs of 
         intoxication were observed.
    

    chemistry throughout the experiment. No changes in organ weights or
    pathological lesions attributable to "MIX D/D" were detected at any
    dose level. 

         When rats were dosed with 3.125 mg/kg body weight, there were
    slight reductions in the haemoglobin concentration and erythrocyte
    count in the males, and at 0.125 mg/kg body weight there were
    reductions in the erythrocyte and total leukocyte counts in the
    females, but since these reductions were not dose-related, they were
    of doubtful toxicological significance. With a dose of 0.025 mg/kg
    body weight there were no effects attributable to the "MIX D/D"
    (Walker, 1968a). (Remark: The Task Group noted that the dose levels
    used were too low for a proper assessment of the toxicity).

    8.2.1.2  Dog

         Beagle dogs (3 of each sex per dose group, with 5 of each sex
    as controls) were orally dosed by capsule with 0, 0.0125, 0.025, or
    3.125 mg "MIX D/D"/kg body weight per day, for 3 months. The
    composition of the "MIX D/D" was 55% 1,3-dichloropropenes, 26% 1,2-
    dichloropropane, and 0.7% epichlorohydrin. There were no effects on
    general health, behaviour, growth rate, haematology, or clinical
    chemistry at any dose level. No pathological lesions attributable to
    "MIX D/D" were detected, even at the highest dose level (Walker,
    1968b). (Remark: The Task Group noted that the dose levels used were
    too low for a proper assessment of the toxicity).

         Groups of 4 pure-bred Beagle dogs and 4 bitches were dosed with
    0, 0.25, 0.75, 2.50, or 7.50 mg/kg body weight "MIX D/D" (containing
    28.2%  cis-, 29.0%  trans-1,3-dichloropropene, and 34.0% 1,2-
    dichloropropane, without epichlorohydrin), suspended in olive oil in
    gelatin capsules, 7 days/week, for 2 years. Haematological and blood
    chemistry studies and urinalyses were conducted on each animal just
    prior to the inception of the study and after 3, 6, 9, 12, 18, and
    24 months of testing. Ten organs were weighed and histopathological
    examination was carried out of 28 organs and tissues.

         The overall body weights of the bitches were lower in the 7.5
    mg/kg group compared to untreated bitches. The mean corpuscular
    volume and mean corpuscular haemoglobin level were lower in the
    bitches of the 7.5 mg/kg group, while their erythrocyte count was
    raised above that of untreated bitches. No other effects were found.
    At the dose level of 2.5 mg/kg, no differences were found in the
    body weight, food intake, behaviour, mortality, haematology,
    clinical chemistry, urinalysis, organ weight, or gross or
    histopathological appearance between treated and control animals
    (Industr. Biotest Lab., 1977b). An audit of the study data concluded
    that no deviations from the protocol were observed which influenced
    the overall interpretation. Repeated oral dosing of dogs with 7.5 mg

    "MIX D/D"/kg body weight per day, for 2 years, did not result in any
    significant biological effects (Schweizer & Parker, 1980; Parker,
    1980). 

    8.2.2  Inhalation

         Male or female Long-Evans rats (6 per group) were exposed,
    whole body, in concentrations of 0, 340.5, 1362, or 2724 mg "MIX
    D/D"/m3, 1 h/day, 5 days a week, for 2 weeks, or until the animals
    died. Rats exposed to the two highest dose levels showed evidence of
    weight loss, central nervous system depression, and moderate
    irritation. At 2724 mg/m3, 3 animals died. There were no deaths in
    the other groups and no gross or microscopic lesions were observed.
    No effects were seen in the 340.5 mg/m3 group (Hine et al., 1952).
    A further group of six rats was exposed to 1362 mg "MIX D/D"/m3, 1
    h/day, for 3 days. They were killed to find out whether there were
    any lesions immediately after exposure. No gross or microscopic
    lesions were found (Hine et al., 1952).

         Groups of 28 male and 28 female Fischer 344 albino rats and CD-
    1 albino mice were exposed to atmospheres containing 0, 22.7, 68.1,
    or 227 mg "MIX D/D"/m3, for 6 h/day, 5 days/week for 6 or 12
    weeks. The actual mean concentrations were 0, 21.16, 65.38, and
    243.8 mg/m3. No unusual signs of toxicity were observed in rats or
    mice during the study. Body weights and mortality were similar in
    all groups at both 6 and 12 weeks. There were no treatment-related
    changes in haematology, clinical chemistry, or urinalysis apart from
    the detection of small to moderate amounts of occult blood in the
    urine of female mice exposed to 22.7, 68.1, or 227 mg "MIX D/D"/m3
    for 6 weeks. No treatment-related changes were observed in absolute
    organ weights of rats or mice exposed to "MIX D/D" atmospheres up
    to, and including, 227 mg/m3, for 6 or 12 weeks. Small changes
    attributable to "MIX D/D" exposure were observed in male rats
    exposed to 227 mg/m3 (increased liver/body weight ratio) at 6 and
    12 weeks and in female rats exposed to 227 mg/m3 (increased
    kidney/body weight ratio) at 12 weeks. No treatment-related
    histopathological changes were observed in either rats or mice,
    other than slight to moderate diffuse hepatocytic enlargement in
    male mice (12/21) after 12 weeks exposure to 227 mg "MIX D/D"/m3.
    No significant changes related to toxicity were found in the body
    weight, behaviour, haematology, clinical chemistry, or gross or
    histological appearance of rats or mice exposed to atmospheres
    containing up to, and including, 227 mg "MIX D/D"/m3, for 6 or 12
    weeks. No adverse effects were seen at the top dose level (Hazleton
    Laboratories America Inc., 1979; Parker et al., 1982). 

         Groups of 30 male and 24 female Wistar SPF albino rats were
    exposed to actual concentrations of 0, 64, 145, or 443 mg "MIX
    D/D"/m3, 6 h/day 5 days per week, for 10 weeks. The "MIX D/D"
    contained 28.1%  cis-1,3-dichloropropene, 25.6%  trans-1,3-

    dichloropropene, and 25.6% 1,2-dichloropropane, without
    epichlorohydrin. A subgroup was used for the reproduction study (see
    also section 8.5.1.2). There were no compound-related changes in the
    urinalysis, haematology, clinical chemistry, or in the gross or
    histological appearance of the reproductive tract in male and female
    rats. Males and females exposed to 443 mg "MIX D/D"/m3 showed a
    reduced weight gain compared to controls, indicative of a mild toxic
    response at this top dose. Absolute kidney weights in females were
    higher in the 443 mg/m3 group compared to controls, but apart from
    a slight increase in amorphous protein casts in the proximal
    convoluted tubular lumina, no histopathological effects were
    observed. This increase in kidney weight was probably related to the
    efficient renal excretion of "MIX D/D". A no-observed-effect level
    (NOEL) of 145 mg/m3 was considered (Clark, 1980).

    8.3  Skin and eye irritation; sensitization

    8.3.1  Skin and eye irritation

         Undiluted "MIX D/D" was applied to the skin of 12 rabbits in
    single doses of 0.5 ml. The liquid was allowed to be in contact with
    the skin for 24 h. The mean score was 7 on the scale (up to 8) of
    the method of Draize et al. (1944): rating it as a severe irritant.
    Signs were severe eschar, intense oedema, and black necrotic tissue
    (Hine et al., 1952, 1953; Coombs & Carter, 1976a). 

         Six young New Zealand albino rabbits were used in a primary
    skin-irritation test. 0.5 ml of undiluted "MIX D/D" soil fumigant
    was applied on the skin for 4 h. The mean scores for erythema and
    oedema after 4, 24, and 72 h were averaged. The primary irritation
    score was 8, rating it as corrosive. The signs were erythema,
    oedema, escharosis, and necrosis (Industr. Biotest Lab., 1972).

         Undiluted "MIX D/D" was instilled into the eyes of 10 rabbits
    in doses of 0.005 or 0.02 ml. After 18-24 h, the eyes were examined
    and the reactions scored. The eye injury was scored as grade 5
    (severe irritation) (Hine et al., 1952, 1953). 

    8.3.2  Sensitization

         In a test with 20 "P" strain guinea-pigs, a 5% w/v
    concentration of "MIX D/D" in corn oil was used and three topical
    induction applications were followed by a 1% w/v concentration for
    the topical challenge (method of Buehler, 1965). In 13 out of the 20
    guinea-pigs, a positive reaction was obtained. "MIX D/D" has a
    moderate skin sensitizing potential (Coombs & Carter, 1976a).

    8.4  Long-term exposures/carcinogenicity

    8.4.1  Oral

    8.4.1.1  Rat

         Groups of 50 male and 50 female albino rats (age 5 weeks) were
    fed diets containing nominal concentrations of 0, 10, 30, 100, or
    300 mg "MIX D/D"/kg diet for 2 years. Blood samples were collected
    by suborbital sinus puncture at 3, 6, 12, 18, and 24 months. The
    "MIX D/D" contained 28.2%  cis-, 29.0%  trans-1,3-dichloropropene
    and 34% 1,2-dichloropropane, without epichloro- hydrin. 

         There were no significant differences throughout the 2-year
    period between the body weights, food intakes, behaviour, or
    mortalities of male and female rats fed diets containing "MIX D/D"
    and those of control animals. There were no consistent compound-
    related changes in the haematological parameters. 

         Statistically significant increases were noted, at 3, 6, and 24
    months, in the fasting serum glucose values of rats receiving 300
    mg/kg diet and in the serum alkaline phosphatase levels at 12 months
    compared with controls. These effects were not considered to be
    biologically significant, because of the size of the response and
    the lack of a consistent response throughout the study. No other
    changes were observed in the haematology and clinical chemistry of
    rats exposed to "MIX D/D" for 2 years. 

         Urinalyses were performed at 3, 6, 12, 18, and 24 months, and
    the only statistically significant difference recorded was a lowered
    specific gravity of urine at 3 months in males receiving 300 mg/kg
    diet compared with controls. This effect was not correlated with any
    other changes, and the effect did not occur consistently throughout
    the study; it was therefore considered to be of doubtful biological
    significance. No changes attributable to feeding diets containing
    "MIX D/D" were observed in the organ weights and histopathology at 1
    and 2 years (Industr. Biotest Lab., 1978). An audit performed on the
    study data revealed no major factors that would affect the
    conclusions of this study. The nominal concentrations of "MIX D/D"
    specified in the protocol could not be considered representative of
    the actual concentrations fed to animals. Subsequent work on the
    volatility of "MIX D/D" in the diet revealed that the average
    dietary concentrations present at the time of feeding were 40% of
    the nominal values. 

         In conclusion, no compound-related effects were observed in
    rats fed diets containing an average concentration of up to and
    including 120 mg/kg diet (= nominal concentration of 300 mg/kg diet)
    "MIX D/D" for two years (Jud et al., 1980a).

    8.5  Reproduction, embryotoxicity, and teratogenicity

    8.5.1  Reproduction

    8.5.1.1  Oral

         Charles River CD-strain albino rats (10 males and 20 females)
    were fed diets containing 0, 10, 30, or 100 mg "MIX D/D" ( cis-1,3-
    dichloropropene 28.2%,  trans-1,3-dichloropropene 29%, 1,2-
    dichloropropane 34%, without epichlorohydrin) per kg diet in a 3-
    generation, 2-litter, reproduction study. No statistically
    significant differences were observed in parental body weights, food
    consumption, behaviour, or mortalities throughout each 10-week pre-
    breeding period. Gross pathology, histopathology, and organ weights
    were similar in all groups. The feeding of diets containing "MIX
    D/D" did not affect the reproductive performance (mating, fecundity,
    fertility indices, and parturition incidence) or dam body weights
    during gestation or post-partum and post-weaning periods. There were
    no signs of external abnormalities in newborn pups. There were
    significantly more pups alive at day 1 of lactation in the F3a
    litters of the 30 mg/kg group, compared with controls. No
    differences that were directly related to treatment were noted for
    survival over a 21-day period, number of pups delivered, or
    stillbirths. No gross pathological or histopathological differences
    were observed between treatment and control offspring. Significantly
    higher mean body weights were recorded at weaning in the F2b males
    of the 30 mg/kg group and in males and females of the 100 mg/kg
    group. Increases were also recorded at weaning in the F3b
    generation of 10 mg/kg males and 100 mg/kg females. These increases
    in mean body weight did not show any consistent relationship with
    dose or sex and were not considered attributable to "MIX D/D"
    exposure (Industr. Biotest Lab., 1977a).

         An audit of the study data demonstrated that compliance with
    the protocol was satisfactory and that agreement of the results with
    more recent data was sufficient to support the conclusions of this
    study. Subsequent work on the volatility of "MIX D/D" in diet
    revealed that average concentrations present at the time of feeding
    were 40% of the nominal values. Thus "MIX D/D" did not produce any
    effects on the reproductive performance or growth of offspring of
    rats fed diets containing up to and including 40 mg "MIX D/D"/kg
    diet (= nominal concentration of 100 mg/kg diet) for 3 generations
    (40 mg/kg diet, the highest dose level tested is equivalent with 2
    mg/kg body weight) (Jud et al., 1980b). 

    8.5.1.2  Inhalation

         In one study (Linnett et al., 1988), groups of 20 male SPF
    Wistar-derived rats (15 weeks old) and 24 virgin female rats (10
    weeks old) were exposed by inhalation to nominal concentrations of

    0, 45.4, 136, or 408 mg "MIX D/D"/m3 (actual concentrations of 0,
    64, 145, or 443 mg/m3 for 6 h/day, 5 days/week, for 10 weeks. The
    composition of the "MIX D/D" was 28.1% (w/w)  cis-1,3-
    dichloropropene, 25.6%  trans-1,3-dichloropropene, and 25.6% 1,2-
    dichloropropane and a number of other chlorinated components in
    percentages up to 5%, but it contained no epichlorohydrin.

         Treated males of proven fertility were paired with untreated
    virgin females at intervals during and after exposure. Groups of 15
    treated females were paired with untreated males immediately after
    the 10-week period. Various aspects of reproduction performance and
    general toxicity were assessed. Mortality and haematological,
    clinical-chemical, and urinary parameters were comparable with the
    controls. Exposure to "MIX D/D" did not produce any adverse effects
    on the libido, fertility, or morphology of the reproductive tracts
    of rats of either sex. No treatment-related dominant lethal effects
    were observed in male rats. Mean body weights of male and female
    rats at 408 mg/m3 were significantly decreased. The mean liver and
    kidney weights were significantly increased in the animals of both
    sexes exposed to the highest dose level. Histological examination of
    the organs did not reveal treatment-related changes. This study
    demonstrates that male and female rats exposed to atmospheres
    containing up to 443 mg/m3 "MIX D/D" vapour for 10 weeks did not
    suffer any impairment of reproductive performance.

    8.5.2  Embryotoxicity and teratogenicity

    8.5.2.1  Oral

         Charles River, albino, female rats received gastric intubations
    of 0, 30, or 100 mg "MIX D/D"/kg body weight (containing 28%  cis-
    1,3-dichloropropene, 29%  trans-1,3-dichloropropene, and 34% 1,2-
    dichloropropane, without epichlorohydrin) dissolved in corn oil,
    during days 6 through 15 of pregnancy. The control group was dosed
    with corn oil. A significant decrease in body weight of the dams
    receiving 100 mg/kg, compared with the controls, was observed at day
    15 of gestation. While no statistically significant reproductive
    effects occurred, there appears to have been a trend for an increase
    in the percentage of females with one or more resorption sites. The
    lack of statistical significance is probably due to the small
    numbers of animals involved (3 of 17, 6 of 19, and 5 of 15, for the
    0, 30, and 100 mg/kg groups, respectively). The maternal toxicity
    observed in the highest-dose group would account for the apparent
    increase in resorption sites. 

         There was a dose-related increase in the incidence of
    supernumerary ribs (2.8% for controls, 7.6% for the 30 mg/kg group,
    and 32.3% for the 100 mg/kg per group) and the same was found for

    the occurrence of non-ossified sternum sections. The incidence of
    supernumerary ribs over approximately 50 rat teratology studies, in
    this laboratory, has been within the range 0-26%. 

         A significant decrease in mean body weight of fetuses from
    females dosed with 100 mg "MIX D/D"/kg was observed. Maternal
    toxicity was observed in the 100 mg/kg group, but no malformations,
    other than supernumerary ribs and non-ossified sternebrae, were
    observed in this group (Industr. Biotest Lab., 1975).

         An audit of the study data demonstrated that there were no
    major factors to alter the conclusions of this study (O'Sullivan et
    al., 1980).

    8.6  Mutagenicity and related end-points

    8.6.1  In vitro studies (microorganisms)

         DeLorenzo et al. (1977) tested "MIX D/D" (40% 1,3-
    dichloropropene and 40% 1,2-dichloropropane) on  Salmonella
     typhimurium strains TA98, TA100, TA1535, TA1537, and TA1978, with
    and without activation. Dose levels of 0, 0.5, 5, 15, and 25
    mg/plate were tested. Mutagenic effects were seen with TA100,
    TA1535, and TA1978, but not with TA98 and TA1537. 

         Shirasu et al. (1981) studied the mutagenicity of "MIX D/D" in
    reverse mutation tests using  Salmonella typhimurium strain TA100,
    and Moriya et al. (1983) used 5 strains of  Salmonella typhimurium,
    TA98, TA100, TA1535, TA1537, and TA1538, and  Escherichia coli
    strain WP2  hcr, with and without metabolic activation. "MIX D/D"
    was tested in dose levels up to 5000 µg/plate. The mutagenic potency
    in  Salmonella typhimurium TA100 was 0.0087 revertants/nmole. "MIX
    D/D" was a direct-acting mutagen in TA100, TA1535, and  E. coli WP2
     hcr, but was not mutagenic in TA1537, TA1538, or TA98.

    8.6.2  In vivo studies

         Dominant lethality was tested in rats exposed to an atmosphere
    containing "MIX D/D" vapour for 10 weeks (Linnett et al., 1988, see
    section 8.5.1.2). No effects on fertility or on implantations were
    observed even at 443 mg/m3, the highest concentration tested. This
    result demonstrates the lack of any significant effects on germ-cell
    production in rats.

         Further evidence of rapid detoxification was found in the
    negative results of a host-mediated assay using  S. typhimurium,
    strain G46, in mice dosed orally with either 60 or 200 mg "MIX
    D/D"/kg over a 24-h period (Shirasu et al., 1981).

    9.  EFFECTS ON HUMANS

    9.1  General population exposure

         A case of acute poisoning occurred a few hours after the
    accidental ingestion of "MIX D/D". The victim experienced abdominal
    pain and vomiting. He became semicomatose and exhibited muscle
    twitching and died (Gosselin et al., 1976; NTP, 1985).

    9.2  Occupational exposure

         In the period from 1966 to 1971, a total of 13 cases of
    untoward skin reactions to pesticides were reported in the northern
    part of the Netherlands. Seven were due to contact with "MIX D/D"
    caused by inadvertent dripping into the shoes of the applicators
    during spraying operations. In all cases, acute vesicular dermatitis
    occurred. Three other cases of dermatitis were described, one being
    of a contact allergic nature, as confirmed by patch testing, and
    were diagnosed as orthoergic contact reactions (Nater & Gooskens,
    1976).

         Nater & Gooskens (1976) and Van Joost & De Jong (1988)
    described dermatitis in a farmer who had sprayed "MIX D/D" and in a
    process operator, caused by direct contact. The persons had had
    previous contact with this substance. Both patients reacted
    positively in a patch test, with 1% and 0.02% "MIX D/D",
    respectively.

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    RESUME ET EVALUATION, CONCLUSIONS, ET RECOMMANDATIONS
    1,3-DICHLOROPROPENE

    1.  Résumé et évaluation

    1.1  Usage, destinée et concentrations dans l'environnement

         Le "1,3-dichloropropène" a été introduit en agriculture en
    1956, mélangé à des 1,3-dichloropropènes, du 1,2-dichloropropane et
    d'autres hydrocarbures halogénés. On l'utilise depuis largement
    comme fumigant du sol avant plantation pour lutter contre les
    nématodes qui parasitent les légumes, les pommes de terre et le
    tabac. L'application s'effectue essentiellement par injection dans
    le sol. La formulation du commerce consiste en un mélange d'isomères
     cis et  trans (en proportions approximativement égales), et se
    présente sous la forme d'un liquide incolore à ambré dont l'odeur
    pénétrante et irritante rappelle celle du chloroforme. Sa tension de
    vapeur est de 3.7 kPa à 20 °C. Le produit technique a une pureté de
    92% et peut contenir certaines impuretés, comme le 1,2-
    dichloropropane. Le coefficient de partage octanol/eau (log Kow)
    est égal à 1,98.

         Dans l'air, la décomposition du 1,3-dichloropropène s'effectue
    principalement par réaction avec des radicaux libres et l'ozone.
    Dans le cas de la réaction avec les radicaux libres, la demi-vie des
    isomères  cis- et  trans- est respectivement égale à 12 et 7
    heures et dans le cas de la réaction avec l'ozone, de 52 et 12
    jours. Il semble que la phototransformation directe soit négligeable
    mais elle pourrait être favorisée par la présence de particules en
    suspension dans l'atmosphère.

         Dans l'eau, il est probable que le 1,3-dichloropropène
    disparaît rapidement du fait de sa solubilité relativement faible et
    de sa forte volatilité; on a fait état d'une demi-vie de moins de 5
    heures.

         La distribution du 1,3-dichloropropène dans les différents
    compartiments du sol dépend de la tension de vapeur, du coefficient
    de diffusion, de la température et de la teneur en eau. La
    persistance du 1,3-dichloropropène dans le sol dépend de sa
    volatilisation, des transformations chimiques, photo-chimiques ou
    biologiques qu'il subit et de sa fixation par les êtres vivants. La
    volatilisation et la diffusion en phase gazeuse sont les mécanismes
    les plus importants de sa dispersion et de la dilution dans le
    milieu.

         Dans l'environnement, la transformation du 1,3-dichloropropène
    commence par une hydrolyse en alcool 3-chloro-allylique puis, sous
    l'action des microorganismes, en 3-chloro-acroléine et en acide 3-

    chloro-acrylique. Une étude de laboratoire a montré que le temps de
    demi-hydrolyse des isomères  cis- et  trans- du 1,3-
    dichloropropène à 15 °C et à 29 °C était respectivement égal, pour
    l'isomère  cis, à 11 et 2 jours et pour l'isomère  trans, à 13 et
    2 jours. Dans le sol, à un pH de 7, on a observé un temps de demi-
    hydrolyse à 25 °C de 4,6 jours pour les deux isomères. Du fait que
    le composé disparaît relativement vite du sol, il est peu probable
    que des résidus s'y accumulent après application du fumigant à la
    dose et selon la périodicité recommandées. 

         Le 1,3-dichloropropène est potentiellement mobile dans le sol,
    en particulier dans les sols sableux à texture lâche dont la teneur
    en eau est faible. Son cheminement en profondeur est favorisé par
    les cultures profondes dans des sols de faible porosité. On a décelé
    du 1,3-dichloropropène dans les nappes souterraines peu profondes
    (jusqu'à 2 m en-dessous de la surface) mais non dans les eaux
    profondes, c'est-à-dire celles qui ont le plus de chances d'être
    utilisées pour la consommation humaine. 

         Le 1,3-dichloropropène peut-être fixé par les plantes
    cultivées. Toutefois, il est peu probable qu'il donne lieu à des
    résidus importants dans les cultures vivrières car celles-ci sont en
    principe plantées lorsque la majeure partie du fumigant s'est
    dissipée. 

         La bioaccumulation du 1,3-dichloropropène est peu probable car
    il possède une solubilité dans l'eau relativement forte (> 1 g/kg),
    un coefficient de partage octanol/eau faible (log Kow) et il est
    rapidement éliminé chez les mammifères et autres organismes.

    1.2  Cinétique et métabolisme

         Après administration par voie orale à des rongeurs, le 1,3-
    dichloropropène est rapidement éliminé. La principale voie
    d'élimination est la voie urinaire, avec 81% de l'isomère  cis et
    56% de l'isomère de  trans excrétés dans les 24 heures suivant
    l'administration. La demi-vie d'élimination dans l'urine est de 5 à
    6 heures. L'élimination dans les matières fécales est minime. Le
    1,3-dichloropropène est éliminé à hauteur de 4% (isomère  cis) et
    de 24% (isomère  trans) dans le dioxyde de carbone expiré. Après
    l'administration, les concentrations tissulaires sont faibles; les
    concentrations résiduelles les plus élevées se retrouvent dans la
    paroi gastrique, puis, à des valeurs plus faibles, dans les reins,
    le foie et la vessie.

         On ne retrouve pas de 1,3-dichloropropène non modifié dans les
    urines. Les isomères  cis et  trans tiennent lieu de substrats à
    la glutathion- S-alkyltransférase hépatique qui les transforme en
    acides mercapturiques, excrétés ensuite dans les urines. Le
    principal métabolite urinaire chez le rat et la souris est la  N-

    acétyl- S-(3-chloroprop-2-ényl)L-cystéine; ce composé peut être
    utilisé pour la surveillance biologique chez l'homme. On a observé
    une deuxième voie métabolique d'importance secondaire dans le cas de
    l'isomère  cis; il s'agit d'une mono-oxygénation en  cis-1,3-
    dichloropropène oxyde, composé qui peut ensuite être conjugué avec
    le glutathion. La forte proportion d'isomère  trans présente dans
    l'air expiré résulte d'une autre voie métabolique conduisant à la
    conjugaison, voie qui est plus spécifique de l'isomère  trans que
    de l'isomère  cis.

         Exposés par voie respiratoire à du 1,3-dichloropropène, des
    rats n'ont pas présenté une augmentation du taux sanguin
    proportionnelle à la dose. A la dose de 408,6 mg/m3 (90 ppm), la
    fréquence respiratoire et le volume expiratoire-minute étaient
    réduits et l'on notait une saturation du métabolisme à 1362 mg/m3
    (300 ppm). Les isomères  cis et  trans ont été rapidement éliminés
    du courant sanguin, avec une demi-vie d'élimination de 3 à 6 minutes
    pour des concentrations inférieures à 1362 mg/m3, mais beaucoup
    plus longue (33 à 43 minutes) à plus forte concentration. 

    1.3   Effets sur les êtres vivant dans leur milieu naturel

         Les valeurs de la CE50 relatives à la croissance (à 96 h)
    chez une algue d'eau douce,  Selenastrum capricornutum, et chez une
    diatomée estuarielle,  Skeletoneria costatum, sont respectivement
    égales à 4,95 mg/litre et 1 mg/litre. Pour les poissons, la toxicité
    aiguë du 1,3-dichloropropène (CL50 à 96 h), est de l'ordre de 1 à
    7,9 mg/litre. Un test effectué sur les stades embryo-larvaires d'un
    vairon,  Pimephales promelas, ont donné une dose maximale sans
    effet observable de 0,24 mg/litre. Ces données, jointes au fait que
    le 1,3-dichloropropène ne persiste vraisemblablement pas dans l'eau,
    indiquent que le danger pour les poissons réside dans les effets
    toxiques aigus de ce composé, mais qu'il y a peu de risques d'effets
    supplémentaires résultant d'une exposition à long terme. 

         Aux doses de 30 à 60 mg/kg, le 1,3-dichloropropène peut réduire
    l'abondance des champignons et l'activité des enzymes microbiennes,
    mais cet effet n'est généralement pas de longue durée (< 7 jours)
    et ne se produit pas dans tous les types de sol. Certaines études
    ont fait ressortir un accroissement sensible du nombre de
    microorganismes après application du fumigant. 

         Le 1,3-dichloropropène est phytotoxique mais en revanche, il
    est peu toxique pour les abeilles. On a constaté, en épandant du
    1,3-dichloropropène par poudrage, que la DL50 à 48 h était de 6,6
    µg/abeille. Les oiseaux sont relativement insensibles au 1,3-
    dichloropropène. La CL50 (8 jours) est inférieure à 10 g/kg de
    nourriture pour le col-vert et les cailles du genre  Colinis.

    1.4  Effets sur les animaux d'expérience et les systèmes d'épreuve
         in vitro

         La toxicité aiguë par voie orale du 1,3-dichloropropène est
    modérée à forte chez les animaux d'expérience. En ce qui concerne le
    rat, on a fait état, pour la DL50, de valeurs se situant entre 127
    et 713 mg/kg de poids corporel. Par voie orale, ces valeurs étaient
    respectivement de 85 et 94 mg/kg de poids corporel pour les isomères
     cis et  trans.

         En cas d'exposition cutanée, le composé est modérément toxique.
    Chez le rat et le lapin, on a obtenu pour la DL50 des valeurs
    respectivement égales à 423 et 504 mg/kg de poids corporel. Ces
    valeurs étaient respectivement de 1090 mg pour l'isomère  cis et de
    1575 mg/kg de poids corporel pour l'isomère  trans.

         Chez des rats exposés pendant 4 h par la voie respiratoire à du
    1,3-dichloropropène, on a obtenu une CL50 de 3310 mg/m3 (729
    ppm); les valeurs allaient de 3042 mg/m3 à 3514 mg/m3 pour
    l'isomère  cis et de 4880 mg/m3 à 5403 mg/m3 pour l'isomère
     trans.

         En cas d'intoxication aiguë, on observe une atteinte nerveuse
    centrale et une atteinte respiratoire.

         Des réactions graves ont été observées chez le lapin lors
    d'épreuves d'irritation cutanée et oculaire mais les animaux ont
    récupéré en l'espace de 14 à 21 jours. Les épreuves de
    sensibilisation cutanée chez le cobaye se sont révélées positives. 

         Plusieurs études de toxicité respiratoire à court terme ont été
    effectuées sur des souris, des rats, des cobayes, des lapins et des
    chiens. Chez la souris, c'est les muqueuses nasales et la vessie qui
    étaient les organes cibles. On a observé une dégénérescence de
    l'épithélium olfactif et une hyperplasie de l'épithélium
    respiratoire. Au niveau de la vessie, on a observé une hyperplasie
    modérée de l'épithélium de transition. On a pu fixer à 136 mg/kg,
    soit 30 ppm, la dose sans effet observable chez la souris. 

         Chez le rat, on a observé également une hyperplasie ainsi que
    des modifications dégénératives analogues au niveau de l'épithélium
    olfactif. Une étude bien conçue a permis d'obtenir une valeur de
    4,35 mg/m3 pour la dose sans effet observable; dans le cas précis
    de l'isomère  cis, cette dose était égale à 136 mg/m3. 

         Une étude de 90 jours consistant à administrer le composé par
    voie orale à des rats a permis de fixer à 3 mg/kg de poids corporel
    la dose sans effet observable. Le seul effet observé à la dose
    immédiatement supérieure (10 mg/kg de poids corporel) consistait en
    une augmentation du poids relatif des reins chez les mâles. 

         Une étude de reproduction portant sur deux générations et deux
    portées de rats, à des doses allant jusqu'à 408,6 mg/m3 (90 ppm),
    n'a pas fait ressortir d'effets indésirables sur les paramètres
    examinés. Toutefois, la dose la plus forte (408,6 mg/m3) était
    toxique pour les mères, comme l'ont montré les deux anomalies
    observées: réduction de la croissance et modification
    histopathologique au niveau de la muqueuse nasale. Les résultats de
    cette étude ont permis de fixer à 136,2 mg/m3 (30 ppm) la dose
    maximale sans effet toxique observable chez les mères. 

         Des études de tératogénicité au cours desquelles du 1,3-
    dichloropropène a été administré à des rats et à des lapins par la
    voie respiratoire, n'ont pas permis de relever d'indices de
    tératogénicité jusqu'à la dose de 1362 mg/m3, mais on a observé
    une embryotoxicité chez le rat (réduction de la taille des portées
    et augmentation du taux de résorption). Le composé s'est révélé
    toxique pour les mères, tant chez les rattes que chez les lapines,
    aux doses supérieures ou égales à 544,8 mg/m3 (120 ppm). 

         Dans la plupart des études, les isomères  cis et  trans du
    1,3-dichloropropène, ainsi que les mélanges, se sont révélés
    mutagènes chez les bactéries, sans ou avec activation métabolique. A
    l'état pur, le 1,3-dichloropropène et le  cis-1,3-dichloropropène
    étaient négatifs à cet égard chez les bactéries. On a montré que le
    glutathion bloquait l'activité mutagène du 1,3-dichloropropène chez
    les bactéries. Lors d'une épreuve de mutation génique sur des
    cellules V79 de hamster chinois ainsi que dans une épreuve HGPRT sur
    des cellules ovariennes du même animal, le  cis-1,3-dichloropropène
    a donné des résultats négatifs.

         Le  cis- et le  trans-1,3-dichloropropène provoquent une
    synthèse non programmée de l'ADN dans les cellules HeLa S3. Dans
    des hépatocytes de rat, le 1,3-dichloropropène n'a pas entraîné de
    réparation importante de l'ADN. L'épreuve rec sur des microsomes de
    la souche H17 de  Bacillus subtilis a donné un résultat positif
    avec le 1,3-dichloropropène en présence d'activation métabolique.

         Dans des cellules ovariennes de hamster chinois, le  cis- et
    le  trans-1,3-dichloropropène ont entraîné des lésions
    chromosomiques en présence d'activation métabolique; toutefois dans
    une autre étude, le 1,3-dichloropropène a produit les mêmes effets
    sans activation métabolique. Le  cis-1,3-dichloropropène n'a pas
    provoqué de lésions chromosomiques dans des cellules de foie de rat,
    mais il a entraîné des échanges entre chromatides soeurs dans des
    cellules ovariennes de hamster chinois, en présence ou en l'absence
    d'activation métabolique, ainsi que dans des cellules V79 du même
    animal, cette fois sans activation métabolique. 

         Une épreuve de recherche des micronoyaux dans la moelle osseuse
    de souris a donné des résultats négatifs avec le 1,3-

    dichloropropène. Les résultats ont été également négatifs dans le
    cas d'une épreuve de mutation létale récessive liée au sexe sur
     Drosophila melanogaster.

         Des études de cancérogénicité ont été effectuées sur des souris
    et des rats. On leur a administré par gavage pendant deux ans du
    1,3-dichloropropène technique contenant 1% d'épichlorhydrine. Chez
    les souris, on a noté un accroissement sensible des hyperplasies
    épithéliales ainsi que des carcinomes de type transitionnel au
    niveau de la vessie, un accroissement des tumeurs pulmonaires, une
    légère augmentation des tumeurs hépatiques et, au niveau de la
    portion cardiaque de l'estomac, une augmentation de l'hyperplasie
    épithéliale ainsi que des papillomes ou des carcinomes spino-
    cellulaires. Chez le rat, on a observé une augmentation de
    l'incidence des nodules néoplasiques au niveau du foie ainsi que des
    papillomes ou des carcinomes spino-cellulaires dans la portion
    cardiaque de l'estomac.

         Une étude par inhalation de deux ans a permis d'étudier la
    cancérogénicité du 1,3-dichloropropène (sans épichlorhydrine) sur
    des rats et des souris. Chez les souris, on a observé une incidence
    accrue des hyperplasies, au niveau de la vessie, de la portion
    cardiaque de l'estomac et des muqueuses nasales. Il y avait
    également augmentation dans l'incidence des tumeurs pulmonaires
    bénignes. Un certain nombre de modifications d'origine toxique ont
    été constatées dans la muqueuse olfactive nasale chez le rat, mais
    sans accroissement de l'incidence tumorale. 

         On a montré que l'épichlorhydrine provoquait des tumeurs de la
    partie proximale de l'estomac lors d'une étude où cette substance
    était administrée par gavage ainsi que des tumeurs des fosses
    nasales lors d'une étude par inhalation sur des rats; les résultats
    de l'étude au cours de laquelle du 1,3-dichloropropène a été
    administré par voie orale à des souris ne permettent pas d'exclure
    un effet cancérogène sur la vessie.

    Mode d'action

         Etant donné que la principale voie métabolique d'élimination du
    1,3-dichloropropène consiste dans une conjugaison avec le
    glutathion, on peut penser que toute situation affectant la
    concentration en glutathion tissulaire (groupements sulfhydriles non
    protéiques) est susceptible de modifier les effets du composé. Le
    1,3-dichloropropène lui-même provoque une déplétion en glutathion
    dans les divers tissus, en particulier ceux qui constituent la porte
    d'entrée dans l'organisme, c'est-à-dire essentiellement la portion
    cardiaque de l'estomac et le foie dans le cas où l'administration se
    fait par gavage et les tissus des fosses nasales dans le cas des
    études par inhalation. On a observé chez la souris une diminution du
    glutathion, au niveau de l'épithélium nasal aux doses supérieurs

    22,7 mg/m3 (5 ppm) et au niveau de la portion cardiaque de
    l'estomac aux doses supérieurs à 113,5 mg/m3 (25 ppm).

         La toxicité du 1,3-dichloropropène pour les animaux
    d'expérience se manifeste lorsque l'exposition entraîne une
    déplétion en glutathion et une réduction préalable de la teneur en
    glutathion tissulaire exacerbe cet effet toxique. L'inhalation
    pendant une longue période de concentrations supérieures à 90,8
    mg/m3 (20 ppm) entraîne une dégénérescence et une hyperplasie de
    l'épithélium nasal et stomacal chez la souris; chez le rat et dans
    les mêmes conditions, la dose de 272,4 mg/m3 (60 ppm) a également
    provoqué une dégénérescence du tissu des fosses nasales.

         Le rôle protecteur du glutathion a également été mis en lumière
    par des études chez la souris qui ont montré que lorsque la teneur
    en groupements sulfhydriles non protéiques diminuait, il y avait
    augmentation du taux de liaison covalente du dichloropropène
    radiomarqué (au carbone 14) aux cellules de la portion cardiaque de
    l'estomac. De même, on a observé, dans des systèmes d'épreuves  in
     vitro, que la présence de glutathion réduisait sensiblement la
    génotoxicité du 1,3-dichloropropène et d'un des ses métabolites
    mineurs d'oxydation (cytochrome P-450), à savoir le 1,3-
    dichloropropène-oxyde.

    1.5  Effets sur l'homme

         Il est improbable qu'il y ait exposition de la population
    générale par l'intermédiaire de l'air, de l'eau ou des aliments. 

         On a montré que l'exposition professionnelle se situe en
    général en-dessous de 4,54 mg/m3 (1 ppm), mais on a également fait
    état de concentrations plus élevées (jusqu'à 18,3 mg/m3 lors
    d'opérations de remplissage ou de changement de buses). L'exposition
    professionnelle se produit vraisemblablement par la voie
    respiratoire ou par la voie cutanée. Très peu de temps après
    l'exposition, il y a irritation des yeux et des muqueuses des voies
    respiratoires supérieures. On a observé de graves symptômes
    d'intoxication après inhalation d'air contenant des concentrations
    supérieures à 6810 mg/m3 (> 1500 ppm); à plus faible
    concentration, il y avait dépression du système nerveux central et
    irritation des voies respiratoires. L'exposition de la peau entraîne
    également de graves irritations à ce niveau. 

         Chez un groupe de personnes chargées d'épandre du 1,3-
    dichloropropène, on a observé en fin de saison un certain nombre
    d'anomalies de la fonction hépatique et rénale. Toutefois,
    l'existence d'une relation de cause à effet reste controversée. 

         Il y a eu des cas d'intoxication qui ont entraîné
    l'hospitalisation des intéressés avec des symptômes d'irritation des
    muqueuses, une sensation de gêne thoracique, des maux de tête, des

    nausées, des vomissements, des vertiges et parfois une perte de
    conscience et une diminution de la libido. En outre, trois cas
    d'affections hématologiques malignes ont été attribués à une
    surexposition accidentelle antérieure au 1,3-dichloropropène, mais
    là encore, l'existence d'une relation de cause à effet reste
    incertaine. 

         En comparant à un groupe témoin la fécondité d'employés
    travaillant à la production d'hydrocarbures chlorés à trois atomes
    de carbone, on n'a pas mis en évidence d'association entre
    l'exposition et une réduction éventuelle de la fécondité. 

    2.  Conclusions

    Population générale: Du fait que l'exposition au 1,3-dichloropropène
    est faible voire inexistante, le risque pour la population générale
    est négligeable.

    Exposition professionnelle: Lors d'opérations de remplissage et lors
    des épandages, il peut y avoir exposition des opérateurs à des
    concentrations dépassant la limite maximale autorisée, si des
    mesures de sécurité appropriées ne sont pas prises. 

    Environnement: Dans la mesure où le 1,3-dichloropropène est utilisé
    à la dose recommandée, il est vraisemblable qu'il ne s'accumulera
    pas dans l'environnement à des concentrations susceptibles de poser
    un problème écologique et il est improbable qu'il puisse avoir des
    effets nocifs sur les organismes terrestres et aquatiques.

    3.  Recommandations

    *    Les opérations de remplissage et l'épandage du 1,3-
         dichloropropène doivent obligatoirement s'accompagner des
         mesures de sécurité appropriées afin de faire en sorte que
         l'exposition ne dépasse pas les concentrations maximales
         autorisées. 

    *    Il faudrait étudier la destinée métabolique du  trans-1,3-
         dichloropropène chez les mammifères ainsi que le rôle que
         pourraient avoir les métabolites d'oxydation de cet isomère
         dans la toxicité du composé.

    *    L'effet protecteur du glutathion vis-à-vis du 1,3-
         dichloropropène est dû à l'action de la glutathion-transférase.
         Il est donc recommandé de procéder à des études afin de
         comparer la cinétique de l'action enzymatique de la glutathion-
          S-transférase humaine provenant des divers tissus à
         l'activité de l'enzyme d'origine animale provenant des tissus
         correspondants. 

    *    Il conviendrait de rassembler et de publier les données dont on
         dispose sur le rôle protecteur du glutathion. 

    *    La génotoxicité du dichloropropène est due pour une part à son
         métabolisme oxydatif. Il est recommandé d'entreprendre des
         études pour identifier l'isoenzyme responsable et la comparer à
         l'activité des isoenzymes du cytochrome P-450 humain. 

    *    Dans les études de cancérogénicité où l'on procède par gavage
         des animaux, il conviendrait d'élucider le rôle de
         l'épichlorhydrine en tant que facteur de confusion éventuel. 

    RESUME ET EVALUATION, CONCLUSIONS, ET RECOMMANDATIONS
    1,2-DICHLOROPROPANE

    1.  Résumé et évaluation

    1.1  Usage, destinée et concentrations dans l'environnement

         Le 1,2-dichloropropane est un liquide dont le point
    d'ébullition est de 96,8 °C et la tension de vapeur de 42 mmHg à 20
    °C. Il est soluble dans l'eau, l'éthanol et l'éther éthylique. Par
    chauffage, il émet des vapeurs de phosgène hautement toxiques. Son
    coefficient de partage entre l'octanol et l'eau (log Kow) est égal
    à 2,28. 

         Ce produit entre dans la composition des vernis pour meubles,
    des liquides de nettoyage à sec, des décapants pour peintures, des
    produits pour le dégraissage des surfaces métalliques, le traitement
    des huiles; il sert à la fabrication de caoutchoucs et de cires,
    ainsi que comme intermédiaire dans la production du
    tétrachloréthylène et du tétrachlorure de carbone. Il entre
    également dans la composition du mélange appelé D/D que l'on utilise
    comme fumigant avant la plantation.

         Les mesures de la concentration du 1,2-dichloropropane dans
    l'air urbain ont donné des valeurs respectives de 1,2 µg/m3
    (valeur moyenne), 0,021-0,040 µg/m3 et 0,0065-1,4 µg/m3
    respectivement à Philadelphie, Portland et au Japon. La
    décomposition dans l'atmosphère est lente; sur la base de la
    réaction avec les radicaux hydroxyles, on a évalué le temps de demi-
    décomposition du 1,2-dichloropropane à plus de 313 jours. Il est
    probable que la décomposition est essentiellement de nature
    photochimique. Pour que cette décomposition photochimique soit
    appréciable, il est nécessaire que le composé soit adsorbé sur des
    particules. C'est, semble-t-il, principalement par volatilisation
    que le 1,2-dichloropropane s'élimine de l'eau.

         Dans le sol, les principales voies d'élimination sont la
    volatilisation et la diffusion. Le 1,2-dichloropropane persiste dans
    le sol. Plus de 98% du 1,2-dichloropropane appliqué sur du terreau
    ont été récupérés 12 à 20 semaines après ce traitement. 

         Il peut y avoir lessivage du 1,2-dichloropropane présent dans
    le sol et contamination des eaux souterraines à faible ou grande
    profondeur dans les secteurs traités avec des fumigants du type "MIX
    D/D". Aux Etats-Unis d'Amérique, on a trouvé des concentrations dans
    l'eau de puits et les eaux souterraines allant respectivement
    jusqu'à 440 µg/litre et 51 µg/litre. Aux Pays-Bas, des
    concentrations atteignant 160 µg/litre ont été observées dans l'eau
    de puits et on a retrouvé du 1,2-dichloropropane jusqu'à une
    profondeur de 13 mètres.

         Les plantes vivrières peuvent fixer le 1,2-dichloropropane mais
    les résidus qu'on y a décelés sont faibles (< 0,01 mg/kg) et
    probablement sans conséquence biologique.

         La bioaccumulation du 1,2-dichloropropane est improbable en
    raison de sa forte solubilité dans l'eau (2,7 g/kg) et de la faible
    valeur de son coefficient de partage entre l'octanol et l'eau (log
    Kow).

    1.2  Cinétique et métabolisme

         Administré par voie orale à des rats, le 1,2-dichloropropane
    est rapidement éliminé (80 à 90% en 24 h). Il n'y a pas de
    différences majeures dans la cinétique ou dans l'élimination entre
    les mâles et les femelles. La principale voie d'élimination est la
    voie urinaire, et jusqu'à la moitié de la dose orale initiale est
    éliminée dans les 24 h. La proportion éliminée par la voie fécale
    est inférieure à 10%. Le 1,2-dichloropropane est éliminé à hauteur
    de 33% dans l'air expiré, à la fois sous forme de dioxyde de carbone
    et d'un mélange de produits volatils. Les concentrations tissulaires
    sont faibles, la plus élevée étant observée au niveau du foie. Après
    exposition de rats par la voie respiratoire on note une élimination
    rapide du 1,2-dichloropropane; 55 à 65% de la dose initiale sont
    éliminés dans les urines et 16 à 23% dans l'air expiré. La demi-vie
    d'élimination à partir du sang est de 24 à 30 minutes. 

         On ne retrouve pas le 1,2-dichloropropane initial dans les
    urines. On y a identifié trois métabolites principaux. Ces
    métabolites résultent de l'oxydation et de la conjugaison du composé
    et aboutissent à la formation de mercapturates, de  N-acétyl- S-
    (2-hydroxypropyl)-L-cystéine, de  N-acétyl- S-(2-oxypropyl)-L-
    cystéine et de  N-acétyl- S-(1-carboxyéthyl)-L-cystéine. Le 1,2-
    dichloropropane peut également subir une oxydation en lactate avec
    production de dioxyde de carbone ou d'acétyl-coenzyme A.

         Après administration de 1,2-dichloropropane par voie orale à
    des rats à raison de 2 mg/kg, on a constaté une forte diminution du
    glutathion tissulaire. Il y avait également corrélation entre la
    diminution du glutathion tissulaire et les manifestations toxiques
    au niveau du foie, des reins et des hématies. Une réduction
    préalable du glutathion intracellulaire a provoqué une exacerbation
    de la toxicité du 1,2-dichloropropane, alors qu'un traitement
    préalable par des précurseurs de la synthèse du glutathion réduisait
    cette toxicité. Ces résultats montrent que le glutathion a un effet
    protecteur vis-à-vis des propriétés toxiques du 1,2-dichloropropane.

    1.3  Effets sur les êtres vivant dans leur milieu naturel

         On n'a pas déterminé la CE50 pour les algues d'eau douce car
    la volatilisation du composé à partir de la solution d'épreuve rend

    cette détermination difficile. La toxicité aiguë du 1,2-
    dichloropropane pour les invertébrés aquatiques et les poissons est
    faible à modérée; pour les invertébrés, les valeurs de la CL50 à
    48 h varient de 52 à > 100 mg/litre, tandis que la CL50 à 96 h pour
    les poissons se situe entre 61 et 320 mg/litre. Une épreuve de
    toxicité à court terme effectuée sur des vairons du genre
     Pimephales promelas a montré que la dose maximale sans effet était
    de 82 mg/litre. Lors d'une épreuve de 32 jours sur les larves de ce
    vairon, on a constaté que les paramètres biologiques les plus
    sensibles à la toxicité du 1,2-dichloropropane étaient la croissance
    des larves et leur survie. On estime que la concentration maximale
    acceptable de substance toxique est de 6 à 11 mg/litre. Chez des
    poissons du genre  Pimelometopon on a constaté une inhibition de la
    croissance après exposition de 33 jours à une concentration de 164
    mg/litre.

         Le 1,2-dichloropropane est phytotoxique. 

         Des épreuves par contact effectuées sur quatre espèces de
    lombrics ont montré que la CL50 se situait entre 44 et 84 µg/cm2
    (valeur moyenne) de papier filtre. Sur sol artificiel, les valeurs
    de la CL50 oscillaient entre 3880 et 5300 mg/kg de sol (en poids
    sec). 

    1.4  Effets sur les animaux d'expérience et les systèmes d'épreuve
         in vitro

         Chez les animaux d'expérience, la toxicité aiguë par voie orale
    de ce composé est faible. Ainsi, la DL50 par voie orale est de 1,9
    g/kg de poids corporel pour le rat et la DL50 cutanée est de 8,75
    mg/kg de poids corporel chez le lapin.

         Des études de toxicité de courte durée comportant
    l'administration de 1,2-dichloropropane par voie orale à des souris
    et à des rats ont montré qu'à des doses quotidiennes égales ou
    supérieures à 250 mg/kg de poids corporel, il y avait inhibition de
    la croissance, apparition de signes cliniques d'intoxication
    correspondant à une dépression du système nerveux central et
    accroissement de la mortalité. A la dose quotidienne de 250 mg/kg
    pendant dix jours, on a noté chez des rats une modification des
    enzymes sériques trahissant une légère hépatotoxicité, la dose sans
    effet observable étant de 100 mg/kg par jour.

         Lors d'une étude par inhalation de 13 semaines effectuée sur
    des souris (à la dose maximale de 681 mg/m3), on n'a pas observé
    d'effets nocifs. Lors d'une étude analogue sur des rats exposés à
    des doses de 68,1, 227 et 681 mg/m3, on a observé une réduction du
    poids corporel et des lésions mineures du tissu des fosses nasales
    dans les groupes soumis aux deux plus fortes doses. 

         Lors d'une étude de reproduction portant sur deux générations
    de rats, on a donné aux animaux une eau de boisson contenant des
    concentrations de 1,2-dichloropropane respectivement égales à 0,024,
    0,1, 0,24% (soit l'équivalent de 33,6, 140 et 336 mg/kg de poids
    corporel par jour); il en est résulté une réduction du gain de poids
    maternel et une diminution de la consommation d'eau, à la dose
    médiane et à la plus forte dose. Chez les animaux nouveaunés, le
    poids corporel était réduit à la dose la plus forte. La dose sans
    effet nocif observable s'établissait respectivement à 33,6 et 140
    mg/kg de poids corporel par jour pour les effets toxiques sur la
    mère et sur la fonction de reproduction.

         Les études ne mettent en évidence aucune activité tératogène du
    1,2-dichloropropane à des doses orales allant jusqu'à 125 mg/kg de
    poids corporel chez le rat et 150 mg/kg de poids corporel chez le
    lapin. Toutefois à ces doses, on a observé une toxicité du produit
    pour les mères et pour les foetus, à en juger d'après certains
    signes cliniques témoignant d'une atteinte du système nerveux
    central, la réduction du gain de poids maternel et, chez les foetus,
    un retard d'ossification. La dose sans effet observable est égale à
    30 mg/kg de poids corporel par jour chez le rat et à 50 mg/kg de
    poids corporel par jour chez le lapin. 

         La plupart des études ont mis en évidence une mutagénicité du
    1,2-dichloropropane chez les bactéries avec ou sans activation
    métabolique, mais il est vrai qu'on avait utilisé des doses
    extrêmement élevées (jusqu'à 10 mg/boîte). Le 1,2-dichloropropane
    provoque des aberrations chromosomiques et des échanges entre
    chromatides soeurs dans les cellules ovariennes de hamster chinois;
    il y a également accroissement des échanges entre chromatides soeurs
    dans des cellules V79 de hamster chinois en présence de 1,2-
    dichloropropane. Des lymphocytes humains ont été cultivés en
    présence ou en l'absence d'un système métabolisant de foie de rat;
    on a constaté que ces cellules fixaient la thymidine tritiée de la
    même manière que les cultures témoins et qu'elles présentaient la
    même viabilité. Une épreuve de mutation létale récessive liée au
    sexe effectuée sur  Drosophila melanogaster a donné des résultats
    négatifs. Une épreuve de létalité dominante chez des rats soumis
    pendant 14 semaines à des doses de 1,2-dichloropropane mêlé à leur
    eau de boisson, puis accouplés au cours des deux semaines suivantes,
    a donné des résultats également négatifs.

         Lors d'une étude de cancérogénicité effectuée sur des souris,
    on a administré aux animaux par gavage, 125 ou 250 mg de 1,2-
    dichloropropane par kg de poids corporel; on a observé une
    augmentation, liée à la dose, de l'incidence des adénomes
    hépatiques. L'incidence des adénomes était plus élevée dans les
    groupes traités que dans le groupe témoin mais elle se situait
    malgré tout dans les limites normales pour les témoins historiques. 

         Chez des rats soumis à des doses de 125 et de 250 mg/kg de
    poids corporel (femelles) ou 62 et 125 mg/kg de poids corporel
    (mâles) par gavage, cinq jours par semaines pendant 113 semaines, on
    a noté une légère augmentation dans l'incidence des adénocarcinomes
    mammaires chez les femelles soumises à la dose la plus forte,
    augmentation qui était supérieure aux limites normales pour les
    témoins historique.

    1.5  Effets sur l'homme

         Il est improbable que la population générale soit exposée au
    1,2-dichloropropane par l'intermédiaire de l'air et de l'eau, sauf
    dans les zones où l'on utilise largement le 1,2-dichloropropoane ou
    le "D/D MIX" à des fins agricoles. Les résidus de 1,2-
    dichloropropane présents dans les plantes vivrières sont
    généralement inférieurs à la limite de détection. L'exposition étant
    faible, on peut considérer que le risque est négligeable pour la
    population générale.

         On a signalé plusieurs cas d'intoxication aiguë accidentelle ou
    intentionnelle (suicide) dus à une surexposition au 1,2-
    dichloropropane. Les effets en étaient essentiellement observables
    au niveau du système nerveux central, du foie et des reins. On a
    également fait état d'une anémie hémolytique et d'une coagulation
    intravasculaire disséminée. Dans un cas, le malade se trouvait dans
    un état de délire qui a évolué vers un état de choc irréversible et
    une insuffisance cardiaque fatale.

         Il peut y avoir exposition professionnelle par voie cutanée ou
    respiratoire. On a fait état de plusieurs cas de dermatite ou de
    sensibilisation cutanée chez des travailleurs qui utilisaient des
    solvants contenant du 1,2-dichloropropane.

    2.  Conclusions

    *    Population générale: L'exposition de la population générale au
         1,2-dichloropropane à partir de l'air ou de la nourriture est
         faible, voire inexistante. Toutefois dans certains secteurs, il
         peut y avoir exposition en cas de contamination des eaux
         souterraines.

    *    Exposition professionnelle: Moyennant de bonnes méthodes de
         travail et des précautions d'hygiène et de sécurité, il est peu
         probable que l'utilisation du 1,2-dichloropropane comporte un
         risque pour les personnes qui y sont exposées de par leur
         profession.

    *    Environnement: Il est improbable que le 1,2-dichloropropane
         s'accumule dans l'environnement à des concentrations
         écologiquement nocives lorsqu'on l'utilise à la dose
         recommandée. Il est également improbable qu'il produise des
         effets nocifs sur les populations d'organismes terrestres ou
         aquatiques.

    3.  Recommandations

    *    Il faudrait évaluer la toxicité aiguë par voie respiratoire
         ainsi que le pouvoir irritant pour les yeux et la peau et le
         pouvoir sensibilisant cutané de ce composé.

    *    Lorsqu'on manipule du 1,2-dichloropropane il faut prendre des
         mesures de sécurité appropriées afin d'éviter toute exposition
         supérieure à la concentration maximale admissible. 

    RESUME ET EVALUATION, CONCLUSIONS, ET RECOMMANDATIONS
    "MIX D/D"

    1.  Résumé et évaluation

    1.1  Usage, destinée et concentrations dans l'environnement

         Le mélange technique de dichloropropènes et de dichloropropane
    (désignés dans la suite du texte par l'abréviation "MIX D/D") est un
    liquide limpide de couleur ambrée doté d'une odeur piquante; sa
    tension de vapeur est de 35 mmHg à 20 °C et il est soluble dans les
    solvants halogénés, les esters et les cétones. 

         Le MIX D/D présente une composition caractéristique, à savoir:
    au moins 50% de 1,3-dichloropropènes (proportion des isomères  cis-
    et  trans-, environ 1/1), les autres constituants principaux étant
    le 1,2-dichloropropane et les composés voisins. On l'a beaucoup
    utilisé comme nématocide en application sur le sol avant la
    plantation.

         Le transport, la distribution et la destinée des principaux
    constituants du MIX D/D dans l'air, l'eau et le sol sont décrits à
    la section 4 des chapitres consacrées au 1,3-dichloropropène et au
    1,2-dichloropropane.

         Le 1,2-dichloropropane provenant du MIX D/D présent dans le sol
    a une certaine tendance à contaminer l'eau des puits et les eaux
    souterraines en général, par suite d'un phénomène de lessivage. Lors
    d'une opération de forage à des fins d'irrigation en Europe
    occidentale (68 m de profondeur) on a constaté que les
    concentrations moyennes de 1,2-dichloropropane à différentes
    profondeurs variaient entre 0,8 et 8,5 µg/litre, la concentration la
    plus élevée étant de 165 µg/litre.

         Il est peu probable que les cultures fixent en proportion
    importante les constituants du MIX D/D (voir les autres chapitres de
    la présente monographie). Il est également peu probable que ces
    constituants subissent une bioaccumulation du fait que leur
    coefficient de partage entre l'octanol et l'eau (log Kow) est
    faible et que leur solubilité dans l'eau est relativement forte. 

    1.2  Cinétique et métabolisme

         On n'a pas procédé à des études métaboliques sur le MIX D/D.
    Les deux principaux constituants, le 1,3-dichloropropène et le 1,2-
    dichloropropane sont rapidement éliminés, essentiellement dans
    l'urine et en moindre proportion, dans l'air expiré. Les
    constituants du MIX D/D sont métabolisés selon un processus qui 

    comporte une oxydation et une conjugaison. Les principaux
    métabolites urinaires sont des acides mercapturiques. 

    1.3  Effets sur les organismes vivants dans leur milieu naturel

         Le MIX D/D est modérément toxique pour les poissons; les
    valeurs de la CL50 à 96 h varient de 1 à 6 mg/litre. La toxicité
    du MIX D/D est largement imputable au 1,3-dichloropropène. 

         Lorsqu'on utilise ce mélange aux doses recommandées, ses effets
    principaux consistent dans une diminution passagère (moins de sept
    jours) des populations de champignons terricoles et une inhibition
    de l'oxydation de ions ammonium en nitrates. Le MIX D/D est toxique
    pour les bactéries nitrifiantes. Peu après la disparition du MIX
    D/D, le sol est recolonisé par les bactéries. Lors d'essais en
    situation réelle, on a constaté que le MIX D/D, appliqué à raison de
    600 litres/hectare, provoquait la destruction des invertébrés
    terricoles. Il faut de 6 à 24 mois pour que la recolonisation
    s'effectue.

         Le MIX D/D est extrêmement phytotoxique. 

    1.4  Effets sur les animaux d'expérience et les systèmes d'épreuve
         in vitro

         Le MIX D/D présente une toxicité aiguë modérée à forte pour les
    animaux de laboratoire. Chez le rat et la souris, la DL50 par voie
    orale varie de 132 à 300 mg/kg de poids corporel. En ce qui concerne
    la DL50 par voie cutanée, les valeurs pour le rat et le lapin sont
    respectivement de 779 et de 2100 mg/kg de poids corporel. Chez le
    rat, la CL50 à 4 h par inhalation est approximativement égale à
    4540 mg/m3. En cas d'exposition, les signes cliniques observés
    sont ceux d'une dépression du système nerveux central. Le MIX D/D
    est fortement irritant pour les yeux et la peau et il est doté d'un
    pouvoir sensibilisateur cutané modéré. 

         Les résultats des études toxicologiques à court terme
    effectuées sur des rats et des chiens sont insuffisants pour qu'on
    puisse déterminer convenablement la toxicité du MIX D/D, car aux
    doses relativement faibles que l'on a étudiées, on n'observe pas
    d'effets biologiquement significatifs. Plusieurs études d'inhalation
    de courte durée (corps entier) ont été effectuées sur des rats. A
    des doses allant jusqu'à 145 mg/m3, le MIX D/D n'a pas produit
    d'effets toxiques. A partir de 1362 mg/m3, les effets toxiques
    étaient évidents et correspondaient à une dépression du système
    nerveux central. L'exposition des animaux à la dose de 443 mg/m3
    pendant 10 semaines a entraîné une réduction du gain de poids et une
    augmentation du poids des reins.

         Une étude tératologique comportant l'administration de MIX D/D
    par voie orale n'a pas permis, en raison de ses insuffisances,
    d'évaluer le pouvoir tératogène de ce composé chez le rat. 

         Lors d'une étude d'inhalation chez le rat destinée à étudier
    les effets du MIX D/D sur la fécondité des mâles et des femelles, on
    n'a pas observé d'effets à des doses allant jusqu' 443 mg/m3 sur
    une durée de dix semaines. Il n'a pas été possible de procéder à une
    évaluation complète des effets du MIX D/D sur la reproduction, en
    raison du caractère incomplet du protocole de ces études.

         Le MIX D/D s'est révélé mutagène pour les souches TA100 et
    TA1535 de  Salmonella typhimurium ainsi que pour la souche WP2 HCR
     d'Escherichia coli, sans activation métabolique. Cet effet n'a pas
    été observé sur les souches TA98, TA1537 et TA1538 de salmonelles.

         Lors d'une étude à long terme, au cours de laquelle on avait
    administré à des rats un régime alimentaire contenant jusqu'à 120
    mg/kg (soit 6 mg/kg de poids corporel) pendant deux ans, on n'a pas
    observé d'effets toxiques ou cancérogènes. 

    1.5  Effets sur l'homme

         Le MIX D/D n'est plus guère utilisé et par conséquent il est
    peu probable que la population générale puisse être exposée par
    l'intermédiaire de l'air, de l'eau et des aliments. L'exposition des
    personnels qui remplissent les fûts ou qui sont chargés de
    l'épandage du produit s'est en général située en-dessous de 4,5 mg
    de 1,3-dichloropropène/m3 lorsque l'on respectait la marche à
    suivre recommandée; dans d'autres cas, on a mesuré des
    concentrations allant jusqu'à 36,32 mg/m3.

         On a cité un cas d'intoxication aiguë mortelle par suite de
    l'ingestion accidentelle de MIX D/D.

    2.  Conclusions

    *    Population générale. Etant donné que l'on l'utilise plus guère
         le MIX D/D, l'exposition de la population générale au 1,3-
         dichloropropène par l'intermédiaire de l'air, de l'eau et des
         aliments est négligeable, mais dans certaines zones, il peut y
         avoir exposition au 1,2-dichloropropane en cas de contamination
         des eaux souterraines.

    *    Exposition professionnelle. Lors du remplissage des fûts et de
         l'épandage du MIX D/D, il peut y avoir exposition des
         personnels concernés au 1,3-dichloropropène, à des
         concentrations qui dépassent les valeurs maximales admissibles,
         en particulier sous les climats chauds.

    *    Environnement. Il est peu probable que le MIX D/D atteigne dans
         l'environnement des concentrations biologiquement nocives pour
         la faune et la flore terrestre ou aquatique, lorsqu'on utilise
         la dose recommandée. Il est également improbable qu'il puisse
         exercer des effets nocifs durables sur les organismes vivants
         dans leur milieu naturel. 

    3.  Recommandations

    *    Le MIX D/D ne doit pas être utilisé comme fumigant pour traiter
         le sol du fait qu'il risque de passer dans les eaux
         souterraines par lessivage.

    *    Dans les zones où l'on a utilisé du MIX D/D, il faut surveiller
         les eaux de surface et les eaux souterraines à la recherche de
         résidus éventuels.

    RESUMEN Y EVALUACION, CONCLUSIONES, Y RECOMENDACIONES
    1,3-DICLOROPROPENO

    1.  Resumen y evaluación

    1.1  Uso, destino y niveles en el medio ambiente

         El "1,3-dicloropropeno" se introdujo en 1956 como parte de una
    mezcla, que contenía 1,3-dicloropropeno, 1,2-dicloropropano y otros
    hidrocarburos halogenados, y se ha utilizado ampliamente en la
    agricultura como fumigante del suelo que se destina a nuevas
    plantaciones para combatir los nematodos de las hortalizas, las
    papas y el tabaco. Se aplica fundamentalmente mediante inyección en
    el suelo. La formulación comercial del 1,3-dicloropropeno es una
    mezcla de isómeros  cis y  trans (aproximadamente en proporciones
    iguales), que forman un líquido entre incoloro y ámbar, con un olor
    penetrante e irritante, parecido al del cloroformo. La presión del
    vapor es de 3,7 kPa a 20 °C. El producto técnico tiene una pureza
    del 92% y puede contener varias impurezas, como 1,2-dicloropropano.
    El log P del coeficiente de reparto octanol/agua es de 1,98.

         En el aire, la descomposición del 1,3-dicloropropeno tiene
    lugar sobre todo por reacción con radicales libres y con el ozono.
    La semivida de los isómeros  cis y  trans en la reacción con
    radicales libres es de 12 y 7 horas respectivamente, y en la
    reacción con el ozono de 52 y 12 días respectivamente. La
    fototransformación directa parece ser insignificante, pero puede
    aumentar en presencia de partículas atmosféricas.

         En el agua, el 1,3-dicloropropeno tiende a desaparecer con
    rapidez, debido a su solubilidad relativamente baja en ella y su
    elevada volatilidad; se han notificado semividas de menos de 5 h. 

         La distribución del 1,3-dicloropropeno en los compartimentos
    del suelo depende de la presión del vapor, el coeficiente de
    difusión, la temperatura y el contenido de humedad del mismo. En la
    persistencia del 1,3-dicloropropeno en el suelo influyen la
    volatilización, la transformación química y biológica, la
    transformación fotoquímica y la absorción por los organismos. Los
    mecanismos más importantes de dispersión y dilución en el medio
    ambiente son la volatilización y la difusión en la fase de vapor. 

         La transformación del 1,3-dicloropropeno se produce
    inicialmente por hidrólisis a 3-cloroalilalcohol y luego por
    transformación microbiana a 3-cloroacroleína y ácido 3-
    cloroacrílico. En un estudio de laboratorio, la semivida de la
    hidrólisis de los isómeros  cis y  trans del 1,3-dicloropropeno a
    15 °C y 29 °C fue de 11,0 y 2,0 días respectivamente para el isómero
     cis y de 13,0 y 2,0 días para el isómero  trans. En el suelo, con

    un pH 7 y una temperatura de 25 °C, la semivida de la hidrólisis fue
    de 4,6 días para ambos isómeros. Debido a su desaparición
    relativamente rápida del suelo, no es probable que se acumulen
    residuos cuando se aplica el fumigante con la dosis y la frecuencia
    recomendadas. 

         El 1,3-dicloropropeno puede desplazarse en el suelo, sobre todo
    si es arenoso, de textura gruesa y con un contenido bajo de humedad.
    El desplazamiento descendente se ve favorecido por el cultivo
    profundo de los suelos con escasa porosidad. Se ha detectado 1,3-
    dicloropropeno en "aguas subterráneas altas" (hasta 2 m por debajo
    de la superficie), pero no en las profundas, que son las que suelen
    utilizarse para beber.

         Los cultivos pueden absorber 1,3-dicloropropeno. Sin embargo,
    no es probable que aparezca una cantidad apreciable de residuos en
    las plantas cultivadas comestibles, que se suelen sembrar cuando ya
    ha desaparecido la mayor parte del fumigante. 

         Es poco probable la bioacumulación de 1,3-dicloropropeno,
    debido a su solubilidad relativamente alta en agua (< 1 g/kg), al
    bajo log P del coeficiente de reparto octanol/agua y a la
    eliminación rápida en mamíferos y otros organismos. 

    1.2  Cinética y metabolismo

         El 1,3-dicloropropeno se elimina rápidamente tras su
    administración oral a roedores. La principal vía de eliminación es
    la orina, donde a ella el 81% de los isómeros  cis y el 56% de los
     trans se eliminan en las 24 horas siguientes a la dosificación. La
    semivida de la eliminación en la orina es de 5 a 6 horas. La
    eliminación fecal es escasa. El anhídrido carbónico representa el 4
    y el 24%, respectivamente, de los isómeros  cis y  trans del 1,3-
    dicloropropeno eliminados. Las concentraciones en los tejidos tras
    la administración oral son bajas; los niveles residuales más
    elevados se encuentran en la pared estomacal, seguidos por
    cantidades más bajas en los riñones y la vejiga.

         No se ha detectado en la orina la presencia de 1,3-
    dicloropropeno inalterado. La glutatión- S-alquiltransferasa actúa
    sobre los isómeros  cis y  trans formando ácidos mercaptúricos,
    que se excretan por la orina. El isómero  trans se conjuga de 4 a 5
    veces más lentamente que el  cis. El principal metabolito urinario
    en ratas y ratones es la  N-acetil- S-(3-cloroprop-2-enil)L-
    cisteína; este metabolito se puede utilizar para la vigilancia
    biológica en el ser humano. Para el isómero  cis se ha identificado
    una segunda ruta metabólica de menor importancia, en la que se
    produce una monooxigenación a óxido de  cis-1,3-dicloropropeno, que
    se puede conjugar también con el glutatión. La elevada proporción
    del isómero  trans que se encuentra en el aire expirado procede de

    una ruta metabólica distinta de la conjugación, que tiene una
    especificidad más elevada para el isómero  trans que para el  cis.

         La exposición de ratas al 1,3-dicloropropeno por inhalación no
    produce un aumento de la concentración en sangre proporcional a la
    dosis. A una dosis de 408,6 mg/m3 (90 ppm), disminuyeron la
    frecuencia respiratoria y el volumen respiratorio por minuto, y la
    saturación del metabolismo se produjo a 1362 mg/m3 (300 ppm). Los
    isómeros  cis y  trans se eliminaron rápidamente de la sangre,
    siendo la semivida de la eliminación de 3 a 6 minutos para
    concentraciones inferiores a 1362 mg/m3, pero considerablemente
    más larga (33-43 min.) a concentraciones más elevadas. 

    1.3  Efectos en los seres vivos del medio ambiente

         Los valores de la CE50 para el crecimiento (96 h) del alga de
    agua dulce  Selenastrum capricornutum y la diatomea de los
    estuarios  Skeletoneria costatum son 4,95 mg/litro y 1 mg/litro
    respectivamente. La toxicidad aguda (CL50 a las 96 h) del 1,3-
    dicloropropeno para los peces es del orden de 1 a 7,9 mg/litro. En
    una prueba en embriones-larvas de  Pimephales promelas, el nivel
    máximo sin efectos fue de 0,24 mg/litro. Estos datos, junto con el
    hecho de que no es probable que el 1,3-dicloropropeno persista en el
    agua, indican que el peligro para los peces lo constituyen los
    efectos tóxicos agudos, con escasas posibilidades de efectos
    adicionales debidos a la exposición durante un tiempo prolongado. 

          En dosis de 30 a 60 mg/kg, el 1,3-dicloropropeno puede reducir
    la concentración de hongos y la tasa de actividad enzimática
    microbiana, pero el efecto no suele ser duradero (< 7 días) y no se
    produce en todos los tipos de suelos. En algunos estudios, aumentó
    significativamente el número de microorganismos tras la aplicación.

         El 1,3-dicloropropeno es fitotóxico, pero su toxicidad para las
    abejas es escasa. Utilizando una técnica de espolvoreo, la DL50 a
    las 48 horas fue de 6,6 µg/abeja. Las aves tienen una sensibilidad
    relativamente baja al 1,3-dicloropropeno. Para el pato real  (Anas
     platyrhynchos) y la codorniz  (Colinus virginianus) se ha
    informado de CL50 (8 días) de > 10 g/kg de la dieta.

    1.4  Efectos en los animales de experimentación y en sistemas de
         prueba in vitro

         La toxicidad aguda por vía oral del 1,3-dicloropropeno en
    animales es de moderada a alta. Se han notificado valores de la
    DL50 en ratas que oscilan entre 127 y 713 mg/kg de peso corporal.
    Los valores de la DL50 por vía oral en ratas para los isómeros
     cis y  trans fueron de 85 y 94 mg/kg de peso corporal,
    respectivamente. 

         La exposición aguda cutánea es moderadamente tóxica. En ratas y
    conejos se ha reportado de una DL50 de 423 mg/kg y 504 mg/kg de
    peso corporal, respectivamente. Los valores de la DL50 para los
    isómeros  cis y  trans fueron 1090 y 1575 mg/kg de peso corporal,
    respectivamente.

         La exposición por inhalación (4 h) en ratas dio como resultado
    valores de la DL50 de 3310 mg/m3 (729 ppm) para el 1,3-
    dicloropropeno; 3042 mg/m3 -3514 mg/m3 para el isómero  cis y
    4880 mg/m3 - 5403 mg/m3 para el  trans.

         La intoxicación aguda afectó el sistema nervioso central y el
    aparato respiratorio.

         En pruebas cutáneas y de irritación ocular con conejos se
    observaron reacciones graves, pero la recuperación se produjo en un
    período de 14-21 días. Los resultados de las pruebas de
    sensibilización en cobayos fueron positivos. 

         Se han realizado varios estudios de toxicidad por inhalación
    durante un tiempo breve en ratones, ratas, cobayos, conejos y
    perros. En los ratones los órganos afectados fueron la mucosa nasal
    y la vejiga urinaria. Se observó degeneración del epitelio olfatorio
    e hiperplasia del epitelio respiratorio. Se detectó hiperplasia del
    epitelio de transición de la vejiga urinaria. En ratones se puede
    estimar que el nivel sin efectos observados (NOEL) es de 136 mg/m3
    (30 ppm).

         En ratas también se han detectado cambios degenerativos
    similares en el epitelio olfatorio, así como hiperplasia. En un
    estudio bien diseñado se encontró un valor del NOEL para el 1,3-
    dicloropropeno de 45,4 mg/m3, siendo el valor del NOEL para el
    isómero  cis de 136 mg/m3.

         En un estudio de administración por vía oral durante 90 días a
    ratas, el NOEL fue de 3 mg/kg de peso corporal. El único efecto
    observado con la dosis inmediatamente superior, de 10 mg/kg de peso
    corporal, fue un aumento relativo del peso de los riñones en los
    machos.

         En un estudio de inhalación sobre la reproducción de dos
    camadas en dos generaciones de ratas, las dosis de hasta 408,6
    mg/m3 (90 ppm) no produjeron efectos adversos sobre los parámetros
    de la reproducción examinados. Sin embargo, la dosis más alta, de
    408,6 mg/m3, indujo toxicidad materna, que se puso de manifiesto
    por la disminución del crecimiento y por cambios histopatológicos de
    la mucosa nasal. Se estableció un NOEL para la toxicidad materna de
    136,2 mg/m3 (30 ppm). 

         En estudios de teratogenicidad por inhalación en ratas y
    conejos, el 1,3-dicloropropeno no mostró potencial teratogénico a
    niveles de exposición de hasta 1362 mg/m3, pero se observó
    embriotoxicidad (reducción del tamaño de la camada y aumento del
    índice de reabsorciones) en ratas. Con dosis de 544,8 mg/m3 (120
    ppm) o superiores se advirtió toxicidad materna tanto en ratas como
    en conejos.

         En la mayor parte de los estudios, el 1,3-dicloropropeno  cis 
    y  trans y la mezcla de ambos fueron mutagénicos en bacterias, con
    y sin activación metabólica. Se encontró que el 1,3-dicloropropeno
    puro y el  cis-1,3-dicloropropeno puro carecían de efecto sobre las
    bacterias. Se demostró que el glutatión impedía la actividad
    mutagénica del 1,3-dicloropropeno en bacterias. En un ensayo de
    mutación genética con células de hámster chino V79, así como en la
    prueba del locus HPRT de ovario de hámster chino, el  cis-1,3-
    dicloropropeno dio un resultado negativo. 

         El 1,3-dicloropropeno  cis y  trans indujo una síntesis no
    programada de ADN en células S3 HeLa. En hepatocitos de rata, el
    1,3-dicloropropeno no produjo una reparación significativa del ADN.
    En el ensayo del locus rec con microsomas de la cepa H17 de
     Bacillus subtilis con activación metabólica, el 1,3-dicloropropeno
    dio resultado positivo.

         En células de ovario de hámster chino, el 1,3-dicloropropeno
     cis y  trans indujo daños cromosómicos en condiciones de
    activación metabólica, pero en otro estudio también dio resultado
    positivo sin que hubiera activación. El isómero  cis no indujo
    lesiones cromosómicas en células hepáticas de rata, pero sí un
    intercambio de cromátidas hermanas en células de ovario de hámster
    chino con activación metabólica y sin ella, y en células de hámster
    chino V79 sin activación.

         En una prueba con micronúcleos de médula ósea en ratones, y en
    otra de letalidad recesiva ligada al sexo en  Drosophila
     melanogaster, el 1,3-dicloropropeno fue negativo. 

         Se realizaron estudios de carcinogenicidad en ratones y ratas.
    Se administró 1,3-dicloropropeno de calidad técnica (con un 1% de
    epiclorhidrina) mediante sonda durante dos años. En los ratones se
    observó un aumento significativo de la hiperplasia epitelial y los
    carcinomas celulares transitorios en la vejiga urinaria, una
    incidencia mayor de tumores pulmonares, un ligero aumento de tumores
    hepáticos y una mayor proporción de hiperplasia epitelial y
    papilomas o carcinomas de las células escamosas de la parte cardíaca
    del estómago.

          En estudios de inhalación de dos años se investigó la
    carcinogenicidad del 1,3-dicloropropeno (sin epiclorhidrina) en
    ratones y ratas. En ratones se detectó una mayor incidencia de
    hiperplasia en la vejiga urinaria, la parte cardíaca del estómago y
    la mucosa nasal. Aumentó la incidencia de los tumores pulmonares
    benignos. También se observaron en ratas algunos cambios tóxicos en
    la mucosa olfativa de la cavidad nasal, pero sin aumento de la
    incidencia de tumores.

         En un estudio de administración con sonda se puso de manifiesto
    que la epiclorhidrina producía tumores en la parte cardíaca del
    estómago, y en otro estudio de inhalación en ratas aparecieron
    tumores en la cavidad nasal; en el caso de la administración de 1,3-
    dicloropropeno por vía oral a ratones no se puede excluir un efecto
    carcinogénico sobre la vejiga urinaria. 

    Mecanismo de acción

         Dado que la principal ruta metabólica de eliminación del 1,3-
    dicloropropeno es mediante la conjugación con el glutatión, cabe
    esperar que las condiciones que alteran la concentración de
    glutatión (sulfhidrilo no proteico) en los tejidos puedan modificar
    los efectos del compuesto. El mismo 1,3-dicloropropeno agota el
    contenido de glutatión de diversos tejidos, especialmente los
    situados en puntos de entrada en el organismo, es decir, sobre todo
    la parte cardíaca del estómago y el hígado tras la administración
    con sonda y el tejido nasal después de la exposición por inhalación.
    Tras la inhalación de concentraciones de 1,3-dicloropropeno
    superiores a 22,7 mg/m3 (5 ppm) y 113,5 mg/m3 (25 ppm) se
    produjo, respectivamente, una disminución de los niveles de
    glutatión en el epitelio nasal y en la parte cardíaca del estómago
    en ratones.

         La toxicidad del 1,3-dicloropropeno en animales se produce con
    niveles de exposiciones que agotan el glutatión de los tejidos y la
    disminución previa de la concentración de éste la agrava. La
    inhalación durante un tiempo prolongado de concentraciones
    superiores a 90,8 mg/m3 (20 ppm) da lugar en ratones a
    degeneración e hiperplasia del epitelio nasal y gástrico, mientras
    que en ratas la inhalación durante un tiempo prolongado de una
    concentración de 272,4 mg/m3 (60 ppm) produce degeneración del
    tejido nasal.

         La función protectora del glutatión se ha puesto de relieve
    ulteriormente en estudios que han demostrado que la unión mediante
    enlaces covalentes del 14C-1,3-dicloropropeno a la parte cardíaca
    del estómago de ratón aumentaba a medida que disminuía el contenido
    de sulfhidrilo no proteico. De igual forma, en sistemas de prueba
     in vitro el glutatión mejoró notablemente la genotoxicidad del
    1,3-dicloropropeno y del óxido 1,3-dicloropropeno, su metabolito
    oxidativo secundario (citocromo P-450). 

    1.5  Efectos en el ser humano

         No es probable la exposición de la población general a través
    del aire, el agua o los alimentos.

         En los estudios realizados se ha puesto de manifiesto que la
    exposición profesional está en general por debajo de 4,54 mg/m3 (1
    ppm), pero también se han notificado niveles más elevados (hasta
    18,3 mg/m3 durante el llenado o el cambio de la boquilla). Es
    probable que la exposición profesional se produzca por inhalación y
    por vía cutánea. Tras la exposición aparece inmediatamente
    irritación de los ojos y de la parte superior de la mucosa
    respiratoria. La inhalación de aire con concentraciones de > 6810
    mg/m3 (> 1500 ppm) produjo signos y síntomas de intoxicación
    grave; las exposiciones más bajas dieron lugar a una depresión del
    sistema nervioso central y a la irritación del aparato respiratorio.
    La exposición cutánea produjo una irritación grave de la piel. 

         Se notificó que un grupo de aplicadores de 1,3-dicloropropeno
    tuvieron algunos cambios en las funciones renal y hepática al final
    de la temporada de aplicación. Sin embargo, se ha rebatido la
    relación causa-efecto.

         Se han producido algunos casos de intoxicación con
    hospitalización de los afectados, que presentaban signos y síntomas
    de irritación de la membrana mucosa, malestar torácico, dolor de
    cabeza, náuseas, vómitos, mareos y, en ocasiones, pérdida del
    conocimiento y disminución de la libido. Se han atribuido tres casos
    de enfermedades malignas sanguíneas a una sobreexposición accidental
    anterior al 1,3-dicloropropeno, pero la relación causa-efecto sigue
    siendo dudosa.

         Se comparó el estado de fecundidad de un grupo de personas que
    trabajaban en la producción de compuestos clorados de tres carbonos
    con otro testigo. No se demostró la existencia de una asociación
    entre la disminución de la fecundidad y la exposición. 

    2.  Conclusiones

    Población general: A la vista del grado de exposición bajo o nulo
    al 1,3-dicloropropeno, el riesgo para la población general es
    insignificante.

    Exposición profesional: Cuando no se adoptan las precauciones
    adecuadas de seguridad, las actividades de llenado y aplicación en
    el campo pueden dar lugar a una exposición del operador a
    concentraciones que superan el máximo permisible. 

    Medio ambiente: Siempre que se utilice el 1,3-dicloropropeno en la
    proporción recomendada, no es probable que se alcancen niveles
    importantes para el medio ambiente, y tampoco es probable que
    produzca efectos secundarios sobre poblaciones de seres vivos
    terrestres y acuáticos.

    3.  Recomendaciones

    *    Las actividades de llenado y la aplicación en el campo del 1,3-
         dicloropropeno sólo deben realizarse tomando las precauciones
         de seguridad adecuadas, a fin de tener la garantía de que los
         niveles de exposición no exceden las concentraciones máximas
         permisibles de este producto.

    *    Se deben realizar estudios a fin de investigar el destino
         metabólico del isómero  trans del 1,3-dicloropropeno en
         mamíferos y la posible función que los metabolitos oxidativos
         de este isómero pueden tener como intermediarios en la
         toxicidad del 1,3-dicloropropeno.

    *    La glutatión transferasa interviene en el efecto protector del
         glutatión frente a la toxicidad del 1,3-dicloropropeno. Se
         recomienda la realización de estudios que permitan comparar la
         cinética enzimática relativa de la glutatión  S-transferasa
         humana de diversos tejidos con la actividad enzimática de
         tejidos animales comparables.

    *    Se deben agrupar y publicar en revistas con una difusión amplia
         los datos disponibles acerca de la función protectora del
         glutatión.

    *    Parte de la genotoxicidad del dicloropropeno se debe al
         metabolismo oxidativo. Se recomienda la realización de estudios
         para identificar la isoenzima del citocromo P-450 que lleva a
         cabo esta acción y comparar su actividad con la de las
         isoenzimas del citocromo P-450 humano.

    *    Hay que aclarar la confusa función de la epiclorhidrina en los
         estudios de carcinogenicidad por vía oral con sonda. 

    RESUMEN Y EVALUACION, CONCLUSIONES Y RECOMENDACIONES
    1,2-DICLOROPROPANO

    1.  Resumen y evaluación

    1.1  Uso, destino y niveles en el medio ambiente

         El 1,2-dicloropropano es un líquido con un punto de ebullición
    de 96,8 °C y una presión del vapor de 42 mm de Hg a 20 °C. Es
    soluble en agua, etanol y éter etílico. Al calentarlo desprende
    vapores de fosgeno enormemente tóxicos. El log P del coeficiente de
    reparto octanol/agua es de 2,28.

         Es una sustancia que se usa en el acabado de muebles, líquidos
    de limpieza en seco, decapantes para pinturas, tratamiento de la
    cola, desengrasado de metales, tratamiento del petróleo y como
    ingrediente en la fabricación de caucho y de cera y como producto
    químico intermedio en la fabricación de tetracloroetileno y
    tetracloruro de carbono. Forma parte de la mezcla D/D, utilizada
    como fumigante antes de la siembra.

         Se han determinado las concentraciones de 1,2-dicloropropano en
    el aire de las ciudades, con 1,2 µg/m3 (valor medio), 0,021-0,040
    µg/m3 y 0,0065-1,4 µg/m3 en Filadelfia, Portland y Japón,
    respectivamente. Su descomposición en la atmósfera es lenta; en
    función de su reacción con los radicales oxhidrilos, la semivida del
    1,2-dicloropropano fue de > 313 días. Probablemente el proceso
    predominante en su descomposición es la fototrans-formación. Para
    que ésta sea apreciable es necesario que haya adsorción sobre
    material particulado. Es probable que la volatilización sea la
    principal vía de escape del agua. 

         En el suelo, los principales mecanismos de eliminación son la
    volatilización y la difusión. El 1,2-dicloropropano es persistente
    en el suelo. Más del 98% del aplicado a suelos de marga se recuperó
    a las 12-20 semanas del tratamiento. 

         En zonas en las que se ha utilizado la "mezcla D/D" para
    fumigar el suelo, el 1,2-dicloropropano puede contaminar por
    lixiviación las aguas subterráneas altas y profundas. En los Estados
    Unidos se han encontrado en el agua de pozo y la subterránea
    concentraciones de hasta 440 µg/litro y 51 µg/litro,
    respectivamente. En los Países Bajos se han medido concentraciones
    de hasta 160 µg/litro en agua de pozo, y se ha encontrado 1,2-
    dicloropropano a una profundidad de 13 metros.

         El 1,2-dicloropropano se puede ingerir con los cultivos
    comestibles, pero los residuos detectados eran bajos (< 0,01 mg/kg)
    y no parece que puedan tener significación biológica. 

         No es probable la bioacumulación de 1,2-dicloropropano, debido
    a su elevada solubilidad en agua (2,7 g/kg) y al bajo log P del
    coeficiente de reparto octanol/agua.

    1.2  Cinética y metabolismo

         El 1,2-dicloropropano administrado a ratas por vía oral se
    elimina rápidamente (80-90% en 24 horas). No existen grandes
    diferencias entre machos y hembras en cuanto a la cinética o la
    eliminación. La principal vía de eliminación es la orina,
    excretandose en 24 horas hasta la mitad de una dosis oral. Por las
    heces se elimina menos del 10%. Un tercio se expulsa en el aire
    expirado, en forma de anhídrido carbónico y como mezcla de productos
    volátiles. Las concentraciones en los tejidos son bajas,
    detectándose la más alta en el hígado. Tras la exposición de ratas
    por inhalación, también se produce una eliminación rápida; en la
    orina se expulsa el 55-65% de la dosis, y el 16-23% en el aire
    expirado. La semivida en la sangre es de 24-30 minutos. 

         No se ha encontrado en la orina 1,2-dicloropropano inalterado.
    Se han identificado tres metabolitos urinarios principales. Estos
    proceden de las vías oxidativa y de conjugación, que dan lugar a los
    mercapturatos,  N-acetil- S-(2-hidroxipropil)-L-cisteína,  N-
    acetil- S-(2-oxipropil)-L-cisteína y  N-acetil- S-(1-
    carboxietil)-L-cisteína. El 1,2-dicloropropano también se puede
    oxidar a lactato y dar anhídrido carbónico o acetil-CoA como
    producto final. 

         La administración de 1,2-dicloropropano por vía oral a ratas (2
    ml/kg) produjo una notable reducción de la concentración de
    glutatión en los tejidos. Había una correlación entre la pérdida de
    glutatión y las características de la toxicidad en el hígado, los
    riñones y los eritrocitos. La disminución previa del glutatión
    intracelular agravaba la toxicidad del 1,2-dicloropropano, mientras
    que un tratamiento anterior con precursores de la síntesis del
    glutatión mejoraba la toxicidad. Estos resultados demuestran el
    efecto protector del glutatión frente a la toxicidad del 1,2-
    dicloropropano.

    1.3  Efectos en los seres vivos del medio ambiente

         No se ha calculado la CE50 para las algas de agua dulce por
    las dificultades que plantea la volatilización del producto de la
    solución de prueba. La toxicidad aguda del 1,2-dicloropropano para
    los invertebrados acuáticos y los peces es de baja a moderada; los
    valores de la CL50 a las 48 h para los invertebrados oscila entre
    52 y > 100 mg/litro, y para los peces a las 96 h varía entre 61 y
    320 mg/litro. En las pruebas de toxicidad durante un período corto
    con  Pimephales promelas se calculó un nivel máximo sin efectos
    observados de 82 mg/litro. En una prueba de toxicidad de 32 días en

    las primeras fases de vida de la misma especie se puso de manifiesto
    que el crecimiento y la supervivencia de las larvas eran los
    parámetros más sensibles. La máxima concentración tóxica aceptable
    (MCTA) se estimó entre 6 y 11 mg/litro. A los 33 días de exposición
    a concentraciones de 164 mg/litro de 1,2-dicloropropano se advirtió
    inhibición del crecimiento en Cyprinodon variegatus.

         El 1,2-dicloropropano es fitotóxico.

         En las pruebas de contacto con cuatro especies de lombrices de
    tierra se obtuvo una CL50 de 44-84 µg/cm2 (valores medios) de
    papel de filtro. Los valores de la CL50 en suelo artificial fueron
    de 3880-5300 mg/kg de suelo (peso seco).

    1.4  Efectos en los animales de experimentación y en
    sistemas de prueba in vitro

         La toxicidad aguda por vía oral del 1,2-dicloropropano en
    animales de experimentación es baja. La DL50 por vía oral para la
    rata es de 1,9 g/kg de peso corporal, y por vía cutánea en conejos
    de 8,75 ml/kg de peso corporal.

         En los estudios de toxicidad oral durante un período corto en
    ratones y ratas se puso de manifiesto una inhibición del
    crecimiento, signos clínicos de toxicidad asociados con una
    depresión del sistema nervioso central y/o un aumento de la
    mortalidad con dosis de 250 mg/kg de peso corporal al día o
    superiores. En ratas con una dosis diaria de 250 mg/kg de peso
    corporal durante 10 días se observaron cambios en las enzimas del
    suero que indicaban una ligera hepatotoxicidad, con un NOEL de 100
    mg/kg al día. 

         En un estudio de inhalación durante 13 semanas en ratones
    (dosis máxima de 681 mg/m3) no se observaron efectos adversos. En
    un estudio similar en el que se expusieron ratas a 68,1, 227 ó 681
    mg/m3, se produjo una disminución del peso corporal y ligeras
    lesiones en el tejido nasal en los grupos con las dos dosis más
    elevadas.

         En un estudio de reproducción en dos generaciones, la
    exposición de ratas a proporciones de 1,2-dicloropropano en el agua
    de bebida del 0,024, el 0,1 y el 0,24% (equivalentes a 33,6, 140 y
    336 mg/kg de peso corporal al día) dio lugar a un menor aumento del
    peso corporal en la madre y a un consumo reducido de agua con las
    dosis media y alta. El peso corporal de los recién nacidos fue menor
    con las dosis más altas. Se estableció un NOAEL para la toxicidad en
    las madres y en la reproducción de 33,6 y 140 mg/kg de peso corporal
    al día, respectivamente. 

         En los estudios realizados no se observó actividad teratogénica
    alguna del 1,2-dicloropropano con dosis orales de hasta 125 mg/kg de
    peso corporal en la rata y 150 mg/kg de peso corporal en el conejo.
    Sin embargo, a estas dosis el 1,2-dicloropropano era tóxico para las
    madres y los fetos, como pusieron de manifiesto los signos clínicos
    asociados al sistema nervioso central, el menor aumento del peso
    corporal de las madres y el retraso de la osificación en los fetos.
    Los NOEL son de 30 y 50 mg/kg de peso corporal al día para la rata y
    el conejo, respectivamente. 

         En la mayor parte de los estudios con bacterias, con activación
    metabólica o sin ella, el 1,2-dicloropropano mostró efectos
    mutagénicos, pero se utilizaron dosis muy elevadas, de hasta 10
    mg/placa. En células de ovario de hámster chino se produjeron
    aberraciones cromosómicas e intercambio de cromátidas hermanas. En
    células V79 de hámster chino aumentó el intercambio de cromátidas.
    En un sistema  in vitro con linfocitos humanos, la absorción de
    timidina tritiada y la viabilidad de las células cultivadas con un
    sistema metabolizante hepático de la rata y sin él fueron análogas a
    las de los cultivos testigo. Los resultados de una prueba de
    letalidad recesiva ligada al sexo en  Drosophila melanogaster 
    fueron negativos. En una prueba de letalidad dominante en ratas, en
    la que se administró el 1,2-dicloropropano con el agua de bebida
    durante 14 semanas, seguidas de dos semanas de apareamiento, se
    obtuvieron resultados negativos. 

         En un estudio de carcinogenicidad en ratones se administraron
    125 ó 250 mg de 1,2-dicloropropano/kg de peso corporal mediante
    sonda, observándose un aumento relacionado con la dosis en la
    incidencia de adenomas hepáticos. Esta fue mayor en los grupos
    tratados que en el grupo testigo, pero se mantuvo dentro de los
    valores habituales de los testigos.

         La administración por sonda en ratas, a concentraciones de 125
    y 250 mg/kg de peso corporal (hembras) y 62 y 125 mg/kg de peso
    corporal (machos), cinco días a la semana durante 113 semanas,
    produjo en las hembras con la dosificación más alta un ligero
    aumento de la incidencia de adenocarcinomas de las glándulas
    mamarias, por encima de los valores habituales. 

    1.5  Efectos en el ser humano

         No es probable la exposición de la población general al 1,2-
    dicloropropano a través del aire y el agua, excepto en zonas con un
    uso abundante de 1,2-dicloropropano y de mezcla D/D en la
    agricultura. Los residuos de 1,2-dicloropropano en los cultivos
    comestibles se suelen mantener por debajo del límite de detección.
    En vista de estos bajos niveles de exposición, el riesgo para la
    población general es insignificante.

         Se han notificado varios casos de intoxicación aguda por 1,2-
    dicloropropano, debidos a una exposición excesiva accidental o
    intencionada (suicidio). Los efectos se han concentrado
    principalmente en el sistema nervioso central, el hígado y los
    riñones. También se ha descrito la aparición de anemia hemolítica y
    coagulación intravascular diseminada. En un caso, el delirio
    evolucionó hacia un shock irreversible, insuficiencia cardíaca y la
    muerte.

         Se puede producir exposición profesional a través de la piel o
    por inhalación. Se ha informado de varios casos de dermatitis y de
    sensibilización cutánea en trabajadores que utilizaban mezclas de
    disolventes con 1,2-dicloropropano.

    2.  Conclusiones

    *    Población general: La exposición de la población general al
         1,2-dicloropropano a partir del aire o los alimentos es baja o
         nula. Sin embargo, se puede producir en determinadas zonas una
         exposición debida a la contaminación de las aguas subterráneas.

    *    Exposición profesional: Con unas buenas prácticas de trabajo,
         medidas higiénicas y precauciones de seguridad, no es probable
         que el 1,2-dicloropropano represente un riesgo para las
         personas profesionalmente expuestas a él.

    *    Medio ambiente: Utilizado en las dosis recomendadas, no es
         probable que el 1,2-dicloropropano alcance niveles
         significativos en el medio ambiente. Tampoco es probable que
         tenga efectos adversos sobre las poblaciones de seres vivos
         terrestres y acuáticos.

    3.  Recomendaciones

    *    Se deben realizar estudios a fin de evaluar la toxicidad aguda
         por inhalación, la irritación ocular y cutánea y la posible
         sensibilización de la piel.

    *    Se han de adoptar las precauciones de seguridad apropiadas
         cuando se maneje 1,2-dicloropropano, a fin de evitar
         exposiciones que superen la concentración máxima permisible. 

    RESUMEN Y EVALUACION, CONCLUSIONES Y RECOMENDACIONES
    "MEZCLA D/D"

    1.  Resumen y evaluación

    1.1  Uso, destino y niveles en el medio ambiente

         La mezcla técnica de dicloropropenos y dicloropropano
    (abreviada en el presente texto como "mezcla D/D") es un líquido de
    color ámbar claro y olor acre; la presión del vapor es de 35 mm de
    Hg a 20 °C, y es soluble en disolventes halogenados, ésteres y
    cetonas.

         La "mezcla D/D" suele contener no menos del 50% de 1,3-
    dicloropropeno (con isómeros  cis y  trans en una proporción
    aproximada de 1:1), y los demás ingredientes principales son el 1,2-
    dicloropropano y compuestos afines. Esta mezcla se utiliza mucho
    como nematocida del suelo antes de la siembra. 

         El transporte, la distribución y el destino en el medio
    ambiente de los componentes principales de la "mezcla D/D" en el
    aire, el agua y el suelo se describen en sección 4 de los apartados
    de la presente monografía de EHC que tratan del 1,3-dicloropropeno y
    el 1,2-dicloropropano.

         El 1,2-dicloropropano procedente de la "mezcla D/D" tiene
    considerables posibilidades de escapar del suelo por lixiviación y
    contaminar las aguas de los pozos y las subterráneas. En un pozo de
    riego (68 m de profundidad) de Europa occidental se registraron unas
    concentraciones medias de 1,2-dicloropropano a diferentes
    profundidades que oscilaban entre 0,8 y 8,5 µg/litro, con una
    concentración máxima de 165 µg/litro. 

         No es probable que los cultivos absorban cantidades importantes
    de los componentes de la "mezcla D/D" (véase en otros apartados de
    la presente monografía). Tampoco es probable la bioacumulación de
    los componentes de la mezcla debido a su bajo log P del coeficiente
    de reparto octanol/agua y a su solubilidad relativamente grande en
    agua.

    1.2  Cinética y metabolismo

         No se han realizado estudios metabólicos con la "mezcla D/D".
    Los dos componentes principales, el 1,3-dicloropropeno y el 1,2-
    dicloropropano, se eliminan con rapidez, principalmente por la orina
    y, en menor cantidad, por el aire expirado. Los componentes de la
    "mezcla D/D" se metabolizan por oxidación y conjugación. Los
    principales metabolitos urinarios son los ácidos mercaptúricos. 

    1.3  Efectos en los seres vivos del medio ambiente

         La "mezcla D/D" es moderadamente tóxica para los peces; los
    valores de la CL50 a las 96 h oscilan entre 1 y 6 mg/litro. La
    toxicidad de la mezcla se debe fundamentalmente al 1,3-
    dicloropropeno.

         Cuando se utilizan las dosis de aplicación recomendadas, los
    principales efectos de la "mezcla D/D" son la reducción transitoria
    (< 7 días) de los hongos del suelo y la inhibición de la oxidación
    de los iones amonio a nitrato. La mezcla es tóxica para las
    bacterias nitrificantes. Inmediatamente después de desaparecer del
    suelo, las bacterias comienzan a colonizar la zona de nuevo. En
    ensayos de campo, la "mezcla D/D" (aplicada a 600 litros/ha) eliminó
    los invertebrados del suelo. La recolonización requirió entre 6 y 24
    meses.

         La "mezcla D/D" tiene una elevada fitotoxicidad. 

    1.4  Efectos en los animales de experimentación y en sistemas de
         prueba in vitro

         La toxicidad aguda de la "mezcla D/D" para los animales de
    laboratorio es de moderada a alta. Los valores de la DL50 por vía
    oral en ratas y ratones oscilan entre 132 y 300 mg/kg de peso
    corporal. Los valores de la DL50 por vía cutánea en ratas y
    conejos son de 779 y 2100 mg/kg de peso corporal, respectivamente.
    La CL50 (4 h) por vía respiratoria para ratas es aproximadamente
    de 4540 mg/m3. La exposición aguda produjo signos clínicos
    asociados a depresión del sistema nervioso central. La "mezcla D/D"
    tiene un fuerte efecto irritante en los ojos y la piel y una
    moderada capacidad de sensibilización cutánea. 

         Los resultados de los estudios disponibles de toxicidad durante
    un período breve en ratas y perros son insuficientes para evaluar de
    manera correcta la posible toxicidad de la mezcla, porque las dosis
    relativamente bajas ensayadas no demuestran ningún efecto
    biológicamente significativo. Se han realizado varios estudios de
    exposición por inhalación (todo el cuerpo) durante un período corto
    en ratas. Las concentraciones de hasta 145 mg/m3 de la "mezcla
    D/D" no tienen ningún efecto tóxico. Con niveles de 1362 mg/m3 o
    superiores se detectan claramente efectos tóxicos asociados con
    depresión del sistema nervioso central. Una exposición a 443 mg/m3
    durante 10 semanas da lugar a una disminución del aumento del peso
    corporal y a un mayor peso absoluto de los riñones.

         Un estudio teratológico en ratas por vía oral de la "mezcla
    D/D" fue inadecuado para evaluar su posible acción en este sentido.

         En un estudio de inhalación en ratas con dosis de hasta 443
    mg/m3 durante 10 semanas, para investigar la fecundidad de machos
    y hembras, no se observó ningún efecto. Debido a un diseño
    inadecuado del procedimiento, no fue posible evaluar completamente
    los efectos de la "mezcla D/D" sobre la reproducción.

         La mezcla tiene efectos mutagénicos en las cepas TA100 y TA1535
    de  Salmonella typhimurium, así como en la WP2 HCR de  Escherichia
     coli, sin activación metabólica. Sin embargo, no se produjeron
    tales efectos en las cepas TA98, TA1537 y TA1538 de  Salmonella.

         En un estudio prolongado en ratas alimentadas con dietas que
    contenían hasta 120 mg de la "mezcla D/D" por kg (equivalentes a 6
    mg/kg de peso corporal) durante dos años no se detectaron efectos
    tóxicos ni carcinógenos.

    1.5  Efectos en el ser humano

         Ya no se utiliza la "mezcla D/D" tanto como antes, por lo que
    es improbable la exposición de la población general a través del
    aire, el agua y los alimentos.

         Cuando se utilizaban los procedimientos recomendados, la
    exposición de los trabajadores que llenaban los bidones y de los
    aplicadores en el campo fue en general inferior a 4,5 mg de 1,3-
    dicloropropeno/m3. En otras condiciones se han medido
    concentraciones de hasta 36,32 mg/m3.

         Se ha informado de un caso de intoxicación aguda con desenlace
    fatal tras la ingestión accidental de la mezcla. 

         Se han notificado varios casos de dermatitis por contacto y de
    sensibilización cutánea debidas a la exposición accidental a la
    "mezcla D/D".

    2.  Conclusiones

    *    Población general: Dado que la "mezcla D/D" no tiene ya un uso
         tan generalizado, la exposición de la población al 1,3-
         dicloropropeno a través del aire, el agua y los alimentos es
         insignificante, pero, en ciertas zonas, cuando se contaminan
         las aguas subterráneas, se puede producir una exposición al
         1,2-dicloropropano.

    *    Exposición profesional: Durante las actividades de llenado y de
         aplicación de la "mezcla D/D" en los campos se puede producir
         una exposición de los manipuladores a concentraciones de 1,3-
         dicloropropeno superiores a la máxima permisible, especialmente
         en condiciones climáticas cálidas.

    *    Medio ambiente: No es probable que la "mezcla D/D" alcance
         niveles biológicamente significativos en el medio terrestre o
         acuático, siempre que se utilice en las dosis recomendadas.
         Tampoco es probable que se produzcan efectos adversos duraderos
         en los organismos vivos del medio ambiente.

    3.  Recomendaciones

    *    No se debe utilizar la "mezcla D/D" para fumigar el suelo,
         debido a su capacidad de lixiviar y alcanzar las aguas
         subterráneas.

    *    En las zonas en las que se use la mezcla, se han de vigilar los
         residuos en las aguas superficiales y subterráneas.


See Also:
        1,3-Dichloropropene (PIM 025)