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    UNITED NATIONS ENVIRONMENT PROGRAMME
    INTERNATIONAL LABOUR ORGANISATION
    WORLD HEALTH ORGANIZATION


    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 183





    CHLOROTHALONIL




    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.


    First draft prepared by Dr. M.H. Litchfield, Arundel, United Kingdom


    Published under the joint sponsorship of the United Nations
    Environment Programme, the International Labour Organisation, and the
    World Health Organization, and produced within the framework of the
    Inter-Organization Programme for the Sound Management of Chemicals.


    World Health Organization
    Geneva, 1996


        The issue of this document does not constitute formal publication.
    It should not be reviewed, abstracted, or quoted without the written
    permission of the Manager, International Programme on Chemical Safety,
    WHO, Geneva, Switzerland.


         The International Programme on Chemical Safety (IPCS) is a joint
    venture of the United Nations Environment Programme (UNEP), the
    International Labour Organisation (ILO), and the World Health
    Organization (WHO). The main objective of the IPCS is to carry out and
    disseminate evaluations of the effects of chemicals on human health
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    development of epidemiological, experimental laboratory, and risk-
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    Other activities carried out by the IPCS include the development of
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         The Inter-Organization Programme for the Sound Management of
    Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and
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    is to promote coordination of the policies and activities pursued by
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    WHO Library Cataloguing in Publication Data

    Chlorothalonil

    (Environmental health criteria ; 183)

    1.Fungicides, Industrial  2.Pesticides  3.Agrochemicals
    4.Environmental exposure  I.Series

    ISBN 92 4 157183 7                 (NLM Classification: WA 240)
    ISSN 0250-863X

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    (c) World Health Organization 1996

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    CONTENTS


    ENVIRONMENTAL HEALTH CRITERIA FOR CHLOROTHALONIL


    Preamble

    1. SUMMARY AND EVALUATION; CONCLUSIONS AND RECOMMENDATIONS

         1.1. Summary
              1.1.1. Identity, physical and chemical properties, and
                        analytical methods
              1.1.2. Sources of human and environmental exposure
              1.1.3. Environmental transport, distribution and
                        transformation
              1.1.4. Environmental levels and human exposure
              1.1.5. Kinetics and metabolism in laboratory animals
              1.1.6. Effects on laboratory mammals and  in vitro test
                        systems
              1.1.7. Effects on humans
              1.1.8. Effects on other organisms in the laboratory and
                        field
         1.2. Evaluation
              1.2.1. Evaluation of human health risks
              1.2.2. Evaluation of effects on the environment
                        1.2.2.1   Transport, distribution and
                                  transformation
                        1.2.2.2   Aquatic organisms
                        1.2.2.3   Terrestrial organisms
              1.2.3. Toxicological criteria for setting guidance values
         1.3. Conclusions and recommendations

    2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

         2.1. Identity
         2.2. Physical and chemical properties
         2.3. Analytical methods
              2.3.1. Sample preparation
              2.3.2. Analytical determination

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1. Natural occurrence
         3.2. Production levels and processes
         3.3. Uses

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

         4.1. Transport and distribution between media
         4.2. Transformation
              4.2.1. Biodegradation
              4.2.2. Abiotic degradation
              4.2.3. Bioaccumulation
         4.3. Waste disposal

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1. Environmental levels
              5.1.1. Air
              5.1.2. Water
              5.1.3. Soil
              5.1.4. Food crops
              5.1.5. Dairy produce
              5.1.6. Animal feed
         5.2. General population exposure
              5.2.1. Food
         5.3. Occupational exposure

    6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

         6.1. Absorption
         6.2. Distribution
         6.3. Metabolic transformation
              6.3.1. Rat
              6.3.2. Dog
              6.3.3. Monkey
         6.4. Elimination and excretion
              6.4.1. Rat
              6.4.2. Mouse
              6.4.3. Dog
              6.4.4. Monkey
         6.5. Reaction with body components

    7. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         7.1. Single exposure
         7.2. Short-term exposure
              7.2.1. Oral
                        7.2.1.1   Rat
                        7.2.1.2   Mouse
                        7.2.1.3   Dog
              7.2.2. Dermal: Rabbit
         7.3. Long-term exposure
              7.3.1. Rat
              7.3.2. Mouse
              7.3.3. Dog
              7.3.4. Summary of key dietary studies

         7.4. Skin and eye irritation; sensitization
         7.5. Reproductive and developmental toxicity
         7.6. Mutagenicity
         7.7. Carcinogenicity
         7.8. Other special studies
         7.9. Toxicity of metabolites

    8. EFFECTS ON HUMANS

         8.1. General population exposure
         8.2. Occupational exposure

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         9.1. Laboratory experiments
              9.1.1. Microorganisms
                        9.1.1.1   Aquatic microorganisms
                        9.1.1.2   Soil microorganisms
              9.1.2. Aquatic organisms
              9.1.3. Terrestrial organisms
                        9.1.3.1   Plants
                        9.1.3.2   Earthworms
                        9.1.3.3   Earwigs and honey-bees
                        9.1.3.4   Birds
         9.2. Field observations
              9.2.1. Soil microorganisms
              9.2.2. Plants

    10. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    RESUME

    RESUMEN
    

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

         Every effort has been made to present information in the criteria
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    Criteria monographs, readers are requested to communicate any errors
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    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, Case postale
    356, 1219 Châtelaine, Geneva, Switzerland (Telephone No. 9799111).



                                *     *     *



         This publication was made possible by grant number 5 U01 ES02617-
    15 from the National Institute of Environmental Health Sciences,
    National Institutes of Health, USA, and by financial support from the
    European Commission.

    Environmental Health Criteria

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    *    Kinetics and metabolism in laboratory animals and humans
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    Procedures

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    FIGURE 1

    additional material.  The contact points, usually designated by
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    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR CHLOROTHALONIL

    Members

    Dr T. Bailey, US Environmental Protection Agency, Washington DC, USA

    Dr A.L. Black, Department of Human Services and Health, Canberra,
       Australia

    Mr D.J. Clegg, Carp, Ontario, Canada

    Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood, Abbots
       Ripton, Huntingdon, Cambridgeshire, United Kingdom  (Vice-
        Chairman)

    Dr P.E.T. Douben, Her Majesty's Inspectorate of Pollution, London,
       United Kingdom  (EHC Joint Rapporteur)

    Dr P. Fenner-Crisp, US Environmental Protection Agency, Washington DC,
       USA

    Dr R. Hailey, National Institute of Environmental Health Sciences,
       National Institutes of Health, Research Triangle Park, USA

    Ms K. Hughes, Environmental Health Directorate, Health Canada, Ottawa,
       Ontario, Canada  (EHC Joint Rapporteur)

    Dr D. Kanungo, Central Insecticides Laboratory, Government of India,
       Ministry of Agriculture & Cooperation, Directorate of Plant
       Protection, Quarantine & Storage, Faridabad, Haryana, India

    Dr L. Landner, MFG, European Environmental Research Group Ltd,
       Stockholm, Sweden

    Dr M.H. Litchfield, Melrose Consultancy, Denmans Lane, Fontwell,
       Arundel, West Sussex, United Kingdom  (CAG Joint Rapporteur)

    Professor M. Lotti, Institute of Occupational Medicine,
       University of Padua, Padua, Italy  (Chairman)

    Professor D.R. Mattison, University of Pittsburgh, Graduate
       School of Public Health, Pittsburgh, Pennsylvania, USA

    Dr J. Sekizawa, National Institute of Health Sciences, Tokyo, Japan

    Dr P. Sinhaseni, Chulalongkorn University, Bangkok, Thailand

    Dr S.A. Soliman, King Saud University, Bureidah, Saudi Arabia

    Dr M. Tasheva, National Centre of Hygiene, Medical Ecology and
       Nutrition, Sofia, Bulgaria  (CAG Joint Rapporteur)

    Mr J.R. Taylor, Pesticides Safety Directorate, Ministry of
       Agriculture, Fisheries and Food, York, United Kingdom

    Dr H.M. Temmink, Wageningen Agricultural University, Wageningen, The
       Netherlands

    Dr M.I. Willems, TNO Nutrition and Food Research Institute, Zeist,
       The Netherlands

     Representatives of GIFAPa (Groupement International des
    Associations Nationales de Fabricants de Produits Agrochimiques)

    Dr M. Bliss, Jr., ISK Biosciences Corporation, Mentor, Ohio, USA

    Dr A.C. Dykstra, Registration Department BPID, Solvay-Duphar BV, CP
       Weesp, The Netherlands

    Dr H. Frazier, ISK Biosciences Corporation, Mentor, Ohio, USA

    Dr R. Gardiner, GIFAP, Brussels, Belgium

    Dr B. Julin, Regulatory Affairs, Du Pont de Nemours (Belgium),
       Agricultural Products Department, Mercure Centre, Brussels, Belgium

    Dr S.M. Kennedy (Environmental Science), Du Pont de Nemours (Belgium),
       Agricultural Products Department, Mercure Centre, Brussels, Belgium

    Dr J. Killeen, ISK Biosciences Corporation, Mentor, Ohio, USA

    Dr Th. S.M. Koopman, Toxicology Department, Solvay-Duphar BV, CP
       Weesp, The Netherlands

    Dr R.L. Mull, Du Pont Agricultural Products, Wilmington, Delaware, USA

    Dr J.L.G. Thus, Environmental Research Department, Solvay-Duphar BV,
       CP Weesp, The Netherlands

     Secretariat

    Ms A. Sundén Byléhn, International Register of Potentially Toxic
       Chemicals, United Nations Environment Programme, Châtelaine,
       Switzerland

    Dr P. Chamberlain, International Programme on Chemical Safety, World
       Health Organization, Geneva, Switzerland

           
    a   Participated as required for exchange of information.

    Dr J. Herrman, International Programme on Chemical Safety, World
       Health Organization, Geneva, Switzerland

    Dr K. Jager, International Programme on Chemical Safety, World Health
       Organization, Geneva, Switzerland

    Dr P. Jenkins, International Programme on Chemical Safety, World
       Health Organization, Geneva, Switzerland

    Dr W. Kreisel, World Health Organization, Geneva, Switzerland

    Dr M. Mercier, International Programme on Chemical Safety, World
       Health Organization, Geneva, Switzerland

    Dr M.I. Mikheev, Occupational Health, World Health Organization,
       Geneva, Switzerland

    Dr G. Moy, Food Safety, World Health Organization, Geneva, Switzerland

    Mr I. Obadia, International Labour Organisation, Geneva, Switzerland

    Dr R. Pleœtina, International Programme on Chemical Safety, World
       Health Organization, Geneva, Switzerland

    Dr E. Smith, International Programme on Chemical Safety, World Health
       Organization, Geneva, Switzerland  (EHC Secretary)

    Mr J. Wilbourn, International Agency for Research on Cancer, Lyon,
       France

    ENVIRONMENTAL HEALTH CRITERIA FOR CHLOROTHALONIL

         The Core Assessment Group (CAG) of the Joint Meeting on
    Pesticides met in Geneva from 25 October to 3 November 1994.  Dr W.
    Kreisel of the WHO welcomed the participants on behalf of WHO, and
    Dr M. Mercier, Director, IPCS, on behalf of the IPCS and its
    cooperating organizations (UNEP/ILO/WHO).  The Group reviewed and
    revised the draft monograph and made an evaluation of the risks for
    human health and the environment from exposure to chlorothalonil.

         The first draft of the monograph was prepared by Dr M.H.
    Litchfield, Arundel, United Kingdom.  The second draft, incorporating
    comments received following circulation of the first draft to the IPCS
    contact points for Environmental Health Criteria monographs, was
    prepared by the IPCS Secretariat.

         Dr K.W. Jager and Dr P.G. Jenkins, both members of the IPCS
    Central Unit, were responsible for the overall scientific content and
    technical editing, respectively.

         The fact that ISK Biosciences Corporation made available to the
    IPCS its proprietary toxicological information on chlorothalonil is
    gratefully acknowledged.  This allowed the CAG to make its evaluation
    on a more complete database.

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

    ABBREVIATIONS

    BCF       bioconcentration factor
    BUN       blood urea nitrogen
    ECD       electron capture detector
    EDB       1,2-dibromoethane (ethylene dibromide)
    FID       flame ionization detector
    GC        gas chromatography
    GSH       glutathione
    gamma-GT  gamma-glutamyltranspeptidase
    HECD      Hall electron capture detector
    LOEL      lowest-observed-effect level
    MS        mass spectrometry
    NADPH     reduced nicotinamide adenine dinucleotide phosphate
    NOEL      no-observed-effect level
    PIB       piperonyl butoxide
    SGOT      serum glutamic-oxalic transaminase
    SGPT      serum glutamic-pyruvic transaminase
    TEAM      total exposure assessment methodology
    TWA       time-weighted average
    UDS       unscheduled DNA synthesis
    VHH       volatile halogenated hydrocarbon
    VOC       volatile organic carbon compound

    1.  SUMMARY AND EVALUATION; CONCLUSIONS AND RECOMMENDATIONS

    1.1  Summary

    1.1.1  Identity, physical and chemical properties, and analytical
           methods

         Chlorothalonil is a colourless, odourless, crystalline solid with
    a melting point of 250°C and a vapour pressure of 7.63 × 10-5 Pa
    (5.72 × 10-7 mmHg) at 25°C.  It has low water solubility
    (0.6-1.2 mg/litre at 25°C) and an octanol/water partition coefficient
    (log Kow) of 2.882.  It is hydrolysed in water slowly at pH 9 but is
    stable at pH 7 or below (at 25°C).

         The most prevalent analytical method, after sample extraction and
    clean-up, is gas-liquid chromatography using an electron-capture
    detector.

    1.1.2  Sources of human and environmental exposure

         Chlorothalonil has been produced commercially since 1969 by
    chlorination of isophthalonitrile or by treatment of
    tetrachloroisophthaloyl amide with phosphorus oxychloride.  It is a
    fungicide with a broad spectrum of activity used mainly in agriculture
    but also on turf, lawns and ornamental plants.  Crops protected
    include pome and stone fruit, citrus, currants, berries, bananas,
    tomatoes, green vegetables, coffee, peanuts, potatoes, onions and
    cereals.  In addition, it is used in wood preservatives and in paints.

         The three main formulations are a suspension concentrate, a water
    dispersible granule and a wettable powder.  They are readily diluted
    with water and applied by ground spray systems or by air.  Typical
    active ingredient rates are 1.2-2.5 kg/ha for crops such as beans,
    celery and onions.  The main sources of human exposure will be during
    preparation and application of the products and from ingestion of crop
    residues in foodstuff (see section 1.1.4).

    1.1.3  Environmental transport, distribution and transformation

         Chlorothalonil is removed from aqueous media by strong adsorption
    on suspended matter.  Modelled data suggest little or no partition to
    bottom sediment.  Biodegradation may occur in natural waters with
    enzyme processes being involved.  Chlorothalonil is rapidly degraded
    in soil, and degradation may occur in water with the production of the
    4-hydroxy metabolite, 4-hydroxy-2,5,6-trichloroisophthalonitrile. 
    Half-lives for dissipation of the 4-hydroxy metabolite in soils range
    between 6 and 43 days.

         Chlorothalonil does not translocate from the site of application
    to other parts of a plant.  It is metabolized only to a limited extent
    on plants and the 4-hydroxy metabolite is usually < 5% of the
    residue.

         Chlorothalonil is metabolized in fish via glutathione conjugation
    to give more polar excretory products.  The enzyme glutathione-
     S-transferase is involved with this conversion.  High concentrations
    of radiolabel found in the gall bladder and bile, after exposure of
    rainbow trout to 14C-chlorothalonil, are consistent with the
    excretion of the compound as glutathione conjugates.  The
    concentrations of radiolabel accumulating in the gall bladder and
    other organs fell rapidly when the fish were placed in clean water.

         Chlorothalonil does not bioaccumulate in aquatic organisms.

    1.1.4  Environmental levels and human exposure

         In a potato crop study, a small stream was oversprayed with
    chlorothalonil.  Subsequent sampling/analysis of down-stream water
    demonstrated rapid disappearance of chlorothalonil (i.e. 450 µg/litre
    at 30 min post-spraying to 2-6 µg/litre at 12 h post-spraying).  The
    routine spraying of irrigated field crops such as potatoes and barley
    gave rise to low concentrations of chlorothalonil (0.04-3.6 µg/litre)
    in tile drain water on a small number of sampling occasions.

         Crop residues are composed mainly of chlorothalonil itself.  The
    residue levels are dependent upon the applied rate, time interval
    between the last application and harvest, and the type of crop. 
    Residue levels at harvest can be derived from the numerous supervised
    trials that have taken place on many crops worldwide and reported to
    FAO/WHO.  Residues of chlorothalonil in dairy products are expected to
    be undetectable or very low.  Dairy cows given high concentrations (up
    to 250 mg/kg) of chlorothalonil in their feed for 30 days showed no
    detectable residue in milk and only very low levels in tissues.

         Total diet and individual food analysis in several countries have
    shown undetectable or low concentrations of chlorothalonil in sampling
    surveys. Residue levels on foodstuffs are further reduced by
    preparation processes such as washing, peeling and cooking.

    1.1.5  Kinetics and metabolism in laboratory animals

         About 30% of an oral dose of chlorothalonil is absorbed within
    48 h in rats at doses up to 50 mg/kg body weight.  At higher doses,
    absorption is lower, indicating a saturation process.  When
    14C-chlorothalonil is given orally the radioactivity is distributed
    into blood and tissues within 2 h.  The greatest concentration is
    found in the kidney, followed by liver and blood.  The kidneys contain
    0.3% of a 5 mg/kg body weight dose after 24 h.

         Most of an oral dose of chlorothalonil in rats is found in faeces
    (> 82% within 48-72 h, regardless of dose).  Biliary excretion is
    rapid, peaking within 2 h after a 5 mg/kg body weight oral dose, and
    is saturated at 50 mg/kg body weight and above.  Urinary excretion
    accounts for 5-10% of the dose in rats.  Faecal excretion is the main
    route in dogs and monkeys but urinary excretion (< 4%) is less than
    in rats.

         Metabolic studies in rats indicate that chlorothalonil is
    conjugated with glutathione in the liver as well as in the
    gastrointestinal tract.  Some of the glutathione conjugates may be
    absorbed from the intestine and transported to the kidneys, where they
    are converted by cytosolic ß-lyase to thiol analogues that are
    excreted in the urine.  When germ-free rats are dosed with
    chlorothalonil, the thiol metabolites appear in urine in much smaller
    amounts than with normal rats, indicating the involvement of
    intestinal microflora in the metabolism of chlorothalonil.  Dogs or
    monkeys dosed orally with chlorothalonil excrete little or no thiol
    derivatives in urine.

         When 14C-chlorothalonil was applied to rat skin, approximately
    28% of the dose was absorbed within 120 h.  About 18% of the dose was
    found in faeces and 6% in urine within 120 h.

    1.1.6  Effects on laboratory mammals and in vitro test systems

         Chlorothalonil has low acute oral and dermal toxicity in rats and
    rabbits, respectively (acute oral and dermal LD50 values are
    > 10 000 mg/kg body weight).  Hammer-milled technical chlorothalonil
    (MMAD 5-8 µm) exhibited high toxicity in rats in an inhalation study,
    with a 4-h LC50 of 0.1 mg/litre.

         Chlorothalonil is a skin and eye irritant in the rabbit.  Skin
    sensitization studies in the guinea-pig were inconclusive.

         The main effects of repeated oral dosing in rats are on the
    stomach and kidney.  Groups of 25 rats of each sex per group were fed
    chlorothalonil at 0, 1.5, 3, 10 or 40 mg/kg body weight per day in the
    diet for 13 weeks, and this was followed by a 13-week recovery period. 
    Increased incidences of hyperplasia and hyperkeratosis of the
    forestomach occurred at 10 and 40 mg/kg; these reversed when treatment
    ceased.  At 40 mg/kg, there was an increased incidence of hyperplasia
    of kidney proximal tubular epithelium in males at 13 weeks and after
    the recovery period.  The NOEL was 3 mg/kg body weight per day based
    upon lack of forestomach lesions.  The onset of the forestomach and
    kidney changes was shown to be rapid, with the lesions developing
    within 4-7 days in male rats at a dietary level of 175 mg/kg body
    weight per day.

         In a 13-week study on mice (0, 7.5, 15, 50, 275 or 750 mg/kg in
    the diet), increased incidences of hyperplasia and hyperkeratosis of
    the squamous epithelial cells of the forestomach occurred in males and
    females at 50 mg/kg diet and above.  The NOEL, based upon these
    changes, was 15 mg/kg chlorothalonil in the diet, equivalent to
    3 mg/kg body weight per day.

         A 16-week study in dogs with dietary levels of 0, 250, 500 or
    750 mg/kg showed no treatment-related changes.

         The forestomach and kidney lesions were investigated further in
    2-year studies on rats, mice and dogs.  In a study on rats (0, 1.8,
    3.8, 15 or 175 mg/kg body weight per day), the effects were
    characterized histologically as an increase in the incidence and
    severity of hyperplasia, hyperkeratosis, and ulcers and erosions of
    the squamous mucosa of the forestomach, and as epithelial hyperplasia
    of the kidney proximal convoluted tubules at 3.8 mg/kg and above.  The
    NOEL for non-neoplastic effects was therefore 1.8 mg/kg.  The
    incidence of renal tumours (adenomas and carcinomas) and forestomach
    tumours (papillomas and carcinomas) was markedly increased at
    175 mg/kg.  There was evidence for an increased incidence of kidney
    tumours in males at 15 mg/kg and of stomach tumours at 3.8 and
    15 mg/kg in males and females.  The NOEL for neoplastic effects was

    therefore 1.8 mg/kg body weight per day based upon changes in
    forestomach tumour incidence.  Supporting evidence for the
    carcinogenic potential of chlorothalonil in the kidney and forestomach
    of rats was provided by the results from other 2-year studies at
    higher dose levels.

         In a study on mice (0, 15, 40, 175 or 750 mg/kg in the diet), an
    increased incidence of renal tubular hyperplasia occurred at 175 mg/kg
    and above and of hyperplasia and hyperkeratosis of the forestomach at
    40 mg/kg and above.  The incidence of squamous tumours of the
    forestomach was slightly increased at 750 mg/kg.  The NOELs for
    neoplastic and non-neoplastic changes were therefore 175 and 15 mg/kg
    in the diet (equivalent to 17.5 and 1.6 mg/kg body weight per day,
    respectively).  Supporting evidence for these effects in the mouse was
    provided in another study at higher dose levels, but a study in
    B6C3F1 mice did not show any evidence for carcinogenic potential at
    high dose levels.

         In a 2-year study on dogs (60 and 120 mg/kg in the diet), no
    effects attributable to chlorothalonil were found.  The NOEL was
    therefore 120 mg/kg in the diet (equivalent to 3 mg/kg body weight per
    day).

         Chlorothalonil was not mutagenic in several  in vitro and  in
     vivo tests, although it was positive in a small number of assays.

         The monothio, dithio, trithio, dicysteine, tricysteine and
    monoglutathione derivatives of chlorothalonil, which are potential
    nephrotoxicants, were shown to be negative in the Ames assay.

         Chlorothalonil was not teratogenic in rats or rabbits at doses up
    to 400 and 50 mg/kg body weight per day, respectively.  Reproductive
    parameters such as mating, fertility and gestation length were not
    affected by chlorothalonil at levels up to 1500 mg/kg in the diet in a
    two-generation study in rats.

         The acute oral toxicity of the 4-hydroxy metabolite is greater
    than that of chlorothalonil itself (acute oral LD50 of 332 mg/kg body
    weight versus > 10 000 mg/kg body weight).  Several studies have been
    undertaken to characterize the toxicological profile of this
    metabolite and to establish NOELs.

    1.1.7  Effects on humans

         Contact dermatitis has been reported for personnel working in
    chlorothalonil manufacturing and in farmers and horticultural workers. 
    Workers in the manufacture of wood products have also developed
    contact dermatitis on the hands and face when wood preservatives
    containing chlorothalonil were used.

    1.1.8  Effects on other organisms in the laboratory and field

         Chlorothalonil is highly toxic to fish and aquatic invertebrates
    in laboratory studies, the LC50 values being below 0.5 mg/litre.  The
    maximum acceptable toxicant concentration (MATC) in a two-generation
    reproduction study in  Daphnia magna was 35 µg/litre.

         With minor exceptions, chlorothalonil is not phytotoxic.

         The LC50 of a suspension concentrate formulation (500 g
    chlorothalonil/litre) in artificial soil for earthworms was
    > 1000 mg/kg soil (14 days).  Earwigs suffered increased mortality
    when in contact with chlorothalonil residues on peanut foliage or
    ingesting it as a food source in laboratory tests; there was no other
    indication of insecticidal action.

         Chlorothalonil is of low toxicity to birds with a reported acute
    oral LD50 of 4640 mg/kg diet in the mallard duck.  No significant
    reproductive effects were reported.

         A field study of aquatic organisms exposed following
    chlorothalonil application suggests that the toxicity is less than
    that predicted from laboratory studies; this is again consistent with
    the physicochemical properties of the compound.  Deaths were seen in
    some species exposed experimentally in the field.  There have been no
    reported incidents of kills in the environment.  However, despite the
    short residence time of chlorothalonil in environmental media, kills
    would be expected to occur.  Linking kills to the compound would be
    difficult given that residues would not persist long enough for
    chlorothalonil to be identified.

    1.2  Evaluation

    1.2.1  Evaluation of human health risks

         The review of the toxicological data for chlorothalonil revealed
    that the most important studies for human risk estimation were the
    long-term studies in rodents and dogs.

         In the rodent studies, chlorothalonil caused lesions in the
    forestomach and kidney.  The lesions in the forestomach were
    characterized as hyperplasia and hyperkeratosis of the squamous
    epithelial cells.  These occurred soon after dosing and were shown to
    be reversible after dosing ceased.  Long-term administration led to
    the formation of tumours (papilloma and carcinoma).  The renal lesions
    in rodents were of rapid onset and characterized as hyperplasia of the
    proximal tubular epithelium.  On longer-term administration, renal
    tumours (adenoma and carcinoma) occurred in the rat and in one study
    on mice.

         In order to interpret the significance of these findings, the
    results of the mutagenic studies were taken into account. 
    Chlorothalonil gave negative results in  in vitro and  in vivo
    mutagenic assays in which a variety of end-points were studied.  Thiol
    derivatives of chlorothalonil were negative in the Ames test, and
    14C-chlorothalonil did not bind to rat kidney DNA  in vivo.  The
    compound does not appear to have genotoxic potential on this basis,
    indicating that it probably exerts its carcinogenic effect in rodents
    via a non-genotoxic mechanism.  The initial forestomach lesions in
    rodents were attributed to the irritant action of chlorothalonil, and,
    where this does not occur, a NOEL can be attained. The irritant action
    on rodent forestomach in conjunction with the relatively long
    residence time of the compound in this organ were seen to be factors
    presenting the opportunity for the initiation of the lesions and
    leading to carcinogenic action on prolonged administration.  It was
    concluded that, since humans do not possess a comparable organ,
    rodents are probably not representative of the action of this compound
    in man in this respect.  This reasoning is also supported by the fact
    that another animal species, the dog, is not affected by the compound
    at similar or higher doses.

         In the assessment of the relevance of the rodent renal lesions,
    the metabolic conversion of chlorothalonil to metabolites which act
    directly upon the kidney was seen to be a major factor.  In the kidney
    glutathione conjugates are converted by ß-lyase to chlorothalonil
    thiol derivatives.  Chlorothalonil is thought to be conjugated with
    glutathione (GSH) mostly in the gastrointestinal tract prior to
    absorption, although there is evidence of glutathione conjugation at
    other sites.  After absorption the conjugates pass to the kidney where
    they are converted to chlorothalonil thiol derivatives following the
    action of ß-lyase.  It has been shown  in vitro that the di- and
    trithiol metabolites inhibit the function of renal cortical
    mitochondria.  Therefore, a cycle of cell death and regenerative renal
    hyperplasia may be initiated.

         In adducing the relevance of these findings for humans, the
    species differences in the metabolic pathway for chlorothalonil were
    taken into account.  It was noted that the formation of the thiol
    metabolites, as determined by urinary excretion, was considerably
    diminished when chlorothalonil was fed to germ-free rats.  This
    indicates that the type and/or quantity of gut microflora has a
    determining role in the production of the thiol derivatives.  Studies
    in dogs and monkeys showed that the excretion of the thiol derivatives
    was barely detectable after oral administration of chlorothalonil. 
    This suggests that the rat is rather different from other species in
    this respect.  Furthermore there is some evidence that ß-lyase
    activity in the kidney varies among species, being an order of
    magnitude lower in humans than in rats.

         For all the reasons stated above it was concluded that the rodent
    was not the most relevant species for evaluating the long-term effect
    of chlorothalonil in humans and that the dog was a more representative
    species for this purpose.  The NOEL of 120 mg/kg in the diet in the
    2-year study on dogs, equivalent to 3 mg/kg body weight per day,
    should therefore be used for the purpose of human risk estimation.

    1.2.2  Evaluation of effects on the environment

         Chlorothalonil is algicidal for a number of algal species.  The
    fungicide does not inhibit bacterial growth except at very high
    concentrations in laboratory culture.  Field and laboratory evidence
    shows no effects on nitrogen fixation or nitrification at recommended
    application rates and minimal effects at higher application rates in
    temperate soils.  There was insufficient information to assess effects
    on the nitrogen cycle in tropical soils.

         Laboratory acute toxicity tests show chlorothalonil to be very
    highly toxic to many aquatic animals including fish and  Daphnia,
    although molluscs appear to be insensitive.  The LC50 concentrations
    for a range of fish and invertebrates are similar and below
    0.5 mg/litre.

         A single study indicated reproductive effects in fish following
    continuous exposure for 35 days.  Since the compound both adsorbs to
    suspended material and is degraded rapidly, the significance of this
    finding was considered to be questionable.

         A field study of aquatic organisms exposed following
    chlorothalonil application suggests that the toxicity is less than
    that predicted from laboratory studies; this is again consistent with
    the physicochemical properties of the compound.  Deaths were seen in
    some species exposed experimentally in the field.  There have been no
    reported incidents of kills in the environment.  However, despite the
    short residence time of chlorothalonil in environmental media, kills
    would be expected to occur immediately after application.  Linking
    kills to the compound would be difficult given that residues would not
    persist long enough for chlorothalonil to be identified.

         With minor exceptions, chlorothalonil is not phytotoxic.

         Several studies have shown no toxicity of chlorothalonil to
    earthworms at recommended application rates.  At an exposure of five
    times the maximum recommended rate, the compound severely reduced worm
    reproduction.

         Chlorothalonil is classified as "relatively non-toxic" to
    honey-bees.  Earwigs exposed to residues topically and via food showed
    some mortality (20-55%), but there is no other evidence of
    insecticidal action.

         Chlorothalonil has low toxicity to birds in acute or dietary
    tests.  The low acute toxicity of chlorothalonil to laboratory mammals
    tempered with its short persistence in the environment suggests
    minimal hazard to wild mammal species.

    1.2.2.1  Transport, distribution and transformation

         Chlorothalonil adsorbs strongly to organic matter in soil and
    suspended material in water.  It is not, therefore, leached from soil
    to groundwater.  It is removed rapidly from surface water to suspended
    material and to a lesser extent to bottom sediment.  Chlorothalonil is
    not translocated in plants from the site of application.

         Abiotic degradation of chlorothalonil in water through photolysis
    does not occur.  Some hydrolysis does take place at higher pH.

         Microbial degradation is the major cause of dissipation in soil
    and may take place to some extent in water; this involves several
    parallel processes, one of which leads to formation of the 4-hydroxy
    metabolite.  Half-lives for dissipation of this metabolite from non-
    sterile soils range between 6 and 43 days.  Biodegradation on plants
    is limited and the 4-hydroxy metabolite comprises less than 5% of the
    total residues.

         During exposure, fish bioconcentrate chlorothalonil, but almost
    total degradation occurs within 2 weeks after termination of exposure. 
    Chlorothalonil is metabolized in fish through glutathione conjugation
    and the conjugates are excreted through the bile.

    1.2.2.2  Aquatic organisms

    The results of a single field study measuring concentrations of
    chlorothalonil in water following overspray of the water were
    available; corresponding data on concentrations in suspended and
    bottom sediment were unreliable.  Output from the EXAMS II fate model
    using the same application scenario produced estimated water
    concentrations which closely corresponded to the measured ones. 
    Little or no chlorothalonil was predicted in bottom sediment.

         Based on this combination of measured and modelled data, the
    ratio between a "toxic" concentration (the rainbow trout LC50) and
    expected concentration is less than 1 for up to 5 h after overspray
    and increases rapidly thereafter.  Similar results were obtained for
    daphnids.  Therefore, despite its rapid removal from water and
    degradation, the high toxicity of chlorothalonil is expected to cause
    deaths of aquatic organisms in the period immediately after spraying.
    This is the worst case situation of direct water overspray.

         There were no data to extend this quantitative evaluation to
    other field situations or climates.

    1.2.2.3  Terrestrial organisms

    A calculated maximum soil concentration, based on application of
    chlorothalonil at 2.5 kg a.i./ha and complete bioavailability, is 3
    orders of magnitude higher than the lowest estimate of LC50 for
    earthworms.

         For grazing birds (ducks and geese) total daily intake is at
    least a factor of 100 below the NOEL for oral toxicity.  For rabbits,
    total daily intake is also at least 2 orders of magnitude lower than
    the reported NOEL.  This is based on a maximum recommended application
    rate of 2.5 kg a.i./ha, an estimated worst case value for residues on
    grass, no degradation of the compound, consumption of the total daily
    intake at a single time and no choice but to eat contaminated food. 
    Table 1 contains a summary of risk quotients for birds, fish and
    aquatic invertebrates.


        Table 1.  Toxicity/exposure ratios for birds, fish and aquatic invertebrates based
              on application rates of 2.5 kg a.i./ha of chlorothalonil to soybeans
              (worst case)
                                                                                                 

    Risk category               LC50 (mg/litre      Estimated exposure       Toxicity/exposure
                                or mg/kg diet)      (mg/litre or             ratio (TER)c
                                                    mg/kg diet)a,b
                                                                                                 

    Acute bird                  4640                73.7-535.7               63.0-8.7

    Acute fish (stream)         0.01                0.009-0.04               1.1-0.25

    Acute fish (pond)           0.01                0.01                     1.0

    Acute aquatic
     invertebrate (stream)      0.07                0.009-0.04               7.8-1.8

    Acute aquatic
     invertebrate (pond)        0.07                0.01                     7.0
                                                                                                 

    a   Estimated environmental concentration in the terrestrial environment (for bird exposure)
        is based on the stated application rate and the assumption of deposition on short grass
        using the US EPA nomogram.

    b   Aquatic exposure concentrations were taken from the STREAM model based on a single
        application and estimated run-off into water; no direct overspray is included.

    c   TER is the toxicity (as LC50) divided by the exposure; values at or below 1.0 indicate
        likely exposure to toxic concentrations by organisms in the different risk categories.
    
    1.2.3  Toxicological criteria for setting guidance values

         The toxicological studies on chlorothalonil of relevance for
    setting guidance values are displayed in Table 2.  The study results
    and their significance are described briefly and gaps in test
    requirements are indicated.

        Table 2.  Toxicological criteria for setting guidance values for chlorothalonil

                                                                                        

    Exposure        Relevant route/effect/        Result/remarks
    scenario        species

                                                                                        

    Short-term      skin, irritation, rabbit      irritant
    (1-7 days)
                    eye, irritation, rabbit       irritant

                    skin, sensitization,          tests were inconclusive
                    guinea-pig
                                                  evidence in humans of contact
                                                  dermatitis

                    inhalation, lethality,        high toxicity in 4-h study with
                    rat                           hammermilled technical chlorothalonil
                                                  (MMAD 5-8 µm); not relevant for most
                                                  human exposure situations

    Medium-term     repeat dermal, rabbit         21-day study; irritant at 2.5 mg/kg
    (1-26 weeks)                                  body weight per day and above; no
                                                  systemic effects at 50 mg/kg body
                                                  weight per day

                    repeat oral, mice and         13-22 week studies; NOEL = 3 mg/kg
                    rats                          body weight per day in rats and mice

                    maternal, oral, rabbit        teratology study; maternal toxicity
                                                  NOEL = 10 mg/kg body weight per day
                                                  by gavage; no fetotoxic or teratogenic
                                                  effect

    Long-term       repeat oral, dog              2-year study; NOEL = 3 mg/kg body
                                                  weight per day

                                                                                        
    
    1.3  Conclusions and recommendations

         Considering the toxicological characteristics of chlorothalonil,
    both qualitatively and quantitatively, it was concluded, on the basis
    of the NOEL of 3 mg/kg body weight per day derived in the 2-year study
    on dogs and applying a 100-fold uncertainty factor, that 0.03 mg/kg
    body weight per day will probably not cause adverse effects in humans
    by any route of exposure.

         A study to assess the skin irritation potential is needed.

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1  Identity

    Chemical structure

    CHEMICAL STRUCTURE 1

    Molecular formula       C8Cl4N2

    Relative molecular mass 265.9

    CAS chemical name       2,4,5,6,-tetrachloro-1,3-benzenedi
                            carbonitrile

    CAS registry number     1897-45-6

    RTECS registry number   NT2600000

    Common name             chlorothalonil

    IUPAC name              tetrachloroisophthalonitrile

    Synonyms                m-TCPN; 2,4,5,6-tetrachloro-3-cyano
                            benzonitrile

    Trade names             Bravo (ISK Biotech)
     (manufacturers &       Daconil (ISK Biotech)
     suppliers)             Faber (Tripart Farm Chemicals)
                            Repulse (ICI); Exotherm (Alto Elite)
                            Nopocide (a preservative in paints and
                            adhesives)

    Technical product       > 97%
     purity

    Technical product       tetrachlorophthalonitrile (< 0.1),
     impurities (%)         tetrachloroterephthalonitrile (0.1-1.6),
                            pentachlorobenzonitrile (0.5-2.5),
                            partially chlorinated dicyanobenzenes
                            (0.2-1.0), unchlorinated dicyano
                            benzenes (0.1-1.6), HCB (0.03),
                            insoluble in xylene (0.1-1.0)

    2.2  Physical and chemical properties

         The physical properties of chlorothalonil are listed in Table 3.

        Table 3.  Physical properties of chlorothalonil

                                                                                                

    Physical state                                    crystalline solid

    Colour                                            colourless

    Odour                                             odourless

    Melting point (°C)                                250-251

    Boiling point (°C)                                350 (760 mmHg)

    Vapour pressure at 25°C                           5.72 × 10-7

    Relative density                                  1.8

    Octanol-water partition coefficient               2.88-3.86
     (log Kow)

    Solubility in water (mg/litre) at 25°C            0.6-1.2

    Solubility in organic solvents (g/litre)          acetone 20, dimethylformamide 30,
                                                      dimethylsulfoxide 20, xylene 80, readily
                                                      soluble in benzene
                                                                                                
    
         Chlorothalonil is non-flammable and non-explosive.  It is
    thermally stable under normal storage conditions and to UV radiation,
    and it is chemically stable in neutral or acidic aqueous solutions. 
    It breaks down at pH 9, the rate following first-order kinetics at
    1.8% per day (at 25°C) (Szalkowski & Stallard, 1977). It has been
    shown that chlorothalonil is unstable to light when dissolved in
    benzene and that 2,3,5-trichloro-4,6-dicyanobiphenyl is a condensation
    product (Kawamura et al., 1978). Chlorothalonil is not corrosive.

    2.3  Analytical methods

         Analytical methods for determining chlorothalonil in
    formulations, fruit, vegetables, soil and water are summarized in
    Table 4.  In general, the methods also detect the principal metabolite
    4-hydroxy-2,5,6-trichloroisophthalonitrile.

    2.3.1  Sample preparation

         Samples are extracted initially with an organic solvent such as
    acetone.  For samples where interference with the analytical method is
    expected, e.g., plant material, further partitioning with organic
    solvents is required, followed by clean-up on alumina or Florisil
    columns if necessary.  The sample extracts are submitted for
    analytical determination.

    2.3.2  Analytical determination

         In most cases the cleaned-up sample extracts are analysed by
    gas-liquid chromatography using an electron capture detector.  This
    provides sufficient sensitivity for the analysis of trace quantities
    of chlorothalonil residues at detection limits down to 0.01 mg/kg in
    many cases.

         Where less sensitive determination is required, e.g., for
    formulation analysis, a flame ionization detector gives sufficient
    sensitivity.  A method for formulation analysis using infrared
    spectroscopy after dichloromethane extraction has been reported (US
    EPA, 1976).

         The Joint FAO/WHO Codex Alimentarius Commission has given
    recommendations for the methods of analysis to be used for the
    determination of chlorothalonil residues (FAO/WHO, 1989).

        Table 4.  Methods for the determination of chlorothalonil

                                                                                                                                       

    Sample type         Sample preparation                               Analytical       Limit of detection       Reference
                        extraction/clean-up                              methoda          (µg/kg or µg/litre)
                                                                                                                                       

    Formulation         extract (1,4-dioxane or methylethylketone/       GC/TCD or            -                    Ballee et al. (1976)
                        carbon disulfide/1,2-dimethoxyethane)            GC/FID               -

    Fruit & vegetable   Strip (dichloromethane)                          GC/ECD               10                   Ballee et al. (1976)
     surfaces           evaporate, dilute (benzene)

    Green leafy         extract (acidified acetone), evaporate,          GC/ECD               10                   Ballee et al. (1976)
     vegetables         dissolve (aqueous NaHCO3), adjust pH,
                        extract (diisopropyl ether), evaporate,
                        dilute (benzene), chromatograph (alumina)

    Fruit and           extract (acetone), evaporate, acidify            GC/ECD               20                   Burchfield & Storrs
     vegetables         and extract (ether), evaporate, chromatograph                                              (1977)
                        (Florisil), elute (acetone/dichloromethane)

    Non-fatty products  extract (toluene/isopropanol), aqueous           GC/ECD               10-50                Holmes & Wood
     especially with    separation, evaporate, chromatograph                                                       (1972)
     S interference,    (alumina/AgNO3), elute (hexane)
     onion, cabbage,
     celery

    Potatoes            extract (acidified acetone), chromatograph       GC/ECD               10                   Markus & Puma
                        (Florisil) derivatize (diazomethane)             GC/MCD               20                   (1973)

                                                                                                                                       

    Table 4.  (Cont'd)

                                                                                                                                       

    Sample type         Sample preparation                               Analytical       Limit of detection       Reference
                        extraction/clean-up                              methoda          (µg/kg or µg/litre)
                                                                                                                                       

    Apples              rinse (acidified acetone), adjust pH, partition  GC/ECD               50                   Suzuki & Oda (1977)
                        (hexane), extract tissue (acidified acetone),
                        concentrate, partition (hexane), acidify
                        aqueous fraction, partition (diisopropyl ether)

    Cranberries         extract (acetone), filter, (Celite 545), adsorb  GC/ECD               not quoted           Camoni et al. (1991)
                        (Extrelut-20), elute (petroleum ether),
                        evaporate, dissolve (benzene)

    Fresh fruit         extract (acetone), partition (petroleum ether    HPLC/UV (232 nm)     < 50                 Gidvydis & Walters
                        and methylene chloride), concentrate             and HPLC/                                 (1988)
                                                                         photoconductivity
                                                                         detection (PC)

    Soil                extract (acidified acetone), extract             GC/ECD               10                   Ballee et al. (1976)
                        (acetonitrile/hexane), partition (aqueous
                        layer) extract (diisopropyl ether) concentrate,
                        dilute (benzene) chromatograph (alumina)

                        extract (acetone: sulfuric acid), partition      GC/ECD               10                   Kenyon & Wiedmann
                        (petroleum ether), evaporate, redissolve in                                                (1992b)
                        hexane/methylene chloride, elute, concentrate
                                                                                                                                       

    Table 4.  (Cont'd)

                                                                                                                                       

    Sample type         Sample preparation                               Analytical       Limit of detection       Reference
                        extraction/clean-up                              methoda          (µg/kg or µg/litre)
                                                                                                                                       

    Water               adjust pH to 4.5, extract (diisopropyl ether),   GC/ECD               10                   Ballee et al. (1976)
                        concentrate, dilute (benzene)

                        adjust pH, extract (petroleum ether), add        GC/ECD               0.05                 Kenyon & Wiedmann
                        keeper, concentrate, redissolve (hexane/                                                   (1992a)
                        methylene chloride), elute (methylene
                        chloride/hexane/acetonitrile)

    Air samples,        extraction (methional 2-propanol, n-hexane)      HPLC with UV         0.5                  Jongen et al. (1991)
     dislodgeable                                                        detection at 254
     residues                                                            or 325 nm

                                                                                                                                       

    a    GC = gas chromatography; ECD = electron capture detector; FID = flame ionization detector; HPLC = high performance liquid
         chromatography; MCD = microcoulometric detection; TCD = thermal conductivity detection

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         Chlorothalonil does not occur naturally in the environment.

    3.2  Production levels and processes

         Chlorothalonil is produced by the chlorination of
    isophthalonitrile or by treatment of tetrachloroisophthaloyl amide
    with phosphorus oxychloride.  It has been produced commercially in the
    USA since 1969.  No data on production are available but it has been
    estimated at 5000 tonnes annually (IARC, 1983).  The annual production
    in Japan has been estimated to be 3000 tonnes (IARC, 1983).

         Imports into the USA were 1650 tonnes in 1976 and 175 tonnes in
    1980 (IARC, 1983).

         No data are available on possible releases to the environment
    from production processes or transportation.

    3.3  Uses

         Chlorothalonil is a fungicide with a broad spectrum of activity
    used mainly in agriculture but also on turf, lawns and ornamental
    plants.  It protects plants against a variety of fungal infections
    such as rusts, downy mildew, leaf spot, scabs, blossom blight and
    black pod.  Crops protected include pome fruit, stone fruit, citrus,
    currants, cranberries, strawberries, bananas, vines, hops, tomatoes,
    green vegetables, tobacco, coffee, tea, soya bean, groundnuts,
    potatoes, onions, cereals and sugar beet.  In addition, it is used in
    wood preservatives, fish net coatings and anti-fouling paints.

         Global estimates of chlorothalonil use for these purposes are not
    available.  The extent of use in various countries on an annual basis
    is shown in Table 5.

         Chlorothalonil is used in agriculture in formulated products. 
    The three main formulations are a suspension concentrate containing
    500 g chlorothalonil/litre, a water dispersible granule and a wettable
    powder containing 75% chlorothalonil.  The formulations mix readily
    with water and are diluted to give a spray mixture which can be
    applied by ground spray systems or by air, and as dilute or
    concentrated sprays.

         The dose rates recommended for crop protection have been derived
    from efficacy studies conducted in a variety of climatic conditions in
    various parts of the world.  The label recommendations are designed to
    give satisfactory fungal disease control and to keep residues within
    national and international limits.  Typical active ingredient rates
    are 1.25-2.5 kg/ha for crops such as beans, celery and onions.  Rates

        Table 5.  Quantities of chlorothalonil used in various countries

                                                                                                           

    Country               Year          Consumption      Usage                              Reference
                                        (tonnes)

                                                                                                           

    Canada                1982          5.1              potatoes                           O'Neill (1991)
    (New Brunswick)

    Colombia              1980          14.5             fruit, flowers, ornamentals        IRPTC (1989)
                          1981          22.2             fruit, flowers, ornamentals        IRPTC (1989)
                          1982          12.5             fruit, flowers, ornamentals        IRPTC (1989)

    Mexico                1983          250              broccoli, potatoes, etc.           IRPTC (1989)

    Sweden                1981          30               agricultural crops                 IRPTC (1989)
                                        3                paint, wood

    Thailand              1976          6                agriculture                        IRPTC (1989)
                          1982          10.4

    United Republic       1981-2        640              coffee beans, tomatoes             IRPTC (1989)
    of Tanzania

    USA                   1976          2000             by farmers on major crops          IARC (1983)
                          1978          300              mildewcide in paint                IARC (1983)
                          1980          5000             53% peanuts, 31% vegetables,       IARC (1983)
                                                         12% turf, 5% potatoes

                                                                                                           
    
    of use for a variety of purposes are shown in Table 6.  Spray volumes
    usually range from about 200 to 400 litres/ha for dilute sprays and 45
    to 95 litres/ha for concentrated sprays.  Applications should commence
    when weather conditions favour disease, e.g., high humidity, and prior
    to initial infection.  Repeat applications may be needed as directed
    on the label for the country concerned.  Examples of crops, diseases
    controlled, agronomic importance, application rates, timing of
    treatment and pre-harvest intervals on a variety of crops in the
    Netherlands have been given by FAO (1982).  A summary of approved uses
    for grapes, including formulation used, application rates, number of
    treatments and pre-harvest interval for a variety of countries, has
    been given by FAO/WHO (1986a).

         Chlorothalonil formulations are compatible in use with many other
    fungicides and insecticides and combined formulations are registered
    and available for use in many countries.

    Table 6.  Ranges of application rates for chlorothalonil

                                                                      

                                               Application rate
                                        (kg active ingredient per ha)
                                                                      

    Agronomic crops:
       Corn, lentils, peanuts, potatoes,            0.875-2.0
       soybeans, wheat, barley, rice

    Tree fruit crops:
       Stone, citrus, nut, pome                     1.25-3.5

    Small fruit:
       Cranberry, blackberry, grape                 1.25-5.85

    Vegetable crops                                 0.875-2.5

    Ornamentals                                     1.25-2.5

    Turf                                            4.5-25.0
                                                                      

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    4.1  Transport and distribution between media

         The sorptive characteristics of chlorothalonil have been
    investigated to estimate its potential for contamination of aquifers
    after application to a cranberry bog (Reduker et al., 1988).  The soil
    studied was mainly sandy in character.  The studies included a kinetic
    and an absorption equilibrium assessment, the soil being shaken with
    chlorothalonil in water for periods up to 48 h, and a soil column
    study with 2.8 mg chlorothalonil/100 ml at a flow rate of 642 ml/day
    for 64 days.  A linear adsorption relationship was established with a
    partition coefficient for chlorothalonil of 74.4 ml/g for this soil. 
    Very little (< 22%) of the adsorbed chemical was recovered.  The soil
    column study produced a dispersion coefficient of 100 cm2/day.  Only
    a small proportion (less than 2.8%) of chlorothalonil appeared in the
    effluent or was extracted from the soil, indicating either
    irreversible adsorption, degradation, or both.

         The movement of chlorothalonil in a sandy soil was observed on a
    commercial farm with a high water table and a tile drain system in
    Manitoba, Canada.  Chlorothalonil was routinely sprayed on irrigated
    crops such as potatoes and barley.  In one season it was detected in
    the tile drain water on 4 out of 66 sampling days at concentrations of
    0.04-3.66 µg/litre.  In the same period chlorothalonil was also found
    in groundwater from a well on the site at levels of 10-272 µg/litre. 
    There was some evidence of a small amount of carry-over into the
    following season (Krawchuk & Webster, 1987).  They also reported
    serious background contamination problems due to the autosampler. 
    When these problems were corrected (i.e., 1983), the residue levels in
    the well ranged from 0.9 to 8.6 µg/litre.  In this report, the authors
    interpreted their data to demonstrate both leaching and potential 
    carry-over.  However, it should be noted that an initial tile water
    outflow sample, taken in 1981, showed no detectable chlorothalonil
    (i.e., < 0.02 µg/litre), although chlorothalonil was applied to the
    site that year.

         Water/sediment measurements were made after aerial spraying of a
    potato crop in Canada (O'Neill, 1991).  The area oversprayed included
    a small water course with a pond.  The results showed a rapidly
    decreasing chlorothalonil content in the water phase after
    overspraying, little or no compound being found in the sediment
    (63-91% sand).  The author indicated that sediments with greater clay
    or silt content would play a greater role in chlorothalonil transport.

         Analysis of stream water samples containing chlorothalonil showed
    significant binding to suspended material, with an average log
    partition coefficient (log PSm/w) of 5.695 and an average of 81% 

    chlorothalonil being bound to the suspended matter. Algal growths on
    stream pebbles played a dominant role in chlorothalonil removal by
    absorption and biodegradation.  It was also shown that  Galaxias
     auratus enhanced chlorothalonil loss in fish tanks by a factor of 25
    times (Davies, 1988).

         Chlorothalonil does not translocate from the site of
    application to other parts of a plant.  For example, ring-labelled
    14C-chlorothalonil does not translocate when applied topically to
    cucumber, bean or tomato leaves.  It was not translocated into the
    aerial parts of corn or tomato plants when they were cultivated for 23
    days in soil treated with 14C-chlorothalonil.  There was no movement
    or translocation of radioactivity within the root systems of sweet
    corn, cucumber or tomato grown in soil treated with ring-labelled
    chlorothalonil.  This also indicated that the major 4-hydroxy
    metabolite in soil was not translocated (Kunkel, 1967a,b).

         Chlorothalonil residues remaining on food crops at harvest may
    enter the human food chain.  Residues in foodstuffs may be further
    reduced by processing and cooking (see sections 5.1 and 5.2).

    4.2  Transformation

    4.2.1  Biodegradation

         Studies with river water from two sources in Tasmania showed that
    loss of chlorothalonil was slow in still water.  Comparison of loss
    rates at 5 and 15°C indicated involvement of enzymic processes. 
    Uptake by algal growths also indicated biodegradation with the
    appearance of polar metabolites. However, biodegradation is unlikely
    to play a major role in the fate of chlorothalonil in moderate to fast
    flowing streams, where volatilization and adsorption are liable to be
    dominant factors (Davies, 1988).

         Chlorothalonil is rapidly degraded in soil under both laboratory
    and field conditions.  In laboratory experiments its half-life ranged
    from 4 to 40 days in various types of soil.  The rate increased with
    increasing organic matter content, moisture and temperature.  It
    appeared that little was lost due to volatilization.  On turf plots at
    three locations in the USA, the half-life of chlorothalonil ranged
    from 26 to 45 days after treatments (Stallard & Wolfe, 1967).  The
    major soil degradation product is the 4-hydroxy metabolite,
    4-hydroxy-2,5,6-trichloroisophthalonitrile.  Laboratory studies in
    five soils showed half-lives for the 4-hydroxy metabolite of 36 days
    in a sandy loam and up to 220 days in clay type soil (Wolfe &
    Stallard, 1968).  It has been shown that bacteria isolated from soil
    are capable of metabolizing chlorothalonil in culture media.  It can
    be deduced that soil microorganisms play a role in the rapid
    degradation of chlorothalonil in soil (Duane, 1970).

         Degradation of chlorothalonil in soil involves a series of
    parallel processes, one of which involves formation and dissipation of
    4-hydroxy-2,5,6-trichloroisophthalonitrile (SDS-3701).  Chlorothalonil
    dissipation data were re-analysed to obtain half-life estimates for
    SDS-3701 soil dissipation.  Assuming first order kinetics, non-linear
    least-squares regression modelling was used to estimate the values of
    the model parameters.  For SDS-3701, half-lives between 6 and 43 days
    were determined for the various non-sterile soils.  An alternative
    method of data analysis, utilizing a transformation and a linearizing
    approximation, was also used and gave a similar range of half-lives
    (Jacobson & Schollenberger, 1992).

         The dissipation of chlorothalonil in soils was suppressed by the
    repeated applications of this fungicide to the soils.  The dissipation
    was due to microbial action, since chlorothalonil disappeared in a
    nonsterile soil but not in an autoclaved soil.  The amendments of the
    soil with easily decomposable organic materials recovered the
    suppressed dissipation ability of the soil.  The results suggested
    that easily decomposable organic materials play an important role in
    the microbial degradation of chlorothalonil in soil (Katayama, et al.,
    1991).

         Fig. 1 lists the structure and identification code of the five
    soil metabolites that have been identified in aerobic soil studies
    involving 14C-chlorothalonil in the laboratory.  Identifications were
    based on independent synthesis of authentic standard and GLC or
    HPLC/MS confirmations.  It should be noted that the scheme is a
    suggested pathway (Frazier, 1993).  There is no direct evidence that
    any of the five soil metabolites are converted directly to "bound"
    residue. Typical dissipation curves (Figs. 2, 3, 4) show the
    dissipation of chlorothalonil and the formation/dissipation of the
    4-hydroxy-metabolite (SDS-3701); note that the scale for time is not
    linear. These same dissipation curves show the formation of bound
    residue. Attempts to liberate and characterize this bound residue have
    produced limited characterization data and no definitive structure
    identifications.

         A complete picture of all of the known transformations which
    occur with chlorothalonil under various environmental conditions is
    given in Fig. 5 (ISK Biosciences, 1995).

    FIGURE 2

    FIGURE 3

    FIGURE 4

    FIGURE 5

    FIGURE 6

         On plants, chlorothalonil is metabolized only to a limited extent
    to the 4-hydroxy metabolite.  The majority of the residue remains as
    the parent compound.  Generally less than 5% of the total residue is
    present as the 4-hydroxy metabolite.  A review of plant residues
    worldwide showed that the 4-hydroxy metabolite level was < 0.1 mg/kg
    in most of the crops analysed.  It accounted for approximately 10% of
    the total residue in lima beans, 5% in cantaloupes, 2% in peaches and
    onions, 1% in celery and 0.1% in peanuts (FAO/WHO, 1985).  The decline
    of chlorothalonil residues and the appearance and decline of the
    4-hydroxy metabolite on onions is shown in Table 7 (personal
    communication to the IPCS by the Government of Canada, 1979).  The
    chlorothalonil residue decayed with a half-life of about 3 days.

         Studies with corn silage showed that 90% of chlorothalonil
    degraded within 18 days (30 to 3 mg/kg).  The half-life was
    approximately 4 days.  In a second experiment, the 4-hydroxy
    metabolite formation was very low in the bound materials (which were
    converted to an extractable form), representing only about 2% of the
    chlorothalonil on the first day of ensiling (FAO/WHO, 1978).

         After chlorothalonil was applied to growing peanut foliage at
    1.26 kg/ha its half-life was 13.6 days (range 7-19 days) under the
    field conditions of use (Elliott & Spurr, 1993).

         In the excretion of 14C-chlorothalonil metabolites from rainbow
    trout  (Salmo gairdneri), the almost complete absence of
    chlorothalonil itself and the accumulation of 14C entities in the
    bile indicated the possibility of glutathione conjugation as the first
    step in chlorothalonil metabolism (Davies & White, 1985).  Further
    studies showed the existence of mono- and diglutathione conjugates of
    chlorothalonil in the bile of rainbow trout exposed to
    14C-chlorothalonil (Davies, 1985a).

         Studies with liver cytosol from five fish species showed that the
    enzyme glutathione- S-transferase (GST) is involved in the conversion
    of chlorothalonil to polar conjugates.  Comparisons of GST activity in
    rainbow trout organs revealed that the potential for chlorothalonil
    transformation was in the order liver » kidney > spleen, with no
    activity in bile.  Low concentrations of chlorothalonil in water
    induced fish GST activity for its biotransformation.  Hepatic
    glutathione (GSH) and GST activity for chlorothalonil transformation
    were compared in three species of fish  (Oncorhynchus mykiss,
     Galaxias maculatus and  Galaxias auratus).  The order of their
    asymptotic LC50 values agreed with that of their hepatic GST
    activities for chlorothalonil transformation and was consistent with a
    detoxification role for GSH-chlorothalonil conjugation (Davies,
    1985b).  A study involving co-exposure to zinc and chlorothalonil
    indicated that metallothionein does not play a significant role in
    chlorothalonil detoxification in fish at sublethal exposures (Davies,
    1985c).

         Small amounts of the 4-hydroxy metabolite were found in the milk
    and kidney of a cow fed 250 mg chlorothalonil/kg in its feed.  Only
    0.2% of the ingested chlorothalonil was eliminated in the milk as the
    4-hydroxy metabolite (Ladd et al., 1971).

    4.2.2  Abiotic degradation

         Chlorothalonil does not break down in aqueous solution
    (0.5 mg/litre) in the dark at pH 5 or 7.  It is hydrolysed at pH 9,
    over 50% disappearing in 49 days, with the formation of 4-hydroxy-
    2,5,6-trichloroisophthalonitrile  and  3-cyano-2,4,5,6-tetrachloro-
    benzamide (Szalkowski & Stallard, 1977).

         Chlorothalonil degrades very slowly under aqueous photolytic
    conditions to the 4-hydroxy metabolite.  The half-life was found to be
    approximately 65 days (ISK Biotech proprietary information).

    4.2.3  Bioaccumulation

         In a study of the uptake and elimination of 14C-chlorothalonil
    in rainbow trout, two groups of fish were exposed to 10 µg/litre of
    the compound in flow-through tanks for 96 h (Davies & White, 1985). 
    After exposure was discontinued, the depuration rate was followed for
    96 h.  There was a very high uptake in the gall bladder and bile
    (concentration factors up to 4.4 × 105).  Uptake was also high in the
    hind gut, liver, fat and kidney with concentration factors of
    2-11 × 103.  After 96 h of exposure, the concentration factor in
    muscle was 940 and 740, respectively, for the two groups of fish, a
    level which may give an indication of the magnitude of the whole body
    bioconcentration factor (BCF) for rainbow trout (not measured).

         After transfer to clean water, gall bladder levels dropped
    rapidly, and so did gill and blood levels.  In one group of fish,
    concentrations in both liver and kidney doubled until 24 h after
    transfer and thereafter dropped to the levels in the other group. 
    Concentrations in the spleen in both groups continued to increase
    throughout the depuration period.  Muscle levels dropped only slowly
    and remained around 1 µg/g.  The high concentrations found in the gall
    bladder and bile are consistent with the fact that chlorothalonil is
    excreted from fish as glutathione conjugates (Davies & White, 1985).

         Bluegill sunfish exposed to 8 µg 14C-chlorothalonil/litre in a
    flow-through system for 30 days showed a plateau of 14C uptake within
    14 days.  The residues in whole fish at 30 days were 264 times the
    water concentration.  When the fish were placed in clean water, 80% of
    the radioactive residues were lost within 14 days. Bioaccumulation in
    catfish, in a static system, showed a 16-fold concentration at 26
    days.  In this case 90% of the 14C residues were depurated in 14 days
    after removal from the treated water.  The 4-hydroxy metabolite did
    not bioaccumulate in fish (SDS Biotech Corporation, 1972).

         In tanks containing stream water with chlorothalonil at
    20 µg/litre, uptake of the compound occurred in algal growths attached
    to bottom pebbles.  Analysis of the algal growths showed a
    concentration factor for chlorothalonil of 270 times after 14 days of
    static exposure.  Since this represented only 9.5% of the initial dose
    it seems that the removal of chlorothalonil from the water is enhanced
    by its conversion to polar metabolites in addition to bioconcentration
    (Davies, 1988).

    4.3  Waste disposal

         Chlorothalonil can be incinerated in units operating at 850°C
    fitted with off-gas scrubbing equipment (Lawless et al., 1975).

         The disposal methods for waste pesticides and containers
    advocated by FAO and GIFAP should be applied to unused chlorothalonil
    products and their empty packages (FAO, 1985; GIFAP, 1987).

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Air

         Chlorothalonil was detected (amongst other pesticides) in 3 out
    of 9 outdoor and indoor samples and 1 out of 9 personal monitoring
    samples in 9 homes in Jacksonville, Florida, USA.  No actual figures
    were reported (Lewis et al., 1988).

         Average exposures to chlorothalonil of 173 persons in
    Jacksonville, Florida and Springfield, Massachusetts, USA were
    0.7 ng/m3 (personal exposure) and 0.5 ng/m3 (outdoor air
    concentrations) (Wallace, 1991).

         Chlorothalonil was not detected in 51 samples in an Environmental
    Survey of Chemicals in Japan in 1991 (personal communication by the
    Office of Health Studies Environment Agency, Tokyo, 1992).

    5.1.2  Water

         O'Neil (1991) studied concentrations of chlorothalonil in water
    and sediment following overspraying of a pond (0.2 ha and 0.5 m deep)
    at 875 g a.i./ha (Ernst, 1991).  Water and sediment were monitored in
    a stream flowing out of the pond at the outlet and 30 m downstream. 
    The stream was approximately 1 m wide and 0.5 m deep and ran at
    0.033 m3/sec for the first overspray and at 0.015 m3/sec for the
    repeat spray.  Whole water samples were filtered for separate
    measurement of chlorothalonil in water and sediment.  Following the
    first spraying, samples were taken at the downstream site at 30 min
    intervals up to 6 h after spraying and further samples were collected
    10 and 24 h after spraying.  Initial water concentrations of up to
    60 µg/litre fell rapidly to around 15 µg/litre 2 h after spraying. 
    The water concentration was 1.9 µg/litre 10 h after spraying, and at
    24 h there was no measurable chlorothalonil.  In the second spraying
    at the lower stream flow rate, whole water samples were taken more
    frequently over the 2 h following application.  Concentrations peaked
    at 350 to 450 µg/litre at the pond outlet and 30 m downstream,
    respectively, 20 to 30 min after application, falling to between 50
    and 100 µg/litre at 2 h.  A concentration of 6.3 µg/litre was found
    12 h after spraying.  Total chlorothalonil mass was measured on
    suspended sediment following the first spraying and showed 10 µg
    persisting for 1.5 h after spraying and thereafter falling to
    approximately 0.01 µg at 10 and 24 h.  The report did not make clear
    the volume of water filtered, which appears, however, to have been
    1 litre.  Environmental conditions such as total organic carbon (TOC),
    pH, temperature and water hardness were not reported; consequently
    their impacts on degradation could not be evaluated.

         Chlorothalonil was detected on occasions at concentrations up to
    3.6 µg/litre in a tile drainage system from a farm in Manitoba,
    Canada, where the fungicide was sprayed routinely.  It was detected on
    one occasion (0.06 µg/litre) in the sump well outflow draining to a
    municipal ditch (Krawchuk & Webster, 1987).

         Over a 5-year period (1986-1990), water was sampled and analysed
    from 1300 community water systems and rural domestic wells for 101
    pesticides, including chlorothalonil.  Chlorothalonil was not detected
    in any of these samples although the reporting limit was 0.12
    µg/litre, which represented the minimum quantification limits for this
    particular pesticide in the study (US EPA, 1990).

         Chlorothalonil was not detected in 57 water samples, 30 sediment
    samples and 30 fish samples in an Environmental Survey of Chemicals in
    Japan in 1991 (personal communication by the Office of Health Studies,
    Environment Agency, Tokyo, 1992).

    5.1.3  Soil

         Levels of chlorothalonil and its metabolite SDS-3701 (see section
    4.2.1) in soil were reported after three annual treatments (Kenyon &
    Ballee, 1990; King et al., 1991, 1992).  Four plots were established
    of bare untreated and treated, winter wheat treated and untreated at
    two different sites, Osterwede and Rohlstof (Germany).  Treatment
    consisted of an annual chlorothalonil application of 2.2 kg a.i./ha. 
    Soil samples were taken before and after each treatment.  No
    chlorothalonil was detected in any of the untreated samples. 
    Consistently there was no carry over from one year to another.  Levels
    in soil were highest 2 or 3 days after the treatment (sampling
    depended on the sites), with mean levels in the bare plots around 0.40
    mg/kg and in those with wheat around 0.34 mg/kg (values ranging
    between 0.07 and 0.64 mg/kg).  Between 52 and 60 days after each
    treatment, levels were 0.02-0.03 mg/kg in plots with wheat while in
    bare plots they were generally below the detection limit of 0.01
    mg/kg.  Before each treatment in the previously treated plots the
    level of metabolite SDS-3701 ranged from the limit of detection (0.01)
    to 0.03 mg/kg, which was the same as the level 2 or 3 days after
    treatment.  However, between 52 and 60 days after treatment (depending
    on the site) levels rose at the Osterwede site to 0.07 mg/kg for the
    bare treated plot.  One year after the last treatment, levels of
    SDS-3701 ranged from the detection limit to 0.03 mg/kg.

    5.1.4  Food crops

         Chlorothalonil is used as a broad spectrum fungicide on
    vegetables, fruit trees, small fruit bushes and other agricultural and
    horticultural food crops.  Its use is intended to protect crops up to
    harvesting, hence small residues will be present at that time.  The 

    residue levels expected in crops at harvest can be derived from the
    numerous supervized trials that have taken place on many crops in
    countries all over the world (FAO/WHO, 1975, 1978, 1979, 1980, 1982,
    1985a, 1986a, 1990a).

         The amount of residue at harvest depends upon factors such as the
    application rate, time interval between the last application and
    harvest, and the type of crop.  Residues are composed mainly of
    chlorothalonil, and only negligible amounts of the metabolite
    4-hydroxy-2,5,6-trichloroisophthalonitrile (SDS-3701) are present (see
    Table 7 for example).

         The decline of chlorothalonil residues on food crops after
    application is shown by the field treatment of apples and pears
    against  Botryris cynerea by spraying with a chlorothalonil flowable
    formulation and then harvesting at intervals after treatment (Camoni
    et al., 1991).  The results are shown in Table 8.

    Table 8.  Decline of chlorothalonil residues

                                                                      

         Days after treatment            Pears             Apples
                                         (mg/kg)           (mg/kg)
                                                                      

         0                               3.85              2.35
         7                               2.48              1.73
         14                              2.00              0.92
         28                              1.35              0.98
                                                                      

    From: Camoni et al. (1991)

         Similar examples of the decline of chlorothalonil residues have
    been given for grapes in Australia, Germany and South Africa (FAO/WHO,
    1985a).  The decline of residues in onions is shown in Table 7.  The
    distribution of the residues on this plant showed that the levels in
    the older outer leaves were about 5 times above those in the younger
    leaves (2.4 and 0.51 mg/kg, respectively).

         Pre-harvest intervals are set on the basis of supervized trials,
    e.g., 7 days for apricots, and cherries in Australia, 7-14 days for
    grapes in Australia and 7 days for onions in the Netherlands (FAO/WHO,
    1990a).

         One of two samples of currants from growers in the United Kingdom
    had a residue level of 7.5 mg/kg 54 days after the last of three
    treatments at half the recommended rate of application.  The residue
    level on the second sample was < 0.5 mg/kg 76 days after two
    applications at the maximum rate (UK, 1985).

    5.1.5  Dairy produce

         There have been no reports of chlorothalonil residues in dairy
    produce.  However, some indication can be gained from studies on dairy
    cattle fed high levels of the compound.  In one cow fed 250 mg
    chlorothalonil/kg feed for 44 days, no chlorothalonil was detected in
    the milk and only 0.2% of the dose appeared as the 4-hydroxy
    metabolite.  Neither compound could be detected in muscle or fat and
    only a low level of the 4-hydroxy metabolite (0.7 mg/kg) was found in
    the kidney (Ladd et al., 1971; Wolfe & Stallard, 1971).  In another
    study, groups of four cows were fed chlorothalonil combined with the
    4-hydroxy metabolite at levels up to 250 and 0.6 mg/kg, respectively,
    for 30 days.  At the end of the period half the cows were sacrificed
    and half continued for a 32-day recovery period.  No chlorothalonil
    (< 0.02 mg/kg) was found in milk.  Small residues of chlorothalonil
    and the 4-hydroxy metabolite were detected in muscle, fat, liver and
    kidney after 30 days administration but none were detected in these
    organs after the 32-day recovery period (FAO/WHO, 1975).  No
    chlorothalonil (< 0.03 mg/kg) was detected in milk from a cow fed the
    compound at 5 mg/kg in its rations for 4 days (Gutenmann & Lisk,
    1966).

    5.1.6  Animal feed

         Dry cannery waste (tomato pommace), sometimes used for animal
    feed, contained < 1 mg/kg chlorothalonil plus its 4-hydroxy
    metabolite (in the ratio 6:1) as a residue (FAO/WHO, 1978).

    5.2  General population exposure

    5.2.1  Food

    In a study of imported fruit and vegetables in Finland, chlorothalonil
    levels of 0.02-0.15 mg/kg in strawberries, 0.01-0.86 mg/kg in Chinese
    lettuce and 0.12-1.2 mg/kg in peaches were found (personal
    communication to the IPCS by the Government of Finland, 1979).

         No chlorothalonil (< 0.01 mg/kg) was detected in a US Food and
    Drug Administration (FDA) total diet study in the USA in 1976 or 1977
    (personal communication to the IPCS by J.R. Wessel, 1979).  In a
    Canadian total diet survey, chlorothalonil was detected in one out of
    six composite samples of garden fruits at the detection level (0.02
    mg/kg).  On the basis of this one sample, a dietary intake of 0.04 µg
    per person per day was estimated (McLeod et al., 1980).

         Chlorothalonil was detected (0.001-1.35 mg/kg) in most samples of
    apples, peaches and other fruit and vegetables marketed in Tokyo
    (Koseki et al., 1980).

         No chlorothalonil (< 0.005 mg/kg) was detected in samples of
    potatoes in Sweden in 1979.  During 1981-1983, 1070 out of 1085
    samples of domestic and imported commodities in Sweden had
    chlorothalonil residues below 0.21 mg/kg.  Samples having higher
    residues included one of cauliflowers (out of 165) at 0.41 mg/kg, one
    of cucumbers (out of 580) at 0.23 mg/kg and two of strawberries (out
    of 143) at 2.9 mg/kg (personal communication: data submitted to the
    IPCS by the Government of Sweden and entitled "Chlorothalonil residues
    in imported and domestic commodities - 1981 to 1983").

         In 1982, analysis at the point of retail in the United Kingdom
    showed chlorothalonil residues below 0.5 mg/kg in 41 samples of
    strawberries, 15 of gooseberries, 13 of currants and 9 of berries. 
    Other analyses during 1981-3 showed that only one out of 30 samples of
    imported strawberries, 2 out of 15 samples of domestic celery and 5
    out of 40 of gooseberries had chlorothalonil residues above 0.1 mg/kg
    (UK, 1985).

         In the United Kingdom, chlorothalonil residues in bananas
    (imported), chinese cabbage (all origins) and parsnips (United Kingdom
    origin) were below the reporting levels of 0.2, 1.0 and 0.01 mg/kg,
    respectively, in 1988-1989.  During the same period, one sample out of
    ten of imported strawberries contained 0.1 mg/kg (UK MAFF & HSE,
    1990).

         Residues of chlorothalonil in foodstuffs are decreased by
    processes such as washing.  For example, it was shown that 94% of the
    residue could be removed by washing tomatoes and that there was no
    detectable residue in canned tomato pulp, paste or juice.  Peaches
    washed in water followed by a caustic rinse showed a 97% removal of
    field residues.  No chlorothalonil was detected in canned peach puree
    (FAO/WHO, 1978).

         In a Honduran study, unwashed bananas had a maximum residue level
    of 0.17 mg/kg and a mean of 0.08 mg/kg.  This was reduced to 0.02
    mg/kg after washing.  No chlorothalonil was found in the edible pulp
    (< 0.01 mg/kg).  Similar results were obtained in the Philippines
    (FAO/WHO, 1980).

         Trimming and peeling also removes a large proportion of residues
    from some foodstuffs.  For example there are significant reductions
    after trimming the outer leaves from cabbages and lettuces.  Most of
    the residue is removed when cucumbers, melons, peanuts and potatoes
    are peeled (Diamond Shamrock, 1974).

         As much as 85-98% of chlorothalonil added to tomatoes or green
    beans was lost during cooking in open vessels.  Only 2.4% was
    converted to the 4-hydroxy metabolite, which was stable to cooking
    (SDS Biotech Corporation, 1983a).

    5.3  Occupational exposure

         The exposure of a tractor driver applying chlorothalonil to
    ornamental plants in Florida, USA, was assessed.  Total-body exposure
    rates, estimated from external exposure pads and air sampling, were
    low (approximately 5 mg a.i./h) (Stamper et al., 1989a).  In the case
    of a greenhouse drencher, this exposure was approximately 100 mg
    a.i./h (Stamper et al., 1989b).

         Occupational exposure to four insecticides and two fungicides was
    measured for 151 commercial tree and shrub applicators in the USA who
    used hand-held equipment when spraying pesticides.  The study was
    conducted for 3 consecutive years: 1985, 1986 and 1987.  Worker
    exposure was determined by collecting full-shift, breathing zone air
    samples.  Sampling was conducted with battery-operated constant-flow
    air-sampling devices.  Chlorothalonil was detected in only one out of
    14 samples at 0.011 mg/m3 (Leonard & Yeary, 1990).

         Spencer et al. (1991) estimated the dermal exposure of workers on
    mechanical tomato harvesters to residues of chlorothalonil.  An
    average of 499.6 µg/h was obtained by gauze pad dosimeters placed
    outside the workers' clothing, whereas 43.4 µg/h was obtained by
    undershirt dosimetry.  The results showed that regular work clothing
    provides an excellent protection (90% reduction in dermal exposure)
    against chlorothalonil.  Air concentrations in the field were also
    determined and averaged 0.002 to 0.02 µg/litre, which contributed 8 to
    28% to the total exposure.

         The exposure of 11 pesticide operators mixing, loading or
    applying chlorothalonil fungicide formulations by aerial or ground
    applicators has been assessed.  The highest exposure was on the hands
    (1.7 mg/m2 per h) (Diamond Shamrock, 1980).

    6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

    6.1  Absorption

         Biliary excretion of radioactivity was studied in groups of six
    male Sprague-Dawley rats administered a single oral dose of 1.5, 5, 50
    or 200 mg/kg body weight 14C-chlorothalonil (98% radiochemically
    pure), uniformly labelled in the aromatic ring, as a suspension with a
    mean particle size of 3.6 to 5.0 µm in 0.75% methylcellulose in water. 
    The bile duct was cannulated and bile was collected in 1-h fractions
    for 48 h after dosing.  Blood, urine and faeces were also collected at
    various times after dosing and at termination.  During the 48 h after
    a single dose of 1.5, 5, 50 and 200 mg/kg body weight, biliary
    excretion was 22.5, 16.4, 16.3, and 7.7% of the administered dose,
    respectively.  Profiles of radioactivity excretion after the two low
    doses were quantitatively different from those obtained after the two
    high doses.  The authors interpreted these results as indicative of a
    change in metabolism occurring between 5 and 50 mg/kg body weight,
    possibly due to saturation of biliary excretion.  Mean urinary
    excretion during the 48 h after dosing was 8.0, 8.2 and 7.6% of the
    administered dose at 1.5, 5 and 50 mg/kg body weight, respectively,
    and only 4.7% at the high dose level of 200 mg/kg body weight. 
    Excretion of radioactivity in the urine within 6 h after dosing was
    inversely related to the dose administered.  Total recovery of
    radioactivity in this study was 89-99% in the three low-dose groups
    and 74% in the high-dose group.  After doses of 1.5, 5, 50 and
    200 mg/kg body weight, rats absorbed 32, 25.7, 25.9 and 15.5% of the
    administered dose, respectively. It was concluded by the authors that
    enterohepatic circulation or reabsorption of biliary metabolites from
    the gastrointestinal tract did not contribute significantly to the
    amount of radiolabel in the kidney.  Based on a one-compartment model
    for chlorothalonil absorption and excretion and using several
    assumptions, it was calculated that the rate of absorption of the
    200 mg/kg body weight dose was only twice as fast as that of the
    50 mg/kg body weight dose (Marciniszyn et al., 1986).

         In a study by Chin et al. (1981), absorption was compared by the
    oral, dermal and endotracheal routes with a 1 mg/kg body weight dose
    of 14C-chlorothalonil in male Sprague-Dawley rats.  The comparisons
    were made on the basis of blood levels and urine excretion.  In each
    case, absorption was highest by endotracheal administration and lowest
    by the dermal route.  Less than 6% of the administered dose was
    recovered in blood and urine within 48 h after dosing.

         When 14C-chlorothalonil was introduced into sacs formed from the
    upper section of rat small intestine, no unchanged substance passed
    through the mucosa and was transferred to the serosal side of the sac.
    These data suggest that chlorothalonil is very rapidly conjugated,
    since  in vivo studies have not identified chlorothalonil itself in
    body fluids or tissues after oral administration to rats (Savides et
    al., 1986e).

         14C-chlorothalonil was applied to the skin of male rats at an
    averaged dose of 1167 µg/rat (= 5 mg/kg) on an area of 25 cm2.  The
    amount absorbed was deduced from the amount remaining on the treated
    skin area and the amount of radioactivity found at each time interval
    in urine, faeces and carcass.  Approximately 28% of the applied dose
    was absorbed over the experimental exposure period of 120 h.  The
    absorption appeared to be time-dependent, about 6.3% of the applied
    dose being absorbed during each 24 h period.  Radioactivity appeared
    quickly in blood and rose steadily up to 72 h, when it reached a
    plateau (Marciniszyn et al., 1984a).

         In a study by Magee et al. (1990), four monkeys were treated
    dermally with 5 mg/kg body weight of 14C-chlorothalonil under a
    non-occlusive patch.  After 48 h the patch was taken off and the skin
    was washed.  About 90% of the dose was recovered from the surface and
    about 2.26% was completely absorbed through the skin.  The urine
    contained 1% of the dose, but methylated mono-, di- and trithiols were
    not detectable in the urine.

    6.2  Distribution

         Groups of male and female rats were administered
    14C-chlorothalonil orally, in microparticulate suspension, as single
    doses of 5, 50 or 200 mg/kg, and tissue activity was determined after
    2, 9, 24, 96 and 168 h (Marciniszyn et al., 1984b, 1985a).  With the
    exception of gastrointestinal tract tissues the greatest concentration
    of radioactivity was found in the kidneys, at each dose level,
    followed by those in liver and whole blood.  The peak concentrations
    in kidney occurred at 2 h after 5 mg/kg, 9 h after 50 mg/kg and 24 h
    after 200 mg/kg.  Similar shifts in peak time with dose occurred in
    the liver and blood.  In terms of the original dose, kidneys, liver
    and blood each contained 0.7% of the label 2 h after 5 mg/kg and 0.3%
    (kidney), 0.14% (liver) and 0.23% (blood) after 24 h in female rats.

         Distribution of radioactivity was also studied after repeated
    oral administration of 14C-chlorothalonil to male rats.  Five doses
    were given at 24 h intervals at concentrations of 1.5, 5, 50 or
    160 mg/kg.  The rats were killed 2, 9, 24, 96 and 168 h after the last
    dose.  The distribution of activity showed a similar profile to that
    after single dosing, i.e. the highest concentrations occurred in
    kidneys, followed by liver and blood, at all doses and times.  At all
    dose levels, the concentrations peaked 2 h after the last dose.  The
    percentage of the dose found in the kidney at this time was 0.28% and
    0.20% at the 1.5 and 5 mg/kg dose levels, which was significantly
    higher than that found at the higher doses (about 0.09%).  At dose
    levels up to 50 mg/kg there was significant depletion of radioactivity
    from the blood during the 24 h between doses.  In the kidney there was
    a trend to slower overall depletion with increase in dose (Savides et
    al., 1986a).

         A study in mice showed that the distribution of activity in
    non-gastrointestinal tract tissues was similar to that in rats after a
    single oral dose of 14C-chlorothalonil.  The kidney had the highest
    concentration of radioactivity after doses of 1.5, 15 or 105 mg/kg
    (Ribovich et al., 1983).

    6.3  Metabolic transformation

    6.3.1  Rat

         Male Sprague-Dawley rats were administered, via oral gavage,
    14C-chlorothalonil (purity 99.7%) at a dose level of 200 mg/kg in
    order to isolate and identify the urinary metabolites.  Urine was
    collected 17, 24 and 48 h after dosing.  Urinary metabolites accounted
    for 2.4% of the administered dose and, except for 30% of the
    radiolabel which was non-extractable from the urine, were found to be
    trimethylthiomonochloro-isophthalonitrile and dimethylthiodichloro-
    isophthalonitrile.  These thiols were excreted in urine both as free
    thiols and as their methylated derivatives.  The authors suggested a
    metabolic pathway such that hepatic metabolism proceeds through
    conjugation with GSH followed by enzymatic degradation.  The smaller
    conjugates are then transported via the bloodstream to the kidney,
    where they are converted to thiol metabolites and excreted in the
    urine (Marciniszyn et al., 1985b).

         A study was also carried out in rats given five daily oral doses
    of 14C-chlorothalonil (1.5, 5, 50 or 160 mg/kg per day).  Urine
    samples, acidified and extracted with ethyl acetate, showed decreasing
    extractability of radioactivity with increasing dose.  GC/MS analysis
    identified methylated or partly methylated dithiol and trithiol
    derivatives of chlorothalonil from the first dose onwards.  The
    percentage of the trithiol derivative excreted was constant with
    increasing dose while the dithiol increased with dose.  Multiple
    dosing resulted in a decreasing daily excretion of total thiol
    derivatives.  These results emphasize the probable involvement of
    glutathione in the metabolic pathway for chlorothalonil (Savides et
    al., 1986b).

         A group of three rats, pretreated with the gamma-glutamyl
    transpeptidase inhibitor AT-125, were dosed with 50 mg/kg
    14C-chlorothalonil, while three other rats were given chlorothalonil
    only.  Urine samples were acidified and extracted with ethyl acetate. 
    The group of rats pre-treated with AT-125 showed only 15% of
    radioactivity extractable after 12 h, while the other group showed 75%
    extractability.  The non-extractable fraction from the
    inhibitor-treated rats contained glutathione conjugates of
    chlorothalonil. The kidneys contained 2-3 times more radioactivity
    than those of the untreated rats.  These results gave further support
    to the hypothesis that glutathione is involved with chlorothalonil
    metabolism (Marciniszyn et al., 1988).

         The production of metabolites was also studied in groups of rats
    following dermal administration.  14C-chlorothalonil (4.6 mg/kg) was
    applied to a shaved area of the dorsal region.  The area was covered
    and exposure continued for 48 h.  Urine samples collected at 24 and
    48 h were acidified and extracted with ethyl acetate.  The extracts
    were submitted to reverse-phase HPLC/LSC followed by methylation and
    further clean-up.  The trithiol derivative of chlorothalonil was the
    major metabolite in all samples.  The excretion of total thiol
    metabolites was at least 20-fold less than that resulting from oral
    dosing at the same dose level (Savides et al., 1987a).

         The radiolabelled monoglutathione derivative of chlorothalonil
    was administered to male rats (115 mg/kg) as a single oral or
    intraperitoneal dose.  Six hours after intraperitoneal dosing the
    blood level was 10 times higher than after oral dosing.  The
    proportion of the administered intraperitoneal dose in the kidney was
    16 times higher than after oral dosing.  Urine from the orally dosed
    rats contained 9% trithiol derivative and 5% dithiol, while
    intraperitoneally dosed rats showed < 1% dithiol derivative and none
    of the trithiol in urine.  This indicates that the orally administered
    monoglutathione conjugate is further conjugated with glutathione in
    the gastrointestinal tract prior to absorption (Savides et al.,
    1986f).

         Nine germ-free male rats each received approximately 56 µCi
    14C-chlorothalonil in a single oral dose of 50 mg/kg.  Urine and
    faeces were collected over a 96-h period, and the urine was processed
    to identify and quantify thiol derivatives of chlorothalonil.  These
    derivatives were detected in only three of the nine rats and
    represented < 0.03% of the dose.  This is fifty times less than that
    obtained for normal rats.  There is therefore strong evidence that
    intestinal microflora make a significant contribution to the
    metabolism of chlorothalonil after oral administration in the rat
    (Savides et al., 1990a).

         The HPLC analysis of faecal extracts from rats dosed with 200 mg
    chlorothalonil/kg showed that 28% was excreted unchanged and 5% was
    converted to 4-hydroxy 2,3,5-trichloroisophthalonitrile.  The amounts
    after a dose of 5 mg/kg were 1.6 and 6.2%, respectively (Ignatoski et
    al., 1983).

         The HPLC analysis of faeces from rats given 14C-chlorothalonil
    orally at 5, 50 and 200 mg/kg showed the presence of at least seven
    radioactive components.  Two of the peaks had the same retention times
    as chlorothalonil and its 4-hydroxy metabolite.  A higher proportion
    of the metabolite was present after the 5 mg/kg dose than after the
    higher doses.  The majority of the activity was unextractable and was
    therefore bound to faecal components (Lee et al., 1982).

    6.3.2  Dog

         Male beagle dogs were given 14C-chlorothalonil at a dose level
    of 50 mg/kg either by gelatin capsule or by gavage.  In each case the
    urinary excretion of radioactivity was very small and none of the
    methylated thiol derivatives of chlorothalonil were detected (Savides
    et al., 1989, 1990b).

    6.3.3  Monkey

         Four male Chinese rhesus monkeys were dosed with
    14C-chlorothalonil by gavage at 50 mg/kg body weight suspended in
    0.75% aqueous methylcellulose.  Extraction of urine, collected over
    48 h, with acidified ethyl acetate showed that 32-65% of the
    radioactivity was extractable.  The total amount of chlorothalonil
    thiol derivatives excreted was 0.001-0.01% of the administered dose,
    mainly as the trimethylthiol entity.  This was more than 100 times
    less than that excreted from the rat (Savides et al., 1990c).

    6.4  Elimination and excretion

    6.4.1  Rat

         The main route of elimination of chlorothalonil from the rat
    after oral dosing is via the faeces.  The percentage eliminated was
    consistent for males and females, at doses of 1.5-200 mg/kg and from
    single or repeated doses.  The amount eliminated was consistently
    above 82%, the majority appearing in the first 48 h at low doses and
    within 72 h at high doses (Marciniszyn et al., 1984b, 1985a).

         Biliary excretion at dose levels up to 5 mg/kg is rapid, peaking
    at 2 h, and is more prolonged at levels of 50 mg/kg or more. 
    Excretion decreases with increasing dose, from 22.5% at 1.5 mg/kg to
    7.7% at 200 mg/kg over 48 h.  Studies using bile duct cannulation
    indicate that the excretion is saturated at 50 mg/kg or more. 
    Comparison with non-cannulated rats showed that there was no
    difference in the radioactive concentration found in the kidney,
    indicating that enterohepatic circulation of biliary metabolites did
    not play a significant role (Savides et al., 1986c).

         The fate of orally administered 14C-chlorothalonil (purity
    99.7%) at three dose levels (5, 50 and 200 mg/kg) was investigated in
    Sprague-Dawley rats to determine the effects of increasing doses of
    the test material.  Four animals of each sex at each dose level were
    killed 2, 9, 24, 96 and 168 h after dosing and urine, faeces and
    selected tissues were assayed for radioactivity.  The average recovery
    of the radiolabel at each of the dose levels was approximately 89% for
    males and 96% for females.  The major route of elimination was via the
    faeces (83-87%) and was essentially complete by 48 h in low-dose
    females and low/mid-dose males, and by 72 h in the mid/high-dose 

    females and high-dose males.  A delay in stomach-emptying time was
    observed for mid- and high-dose males and females.  Urinary excretion
    was 92-93% complete for low-dose rats within 24 h, mid-dose rats
    within 48 h, and 95% complete for high-dose rats within 72 h.  Urinary
    excretion of the radiolabel at the three dose levels was 5-7% of the
    administered dose in males and 5-11.5% in females.  Urinary excretion
    was essentially saturated as the dose level increased.  The highest
    concentrations of radiolabelled material in non-gastrointestinal
    tissues were found in the kidney, being approximately 0.7% of the dose
    per gram of kidney for males and 0.4% in females at peak concentration
    (2 h) for the 5 mg/kg dose level.  Kidney concentrations were greatest
    at 2, 9 and 24 h for the low, mid and high doses, respectively
    (Marciniszyn et al., 1984b, 1985a).

         When 14C-chlorothalonil was applied dermally to male rats at
    5 mg/kg the major route of excretion was the faeces.  Approximately 18%
    of the dose was excreted by this route in 120 h compared to about 6%
    via urine (Marciniszyn et al., 1984a).

         After administration of 1 mg chlorothalonil/kg by the oral,
    dermal or endotracheal routes, the excretion in urine during 24 h was
    2.9, 0.9 and 5.7%, respectively (Chin et al., 1981).

         A study involving intubation of the 4-hydroxy metabolite of
    chlorothalonil to rats at 4 or 43 mg/kg showed that the majority of
    the dose was excreted in the faeces and a small amount in the urine
    (Jarrett et al., 1978).

    6.4.2  Mouse

         In male mice, dosed orally with 1.5, 15 or 105 mg
    14C-chlorothalonil/kg, the major route of elimination was via the
    faeces.  This was complete by 24 h for the two lower doses and by 96 h
    for the highest dose.  Urinary excretion at all doses varied between 5
    and 10% of the administered dose (Ribovich et al., 1983).

    6.4.3  Dog

         Most of an oral dose of chlorothalonil was excreted in the faeces
    of beagle dogs.  Over 12 days, 99.6% was excreted from two dogs given
    50 mg 14C-chlorothalonil/kg by gelatin capsule, and 76-98% was
    excreted over 24 h when three dogs were given the same dose by gavage. 
    In both studies the amount excreted in urine was very small, and this
    occurred mostly within the first 10 h (Savides et al., 1989, 1990b).

    6.4.4  Monkey

         Oral administration of 14C-chlorothalonil to four male Chinese
    rhesus monkeys showed faecal elimination to be the main route of
    excretion, 52-92% of the dose (50 mg/kg) being excreted in 96 h. 
    Urinary excretion amounted to 1.8-4.1% of the dose.  Most of the
    radiolabel was eliminated in the first 48 h (Savides et al., 1990c).

    6.5  Reaction with body components

         Incubation of 14C-chlorothalonil with glutathione in aqueous
    medium in the presence or absence of glutathione- S-transferase
    resulted in the rapid disappearance of chlorothalonil and the
    appearance of more polar compounds.  These were identified as
    conjugates of chlorothalonil with glutathione, their formation
    following a step-wise process, i.e., from mono->di->triglutathione
    conjugates (Savides et al., 1985).  This reaction with glutathione
    parallels similar findings with chlorothalonil in other biological
    systems such as  Saccharomyces pastorianus (Tillman et al., 1973).

         The incubation of chlorothalonil with rat stomach or intestinal
    mucosal cells indicated that polar metabolites were formed which were
    chromatographically similar to glutathione conjugates of
    chlorothalonil (Savides et al., 1986d).

         The  in vivo action of chlorothalonil on glutathione (GSH) was
    shown in a rat study where chlorothalonil was dosed orally at
    5000 mg/kg.  Hepatic GSH was decreased by 40% 18 h later but recovered
    to a normal value after 48 h.  Kidney GSH increased to two times its
    control level after 48 h (Sadler et al., 1985).

         Chlorothalonil has been shown to bind to calf thymus histones,
    the rate and amount depending upon pH and type of histones.  There was
    little binding to DNA.  Treatment of rat liver nuclei indicated
    similar binding patterns to those for histones (Rosanoff & Siegel,
    1981).

         Groups of four rats were administered 50 mg 14C-chlorothalonil
    per kg orally, killed after 6 h and their kidneys excised.  The kidney
    tissue was homogenized, and protein and DNA were isolated.  Radiolabel
    was found to be bound to kidney protein but not to DNA (Savides et
    al., 1987b).  Kidney tissue from rats dosed 50 mg
    14C-chlorothalonil/kg orally was separated by ultracentrifugation
    into subcellular organelles.  The kidneys contained about 0.38% of the
    original dose, the majority of this activity (81%) being in the
    soluble fraction.  About 10% of the remaining activity was contained
    in the mitochondrial subfractions (Savides et al., 1987c).

         Studies with rat liver and kidney mitochondrial preparations
    showed that the dithiol derivative of chlorothalonil completely
    inhibited state 3 mitrochondrial respiration.  The monothiol
    derivative affected oxygen uptake by liver mitochondria but not by
    kidney mitochondria.  The mono- and diglutathione conjugates of
    chlorothalonil did not affect oxygen uptake by mitochondria.  Since
    cleavage of the glutathione conjugates to give the thiol derivatives
    takes place in the kidney, this may explain the toxic action of
    chlorothalonil in this organ (Savides et al., 1988; see also section
    7.8).

         Available evidence indicates that the enzyme ß-lyase is required
    for the formation of thiol derivatives from cysteine conjugates.  The
    activity of this enzyme has been assessed in rat, mouse and human
    kidney cytosolic fractions using the perchloroethylene metabolite
     S-(1,2,2-trichlorovinyl)-l-cysteine as substrate.  The activity of
    renal ß-lyase in human kidney was comparable to that of mouse, but was
    an order of magnitude lower than that in the rat (Green et al., 1990).

         The proposed metabolic pathway for the production of thiol
    derivatives from chlorothalonil in the kidney is shown in Fig. 6.

    FIGURE 7

    7.  EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

    7.1  Single exposure

         The acute toxicity of chlorothalonil by oral, dermal and
    inhalation routes of administration is shown in Table 9.  Signs of
    poisoning include depression, diarrhoea and unkempt appearance.  An
    oral LD50 could not be attained in the dog because of emesis. 
    Chlorothalonil administered orally (1 g/kg) to mice increased
    intestinal motility.  The laxative action was reduced by pre-treatment
    with corn oil (Teeters, 1966).
        Table 9.  The acute toxicity of chlorothalonil

                                                                           

    Species         LD50             Route         Reference
                    (mg/kg)
                                                                           

    Rat             > 10 000         oral          Powers (1965)

    Dog             > 5000           oral          Paynter (1965a)

    Mouse           6000             oral          Yoshikawa & Kawai (1966)

    Rat             332              oral          Wazeter (1971)
    (4 hydroxy
     metabolite)

    Rabbit          > 10 000         dermal        Doyle & Elsea (1963)

    Rat (f & m)a    0.22 mg/litre    inhalation    Danks & Fowler (1988)

    Rat (f & m)b    0.52 mg/litre    inhalation    Shults et al. (1991)

    Rat (f & m)c    0.10 mg/litre    inhalation    Shults et al. (1993)

                                                                           

    a   LC50 actual concentration
    b   Hammermilled technical chlorothalonil - 1 h exposure
    c   Hammermilled technical chlorothalonil - 4 h exposure
    
         The acute oral toxicity of the metabolite 4-hydroxy-2,5,6-
    trichloroisophthalonitrile is greater than that of chlorothalonil
    itself, the acute oral LD50 values being 332 and 10 000 mg/kg,
    respectively).

    7.2  Short-term exposure

    7.2.1  Oral

    7.2.1.1  Rat

         When groups of 35 male and 35 female rats were fed chlorothalonil
    in the diet at dose levels of 0, 250, 500, 750 or 1500 mg/kg diet for
    22 weeks, growth was slightly reduced at all levels in males and in
    the highest two levels in females.  Liver and kidney weight was
    increased in the two highest dose groups in males.  Kidney changes,
    more evident in males than females, occurred at all dose levels and
    included irregular swelling of the tubular epithelium, epithelial
    degeneration and tubular dilation (Blackmore & Shott, 1968).  In a
    separate study, no compound-related effects were seen in the kidneys
    of rats fed chlorothalonil at seven dietary levels from 1-120 mg/kg
    diet for 17 weeks (Busey, 1975).

         When groups of 20 male and 20 female rats were fed chlorothalonil
    in the diet (0, 40, 80, 175, 375 and 1500 mg/kg body weight per day)
    for 90 days, a significant dose-related reduction in body weight gain
    was seen at levels of 375 mg/kg per day or more which was allied to
    cathartic action at the two highest doses.  Male urine output
    decreased and specific gravity increased at the two highest dose
    levels.  Relative kidney weight was increased in both sexes at all
    dose levels.  A histopathological re-evaluation of the kidneys showed
    the presence of epithelial hyperplasia of the proximal convoluted
    tubules at all levels in males and at levels of 175 mg/kg per day or
    more in females (Wilson, 1981; Wilson et al., 1985c).

         Groups of 25 male and 25 female rats were fed chlorothalonil for
    13 weeks at 0, 1.5, 3, 10 and 40 mg/kg body weight per day.  Five rats
    of each sex per group were killed at 6 weeks, ten at 13 weeks and the
    survivors were killed after a further 13-week recovery period.  There
    was no effect on mortality, clinical condition, body weight, food and
    water consumption, haematology or urinalysis.  Increases in kidney
    (> 3 mg/kg per day) and liver (highest dose) weights and the
    incidence of hyperplasia and hyperkeratosis of the forestomach
    squamous epithelium (at 10 and 40 mg/kg per day) returned to normal
    when treatment ceased.  Histopathological re-examination of the kidney
    revealed (in males at the highest dose level) an increased incidence
    of hyperplasia of the epithelium of the proximal tubules at 6 and
    13 weeks and after a 13-week recovery period.  In a few animals this
    resulted in an increase in the size of the tubules.  An overall
    no-observed-effect level of 3 mg/kg body weight per day was
    established, based upon the lack of lesions in the squamous epithelium
    of the forestomach (Wilson et al., 1983a, 1985a).

         The kidney and stomach changes were investigated further in a
    study where 90 male rats were fed chlorothalonil (175 mg/kg body
    weight per day) for up to 91 days.  Groups of ten rats were killed 

    after 4 or 7 days and 2, 4, 6, 8, 10 or 12 weeks, the kidney and
    stomach taken for histopathological examination.  Groups of ten rats
    at each interval were taken from a control group and examined.  The
    forestomach effects of chlorothalonil were characterized initially as
    multifocal ulceration and erosion of the mucosa, developing to
    squamous epithelial hyperplasia and hyperkeratosis.  Within the first
    week there was vacuolar degeneration, cell death, karyomegaly and
    regeneration of the proximal tubular epithelium.  There was apparent
    recovery at day 14 with few lesions present in treated animals. 
    Continued administration led to tubular epithelial vascularization,
    regeneration, hyperplasia and hypertrophy (Ford et al., 1987a).

         Chlorothalonil or the monoglutathione conjugate of chlorothalonil
    was administered in the diet to male Fischer-344 rats in a 90-day
    study.  A third group of rats received only the vehicle (0.5%
    methylcellulose).  The oral administration of approximately equimolar
    doses of chlorothalonil (75 mg/kg per day) or the monoglutathione
    conjugate of chlorothalonil (150 mg/kg per day) resulted in
    significantly increased kidney weight and in treatment-related
    histopathological changes in the kidney.  The primary changes observed
    were morphologically similar for both compounds and were characterized
    by proximal tubular hyperplasia, tubular dilation (hypertrophy),
    vacuolar degeneration and interstitial fibrosis.  The oral
    administration of chlorothalonil resulted in gross and microscopic
    changes in the non-glandular portion of the forestomach.  The oral
    administration of the monoglutathione conjugate of chlorothalonil did
    not produce alterations in the rat forestomach.  The gross and
    microscopic changes observed in the forestomach of animals given
    chlorothalonil were considered to be due to the local irritational
    effects of chlorothalonil.  The alteration of the molecule by the
    addition of a single glutathione residue appeared to eliminate the
    irritation to the forestomach.  Thiol metabolites of chlorothalonil
    were detected in the urine of animals given either the monoglutathione
    conjugate of chlorothalonil or chlorothalonil itself.  The presence of
    the thiol metabolites, coupled with the similar histopathological
    changes in the kidney, suggests a common metabolic pathway.  The data
    support the conclusion that the nephrotoxicity produced by
    chlorothalonil is associated with conjugation with glutathione (Ford
    et al., 1987b; Wilson et al., 1990).

    7.2.1.2  Mouse

         Groups of 15 male and 15 female CD-1 mice were administered
    chlorothalonil in diets at levels of 0, 7.5, 15, 50, 275 or 750 mg/kg
    diet for 13 weeks.  Five animals per group were killed at 6 weeks. 
    There was no effect on clinical condition, mortality, body weight gain
    or food consumption.  Kidney weight was increased in females at 275
    and 750 mg/kg.  Microscopic re-examination revealed hyperplasia of the
    epithelium of the proximal convoluted tubules, minimal or slight in
    severity, in only 4 out of 15 males. This was not considered to be a 

    clear treatment-related effect.  There was an increased incidence of
    hyperplasia and hyperkeratosis of the squamous epithelial cells of the
    stomach in males and females at levels of 50 mg/kg or more.  Mucosal
    ulceration and submucosal inflammation were observed in some treated
    animals.  The no-observed-effect level was considered to be 15 mg/kg
    (3 mg/kg body weight per day) (Shults et al., 1983; Busey, 1985).

    7.2.1.3  Dog

         In a 30-day feeding study, encapsulated chlorothalonil (97.9%
    purity) was administered daily to groups of two male and two female
    beagle dogs at 0, 50, 150, or 500 mg/kg body weight per day.  The
    following tissues were examined macroscopically and microscopically at
    necropsy: brain, liver, kidneys, testes with epididymis, ovaries,
    adrenals, heart, thyroid, and parathyroid.  During treatment the
    high-dose dogs exhibited emesis and weight loss and reduced food
    consumption (males only).  Female dogs had slightly reduced body
    weight gains at all doses.  At necropsy, the liver weights of
    high-dose females were slightly increased.  There were no microscopic
    changes in the tissues examined.  Due to the reduced body-weight gains
    of treated females, a no-observed-adverse-effect level (NOAEL) was not
    established in this study (Fullmore & Laveglia, 1992; FAO/WHO, 1993b).

         In a 16-week dietary study, chlorothalonil (purity unspecified)
    was fed at 0, 250, 500 or 750 mg/kg to groups of four beagle dogs. 
    There were no compound-related effects on appearance, behaviour,
    appetite or body weight.  No changes in haematological parameters were
    found at weeks 0, 4, 13 or 16.  At termination, protein-bound iodine
    was found to be increased in all treated dogs.  Urinalysis at weeks 6,
    9, 13 and 16 was unremarkable.  No compound-related macroscopic or
    microscopic changes were found at necropsy.  In particular, only
    incidental changes were observed in liver and kidneys.  A NOAEL was
    not established in this study (Paynter & Murphy, 1967; FAO/WHO,
    1993b).

    7.2.2  Dermal: Rabbit

         Chlorothalonil (75% formulation) was applied to the intact or
    abraded skin of groups of rabbits at 0, 500 or 1000 mg/kg per day, 5
    days/week, for 3 weeks.  The treated groups comprised five males and
    five females per group, with two males and two females as controls. 
    Treatment resulted in dose-related irritation which was more severe
    with abraded skin.  Histopathological examination revealed a moderate
    degree of acanthosis, hyperkeratosis and slight to moderate leucocytic
    infiltration.  No abnormality was detected in other tissues (Paynter,
    1965b).

         Chlorothalonil was applied dermally each day for 21 days to
    groups of six male and six female rabbits at 0.1, 2.5 and 50 mg/kg per
    day.  The fungicide was suspended in 0.125% aqueous methylcellulose
    and covered 10% of the body surface when applied to the back.  Contact

    was for 6 h daily.  The only effect revealed by a wide range of
    observations and examinations was dermal irritation at 2.5 and 50
    mg/kg per day.  The histopathological changes seen were minimal to
    slight acanthosis and hyperkeratosis. The no-observed-effect level
    (NOEL) for dermal irritation was 0.1 mg/kg per day (Shults et al.,
    1986).

    7.3  Long-term exposure

    7.3.1  Rat

         An early study, lasting 76 weeks, produced evidence of kidney
    changes in rats (15 male and 15 female per group) fed high levels of
    chlorothalonil at 500, 1000 and 5000 mg/kg diet.  There was no
    overall effect on mortality, clinical condition or growth.  The
    compound-related changes in the kidney, at all levels, consisted of
    tubular hypertrophy, epithelial irregularities and vacuolation.  Males
    were more affected than females (Paynter & Busey, 1967).

         A 2-year study, reported in 1967, was initiated with
    chlorothalonil levels of 1500, 15 000 and 30 000 mg/kg diet with
    groups of 35 male and 35 female rats (70 of each sex in control
    group).  Because of cathartic effects, the top dose administration was
    curtailed after 15 weeks.  The rats in the two remaining treatment
    groups continued for the full 2 years with evaluations including
    haematology, biochemistry and histopathology.  There was no effect on
    survival, but the effect on growth was dose-related.  The relative
    organ weights of liver and kidney were increased at 15 000 mg/kg. 
    Microscopic changes in the forestomach were described as acanthosis
    and hyperkeratosis of the squamous epithelium at 15 000 mg/kg and, in
    the kidney, as tubular hypertrophy and hyperplasia at both 1500 and
    15 000 mg/kg diet (Paynter, 1967a).

         A supplementary study, run concurrently with the previous study,
    assessed chronic toxicity at 5000 mg/kg diet.  Growth rate was
    depressed and a cathartic action was expressed as increased water
    consumption and faecal excretion.  Relative organ weights were
    increased for caecum and kidneys.  Histopathological examination
    showed kidney changes as tubular hypertrophy and occasional
    degeneration of the proximal tubular epithelium (Paynter & Crews,
    1967).

         A 2-year study at six chlorothalonil dose levels between 4 and 60
    mg/kg diet was designed to determine an NOEL (50 males and 50 females
    per group).  No effects were seen on survival, clinical observations,
    growth, haematological or biochemical parameters.  No changes of
    toxicological significance were found for organ weights or during
    gross and microscopic examination of tissues.  The highest dose level
    (3 mg/kg body weight per day) was considered the NOEL (Holsing &
    Shott, 1970).

         A long-term study was undertaken to evaluate the carcinogenic
    potential of chlorothalonil in Fischer-344 rats.  Males were studied
    for 27 months and females for 30 months.  Chlorothalonil was
    administered in the diet to groups of 60 males and 60 females at dose
    levels of 0, 40, 80 and 175 mg/kg body weight per day.  There was no
    effect on survival of females or males up to 2 years.  However, at the
    highest dose level, there was increased mortality after 2 years, but
    only in males.  Decreases in body weight gain were dose-related at 80
    and 175 mg/kg per day. Treatment-related effects on other parameters
    appeared to be related to nephrotoxicity.  These included increases in
    serum urea nitrogen and creatinine, increased urine volume and
    decreased specific gravity, and increased kidney weight.
    Histopathological examination of the kidney showed a dose-related
    increase in chronic glomerulonephritis (nephropathy) compared with
    controls.  A re-examination of the kidneys also revealed tubular
    hyperplasia (a sign of preneoplastic change) and chronic progressive
    nephropathy in the treated groups.  Secondary lesions in other organs
    included periarteritis and parathyroid hyperplasia.  There was
    increased incidence or severity of hyperplasia and hyperkeratosis of
    the squamous mucosa of the oesophagus and forestomach in all dosed
    groups, which was probably the result of the irritant effect of
    chlorothalonil.  Neoplastic changes in the kidney and forestomach are
    evaluated in section 7.7 (Wilson et al., 1985b, 1986a).

         A further study was carried out to evaluate the neoplastic
    findings in the kidney and stomach seen in the previous study and to
    determine a NOEL for non-neoplastic effects.  Groups of 65 male and
    65 female rats were administered chlorothalonil in the diet at doses
    of 0, 1.8, 3.8, 15 and 175 mg/kg body weight per day.  Males were
    killed at 23 months (highest dose) and 26 months and females at
    29 months.  The effects at 175 mg/kg per day were similar to those
    described above, i.e. changes associated with the kidney and stomach. 
    At 15 mg/kg per day there was elevated serum urea nitrogen and
    slightly increased kidney weight.  At 3.8 mg/kg per day there was a
    small increase in kidney weight, but there were no effects at 1.8
    mg/kg per day.  Microscopic examination revealed an increased
    incidence and severity of epithelial hyperplasia in the proximal
    convoluted tubules at 3.8 mg/kg per day or more.  Clear cell
    hyperplasia of the proximal convoluted tubules was increased at
    15 mg/kg per day in females and at 175 mg/kg per day in both sexes. 
    In addition, at 3.8 mg/kg per day or more, there was an increased
    incidence and severity of hyperplasia, hyperkeratosis, ulcers and
    erosions of the squamous mucosa of the forestomach.  At 175 mg/kg per
    day, the incidence of erosions of the glandular stomach was
    significantly increased compared to controls.  Renal tumours at levels
    of 15 and 175 mg/kg per day and stomach tumours at 3.8 mg/kg per day
    or more are evaluated in section 7.7.  An NOEL of 1.8 mg/kg body
    weight per day was established for non-neoplastic effects seen in the
    study (Wilson et al., 1989a).

    7.3.2  Mouse

         A 2-year mouse study was carried out with 60 males and 60 females
    per group at 0, 750, 1500 and 3000 mg chlorothalonil/kg in diet. 
    There was a slightly increased mortality in males at the highest dose
    level but no effect was seen on body weight, food consumption,
    clinical condition or haematological parameters.  Kidney weight was
    increased in all treated groups compared to controls.  Non-neoplastic
    changes in the kidney were characterized as glomerulonephritis,
    cortical tubular degeneration and cysts.  The incidence of these
    changes, found at all treatment levels, was not dose-related but was
    considered to be due to treatment.  A histopathological re-evaluation
    of the kidneys revealed a high incidence of tubular hyperplasia in all
    male groups and a lower incidence in females.  Non-neoplastic effects
    in the stomach and oesophagus included hyperplasia and hyperkeratosis
    of the squamous mucosa, probably due to the irritant action of
    chlorothalonil.  The evaluation of kidney and stomach tumours found in
    this study is described in section 7.7 (Wilson et al., 1983b, 1986b).

         A second mouse study was undertaken to determine the NOEL for
    stomach and kidney changes in male mice.  Sixty males per group were
    fed chlorothalonil at levels of 0, 15, 40, 175 and 750 mg/kg diet for
    2 years.  Kidney weight and incidence of tubular hyperplasia were
    increased at 750 mg/kg and, very slightly, at 175 mg/kg.  The
    increased incidence of hyperplasia and hyperkeratosis of the
    forestomach was dose-related between 40 and 750 mg/kg.  The dietary
    NOEL for non-neoplastic effects was determined to be 15 mg/kg (1.6
    mg/kg body weight per day).  The tumour evaluation is considered in
    section 7.7 (Wilson et al., 1987).

    7.3.3  Dog

         In a 2-year study, chlorothalonil (93.6% purity) was fed to
    groups of four beagle dogs at dietary concentrations of 0, 1500,
    15 000 or 30 000 mg/kg (equivalent to 0, 37.5, 375, or 750 mg/kg body
    weight per day).  Eight dogs, one of each sex and of each group, were
    killed at 12 months and the remainder at 24 months.  One dog of each
    treatment group lost weight during the study.  There was a tendency
    towards mild anaemia in four of the mid-dose dogs at 2 years and at
    earlier intervals in two of the high-dose dogs.  Biochemical and urine
    analyses were unremarkable.  Absolute and relative thyroid and kidney
    weights, and liver to body weight ratios were increased at the
    mid- and high-dose levels.  Histopathological treatment-related
    changes occurred in the liver, thyroid, kidney and stomach of mid- and
    high-dose dogs; changes in low-dose dogs were equivocal.  In the
    liver, the findings were similar in nature (though slightly more
    pronounced) at low-dose levels to those in the control dogs, but they
    increased in severity at mid- and high-dose levels.  They included
    pericholangitis with associated portal fibrosis, bile duct hyperplasia
    and pigmentation of hepatic cytoplasm and of macrophages of sinusoids 

    and portal triads. Renal glomerulosclerosis and degenerative renal
    tubular changes (tubular hypertrophy and dilation) were found in the
    kidneys of mid- and high-dose dogs.  In the thyroid, markedly
    increased pigmentation of follicular epithelia occurred in mid- and
    high-dose dogs.  Moderate to severe gastritis was found irregularly in
    mid- and high-dose animals.  In summary, administration of
    chlorothalonil in the diet of dogs at concentrations of 15 000 and
    30 000 mg/kg caused irregular body weight reduction, borderline
    anaemia and histopathological changes in the liver, kidney, thyroid
    and stomach.  At 1500 mg/kg, the histopathological changes found in
    the liver were qualitatively similar but minimally to slightly
    increased in comparison to those found in control animals. 
    Histopathological changes to the other tissues were unremarkable at
    the low dose.  A NOAEL was not established in this study (Paynter &
    Busey, 1966; FAO/WHO, 1993b).

         Groups of beagle dogs (eight males and eight females per group)
    were fed chlorothalonil in the diet at dose levels of 0, 60 and
    120 mg/kg.  Four dogs of each sex per group were killed at one year
    and the remaining animals at 2 years.  There were no effects on
    behaviour or growth over the course of the study.  Clinical chemistry
    values, including haematological, biochemical and urine analyses, were
    comparable to the controls at all dose levels.  Gross and microscopic
    examination of tissues and organs performed on animals killed at 12
    months indicated a slight increase in the severity of renal tubule
    vacuolation in high-dose males.  Examination of tissues and organs at
    24 months showed a slight degree of renal tubule vacuolation in two
    out of four males at 120 mg/kg.  In the absence of other changes
    (urinalyses values) this finding was considered questionable,
    especially as a slight degree of vacuolation was noted in controls as
    well as other treated animals.  The NOAEL was considered to be
    120 mg/kg diet, equivalent to 3 mg/kg body weight per day (Holsing &
    Voelker, 1970; FAO/WHO, 1991, 1993b).

    7.3.4  Summary of key dietary studies

         A summary of the key dietary studies with chlorothalonil is given
    in Table 10.

    7.4  Skin and eye irritation; sensitization

         Chlorothalonil is an irritant to rabbit skin, as shown by
    repeated dose studies (5 days/week for 3 weeks at 500 or 1000 mg/kg
    per day or daily for 21 days at 2.5 or 50 mg/kg per day; details in
    section 7.2.2).

         The influence of the vehicle on the skin irritant potential of
    chlorothalonil was shown by a rabbit study with 0.1% chlorothalonil in
    saline, petrolatum or acetone.  Compared to the vehicle alone,
    chlorothalonil did not cause a significant increase in irritation in 

        Table 10.  Summary of key dietary studies with chlorothalonil

                                                                                                                                      

    Species  Duration       Dose levels         NOEL             LOEL            Key effects                               Reference
                                                                                                                                      

    Rat      13 weeks       0, 1.5, 3, 10,      3 mg/kg per      10 mg/kg per    40 mg/kg per day: increased kidney and    Wilson et
                            40 mg/kg body       day              day             liver weight, incidence of hyperplasia    al. (1983a,
                            weight per day                                       and hyperkeratosis of forestomach,        1985a)
                                                                                 incidence of epithelial hyperplasia in
                                                                                 proximal tubules 10 mg/kg per day:
                                                                                 increased kidney weight, hyperplasia
                                                                                 and hyperkeratosis of forestomach

    Rat      23-29 months   0, 1.8, 3.8, 15,    1.8 mg/kg        3.8 mg/kg       175 mg/kg per day: increases in serum     Wilson et
                            175 mg/kg body      per day          per day         urea nitrogen, urine volume, kidney       al. (1989a)
                            weight per day                                       weight, renal tubular hyperplasia,
                                                                                 hyperplasia and hyperkeratosis of
                                                                                 forestomach; increased incidence of
                                                                                 renal and forestomach tumours
                                                                                 15 mg/kg per day: similar but less
                                                                                 intense changes to those shown at
                                                                                 highest dose level 3.8 mg/kg per day:
                                                                                 small increase in kidney weight, renal
                                                                                 tubular hyperplasia, hyperplasia
                                                                                 and hyperkeratosis of forestomach and
                                                                                 forestomach tumours

    Mouse    13 weeks       0, 7.5, 15, 50,     15 mg/kg diet    50 mg/kg diet   275 and 750 mg/kg: increased kidney       Shults et
                            275, 750 mg/kg      (= 3 mg/kg       (= 10 mg/kg     weight 50, 275 and 750 mg/kg:             al. (1983);
                            diet                per day)         body weight     dose-related increased incidence          Busey (1985)
                                                                 per day)        of hyperplasia and hyperkeratosis
                                                                                 of forestomach
                                                                                                                                      

    Table 10.  (Cont'd)

                                                                                                                                      

    Species  Duration       Dose levels         NOEL             LOEL            Key effects                               Reference

                                                                                                                                      

    Mouse    2 years        0, 15, 40, 175,     15 mg/kg diet    40 mg/kg diet   750 mg/kg: increased kidney weight,       Wilson et
                            750 mg/kg diet      (= 1.6 mg/kg     (= 4.5 mg/kg    renal tubular hyperplasia, forestomach    al. (1987)
                                                body weight      body weight     hyperplasia and hyperkeratosis,
                                                per day)         per day)        slightly increased incidence of
                                                                                 forestomach tumours 175 mg/kg: slightly
                                                                                 increased incidence of renal tubular
                                                                                 hyperplasia, increased forestomach
                                                                                 hyperplasia and hyperkeratosis
                                                                                 40 mg/kg: increased incidence of
                                                                                 forestomach hyperplasia and
                                                                                 hyperkeratosis

    Dog      2 years        0, 1500, 15 000,         -           1500 mg/kg in   15 000 and 30 000 mg/kg: increased        Paynter &
                            30 000 mg/kg                         diet (= 37.5    kidney, liver and thyroid weights and     Busey (1966)
                            diet                                 mg/kg body      histopathological changes, gastritis
                                                                 weight per      1500 mg/kg: slightly increased incidence
                                                                 day)            hepatic findings

    Dog      2 years        0, 60, 120 mg/kg    120 mg/kg diet         -         no changes of toxicological significance  Holsing &
                            diet                (= 3 mg/kg                                                                 Voelker 
                                                body weight                                                                (1970); 
                                                per day                                                                    FAO/WHO
                                                                                                                           (1991, 1993)
                                                                                                                                      
        saline, but doubled the mild irritation caused by petrolatum.  Acetone
    itself caused no irritation but the addition of chlorothalonil
    produced mild skin irritation (Flannigan & Tucker, 1985).

         A further study in rabbits using a cumulative irritation assay
    confirmed the irritant properties of 0.1% chlorothalonil in acetone. 
    A concentration of 0.01% gave evidence of mild irritation, probably of
    no clinical significance, and 0.001% was not irritant to the skin
    (Flannigan et al., 1986).

         Chlorothalonil irritancy to the eye was evaluated in a modified
    Draize system, 0.1 mg being instilled into one eye of each of three
    male and three female rabbits.  The eyes were examined and the results
    scored after 24, 48 and 72 h, 7 and 14 days.  Ocular irritation
    occurred in all animals and corneal opacity persisted to day 14 (Major
    et al., 1982).

         Skin sensitization was tested in a guinea-pig maximization test
    using 10 Hartley female guinea-pigs.  Topical concentrations of 0.5
    and 5% chlorothalonil were used.  Upon challenge, chlorothalonil was
    shown to be a strong sensitizer.  Moderate cross-sensitization with
    benomyl was also demonstrated (Matsushita & Aoyama, 1981).  By
    contrast, chlorothalonil did not produce skin sensitization in a
    Draize test.  The test substance (0.2 g) was applied to the shaved
    backs of Hartley-derived guinea-pigs.  The material was occluded for
    24 h and then removed.  This procedure was performed 3 times a week
    for a total of 10 applications.  On day 36 of the study a challenge
    application of 0.2 g chlorothalonil was applied to the shaved flanks
    and occluded.  The skin was assessed 24 h later after removal of the
    occlusive dressing.  The positive control substance DNCB showed the
    expected dermal sensitization but chlorothalonil was shown not to be a
    sensitizer in this test (Wilson et al., 1982).

         Luperi & Forster (1988) studied the ability of chlorothalonil to
    induce delayed contact hypersensitivity in the guinea-pig using the
    maximization test of Magnusson and Kligman.  There was no evidence of
    an induced sensitization response, but adequate evaluation was impeded
    by a diffuse irritant reaction following the challenge.

    7.5  Reproductive and developmental toxicity

         Teratological evaluations have been carried out in the rat and
    rabbit.

         Chlorothalonil was administered orally via gavage to pregnant
    Sprague-Dawley rats (25 per group) on days 6-15 of gestation at dose
    levels of 0, 25, 100 or 400 mg/kg body weight per day, and the animals
    were killed on day 20.  Clinical signs of maternal toxicity were
    evident at the highest dose level.  There were 3 deaths and lowered
    body weight during the dosing period.  There was a slight increase in 

    the number of early embryonic deaths at the highest dose level,
    probably associated with the maternal toxicity.  There were no
    compound-related incidences of external, internal or skeletal
    malformations in the fetuses in treated animals.  It was concluded
    that chlorothalonil is not teratogenic to the rat (Mizens et al.,
    1983).

         Chlorothalonil was given orally to pregnant rabbits on days 8-16
    of gestation at dose levels of 0, 180 or 375 mg/kg per day (days 8 and
    9) and 0, 62.5 or 31.25 mg/kg per day (day 10 to day 16).  There were
    marked effects on food intake and maternal mortality occurred in both
    treated groups, which imposed limitations on the evaluation of the
    study.  However no teratogenic effect was observed (Paynter, 1966b).

         Rabbits were dosed with chlorothalonil (0, 5, or 50 mg/kg per
    day) during days 6-18 of pregnancy (8 in control group, 9 in each dose
    group) and killed on day 29. Four out of nine does aborted at the
    highest dose level, and body weight was reduced in this group.
    Although the incidence of fetal deaths appeared to increase with dose,
    the difference was not statistically significant.  The number of
    implants and live fetuses per pregnancy and the fetal weights were
    reduced in the high-dose group compared to controls.  No treatment-
    related effects were seen during external, internal or skeletal
    examinations.  It was concluded that chlorothalonil was not
    teratogenic to the rabbit (Shirasu & Teramoto, 1975).

         Chlorothalonil was administered by gavage to groups of 20
    pregnant rabbits on days 7-19 of gestation at dose levels of 0, 5, 10
    or 20 mg/kg per day.  All survivors were weighed, killed on day 30 and
    examined for live, dead or resorbed fetuses.  Live and dead fetuses
    were weighed and examined for external, visceral and skeletal
    abnormalities.  The highest dose level caused maternal body weight
    loss and decreased food consumption.  The pregnancy rate was > 95%
    in each group.  Examinations revealed no fetotoxicity or
    teratogenicity due to chlorothalonil (Wilson et al., 1988).

         A three-generation reproduction study was undertaken in rats at
    dietary levels of 0, 1500 or 15 000 mg chlorothalonil/kg diet.  A
    supplementary study with 0 or 5000 mg/kg was also carried out 6 months
    later.  Groups consisted of 10 males and 20 females which were fed the
    test diet for 11 or 12 weeks prior to mating.  The study design was
    for three generations with two matings per generation to give A and B
    litters.  Growth suppression occurred in the nursing A and B litters
    in all generations at all dose levels and the pups appeared smaller
    than the controls.  There were no malformations due to treatment. 
    However, there were difficulties in execution, and this study is not
    considered adequate by present-day standards (Paynter, 1967b).

         Reproductive performance was also assessed in a one-generation
    study on rats at dietary levels of 0, 200, 375, 750, 1500 or 3000
    mg/kg diet with groups of 15 males and 15 females.  The parents were 

    treated for 10 weeks prior to mating.  No clinical signs of toxicity
    were evident in the parents, but male body weight gain was reduced at
    1500 and 3000 mg/kg and the kidneys were enlarged at 3000 mg/kg. 
    Reproductive parameters such as mating, fertility and gestation length
    were not affected.  There were no treatment-related abnormalities in
    the offspring.  The only effect on the offspring was lower body weight
    at 3000 mg/kg on lactation days 14 and 21 (Wilson et al., 1989b).

         In a two-generation reproduction study with two litters per
    generation, technical chlorothalonil was administered to Charles River
    CD rats by dietary admixture at concentrations of 0, 500, 1500 and
    3000 mg/kg diet.  There were 35 rats of each sex in each group.  The
    parental animals from each generation were treated continuously during
    the growth period prior to mating and then throughout the mating,
    gestation, lactation and resting phases of the study.  The growth
    period was 10 weeks for the F0 animals and 14 weeks for the F1
    animals.  Each generation of parental animals was mated twice to
    produce the F1a, F1b, F2a and F2b litters.  The offspring were
    exposed to the test diets throughout the lactation period.  Thirty-
    five F1b males and females per group were selected to become the F1
    generation after weaning.  No mortalities or clinical signs of
    toxicity associated with administration of chlorothalonil were
    observed in the F0 or F1 parent animals.  There was a
    treatment-related effect towards lowered body weight in both males and
    females in the F0 and F1 adults.  The NOEL for body weight was 500
    mg/kg in diet.  Increased relative food consumption was observed in
    the groups that showed lower body weights.  The anticipated
    treatment-related lesions in the kidneys and stomachs of adult animals
    were observed in the F0 and F1 generations by gross and microscopic
    pathology.  These effects were observed in the kidney at all dose
    levels in males and at 1500 and 3000 mg/kg in females.  Stomach
    effects were observed at all dose levels in both sexes.  Reproductive
    parameters in F0 and F1 animals, including mating and fertility
    indices and gestation length, were not affected by treatment with
    chlorothalonil.  No gross malformations which were considered
    treatment-related were observed in offspring in any of the groups
    throughout the study.  Litters were culled at day 4 to 8 pups/litter. 
    No effects on the number of live and stillborn pups, pup sex ratio,
    pup survival and physical condition of the pups during lactation were
    observed.  No findings which were considered treatment-related were
    observed during necropsy of the pups.  The only effect observed in
    pups in this study was lowered body weight compared to the controls on
    day 21 of lactation.  The NOEL for this effect was considered to be
    1500 mg/kg diet, equal to 75 mg/kg body weight per day (Lucas & Benz,
    1990).

    7.6  Mutagenicity

         Chlorothalonil has been assessed for mutagenic potential in a
    wide range of  in vitro and  in vivo assays as shown in Tables 11
    and 12.  Most of the tests showed chlorothalonil not to be mutagenic
    or clastogenic.  A positive result in the DNA repair test with
     Salmonella typhimurium  was not reproduced in  Bacillus subtilis,
    nor was DNA binding shown in an  in vivo study (see section 6.5).  A
    positive result in Chinese hamster ovary cells without metabolic
    activation was not seen in the presence of activation nor confirmed by
     in vivo chromosomal tests in rats and mice.  Equivocal results were
    obtained with Chinese hamster bone marrow  in vivo.

         In addition to the results shown in the Tables 11 and 12, a
    series of studies was reported by IARC (1983).  The results, which
    were all negative, included those with  S. typhimurium in the
    presence and absence of a metabolic activating system and
     Saccharomyces cerevisiae and  Aspergillus nidulans in the presence
    of activation.  Chlorothalonil also failed to induce mutations in
    silkworms and chromosomal aberrations in barley shoot tips or hamster
    lung fibroblasts.

         Chlorothalonil is not a transforming agent in Fischer rat embryo
    cell lines (Price, 1978a).

         The monothio, dithio, trithio, dicysteine, tricysteine and
    monoglutathione metabolites of chlorothalonil have been shown to be
    negative in the Ames assay with or without rat kidney metabolic
    activation (see section 7.9).

         Considering all the results of mutagenicity testing, it is
    unlikely that chlorothalonil will show mutagenic activity in intact
    mammalian systems.

    7.7  Carcinogenicity

         Several long-term rodent studies have been carried out on
    chlorothalonil and have included carcinogenic evaluation.  The design
    of these studies and the chronic toxicity results have been described
    in section 7.3.  Some of the earlier rat studies did not show any
    carcinogenic effect but it is probable that their design was not
    sufficient to provide a  critical test.  The carcinogenic evaluation
    in this section therefore concentrates upon the more recent rat and
    mouse studies.  Detailed evaluations of these studies have already
    appeared in the Joint FAO/WHO Meeting on Pesticide Residues (JMPR)
    reviews of 1983, 1985 and 1990 (FAO/WHO, 1985, 1986b, 1990b). 
    Therefore, for most of these studies, only the salient points will be
    described here.

        Table 11.  In vitro mutagenicity tests

                                                                                                                                  

    Test               Organism                  Metabolic             Dose range                 Mutagenic    Reference
                                                 activation (+ or -)                              potential
                                                                                                                                  

    Prokaryotes
    Point mutation     Salmonella typhimurium    + and -               0.33-6.6 µg/plate          negative     Banzer (1977a)
                       (5 strains)

    Point mutation     S. typhimurium            + and -               0.16-50 µg/plate           negative     Jones et al. (1984)
                       (5 strains)               (renal)

    Point mutation     S. typhimurium            -                     1-10 µg/plate              negative     Shirasu et al. 
                       (5 strains)               +                     2-10 µg/plate              negative     (1977)

                       Escherichia coli WP2      -                     10-500 µg/plate            negative
                                                 +                     10-100 µg/plate            negative

    Point mutation     S. typhimurium TA98,      + and -               0.76, 7.6, 76 µg/plate     negative     Wei (1982)
                       TA100, TA1535, TA1537,    (hepatic and
                       TA1538                    renal)

    DNA repair tests   S. typhimurium            + and -               2, 10, 20 µg               positive     Banzer (1977b)
                       TA1978, TA1538

                       Bacillus subtilis         -                     2-200 µg                   negative     Shirasu et al.
                       H17/M45 rec-assay                                                                       (1977)
                                                                                                                                       

    Table 11.  (Cont'd)

                                                                                                                                  

    Test               Organism                  Metabolic             Dose range                 Mutagenic    Reference
                                                 activation (+ or -)                              potential
                                                                                                                                  

    Mammalian cells
    Gene mutation      Chinese hamster V79       + and -               0.3 µg/ml                  negative     Banzer (1977c)

                       mouse fibroblast          + and -               0.03 µg/ml                 negative
                       BALB/3T3

    Chromosome         Chinese hamster           -                     0.03-0.3 µg/ml             positive     Mizens et al.
     aberration        ovary cells               +                     0.6-6.0 µg/ml              negative     (1986a)

    Chromosome         Human lymphocytes         -                     0.54-2.5 µg/ml             negative     Mosesso & Forster
     aberrations                                 +                     1.16-5.38 µg/ml            negative     (1988)

                                                                                                                                  

    Table 12.  In vivo mutagenicity tests

                                                                                                                                  

    Species     Test                                Dose                               Mutagenic potential    Reference
                                                                                                                                  

    Mouse       in vivo                             6.5 mg/kg per day                  negative               Legator (1974a)
                cytogenetics                        5 days orally

    Mouse       host-mediated assay; 8 strains      6.5 mg/kg per day                  negative               Legator (1974a)
                Salmonella typhimurium              5 days orally

    Mouse       dominant lethal assay, 5 days       6.5 mg/kg per day                  negative               Legator (1974a)
                dosing, 8 weeks mating              5 days orally

    Mouse       micronucleus                        4-2500 mg/kg orally, twice with    negative               Siou (1981a)
                (polychromatic erythrocytes)        24 h interval

    Mouse       chromosome aberration (bone         4-2500 mg/kg orally, twice with    negative               Siou (1981b)
                marrow 6 h after last dose)         24 h interval 250, 1250, 2500      negative               Mizens et al.
                (bone marrow at 6, 24 and 48 h)     mg/kg oral single dose                                    (1985a)

    Rat         micronucleus                        8-5000 mg/kg orally, twice with    negative               Siou (1981a)
                (polychromatic erythrocytes)        24 h interval

    Rat         chromosome aberration (bone         doses as above                     negative               Siou (1981b)
                marrow 6 h after last dose)
                (bone marrow 6, 24 and 48 h)        500, 2500, 5000 mg/kg oral         negative               Mizens et al. (1985b)
                                                    single dose
                                                                                                                                  

    Table 12.  (Cont'd)

                                                                                                                                  

    Species     Test                                Dose                               Mutagenic potential    Reference

                                                                                                                                  
    


    Chinese     micronucleus                        4-2500 mg/kg orally, twice with    negative               Siou (1981a)
     hamster    (polychromatic erythrocytes)        24 h interval

    Chinese     chromosome aberration               8-5000 mg/kg for 2 days            inconclusive           Siou (1981b)
     hamster    (bone marrow 6 h after last dose)
                (bone marrow at 6, 24 and 48 h)     500, 2500, 5000 mg/kg oral         equivocal              Mizens et al. (1985c)
                                                    single dose                        (± at 48 h)
                (bone marrow 6 h after last dose)   50, 125, 250 mg/kg per day         weak response          Mizens et al. (1985c)
                                                    orally for 5 days                  not dose-related

                                                                                                                                  
             A bioassay of technical grade chlorothalonil for possible
    carcinogenicity was conducted by administering the test chemical in
    the diet to Osborne-Mendel rats and B6C3F1 mice.  Groups of 50 rats
    of each sex were administered chlorothalonil at one of two dose levels
    for 80 weeks and then observed for 30-31 weeks.  Time-weighted average
    doses for both males and females were 5063 or 10 126 mg/kg diet. 
    Matched controls consisted of groups of 10 untreated rats of each sex;
    pooled controls consisted of the matched control groups combined with
    55 untreated male or female rats from similar bioassays of five other
    test chemicals.  All surviving rats were killed at 110-111 weeks. 
    Groups of 50 mice of each sex were administered chlorothalonil at one
    of two dose levels for 80 weeks, then observed for 11-12 weeks.  Time-
    weighted average doses for males were 2688 or 5375 mg/kg diet, and for
    females, 3000 or 6000 mg/kg diet.  Matched controls consisted of
    groups of 10 untreated mice of each sex; pooled controls consisted of
    the matched control groups combined with 50 untreated male or female
    mice from similar bioassays of five other test chemicals.  All
    surviving mice were killed at 91-92 weeks.  Clinical signs that
    appeared with increasing frequency in dosed rats included haematuria
    and, from week 72 until termination of the study, bright yellow urine. 
    Since the dosed female mice did not have depression in mean body
    weights or decreased survival compared with the controls, they may
    have been able to tolerate a higher dose.  In rats, adenomas and
    carcinomas of the renal tubular epithelium occurred with a significant
    dose-related trend in both the males and females (males: pooled
    controls 0/62, low dose 3/46, high dose 4/49; females: pooled controls
    0/62, low dose 1/48, high dose 5/50).  These tumours included both
    adenomas and carcinomas which are considered to be histogenically
    related.  In mice, no tumours were found to occur at a greater
    incidence among dosed animals than among controls.  It was concluded
    that under the conditions of this bioassay, technical grade
    chlorothalonil was carcinogenic to Osborne-Mendel rats, producing
    tumours of the kidney.  However, chlorothalonil was not carcinogenic
    for B6C3F1 mice (US NCI, 1978).

         In a lifetime study on Fischer-344 rats at dietary doses of 0,
    40, 80 or 175 mg/kg body weight per day (see section 7.3), a higher
    incidence of primary renal tumours of epithelial origin (adenomas and
    carcinomas) was seen in the treated groups (0/60, 7/60, 7/60 and 19/60
    for males and 0/60, 3/60, 6/60 and 23/60 for females).  It was
    considered that the increased incidence of renal hyperplasia seen in
    this study was associated with the formation of these tumours and
    constituted a pre-neoplastic change.  Papillomas and carcinomas of the
    squamous mucosa of the forestomach were found in rats in the treated
    groups (0/60, 1/60, 1/60, 3/60 for males and 0/60, 1/60, 2/60, 7/60
    for females).  These are probably related to the proliferative non-
    neoplastic effects on the squamous mucosa as a result of the chronic
    irritation by chlorothalonil (Wilson et al., 1985a, 1986b).

         A further dietary study evaluated the carcinogenicity of
    chlorothalonil at lower doses of 1.8, 3.8 and 15 mg/kg body weight per
    day as well as at 175 mg/kg body weight per day (see section 7.3).
    Rats with renal tumours (adenomas and carcinomas) occurred at 1/55,
    1/54, 1/54, 4/54, 23/55 (male groups) and 0/55, 0/54, 0/55, 0/53,
    32/55 (female groups).  This confirmed the effect at 175 mg/kg per day
    and an NOEL of 3.8 mg/kg per day was determined for these tumours.
    Animals with papillomas and carcinomas of the forestomach occurred at
    0/55, 0/54, 3/54, 2/54, 5/55 (male groups) and 1/55, 1/54, 2/55, 5/53,
    9/55 (female groups) giving an NOEL of 1.8 mg/kg per day (Wilson et
    al., 1989a).

         A 2-year study with Charles River CD-1 mice at 750, 1500 or 3000
    mg chlorothalonil/kg diet (section 7.3) showed increased incidences of
    gastric and renal tumours in the treated groups.  Mice with tumours of
    the squamous epithelium of the forestomach occurred at 0/60, 2/60,
    5/60, 2/60 (male groups) and 0/60, 2/60, 4/60, 5/59 (female groups). 
    Although not strictly dose-related, these results were considered to
    be a treatment effect and linked to the irritant properties of
    chlorothalonil.  There was also a low incidence of renal tubular
    tumours in male treated groups, not seen in controls, at 0/60, 6/60,
    4/60, 5/60 (not dose-related).  These were probably linked to the high
    incidence of renal tubular hyperplasia seen in male mice in the
    treated groups (Wilson et al., 1983b, 1986b).

         A second study at 0, 15, 40, 175 and 750 mg/kg diet was
    undertaken to establish an NOEL for kidney and stomach changes in male
    mice (section 7.3).  Only two renal tumours (one at 40 mg/kg and one
    at 175 mg/kg) were found.  There was a slightly higher incidence of
    squamous tumours of the forestomach at 750 mg/kg.  Taking account of
    the overall results of the two studies it was considered that the
    tumorigenic NOEL was at least 175 mg/kg diet.  In this study, the NOEL
    for tubular hyperplasia was 40 mg/kg (equal to 4.5 mg/kg per day) and
    the NOEL for hyperplasia/hyperkeratosis in the forestomach was 1.6
    mg/kg per day (Wilson et al., 1987).

    7.8  Other special studies

         Rats fed 0, 1500 or 15 000 mg chlorothalonil/kg diet showed a
    dose-related decrease in the retention of a dye, indicating a laxative
    effect.  A more detailed study attempted to determine the effect of
    chlorothalonil on the absorption and utilization of proteins, fats and
    amino acids during a 10-week feeding study on a group of 10 male and
    10 female rats.  It was concluded that the compound did not interfere
    directly with the absorption and utilization and that the depressed
    weight gain was probably due to catharsis (Paynter, 1967c).

         In a study by Andre et al. (1991), mitochondria were obtained
    from fresh kidney cortical tissue by homogenization and differential
    centrifugation.  The mitochondria were incubated in the presence or
    absence of sulfur-containing analogues of chlorothalonil and the 

    degree of mitochondrial respiratory control was evaluated by
    polarographic techniques.  The following sulfur-containing analogues
    of chlorothalonil were tested: the mono-, di-, and tri-thiol analogues
    and the mono-, di-, and tri-glutathione analogues.  Kidney
    mitochondria were incubated with succinate, a site 2 substrate, or
    with glutamate, a site 1 substrate, in the presence or absence of the
    test material.  Mitochondrial respiratory control, expressed as the
    acceptor control ratio (ACR), was determined by taking the ratio of
    the rate of oxygen consumption in the presence of ADP (state 3) to the
    rate of oxygen consumption after the ADP had been consumed (state 4). 
    When the mono-thiol, mono-, di-, or tri-glutathione analogues of
    chlorothalonil and succinate were added to kidney mitochondria, no
    significant differences were found in the ACR from the controls. 
    Incubation of the di- or tri-thiol analogues of chlorothalonil and
    succinate with kidney mitochondria resulted in significant differences
    of the experimental ACR from the control ACR.  When glutamate was used
    as the substrate for the electron transport system in kidney
    mitochondria, no significant differences from the control were
    detected for any of the six test materials.  These data suggest that
    the effects of the di- or tri-thiol analogues of chlorothalonil may
    impair the respiratory control of kidney mitochondria by inhibiting
    the transfer of reducing equivalents from succinate to coenzyme Q. 
    The effects on mitochondrial respiration may be due to the formation
    of disulfide bonds between the thiol analogues and proteins.

    7.9  Toxicity of metabolites

         Most studies have centred on the 4-hydroxy-2,5,6-
    trichloroisophthalonitrile metabolite.  This is found as a small
    proportion of chlorothalonil plant residues (section 4.2.1) and is
    also a breakdown product of chlorothalonil in the environment.  It has
    been identified in faeces of laboratory animals after chlorothalonil
    dosing.  It is more acutely toxic than chlorothalonil itself (acute
    oral LD50 values are 332 and 10 000 mg/kg, respectively).

         Several laboratory animal studies have been undertaken with the
    4-hydroxy metabolite and have been described in some detail in JMPR
    reviews (FAO/WHO, 1978, 1982, 1985).  The following is a brief summary
    of the studies and their results.

         Various effects were noted in rats fed the 4-hydroxy metabolite
    at eight dose levels (10 to 750 mg/kg body weight per day) for 61-69
    days.  Mortality was increased in males at 125 mg/kg per day or more,
    and in females at 75 mg/kg per day or more.  Body weight was depressed
    in both sexes at > 40 mg/kg per day.  Anaemia was evident at 75
    mg/kg per day or more in males and 40 mg/kg per day or more in
    females.  Histopathological examination revealed treatment-related
    effects in bone marrow and spleen (in the form of erythroid
    hyperplasia and depressed granulopoiesis) at > 40 mg/kg per day and

    in the liver (haemosiderosis, centrilobular hepatitis) and kidney
    (cortical atrophy) at > 75 mg/kg per day.  The overall NOEL was 20
    mg/kg body weight per day (Murchison, 1979).

         A rabbit teratology study was undertaken with oral doses of 0, 1,
    2.5 and 5 mg/kg per day during days 6-18 of gestation, with necropsy
    at day 28.  There was a marginal effect on dams at day 5 but no
    evidence of a teratogenic effect in the study (Wazeter & Goldenthal,
    1976).

         The 4-hydroxy metabolite was evaluated in a three-generation, two
    litters/generation study in groups of 15 male and 30 female rats at
    dose levels of 0, 10, 60 and 125 mg/kg diet.  There were no
    treatment-related changes except for body weight reductions at 60 and
    125 mg/kg (FAO/WHO, 1982).

         In a one-generation follow-up study, groups of rats were fed
    diets containing the 4-hydroxy metabolite at 0, 10, 20, 30, 60 and 120
    mg/kg diet for 18 weeks before mating (12 males and 24 females per
    group).  Two sets of mating were undertaken.  There was some effect on
    live pup weights at 60 and 120 mg/kg.  The clear NOEL was considered
    to be 30 mg/kg diet (Ford, 1982).

         The metabolite was assessed for chronic toxicity and
    carcinogenicity in long-term rodent studies.  A 2-year rat study was
    undertaken at dose levels of 0, 0.5, 3 and 10 mg/kg body weight per
    day with groups of 75 males and 75 females.  Anaemia was evident at
    the highest dose.  The NOEL was determined to be 3 mg/kg body weight
    per day.  There was no evidence for a carcinogenic effect.  In the
    mouse study, the dietary dose levels were 0, 375, 750 and 1500 mg/kg
    diet using groups of 60 males and 60 females.  The study was
    terminated at 20-22 months because of increasing and high mortality. 
    A series of effects, including amyloidosis, haemosiderin in the spleen
    and increases in reticulocyte counts and red cell haemolysis,
    precluded the establishment of an NOEL.  No carcinogenic effect was
    evident (Hozan & Auletta, 1981; McGee, 1983).

         The 4-hydroxy metabolite was not mutagenic in a number of  in
     vitro and  in vivo assays. These were the  Salmonella mutagenicity
    assay with and without metabolic activation (Banzer, 1977d), a
    host-mediated assay in mice given a single intraperitoneal dose of
    6.5 mg/kg (Legator, 1974b), Chinese hamster (V-79) and mouse
    fibroblast (Balb/3T3) cells in culture with and without activation
    (Banzer, 1977e), a micronucleus test in mice at 6.5 mg/kg per day for
    5 days (Legator, 1974b), a dominant lethal study in male rats given
    single oral doses (0, 2, 4 or 8 mg/kg) singly or daily for 5 days
    (Hastings & Clifford, 1975), a dominant lethal study in male mice
    given 1, 3 or 6.5 mg/kg per day for 5 days (Legator, 1974b), a DNA
    repair assay using  S. typhimurium in a spot test with or without
    activation (Banzer, 1977f), and a cell transformation assay with rat
    embryo cell lines in culture at 0.1, 1 or 10 µg/ml (Price 1978b).

         A series of  in vitro gene mutation assays with  S. typhimurium
    tester strains with and without renal metabolic activation were
    undertaken with chlorothalonil, four manufacturing impurities and
    eight known or potential metabolites.  No mutagenic potential was
    shown by any of the compounds.  Full details were given in the 1985
    JMPR evaluation (FAO/WHO, 1986b).

         The mutagenic potential of the thiol and cysteine derivatives of
    chlorothalonil has been evaluated in the Ames test with and without
    metabolic activation with S9 from the kidney of male Fischer rats.
    These compounds were 2,5-dichloro-4,6-bismercaptoiso-phthalonitrile,
    5-(2,4-dicyano-3,5,6-trichlorophenyl) glutathione, 5-chloro-2,4,6-
    trimercaptoisophthalonitrile,  S,S'-(2,4-dicyano-3,6-dichloro
    phenyl)dicysteine and  S,S',S"-(2,4-dicyano-6-chlorophenyl)-
    tricysteine (purity ranging from 90.5 to 97.5%).  Four other compounds
    were used as positive controls.  The  Salmonella typhimurium tester
    strains TA98, TA100, TA1535, TA1537 and TA1538 were used.  In all
    these studies, there was no significant increase (doubling) over
    solvent control values in the number of revertants for any of the five
    tester strains used either with or without metabolic activation
    (Mizens et al., 1985d,e, 1986b,c, 1987).

         A description of a 90-day rat study on the monoglutathione
    conjugate of chlorothalonil is given in section 7.3.

    8.  EFFECTS ON HUMANS

    8.1  General population exposure

         A case of acute facial dermatitis in a 53-year-old man, caused by
    staying in a summer cottage, has been reported.  Patch testing
    revealed contact allergy to the paint that was applied to all the
    window-frames, and to the chlorothalonil contained in the paint. 
    After removal of the frames, there were no further recurrences of
    facial dermatitis.  The authors suggested that products containing
    chlorothalonil are not suitable for indoor use (Liden, 1990; Eilrich &
    Chelsky, 1991).

    8.2  Occupational exposure

         Chlorothalonil contact dermatitis was observed in a number of
    employees in a chlorothalonil manufacturing plant.  There were 19
    cases out of 103 employees.  About 60% of the employees showed some
    kind of skin abnormality compared with 18.5% of employees not working
    with chlorothalonil.  When the hygiene conditions of the plant were
    improved the overall proportion of skin abnormalities fell to about
    20% and there were no cases of chlorothalonil contact dermatitis
    (Diamond Shamrock, 1980).

         Wood preservatives containing chlorothalonil have also been
    implicated in the appearance of allergic contact dermatitis.  One
    report concerned a Danish cabinet maker who developed dermatitis on
    his hands after 9 months of painting furniture with preservative
    containing the compound.  This was possibly caused by contact via the
    wood dust after sandpapering (Bach & Pedersen, 1980).  Another report
    referred to three cases, two with erythema on the face, particularly
    periorbitally, and one with eczema of the hands, in people engaged in
    similar work (Spindeldreier & Deichmann, 1980).  The four people in
    these cases showed a positive reaction to patch tests with 0.01%
    chlorothalonil in acetone.

         A further case of contact dermatitits was described by Meding
    (1986) in a 33-year-old male painter, who regularly worked with paint
    containing chlorothalonil.  A patch test with chlorothalonil was
    positive.

         Work-related skin complaints occurred in a Norwegian factory
    producing wooden window frames.  The wood preservative used was white
    spirit containing 0.5% chlorothalonil.  Fourteen out of 20 workers
    experienced some kind of skin reaction including pruritus, erythema
    and oedema of the eyelids and other facial regions, and eruptions on
    arms and hands.  Seven of these 14 subjects yielded a positive patch
    test reaction with 0.01% chlorothalonil in acetone compared with 1 out
    of 14 controls (Johnsson et al., 1983).

         Allergic contact dermatitis has also been described in Japanese
    farmers (Horiuchi & Ando, 1980) and in Dutch horticultural workers
    (Bruynzeel & van Ketel, 1986) using chlorothalonil fungicide
    formulations.

         In a group of 84 tea growers, two showed a positive skin patch
    test with 0.02% chlorothalonil in petrolatum (Fujita, 1985).

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    9.1  Laboratory experiments

    9.1.1  Microorganisms

    9.1.1.1  Aquatic microorganisms

         The algicidal activity of chlorothalonil was examined by Goulding
    (1971).  It was shown that this compound is effective against a range
    of algae including  Chlorella,  Chlamydomonas,  Ulothrix ,  Anabaena,
     Oscillatoria and  Microcystis at low concentrations, often
    less than 1 µg/litre.  It was also effective on natural populations
    of algae obtained from lakes, rivers, and reservoirs.  The effect
    was generally less after 300 h than after 150 h and was dependent upon
    the size of the initial cell inoculum.

         Walker et al. (1984) describe a simple shake-flask screening test
    to evaluate pesticide persistence and aquatic toxicity in the
    laboratory.  Four systems were used: active sediment, sterile
    sediment, active water and sterile water.  Chlorothalonil at
    162 µg/litre did not increase the mortality of  Mysidopsis above the
    control level within 96 h.  The authors concluded that degradation of
    chlorothalonil involved microorganisms and that the degradation
    products did not enhance the aquatic toxicity of chlorothalonil.

    9.1.1.2  Soil microorganisms

         Chlorothalonil, at dose levels up to 5000 mg/litre in bacterial
    suspensions, inhibited the growth of three strains of  Rhizobium
     japonicum (Tu, 1980).

         Chlorothalonil, at concentrations up to 1000 mg/kg medium, did
    not inhibit or stimulate the growth of any one of 25 strains of
    Rhizobium bacteria isolated from red clover root nodules
    (Heinonen-Tanski et al., 1982).

         Several studies were conducted with chlorothalonil in soil to
    determine the effects (if any) on normal soil processes such as
    nitrogen fixation, nitrification and degradation of substrates such as
    protein, pectin, cellulose and starch.  These studies were conducted
    at two rates: use rate (2.5 mg/kg) and 10 times the use rate
    (25 mg/kg).  In general, any inhibitory effects observed were
    temporary in nature and more pronounced at the high rate.  No effects
    on the use of protein, pectin or cellulose by soil microorganisms were
    observed, but there was increased utilization of starch (Szalkowski et
    al., 1980).

         The results obtained by Szalkowski et al. (1981a), who studied
    the effect of chlorothalonil on non-symbiotic nitrogen-fixing soil
    microorganisms, are given in Table 13.

        Table 13.  The effect of chlorothalonil on non-symbiotic nitrogen-fixing soil microorganisms

                                                                                                

                                      Sandy loam                             Clay loam
                                                                                                

                          Application            Ten times           Application    Ten times
                          rate                   application         rate           application
                                                 rate                               rate
                                                                                                 

    Aerobic nitrogen      initial inhibition     inhibition at       no effect      stimulation
     fixation                                    days 0, 21 and
                                                 28

    Anaerobic nitrogen    general stimulation    inhibition up       no effect      stimulation
     fixation                                    to day 21
                                                                                                 
    
         Szalkowski et al. (1981b) studied the effect of chlorothalonil on
    nitrogen transformation in sandy loam and clay loam soils at two
    rates: one equivalent to the application rate and one equivalent to
    ten times this rate.  In sandy loam soil, there was a consistent
    inhibitory effect at the higher rate, which was reduced with time.  In
    clay loam soil, at the higher rate, inhibition was no longer observed
    after day 21.  In both types of soil at the normal rate, there was
    little if any inhibition.

    9.1.2  Aquatic organisms

         The acute toxicity of chlorothalonil to various aquatic species
    is shown in Table 14.  Some of these toxicity tests were carried out
    in static or semi-static systems and others in flow-through systems. 

        Table 14.  Acute toxicity of chlorothalonil to aquatic organisms

                                                                                                                                      

    Stage (weight  Test          Freshwater/      pH       O2        Temperature  Solvent  Purity     48-h LC50  96-h LC50  Reference
    or length)     systems       marine                              (°C)                             (µg/litre) (µg/litre)
                                 (hardness)
                                                                                                                                      

    Rainbow trout
     (Oncorhynchus mykiss)

    6-11 g         flow through  freshwater                80%       14           acetone  > 99%      19.0       17.1       Davies &
    6-11 g         flow through  freshwater                53%       16           acetone  > 99%      18.8       10.5       White
    6-11 g         semi-static   freshwater                90%       10           acetone  > 99%                 18.0       (1985)
                   (24 h)
      -            static        freshwater                -         12           acetone  96%        56         49         SDS Biotech
                                 (soft)                                                                                     Corporation
                                                                                                                            (1980a)
    3.5-4.0 g      static        freshwater       6.5-7.4  8.4-11.2  12.5-15.5    acetone  97.8%                 76         Ernst et
                                 (12.3 mg/litre)           mg/litre                                                         al. (1991)
    3.5-4.0 g      static        freshwater       6.5-7.4  8.4-11.2  12.5-15.5             Bravo 500             69         Ernst et
                                 (12.3 mg/litre)           mg/litre                                                         al. (1991)

    Bluegill
     (Lepomis macrochirus)

      -            static        freshwater                          22           acetone  96%        46-77      62         SDS Biotech
                                 (soft)                                                                                     Corporation
                                                                                                                            (1979)
                                                                                                                                      

    Table 14.  (Cont'd)

                                                                                                                                      

    Stage (weight  Test          Freshwater/      pH       O2        Temperature  Solvent  Purity     48-h LC50  96-h LC50  Reference
    or length)     systems       marine                              (°C)                             (µg/litre) (µg/litre)
                                 (hardness)
                                                                                                                                      

    Common jolly tail
     (Galaxias maculatus)

    7-10 g         flow through  freshwater                75%       16           acetone  99%        18.2       16.3       Davies &
                                                                                                                            White (1985)

    Spotted galaxis
     (G. fruttaceus)

    8-20 g         flow through  freshwater                75%       16           acetone  99%        25.8       18.9       Davies &
                                                                                                                            White (1985)

    Golden galaxias
     (G. auratus)

    7-11 g         flow through  freshwater                75%       13           acetone  99%        46.6       29.2       Davies &
                                                                                                                            White (1985)

    Three spine stickleback
     (Gasterosteus aculeatus)

    0.3 g          static        freshwater       7.7-8.0  9.2-9.5   9-10                  Bravo 500             < 73       Ernst et
                                                           mg/litre                                                         al. (1991)
                                                                                                                                      

    Table 14.  (Cont'd)

                                                                                                                                      

    Stage (weight  Test          Freshwater/      pH       O2        Temperature  Solvent  Purity     48-h LC50  96-h LC50  Reference
    or length)     systems       marine                              (°C)                             (µg/litre) (µg/litre)
                                 (hardness)
                                                                                                                                      

    Channel catfish
     (Ictalurus punctalus)

    40-80 g        semi-static,  freshwater       7.0-7.2  5.0-6.0   23           acetone  99%        62         52         Gallagher et
                   24 h          (30 mg/litre)             mg/litre                                                         al. (1992)

      -            static        freshwater                          22           acetone  96%        55         44         SDS Biotech
                                 (soft)                                                                                     Corporation
                                                                                                                            (1980b)
    Spot
     (Leiosfomus xanthurus)

    -              flow through  brackish water                      11                    technical  32                    Mayer (1987)
                                 (22 ppt)

    Sheepshead minnow
     (Cyprinodor variegatus)

    3-7 days       static        marine                                                    technical             32         SDS Biotech
                                                                                                                            Corporation
                                                                                                                            (1982b)
                                                                                                                                      

    Table 14.  (Cont'd)

                                                                                                                                      

    Stage (weight  Test          Freshwater/      pH       O2        Temperature  Solvent  Purity     48-h LC50  96-h LC50  Reference
    or length)     systems       marine                              (°C)                             (µg/litre) (µg/litre)
                                 (hardness)
                                                                                                                                      

    Water flea
     (Daphnia magna)

     -             static        freshwater       7.7-8.1  9.1-9.3   20-22                 Bravo 500  97a                   Ernst et
                                 (250 mg/litre)            mg/litre                                                         al. (1991)
    Dungeness crab
     (Cancer magister)

    larvae         semistatic,   marine                              13                    Bravo, 75% 560        140        Armstrong
                   24h           (25 ppt)                                                                                   et al. (1976)

    Clam
     (Mya arenaria)

    5.2 cm         static        marine           7.3-8.0  8.5-9.9   10.5-12               Bravo 500             35 000     Ernst et
                                 (30-31 ppt)               mg/litre                                                         al. (1991)
    Blue mussel
     (Mytilus edulis)

    5.9 cm         static        marine           7.3-8.0  8.5-9.9   10.5-12               Bravo 500             5940       Ernst et
                                 (30-31 ppt)               mg/litre                                                         al. (1991)
                                                                                                                                      

    Table 14.  (Cont'd)

                                                                                                                                      

    Stage (weight  Test          Freshwater/      pH       O2        Temperature  Solvent  Purity     48-h LC50  96-h LC50  Reference
    or length)     systems       marine                              (°C)                             (µg/litre) (µg/litre)
                                 (hardness)
                                                                                                                                      

    Eastern oyster
     (Crassostrea virginica)

     -             flow through  marine                              29                    technical             26b        Mayer (1987)
                                 (27 ppt)
                                                                                                                                      

    a    EC50 - immobility
    b    EC50 - shell deposition
        In view of the strong adsorption  and degradation characteristics of
    chlorothalonil, nominal concentrations in static systems are likely to
    underestimate the toxicity (overestimate the LC50) of chlorothalonil. 
    At the same time, it should be pointed out that the static test
    systems more closely resemble the field situation.

         Davies & White (1985) described the reactions of fish to
    exposure.   Oncorhynchus mykiss and  Galaxias sp showed marked
    lethargy, the degree increasing with time and concentration of
    exposure.  O. mykiss showed normal startle reactions at
    concentrations below 8.7 µg/litre, and  G. maculatus,  G. truttaceus
    and  G. auratus at 8.8, 9.0 and 13.3 µg/litre, respectively, over
    96 h.  In  O. mykiss, loss of startle reaction was followed by
    reduction of activity, and permanent lethargy was followed by loss of
    righting ability and death.  In  Galaxias sp, the onset of lethargy
    was accompanied by varying degrees of fin collapse.

         Davies & White (1985) commented on the fact that most acute
    toxicity values have been obtained in tests where solvent was added to
    the chlorothalonil.

         A 48-h EC50 has been reported for the pink shrimp ( Penaeus
     duorarum) at 320 µg/litre and a 96-h EC50 for the eastern oyster
    ( Crassostrea virginica) at 26 µg/litre.  The value for the pink
    shrimp was based on immobility or loss of equilibrium and that for the
    eastern oyster on shell deposition (Mayer, 1987).  Oysters suffered a
    42% mortality when exposed to 1000 µg chlorothalonil per litre for
    96 h and a 25% reduction in growth at 10 µg/litre (SDS Biotech
    Corporation, 1983b).

         Ernst et al. (1991) used both laboratory bioassay and field
    treatments of a pond system to determine the toxic effects of
    chlorothalonil on aquatic fauna.  The acute toxicity of technical
    chlorothalonil and a commercial formulation on five species, including
    mussel and clams, was determined (Table 14).  In the field study also
    reported by O'Neill (1991) (see section 5.1.2 for measured
    concentrations after spraying), the mortality of caged invertebrate
    and vertebrate species was monitored.  Seven species were caged in the
    stream flowing from the treated pond: water boatman  (Sigara
     alternata), caddisfly larva ( Limnephilus sp), freshwater clam
    ( Pisidium, sp), crawling water beetle ( Haliplus sp), scud
    ( Gammarus spp.), stickleback  (Gasterosteus aculeatus) and midge
    larva  (Chironomidae).  The floating cages were placed near the
    surface of the water.  The water boatman suffered the highest
    mortality, ranging from 49 to 84% in replicate cages; mortality in a
    control pond was 16-20% over the same period (24 h).  Midge larva
    mortality (69%) was judged by the authors to be a consequence of
    handling.  Stickleback mortality was 37 to 56% in the treated pond,
    compared to 2 to 6% in the controls.  Caddisfly larvae, clams, beetles

    and scud showed no deaths during the 24 h.  Rainbow trout
     (Oncorhynchus mykiss) also showed no mortality following spraying. 
    An estimate of total invertebrate numbers before and after spraying in
    the pond showed a slight increase following the first spray and a
    slight reduction after the second (not statistically significant). 
    The control pond also showed fluctuations.  The total was heavily
    influenced by  Chironomid midge larvae, which was by far the most
    frequently occurring species.  This study showed that a lower
    toxicological effect was observed in the field study than in the
    laboratory bioassays, indicating a reduction in exposure to the
    available chlorothalonil and thus less severe impacts in the pond
    system through physical and chemical processes.

         Gallagher et al. (1992) showed that sublethal chlorothalonil
    exposure may cause acute necrosis of the intestinal epithelial lining
    in channel catfish.  Exposure to 13 µg/litre for 72 h resulted in
    increased tissue GSH concentrations in liver, posterior kidney and
    gills, which suggests a protective role for tissue GSH against
    chlorothalonil exposure.

         When two generations of  Daphnia magna were exposed to technical
    chlorothalonil at levels of 6.2, 12, 25, 50 and 100 µg/litre for 21
    consecutive days during each generation, adverse effects on adult
    survival and reproduction were observed at a nominal concentration of
    100 µg/litre.  The maximum acceptable toxicant concentration (MATC)
    for technical chlorothalonil, based upon nominal concentrations, was
    50 µg/litre (35 µg/litre was the measured concentration) (Shults et
    al., 1982).

         Fathead minnows  (Pimephales promelas) were continuously exposed
    in duplicate aquaria to nominal concentrations of 25, 12.5, 6.3, 3.1
    and 1.5 µg/litre (measured concentrations 16, 6.5, 3.0, 1.4 and
    0.6 µg/litre, respectively) technical chlorothalonil, a diluent water
    control, and a solvent (acetone) control throughout a complete (egg to
    egg) life cycle.  No significant effects were observed in either
    generation at mean measured concentrations < 3.0 µg/litre.  The
    first generation (F0) eggs exhibited a significantly reduced
    hatchability and survival of fry after 35 days when exposed to a mean
    measured concentration of 16 µg/litre.  The reproductive success of
    Fo fish was adversely affected (reduction in the number of eggs per
    spawn) by exposure to concentrations > 6.5 µg/litre.  The second
    generation (F1) eggs exhibited a significantly reduced hatchability
    when exposed to a mean measured concentration of 6.5 µg/litre.  The
    survival of fry at this concentration was not affected.  Based on
    these data, the MATC (mean measured) of technical chlorothalonil in
    water for fathead minnows was estimated to be in the range of 3.0 to
    6.5 µg/litre (Shults et al., 1980).

    9.1.3  Terrestrial organisms

    9.1.3.1  Plants

         In a study by Stephenson et al. (1980), 30-day-old tomato plants
    were treated with chlorothalonil (at 2.5 kg/ha) or chlorothalonil in
    combination with metribuzine.  The effect was assessed as the tomato
    shoot dry weight (as a percentage of control plant weight).  On this
    basis, the weight of the chlorothalonil-treated plants was 89% of the
    control plant weight, a difference which was statistically significant
    (P > 0.05).  The effect was additive when chlorothalonil was used in
    combination with metribuzine.

    9.1.3.2  Earthworms

         When chlorothalonil suspension concentrate (500 g/litre) was
    added to artificial soil containing earthworms  (Eisenia foetida),
    the treated soil was non-toxic after 7 and 14 days.  The LC50 was
    found to be > 1000 mg/kg soil (on a dry weight basis) (Wuthrich,
    1990).

         When earthworms  (Eisenia foetida) were immersed for 1 min in
    solutions of chlorothalonil (0.1, 1 and 2% w/v); there was no effect
    on survival.  Bermuda grass clippings were air dried and ground; 15 g
    samples were then stirred into 100 ml of 0.1% chlorothalonil and
    subsequently fed to earthworms after filtration of excess liquid. 
    There was no effect on longevity.  Worms reared in soil in which
    chlorothalonil had been incorporated showed reduction in longevity of
    about 50% compared to controls 52-84 days after the beginning of
    treatment.  The amount of chlorothalonil added was equivalent to 5
    times the recommended application rate at 0.9 g in 4700 cm3 of soil,
    and reproduction was virtually eliminated (Roark & Dale, 1979).

    9.1.3.3  Earwigs and honey-bees

         Earwigs  (Labidura riparia) were exposed to chlorothalonil in
    three ways: a) on glass; b) as a residue on peanut foliage; and c) as
    a residue on a food source (i.e. 7-day-old armyworms). In the first
    treatment, chlorothalonil at a rate of 0.72 kg/ha produced up to 20%
    mortality in 24 h and up to 30% in 48 h.  In the second experiment,
    chlorothalonil was applied, at the same rate, to peanut foliage which
    was then used for the test.  There was a 10% mortality within 24 h and
    20% in 48 h on 4-day-old residues and no mortality on 8-day-old
    residues.  In the food source experiment there was 25-30% mortality
    within 24 h of the larvae being consumed and up to 55% mortality
    within 48 h (DeRivero & Poe, 1981).

         Atkins et al. (1975) found no contact toxicity of chlorothalonil
    (11 µg/bee), and classified it as relatively non-toxic to honey-bees. 
    The oral LD50 for chlorothalonil in 20% sucrose solution for
    honey-bees was > 0.2 µg/bee and the contact LD50 > 65 µg/bee
    (Davies, 1986).

    9.1.3.4  Birds

         The following toxicity values have been reported for birds, but
    without descriptions of the experimental methodology.  The acute oral
    LD50 in the mallard duck was reported to be > 4640 mg/kg.  The 8-day
    dietary LC50 in the same species and in the bobwhite quail  (Colinus
     virginianus) was given as > 10 000 mg/kg diet in each case (SDS
    Biotech Corporation, 1981a,b).  Dietary 8-day LC50 values were also
    reported as > 21 500 mg/kg diet for the mallard duck and 5200 mg/kg
    diet for the bobwhite quail (Worthing, 1991).

         Shults et al. (1988a) evaluated the effect of chlorothalonil on
    reproduction in the bobwhite quail.  Four groups (16 pairs per group)
    of quail were administered chlorothalonil in the diet at levels of
    1000, 5000 and 10 000 mg/kg for a period of 21 weeks.  Quail were fed
    the amended diet for 11 weeks prior to egg laying and for the duration
    of the egg laying period.  Adult and offspring were examined for body
    weight, general health, adult food consumption, egg production,
    eggshell thickness, embryo viability, hatching success survivability
    of offspring and gross pathology.  At a dietary concentration of
    10 000 mg/kg, the birds experienced reproductive impairment, which
    included mortality, general health, body weight, food consumption,
    gross pathology and other reproductive end-points.  Hatching survival
    was also affected at the highest dosage.  General health and
    reproductive parameters were also affected at 5000 mg/kg.  Other
    effects observed at this dose level included decreased body weight
    gain and survivability of offspring.  The lowest test dosage showed no
    apparent affects on either adult quail or offspring.  A
    no-observed-effect concentration (NOEC) of 1000 mg/kg diet was
    established for chlorothalonil regarding reproductive effects.

         In a separate but similar reproductive study with mallard ducks
     (Anas platyrhynchos), Shults et al. (1988b) reported that
    10 000 mg/kg diet reduced egg production and the percentage of
    hatchlings per incubated egg.  No reproductive impairments were
    observed for ducks dosed at 1000 or 5000 mg/kg.  Shults et al. (1988b)
    reported no effect on eggshell thickness at these chlorothalonil
    concentrations.  The NOEC for reproductive effects in mallard duck was
    5000 mg/kg diet.

    9.2  Field observations

    9.2.1  Soil microorganisms

         Smiley & Craven (1979) applied chlorothalonil (as Daconil 2787)
    at the normal rate (actual dose not given) every 21 days between April
    and September (9 applications for 3 consecutive years) to an
    experimental plot of Sward Kentucky blue grass  (Pia pratensis).
    Treated plots were 1 × 5 m and were replicated.  Samples of soil cores
    2.54 cm in diameter and 3 cm deep were taken (n = 5) from each
    replicate plot.  The cores included thatch and were chopped and mixed
    well, and 10 g was suspended in sterile distilled water.  A dilution
    series was plated out to estimate bacterial, actinomycete and fungal
    populations. None of the organisms were affected by chlorothalonil.
    The fungicide did not affect numbers of  Nitrosomonas or  Nitrobacter
    bacteria and had no effect on the disappearance of added ammonium by
    nitrification.  Treatments alternating different fungicides had a
    greater effect than one fungicide alone.

    9.2.2  Plants

         Many crop plants are tolerant of chlorothalonil and do not suffer
    any phytotoxicity when sprays of chlorothalonil formulations are
    applied according to recommended practices.  However, a few phytotoxic
    effects have been observed with certain species as a direct result of
    chlorothalonil applications and also as a result of physiologically
    incompatible mixtures of chlorothalonil formulations with additives or
    other pesticides.

         Chlorothalonil applied at a rate of 2.52 kg/ha did not affect
    yields of tomato plants grown in field conditions.  In addition,
    chlorothalonil did not enhance metribuzin damage when the two
    compounds were used in combination on tomato plants.  These results
    are contrary to those obtained in laboratory studies (section 9.1.3)
    and indicate that under field conditions phytotoxic reactions between
    chlorothalonil and metribuzin are unlikely to occur (Stephenson et
    al., 1980).

         Clear results were not obtained concerning the effect of
    chlorothalonil on perennial rye grass  (Lolium perenne) when it was
    sprayed regularly for the control of leaf-spotting disease.  In the
    first year of treatment the grass yield was increased by 15% at the
    third harvest, but at the following harvest, when disease incidence
    was greater, the yield was not increased.  The authors concluded that
    chlorothalonil did not have a direct stimulatory effect on grass
    growth (Lam & Lewis, 1983).

         Chlorothalonil was used to treat onion beds at a rate of
    2.34 litres formulation/ha with 10 weekly applications. The onions
    (two short-day cultivars) were harvested either 146 or 167 days after 

    planting.  Chlorothalonil reduced the weight and size of marketable
    bulbs by 44 and 32%, respectively, but did not influence the
    maturation rate.  Alternate application of chlorothalonil and mancozeb
    reduced these values by 27 and 33%, respectively.  The disease
    incidence was nil in all treatments (Stoffella & Sonoda, 1982).

    10.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         The Joint FAO/WHO Meeting on Pesticide Residues (JMPR) discussed
    and evaluated chlorothalonil at its meetings in 1974, 1977, 1978,
    1979, 1981, 1983, 1985, 1987, 1990 and 1992 (FAO/WHO, 1975, 1978,
    1979, 1980, 1982, 1985, 1986a,b, 1988, 1990a,b, 1993b).  In 1990 an
    acceptable daily intake (ADI) of 0-0.03 mg/kg body weight was
    established.  This ADI was confirmed in 1992, based on the NOAEL of 3
    mg/kg body weight/day established in the two-year dog study (FAO/WHO,
    1993a,c).

         The Joint FAO/WHO Codex Alimentarius Commission has established
    maximum residue limits (MRLs) for chlorothalonil in various
    commodities (FAO/WHO, 1993c).

         WHO has classified chlorothalonil as a technical product unlikely
    to present an acute hazard in normal use (WHO, 1992).

         On the basis of data available at the time, the International
    Agency for Research on Cancer evaluated chlorothalonil as showing
    limited evidence of carcinogenicity in animal studies and categorized
    it as an agent not classifiable as to its carcinogenicity to humans
    (IARC, 1987).

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    Paynter OE & Busey W (1967) Long-term (76 weeks) feeding study: rats
    DAC 2787. Hazleton Laboratories, Inc. (Unpublished report submitted to
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    Paynter OE & Murphy JC (1967) 16-Week dietary administration: dogs
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    Powers M (1965) Acute oral administration: rats. Hazleton
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    Price P (1978a) The activity of compound DTX-77-0037 in the Fischer
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    Price P (1978b) The activity of compound DTX-77-0041 in the Fischer
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    Reduker S, Uchrin CG, & Winnett G (1988) Characteristics of the
    sorption of chlorothalonil and azinphos-methyl to a soil from a
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    Ribovich ML, Pollock GA, Marciniszyn JP, Killeen JC, & Ignatoski JA
    (1983) Balance study of the distribution of radioactivity following
    oral administration of 14C-chlorothalonil (14C-DS-2787) to male mice.
    Mentor, Ohio, Fermenta ASC (Unpublished report No. 613-4AM-82-0178-
    001).

    Roark JH & Dale JL (1979) The effect of turf fungicides on earthworms.
    Arkansas Acad Sci Proc, 33: 71-74.

    Rosanoff KA & Siegel MR (1981) Mechanism of action and fate of the
    fungicide chlorothalonil in biological systems. 3. Interaction with
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    Physiol, 16: 120-128.

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    Savides MC, Marciniszyn JP, Killeen JC, & Ignatoski JA (1985)
    Isolation and identification of metabolites in the bile of rats orally
    administered 14C-chlorothalonil I.  Synthesis and characterisation of
    glutathione conjugates of chlorothalonil. Mentor, Ohio, Fermenta ASC
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    Savides MC, Marciniszyn JP, Killeen JC, & Ignatoski JA (1986a) Study
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    Sprague-Dawley rats. Mentor, Ohio, Fermenta ASC (Unpublished report
    No. 1173-84-0079-AM-003).


    Savides MC, Marciniszyn JP, Killeen JC, & Ignatoski JA (1986b)
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    administration of 14C-chlorothalonil to male rats. II. Effects of
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    urine. Mentor, Ohio, Fermenta ASC (Unpublished report No. 621-4AM-83-
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    Savides MC, Marciniszyn JP, Killeen JC, & Ignatoski JA (1986c) Study
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    372-3EF-83-0004-001, submitted to WHO by SDS Biotech Corporation,
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    report No. 00-5TX-61-0002-001).

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     Daphnia magna with technical chlorothalonil. Cleveland, Ohio,
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    chlorothalonil. Mentor, Ohio, Fermenta ASC (Unpublished report No.
    754-5TX-85-0023-007).

    Shults SK, Wilson NH, & Killeen JC (1988a)  Reproduction study in
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    ISK-Biotech, Mentor, USA).

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    Krieger RI (1991) Chlorothalonil exposure of workers on mechanical
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    88-90 (in German).

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    tetrachloroisophthalonitrile (Daconil 2787) in soil. Mentor, Ohio,
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    No. 1000-3EF-76-2087-001, submitted to WHO by ISK Biosciences
    Corporation, Mentor, USA).

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    Applicator exposure to fluvalinate, chlorpyrifos, captan, and
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    Pesticide exposure to a greenhouse drencher. Bull Environ Contam
    Toxicol, 42: 209-217.

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    interactions involving metribuzin and other pesticides in tomatoes.
    Can J Plant Sci, 60: 167-175.

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    chlorothalonil.  Hortscience, 17(4): 628-629.

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    captan and diazinon in apples. Bull Agric Chem Insp Stn (Tokyo),
    17:43-45.

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    chlorothalonil.  J Agric Food Chem, 25(1): 208-210.

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    tetrachloroisophthalonitrile (chlorothalonil, DS-2787) upon the
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    Ohio, ISK-Biotech (Proprietary report No. 326-3EI-79-0009-001).

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    tetrachloroisophthalonitrile (chlorothalonil, DS-2787) upon
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    ISK-Biotech (Proprietary report No. 327-3EI-79-0010-001).

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    tetrachloroisophthalonitrile (chlorothalonil, DS-2787) upon nitrogen
    transformation in soil. Mentor, Ohio, ISK-Biotech (Proprietary report
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    of the fungicide chlorothalonil (2,4,5,6-tetrachloroisophthalonitrile)
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    Wilson NH, Killeen JC, & Ignatoski JA (1982) Dermal sensitization
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    submitted to WHO by ISK Biosciences Corporation, Mentor, USA).

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    toxicity study of technical chlorothalonil in rats. Mentor, Ohio,
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    re-evaluation of renal tissue from a sub-chronic toxicity study of
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    RESUME

    1.  Identité, propriétés physiques et chimiques et méthodes d'analyse

         Le chlorothalonil est un solide cristallin incolore et inodore,
    dont le point de fusion est de 250°C et la tension de vapeur de 7,63 ×
    10-5 Pa (5,72 × 10-7 mmHg) à 25°C.  Il est peu soluble dans l'eau
    (0,6-1,2 mg/litre à 25°C) et son coefficient de partage entre
    l'octanol et l'eau (log Kow) est de 2,882.  Dans l'eau, il
    s'hydrolyse lentement à pH 9 mais il est stable à pH < 7 (à 25°C).

         La méthode d'analyse la plus courante, après extraction et
    purification, est la chromatographie gaz-liquide avec détection par
    capture d'électrons.

    2.  Sources d'exposition humaine et environnementale

         Le chlorothalonil est produit depuis 1969 à des fins
    commerciales, soit par chloration de l'isophtalonitrile, soit en
    traitant le tétrachlorisophtaloylamide par l'oxychlorure de phosphore. 
    C'est un fongicide à large spectre utilisé non seulement en
    agriculture, mais aussi pour traiter le gazon et les plantes
    ornementales.  On l'utilise pour protéger les fruits à pépins et à
    noyaux, les agrumes, les groseilles, les baies, les bananes, les
    tomates, les légumes verts, le café, les arachides, les pommes de
    terre, les oignons et les céréales.  En outre, il entre dans la
    composition de certains produits pour la conservation du bois et de
    certaines peintures.

         Il existe en trois formulations principales, un concentré pour
    suspensions, des granulés dispersables dans l'eau et une poudre
    mouillable.Ces produits sont facilement dilués dans l'eau et épandus
    par pulvérisations au sol ou aériennes.  La dose d'emploi est
    habituellement de 1,2 à 2,5 kg de matière active par hectare pour le
    traitement des haricots, des céleris et des oignons.  L'exposition
    humaine a lieu principalement pendant la préparation et l'épandage du
    produit ou lors de l'ingestion de résidus présents dans certaines
    denrées alimentaires (voir section 1.1.4).

    3.  Transport, distribution et transformation dans l'environnement

         Le chlorothalonil s'élimine des milieux aqueux par une forte
    adsorption sur les particules en suspension.  La modélisation des
    données disponibles montre qu'il ne migre pratiquement pas vers les
    sédiments du fond.  Il est possible qu'il subisse une biodégradation
    enzymatique dans les eaux naturelles.  Dans le sol, il est rapidement
    dégradé, cette dégradation pouvant également avoir lieu dans l'eau
    avec production du métabolite hydroxylé en position 4, c'est-à-dire le
    4-hydroxy-2,5,6-trichlorisophtalonitrile.  La demi-vie de dissipation
    du métabolite 4-hydroxy dans le sol est comprise entre 6 et 43 jours.

         Une fois entré en contact avec une plante, le chlorothalonil ne
    migre pas vers d'autres zones du végétal.  Les végétaux ne le
    métabolisent que dans une proportion limitée et le métabolite
    4-hydroxy constitue en général moins de 5% du résidu.

         Chez les poissons, la métabolisation du chlorothalonil comporte
    une conjugaison avec le glutathion, qui aboutit à des produits
    d'excrétion plus polaires.  Elle s'effectue sous l'action de la
    glutathion- S-transférase.  L'excrétion du composé sous forme de
    conjugué avec le glutathion est corroborée par le fait que, chez la
    truite arc-en-ciel, on trouve une forte concentration de marqueur dans
    la vésicule biliaire et dans la bile après exposition à du
    14C-chlorothalonil.Une fois les poissons replacés en eau propre, on a
    constaté une chute rapide de la concentration du marqueur qui s'était
    accumulé dans la vésicule biliaire et les autres organes.

         Le chlorothalonil ne s'accumule pas chez les organismes
    aquatiques.

    4.  Concentrations dans l'environnement et exposition humaine

         Lors d'une étude sur des cultures de pommes de terre, on a
    pulvérisé du chlorothalonil sur un petit cours d'eau.  Après
    prélèvement et analyse de l'eau en aval du secteur traité, on a
    constaté que le composé disparaissait rapidement (par ex. la
    concentration passait de 450 µg/litre 30 minutes après le traitement à
    2-6 µg/litre 12 h après le traitement).  Les traitements de routine
    effectués sur des cultures irriguées de plein champ, comme les pommes
    de terre ou l'orge, n'ont donné lieu qu'à de faibles concentrations de
    chlorothalonil (0,04-3,6 µg/litre), comme l'ont montré un certain
    nombre d'analyses pratiquées sur de l'eau prélevée à quelques
    occcasions dans des drains en grès vernissé.

         Les résidus qui subsistent sur les récoltes sont essentiellement
    constitués par le chlorothalonil lui-même.  Leur concentration est
    fonction de la dose d'emploi, du temps écoulé depuis le dernier
    épandage et la dernière récolte ainsi que du type de culture.  A
    partir des nombreux essais effectués sous contrôle un peu partout dans
    le monde et dont les résultats ont été communiqués à la FAO et à
    l'OMS, il est possible de déterminer les concentrations de résidus
    présentes au moment de la récolte.  En ce qui concerne les produits
    laitiers, il est vraisemblable que les résidus sont soit
    indétectables, soit très faibles.  Dans le lait de vaches laitières
    qui avaient reçu pendant 30 jours du chlorothalonil mêlé à leur
    nourriture (jusqu'à 250 mg/kg), on n'a pas trouvé trace du composé,
    mais celui-ci était présent dans les tissus à très faible
    concentration.

         Des analyses pratiquées dans plusieurs pays, soit sur la ration
    totale, soit sur tel ou tel alliment, ont montré, à l'occasions
    d'enquêtes par sondage, que le chlorothalonil n'était présent qu'en 

    quantités indétectables ou du moins très faibles.  Les diverses
    préparations que subissent les produits alimentaires, comme le pelage,
    le lavage et la cuisine en général contribuent d'ailleurs à abaisser
    encore leur teneur en résidus.

    5.  Cinétique et métabolisme chez les animaux de laboratoire

         Chez des rats qui en recevaient par voie orale des doses allant
    jusqu'à 50 mg/kg de poids corporel, le composé a été absorbé à hauteur
    d'environ 30% en l'espace de 48 h.  A plus forte dose, l'absorption
    est moindre, ce qui est le signe d'un processus de saturation.  Après
    administration de 14C-chlorothalonil par voie orale, on a observé une
    répartition tissulaire et sanguine de la radioactivité en 2 h.  C'est
    au niveau des reins, du foie et du sang - dans cet ordre - qu'ont été
    relevées les concentrations les plus imporantes.  Au bout de 24 h, on
    a mesuré, au niveau des reins, une concentration égale à 0.3% d'une
    dose initiale de 5 mg/kg de poids corporel.

         La majeure partie d'une dose administrée par voie orale à des
    rats a été retrouvée dans leurs matières fécales (> 82% en l'espace
    de 48-72 h, quelle que soit la dose initiale).  L'excrétion biliaire
    est rapide, culminant au bout de 2 h après ingestion d'une dose de 5
    mg/kg de poids corporel et la saturation est atteinte à partir de 50
    mg/kg de poids corporel.  Chez le rat, la dose est excrétée à hauteur
    de 5-10% par la voie urinaire.  Chez le chien et le singe, la
    prncipale voie d'excrétion est la voie fécale, la voie urinaire étant
    moins importante que chez le rat (< 4%).

         Les études métaboliques menées sur des rats montrent que le
    chlorothalonil est conjugué avec le glutathion dans le foie ainsi que
    dans les voies digestives.  Certains de ces conjugués peuvent être
    absorbés dans l'intestin et parvenir jusqu'aux reins où ils sont
    transformés par la ß-lyase du cytosol en analogues thioliques,
    excrétés ensuite par la voie urinaire.  Lorsqu'on administre du
    chlorothalonil à des rats axéniques, les métabolites thioliques
    apparaissent dans l'urine en quantité bien moindre que chez des rats
    normaux, ce qui indique que la flore intestinale intervient dans le
    métabolisme de ce composé.  Des chiens et des singes à qui on
    administre du chlorothalonil par voie orale, n'excrètent que peu ou
    pas de métabolites thioliques dans leurs urines.

         Après application cutanée de 14C-chlorothalonil à des rats,
    environ 28% de la dose ont été absorbés en 120 h.  On a retrouvé
    environ 18% de la dose dans les matières fécales et 6% dans les urines
    au bout de 120 h.


    6.  Effets sur les mammifères de laboratoire et les systèmes d'épreuve
         in vitro

         Chez le rat et le lapin, la toxicité aiguë du chlorothalonil est
    faible, que ce soit par voie orale ou en applications cutanée (DL50
    > 10 000 mg/kg de poids corporel).  Du chlorothalonil broyé au
    mortier (D médian des particules égal à 5-8 µm) s'est révélé très
    toxique pour des rats lors d'une étude toxicologique par inhalation,
    avec une CL50 à 4 h de 0,1 mg/litre.

         Le chlorothalonil est irritant pour la peau et les yeux chez le
    lapin.  Les études de sensibilisation cutanée effectuées sur des
    cobayes n'ont pas été concluantes.

         Chez le rat, les principaux effets de doses orales répétées
    s'exercent au niveau des reins et de l'estomac.Pendant 13 semaines, on
    fait ingérer quotidiennement à des rats, répartis en groupes de 25
    animaux de chaque sexe, du chlorothalonil mêlé à leur nourriture aux
    doses de 0, 1,5, 3, 10, ou 40 mg/kg de poids corporel.  Après une
    période de récupération de 13 semaines, les rats ont été sacrifiés et
    l'on a observé une hyperplasie et une hyperkératose au niveau de la
    portion cardiaque de l'estomac aux doses de 10 et 40 mg/kg; ces
    lésions ont regressé lorsque le traitement a cessé.  A la dose de 40
    mg/kg, on notait chez les mâles une augmentation de l'incidence des
    hyperplasies épithéliales au niveau des tubules proximaux du rein au
    bout des 13 semaines de traitement ainsi qu'après la période de
    récupération.  La dose sans effet observable a été évaluée à 3 mg/kg
    de poids corporel par jour, le critère retenu étant l'absence de
    lésions au niveau de la portion cardiaque de l'estomac.  Les lésions
    interessant cette partie de l'eatomac ainsi que les reins sont
    apparues rapidement, à savoir en 4 à 7 jours chez les mâles lorsqu'on
    a porté la dose alimentaire quotidienne à 175 mg/kg de poids corporel.

         Lors d'une étude de 13 semaines sur des souris (0, 7,5, 15, 50,
    275, ou 750 mg/kg en mélange à la nourriture), on a constaté une
    incidence accrue des hyperplasies et des hyperkératoses de
    l'épithélium pavimenteux au niveau de la portion cardiaque de
    l'estomac.  Ces lésions ont été observées chez les mâles comme chez
    les femelles à partir de 50 mg/kg de nourriture.  En se basant sur la
    présence ou l'absence de ces lésions, on a évalué à 15 mg/kg de
    nourriture la dose de chlorothalonil sans effet observable, soit
    l'équivalent quotidien de 3 mg/kg de poids corporel.

         Une étude de 16 semaines sur des chiens aux doses alimentaires de
    0, 250, 500, ou 750 mg/kg n'a pas révélé de d'effets qui soient
    imputables au traitement.

         Les lésions observées au niveau des reins et de la portion
    cardiaque de l'estomac ont fait l'objet, pendant 2 ans, d'études plus
    approfondies sur des souris et des chiens.  Une autre étude, portant
    cette fois sur des rats (aux doses quotidiennes de 0, 1,8, 3,8, 15 ou

    175 mg/kg de poids corporel), a permis de caractériser histo-
    logiquement les effets observés: il s'agissait d'une part, d'une 
    augmentation de l'incidence des hyperplasies, des hyperkératoses, des
    ulcérations et des abrasions de l'épithélium pavimenteux au niveau de
    la portion cardiaque de l'estomac et, d'autre part, de la présence
    d'une hyperplasie au niveau des tubules contournés proximaux du rein. 
    Ces anomalies ont été observées à partir de 3,8 mg/kg.  A la dose de
    175 mg/kg, on notait un accroisssement sensible de l'incidence des
    tumeurs rénales (adénomes et carcinomes) et des tumeurs interessant la
    portion cardiaque de l'estomac (papillomes et carcinomes).  On est
    fondé à penser que l'incidence des tumeurs rénales était augmentée
    chez les mâles à partir de la dose de 15 mg/kg, de même que celle des
    tumeurs gastriques chez les deux sexes aux doses de 3,8 mg/kg et de 15
    mg/kg.  La dose sans effets néoplasiques observables a donc été prise
    égale à 1,8 mg/kg, en prenant comme critère l' incidence des tumeurs
    au niveau de la portion cardiaque de l'estomac.  Une autre étude de 2
    ans, au cours de laquelle des doses plus élevées ont été utilisées, a
    confirmé le pouvoir cancérogène du chlorothalonil, tant au niveau du
    rein que de la portion cardiaque de l'estomac.

         Une étude sur des souris (doses de 0, 15, 40, 175, ou 750 mg/kg
    de nourriture) a révélé une augmentation de l'incidence des
    hyperplasies au niveau des tubules rénaux à partir de 175 mg/kg, le
    même phénomène étant observé à partir de 40 mg/kg au niveau de la
    portion cardiaque de l'estomac, avec en outre une hyperkératose.  A la
    dose de 750 mg/kg, il y avait une légère augmentation des tumeurs
    spinocellulaires au niveau de la portion cardiaque de l'estomac.  On
    en a donc conclu que les doses sans effets néoplasiques ou non
    néoplasiques étaient respectivement égales à 175 et 15 mg/kg de
    nourriture (soit l' équivalent quotidien de 17,5 et 1,6 mg/kg de poids
    corporel, respectivement).  Ces effets constatés chez la souris sont
    corroborés par les résultats d'une autre étude avec des doses plus
    élevées, mais une troisième investigation portant sur des souris
    B6C3F1 n'a pas mis en évidence d'effets cancérogènes à dose élevée.

         Lors d'une étude de 2 ans sur des chiens (60 et 120 mg/kg de
    nourriture), aucun effet attribuable au chlorothalonil n'a été
    observé.  On en conclu que la dose sans effet observable était de 120
    mg/kg de nourriture (soit l'équivalent quotidien de 3 mg/kg de poids
    corporel).

         Plusieurs épreuves de mutagénicité  in vivo et  in vitro se
    sont révélées négatives, mais il y en a tout de même eu quelques unes
    de positives.

         Les dérivés monothio, dithio, trithio, dicystéinyl, tricystéinyl
    et monoglutathionyl du chlorothalonil, qui sont potentiellement
    néphrotoxiques, se sont révélés négatifs dans l'épreuve d'Ames.

         Le chlorothalonil ne s'est pas montré tératogène pour le rat ou
    le lapin à des doses quotidiennes atteignant respectivement 400 et 50
    mg/kg de poids corporel. Lors d'une étude sur deux générations de 

    rats, on n'a pas constaté d'effets sur l'accouplement, la fécondité ou
    la gestation jusqu'à des doses atteignant 1500 mg/kg de nourriture.

         La toxicité aiguë par voie orale du métabolite 4-hydroxy est
    supérieure à celle du chlorothalonil lui-même (DL50 aiguë par voie
    orale égale à 332 mg/kg de poids corporel contre > 10 000 mg/kg de
    poids corporel).  Plusieurs études ont été entreprises pour
    caractériser le profil toxicologique de ce métabolite et établir les
    doses sans effets observables.

    7.  Effets sur l'homme

         On a signalé des cas de dermatite de contact parmi des personnes
    employées à la fabrication de chlorothalonil, chez des agriculteurs et
    des horticulteurs.  D'autres cas de dermatite siégeant au niveau des
    mains et de la face ont été observés chez des personnes qui
    utilisaient des produits de protection du bois à base de
    chlorothalonil.

    8.  Effets sur les autres êtres vivants au laboratoire et dans leur
        milieu naturel

         Le chlorothalonil est extrêmement toxique pour les poissons et
    les invertébrés aquatiques, comme le montrent un certain nombre
    d'études en laboratoire, avec des valeurs de la CL50 inférieures à
    0,5 mg/litre.  La concentration maximale acceptable de produit toxique
    (MATC) s'est révélée être égale à 35 µg/litre lors d'une étude sur
    deux générations de daphnies.

         A quelques exceptions près, d'ailleurs sans grande importance, le
    chlorothalonil n'est pas phytotoxique.

         La CL50 d'un concentré pour suspension (500 g de chlorothalonil
    par litre) répandu sur un sol artificiel pour lombrics, a été évaluée
    à > 1000 mg/kg de terre (14 jours).  On a observé une surmortalité
    parmi des scolopendres qui s'étaient trouvés en contact avec des
    résidus de chlorothalonil présents sur des feuilles d'arachide ou s'en
    étaient nourris au laboratoire; il n'y a pas eu d'autre indice d'une
    action insecticide.

         Le chlorothalonil est peu toxique pour les oiseaux, comme le
    montre la valeur de la DL50 aiguë par voie orale chez le colvert
    (4640 mg/kg).  Aucun effet important sur la reproduction n'a été
    signalé.

         D'après une étude effectuée sur le terrain, la toxicité du
    chlorothalonil pour les organismes aquatiques est moindre que ne le
    font craindre les expériences de laboratoire; ce résultat est en
    accord avec les propriétés physico-chimiques de ce composé.  On a tout
    de même enregistré une mortalité chez des espèces exposées
    expérimentalement sur le terrain.  En revanche, on n'a pas signalé 

    d'accidents écologiques ayant entraîné une mortalité.  Malgré la
    faible persistance du chlorothalonil dans les divers compartiments du
    milieu, il faut tout de même s'attendre à une certaine mortalité.  En
    pareil cas, il sera difficile d'établir un lien de cause à effet étant
    donné que les résidus de chlorothalonil ne subsistent pas suffisamment
    lontemps pour que l'on puisse identifier le composé.

    RESUMEN

    1.  Identidad, propiedades físicas y químicas, y métodos analíticos

         El clorotalonilo es un sólido cristalino inodoro e incoloro con
    un punto de fusión de 250°C y una presión de vapor de 7,63 × 105 Pa
    (5,72 × 10-7 mmHg) a 25°C. Es poco soluble en agua (0,6 a 1,2 mg/litro
    a 25°C) y tiene un coeficiente de partición octanol/agua (log
    Koa) de 2,882. Se hidroliza lentamente en agua con un pH de 9, pero
    es estable a un pH de 7 o inferior (a 25°C).

         El método analítico más corriente, después de la extracción y
    depuración de las muestras, es la cromatografía gas-liquido empleando
    un detector de captura de electrones.

    2.  Fuentes de exposición del ser humano y del medio ambiente

         El clorotalonilo se viene produciendo a escala comercial desde
    1969 por cloración del isoftalonitrilo o mediante el tratamiento de la
    amida tetracloroisoftalolil con oxicloruro de fósforo. Es un fungicida
    con amplio espectro de actividad empleado principalmente en la
    agricultura pero también en el césped, los pastos y las plantas
    ornamentales. Los cultivos protegidos incluyen frutas de pepitas y de
    hueso, cítricos, grosellas, fresas, bananas, tomates, verduras, café,
    cacahuete, patatas, cebollas y cereales. Se emplea también en
    sustancias protectoras de la madera y en pinturas.

         Las tres formulaciones principales son una suspensión
    concentrada, un gránulo hidrodispersible y un polvo humectable. Se
    disuelven fácilmente en agua y se aplican empleando sistemas de
    pulverización en los suelos o rociado aéreo. Las tasas típicas del
    ingrediente activo oscilan entre 1,2 y 2,5 kg/ha en el caso de
    cultivos tales como frijoles, apio y cebollas. Las principales fuentes
    de exposición del ser humano son la preparación y aplicación de los
    productos, así como la ingestión de residuos de las cosechas en los
    alimentos (véase la sección 1.1.4).

    3.  Transporte, distribución y transformación en el medio ambiente

         El clorotalonilo se elimina de los medios acuosos mediante
    intensa adsorción en las materias en suspensión. Los datos de los
    modelos parecen indicar poca, o ninguna, partición detectable en el
    sedimento del fondo. Puede producirse biodegradación en aguas
    naturales, con la participación de procesos enzimáticos. El
    clorotalonilo se degrada rápidamente en el suelo, y puede haber
    degradación en el agua con la producción del metabolito 4-hidroxi-
    2,5,6-tricloroisoftalonitrilo. La semivida para la disipación en el
    suelo de ese metabolito varía entre 6 y 43 días.

         El clorotalonilo no se transloca del punto de aplicación a otras
    partes de la planta. Su metabolización en las plantas es limitada y,
    por o general, ese metabolito representa < 5% del residuo.

         En cuanto a los peces, el clorotalonilo se metaboliza mediante la
    conjugación con glutatión para producir productos de degradación más
    polares. En esa conversión interviene la enzima glutatión-
     S-transferasa. Las elevadas concentraciones del radioisótopo
    marcador detectadas en la vesícula biliar y la bilis después de la
    exposición de la trucha arco iris al 14C-clorotalonilo son
    compatibles con la excreción del compuesto en forma de conjugados de
    glutatión. Las concentraciones de los radioisótopos de trazado que se
    acumulan en la vesícula biliar y otros órganos disminuyen rápidamente
    al colocar los peces en agua no contaminada.

         El clorotalonilo no experimenta bioacumulación en los organismos
    acuáticos.

    4.  Niveles ambientales y exposición humana

         En un estudio de un cultivo de patatas, se procedió a rociar un
    pequeño arroyo con clorotalonilo. Muestreos y análisis posteriores del
    agua río abajo demostraron la rápida desaparición del clorotalonilo
    (las concentraciones eran de 450 µg/litro a los 30 minutos después del
    rociado, y oscilaban entre 2 y 6 µg/litro a las 12 h después del
    rociado). El rociado sistemático de los cultivos irrigados como, por
    ejemplo, patatas y cebada, estuvo acompañado de bajas concentraciones
    de clorotalonilo (0,04 a 3,6 µg/litro) en el agua de los tubos de
    drenaje en un pequeño número de muestras.

         Los residuos de las cosechas están compuestos principalmente de
    clorotalonilo propiamente dicho. Las concentraciones residuales
    dependen del nivel aplicado, del tiempo transcurrido entre la última
    aplicación y la cosecha, y del tipo de cosecha. Los niveles residuales
    en la cosecha pueden deducirse de los numerosos ensayos supervisados
    realizados con muchas cosechas en todo el mundo y comunicados a la FAO
    y la OMS. Se prevé que los residuos de clorotalonilo en los productos
    lácteos serán imposibles de detectar, o las concentraciones muy bajas.
    En un estudio con vacas lecheras alimentadas durante 30 días con
    pienso al que se habían añadido elevadas concentraciones (hasta 250
    mg/kg) de clorotalonilo no se observó ningún residuo detectable en la
    leche y sólo niveles muy bajos en los tejidos.

         Los análisis del régimen alimenticio total y de alimentos
    específicos realizados en varios países han revelado concentraciones
    no detectables, o muy bajas, de clorotalonilo en los estudios por
    muestreo. Los procesos de preparación tales como el lavado, el pelado
    y la cocción permiten reducir aún más los niveles residuales en los
    alimentos.

    5.  Cinética y metabolismo en animales de laboratorio

         En estudios con ratas a las que se administraron dosis de hasta
    50 mg/kg de peso corporal, se observó que un 30% de la dosis oral de
    clorotalonilo se absorbía dentro de las 48 horas. La absorción es
    inferior con posologías más elevadas, lo que indica un proceso de
    saturación. Cuando se administra oralmente 14C-clorotalonilo, la
    radioactividad se distribuye en la sangre y los tejidos en menos de
    dos horas. Las mayores concentraciones se encuentran en el riñón, el
    hígado y la sangre, en ese orden. Con una posología de 5 mg/kg de peso
    corporal, la concentración en los riñones es 0,3% a las 24 horas.

         Por lo que respecta a las ratas, la mayor parte de la dosis oral
    de clorotalonilo se encuentra en las heces (> 82% dentro de las 48 a
    72 horas, independientemente de la dosis). Con una dosis oral de 5
    mg/kg de peso corporal, la excreción biliar es rápida, alcanzando su
    valor máximo dentro de las 2 horas, ocurriendo saturación con
    posologías de 50 mg/kg de peso corporal y superiores. En el caso de
    las ratas, la excreción urinaria representa entre un 5 y 10% de la
    dosis. En perros y monos, la excreción fecal es la vía principal, pero
    la excreción urinaria (< 4%) es inferior a la observada en las ratas.

         Estudios metabólicos llevados a cabo con ratas indican que el
    clorotalonilo se conjuga con el glutatión tanto en el hígado como en
    el tracto gastrointestinal. Algunos de los conjugados del glutatión
    pueden ser absorbidos en el intestino y transportados a los riñones
    donde son convertidos por la ß-liasa citosólica en análogos del tiol
    que se excretan por la orina. Cuando se dan dosis de clorotalonilo a
    ratas axénicas, se observan en la orina metabolitos del tiol en
    cantidades muy inferiores a las registradas en ratas normales, lo que
    indica que la microflora intestinal interviene en el metabolismo del
    clorotalonilo. En el caso de los perros o monos que reciben dosis
    orales de clorotalonilo, la excreción de derivados del tiol por la
    orina no es detectable, o es muy baja.

         Cuando se aplicó 14C-clorotalonilo a la piel de la rata, un 28%
    de la dosis fue absorbida en menos de 120 horas. Se observaron
    concentraciones del 18% de la dosis en las heces y del 6% en la orina
    al cabo de 120 horas.

    6.  Efectos en mamíferos de laboratorio y sistemas de pruebas
         in vitro

         El clorotalonilo tiene baja toxicidad oral y cutánea en ratas y
    conejos, respectivamente (los valores agudos orales y cutáneos de la
    DL50 son > 10 000 mg/kg de peso corporal). Por lo que respecta a
    las ratas, en un estudio de inhalación se observó que el clorotalonilo
    técnico pulverizado (MMAD 5 a 8 µm) presentaba elevada toxicidad, con
    una CL50 de 0,1 mg/litro a las 4 h.

         El clorotalonilo es un irritante de la piel y los ojos en el
    conejo. Los estudios de sensibilización cutánea en el conejillo de
    indias no arrojaron resultados concluyentes.

         En el caso de las ratas, los efectos principales de dosis orales
    repetidas de clorotalonilo se observan en el estómago y los riñones.
    En un estudio con grupos de 25 ratas, en que se separaron los sexos,
    se emplearon posologías de 0, 1,5, 3, 10 ó 40 mg/kg de peso corporal
    por día en la dieta durante 13 semanas, lo que estuvo seguido de un
    período de recuperación de 13 semanas. Se observó mayor frecuencia de
    hiperplasis y hiperketarosis del preestómago con las posologías de 10
    y 40 mg/kg; los efectos desaparecieron cuando cesó el tratamiento. Con
    una concentración de 40 mg/kg, se registro mayor incidencia de
    hiperplasia del epitelio tubular proximal del riñón en los machos a
    las 13 semanas y después del período de recuperación. El nivel sin
    efecto observado fue de 3 mg/kg de peso corporal por día en base a la
    ausencia de lesiones en el preestómago. Se ha demostrado que los
    cambios observados en el preestómago y los riñones son de rápida
    aparición, presentándose las lesiones dentro de un período de 4 a 7
    días en el caso de los machos, cuyo régimen alimenticio incluía una
    concentración de 175 mg/kg de peso corporal al día.

         En un estudio de 13 semanas de duración realizado con ratones
    (empleando dosis de 0, 7,5, 15, 50, 275 ó 750 mg/kg en el alimento),
    se observó mayor incidencia de hiperplasia e hiperkeratosis de las
    células epiteliales escamosas del preestómago en el caso de los machos
    y las hembras cuando se emplearon posologías de 50 mg/kg y superiores.
    Atendiendo a esos cambios, el nivel sin efecto observado fue de 15
    mg/kg de clorotalonilo en la dieta, lo que equivale a 3 mg/kg de peso
    corporal por día.

         Un estudio de 16 semanas de duración con perros cuyo alimento
    contenía concentraciones de 0, 250, 500 ó 750 mg/kg no reveló cambios
    relacionados con el tratamiento.

         Se llevaron a cabo investigaciones adicionales de las lesiones en
    el preestómago y los riñones, llevándose a cabo estudios con ratas,
    ratones y perros durante un período de 2 años. En un estudio realizado
    con ratas (empleando dosis de 0, 1,8, 3,8, 15 ó 175 mg/kg de peso
    corporal al día), los efectos estuvieron caracterizados
    histológicamente por una mayor incidencia e intensidad de hiperplasia,
    hiperkeratosis, y úlceras y erosiones de la mucosa escamosa del
    preestómago, y por hiperplasia del epitelio de los túbulos
    contorneados proximales de los riñones con posologías de 3,8 mg/kg y
    superiores. Por lo que respecta a los efectos no neoplásicos, el nivel
    sin efecto observado fue, por lo tanto, de 1,8 mg/kg. La incidencia de
    tumores renales (adenomas y carcinomas) y de tumores del preestómago
    (papilomas y carcinomas) fue considerablemente superior, alcanzando
    175 mg/kg. Hubo pruebas de mayor incidencia de tumores renales en los
    machos con dosis de 15 mg/kg, así como de tumores estomacales en los 

    machos y las hembras con dosis de 3,8 y 15 mg/kg. Por lo que respecta
    a los efectos neoplásicos, el nivel sin efecto observado fue, por lo
    tanto, de 1,8 mg/kg de peso corporal por día sobre la base de los
    cambios en la incidencia de tumores en el preestómago. El riesgo
    carcinogénico del clorotalonilo en los riñones y preestómago de las
    ratas se vio corroborado por los resultados de otros estudios de 2
    años de duración en que emplearon dosis más elevadas.

         En un estudio con ratones (empleando dosis de 0, 15, 40, 175 ó
    750 mg/kg en el alimento), se observó mayor incidencia de hiperplasia
    tubular renal con dosis de 175 mg/kg y superiores, así como de
    hiperplasia y hiperkeratosis del preestómago con concentraciones de 40
    mg/kg y superiores. La incidencia de tumores escamosos del preestómago
    aumentó ligeramente con dosis de 750 mg/kg. Por consiguiente, por lo
    que respecta a los cambios neoplásicos y no neoplásicos, los niveles
    sin efecto observado fueron de 175 y 15 mg/kg en la dieta (lo que
    equivale a 17,5 y 1,6 mg/kg de peso corporal por día respectivamente).
    Otro estudio con posologías superiores corroboró esos efectos en el
    ratón, pero un estudio con ratones B6C3F1 no señaló ningún riesgo
    carcinogénico con dosis elevadas.

         En un estudio de 2 años de duración con perros (empleando 60 y
    120 mg/kg en el alimento), no se detectó ningún efecto atribuible al
    clorotalonilo. Por lo tanto, el nivel sin efecto observado fue de 120
    mg/kg en el alimento (lo que equivale a 3 mg/kg de peso corporal al
    día).

         El clorotalonilo no resultó mutagénico en varias pruebas  in
     vitro e in vivo, aunque fue positivo en un pequeño número de
    valoraciones.

         Los derivados monotio, ditio, tritio, dicisteina, tricisteina y
    monoglutatión del clorotalonilo, que son posibles substancias
    nefrotóxicas, arrojaron resultados negativos en el análisis de Ames.

         El clorotalonilo no resultó teratogénico en las ratas o conejos
    con dosis de hasta 400 y 50 mg/kg de peso corporal al día,
    respectivamente. En un estudio realizado con dos generaciones de
    ratas, los parámetros reproductivos tales como el apareamiento, la
    fertilidad y el período de gestación no se vieron afectados por el
    clorotalonilo con concentraciones de hasta 1500 mg/kg en la dieta.

         La toxicidad oral aguda del metabolito 4-hidróxido es superior a
    la del clorotalonilo propiamente dicho (DL50 oral aguda de 332 mg/kg
    de peso corporal en comparación con > 10 000 mg/kg de peso corporal).
    Se han llevado a cabo varios estudios destinados a caracterizar el
    perfil toxicológico de ese metabolito y a establecer los niveles sin
    efecto observado.

    7.  Efectos en el ser humano

         Se ha informado de dermatitis por contacto en el caso de personas
    que trabajan en la producción de clorotalonilo, así como en el de
    agricultores y hortelanos. Se tienen noticias también de trabajadores
    de fábricas de productos de la madera que han contraído dermatitis por
    contacto en las manos y el rostro cuando empleaban preservativos de la
    madera que contenían clorotalonilo.

    8.  Efectos en otros organismos en el laboratorio y sobre el terreno

         El clorotalonilo es sumamente tóxico para los peces y los
    invertebrados acuáticos en los estudios de laboratorio, siendo los
    valores de CL50 inferiores a 0,5 mg/litro. En un estudio sobre
    reproducción realizado con dos generaciones de  Daphnia magna, la
    concentración tóxica máxima aceptable (CTMA) fue de 35 µg/litro.

         Con pocas excepciones, el clorotalonilo no es fitotóxico.

         En lombrices, la CL50 de una formulación de una suspensión
    concentrada (500 g de clorotalonilo/litro) en suelo artificial fue
    > 1000 mg/kg de suelo (14 días). Las tijeretas experimentaron mayor
    mortalidad cuando estaban en contacto con residuos de clorotalonilo en
    las hojas del cacahuete o lo ingerían en su fuente de alimentos en las
    pruebas de laboratorio; no hubo ningún otro indicio de efecto
    insecticida.

         El clorotalonilo tiene poca toxicidad para las aves, habiéndose
    informado de una DL50 oral aguda de 4640 mg/kg de alimento en el
    pato real. No se informó de ningún efecto considerable sobre la
    reproducción.

         Un estudio sobre el terreno de organismos acuáticos expuestos
    después de la aplicación de clorotalonilo parece indicar que la
    toxicidad es inferior a la que cabría esperar atendiendo a los
    estudios de laboratorio; esto es también compatible con las
    propiedades fisicoquímicas de los compuestos. Se observaron muertes en
    algunas especies expuestas experimentalmente en el campo. No se ha
    informado de incidentes de muertes en el medio ambiente. Sin embargo,
    a pesar del corto tiempo de presencia del clorotalonilo en el medio
    ambiente, cabría esperar que ocurran muertes. Resultaría difícil
    establecer vínculos entre las muertes y los compuestos ya que la
    persistencia de los residuos no seria suficientemente prolongada para
    poder identificar el clorotalonilo.
    



See Also:
        Chlorothalonil (IARC Summary & Evaluation, Volume 30, 1983)
        Chlorothalonil (IARC Summary & Evaluation, Volume 73, 1999)