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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 123





    ALPHA- and BETA-HEXACHLOROCYCLOHEXANES












    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. G.J. van Esch,
    Bilthoven, The Netherlands



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


    World Health Organization
    Geneva, 1992

         The International Programme on Chemical Safety (IPCS) is a joint
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    the effects of chemicals on human health and the quality of the
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    carried out by the IPCS include the development of know-how for coping
    with chemical accidents, coordination of laboratory testing and
    epidemiological studies, and promotion of research on the mechanisms
    of the biological action of chemicals.

    WHO Library Cataloguing in Publication Data

    Alpha- and Beta-hexachlorocyclohexanes.

    (Environmental health criteria ; 123)

    1.Benzene hexachloride - adverse effects    2.Benzene hexachloride -
    toxicity     3.Environmental exposure     4.Environmental pollutants
    I.Series

    ISBN 92 4 157123 3                      (NLM Classification: QV 633)
    ISSN 0250-863X

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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR ALPHA- AND BETA-HEXACHLOROCYCLOHEXANES

    A.  ALPHA-HEXACHLOROCYCLOHEXANE

    B.  BETA-HEXACHLOROCYCLOHEXANE

    CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH AND THE
    ENVIRONMENT (ALPHA- AND BETA-HEXACHLOROCYCLOHEXANES)

    FURTHER RESEARCH (ALPHA- AND BETA-HEXACHLOROCYCLOHEXANES)

    PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    APPENDIX 1.  CHEMICAL STRUCTURE

    RESUME ET EVALUATION

    1. Alpha-hexachlorocyclohexane
    2. Béta-hexachlorocyclohexane

    CONCLUSIONS ET RECOMMANDATIONS

    RECHERCHES A EFFECTUER (ALPHA- ET BETA-HEXACHLOROCYCLOHEXANES)

    RESUMEN Y EVALUACION

    1. Alpha-hexaclorociclohexano
    2. Beta-hexaclorociclohexano

    CONCLUSIONES Y RECOMENDACIONES

    OTRAS INVESTIGACIONES (ALPHA- Y BETA-HEXACLOROCICLOHEXANOS)
    

    WHO TASK GROUP MEETING ON ENVIRONMENTAL HEALTH CRITERIA FOR ALPHA-
    AND BETA-HEXACHLOROCYCLOHEXANES

     Members

    Dr S. Dobson, Institute of Terrestrial Ecology, Monkswood Experimental
    Station, Abbots Ripton, Huntingdon, United Kingdom

    Dr M. Herbst, ASTA Pharma A.G., Frankfurt, Germany  (Joint Rapporteur)

    Professor J.S. Kagan, Department of General Toxicology and
    Experimental Pathology, All-Union Scientific Research Institute of
    Hygiene and Toxicology of Pesticides, Polymers, and Plastics, Kiev,
    USSR  (Vice-Chairman)

    Dr S.G.A. Magwood, Pesticides Division, Environmental Health Centre,
    Health & Welfare Canada, Tunney's Pasture, Ottawa, Ontario, Canada

    Professor Wai-On Phoon, National Institute of Occupational Health and
    Safety, University of Sydney, Sydney, Australia  (Chairman)

    Dr J.F. Risher, US Environmental Protection Agency, Environmental
    Criteria and Assessment Office, Cincinnati, Ohio, USA

    Dr Y. Saito, Division of Foods, National Institute of Hygienic
    Sciences, Setagaya-ku, Tokyo, Japan

    Dr V. Turusov, Laboratory of Carcinogenic Substances, All-Union Cancer
    Research Centre, Moscow, USSR

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

     Representatives of Non-Governmental Organizations

    Dr P.G. Pontal, International Group of National Associations of
    Manufacturers of Agrochemical Products (GIFAP), Rhône-Poulenc Agro,
    Lyon, France

     Observers

    Dr A.V. Bolotny, All-Union Scientific Research Institute of Hygiene
    and Toxicology of Pesticides, Polymers, and Plastics, Kiev, USSR

    Dr D. Demozay, International Centre for Study on Lindane (CIEL),
    Rhône-Poulenc Agro, Lyon, France

     Secretariat

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

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

    Dr V.A. Rezepov, Centre for International Projects, USSR State
    Committee for Environmental Protection, Moscow, USSR

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

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

                                 *     *     *

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

    ENVIRONMENTAL HEALTH CRITERIA FOR ALPHA- AND BETA-HEXACHLOROCYCLOHEXANES

         A WHO Task Group on Environmental Health Criteria for Alpha- and
    Beta-hexachlorocyclohexanes met in Moscow from 20 to 24 November 1989. 
    The meeting was convened with the financial assistance of the United
    Nations Environment Programme (UNEP) and was hosted by the Centre for
    International Projects (CIP), USSR State Committee for Environmental
    Protection. Dr V.A. Rezepov opened the meeting on behalf of the CIP
    and welcomed the participants. Dr K.W. Jager welcomed the participants
    on behalf of the three IPCS cooperating organizations (UNEP/ILO/WHO). 
    The Task Group reviewed and revised the draft criteria monograph and
    made an evaluation of the risks for human health and the environment
    from exposure to alpha- and beta-hexa-chlorocyclohexanes.

         The first and second drafts of this monograph were prepared by
    Dr G.J. van Esch (on behalf of the IPCS).  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 efforts of all who helped in the preparation and finalization
    of the document are gratefully acknowledged.

    ABBREVIATIONS

    cGMP      cyclic guanosine monophosphate
    CNS       central nervous system
    EEG       electroencephalogram
    EMG       electromyogram
    FDA       Food and Drug Administration (USA)
    FSH       follicle-stimulating hormone
    GABA      gamma-aminobutyric acid
    GGT       gamma-glutamyltransferase
    GLC       gas-liquid chromatography
    HCB       hexachlorobenzene
    HCCH      hexachlorocyclohexene
    HCH       hexachlorocyclohexane
    ip        intraperitoneal
    LH        luteinizing hormone
    MTD       maximum tolerated dose
    nd        not detected
    NOEL      no-observed-effect level
    PCB       polychlorinated biphenyl
    PCCH      pentachlorocyclohexane
    PIC       picrotoxin
    PTZ       pentylenetetrazole
    SEM       smooth endoplasmic reticulum

    PART A

    ENVIRONMENTAL HEALTH CRITERIA FOR
    ALPHA-HEXACHLOROCYCLOHEXANE

    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR ALPHA-HEXACHLOROCYCLOHEXANE

    1. SUMMARY AND EVALUATION

        1.1. General properties
        1.2. Environmental transport, distribution, and
              transformation
        1.3. Environmental levels and human exposure
        1.4. Kinetics and metabolism
        1.5. Effects on organisms in the environment
        1.6. Effects on experimental animals and
               in vitro test systems 
        1.7. Effects on humans

    2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

        2.1. Identity of primary constituent
        2.2. Physical and chemical properties
        2.3. Analytical methods

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

        4.1. Transport and distribution between media
        4.2. Biotransformation
              4.2.1. Biodegradation
              4.2.2. Abiotic degradation
              4.2.3. Bioaccumulation/biomagnification
                      4.2.3.1   Algae
                      4.2.3.2   Invertebrates
                      4.2.3.3   Fish
                      4.2.3.4   Bioconcentration in humans
        4.3. Isomerization

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

        5.1. Environmental levels
              5.1.1. Air
              5.1.2. Water
                      5.1.2.1   Rain water
                      5.1.2.2   Fresh water
                      5.1.2.3   Sea water

              5.1.3. Soil/sediment
                      5.1.3.1   Dumping grounds
              5.1.4. Food and feed
              5.1.5. Terrestrial and aquatic organisms
                      5.1.5.1   Plants
                      5.1.5.2   Fish and mussels
                      5.1.5.3   Birds
                      5.1.5.4   Mammals
        5.2. General population exposure
              5.2.1. Total-diet studies
              5.2.2. Air
              5.2.3. Concentrations in human samples
                      5.2.3.1   Blood
                      5.2.3.2   Adipose tissue
                      5.2.3.3   Breast milk

    6. KINETICS AND METABOLISM

        6.1. Absorption and elimination
        6.2. Distribution
        6.3. Metabolic transformation
              6.3.1. Rat
              6.3.2. Bird
              6.3.3. Human
        6.4. Retention and biological half-life

    7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

        7.1. Single exposure
              7.1.1. Acute toxicity
        7.2. Short-term exposure
              7.2.1. Oral
              7.2.2. Other routes
                      7.2.2.1   Intravenous
                      7.2.2.2   Subcutaneous
        7.3. Skin and eye irritation; sensitization
        7.4. Long-term exposure
              7.4.1. Rat oral study
        7.5. Reproduction, embryotoxicity, and teratogenicity
        7.6. Mutagenicity and related end-points
        7.7. Carcinogenicity
              7.7.1. Mouse
              7.7.2. Rat
              7.7.3. Initiation-promotion
              7.7.4. Mode of action
        7.8. Special studies
              7.8.1. Effect on liver enzymes
              7.8.2. Neurotoxicity

    8. EFFECTS ON HUMANS

        8.1. Acute toxicity - poisoning incidents
        8.2. General population
        8.3. Occupational exposure

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

        9.1. Algae
        9.2. Protozoa
        9.3. Invertebrates
              9.3.1. Acute toxicity
              9.3.2. Short- and long-term toxicity
                      9.3.2.1   Crustaceae
                      9.3.2.2   Molluscs
        9.4. Fish
              9.4.1. Acute toxicity
              9.4.2. Short- and long-term toxicity
        9.5. Terrestrial organisms
    

    1.  SUMMARY AND EVALUATION

    1.1  General properties

         Alpha-hexachlorocyclohexane (alpha-HCH) is a major by-product
    (65-70%) in the manufacture of lindane (> 99% gamma-HCH).  Its
    solubility in water is low, but it is very soluble in organic solvents
    such as acetone, chloroform, and xylene. It is a solid with a low
    vapour pressure.  The  n-octanol/water partition coefficient (log
    Pow) is 3.82. It is an environmental pollutant.

         Alpha-HCH can be determined separately from the other isomers by
    gas chromatography with electron capture detection and other methods
    after extraction by liquid/liquid partition and purification by column
    chromatography.

    1.2  Environmental transport, distribution, and transformation

         Biodegradation and abiotic degradation (dechlorination) by
    ultraviolet irradiation occur in the environment and produce,
    respectively, delta-3,4,5,6-tetrachloro-hexene and
    pentachlorocyclohexene.  This breakdown process is slower than in the
    case of lindane. The persistence of alpha-HCH in soil is determined by
    environmental factors such as the action of microorganisms, organic
    matter content, and co-distillation and evaporation from soils.  No
    isomerization occurs from lindane to alpha-HCH.

         Rapid bioconcentration takes place in microorganisms (the
    bioconcentration factor equals 1500-2700 on a dry-weight basis, or
    approximately 12 000 on a lipid basis within 30 min), invertebrates
    (60-2750 (dry weight basis) or > 8000 (lipid basis) within 24-72 h),
    and fish (313-1216 within 4-28 days; up to 50 000 in the River Elbe).
    However, biotransformation and elimination is also fairly rapid in
    these organisms (15 min to 72 h).

    1.3  Environmental levels and human exposure

         Alpha-HCH is found in air over the oceans at a concentration of
    0.02-1.5 ng/m3. In Canada, it was found to be present in rain water
    at a concentration of 1-40 ng/litre, but only traces were present in
    snow.

         During the period 1969-1974, the River Rhine and its tributaries
    contained alpha-HCH levels of 0.01-2.7 µg per litre, but more recently
    the levels have been below 0.1 µg/litre.  In the River Elbe, levels
    decreased from a mean of 0.023 µg/litre in 1981 to below 0.012 µg per
    litre in 1988.  Selected rivers in the United Kingdom were found in
    1966 to contain 0.001-0.43 µg/litre. Alpha-HCH has been found in North
    Frisian Wadden Sea sediment at concentrations of between 0.3 and
    1.4 µg/kg (0.002 µg per litre in water).

         Alpha-HCH levels in different plant species from various
    countries varied from 0.5-2140 µg/kg on a dry-weight basis, but were
    much higher in polluted areas. Even in Antarctica, levels ranging from
    0.2-1.15 µg/kg have been found.

         Alpha-HCH is regularly detected in fish and aquatic
    invertebrates, as well as in ducks, herons, and barn-owls.  In
    reindeer and Idaho moose, living in areas with negligible use of
    pesticides, average amounts of alpha-HCH of approximately 70-80 µg/kg
    were found in the subcutaneous fat. The adipose tissue of Canadian
    polar bears contained 0.3-0.87 mg alpha-HCH/kg (on a fat basis).

         In a number of countries, important food items have been analysed
    for the presence of alpha-HCH.  The levels, mainly in fat-containing
    food products, ranged up to 0.05 mg/kg product, except in milk and
    milk products (up to 0.22 mg/kg) and in fish and processed meat
    products (up to 0.5 mg/kg on a fat basis).  A slow decrease over the
    years has been noted.

         Food is the main source for general population exposure to
    alpha-HCH.  In total-diet studies in the Netherlands and the United
    Kingdom, mean concentrations of 0.01 and 0.002-0.003 mg/kg food,
    respectively, were found.  The United Kingdom data indicate a downward
    trend since 1967.  In the USA, the average daily intake of alpha-HCH
    was 0.009-0.025 µg/kg body weight during the period 1977-1979, and
    0.003-0.016 µg/kg body weight during the period 1982-1984.

         In a few countries, the concentration of alpha-HCH has been
    determined in human blood, serum, or plasma. The mean (in some cases
    median) concentration was < 0.1 µg per litre (ranging from
    undetectable levels to 0.6 µg per litre).  In one country, however, a
    mean concentration of 3.5 (range 0.1-15.0) µg/litre was reported.
    Alpha-HCH was detected in approximately one third of the blood
    samples.

         The concentrations in human adipose tissue and breast milk are
    reported to be low (respectively < 0.01-0.1 and < 0.001-0.04 mg/kg
    on a fat basis). Total-diet studies have  shown  daily  intake  levels
    of the order of 0.01 µg/kg body weight per day or lower. These
    concentrations are decreasing slowly over the years.

         Alpha-HCH appears to be a universal environmental contaminant.
    Concentrations are only decreasing slowly, in spite of measures taken
    to prevent its spread into the environment.

    1.4  Kinetics and metabolism

         In rats, alpha-HCH is rapidly and almost completely absorbed from
    the gastrointestinal tract. After intraperitoneal injection,
    approximately 40-80% of the alpha-HCH was excreted via the urine and
    5-20% via the faeces.  In rats, the highest concentrations have been

    found in liver, kidneys, body fat, brain and muscles, and substantial
    deposition occurs in fatty tissue. The alpha-HCH concentrations in the
    liver of sucklings were twice as high as those observed in the liver
    of the mothers.  In rats, the brain to blood and depot fat to blood
    ratios were 120:1 and 397:1, respectively.

         The biotransformation of alpha-HCH in rats involves
    dechlorination. The major urinary metabolite is 2,4,6-tri-
    chlorophenol; other identified metabolites include 1,2,4-, 2,3,4-, and
    2,4,5-trichlorophenol and 2,3,4,5- and 2,3,4,6-tetrachlorophenol.
    1,3,4,5,6-Pentachlorocyclohex-1-ene has been found in rat kidneys and
    also in  in vitro studies on chicken liver. A glutathione conjugate
    is formed in the liver.

         The half-life for clearance from the fat depot is 6.9 days in
    female rats and 1.6 days in males.

    1.5  Effects on organisms in the environment

         Alpha-HCH has low toxicity for algae, 2 mg/litre generally being
    the no-observed-effect level.

         In a long-term study,  Daphnia magna showed a no-observed-effect
    level of 0.05 mg/litre. Alpha-HCH is moderately toxic for
    invertebrates and fish.  The acute L(E)C50 values for these
    organisms are in the order of 1 mg/litre. In short-term studies with
    guppies and  Oryzia latipes, 0.8 mg/litre was without effect.

         In three-month studies with  Salmo gairdneriat dose levels of
    10-1250 mg/kg diet, there were no effects on mortality, behaviour,
    growth, or enzyme activities in liver and brain.

         Short- and long-term studies with a snail  (Lymnea stagnalis)
    showed an EC50 (based on mortality and immobilization) of
    1200 µg/litre. Inhibition of egg production occurred at a
    concentration of 250 µg/litre.  A 50% reduction in the overall
    reproductivity was found at 65 µg/litre.

         No data are available on effects on populations and ecosystems.

    1.6  Effects on experimental animals and in vitro test systems

         The acute oral LD50 values for mice lie between 1000-4000 and
    for rats between 500-4670 mg/kg body weight.  The poisoning signs are
    mainly those of stimulation of the central nervous system.

         A 90-day study with rats showed growth depression at a
    concentration of 250 mg/kg diet.  Histological and enzyme level
    changes in the liver indicated enzyme induction at 50 mg/kg or more.
    At these dose levels there were also indications of immunosuppression.

    Liver weights were already increased at 10 mg/kg diet (equivalent to
    0.5 mg/kg body weight).  The no-observed-adverse-effect level in this
    study appeared to be 2 mg/kg diet (equivalent to 0.1 mg/kg body weight
    per day).

         No adequate long-term toxicity studies or reproduction and
    teratogenicity studies have been reported.

         Studies with various strains of  Salmonella typhimurium yielded
    no evidence of mutagenicity either with or without metabolic
    activation.  Tests with  Saccharomyces cerevisiae were also negative,
    but a test for unscheduled DNA synthesis in rat hepatocytes  in vitro
    gave an equivocal result.

         Studies to determine carcinogenic potential have been carried out
    with mice and rats at dose levels from 100 to 600 mg/kg diet.
    Hyperplastic nodules and/or hepatocellular adenomas were found in
    studies on mice.  In one study the dose levels exceeded the maximum
    tolerated dose. Two mice studies and one rat study, using dose levels
    of up to 160 mg/kg diet in mice and 640 mg/kg diet in rats, did not
    show any increase in the incidence of tumours.

         The results of the studies on initiation-promotion and mode of
    action and the mutagenicity studies indicate that the
    alpha-HCH-induced tumorigenicity observed in mice has a non-genetic
    mechanism.

         Alpha-HCH has been shown to cause a clear increase in the
    activity of liver enzymes even at 5 mg/kg diet (equivalent to
    0.25 mg/kg body weight).  A dose of 2 mg/kg body weight did not affect
    aminopyrine demethylation or the DNA content of the liver.

    1.7  Effects on humans

         When workers at a lindane-producing factory, with a geometric
    mean exposure of 7.2 years (1-30), were investigated, it was concluded
    that occupational HCH exposure did not induce signs of neurological
    impairment or perturbation of "neuromuscular function".

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1  Identity of primary constituent

    Common name              Alpha-hexachlorocyclohexane (alpha-HCH)

    Chemical formula         C6H6Cl6

    Chemical                 Alpha-HCH is a stereoisomer of gamma-
    structure                HCH, the active ingredient of lindane
    (see Appendix 1)         (> 99% gamma-HCH).  It differs in the
                             spatial orientation of the hydrogen and
                             chlorine atoms on the carbon atoms:

    FIGURE 01

    Relative
    molecular mass           290.9

    CAS chemical             1alpha,2alpha,3ß,4alpha,5ß,6ß-hexachloro-
    name                     cyclohexane

    Common
    synonyms                 Alpha-benzenehexachloride (alpha-BHC)

    CAS registry
    number                   319-84-6

    RTECS registry
    number                   GV3500000

    2.2  Physical and chemical properties

         Some physical and chemical properties are summarized in Table 1.

                                                                   

    Table 1.  Some physical and chemical properties of alpha-
              hexachlorocyclohexane
                                                                   

    Melting point                 158°C

    Boiling point                 288°C

    Vapour pressure (20°C)        2.67 Pa (0.02 mmHg)

    Relative density (20°C)       1.87 g/cm3

    Solubility
       water (28°C)               2 mg/litre
       organic solvents (20°C)    acetone             139 g/litre
                                  chloroform           63 g/litre
                                  ethanol              18 g/litre
                                  petroleum ether    7-13 g/litre
                                  xylene               85 g/litre

    Stability                     considerable stability in acids,
                                  unstable in alkaline conditions

     n-Octanol/water partition
     coefficient (log Pow)        3.82
                                                                   

    2.3  Analytical methods

         Hildebrandt et al. (1986) and Wittlinger & Ballschmiter (1987)
    described in detail the appropriate analytical methods, i.e. air
    sampling by adsorption, extraction, purification, and determination
    using high resolution gas chromatography. Sampling was conducted by
    pumping air first through a glass fiber filter and then a layer of
    silica gel.  An internal standard was used.  The extraction was
    carried out with dichloromethane, and the extract was evaporated. 
    Preseparation was on silica gel and elution with a mixture of hexane
    and dichloromethane. For the determination, use was made of high
    resolution capillary gas chromatography with electron capture
    detection and a mass selective detector.

         Eder et al. (1987) described in detail three different analytical
    methods for the determination of HCHs in sediments.  Sediments are
    extracted with a solvent or mixture of solvents and are concentrated
    or fractionated. The alpha-HCH is determined by gas chromatography
    with electron capture detection or other methods.

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         Alpha-HCH does not occur naturally. It is released to the
    environment as a result of the use of technical-grade HCH and the
    inappropriate disposal of the residue resulting from the purification
    of lindane.

         Alpha-HCH is basically a by-product (and impurity) in the
    manufacturing of lindane (> 99% gamma-HCH). Technical-grade HCH,
    which is synthesized from benzene and chlorine in the presence of
    ultraviolet light, consists of:

    65-70%           alpha-HCH
     7-10%           beta-HCH
    14-15%           gamma-HCH (lindane)
    approx. 7%       delta-HCH
    approx. 1-2%     epsilon-HCH
    approx. 1-2%     other components

         Purification of lindane produces a residue, consisting almost
    entirely of non-insecticidal HCH isomers (mainly alpha- and beta-),
    which can be used as an intermediate for the production of
    trichlorobenzene and other chemicals.

         Alpha- and beta-HCH have been used in mixtures with gamma-HCH (as
    "HCH" or "fortified HCH") in agriculture and in wood protection.

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1  Transport and distribution between media

         MacRae et al. (1967) studied the persistence and
    bio-degradability of alpha-HCH in two clay soils.  The rate of
    treatment was 15 mg/kg soil, and incubation periods of 0, 15, 30, 50,
    70, and 90 days were used.  Only very small amounts of alpha-HCH could
    be detected in non-sterilized soils after 70 days, indicating a low
    level of persistence and biodegradation.  However, the losses were
    much slower in sterilized soils, and were probably due to
    volatilization.

         Tsukano (1973) studied the factors affecting the disappearance of
    alpha-HCH from rice field soil after granular application
    (0.05 mg/litre) to the surface water.  The surface water and soil were
    analysed at intervals, and alpha-HCH was found to disappear rapidly
    with a half-life of about 5 days.  Following translocation of
    alpha-HCH (1 mg/litre) onto flooded levelled soil, a decrease in the
    level in water and steady increase in the level in soil occurred. 
    After 7 days the concentration in soil reached a maximum.  Data from a
    soil column study showed that alpha-HCH moved downwards with the
    percolating water.

         Suzuki et al. (1975) studied the persistence of alpha-HCH in
    three different types of soil. The persistence was found to be
    determined by environmental factors such as the action of
    microorganisms, co-distillation, evaporation from soil, and the
    contents of water and organic matter in the soil.

         In a study by Wahid & Sethunathan (1979), the sorption and
    desorption of alpha-HCH by 12 soils from rice-growing areas in India
    were studied using 14C label.  The soils showed striking differences
    in their ability to adsorb alpha-HCH, the sorption values ranging from
    40 to 95% of total added alpha-HCH.  After oxidation of the soil with
    hydrogen peroxide, the sorption was lower (5-46%). Organic matter was
    the most important factor governing the sorption and desorption, but
    pH, exchange acidity, exchangeable sodium and magnesium, and
    electrical conductivity also affected the results.

         Korte (1980) summarized the behaviour of alpha-HCH in the
    environment, especially in soil and plants.

    4.2  Biotransformation

    4.2.1  Biodegradation

         Heritage & MacRae (1977, 1979) investigated the degradation of
    alpha-HCH (final concentration 5 mg/litre) by a washed suspension of
    Clostridium sphenoidesin the absence of oxygen at 30°C. The
    alpha-isomer was no longer detectable after 4 h.  Apparently the

    degradation proceeded via delta-3,4,5,6-tetrachlorocyclohexene
    (delta-TCCH). Aerobically grown facultative anaerobes actively
    dechlorinated 36Cl-alpha-HCH during anaerobic incubation with
    glucose, pyruvate or formate as substrates, but this dechlorination
    was slower than in the case of lindane.

         When incubation studies were performed under anaerobic or aerobic
    conditions, the dechlorination of 36Cl-labelled alpha-HCH by mixed
    soil flora and by pure cultures of  Citrobacter freundii, C.
     butyricum, and  C. pasteurianumwas 6.5%, 13.9%, 97.4%, and 53.2%,
    respectively, within 6 days of incubation. Again, alpha-HCH degraded
    more slowly than lindane (Jagnow et al., 1977).

         Screening experiments to study the possible isomerization of
    lindane to alpha-HCH, using  C. freundii, Serratia marcescens,
     Pseudomonas putida, and other bacterial species, gave negative
    results (Haider, 1979).

         Doelman et al. (1985) carried out laboratory studies on the
    degradation of alpha-HCH, at a concentration of approximately
    5300 mg/kg, in a polluted Dutch sandy loam soil with 6.5% organic
    matter. They found during 20 weeks constant degradation rates of
    10 mg/kg per day under anaerobic conditions and 14 mg/kg per day under
    aerobic conditions. At a lower concentration (approximately
    3900 mg/kg) the average degradation rate appeared to be higher
    (24 mg/kg per day) under both aerobic and anaerobic conditions.  The
    degradation was ascribed to microbial processes.

         Studies in 1986 on HCH-polluted soil (personal communication by
    P. Doelman and A. Zehnder to the IPCS) indicate that alpha-HCH
    degrades considerably better in aerobic conditions (aerated slurry)
    than in anaerobic conditions (non-aerated slurry) both in the
    laboratory  and in soil in greenhouses (Slooff & Matthijsen, 1988). 
    Assuming the degradation process to be a first-order reaction, MacRae
    et al. (1984) calculated from laboratory studies (soil with 4.0%
    organic carbon) half-lives of 125 and 48 days under aerobic and
    anaerobic conditions, respectively.

         In a study by Doelman et al. (1988a), microbial soil sanitation
    was applied to calcareous alkaline sandy loam soil that was polluted
    with a mixture of HCH isomers.  Under anaerobic conditions, microbial
    degradation in the Dutch climate (soil temperature of 5-17°C) did not
    occur, and even the low concentration of the easily degradable
    gamma-HCH did not decrease.

         Microbial soil sanitation of alpha-HCH-polluted calcareous sandy
    loam soil systems has been investigated. The soil systems involved
    were aerated moist soil and continuously aerated and intermittently
    aerated soil slurries.  Degradation of alpha-HCH appeared to proceed
    according to a first-order reaction.  It was fastest during the first 
    4 weeks, even though soil temperatures were lowest during this period.

    The percentage degradation during the first 4 weeks was 40, 80, and
    37%, respectively, for the three soil systems. The degradation rate
    gradually decreased with time even if the temperature increased. 
    Addition of microbial biomass did not significantly affect the
    alpha-HCH degradation. In a continuously aerated thick slurry system,
    the alpha-HCH concentration was reduced from approximately 420 to
    15 mg/kg. Thus, alpha-HCH degradation will occur in regions with a
    temperate climate, provided that the soil is aerobic (Doelman et al.,
    1988b).

         A field investigation into the distribution of HCHs was carried
    out by Chessells et al. (1988) using soil from an agricultural area
    treated with BHC-20 (HCH composition:  70% alpha-HCH, 6.5% beta-HCH,
    13.5% gamma-HCH, and 5% delta-HCH. Although the concentration of
    alpha-HCH was the highest of the HCHs, the alpha-isomer disappeared
    more rapidly than beta-HCH.  Furthermore, soil organic carbon content
    was found to be of primary importance. A significant decrease in
    isomer concentration was observed when soil moisture content was high
    and was attributed to microbial degradation favoured by these
    conditions.

    4.2.2  Abiotic degradation

         Alpha-HCH is broken down by ultraviolet light but at a slower
    rate than lindane. Ultraviolet irradiation, using a 15-watt low
    pressure mercury lamp, of alpha-HCH in 2-propanol solution for 10 h
    resulted in the production of an isomer of pentachlorocyclohexene.
    This substance may be produced by hydrogen abstraction of the
    radiation-induced pentachlorocyclohexyl radicals (Hamada et al.,
    1982).

    4.2.3  Bioaccumulation/Biomagnification

    4.2.3.1  Algae

         A study was carried out to determine the bioconcentration of
    alpha-HCH by an alga  (Cladophora) during a period of 48 h.  At
    concentrations of alpha-HCH in water of 4.4 and 31 µg/litre, the
    bioconcentration factors were 341 and 180, respectively (Bauer, 1972).

         In a study by Canton et al. (1975),  Chlorella pyrenoidosacells
    taken from a log-phase culture were exposed for 96 h to alpha-HCH
    (> 95%) concentrations of 10, 50 or 800 µg/litre, and after 15, 30, and
    180 min the cells were analysed. At all dosage levels the average
    bioconcentration from water was about 200-fold (153-267).  There
    seemed to be a tendency for alpha-HCH to accumulate in the cytoplasm
    rather than the cell wall. When the cells were subsequently placed in
    clean water, the elimination was rapid (15 min).

         When Canton et al. (1977) investigated the accumulation and
    elimination of alpha-HCH (> 95%) in marine algae  (Chlamydomonas and

     Dunaliella) in studies lasting a few days, both processes were found
    to take place rapidly, (i.e. in less than 30 min). The average
    concentration factor was 2700 in  Chlamydomonas and 1500 in
     Dunaliella (on a dry weight basis) and was 12 000 and 13 000,
    respectively, on a lipid basis. The accumulated alpha-HCH was found
    primarily in the lipophyllic parts of the cells.

    4.2.3.2  Invertebrates

         In a study by Canton et al. (1978),  Artemia was exposed to
    alpha-HCH (> 95%) levels of 0.01, 0.05 or 0.25 mg/litre and sampled
    after 0.5, 3, 24, 48, 72, and 96 h.  Once equilibrium was reached, the
    animals were transferred to alpha-HCH-free water and were sampled
    after 0, 3, 24, 48, 96, and 144 h.  The bioconcentration factor was
    about 60-90 (8000-11 000 on a lipid basis), and equilibrium was
    reached within 24 h. The elimination half-life was 48-72 h.

         Ernst (1979) measured alpha-HCH bioconcentration factors in two
    marine invertebrates, the mussel  (Mytilus edulis) and the polychaete
     (Lanice conchilega), of 105 and 2750, respectively, at 10°C and an
    alpha-HCH concentration of 2-5 µg/litre.  Species differences and the
    lipid content of the animals appeared clearly to affect the
    bioconcentration factor, whereas the effect of temperature seemed to
    be minimal.

         In a study by Yamato et al. (1983), the short-necked clam
     (Venerupis japonica) rapidly absorbed alpha-HCH and the
    concentration reached a plateau on the third day.  The
    bioconcentration factor was 161 at an alpha-HCH concentration of
    1 µg/litre water. The alpha-HCH concentrations on day 6 in organs and
    tissues were 0.060 and 0.029 mg/kg, respectively. After a 3-day
    elimination period, the levels were 0.033 and 0.024 mg/kg,
    respectively.

         Mouvet et al. (1985) investigated the presence of alpha-HCH in
    the aquatic moss  Cinclidotus danubicus to examine the potential use
    of this species as an indicator of chlorinated pollutants in fresh
    water. The moss was sampled 0, 13, 24, and 51 days after having been
    transplanted in a polluted river, and levels of 0.20-1.33 µg per litre
    water were found 4 km downstream of an area of industrial discharge.
    The levels of alpha-HCH in the moss were < 0.025, 0.04-0.57,
    0.08-2.37, and 0.81 mg/kg dry weight, respectively, at the time
    intervals indicated above.

    4.2.3.3  Fish

         Canton et al. (1975) studied the accumulation and elimination of
    alpha-HCH by  Chlorella, Daphnia, and  Poecilia reticulata, and in
     Chlorella-Daphnia and  Daphnia-Poecilia reticulata systems. In this
    food-chain study, the following concentration ratios were measured:

    FIGURE 02

    The direct uptake of alpha-HCH from contaminated water appeared to be
    much greater than the uptake from contaminated food.

         In a study with  Salmo gairdneri, pellets containing alpha-HCH
    (> 95%) levels of 0, 10, 50, 250, or 1250 mg/kg were fed to the fish,
    and organs and tissues were analysed after 2, 4, 8, and 12 weeks. 
    There was a dose-related increase in the concentration of alpha-HCH
    in the organs and tissues.  After about 4-8 weeks (depending on the
    type of tissue and dose level) a maximum concentration was reached,
    which then slowly decreased. This suggests that after a few weeks a
    balance is reached between the accumulation process (absorption of
    alpha-HCH by the intestinal wall) and the elimination process (via the
    gills and faeces). There is probably also a dilution effect resulting
    from growth and biotransformation (Canton et al., 1975).

         Ernst (1977) concluded from kinetic studies that biomagnification
    of alpha-HCH does not occur. Compared with bioaccumulation from water
    alone, the entry of alpha-HCH into the food chain  Chlorella ->
     Daphnia ->  Poecilia (guppy) caused only a slight increase in
    biomagnification in daphnids (factor 1.5), although in the case of the
    guppies a greater increase in concentration ratio (3-4) was noted.

         In a study by Canton et al. (1978), guppies (3-4 weeks old) were
    exposed to alpha-HCH (> 95%) concentrations of 0.01, 0.05, or
    0.14 mg/litre. When after 0.5, 3, 24, 48, 72, 96, and 120 h the
    animals were analysed, the average concentration factor was about 500
    for all alpha-HCH concentrations (about 17 000 on a lipid basis). 
    Equilibrium was reached within 24 h for the lower concentrations and
    within 48 h at the highest concentrations. The elimination was rapid,
    the initial concentration being halved in 10 h.

         Sugiura et al. (1979) studied bioaccumulation in the carp
     (Cyprinus carpio), brown trout  (Salmo trutta fario), golden orfe
     (Leuciscus idus melanotus), and guppy  (Poecilia reticulata).
    Alpha-HCH was dissolved in water to a concentration of 1 mg/litre
    under steady-state conditions (time period not specified), and the
    equilibrium bioconcentration factors for the four types of fish were
    330, 605, 1216, and 588, respectively.

         Based on the data given in section 5.1.5.2 concerning the
    concentration of alpha-HCH in the muscle and fat of bream collected in
    the River Elbe, the bioconcentration factor is between 10 000 and
    50 000 (Arbeitsgemeinschaft für die Reinhaltung der Elbe, 1982).

         In a study by Yamato et al. (1983), guppies  (Poecilia
     reticulata) rapidly bioaccumulated HCH isomers and the tissue
    concentration reached a plateau on the fourth day (the alpha-HCH
    concentration in the water was 1 µg per litre).  The bioconcentration
    factor (concentration in fish/concentration in water) was 706. The
    concentration in the guppies decreased on the first day after the fish
    were transferred to HCH-free water.

    4.2.3.4  Bioconcentration in humans

         Geyer et al. (1986) found that in industrialized countries more
    than 90% of the exposure to HCHs derives from food.  The mean
    concentration of alpha-HCH in human adipose tissue (on a fat basis)
    was found to be 0.03 mg/kg in the Federal Republic of Germany and
    0.02 mg/kg in the Netherlands. The mean bioconcentration factor (on a
    lipid basis), calculated on the basis of the concentration in the diet
    (1.3 and 0.3 µg/kg, respectively) and levels in adipose tissue, was
    20.0 ± 8 (range 11.5-32.5).

    4.3  Isomerization

         Deo et al. (1981) studied the isomerization of alpha-HCH in
    sterile aqueous solution over a period of 4 weeks and found a slow
    conversion of alpha-HCH to other HCH isomers.

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Air

         Tanabe et al. (1982) found alpha-HCH in 24 samples of air over
    the Western Pacific, Eastern Indian, and Antarctic Oceans at an
    average concentration of 0.29 ng/m3 (0.022-1.4 ng/m3).

         In a study by Strachan et al. (1980), samples of atmospheric
    precipitation in the form of snow (1976; 17 samples) and rain (1976
    and 1977; 81 samples) collected around the Canadian side of the Great
    Lakes, as well as inland, were analysed.  Alpha-HCH was found in the
    snow samples as a trace (1 ng/litre) and in the rain samples at levels
    of 1-40 ng/litre.

         Air samples were taken near a road with heavy traffic, as well as
    in a suburban residential area, near Ulm, in Germany. The alpha-HCH
    levels were 0.22-1.3 ng/m3 in the location with heavy traffic and
    0.11-1.1 ng/m3 in the rural area. It was concluded that the
    concentrations in the lower troposphere under various meteorological
    conditions reflect regional input and long-range transport (Wittlinger
    & Ballschmiter, 1987).

         In 1972, alpha-HCH air concentrations of 0.28 ng per m3 in
    non-polluted areas of Germany, and 2.15 ng/m3 in the polluted Ruhr
    area were determined (Hildebrandt et al., 1986).

         The average concentration of alpha-HCH in 55 air samples
    collected in Delft, the Netherlands, in 1979-1980 was 0.25 ng/m3
    (maximum concentration: 1.2 ng/m3) (Slooff & Matthijsen, 1988).

    5.1.2  Water

    5.1.2.1  Rain water

         Rain water sampled in 1983 in Bilt, the Netherlands, contained an
    average alpha-HCH concentration of 0.01 (< 0.01-0.02) µg/litre
    (Slooff & Matthijsen, 1988).

    5.1.2.2  Fresh water

         During the period 1969-1977, 1826 water samples were taken at 99
    sampling sites in the Netherlands. The highest concentrations of
    alpha-HCH were found in the River Rhine and its tributaries.  The
    concentrations varied between 0.01-0.3 µg/litre during the period
    1969-1974, but in 1974 there was a sudden decrease and the subsequent
    concentrations were all below 0.1 µg/litre.  A sampling trip by boat
    made along the River Rhine from Rheinfelden in Switzerland to
    Rotterdam in the Netherlands proved that the source of alpha-, beta-,

    and gamma-HCH was located in the upper Rhine.  In the River Meuse, the
    levels were all below 0.1 µg/litre during the period 1969-1977 (Wegman
    & Greve, 1980).

         Since 1969, alpha-, beta-, and gamma-HCH concentrations have been
    measured regularly in the Rivers Rhine, Meuse, and West-Scheldt and in
    other surface waters in the Netherlands. Alpha-HCH levels have been
    below 0.05 µg per litre in the River Rhine since 1974/1975, and were
    of the order of 0.02 µg/litre or less in the West-Scheldt during the
    period 1973-1985. In the River Meuse, the concentration of alpha-HCH
    was between 0.01-0.02 µg/litre.  In other areas, for instance
    agricultural and greenhouse horticulture areas, the levels of the
    individual HCHs ranged from 0.01-1.0 µg/litre with incidental higher
    peaks (up to 0.5 µg/litre) probably resulting from the use of lindane
    (Slooff & Matthijsen, 1988).

         Concentrations of HCH isomers in solution and in suspension
    (particle-bound) in the Meuse and Rhine estuary were determined in
    1974.  The average concentrations of dissolved and suspended alpha-HCH
    were 20 and 0-6 ng per litre, respectively.  In 1981, the
    concentration of dissolved alpha-HCH in coastal waters of the
    Netherlands was 0.9-1.6 ng/litre, whereas that of suspended alpha-HCH
    (only one measurement) was 5.3 ng/litre (Slooff & Matthijsen, 1988).

         In 1970-1971, the levels of alpha-HCH were 0.66-1.5 µg/litre in
    the surface water of the River Elbe near Hamburg, Germany, and
    0.155-2.4 µg/litre in the River Rhine near Karlsruhe. However, a
    significant decrease was observed in the mid-1970s. In 1974, 2.7 µg
    per litre was found in the upper Rhine, but by 1976-1977 the levels
    had decreased to 1-9 ng/litre (Hildebrandt et al., 1986).

         The Arbeitsgemeinschaft der Elbe (the Elbe Study Group)
    investigated the presence of alpha-HCH in the River Elbe from
    Schnackenburg to the North Sea in 1981-1982 and found a mean
    concentration of 0.023 (< 0.001-0.15) µg per litre. During the period
    February to November 1988, the alpha-HCH concentration was 
    0.001-0.022 µg/litre  (Arbeitsgemeinschaft der Elbe, 1988).

         When certain rivers in Yorkshire, England, were analysed for
    alpha-HCH in 1966, the concentration varied from 0.001 to
    0.43 µg/litre.  In 1968, the highest value was 0.543 µg/litre, and
    the water from six other rivers contained an average of
    0.001-0.004 µg/litre (highest level:  0.34 µg/litre) (Lowden et al.,
    1969).

         In Japan, 60 water samples were examined in 1974 and 0.1 µg
    alpha-HCH/litre was detected in three of the samples (personal
    communications by A. Hamada and by T. Onishi to the IPCS, July 1989).

    5.1.2.3  Sea water

         Atlas & Gias (1981); Bidleman & Leonard (1982); Oehme & Stray
    (1982); and Oehme & Mano (1984) analysed sea water from areas such as
    the North Pacific, Arabic Sea, Persian Gulf, Red Sea, Lillestrum, Bear
    Island, and Spitsbergen.  The alpha-HCH concentrations varied from
    0.03 to 1.8 ngper litre (Slooff & Matthijsen, 1988).

         In June-July 1986, the alpha-HCH in the surface water (5 m) of
    the North Sea ranged from 1-2 ng/litre (Umweltbundesamt, 1989).

    5.1.3  Soil/Sediment

         Herrmann et al. (1984) studied the presence of alpha-HCH in
    sediment along the Husum estuary and in the adjacent North Frisian
    Wadden Sea.  The mean concentrations varied in the different sampling
    stations from 0.33 to 1.40 µg/kg sediment, while the concentrations in
    bladder wrack(Fucus vesiculosus)varied from 0.7-1.2 µg/kg.

         Edelman (1984) analysed 96 samples of the upper 10 cm of the soil
    from 38 natural reserves in the Netherlands for alpha-HCH and
    gamma-HCH.  In 94 of the samples alpha-HCH was detected at levels
    below 1 µg/kg (Slooff & Matthijsen, 1988).

         When sediment from eight different rivers, harbours, and sites
    close to dumping areas in the Netherlands were analysed for the
    presence of alpha-, beta-, and gamma-HCH, the median alpha-HCH levels
    were between 4 and 213 µg per kg dry matter (Slooff & Matthijsen,
    1988).

         In 1974, 60 sediment samples were analysed in Japan and 10 µg
    alpha-HCH/kg was detected in five of the samples (personal
    communications by A. Hamada and by T. Onishi to the IPCS, July 1989).

    5.1.3.1  Dumping grounds

         In the Netherlands, soil has been polluted with HCHs at various
    locations as a result of their manufacture during the 1950s (spillage
    during production, storage, and handling), and concentrations up to a
    few grams of HCHs/kg dry soil have been found.  Further pollution has
    been caused by the dumping of chemical waste and its use in the
    levelling of certain areas.  From these dumping areas dispersal of the
    chemical waste can occur by leaching or wind erosion from open storage
    depots. In certain polluted areas, high concentrations of HCHs, mainly
    alpha- and beta-HCH, have been found more than 2 m below ground level.
    In 18 locations in the Netherlands, the average concentration of
    alpha-HCH in sewage sludge in 1981 was between 5 and 70 µg/kg dry
    matter.  Pollution of ground water was also detected, but this was
    restricted to the vicinity of the production areas. Horizontal
    transportation of HCHs in ground water appeared to be limited (Slooff
    & Matthijsen, 1988).

    5.1.4  Food and feed

         The presence of alpha-HCH in a number of important food items has
    been determined in France by Laugel (1981).  In milk and milk products
    (2688 samples) the average level was 0.05 mg/kg (ranging from
    undetectable to 0.22 mg/kg), in meat (37 samples) it was 0.01 mg/kg
    (ranging from undetectable to 0.02 mg/kg), and in animal fat (67
    samples) it was 0.02 mg/kg product (ranging from undetectable to
    0.06 mg/kg. In other food items alpha-HCH was not detectable
    (< 0.005 mg/kg).

         Table 2 gives the mean alpha-HCH levels in a large number of
    samples of various food items from the Federal Republic of Germany
    reported by Hildebrandt et al. (1986).


    
    Table 2.  Alpha-hexachlorocyclohexane concentrations (mg/kg)
              in various food itemsa
                                                                             

    Food items           1973-78              1979-83            1973-83
                                                                             

    Meatb                                                      0.003-0.02

    Meat productsb                          0.007-0.037
                                              (0.26)e

    Animal fatb                                                0.003-0.008
                                                                 (0.09)e

    Gameb                                                      0.019-0.367

    Poultryb           0.003-0.004          0.003-0.016
                                              (0.17)e

    Chicken eggs                                              < 0.001-0.003

    Fish                                    0.002-0.011

    Milk and milk
     productsb           0.015e              0.01-0.03

    Cow's milkb,c                              0.004

    Butterb,d                                0.02-0.03
                                                                             

    Table 2 (contd)

                                                                             

    Food items           1973-78              1979-83            1973-83
                                                                             

    Vegetable oil and
     margarineb           0.01

    Oil seeds, nuts,
     pulses                                 0.001-0.042

    Fruit, vegetables,                                          < 0.0001
    potatoes

    Cereals                                                   0.0002-0.007

    Cereal products                                            up to 0.14
                                                                             

    a  From: Hildebrandt et al. (1986).
    b  Determinations made on a fat basis
    c  WHO (1986).
    d  Anon (1984).
    e  Maximum value
    
         In six samples of cows milk collected from six locations in
    Switzerland, the levels of alpha-HCH were 9.5-27 mg/kg on a fat basis
    (Rappe et al., 1987).

         Skaftason & Johannesson (1979) analysed 35 samples of butter from
    Iceland during 1968-1970 and found a level of mean alpha-HCH of 87 ±
    38 µg/kg. In 1974-1978, 32 samples were studied and all contained
    alpha-HCH, the mean concentration being 58 ± 21 µg/kg.

         In a total-diet study in the United Kingdom, 24 samples of each
    food group were analysed for alpha-HCH.  The following concentrations
    (mean and range) were found: bread, not detected (nd); other cereal
    products, < 0.0005 (nd-0.002); carcass meat, < 0.0005 (nd-0.006);
    offal, < 0.0005 (nd-0.007); meat products, eggs, green vegetables,
    potatoes, fresh fruit, nd; poultry, 0.003  (nd-0.025); fish, 0.0005
    (nd-0.008); oil and fats, 0.0005 (nd-0.003); milk, 0.0005 (nd-0.002);
    dairy products, 0.006 (nd-0.02) mg/kg product.  Imported meat products
    were also analysed during the period 1981-1983, and concentrations of
    up to 0.5 mg/kg were measured. Imported retail cereal products
    collected in 1982 contained alpha-HCH levels of up to 0.03 mg/kg and
    animal feed stuffs collected in 1984 had levels of up to 0.02 mg/kg
    (HMSO, 1986).

         Various types of pulses were analysed during the period
    1986-1987, and 31 out of 142 samples contained alpha-HCH residues at
    levels of up to 0.03 mg/kg.  Processed pork and poultry, sampled
    during the period 1985-1987, contained alpha-HCH at levels of up to
    3.2 (mean 0.2) and 0.1-2.0 (mean 0.8) mg/kg product, respectively (26
    out of the 86 samples were positive). Of other processed meat
    products, 631 samples were negative. Retail milk and dairy products
    were analysed during the period 1984-1987, and 499  of the 849
    samples contained alpha-HCH residues at a mean concentration of
    0.01-0.03 mg/kg (highest level, 0.06 mg/kg). Samples of eel muscle
    (1124 eels from 62 sites) were analysed during the period 1986-1987,
    and mean concentrations were 0.001-0.03 mg/kg (highest level,
    0.4 mg/kg). Peanut butter and vegetable oils were analysed during the
    period 1985-1987, and 95 samples showed mean concentrations of <
    0.01-0.03 mg/kg product (16 of the samples were positive) (HMSO,
    1989).

         The mean residue level of alpha-HCH in milk samples collected
    during spring 1983 from 359 bulk transporters representing 16
    counties, municipalities, and districts of Ontario was 5.3 µg/kg
    butter fat.  Alpha-HCH was found in over 90% of the samples (Frank et
    al., 1985).


    5.1.5  Terrestrial and aquatic organisms

    5.1.5.1  Plants

         Samples of three types of mosses and four types of lichens (in
    total 13 samples) were collected in the Antarctic Peninsula (Graham
    Land) in 1985, and alpha-HCH was detected in most of them at a mean
    concentration of 0.4 (0.20-1.15) µg/kg (Bacci et al., 1986).

         In a study by Gaggi et al. (1986), fallen leaves (at the end of
    their natural life-cycle) and lichens were collected in 1984 at sites
    near Florence and Siena, Italy, in a woodland hilly area away from
    primary pollution sources.  The leaves were from ten different species
    of trees and two different lichen species were involved.  The average
    levels of alpha-HCH in leaves and lichen were 37 (16-61) µg/kg dry
    weight and 27 (25-29) µg/kg dry weight, respectively.  The same
    authors reported that the levels of alpha-HCH in various plant species
    collected in 14 countries were 0.5-2140 µg/kg dry weight.

    5.1.5.2  Fish and mussels

         Martin & Hartman (1985) analysed 60 fish samples from nine
    locations in the north-central part of the USA and found
    concentrations of 5-27 µg alpha-HCH/kg (wet weight)  in 36% of the
    samples.  The frequency with which alpha-HCH was detected in fish from
    the different rivers varied between 17 and 100%.

         In a study by Saiki & Schmitt (1986), samples of three to five
    adult bluegills  (Lepomis macrochirus) and common carp  (Cyprinus
     carpio) were collected at eight sites in three rivers in California,
    USA, in 1981. Alpha-HCH concentrations in carp of up to 0.036 mg/kg on
    fat basis were reported, but the concentrations in bluegill were
    lower.

         Cowan (1981) studied the extent of pollution of Scottish coastal
    waters by HCHs using  Mytilus edulis as biological indicator.  The
    levels of alpha-HCH at the 118 sites sampled ranged from < 6 to
    23 µg/kg dry weight.

         The fish and shellfish sampling programme carried out by the
    United Kingdom Ministry of Agriculture, Fisheries, and Food between
    1977-1984 was directed mainly to areas around the coasts of England
    and Wales.  The levels of alpha-HCH, which varied between the
    different fish and shellfish species and also between the collection
    sites, ranged from < 0.001 (nd) to 0.06 mg/kg wet weight.  The
    concentration in fish muscle was < 0.001 mg/kg wet weight (Franklin,
    1987).

         The mean alpha-HCH concentration in the muscle of flounders
    collected off the North Sea coast of Germany in 1986 was 2.5 µg/kg
    (nd-5.0 µg/kg) (Umweltbundesamt, 1989). Bream collected from different
    locations in the River Elbe (between Schnackenburg and the North Sea) 
    contained 0.007-0.066 mg alpha-HCH/kg in muscle tissue and

    0.9-2.2 mg/kg in adipose tissue (Arbeitsgemeinschaft für die
    Reinhaltung der Elbe, 1982), while the same species collected from 15
    rivers and lakes in the Federal Republic of Germany contained (on a
    fat basis) up to 468 µg per kg (Umweltbundesamt, 1989).

         Freshwater fish from different rivers in the Federal Republic of
    Germany were analysed during the period 1973-1981, and in the first
    3-4 years the alpha-HCH levels were mainly between 0.01 and 0.02 mg/kg
    fresh weight. However, a clear decrease then took place and most of
    the samples were below 0.01 mg/kg fresh weight, with the exception of
    certain types of fish such as the eel and fish from industrially
    contaminated areas (Hildebrandt et al., 1986).

         In 1981-1983, shellfish and molluscs collected in the Federal
    Republic of Germany contained < 0.001-0.20 mg alpha-HCH/kg fresh
    weight.  Eels collected in the North Sea and Baltic Sea contained
    alpha-HCH levels of 0.011 mg per kg and 0.033 mg/kg fresh weight,
    respectively. Flounders and herrings caught in the North Sea contained
    0.002 and 0.008 mg/kg fresh weight, respectively, but in the Baltic
    Sea the levels were about twice as high (Hildebrandt et al., 1986).

    5.1.5.3  Birds

         An average alpha-HCH residue level of 0.05 mg/kg was found in 17
    adult herons in 1964 (HMSO, 1969).

         In a study by Sierra & Santiago (1987), alpha-HCH concentrations
    were determined in 23 barn owls  (Tyto alba Scop.) from Leon, Spain.
    The mean levels (and range) in muscle, liver, fat, brain, and
    kidneys (in total 91 samples) were 0.242 (0.019-0.591), 0.323
    (0.009-0.830), 1.073 (0.691-1.499), 0.238 (0.007-0.676), and 0.710
    (0.051-2.381) mg/kg (wet weight), respectively.

         Faladysz & Szefer (1982) analysed adipose fat from seven species
    of diving ducks at their winter quarters in the Southern Baltic. 
    Residues of alpha-HCH were found in all of the 37 specimens of
    long-tailed duck at mean concentrations (on a fat basis) of 3.4
    (0.17-18) and 1.5 (0.23-6) mg/kg for female and male ducks,
    respectively.

    5.1.5.4  Mammals

         Skaftason & Johannesson (1979) analysed 24 samples of the fat of
    reindeer living in an area of the eastern and south-eastern parts of
    Iceland where the use of pesticides is negligible.  Alpha-HCH was
    found in all samples at a mean level of 70 ± 22 µg/kg.  These results
    are in agreement with those of Benson et al. (1973), who found an
    average of 77.5 µg/kg in the subcutaneous fat of wild Idaho moose
    living in a forest area where pesticides were used very restrictively. 
    Skaftason & Johannesson (1979) analysed samples of body fat from
    10-year-old sheep in 1974 and found an average of 51 ± 12 µg/kg.

         Norström et al. (1988) investigated the contamination by
    organochlorine compounds of Canadian arctic and subarctic marine
    ecosystems by analysing the adipose tissue and liver of polar bears
    ( Ursus maritimus; 6-20 animals per area) collected from 12 areas
    between 1982 and 1984. There was a difference in tissue distribution;
    liver contained only alpha-HCH, but 29% of the HCH in adipose tissue
    was beta-HCH. Adipose tissue contained 0.3-0.87 mg alpha-HCH per kg on
    a fat basis.

         The mean concentrations of alpha-HCH in the kidney  fat of roe
    (86 samples) collected in five areas of  Germany in 1985-1986 were
    about 7-12 µg/kg fat, the maximum value being about 50 µg/kg fat
    (Umweltbundesamt, 1989).

    5.2  General population exposure

         From the data presented in section 5.1 it is evident that food is
    the main source of exposure of the general population to alpha-HCH.

    5.2.1  Total-diet studies

         In a total-diet study carried out in the United Kingdom during
    1966-1985, food purchased in 21 towns throughout the country was
    prepared by cooking. The study covered 20 to 24 food groups, and the
    number of total-diet samples examined varied from 22 to 25 samples.
    The calculated mean alpha-HCH residue levels in the total diet for the
    periods 1966-1967, 1970-1971, 1974-1975, 1975-1977, 1979-1980, 1981,
    and 1984-1985 were 0.003, 0.002, 0.002, 0.0015, 0.001, < 0.0005, and
    < 0.0005 mg/kg, respectively (Egan & Hubbard, 1975; HMSO, 1982, 1986,
    1989).

         Gartrell et al. (1985a) conducted a study to determine the
    dietary intake of pesticides in the USA in 1978-1979. The samples,
    purchased from retail outlets, were representative of the diets of
    adults in 20 cities, and consisted of about 120 individual food items.
    The daily intake of alpha-HCH in 1977, 1978, and 1979 was 0.011,
    0.009, and 0.010 µg/kg body weight, respectively. In a similar way,
    samples were collected in 10 cities in 1978-1979 consisting of about
    50 items of infant food and 110 items of toddler food.  The daily
    intake of alpha-HCH in 1977, 1978, and 1979 was, respectively, 0.031,
    0.034, 0.033 µg/kg for infants and 0.025, 0.029, and 0.029 µg/kg body
    weight for toddlers, respectively (Gartrell et al., 1985b).

         Total-diet studies conducted in the USA by the FDA before 1982
    were based on a "composite sample approach" regardless of the diet
    involved.  Later on they were based on dietary survey information and
    allowed the "total diet" of the population to be represented by a
    relatively small number of food items for a greater number of age-sex
    groups.  The daily intakes of alpha-HCH during 1982-1984 for the age
    groups 6-11 months, 2 years, 14-16-year-old females, 14-16-year-old
    males, 25-30-year-old females, 25-30-year-old males, 60-65-year-old

    females, and 60-65-year-old males were 7.2, 16.1, 6.1, 7.3, 4.5, 5.9,
    3.3, and 3.7 ng/kg body weight, respectively (Gunderson, 1988).

         In a total-diet study in the Netherlands in 1977, the average
    concentration of alpha-HCH in 100 samples was 0.01 mg/kg on a fat
    basis.  The highest level was 0.05 mg/kg (Greve & van Hulst, 1977).

    5.2.2  Air

         Guicherit & Schulting (1985) measured the atmospheric
    concentration of alpha-HCH in the Netherlands and calculated an
    average daily intake by inhalation for a 70-kg person of 5 ng. The
    equivalent value for the Federal Republic of Germany was calculated to
    be 32 ng, which is about 1% of the total daily intake via the various
    routes (Hildebrandt et al., 1986).

    5.2.3  Concentrations in human samples

         Alpha-HCH concentrations in human samples are a good indication
    of the total exposure of the general population.

    5.2.3.1  Blood

         Blood samples of Dutch citizens analysed in 1978, 1980, 1981, and
    1982 (70, 48, 127, and 54 samples,  respectively), contained less than
    0.1 µg alpha-HCH/litre (Greve & Wegman, 1985).  Blok et al. (1984)
    analysed the blood of 65 healthy volunteers in the Netherlands (34
    female and 31 male) and detected alpha-HCH in less than one third of
    the samples. The median concentration for both groups was below the
    detection limit (0.1 µg per litre), but levels of up to 0.4 µg/litre
    were measured.

         Polishuk et al. (1970) studied the presence of alpha-HCH in the
    blood of 24 pregnant women and 23 infants living in Israel. The
    mean concentration was 0.6 ± 0.3 µg per litre in the women and 0.5 ±
    0.3 µg/litre in the infants.

         In 1975, Reiner et al. (1977) analysed the serum and plasma of 82
    women and 65 men (with an average age of 42) living in a town in
    Yugoslavia. In 57 of the 147 samples, alpha-HCH was found at a mean
    concentration of 3.3 ± 0.5 µg/litre (range, 0.1-15.0 µg/litre).
    Similar values were found in other parts of the country in 1976-1979
    (Krauthacker et al., 1980).

         The median concentration of alpha-HCH in whole blood of 118
    people in the Federal Republic of Germany was reported to be
    0.98 µg/litre (range, nd-2.06) (Bertram et al., 1980).

    5.2.3.2  Adipose tissue

         The alpha-HCH concentrations of 567 samples of adipose tissues of
    Dutch citizens analysed during 1968-1983 varied from < 0.01 to
    0.1 mg/kg (on a fat basis). The highest levels occurred during the
    period 1968-1976 (Greve & van Harten, 1983; Greve & Wegman, 1985).

         In a study by Niessen et al. (1984), specimens of subcutaneous
    adipose tissue from 48 infants (34 under the age of 1 year, 14 in
    their second year of life) were examined during 1982-1983 in the
    Federal Republic of Germany. The average concentration of alpha-HCH
    was 0.01 mg/kg fat (range, nd-0.02 mg/kg). The average concentration
    was highest (0.02 mg/kg fat) for the age-range 0-6 weeks. Bertram et
    al. (1980) found a median concentration of 0.03 mg/kg fat (range,
    nd-0.35) in 72 samples of adipose tissue from people in the Federal
    Republic of Germany. Hildebrandt et al. (1986) summarized the results
    of nine studies carried out in the Federal Republic of Germany during
    1969-1983.  The mean alpha-HCH concentrations (568 samples) ranged
    from 0.01 to 0.03 mg/kg fat.

         Mes et al. (1982) analysed 99 samples of adipose tissue from
    autopsies of accident victims from different areas of Canada. Nearly
    all the samples (97%) contained alpha-HCH, the average concentration
    of which was 0.004 mg/kg wet weight (range, 0.001-0.043 mg/kg).

         In 1974, 360 samples of adipose tissue were collected in eight
    regions of Japan and the mean level of alpha-HCH was 0.031 mg/kg
    tissue (Takabatake, 1978).

         Twenty-nine samples of adipose tissue were taken at necropsy and
    24 at surgery in the Poznan district of Poland and compared with 100
    samples from residents of the Warsaw area. In Poznan the mean
    concentration of alpha-HCH was 0.013 ± 0.033 mg/kg, while in Warsaw it
    was 0.008 ± 0.001 mg/kg (Szymczynski et al., 1986).

    5.2.3.3  Breast milk

         Breast milk is a major route for the elimination of
    organochlorine pesticides in women. In a Swedish study, the levels of
    alpha-HCH in breast milk were found to be related to the dietary
    habit. Levels in lacto-vegetarians were lower than those in women
    eating a mixed diet, and these were lower than those found in mothers
    using a mixed diet that regularly included fatty fish from the Baltic
    (Noren, 1983).

         In a study by Fooken & Butte (1987), the variation of residue
    levels in breast milk during lactation was investigated in five women
    (aged 23-36) in the Federal Republic of Germany. Alpha-HCH
    concentrations of up to 0.009 mg/kg fat were measured, and no
    essential changes in residue level occurred over the lactation period.

         Residues of alpha-HCH in breast milk during the periods,
    1974-1975 and 1979-1980 in the Federal Republic of Germany were
    reported to be 0.03 and 0.02 mg/kg milk on a fat basis, respectively
    (Anon., 1984).

         In the Federal Republic of Germany, more than 7100 samples of
    breast milk were analysed from 1969-1984. These studies were carried
    out by 20 authors, and the results were summarized by Hildebrandt et
    al. (1986).  The mean concentrations of alpha-HCH ranged from
    0.01-0.04 mg/kg on a fat basis. In one case a mean concentration of
    0.21 mg/kg was found in 320 samples. During the period investigated, a
    slow decrease in the mean concentration of alpha-HCH was observed. The
    average concentration in breast milk in the same country (2709
    samples) in 1979-1981 was 0.024 mg/kg on a fat basis (Fooken & Butte,
    1987). In 1981-1983, 132 samples of breast milk were analysed and the
    average level was 0.001 mg alpha-HCH/kg milk fat (Cetinkaya et al.,
    1984).

         Tuinstra (1971) analysed 36 individual samples of breast milk,
    collected in 1969, from young mothers (18-32 years of age) living in
    the Netherlands. A median alpha-HCH concentration of 0.01 mg/kg milk
    (on a fat basis) was found (range, nd-0.04).  When 278 samples of
    breast milk, collected in 11 maternity centres in the Netherlands,
    were analysed for the presence of alpha-HCH, the median alpha-HCH
    concentration was < 0.01 mg/kg (on a fat basis) (Greve & Wegman,
    1985).

         Vukavic et al. (1986) measured the alpha-HCH concentration in 59
    samples of colostrum collected during autumn 1982 (26 samples) and
    spring 1983 (33 samples) in Yugoslavia from healthy nursing mothers on
    the third day after delivery.  The alpha-HCH levels were significantly
    lower in the autumn than in the spring (mean concentrations of 0.49 ±
    0.09 and 1.50 ± 0.26 µg/litre whole colostrum, respectively).

         Mes et al. (1986) studied 210 breast milk samples from five
    different regions of Canada and measured a mean alpha-HCH
    concentration of 7 µg/kg (on a fat basis).  Davies & Mes (1987)
    studied 18 breast milk samples from Canadian, Indian, and Inuit
    mothers in Canada, whose fish consumption was comparable to the
    national level. The level of alpha-HCH in milk fat of the indigenous
    population was 5 µg/kg, which was the same value as that obtained from
    a national survey.

    6.  KINETICS AND METABOLISM

    6.1  Absorption and elimination

         The intestinal absorption rate for alpha-HCH was 97.4% after the
    administration of an HCH mixture to male rats (Albro & Thomas, 1974).

         The total excretion in rats after a single intraperitoneal (ip)
    36Cl-labelled alpha-HCH dose of 200 mg/kg body weight was 80% of the
    dose in the urine and 20% in the faeces (Koransky et al., 1963;
    Koransky et al., 1964; Noack et al., 1975).  In a study in rats with
    36Cl-labelled alpha-HCH, a low excretion rate was found. 36Cl was
    detected in the excreta up to 40 days after a single ip dose (Koransky
    et al., 1963).  During continued dosing alpha-HCH was observed to
    stimulate its own degradation (Noack et al., 1975).  The decrease in
    rat liver alpha-HCH levels after an initial increase, observed by
    Eichler et al.  (1983), was assumed to be due to this effect.

         When 14C-labelled alpha-HCH was administered intraperitoneally
    to male mice (ddY-strain, 4 weeks old) at a dose level of 22 µg, the
    average percentage of urinary excretion of radioactivity in 3 days was
    37% (Kurihara & Nakajima, 1974).

    6.2  Distribution

         One day after an ip injection of a mixture of 14C- and
    36Cl-labelled alpha-HCH into rats (200 mg/kg body weight in rapeseed
    oil), the highest level of radioactivity was found in fat, skin, and
    bones plus muscles (18.2, 13.1, and 11.9%, respectively, after 4
    days). Much lower levels were found in other organs or tissues (up to
    1% in liver and kidneys and 0.28% in the central nervous system.  In
    the faeces and urine, 3.9 and 7.9%, respectively, were found after 4
    days (Koransky et al., 1963).  In other studies with rats, higher
    concentrations were found in liver, kidneys, body fat, brain, and
    muscle (Portig & Vohland, 1983; Kuiper et al., 1985).  In a 90-day
    study in rats, marked deposition of alpha-HCH was found in renal fat;
    the concentrations exceeded those obtained in a similar study on
    beta-HCH (Greve & van Hulst, 1980; Kuiper et al., 1985).  In lactating
    rats given a single oral dose 5 days after birth, the alpha-HCH
    concentrations in the livers of the sucklings were twice as high as
    those observed in the livers of the mothers (Wittich &
    Schulte-Hermann, 1977).

         Vohland et al. (1981) studied the distribution of alpha-HCH in
    the brain and depot fat of rats after the administration of 200 mg/kg
    body weight by gavage. With an average blood concentration of
    1.5 µg/litre, the brain to blood, and depot fat to blood ratios were
    120:1 and 397:1, respectively, whereas with a blood concentration of
    17.7 mg/litre the ratios were 5:1 and 82:1, respectively.

         Nagasaki (1973) orally administered alpha-HCH to male mice at
    concentrations of 100, 250 or 500 mg/kg for 24 weeks, and found high
    residual levels of this isomer in liver and adipose tissue. Similarly,
    Macholz et al. (1986)  reported that a 30-day administration of
    alpha-HCH to rats resulted in high residues of this isomer in fat,
    kidneys, and adrenal tissue.

         In the brain, alpha-HCH is stored preferentially in the white
    matter (Stein et al., 1980; Portig et al., 1989).

    6.3  Metabolic transformation

    6.3.1  Rat

         When Sprague-Dawley weanling female rats were administered 2 mg
    alpha-HCH/rat per day in peanut oil for 7 days, the alpha-HCH was
    metabolized to 2,4,6- and 2,4,5-trichlorophenol, with an excretion
    ratio of 2,4,6- to 2,4,5-trichlorophenol of 1.3:1.  This study also
    indicated that pre-treatment with alpha-HCH alters the metabolism of
    lindane in rats (Freal & Chadwick, 1973).

         The biotransformation of alpha-HCH in rats involves
    dechlorination (Kraus, 1975).  The dose-dependent decrease in liver
    glutathione concentrations indicates the formation of a glutathione
    conjugate in this organ (Noack & Portig, 1973; Portig et al., 1973;
    Kraus, 1975).  Such a decrease does not occur in the brain or kidneys
    (Noack & Portig, 1973).

         The major urinary metabolite in rats is 2,4,6-trichlorophenol, a
    compound reported by IARC (1987) to be carcinogenic for animals
    (Portig et al., 1973; Stein & Portig, 1976; Stein et al., 1977). Other
    metabolites that have been identified are 1,2,4-trichlorophenol,
    2,3,4-trichlorophenol, 2,4,5-trichlorophenol, 2,3,4,5-
    tetrachlorophenol, and 2,3,4,6-tetrachlorophenol (Noack et al., 1975;
    Stein et al., 1977; Macholz et al., 1982).  In addition,
    chlorothiophenols (not specified) have been detected, and
    1,3,4,5,6-pentachlorocyclohex-1-ene has been identified in the kidneys
    of rats (Macholz et al., 1983).

         Artigas et al. (1988) have identified several lindane metabolites
    (tetra-, penta-, and hexachlorocyclohexenes, and tetra- and
    pentachlorobenzenes) in rat brain homogenates by gas
    chromatography-mass spectrometry. Male Wistar rats were orally
    administered 30 mg alpha-HCH/kg and were sacrificed 5 h later.  The
    cerebella of the animals were analysed and the following metabolites
    were found:  3.6/4.5-PCCH, 3.5/4.6-PCCH, HCCH, pentachlorobenzene, and
    HCB. HCCH was the major metabolite (about 100 µg per kg)  while levels
    of the other metabolites were mainly below 5 µg/kg. Alpha-HCH was
    present at 17.2 mg/kg tissue. This study showed that the HCH isomers
    are cleared from the brain via different metabolic pathways.

         Isomerization of alpha-HCH to lindane did not occur after
    repeated dosage (Eichler et al., 1983).

    6.3.2  Bird

         In a model 4-week feeding study on poultry using four HCH
    isomers, the rate of degradation of the individual HCH isomers in
    broilers followed the order: delta > gamma > alpha > beta.
    Biotransformation (to one or more of the other HCH isomers) was not
    detected (Szokolay et al., 1977b).

         In a study by Foster & Saha (1978) on the  in vitro metabolism
    of alpha-HCH in chicken livers, the first metabolite was identified as
    an isomer of pentachlorocyclohexane.

    6.3.3  Human

         When Engst et al. (1978) analysed the urine of occupationally
    exposed workers (apparently to technical-grade HCH in manufacturing
    processes), they found, apart from alpha-, beta-, gamma-, and
    delta-HCH, traces of hexa- and pentachlorobenzene, gamma- and
    delta-pentachlorocyclohexane, pentachlorophenol, 2,3,4,5-, 2,3,4,6-,
    and 2,3,5,6-tetrachlorophenol, and several trichlorophenols, as well
    as the glucuronides of several of these metabolites.  The
    pentachlorocyclohexenes, tetrachlorophenol, hexachlorobenzene, and
    pentachlorophenol were also identified in the blood.

    6.4  Retention and biological half-life

         The half-life for the clearance of alpha-HCH from depot fat was
    found to be 6.9 days in female rats and 1.6 days in male rats (Stein
    et al., 1980; Portig, 1983).

         Vohland et al. (1981) and Portig & Vohland (1983) studied the
    kinetics of alpha-HCH in Wistar rats, and observed that, after a
    single oral dose of 200 mg/kg body weight, the approximate half-life
    in females for the elimination from brain was 6 days.

         The retention of alpha-HCH in rat brain after a single dose is
    greater than that of beta- and gamma-HCH (Stein et al., 1980).

    7.  EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

    7.1  Single exposure

    7.1.1  Acute toxicity

         In mice oral LD50 values have been found to range from 1000 to
    4000 mg/kg body weight, depending on the vehicule, while in rats
    values of 500-4674 mg/kg body weight have been obtained. Riemschneider
    (1949) determined a LD50 (oral intubation in olive oil) for rats of
    1500 mg/kg body weight.  The signs of poisoning were those of nervous
    system stimulation:  excitation, hunched posture, rough fur, dyspnoea,
    anorexia, tremors, convulsions, and cramps (Hoffmann, 1983; WHO,
    1986).

    7.2  Short-term exposure

    7.2.1  Oral

         In a 90-day study on rats carried out with dose levels of 0, 2,
    10, 50, or 250 mg alpha-HCH/kg diet, reductions in white blood cell
    count were noted in several groups of animals.  Growth was decreased
    at 250 mg/kg diet, and at this dose level the number of erythrocytes
    and protein excretion in the urine were elevated in female animals. At
    levels of 50 and 250 mg/kg, the activities of liver
    amino-pyrine- N-demethylase and aniline hydroxylase were increased
    while those of blood aspartate aminotransferase (ASAT) and creatine
    phosphokinase were decreased.  Liver weights were increased at dose
    levels of 10, 50, and 250 mg/kg. Enlargement of liver parenchyma cells
    (with a foamy/hyaline appearance of the cytoplasm) and accentuation of
    the plasmalemma, indicative of proliferation of smooth endoplasmatic
    reticulum (SER), occurred at levels of 50 and 250 mg/kg. At the
    250-mg/kg level, there were increases in the relative weights of
    heart, kidneys, and adrenals.  In addition, serum levels of
    immunoglobulins G and M showed a decrease at 50 and 250 mg/kg diet
    (Kuiper et al., 1985).

         Macholz et al. (1986) reported that the administration of 1000 mg
    alpha-HCH/kg to rats for 30 days resulted in growth retardation and
    liver mass increase. High residue levels of alpha-HCH were identified
    in fat, kidneys, and adrenal tissue.

    7.2.2  Other routes

    7.2.2.1  Intravenous

         In a study by van Asperen (1954), groups of 12-15 male and female
    albino mice (8-10 weeks of age) were given an intravenous injection of
    alpha-HCH (in peanut oil).  The dose levels were 480 or 960 µg/mouse
    (equivalent to approximately 32 and 64 mg/kg body weight,
    respectively). No deaths occurred within 7 days.

    7.2.2.2  Subcutaneous

         Groups of 13-21 male and female albino mice (8-10 weeks of age)
    were given a subcutaneous injection of alpha-HCH at dose levels
    ranging from 3 to 20 mg/animal (equivalent to approximately 200 to
    1330 mg/kg body weight, respectively). With doses of up to 4 mg, no
    death occurred within 7 days, but with 4.5 mg, 8 mg, and 20 mg, 8, 25,
    and 90%, respectively, of the animals died (van Asperen, 1954).

    7.3  Skin and eye irritation; sensitization

         No data on skin and eye irritation or sensitization have been
    reported.

    7.4  Long-term exposure

    7.4.1  Rat oral study

         When groups of 10 female and 10 male weanling Wistar rats were
    administered diets containing 0, 10, 50, 100, or 800 mg alpha-HCH/kg
    diet (in corn oil) for 107 weeks, the highest dose level resulted in
    growth retardation, increased mortality, and slight kidney damage.
    With dose levels of 100 or 800 mg/kg, liver enlargement and
    histo-pathological changes in the liver were found. However, there
    were no liver changes at 50 mg/kg diet (Fitzhugh et al., 1950).

    7.5  Reproduction, embyrotoxicity, and teratogenicity

         No information on reproduction, embryotoxicity, or teratogenicity
    is available.

    7.6  Mutagenicity and related end-points

         Alpha-HCH did not induce mutations in  Salmonella typhimurium
    test strains TA98, TA100, TA1535 or TA1537 either with or without rat
    liver metabolic activation (Lawlor & Haworth, 1979). A test for point
    mutations in  Saccharomyces cerevisiae XV 185 14 C was also negative
    (Shahin & von Borstel, 1977).  In addition, the compound produced no
    mutations in  Allium cepa roots (Nybom & Knutsson, 1947).  A test for
    unscheduled DNA synthesis in rat hepatocytes  in vitro produced an
    equivocal result (Althaus et al., 1982).

         A mutagen test strain of  Bacillus subtilis (TKJ5211) showed a
    higher sensitivity for hisw+ reversion than the parental strain
    HA101 when treated with UV and UV-mimetic chemicals.  However, a
    negative result was obtained when alpha-HCH dissolved in DMSO was used
    at a dose level of 5 mg/ml (Tanooka, 1977).

         A DNA repair test was carried out with stationary-phase cultures
    of  B. subtilis HLL3g and HJ-15 strains in which the size of growth
    inhibition zones of repair-proficient and repair-deficient cells for
    vegetative cells and spores was determined.  There was no effect at a
    dose level of 5 mg alpha-HCH (in benzene) per ml (Tanooka, 1977).

         The available data are inadequate to make an assessment of the
    mutagenic potential.

    7.7  Carcinogenicity

    Appraisal

          The reported studies on the carcinogen effects of alpha-HCH on
     mice and rats have some short-comings.  In most cases, very high dose
     levels were tested. Nevertheless, it is clear from the results that
     alpha-HCH, at high dose levels, produces nodular hyperplasia and
     hepatocellular carcinomas in mice (the incidence varying according to
     the strain) and also in rats (low incidence), but only at higher dose
     levels.

          The results of the studies on initiation-promotion and mode of
     action indicate that the neoplastic response observed with alpha-HCH
     is most likely due to a non-genotoxic mechanism.

    7.7.1  Mouse

         When 20 male ICR/JCL mice (aged 5 weeks) were administered a diet
    containing 600 mg alpha-HCH/kg diet for 26 weeks, increased liver
    weight was observed. In all treated mice there were liver tumours,
    which were characterized histologically as benign tumours and
    malignant tumours with atypical liver cells.  Unfortunately,
    insufficient details were reported (Goto et al., 1972a,b).

         In a study by Hanada et al. (1973), 6-week-old DD mice (10-11 of
    each sex per group) were given diets containing 0, 100, 300, or 600 mg
    alpha-HCH/kg diet for 32 weeks, followed by a control diet for 5-6
    weeks.  The control group consisted of 20 female and 21 male animals. 
    During the experiment several animals died. The numbers of hepatomas
    in the four groups surviving for 36-38 weeks were 0/29 (control), 1/16
    (100 mg/kg), 9/10 (300 mg/kg), and 13/15 (600 mg/kg).
    Alpha-fetoprotein was not detected in the serum of animals with
    hepatomas.

         When 8-week-old male DD mice, divided into groups of 20 or 38
    animals, were fed a diet containing 0, 100, 250, or 500 mg
    alpha-HCH/kg for 24 weeks, the two highest dose levels induced an
    increase in liver weight.  At the four respective dose levels, the
    incidence of nodules classified as nodular hyperplasia was 0/20, 0/20,
    30/38 (79%), and 20/20 (100%) and that of hepatocellular carcinoma was
    0/20, 0/20, 10/38 (26%), and 17/20 (85%) (Ito et al., 1973b).

         Following the oral administration of 100, 250 or 500 mg
    alpha-HCH/kg to male DD mice for 24 weeks, hepatocellular tumours were
    found in all mice treated with 500 mg/kg and in 17 of the 20 mice that
    received 250 mg/kg (Nagasaki, 1973).

         Nagasaki et al. (1975) studied the tumorigenic effects of a diet
    containing 0 or 500 mg alpha-HCH/kg, fed for 24 weeks to groups of
    male and female DDY, ICR, DBA/2, C57BL/6, and C3H/He mice (13-29 of
    each sex per group), male Wistar rats, and male golden Syrian
    hamsters.  It was found that alpha-HCH induced liver tumours in male
    and female mice but not in rats and hamsters. The histological changes
    in the liver of mice were much greater than those induced in rats and
    hamsters.  Male animals were more susceptible to the tumorigenic
    action (i.e. liver nodules)  than females. Among the different strains
    of mice, a difference in susceptibility was observed.  The occurrence
    of liver nodules varied from 16.7 to 100% and the incidence of
    hepatocellular carcinomas varied from none to 65%.  The DDY mouse
    strain was the most sensitive and the C57BL/6 the least sensitive
    strain.

         Ito et al. (1976) studied the reversibility of liver tumours
    induced by alpha-HCH (99.0%).  Male 8-week-old DDY mice were fed a
    diet containing 0 or 500 mg/kg for 16, 20, 24, and 35 weeks and then
    fed a basal diet without alpha-HCH for 4, 8, and 12, or 4, 8, 12, 16,
    24, and 36 weeks.  In total 341 mice were used, of which 21 were fed
    the compound for 16 weeks. A total of 300 mice were fed the diet with
    alpha-HCH for 20 or more weeks and 20 control mice were fed the basal
    diet for 72 weeks. At the various intervals indicated, 12-20 mice were
    killed. The incidence of liver tumours increased progressively during
    continuous administration of alpha-HCH, but when its administration
    was discontinued some tumours disappeared.  After 24 weeks of
    administration most tumours were nodular hyperplasias with only a few
    well-differentiated hepatocellular carcinomas.  However, 60 or 72
    weeks after the beginning of the study most of the liver tumours were
    hepatocellular carcinomas.  The findings suggested that nodular
    hyperplasia was usually reversible.

         Two groups of male HPBC57B1 black mice (6-9 weeks old)  were fed
    a diet containing 500 mg/kg alpha-HCH (99.8%) per diet, 48 mice being
    used as controls and 75 mice being administered alpha-HCH. From each
    group, 4-9 mice were killed at 1, 3, 4, 8, 14, 21, 30, 33, 44, and 50
    weeks after the initiation of treatment.  Progressive liver
    enlargement was first noticed at 3 weeks, hepatic nodules at 21 weeks,
    and emaciation at 30 weeks. Histopathological liver alterations
    included hypertrophy of centrolobular hepatocytes first seen at 1 week
    and the merging of adjacent megalocytic zones at 3 weeks.  At 21
    weeks, adenomas were seen in two out of seven mice, at 30 weeks in
    seven out of eight mice, and at 33, 44, and 50 weeks in all the mice
    studied.  Under the condition of this study, neither hepatocellular
    carcinomas nor metastases in the lungs were detected (Tryphonas &
    Iverson, 1983).

    7.7.2  Rat

         When groups of 10 male and 10 female weanling Wistar rats were
    fed throughout their life on diets containing 10, 50, 100, or 800 mg
    alpha-HCH (> 98% pure) per kg, no increase in tumour incidence was
    found. However, only a limited number of organs were examined
    microscopically (Fitzhugh et al., 1950).

         In a study by Ito et al. (1975), male Wistar rats (5-8-weeks old)
    were divided into seven groups and administered alpha-HCH diets
    containing 0, 500 (two groups), 1000 (three groups), or 1500 mg 
    alpha-HCH/kg diet. The duration of the treatment for the different
    groups was 72 weeks for the controls, 24 or 48 weeks at 500 mg/kg, 24,
    48, or 72 weeks at 1000 mg/kg, and 72 weeks at 1500 mg/kg.  In the
    liver, oval cells and bile duct cell proliferation were found in the
    groups fed 1000 or 1500 mg/kg after 48 and 72 weeks. Cell hypertrophy
    was found in all the groups, the increase in severity depending on the
    dose level and the duration of administration. In the two groups fed
    500 mg/kg and the group fed 1000 mg/kg for 24 weeks no nodular
    hyperplasia or hepatocellular carcinomas were found.  Nodular
    hyperplasia developed in the groups fed 1000 mg/kg (48 and 72 weeks)
    or 1500 mg/kg (72 weeks) in 42, 76, and 77% of the animals,
    respectively. Hepatocellular carcinomas were found only in the groups
    fed  1000 or 1500 mg/kg for 72 weeks (1/16 and 3/13 animals,
    respectively).

         In a series of studies, an oral dose of 20 mg/kg body weight was
    administered daily to female rats during periods of 4.5, 13.5, or 23.5
    months. Liver enzyme induction was found at all intervals, white foci
    and nodules were present after 13.5 months, and one animal had a
    hepatocellular carcinoma after 23.5 months (Schulte-Hermann &
    Parzefall, 1981).  The value of this study was reduced by the very low
    number of animals (4-6 per group) used at each interval.

    7.7.3  Initiation-promotion

         In a study on 8-week-old white male mice (25-30 per group) of
    strain DD, the influence of alpha-HCH on tumour induction by
    polychlorinated biphenyls (PCBs) was tested and vice versa. Whereas
    500 mg PCB/kg diet induced nodular hyperplasia and hepatocellular
    carcinomas in the liver of male mice after 32 weeks, exposure to
    alpha-HCH at dose levels of 50, 100, or 250 mg/kg diet, only resulted
    in both type of tumours at the highest dose level. The incidence of
    nodular hyperplasia was 23/30 (77%) and that of hepatocellular
    carcinoma was 8/30 (27%).  However, 50 or 100 mg alpha-HCH/kg diet, in
    combination with 250 mg PCB per kg diet (PCB alone did not induce
    tumours), induced nodular hyperplasia (approximately 30%) and
    hepatocellular carcinoma (approximately 5%).  It seems that PCBs
    promote the induction of liver tumours by alpha-HCH (Ito et al.,
    1973a).

         In studies on rats, alpha-HCH showed a tumour-promoting action
    towards the hepatocarcinogenic effects of aflatoxin B1,
    diethylnitrosamine, and nitrosomorpholine (Schulte-Hermann &
    Parzefall, 1981; Schulte-Hermann et al., 1981; Angsubhakorn et al.,
    1981). In one test, alpha-HCH produced only a slight liver
    tumour-promoting effect in rats after initiation with
     N-nitrosodiethylamine (Ito et al., 1983).  However, in another study
    on the same species the compound had an inhibitory effect on the
    hepa-tocarcinogenic action of 3-methyl-4-dimethylaminoazobenzene and
    DL-ethionine (Thamavit et al., 1974).

         Nagasaki et al. (1975) studied the influence of
    3-methylcholanthrene, 1-naphthyl isothiocyanate, and
     p-hydroxypropiophenone on the induction of liver tumours by
    alpha-HCH.  Eight groups of 24 mice received a diet containing either
    500 mg alpha-HCH/kg diet in combination with 67 mg
    methylcholanthrene/kg, 600 mg 1-naphthyl isothiocyanate/kg or 1000 mg
     p-hydroxypropiophenone/kg or just one of the four compounds. A
    control group with the basal diet was also used. The induction of
    mouse liver tumours by alpha-HCH was not inhibited by the concomitant
    feeding of 1-naphthyl isothiocyanate or  p-hydroxypropiophenone. 
    However, 3-methylcholanthrene slightly inhibited their induction by
    alpha-HCH.

         In a study by Schröter et al. (1987), the tumour-initiating
    activity of alpha-HCH was studied by examining for phenotypically
    altered foci in female Wistar rats.  Groups of three to eight rats
    were used and, after removing the median and right liver lobes, 200 mg
    alpha-HCH/kg body weight was administered followed by phenobarbital at
    50 mg/kg body weight per day for 15 weeks. Liver foci were identified
    by means of the gamma-glutamyltransferase (GGT) reaction and by
    morphological alterations. No evidence of initiating activity was
    found. In another part of the study, the promoting activity was
    investigated. A single dose of  N-nitrosomorpholine (250 mg/kg body
    weight by gavage) was followed by the administration of 0.1, 0.5, 2.0,
    7.0, or 20.0 mg alpha-HCH/kg body weight per day for 4, 15, and 20
    weeks.  The criteria used were growth and phenotypic changes of foci
    as end-points.  It was concluded from the study that alpha-HCH is a
    tumour promotor.  Both the number and size of altered foci were
    enhanced by alpha-HCH doses of 2 mg/kg or more. The tumour-promoting
    action was generally associated with liver enlargement and induction
    of monooxygenases or other specific enzymes.

         Schulte-Hermann et al. (1983) carried out three experiments with
    Han-Wistar rats using, in experiment 1, 39 female rats (8-24 months
    old) and, in experiments 2 and 3, 41 male (2 years old) rats.
    Alpha-HCH (200 mg/kg in corn oil) was administered orally as a single
    dose, while the control group received only corn oil. Beginning 25 h
    after the dosing, 3H-thymidine was injected intravenously five times
    at intervals of 6 h (experiment 2) or 8 h (experiment 3) , and the
    animals were killed 18 (experiment 2) or 3 h (experiment 3) after the

    last dose of 3H-thymidine.  The effect of age on the incidence of
    spontaneous foci was studied in experiment 1.  Foci of putative
    preneoplastic cells were detected in the livers of untreated rats of
    both sexes, especially at 1 and 2 years of age. These foci exhibited
    markers similar to those of their counterparts in carcinogen-treated
    rats, such as cytoplasmic basophilia, clearness of cytoplasm, or
    expression of gamma-glutamyl transferase.  Rates of DNA synthesis in
    foci were higher than in normal liver cells and were increased by
    single doses of liver mitogens assumed to promote liver tumour
    development. Thus cells in the spontaneous foci appeared to possess a
    defect in the growth control, rendering them more susceptible to
    endogenous and exogenous growth stimuli.

         The incorporation of orally administered radiolabelled thymidine
    into liver DNA was determined in SIV-50-SD rats 24 h after a single
    oral gavage dose of 2.9, 29.1, 58.2, or 291 mg alpha-HCH/kg. Alpha-HCH
    was found to stimulate liver DNA synthesis at 58.2 mg/kg (Büsser &
    Lutz, 1987).

    7.7.4  Mode of action

         Sagelsdorff et al. (1983) studied the relevance to the
    carcinogenic action of alpha-HCH of covalent binding to mouse liver
    DNA. Three strains of mice were used (NMRI, CF1, and C6B3F1), and
    alpha-HCH was administered by oral gavage and 14C-thymidine by the
    intraperitoneal route. In all three strains, a similar low covalent
    binding index or DNA damage/dose (values ranging from 0.17-0.28) was
    found.  There was no quantitative correlation with the carcinogenicity
    potency of alpha-HCH.

         Iverson et al. (1984) studied the ability of alpha-HCH to bind to
    macromolecules from male HPB black mouse liver.   In vivo and  in
     vitro binding studies with 14C-alpha-HCH and hepatic microsomes
    from untreated and phenobarbital-pretreated mice showed no
    preferential binding of alpha-HCH to protein or DNA. The results
    suggest that the neo-plastic response observed with alpha-HCH results
    from a non-genotoxic mechanism.

    7.8  Special studies

    7.8.1  Effect on liver enzymes

         After a single oral administration to female rats of 5 mg
    alpha-HCH/kg body weight or more the rate of aminopyrine demethylation
    and the liver DNA content were both increased, but at 2 mg/kg body
    weight these effects did not occur (Schulte-Hermann et al., 1974).  In
    a further study, the liver cytochrome P450 concentration in male rats
    after a single oral administration was elevated at all tested dose
    levels, 25 mg/kg body weight being the lowest (Seifart & Buchar,
    1978). After alpha-HCH was given to male rats at dose levels of 5, 10,

    20, 50, or 200 mg/kg feed for 2 weeks, aniline hydroxylase and
    aminopyrine demethylase activities were increased at all dose levels
    (den Tonkelaar et al., 1981).

    7.8.2  Neurotoxicity

    Appraisal

          Alpha-HCH has been shown to have no effect on motor nerve
     conduction velocity or the fronto-occipital EEG in rats fed 1000 mg
     alpha-HCH/kg diet for 30 days.  This isomer is a mild antagonist of
     pentylenetetrazol-induced convulsions but increases the tonic/clonic
     activity and the lethality of picro-toxin when administered
     intraperitoneally to mice. It decreases the accumulation of
     cerebellar cyclic GMP and prohibits the increase of cGMP caused by
     gamma-HCH in mouse brain.  Alpha-HCH has been demonstrated to inhibit
     GABA-mediated chloride ion uptake in mouse brain, and this effect is
     believed to play a primary role in the CNS action of this isomer.

         In a study by Vohland et al. (1981), alpha-HCH did not give rise
    in brain tissue to appreciable quantities of hydrophobic metabolites
    such as 2,4,6-trichlorophenol.  It had a weak protecting action
    against convulsions induced by pentylenetetrazole (PTZ). The intensity
    and duration of the PTZ-antagonistic effects after a single oral dose
    were related to the alpha-HCH content of the brain.

         In a 30-day study on groups of 15 male Wistar rats fed alpha-HCH
    at levels of up to 1000 mg/kg diet, there was no effect on the
    fronto-occipital electroencephalogram or on the motor conduction
    velocity of the tail nerve (Müller et al., 1981).

         The effect of alpha-HCH on body temperature, food intake, and
    body weight was studied in Wistar rats (eight males and eight females)
    given a single 30-mg/kg oral dose of alpha-HCH in olive oil. Controls
    received only olive oil.  Alpha-HCH treatment induced no significant
    decrease in core temperature 5 h after treatment, and no decrease in
    food intake or growth was observed (Camon et al., 1988).

         Fishman & Gianutsos (1987) studied the effects of an
    intraperitoneal injection of alpha-HCH (99.0%) in corn oil
    (80-480 mg/kg body weight) on the accumulation of cerebellar cyclic
    GMP in male CD-1 mice.  Alpha-HCH decreased  the accumulation of
    cerebellar cyclic GMP and also prevented the increase in cyclic GMP
    resulting from lindane treatment.  Furthermore, alpha-HCH inhibited
    the binding of 3H-TBOB (a ligand for the GABA-A-receptor-linked
    chloride channel) in mouse cerebellum.

         Fishman & Gianutsos (1988) compared the CNS-related
    pharmacological and biochemical effects of gamma-HCH and the
    non-convulsant isomer alpha-HCH.  The studies were carried out on male
    CD-1 mice injected intraperitoneally with a single alpha-HCH (in corn

    oil) dose of 80-400 mg/kg body weight. Alpha-HCH inhibited the
    myoclonic jerk and tonic/clonic activity of PTZ but increased the
    tonic/clonic activity and lethality of picrotoxin (PIC) (PTZ and PIC
    were given as a single ip injection of 50 mg/kg and 20 mg/kg body
    weight, respectively).  The highest dose of alpha-HCH caused a
    significant decrease in motor activity.  Gamma-HCH inhibited the
    binding of 3H-TBOB to mouse whole brain membranes. Furthermore, this
    isomer is a weak inhibitor of GABA-stimulated uptake of 36wCl into
    mouse brain neurosynaptosome preparations  in vitro. The
    non-seizure-inducing alpha-HCH has biochemical and pharmacological 
    effects in the CNS which differ from those of the gamma-HCH.

         Matsumoto et al. (1988) provided evidence that all HCH isomers
    are capable of inhibiting GABA-A-mediated chloride channels in the
    brain, the relative potency being alpha = gamma > delta > beta.
    Alpha-HCH was also found to be a potent inhibitor of the
    batrachotoxin-stimulated action potential flux of sodium ions in N18
    neuroblastoma cell cultures (Shain et al., 1987).

    8.  EFFECTS ON HUMANS

    8.1  Acute toxicity - poisoning incidents

         Several cases of acute poisoning by technical-grade HCH,
    resulting either from accidents or occupational exposure, have been
    described (WHO, 1991).  Although alpha-HCH constitutes 65-70% of the
    technical product, it is likely that the most acutely toxic component,
    i.e. gamma-HCH, played the major role in these incidents. These cases
    cannot, therefore, assist in the evaluation of alpha-HCH.

    8.2  General population

         No specific studies relating to alpha-HCH are available.

         A study comparing liver cancer deaths in the USA and the
    "domestic disappearance" of organochlorine pesticides revealed that in
    1962, 18 and 15 years after the introduction of DDT and
    technical-grade HCH, respectively (when an increase in primary liver
    cancer due to the organochlorines would be manifest), the number of
    cases of primary liver cancer as a percentage of the total number of
    liver cancer deaths began a gradual and steady decline (from 61.3% in
    1962 to 56.9% in 1972). The death rate (per 100 000 per year) due to
    primary liver cancer declined from 3.46 to 3.18 during this period
    (Deichmann & MacDonald, 1977).

    8.3  Occupational exposure

         The evaluation of the effects of alpha-HCH on occupationally
    exposed workers is seriously hampered by the fact that most of the
    relevant studies concern workers who were exposed during the
    manufacture and handling of lindane or the handling and spraying of
    technical-grade HCH among other pesticides, and were thus exposed to
    all HCH isomers plus impurities and other (process) chemicals. 
    Therefore, it is difficult, if not impossible, to relate the observed
    effects to individual substances. Consequently these studies have only
    been described in this monograph where they aid the evaluation.

         Behrbohm & Brandt (1959) described 26 cases of allergic and toxic
    dermatitis that arose during the manufacture of technical-grade HCH.
    Patch testing with pure alpha-, beta-, gamma-, and delta-HCH yielded
    negative results, but positive reactions were obtained with the
    residual fractions.

         The level of alpha-HCH in 57 healthy workers (with normal liver
    function, EMG and EEG) at a lindane-manufacturing plant ranged from 10
    to 273 µg/litre, whereas it was below the detection limit in control
    workers. The concentration in the adipose tissue of eight of the
    exposed workers ranged from 1 to 15 mg alpha-HCH/kg (in extractable
    lipids) (Baumann et al., 1980, 1981; Brassow et al., 1981; Tomczak et
    al., 1981).

         The mean serum alpha-HCH level of malaria-control workers that
    sprayed technical-grade HCH for 16 weeks increased from 10 to
    78 µg/litre in previously non-exposed workers and from 18 to
    77 µg/litre in those that had been exposed during three previous
    spraying seasons (Gupta et al., 1982).

         Nigam et al. (1986) studied 64 employees from a plant
    manufacturing HCH who were directly or indirectly associated with the
    production of this insecticide and thus also exposed to chemicals such
    as benzene and chlorine.  The exposed group was composed of 19
    "handlers" (who handled and packed the insecticide), 26 "non-handlers"
    (plant operators and supervisors exposed indirectly to HCH), and 19
    maintenance staff (who visited the plant frequently). The control
    group consisted of 14 workers who had no occupational contact with the
    insecticide. The exposure period varied up to 30 years.  The mean
    serum alpha-HCH concentrations in the four groups were 21.1 µg/litre
    (controls), 21.8 µg/litre (maintenance staff), 41.2 µg per litre
    (non-handlers), and 100 µg/litre (handlers). Lindane and beta- and
    delta-HCH were also present. The total HCH concentrations were 51.4,
    143.6, 265.6, and 604 µg per litre, respectively. Clinical examination
    revealed that the majority of the workers from the "handler" and
    "non-handler" groups exhibited paraesthesia of the face and
    extremities, headache, and giddiness, and some of them also showed
    symptoms of malaise, vomiting, tremors, apprehension, confusion, loss
    of sleep, impaired memory, and loss of libido.  The same symptoms were
    found among the maintenance staff but were less severe and less
    frequent.

         Chattopadhyay et al. (1988) studied 45 male workers exposed to
    HCH during its manufacture and compared them with 22 matched controls.
    Exposure was mainly via the skin.  Paraesthesia of face and
    extremities, headache, giddiness, vomiting, apprehension, and loss of
    sleep, as well as some changes in liver function tests, were reported
    and were found to be related more to the intensity of exposure (as
    measured by the HCH levels in blood serum) than to the duration of
    exposure.  The measured exposures to total HCH were 13 to 20 times
    higher than those in the control groups (no detailed figures were
    reported). Of the total serum HCH, 60-80% was beta-HCH.

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    9.1  Algae

         Palmer & Maloney (1955) used alpha-HCH in a preliminary screening
    test with two cyanobacterium (blue-green alga), two green alga, and
    two diatom species. The test concentration was 2 mg/litre of water,
    and the incubation period was 3-21 days.  Alpha-HCH was not toxic at
    this concentration.

         When Canton et al. (1975) exposed  Chlorella pyrenoidosa to
    alpha-HCH for 96 h at 28°C (static system), the EC50 (growth
    inhibition) was > 10 mg/litre (maximum solubility in the medium).

         In a study by Krishnakumari (1977), cultures of the green alga
     Scenedesmus acutus of 1, 3, or 5 days of age were tested for
    sensitivity to alpha-HCH at 28°C, the growth rate being used as a
    parameter. Alpha-HCH dissolved in ethanol was added at nominal
    concentrations of 0.5-100 mg/litre water. The alpha-HCH concentrations
    that caused a reduction in growth in 1-, 3-, and 5-day-old cultures
    were 10 (or more), 5, and 0.5 mg/kg, respectively.

         When  Chlamydomonas sp. was exposed at a temperature of 20-25°C
    in a static system, the no-observed-effect level (based on the growth
    in 48 h) was > 1.4 mg/litre. A similar result was obtained with
     Dunaliella sp. at 15°C and a study duration of 48 and 96 h, the
    NOEL for growth being 1.4 mg/litre (maximum solubility) (Canton et
    al., 1978).

    9.2  Protozoa

         The EC50 for  Tetrahymena pyriformis (3 days in closed system
    at 27°C) was reported to be 0.75 mg/litre (Mathur et al., 1984).

    9.3  Invertebrates

    9.3.1  Acute toxicity

         The result of acute or short-term toxicity studies lasting a few
    days on  Artemia salina, Daphnia magna, and  Lymnaea stagnalis are
    summarized in Table 3.



    
    Table 3.  Acute or short-term toxicity of alpha-hexachlorocyclohexane for invertebrates
                                                                                                                             

    Species                     Age         Temperature       Parameter       Concentration      References
                                               (°C)                            (mg/litre)
                                                                                                                             

    Artemia salina            3 weeks           24             LC50a,b             0.5           Canton et al. (1978)

    Daphnia magna             < 1 day           20             LC50c,d             0.8           Canton et al. (1975)

    Lymnaea stagnalis         6 months          22             EC50c,e             1.2           Canton & Slooff (1977)
                                                                                                                             

    a  synthetic saltwater
    b  35 days (but exposure time was 4 days)
    c  48 h
    d  closed system
    e  growth inhibition/mortality or immobilization
    


    9.3.2  Short- and long-term toxicity

    9.3.2.1  Crustaceae

         In a study by Canton et al. (1975),  Daphnia magna was exposed
    to 0, 10, 50, 200, 1000, or 2000 µg alpha-HCH (> 95%) per litre for
    25 days.  The daphnids were fed  Chlorella pyrenoidosa. The
    sensitivity of daphnids to alpha-HCH markedly increased with exposure
    time. A concentration of approximately 50 µg/litre or less did not
    lead to death at any time during the whole life cycle of 2 months.
    Only with 2000 µg/litre was there an influence on reproduction, the
    EC50 for reproduction inhibition being 100 (54-186) µg/litre.
    The EC50 based on mortality and immobilization was 800
    (600-1000) µg/litre (see Table 4).

    9.3.2.2  Molluscs

         In a short-term (2-day) study, groups of five adult snails
     (Lymnaea stagnalis L.) (6 months of age) were exposed to various
    dose levels. Based on mortality and immobility, the EC50 was
    estimated to be 1200 (600-2300) µg alpha-HCH (> 95%) per litre
    (Canton & Slooff, 1977).

         In a long-term (70-day) study, groups of 10 snails (5 months of
    age) were exposed to 20, 100, 300, or 600 µg per litre.  The study was
    divided into a pre-exposure period (14 days) during which all egg
    capsules and the number of eggs per capsule were counted, an exposure
    period of 40 days during which four groups of adults and five capsules
    of each group were exposed to alpha-HCH, and a post-exposure period
    (16 days) during which snails were placed in water to recover. Based
    on egg production inhibition, the 40-day EC50 was 250 µg/litre. The
    percentage of fertilized eggs per capsule was not affected, and no
    morphological abnormalities were noticed during embryonic development. 
    Based on the number of eggs that did not hatch, an EC50 of
    230 µg/litre was determined. Considering a combination of the
    inhibition of egg production and the mortality of the young during
    their development, a 50% reduction of the overall reproductivity was
    found at 65 µg alpha-HCH/litre. These effects did not disappear during
    the recovery period of 16 days (Canton & Slooff, 1977) (see Table 4).



        Table 4.  Long-term toxicity of alpha-hexachlorocyclohexane for invertebrates

                                                                                                                                       

    Species                    Age     Temperature    Duration    Criteria                         Concentration    References
                                          (°C)         (days)                                       (mg/litre)
                                                                                                                                       

    Daphnia magna                          19            21       no mortality;                        0.27a        Janssen et al.
                                                                  no effects on behaviour,             0.09         (1987)
                                                                  appearance or growth;
                                                                  no influence on reproduction         0.27
                                                                  (4 groups of offspring)

    Lymnaea stagnalis        adults        22            40       EC50 (egg production inhibition)     0.25         Canton & Slooff
                             eggs and      22            40       hatching, overall productivity       0.065        (1977)
                             adults
                                                                                                                                       

    a  water renewal system
    
    9.4  Fish

    9.4.1  Acute toxicity

         LC50 and EC50 (mortality and immobilization) values for fish
    are summarized in Table 5.

    9.4.2  Short- and long-term toxicity

         During a 3-month study, rainbow trout  (Salmo gairdneri)
    (200-250 g) were fed pellets containing 0, 10, 50, 250, or 1250 mg
    alpha-HCH (purity > 95%) per kg diet. After 2, 4, 8, and 12 weeks,
    the fish were examined.  Growth, microsomal liver enzymes (aniline
    hydroxylase and aminopyrine demethylase), brain cholinesterase, serum
    alkaline phosphatase, and the histopathology of the brain, liver, and
    kidneys were all investigated but no effects were found (Canton et
    al., 1975).

         When guppies  (Poecilia reticulata) aged 3-4 weeks were exposed
    to 0, 200, 800, or 2000 µg alpha-HCH (> 95%) per litre in a 50-day
    study, the EC50, based on mortality and immobilization, was 800
    (600-1200) µg/litre (Canton et al., 1975).

         In a study by Janssen et al. (1987), fertilized eggs of  Oryzia
     latipes were exposed for 35 days (up to 28 days after hatching) to
    alpha-HCH.  No influence on growth, mortality or behaviour was seen at
    800 µg/litre.

    9.5  Terrestrial organisms

         No data on terrestrial organisms are available.



        Table 5.  Acute toxicity (48 h) of alpha-hexachlorocyclohexane for fish (growth inhibition/mortality or immobilization)

                                                                                                                             

    Species                        Age        Temperature     Parameter      Concentration       References
                                                 (°C)                        (mg/litre)
                                                                                                                             

    Freshwater

    Poecilia reticulata         3-4 weeks         24            EC50a        0.8  (0.6-1.2)      Canton et al. (1975)

    Salmo gairdneri              4 weeks          12            EC50a        1.05 (0.9-1.2)      Canton et al. (1975)

    Saltwatera

    Poecilia reticulata          3 weeks          24            EC50b        1.38 (1.35-1.42)    Canton et al. (1978)

    Poecilia reticulata                                         LC50         3.5                 Boulekbache (1980
                                                                                                                             

    a  closed system
    b  water renewal system
    


    PART B

    ENVIRONMENTAL HEALTH CRITERIA FOR BETA-HEXACHLOROCYCLOHEXANE

    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR BETA-HEXACHLOROCYCLOHEXANE

    1. SUMMARY AND EVALUATION

        1.1. General properties
        1.2. Environmental transport, distribution, and
              transformation
        1.3. Environmental levels and human exposure
        1.4. Kinetics and metabolism
        1.5. Effects on organisms in the environment
        1.6. Effects on experimental animals and
               in vitro test systems
        1.7. Effects on humans

    2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

        2.1. Identity of primary constituent
        2.2. Physical and chemical properties
        2.3. Analytical methods

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

        4.1. Transport and distribution between media
        4.2. Biotransformation and bioaccumulation
              4.2.1. Biodegradation
              4.2.2. Abiotic degradation
              4.2.3. Bioaccumulation
                      4.2.3.1   Aquatic invertebrates
                      4.2.3.2   Fish
                      4.2.3.3   Birds
                      4.2.3.4   Bioaccumulation in humans
        4.3. Isomerization

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

        5.1. Environmental levels
              5.1.1. Air
              5.1.2. Water
                      5.1.2.1   Fresh water
                      5.1.2.2   Sea water
              5.1.3. Soil/sediment
                      5.1.3.1   Dumping grounds
              5.1.4. Food and feed
              5.1.5. Terrestrial and aquatic organisms
                      5.1.5.1   Aquatic organism
                      5.1.5.2   Birds
                      5.1.5.3   Mammals

        5.2. General population exposure
              5.2.1. Total-diet studies
              5.2.2. Concentrations in human samples
                      5.2.2.1   Blood
                      5.2.2.2   Adipose tissue
                      5.2.2.3   Breast milk

    6. KINETICS AND METABOLISM

        6.1. Absorption and elimination
        6.2. Distribution
        6.3. Transplacental transfer and transfer via lactation
        6.4. Metabolic transformation
              6.4.1. Rat
              6.4.2. Mouse
              6.4.3. Human

    7. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

        7.1. Acute toxicity data
              7.1.1. Oral
              7.1.2. Intraperitoneal
        7.2. Short-term exposure
              7.2.1. Mouse oral studies
              7.2.2.  Rat oral studies
        7.3. Skin and eye irritation; sensitization
        7.4. Long-term exposure
              7.4.1. Rat oral studies
        7.5. Reproduction, embryotoxicity, and
              teratogenicity
              7.5.1. Reproduction
              7.5.2. Teratogenicity
        7.6. Mutagenicity and related end-points
        7.7. Carcinogenicity
              7.7.1. Mouse
              7.7.2. Rat
              7.7.3. Initiation-promotion
              7.7.4. Mode of action
        7.8. Special studies
              7.8.1. Effects on endocrine organs
              7.8.2. Neurotoxicity
              7.8.3. Effect on liver enzymes
              7.8.4. Immunosuppression

    8. EFFECTS ON HUMANS

        8.1. Acute toxicity - poisoning incidents
        8.2. General population
        8.3. Occupational exposure

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

        9.1. Algae
        9.2. Protozoa
        9.3. Invertebrates
        9.4. Fish
              9.4.1. Acute toxicity
              9.4.2. Longer-term toxicity
        9.5. Terrestrial organisms
              9.5.1. Birds
        9.6. Model ecosystem studies
    

    1.  SUMMARY AND EVALUATION

    1.1  General properties

        Beta-hexachlorocyclohexane (beta-HCH) is a by-product (7-10%) in
    the manufacture of lindane (> 99% gamma-HCH). Its solubility in water
    is low, but it is very soluble in organic solvents such as acetone,
    cyclohexane, and xylene.  It is a solid with a low vapour pressure.
    The  n-octanol/water partition coefficient (log Pow) is 3.80.  It
    is an environmental pollutant.

        Beta-HCH can be determined separately from the other isomers by
    gas chromatography with electron capture detection and other methods
    after extraction by liquid/liquid partition and purification by column
    chromatography.

    1.2  Environmental transport, distribution, and transformation

        Biodegradation and abiotic degradation (dechlorination) by
    ultraviolet irradiation occur in the environment and produce
    pentachlorocyclohexane, but at a much slower rate than in the case of
    lindane (gamma-HCH).

        Beta-HCH is the most persistent HCH isomer. Its persistence in
    soil is determined by environmental factors such as the action of
    microorganisms, content of organic matter and water, and
    co-distillation and evaporation from soil.

        Owing to the persistence of beta-HCH, rapid bioconcentration takes
    place in invertebrates (the bioconcentration factor is approximately
    125 within 3 days), fish (250-1500 on a dry weight basis or
    approximately 500 000 times on a lipid basis within 3-10 days), birds
    and man (approximately 525). The bioconcentration is higher and the
    elimination is slower for beta-HCH than for the other HCH isomers.

    1.3  Environmental levels and human exposure

        Beta-HCH is found in air over the oceans at a concentration of
    0.004-0.13 ng/m3.

        Until 1974, the River Rhine and its tributaries contained beta-HCH
    levels of 0.14-0.22 µg/litre, but thereafter the levels were
    consistently below 0.1 µg per litre.  Samples from the River Meuse
    also contained < 0.1 µg/litre.  In the River Elbe, levels decreased
    from an average of 0.009 to 0.004 µg/litre between 1981 and 1988.

        Beta-HCH has been measured in birds such as sparrowhawks,
    kestrels, owls, herons, and grebe over a number of years and the
    concentrations ranged from 0.1 to 0.3 mg/kg.  Up to 0.87 mg/kg (on a
    fat basis) has been found in the liver and adipose tissue of the polar
    bear.

        Important food items have been analysed in a few countries for the
    presence of beta-HCH. The mean concentrations, mainly in
    fat-containing food products, ranged up to 0.03 mg/kg (on a fat
    basis), but in milk products levels up to 4 mg/kg (on a fat basis)
    were found.  In non-fatty food items, the levels were < 0.005 mg/kg
    product.  In general, levels are slowly decreasing.

        Food is the main source for general population exposure to
    beta-HCH. In total-diet studies in the United Kingdom, 0.003, 0.0005,
    and < 0.0005 mg/kg were found for the years 1966-1967, 1975-1977, and
    1981, respectively. In the USA, the average daily intake of beta-HCH
    in 1982-1984 ranged from < 0.1-0.4 ng/kg body weight for various age
    groups.

        In a number of countries, the concentration of beta-HCH has been
    determined in the blood, serum, or plasma of the general population.
    The concentrations varied between the different countries and ranged
    up to 25 µg/litre.

        Many studies have been carried out to determine the presence of
    beta-HCH in human adipose tissues. The concentrations found in Canada,
    Germany, Kenya, the Netherlands, and the United Kingdom ranged up to
    4.4 mg/kg (on a fat basis).  A gradual increase with age was found up
    to approximately 50 years; thereafter levels decreased. Beta-HCH
    concentrations in adipose tissues are higher than those of the other
    HCH isomers, a phenomenon that reflects the accumulative properties of
    beta-HCH. There is, in general, no clear trend for a decrease in
    beta-HCH concentrations over the period that studies have been made.
    There is a relationship between the concentrations in adipose tissue
    and breast milk and the consumption of meat products, animal fat, and
    fatty fish.

        In a few countries (Canada, Germany, the Netherlands, and the
    United Kingdom), breast milk has been analysed and beta-HCH levels of
    between 0.1 and 0.69 mg/kg (on a fat basis) have been found. The
    levels in the milk of women living in rural areas appears to be higher
    than in urban areas.

        The high beta-HCH levels that have been found in breast milk
    exceed permissible concentrations temporarily and locally.  The
    beta-HCH concentrations in the blood of babies lie within the same
    range as those in the mothers.

        Beta-HCH appears to be a universal environmental contaminant.
    Concentrations are only decreasing very slowly in spite of measures
    taken to prevent its spread into the environment.

    1.4  Kinetics and metabolism

        Up to 95% of beta-HCH in the mouse gastrointestinal tract is
    absorbed, most of it being subsequently accumulated in adipose tissue.

    The elimination follows a 2-stage mechanism, the half-life for the
    first stage being 2.5 days and for the second stage 18 days.

        After absorption, beta-HCH is rapidly distributed to the liver,
    brain, kidneys, and adipose tissues. The maximum concentration in the
    liver is reached in rats after 4 days.  At an average blood
    concentration of 92 µg/litre (but also with concentrations of 540 and
    2100 µg per litre), the brain to blood and adipose tissue to blood
    ratios were 2:1 and 170:1, respectively.  After lethal acute human
    poisoning with HCH isomers, the beta-HCH concentration, relative to
    that of blood, was 363 in fat, 3 in the brain, and 15 in the liver.
    Beta-HCH passes the blood-brain barrier much less readily than the
    other HCH isomers.

        Transplacental transfer from pregnant mice to their fetuses was
    about 2% of the dose, but in rats a transfer of 40% was found. 
    Lactational transfer in rats from dams to sucklings via milk was about
    60% of the dose.

        In rats 70% of beta-HCH is eliminated during 28 days, one third of
    this being excreted in the urine. No unchanged beta-HCH is present in
    the urine. The major metabolite resulting from cis-dehydrochlorination
    is 2,4,6-trichlorophenol in a conjugated form.

        Pretreatment with beta-HCH alters the metabolism of lindane in
    rats.  From intraperitoneal studies with mice, it seems that beta-HCH
    is metabolized more slowly than lindane.

    1.5  Effects on organisms in the environment

        Beta-HCH generally has moderate toxicity for algae, invertebrates,
    and fish.  The acute LD50 values for these organisms are of
    the order of 1 mg/litre, but the EC50 values are lower
    (0.05-0.5 mg/litre).  The no-observed-effect level for  Oryzia latipes
    and  Poecilia reticulata, two freshwater fish exposed for 1 or 3
    months, was 0.03 mg/litre.

        No data are available on effects on populations and ecosystems.

    1.6  Effects on experimental animals and  in vitro test systems

        The acute oral LD50 values for mice and rats were reported in
    1968 to lie between 1500 and 2000 mg/kg body weight.  However, more
    recent studies yielded values of 16 g/kg body weight for mice and
    8 g/kg body weight for rats.  Signs of intoxication were mainly of
    neurological origin.

        Two short-term mouse studies, with dose levels of up to 600 mg/kg
    diet for 26-32 weeks, showed increased liver weight and nodular
    hyperplasia and atypical proliferations in the liver. In a third

    study, dose levels of up to 500 mg/kg diet for 24 weeks did not result
    in liver tumours or nodular hyperplasia.

        A 90-day study with rats fed 50 or 250 mg/kg diet revealed liver
    changes, i.e. hypertrophy and proliferation of smooth endoplasmic
    reticulum and increased activity of microsomal enzymes.  Changes in
    the gonads occurred at the highest dose levels but these were
    associated with severe effects on body weight. Hormonal changes
    associated with the gonadal atrophy showed no consistent endocrine
    effect.  There were no adverse effects at a dose level of 2 mg/kg diet
    (equivalent to 0.1 mg/kg body weight).

        In a long-term rat study (reported in 1950), doses of 10 mg/kg
    diet (equivalent to 0.5 mg/kg body weight) or more led to liver
    enlargement and histological changes.

        In a two-generation reproduction study on rats, the same effects
    were found as in the 90-day study. There were no effects at 2 mg/kg
    diet (equivalent to 0.1 mg/kg body weight), but a dose level of
    10 mg/kg diet resulted in increased mortality and infertility.  No
    compound-related teratogenic effects were found in an extension to
    this study.

        A weak "estrogenic" effect has been described.  The uterus was the
    target organ for this effect; there were no clear effects on endocrine
    control systems.  The mechanism and significance of this effect are
    uncertain.

        The mutagenicity studies reported did not show any increase in
    mutation frequency in  Salmonella typhimurium strains.  An  in vivo
    bone marrow metaphase analysis in rats yielded positive results.

        Two studies have been carried out on mice to determine
    carcinogenic potential.  In one study, 200 mg/kg diet was given for
    110 weeks, and liver enlargement, hyperplastic changes, and an
    increase in benign and malignant tumours were reported.  In the other
    study, where 500 mg/kg diet was administered for 24 weeks, no tumours
    were observed.

        Studies in which rats were fed combinations of beta-HCH with
    polychlorinated biphenyls suggested a promoting effect of beta-HCH.

        At 300 mg/kg diet, beta-HCH caused significant changes in several
    immune functions in mice within one month.

    1.7  Effects on humans

        When workers at a lindane-producing factory, with a geometric mean
    exposure of 7.2 years (1-30), were investigated, it was concluded that
    occupational HCH exposure did not induce signs of neurological
    impairment or perturbation of "neuromuscular function".

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1  Identity of primary constituent

    Common name              Beta-hexachlorocyclohexane (beta-HCH)

    Chemical formula         C6H6Cl6

    Chemical                 Beta-HCH is a stereoisomer of gamma-HCH,
    structure                the active ingredient of lindane (> 99%
    (see Annex I)            gamma-HCH).  It differs in the spatial
                             orientation of the hydrogen and chlorine
                             atoms on the carbon atoms:

    FIGURE 03

    Relative
    molecular mass           290.9

    CAS chemical             1alpha,2ß,3alpha,4ß,5alpha,6ß-hexachloro-
    name                     cyclohexane

    Common
    synonym                  Beta-benzenehexachloride (beta-BHC)

    CAS registry
    number                   319-85-7

    RTECS registry
    number                   GV4375000

    2.2  Physical and chemical properties

         Some physical and chemical properties are summarized in Table 6.

                                                                   

    Table 6.  Some physical and chemical properties of beta-
              hexachlorocyclohexane
                                                                   

    Melting point                 309°C

    Vapour pressure (20°C)        0.67 Pa (0.005 mmHg)

    Relative density (20°C)       1.89 g/cm3

    Solubility
       water (20°C)               1.5 mg/litre
       water (28°C)               0.2 mg/litre
       organic solvents (20°C)
                                  acetone            103.9 g/litre
                                  chloroform             3 g/litre
                                  ethanol               11 g/litre
                                  petroleum ether      1-2 g/litre
                                  xylene                33 g/litre
                                  cyclohexane          121 g/litre

    Stability                     considerable stability in acids,
                                  unstable in alkaline conditions

     n-Octanol/water partition
       coefficient (log Pow)      3.80
                                                                   

    2.3  Analytical methods

         The same methods can be used as for alpha-HCH (see section 2.3
    alpha-HCH).

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         Beta-HCH does not occur naturally. It is released to the
    environment as a result of the use of technical-grade HCH and the
    inappropriate disposal of the residue resulting from the purification
    of lindane.

         Beta-HCH is basically a by-product (and impurity) in the
    manufacturing of lindane (> 99% gamma-HCH) (van Velsen, 1986). 
    Technical-grade HCH, which is synthesized from benzene and chlorine in
    the presence of ultraviolet light, consists of:

    65-70%          alpha-HCH
     7-10%          beta-HCH
    14-15%          gamma-HCH (lindane)
    approx.7%       delta-HCH
    approx.1-2%     epsilon-HCH
    approx.1-2%     other components

         Purification of lindane produces a residue, consisting almost
    entirely of non-insecticidal HCH isomers (mainly alpha- and beta-),
    which can be used as an intermediate for the production of
    trichlorobenzene and other chemicals.

         Alpha- and beta-HCH have been used in mixtures with gamma-HCH (as
    "HCH" or "fortified HCH") in agriculture and in wood protection.

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1 Transport and distribution between media

         Tsukano (1973) studied the factors affecting the disappearance of
    beta-HCH from rice field soil. After granular application of
    technical-grade HCH (0.05 mg/litre) into surface water, beta-HCH
    disappeared very slowly (half-life > 28 days). After the
    translocation of beta-HCH (1 mg/litre) onto flooded levelled soil, the
    surface water and soil was analysed at intervals. A decrease in the
    beta-HCH concentration in water and a steady increase in soil was
    found.  After 7 days a maximum concentration in soil was reached. 
    From a soil column study it was found that beta-HCH did not move
    through the soil.

         Suzuki et al. (1975) studied the persistence of beta-HCH in three
    different types of soils.  Beta-HCH is the most persistent isomer of
    HCH, the persistence being dependent on environmental factors such as
    the action of soil microorganisms, co-distillation, and evaporation
    from soil.  Furthermore, the water content and the content of organic
    matter in the soil are of importance.

         Siddaramappa & Sethunathan (1975) studied the persistence of
    14C-labelled beta-HCH in five Indian rice soils under flooded
    conditions, using incubation times of 0, 20, and 41 days.  The
    degradation of beta-HCH was much slower than that of lindane. However,
    there was a great difference in the degradation rates between the
    soils.  In two types of soils (sandy and kari soils) both isomers
    persisted even after 41 days of flooding.

         Sorption and desorption of beta-HCH by 12 soils from rice-growing 
    areas in India were studied using a 14C-label.  The soils showed
    striking differences in their ability to adsorb beta-HCH, the sorption
    values ranging from 46 to 96% of total added beta-HCH. After oxidation
    of the soil with hydrogen peroxide, the sorption was lower (14-58%). 
    Organic matter was the most important factor governing the sorption
    and desorption, but pH, exchange acidity, exchangeable sodium and
    magnesium, and electrical conductivity also affected the results
    (Wahid & Sethunathan, 1979).

         Kampe (1980) concluded from experimental data that the transport
    of beta-HCH to ground water is unlikely, owing to low water solubility
    and anaerobic degradation.

         Korte (1980) summarized the behaviour of beta-HCH in the
    environment, especially in soil and plants.


    4.2  Biotransformation and bioaccumulation

    4.2.1  Biodegradation

         MacRae et al. (1967) studied the persistence and biodegradability
    of beta-HCH in two clay soils. Beta-HCH was applied at a level of
    15 mg/kg soil and the incubation periods were 0, 15, 30, 50, 70, and
    90 days. In non-sterilized soils only very small amounts could be
    detected after 70 days, indicating biodegradation, whereas in
    sterilized soils the losses were much slower and probably due to
    volatilization.

         In studies using either mixed or pure bacterial cultures under
    anaerobic or aerobic conditions, the dechlorination of 36Cl-labelled
    beta-HCH by mixed soil flora and by pure cultures of  Citrobacter
     freundii, C. butyricum, and  C. pasteurianum was 7.4, 15.3, 23.8,
    and 10.1%, respectively, within 6 days of incubation.  Aerobically
    grown facultative anaerobes dechlorinated actively. Beta-HCH degraded
    more slowly than lindane (Jagnow et al., 1977; Haider, 1979).

         Cell suspensions of  Clostridium sphenoides cultured under
    anaerobic conditions did not degrade beta-HCH (10 mg/litre) within
    24 h.  Even with more concentrated cell suspensions of the organism
    and conditions most conducive to lindane degradation (pH 8.0, 40°C),
    there was no indication of any degradation (Heritage & MacRae, 1979).

         MacRae et al. (1984) carried out laboratory studies on the
    transformation of beta-HCH (dosage: 20 mg beta-HCH/g of soil) in a
    Japanese soil containing 4% organic carbon under both aerobic and
    anaerobic conditions.  From the transformation rates, half-life values
    of 91 and 122 days, respectively, were calculated.

         In a study by Doelman et al. (1988a), microbial soil sanitation
    was applied to calcareous alkaline sandy loam soil that was polluted
    with a mixture of HCH isomers. Under anaerobic conditions, microbial
    degradation in the Dutch climate (soil temperature of 5-17°C) did not
    occur, and even the low concentration of the easily degradable
    gamma-HCH did not decrease. Microbial soil sanitation of
    beta-HCH-polluted sandy loam soil systems have been investigated. The
    soil systems involved were aerated moist soil and continuously aerated
    and intermittently aerated thick soil slurry.  Degradation of beta-HCH
    did not take place during a 40-week incubation period (Doelman et al.,
    1988b).

         A field investigation into the distribution of HCHs was carried
    out by Chessells et al. (1988) using soil from an agricultural area
    treated with BHC-20 (HCH composition:  70% alpha-HCH, 6.5% beta-HCH,
    13.5% gamma-HCH, and 5% delta-HCH. The beta-HCH concentration
    decreased only very slowly, probably owing to its comparatively high

    stability and low water solubility. Furthermore, soil organic carbon
    content was found to be of primary importance. A significant decrease
    in isomer concentration was observed when soil moisture content was
    high and was attributed to microbial degradation favoured by these
    conditions.

    4.2.2  Abiotic degradation

         Ultraviolet irradiation, using a 15-watt low pressure mercury
    lamp, of beta-HCH in 2-propanol solution for 16 h resulted in the
    production of an isomer of pentachloro-cyclohexene. This substance
    seems to be formed by the migration of an equatorial chlorine atom to
    the vicinal axial position at the intermediate pentachlorocyclohexyl
    radical (Hamada et al., 1982).

    4.2.3  Bioaccumulation

    4.2.3.1  Aquatic invertebrates

         In a study by Yamato et al. (1983), short-necked clam  (Venerupis
     japonica) rapidly absorbed beta-HCH and the concentration reached a
    plateau on the third day. The bioconcentration factor was 127 at a
    beta-HCH concentration in water of 2 µg/litre.  The beta-HCH
    concentrations on day 6 in internal organs and tissues were 0.194 and
    0.076 mg/kg, respectively. After a 3-day elimination period, the
    levels were 0.115 and 0.075 mg/kg, respectively.

    4.2.3.2  Fish

         Sugiura et al. (1979) studied bioaccumulation in the carp
     (Cyprinus carpio), brown trout  (Salmo trutta fario), golden orfe
     (Leuciscus idus melanotus), and guppy  (Poecilia reticulata).
    Beta-HCH was dissolved in water to a concentration of 1 mg/litre under
    steady-state conditions (time period not specified), and the
    equilibrium bioconcentration factors for the four types of fish were
    273, 658, 973, and 1485, respectively.

         In a study by Yamato et al. (1983), guppies  (Poecilia
     reticulata) rapidly bioaccumulated beta-HCH and the tissue
    concentration reached a plateau on the fourth day. The beta-HCH
    concentration in the water was 2 µg/litre and the bioconcentration
    factor 1043. The concentration in the guppy slowly decreased on the
    first day after the fish were transferred to HCH-free water.

         In general, the equilibrium levels were reached within 3-10 days.
    A bioconcentration factor of 100 000 to 500 000 has been calculated
    using data on the concentration of beta-HCH in the muscle and fat of
    bream collected in the River Elbe (Arbeitsgemeinschaft für die
    Reinhaltung der Elbe, 1982).

    4.2.3.3  Birds

         When low levels of HCH were administered together with other
    organochloropesticides in the feed to broilers for 6-16 weeks, of the
    three HCH isomers tested (alpha, beta, and gamma), beta-HCH showed the
    greatest bioaccumulation  (the mean bioconcentration factors for eggs
    and fat were 13 and 15, respectively). The half-life (after
    administration of uncontaminated food for 12 weeks) was about 6-8
    weeks (Kan & Jonker-den Rooyen, 1978a,b; Kan et al., 1978).

         This relatively higher accumulation of beta-HCH was also observed
    in chickens after feeding diets fortified with 1 mg beta-HCH/kg for 4
    weeks. The order of the degradation rate for the four HCH isomers was
    delta > gamma > alpha > beta. Biotransformation to one or more of
    the other HCH isomers did not occur (Szokolay et al., 1977a).

    4.2.3.4  Bioaccumulation in humans

         Geyer et al. (1986) found that in industrialized countries more
    than 90% of the non-occupation exposure to HCHs derives from food. 
    The mean concentration (on a fat basis) of beta-HCH in human adipose
    tissue was found to be 0.33-0.38, 0.40, 0.31, 0.90, 0.27, and
    0.31 mg/kg in the Federal Republic of Germany, the Netherlands, USSR,
    Switzerland, USA, and United Kingdom, respectively. The mean
    bioconcentration factor (on a lipid basis), calculated on the basis of
    the concentration in the diet (0.68, 0.62, 1.0, 1.21, 0.56, and
    0.67 µg/kg, respectively) and the levels in adipose tissue, was 527.0
    ± 140 (range 310-744).

    4.3  Isomerization

         Deo et al. (1980, 1981) studied the isomerization of beta-HCH by
    shaking it with distilled water at 25°C for various time intervals
    (5 min to 4 days).  The results of GLC analysis of the extracts
    indicated that a small portion of the beta-HCH isomerized into alpha-,
    gamma-, and delta-HCH. There were indications that other compounds
    were also formed by reactions such as dehydrochlorination.  Toxicity
    studies with mosquito larvae, flour beetle larvae, and houseflies
    exposed to the extracts demonstrated that the resulting aqueous
    solution contained substances that were more toxic than beta-HCH.

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Air

         Tanabe et al. (1982) found an average of 0.03 ng beta-HCH/m3
    (0.004-0.13 ng/m3) in 24 samples of air over the Western Pacific,
    Eastern Indian, and Antarctic Oceans.

         The concentrations of beta-HCH measured in the air of Delft,
    the Netherlands, in 1979-1980 were below the limit of detection
    (2-3 pg/m3) (Slooff & Matthijsen, 1988).

    5.1.2  Water

    5.1.2.1  Fresh water

         During the period 1969-1977, 1826 water samples were taken at 99
    sampling sites in the Netherlands. The highest concentrations of
    beta-HCH were found in the River Rhine and its tributaries.  The
    concentrations during the period 1969-1974 were 0.14-0.22 µg/litre,
    but from 1974 on, the concentrations were all below 0.1 µg/litre.  A
    sampling trip by boat made along the River Rhine from Rheinfelden in
    Switzerland to Rotterdam in the Netherlands proved that the source of
    alpha-, beta-, and gamma-HCH was located in the upper Rhine.  In the
    River Meuse, the levels were all below 0.1 µg/litre during the period
    1969-1977 (Wegman & Greve, 1980).  Since 1983 the contents of beta-HCH
    in the Rivers Rhine, Meuse, and West-Scheldt and in other surface
    waters in the Netherlands have generally been below 0.001 µg/litre
    (Slooff & Matthijsen, 1988).  The average concentration of dissolved
    beta-HCH in the Meuse-Rhine estuary in 1974 was 6 ng/litre whereas
    that of suspended beta-HCH was < 1 to 3 ng/litre (Slooff &
    Matthijsen, 1988).

         The Arbeitsgemeinschaft der Elbe (the Elbe Study Group)
    investigated the presence of beta-HCH in the River Elbe from
    Schnackenburg to the North Sea in 1981-1982 and found a mean
    concentration of 0.009 (< 0.001-0.072) µg per litre. During the
    period February to November 1988 the concentrations varied from 0.001
    to 0.009 µg per litre (Arbeitsgemeinschaft der Elbe, 1988).

         In the surface water of the Upper Rhine, the beta-HCH
    concentration was 200 ng/litre in 1974 but decreased in 1976-1977 to
    2-25 ng/litre (Hildebrandt et al., 1986).  LWA (1987) failed to detect
    beta-HCH in the River Rhine (three locations) and in six tributaries.

    5.1.2.2  Sea water

         Beta-HCH was detected in the North Sea at a level of 1.4 µg/litre
    in 1972 (Mestres, 1974), but in June-July 1986 the levels in surface
    water (5 m) were < 0.03-0.2 ng/litre (Umweltbundesamt, 1989).

         The concentration of beta-HCH in the Japan Sea and the Pacific
    Ocean around Japan was below the detection limit of 0.1 µg/litre in
    1974 (personal communications by A. Hamada and by T. Onishi to the
    IPCS, July 1989).

    5.1.3  Soil/sediment

         In 1974 beta-HCH was found in 9 out of 60 sediment samples
    collected in Japan, the range of concentration being 30-50 µg/kg
    (personal communications by A. Hamada and by T. Onishi to the IPCS,
    July 1989).

         Slooff & Matthijsen (1988) analysed sediments from eight
    different locations close to dumping places in the Netherlands for the
    presence of alpha-, beta-, and gamma-HCH and obtained median values
    for beta-HCH of 9-214 µg per kg dry matter.

    5.1.3.1  Dumping grounds

         In the Netherlands soil has been polluted with HCHs at various
    location as the result of their manufacture in the 1950s (spillage
    during production, storage, and handling), and concentrations up to a
    few grams of HCHs/kg dry soil have been found. Further pollution has
    been caused by both the dumping of chemical waste and its use in the
    levelling of certain areas.  From these dumping areas dispersal of the
    chemical waste can occur by leaching or wind erosion from open storage
    depots.  In certain polluted areas, high concentrations of HCHs,
    mainly the alpha and beta-isomers, have been found more than 2 m below
    ground level. In 18 locations in the Netherlands, the average
    concentrations of beta-HCH in sewage sludge in 1981 were between 30
    and 150 µg/kg dry matter.  Pollution of ground water also occurred,
    but this was restricted to the vicinity of the production areas.
    Horizontal transportation of HCHs in ground water appeared to be
    limited (Slooff & Matthijsen, 1988).

    5.1.4  Food and feed

         The concentration of beta-HCH has been determined in a number of
    important food items in France. The mean concentration was 0.03
    (nd-0.25) mg/kg in milk and milk products (2688 samples), 0.02
    (nd-0.04) mg/kg in meat (27 samples), 0.01 (nd-0.03) mg/kg in meat
    products (34 samples), and 0.01 (nd-0.1) mg/kg in animal fat
    (67 samples). In other food items, beta-HCH was not detected
    (<0.005 mg/kg) (Laugel, 1981).

         In a survey of milk contamination carried out in various areas of
    Japan in 1970, the average beta-HCH content in cow's milk ranged from
    0.009 mg/litre in the Hokkaido area to 1.288 mg/litre in the Nagasaki
    area (Matsushima, 1972).

         Table 7 gives the mean beta-HCH levels in a large number of
    samples of various food items from the Federal Republic of Germany
    reported by Hildebrandt et al. (1986).

         Skaftason & Johannesson (1979) analysed a total of 32 samples of
    butter from Iceland between 1974 and 1978 and found beta-HCH, at a
    mean concentration of 23 ± 16 µg per kg, in 31 out of 32 samples.

         In six samples of cow's milk collected from six locations in
    Switzerland, the levels of beta-HCH were 1.0-4.0 mg/kg on a fat basis
    (Rappe et al., 1987).

         In a study carried out in the United Kingdom, 24 samples of each
    food group were analysed. Bread, other cereal products, meat products,
    fish, oils and fats, eggs, green vegetables, potatoes, other
    vegetables, and fresh fruit contained no detectable amounts of
    beta-HCH. Carcass meat contained < 0.0005 (nd-0.003) mg/kg, offals <
    0.0005 (nd-0.003) mg/kg, poultry 0.008 (nd-0.08) mg/kg, milk < 0.0005
    (nd-0.001) mg/kg, and dairy products 0.001 (nd-0.008) mg/kg. Imported
    meat products collected in 1981-1983 contained up to 1.4 mg/kg
    product, imported retail cereal products collected in 1982 contained
    up to 0.03 mg/kg and animal feed collected in 1984 contained up to
    0.08 mg/kg (HMSO, 1986).

         No beta-HCH was found in meat and poultry products including
    eggs (976 samples) collected during 1984-1986. Peanut butter and
    vegetable oils (in total 95 samples) showed mean beta-HCH levels of
    0.01-0.02 mg/kg product, whereas processed pork and poultry products
    collected in 1985-1987 contained mean levels of 0.2 and 1.9 mg/kg,
    respectively.  Twenty-six out of 86 samples were positive and the
    highest level that was found was 6.3 mg/kg.  Other processed meat
    products (631 samples) contained up to 0.01 mg/kg product. In
    1984-1987, retail milk and dairy products were analysed, and 499 out
    of 849 samples contained beta-HCH at a mean concentration of
    0.01-0.03 mg/kg product (the highest level was 0.08 mg/kg). Samples of
    eel muscle (1124 eels from 62 sites) collected during 1986-1987 showed
    mean beta-HCH concentration of up to 0.02 mg/kg. The highest level
    found was 0.05 mg/kg (HMSO, 1989).


        Table 7.  Beta-hexachlorocyclohexane concentrations (mg/kg) in various
              food itemsa

                                                                             

    Food items           1973-78              1979-83            1973-83
                                                                             

    Meatb                                   0.01-0.083
                                              (0.26)d

    Meat productsb                          0.003-0.055
                                              (0.15)d

    Animal fatb                                                0.003-0.024
                                                                (0.075)d

    Gameb                                                      0.025-0.285

    Poultryb                                0.001-0.016
                                              (0.42)d

    Chicken eggs                                                  0.001

    Fish                                    0.001-0.007

    Milk and milk
     productsb            0.05                < 0.01

    Butterb,c                               < 0.01-0.02

    Cereals                                                    up to 0.001

    Cereal products                                            up to 0.01
                                                                             

    a  From: Hildebrandt et al. (1986).
    b  Determinations made on a fat basis
    c  Anon (1984)
    d  maximum value
        5.1.5  Terrestrial and aquatic organisms

    5.1.5.1  Aquatic organism

         Mouvet et al. (1985) measured the presence of beta-HCH in the
    aquatic mossCinclidotus danubicusin order to examine its potential use
    as an indicator of chlorinated pollutants in fresh water. The level in
    water 4 km down-stream of an industrial discharge was 0.5-2.6 µg per
    litre, while the levels in moss 0, 13, 24, and 51 days after
    transplant to the polluted river were < 0.025, 0.025-0.33,
    0.025-1.29, and 0.4 mg/kg dry weight, respectively.

         Bream collected from various locations in the River Elbe (between
    Schnackenburg and the North Sea) contained beta-HCH levels of
    0.008-0.063 mg/kg in muscle tissue and 0.7-2.8 mg/kg in adipose tissue
    (Arbeitsgemeinschaft für die Reinhaltung der Elbe, 1982).

         Freshwater fish from different rivers in the Federal Republic of
    Germany were analysed during the period 1973-1981. In the first 3-4
    years the beta-HCH levels were mainly between 0.01-0.02 mg/kg fresh
    weight. However, a decrease then took place and most of the samples
    were below 0.01 mg/kg fresh weight, with the exception of certain
    types of fish such as the eel and fish from industrially contaminated
    areas.  In 1981-1983, shell-fish and molluscs were analysed in the
    Federal Republic of Germany, and the beta-HCH concentration ranged
    from < 0.001 to 0.011 mg/kg fresh weight (Hildebrandt et al., 1986).

    5.1.5.2  Birds

         Organochlorine pesticides were determined in the livers of
    predatory birds in the United Kingdom during 1963-1966.  The average
    residues (arithmetic means) of beta-HCH found are given in Table 8.

    5.1.5.3  Mammals

         Skaftason & Johannesson (1979) analysed samples of body fat from
    10-year-old sheep, collected in 1974 in Iceland, and found an average
    of 79 ± 48 µg beta-HCH/kg.

         Norström et al. (1988) determined the contamination of Canadian
    arctic and subarctic marine ecosystems by analysing the adipose tissue
    and liver of polar bears ( Ursus maritimus; 6-20 animals per area)
    collected from 12 areas between 1982-1984. Of the total HCH in adipose
    tissue, 29% was beta-HCH (0.3-0.87 mg/kg on a fat basis).


        Table 8.  Residues of beta-hexachlorocyclohexane in the livers of
              predatory birdsa

                                                                             

    Species                     Year          Number of        Concentration
                                               samples             (mg/kg)
                                                                             

    Sparrowhawk                 1963             11                0.3
                                1964              8                0.23
                                1965              9                0.25

    Kestrel                     1964             28                0.1
                                1965             60                0.01

    Tawny owl                   1963             12                0.02
                                1965             29                0.01

    Barn owl                    1964             23                0.07

    Heron (adults)              1964             17                0.1
    Heron (nestlings)           1965             20                0.005

    Great crested grebe       1963/1966          15                0.1
                                                                             

    a  From: HMSO (1969)
    
    5.2  General population exposure

         From the data presented in section 5.1 it is evident that food is
    the main source of exposure of the general population to beta-HCH.

    5.2.1  Total-diet studies

         In a total-diet study carried out in the United Kingdom during
    1966-1985, food purchased in 21 towns throughout the country was
    prepared by cooking.  The study covered 20 to 24 food groups, and the
    number of total-diet samples examined varied from 22 to 25 samples.
    The calculated mean beta-HCH residue levels in the total diet for the
    periods 1966-1967, 1970-1971, 1974-1975, 1975-1977, 1979-1980, 1981,
    and 1984-1985 were 0.003, 0.001, 0.0005, 0.005, 0.001, < 0.0005, and
    < 0.0006 mg/kg, respectively (Egan & Hubbard, 1975; HMSO, 1982, 1986,
    1989).

         Samples consisting of 50 items of infant food and 110 items of
    toddler food were collected in 1978-1979 in 10 USA cities. The daily
    intake of beta-HCH in 1977, 1978, and 1979 in infant food was below
    the limit of detection. In toddler food beta-HCH was only detectable
    in 1977, the daily intake being 0.002 µg/kg body weight per day
    (Gartrell et al., 1985b).

         Total-diet studies conducted by the FDA in the USA before 1982
    were based on a "composite sample approach" regardless of the diet
    involved.  Later on they were based on dietary survey information and
    allowed the "total diet" of the population to be represented by a
    relatively small number of food items for a greater number of age-sex
    groups. The daily intakes of beta-HCH during 1982-1984 for the age
    groups 6-11 months, 2 years, 14-16-year-old females, 14-16-year-old
    males, 25-30-year-old females, 25-30-year-old males, 60-65-year-old
    females and 60-65-year-old males were < 0.1, 0.3, 0.2, 0.2, 0.2,
    0.4, 0.2, and 0.2 ng/kg body weight, respectively (Gunderson, 1988).

         Matsushima (1972) reported that the total diet of an average
    citizen of Matsuyama City, Japan, contained about 0.177 mg HCH/day,
    the major portion being the beta isomer.  Of the beta-HCH intake 90%
    was identified as originating from meat and dairy products.

         In a total-diet study in the Netherlands in 1977, the average
    concentration of beta-HCH in 100 samples was < 0.02 mg/kg on a fat
    basis.  The highest level was 0.19 mg/kg (Greve & van Hulst, 1977).

    5.2.2  Concentrations in human samples

         Beta-HCH concentrations in human samples are a good indication of
    the total exposure of the general population. Concentrations in human
    tissues are markedly higher than those of the other HCH isomers, a
    phenomenon which reflects the cumulative properties of the beta
    isomer.  There has been a trend, but only a very slow one, towards
    lower values in recent data.

         Greve (1985) was unable to detect any correlation between life
    style, such as type of food, and the beta-HCH concentrations in
    tissues of Dutch citizens. However, in a Swedish study the levels of
    beta-HCH (and of other organochlorine contaminants) in breast milk
    were found to be related to dietary habit. Levels in lacto-vegetarians
    were lower than those in women eating a mixed diet, and the latter
    were in turn lower than those in women using a mixed diet that
    regularly included fatty fish from the Baltic (Noren, 1983).

    5.2.2.1  Blood

         Eckenhausen et al. (1981) detected beta-HCH at a concentration of
    < 0.5 to 25 µg/litre in the blood of 19 out of 47 pregnant women in
    the Netherlands. A concentration range of < 1.0 to 12 µg/litre was
    found in 30 out of 69 women after they had given birth and beta-HCH
    was detected in the blood of 17 out of 46 babies (< 1.0 to
    6.0 µg/litre).

         When Blok et al. (1984) studied the presence of beta-HCH in the
    blood of 65 healthy Dutch volunteers (34 females and 31 males),
    beta-HCH was found in approximately half of the volunteers. The median
    concentration was 0.4 µg/litre (range nd-1.4 µg/litre) in both males
    and females.

         Blood samples of Dutch citizens analysed in 1978, 1980, 1981, and
    1982 (70, 48, 127, and 54 samples, respectively), contained 0.3-1.4 µg
    beta-HCH/litre (Greve & Wegman, 1985).

         Polishuk et al. (1970) found beta-HCH in the blood of 24 pregnant
    women and 23 infants living in Israel. The mean concentrations was 0.5
    ± 0.6 µg/litre in the women and 0.3 ± 0.5 µg/litre in the infants.

         The average concentrations of beta-HCH in the plasma of five
    subjects in the USA, who were not occupationally exposed, were
    0.83-0.94 µg/litre, and were remarkably consistent throughout the 5
    days during which samples were taken (Radomski et al., 1971a).

         Starr et al. (1974) analysed the blood of 187 men and 171 women
    living in Colorado, USA. In men, a mean concentration of 4.9 µg
    beta-HCH/litre was found in 15 samples, while in women the mean
    concentration in 7 samples was 10.9 µg/litre (range, 9.0-15.0).

         In a 4-year study to assess the exposure of the general
    population, 6252 blood samples were collected from people (12-74 years
    of age) living in 64 locations across the USA. Beta-HCH was detected
    in 13.9% of the samples at a mean level of 1.7 µg/litre (range,
    1-28 µg/litre). The percentage of positive samples increased from the
    youngest to oldest age group (from 3.2 to 26.8%) (Murphy & Harvey,
    1985).

         Bertram et al. (1980) found a median concentration of 1.32 µg
    beta-HCH/litre (range, nd-4.81) in whole blood (18 samples) of
    citizens of the Federal Republic of Germany.

    5.2.2.2  Adipose tissue

         In fifteen samples of adipose tissue from the general population
    of the Federal Republic of Germany, the median concentration of
    beta-HCH was 0.33 mg/kg on a fat basis (range, nd-0.66) (Bertram et
    al., 1980).

         Specimens of subcutaneous adipose tissue from 48 children (34
    under the age of 1 year, 14 in the second year of life) were analysed
    during the period 1982-1983 in the Federal Republic of Germany. The
    average concentration of beta-HCH was 0.15 (range, nd-1.02) mg/kg fat.
    The average concentration was highest, 0.17 (nd-0.38) mg/kg fat, at
    the age of 0-6 weeks (Niessen et al., 1984).

         Hildebrandt et al. (1986) summarized the results of nine studies
    carried out in the Federal Republic of Germany in 1969-1983. The mean
    beta-HCH concentrations (636 samples) ranged from 0.01 to 1.30 mg/kg
    on a fat basis.

         Mes et al. (1982) analysed 99 samples of adipose tissue from
    autopsies of accident victims from different areas of Canada. All
    samples contained beta-HCH, the average concentration of which was
    0.151 ± 0.459 (range, 0.016-4.413) mg/kg wet weight.  In males (53)
    the average value was 0.183 ± 0.612 mg/kg, whereas in women (45) it
    was 0.116 ± 0.166 mg/kg. The influence of age was evident.  The
    average concentration in 33 people aged up to 25 was 0.067 ±
    0.051 mg/kg, in 41 people aged 26-50 it was 0.260 ± 0.698 mg/kg, and
    in 24 people aged 51 or more it was 0.082 ± 0.037 mg/kg.

         Human adipose tissue was analysed during the periods 1965-1967,
    1969-1971, and 1976-1977 (male and female) in the United Kingdom, the
    number of samples being 66, 248, 201 (male), and 236 (female),
    respectively. The arithmetic means of the beta-HCH concentrations were
    0.28, 0.27, 0.30 (male), and 0.33 (female) mg/kg, respectively (HMSO,
    1982). During 1982-1983, the beta-HCH concentrations were 0.24 (male)
    and 0.31 (female) with a range of 0.01-0.81 mg/kg (HMSO, 1986).

         Kutz et al. (1979) studied the presence of organochlorine
    pesticides in human adipose tissue in 48 states of the USA in
    1970-1975.  Beta-HCH was widely distributed at low levels (geometric
    means of between 0.2 and 0.4 mg/kg tissue on a fat basis) during this
    period, and there was a slow downward trend. Residues of alpha-HCH and
    gamma-HCH were found at a very low frequency.

         In 1980, eight adipose tissue samples were taken as part of the
    US EPA National Human Monitoring Program in North East Louisiana and
    in 1984 10 samples were collected.  The average beta-HCH concentration
    (on a lipid basis) was 0.77 mg/kg (nd-2.31) in 1980 and 0.62 mg/kg
    (0.31-1.03) in 1984 (Holt et al., 1986).

         In a study by Szymczynski et al. (1986), 29 samples of adipose
    tissue were taken at necropsy and 24 at surgery in the Poznan region
    of Poland and were compared with 100 samples from residents of the
    Warsaw region. In Poznan, the mean concentration of beta-HCH was 0.211
    ± 0.154 mg/kg, while in Warsaw it was 0.184 ± 0.017 mg/kg.

         In Kenya, Wassermann et al. (1972) analysed 83 adipose tissue
    samples collected during autopsy in 1969-1970 from people without
    occupational exposure to insecticides. The mean concentration of
    beta-HCH in the age group 5-24 (32 samples) was 0.0686 ± 0.064 mg/kg,
    in the age group 25-44 (28 samples) it was 0.263 ± 0.266 mg/kg, and in
    people aged 45 or more (23 samples) it was 0.186 ± 0.228 mg/kg.

         In 1974, 360 adipose tissue samples were collected in 8 regions
    of Japan, and the mean concentration of beta-HCH was 6.55 mg/kg on a
    fat basis (Takabatake, 1978).

         The beta-HCH concentration of 567 samples of adipose tissues of
    Dutch citizens analysed during 1968-1983 ranged from 0.21 to 0.6 mg/kg
    (on a fat basis). The highest levels were found in 1968-1976 (Greve &
    van Harten, 1983; Greve & Wegman, 1985).

    5.2.2.3  Breast milk

         Breast milk is a major route for the elimination of
    organochlorine pesticides and PCBs in women. In a study by Cetinkaya
    et al. (1984), a significant correlation was found between the
    concentration of beta-HCH in breast milk and the level of consumption
    of meat products and animal fat.  In addition, concentrations of
    beta-HCH in breast milk in rural areas appeared to be higher than
    those in urban areas.

         The variation during lactation of residue levels in breast milk
    was investigated in five women aged 23-36 in the Federal Republic of
    Germany. The beta-HCH concentrations were between 0.04 and 0.20 mg/kg
    fat, and no significant changes in residue level occurred during the
    lactation period (Fooken & Butte, 1987).

         The residues of beta-HCH in breast milk during the periods
    1974-1975 and 1979-1980 in the Federal Republic of Germany were 0.6
    and 0.3 mg/kg fat, respectively (Anon., 1984).

         More than 7100 samples of breast milk were analysed in the
    Federal Republic of Germany from 1969 to 1984.  These studies were
    carried out by 20 authors, and the results were summarized by

    Hildebrandt et al. (1986).  The mean concentrations of beta-HCH ranged
    from 0.02 to 0.56 mg/kg fat. There was no clear decrease in the mean
    concentrations during the period 1969-1979, but thereafter a slow
    decrease was observed. A further study carried out  in the Federal
    Republic of Germany (2709 samples in   1979-1981) yielded an average
    concentration of 0.37 mg/kg fat (Fooken & Butte, 1987). In 1981-1983,
    132 samples of breast milk were analysed and the average level was
    0.209 mg beta-HCH/kg milk fat (Cetinkaya et al., 1984).

         Tuinstra (1971) analysed 42 individual samples of breast milk
    collected in 1969 from young mothers (18-32 years of age) living in
    the Netherlands and determined a median beta-HCH concentration of
    0.28 mg/kg milk fat (range, 0.1-0.69 mg/kg). When 278 samples of
    breast milk, collected in 11 maternity centres in the Netherlands,
    were analysed for the presence of beta-HCH, the median beta-HCH
    concentration was 0.1 mg/kg (on a fat basis).  The maximum value was
    0.3 mg/kg (Greve & Wegman, 1985).

         Samples of maternal blood, milk, and umbilical cord blood were
    collected from 43 mothers and their infants during 1981-1982 in Oslo,
    Norway. The residue levels in maternal and umbilical cord serum were
    below < 1 µg per kg.  In colostrum and milk, concentrations ranging
    from 0.05 to 0.45 mg/kg fat were found (Skaare et al., 1988).

         Vukavic et al. (1986) measured beta-HCH in 59 samples of
    colostrum collected during autumn 1982 (26 samples)  and spring 1983
    (33 samples) from healthy nursing mothers on the third day after
    delivery.  The beta-HCH concentrations in the autumn and spring were
    not significantly different (mean concentrations of 0.95 ± 0.21 and
    0.88 ± 0.16 µg/litre whole colostrum, respectively).

         Mes et al. (1986) studied 210 breast milk samples from five
    different regions of Canada and measured a mean beta-HCH concentration
    of 0.214 mg/kg (on a fat basis).  Davies & Mes (1987) studied 18
    breast milk samples from Canadian, Indian, and Inuit mothers in
    Canada, whose fish consumption was comparable to the national
    consumption. The level of beta-HCH in milk fat of the indigenous
    population was 0.022 mg/kg, compared with a value of 0.206 mg/kg from
    a national survey.

         In Japan, the average beta-HCH content in breast milk was found
    to be 0.120 mg/kg (Matsushima, 1972).

         In Japan, 378, 328, 87, and 77 samples of breast milk,
    respectively, were analysed in 1980, 1981, 1982, and 1983.  The mean
    concentrations were 0.031, 0.034, 0.043, and 0.020 mg beta-HCH/kg
    whole milk, respectively (WHO, 1986).

         Breast milk was analysed for the presence of beta-HCH during
    1979-1980 and 1983-1984 in the United Kingdom.  In these two

    periods, 30 and 40 samples, respectively, were collected in Scotland. 
    The mean concentrations were 0.008 (< 0.001-0.14) and 0.005
    (< 0.001-0.032) mg/kg milk, respectively (HMSO, 1986).

    6.  KINETICS AND METABOLISM

    6.1  Absorption and elimination

         Shibata (1978) reported that the absorption of beta-HCH from the
    gastrointestinal tract in mice was 80-95%, most of this being
    accumulated in adipose tissue. The elimination followed a 2-stage
    mechanism, the half-life for the first stage being 2.5 days and that
    for the second stage being 18 days. The half-life for clearance from
    blood in rats (sex not specified) was 1 month (Altmann et al., 1980),
    and the half-life for clearance from fat was 14 days in male rats and
    28 days in female rats (Portig, 1983).  Vohland & Koransky (1983)
    reported a half-life for clearance from "internal organs" of 22 days
    in female rats. A half-life of 20 days for the clearance from the
    brain of female rats was reported by Portig & Vohland (1983) and
    Vohland et al. (1981). In cows the half-life for clearance from fat
    was 4.2-22.0 weeks (Wolf, 1983).  The elimination in humans was slow
    after continuous exposure ceased, the concentration in fatty tissues
    decreasing only slightly over several years (Vohland & Koransky,
    1983).

    6.2  Distribution

         Oshiba (1972) fed groups of six rats a diet containing 10 mg
    beta-HCH/kg for up to 56 days. The beta-HCH level in adipose tissue
    was 60 mg/kg tissue and in the liver was 45 mg/kg tissue after 56
    days.  The maximum concentration in the liver was reached after 4
    weeks.  During subsequent starvation, beta-HCH was mobilized from
    adipose tissue by an enhanced lipid metabolism.  Furthermore, there
    was a tendency for deposition in other organs and tissues.

         Vohland et al. (1981) and Portig &  Vohland (1983)  studied the
    distribution of beta-HCH in the brain and depot fat of rats. With an
    average concentration in blood of 92 µg beta-HCH/litre, a brain to
    blood ratio of 2:1 and depot fat to blood ratio of 170:1 were found,
    whereas with blood concentrations of 540 µg/litre and 2100 µg per
    litre the ratios were 2:1 and 177:1 and 2:1 and 168:1, respectively.

         After lethal acute intoxication of humans by HCH, the HCH
    concentration, relative to that in blood, was in the ratio of 363:1
    for fat, 3:1 for brain, and 15:1 for liver (Vohland & Koransky, 1983).

         When beta-HCH is applied repeatedly to rats, mice, and mini-pigs
    there is marked storage in fat, especially in females, and the fat
    levels increase continuously as dosing progresses (Nakajima et al.,
    1970; Oshiba & Kawakita, 1972; Altmann et al., 1980; van Velsen et
    al., 1982; Srinivasan & Radhakrishnamurty, 1983). Data on
    concentrations in organs are contradictory: according to one report
    the levels in the kidneys, brain, and liver of rats reached a plateau
    after 4 weeks (Oshiba & Kawakita, 1972), whereas other sources
    reported steady increases in these organs throughout a 12-week dosing
    period (van Velsen et al., 1982).

    6.3  Transplacental transfer and transfer via lactation

         Hori & Kashimoto (1974) found, after oral dosing of pregnant
    mice, a carry-over from dam to fetus of approximately 2% of the dose.
    Shibata (1978), however, reported a placental transfer of beta-HCH in
    rats of approximately 40%.

         During lactation the transfer of beta-HCH to milk was 85% from
    adipose tissue and 64% from administered beta-HCH (Shibata, 1978).
    Carry-over from dam to suckling via the milk was about 60% of the dose
    during lactation.

         In a study by Hapke & Hollmann (1985), significant carry-over via
    milk was found after female rats were dosed for a period of 8 weeks
    that terminated 3 weeks before mating. At both the dose levels tested
    (i.e. 1 and 5 mg/kg body weight) beta-HCH concentrations in milk were
    elevated and signs of liver enzyme induction were found in the pups.

         As significant excretion in milk was shown to occur in cows after
    oral dosing (the carry-over was 30-37%)  (Heeschen, 1985).

    6.4  Metabolic transformation

    6.4.1  Rat

         In a study by Freal & Chadwick (1973), Sprague-Dawley weanling
    female rats were administered 2 mg beta-HCH/rat per day orally in
    peanut oil for 7 days.  Since beta-HCH was metabolized to
    2,4,6-trichlorophenol but to no other chlorophenols, it appears  that
     cis-dehydrochlorination may lead exclusively to this metabolite.
    This study also indicated that pre-treatment with beta-HCH alters the
    metabolism of lindane in rats.

         Rats fed 1.5 mg 14C-labelled beta-HCH/kg diet for 7 days
    excreted 70% of the dose during these 7 days and the following 28
    days.  One third of the eliminated radiolabel was found in the urine.
    There was no unchanged beta-HCH in urine; the major urinary metabolite
    was 2,4,6-trichlorophenol and small amounts of trichlorohydroxy-
    methoxybenzene, a dichlorophenol, and a trace of a tetrachloro-
    cyclohexane isomer were found. In faeces, only 2,4,6-trichlorophenol
    was identified (Lay et al., 1981).

         Artigas et al. (1988) applied a new method of gas
    chromatographymass spectrometry (GC-MS) to identify several lindane
    metabolites (tetra-, penta-, and hexachlorocyclohexenes, and tetra-
    and pentachlorobenzene) in rat brain homogenates.  Male Wistar rats
    were administered orally 30 mg beta-HCH/kg and were sacrificed 5 h
    later.  The cerebella of the animals were analysed and 3.6/4.5-PCCH,
    3.5/4.6-PCCH, HCCH, pentachlorobenzene, HCB, and beta-HCH were found
    at levels below 5 µg/kg. Beta-HCH was present at a concentration of
    4.2 mg/kg tissue. This study revealed that the various HCH isomers are
    cleared from the brain via different metabolic pathways.

    6.4.2  Mouse

         When 14C-labelled beta-HCH was administered intraperitoneally
    to male mice (strain ddY, 4 weeks old) as a single dose of 32 µg, the
    average urinary excretion of radioactivity within 3 days was 10%.
    Beta-HCH seemed to be metabolized more slowly than lindane. The
    principal metabolite of beta-HCH in the urine was
    2,4,6-trichlorophenol (25%), but 2,4-dichlorophenol (up to 5%) was
    also found.  These metabolites were mainly conjugated with glucuronide
    or sulfate (Kurihara & Nakajima, 1974; Kurihara, 1975).

    6.4.3  Human

         When Engst et al. (1978) analysed the urine of occupationally
    exposed workers (apparently to technical-grade HCH in manufacturing
    processes), they found, apart from alpha-, beta-, gamma-, and
    delta-HCH, traces of hexa- and pentachlorobenzene, gamma- and
    delta-pentachlorocyclohexene, pentachlorophenol, 2,3,4,5-, 2,3,4,6-,
    and 2,3,5,6,-tetrachlorophenol, and several trichlorophenols, as well
    as the glucuronides of several of these metabolites.  The
    pentachlorocyclohexenes, tetrachlorophenol, hexachlorobenzene, and
    pentachlorophenol were also identified in the blood.

    7.  EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

    7.1  Acute toxicity data

    7.1.1  Oral

         Coper et al. (1951) reported the death of three out of five rats
    that received a oral dose of 150 mg beta-HCH/kg body weight.  Oral
    LD50 values of 1500 and 2000 mg/kg body weight for mice and rats,
    respectively, have been reported (WHO, 1986). However, a more recent
    study reported the LD50 to be > 16 000 mg/kg body weight in mice
    and > 8000 mg/kg body weight in rats (Hoffmann, 1983). Symptoms of
    poisoning were decreased activity, ataxia, tremors, dyspnoea,
    anorexia, convulsions, and rough fur.  Portig (1983) reported a rat
    LD50 of 9000 mg/kg body weight.

    7.1.2  Intraperitoneal

         In a study by Coper et al. (1951), no deaths occurred among 6
    rats given an intraperitoneal dose of 160 mg beta-HCH/kg body weight.

    7.2  Short-term exposure

    7.2.1  Mouse oral studies

         Groups of 10-11 DD mice of each sex (6 weeks of age)  received
    diets containing 0, 100, 300, or 600 mg beta-HCH per kg diet for 32
    weeks, followed by a control diet for 5-6 weeks.  The control group
    consisted of 20 animals.  During the experiment a number of animals
    died. The frequency of atypical proliferation in the liver was 0/29 in
    the control group, 0/18 at 100 mg/kg, 6/16 at 300 mg/kg, and 11/12 at
    600 mg/kg. No tumours were found (Hanada et al., 1973).

         Ito et al. (1973b) fed DD mice 0, 50, 100, 200, or 500 mg
    beta-HCH/kg diet for 24 weeks but found no liver tumours or nodular
    hyperplasia.

    7.2.2  Rat oral studies

         In a study by Doisy & Bocklage (1950), all rats (20 weanling
    male) administered 0.6 g beta-HCH/kg diet for 4 weeks died within 3
    weeks.

         Rats administered beta-HCH at a dietary concentration of
    600 mg/kg were reported to undergo growth retardation, liver mass
    enlargement, and a decrease in absolute brain mass, beta-HCH residues
    being found primarily in the fat and adrenals (Macholz et al., 1986).

         A 13-week oral toxicity study with beta-HCH (> 98%) in
    SPF-derived Wistar RIV:Tox rats (10 male and 10 female per group) has
    been carried out.  The levels were 0 (< 0.01), 2, 10, 50, or

    250 mg/kg diet, clinical signs, growth, food intake, and organ weights
    were checked, and biochemical, haematological, and extensive
    histopathological investigations were carried out. At the highest
    concentration, half of the animals died following ataxia, progressive
    inactivity, and coma. Growth inhibition was only observed in this
    concentration, and red and white blood cell concentrations were
    decreased. The liver glycogen level was significantly higher in the
    group fed 250 mg/kg than in control rats. Furthermore, a significantly
    higher activity of aniline hydroxylase (AH) and aminopyrin-
     N-demethylase (APDM) microsomal enzymes and a higher concentration
    of cytochrome P450 were observed.  In the group fed 50 mg/kg only APDM
    activity was increased. In all groups of treated rats, liver effects
    were observed (increase in organ weight, centrilobular hepatocytic
    hypertrophy, and proliferation of smooth endoplasmic reticulum or
    increased activity of microsomal enzymes). The thymus weight was
    significantly decreased at 50 and 250 mg/kg and the testes weight at
    250 mg. At 2 mg/kg the only effect found was liver enzyme induction
    (van Velsen, 1986; van Velsen et al., 1986).

         When young male Wistar rats were administered 800 mg beta-HCH/kg
    diet for 2 weeks, liver weight was increased but no differences in the
    content of water, nitrogen, protein, or glycogen were found.  Liver
    fat content was increased and the DNA content per kg tissue was
    decreased, but the whole liver DNA content was increased.  The most
    predominant change in the liver was hypertrophy of the liver cells.
    The testes weight was not different from that of the control animals
    but the protein content was higher.  The testicular DNA content was
    lower than in control animals.  The histological changes reported were
    testicular tubular atrophy, interstitial oedema, and spermatogenic
    arrest (Srinivasan et al., 1988).

         In a study by Srinivasan et al. (1984), eight young male Wistar
    rats were fed 800 mg beta-HCH/kg diet for two weeks, and a control
    group of five rats was used. Special attention was given to the
    urinary excretion of body constituents reflecting renal function.
    Glucosuria, increased excretion of creatinine and urea, and
    hypertrophy and degeneration of the renal tubular epithelia were
    observed.

         In another study with male Wistar rats fed 0 or 800 mg
    beta-HCH/kg diet for two weeks, special attention was given to liver
    function. The control group consisted of 8 rats and the treated group
    of 12 animals. The HCH isomer produced effects on various enzyme
    systems: serum aminotransferase, hepatic glucose-6-phosphate
    dehydrogenase, and aldolase activities were increased, while liver
    glucose-6-phosphatase activity was decreased. The activities of liver
    mitochondrial DNP/Mg/Ca-activated ATPase and liver microsomal
    Na±/K±-ATPase were lower in the treated animals (Srinivasan &
    Radhakrishnamurty, 1988).

         Two 13-week feeding studies (Loeber & van Velsen, 1985; van
    Velsen et al., 1986) showed similar atrophy of the testes, with
    reduced tubular area, lack of mature spermatozoa, and oedema of the
    interstitial spaces. In both studies, only the highest beta-HCH
    concentration (150 mg/kg diet in one study and 250 mg/kg diet in the
    other) produced these effects and resulted in a significantly reduced
    weight gain in the affected animals. The measurement of circulating
    hormone levels (testosterone, FSH, LH) showed no dose-related effects.
    No clear endocrine effects on the testes or on male reproductive
    hormones were demonstrated (van Velsen, 1986).

    7.3  Skin and eye irritation; sensitization

         No data are available on skin and eye irritation or
    sensitization.

    7.4  Long-term exposure

    7.4.1  Rat oral studies

         In a study by Fitzhugh et al. (1950), groups of 10 female and 10
    male weanling Wistar rats were administered diets containing 0, 10,
    100, or 800 mg beta-HCH/kg (in corn oil) for 107 weeks.  With
    concentrations of 100 mg/kg diet or more, there was growth depression,
    and with 800 mg/kg increased mortality was found.  Concentrations of
    10 mg/kg or more led to liver enlargement and slight or moderate
    histopathological changes in the liver.

    7.5  Reproduction, embryotoxicity, and teratogenicity

    7.5.1  Reproduction

         A 2-generation study with SPF-derived Wistar RIV:Tox rats (13
    males and 26 females per group) was carried out to study fertility,
    reproduction, and development of the offspring.  The parents (F0)
    were fed beta-HCH (> 98%)  from weaning at levels of 0 (< 0.01), 2,
    10, or 50 mg/kg, and, following a 12-week premating period, F1a and
    F1b litters were produced. The F1b generation was used to produce
    F2a, F2b, and F2c litters, the last-mentioned being used for
    teratological investigations (see section 7.5.2). In the highest-dose
    group, the F1a litter size was reduced and there was almost complete
    infertility when mating for the Fw1bgeneration took place. All pups in
    this group died before weaning. At a concentration of 10 mg/kg diet,
    increased mortality in F1a and F1b litters was observed.  In this
    group, precocious vaginal opening and complete infertility in the
    second generation were observed.  There were no effects in the 2-mg/kg
    group (van Velsen, 1986).

         The parental animals (F0) from the above study were used to
    investigate the influence of beta-HCH on the endocrine organs after 40
    weeks of exposure.  In females, mean autopsy body weight and ovary

    weight were decreased, but adrenal gland and uterus weight increased.
    The organ weight changes in males were less clear, except for an
    increase in the weight of pituitary and adrenal glands. The proportion
    of animals without corpora lutea in the ovaries was greater in the
    group fed 50 mg/kg than it was in control rats. The testes in the
    animals fed at this level showed a reduced number of Leydig cells. 
    Atrophy of the dorsolateral prostate, seminal vesicles, and
    coagulation glands was found in one animal. The pituitary glands of 
    the treated animals revealed no differences in the immunoreactivity
    for prolactin. The pregnancy index (number of females with
    litters/number of females mated) was less than 0.5 in all groups of
    rats. Normally this strain produced pregnancy indices of nearly 1.0.
    The study was performed using a semi-synthetic purified feed as
    compared to the conventional feed used in the breeding colony. The age
    of females at first delivery was 20 weeks, much higher than normal. 
    These factors cast some doubt on the results (van Velsen, 1986).

    7.5.2  Teratogenicity

         The F2c litter from the study described in 7.5.1 was used to
    investigate the teratogenic effects of beta-HCH.  The females were
    killed 20 days following sperm detection or 20 days after the last
    mating of the F1b generation, and fetuses were inspected for
    internal and skeletal abnormalities. No compound-related increase in
    teratogenic effects was found (van Velsen, 1986).

    7.6  Mutagenicity and related end-points

         The available data are limited. Beta-HCH did not induce mutations
    in  Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537
    (Lawlor & Haworth, 1979; Nishimura, 1982).  The result of an  in vivo
    bone marrow metaphase analysis in rats was reported to be positive
    (Shimazu et al., 1976; IARC, 1979). Beta-HCH did not induce mutations
    inAllium ceparoots (Nybom & Knutsson, 1947).

         A mutagen test strain of  Bacillus subtilis (TKJ5211)  showed a
    higher sensitivity for his± reversion than the parental strain
    (HA101) when treated with UV and UV-mimetic chemicals. However, a
    negative result was obtained at a level of beta-HCH (dissolved in
    DMSO) of 5 mg/ml (Tanooka, 1977).

         In a repair test using stationary phase cultures of HLL3g and
    HJ-15 strains, in which the size of growth inhibition zones of
    repair-proficient and repair-deficient cells (for vegetative cells and
    spores) was determined, a level of 5 mg beta-HCH (in benzene) per ml
    was without effect (Tanooka, 1977).

         A thorough evaluation of the mutagenic potency of beta-HCH
    requires additional tests.

    7.7  Carcinogenicity

    Appraisal

          In one study on mice, a beta-HCH dose exceeding the MTD produced
     an increased incidence of benign and malignant liver tumours. All
     other reported studies on mice were inadequate for the evaluation of
     beta-HCH carcinogenicity due to the very short duration of treatment
     and/or observation.

          Two studies on rats were inadequate for evaluation due to the
     small number of animals in one and the short duration of treatment in
     the other.

          The results of the studies on initiation-promotion and mode of
     action and the mutagenicity studies suggest that the neo-plastic
     response observed with beta-HCH is most likely due to a non-genotoxic
     mechanism.

    7.7.1  Mouse

         In a study by Goto et al. (1972a), 20 male ICR/JCL mice (5-week
    old) were fed 0 or 600 mg beta-HCH/kg diet for 26 weeks.  Increased
    liver weights were reported and hepatomas described as benign liver
    tumours were induced. However, insufficient details were reported.

         Nagasaki (1973) administered beta-HCH orally to male DD mice at
    concentrations of 100, 250, or 500 mg/kg for 24 weeks. There were no
    signs of tumour development at any treatment level.

         Groups of 10-11 DD mice of both sexes (6-weeks old) received
    diets containing 0, 100, 300, or 600 mg beta-HCH per kg for 32 weeks,
    followed by a control diet for 5-6 weeks.  The control group consisted
    of 20 animals.  During the experiment a number of animals died. In the
    treated mice, atypical proliferation was found in the liver in the two
    highest dose levels, but no hepatomas were observed. Alpha-fetoprotein
    was not detected in the serum of animals with hepatomas (Hanada et
    al., 1973).

         Thorpe & Walker (1973) performed a 110-week study, using a
    dietary concentration of 200 mg beta-HCH (> 99%) per kg, on CF1 mice
    (groups of 30 males and 30 females).  During the first 3 months of the
    study 12% of the males and 25% of the females died. Liver enlargement
    was detected by week 50 in both females and males.  Hyperplastic
    changes were found in the liver (hyperplastic nodules and
    hepatocellular carcinomas), sometimes with lung metastases.  The
    combined incidence of benign and malignant liver tumours for males and
    females was 24 and 23%, respectively, in the control group and 73 and
    43%, respectively, in the treated group.

         When male DD mice (8 weeks old), in groups of 20 or 29 animals,
    were fed a diet containing 0, 100, 250, or 500 mg beta-HCH per kg for
    24 weeks, there was a moderate increase in liver weight at the two
    highest levels.  No nodules classified as nodular hyperplasia or
    hepatocellular carcinoma were detected (Ito et al., 1973b).

    7.7.2  Rat

         In a study by Fitzhugh et al. (1950), groups of 10 male and 10
    female weanling Wistar rats were fed throughout their lives on a diet
    containing beta-HCH > 98% pure (10, 100, or 800 mg/kg diet). No
    increase in tumour incidence was reported in the treated animals, but
    only a limited number of organs were examined microscopically.

         Male W rats (5-8 weeks old, 18-24 animals per group) were
    administered diets containing beta-HCH at a concentration of 500 mg/kg
    (for 24 or 48 weeks) or 1000 mg/kg (for 24 weeks). Only slight cell
    hypertrophy was found, but no nodular hyperplasia, bile duct
    proliferation or hepatocellular carcinomas were detected (Ito et al.,
    1975).

    7.7.3  Initiation-promotion

         The influence of beta-HCH on tumour induction by PCBs (and vice
    versa) was tested with male DD mice (26-30 animals per group). 
    Whereas 500 mg PCBs/kg diet induced nodular hyperplasia and
    hepatocellular carcinomas in the liver of male mice after 32 weeks,
    exposure to beta-HCH at levels of 50, 100, or 250 mg/kg diet or to
    PCBs at a level of 250 mg/kg diet did not. However, the combination of
    100 mg beta-HCH/kg and 250 mg PCB/kg caused the induction of nodular
    hyperplasia in 17% (5/30) of the mice and hepatocellular carcinoma in
    3.3% (1/30). The corresponding values for the combination of 250 mg
    beta-HCH/kg and 250 mg PCB/kg were 55% (16/29) and 21% (6/29),
    respectively. These results showed that PCBs promoted the
    hepatocarcinogenic action of beta-HCH (Ito et al., 1973a).

         The tumour-initiating activity of beta-HCH has been studied by
    examining for phenotypically altered foci in female Wistar rats. 
    Groups of three to eight rats were used and, after the median and
    right liver lobes had been removed, the rats were administered 100 mg
    beta-HCH/kg body weight followed by phenobarbital at 50 mg/kg body
    weight per day for 15 weeks. Liver foci were identified by means of
    the gamma-glutamyltransferase (GGT) reaction and by morphological
    alterations. No evidence of initiating activity was found. In another
    part of the study, the promoting activity was investigated. A single
    dose of  N-nitrosomorpholine (250 mg/kg body weight by gavage) was
    followed by the administration of beta-HCH (0.03, 0.2, 1.0, 3.0, or
    10.0 mg/kg body weight per day) for 4, 15, and 20 weeks. The criteria
    used were growth and phenotypic changes of foci as end-points.  It was
    concluded from the study that beta-HCH is a tumour promotor.  Both the
    number and size of altered foci were enhanced by a beta-HCH dose of

    3 mg/kg. The tumour-promoting action was generally associated with
    liver growth and induction of monooxygenases or other specific enzymes
    (Schröter et al., 1987).

    7.7.4  Mode of action

         Sagelsdorff et al. (1983) studied the relevance to the
    carcinogenic action of HCH isomers of covalent binding to mouse liver
    DNA. NMRI mice were given 7.3-7.7 mg beta-HCH per kg body weight
    orally and 14C-thymidine intraperitoneally.  A very low covalent
    binding index (CBI) of < 0.08 was found.

    7.8  Special studies

    7.8.1  Effects on endocrine organs

         Juvenile female Swiss mice and SPF-derived Wistar rats (RIV:Tox)
    were used to study the uterotropic effect of beta-HCH, in comparison
    with that of 17-alpha-ethynyl-estradiol, using the method of Tiecco
    (1961). Beta-HCH levels of up to 500 mg/kg diet were fed for 5 days,
    and in both animal species there were clear uterotropic effects at
    50 mg/kg or more. In quantitative terms, the estrogenic potency of
    beta-HCH was, however, minimal in comparison to that of
    17-alpha-ethynylestradiol (Loeber & van Velsen, 1985).

         Other parameters of estrogenic potency have also been studied.
    Beta-HCH has been shown to increase the uterine concentration of
    progesterone receptors and the immunoreactivity of the adenohypophysis
    for prolactin in rats, and to cause the redistribution of human tumour
    cell receptors for progesterone.  Adrenalectomy and ovariectomy did
    not counteract the uterotropic effect of beta-HCH in rats.  However,
    the principal metabolite of beta-HCH, 2,4,6-tri-chlorophenol, had no
    estrogenic effect, and beta-HCH did not displace 17-beta-estradiol
    from its receptors (van Velsen, 1986). Both the significance of these
    observations and the possible mechanisms of action are unclear.

    7.8.2  Neurotoxicity

         Beta-HCH may raise the threshold for electrically induced
    seizures in rats.  The ratio of the beta-HCH concentration in the
    brain to that in blood indicates that this isomer passes the
    blood-brain barrier less readily than the other HCH isomers.

         Vohland et al. (1981) studied the neuropharmacological effects of
    beta-HCH in Wistar rats.  The kinetics of beta-HCH concentrations in
    the brain were established after the administration of a single oral
    dose of 200 mg/kg body weight. The approximate half-life for
    elimination from the brain was 20 days in females. Beta-HCH did not
    give rise to appreciable quantities of hydrophobic metabolites in the
    brain.  In rats 4-5 mg beta-HCH/kg in the brain had an anti-convulsive
    effect (i.e. there was protection against the action of pentylene

    tetrazole).  Neurotoxic effects (ataxia and adynamia) occurred at
    brain levels of 15-20 mg beta-HCH/kg (Vohland et al., 1981; Portig &
    Vohland, 1983).

         Beta-HCH has been demonstrated to cause a decrease in peripheral
    nerve conduction velocity in rats fed 600 mg beta-HCH/kg diet for 30
    days, but did not cause a change in the fronto-occipital
    electroencephalogram at 3000 mg/kg diet (Müller et al. 1981).  A
    decrease in absolute brain mass was reported in one study in which
    rats were fed beta-HCH for 30 days at a dietary concentration of
    600 mg/kg (Macholz et al. 1986).  Beta-HCH has been reported to raise
    the seizure threshold for pentylenetetrazol, a known convulsant
    (Vohland et al., 1981; Portig & Vohland, 1983).  It has been shown
    that beta-HCH blocks the binding of  tert-butylbicyclo-
    phosphorothionate (TBPS), a ligand known to bind to the GABA receptors
    in chloride channels in the brain, but was the least effective of the
    various HCH isomers in this respect (Fishman, 1987; Matsumoto et al.,
    1988).

    7.8.3  Effect on liver enzymes

         Several short-term studies on enzyme induction have been
    performed in rats, using levels ranging from 0.4 to 800 mg/kg feed.
    The highest dose level without effect in one study was 10 mg/kg body
    weight (van Hoof et al., 1982). However, in other studies, in which
    the same parameters were determined, the levels without effects
    included 50 mg/kg body weight.  Histopathological changes in the liver
    correlated with the induction of microsomal enzymes (den Tonkelaar et
    al., 1981; van Hoof et al., 1982; van Giersbergen et al., 1984).

         Weanling male rats fed diets of 800 mg beta-HCH/kg for 14-18 days
    showed significant increases in hepatic alanine aminotransferase (80%)
    and glucose-6-phosphate dehydrogenase (130%) and statistically
    significant decreases in hepatic aspartate aminotransferase (130%),
    alkaline phosphatase (45%), and acid phosphatase (40%) (Srinivasan &
    Radhakrishnamurty, 1977). Similarly, the dietary administration of
    800 mg/kg to albino rats for two weeks resulted in noticeable
    hepatocellular damage, as indicated by elevations in the activity of
    serum aminotransferases and decreases in that of hepatic soluble
    enzymes. An increase in glucose-6-phosphate dehydrogenase and aldolase
    activities was reported to suggest a higher rate of glucose oxidation,
    while a decrease in liver glucose-6-phosphatase activity was
    attributed to an inactivation of hepatic gluconeogenesis (Srinivasan &
    Radhakrishnamurty, 1988).

    7.8.4  Immunosuppression

         To investigate potential effects on the reproductive and immune
    systems, beta-HCH (0, 100, or 300 mg/kg diet) was fed to groups of six
    female B6C3F1 mice for 30 days.  Investigations were conducted on
    changes in ovarian and uterine histology, body weight, lymphoid organ

    weight and histology, splenic cellularity, antigen-specific IgM and
    IgG plaque-forming cells (PFC), proliferative responses to mitogens,
    natural killer cell activity, and induction of cytosolic T
    lymphocytes. Significant changes in several immune functions were
    only found at a beta-HCH concentration of 300 mg/kg. The proliferation
    of splenocytes to the mitogens lipopolysaccharide (LPS), phytohaemag-
    glutinin (PHA), and concanavalin A and T-lymphocyte-mediated cytolysis
    of tumour targets were decreased, and a concurrent reduction in natural
    killer activity was found. These data indicate that beta-HCH causes
    non-estrogenic immune function changes without significant changes in
    lymphoid organ weight, histology or cellularity (Cornacoff et al., 1988).

    8.  EFFECTS ON HUMANS

    8.1  Acute toxicity - poisoning incidents

         Several cases of acute poisoning by technical-grade HCH,
    resulting either from accident or occupational exposure have been
    described (WHO, 1991).  It is likely that gamma-HCH, the most acutely
    toxic component, played the major role in these incidents.  These
    cases cannot, therefore, assist in the evaluation of beta-HCH.

    8.2  General population

         No specific studies relating to beta-HCH are available.

         A study comparing liver cancer deaths in the USA and the
    "domestic disappearance" of organochlorine pesticides revealed that in
    1962, 18 and 15 years after the introduction of DDT and
    technical-grade HCH, respectively (when an increase in primary liver
    cancer due to the organochlorines would be manifest), the number of
    cases of primary liver cancer as a percentage of the total number of
    liver cancer deaths began a gradual and steady decline (from 61.3% in
    1962 to 56.9% in 1972). The death rate (per 100 000 per year) due to
    primary liver cancer declined from 3.46 to 3.18 during this period
    (Deichmann & MacDonald, 1977).

    8.3  Occupational exposure

         The evaluation of the effects of beta-HCH on occupationally
    exposed workers is seriously hampered by the fact that most of the
    relevant studies relate to workers who were exposed during the
    manufacture and handling of lindane, or the handling and spraying of
    technical-grade HCH among other pesticides, and were thus exposed to
    all HCH isomers plus impurities and other (process) chemicals. 
    Therefore, it is difficult, if not impossible, to relate the observed
    effects to individual substances. Consequently these studies have only
    been described in this monograph where they aid the evaluation.

         Behrbohm & Brandt (1959) described 26 cases of allergic and toxic
    dermatitis that arose during the manufacture of technical-grade HCH.
    Patch testing with pure alpha-, beta-, gamma-, and delta-HCH yielded
    negative results, but positive reactions were obtained with the
    residual fractions.

         The level of beta-HCH was determined in the serum of 57 workers
    at a lindane-manufacturing plant.  No beta-HCH was detected in
    controls, but the levels in exposed workers ranged from 17 to
    760 µg/litre and increased with the duration of exposure. The beta-HCH
    levels found in the adipose tissue of eight of these workers was
    18-103 mg/kg (in extractable lipids). There were no clinical signs or
    symptoms and no significant changes were found in extensive
    biochemical, haematological, and neurophysiological tests, or in the

    EMG or EEG.  Serum leutinizing hormone levels were higher than in the
    controls, but FSH and testosterone levels showed only insignificant
    and inconclusive changes (Baumann et al., 1980, 1981; Brassow et al.,
    1981; Tomczak et al., 1981).

         The serum beta-HCH level of malaria-control workers who sprayed
    technical-grade HCH for 16 weeks increased from 58 to 250 µg/litre in
    previously non-exposed workers and from 294 to 385 µg/litre in those
    that had been exposed during three previous spraying seasons (Gupta et
    al., 1982).  Although beta-HCH is only a minor component of
    technical-grade HCH (7-10%), it reached higher levels and persisted
    longer in the serum than either alpha- or gamma-HCH.

         Nigam et al. (1986) studied 64 employees from a HCH-manufacturing
    plant who were directly or indirectly associated with the production
    of this insecticide. The exposed group was composed of 19 "handlers"
    (who handled and packed the insecticide), 26 "non-handlers" (plant
    operators and supervisors exposed indirectly to HCH), and 19
    maintenance staff (who visited the plant frequently). The control
    group consisted of 14 workers who had no occupational contact with the
    insecticide.  The exposure period varied up to 30 years. The mean
    serum beta-HCH concentrations in the four groups were 28.5 µg/litre
    (controls), 97.2 µg/litre (maintenance staff), 206.7 µg per litre
    (non-handlers), and 413.1 µg/litre (handlers).  Alpha-, gamma-, and
    delta-HCH were also present.  The total HCH concentrations were 51.4,
    143.6, 265.6, and 604 µg/litre, respectively. Clinical examination
    revealed that the majority of the workers from the "handler" and
    "non-handler" groups exhibited paraesthesia of the face and
    extremities, headache, and giddiness, and some of them also showed
    symptoms of malaise, vomiting, tremors, apprehension, confusion, loss
    of sleep, impaired memory, and loss of libido.  The same symptoms were
    found among the maintenance staff but were less severe and less
    frequent.

         Chattopadhyay et al. (1988) studied 45 male workers exposed to
    HCH during its manufacture and compared them with 22 matched controls. 
    Exposure was mainly via the skin.  Paraesthesia of face and
    extremities, headache, giddiness, vomiting, apprehension, and loss of
    sleep, as well as some changes in liver function tests, were reported
    and were found to be related more to the intensity of exposure (as
    measured by the HCH levels in blood serum)  than to the duration of
    exposure.  The measured exposures to total HCH were 13 to 20 times
    higher than those in the control groups (no detailed figures were
    reported). Of the total HCH, 60-80% was beta-HCH.

         Fitzhugh et al. (1950) drew attention to the importance of
    beta-HCH for the long-term toxicity of HCH.  The slower metabolism of
    the beta isomer and its consequent longer persistence in the body are
    significant factors.

         A significant correlation between the beta-HCH levels in human
    blood and adipose tissue has been described by Radomski et al. (1971a)
    and Baumann et al. (1980).

         In a group of workers that were no longer exposed to HCH for at
    least 5 years, mean beta-HCH levels of 50 µg/litre were found, i.e.
    twice as much as in the general population of that area at that time
    (Radomski et al., 1971b).

         Similar findings were reported by Morgan & Lin (1978), who found
    20-348 µg/litre in the serum of 38 healthy workers whose last
    occupational exposure to HCH was 10-15 years previously. Liver
    function was normal and there were no indications of bone-marrow
    damage.

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    9.1  Algae

         Palmer & Maloney (1955) used beta-HCH in a preliminary screening
    test with two cyanobacterium (blue alga), two green alga, and two
    diatom species. The test concentration was 2 mg/litre water and the
    incubation period was 3-21 days.  Beta-HCH was not toxic at this
    concentration.

         Zhou et al. (1986) studied the effects of alpha-, beta-, gamma-,
    and delta-HCH on the photosynthetic evolution of oxygen by the green
    algae  Chlorella vulgaris and  Scenedesmus obliquus, and reported
    that the beta- and gamma-isomers showed low toxicity, compared to the
    alpha- and delta-isomers, in this respect.

         In a study by Krishnakumari (1977), cultures of the green alga
     Scenedesmus acutus (1, 3, or 5 days of age) were tested for
    sensitivity to beta-HCH at 28°C, growth rate being used as parameter.
    The nominal concentrations of beta-HCH (dissolved in ethanol) were
    0.5-100 mg/litre. A decrease in growth rate was observed in the 1, 3,
    and 5 day cultures exposed to 100, 10, and 5 mg/litre, respectively.

    9.2  Protozoa

         In short-term tests on  Tetrahymena, the EC50 (growth) was
    1.2 mg/litre (Mathur et al., 1984).

    9.3  Invertebrates

         In short-term tests on daphnids no effects were found at
    concentrations up to the limit of solubility of beta-HCH in water
    (about 1 mg/litre) (Janssen et al., 1987).

         Canton et al. (1982) investigated long-term toxicity using
     Daphnia and obtained a no-observed-effect level (NOEL) for
    reproduction of 0.32 mg beta-HCH/litre.

    9.4  Fish

    9.4.1  Acute toxicity

         In 4-day tests, beta-HCH affected the behaviour of fish. The NOEL
    and EC50 values for  Oryzias (as well as for  Poecilia) were 0.026
    and 0.047 mg/litre, respectively (Wester et al., 1985; Wester &
    Canton, 1986).

         In a study by Boulekbache (1980), the 48-h LC50 of beta-HCH
    (98.9%) for the guppy  (Poecilia reticulata) was 0.9 mg/litre. Female
    fish were less sensitive than males.

    9.4.2  Longer-term toxicity

         Two tests were carried out with beta-HCH (98.9%) in Japanese
    ricefish (medaka,  Oryzias latipes) using fertilized eggs (40
    eggs/group) or 25 young fish (1 month after hatching). The exposure
    levels ranged from 0.032-1.0 mg beta-HCH/litre water and
    histopathological examinations were performed after 1 and 3 months. In
    the experiment on eggs, decreased growth was noted at 0.56 mg/litre;
    with young fish this occurred at 0.1 mg/litre.  The NOELs for abnormal
    behaviour (loss of buoyancy and balance, uncoordinated movements) were
    0.056 mg/litre and 0.032 mg/litre, respectively, for the two
    experiments.  Histopathological lesions indicating an estrogenic
    activity were detected.  Furthermore, lesions were observed in the
    liver (vacuolation), kidneys (glomerular hyalinosis), and thyroid
    (hypertrophy) (Wester & Canton, 1986).

         In a study by Wester et al. (1985), groups of 35 young guppies
     (Poecilia reticulata) (3-4 weeks old) were exposed to various
    concentrations of beta-HCH (98.9%) ranging from 0.0032 to
    1.0 mg/litre.  After 1 and 3 months of exposure, toxicological and
    histopathological parameters were studied.  The gross NOEL was
    0.032 mg/litre after both 1 and 3 months. Changes in the liver
    (hypertrophy of rough endoplasmic reticulum) and kidneys (accumulation
    of hyaline droplets in epithelium) were detected. Hypertrophy of the
    endocardial lining cells (attributed to the accumulation of hyaline
    droplets within lysosomes) was also reported.

         After 3 months dysvitellogenesis was noted in the females. In
    males the pituitary gland cells producing gonadotrophic hormone
    appeared to be stimulated and testicular development was retarded at
    0.32 mg/litre or more.  It was suggested that all the observed effects
    were attributable to an excessive production of the yolk precursor
    vitellogenin by the liver as a result of an estrogen-like activity of
    beta-HCH or its metabolites.

    9.5  Terrestrial organisms

    9.5.1  Birds

         No toxic effects (e.g., effects on body weight, food consumption,
    growth, egg production, egg weight, shell quality, mortality) were
    observed in chickens fed diets containing 1-625 mg beta-HCH/kg for 12
    weeks (Kan et al., 1979).

    9.6  Model ecosystem studies

         Sugiura et al. (1976) studied the effects of 0.01, 0.1, 1, 3, and
    5 mg beta-HCH/litre on an aquatic microcosm consisting of bacteria,
    ciliata, rotifera, oligochaeta, green algae, and blue-green algae. 
    The specific growth rates of protozoans and a rotifer were increased
    by 0.01 and 0.1 mg/litre.  No effects were found on the total
    community respiration, although the gross primary production
    increased.

    CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH
    AND THE ENVIRONMENT (ALPHA- AND BETA-HEXACHLOROCYCLOHEXANES)

    1.  Conclusions

         The potential adverse effects of alpha- and beta-
    hexachlorocyclohexanes (HCHs) on humans and the environment cannot be
    balanced against benefits, since these isomers have no insecticidal
    action. Their presence in the environment is thus of serious concern.
    Consequently, the use of technical-grade HCH products containing high
    concentrations of alpha- and beta-HCH is never justified.

    1.1  General population

         Alpha- and beta-HCH are circulating in the environment and
    present in food chains. Thus there is a continuous potential for human
    exposure. This exposure is low and is expected to decrease slowly in
    the coming years. Therefore, there is no serious health concern for
    the general population.

    1.2  Sub-populations at special risk

         Alpha-HCH concentrations in breast milk are low.

         The exposure of babies resulting from present beta-HCH
    concentrations in breast milk is a matter of concern but is no reason
    for not promoting the use of breast-feeding.

         However, every possible effort should be made to decrease dietary
    and all other exposure to these isomers. Decreased dietary exposure is
    expected to result in decreased levels of alpha- and beta-HCH in
    breast milk.

    1.3  Occupational exposure

         As long as recommended precautions to minimize the exposure of
    workers involved in lindane manufacturing are observed, alpha- and
    beta-HCH pose no health risk to process operators.

    1.4  Environmental effects

         Apart from spills into the aquatic environment, there is no
    evidence to suggest that the presence of alpha- and beta-HCH in the
    environment poses a significant hazard to populations of organisms.

    2.  Recommendations for protection of human health and
        the environment

    a)   In order to minimize environmental pollution with alpha- and
    beta-HCH, lindane (> 99% gamma-HCH) must be used instead of
    technical-grade HCH.

    b)   In order to avoid environmental pollution with alpha- and
    beta-HCH, by-products and effluents from the manufacturing of lindane
    must be disposed of in an appropriate way, and contamination of
    natural waters and soil must be avoided.

    c)   Monitoring of alpha- and beta-HCH in food should continue.  It is
    essential that a mechanism for setting internationally acceptable
    levels of alpha- and beta-HCH in food be initiated.

    d)   Monitoring of the daily intake of the general population and the
    levels of alpha- and beta-HCH in breast milk should continue.

    FURTHER RESEARCH (ALPHA- AND BETA-HEXACHLOROCYCLOHEXANES)

         The following experimental studies are needed to allow a better
    evaluation of the hazards of alpha- and beta-HCH:

    *    mutagenicity studies, especially with chromosome mutagenic
         end-points;

    *    reproduction and fetotoxicity/teratogenicity studies;

    *    pharmacokinetic and toxicokinetic studies;

    *    carcinogenicity studies;

    *    neurotoxicity studies;

    *    surveillance studies on populations at risk.

    PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         The International Agency for Research on Cancer (IARC, 1987)
    evaluated the hexachlorocyclohexanes and concluded that for the
    technical grade and the alpha isomer there is sufficient evidence for
    carcinogenicity to animals, whereas this evidence is limited for the
    beta and gamma isomers. There is inadequate evidence for their
    carcinogenicity to human beings.  The hexachlorocyclohexanes were
    classified in group 2B.

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    APPENDIX 1. CHEMICAL STRUCTURE

         The basic structure of HCH is a closed chain of six carbon atoms. 
    The structure can have two spatial forms, i.e. cis and trans
    configurations. Every carbon atom is bound to a hydrogen and a
    chlorine atom.  One of these substituents forms a plane with the two
    connecting carbon atoms.  Since this plane parallels the "equator" of
    the molecule, this atom is said to be in the equatorial position.  The
    binding with the other atom parallels the "axis" of the molecule. 
    Therefore, this one is in the axial position.  Due to the size of the
    chlorine atom the carbon atoms are not free to rotate.  Hence the
    positions of the chlorine and hydrogen atoms are fixed, one being
    always in the equatorial position and the other in the axial position.

         The various combinations of the spatial orientation of the
    hydrogen and chlorine atoms on each of the carbon atoms of cyclohexane
    results in different isomeric compounds. Theoretically, 17 isomers of
    HCH are possible,  but, due to spatial incompatibilities and
    thermodynamic instability, only nine isomers have in fact been
    detected.  They all have the trans configuration.

         In the beta-isomer, all chlorine atoms are in the equatorial
    position.

         The positions of the chlorine atoms in the major isomers of HCH
    are presented in Table 9 (Demozay & Marechal, 1972; Van Velsen, 1986).


    
    Table 9.  Positions of chlorine atoms in the major HCH isomers
                                                                                 

    Isomer       Chlorine positionsb   Physical structure
                                                                                 

    Alphaa       A A E E E E           monoclinic prisms
    Beta         E E E E E E           octahedral cubic crystals
    Gamma        A A A E E E           monoclinic crystals
    Delta        A E E E E E           crystals/fine platelets
    Epsilon      A E E A E E           monoclinic needles or hexagonal mono-
                                        clinic crystals
                                                                                 

    a  racemate of two optical isomers
    b  A = axial position; E = equatorial position      From: van Velsen (1986).
    
    RESUME ET EVALUATION

    1.  Alpha-hexachlorocyclohexane

    1.1  Propriétés générales

         L'Alpha-hexachlorocyclohexane (alpha-HCH) est un important
    sous-produit (60-70%) de la fabrication du lindane (> 99% de
    gamma-HCH).  Il est peu soluble dans l'eau mais très soluble dans les
    solvants organiques comme l'acétone, le chloroforme et le xylène. 
    C'est un solide de faible tension de vapeur.  Son coefficient de
    partage entre le  n-octanol et l'eau (log Pow) est de 3,82.  C'est
    un polluant de l'environnement.

         L'alpha-HCH peut être dosé séparément des autres isomères par
    chromatographie en phase gazeuse avec détection par capture
    d'électrons ou par d'autres méthodes après extraction par partage
    liquide/liquide et purification sur colonne chromatographique.

    1.2  Transport, distribution et transformation dans l'environnement

         Il se produit dans l'environnement une biodégradation ainsi
    qu'une dégradation abiotique (déchloration) sous l'action du
    rayonnement ultraviolet, qui aboutissent respectivement, au
    delta-3,4,5,6-tétrachlohéxène et au pentachlorocyclohéxène Ce
    processus de décomposition est plus lent que dans le cas du lindane. 
    La persistance de l'alpha-HCH dans le sol dépend de facteurs
    environnementaux comme l'action des microorganismes, la teneur en
    matières organiques, la co-distillation et l'évaporation. Il n'y a pas
    d'isomérisation du lindane en alpha-HCH.

         La bioconcentration est rapide chez les microorganismes (facteur
    de bioconcentration allant de 1500 à 2700, calculé en poids à sec ou
    environ 12 000 calculé par rapport aux lipides en l'espace de 30
    minutes): chez les invertébrés, il est de 60 à 2750 (poids à sec) ou
    > 8000 (par rapport aux lipides) sur une durée de 24 à 72 heures. 
    Dans le cas des poissons ces chiffres vont de 313 à 1216 sur 4 à 28
    jours, les valeurs pouvant atteindre 50 000 pour les poissons de
    l'Elbe. Toutefois la biotransformation et l'élimination sont également
    assez rapide chez ces organismes (15 minutes à 72 heures).

    1.3  Concentrations dans l'environnement et exposition humaine

         L'alpha-HCH est présent dans l'air des océans à la concentration
    de 0,02 à 1,5 mg/m3.  Au Canada, on en a trouvé dans l'eau de pluie
    à des teneurs de 1 à 40 ng par litre, mais la neige n'en contenait que
    des traces.

         Au cours de la période 1969-1974, on a constaté dans le Rhin et
    ses affluents des concentrations d'alpha-HCH comprises entre 0,01 et
    2,7 µg/litre; toutefois, plus récemment, ces concentrations sont
    descendues en-dessous de 0,01 µg/litre.  Dans l'Elbe, les
    concentrations sont passées de 0,023 µg/litre en moyenne en 1981, à
    moins de 0,012 µg/litre en 1988.  Dans un certain nombre de cours d'eau
    du Royaume-Uni on a trouvé en 1966 des concentrations allant de 0,001 à
    0,43 µg/litre. En Frise, dans le nord de la Mer des Wadden on a trouvé
    dans les sédiments des concentrations d'alpha-HCH allant de 0,3 à
    1,4 µg/kg (0,002 µg/litre d'eau).

         Les teneurs en alpha-HCH de différentes espèces végétales en
    provenance de divers pays vont de 0,5 à 2140 µg/kg de poids sec mais
    elles peuvent être encore beaucoup plus élevées dans les régions
    polluées. Même dans l'Antarctique, on a rencontré des concentrations
    allant de 0,2 à 1,15 µg/kg.  On trouve régulièrement du alpha-HCH
    dans les poissons et les invertébrés aquatiques ainsi que chez des
    canards, des hérons et des effraies.  On a trouvé dans la graisse
    sous-cutanée de rennes et d'orignaux vivant dans des régions où
    l'épandage de pesticides est négligeable, des quantités d'alpha-HCH
    égales en moyenne à 7-80 µg/kg.  Dans les tissus adipeux d'ours
    polaires canadiens on a trouvé des teneurs d'alpha-HCH allant de
    0,3 à 0,87 mg/kg (calculées par rapport au tissu adipeux).

         Dans un certain nombre de pays on a procédé à l'analyse de
    denrées alimentaires importantes à la recherche d'alpha-HCH. Les
    teneurs mesurées, présentes essentiellement dans des produits
    contenant des graisses, allaient jusqu'à 0,05 mg/kg de produit,
    sauf dans le lait et les produits laitiers (jusqu'à 0,22 mg/kg)
    et dans le poisson et les produits carnés industriels (jusqu'à
    0,5 mg/kg par rapport aux graisses).  On a constaté un léger recul
    des teneurs au cours des années.

         C'est principalement par les aliments que la population dans
    son ensemble est exposée à l'alpha-HCH.  Des études de ration totale
    effectuées aux Pays-Bas et au Royaume-Uni ont révélé des
    concentrations moyennes respectivement égales à 0,01 et
    0,002-0,003 mg/kg.  Les données concernant le Royaume-Uni montrent
    qu'il existe une tendance à la baisse depuis 1967.  Aux Etats-Unis
    d'Amérique, l'apport alimentaire moyen d'alpha-HCH a été de 0,09 à
    0,025 mg/kg de poids corporel par jour, au cours de la période
    1977-1979 et de 0,003 à 0,016 µg/kg de poids corporel au cours de
    la période 1982-1984.

         Dans quelques pays, on a mesuré la concentration d'alpha-HCH
    dans le sang, le sérum et le plasma humain.  La concentration moyenne
    (dans certains cas, la médiane) était inférieure à 0,1 µg/litre
    (intervalle de variation: de non décelable à 0,6 µg/litre). Dans un


    des pays cependant on a relevé une concentration moyenne de
    3,5 µg/litre (intervalle de variation 0,1 à 15,0) dans le tiers
    environ des échantillons de sang.

         Dans le tissu adipeux humain et le lait maternel, les
    concentrations d'alpha-HCH qui ont été relevées sont faibles
    (respectivement moins de 0,01-0,1 et moins de 0,001-0,04 mg/kg
    calculées par rapport aux graisses).  Des études de ration totale
    ont montré que l'apport alimentaire quotidien était de l'ordre de
    0,01 µg/kg de poids corporel ou moins.  Ces concentrations ont
    tendance à diminuer avec le temps.

         L'alpha-HCH se présente comme un contaminant universel de
    l'environnement.  Les teneurs ne diminuent que lentement malgré les
    mesures prises en vue d'en éviter la propagation dans le milieu.

    1.4  Cinétique et métabolisme

         Chez le rat, l'alpha-HCH est rapidement et presque complètement
    résorbé au niveau des voies digestives. Après injection intra-
    péritonéale, environ 40 à 80% de l'alpha-HCH administré a été
    excrété dans les urines et 50 à 20% dans Les matières fécales.  Chez
    le rat également, les concentrations les plus élevées se rencontrent
    dans le foie, les reins, les tissus adipeux, l'encéphale et les
    muscles, avec une accumulation importante dans la fraction Lipidique.
    On a constaté que chez des rats à la mamelle, la concentration
    hépatique d'alpha-HCH était deux fois plus élevée que chez les mères.
    Chez le rat également, le rapport de la concentration dans l'encéphale
    à la concentration sanguine et de la concentration dans la masse
    grasse à la concentration sanguine était respectivement de 120:1 et
    397:1.

         Chez le rat, la biotransformation de l'alpha-HCH comporte une
    déchloration. Le principal métabolite urinaire est le 2,4,6-
    trichlorophénol; on a également identifié d'autres métabolites tels
    que le 1,2,4, le 2,3,4 et le 2,4,5-trichlorophénol ainsi que le 2,3,4,5-
    et le 2,3,4,6-tétrachlorophénol.  On a trouvé dans les reins de rats du
    1,3,4,5,6-pentachlorocyhex-1-ène, substance dont la présence a été
    également observée dans le foie de poulets lors d'études  in vitro.
    Dans le foie, il y a conjugaison avec le glutathion.

         Le demi-vie de libération à partir de la masse grasse est de 6,9
    jours chez la ratte et de 1,6 jour chez le rat.

    1.5  Effets sur les êtres vivants dans leur milieu naturel

         L'alpha-HCH est faiblement toxique pour les algues,  la dose sans
    effet observable se situant en général à 2 mg/litre.

         Une étude de longue durée sur  Daphnia magna a montré que la
    dose sans effet observable était de 0,05 mg/litre pour cette espèce.
    L'alpha-HCH est modérément toxique pour les invertébrés et les
    poissons.  Pour ces organismes, les valeurs de la CL(E)50 sont de
    l'ordre de 1 mg/litre. Lors d'études de courte durée effectuées sur
    des guppies et sur  Oryzia latipes, on a constaté qu'une dose de
    0,8 mg/litre était sans effet.

         Lors d'études de trois mois sur  Salmo gairdneri soumis à des
    doses allant de 10 à 1250 mg/kg de nourriture, on n'a observé aucun
    effet sur la mortalité, le comportement, la croissance ou l'activité
    enzymatique du foie et du cerveau.

         Des études de courte et de longue durée sur un mollus-que
     (Lymnea stagnalis) ont montré que la CE50 était dans ce cas de
    1200 µg/litre (déterminée d'après la mortalité et l'immobilisation des
    mollusques).  A la concentration de 250 µg/litre il y a eu inhibition
    de la ponte.  Une réduction de 50% a été notée dans le taux global de
    reproduction à la concentration de 65 µg/litre.

         On ne dispose d'aucune donnée concernant les effets sur les
    populations et les écosystèmes.

    1.6  Effets sur les animaux d'expérience et les systèmes
         d'épreuve  in vitro

         La DL50 se situe entre 1000 et 4000 mg/kg pour la souris et
    entre 500 et 4670 mg/kg de poids corporel pour le rat.  Les signes
    d'intoxication sont essentiellement ceux d'une stimulation du système
    nerveux central.

         Lors d'une étude de 90 jours sur des rats, on a constaté une
    baisse de la croissance à la concentration de 250 mg/kg de nourriture.
    A partir de 50 mg/kg, des modifications au niveau histologique et
    enzymatique témoignaient d'une induction des enzymes. A ces doses on a
    également noté des signes d'immunodépression. Il y avait déjà
    accroissement du poids du foie à partir de 10 mg/kg de nourriture
    (soit l'équivalent de 0,5 mg/kg de poids corporel). La dose sans effet
    nocif observé se situait à 2 mg/kg de nourriture (soit l'équivalent de
    0,1 mg/kg de poids corporel par jour).

         Il n'y a pas eu d'études convenables de toxicité à long terme ni
    d'études sur la reproduction et le pouvoir tératogène.

         Des études effectuées sur diverses souches de  Salmonella
     typhimurium n'ont révélé aucun signe de mutagénicité, que ce soit en
    présence ou en l'absence d'une activation métabolique.  Les tests sur

     Saccharomyces cerevisiae ont également été négatifs, toutefois la
    recherche d'une synthèse non programmée de l'ADN sur des hépatocytes
    de rat  in vitro a donné un résultat équivoque.

         On a effectué des travaux en vue de déterminer le pouvoir
    cancérogène de l'alpha-HCH sur des rats et des souris à des doses
    allant de 100 à 600 mg/kg de nourriture. Chez des souris, on a observé
    des nodules hyperplastiques et/ou des adénomes hépatocellulaires. Dans
    une des études, les doses dépassaient la dose maximale tolérable. Lors
    de trois autres études, deux sur des souris et une sur des rats, on
    n'a observé aucune augmentation dans l'incidence des tumeurs à des
    doses allant jusqu'à 160 mg/kg de nourriture (souris) et 640 mg/kg de
    nourriture (rats).

         Les résultats des études sur le pouvoir d'initiation et de
    promotion ainsi que sur le mode d'action de l'alpha-HCH, de même que
    les tests de mutagénicité, montrent que les tumeurs induites par
    l'alpha-HCH chez la souris ne sont pas d'origine génétique.

         On a montré que l'alpha-HCH provoquait une nette augmentation de
    l'activité des enzymes hépatiques, même à des doses de 5 mg/kg de
    nourriture (soit l'équivalent de 0,25 mg/kg de poids corporel).  A la
    dose de 2 mg/kg de poids corporel, l'alpha-HCH n'a eu aucun effet sur
    la déméthylation de l'aminopyrine ni sur la teneur du foie en ADN.

    1.7  Effets sur l'homme

         L'examen de travailleurs d'une usine produisant du lindane, qui
    avaient été exposés pendant 7,2 années (en moyenne géométrique, avec
    des limites de 1 à 30 ans), a permis de conclure qu'une exposition
    professionnelle au HCH ne produit pas de signes de troubles
    neurologiques ni de perturbation de la fonction neuromusculaire.

    RESUME ET EVALUATION

    2.  Béta-hexachlorocyclohexane

    2.1  Propriétés générales

         Le béta-hexachlorocyclohexane (béta-HCH) est un sous-produit
    (7-10%) de la fabrication du lindane (> de 99% de gamma-HCH). Peu
    soluble dans l'eau, il est très soluble dans les solvants organiques
    tels que l'acétone, le cyclohexane et xylène.  C'est un solide de
    faible tension de vapeur. Son coefficient de partage entre le
     n-octanol et l'eau (log Pow) est égal à 3,80.  C'est un polluant
    de l'environnement.

         On peut doser le béta-HCH séparément des autres isomères par
    chromatographie en phase gazeuse avec détection par capture
    d'électrons ainsi que par d'autres méthodes après extraction par
    partage liquide/liquide et purification sur colonne chromatographique.

    2.2  Transport, distribution et transformation dans l'environnement

         La biodégradation et la dégradation abiotique (déchloration) sous
    l'effet du rayonnement ultraviolet, produisent du
    pentachlorocyclohexane, mais beaucoup plus lentement que dans le cas
    du lindane (gamma-HCH).

         Le béta-HCH est l'isomère le plus persistant de l'HCH.  Sa
    persistance dans le sol dépend de facteurs environnementaux tels que
    l'action des microorganismes, la teneur en matières organiques et en
    eau ainsi que la co-distillation et l'évaporation.

         En raison de sa persistance, le béta-HCH subit une
    bioconcentration rapide chez les invertébrés (le facteur de
    bioconcentration est d'environ 125 en l'espace de trois jours), chez
    les poissons (250-1500 calculé à partir du poids à sec ou environ
    500 000 fois calculé sur la base des lipides en l'espace de 3 à
    10 minutes), ainsi que chez les oiseaux et l'homme (environ 525).  Le
    béta-HCH se concentre davantage et s'élimine plus lentement que les
    autres isomères de l'HCH.

    2.3  Concentrations dans l'environnement et exposition humaine

         On rencontre le béta-HCH dans l'air des océans à des
    concentrations de 0,004 à 0,13 ng/m3.

         Jusqu'en 1974, le Rhin et ses affluents présentaient des teneurs
    en béta-HCH allant de 0,14 à 0,22 µg par litre, mais depuis on
    constate que ces valeurs sont systématiquement inférieures à
    0,12 µg/litre. Des échantillons prélevés dans la Meuse présentaient
    des teneurs inférieures à 0,12 µg/litre. Dans l'Elbe, les

    concentrations sont passées en moyenne de 0,009 à 0,004 µg/litre entre
    1981 et 1988.

         On a dosé le béta-HCH chez des oiseaux tels que les éperviers,
    les faucons crécerelles, les hiboux, les hérons et les grèbes pendant
    un certain nombre d'années et l'on a observé des concentrations allant
    de 0,1 à 0,3 mg/kg. Chez les ours polaires on a mesuré des
    concentrations allant jusqu'à 0,87 mg/kg (par rapport au tissu
    adipeux) dans le foie et les graisses.

         Dans quelques pays on a procédé à l'analyse de denrées
    alimentaires importantes en vue d'y rechercher la présence de
    béta-HCH. Les concentrations moyennes, mesurées essentiellement dans
    des denrées contenant des graisses, allaient jusqu'à 0.03 mg/kg (par
    rapport au contenu lipidique), mais on en a trouvé jusqu'à 4 mg/kg
    (par rapport au contenu lipidique) dans des produits laitiers.  Dans
    les denrées non grasses, les teneurs étaient inférieures à 0,05 mg/kg
    de produit. En général, ces teneurs sont en lent recul.

         C'est principalement par les aliments que la population dans son
    ensemble est exposée au béta-HCH.  Lors d'études de ration totale
    effectuées au Royaume-Uni, on a mesuré des concentrations de 0,003,
    0,0005 et moins de 0,0005 mg/kg respectivement en 1966/67, 1975/77 et
    1981.  Aux Etats-Unis d'Amérique, l'apport moyen quotidien d'origine
    alimentaire allait en 1982-84 de moins de 0,1 à 0,4 ng/kg de poids
    corporel dans les différents groupes d'âge.

         Dans un certain nombre de pays, on a procédé au dosage du
    béta-HCH dans le sang, le sérum ou le plasma au sein de la population
    générale.  Les concentrations varient d'un pays à l'autre, atteignant
    parfois 25 µg/litre.

         De nombreuses études ont été menées afin de rechercher la
    présence de béta-HCH dans les tissus adipeux humains.  Les
    concentrations relevées au Canada, en République fédérale d'Allemagne,
    au Kenya, aux Pays-Bas et au Royaume-Uni atteignaient jusqu'à
    4,4 mg/kg (par rapport au contenu lipidique).  On a constaté une
    augmentation progressive avec l'âge jusqu'à environ 50 ans, après quoi
    les teneurs déclinaient.  Dans les tissus adipeux, les concentrations
    de béta-HCH sont plus élevées que celles des autres isomères,
    phénomène qui traduit la tendance à l'accumulation de cette substance.
    Il n'y a pas de tendance claire à la baisse des concentrations de
    béta-HCH sur la période au cours de laquelle ces études ont été
    effectuées.  On a constaté l'existence d'une relation entre les
    concentrations de béta-HCH dans les tissus adipeux et le lait maternel
    d'une part, et la consommation de produits carnés, de graisses
    animales et de poissons gras, d'autre part.

         Dans quelques pays (Canada, République fédérale d'Allemagne,
    Pays-Bas et Royaume-Uni) on a procédé au dosage du béta-HCH dans le
    lait maternel et obtenu des concentrations allant de 0,1 à 0,69 mg/kg
    (par rapport au contenu lipidique).  Il ressort de ces analyses que la

    concentration du béta-HCH est plus élevée dans le lait des femmes des
    zones rurales que dans celui des femmes des zones urbaines.

         Le béta-HCH apparaît comme un contaminant universel de
    l'environnement. Les concentrations n'accusent qu'une très lente
    tendance à la baisse malgré les mesures prises en vue d'en empêcher la
    propagation dans l'environnement.

    2.4  Cinétique et métabolisme

         Le béta-HCH est absorbé jusqu'à 95% dans les voies digestives de
    la souris, et s'accumule ensuite en majeure partie dans les tissus
    adipeux.  L'élimination s'effectue selon un mécanisme en deux étapes,
    la demi-vie étant de 2,5 jours pour la première et de 18 jours pour la
    seconde.

         Une fois résorbé, le béta-HCH se répartit rapidement dans les
    divers organes et tissus: foie, encéphale, reins et tissus adipeux. 
    Chez le rat, la concentration maximale dans le foie est atteinte en
    quatre jours. Pour une concentration sanguine moyenne de 92 µg/litre
    (mais également pour des concentrations de 540 et 2100 µg/litre), le
    rapport des concentrations dans le cerveau et le sang d'une part et
    dans le tissu adipeux et le sang d'autre part était respectivement de
    2:1 et de 170:1.  Après une intoxication mortelle chez l'homme par des
    isomères de l'HCH, on a constaté que la concentration en béta-HCH
    mesurée par rapport à la teneur du sang était de 363 dans les tissus
    adipeux, de 3 dans le cerveau et de 15 dans le foie.  Le béta-HCH
    franchit la barrière hémo-méningée beaucoup moins facilement que les
    autres isomères de la l'HCH.

         Chez des souris gravides, le passage transplacentaire du béta-HCH
    au foetus était d'environ 2% de la dose, mais atteignait 40% chez des
    rattes gravides.  Chez le rat, le passage de la mère aux ratons à la
    mamelle par l'intermédiaire du lait correspondait à environ 60% de la
    dose.

         Chez le rat, 70% du béta-HCH est éliminé dans les 28 premiers
    jours, dont un tiers par la voie urinaire.  On ne retrouve pas de
    béta-HCH inchangé dans l'urine. Le principal métabolite résultant de
    la cis-déshydrochloration est le 2,4,6-trichlorophénol sous forme
    conjuguée.

         Un prétraitement au moyen de béta-HCH modifie le métabolisme du
    lindane chez le rat.  D'après des études comportant l'administration
    de béta-HCH par voie intrapéritonéale à des souris, il semble que
    celui-ci soit métabolisé plus lentement que le lindane.

    2.5  Effets sur les êtres vivants dans leur milieu naturel

         En général le béta-HCH est modérément toxique pour les algues,
    les invertébrés et les poissons. La DL50 aiguë pour ces organismes

    est de l'ordre de 1 mg/litre mais les valeurs de la CE50 sont plus
    faibles (0,05-0,5 mg/litre).  Dans le cas de deux espèces de poisson
    d'eau douce,  Oryzia latipes et  Poecilia reticulata, la dose sans
    effet observable a été fixée à 0,03 mg/litre sur une durée de un et
    trois mois respectivement.

         On ne dispose d'aucune donnée concernant les effets sur les
    populations et les écosystèmes.

    2.6  Effets sur les animaux d'expérience et les systèmes
         d'épreuve  in vitro

         Les valeurs de la DL50 aiguë par voie orale pour les souris et
    les rats publiées en 1968, se situaient entre 1500 et 2000 mg/kg de
    poids corporel. Toutefois des études plus récentes ont fourni des
    valeurs de 16 g/kg de poids corporel pour les souris et de 8 g/kg de
    poids corporel pour les rats. Les signes d'intoxication sont
    essentiellement neurologiques.

         Des études de courte durée sur des souris avec des doses allant
    jusqu'à 600 mg/kg de nourriture pendant 26 à 32 semaines, ont révélé
    la présence d'une hyperplasie nodulaire et de proliférations atypiques
    au niveau du foie ainsi qu'une augmentation du poids de cet organe. 
    Lors d'une troisième étude, consistant dans l'administration de doses
    allant jusqu'à 500 mg/kg de nourriture pendant 24 semaines, on a
    observé ni tumeurs hépatiques ni hyperplasie nodulaire.

         Une étude de 90 jours au cours de laquelle des rats ont reçu soit
    50 soit 250 mg de béta-HCH par kg de nourriture, a révélé des
    altérations au niveau du foie, notamment une hypertrophie et une
    prolifération du réticulum endoplasmique lisse ainsi qu'un
    accroissement de l'activité des enzymes microsomiques.  Aux doses les
    plus élevées on a également observé des altérations au niveau des
    gonades qui s'accompagnaient également d'effets graves sur le poids du
    corps.  Les modifications hormonales accompagnant l'atrophie des
    gonades ne correspondaient pas à un effet endocrinien systématique.
    Aucun effet nocif n'a été constaté à la dose de 2 mg/kg de nourriture
    (soit l'équivalent de 0,1 mg/kg de poids corporel).

         Une étude de longue durée sur des rats (publiée en 1950) au cours
    de laquelle on a administré des doses de 10 mg/kg de nourriture (soit
    l'équivalent de 0,5 mg/kg de poids corporel) ou davantage, a révélé
    que ce régime conduisait à une hypertrophie du foie et à des
    modifications histologiques.

         Lors d'une étude de reproduction portant sur deux générations de
    rats, on a observé les mêmes effets que dans l'étude de 90 jours citée
    plus haut.  Aucun effet n'a été observé à la dose de 2 mg/kg de
    nourriture (soit l'équivalent de 0,1 mg/kg de poids corporel), mais à
    la dose de 10 mg/kg, il y avait accroissement de la mortalité et de la
    stérilité.  L'étude a également porté sur les effets tératogènes

    éventuels du béta-HCH mais aucun effet de ce genre imputable au
    produit n'a été observé.

         On a décrit un effet "oestrogénique" faible dont l'organe cible
    serait l'utérus. En fait il n'y a pas d'effet bien net sur le système
    de régulation endocrinienne.  Le mécanisme et la portée de cet effet
    demeurent incertains.

         Les études de mutagénicité publiées ne font état d'aucune
    augmentation dans la fréquence des mutations chez les souches de
     Salmonella typhimurium. Une étude  in vivo chez le rat sur des
    cellules de moelle osseuse en métaphase a donné des résultats
    positifs.

         Deux études ont été effectuées sur des souris afin de déterminer
    le pouvoir cancérogène du béta-HCH.  Dans l'une d'elles, on a
    administré pendant 110 semaines une dose de 100 mg/kg de nourriture et
    l'on a observé une hyperplasie du tissu hépatique et une hypertrophie
    de cet organe.  Il y avait également augmentation des tumeurs bénignes
    et malignes.  Dans une autre étude, où la dose administrée était de
    500 mg/kg de nourriture pendant une période de 24 semaines, aucune
    tumeur n'a été observée.

         Des études au cours desquelles des rats ont reçu des mélanges de
    béta-HCH et de biphényles polychlorés donnent à penser que le béta-HCH
    aurait un effet promoteur.

         A la dose de 300 mg/kg de nourriture, le béta-HCH a provoqué une
    altération sensible de plusieurs des fonctions du système immunitaire
    en l'espace d'un mois chez la souris.

    2.7  Effets sur l'homme

         L'examen de travailleurs d'une usine produisant du lindane,
    exposés à cette substance pendant 7,2 années (en moyenne géométrique,
    avec des limites de 1 à 30 ans), a permis de conclure que l'exposition
    professionelle au HCH ne produisait pas de signes d'une atteinte
    neurologique ni d'une perturbation des fonctions neuromusculaires.

    CONCLUSIONS ET RECOMMANDATIONS EN VUE DE LA PROTECTION DE LA SANTE
    HUMAINE ET DE L'ENVIRONNEMENT (ALPHA- ET BETA-HEXACHLOROCYCLOHEXANES)

    1.  Conclusions

         On ne peut pas comparer les effets nocifs potentiels de l'alpha-
    et du béta-hexachlorocyclohexane sur l'homme et l'environnement à
    leurs avantages éventuels, étant donné que ces produits n'ont aucune
    action insecticide.  Leur présence dans l'environnement est donc fort
    préoccupante.  Dans ces conditions, l'usage de produits à base d'HCH
    technique contenant de fortes concentrations d'alpha- et de béta-HCH
    n'est en aucun cas justifié.

    1.1  Population générale

         L'alpha- et le béta-HCH circulent dans l'environnement et sont
    présents dans les chaînes alimentaires.  Il existe donc un risque
    permanent d'exposition humaine. Cette exposition est faible et devrait
    lentement diminuer dans les années à venir.  Dans ces conditions, il
    n'y a pas lieu de s'inquiéter sérieusement pour la santé de la
    population dans son ensemble.

    1.2  Sous-groupes de population exposés à un risque particulier

         La concentration de l'alpha-HCH dans le lait maternel est faible.

         On peut se préoccuper de l'exposition des nourrissons au béta-HCH
    actuellement présent dans le lait maternel mais il faut malgré tout
    continuer à encourager l'allaitement maternel.

         Il faut cependant faire un maximum d'efforts pour réduire
    l'exposition par voie alimentaire ou autre à ces isomères.  Une
    moindre exposition d'origine alimentaire à ces substances devrait
    entraîner une diminution de la teneur du lait maternel en alpha- et
    béta-HCH.

    1.3  Exposition professionnelle

         Dans la mesure où elles observent les précautions recommandées en
    vue réduire au minimum l'exposition à l'alpha- et au béta-HCH, les
    personnes employées à la fabrication du lindane ne courent pas de
    risque particulier.

    1.4  Effets sur l'environnement

         A part le cas de décharge dans le milieu aquatique, rien
    n'indique que la présence d'alpha- et de béta-HCH dans l'environnement
    constitue une menace particulière pour la faune et la flore.

    2.  Recommandations pour la protection de la santé humaine et de
        l'environnement

    a)   Afin de réduire au minimum la pollution de l'environnement par
    l'alpha- et le béta-HCH, il faut utiliser du lindane (> de 99% de
    gamma-HCH) à la place de l'HCH technique.

    b)   Pour éviter la pollution de l'environnement par l'alpha- et le
    béta-HCH, les sous-produits et les effluents issus de la fabrication
    du lindane doivent être évacués de façon convenable et il faut en
    particulier éviter la contamination des eaux et du sol.

    c)   Il faut poursuivre la surveillance de l'alpha- et du béta-HCH
    dans les denrées alimentaires. Il est essentiel d'instituer un
    mécanisme par lequel seront fixées des doses limites acceptables sur
    le plan international pour l'alpha- et le béta-HCH.

    d)   Il faut poursuivre la surveillance de l'apport quoti-dien
    d'alpha- et de béta-HCH et continuer à en contrôler les concentrations
    dans le lait maternel.

    RECHERCHES A EFFECTUER (ALPHA- ET BETA-HEXACHLOROCYCLOHEXANES)

         Les études expérimentales suivantes sont nécessaires pour
    permettre une meilleure évaluation des dangers que représentent
    l'alpha- et le béta-HCH:

    *    études de mutagénicité portant en particulier sur les    
         chromosomes;

    *    études de reproduction, études de foetotoxicité et de    
         tératogénicité;

    *    études pharmacocinétiques et toxicocinétiques;

    *    études de cancérogénicité;

    *    études de neurotoxicité;

    *    surveillance des populations à risque.

    RESUMEN Y EVALUACION

    1.  Alpha-hexaclorociclohexano

    1.1  Propiedades generales

         El alpha-hexaclorociclohexano (alpha-HCH) es uno de los
    principales subproductos (65-70%) de la fabricación del lindano (>
    99% gamma-HCH).  Su solubilidad en agua es baja, pero es muy soluble
    en disolventes orgánicos como la acetona, el cloroformo y el xileno.
    Es una sustancia sólida con baja presión de vapor. El coeficiente de
    partición  n-octanol/agua (log Poa) es 3,82.  Se trata de un
    contaminante ambiental.

         El alpha-HCH puede determinarse por separado de los otros
    isómeros mediante cromatografía de gases con detección de captura
    electrónica y otros métodos, tras la extracción por partición
    líquido/líquido y la purificación en cromatografía de columna.

    1.2  Transporte, distribución y transformación en el medio ambiente

         La biodegradación y la degradación abiótica (decloración) por
    irradiación ultravioleta tienen lugar en el medio ambiente y producen,
    respectivamente, delta-3,4,5,6-tetraclorohexeno y pentacloro-
    ciclohexeno.  Este proceso de degradación es más lento que en el caso
    del lindano.  La persistencia del alpha-HCH en el suelo depende de
    factores ambientales como la acción de los microorganismos, el
    contenido de materia orgánica y la codestilación y la evaporación a
    partir de los suelos.  No se produce isomerización del lindano a
    alpha-HCH.

         En los microorganismos se produce una bioconcentración rápida (el
    factor de bioconcentración es igual a 1500-2700 en peso seco, o
    aproximadamente 12 000 en lípidos al cabo de 30 minutos),
    invertebrados (60-2750 (peso seco) o > 8000 (lípidos) al cabo de
    24-72 h), y peces (313-1216 al cabo de 4-28 días; hasta 50 000 en el
    río Elba). No obstante, la biotransformación y la eliminación también
    son relativamente rápidas en esos organismos (de 15 minutos a 72 h).

    1.3  Niveles en el medio ambiente y exposición humana

         El alpha-HCH se encuentra en el aire oceánico con una
    concentración de 0,02-1,5 ng/m3. En el Canadá, se encontró en el
    agua de lluvia con una concentración de 1-40 ng/litro, pero sólo se
    detectaron indicios en la nieve.

         Durante el periodo 1969-1974, se encontraron en el río Rin y sus
    afluentes niveles de alpha-HCH de 0,01-2,7 µg por litro, pero
    últimamente los niveles han sido inferiores a 0,1 µg/litro. En el río
    Elba, los niveles disminuyeron desde un promedio de 0,023 mg/litro en
    1981 hasta menos de 0,012 µg/litro en 1988. En 1966 se encontró que
    ciertos ríos del Reino Unido contenían 0,001-0,43 µg por litro.  Se ha

    encontrado alpha-HCH en sedimentos de la región norte del mar de
    Wadden en concentraciones de 0,3 a 1,4 µg/kg (0,002 µg/litro en el
    agua).

         Las concentraciones de alpha-HCH en diferentes especies vegetales
    de distintos países variaron entre  0,5-2140 µg/kg en peso seco, pero
    fueron mucho más altos en zonas contaminadas.  Incluso en la Antártida
    se han encontrado niveles que varían entre 0,2 y 1,15 µg/kg.

         El alpha-HCH se detecta con regularidad en peces e invertebrados
    acuáticos, así como en patos, garzas y lechuzas.  En renos y alces de
    Idaho, que viven en zonas en las que el uso de plaguicidas es
    prácticamente insignificante, se encontraron niveles medios de
    alpha-HCH de aproximadamente 70-80 µg/kg en la grasa subcutánea.  El
    tejido adiposo de los osos polares del Canadá contenía 0,3-0,87 mg de
    alpha-HCH/kg (en grasa).

         En varios países se han analizado importantes alimentos en busca
    de alpha-HCH. Las concentraciones, principalmente en alimentos que
    contienen grasas, variaron hasta un máximo de 0,05 mg/kg de producto,
    salvo en la leche y los productos lácteos (hasta 0,22 mg/kg) y en el
    pescado y en preparaciones de carne (hasta 0,5 mg/kg en grasa).  Se ha
    observado una ligera disminución con los años.

         Los alimentos son la principal fuente de exposición de la
    población general al alpha-HCH.  En estudios de la dieta total
    realizados en los Países Bajos y en el Reino Unido, se encontraron
    concentraciones medias de 0,01 y 0,002-0,003 mg/kg de alimento,
    respectivamente.  Los datos procedentes del Reino Unido indican una
    tendencia decreciente desde 1967.  En los EE.UU., la ingesta diaria
    media de alpha-HCH fue de 0,009-0,025 µg/kg de peso corporal durante
    el periodo 1977-1979, y de 0,003-0,016 µg/kg de peso corporal durante
    el periodo 1982-1984.

         En unos pocos países, se ha determinado la concentración de
    alpha-HCH en la sangre, el suero o el plasma humanos.  La
    concentración promedio (mediana en algunos casos) fue < 0,1 µg/litro
    (desde niveles no detectables hasta 0,6 µg/litro). En un país, no
    obstante, se notificó  una concentración media de 3,5 (margen
    0,1-15,0) µg por litro. Se detectó alpha-HCH en aproximadamente la
    tercera parte de las muestras de sangre.

         En el ser humano las concentraciones en el tejido adiposo y la
    leche que se han comunicado son bajas (respectivamente < 0,01-0,1 y
    < 0,001-0,04 mg/kg en grasa). Los estudios de la dieta total han
    revelado niveles diarios de ingesta del orden de 0,01 µg/kg de peso
    corporal por día o menos.  Esas concentraciones están disminuyendo
    poco a poco con los años.

         El alpha-HCH parece ser un contaminante ambiental universal.  Las
    concentraciones están disminuyendo muy despacio, a pesar de las
    medidas adoptadas para impedir su dispersión en el medio ambiente.

    1.4  Cinética y metabolismo

         En las ratas, el alpha-HCH se absorbe rápida y casi completamente
    a partir del tracto gastrointestinal.  Después de una inyección
    intraperitoneal, aproximadamente el 40-80% del alpha-HCH se excretó en
    la orina y el 5-20% en las heces. En la rata, las concentraciones más
    elevadas se han encontrado en el hígado, los riñones, la grasa, el
    cerebro y los músculos; el tejido adiposo constituye un importante
    depósito.  Las concentraciones de alpha-HCH en el hígado de las crías
    lactantes duplicaron las observadas en el hígado de las madres.  En la
    rata, los cocientes cerebro-sangre y grasa de depósito-sangre fueron
    de 120:1 y 397:1, respectivamente.

         La biotransformación del alpha-HCH en la rata entraña la
    decloración.  El principal metabolito urinario es el
    2,4,6-triclorofenol; entre otros metabolitos identificados figuran el
    1,2,4-, 2,3,4-, y 2,4,5-triclorofenol y el 2,3,4,5- y
    2,3,4,6-tetraclorofenol.  En el riñón de rata y también en estudios
     in vitro en hígado de pollo se ha encontrado 1,3,4,5,6-
    pentaclorociclohex-1-eno. En el hígado se forma un conjugado de
    glutatión.

         En la rata, la semivida de eliminación de la sustancia presente
    en del depósito graso es de 6,9 días en la hembra y 1,6 días en el
    macho.

    1.5  Efectos en los organismos del medio ambiente

         El alpha-HCH tiene baja toxicidad para las algas, siendo por lo
    general 2 mg/litro el nivel sin efectos observados.

         En un estudio a largo plazo,  Daphnia magna mostró un nivel sin
    efectos observados de 0,05 mg/litro.  El alpha-HCH es moderadamente
    tóxico para los invertebrados y los peces.  Los valores de la
    C(E)L50 aguda para esos organismos son del orden de 1 mg/litro.  En
    estudios a corto plazo con Lebistes reticulatus y Oryzia latipes se
    observó que 0,8 mg/litro no ejercían efecto alguno.

         En estudios de tres meses de duración con  Salmo gairdneri con
    dosis de 10-1250 mg/kg de dieta no se observaron efectos en la
    mortalidad, la conducta, el crecimiento ni las actividades enzimáticas
    del hígado y el cerebro.

         En estudios a corto y a largo plazo con un gasterópodo  (Lymnea
     stagnalis) se observó una CE50 (basada en la mortalidad y la
    inmovilización) de 1200 µg/litro.  La inhibición de la producción de
    huevos se produjo con una concentración de 250 µg/litro.  Con
    65 µg/litro se observó una reducción del 50% en la reproductividad
    general.

         No se dispone de datos sobre los efectos en las poblaciones y los
    ecosistemas.

    1.6  Efectos en animales de experimentación y sistemas de ensayo
          in vitro

         Los valores de la DL50 aguda por vía oral en ratones se
    encuentran entre 1000-4000 y en ratas entre 500 y 4670 mg/kg de peso
    corporal.  Los signos de envenenamiento coinciden principalmente con
    los de la estimulación del sistema nervioso central.

         En un estudio de 90 días de duración en ratas se observó
    depresión del crecimiento con una concentración de 250 mg/kg de dieta.
    Los cambios histológicos y enzimáticos en el hígado indicaron
    inducción enzimática con 50 mg/kg o más.  Con esas dosis se observaron
    también signos de inmunosupresión.  Ya se observó aumento del peso
    hepático con 10 mg/kg de dieta (equivalente a 0,5 mg/kg de peso
    corporal).  El nivel sin efectos adversos observados resultó en este
    estudio ser 2 mg/kg de dieta (equivalente a 0,1 mg/kg de peso corporal
    al día).

         No se han comunicado estudios adecuados a largo plazo de
    toxicidad ni estudios de reproducción y teratogenicidad.

         Los estudios realizados con diversas cepas de  Salmonella
     typhimurium no dieron prueba alguna de mutagenicidad ni con
    activación metabólica ni sin ella.  Los ensayos realizados con
     Saccharomyces cerevisiae también dieron resultado negativo, pero un
    ensayo de síntesis no programada de ADN en hepatocitos de rata  in
     vitro dio resultados ambiguos.

         Se ha intentado determinar el potencial carcinogénico en ratones
    y ratas con dosis de 100 a 600 mg/kg de dieta. En estudios realizados
    en ratones se encontraron nódulos hiperplásicos y/o adenomas
    hepatocelulares.  En un estudio los niveles de administración
    excedieron la dosis máxima tolerada.  En dos estudios en ratones y uno
    en ratas, en los que se administraron hasta 160 mg/kg de dieta a
    ratones y 640 mg/kg de dieta a ratas, no se observó aumento alguno en
    la incidencia de tumores.

         Los resultados de los estudios sobre la iniciación-promoción y el
    modo de acción, y los estudios de mutagenicidad indican que la
    tumorigenicidad inducida por el alpha-HCH observada en ratones tiene
    un mecanismo no genético.

         Se ha demostrado que el alpha-HCH provoca un aumento neto de la
    actividad de los enzimas hepáticos incluso con 5 mg/kg de dieta
    (equivalente a 0,25 mg/kg de peso corporal).  Una dosis de 2 mg/kg de
    peso corporal no afectó la desmetilación de la aminopirina ni el
    contenido de ADN en el hígado.

    1.7  Efectos en el ser humano

         Cuando se examinó a trabajadores de una fábrica de producción de
    lindano, con una exposición media geométrica de 7,2 años (1-30), se
    concluyó que la exposición profesional al HCH no induce síntomas de
    trastornos neurales ni perturbaciones de la "función neuromuscular".

    RESUMEN Y EVALUACION

    2.  Beta-hexaclorociclohexano

    2.1  Propiedades generales

         El beta-hexaclorociclohexano (beta-HCH) es un subproducto (7-10%)
    de la fabricación del lindano (> 99% gamma-HCH).  Su solubilidad en
    agua es baja, pero es muy soluble en disolventes orgánicos como la
    acetona, el ciclohexano y el xileno.  Es un sólido con una baja
    presión de vapor. El coeficiente de partición  n-octanol/agua (log
    Poa) es 3,80.  Es un contaminante ambiental.

         El beta-HCH puede determinarse por separado de los otros isómeros
    mediante cromatografía de gases con detección de captura electrónica y
    otros métodos tras la extracción por partición líquido/líquido y la
    purificación en cromatografía de columna.

    2.2  Transporte, distribución y transformación en el medio ambiente

         La biodegradación y la degradación abiótica (decloración) por
    irradiación ultravioleta tienen lugar en el medio ambiente y producen
    pentaclorociclohexano, pero a una velocidad mucho menor que en el caso
    del lindano (gamma-HCH).

         El beta-HCH es el isómero más persistente del HCH.  Su
    persistencia en el suelo depende de factores ambientales como la
    acción de los microorganismos, el contenido de materia orgánica y de
    agua, y la codestilación y la evaporación a partir del suelo.

         Dada la persistencia del beta-HCH, tiene lugar una rápida
    bioconcentración en invertebrados (el factor de bioconcentración es de
    aproximadamente 125 al cabo de tres días), peces (250-1500 en peso
    seco o aproximadamente 500 000 veces en lípidos al cabo de 3-10 días),
    aves y el hombre (aproximadamente 525).  La bioconcentración es más
    elevada y la eliminación más lenta en el caso del beta-HCH que en los
    otros isómeros del HCH.

    2.3  Niveles ambientales y exposición humana

         El beta-HCH se encuentra en el aire oceánico con una
    concentración de 0,004-0,13 ng/m3.

         Hasta 1974, el río Rin y sus afluentes contenían niveles de
    beta-HCH de 0,14-0,22 µg/litro, pero después los niveles estuvieron
    siempre por debajo de 0,1 µg por litro.  Las muestras tomadas en el
    río Mosa también contenían < 0,1 µg/litro. En el río Elba, los
    niveles descendieron desde un promedio de 0,009 hasta 0,004 µg por
    litro entre 1981 y 1988.

         El beta-HCH se ha medido en aves como el gavilán, el cernícalo,
    el búho, la garza y el colimbo durante varios años y las
    concentraciones variaron entre 0,1 y 0,3 mg/kg.  Se han encontrado
    hasta 0,87 mg/kg (en grasa) en el hígado y el tejido adiposo del oso
    polar.

         Se han analizado importantes alimentos en algunos países en busca
    de beta-HCH.  Las concentraciones medias, principalmente en alimentos
    que contienen grasas, variaron entre 0,03 mg/kg (en grasa), pero en
    los productos lácteos se encontraron niveles de hasta 4 mg/kg (en
    grasa).  En alimentos no grasos, los niveles fueron < 0,005 mg/kg de
    producto.  En general, los niveles están descendiendo lentamente.

         Los alimentos son la principal fuente de exposición de la
    población general al beta-HCH.  En estudios de la dieta total en el
    Reino Unido, se encontraron 0,003, 0,0005, y < 0,0005 mg/kg durante
    los años 1966/67, 1975/77 y 1981, respectivamente.  En los EE.UU., la
    ingesta diaria media de beta-HCH en 1982-1984 varió entre <
    0,1-0,4 ng/kg de peso corporal en distintos grupos de edad.

         En varios países, la concentración de beta-HCH se ha determinado
    en la sangre, el suero o el plasma de la población general.  Las
    concentraciones variaron entre los distintos países y el máximo
    encontrado fue de 25 µg por litro.

         Se han llevado a cabo numerosos estudios para determinar la
    presencia de beta-HCH en los tejidos adiposos humanos.  Las
    concentraciones encontradas en el Canadá, Kenya, los Países Bajos, el
    Reino Unido, y la República Federal de Alemania, variaron hasta
    4,4 mg/kg (en grasa). Se encontró que hasta los 50 años se produce un
    aumento gradual con la edad; en adelante, los niveles disminuyen. Las
    concentraciones de beta-HCH en los tejidos adiposos son más altas que
    las de los otros isómeros del HCH, fenómeno que refleja las
    propiedades acumulativas del beta-HCH.  En general no se ha observado
    una tendencia clara de disminución de las concentraciones de beta-HCH
    durante el periodo en que se han hecho los estudios.  Existe una
    relación entre las concentraciones en el tejido adiposo y la leche
    materna y el consumo de productos cárnicos, grasas animales y pescados
    grasos.

         En unos pocos países (Canadá, Países Bajos, Reino Unido y
    República Federal de Alemania), se ha analizado la leche humana y se
    han encontrado niveles de beta-HCH entre 0,1 y 0,69 mg/kg (en grasa). 
    Los niveles medidos en la leche de mujeres de zonas rurales parece ser
    más elevado que en las de zonas urbanas.

         Los elevados niveles de beta-HCH que se han encontrado en la
    leche materna exceden las concentraciones permisibles a título
    temporal y local.  Las concentraciones de beta-HCH en la sangre de
    lactantes se encuentran entre los mismos límites que las medidas en
    las madres.

         El beta-HCH parece ser un contaminante ambiental universal.  Las
    concentraciones están disminuyendo muy despacio a pesar de las medidas
    adoptadas para evitar su dispersión en el medio ambiente.

    2.4  Cinética y metabolismo

         Hasta el 95% del beta-HCH en el tracto gastrointestinal del ratón
    es absorbido y a continuación se acumula en su mayor parte en el
    tejido adiposo.  La eliminación sigue un mecanismo de dos etapas;
    durante la primera, la semivida es de 2,5 días y durante la segunda,
    18 días.

         Después de la absorción, el beta-HCH se distribuye rápidamente al
    hígado, el cerebro, los riñones y los tejidos adiposos.  En la rata,
    la concentración máxima en el hígado se alcanza al cabo de cuatro
    días. Con una concentración sanguínea media de 92 µg/litro (pero
    también con concentraciones de 540 y 2100 µg/litro), los cocientes
    cerebro-sangre y tejido adiposo-sangre fueron 2:1 y 170:1,
    respectivamente.  Tras el envenenamiento agudo y mortal de un hombre
    con isómeros de HCH, la concentración de beta-HCH, en relación con la
    de la sangre, fue de 363 en la grasa, 3 en el cerebro y 15 en el
    hígado.  El beta-HCH atraviesa la barrera hematoencefálica con mucha
    menos facilidad que los demás isómeros del HCH.

         En el ratón, el paso transplacentario de la hembra gestante al
    feto fue de aproximadamente el 2% de la dosis, pero en la rata se
    observó un paso del 40%. En la rata, la transferencia de la madre al
    lactante en la leche fue de aproximadamente el 60% de la dosis.

         En la rata, el 70% del beta-HCH se elimina durante 28 días; un
    tercio de esa cantidad se excreta en la orina.  No aparece beta-HCH
    sin modificar en la orina. El principal metabolito procedente de la
    cis-deshidrocloración es el 2,4,6-triclorofenol en forma conjugada.

         El pretratamiento con beta-HCH altera el metabolismo del lindano
    en las ratas. Según estudios intraperitoneales realizados en ratones,
    parece que el beta-HCH se metaboliza con más lentitud que el lindano.

    2.5  Efectos en los organismos del medio ambiente

         En general, el beta-HCH tiene una toxicidad moderada para las
    algas, los invertebrados y los peces. Los valores de la DL50 aguda
    para esos organismos son del orden de 1 mg/litro, pero los valores de
    la CE50 son más bajos (0,05-0,5 mg/litro).  El nivel sin efectos
    observados en  Oryzia latipes y  Poecilia reticulata, dos peces de
    agua dulce expuestos durante 1 ó 3 meses, fue de 0,03 mg por litro.

         No se dispone de datos sobre los efectos en las poblaciones y los
    ecosistemas.

    2.6  Efectos en animales de experimentación y sistemas de ensayo
          in vitro

         Los valores de DL50 aguda por vía oral en ratones y ratas
    comunicados en 1968 se encontraban entre 1500 y 2000 mg/kg de peso
    corporal.  No obstante, en estudios más recientes se han obtenido
    valores de 16 g/kg de peso cor poral en ratones y 8 g/kg de peso
    corporal en ratas.  Los signos de intoxicación fueron principalmente
    de origen neural.

         En dos estudios en ratones a corto plazo, con dosis de hasta
    600 mg/kg de dieta durante 26-32 semanas, se observó  un aumento del
    peso hepático, así como hiperplasia nodular y proliferaciones atípicas
    en el hígado.  En un tercer estudio, la administración de hasta
    500 mg/kg de dieta durante 24 semanas no produjo tumores hepáticos ni
    hiperplasia nodular.

         En un estudio a 90 días con ratas a las que se administraron 50 ó
    250 mg/kg de dieta se observaron cambios hepáticos, a saber,
    hipertrofia y proliferación del retículo endoplásmico liso y mayor
    actividad de los enzimas microsómicas. Con las dosis más altas se
    produjeron cambios en las gónadas pero éstos estuvieron asociados a
    modificaciones muy acusadas del peso corporal.  Los cambios hormonales
    asociados a la atrofia gonadal no mostraron un efecto endocrino
    consecuente. No se observaron efectos adversos con una dosis de
    2 mg/kg de dieta (equivalente a 0,1 mg/kg de peso corporal).

         En un estudio en ratas a largo plazo (comunicado en 1950), la
    administración de dosis de 10 mg/kg de dieta (equivalente a 0,5 mg/kg
    de peso corporal) o superiores produjo dilatación y cambios
    histológicos en el hígado.

         En un estudio de reproducción de ratas en dos generaciones, se
    observaron los mismos efectos que en el estudio de 90 días.  No se
    observaron efectos con 2 mg/kg de dieta (equivalente a 0,1 mg/kg de
    peso corporal), pero con una dosis de 10 mg/kg de dieta aumentaron la
    mortalidad y la infecundidad.  En una ampliación de este estudio no se
    observaron efectos teratogénicos relacionados con el compuesto.

         Se ha descrito un ligero efecto "estrogénico".  El órgano diana
    de este efecto era el útero; no se apreciaron efectos claros en los
    sistemas de control endocrino.  No se sabe con seguridad cuál es el
    mecanismo ni el significado de este efecto.

         Los estudios de mutagenicidad comunicados no mostraron aumento
    alguno en la frecuencia de mutaciones en cepas de  Salmonella
     typhimurium. En un análisis  in vivo de la metafase en médula ósea
    de ratas se obtuvieron resultados positivos.

         Se han llevado a cabo dos estudios en el ratón para determinar el
    potencial carcinogénico.  En uno de los estudios, se administraron
    200 mg/kg de dieta durante 110 semanas, y se notificaron dilatación

    del hígado, cambios hiperplásicos y aumento de tumores tanto benignos
    como malignos. En el otro estudio, en el que se administraron
    500 mg/kg de dieta durante 24 semanas, no se observaron tumores.

         En estudios en los que se administró a ratas combinaciones de
    beta-HCH con bifenilos policlorados se sugirió que el beta-HCH tenía
    un efecto de promoción.

         Con 300 mg/kg de dieta, el beta-HCH provocó cambios
    significativos en varias funciones inmunitarias en el ratón al cabo de
    un mes.

    2.7  Efectos en el ser humano

         Cuando se examinó a trabajadores de una fábrica de producción de
    lindano, con una exposición media geométrica de 7,2 años (1-30), se
    concluyó que la exposición profesional al HCH no induce signos de
    trastornos neurales ni de perturbación de la "función neuromuscular".

    CONCLUSIONES Y RECOMENDACIONES PARA LA PROTECCION DE LA SALUD
    HUMANA Y DEL MEDIO AMBIENTE (ALPHA- Y BETA-HEXACLOROCICLOHEXANOS)

    1.  Conclusiones

         Los efectos adversos potenciales del alpha- y el beta-
    hexaclorociclohexano (HCH) en el ser humano y el medio ambiente
    no pueden sopesarse frente a sus beneficios, puesto que estos isómeros
    no tienen acción insecticida.  Su presencia en el medio ambiente es
    por tanto causa de gran inquietud. En consecuencia, en ningún caso se
    justifica el uso de productos técnicos del HCH que contengan elevadas
    concentraciones de alpha- y beta-HCH.

    1.1  Población general

         El alpha- y el beta-HCH circulan en el medio ambiente y están
    presentes en las cadenas alimentarias.  Así pues, existe un potencial
    continuo de exposición humana.  Esta exposición es baja y se espera
    que disminuya lentamente en los años por venir.  Así pues, no hay
    motivos de gran inquietud en cuanto a la salud de la población
    general.

    1.2  Subpoblaciones especialmente expuestas

         Las concentraciones de alpha-HCH en la leche humana son bajas.

         La exposición de lactantes debida a las actuales concentraciones
    de beta-HCH en la leche materna es preocupante, pero no suficiente
    para dejar de fomentar la lactancia natural.

         No obstante, debe hacerse todo lo posible para disminuir la
    exposición a esos isómeros por la vía alimentaria y por toda otra vía. 
    Se espera que la menor exposición por la dieta dé como resultado
    menores niveles de alpha- y beta-HCH en la leche humana.

    1.3  Exposición profesional

         Mientras se observen las precauciones recomendadas para reducir
    al mínimo la exposición del personal que tra-baja en la fabricación
    del lindano, el alpha- y el beta-HCH no plantean riesgos para la salud
    de los operarios.

    1.4  Efectos en el medio ambiente

         Aparte de los vertidos en el medio acuático, no hay pruebas que
    sugieran que la presencia de alpha- y beta-HCH en el medio ambiente
    plantee un riesgo significativo para las poblaciones de seres vivos.

    2.  Recomendaciones para la protección de la salud humana y el medio
        ambiente

    a)   A fin de reducir al mínimo la contaminación ambiental con alpha-
    y beta-HCH, debe usarse lindano (< 99% gamma-HCH) en lugar de HCH
    técnico.

    b)   A fin de evitar la contaminación ambiental con alpha- y beta-HCH,
    los subproductos y los efluentes de la fabricación del lindano deben
    evacuarse de modo apropiado, y debe evitarse la contaminación de aguas
    naturales y del suelo.

    c)   Debe proseguir la vigilancia del alpha- y del beta-HCH en los
    alimentos. Es imprescindible poner en marcha un mecanismo para
    establecer niveles internacionalmente aceptables de alpha- y beta-HCH
    en los alimentos.

    d)   Debe proseguir la vigilancia de la ingesta diaria de la población
    general y de los niveles de alpha- y beta-HCH en la leche materna.

    OTRAS INVESTIGACIONES (ALPHA- Y BETA-HEXACLOROCICLOHEXANOS)

         Deben hacerse los estudios siguientes para evaluar mejor los
    riesgos del alpha- y el beta-HCH:

    *    oestudios de mutagenicidad, especialmente con puntos
         terminales mutagénicos en los cromosomas;

    *    oestudios de reproducción y fetotoxicidad/teratogenicidad;

    *    oestudios farmacocinéticos y toxicocinéticos;

    *    oestudios de carcinogenicidad;

    *    oestudios de neurotoxicidad;

    *    oestudios de vigilancia de poblaciones en riesgo.

    


See Also:
        Hexachlorocyclohexane (IARC Summary & Evaluation, Volume 20, 1979)
        Hexachlorocyclohexane (Mixed Isomers)