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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 128




    CHLOROBENZENES OTHER THAN HEXACHLOROBENZENE




    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 Ms M.E. Meek and Ms M.J. Giddings,
    Health and Welfare Canada


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


    World Health Orgnization
    Geneva, 1991

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

    WHO Library Cataloguing in Publication Data

    Chlorobenzenes other than hexachlorobenzene

          (Environmental health criteria: 128)

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

          ISBN 92 4 157128 4         (NLM Classification QV 633)
          ISSN 0250-863X

          (c) World Health Organization 1991


          Publications of the World Health Organization enjoy copyright
    protection in accordance with the provisions of Protocol 2 of the
    Universal Copyright Convention.  For rights of reproduction or
    translation of WHO publications, in part or  in toto,  application
    should be made to the Office of Publications, World Health
    Organization, Geneva, Switzerland.  The World Health Organization
    welcomes such applications.

          The designations employed and the presentation of the material in
    this publication do not imply the impression of any opinion whatsoever
    on the part of the Secretariat of the World Health Organization
    concerning the legal status of every country, territory, city, or area
    or of its authorities, or concerning the delimitation of its frontiers
    or boundaries.


          The mention of specific companies or of certain manufacturers'
    products does not imply that they are endorsed or recommended by the
    World Health Organization in preference to others of a similar nature
    that are not mentioned.  Errors and omissions excepted, the names of
    proprietary products are distinguished by initial capital letters.

    CONTENTS

    1. SUMMARY
         1.1. Identity, physical and chemical properties, analytical
                methods
         1.2. Sources of human and environmental exposure
                1.2.1. Production figures
                1.2.2. Uses      
                1.2.3. Release of chlorobenzenes into the environment
         1.3. Environmental transport, distribution, and transformation
                1.3.1. Degradation
                1.3.2. Fate      
         1.4. Environmental levels and human exposure
                1.4.1. Chlorobenzenes in the environment
                1.4.2. Human exposure
                        1.4.2.1   General population
                        1.4.2.2   Occupational
         1.5. Kinetics and metabolism
         1.6. Effects on aquatic organisms in the environment
         1.7. Effects on experimental animals and  in vitro systems
         1.8. Effects on humans
                1.8.1. General population
                1.8.2. Occupational exposure
         1.9. Conclusions

    2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
         2.1. Identity          
                2.1.1. Primary constituent
                2.1.2. Technical product
         2.2. Physical and chemical properties
         2.3. Organoleptic properties
         2.4. Conversion factors
         2.5. Analytical methods

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE                 
         3.1. Natural occurrence
         3.2. Man-made sources  
                3.2.1. Production
                3.2.2. Uses      
                3.2.3. Sources in the environment

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION 
         4.1. Transport and distribution 
         4.2. Persistence and fate
                4.2.1. Persistence
                4.2.2. Abiotic degradation
                        4.2.2.1   Photolysis 
                        4.2.2.2   Hydrolytic and oxidative reactions

                4.2.3. Biodegradation and biotransformation
                4.2.4. Bioaccumulation
                4.2.5. Biomagnification
                4.2.6. Ultimate fate following use

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
         5.1. Environmental levels
                5.1.1. Air       
                5.1.2. Water     
                5.1.3. Soil      
                5.1.4. Food      
                5.1.5. Human milk
                5.1.6. Consumer products
         5.2. Human exposure from all sources
                5.2.1. General population
                5.2.2. Occupational exposure
         5.3. Human monitoring data

    6. KINETICS AND METABOLISM  
         6.1. Absorption        
         6.2. Distribution      
         6.3. Metabolic transformation
         6.4. Elimination and excretion
         6.5. Binding to protein
         6.6. Effects on metabolizing enzymes

    7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
         7.1. Microorganisms    
                7.1.1. Bacteria and protozoa
                7.1.2. Unicellular algae
         7.2. Aquatic organisms 
                7.2.1. Plants    
                7.2.2. Invertebrates
                7.2.3. Fish      
         7.3. Terrestrial biota 
         7.4. Model ecosystems  

    8. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS
         8.1. Single exposure   
         8.2. Skin and eye irritation, skin sensitization
         8.3. Short-term exposures
         8.4. Long-term exposures
         8.5. Chronic toxicity and carcinogenicity
         8.6. Mutagenicity and related endpoints
                8.6.1.  In vitro systems
                8.6.2.  In vivo tests on experimental animals
                8.6.3. Human  in vivo studies
         8.7. Developmental and reproductive effects

    9. EFFECTS ON HUMANS        
         9.1. Case reports      
                9.1.1. General population exposure
                9.1.2. Occupational exposure
         9.2. Epidemiological Studies

    10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
         10.1. Evaluation of human health risks
                10.1.1. Exposure of the general population
                10.1.2. Occupational exposure
                10.1.3. Toxic effects
                10.1.4. Risk evaluation
                        10.1.4.1  General population
                        10.1.4.2  Occupationally exposed population
         10.2. Evaluation of effects on the environment
                10.2.1. Levels of exposure
                10.2.2. Fate      
                10.2.3. Bioavailability and bioaccumulation
                10.2.4. Degradation
                10.2.5. Persistence
                10.2.6. Toxic effects on organisms
                10.2.7. Risk evaluation

    11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH
         AND THE ENVIRONMENT              
         11.1. Conclusions       
         11.2. Recommendations   
                11.2.1. Public health measures 
                11.2.2. Human health risk evaluation 
                11.2.3. Environmental risk evaluation

    12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES                   

    REFERENCES                    

    RESUME                        

    RESUMEN                       
    

    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR CHLOROBENZENES
    OTHER THAN HEXACHLOROBENZENE

    Members

    Dr U. G. Ahlborg, Karolinska Institute, Institute of Environmental
    Medicine, General Toxicology, Stockholm, Sweden

    Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood
    Experimental Station, Huntingdon, Cambridgeshire, England
     (Vice-Chairman)

    Dr P. E. T. Douben, Research Institute for Nature Management, Arnhem,
    Netherlands

    Dr R. J. Fielder, Department of Health, MED TEH Division, Hannibal
    House, London, England

    Dr R. A. Jedrychowski, Institute of Occupational Medicine, Lodz,
    Poland

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

    Dr T. Lakhanisky, Institut d'Hygiène et d'Epidémiologie, Brussels,
    Belgium

    Dr D. C. Villeneuve, Health Protection Branch, Environmental Health
    Centre, Tunneys Pasture, Ottawa, Ontario, Canada

    Dr R. S. H. Yang, National Institute of Environmental Health Sciences,
    Research Triangle Park, North Carolina, USA (present address: College
    of Veterinary Medicine and Biomedical Sciences, Colorado State
    University, Fort Collins, Colorado, USA)

    Observers

    Dr L. Caillard, Rhone-Poulenc, Service Toxicologie, Les Miroirs,
    Paris, France

    Secretariat

    Dr G.C. Becking, International Programme on Chemical Safety,
    Interregional Research Unit, World Health Organization, Research
    Triangle Park, North Carolina, USA  (Secretary)

    Ms M.J. Giddings, Environmental Health Directorate, Health Protection
    Branch, Environmental Health Centre, Tunneys Pasture, Ottawa, Ontario,
    Canada  (Temporary Adviser, Co-Rapporteur)

    Ms M.E. Meek, Environmental Health Directorate, Health Protection
    Branch, Environmental Health Centre, Tunneys Pasture, Ottawa, Ontario,
    Canada  (Temporary Adviser, Co-Rapporteur)


    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR CHLOROBENZENES
    OTHER THAN HEXACHLOROBENZENE

    A WHO Task Group on Environmental Health Criteria for Chlorobenzenes
    other than Hexachlorobenzene met at the Institut d'Hygiène et
    d'Epidémiologie, Brussels, Belgium, from 25 to 29 June 1990. Dr T.
    Lakhanisky opened the meeting and welcomed the Members on behalf of
    the host institute, and on behalf of the Ministère de la Santé
    Publique et de l'Environnement, who sponsored the meeting. Dr G.C.
    Becking addressed the meeting on behalf of the three cooperating
    organizations of the IPCS (UNEP, ILO, WHO). The Task Group reviewed
    and revised the draft criteria document, and made an evaluation of the
    risks for human health and the environment from exposure to
    chlorobenzenes other than hexachlorobenzene.

    The drafts of this document were prepared by Ms M.E. Meek and Ms M.J.
    Giddings, Health and Welfare Canada, Health Protection Branch, Ottawa,
    Canada. Dr G.C. Becking, IPCS Interregional Research Unit, WHO,
    Research Triangle Park, North Carolina, was responsible for the
    overall scientific content of the document, and Mrs M.O. Head, Oxford,
    England, for the editing.

    The Secretariat wishes to acknowledge the extensive comments from: Dr
    U. Schlottmann, Federal Ministry of the Environment, Germany
    (chemistry and environmental effects), and Dr R. Fielder, Department
    of Health, United Kingdom (effects on experimental animals), during
    the initial review of the document.

    Dr S. Dobson, Co-Chairman of the Task Group, and Dr P.E.T. Douben
    deserve special thanks for their significant contributions and
    revisions of the draft document during the meeting, particularly the
    sections dealing with environmental effects.

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

    NOTE TO READERS OF THE CRITERIA DOCUMENTS

    Every effort has been made to present information in the criteria
    documents as accurately as possible without unduly delaying their
    publication. In the interest of all users of the environmental health
    criteria documents, 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, which
    will appear in subsequent volumes.



                                   *  *  *



    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. 7988400/7985850).

    1. SUMMARY

    This publication focuses on the risks for human health and the
    environment from exposures to: monochlorobenzene (MCB);
    dichlorobenzenes (DCB); trichlorobenzenes (TCB); tetrachloro-benzenes
    (TeCB); and pentachlorobenzene (PeCB). Chlorine substitution is
    indicated as follows: 1,2-dichlorobenzene (1,2-DCB);
    1,2,3-trichlorobenzene (1,2,3-TCB), etc.

    1.1  Identity, Physical and Chemical Properties, Analytical Methods

    Chlorobenzenes are cyclic aromatic compounds formed by the addition of
    1-6 atoms of chlorine to the benzene ring. This yields 12 compounds:
    monochlorobenzene, three isomeric forms each of di-, tri-, and
    tetrachlorobenzenes, as well as penta- and hexachlorobenzenes.

    Chlorobenzenes are white crystalline solids at room temperature,
    except for MCB, 1,2-DCB, 1,3-DCB, and 1,2,4-TCB, which are colourless
    liquids. In general, the water solubility of chlorobenzene compounds
    is low, decreasing with increased chlorination. Flammability is low,
    the octanol/water partition coefficients are moderate to high,
    increasing with increasing chlorination, and the vapour pressures are
    low to moderate, decreasing with increasing chlorination. The taste
    and odour thresholds are low, particularly for the lower chlorinated
    compounds.

    Commercial chlorobenzenes, even when purified, contain various amounts
    of closely related isomers. For example, pure MCB may contain as much
    as 0.05 % benzene and 0.1 % DCBs, while technical 1,2-DCB may contain
    up to 19 % of the other DCBs, 1 % TCBs, and up to 0.05 % MCB. No
    evidence of contamination by polychlorinated dibenzo- p-dioxins
    (PCDDs) and dibenzofurans (PCDFs) has been reported.

    A large number of sampling techniques have been developed for
    chlorobenzenes, depending on the medium. These range from solvent
    extraction procedures for aqueous media, to the use of absorbents for
    airborne compounds. The analytical technique of choice for the
    determination of chlorobenzenes in environmental samples is gas-liquid
    chromatography (GLC).

    1.2  Sources of Human and Environmental Exposure

    1.2.1  Production figures

    Available data on chlorobenzene production levels are from the period
    1980-83, when global production was estimated to be 568 x 106 kg,
    though the use of chlorobenzenes has declined in some countries since
    then. About 50 % of this amount was manufactured within the USA and

    the remainder primarily in Western Europe and Japan. MCB accounted for
    70 % of the global production, 1,2-DCB, 1,4-DCB, and 1,2,4-TCB being
    produced at 22 x 106, 24 x 106, and 1.2-3.7 x 106 kg,
    respectively.

    MCB and DCBs are produced by the direct chlorination of benzene in the
    liquid phase, using a catalyst, while TCBs and TeCBs are produced by
    the direct chlorination of appropriate chlorobenzene isomers, in the
    presence of a metal catalyst.

    1.2.2  Uses

    Chlorobenzenes are used mainly as intermediates in the synthesis of
    pesticides and other chemicals; 1,4-DCB is used in space deodorants
    and as a moth repellent. The higher chlorinated benzenes (TCBs and
    1,2,3,4-TeCB) have been used as components of dielectric fluids.

    1.2.3  Release of chlorobenzenes into the environment

    The release of chlorobenzenes into the environment occurs primarily
    during manufacture, and through the dispersive nature of their uses.
    For example, in the USA, between 0.1 and 0.2 % of the 1983 production
    of 130 x 106 kg of MCB was estimated to have been lost to the
    environment. Releases of chlorobenzenes from waste disposal, including
    incineration of municipal waste, are much lower. However, the
    incineration of chlorobenzenes may lead to the emission of PCDDs and
    PCDFs.

    1.3  Environmental Transport, Distribution, and Transformation

    1.3.1  Degradation

    Chlorobenzenes are removed from the environment principally by
    biological, and, to a lesser extent, by non-biological mechanisms;
    however, they are considered moderately persistent in water, air, and
    sediments. Residence times in water of 1 day in rivers and over 100
    days in ground water have been reported. In air, chemical and
    photolytic reactions are presumed to be the predominant pathways for
    chlorobenzene degradation, with residence times in the range of 13-116
    days reported for MCB, DCBs, and an unspecified TCB isomer.

    Many microorganisms from sediments and sewage sludge have been shown
    to degrade chlorobenzenes. It would appear that the higher chlorinated
    compounds are less readily degraded, and such degradation occurs only
    under aerobic conditions. Under anaerobic conditions in soil and
    ground water, DCB, TCBs, and PeCBs are usually resistant to microbial
    degradation.

    1.3.2  Fate

    Chlorobenzenes released into the aquatic environment will be
    redistributed preferentially to the air and to sediment (particularly
    organically rich sediments). Limited information has shown that levels
    1000 times those found in water have been detected in sediments,
    particularly in highly industrialized regions. Retention of
    chlorobenzenes in soil increases with the organic content of the soil;
    there is a positive correlation between the degree of chlorination of
    the compound and its adsorption on organic matter. Limited evidence is
    available showing that sediment-bound residues are bioavailable to
    organisms; i.e., aquatic invertebrates can take up residues from
    sediment, and plants, from soil.

    1.4  Environmental Levels and Human Exposure

    1.4.1  Chlorobenzenes in the environment

    Mean levels of chlorobenzenes (mono- to tri-) in ambient air are of
    the order of 0.1 µg/m3, with maximum levels of up to 100 µg/m3. No
    data are available on levels of TeCB and PeCB in ambient air, though
    these chemicals have been detected in fly ash from municipal
    incinerators. Levels of chlorobenzenes in indoor air are similar to
    those in ambient air; however, levels much higher than those in the
    ambient air have been reported in heavily polluted areas, and in
    enclosed spaces where chlorobenzene-containing products have been
    used.

    Chlorobenzenes (mono- to penta-) have been detected in surface waters
    in the ng/litre-µg/litre range, with occasional levels of up to tenths
    of one mg/litre reported near industrial sources. Levels of
    chlorobenzenes in industrial waste waters may be higher and vary
    according to the nature of the processes used.

    All chlorobenzene congeners have been detected in the drinking-water
    samples analysed. The lower chlorinated compounds were found most
    frequently and in the highest concentrations, with the 1,4-DCB isomer
    predominating; however, the mean concentrations of any chlorobenzene
    detected have generally been less than 1 µg/litre and have rarely
    exceeded 50 µg/litre.

    Data from well-designed monitoring programmes on chlorobenzene levels
    in food have not been found; available information has mainly been
    confined to concentrations in fish in the vicinity of industrial
    sources and to isolated incidents of contamination of meat products.
    All chlorobenzene isomers (mono- to penta-) were detected in
    freshwater trout, with levels ranging from 0.1 to 16 µg/kg. In another
    study, levels of total chlorobenzenes in freshwater fish varied from
    a mean of 0.2 mg/kg fat in lightly polluted areas to 1.8 mg/kg fat in

    an industrialized area. There is some indication that concentrations
    of chlorobenzenes in freshwater fish increase with increasing degree
    of chlorination of the compound. The few studies available indicate
    levels of 1,4-DCB in some marine fish of 0.05 mg/kg (wet weight).

    In the available studies on chlorobenzene levels in meat and milk,
    limited primarily to samples from contaminated areas, concentrations
    of 0.02-5 µg/kg have been reported.

    In 2 surveys of human milk, the levels of all chlorobenzene congeners,
    except MCB, were quantified. In one study, the levels of DCBs averaged
    25 µg/kg milk, whereas the TCB and TeCB isomers and PeCB were found at
    mean levels of less than 5 µg/kg milk. Levels in the second survey
    were much lower, mean concentrations ranging from 1 µg/kg (1,2,3-TCB
    and PeCB) to a maximum of 6 µg/kg (1,3- and 1,4-dichlorobenzene).

    1.4.2  Human exposure

    1.4.2.1  General population

    On the basis of limited data, the daily intake of chlorobenzenes
    within the general population appears to be greatest from air,
    particularly for the lower, more volatile compounds (0.2-0.9 µ/kg body
    weight). Intake from food compared with that from other sources
    increases with increasing degree of chlorination; food contributes a
    greater percentage of the total daily intake of TeCBs and PeCB than
    air. However, exposure levels for such congeners are likely to be less
    than 0.05 µg/kg body weight. A limited number of studies have shown
    that, on a body weight basis, breast-fed infants may receive a higher
    dose of chlorobenzenes than members of the adult population.

    1.4.2.2  Occupational

    It is not possible to make an accurate quantification of occupational
    exposure to chlorobenzenes on the basis of available data. However,
    levels of 1,4-DCB ranged between 42 and 288 mg/m3 in one plant, and
    levels of MCB of up to 18.7 mg/m3 were found in other chemical
    plants. 

    1.5  Kinetics and Metabolism

    All chlorobenzenes appear to be absorbed readily from the
    gastrointestinal and respiratory tracts in humans and experimental
    animals, with absorption influenced by the position of the chlorine in
    different isomers of the same congener. The chlorobenzenes are less
    readily absorbed through the skin.

    After rapid distribution to highly perfused organs in experimental
    animals, absorbed chlorobenzenes accumulate primarily in the fatty
    tissue, with smaller amounts in the liver and other organs.

    Chlorobenzenes have been shown to cross the placenta, and have been
    found in the fetal brain. In general, accumulation is greater for the
    more highly chlorinated congeners. There is considerable variation,
    however, in the accumulation of different isomers of the same
    congener.

    In both humans and experimental animals, the metabolism of
    chlorobenzenes proceeds via microsomal oxidation to the corresponding
    chlorophenol. These chlorophenols can be excreted in the urine as
    mercapturic acids, or as glucuronic acid or sulfate conjugates. TeCB
    and PeCB are metabolized at a slower rate and remain in the tissues
    for longer periods than the monochloro- to trichloro- congeners. Some
    of the chlorobenzenes induce a wide range of enzyme systems including
    those involved in oxidative, reductive, conjugation, and hydrolytic
    pathways.

    In general, elimination of the higher chlorinated benzenes is slower
    than that of the MCB and DCB congeners, and a greater proportion of
    the tri- to penta- congeners are eliminated unchanged in the faeces.
    For example, 17% of a dose of 1,2,4-TCB was eliminated in the faeces
    after 7 days, whereas 91-97% of 1,4-DCB was eliminated as metabolites
    in the urine after 5 days. The position of the chlorine atoms on the
    benzene ring is also an important determinant of the rate of
    metabolism and elimination, the isomers with two adjacent
    unsubstituted carbon atoms being more rapidly metabolized and
    eliminated.

    1.6  Effects on Aquatic Organisms in the Environment

    Available information on the effects of chlorobenzenes on the
    environment is mainly focused on acute effects on aquatic organisms.
    In general, toxicity increases with the degree of chlorination of the
    benzene ring. While MCB, 1,2-DCB, 1,3-DCB, 1,2,4-TCB, 1,3,5-TCB, and
    1,2,4,5-TeCB all exhibit a low toxicity for microorganisms, the
    toxicity of the TCBs and TeCBs is, with the exception of 1,2,4,5-TeCB,
    slightly higher than that of the other compounds; in unicellular
    aquatic algae, EC50 values for 96-h cell growth or chlorophyll a
    production ranged from over 300 mg/litre for MCB to approximately 1
    mg/litre for 1,2,3,5-TeCB.  Some aquatic invertebrates appear more
    sensitive to chlorobenzenes, but levels required for 48- or 96-h
    lethality are still near, or well above, 1 mg/litre (e.g.,  Daphnia
     magna at 2.4 mg/litre for 1,2-DCB, and up to 530 mg/litre for
    1,2,4,5-TeCB).

    The 96-h LC50 for bluegill sunfish ranged between 0.3 mg/litre for
    PeCB and 24 mg/litre for MCB. In embryo-larval assays, the chronic
    toxicity limits for DCBs varied between 0.76 and 2.0 mg/litre for the
    fathead minnow; in the estuarine sheepshead minnow, the chronic
    toxicity limits for 1,2,4-TCB and 1,2,4,5-TeCB were 0.22 and

    0.13 mg/litre, respectively. Newly-hatched goldfish and large-mouth
    bass were the most susceptible life-stage with LC50s (96-h) of 1 and
    0.05 mg/litre, respectively, for MCB.

    No data are available on the effects of chlorobenzenes on terrestrial
    systems.

    1.7  Effects on Experimental Animals and  In Vitro Systems

    With few exceptions, the chlorobenzenes are only moderately toxic for
    experimental animals, on an acute basis, and, generally, have oral
    LD50s greater than 1000 mg/kg body weight; from the limited data
    available, dermal LD50s are higher. The ingestion of a lethal dose
    leads to respiratory paralysis, while the inhalation of high doses
    causes local irritation and depression of the central nervous system.
    Acute exposures to non-lethal doses of chlorobenzenes induce toxic
    effects on the liver, kidneys, adrenal glands, mucous membranes, and
    brain, and effects on metabolizing enzymes.

    Studies on skin and eye irritation caused by chlorobenzenes have been
    restricted to 1,2,4-TCB and 1,2-DCB. Both produce severe discomfort,
    but no permanent damage was noted after direct application to the
    rabbit eye. 1,2,4-TCB is mildly irritating to the skin and may lead to
    dermatitis after repeated or prolonged contact. No evidence of
    sensitization was found.

    Short-term exposures (5-21 days) of rats and mice to MCB and DCBs at
    hundreds of mg/kg body weight resulted in liver damage and
    haematological changes indicative of bone marrow damage. Liver damage
    was also the major adverse effect noted after the short-term exposure
    of rats or rabbits to other chlorobenzenes (TCB-PeCB), at doses
    slightly lower than those for MCB and DCBs. Several of the
    chlorobenzene isomers studied induced porphyria, the isomers with
     para chlorine atoms being the most active (i.e., 1,4-DCB, 1,2,4-TCB,
    1,2,3,,4-TeCB, and PeCB). The general order of toxicity noted for
    TeCBs and PeCB after short-term exposure was: 1,2,4,5-TeCB
    >PeCB>1,2,3,4- and 1,2,3,5-TeCB, which correlated well with the
    levels found in fat and liver.

    Long-term exposure studies (up to 6 months) on several species of
    experimental animals indicated a trend for the toxicity of
    chlorobenzenes to increase with increased ring chlorination. However,
    there was considerable variation in the long-term toxicities of
    different isomers of the same congener. For example, 1,4-DCB appeared
    to be much less toxic than 1,2-DCB. There was a good correlation
    between toxicity and the degree of accumulation of the compound in the
    body tissues, female animals being less sensitive than males. Major
    target organs were the liver and kidney; at higher doses, effects on
    the haematopoietic system were reported and thyroid toxicity was noted
    in studies on 1,2,4,5-TeCB and PeCB.

    In a bioassay for the carcinogenicity of MCB, there was an increased
    incidence of hepatic neoplastic nodules in the high-dose group
    (120 mg/kg body weight) of male F344 rats, but no treatment-related
    increases in tumour incidence in female F344 rats or male or female
    B6C3F1 mice. There was no evidence for the carcino-genicity of
    1,2-DCB in male or female F344 rats or B6C3F1 mice (60 or 120 mg/kg
    body weight).

    In a bioassay for the carcinogenicity of 1,4-DCB, there was a
    dose-related increase in renal tubular cell adenocarcinomas in male
    F344 rats and an increase in hepatocellular carcinomas and adenomas in
    both sexes of B6C3F1 mice. No evidence of carcinogenicity was
    reported in male and female Wistar rats, or female Swiss mice,
    following inhalation of slightly higher doses of 1,4-DCB (estimated to
    be 400 mg/kg per day for rats and 790 mg/kg per day for mice) for
    shorter periods. However, available data indicate that the induction
    of renal tumours by 1,4-DCB in male F344 rats and the associated
    severe nephropathy and hyaline droplet formation are species- and
    sex-specific responses associated with the reabsorption of
    alpha-2-microglobulin.

    Available data are inadequate for the assessment of the
    carcinogenicity of the higher chlorinated benzenes (tri- to penta-).

    Although available data from  in vitro and  in vivo assays for
    isomers other than 1,4-DCB are limited, chlorobenzenes do not appear
    to be mutagenic.  On the basis of a more extensive database for
    1,4-DCB, it can be concluded that this compound has no mutagenic
    potential, either  in vivo or  in vitro.

    There has been no evidence that chlorobenzenes are teratogenic in rats
    and rabbits. The administration of MCB and DCBs to rats or rabbits via
    inhalation at concentrations >2000 mg/m3 (approximately 550 mg/kg
    body weight per day) and, orally, at concentrations >500 mg/kg body
    weight, resulted in minor embryotoxic and fetotoxic effects.  However,
    such doses were clearly toxic to the mother. Although there is some
    evidence that TCBs, TeCBs, and PeCB are embryotoxic and fetotoxic at
    doses that are not toxic for the mother, available data are
    inconsistent.

    1.8  Effects on Humans

    1.8.1  General population

    Reports on the effects of CBs on the general population are restricted
    to case reports from accidents and/or the misuse of products
    containing the lower chlorinated benzenes (MCB, 1,2-DCB, 1,4-DCB, and
    an unspecified isomer of TCB). Little or no information is available

    on dose, chemical purity, or dose:time relationships and observed
    effects, such as myeloblastic leukaemia, rhinitis, glomerulonephritis,
    pulmonary granulomatosis, dizziness, tremor, ataxia, polyneuritis, and
    jaundice, cannot be quantified.

    No epidemiological studies on the health effects of chlorobenzenes in
    the general population have been reported.

    1.8.2  Occupational exposure

    During the manufacture and use of chlorobenzenes, clinical symptoms
    and signs of excessive exposure include: central nervous system
    effects and irritation of the eyes and upper respiratory tract (MCB);
    haematological disorders (1,2-DCB); and central nervous system
    effects, hardening of the skin, and haematological disorders including
    anaemia (1,4-DCB). However, such symptoms come only from case reports,
    and are difficult to quantify, since little information on actual
    levels, chemical purity, or dose:time relationships is available.

    The few epidemiological studies on workers exposed to chlorobenzenes
    that have been reported concern only MCB, 1,2-DCB, 1,4-DCB, and
    1,2,4,5-TeCB. Although effects on the nervous system, on neonatal
    development, and on the skin have been reported after MCB exposures,
    the 3 studies were not adequate for assessing risk, because of
    methodological problems, such as exposure assessment, mixed exposures,
    and lack of control groups. Similar criticism can be made of the study
    on 1,4-DCB, in which eye and nose irritation was reported, as well as
    the study in which chromosomal aberrations resulting from exposure to
    unspecified levels of 1,2-DCB and 1,2,4,5-TeCB were reported.

    1.9  Conclusions

    If good industrial practices are followed, the risks associated with
    occupational exposure to chlorobenzenes are considered to be minimal.
    The present risk assessment also indicates that current concentrations
    of chlorobenzenes in the environment pose a minimal risk for the
    general population, except in the case of the misuse of
    chlorobenzene-based products or their uncontrolled discharge into the
    environment. However, this assessment is based on limited monitoring
    data and additional information is needed to substantiate this
    conclusion. Reduction of the widespread use and disposal of
    chlorobenzenes should, however, be considered because:

     (a) Chlorobenzenes may act as precursors for the formation of
    polychlorinated dibenzodioxins/polychlorinated dibenzofurans
    (PCDDs/PCDFs), e.g., in incineration processes.

     (b) These chemicals can lead to taste and odour problems in
    drinking-water and fish.

     (c) Residues persist in organically-rich anaerobic sediments and
    soils, and ground water.

    For most chlorobenzenes, the assessment of risk has been based on
    non-neoplastic effects. However, neoplastic effects were taken into
    consideration in the risk assessment for MCB and 1,4-DCB. Available
    data indicate that the observed increase in renal tumours in rats
    caused by 1,4-DCB is a species- and sex-specific response that is
    unlikely to be relevant for humans. On the basis of evidence of
    increased  DNA  replication  in  the mouse  liver  and  the  increased
    incidence of hepatocellular adenomas and carcinomas in mice, 1,4-DCB
    may  act as a non-genotoxic carcinogen in the rodent liver. The
    increased incidence of hepatic neoplastic nodules observed in the
    high-dose group of male rats in a bioassay for carcinogenicity
    indicates that MCB may also be a non-genotoxic carcinogen. 

    2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1  Identity

    2.1.1  Primary constituent

    The chlorinated benzenes are cyclic aromatic compounds in which the
    hydrogen atoms of the benzene ring have been replaced by 1-6 chlorine
    substituents (Fig. 1). This substitution yields 12 compounds,
    including: monochlorobenzene, 3 isomeric forms of dichlorobenzene, 3
    isomers of trichlorobenzene, 3 isomers of tetrachlorobenzene,
    pentachlorobenzene, and hexachlorobenzene. The identification features
    for the congeners ranging from mono to pentachlorobenzene are
    summarized in Table 1.

    FIGURE 1

    Hexachlorobenzene is the subject of a separate Environmental Health
    Criteria publication and will not be evaluated here.

    2.1.2  Technical product

    There are no widely established trade specifications for commercial
    chlorobenzenes. Pure commercial monochlorobenzene may contain 0.05 %
    or less of benzene and up to 0.1 % of dichlorobenzenes. Technical
    grade 1,2-dichlorobenzene contains up to 19 % of the other 2
    dichlorobenzene isomers, 1 % of trichlorobenzenes, and up to 0.05 % of
    monochlorobenzene, while purified 1,2-dichlorobenzene contains up to
    0.05 % of monochlorobenzene and 0.2 % of 1,2,4-trichlorobenzene.

    Technical grade 1,4-dichlorobenzene contains up to a total of 0.1 % of
    mono- and trichlorobenzenes and 0.5 % of each of the other
    dichlorobenzene isomers. Commercial 1,2,4-trichlorobenzene may contain
    up to 0.1 % of mono-chlorobenzene, 0.5 % of dichlorobenzenes, and
    0.5 % of tetrachlorobenzenes (Kao & Poffenberger, 1979).

    Polychlorinated dibenzodioxins or dibenzofurans were not detected in
    trichlorobenzenes, tetrachlorobenzenes, or penta-chlorobenzene (Buser,
    1979).

    2.2  Physical and Chemical Properties

    The physical and chemical properties of the chlorobenzenes (mono- to
    penta-) are presented in Table 2.

    MCB, 1,2-DCB, 1,3-DCB, and 1,2,4-TCB are colourless liquids, while all
    other congeners are white crystalline solids at room temperature. In
    general, the solubility of chlorobenzenes in water is poor (decreasing
    with increasing chlorination), flammability is low, the octanol/water
    partition coefficients are moderate to high (increasing with
    increasing chlorination), and vapour pressures are low to moderate
    (decreasing with increasing chlorination).

    2.3  Organoleptic Properties

    The odour and taste thresholds for different isomers of the same
    chlorobenzene appear to be similar: 0.01-0.02 mg/litre for MCB and 
    0.001-0.002 mg/litre  for  both  1,2-DCB  and  1,4-DCB (Varshavskaya,
    1968). Piet et al. (1980) reported that the odour thresholds for 1,2-
    and 1,4-dichlorobenzenes in Rhine tap water were 10 and 0.3 µg/litre
    respectively, while 1,2,4-TCB was detected at a level of 5 µg/litre.
    Using available experimental data, Amoore & Hautala (1983) determined
    water-dilution odour thresholds for MCB, 1,2-DCB, 1,4-DCB, and
    1,2,4-TCB to be 0.050, 0.024, 0.011, and 0.064 mg/litre (ppm),
    respectively. Odour thresholds in air for these compounds are 0.68,
    0.30, 0.18, and 1.4 µlitre/litre (ppm), respectively. Fomenko (1965)
    reported that the thresholds for smell and taste for 1,2,4,5-TeCB were
    0.006 mg/litre and 0.0064 mg/litre, respectively.

    2.4  Conversion Factors

    At 25 °C and 101.3 kPa, the conversion factors for chlorobenzenes in
    air are as follows:

    monochlorobenzene:       1 ppm=4.55 mg/m3: 1 mg/m3=0.22 ppm
    dichlorobenzenes:        1 ppm=6.00 mg/m3: 1 mg/m3=0.17 ppm
    trichlorobenzenes:       1 ppm=7.42 mg/m3: 1 mg/m3=0.13 ppm
    tetrachlorobenzenes:     1 ppm=8.83 mg/m3: 1 mg/m3=0.11 ppm
    pentachlorobenzene:      1 ppm=10.24 mg/m3: 1 mg/m3=0.10 ppm


    
    Table 1.  Information on the identity of chlorobenzenes
                                                                                                                                    

    Compound                         Congener              Molecular        R.M.M.b          Synonyms
    (CAS number)a                    identification        formula
                                                                                                                                    

    Monochlorobenzene                MCB                   C6H5Cl           112.6            chlorobenzene
    (108-90-7)                                                                               phenyl chloride

    1,2-dichlorobenzene              1,2-DCB               C6H4Cl2          147.0            ortho-dichlorobenzene
    (95-50-1)                                                                                o-dichlorobenzene

    1,3-dichlorobenzene              1,3-DCB               C6H4Cl2          147.0            meta-dichlorobenzene
    (541-73-1)                                                                               m-dichlorobenzene

    1,4-dichlorobenzene              1,4-DCB               C6H4Cl2          147.0            para-dichlorobenzene
    (106-46-7)                                                                               p-dichlorobenzene

    1,2,3-trichlorobenzene           1,2,3-TCB             C6H3Cl3          181.5            vic-trichlorobenzene
    (87-61-6)                                                                                v-trichlorobenzene
                                                                                             1,2,6-trichlorobenzene

    1,2,4-trichlorobenzene           1,2,4-TCB             C6H3Cl3          181.5            1,2,4-trichlorobenzol
    (120-82-1)

    1,3,5-trichlorobenzene           1,3,5-TCB             C6H3Cl3          181.5            s-trichlorobenzene
    (108-70-3)                                                                               TCBA
                                                                                             sym-trichlorobenzene

    1,2,3,4-tetrachlorobenzene       1,2,3,4-TeCB          C6H2Cl4          215.9            benzene, 1,2,3,4-
    (634-66-2)                                                                               tetrachloro-

    1,2,3,5-tetrachlorobenzene       1,2,3,5-TeCB          C6H2Cl4          215.9            benzene, 1,2,3,5-
    (634-90-2)                                                                               tetrachloro-
                                                                                                                                    

    Table 1 (continued)
                                                                                                                                    

    Compound                         Congener              Molecular        R.M.M.b          Synonyms
    (CAS number)a                    identification        formula
                                                                                                                                    

    1,2,4,5-tetrachlorobenzene       1,2,4,5-TeCB          C6H2Cl4          215.9            benzene, tetrachloride
    (95-94-3)                                                                                benzene, 1,2,4,5-
                                                                                             tetrachloro-
                                                                                             s-tetrachlorobenzene

    Pentachlorobenzene               PeCB                  C6HCl5           250.3            1,2,3,4,5-
    (608-93-5)                                                                               pentachloro-benzene
                                                                                             QCB
                                                                                                                                    

    a    Chemical Abstract Services registry number.
    b    R.M.M. - Relative molecular mass.

    Table 2.  Physical and chemical properties
                                                                                                                                              

                                                                     Solubility     Log              Henry's        Soil          Blood/air
    Compound       Melting    Boiling     Vapour      Densityf       in water at    octanol/water    Law            sorption      partition
                   point      point       pressure                   25 °C (mol/    partition        constant       coefficient   coefficientj
                   (°C)a      (°C)a       at 25 °C                   litre)         coefficientg     (kPa m3/       (KOC)i
                                          (Pa)                       (mg/litre)g                     mol)h
                                                                                                                                              

    MCB            -45.6      132.0      1665b        1.105820/4     2.6x10-3       2.98             0.377          466           30.8
                                                                     (293)

    1,2-DCB        -17.0      180.5       197b        1.304820/4     6.2x10-4       3.38             0.198          987           423
                                                                     (91.1)

    1,3-DCB        -24.7      173.0       269b        1.288420/4     8.4x10-4       3.48             0.366          1070          201.4
                                                                     (123)

    1,4-DCB        53.1       174.0        90c        1,247520/4     2.1x10-4       3.38             0.160          1470          NA
                                                                     (30.9)

    1,2,3-TCB      53.5       218.5         17.3d     NA             6.7x10-5       4.04             0.306          3680          NA
                                                                     (12.2)

    1,2,4-TCB      17.0       213.5         45.3d     1.454220/4     2.5x10-4       3.98             0.439          2670          NA
                                                                     (45.3)

    1,3,5-TCB      63.5       208761        24.0d     NA             2.2x10-5       4.02             0.233          NA            NA
                                                                     (3.99)

    1,2,3,4-TeCB   47.5       254.0          5.2c     NA             5.6x10-5       4.55             0.261          NA            NA
                                                                     (12.1)

    1,2,3,5-TeCB   54.5       246.0          9.8c     NA             1.3x10-5       4.65             0.593          8560          NA
                                                                     (2.81)
                                                                                                                                              

    Table 2 (continued)
                                                                                                                                              

                                                                     Solubility     Log              Henry's        Soil          Blood/air
    Compound       Melting    Boiling     Vapour      Densityf       in water at    octanol/water    Law            sorption      partition
                   point      point       pressure                   25 °C (mol/    partition        constant       coefficient   coefficientj
                   (°C)a      (°C)a       at 25 °C                   litre)         coefficientg     (kPa m3/       (KOC)i
                                          (Pa)                       (mg/litre)g                     mol)h
                                                                                                                                              

    1,2,4,5-TeCB   139.5      243.6       0.72c       NA             1.0x10-5       4.51             0.261          6990          NA
                                                                     (2.16)

    PeCB           86.0       277.0       133 at      1.834216.5     3.3x10-6       5.03             0.977          58 700        NA
                                          98.6 °Ce                   (0.83)
                                                                                                                                              

    a    Melting points are rounded to the nearest 0.1 °C;  Boiling points are at atmospheric pressure (760 mm), unless otherwise indicated
         by a superscript (Weast, 1986).
    b    Vapour pressures obtained from the Antoine equation: log10p(kPa) = A-B/(T+C) - 0.8751 presented by Kao & Poffenberger (1979),
         together with the values for the Antoiine constants (A,B,C).T = temperature in °C.
    c    From: MacKay et al. (1982). The value was derived from experimental data obtained above 25 °C and extrapolated to 25 °C, taking into
         account the phase change from liquid to solid.
    d    Vapour pressures obtained from the equation: log10p(10-3torr) = -(A/T) + B and values for the constants (A and B) are presented by
         Sears & Hopke (1949).T = absolute temperature.
    e    From: Stull (1947).
    f    Density is relative to water, otherwise it has the dimensions g/ml.  A superscript indicates the temperature of the liquid and a
         subscript indicates the temperature of water to which the density is referred (Weast, 1986).
    g    From: Miller et al. (1984).
    h    From: MacKay & Shiu (1981).
    i    Derived from: Karlokoff et al. (1979).
    j    From: Sato & Nakajima (1979).
         NA - values either not given in the reference indicated or not found in the literature.

    

    2.5  Analytical Methods

    Some methods for the sampling and determination of chlorobenzenes in
    various environmental media and human tissues and fluids are
    presented in Table 3.

    The analytical technique of choice for the determination of
    chlorobenzenes in environmental samples is gas-liquid chromatography
    (GLC). However, the methods of collection and preparation of samples
    for GLC analysis vary considerably, depending on the medium and the
    laboratory. Columns with silicone-based stationary phases or Tenax
    resins, and electron capture detectors, appear to be the most widely
    used.

    Tenax-GC resins appear to be the most commonly used absorbent for
    the air sampling of chlorobenzenes (Sievers et al., 1980; Krost et
    al., 1982; Pellizzari, 1982), though XAD resins have also been used
    (Langhorst & Nestrick, 1979). Air pollutants collected on Tenax-GC
    resins can be desorbed directly on to the GLC column by heating the
    absorber.  XAD resins can be extracted with carbon tetrachloride, an
    aliquot of which can then be injected into a gas chromatograph
    (Langhorst & Nestrick, 1979).

    Solvent extraction is a simple and effective technique for
    recovering chlorobenzenes from water samples. Hexane, pentane, and a
    1:1 mixture of cyclohexane and diethyl ether have been identified as
    suitable extraction solvents for these compounds (Oliver & Bothen,
    1980; Piet et al., 1980; Otson & Williams, 1981). Alternatively,
    preconcentration of the chlorobenzenes on organic resins, such as
    Chromosorb 102 and Tenax-GC, is also effective (Oliver & Bothen,
    1980; Pankow & Isabelle, 1982). The purge-trap method is also often
    used to concentrate the volatile halogenated benzenes before
    analysis using GC (Jungclaus et al., 1978; Pereira & Hughes, 1980;
    Otson & Williams, 1982).

    The extraction of chlorobenzenes from aquatic sediments or soil can
    be achieved by solvent or Soxhlet extraction (Oliver & Bothen, 1982;
    Lopez-Avila et al., 1983; Onuska & Terry, 1985). Solvents commonly
    used are acetone and/or hexane. The extract is generally dried using
    sodium sulfate, followed by clean-up on a Florisil column before GLC
    analysis.

    For the detection of chlorobenzenes in fish samples, solvent or
    Soxhlet extraction with subsequent clean-up on Florisil and GC
    analysis with electron capture detection have commonly been used
    (Lunde & Ofstad, 1976; Kuehl et al., 1980; Oliver & Bothen, 1982).
    Vacuum extraction and the direct purge and trap method have also
    been used to quantify levels of MCB in fish tissue (Hiatt, 1981).


    
    Table 3.  Analytical methods for chlorobenzenesa
                                                                                                                                              

    Matrix           Sampling, extraction                Analytical method                   Detection limitsb            Reference
                                                                                                                                              

    air              continuous flow, aircraft           trap purged in oven at              NA                           Sievers et al. (1980)
                     sampling port; sorbent traps        220 °C with He; capillary
                     with 4 changes                      column (30 m x 0.3 mm),
                                                         gas chromatography-mass
                                                         spectrometry (GC-MS) data
                                                         system

    air              4-h samples collected on            silanized glass column; GC          MCB           3.2            Langhorst & Nestrick
                     Amberlite XAD-Z resin at            with photoionization detector       DCBs          4.2            (1979)
                     100-200 ml/min; desorbed                                                TCBs          5.9
                                                                                             TeCB          7.1
                                                                                             PeCB          9.2

    water            500 ml with chromosorb 102, or      GC analysis, glass capillary        MCB           0.5            Oliver & Bothen
                     3.1 litres with 75 ml pentane       columns; electron capture           DCBs          0.001          (1980)
                                                                                             TCBs          0.0001
                                                                                             TeCB          0.00005
                                                                                             PeCB          0.00001

    water            40 ml with automated purge and      GC analysis with                    FID                          Otson & Williams
                     trap; inert gas bubbled through     simultaneous use of flame           MCB           < 0.1          (1982)
                     purged compounds directly on        ionization detector (FID)           1,2-DCB       0.2
                     to column                           and Hall electrolytic               1,3-DCB       0.1
                                                         conductivity detector (HECD)        1,4-DCB       0.1
                                                                                             HECD
                                                                                             MCB           0.1
                                                                                             1,2-DCB       0.1
                                                                                             1,3-DCB       0.1
                                                                                             1,4-DCB       0.1
                                                                                                                                              

    Table 3 (continued)
                                                                                                                                              

    Matrix           Sampling, extraction                Analytical method                   Detection limitsb            Reference
                                                                                                                                              

    water            liquid-liquid extraction of 120 ml  GC analysis using 63Ni              FID                          Otson & Williams
                     water with 38:1 water:hexane        electron capture detector           MCB           5              (1981)
                                                         (ECD), FID or HECD                  1,2-DCB       2
                                                                                             1,4-DCB       2
                                                                                             1,2,4-TCB     2
                                                                                             ECD
                                                                                             MCB           ND
                                                                                             1,2-DCB       5
                                                                                             1,4-DCB       5
                                                                                             1,2,4-TCB     < 1
                                                                                             HECD
                                                                                             MCB           1
                                                                                             1,2-DCB       < 1
                                                                                             1,4-DCB       < 1
                                                                                             1,2,4-TCB     < 1

    water            extraction of 4 litres water with   compounds desorbed directly         NA                           Pankow & Isabelle
                     Tenax-GC 35/60 mesh;                from glass column of                                             (1982)
                     centrifugation or vacuum            Tenax-GC into GC by flash
                     dessication of wet cartridge        heating; flame ionization
                     to remove water                     detector

    water            extraction of 1-litre sample with   glass capillary column              NA                           Piet et al. (1980)
                     20 ml cyclohexane-diethylether      coupled to electron detector
                     (1:1)                               on line with FID detector

    water            adsorption on 1 g of activated      GC analysis, FID detector           MCB concentration range:     Blanchard & Hardy
                     charcoal in exposure chamber;                                           0.058-19.4 mg/litre          (1985)
                     charcoal desorbed with 5 ml of
                     carbon disulfide for >30 min
                                                                                                                                              

    Table 3 (continued)
                                                                                                                                              

    Matrix           Sampling, extraction                Analytical method                   Detection limitsb            Reference
                                                                                                                                              

    sediment         Soxhlet extraction of 10-15 g       GC analysis on glass                MCB           1500           Oliver & Bothen
                     with 41% hexane/59% acetone;        capillary columns; electron         DCBs          5              (1982)
                     back-extracted with water to        capture detector                    TCBs          0.4
                     remove acetone, through Na2SO4                                          TeCBs         0.2
                     and evaporated to 10 ml;                                                PeCB          0.05
                     clean-up on Na2SO4 + deactivated
                     Florisil column

    sediment         10 g sediment treated by steam      identification by relative          1,3-DCB       1.5            Onuska & Terry
                     distillation, soxhlet or            retention-time matching after       1,3,5-TCB     1.0            (1985)
                     ultrasonic extraction; clean-up     ECD                                 1,2,4-TCB     0.8
                     with mercury only needed when                                           1,2,3-TCB     0.8
                     sulfur present                                                          1,2,3,5-TeCB  0.5
                                                                                             1,2,4,5-TeCB  0.5
                                                                                             1,2,3,4-TeCB  0.5
                                                                                             PeCB          0.4

    fish             15 g fish soxhlet extracted;        GC analysis on glass                MCB           1500           Oliver & Bothen
                     clean-up with combination of        capillary column, ECD               DCBs          5              (1982)
                     alumina, silica gel, florisil and   detector                            TCBs          0.4
                     acidified florisil (fish), after                                        TeCBS         0.2
                     removal of lipids                                                       PeCB          0.05

    blood            hexane extraction on Synder         borosilicate glass column,          DCBs          approx. 2      Bristol et al.
                     column using 3 g for GC and         GC analysis; electron capture       TCBs          approx. 1.5    (1982)
                     710 g for GC/MS                     detector or GC/MS system            TeCBs         approx. 1
                                                                                             PeCB          approx. 1
                                                                                                                                              

    Table 3 (continued)
                                                                                                                                              

    Matrix           Sampling, extraction                Analytical method                   Detection limitsb            Reference
                                                                                                                                              

    blood            CCl4 extraction of 5 g of blood     silanized glass column; GC          Blood                        Langhorst & Nestrick
    urine            or 20 g urine, silica gel column    analysis with photoionization       MCB           approx.23      (1979)
                     chromatography (CCl4 eluent)        detector                            DCBs          approx. 4
                                                                                             TCBs          approx. 5
                                                                                             TeCBs         approx. 6
                                                                                             PeCB          approx. 9
                                                                                             Urine
                                                                                             MCB           approx. 6
                                                                                             DCBs          approx. 6
                                                                                             TCBs          approx. 1
                                                                                             TeCBs         approx. 2
                                                                                             PeCB          approx. 2

    blood            0.1-1 ml GC sample diluted to       Tenax adsorbent heated and          NA                           Balkon & Leary (1979)
    urine            5 ml with water and placed in a     volatiles analysed by GC/MS
                     bubbler for purging on to Tenax     for detection and
                     in liquid sample concentrator       identification in a screening
                                                         procedure

    blood            hexane/isopropanol extraction of    GC analysis, electron capture       NA                           Lunde & Bjorseth
                     approximately 25 g; H2SO4           detector                                                         (1977)
                     digestion of hexane phase

    adipose tissue   extraction of tissue with           GC analysis, capillary              DCBs          ND             LeBel & Williams
                     acetone-hexane, then fractionated   column, ECD detection;              1,3,5-TCB     11.0 µg/kg     (1986)
                     by gel permeation                   chromatography compounds                          5.9 µg/kg
                     (GPC); clean-up on Florisil column  confirmed by gas                    1,2,3,5-TeCB  13.1 µg/kg
                                                         chromatography-mass spectrometry    1,2,3,4-TeCB  4.8 µg/kg
                                                         with selected ion monitoring        PeCB          1.9 µg/kg
                                                                                                                                              

    Table 3 (continued)
                                                                                                                                              

    Matrix           Sampling, extraction                Analytical method                   Detection limitsb            Reference
                                                                                                                                              

    urine            solutions stirred and heated to     Analysis by GC/FID                  MCB                          Michael et al.
    blood            50 °C, headspace above the                                              blood         98c            (1980)
    adipose tissue   solution purged on to Tenax GC                                          urine         86c
                     cartridges; cartridges dessicated                                       adipose       13c
                     using anhydrous calcium sulfate
                     and thermally desorbed                                                  DCB
                                                                                             blood         86c
                                                                                             urine         79c
                                                                                             adipose       57c

    urine            5 ml samples:                       GC equipped with an electron        urine         94c            McKinney et al.
    blood            Urine: acidified with 0.5 ml        capture (tritium) detector          blood         78c            (1970)
                     concentrated HCl, then extracted
                     with benzene Extracts dried over
                     anhydrous sodium sulfate
                     Blood: plasma extracted with
                     benzene, then dried with
                     anhydrous sodium sulfate

    adipose tissue   2-g samples extracted with          analysis by GC with electron        NA                           Mes et al. (1982)
                     benzene:acetone (1:19 v/v);         capture detector;
                     repeated evaporation with hexane    confirmation by GLC; monitored
                     to remove traces of benzene;        by mass spectrometry
                     fat-free extract chromatographed
                     on Florisil-silicic acid column
                                                                                                                                              

    Table 3 (continued)

    a    Often, the primary aim of the analyses was quantification of organochlorine compounds, other than chlorobenzenes. In these cases,
         the clean-up procedures were quite complicated, because of the need to separate different organochlorine pesticide residues, prior
         to chromatographic analysis.
    b    Detection limits reported in µg/m3 for air and µg/litre or µg/kg for other media, unless noted otherwise.
         NA - information not available in the paper.
         ND - not detected during analysis.
    c    Indicates recovery percentages from spiked samples.

    

    Solvent extraction is also used in the determination of
    chlorobenzenes in biological matrices, such as blood and urine. For
    less volatile compounds (tri-, tetra-, and pentachlorobenzenes),
    solvent extraction is followed by column chromatographic clean up
    and quantification (Lamparski et al., 1980; Mes et al., 1982). For
    the more volatile compounds (mono-, dichlorobenzenes), a modified
    purge-trap method with a capillary GC can be used (Michael et al.,
    1980). The chlorobenzenes are then quantified using a GC with
    detection by electron capture (McKinney et al., 1970; Morita et al.,
    1975; Lunde & Bjorseth, 1977), photoionization (Langhorst &
    Nestrick, 1979), or mass spectrometry (Balkon & Leary, 1979; Bristol
    et al., 1982; LeBel & Williams, 1986).

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural Occurrence

    Natural sources of chlorobenzenes in the general environment have
    not been identified; however, 1,2,3,4-TeCB has been identified in
    the oil of a marsh grass (Miles et al., 1973).

    3.2  Man-made Sources

    3.2.1  Production

    Monochlorobenzene and the dichlorobenzenes are produced commercially
    by the direct chlorination of benzene in the liquid phase, in the
    presence of a Lewis acid catalyst, such as ferric chloride. In the
    liquid-phase chlorination of monochlorobenzene, 1,2-, and
    1,4-dichlorobenzenes are the predominant products. Trichlorobenzenes
    result from the chlorination of dichlorobenzenes with ferric
    chloride, while tetrachlorobenzenes are produced by the addition of
    chlorine to trichlorobenzenes in the presence of an aluminium
    catalyst.  Tetrachlorobenzenes can be used as the precursor in
    pentachlorobenzene production (US EPA, 1985). Pentachloro-benzene is
    also produced by the denitrification of penta-chloronitrobenzene and
    the reductive dechlorination of hexa-chlorobenzene (Renner & Mücke,
    1986).

    About  50%  of  the  world  production  of  all  chlorobenzenes
    (estimated from data in US EPA (1985) to be 568 x 106 kg in 1983)
    is manufactured in the USA. The remainder is produced mainly in
    Western Europe and Japan.  Monochlorobenzene makes up approximately
    70 % of total world production of all chlorobenzenes.

    Data on current, global chlorobenzene production volumes are not
    available in readily retrievable references. Summaries of production
    levels in 1980 and 1983 have been published and are presented in
    Table 4 (IARC, 1982; US EPA, 1985). Although these may provide some
    indication of present production levels, it appears that PeCB
    production has ceased within the USA, and that the use of
    chlorobenzenes as chemical intermediates has decreased. Therefore,
    the actual level of production is probably less than that shown in
    Table 4.

    No information was found on the production of TCB, TeCB, and PeCB
    congeners outside the USA. However, in 1979, the estimated
    production of 1,4-DCB in Japan was 27.5 x 106 kg and that of
    1,2-DCB was 13 x 106 kg (IARC, 1982).


    
    Table 4.  Production levels in the USA and possible uses of chlorinated benzenes
                                                                                                                                              

    Chemical                                Major usesa                                       Estimated annual
                                                                                              production in the USA
                                                                                                                                              

    MCB              Intermediate in the manufacture of chloronitrobenzenes, diphenyl         130 x 106 kg in 1980
                     oxide, DDT, and silicones; as a process solvent for methylene
                     diisocyanate, adhesives, polishes, waxes, pharmaceutical products,
                     and natural rubber; as a degrading solvent

    1,2-DCB          In the manufacture of 3,4-dichloroaniline; as a solvent for a wide       22 x 106 kg in 1980
                     range of organic materials and for oxides of non-ferrous metals; as a
                     solvent carrier in the production of toluene diisocyanate; in the
                     manufacture of dyes; as a fumigant and insecticide; in degreasing
                     hides and wool; in metal polishes; in industrial odour control; in
                     cleaners for drains

    1,3-DCB          As a fumigant and insecticide                                            NA

    1,4-DCB          As a moth repellent, general insecticide, germicide, space deodorant;    24 x 106 kg in 1980
                     in the manufacture of 2,5-dichloroaniline and dyes; as a chemical
                     intermediate; in pharmaceutical products; in agricultural fumigants

    1,2,3-TCB        Apart from use as a chemical intermediate, the uses are the same as      23-74 x 103 kg
                     those 1,2,4-trichlorobenzene

    1,2,4-TCB        As an intermediate in the manufacture of herbicides; dye carrier,        1.2-3.7 x 106 kg
                     dielectric fluid; solvent; heat-transfer medium

    1,3,5-TCB        Solvent for products melting at high-temperatures; coolant in            1.1-2.1 x 105 kg
                     electrical insulators; heat-transfer medium, lubricant, and synthetic
                     transformer oil; termite preparation and insecticide; in dyes
                                                                                                                                              

    Table 4 (continued)
                                                                                                                                              

    Chemical                                Major usesa                                       Estimated annual
                                                                                              production in the USA
                                                                                                                                              

    1,2,3,4-TeCB     Component in dielectric fluids; in the synthesis of fungicides           NA

    1,2,3,5-TeCB     NA                                                                       NA

    1,2,4,5-TeCB     Intermediate for herbicides and defoliants; insecticide;                 NA
                     moisture-resistant impregnant; in electric insulation; in packing
                     protection

    PeCB             Formerly in a pesticide used to combat oyster drills; chemical           Not manufactured in
                     intermediate                                                             the USAa
                                                                                                                                              

    a    From: US EPA (1985).
         NA - not available.

    

    The total production capacity for all chlorobenzenes in Western
    Europe during 1980 was estimated to be greater than 208 x 106 kg
    (IARC, 1982).

    Although data on production levels are scarce, it is apparent from
    available information that chlorobenzenes (in particular MCB and
    DCBs) are produced in high volumes. Use patterns shown in Table 4,
    and estimated losses to the environment shown in Table 5, indicate a
    high potential for human exposure and environmental contamination.

    
    Table 5.  Estimated quantities (kg) of chlorobenzenes lost to the environment
    during manufacture in relation to total 1983 productiona

                                                                                              
    Chlorobenzene           Losses during          Losses to            Total production
                            manufacture            environment

                                                                                              

    MCB                     1.9-3.0 x 105          1.5-2.6 x 105        130 x 106

    1,2-DCB                 1.1-2.1 x 105          30 x 103             22 x 106

    1,3-DCB                 2-6 x 102              NA                   NA

    1,4-DCB                 1.8-2.8 x 105          1.7-2.7 x 105        24 x 106

    1,2,3-TCB               0.6-2 x 103            <1 x 102             23-74 x 103

    1,2,4-TCB               3-10 x 103             3-9 x 102            1.2-3.7 x 106

    1,3,5-TCB               import                 import               1.1-2.1 x 105

    TeCB                    NA                     NA                   NA

    PeCB                    not manufactured       NA                   NA
                                                                                              

    a    Values calculated from US EPA (1985).
         NA - data not available.
    
    3.2.2  Uses

    Use patterns may vary considerably among countries. A summary of the
    uses of chlorinated benzenes in the USA is presented in Table 4.
    Chlorobenzenes are used mainly as intermediates in the synthesis of
    other chemicals, and as pesticides. The 1,4-DCB isomer is commonly
    used in space deodorants and moth repellents, and several of the
    higher chlorinated benzenes (TCBs, 1,2,3,4-TeCB) have been used in
    dielectric fluids.

    MCB also has potential as a functional fluid in external combustion
    Rankine engines (Curran, 1981) and as a component in heat transfer
    fluids in solar energy collectors (Boy-Marcotte, 1980).

    The 1,4-DCB isomer is also being used in the USA as an intermediate
    in the production of polyphenylene sulfide resin, an engineering
    plastic with electrical and automotive applications.

    3.2.3  Sources in the environment

    Incineration of organochlorine and hydrocarbon polymers in the
    presence of chlorine may result in the atmospheric release of
    chlorobenzenes, though quantities are small in relation to the total
    mass of carbon compounds incinerated (Ahling et al., 1978;
    Lahaniatis et al., 1981a). Incineration of chlorobenzenes most
    probably leads to the formation of polychlorinated dibenzodioxins
    and dibenzofurans, as indicated by experimental studies on the
    pyrolysis of various TCBs, TeCBs, and PeCB (Buser, 1979). Although,
    in experimental studies, chlorobenzenes have been formed in
    reactions between benzene and sodium hypochlorite (Hofler et al.,
    1983), evidence that they are generated during public water
    treatment is slight (Otson et al., 1982a).

    On the basis of measurements of concentrations in flue gases from
    all municipal waste incinerators in Sweden (N=24), the maximum
    contribution of chlorobenzenes (di- to hexa-) to ambient air was
    calculated, in 1985, to be 590 kg (Ahlborg & Victorin, 1987).
    Average emissions of total chlorobenzenes from small-scale wood
    burners for dry wood, in closed fireplace ovens, during 2-h sampling
    periods, ranged from 24 to 80 µg/kg dry fuel (Rudling et al., 1980).

    Several of the chlorinated benzenes have been identified as
    microbial metabolites of lindane degradation (Macholz & Kujawa,
    1985).

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    The transport and fate of chlorobenzenes in the environment has not
    been well characterized. However, it is possible to draw some
    conclusions based on the physical and chemical properties of the
    compounds and the results of a limited number of laboratory and
    field studies.

    4.1  Transport and Distribution

    The water solubility, saturated vapour pressure, and partition
    coefficients (Henry's Law constant, KH; soil sorption, Koc;
    octanol/ water, Kow; blood/air), useful for the prediction of the
    transport and distribution of the chlorobenzenes in the environment,
    are presented in Table 2.

    As shown by Henry's Law constant (KH - the equilibrium
    distribution coefficient of a compound between air and water), all
    chlorobenzenes released into the aquatic environment will evaporate
    preferentially from water to the atmosphere, despite their high
    relative molecular masses and comparatively low vapour pressures
    (MacKay & Wolkoff, 1973). From these data, it can also be predicted
    that the preferential distribution from water to air will decrease
    with increasing chlorination. In a study on the volatility of MCB in
    a model aquatic ecosystem, 96% of the compound was released to the
    atmosphere (Lu & Metcalf, 1975). In experimental studies by Garrison
    & Hill (1972), 99% of the test compounds MCB, 1,2-DCB, 1,4-DCB, and
    1,2,4-TCB had evaporated from aerated distilled solutions within 4
    h. In non-aerated solutions, evaporation was complete within 72 h.
    The results of a 1-year field study on Lake Zurich, Switzerland,
    confirmed that most of the 1,4-DCB present in the water was
    transferred to the atmosphere. The half-life of the compound was
    estimated to be approximately 100 days, 67% being lost to the
    atmosphere; 2% entering lake sediments and 31% being present in the
    lake outflow (Schwarzenbach et al., 1979). Wilson et al. (1981)
    studied the transport of a mixture in water of more than 10 organic
    chemicals, including MCB, 1,4-DCB, and 1,2,4-TCB, through a column
    of sandy soil having a low organic matter content, over a 21-day
    period. They reported that up to 50% of the MCB evaporated and
    approximately 50% of all 3 chlorobenzenes was degraded or was
    unaccounted for, indicating that the compounds are likely to leach
    into ground water.

    4.2  Persistence and Fate

    The chlorobenzenes are environmentally persistent compounds, the
    most likely degradation mechanisms being photochemical reactions and
    microbial action. While bioconcentration has been demonstrated, the
    potential for biomagnification in food chains has not been
    investigated. Soils that are rich in organic matter and aquatic
    sediments are probably the major environmental sinks for these
    compounds.

    4.2.1  Persistence

    In water, 1,2-DCB and 1,2,4-TCB are considered moderately persistent
    compounds with half-lives ranging from 1 day in rivers to 10 days in
    lakes and 100 days in ground waters (Zoeteman et al., 1980).
    Concentrations may be rapidly reduced with aerobic biological
    degradation or volatilization, but chlorobenzenes are extremely
    persistent under anaerobic conditions, or where volatilization
    cannot occur, i.e., in ground water.

    Turbulence is a major factor in the elimination of these compounds
    from surface waters. Turbulence increases volatilization and
    bio-degradation. It may also lead to more rapid photochemical
    degradation through the propagation of sensitized photolysis and the
    increased frequency of exposure of water particles to surface
    sunlight (Zoeteman et al., 1980).

    Wakeham et al. (1983) studied the fate and persistence of MCB,
    1,4-DCB, and 1,2,4-TCB in tanks containing seawater and associated
    planktonic and microbial communities, with simulated tidal
    turbulence and seasonal temperature regimes (spring, summer,
    winter). It was suggested that removal processes other than
    volatilization, such as biodegradation and sorption on to particles,
    are probably not very important for 1,4-DCB and 1,2,4-TCB, but that
    MCB is subject to rapid biodegradation under the relatively warm
    spring and summer water temperatures, when microbial activity is
    greater than in winter.

    Chlorobenzenes in the air are degraded by chemical or sunlight-
    catalysed reactions, or they may be adsorbed onto particles that
    settle or are removed with rain. In a 2-week study on air samples
    from California and Arizona, Singh et al. (1981) estimated the
    residence times of MCB, DCBs, and an unspecified TCB isomer to be
    13, 18.6, and 116.0 days, respectively.

    In soils, the DCBs, TCBs, and PeCB are usually resistant to
    micro-bial degradation; primary degradation products are the
    chloro-phenols (Ballschmiter & Scholz, 1980). In experiments using
    radiolabelled 1,2,3- and 1,2,4-TCBs on fresh field soil, the
    observed degradation rates were very slow, 0.35 and 1.00 nmol/day

    per 20 g soil, respectively (Marinucci & Bartha, 1979). These
    investigators also observed that evaporation of the chlorobenzenes
    was reduced by increasing the amounts of organic material in the
    soil. In another experiment using 14C-labelled MCB, 1,2- and
    1,4-DCBs, and 1,2,3- and 1,2,4-TCBs in soil, Haider et al. (1974)
    found that 18.3%, 1.1% and 20.3% of MCB, DCBs, and TCBs,
    respectively, were released as carbon dioxide.

    4.2.2  Abiotic degradation

    The higher chlorinated chlorobenzenes are not particularly reactive
    compounds and would, therefore, be expected to disappear only slowly
    in the environment through chemical degradation. Photolysis and
    oxidative and hydrolytic reactions are pathways by which the
    compounds may be abiotically degraded.

    4.2.2.1  Photolysis 

    Although chlorobenzenes absorb light only weakly above 290 nm, some
    photodegradation can occur when they are irradiated with sunlight,
    or light containing an equivalent broad spectrum of wavelengths.

    Uyeta et al. (1976) demonstrated that chlorobenzenes (other than
    1,2,3,5-TeCB and PeCB, which were not examined) form polychlorinated
    biphenyls when irradiated with sunlight. However, the yields of
    polychlorinated biphenyls were less than 1% of the initial amount of
    chlorobenzene. Of the compounds tested, 1,2,3-TCB and 1,2,4,5-TeCB
    were the most resistant to photodegradation, while 1,2,4-TCB and
    1,2,3,4-TeCB were the most easily degraded. The number of chlorine
    atoms in the polychlorinated biphenyl photoproducts was 1 less than
    the number contained in 2 molecules of the parent chlorobenzene,
    i.e., monochlorobenzene yielded a monochlorobiphenyl,
    dichlorobenzenes yielded tri-chlorobiphenyls and so on. Hydrochloric
    acid was also a reaction product. On the basis of these results, it
    was suggested that the photoformation of polychlorinated biphenyls
    from chlorobenzenes involves free radical reactions based on the
    dehydrochlorination of 1 molecule from 2 molecules of the parent
    chlorobenzene.

    Studies on direct photodegradation, either with direct sunlight or
    artificial light simulating natural conditions, suggest that the
    chlorobenzenes can be photodegraded, though the reactions may be
    slow (Crosby & Hamadmad, 1971; Akermark et al., 1976; Uyeta et al.,
    1976; Choudhry et al., 1979; Choudhry & Webster, 1985). For example,
    the half-life of 1,4-DCB, under artificial sunlight irradiation, was
    estimated to be 115.5 h (Hanai et al., 1985). This value was
    considerably greater than the half-lives of other air pollutants
    (i.e., tetrachloroethylene, trichloroethylene, benzene, toluene,
    ethylbenzene, 1,2,4-trimethylbenzene,  n-octane, and  n-nonane)
    under similar conditions.

    Reductive dechlorination is the main photochemical reaction that
    occurs in proton-donating solvents and there is evidence that the
    solvent is involved with the electronically excited reactant
    molecule in the transition state complex. Photodegradation of the
    tri- and tetrachlorobenzenes, using acetonitrile as the solvent in a
    1:1 ratio with water, has been reported; however, it should be noted
    that acetonitrile would not be present in this ratio under normal
    environmental conditions (Choudhry et al., 1979; Choudhry & Webster,
    1985). Some form of hydrogen-donating entity, such as a solvent
    molecule or another chlorobenzene molecule, appears necessary for
    the photochemical dechlorination of chlorobenzenes at wave-lengths
    above 290 nm. It has been speculated (Akermark et al., 1976) that
    such hydrogen-donating "photosensitizers" may be found  in 
    naturally  occurring  organic  substances  and  that
    photodecomposition may be important as a degradative pathway, given
    the general physical and chemical stability of the chlorobenzenes.

    In addition to direct photolysis, chlorobenzenes may also be removed
    from the environment by reaction with molecular species that are
    photochemically produced from other atmospheric pollutants. Such a
    possibility has been suggested, on the basis of studies involving
    simulated atmospheric environments, for interactions between
    monochlorobenzene or 1,4-dichlorobenzene and oxides of nitrogen
    (Dilling et al., 1976; Kanno & Nojima, 1979; Nojima & Kanno, 1980).
    Reaction mechanisms and rates of disappearance of the compounds were
    poorly defined in these studies.

    4.2.2.2  Hydrolytic and oxidative reactions

    It is unlikely that simple hydrolysis is an important degradation
    pathway for the chlorobenzenes in the environment.

    Cupitt (1980) suggested that MCB and the DCBs may be removed from
    the troposphere by reaction with hydroxyl radicals (considered  to 
    be  the  most  potentially  reactive  species  in  the troposphere),
    and  possibly also by reaction with ozone.  This investigator used
    estimated rate constants for the reaction with hydroxyl radicals
    (assumed to have a tropospheric concentration of 1 x 106
    molecules/cm3) and ozone (tropospheric concentration, 1 x 1012
    molecules/cm3) to predict atmospheric residence times of 28 days
    and 39 days for MCB and the DCBs, respectively.

    Calculations by Cupitt (1980) suggest that ozonolysis contributes
    very little to the removal of the compounds, because the rate
    constants for the reaction of hydroxyl radicals with the
    chlorobenzenes are some 9 or 10 orders of magnitude greater than
    those for the corresponding reactions with ozone.

    4.2.3  Biodegradation and biotransformation

    The degradation of chlorobenzenes by microorganisms has been
    reported in several studies using various substrates, such as soil,
    sediment, and sewage sludge (Table 6). It can be speculated, from a
    perusal of these data, that the more highly chlorinated benzenes are
    not degraded microbiologically as readily as the less chlorinated
    congeners; however, the data are insufficient to draw definitive
    conclusions. Garrison & Hill, (1972) found that MCB, 1,2-DCB, and
    1,4-DCB were completely volatized in less than one day from
    solutions containing mixed cultures of aerobic organisms, but that
    2% of 1,2,4-TCB remained after 80 h.

    The major degradation mechanism is oxidative dechlorination leading
    to the formation of hydroxylated aromatic compounds (mainly
    phenols), followed by ring fission and, eventually, mineralization
    to carbon dioxide and water. It has been suggested that, like
    polychlorinated biphenyls, chlorobenzenes appear to be attacked by
    microorganisms only under aerobic conditions (Kobayashi & Rittman,
    1982; Bouwer & McCarty, 1984).

    Schwarzenbach et al. (1983) studied the movement of 1,4-DCB from a
    polluted river in Switzerland through a ground water aquifer to a
    series of wells. Correlation between the indicators of
    microbiological metabolic activity and the observed decrease in
    concentrations of 1,4-DCB with increasing distance of the wells from
    the river was taken as evidence of the biotransformation of 1,4-DCB
    in the aquifer system. On certain occasions, the persistence of
    1,4-DCB was well correlated with anoxic conditions that prevailed in
    parts of the aquifer, suggesting that the biotransformation of the
    compound is minimal under anaerobic conditions. These findings were
    confirmed in laboratory experiments using sediments from this
    aquifer. Results showed that the DCBs were transformed only under
    aerobic conditions and that the rates of transformation were
    different with each isomer, 1,4-DCB degrading at the faster rate
    (Kuhn et al., 1985).

    4.2.4  Bioaccumulation

    The bioaccumulation of chlorobenzenes by aquatic organisms is
    determined by their relative water and lipid solubility (thus
    reflecting the octanol/water partition coefficients) and the number
    of chlorine substitutions. Uptake from water increases with
    increasing chlorination.  The coefficient of adsorption on sediment
    influences the uptake into terrestrial plants and sediment-living
    aquatic invertebrates; the degree of chlorination is also correlated
    with uptake.


    
    Table 6.  Degradation of chlorobenzenes by miroorganisms
                                                                                                                                              

    Chlorobenzene;       Organism           Substrate           Rate                             Remarks
    Reference
                                                                                                                                              

    MCB, DCBs,           Pseudomonas sp.    synthetic           NAa                              DCBs metabolized to dichlorophenols and
    TCBs and TeCBs                          medium                                               dichloropyrocatechols; MCB, TCBs, and
    Ballschmiter &                                                                               TeCBs metabolized to their respective
    Scholz (1980)                                                                                chlorophenols

    MCB, DCBs, and       NA                 synthetic           no significant degradation       medium seeded with sewage effluent and
    1,2,4-TCB                               medium              observed after 11 weeks          strictly maintained under denitrifying
    Bouwer &                                                                                     conditions
    McCarty(1983)

    MCB                  NA                 estuarine           half-life = 75  days             radiolabelled compound used,
    Lee & Ryan                              sediments;          half-life = 150 days             degradation rate measured by
    (1979)                                  estuarine waters                                     evolution of radiolabelled CO2;
                                                                                                 considerable reduction in rate observed
                                                                                                 when temperature reduced to 9-13 °C

    MCB                  Pseudomonas        synthetic           not measured                     P. putida grown with toluene as the
    Gibson et al.        putida             medium                                               sole carbon source, oxidized MCB to
    (1968)                                                                                       3-chlorocatechol

    MCB                  planktonic and     sea water           spring half-life = 21 days       tanks contained 13 m3 sea water
    Wakeham et al.       microbial                              summer half-life = 4.6 days      with simulated turbulence and
    (1983)                                                      winter half-life = 13 days       seasonal patterns
                                                                                                                                              

    Table 6 (continued)
                                                                                                                                              

    Chlorobenzene;       Organism           Substrate           Rate                             Remarks
    Reference
                                                                                                                                              

    MCB                  microbial strain   synthetic           NAa                              culture isolated from soil and sewage
    Reineke &            WR 1306            medium                                               and was sensitive to sudden increases
    Knackmuss                                                                                    in MCB concentrations, resulting
    (1984)                                                                                       in prolonged lag phase or disturbed
                                                                                                 exponential phase; 3-chlorocatechol
                                                                                                 isolated from culture fluid;
                                                                                                 organisms did not oxidize isomeric DCBs

    1,2-DCB              Acinetobacter      activated           >90% disappearance in            mixture of 4 bacterial genera and 1 yeast,
    Davis et al.               +            sewage sludge       7 days                           glucose as sole carbon source, incubation
    (1981)               Alcaligenes                                                             temperature 28 °C; some DCB may have been
                               +                                                                 lost by evaporation
                         Flavobacterium
                               +
                         Pseudomonas
                               +
                         Rhodotorula

    1,4-DCB              planktonic and     sea water           spring half-life = 18 days       tanks contained 13 m3 sea water with
    Wakeham et al.       microbial                              summer half-life = 10 days       simulated turbulence and seasonal patterns
    (1983)                                                      winter half-life = 13 days

    1,4-DCB              microbial flora    ground water        NAa                              under aerobic conditions, concentrations
    Schwarzenbach        present            aquifer                                              of 1,4-DCB decreased with increasing
    et al. (1983)                                                                                distance of wells from the polluted

    1,2,4-TCB            NA                 activated           after 5 days, 56% converted to   radiolabelled compound used, degradation
    Simmons et al.                          sludge              CO2; 23% converted to polar      measured by evolution of radiolabelled CO2
    (1977)                                                      metabolites; 7% evaporated
                                                                                                                                              

    Table 6 (continued)
                                                                                                                                              

    Chlorobenzene;       Organism           Substrate           Rate                             Remarks
    Reference
                                                                                                                                              

    1,2,3-TCB and        NA                 soil                mineralization rates nmol/day    radiolabelled compounds applied at
    1,2,4-TCB                                                   per 20 g soil: 1,2,3-: 0.33,     50 mg/kg soil, mineralization measured by
    Marinucci &                                                 0.38; 1,2,4-: 1.09, 0.93,        evolution of radiolabelled CO2; both TCBs
    Bartha                                                      1.37                             poisoned metabolic action of soil
    (1979)                                                                                       bacteria; 1,2,3-TCB yielded 2,3- and
                                                                                                 2,6-dichlorophenol; 1,2,4-TCB yielded
                                                                                                 2,4-, 2,5- and 3,4-dichlorophenol

    1,2,4-TCB            planktonic and     sea water           spring half-life = 22 days       tanks contained 13 m3 sea water with
    Wakeham et al.       microbial                              summer half-life = 11 days       simulated turbulence and seasonal patterns
    (1983)                                                      winter half-life = 12 days

    PeCB                 NA                 soil                half-life = 194, 345 days        compounds applied to soil samples at
    Beck & Hansen                                                                                concentrations equivalent to 10 kg/ha,
    (1974)                                                                                       concentrations measured using gas
                                                                                                 chromatography; duplicate experiments, no
                                                                                                 explanation given for differences in
                                                                                                 half-lives measured
                                                                                                                                              

    a    NA - not available.

    

    Topp et al. (1986) compared the uptake in plants of chlorobenzenes
    from the soil and via the air in closed, aerated laboratory systems. 
    A negative correlation was demonstrated between the bioconcentration
    factor (BCF) and the soil adsorption coefficient (based on soil
    organic matter content) for the uptake into the roots of barley. The
    adsorption of chlorobenzenes on soil organic matter increased with
    increasing chlorination. However, expression of uptake in barley
    roots in relation to the soil interstitial water concentration of
    the chlorobenzenes produced a positive correlation between the BCF
    and the octanol/water partition coefficients. Higher chlorinated
    chlorobenzenes, therefore, are most readily taken up by the plant
    roots, when they are available in soil interstitial water. This will
    occur particularly in sandy soils with a low organic matter content.
    Uptake of volatilized chlorobenzenes in leaves was extremely low
    compared with root uptake. The correlation between uptake and
    physical properties demonstrated in barley did not hold for corn;
    the authors stated that the uptake of lipophilic compounds by
    lipid-rich plants, or plants with oil channels, was unpredictable .
    In a later study, Topp et al. (1989) studied the uptake and
    distribution of 14C-labelled 1,2,4-TCB and PeCB in barley. The BCF
    concentration decreased with time of exposure; this was a dilution
    effect as the plant grew. The total load of chlorobenzene increased
    over the whole growing period of the plant, but the rate of uptake
    was greater in the early growth period. Uptake increased with
    increasing chlorination but decreased in relation to the soil
    concentration (BCF fell with increasing chlorination). There was
    evidence of metabolism of the chlorobenzenes in the plant, with the
    level of the parent compound falling over the course of the
    experiment in relation to the rate of metabolism, and the levels of
    uncharacterized"bound" residues. After growth in soil containing 2
    µg each of 1,2,4-TCB and PeCB/kg (dry weight), harvested barley
    grain contained 73 and 82 µg/plant, respectively. The concentrations
    in the dry grain were 0.05 and
    0.06 mg/kg for 1,2,4-TCB and PeCB, respectively.

    Khezovich & Harrison (1988) used closed, flow-through bioassay
    systems to investigate the bioavailability to chiromonid midge
    larvae of sediment-bound MCB, 1,2-DCB, and 1,2,4-TCB.  A sediment
    with a high organic matter content (14.5%) was compared with a
    sediment with a low organic content (3.6%). The bioconcentration of
    the chlorobenzenes increased with increasing chlorination. The
    experiment was run without equilibrium between the sediment and the
    overlying water (flow-through of uncontaminated water) and after
    equilibration of recirculated water. Most of the uptake of
    chlorobenzenes occurred from the interstitial water between sediment
    particles and the results of bioconcentration were best correlated
    with the concentrations of the chlorobenzenes in the interstitial
    water. Under non-equilibrium conditions, bioconcentration factors
    were 5, 29, and 225 for MCB, 1,2-DCB, and 1,2,4-TCB, respectively.

    Köneman & Van Leeuwan (1980) exposed guppies to 116 µg
    1,4-DCB/litre, 48 µg 1,2,3-TCB/litre, 43 µg 1,3,5-TCB/litre, 12 µg
    1,2,3,5-TeCB/litre, or 1.2 µg PeCB/litre for 19 days. The fish were
    fed daily on commercial fish food. Concentrations in fish were
    expressed in mg/kg. The results showed an increase in the rate of
    uptake with increasing level of chlorination of the benzene ring.
    After exposure, the fish were kept for 9 weeks in clear water to
    study the rate of elimination. The rate constant of loss of 1,4-DCB
    was described by a one-compartment model and was relatively high
    (1.00/day). For the other CBs, the losses showed a clear biphasic
    pattern with a decrease in the first, rapid rate of loss with
    increasing level of chlorination. Consequently, the level of
    bioaccumulation went up with increasing chlorination.

    In a study performed by Opperhuizen & Stokkel (1988), 1-year-old
    guppies were exposed for 42 days to 1,2,3,4-TeCB or PeCB at µg/litre
    levels. There were 3 groups of fish: one with contaminated
    Chromosorb (artificial sediment) added, one with uncontaminated
    Chromosorb, and one without Chromosorb. The concentration of PeCB in
    the water was reduced by the presence of contaminated sediment,
    while neither type of particle affected the TeCB concentration in
    the water. Addition of uncontaminated particles did not affect the
    increase in chlorobenzene residues in the fish. However, the
    presence of contaminated particles resulted in higher concentrations
    of PeCB in exposed fish than in control fish. No effects were seen
    with TeCB. The authors attributed this to the low levels of TeCB on
    the particles compared with levels in the water. They concluded that
    the influence of contaminated particles on the bioconcentration of
    hydrophobic chemicals by fish depends on the hydrophobicity of the
    chemicals. The particles may act as a source of the compounds.

    Van Hoogen & Opperhuizen (1988) exposed guppies in acute toxicity
    tests to 1,2,3-TCB, 1,2,3,4-TeCB, or PeCB in a continuous-flow
    system. Fish died having reached the lethal dose of chlorobenzene
    for fish, which was between 2.0 and 2.5 mmol/kg and was independent
    of the exposure concentration. The authors suggested that this value
    was not affected by the route of administration. In addition, the
    level of chlorination did not influence the lethal dose expressed in
    mmol/kg. When uptake and elimination rate constants were calculated,
    any combination of exposure time and concentration required to reach
    the lethal dose could be calculated.

    4.2.5  Biomagnification

    No studies were found concerning the possibility that concentrations
    of chlorobenzenes may increase as they move up the food chain.

    4.2.6  Ultimate fate following use

    As discussed in section 4.1, there is a preferential exchange of
    chlorobenzenes from water to the atmosphere. However, in natural
    waters containing appreciable amounts of suspended organic matter,
    chlorobenzenes may be retained and transported within the aquatic
    environment. The accumulation of chlorobenzenes in aquatic sediments
    is striking, concentrations being at least 1000 times higher than
    those found in the water. Available data suggest, therefore, that
    soils rich in organic matter may be a major environmental sink for
    these compounds (Elder et al., 1981; Oliver & Nicol, 1982).

    Historical evidence for the persistence of chlorobenzenes and for
    sediments acting as an environmental sink for these compounds has
    been reported by Durham & Oliver (1983). Radionuclide measurements
    were used to construct age profiles for Lake Ontario sediments. The
    age of lake bottom sediments near the mouth of the Niagara River was
    correlated with the concentrations of chlorobenzenes found in the
    sediment samples. Over an 80-year period, the concentrations of all
    chlorobenzene isomers increased from 0.4 to 15 µg/litre in 1898-1904
    to a peak of 18 to 1100 µg/litre in 1959-67, and then declined to 6
    to 110 µg/litre in 1980-81. The rise and fall of chlorobenzene
    levels closely followed the rise and fall of the total USA
    production figures for all chlorobenzenes for a similar period. The
    Niagara River is considered to be a major source of chlorobenzene
    pollution in Lake Ontario (Oliver & Nicol, 1982).

    In Canada, recent data indicate that levels of chlorobenzenes in
    sediments are highest in the industrialized Central Region (Ontario
    and Quebec). Mean concentrations of the dichlorobenzenes (the
    congeners that are present at the highest levels) were 130 µg/kg for
    the 1,2-isomer and 46 µg/kg for both the 1,3- and 1,4-isomers. Mean
    levels of other congeners, which were also present at elevated
    concentrations (above individual detection limits), were 43 µg/kg,
    39 µg/kg, and 29 µg/kg for 1,2,3,4-TeCB, PeCB, and 1,2,4-TCB,
    respectively (NAQUADAT, 1987).

    When the proportion of each congener (di- to penta-) to the total
    chlorobenzene content of the water of the Niagara River (a major
    source) was compared with that found in the sediment of Lake
    Ontario, Oliver et al. (1989) concluded that "increasing the
    chlorine content on the benzene ring leads to higher relative
    accumulation of the chemicals in sediments". DCBs, TCBs, TeCBs, and
    PeCB constituted 68%, 21%, 8%, and 2% of the total chlorobenzenes
    (di- to penta-) measured in the water samples from the Niagara
    River; comparable values for sediment in Lake Ontario were 12%, 31%,
    21%, and 9%, respectively.

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental Levels

    5.1.1  Air

    Levels of chlorobenzenes in ambient outdoor air are presented in
    Table 7.  Although the available data are insufficient to make a
    reliable estimate of human exposure from the atmosphere, it can be
    concluded that mean levels of chlorobenzenes (mono- to tri-) in
    ambient air are in the tenths of µg/m3 range; however, maximum
    values can range up to 100 µg/m3. Seasonal variations in the
    concentrations of 1,4-DCB in ambient air have also been reported,
    with concentrations increasing with increasing temperature (Hanai et
    al., 1985). No data are available concerning levels of
    tetrachloro-benzene and pentachlorobenzene in the ambient air,
    though these congeners have been detected (but not quantified) in
    the fly ash from municipal incinerators (Eiceman et al., 1979,
    1981).

    Chlorobenzenes have also been detected in rainwater, presumably
    through transfer from the ambient air; Pankow et al. (1983) found
    all 3 DCB isomers and 1,2,4-TCB, at levels of less than 10 ng/litre
    at selected sites in Oregon and California. In the United Kingdom,
    1,4-DCB was detected in rainwater at a level of 0.01 ± 0.005
    µg/litre (Fielding et al., 1981).

    In general, the levels of the chlorobenzenes in indoor air (Table 8)
    are similar to those in ambient air. However, in several cases,
    levels have been much higher. For example, concentrations found in
    basements in the Love Canal area (up to 190 µg/m3 for total
    dichlorobenzenes) and in the wardrobe of a Tokyo residence (up to
    1700 µg 1,4-DCB/m3 detected in 1 sample) may be explained by the
    proximity of a chemical dump and the use of 1,4-DCB as a moth
    repellent, respectively.

    5.1.2  Water

    Chlorinated benzenes have been detected in sewage sludge, municipal
    waste water, surface and ground waters, and in drinking-water.
    However, in 12 sewage sludges in the United Kingdom, the
    concentrations of chlorobenzenes ranged from <0.01 mg/kg dry weight
    for PeCB to 40.2 mg/kg dry weight for 1,3-DCB, with a general
    reduction in concentration with increased chlorine substitution
    (Rogers et al., 1989).


    
    Table 7.  Chlorobenzenes in outdoor air
                                                                                                                                    

    Compound;                                 Number of      Location                                      Concentrationb
    Reference                                 Samplesa                                                     (µg/m3)
                                                                                                                                    

    MCB
      Singh et al. (1981)                     *              USA; cities:
                                                               Los Angeles, California                     0.9 (2.3)
                                                               Phoenix, Arizona                            0.9 (2.3)
                                                               Oakland, California                         0.45 (1.4)

    Harkov et al. (1983)                      38 (35)        USA; cities:
                                                               Newark, New Jersey                          0.5
                                                               Elizabeth, New Jersey                       0.4
                                                               Camden, New Jersey                          0.3

    Levine et al. (1985)                      9              USA
                                                               Hamilton, Ohio                              ND - 43

    Harkov et al. (1985)                      7 (7)          USA
                                                               Hazardous waste sites                       0.2 - 3.6
                                                               and landfills in New                        (20.4)
                                                               Jersey

    Lebret (1985)                             NA             Netherlands
                                                               Ede and Rotterdam                           median <0.4 (0.4)

    Pellizzari et al. (1986)                                 USA; cities:
                                              20               Greenboro, North Carolina                   median 0.029 (0.57)
                                              11               Houston, Texas                              median 0.045 (1.3)
                                              71               Elizabeth/Bayonnne, New Jersey              median 0.43 (6.3)
                                                                                                                                    

    Table 7 (continued)
                                                                                                                                    

    Compound;                                 Number of      Location                                      Concentrationb
    Reference                                 Samplesa                                                     (µg/m3)
                                                                                                                                    

    Environment Canada (1986)                                Canada
                                              46 (43)          Montreal                                    0.2 (1.0)
                                              100 (83)         Toronto                                     0.38 (2.2)

    1,2-DCB
      Singh et al. (1981)                     *              USA; cities:
                                                               Los Angeles, California                     0.08 (0.3)
                                                               Phoenix, Arizona                            0.14 (1.4)
                                                               Oakland, California                         0.22 (0.2)

    Bauer (1981)                              89c            Germany; city and environs:
                                                               Bochum                                      8.3

    Harkov et al. (1985)                      7 (7)          USA
                                                               Hazardous waste sites                       0.03 - 3.2 (25.1)
                                                               and landfills in New Jersey

    Pellizzari et al. (1986)                                 USA
                                              25               Los Angeles - winter                        median 0.20 (0.55)
                                              23               Los Angeles - summer                        median 0.03 (0.82)
                                              10               Antioch/West, Pittsburgh                    median 0.02 (0.58)

    Wallace (1986);                                          USA
    Wallace et al. (1985)                     24               Los Angeles (February)                      0.2
                                              24               Los Angeles (May)                           0.8
                                              10               Contra Costa (June)                         0.07
                                              175              Elizabeth/Bayonne, New Jersey               0.17
                                                                                                                                    

    Table 7 (continued)
                                                                                                                                    

    Compound;                                 Number of      Location                                      Concentrationb
    Reference                                 Samplesa                                                     (µg/m3)
                                                                                                                                    

    Environment Canada (1986)                                Canada
                                              40 (3)           Montreal                                    0.0 (0.1)
                                              70 (1)           Toronto                                     0.02 (0.1)

    Harkov et al. (1983)                      38 (29)        USA; cities:
                                                               Newark, New Jersey                          0.18
                                                               Elizabeth, New Jersey                       0.12
                                                               Camden, New Jersey                          0.06

    1,3-DCB
      Singh et al. (1981)                     *              USA; cities:
                                                               Los Angeles, California                     0.05 (0.02)
                                                               Phoenix, Arizona                            0.05 (0.17)
                                                               Oakland, California                         0.04 (0.1)

    Bauer (1981)                                             West Germany; city and environs:
                                              89c              Bochum                                      3.7

    Levine et al. (1985)                                     USA
                                              9                Hamilton, Ohio                              ND - 100

    Lebret (1985)                             NA             Netherlands
                                                               Ede and Rotterdam                           median <0.6 (<0.6)

    Environment Canada (1986)                                Canada
                                              67 (8)           Toronto                                     0.02 (0.30)
                                                                                                                                    

    Table 7 (continued)
                                                                                                                                    

    Compound;                                 Number of      Location                                      Concentrationb
    Reference                                 Samplesa                                                     (µg/m3)
                                                                                                                                    

    1,3-, 1,4-DCBs
      Wallace (1986); Wallace et al. (1985,                  USA
      1986)                                   86               Elizabeth/Bayonne, New Jersey (1981)        1.7
                                              60               Elizabeth/Bayonne, New Jersey (1982)        1.3
                                              9                Elizabeth/Bayonne, New Jersey (1983)        1.2
                                              24               Los Angeles (Feb.)                          2.2
                                              24               Los Angeles (May)                           0.8
                                              10               Contra Costa (June)                         0.3

    Pellizzari et al. (1986)                                 USA
                                              85               Elizabeth/Bayonne, New Jersey (1981)        median 0.8 (13)
                                              71               Elizabeth/Bayonne, New Jersey  (1982)       median 1.2 (7.6)
                                              9                Elizabeth/Bayonne, New Jersey (1983)        median 0.32 (4.6)
                                              25               Los Angeles (winter)                        median 1.8 (21)
                                              2                Los Angeles (summer)                        median 0.72 (2.4)
                                              10               Antioch/West, Pittsburgh                    median 0.25 (1.0)

    1-DCB
      Morita & Ohi (1975)                                    Tokyo, Japan
                                              3 (3)            city centre                                 2.7 - 4.2
                                              3 (3)            suburbs                                     1.5 - 2.4

    Harkov et al. (1983)                      38 (32)        USA
                                                               Newark, New Jersey                          0.3
                                                               Elizabeth, New Jersey                       0.4
                                                               Camden, New Jersey                          0.2

    Harkov et al. (1985)                      7 (7)          USA
                                                               Hazardous waste sites and                   0.2 - 5.2 (50.4) 
                                                               landfills in New Jersey
                                                                                                                                    

    Table 7 (continued)
                                                                                                                                    

    Compound;                                 Number of      Location                                      Concentrationb
    Reference                                 Samplesa                                                     (µg/m3)
                                                                                                                                    

    Lebret (1985)                             NA             Netherlands
                                                               Ede and Rotterdam                           median <0.6 (<0.6)

    Environment Canada (1986)                                Canada
                                              46 (46)          Montreal                                    0.3 (0.8)
                                              72 (69)          Toronto                                     0.37 (2.14)

    De Bortoli et al. (1985)                  15 (3)         Northern Italy
                                                               various towns                               <5(4)

    1,2,3-TCB
      Lebret (1985)                           NA             Netherlands
                                                               Ede and Rotterdam                           median <0.8 (<0.8)

    Bauer (1981)                              89c            Germany; city and environs:
                                                               Bochum                                      0.40

    1,2,4-TCB
      Lebret (1985)                           NA             Netherlands
                                                               Ede and Rotterdam                           median <0.8 (<0.8)

    Singh et al. (1981)                       *              USA; cities:
                                                               Los Angeles, California                     0.05 (0.25)
                                                               Phoenix, Arizona                            0.02 (0.08)
                                                               Oakland, California                         0.02 (0.11)

    1,3,5-TCB
      Bauer (1981)                            89c            Germany; city and environs:
                                                               Bochum                                      0.5
                                                                                                                                    

    Table 7 (continued)
                                                                                                                                    

    Compound;                                 Number of      Location                                      Concentrationb
    Reference                                 Samplesa                                                     (µg/m3)
                                                                                                                                    

    Lebret (1985)                                            Netherlands
                                                               Ede and Rotterdam                           median <0.8(<0.8)
                                                                                                                                    

    a  Number of positive observations given in brackets where possible.
       NA - not available.
       * - Samples obtained during 2-weeks mobile sampling in the cities indicated; samples taken hourly, 24 h/day.
    b  Maximum values are in brackets.
       ND - not detected.
    c  Samples obtained sporadically, over a 6-month period, from 3 locations within the city and its environs; averages from 89 samples.

    Table 8.  Chlorobenzenes in indoor air
                                                                                                                                              

    Compound;                         Sample                     Location                          Numbera          Concentrationb
    Reference                                                                                                       (µg/m3)
                                                                                                                                              

    MCB
      Potenta & Saunders (1983)       USA - urban                Office                            2 (2)            1.8 - 3.2

      Pellizzari (1982)               USA - urban                house basements                   6 (5)            ND - 4.2
                                                                 (Love Canal area)

      Lebret (1985)                   Netherlands - urban        Ede - post-war homes              134              median <0.4 (0.4)
                                                                 Ede - <6-year-old homes           96               median <0.4 (27)
                                                                 Rotterdam                         89               median <0.4 (3)

      Wallace et al. (1984)           USA                        Personal air samples:
                                                                 New Jersey subjects               160 (115)        0.05 - 26.5 median 0.61

                                                                 North Carolina subjects           60 (13)          0.05 - 3.66

      Pellizzari et al. (1986)        USA                        Greensboro, North Carolina        20               median 0.026 (0.7)
                                                                 Houston, Texas                    11               median 0.035 (0.75)
                                                                 Elizabeth/Bayonne, New Jersey     71               median 0.42 (6.6)

    DCBc
      Pellizzari et al. (1982)        USA                        house basements                   6 (6)            0.65 - 190
                                                                 (Love Canal area)

      Pellizzari et al. (1986)        USA                        Greensboro, North Carolina        20               median 0.09 (60)
                                                                 Baton Rouge/Geismar,              27               median 2.1 (120)
                                                                 Louisiana
                                                                 Houston, Texas                    11               median 5.5 (21)
                                                                                                                                              

    Table 8 (continued)
                                                                                                                                              

    Compound;                         Sample                     Location                          Numbera          Concentrationb
    Reference                                                                                                       (µg/m3)
                                                                                                                                              

    1,2-DCB
      Wallace (1986)                  USA                        Personal air samples:
                                                                 Los Angeles (Feb)                 115              0.4
                                                                 Los Angeles (May)                 50               0.3
                                                                 Contra Costa (June)               68               0.6

      Pellizzari et al. (1986)        USA                        Los Angeles - winter              25               median 0.12 (2.5)
                                                                 Los Angeles - summer              23               median 0.03 (11)
                                                                 Antioch/West, Pittsburg -         10               median 0.03 (0.49)
                                                                 summer

      Otson & Benoit (1986)           Canada - urban             houses                            9                (6.5)

    1,3-DCB
      Lebret (1985)                   Netherlands                Ede - post-war homes              134              median <0.6 (9)
                                                                 Ede - <6-year-old homes           96               median <0.6 (6)
                                                                 Rotterdam                         89               median <0.6 (6)

    1,4-DCB
      Lebret (1985)                   Netherlands                Ede - post-war homes              134              median 2 (138)
                                                                 Ede - <6-year-old homes           96               median <0.6 (240)
                                                                 Rotterdam                         89               median <0.6 (299)

      Morita & Ohi (1975)             Japan - urban home         bedroom                           1 (1)            105
                                                                 closet                            1 (1)            315
                                                                 wardrobe                          1 (1)            1700

      Potenta & Saunders (1983)       USA - urban                office                            2 (1)            trace
                                                                                                                                              

    Table 8 (continued)
                                                                                                                                              

    Compound;                         Sample                     Location                          Numbera          Concentrationb
    Reference                                                                                                       (µg/m3)
                                                                                                                                              

      De Bortoli et al. (1985)        Northern Italy             houses                            15 (9)           55(230)

    1,3-, 1,4-DCBs
      Wallace (1986); Wallace et al.  USA                        Personal air samples:
      (1985, 1986)                                               Elizabeth/Bayonne,                340              45
                                                                 New Jersey - fall
                                                                 Elizabeth/Bayonne,                150              50
                                                                 New Jersey - summer
                                                                 Elizabeth/Bayonne,                49               71
                                                                 New Jersey - winter
                                                                 Los Angeles - Feb                 115              18
                                                                 Los Angeles - May                 50               12
                                                                 Contra Costa - June               68               5.5

      Pellizzari et al. (1982)        USA                        Elizabeth/Bayonne,                85               median 2.8 (915)
                                                                 New Jersey - fall
                                                                 Elizabeth/Bayonne,                71               median 2.6 (1550)
                                                                 New Jersey - summer
                                                                 Elizabeth/Bayonne,                9                median 1.2 (120)
                                                                 New Jersey - winter
                                                                 Los Angeles - winter              25               median 2.8 (214)
                                                                 Los Angeles - summer              23               median 1.0 (170)
                                                                 Antioch/West, Pittsburgh          10               median 0.44 (7.5)

    TCBsc
      Pellizzari et al. (1986)        USA                        house basements                   6 (6)            0.07 - 33
                                                                 (Love Canal area)
                                                                                                                                              

    Table 8 (continued)
                                                                                                                                              

    Compound;                         Sample                     Location                          Numbera          Concentrationb
    Reference                                                                                                       (µg/m3)
                                                                                                                                              

    1,2,3-TCB
      Lebret (1985)                   Netherlands                Ede - post-war homes              134              median <0.8 (3)
                                                                 Ede - <6-year-old homes           96               median <0.8 (28)
                                                                 Rotterdam                         89               median <0.8 (3)

    1,2,4-TCB
      Lebret (1985)                   Netherlands                Ede - post-war homes              134              median <0.8 (15)
                                                                 Ede - <6-year-old homes           96               median <0.8 (33)
                                                                 Rotterdam                         89               median <0.8 (<0.8)

    1,3,5-TCB
      Lebret (1985)                   Netherlands                Ede - post-war homes              134              median <0.8 (8)
                                                                 Ede - <6-year-old homes           96               median <0.8 (5)
                                                                 Rotterdam                         89               median <0.8 (<0.8)

    TeCBsc
      Pellizzari (1982)               USA                        house basements                   6 (6)            0.03 - 20
                                                                 (Love Canal area)

    PeCB
      Pellizzari (1982)               USA                        house basements                   6 (4)            trace - 0.49
                                                                 (Love Canal area)
                                                                                                                                              

    a  Number of positive observations given in brackets where available.
    b  Mean concentrations in µg/m3; maximum values obtained are given in brackets.
       ND - not detected.
    c  Sum of all isomers.

    

    Data on levels of the lower chlorinated benzenes (MCB, DCBs, and
    TCBs) in waste water indicate that MCB is detected the most often
    and at the highest concentrations, occasionally exceeding 1
    mg/litre. Reported levels of DCB and TCB isomers have been lower. In
    a survey of industrial waste waters in the USA (44 264 samples),
    levels of MCB averaged 667 µg/litre and ranged from 11 to 6400
    µg/litre. Other chlorobenzenes detected were 1,2-DCB (12-860
    µg/litre; mean 141 µg/litre); 1,3-DCB (10-39 µg/litre; mean 21
    µg/litre); 1,4-DCB (10-410 µg/litre; xmean 79 µg/litre); and
    1,2,4-TCB (12-607 µg/litre; mean 161 µg/litre) (Neptune, 1980). In a
    survey of waste water throughout the USA, concentrations of 1,2-DCB
    ranged from 15 to 690 µg/litre and concentrations of 1,2,4-TCB
    ranged from 0.25 to 500 µg/litre (Ware & West, 1977). A survey of 4
    municipal treatment plants in Georgia revealed levels of DCB and TCB
    in the influent of 3-146 µg/litre and 1-60 µg/litre, respectively.
    Concentrations in the effluent ranged from 0 to 268 µg/litre and 0
    to 13 µg/litre, respectively (Gaffney, 1976). The increase in DCB
    levels in the effluent was believed to be the result of chlorination
    during the secondary phase of the waste water treatment. In waste
    water from major municipal treatment plants in Southern California,
    concentrations of DCB ranged from 0.2 to 435 µg/litre, while
    concentrations of 1,2,4-TCB and 1,3,5-TCB were 130 µg/litre and
    <0.2 µg/litre, respectively (Young & Heesen, 1978).

    Oliver & Nicol (1982) reported that the concentrations of
    dichloro-benzenes in raw water in the Great Lakes were much greater
    than those of the more highly chlorinated congeners, the 1,4-isomer
    being present at the highest level. This isomer was particularly
    prevalent in effluent from sewage-treatment plants.

    Data on the levels of chlorobenzenes (mono- to penta-) in surface
    waters are presented in Table 9. It is difficult to draw general
    conclusions concerning levels of chlorobenzenes that are commonly
    present in surface water, because of the paucity of available data
    and the considerable variations in reported concentrations, mainly
    owing to differences in the proximity to industrial sources. In
    general, it appears that levels are in the ng-µg/litre range;
    however, levels in the vicinity of industrial sources may
    occasionally range up to 0.1 mg/litre.

    The levels of chlorobenzenes found in some drinking-water supplies
    are shown in Table 10. Although chlorobenzenes are unlikely to be
    changed chemically during the treatment, it is possible that some
    may be lost at the aeration and chlorination stages, because the
    compounds tend to be redistributed preferentially to air from water.
    It has been suggested, however, that water chlorination itself may
    produce chlorobenzenes by the reaction of chlorine (or one of its
    aqueous species) with organic material (both natural and man-made)
    in the raw water supply (Carlson et al., 1975; Glaze et al., 1978;
    Höfler et al., 1983). For example, Höfler et al. (1983) demonstrated

    that all of the chlorobenzenes were detected following the reaction
    of benzene (tenths of a µmol/litre) with aqueous sodium
    hypochlorite. There is slight evidence from surveys of
    chlorobenzenes in drinking-water that they may be formed during
    treatment; Otson et al. (1982a,b) observed that the frequency of
    detection of MCB at 30 Canadian water treatment facilities was less
    for raw water than for drinking-water samples (5 and 18%,
    respectively); however, levels were too low to permit
    quantification.

    In general, the lower chlorinated benzenes are detected more
    frequently in drinking-water and are present in higher
    concentrations; however, even for these compounds, mean levels are
    generally less than 1 µg/litre and rarely exceed 50 µg/litre. Most
    of the dichloro-benzene in drinking-water is present as the
    1,4-isomer, probably because of its release into surface water from
    urinal deodorant blocks (Oliver & Nichol, 1982).

    5.1.3  Soil

    Very few published data are available on the levels of
    chlorobenzenes in soil. With the exception of soil near poorly
    maintained waste sites, the presence of chlorobenzenes in soil would
    appear to be associated with pesticide use.  For example, PeCB has
    been detected at a level of 0.09 mg/kg in fields treated with
    quintozene in Finland (Rautapaa et al., 1977).

    5.1.4  Food

    Little information is available concerning the presence of
    chloro-benzenes (mono- to penta-) in food, but levels in various
    seafoods have been measured. Concentrations of 1,4-DCB in mackerel,
    caught off the coast of Japan, averaged 0.05 mg/kg on a whole-fish,
    wet-weight basis (Morita et al., 1975). All of the chlorobenzenes
    (mono- to penta-) were detected in trout from the Great Lakes at
    levels ranging from 0.1 to 16 µg/kg whole-fish, wet weight (Oliver &
    Nicol, 1982). With the exception of MCB, chlorobenzenes (di- to
    penta-) were measured in samples of sprats from south-east Norway in
    the vicinity of an unspecified "source of contamination". Levels of
    PeCB were highest, ranging from 0.01 to 3.7 mg/kg, while levels of
    trichloro- and tetrachlorobenzenes ranged between <0.01 and 0.5
    mg/kg (Lunde & Ofstad, 1976). Levels of total chlorobenzenes in the
    edible tissue of freshwater fish from highly polluted and industrial
    areas of Yugoslavia were 1.8 mg/kg, on a fat basis, whereas levels
    in fish from lightly polluted agricultural and woodland areas, and
    in marine fish, were 0.2 mg/kg and 0.4 mg/kg, respectively (Jan &
    Malnersic, 1980). The 1,4-DCB isomer was identified among other
    volatile organic compounds collected from watercress (Spence &
    Tucknott, 1983). The source of the compound in the plant matter was
    not identified, but it is likely that it was present in the water in
    which the plants were grown.


    
    Table 9.  Chlorinated benzenes in surface watersa
                                                                                                                          

    Chemical              Location                               Levelsb                   Reference
                                                                                                                          

    MCB                   Glatt River, Germany                      +                      US EPA (1985)
                          Delaware River                         ND - 7000                 Sheldon & Hites (1978)
                          Ohio River                             ND - >10 000              US EPA (1985)

    DCBs                  Delaware Riverc                        ND - 400                  Sheldon & Hites (1978)
                          Great Lakesd                           32 - 71 (27)              Oliver & Nicol (1982)
                          Grand River, Canada                    ND - 77 (11)              Oliver & Nicol (1982)
                          Niagara Falls, New York                   +                      Elder et al. (1981)

    1,2-DCB               Atlantic Region, Canada                <20                       NAQUADAT (1987)
                          Niagara-on-the-Lake, Canada            3.9 - 240 (23)            Oliver & Nicol (1984)

    1,3-DCB               Atlantic Region, Canada                <2 - 310 (22)             NAQUADAT (1987)
                          Niagara-on-the-Lake, Canada            2.1 - 110 (11)            Oliver & Nicol (1984)

    1,4-DCB               Glatt River, Germany                   30 - 900                  US EPA (1985)
                          Ohio River                             ND - >10 000              US EPA (1985)
                          Atlantic Region, Canada                <20 - 130 (22)            NAQUADAT (1987)
                          Great Lakes                            trace - >100              Otson (1987)
                          Niagara-on-the-Lake, Canada            9.0 - 310 (36)            Oliver & Nicol (1984)

    TCBs                  Merrimack River, Massachusettsc        100 - 500                 Hites (1973)
                          Delaware Riverc                        ND - 1000                 Sheldon & Hites (1978)
                          Niagara Falls, New York                100 - 8000                Elder et al. (1981)
                          Great Lakesd                           0.1 - 1.6 (0.5)           Oliver & Nicol (1982)
                          Grand River, Canadad                   ND - 8.7 (2.1)            Oliver & Nicol (1982)
                          Atlantic Region, Canada                <4.0                      NAQUADAT (1987)
                                                                                                                          

    Table 9 (continued)
                                                                                                                          

    Chemical              Location                               Levelsb                   Reference
                                                                                                                          

    1,2,4-TCB             Niagara-on-the-Lake, Canada            5.8 - 120 (16)            Oliver & Nicol (1984)

    1,2,3-TCB             Niagara-on-the-Lake, Canada            1.4 - 30 (3.5)            Oliver & Nicol (1984)

    1,3,5-TCB             Niagara-on-the-Lake, Canada            0.19 - 6.8 (0.84)         Oliver & Nicol (1984)

    TeCBs                 Niagara Falls, New Yorkc               100 - 200 000             Elder et al (1981)
                          Great Lakesc                           ND - 0.8 (0.12)           Oliver & Nicol (1982)
                          Grand River, Canadad                   ND - 0.2 (0.05)           Oliver & Nicol (1982)

    1,2,3,5-TeCB          Atlantic Region, Canada                <2 - 20 (2.0)             NAQUADAT (1987)
                          Niagara-on-the-Lake, Canada            0.10 - 1.4 (0.41)         Oliver & Nicol (1984)

    1,2,4,5-TeCB          Altantic Region, Canada                <2 - 4 (2.0)              NAQUADAT (1987)
                          Niagara-on-the-Lake, Canada            0.39 - 9.3 (2.0)          Oliver & Nicol (1984)

    1,2,3,4-TeCB          Atlantic Region, Canada                <2                        NAQUADAT (1987)
                          Niagara-on-the-Lake, Canada            1.4 - 36 (4.5)            Oliver & Nicol (1984)

    PeCB                  Niagara Falls, New York                ND - 100 000              Elder et al. (1981)
                          Great Lakes                            ND - 0.6 (0.12)           Oliver & Nicol (1982)
                          Grand River, Canada                    ND - 0.1 (0.05)           Oliver & Nicol (1982)
                          Atlantic Region, Canada                <2.0                      NAQUADAT (1987)
                          Niagara-on-the-Lake, Canada            0.34 - 6.4 (1.3)          Oliver & Nicol (1984)
                                                                                                                          

    a    Modified from US EPA (1985).
    b    Range in ng/litre unless indicated.
         ND - not detected.
         + - detected.
    c    Unidentified isomers.
    d    All isomers.

    Table 10.  Chlorobenzene levels in drinking-water supplies
                                                                                                                                              

    Compound: Reference                         Concentration                             Number of       Remarks
                                                                                          samplesa
                                         Mean                   Range
                                                                                                                                              

    MCB
       Otson et al. (1982a, 1982b)       < 1 µg/litre           NA                        90(16)          samples from 30 water treatment
                                                                                                          plants in Canada; maximum of
                                                                                                          5 µg/litre in one instance

       US EPA (1980a)                    approx 7 µg/litre      0.1-27 µg/litre           NA              8 locations in the USA

       Barkley et al. (1980)             25 ng/litre            10-60 ng/litre            9(9)            Old Love Canal, Niagara Falls, USA

       Wallace et al. (1984)             NA                     0.02-0.02 µg/litre        75(0)           water supply of 9 New Jersey homes

       Wallace et al. (1984)             0.03 µg/litreb         0.03-0.03 µg/litre        45(0)           work water samples of 9 New Jersey
                                                                                                          subjects

       Wallace et al. (1984)             NA                     0.03-3.10 µg/litre        30(2)           Water supply of 3 North Carolina
                                                                                                          homes

       Wallace et al. (1984)             NA                     0.25-0.25 µg/litre        18(0)           work water samples of 3 North
                                                                                                          Carolina homes

    DCBs
       US EPA (1980b)                    NA                     1-3 µg/litre              NA              National survey of the USA

       Barkley et al. (1980)             159 ng/litre           10-800 ng/litre           9(9)            Old Love Canal, Niagara Falls, USA

    1,2-DCB
       Oliver & Nicol (1982)             3 ng/litre             ND-7 ng/litre             NA              3 cities by Lake Ontario
                                                                                                                                              

    Table 10 (continued)
                                                                                                                                              

    Compound: Reference                         Concentration                             Number of       Remarks
                                                                                          samplesa
                                         Mean                   Range
                                                                                                                                              

    1,3-DCB
       Oliver & Nicol (1982)             1 ng/litre             ND-2 ng/litre             NA              3 cities by Lake Ontario

       Otson et al. (1982a,b)            < 1 µg/litre           NA                        90(1)           samples from 30 water treatment
                                                                                                          plants in Canada; maximum of
                                                                                                          1 µg/litre

    1,4-DCB
       Oliver & Nicol (1982)             13 ng/litre            8-20 ng/litre             NA              3 cities by lake Ontario

       Fielding et al. (1981)            0.05 µg/litre          0.01-0.08 µg/litre        26(6)           from 4 selected sites in England;
                                                                                                          reported levels do not include a
                                                                                                          sample affected by the use of "air
                                                                                                          freshener" blocks containing
                                                                                                          1,4-DCB (4 µg/litre)

       Otson et al. (1982a,b)            < 1 µg/litre           NA                        90(6)           samples from 30 water treatment
                                                                                                          plants in Canada; maximum of
                                                                                                          <1 µg/litre

    TCBs
       Barkley et al. (1980)             500 ng/litre           300-760 ng/litre          9(9)            Old Love Canal, Niagara Falls, USA

    1,2,3-TCB
       US EPA (1980a)                    NA                     21-46 µg/litre            NA              Catawba, North Carolina

       Oliver & Nicol (1982)             0.1 ng/litre           0.1-0.1 ng/litre          NA              3 cities by Lake Ontario
                                                                                                                                              

    Table 10 (continued)
                                                                                                                                              

    Compound: Reference                         Concentration                             Number of       Remarks
                                                                                          samplesa
                                         Mean                   Range
                                                                                                                                              

    1,2,4-TCB
       US EPA (1980a)                    33.6 µg/litre          0.007-275 µg/litre        NA              8 locations in the USA (does not
                                                                                                          include one sample where levels of
                                                                                                          500 µg/litre were detected)

       Oliver & Nicol (1982)             2 ng/litre             1-4 ng/litre              NA              3 cities by Lake Ontario

    1,3,5-TCB
       US EPA (1980a)                    2.2 µg/litre           0.006-26 µg/litre         NA              8 locations in the USA

       Oliver & Nicol (1982)             ND                     ND                        NA              3 cities by Lake Ontario

    TeCBs
       Barkley et al. (1980)             927 ng/litre           ND-2000 ng/litre          9(6)            Old Love Canal, Niagara Falls, USA

    1,2,3,5-TeCB
       Oliver & Nicol (1982)             ND                     ND                        NA              3 cities by Lake Ontario

    1,2,4,5-TeCB
       Oliver & Nicol (1982)             0.2 ng/litre           ND-0.3 ng/litre           NA              3 cities by Lake Ontario

    1,2,3,4-TeCB
       Oliver & Nicol (1982)             0.3 ng/litre           0.1-0.4 ng/litre          NA              3 cities by Lake Ontario

    PeCB
       Oliver & Nicol (1982)             0.04 ng/litre          0.03-0.05 ng/litre        NA              3 cities by Lake Ontario
                                                                                                                                              

    Table 10 continued)
                                                                                                                                              

    Compound: Reference                         Concentration                             Number of       Remarks
                                                                                          samplesa
                                         Mean                   Range
                                                                                                                                              

       Barkley et al. (1980)             NA                     ND-240 ng/litre           9(9)            Old Love Canal, Niagara Falls, USA
                                                                                                                                              

    a    Number of positive observations given in brackets where possible.
         NA - not available.
    b    Median concentration.
         ND - not detected.

    

    In an isolated incident in England, tainted pork (lean and fat meat)
    contained 5-20 mg 1,4-dichlorobenzene/kg (Watson & Patterson, 1982). 
    The 1,4-isomer of DCB was also present in other batches of pork from
    the same source, and other meat products from various commercial
    sources; however, concentrations were less than 25 µg/kg. It has
    been suggested that the source of the chlorobenzenes in pork was the
    use of organochlorine pesticides in animal husbandry and their
    subsequent metabolism by the animals to chlorobenzenes (Mottram
    et al., 1983). Chlorobenzenes have been detected in cows' milk as
    well as beef meat in Yugoslavia. In cows' milk, residues ("as in"
    basis) for the DCBs ranged from "not detected" (1,3-DCB) to 5.3
    µg/kg (1,4-DCB). TCB and TeCB levels ranged from 0.7 µg/kg
    (1,2,4-TCB) to 1.5 µg/kg (1,2,3-TCB) and 0.02 µg/kg (1,2,3,4-TeCB)
    to 1.10 µg/kg (1,2,3,5-TeCB), respectively. In beef, the DCB
    concentrations ranged from "not detected" (1,3-DCB) to 5.0 µg/kg
    (1,4-DCB), while TCB and TeCB levels were 1.0 µg/kg (1,2,4-TCB) to
    1.8 µg/kg (1,2,3-TCB) and 0.02 µg/kg (1,2,3,4-TeCB) to 1.00 µg/kg
    (1,2,3,5- and/or 1,2,4,5-TeCB), respectively. PeCB was detected in
    both milk and meat at a concentration of 0.05 µg/kg (Jan, 1983b).

    Jan (1980) identified chlorobenzenes (except MCB) in the oils of 9
    different seeds, the highest level being 0.09 mg/kg (1,4-DCB) in
    corn. DCBs and TCBs have also been detected in dried legumes. Levels
    of DCBs ranged from 1.8 to 52.9 µg/kg, while TCB levels ranged from
    3.0 to 8.9 µg/kg. These vegetables were grown under controlled
    conditions with no pesticide application, indicating that the origin
    of the chlorobenzenes was probably environmental contamination
    (Lovegren et al., 1979). TeCB residues have also been reported in
    potatoes. In composite samples of boiled, fried, and baked potatoes,
    levels of 1,2,4,5-TeCB were 0.095, 0.051, and 0.110 mg/kg,
    respectively. The authors stated that the higher levels in the baked
    potatoes were probably attributable to the fact that the potatoes
    were not peeled prior to analysis (Heikes et al., 1979).

    An isolated instance of PeCB contamination of cooked ham (present in
    only 1 out of 37 samples tested) has also been reported; the level
    measured was 0.05 mg/kg (Greve, 1973). PeCB has also been detected
    in peanut butter in the USA; concentrations in 11 samples ranged
    from 1.8 to 62 µg/kg, the average being 16 µg/kg (Heikes, 1980).
    PeCB at 0.03 mg/kg was reported in Finnish rye grown on soils
    previously treated with Quintozene (Rautapää et al., 1977).

    5.1.5  Human milk

    Available data indicate that human milk may be a source of exposure
    to chlorobenzenes (mono- to penta-) for suckling infants. MCB was
    found in 5 out of 8 samples of human milk in the USA. DCBs (isomers
    not specified) were found in all of the 8 samples, whileTCBs
    (isomers not specified) were found in only 1 out of the 8 samples;
    however, levels were not quantified (Pellizzari et al., 1982). Jan
    (1983a) detected all chlorobenzene isomers (except MCB, for which

    analysis was not conducted) in the breast milk (3-5 days after
    parturition) of women in a Yugoslavian hospital (Table 11). The
    concentrations of DCBs were highest, averaging 25 µg/kg, on a whole
    milk basis, and ranging up to 35 µg/kg for the 1,4-isomer. The mean
    concentrations of the isomers of tri-, tetra, and
    pentachlorobenzenes were <5 µg/kg (whole milk).  Davies &  Mes
    (1987) also detected chlorobenzene residues (di- to penta-) in the
    breast milk (3-4 weeks after parturition) of Canadian women at mean
    levels ranging from <1 µg/kg (1,2,3-TCB and PeCB) to a maximum of 6
    µg/kg (1,3- + 1,4-DCB) in whole milk. Concentrations in the breast
    milk of women of the indigenous population were slightly higher
    (Table 11). Tetrachlorobenzenes were detected, but not quantified.
    Recoveries ranged from 69% (1,2-DCB) to 100% (1,2,4-TCB).

    5.1.6  Consumer products

    As discussed in section 3, chlorobenzenes are used in a wide variety
    of consumer and commercial products. However, there is little
    information concerning the levels of chlorobenzenes present as
    contaminants in consumer products. It is reasonable to expect,
    however, that chlorobenzenes could be incidental contaminants in
    chemical products, such as solvent formulations and pesticides.
    Airborne levels of 1,4-DCB, possibly associated with its use as a
    moth repellent, are presented in Table 8 (section 5).

    5.2  Human Exposure from All Sources

    5.2.1  General population

    Although available data are limited and vary widely, it is possible
    to estimate an approximate intake of chlorobenzenes from various
    sources (Table 12). The limited data suggest that the daily intake
    of chlorobenzenes from the air might be considerably greater than
    that from food and drinking-water. It can also be concluded that the
    intake from air is greatest for the lower, more volatile
    chlorobenzenes and that intake from food, compared with that from
    other sources, increases with the degree of chlorination. These
    conclusions are also supported by data on concentrations of
    chlorobenzenes in human tissues, fluids, and exhaled air, presented
    in Table 13.

    On a body weight basis, breast-fed infants may receive higher doses
    of the chlorobenzenes than members of the adult population. Assuming
    a daily intake of 0.714 litres of milk for a 5-kg infant, estimated
    intakes for infants based on levels measured in breast milk in
    Yugoslavia (Jan, 1983a) are 5.57 µg/kg, 1.0 µg/kg, 0.43 µg/kg, and
    0.1 µg/kg body weight for total DCBs, TCBs, TeCBs, and PeCB,
    respectively. On the basis of recent Canadian data (Mes et al.,

    
    Table 11.  Levels of chlorobenzenes (mono- to penta-) in human milk
                                                                                            

    Compound                Country                                   Average level
                                                                      µg/kg whole milk
                                                                      (range)c
                                                                                            

    1,2-DCB                 Yugoslaviaa                               9(5-12)
                            Canada-national surveyb                   2.9
                            Canada-indigenous populationb             8.1

    1,3-DCB                 Yugoslavia                                <5

    1,4-DCB                 Yugoslavia                                25(5-35)

    1,3- & 1,4-DCB          Canada-national survey                    6.1
                            Canada-indigenous population              ND

    1,2,3-TCB               Yugoslavia                                5(2-10)
                            Canada-national survey                    0.3
                            Canada-indigenous population              0.1

    1,2,4-TCB               Yugoslavia                                1(ND-4)
                            Canada-national survey                    0.6
                            Canada-indigenous population              1.2

    1,3,5-TCB               Yugoslavia                                1(ND-3)
                            Canada-national survey                    ND
                            Canada-indigenous population              0.4

    1,2,3,4-TeCB            Yugoslavia                                1(ND-3)

    1,2,3,5- &              Yugoslavia                                2(ND-5)
    1,2,4,5-TeCB

    PeCB                    Yugoslavia                                0.7(ND-3)
                            Canada-national survey                    0.1
                            Canada-indigenous population              trace
                                                                                            

    a    Jan (1983a).
    b    Davies & Mes (1987).
    c    ND - not detectable (detection limits not specified).

    Table 12.  Possible daily exposure (µg/kg) body weight to total chlorobenzenes from
               various sources
                                                                                            

                Ambient air       Ambient air     Drinking-water             Food
                   (US)a           (Canada)a        (Canada)b              (Canada)c
                                                                                            

    MCB            0.882             0.166        < 0.029                     NAd

    DCB            0.930             0.203          0.00049                 0.0013

    TCB            0.039              NAd           0.00006                 0.0010

    TeCB            NAd               NAd           0.000014                0.0015

    PeCB            NAd               NAd           0.0000011               0.0011
                                                                                            

    a    Air intakes, calculated from mean outdoor levels in Canada and the USA
         presented in Table 7, assuming a daily inspired volume of 20 m3 for a
         70-kg adult.
    b    Drinking-water intakes for chlorobenzenes were estimated from the levels in
         Canadian drinking-water presented in Table 10, and assuming a daily tapwater
         consumption of 2 litres for a 70 kg adult.
    c    Food intakes were estimated using the mean concentrations of chlorobenzenes
         in the tissues of fish from the Great Lakes (Oliver & Nicol, 1982), assuming
         a daily intake of 18.5 g fish for a 70-kg adult (Statistics Canada, 1981).
    d    NA - not available.

    
    1986), estimated intakes are 1.29 µg/kg, 0.29 µg/kg, and <0.14µg/kg
    body weight for total DCBs, TCBs, and PeCB, respectively. In view of
    the small number of samples analysed and the lack of relevant data
    for most regions, these figures should be considered to provide only
    rough approximations of the relative intakes from various sources.

    5.2.2  Occupational exposure

    Few data are available on the levels of the chlorobenzenes in the
    workplace. Levels of 1,4-DCB in the atmosphere of facilities
    manufacturing, for example, air fresheners, urinal cakes, or moth
    repellents, could be quite high, taking into account the volatile
    nature of the compound. In one manufacturing plant, concentrations
    of 1,4-DCB ranged from 42 to 288 mg/m3, the average being
    204 mg/m3 (Ware & West, 1977). Levels of MCB in chemical plants
    ranging up to 18.7 mg/m3 have been reported (Cohen et al., 1981).

    Very low levels of MCB (1.8-3.2 µg/m3) and a trace of 1,4-DCB have
    been found in office air (Table 8). These values are less than the
    occupational standards in several countries, which vary between 350
    and 450 mg/m3 (IRPTC, 1986). 

    5.3  Human Monitoring Data

    Some data are available on the concentrations of chlorobenzenes in
    human blood and adipose tissue (Table 13). The 1,4-isomer of DCB was
    detected in all samples of adipose tissue (49/49), from hospitals in
    Tokyo, at levels ranging from 0.2 to 11.7 mg/kg (Morita & Ohi, 1975;
    Morita et al., 1975). The 1,2,4,5-isomer of TeCB was detected in all
    samples (15/15), but levels were several orders of magnitude less
    than those for 1,4-DCB (0.008-0.039 mg/kg) (Morita et al., 1975).
    Levels of PeCB, detected in 92 out of 99 samples of adipose tissue
    from autopsies of accident victims throughout Canada were somewhat
    similar to those reported for 1,2,4,5-TeCB in Tokyo; concentrations
    ranged from 0.001 to 0.020 mg/kg (Mes et al., 1982).

    MCB was detected in the blood of 8 out of 9 residents of the
    polluted Love Canal area at concentrations up to 17µg/litre;
    however, levels in a control population were not determined (Barkley
    et al., 1980). Although the different isomers of DCB were detected
    more frequently in the blood of residents of the Love Canal area
    (7-18 out of 36 compared with 2 out of 12 in the control
    population), the levels of 1,2- and 1,3-DCB were not significantly
    different from those in"unexposed" volunteers (i.e., <10 ng/g).
    Levels of 1,4-DCB in the blood of Love Canal residents ranged from 4
    to 36 ng/g, whereas concentrations in "unexposed" volunteers ranged
    from 2 to 9 ng/g (Bristol et al., 1982). The 1,4-isomer of DCB was
    detected in all samples of the blood of 6 Tokyo residents at levels
    ranging from 4 to 16 µg/litre (Morita & Ohi, 1975). The 1,2,4,5-TeCB
    isomer was detected in the blood of 1 out of 36 residents of the
    Love Canal area at a concentration of 2 ng/g, but was not detected
    in any of 12 "unexposed" volunteers (Bristol et al., 1982). Even in
    occupationally exposed populations, levels of chlorobenzenes in the
    blood are low; Lunde & Bjorseth (1977) reported detecting PeCB in
    the blood of 9 out of 17 workers at concentrations ranging from 0.06
    to 0.26 ng/g.


    
    Table 13.  Chlorobenzenes in human tissues, fluids, and exhaled air
                                                                                                                                              

    Compounda;  Reference        Populationb                                                         Sample     Concentration
                                                                                                     matrix     (no. of positives/no. of
                                                                                                                samples)c
                                                                                                                                              

    MCB
       Barkley et al. (1980)     residents of the Old Love Canal area                                urine      ND - 120 ng/litre (6/9)
                                                                                                     blood      ND - 17 µg/litre (8/9)
                                                                                                     breath     ND - trace (1/9)

       Wallace et al. (1984)     samples from 9 individuals from New Jersey and 3 from North         breath     0.07 - 8.15 µg/m3 (31/66)
                                 Carolina

    DCB
       Barkley et al. (1980)     residents of the Old Love Canal area                                urine      ND - 39 µg/litre (7/9)
                                                                                                     blood      0.15 - 68 µg/litre (9/9)
                                                                                                     breath     ND - 5000 ng/m3 (7/9)

       Antoine et al. (1986)     patients in the USA with possible sensitivities to                  blood      ND - 31 µg/litre (NA/250)
                                 synthetic chemicals

    1,3- + 1,4-DCB
       Wallace et al. (1984)     samples from individuals from North Carolina                        breath     0.09 - 0.76 µg/m3 (4/5)

       Wallace (1986)            samples from residents of cities in New Jersey and California       breath     2.9 - 8.1 µg/m3 (NA/660)

    1,2-DCB
       Wallace (1986)            samples from residents of Los Angeles                               breath     0.08 - 0.1 µg/m3 (NA/201)

       Bristol et al. (1982)     residents of the Love Canal area and 9 volunteers (laboratory       blood      residents: 1-4 µg/litre (9/36)
                                 workers)                                                                       volunteers: 3-4 µg/litre (2/12)
                                                                                                                                              

    Table 13 (continued)
                                                                                                                                              

    Compounda;  Reference        Populationb                                                         Sample     Concentration
                                                                                                     matrix     (no. of positives/no. of
                                                                                                                samples)c
                                                                                                                                              

    1,3-DCB
       Bristol et al. (1982)     residents of the Love Canal area and 9 volunteers (laboratory       blood      residents: 3-8 µg/kg (7/36)
                                 workers)                                                                       volunteers: 3-8 µg/kg (2/12)

    1,4-DCB
       Bristol et al. (1982)     residents of the Love Canal area and 9 volunteers (laboratory       blood      residents: 4-26 µg/kg (18/36)
                                 employees)                                                                     volunteers: 2-9 µg/kg (2/12)

       Morita & Ohi (1975)       adipose tissue samples from medical examiners and 3 Tokyo           adipose    0.2 - 11.7 mg/kg (34/34)
                                 hospitals;                                                          tissue
                                 blood from 6 healthy volunteers                                     blood      4 - 16 µg/litre (6/6)

       Morita et al. (1975)      samples from hospitals or medical examiners in Tokyo                adipose    0.2 - 9.9 mg/kg (15/15)
                                                                                                     tissue

       Pagnotto & Walkley (1965) analysis for urinary dichlorophenol in workers in                   urine      10 - 233 mg/litred
                                 various stages of p-dichlorobenzene production

    TCB
       Barkley et al. (1980)     residents of the Old Love Canal area                                breath     ND - 90 ng/m3 (2/9)

    1,3,5-TCB
       Bristol et al. (1982)
                                 residents of the Love Canal area and 9 volunteers (laboratory       blood      residents: 0.7 µg/kg (1/36)
                                 employees)                                                                     volunteers: ND (0/12)

    TeCB
       Barkley et al. (1980)
                                 residents of the Old Love Canal area                                blood      ND - 2.6 µg/litre (1/99)
                                                                                                     breath     ND - 180 ng/m3 (2/9)
                                                                                                                                              

    Table 13 (continued)
                                                                                                                                              

    Compounda;  Reference        Populationb                                                         Sample     Concentration
                                                                                                     matrix     (no. of positives/no. of
                                                                                                                samples)c
                                                                                                                                              

    1,2,4,5-TeCB
       Bristol et al. (1982)     residents of the Love Canal area and 9 volunteers (laboratory       blood      residents: 2 µg/kg (1/36)
                                 employees)                                                                     volunteers: ND (0/12)

       Morita et al. (1975)      samples from hospitals or medical examiners in Tokyo                adipose    0.008 - 0.039 mg/kg (15/15)
                                                                                                     tissue

    PeCB
       Lunde & Bjorseth (1977)   samples obtained from 17 employees working at various stages in     blood      0.06 - 0.26 µg/kg (9/17)
                                 magnesium production

       Mes et al. (1982)         samples obtained from autopsies of accident victims across          adipose    0.001 - 0.020 mg/kg (92/99)
                                 Canada                                                              tissue

       Barkley et al. (1980)     residents of the Old Love Canal area                                breath     ND - 70 ng/m3 (1/90)

       Williams et al. (1988)    samples obtained from autopsies of individuals from 6 Canadian      adipose    ND - 43 mg/kg (9/141)
                                 Great Lakes municipalities                                          tissue
                                                                                                                                              

    a    Isomers specified where available.
    b    Number of subjects specified where available.
    c    ND - not detected.
    d    Levels of dichlorophenol found in urine.

    

    6. KINETICS AND METABOLISM

    With the exception of limited information concerning MCB and 1,4-DCB
    in man, available data on the kinetics and metabolism of
    chlorobenzenes (mono- to penta-) have been obtained from studies on
    experimental animals.

    6.1  Absorption

    Although few quantitative data are available, the results of
    experimental studies on animals (section 8) and human case reports
    of poisonings (section 9) indicate that the chlorobenzenes are
    readily absorbed from the gastrointestinal and respiratory tracts.
    Available data also indicate that the position of the chlorines in
    different isomers of the same congener influences absorption. It is
    probable that the rate of transport of the chlorobenzenes (mono- to
    penta-) across the gut wall also varies as a function of exogenous
    factors, particularly the presence of bile and of dietary lipids in
    the gastrointestinal tract, as is the case for hexachlorobenzene
    (Koss & Koransky, 1977).

    Quantitative data on absorption can be derived from studies on
    experimental animals, the most important of these (summarized in
    Table 14) are limited to the gastrointestinal tract. For example,
    following intragastric administration of 1.5 g of 1,4-DCB to
    Chinchilla rabbits, Azouz et al. (1955) did not detect any of the
    unchanged compound in the faeces, implying that, under the
    conditions of the study, total absorption had occurred. Hawkins et
    al. (1980) reported that only 9% (the unabsorbed portion) of a
    single radio-labelled dose of 250 mg 1,4-DCB/kg body weight was
    present in the faeces of rats with cannulated bile ducts, at 24 h.
    Six days following administration by stomach tube of 500 mg/kg body
    weight of the 1,2,3,4-, 1,2,3,5- and 1,2,4,5-isomers of TeCB to
    Chinchilla rabbits, 5%, 14%, and 16%, respectively, of the
    administered doses were recovered unchanged in the faeces (Jondorf
    et al., 1958). The percentages of the administered doses recovered
    unchanged in the gut contents were 0.5%, 1.4%, and 6.2%,
    respectively, suggesting that gastrointestinal absorption of the
    compounds is relatively efficient and that the chlorine positions on
    the molecule may influence the process. In rhesus monkeys, Rozman
    et al. (1979) reported that 95% of an oral dose of 0.5 mg PeCB/kg
    body weight was absorbed, as indicated by faecal elimination in the
    first 4 days.

    6.2  Distribution

    The results of available studies indicate that, following
    absorption, the chlorobenzenes are initially rapidly distributed to
    highly perfused tissues, but then accumulate in fatty tissues,
    because of their lipophilic nature (Jondorf et al., 1958; Jacobs
    et al., 1974; Villeneuve & Khera, 1975; Jacobs et al., 1977; Kimura
    et al., 1979; Hawkins et al., 1980; Linder et al., 1980; Smith &
    Carlson, 1980; Chu et al., 1983; Sullivan et al., 1983; Tanaka
    et al., 1986; Chu et al., 1987). Transplacental transfer (PeCB) into
    the fetal brain and liver tissues has also been observed (Villeneuve
    & Khera, 1975). Available data also indicate that, in general,
    accumulation is greatest for the more highly chlorinated congeners,
    but that it can vary enormously for different isomers of the same
    chlorobenzene. For example, when 0.59 g of 14C-labelled MCB was
    administered twice daily for 7 days to Dutch rabbits, only 0.05% of
    the radiolabel was found in the tissues over the following 7-day
    period (Smith et al., 1972). Following oral administration of 500 mg
    1,3,5-TCB/kg to Chinchilla rabbits, only 5% of the administered dose
    was present in the fat at 8 days, whereas 22% of a similar dose of
    PeCB, administered subcutaneously, was present in the fat of the
    same species at 10 days (Parke & Williams, 1960). Jondorf et al.
    (1958) reported that 25%, 11%, and 5% of an oral dose of 500 mg/kg
    was recovered in the fat of Chinchilla rabbits for the 1,2,4,5-,
    1,2,3,5- and 1,2,3,4-isomers of TeCB, respectively, at 6 days.
    Similarly, Chu et al. (1983) reported that the 1,2,4,5-isomer of
    TeCB accumulated in the fat and liver at much higher levels (by 2
    orders of magnitude) than the 1,2,3,5 and 1,2,3,4-isomers, following
    oral administration for 28 days to rats of diets containing 0.5,
    5.0, 50, or 500 mg chlorobenzene/kg, reflecting wide differences in
    metabolic rates (section 6.3).

    Peak levels in fat, which occurred 6-12 h after oral administration
    of 200 or 800 mg 1,4-DCB/kg body weight to rats, were 50 times those
    in the blood (Kimura et al., 1979). Braun et al. (1978) reported
    that the ratio of 1,2,4,5-TeCB concentrations in fat to those in
    plasma in beagle dogs was 650, following 1 month of oral
    administration of 5 mg/kg body weight per day. This ratio decreased
    steadily to about 280 by the end of the administration period (2
    years) and increased rapidly in the 20 months following treatment.

    Levels of the same isomer of the chlorobenzenes in various tissues
    appear to be similar, regardless of the route of administration.
    Hawkins et al. (1980) reported that the concentrations in rat
    tissues at 24 h were similar following inhalation of 6000 mg
    14C-labelled 1,4-DCB/m3 (1000 ppm) for 3 h/day or administration
    of 250 mg/kg body weight per day orally, or subcutaneously, for up
    to 10 days. At low levels of exposure, accumulation in adipose
    tissue appears to be dose-related, whereas at high levels there
    appears to be a disproportionate increase in the adipose tissue
    burden. For example, Jacobs et al. (1974) reported a dose-related

    accumulation of 1,2-DCB in the abdominal and renal adipose tissue of
    rats following administration of a mixture of organic chemicals
    including 1,2-DCB at doses of 0.4, 0.8, or 2 mg/kg diet per day for
    4-12 weeks. On the other hand, when rats inhaled 14C-labelled MCB
    at 455, 1820, or 3185 mg/m3 (100, 400, or 700 ppm) for 1 or 5
    days, tissue concentrations increased in proportion to the level of
    exposure, except for those in adipose tissue, which increased more
    than 30-fold between 455 and 3185 mg/m3 (Sullivan et al., 1983).
    Smith & Carlson (1980) demonstrated that starvation for 4 days did
    not have any effects on the distribution of 1,2,4-TCB in the fat or
    liver of rats following oral administration of 181.5 mg/kg
    (1 mmol/kg body weight) per day for 7 days.

    6.3  Metabolic Transformation

    The chlorobenzenes are metabolized by microsomal oxidation and
    proceed principally, either directly or through the formation of a
    metastable arene oxide intermediate, to form the corresponding
    chlorophenols. These chlorophenols can be excreted in the urine as
    mercapturic acids, formed by conjugation with glutathione, or as
    glucuronic acid or sulfate conjugates; they may also be eliminated
    unchanged, mainly in expired air or faeces.

    The results of available studies concerning the metabolism and
    elimination of the chlorobenzenes are presented in Table 14. More
    detailed comparative metabolic profiles for each of the
    chlorobenzenes in rabbits, following oral administration of 0.5 g/kg
    body weight, are presented in Table 15. On the basis of the results
    of such studies, it can be concluded that:  (a) metabolic
    transformation of the chlorobenzenes decreases with increasing
    degree of chlorination; and  (b) metabolism and elimination of the
    higher chlorinated congeners is slower and a greater proportion of
    the compound is eliminated unchanged in the faeces or expired air.
    The position of the chlorine atoms on the benzene ring is also an
    important determinant of the rates of metabolism and elimination,
    with chlorobenzenes with 2 adjacent unsubstituted carbon atoms
    (e.g., 1,2,3-TCB, 1,2,3,4-TeCB) being more rapidly metabolized and
    eliminated than congeners having a similar degree of chlorination,
    but lacking unsubstituted carbon atoms. The presence of the two
    adjacent unsubstituted carbon atoms facilitates the formation of
    arene oxides. For isomers without adjacent unsubstituted carbon
    atoms, intermediate reactions take place in which chlorine atoms are
    shifted to adjacent carbons ("the NIH-shift") to form compounds that
    can then form epoxide intermediates (Daly et al., 1972; Jerina &
    Daly, 1974).


    
    Table 14.  Metabolism and elimination in experimental animals
                                                                                                                                              

    Compound;            Speciesa         Study protocol                           Results
    Reference
                                                                                                                                              

    MCB                  Dutch rabbit     oral administration (gavage) of          19.6% of administered label in urine, 1.05% in
      Smith-                              0.59 g of 14C-MCB, twice a day           faeces and 0.05% in tissues; urinary metabolites
      Lindsay et al.                      for 4 days; collection of urine          were glucuronides (33.6%), ethereal sulfates
      (1972)                              and faeces for 7 days                    (33.9%), mercapturic acids (23.8%), diphenols
                                                                                   (4.17%), monophenols (2.84%) and
                                                                                   3,4-dihydro-3,4-dihydroxy-chlorobenzene (0.57%)

    MCB                  male Wistar      intraperitoneal injection of             urinary metabolites in 24 h: 4-chlorocatechol
      Yoshida &          rat              2 mmol/kg body weight in olive           (1.6%), 2-chlorophenol (1.6%), 4-chlorophenol
      Hara (1985)                         oil; collection of urine for 3           (4.8%), 3-chlorophenol (3.6%), and
                                          days prior to, and for 4 days            4-chlorophenylmercapturic acid (19.9%)
                                          following, the injection

    1,4-DCB              female CFY       inhalation of 6000 mg                    after 5 days dosing, compound metabolized and
      Hawkins            rat              14C-1,4-DCB/m3 3 h/day, or daily         eliminated primarily in the urine (91-97%); for
      et al. (1980)                       oral or subcutaneous doses               all routes of exposure, primarily 2,5-DCP sulfate
                                          (250 mg/kg) for up to 10 days;           (46-54% of total eliminated) and 2,5-DCP
                                          administration of a dose                 glucuronide in the urine (31-34%) and bile
                                          (250 mg/kg) to rats with                 (30-42%)
                                          cannulated bile ducts

    1,4-DCB              Chinchilla       oral administration (intragastric        metabolism primarily through oxidation to 3,4-DCP
    1,2-DCB              rabbit           in olive oil) of 1.5 g (500 mg/kg)       (from 1,2-DCB) and 2,5-DCP (from 1,4-DCB) and
      Azouz et al.                        1,4-DCB or 500 mg/kg 1,2-DCB             eliminated in the urine in the form of glucuronic
      (1955)                              (intragastric in water)                  and sulfuric acid conjugates; metabolism and
                                                                                   elimination complete in 5-6 days for 1,2-DCB and
                                                                                   >6 days for 1,4-DCB; not detected in the faeces
                                                                                                                                              

    Table 14 (continued)
                                                                                                                                              

    Compound;            Speciesa         Study protocol                           Results
    Reference
                                                                                                                                              

    1,2,4-TCB            male Charles     oral (gastric intubation) or             about 84% of the oral dose and 78% of iv dose
      Lingg et al.       River rat and    intravenous administration of            eliminated by rats and 40% (oral) and 22% (iv)
      (1982)             female rhesus    10 mg/kg                                 by rhesus monkeys in the urine in 24 h; faecal
                         monkey                                                    elimination accounted for 11% (oral) and 7% (iv)
                                                                                   in rats, and <1% from both routes in monkeys;
                                                                                   48-61% comprised an isomeric pair of
                                                                                   3,4,6-trichloro-3,5-cyclohexadiene-1,2-diol
                                                                                   glucuronides, 14-37% comprised glucuronides of
                                                                                   2,4,5-TCP and 2,3,5-TCP, and 1-37% was
                                                                                   unconjugated TCPs; in the rats, 60-62% of the
                                                                                   urinary metabolites comprised 2 isomers
                                                                                   (2,4,5- and 2,3,5-) of
                                                                                   N-acetyl-S-(trichlorophenyl)-L-cysteine, 28-33%
                                                                                   comprised the 2,4,5- and 2,3,5-isomers of
                                                                                   trichlorothiophenol, with 1% 2,4,5-, and 10% 2,3,5-TCPs

    1,2,4-TCB            male Wistar      oral administration of                   approximately 66% and 17% eliminated in the urine
      Tanaka et al.      rat              50 mg 14C-1,2,4-TCB/kg                   and faeces, respectively, in 7 days; 2.1%
      (1986)                                                                       exhaled; tissue residues evenly distributed, with
                                                                                   the exception of the adipose tissue in which
                                                                                   concentrations were consistently slightly higher;
                                                                                   principal metabolites in the urine were free
                                                                                   2,4,5- and 2,3,5-TCP and their conjugates; minor
                                                                                   metabolites in the urine were 5- or 6-sulfhydryl,
                                                                                   methylthio, methyl-sulfoxide, and methylsulfone
                                                                                   derivatives of TCB; DCBs and TCB were present in
                                                                                   expired air
                                                                                                                                              

    Table 14 (continued)
                                                                                                                                              

    Compound;            Speciesa         Study protocol                           Results
    Reference
                                                                                                                                              

    1,2,4-TCB            Chinchilla       oral dose (gavage in arachis oil)        at 5 days, the urinary metabolites of the
    1,2,3-TCB            rabbit           of 500 mg/kg body weight                 1,2,4-isomer were glucuronide conjugates (27%),
    1,3,5-TCB                                                                      sulfuric acid conjugates (11%), and 2,3,5- and
      Jondorf                                                                      2,4,5-trichlorophenylmercapturic acid (0.3%),
      et al. (1955)                                                                major phenols being 2,4,5- and 2,3,5-TCP; the
                                                                                   1,2,3-isomer was metabolized to 2,3,4-TCP, and
                                                                                   3,4,5-TCP to a lesser extent and to small amounts
                                                                                   of 3,4,5-trichlorocatechol, with 50% of the dose
                                                                                   being eliminated in the urine as glucuronic acid
                                                                                   conjugates, 12% as sulfuric acid conjugates, and
                                                                                   0.3% as 2,3,4-trichlorophenyl-mercapturic acid;
                                                                                   for the 1,3,5-isomer, 20% was eliminated as
                                                                                   sulfuric acid conjugates, no mercapturic acid was
                                                                                   found, 2,4,6-TCP was the only phenol detected in
                                                                                   the urine and some unchanged 1,3,5-TCB was
                                                                                   present in faeces; the 1,2,3-isomer most rapidly
                                                                                   metabolized; the rate of metabolism in descending
                                                                                   order was: 1,2,3- > 1,2,4- > 1,3,5-TCB

    1,2,3-TCB            male             single oral dose (gavage in corn         elimination data obtained only for 1,3,5- and
    1,2,4-TCB            Sprague-Dawley   oil) of 10 mg/kg body weight of          1,2,3-isomers; both rapidly eliminated in the
    1,3,5-TCB            rat              each 14C-labelled isomer                 urine and faeces:
      Chu et al.                                                                                    urine   faeces   total
      (1987)                                                                          1,3,5- 24 h   47.1%   35.8%    82.9%
                                                                                             48 h   50.3%   38.3%    88.6%

                                                                                      1,2,3- 24 h   56.3%   35.6%    91.9%
                                                                                             48 h   58.5%   36.8%    95.3%
                                                                                                                                              

    Table 14 (continued)
                                                                                                                                              

    Compound;            Speciesa         Study protocol                           Results
    Reference
                                                                                                                                              

    1,2,4-TCB            male rabbit      intraperitoneal injection in             major urinary metabolites of 1,2,4-TCB were
    1,2,3-TCB                             vegetable oil; 60 - 75 mg/kg body        2,4,5- and 2,3,5-TCP; the major metabolite of
    1,3,5-TCB                             weight                                   1,2,3-TCB was 2,3,4-TCP with 2,3,6- and 3,4,5-TCP
      Kohli et al.                                                                 as minor urinary metabolites; 1,3,5-TCB was
      (1976)                                                                       metabolized to 2,3,5- and 2,4,6-TCP and a third
                                                                                   more polar metabolite

    1,3,5-TCB            Chinchilla       oral administration (gavage in           at day 8, 13% of administered dose was in the
      Parke &            female rabbit    arachis oil) of 500 mg/kg                faeces, 12% exhaled, 23% (4% as MCB) in the gut,
      Williams                                                                     5% in the pelt, 5% in depot fat, and 22% in the
      (1960)                                                                       carcass; <10% eliminated as the major urinary
                                                                                   metabolite of 2,4,6-TCP; minor metabolites
                                                                                   included 4-chlorocatechol and 4-MCP

    1,2,4,5-TeCB         Sprague-Dawley   oral gavage in corn oil; 10 mg/kg        for the 1,2,3,4- and 1,2,3,5- isomers,
    1,2,3,5-TeCB         rat              body weight TeCB                         approximately 46-51% eliminated in the urine and
    1,2,3,4-TeCB                                                                   faeces within 48 h following administration,
      Chu et al.                                                                   whereas only 8% of the 1,2,4,5-isomer was
      (1984b)                                                                      eliminated in the same period; most of the
                                                                                   1,2,4,5-isomer was eliminated in the urine, the
                                                                                   1,2,3,4-isomer mainly in the faeces and the
                                                                                   1,2,3,5-isomer equally between the urine and
                                                                                   faeces; metabolites in decreasing order were as
                                                                                   follows:  1,2,3,4-TeCB: 2,3,4,5- and
                                                                                   2,3,4,6-TeCP, and traces of tetrachlorthiophenol
                                                                                   and 2,3,4-TCP; 1,2,3,5-TeCB: 2,3,4,6-TeCP,
                                                                                   isomeric mercaptotrichlorophenols, and a TCP;
                                                                                   1,2,4,5-TeCB: 2,3,5,6-TeCP, tetrachloroquinol,
                                                                                   and a TCP
                                                                                   and a TCP
                                                                                                                                              

    Table 14 (continued)
                                                                                                                                              

    Compound;            Speciesa         Study protocol                           Results
    Reference
                                                                                                                                              

    1,2,4,5-TeCB         male rabbit      intraperitoneal injection in             1,2,3,5-TeCB the most extensively metabolized
    1,2,3,5-TeCB                          vegetable oil; 60-75 mg/kg body          isomer, yielding
    1,2,3,4-TeCB                          weight                                   2,3,4,5-, 2,3,5,6-, and 2,3,4,6-TeCP;
      Kohli et al.                                                                 1,2,3,4-TeCB was metabolized to 2,3,4,5- and
      (1976)                                                                       2,3,4,6-TeCP and 1,2,4,5-TeCB yielded only 2,3,5,6-TeCP

    1,2,3,4-TeCB         Squirrel         oral administration (gavage in           major urinary metabolite was
      Schwartz           monkey           corn oil) of 100 mg/kg 14C-TeCB          N-acetyl-S-(2,3,4,5-tetrachlorophenyl) accounting
      et al. (1985)                                                                for 85% in urine; minor urinary metabolite was 2,3,4,5-TeCP

    1,2,3,4-TeCB         Squirrel         single oral dose of one of the           main pathway of elimination for all isomers was
    1,2,3,5-TeCB         monkey           14C-labelled isomers dissolved           faecal elimination - 38%, 36%, and 18% for
    1,2,4,5-TeCB                          in corn oil, twice a week for 3          1,2,3,4-, 1,2,3,5-, and 1,2,4,5-TeCB isomers,
      Schwartz                            weeks, at the following doses;           respectively; 1.2% of 1,2,3,4- and less than 0.1%
      et al. (1987)                       1,2,3,4- 100 mg/kg body weight;          of the 1,2,3,5- and 1,2,4,5-TeCB isomers were
                                          1,2,3,5- 100 mg/kg body weight           eliminated in the urine; 1,2,3,4-isomer-Faeces:
                                          1,2,4,5- 50 mg/kg body weight;           50% as the parent compound, metabolites included
                                          urine and faeces collected               2,3,4,5-tetrachlorophenol (22%),
                                                                                   N-acetyl-S-(2,3,4,5-tetrachlorophenyl)-cysteine
                                                                                   (18%), 2,3,4,5-tetrachlorophenyl sulfinic acid
                                                                                   (3%), 2,4,5-trichlorophenyl methyl sulfoxide
                                                                                   (0.6%), and 2,3,4,5-tetrachlorophenyl methyl
                                                                                   sulfide (0.2%); urine:
                                                                                   N-acetyl-S-(2,3,4,5-tetrachlorophenyl)-cysteine
                                                                                   (85%) and 2,3,4,5-tetrachlorophenol (15%).
                                                                                   1,2,3,5-isomer-Faeces: 50% as unchanged TeCB,
                                                                                   2,3,4,5-tetrachlorophenol (2%),
                                                                                   2,3,4,6-tetrachlorophenol (14%),
                                                                                                                                              

    Table 14 (continued)
                                                                                                                                              

    Compound;            Speciesa         Study protocol                           Results
    Reference
                                                                                                                                              

                                                                                   2,3,5,6-tetrachlorophenol (9%), and
                                                                                   2,3,4,6-tetrachlorophenyl sulfinic acid (15%);
                                                                                   urine: nondetectable; 1,2,4,5-TeCB-Faeces: >99%
                                                                                   as unchanged parent compound; urine:
                                                                                   nondetectable

    PeCB                 Rhesus           oral gavage of 0.5 mg/kg body            approximately 12% of the administered dose
      Rozman             monkey           weight 14C-PeCB                          eliminated in the urine after
      et al. (1979)                                                                40 days and 24% in the faeces (99%
                                                                                   unmetabolized); the 2,3,4,5-, 2,3,5,6-, and
                                                                                   1,2,3,4- isomers of TeCP identified as
                                                                                   metabolites; no sex-related differences in
                                                                                   metabolism

    PeCB                 male rabbit      intraperitoneal injection in             urinary metabolites were 2,3,4,5-TeCP and PeCP,
      Kohli et al.                        vegetable oil; 300 mg                    both detected at 1% of the administered dose, 10
      (1976)                                                                       days after dosing

    PeCB                 male Wistar      oral administration (gavage in           major urinary metabolites: 2,3,4,5-TeCP and PeCP;
      Engst et al.       rat              sunflower oil) of 8 mg/kg                PeCB, 2,3,4,6-TeCP, and/or 2,3,5,6-TeCP present
      (1976)                                                                       in free form; TCP (isomer not specified),
                                                                                   2,4,6-TCP and 1,2,3,4-TeCB present in small
                                                                                   concentrations

    PeCB                 female rat       intraperitoneal administration (in       over a 4-day period, 3% eliminated in unchanged
      Koss &                              olive oil) of 403 µmol/kg body           form; urinary metabolites: PeCP (9%),
      Koransky                            weight                                   2,3,4,5-TeCP, tetrachlorohydroquinone, a
      (1977)                                                                       hydroxylated chlorothiocompound, and traces of
                                                                                   another isomer of TeCP; PeCP,
                                                                                   tetrachlorohydroquinone, tetrachlorophenol, and
                                                                                   hydroxylated chlorothio- compound present in faeces
                                                                                                                                              

    Table 14 (continued)

    a    Strain specified where available.
         MCP - monochlorophenol.
         DCP - dichlorophenol.
         TCP - trichlorophenol.
         TeCP - tetrachlorophenol.
         PeCP - pentachlorophenol.

    

    MCB is metabolized to an arene oxide as the first stage
    intermediate, the major urinary metabolites being 4-chlorocatechol
    (and conjugates) and 4-chlorophenyl-mercapturic acid. Three isomeric
    chlorophenols (2-, 3-, or 4-chlorophenol) and 3-chloro-catechol are
    minor metabolites.

    The availability of tissue glutathione and the extent of the
    conjugation of the catechol and chlorophenol metabolites appear to
    play an important role in species differences in the metabolism of
    MCB. Examination of the metabolic profile, 24 h following
    administration of MCB (dosage unspecified), in 13 species including
    man, indicated that the pattern was quantitatively similar in all
    species; the profile in man was most similar to that in the
    guinea-pig with metabolites in human urine identified as
    4-chlorocatechol, 4-chlorophenol, and 4-chlorophenylmercapturic acid
    (Williams et al., 1975). Data from an additional comparative study
    indicate that 4-chlorocatechol  is  the  main urinary metabolite  of 
    MCB  in man (Ogata & Shimada, 1983).  In rats,  rabbits,  and mice
    administered 0.5, 1.0, or 2.0 mmol MCB/kg body weight,
    intra-peritoneally, the ratios of urinary 4-chlorophenylmercapturic
    acid: 4-chlorocatechol were 9.1, 7.2, 6.1; 1.6, 1.8, 1.8; and 7.3,
    7.8, 6.4, in the various species, respectively. In man, however,
    following ingestion of 3 repeated doses of 0.3 mmol MCB/kg body
    weight, or inhalation (concentration not specified) of MCB, the
    comparable ratios were considerably lower, 0.002 and 0.007,
    respectively, because of the extremely small amounts of
    4-chlorophenylmercapturic acid present in the urine.

    Saturation of glutathione conjugation capacity has been observed and
    may play a role in the manifestation of toxic effects from MCB
    exposures. For example, Sullivan et al. (1983) reported a
    disproportionate increase in the respiratory elimination of
    unchanged compound and a dose-dependent decrease in the mercapturic
    acid percentage of urinary metabolites from 68% at 455 mg/m3 (100
    ppm) to 51% at 3185 mg/m3 (700 ppm), following inhalation by rats
    for 1 or 5 days. Yoshida & Hara (1985) observed a transient decrease
    in hepatic glutathione related to urinary levels of mercapturic acid
    following intraperitoneal injection of rats with 2 mmol MCB/kg. A
    transient decrease in urinary taurine levels was also observed,
    which the authors attributed to depression of the oxidative
    degradation of cysteine by the increase in glutathione synthesis.
    The authors further suggested that the levels of sulfur-containing
    dietary amino acids may have an effect on the metabolism or toxicity
    of chlorobenzenes for which the major metabolite is mercapturic
    acid.


    
    Table 15.  Metabolites of chlorobenzenes in rabbits following ingestion
    of 0.5 g/kg body weighta

                                                                                                                                              
                                     Percentage of dose eliminated as:
                                                                                                    

    Compound         Time of      Mercapturic      Monophenolsb      Catecholsb      Total O-      Percentage of dose eliminated
                   elimination       Acid                                           conjugatesc            unchanged
                     (days)d
                                                                                                                                              

    MCB                1-2            25                2-3              27             47               27 in expired air

    1,2-DCB             5              5                40                4             69                      NSf

    1,3-DCB             5             11                25                3             37                      NSf

    1,4-DCB             5              0                35               6e             63                      NSf

                                                                                                  in faeces             in tissue
    1,2,3-TCB           5             0.3               78               trg            62            0                    NSf

    1,2,4-TCB           5             0.4               42               trg            38            0                    NSf

    1,3,5-TCB           8              0                 9                0             23           10                    51

    1,2,3,4-TeCB        6              0                34               trg            43            5                    10

    1,2,3,5-TeCB        6              0                 5                0              8           14                    23

    1,2,4,5-TeCB        6              0                 2                0              5           16                    48

    PeCB                6              0                <1                0              9            5                    50
                                                                                                                                              
    Table 15 (cont'd)

    a    From: Williams (1959).
    b    In some cases these numbers give the amounts isolated.
    c    Conjugated glucuronic acid plus ethereal sulfate.
    d    Metabolites produced only at a very low rate after this time.
    e    Quinols.
    f    NS - not stated.
    g    tr - trace.

    

    The metabolism of the dichlorobenzenes in most animal species
    proceeds through the formation of arene oxide intermediates but,
    unlike that of MCB, it results primarily in the excretion of
    dichlorophenols, generally as conjugates of glucuronic and sulfuric
    acids. Mercapturic acids and catechols are only minor metabolites.
    For 1,4-DCB, 2,5-dichloroquinol is also a minor metabolite. In
    general, mercapturic acids and catechols do not appear to be formed
    during the metabolism of 1,4-DCB in animals. However, Hawkins et al.
    (1980) reported the presence of small amounts of "a mercapturic acid
    of 1,4-DCB" in the urine during the 5-day period following exposure
    of rats to 1,4-DCB via inhalation (6000 mg/m3, 3 h/day) or orally
    or subcutaneously at (250 mg/kg body weight per day) for up to 10
    days. Small amounts (<0.03% of the total dose) of sulfur-containing
    metabolites, namely 2,5-dichlorophenyl methyl sulfoxide, and
    2,5-dichlorophenyl methyl sulfone, have also been identified
    following oral administration of 1,4-DCB to rats (Kimura et al.,
    1979).

    Limited available data indicate that the rate of metabolism of
    1,2-DCB is slightly greater than that for the 1,4-isomer. Azouz et
    al. (1955) reported that the metabolism and elimination of 1,2-DCB
    and 1,4-DCB in rabbits was complete in 5-6 days, and >6 days,
    respectively, following oral administration of 500 mg/kg.

    Dichlorophenol has been detected in the urine of workers exposed to
    1,4-DCB. Levels ranged from 10 to 233 mg/litre in an unspecified
    number of workers employed at various stages in the production of
    1,4-DCB (Pagnotto & Walkley, 1965).

    The principal metabolic products of the trichlorobenzenes, which are
    formed following generation of intermediate arene oxides, are
    trichlorophenols (TCP) (2,3,4-TCP for the 1,2,3-isomer; 2,4,6-TCP
    for the 1,3,5-isomer, and both 2,3,5-TCP and 2,4,5-TCP for the
    1,2,4-isomer). Minor metabolites include trichlorocatechols (for the
    1,2,3- and 1,2,4-isomers of TCB), other trichlorophenols (for all
    isomers of TCB), trichlorophenyl-mercapturic acids (for the 1,2,3-
    and 1,2,4-isomers of TCB), and 4-chlorophenol and 4-chloro-catechol
    (for the 1,3,5-isomer of TCB). Kohli et al. (1976) also reported the
    presence of a polar urinary metabolite ("possibly DCB with 2
    hydroxyl and 1 methoxyl substituent") following intraperitoneal
    injection of rabbits with 60-75 mg/kg of 1,3,5-TCB. Several
    additional metabolites have been reported following administration
    of 1,2,4-TCB to various species, including 5- or 6-sulhydryl,
    methylthio, methylsulfoxide, and methylsulfone derivatives of TCB
    (minor metabolites in rats) (Tanaka et al., 1986), 2,4,5- and
    2,3,5-trichlorothiophenol and the 2,4,5- and 2,3,5-isomers of
     N-acetyl- S-(trichlorophenyl)-L-cysteine (major metabolites in
    rats) (Lingg et al., 1982), and an isomeric pair of
    3,4,6-trichloro-3,5-cyclo-hexadiene-1,2-diol glucuronides (major
    metabolites in monkeys) (Lingg et al., 1982).

    The most rapidly metabolized of the 3 isomers is 1,2,3-TCB, with
    over 60% of an orally administered dose of 500 mg/kg body weight
    being eliminated in the urine of rabbits in a 5-day period, compared
    with 38% and 28% for the 1,2,4- and 1,3,5-isomers, respectively
    (Jondorf et al., 1955).

    Available data also indicate that there are considerable species
    differences in the metabolism of the trichlorobenzenes. In a study
    by Lingg et al. (1982), in which 10 mg 1,2,4-TCB/kg body weight was
    administered orally or intravenously to both rats and rhesus
    mon-keys, the metabolic profile of the two species varied
    considerably. In the monkey, a stereo isomeric pair of
    3,4,6-trichloro-3,5-cyclo-hexadiene-
    1,2-diol glucuronides accounted for over half of the urinary
    metabolites while, in the rat, the 2,4,5- and
    2,3,5- N-acetyl- S-(trichlorophenyl)-L-cysteine isomers accounted
    for the majority of the urinary metabolites. In addition to the
    metabolic pathway being species specific, 2-3 times as much
    14C-TCB was excreted in 24 h in the rat as in the monkey.

    The tetrachlorobenzenes are slowly metabolized, principally to 3
    tetrachlorophenols (2,3,4,5-, 2,3,4,6-, and 2,3,5,6-isomers). Arene
    oxides are postulated to be metabolic intermediates and "NIH shifts"
    are required in most of the postulated pathways. Schwartz et al.
    (1985) recently reported that the major urinary metabolite
    (accounting for 85% of the radioactivity in the urine) following
    oral administration of 100 mg 1,2,3,4-TeCB/kg body weight to
    squirrel monkeys was  N-acetyl- S-(2,3,4,5-tetrachlorophenyl)
    cysteine. A minor metabolite of the 1,2,3,4-TeCB isomer was
    2,3,4-trichlorophenol. Tetrachlorophenols are major metabolites of
    TeCBs in rats (Chu et al., 1984b). Isomeric mercaptotrichlorophenols
    and a trichlorophenol have been identified as metabolites of
    1,2,3,5-TeCB in rats; tetrachloroquinol and a trichlorophenol have
    also been detected in this species following administration of
    1,2,4,5-TeCB (Chu et al, 1984b).

    The 1,2,4,5-isomer is not well metabolized and tends to remain in
    the tissues for a considerable time in the unchanged state. For
    example, following the oral administration of 500 mg/kg body weight
    to rabbits, 48% of the 1,2,4,5-isomer was detected unchanged in the
    tissues at 6 days, compared with 10% for the 1,2,3,4 isomer and 23%
    for the 1,2,3,5-isomer (Jondorf et al., 1958). Following oral
    administration of 10 mg/kg body weight to rats, 46-51% of the
    1,2,3,4- and 1,2,3,5-isomers was eliminated in the urine and faeces
    within 48 h, whereas only 8% of the 1,2,4,5-isomer was eliminated in
    the same period (Chu et al., 1984b).

    Available data also indicate that there are species differences in
    the metabolism of tetrachlorobenzenes. In a recent study described
    in Table 14, the tetrachlorobenzenes were not as extensively
    metabolized in squirrel monkeys as in other species, and metabolites
    were eliminated exclusively in the faeces (Schwartz et al., 1987).

    PeCB may be metabolized primarily to pentachlorophenol by direct
    oxidation or to 2,3,4,5-tetrachlorophenol via an arene oxide
    intermediate. Other compounds that have been identified as
    metabolites of PeCB include the 1,2,3,4- and 2,3,5,6-isomers of
    tetrachlorophenol in monkeys (Rozman et al., 1979), and the
    2,3,4,6-isomer of tetrachlorophenol, an unspecified isomer of
    trichorophenol, 2,4,6-trichlorophenol, 1,2,3,4-TeCB, and
    tetra-chlorohydroquinone in rats (Engst et al., 1976; Koss &
    Koransky, 1977).

    In  in vitro studies on rat liver microsomes, the principal primary
    metabolites of pentachlorobenzene were pentachlorophenol and
    2,3,4,6-tetrachlorophenol in a ratio of 4:1 (den Besten et al.,
    1989). Minor metabolites included the 2,3,4,5- and 2,3,5,6-isomers
    of tetrachlorophenol. In addition,  para- and  ortho-
    tetrachlorohydroquinone were formed as secondary metabolites. The
    authors suggested that these compounds may be involved in the
    covalent binding of microsomal protein.

    6.4  Elimination and Excretion

    While there is variation among different isomers of the same
    congener and among species, generally, the metabolism and excretion
    of the higher chlorinated benzenes is slower than that of mono- and
    dichlorobenzenes, and a greater proportion of the compound is
    eliminated unchanged in the faeces or expired air. This is
    illustrated by the data on the metabolism and elimination of the
    various chlorobenzenes in the rabbit following the oral
    administration of 500 mg/kg body weight, which are presented in
    Table 15 (Williams, 1959). Hawkins et al. (1980) reported that
    1,4-DCB was eliminated primarily in the rat urine (91-97%) in the
    5-day period following inhalation, subcutaneous, or oral exposure.
    It has also been reported that 78-84% of an oral or intravenous dose
    of 10 mg 1,2,4-TCB/kg body weight was eliminated in the urine and
    that 7-11% was eliminated in the faeces of rats at 24 h; in monkeys,
    the comparable values were 40% and <1% (Lingg et al., 1982). In
    rats receiving an oral dose of 50 mg 1,2,4-TCB/kg, approximately 66%
    and 17% were eliminated in the urine and faeces, respectively, in 7
    days; 2.1% was exhaled (Tanaka et al., 1986). Rozman et al. (1979)
    reported that approximately 12% of an oral dose of 0.5 mg PeCB/kg
    was eliminated in the urine of rhesus monkeys and 24% in the faeces
    (99% unmetabolized) within 40 days. In a study by Koss & Koransky
    (1977), it was observed that 3% was excreted unchanged during a

    4-day period following administration of 403 µmol PeCB/kg body
    weight. The higher chlorobenzenes tend to be stored in the adipose
    depots of the body at higher levels than monochloro- and
    dichloro-congeners (section 6.2, Table 14).

    Available data on the half-lives of the chlorobenzenes in the
    tissues of experimental animals are restricted to the
    trichlorobenzenes, the 1,2,4,5-isomer of TeCB, and PeCB. Chu et al.
    (1987) reported that the terminal half-lives for 1,2,3-TCB,
    1,2,4-TCB, and 1,3,5-TCB in rats were 145, 93, and 68 h,
    respectively. It was reported by Braun et al. (1978) that the
    half-lives for the elimination of 1,2,4,5-TeCB from the fat and
    plasma of beagle dogs were 111 and 104 days, respectively. In rhesus
    monkeys, the estimated half-life of PeCB (tissue unspecified) was
    2-3 months (Rozman et al., 1979).

    6.5  Binding to Protein

    The results of several studies indicate that the metabolites of MCB
    and DCB, most likely the arene oxide intermediate or unconjugated
    chlorophenols, covalently bind to rat kidney and liver tissues and,
    in some cases, induce damage (Oesch et al., 1973; Reid, 1973; Reid &
    Krishna, 1973). The binding and toxic effects of MCB were prevented
    by piperonyl butoxide, cyclohexene oxide, and glutathione (Oesch et
    al., 1973; Reid, 1973; Reid & Krishna, 1973) and were reduced by
    3-methylcholanthrene (Reid, 1973; Reid & Krishna, 1973). The binding
    of 1,2-DCB to rat liver protein was enhanced by pretreatment with
    phenobarbital; the 1,4-isomer of DCB did not bind to the same extent
    and was less hepatotoxic than the 1,2-isomer (Reid & Krishna, 1973).

    6.6  Effects on Metabolizing Enzymes

    The chlorobenzenes are broad inducers of metabolic reactions
    including both oxidative and reductive, as well as conjugation
    hydrolytic pathways. The effects of the different chlorobenzenes on
    the metabolizing enzymes vary considerably.

    The 1,4-isomer of dichlorobenzene and 1,2,4-trichlorobenzene induced
    cytochrome-c-reductase, cytochrome P-450, EPN-detoxification
    ( O-ethyl  O-p-nitrophenyl phenylphosphonothioate), glucuronyl
    transferase, benzopyrene hydroxylase, and azoreductase following
    oral administration of doses of up to 40 mg/kg per day for 14 days
    in the rat. In contrast, administration of doses of MCB as high as
    800 mg/kg per day had no effects on these enzymes (Carlson &
    Tardiff, 1976).

    The cytochrome P-450 content in rat liver and the enzymes,
    aminopyrine demethylase and aniline hydroxylase, were induced by
    1,4-DCB, 1,3,5-TCB, 1,2,4,5-TeCB, and PeCB, but not by MCB, after
    administration of oral doses of between 125 and 500 mg/kg body
    weight, daily, for 1 or 3 days. Aniline hydroxylase activity did
    increase, however, with high doses of monochlorobenzene (1000 mg/kg
    body weight) (Ariyoshi et al., 1975). MCB has also been reported to
    induce epoxide hydrolase in rat liver (Oesch et al., 1973). There
    was, therefore, no consistent pattern of enzyme induction in
    relation to the degree of chlorination of the chlorobenzenes. The
    most potent inducer was found to be 1,2,4-TCB (Ariyoshi et al.,
    1981).

    The induction of hepatic metabolizing enzymes in rats treated with
    trichlorobenzenes differs from isomer to isomer. The 1,2,4-isomer
    induced NADPH-cytochrome-c-reductase, acetanilide esterase,
    arylesterase, and procaine esterase, but not cytochrome P-450 or
    acetanilide hydroxylase, following oral administration to rats of
    0.1 mmol/kg per day for 14 days. On the other hand, the 1,3,5-isomer
    induced acetanilide hydroxylase, acetanilide esterase, and procaine
    esterase, but not arylesterase (Carlson et al., 1979; Carlson,
    1980).

    In pregnant rats, 1,2,4-TCB, 1,2,4,5-TeCB, and 1,2,3,4-TeCB all
    induced hepatic cytochrome P-450, aninopyrine  N-demethylase, and
    ethoxy resorufin- O-deethylase. In addition, 1,2,4-TCB and
    1,2,3,4-TeCB increased NADPH-cytochrome-c-reductase, glucuronyl
    transferase  for   p-nitrophenol,  and  glutathione- S-transferase
    activities (Kitchin & Ebron, 1983a,b,c).

    Although the induction of metabolizing enzymes by PeCB has been less
    well studied, it has been shown to induce the  O-dealkylation of
    7-ethoxycoumarin in rats following the ingestion of 0.05% in the
    diet, indicating that it stimulates the cytochrome P-450 system
    (Goerz et al., 1978).

    7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    The database on the effects of chlorobenzenes on organisms in the
    environment is restricted to studies on acute toxicity in aquatic
    systems. Only a few studies have been reported on the long-term
    effects of chlorobenzenes on the aquatic environment, and none on
    the effects of chlorobenzenes on non-mammalian terrestrial animals
    and aquatic vascular plants.

    7.1  Microorganisms

    7.1.1  Bacteria and protozoa

    The toxicity thresholds of MCB and 1,2-DCB for protozoa and bacteria
    have been reported by Bringmann & Kuhn (1980). MCB levels in excess
    of 3500 µmol/litre were noted in studies on  Entosiphon sulcatum,
     Uronema parduczi, and  Chilomonas paramecium. The authors studied
    the toxicity threshold over a 72-h period in an open system, where
    an inhibition of cell growth greater than 3% was considered a
    significant effect. Toxicity  thresholds  for 1,2-DCB in the same
    three species were reported to be: >435µmol/litre for  E. sulcatum,
    544 µmol/litre for  U. parduczi , and >410 µmol/litre for  C.
     paramecium. With regard to bacteria, Boyles (1980) reported that a
    level of 270 µmol 1,2-DCB/litre resulted in a 50% reduction in the
    growth rate of  Vibrio natriegens (EC50, 40-min). In  Pseudomonas
     putida, Bringmann & Kuhn (1980) reported 16-h toxicity thresholds
    for MCB and 1,2-DCB of 150 and 100 µmol/litre, respectively.

    Using  Tetrahymena pyriformis, Yoshioka et al. (1985) reported
    EC50 concentrations (cell proliferation) of 51, 130, 20, 0.91, and
    30 mg/litre for 1,2-DCB, 1,3-DCB, 1,2,4,5-TeCB, 1,2,4-TCB, and
    1,3,5-TCB, respectively.

    7.1.2  Unicellular algae

    The acute toxicities of various chlorobenzenes for unicellular algae
    are summarized in Table 16.

    In general, the acute toxicities of chlorobenzenes for aquatic
    unicellular algae, whether measured according to the inhibition of
    chlorophyll a production or cellular proliferation, increase with
    increasing chlorination. MCB was reported to have a 96-h EC50 of
    232 mg/litre in  Selenastrum capricornutum, whereas 1,2,3,5-TeCB
    showed a 96-h EC50 of 17.2 mg/litre in this species; both were
    measured according to the inhibition of chlorophyll a production.
    The estuarine alga,  Skeletonema costatum, appears to be more
    sensitive to the acute effects of 1,2,3,5-TeCB; a 96-h EC50 of 0.7
    mg/litre has been reported by the US EPA (1980a). Calamari et al.
    (1983) demonstrated the comparable toxicity of 1,2-DCB, 1,4-DCB,
    1,2,3-TCB, and 1,2,4-TCB in the green alga  Selenastrum
     capricornutum. MCB was less toxic (Table 16).

    In the freshwater alga  Ankistrodesmus falcatus, a 4-h EC50 for
    primary productivity of 0.005 mmol/litre was shown for PeCB, whereas
    MCB had an EC50 of 0.44 mmol/litre, under the same conditions
    (Wong et al., 1984). Canton et al. (1985) reported EC50s for
    growth of 17, 31, and 31 mg/litre, for 1,2-DCB, 1,3-DCB, and
    1,4-DCB, respectively.

    7.2  Aquatic Organisms

    7.2.1  Plants

    No data have been reported on the effects of chlorinated benzenes on
    freshwater or saltwater vascular plants.

    7.2.2  Invertebrates

    Available data for the acute toxicity of chlorobenzenes in aquatic
    invertebrates are given in Table 17. Most of the studies were
    carried out at high chlorobenzene concentrations, yielding LC50
    values that sometimes exceeded the solubilities of the compounds,
    particularly those with higher levels of chlorination (see for
    example LeBlanc, 1980).

    In a study by Calamari et al. (1983), an enclosed static system was
    used in which the authors measured the concentration of 1,4-DCB
    throughout the test period. A 24-h IC50 (immobilization
    concentration) of 1.6 mg/litre was reported for 1,4-DCB; the 24-h
    IC50 for 1,2-DCB was 0.78 mg/litre. Such experimental data
    probably reflect more accurately the true toxicity values than those
    from an open, static apparatus, relying on nominal concentrations of
    chlorobenzenes.

    Hermens et al. (1985) determined the no-observed-effect
    concentration (NOEC) on growth and the concentration inhibiting
    growth of  Daphnia magna by 50 % (EC50) in acute exposures to
    chlorobenzenes. Values for the NOEC in µmol/litre were 0.59 for
    1,2,3,4-TeCB and 1.14 for PeCB.

    When LC50s (48-h) and LC0s were determined for a range of
    chlorobenzenes (LeBlanc, 1980) for  Daphnia magna, there was no
    trend in toxicity in relation to the degree of chlorination. Wide
    differences in response to different isomers of the same congener
    were seen (Table 17).


    
    Table 16.  Acute toxicity of chlorobenzenes for aquatic unicellular algae
                                                                                                                                              

    Test organism; Reference           Chlorobenzene              Concentration           Criterion
                                                                  (mg/litre)
                                                                                                                                              

    Freshwater species

    Selenastrum capricornutum          MCB                          232.0                 EC50 (96-h) chlorophyll a
      US EPA (1980a)                                                224.0                 EC50 (96-h) cell growth

                                       1,2,4-TCB                     35.3                 EC50 (96-h) chlorophyll a
                                                                     36.7                 EC50 (96-h) cell growth

                                       1,2,3,5-TeCB                  17.2                 EC50 (96-h) chlorophyll a
                                                                     17.7                 EC50 (96-h) cell growth

                                       1,2,4,5-TeCB                  52.9                 EC50 (96-h) chlorophyll a
                                                                     46.8                 EC50 (96-h) cell growth

                                       PeCB                           6.78                EC50 (96-h) chlorophyll a
                                                                      6.63                EC50 (96-h) cell growth

                                                                                          EC50 (96-h) cell growth

    Selenastrum capricornutum          1,2-DCB                       91.6                 EC50 (96-h) chlorophyll a
      US EPA (1980b)                                                 98.0                 EC50 (96-h) cell growth

                                       1,2-DCB                      179.0                 EC50 (96-h) chlorophyll a
                                                                    149.0                 EC50 (96-h) cell growth

                                       1,4-DCB                       98.1                 EC50 (96-h) chlorophyll a
                                                                     96.7                 EC50 (96-h) cell growth
                                                                                          EC50 (96-h) cell growth
                                                                                                                                              

    Table 16 (continued)
                                                                                                                                              

    Test organism; Reference           Chlorobenzene              Concentration           Criterion
                                                                  (mg/litre)
                                                                                                                                              

    Selenastrum capricornutum          MCB                           12.5                 EC50 (96-h) cell growth
      Calamari et al. (1983)a                                        33.0                 EC50 (3-h) decreased photosynthesis

                                       1,2-DCB                        2.2                 EC50 (96-h) cell growth
                                                                     10.0                 EC50 (3-h) decreased photosynthesis

                                       1,4-DCB                        1.6                 EC50 (96-h) cell growth
                                                                      5.2                 EC50 (3-h) decreased photosynthesis

                                       1,2,3-TCB                      0.9                 EC50 (96-h) cell growth
                                                                      2.2                 EC50 (3-h) decreased photosynthesis

                                       1,2,4-TCB                      1.4                 EC50 (96-h) cell growth
                                                                      3.9                 EC50 (3-h) decreased photosynthesis

    Chlorella vulgaris                 MCB                           99.1                 EC50 (3-h) cell growth
      Hutchinson et al. (1980)         1,2,3-TCB                      6.2                 EC50 (3-h) cell growth
                                       1,2,3,5-TeCB                   2.51                EC50 (3-h) cell growth

    Ankistrodesmus falcatus            MCB                           50                   EC50 (4-h) primary productivity 14C uptake
      (acicularis)                     1,2-DCB                       20                   EC50 (4-h) primary productivity 14C uptake
      Wong et al. (1984)a              1,3-DCB                       23                   EC50 (4-h) primary productivity 14C uptake
                                       1,4-DCB                       20                   EC50 (4-h) primary productivity 14C uptake
                                       1,2,3-TCB                      6                   EC50 (4-h) primary productivity 14C uptake
                                       1,2,4-TCB                      6                   EC50 (4-h) primary productivity 14C uptake
                                       1,3,5-TCB                      9                   EC50 (4-h) primary productivity 14C uptake
                                       1,2,3,4-TeCB                   4                   EC50 (4-h) primary productivity 14C uptake
                                       1,2,3,5-TeCB                   3                   EC50 (4-h) primary productivity 14C uptake
                                       1,2,4,5-TeCB                   5                   EC50 (4-h) primary productivity 14C uptake
                                       PeCB                           1.3                 EC50 (4-h) primary productivity 14C uptake
                                                                                                                                              

    Table 16 (continued)
                                                                                                                                              

    Test organism; Reference           Chlorobenzene              Concentration           Criterion
                                                                  (mg/litre)
                                                                                                                                              

    Chlamydomas angulosa               MCB                           56.9                 EC50 (3-h) cell growth
      Hutchinson et al. (1980)         1,2,3-TCB                      3.45                EC50 (3-h) cell growth
                                       1,2,3,5-TeCB                   1.58                EC50 (3-h) cell growth

    Skeletonema costatum               MCB                          343.0                 EC50 (96-h) chlorophyll a
    US EPA (1980a)                                                  341.0                 EC50 (96-h) cell growth

                                       1,2,4-TCB                      8.75                EC50 (96-h) chlorophyll a
                                                                      8.93                EC50 (96-h) cell growth

                                       1,2,3,5-TeCB                   0.83                EC50 (96-h) chlorophyll a
                                                                      0.70                EC50 (96-h) cell growth

                                       1,2,4,5-TeCB                   7.10                EC50 (96-h) chlorophyll a
                                                                      7.30                EC50 (96-h) cell growth

                                       PeCB                           2.23                EC50 (96-h) chlorophyll a
                                                                      1.98                EC50 (96-h) cell growth

    Skeletonema costatum               1,2-DCB                       44.2                 EC50 (96-h) chlorophyll a
      US EPA (1980b)                                                 44.1                 EC50 (96-h) cell growth

                                       1,3-DCB                       52.8                 EC50 (96-h) chlorophyll a
                                                                     49.6                 EC50 (96-h) cell growth

                                       1,4-DCB                       54.8                 EC50 (96-h) chlorophyll a
                                                                     59.1                 EC50 (96-h) cell growth
                                                                                                                                              

    a    Carried out using a closed system, with measured concentrations of chlorobenzenes.

    Table 17.  Acute toxicity of chlorobenzenes for aquatic invertebrates
                                                                                                                                    

    Test organism; Reference           Chlorobenzene              Concentration           Criterion
                                                                  (mg/litre)
                                                                                                                                    

    Freshwater species

    Daphnia magna                      MCB                        86 (64-120)             LC50 (48-h) immobilization
      Le Blanc (1980)a                                            10                      LC0  (48-h) NOEL
                                       1,2-DCB                    2.4 (1.9-3.0)           LC50 (48-h) immobilization
                                                                  0.36                    LC0  (48-h) NOEL
                                       1,3-DCB                    28 (21-34)              LC50 (48-h) immobilization
                                                                  6                       LC0  (48-h) NOEL
                                       1,4-DCB                    11 (6.6-19.0)           LC50 (48-h) immobilization
                                                                  0.68                    LC0  (48-h) NOEL
                                       1,2,4-TCB                  50 (7.2-130)            LC50 (48-h) immobilization
                                                                  <2.4                    LC0  (48-h) NOEL
                                       1,2,3,5-TeCB               9.7 (6.6-14.0)          LC50 (48-h) immobilization
                                                                  <1.1                    LC0  (48-h) NOEL
                                       1,2,4,5-TeCB               >530                    LC50 (48-h) immobilization
                                                                  320                     LC0  (48-h) NOEL
                                       PeCB                       5.3 (4.1-7.2)           LC50 (48-h) immobilization
                                                                  1.3                     LC0  (48-h) NOEL

    Daphnia magna                      MCB                        4.3                     LC50 (24-h) immobilization
      Calarmari et al. (1983)b         1,2-DCB                    0.78                    LC50 (24-h) immobilization
                                       1,4-DCB                    1.6                     LC50 (24-h) immobilization
                                       1,2,3-TCB                  0.35                    LC50 (24-h) immobilization

    Daphnia magna                      MCB                        51.6 mmol/m3            LC50 (48-h) lethality
      Abernethy et al. (1986)          1,2-DCB                    16.0 mmol/m3            LC50 (48-h) lethality
                                       1,4-DCB                    --                      LC50 (48-h) lethality
                                       1,2,3-TCB                  8.0 mmol/m3             LC50 (48-h) lethality
                                       1,2,3,5-TeCB               4.0 mmol/m3             LC50 (48-h) lethality
                                       PeCB                       1.2 mmol/m3             LC50 (48-h) lethality
                                                                                                                                    

    Table 17 (continued)
                                                                                                                                    

    Test organism; Reference           Chlorobenzene              Concentration           Criterion
                                                                  (mg/litre)
                                                                                                                                    

    Seawater species

    Tanytarsus dissimilis              1,2-DCB                    11.76                   LC50 (48-h) lethality
      US EPA (1980b)b                  1,4-DCB                    13.0                    LC50 (48-h) lethality

    Mysidopsis bahia                   MCB                        16.4                    LC50/EC50 (96-h) lethality
      US EPA (1980a)                   1,2,4-TCB                  0.45                    LC50/EC50 (96-h) lethality
                                       1,2,3,5-TeCB               0.34                    LC50/EC50 (96-h) lethality
                                       1,2,4,5-TeCB               1.48                    LC50/EC50 (96-h) lethality
                                       PeCB                       0.16                    LC50/EC50 (96-h) lethality

    Mysidopsis bahia                   1,2-DCB                    1.97                    LC50/EC50 (96-h) lethality
      US EPA (1980b)b                  1,3-DCB                    2.85                    LC50/EC50 (96-h) lethality
                                       1,4-DCB                    1.99                    LC50/EC50 (96-h) lethality

    Paleaemonetes pugio                1,2,4-TCB                  0.54                    LC50 (96-h) lethality
      Clark et al. (1987)c
                                                                                                                                    

    a    Closed static system; nominal concentrations.
    b    Aquatic concentrations of CB measured; static conditions employed.
    c    A flow-through system was used and concentrations of water-borne TCB measured.

    

    Calamari et al. (1983) exposed 30 specimens of  Daphnia magna to a
    range of chlorobenzenes in closed bottles for 14 days, to obtain 3
    broods. The higher chlorinated materials had lower effective
    concentrations on fertility (14-day EC50s) ranging from
    2.5 mg/litre for MCB to 0.20 mg/litre for 1,2,3 TCB.

    When saltwater crustacea were exposed to high chlorobenzene
    concentrations (55 µmol/litre), Grosch (1973) found that a single
    24-h exposure of adult  Artemia salina (brine shrimp) to 1,3,5-TCB
    resulted in a decreased life span, a delay in the onset of the first
    brood, and a decreased number of offspring. The US EPA (1980b)
    reported that the LC50 values for the exposure of  Mysidopsis
    bahia (mysid shrimp) were similar for the 3 DCB isomers (1.97
    mg/litre for 1,2- and 1,4-DCB, and 2.85 mg/litre for 1,3-DCB).
    However, these tests were carried out in open static systems and the
    reported values may not reflect accurately the actual toxicity of
    these chemicals.

    The toxic effects of 1,4-DCB and 1,3,5-TCB on the embryonic and
    larval stages of clams  (Mercenaria mercenaria) and oysters
     (Crassostrea virginica) were studied by Davis & Hidu (1969).
    Embryos, initially at the 2-cell stage, were exposed to 1,4-DCB or
    1,3,5-TCB for 48 h.  The median toxicity levels (TL50) for embryo
    development to normal larvae were >680 µmol/litre and >55
    µmol/litre for clam eggs exposed to 1,4-DCB and 1,3,5-TCB,
    respectively.

    7.2.3  Fish

    The results of studies on the acute toxicity of chlorobenzenes for
    fish are presented in Table 18. A comparison of Tables 17 and 18
    shows a similar degree of sensitivity to chlorobenzenes between
    bluegills  (Lepomis macrochirus) and  Daphnia magna. With a few
    exceptions, open static systems were used in the acute toxicity
    tests on fish, without measurements of actual concentrations in the
    water. With the exception of 1,2,3,5-TeCB, the acute toxicity of
    chlorobenzenes in several fish species increased with increased
    chlorination, and was well correlated with the log P (octanol:water
    partition coefficient) value (Calamari et al., 1983). Buccafusco
    et al. (1981) stated that undissolved, preciptated chlorobenzenes
    were present in the test vessels. The LC50s, therefore, are
    probably underestimates of the toxicity of chlorobenzenes to fish.

    In addition to the acute toxicity studies summarized in Table 18,
    several studies have been reported on the effects of chlorobenzenes
    on various developmental stages (i.e., embryo, larval, juvenile,
    etc.) of freshwater and saltwater fish (Birge et al., 1979; US EPA,
    1980a,b). Such embryo-larval studies more accurately reflect the
    long-term toxicities arising from continuous exposures to low levels
    of chlorobenzenes, at sensitive life-stages, than the acute LC50
    studies.

    Using the freshwater fathead minnow  (Pimephales promelas) in an
    embryo larval assay, long-term toxicity limits of 2.0, 1.51, and
    0.76 mg/litre were reported for 1,2-, 1,3-, and 1,4-DCB,
    respectively, by the US EPA (1980b). Long-term toxicity limits in
    the estuarine sheepshead minnow for 1,2,4-TCB and 1,2,4,5-TeCB were
    0.22 and 0.13 mg/litre, respectively (US EPA, 1980a); in the
    freshwater fathead minnow  (Pimephales promelas), long-term
    toxicity limit values of 0.71, and 0.32 mg/litre were reported for
    1,2,4-TCB and 1,2,3,4-TeCB, respectively (US EPA, 1980a).

    Birge et al. (1979) exposed rainbow trout eggs to MCB at a range of
    concentrations from 0.09 mg/litre, for 16 days; all concentrations
    were lethal and, thus, a no-observed-effect level could not be
    determined.  Goldfish  (Carassius auratus) and largemouth bass
     (Micropterus salmonides) were less sensitive to MCB. Larvae were
    more susceptible to MCB than eggs. For the goldfish, the LC50 with
    exposure up to hatching was 3.5 mg/litre in soft water and 2.4
    mg/litre in hard water. Exposure until 4 days after hatching
    resulted in an LC50 of 1 mg/litre. Largemouth bass showed an
    LC50 of 0.3 mg/litre, at hatching, and an LC50 of 0.05 mg/litre,
    4 days after hatching.

    7.3  Terrestrial Biota

    No data are available.

    7.4  Model Ecosystems

    In a study by Tagatz et al. (1985), sand-filled aquaria were used in
    which macrobenthic animal communities were allowed to develop. In
    one test, colonization of the system by planktonic larvae for 50
    days, was followed by 6 days of exposure to waterborne
    concentrations of 1,2,4-TCB. In a second study, colonization was
    allowed to proceed for 8 weeks in the presence of sediment
    containing 1,2,4-TCB. The same types of organisms were affected,
    whether the TCB was waterborne or sediment bound. However, community
    structure was affected at waterborne concentrations (measured) that
    were 2 orders of magnitude lower than those of the sediment-bound
    TCB. The lowest waterborne TCB concentrations that affected the
    number of individuals were: 0.04 mg/litre for molluscs; 0.4 mg/litre
    for arthropods; and 4 mg/litre for annelids. At 4 mg/litre, the
    average number of species was significantly lower than that in the
    control aquaria.


    
    Table 18.  Acute toxicity of chlorobenzenes for fish
                                                                                                                                    

    Test organism;                Test Conditionsa          Chlorobenzene         Concentration         Criterion
    Reference                                                                     (mg/litre)
                                                                                                                                    

    Freshwater species

    Salmo gairdneri
    (rainbow trout)

      Calamari et al. (1983)      FB; M                     MCB                   4.1                   LC50 (48-h) lethality
                                                            1,2-DCB               2.3
                                                            1,4-DCB               1.18
                                                            1,2,3-TCB             0.71
                                                            1,2,4-TCB             1.95

      US EPA (1980b)              FB; M                     1,2-DCB               1.58                  LC50 (96-h) lethality
                                                            1,4-DCB               1.12

    Pimephales promelas
    (fathead minnow)

      US EPA (1980b)              FB; M                     1,3-DCB               7.79                  LC50 (96-h) lethality
                                                            1,4-DCB               4.0

      US EPA (1980a)              FB; M                     1,2,3,4-TeCB          1.07                  LC50 (96-h) lethality

    Lepomis macrochirus
    (bluegill)

      Buccafusco et al. (1981)    Sb; U                     MCB                   16 (13-20)            LC50 (96-h) lethality
                                                            1,2-DCB               5.6 (4.8-6.6)
                                                            1,3-DCB               5.0 (3.9-6.2)
                                                            1,4-DCB               4.3 (3.9-4.8)
                                                                                                                                    

    Table 18 (continued)
                                                                                                                                    

    Test organism;                Test Conditionsa          Chlorobenzene         Concentration         Criterion
    Reference                                                                     (mg/litre)
                                                                                                                                    

                                                            1,2,4-TCB             3.4 (2.7-4.1)
                                                            1,2,3,5-TeCB          6.4 (5.2-8.1)
                                                            1,2,4,5-TeCB          1.6 (1.3-1.8)
                                                            PeCB                  0.25 (0.18-0.32)

    Salt-water species

    Cyprinodon variegatus
    (sheepshead minnow)

      Heitmuller et al. (1981)    S; U                      MCB                   10 (8.8-12)           LC50 (96-h) lethality

                                                                                  6.2                   LC0 (96-h) NOEL lethality

                                                            1,2-DCB               9.7 (9.0-10.0)        LC50 (96-h) lethality

                                                            1,3-DCB               7.8 (6.8-8.7)         LC50 (96-h) lethality

                                                                                  4.2                   LC0 (96-h) NOEL lethality

                                                            1,4-DCB               7.4 (6.8-7.9)         LC50 (96-h) lethality

                                                                                  5.6                   LC0 (96-h) NOEL lethality

                                                            1,2,4-TCB             21 (17-26)            LC50 (96-h) lethality

                                                                                  15                    LC0 (96-h) NOEL lethality
                                                                                                                                    

    Table 18 (continued)
                                                                                                                                    

    Test organism;                Test Conditionsa          Chlorobenzene         Concentration         Criterion
    Reference                                                                     (mg/litre)
                                                                                                                                    

    Heitmuller et al. (1981)                                1,2,3,5-TeCB          3.7 (3.3-4.1)         LC50 (96-h) lethality
    (continued)

                                                                                  1.0                   LC0 (96-h) NOEL lethality

                                                            1,2,4,5-TeCB          0.8 (0.7-1.1)         LC50 (96-h) lethality

                                                                                  0.3                   LC0 (96-h) NOEL lethality

                                                            PeCB                  0.8 (0.4-1.8)         LC50 (96-h) lethality

                                                                                  0.3                   LC0 (96-h) NOEL lethality

    Menidia beryllina
    (tidewater silverside)

      Dawson et al. (1977)        S; U                      1,2-DCB               7.3                   LC50 (96-h) lethality
                                                                                                                                    

    a    S - static bioassay;
         U - actual concentrations in system not monitored;
         FB - flow-through conditions for bioassay;
         M - concentrations of chlorobenzenes in experimental media determined by monitoring.
    b    Closed system.

    

    The effects of 1,2,4-TCB on a natural freshwater phytoplankton
    community were reported by Schauerte et al. (1985). A water meadow,
    rich in both  Daphnia and phytoplankton, was divided into
    approximately 200 litre test cells to study the effects of 0.25 mg
    1,2,4-TCB/litre over a period of 22 days, with a half-time of 13.7
    days. No chemical-related effects on the abundance and diversity of
    the phytoplankton community were noted. However, the high toxicity
    (greater than 90% death) for  Daphnia may have resulted in algal
    blooms from fewer grazing species. The authors noted that the
    toxicity of 1,2,4-TCB for  Daphnia was much higher in the natural
    system than was observed by Bringman & Kuhn (1982) in the laboratory
    (0.25 mg/litre compared with 1.2-21 mg/litre).

    8. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

    8.1  Single Exposure

    The results of the more recent and well documented acute toxicity
    studies on the chlorobenzenes in experimental animals are presented
    in Table 19. For isomers for which there were few available studies,
    quantitative data (i.e., LC50s or LD50s) from early
    investigations have also been included. A more complete review of
    these early studies is included in US EPA (1985).

    Inhalation of sufficiently high single doses of volatile
    chlorobenzenes causes local respiratory irritation and depression of
    the central nervous system; ingestion of lethal doses leads to
    respiratory paralysis. Effects on the liver, kidneys, adrenal
    glands, mucous membranes, brain ganglion cells, and metabolizing
    enzymes have also been observed following acute exposure to
    non-lethal doses of the chlorobenzenes.

    Data concerning the acute toxicity of the higher chlorinated
    compounds are sparse; some conclusions concerning the relative acute
    toxicity of the different congeners can be drawn, however, from
    examination of the oral LD50s in rats in the more recent and well
    documented studies. On the basis of both mass and molar quantities,
    the higher chlorinated benzenes appear, in general, to be more
    acutely toxic than the mono- and dichlorobenzenes; however, for any
    one isomer, there is a wide range of LD50s. In general, the dermal
    LD50s are considerably higher than those for ingestion, probably,
    in some cases, as a result of evaporation losses from the skin
    (though this is less likely with occlusive dressings) together with
    relatively poor dermal absorption. Inhalation LC50s have varied
    widely, even for the same congeners, principally because of large
    differences in the durations of exposure in the various studies.

    Acute exposure to monochlorobenzene via inhalation causes sensory
    irritation of the respiratory system, after several minutes;
    exposure for periods ranging from several minutes to hours causes
    narcosis and central nervous system (CNS) depression, which can
    result in death. The LC50s (6-h exposure period) for male
    Sprague-Dawley rats and SPF-OF1 female mice were 13 490 mg/m3
    (2965 ppm) and 8581 mg/m3 (1886 ppm), respectively (Bonnet et al.,
    1979, 1982). De Ceaurriz et al. (1981) reported that inhalation of
    4796 mg MCB/m3 (1054 ppm) for 5 min reduced the respiratory rate
    in Swiss-OF1 mice by 50% (RD50), indicating respiratory
    irritation.

    LD50 values for the ingestion of MCB (gavage in corn oil) were
    approximately 4000 mg/kg body weight in male and female F344 rats;
    B6C3F1 mice were more sensitive with 100% lethality at doses

    exceeding 1000 mg/kg and 2000 mg/kg for males and females,
    respectively (Kluwe et al., 1985).  Clinical symptoms included
    hyperpnoea, ataxia, laboured breathing, prostration, and death from
    respiratory paralysis.

    Systemic effects of acute toxic doses of MCB included damage to the
    liver and kidney, and effects on bile and pancreatic flow.
    Circulating alanine aminotransferase (ALT) was increased in 50% of
    CF-1 strain albino mice following a single intraperitoneal
    adminis-tration of approximately 428 mg/kg (Shelton & Weber, 1981).
    In Sprague-Dawley rats, single intraperitoneal administration of the
    two highest doses of 1104 mg/kg and 1655 mg/kg body weight resulted
    in increases in plasma ALT and centrilobular necrosis. Increased
    liver to body weight ratios were observed at all doses
    (225-1655 mg/kg body weight) (Dalich & Larson, 1985). In C57
    Black/6J male mice, coagulation necrosis of the proximal renal
    tubules was observed following intraperitoneal administration of 760
    mg MCB/kg body weight; Sprague-Dawley rats were somewhat less
    sensitive having only swollen, vacuolated convoluted tubules at
    doses of 1047 mg/kg body weight (Reid, 1973). Yang et al. (1979)
    reported increased bile duct-pancreatic flow in Holtzman male rats
    administered 563 mg MCB/kg body weight (5 mmol/kg)
    intraperitoneally. The investigators suggested that these effects
    were distinct from those on the liver, since they occurred in the
    absence of liver damage.

    Effects of acute exposure to the dichlorobenzenes are similar to
    those for MCB, resulting in CNS depression following inhalation, and
    respiratory paralysis following ingestion. Limited available data
    indicate that the 1,2-isomer is more toxic than the 1,4-isomer. In
    the inhalation studies of Bonnet et al. (1979, 1982), the 1,2-isomer
    of dichlorobenzene was somewhat more toxic than MCB, the LC50s
    (6-h exposure) in both Sprague-Dawley rats and SPF-OF1 female mice
    (9192 mg/m3 and 7416 mg/m3, respectively) being less than those
    for MCB (13 490 mg/m3  and 8581 mg/m3, respectively). Increases
    in circulating hepatic enzymes were reported 24 h after exposure of
    Sprague-Dawley rats to levels of 1,2-DCB greater than 1830 mg/m3
    (Brondeau et al., 1983).

    Few recent data are available concerning the acute toxicity of the
    dichlorobenzenes after oral administration. Hollingsworth et al.
    (1958) reported that no deaths occurred in guinea-pigs following
    ingestion (gavage in olive oil) of 800 mg/kg body weight of the
    1,2-isomer, whereas there was 100% lethality at 2000 mg/kg body
    weight. For the 1,4-isomer, these investigators reported that 2800
    mg/kg and 4000 mg/kg body weight were lethal for 100% of guinea-pigs
    and rats, respectively (Hollingsworth et al., 1956). There were no
    deaths in guinea-pigs and rats exposed to 1600 mg/kg and 1000 mg/kg
    body weight, respectively.


    
    Table 19.  Acute toxicity of chlorobenzenes for experimental animals
                                                                                                                                              

    Compound;                  Speciesa                        Routeb               Dosec                          Resultsd
    Reference
                                                                                                                                              

    MCB                        Sprague-Dawley male rat;        inhalation           NA (6-h exposure) 14-day       LC50 in rats: 13 490 mg/m3
      Bonnet et al. (1979,     12 animals/group; SPF-OF1                            observation period             (2965 ppm)
      1982)                    female mouse; 20-25/group                                                           LC50 in mice: 8581 mg/m3
                                                                                                                   (1886 ppm)

    MCB                        Swiss OF1 male mouse;           inhalation           NA (5-min exposure)            RD50: 4796 mg/m3
      De Ceaurriz et al.       6 animals/group                                                                     (1054 ppm)
      (1981)

    MCB                        Fischer 344 rat; B6C3F1         oral (gavage in      0, 250, 500, 1000,             LD50 in rats: about
      Kluwe et al. (1985)      mouse; 5 of each sex/group      corn oil)            4000 mg/kg                     4000 mg/kg (males and
                                                                                                                   females) (35.5 µmol/kg);
                                                                                                                   100% lethality in mice:
                                                                                                                   >1000 mg/kg (males),
                                                                                                                   >2000 mg/kg (females)

    MCB                        Sprague-Dawley male rat;        ip (in corn oil)     0, 225, 552, 1104,             LD50 - 1655 mg/kg
      Dalich & Larson          3-5 animals/group                                    1655 mg/kg (2.0, 4.9, 9.8,     (14.7 mmol/kg); depression
      (1985)                                                                        14.7 mmol/kg); 72-h            in hepatic glutathione and
                                                                                    observation period             increased liver to body
                                                                                                                   weight ratios at all doses;
                                                                                                                   centrilobular necrosis and
                                                                                                                   increase in plasma ALT only
                                                                                                                   at 2 highest doses (1104 and
                                                                                                                   1655 mg/kg)
                                                                                                                                              

    Table 19 (continued)
                                                                                                                                              

    Compound;                  Speciesa                        Routeb               Dosec                          Resultsd
    Reference
                                                                                                                                              

    1,2-DCB                    Sprague-Dawley male rat;        inhalation           NA (6-h exposure); 17-day      LC50 in rats: 9192 mg/m3
      Bonnet et al. (1979,     12 animals/group                                     observation period             (1532 ppm)
      1982)                    SPF-OF1 female mouse;                                                               LC50 in mice: 7416 mg/m3
                               20-25 animals/group                                                                 (1236 ppm)

    1,2-DCB                    rat; 5-20 animals/group         inhalation           0, 3234, 4926, 5646,           LD50 approx. 5862 mg/m3
      Hollingsworth et al.                                                          5862 mg/m3 (0, 539, 821,       (lethal to 4/5); marked
      (1958)                                                                        941, 977 ppm); 7-h             hepatic centrilobular
                                                                                    exposure                       necrosis and cloudy swelling
                                                                                                                   in the renal tubular
                                                                                                                   epithelium; increase in
                                                                                                                   liver and kidney weights

    1,2-DCB                    Sprague-Dawley male rat;        inhalation           0, 1224, 1830, 2556, 3654,     significant increase in
      Brondeau et al.          8 animals/group                                      4644 mg/m3 (0, 204, 305,       serum hepatic enzymes
      (1983)                                                                        426, 609, 774 ppm);            (GLDH, ALT and SDH) at
                                                                                    4-h exposure                   levels >1830 mg/m3 

    1,2-DCB                    Albino guinea-pig;              oral (intubation     800 or 2000 mg/kg              (305 ppm) no deaths at 100%
      Hollingsworth et al.     10 animals (mixed               in olive oil)                                       800 mg/kg; lethality at
      (1958)                   sex)/group                                                                          2000 mg/kg

    1,4-DCB                    guinea-pig; rat; 5-15           oral (intubation     1000 or 4000 mg/kg in rats;    100% lethality in
      Hollingsworth et al.     animals (mixed sex)/group       in olive oil)        1600 or 2800 mg/kg in          guinea-pigs at 2800 mg/kg
      (1956)                                                                        guinea-pigs                    and in rats at 4000 mg/kg;
                                                                                                                   no deaths at 1600 and
                                                                                                                   1000 mg/kg, respectively
                                                                                                                                              

    Table 19 (continued)
                                                                                                                                              

    Compound;                  Speciesa                        Routeb               Dosec                          Resultsd
    Reference
                                                                                                                                              

    1,2-DCB                    male Sprague-Dawley rat or      ip (in sesame oil)   1,2-DCB: 195 mg/kg             1,2-DCB: minimal hepatic
    1,3-DCB                    C57 Black/6J mouse                                   (1.33 mmol/kg)                 necrosis
    1,4-DCB                                                                         1,3-DCB: 193 mg/kg             1,3-DCB: normal to minimal
       Reid (1973)                                                                  (1.31 mmol/kg)                 hepatic necrosis
                                                                                    1,4-DCB: 500 mg/kg             1,4-DCB: little or no
                                                                                    (3.40 mmol/kg)                 effect

    1,2,4-TCB                  CFE rat; CF1 mouse; 4 of        oral (gavage)        NA; 10-day observation         LD50 in rats: 756 mg/kg
       Brown et al. (1969)     each sex/group                                       period                         LD50 in mice: 766 mg/kg

                               CFE rat; 4 of each              percutaneous                                        LD50 in rats: 6139 mg/kg
                               sex/group                       (topical
                                                               administration
                                                               on dorso-lumbar
                                                               region for 24 h)

    1,2,4-TCB                  ddY mouse; 10 of each           oral                 123, 160, 207, 269, 350,       LD50 in males: 300 mg/kg
       Yamamoto et al.         sex/group                                            455, 591, 769 mg/kg            LD50 in females: 305 mg/kg
       (1978)

    1,2,4-TCB                  Holtzman male rat               ip (in sesame oil)   0, 907 mg/kg (0.5 mmol/kg)     increased bile
    1,3,5-TCB                                                                                                      duct-pancreatic flow with
    Yang et al. (1979)                                                                                             both isomers, but
                                                                                                                   1,2,4-isomer 4œ more potent;
                                                                                                                   increase in serum GPT with
                                                                                                                   the 1,3,5-isomer
                                                                                                                                              

    Table 19 (continued)
                                                                                                                                              

    Compound;                  Speciesa                        Routeb               Dosec                          Resultsd
    Reference
                                                                                                                                              

    1,2,3,4-TeCB               Sprague-Dawley rat; 10 of       oral (gavage in      0, 200 - 4000 mg/kg            LD50s in males:
    1,2,3,5-TeCB               each sex/group                  corn oil)            (5 doses)                      1,2,3,4-TeCB: 1470 mg/kg
    1,2,4,5-TeCB                                                                                                   1,2,4,5-TeCB: 3105 mg/kg
       Chu et al. (1983,                                                                                           1,2,3,5-TeCB: 2297 mg/kg
       1984a)                                                                                                      LD50s in females:
                                                                                                                   1,2,3,4-TeCB: 1167 mg/kg
                                                                                                                   1,2,3,5-TeCB: 1727 mg/kg

    1,2,4,5-TeCB               mouse, rat, rabbit              oral (gavage in      NA                             LD50 in mice:
       Fomenko (1965)                                          sunflower oil or                                    1035 mg/kg (sunflower oil)
                                                               starch)                                             2650 mg/kg (starch)
                                                                                                                   LD50 in rats and rabbits:
                                                                                                                   1500 mg/kg (vehicle
                                                                                                                   unspecified)

    PeCB                       Sherman rat - adult (male       oral (gavage in      rats:                          LD50 in male adult rats:
      Linder et al. (1980)     and female) and weanling        peanut oil)          600 - 1500 mg/kg               1125 mg/kg
                               (female); Swiss Webster                              mice:                          LD50 in female adult rats:
                               mouse;                                               750 - 1500 mg/kg               1080 mg/kg
                               10 of each sex/group                                                                LD50 in  weanling female
                                                                                                                   rats: 940 mg/kg
                                                                                                                   LD50 in male mice:
                                                                                                                   1175 mg/kg
                                                                                                                   LD50 in female mice:
                                                                                                                   1370 mg/kg
                                                                                                                                              

    Table 19 (continued)
                                                                                                                                              

    Compound;                  Speciesa                        Routeb               Dosec                          Resultsd
    Reference
                                                                                                                                              

    PeCB                       Sherman rat; 10 of each         percutaneous         2500 mg/kg                     no clinical signs of
       Linder et al. (1980)    sex/group                       (dissolved in                                       toxicity
                                                               xylene and
                                                               applied to back
                                                               and shoulder
                                                               area)
                                                                                                                                              

    a    Strain and number of animals/group specified, where available.
    b    Vehicle specified, where available.
    c    Doses given as mg/kg body weight, unless specified.
         NA - not available.
         ip - intraperitoneal.
    d    LC50 - median lethal concentration.
         LD50 - median lethal dose.
         RD50 - dose producing a 50% decrease in respiratory rate.
         ALT - alanine aminotransferase.
         GLDH - glutamate dehydrogenase.
         SDH - sorbitol dehydrogenase.

    

    Reid (1973) reported minimal hepatic necrosis in Sprague-Dawley rats
    or C57Black/6J mice receiving 1,2- or 1,3-DCB at 195 mg/kg body
    weight (about 1.32 mmol/kg) intraperitoneally; no such effects were
    observed following intraperitoneal administration of 500 mg/kg body
    weight (3.4 mmol/kg) of the 1,4-isomer. Yang et al. (1979) reported
    increased bile duct-pancreatic flow following administration of
    735 mg 1,2-DCB/kg body weight (5 mmol/kg) to male Holtzman rats.
    Similar effects were not observed following the administration of
    the same dose of the 1,4-isomer.

    There are no reliable quantitative data on acute toxicity following
    the inhalation of the trichlorobenzenes.

    Similar LD50s were reported for CFE rats and CF1 mice ingesting
    1,2,4-TCB (756 mg/kg and 766 mg/kg body weight, respectively) (Brown
    et al., 1969). Symptoms included depressed activity at lower doses
    and extensor convulsions at lethal doses.

    The single percutaneous LD50 in CFE rats, determined by the same
    investigators, was about an order of magnitude higher than the oral
    LD50 (6139 mg/kg body weight).

    As was observed for MCB and the 1,2-isomer of DCB, intraperitoneal
    administration of the 1,2,4- and 1,3,5-isomers of trichlorobenzene
    at 907 mg/kg body weight (5.0 mmol/kg) increased bile
    duct-pancreatic flow in Holtzman male rats (Yang et al., 1979). The
    1,2,4-isomer was 4 times more potent in inducing this effect;
    however, an increase in serum alanine aminotransferase (ALT)
    resulted from administration of the 1,3,5-isomer.

    Data on the acute toxicity of the tetrachlorobenzenes are restricted
    to the oral route of administration. In male Sprague-Dawley rats,
    the LD50s for 1,2,3,4-, 1,2,4,5-, and 1,2,3,5-TeCB were
    1470 mg/kg, 3105 mg/kg, and 2297 mg/kg body weight, respectively
    (Chu et al., 1983, 1984a). In females, the LD50 values were
    1167 mg/kg and 1727 mg/kg body weight for 1,2,3,4- and 1,2,3,5-TeCB,
    respectively. Clinical signs included depression, flaccid muscle
    tone, prostration, piloerection, loose stool, hypothermia,
    dacryorrhoea, and coma. At post-mortem, the gastrointestinal tract
    was distended and slightly haemorrhagic.

    Linder et al. (1980) reported LD50s for PeCB (gavage in peanut
    oil) in adult male and female Sherman rats of 1125 mg/kg and
    1080 mg/kg body weight, respectively. The value in weanling female
    rats was 940 mg/kg body weight. In male and female Swiss Webster
    mice, the LD50s were 1175 mg/kg and 1370 mg/kg body weight,
    respectively. Decreased activity and tremors were observed in both

    species at sublethal dosage levels; the kidneys, liver, and adrenal
    glands of rats were also enlarged. In some rats, the gastric mucosa
    was hyperaemic, and a slight reddish fluorescence of the
    gastro-intestinal tract, suggesting porphyria, was observed in both
    rats and mice, under ultraviolet light.

    There were no clinical signs of toxicity in rats following
    percutaneous administration of 2500 mg PeCB/kg body weight.

    8.2  Skin and Eye Irritation, Skin Sensitization

    The results of studies on the potential of chlorobenzenes to induce
    skin and eye irritation and skin sensitization are presented in
    Table 20. These investigations were mainly restricted to the
    1,2,4-isomer of trichlorobenzene, which, on the basis of available
    data, is mildly irritating, and causes dermatitis after repeated or
    prolonged contact, probably because of its degreasing action on the
    skin. Direct contact of the eyes with either 1,2-DCB or 1,2,4-TCB is
    painful, but does not produce permanent damage; moreover, there was
    no evidence of sensitization in the limited studies available.

    8.3  Short-term Exposures

    The results of short-term studies on the effects of chlorobenzenes
    on experimental animals are presented in Table 21. Effects following
    the exposure of rats and mice to repeated daily doses of
    chlorobenzenes for periods of up to 28 days were confined mainly to
    the liver; other target organs included the thyroid, kidney, and
    lung in rats and the bone marrow in mice.

    In evaluating repeated dose studies in which chlorobenzenes were
    administered in the diet, it is important to note that the dose
    received by the exposed animals might have been substantially lower
    than that indicated by the nominal concentrations, particularly for
    the more volatile lower chlorinated congeners. In a short-term
    bioassay for 1,2,4,5-TeCB, conducted recently by NTP (1989a), there
    was an 8% loss from the diet in 7 days, though corn oil had been
    added to minimize volatilization. On the basis of the physical and
    chemical properties of chlorobenzene congeners of lower chlorination
    than 1,2,4,5-TeCB, volatilization from the diet may have been even
    greater.

    The results of 14-day studies, in which relatively high doses of MCB
    and the two isomers of DCB (1,2- and 1,4-) (up to 8000 mg/kg body
    weight) were administered by gavage to F344 rats and B6C3F1 mice,
    were consistent with those of the acute toxicity studies; the
    1,2-isomer of DCB was slightly more toxic than MCB, as indicated by
    the doses that caused decreases in body weight gain and deaths. The
    1,4-isomer of DCB was considerably less toxic (NTP, 1983a,b, 1987).


    
    Table 20.  Skin and eye irritation; sensitization in experimental annimals
                                                                                                                                              

    Compound;                   Speciesa                  Routeb                   Dose                      Results
    Reference
                                                                                                                                              

    Irritation

    1,2-DCB                     rabbit (2)                application to the       2 drops undiluted         slight to moderate pain and slight
      Hollingsworth et al.                                eyes                     compound                  conjunctival irritation, clearing
      (1958)                                                                                                 in 7 days; prompt washing
                                                                                                             immediately after contact reduced
                                                                                                             pain and irritation

    1,4-DCB                     rabbit                    inhalation               4.6 to 4.8 mg/litre       tremors, weakness, lateral
      Pike (1944)                                                                  (765 to 798 ppm)          nystagmous, corneal and optical
                                                                                   8h/day for                nerve oedema, death
                                                                                   62 exposures over
                                                                                   83 days

    1,2,4-TCB                   rabbit - 4 of each        dermal (topical          1 ml, 6 h/day             very weak irritant, based on
      Brown et al. (1969)       sex/group                 application on           (3 days)                  visual inspection and
                                                          shorn backs -                                      histopathology 7 days after first
                                                          covered)                                           application - fissuring typical
                                                                                                             of degreasing action;
                                rabbit - 4 of each        dermal (topical          rabbit: 1 ml
                                sex/group                 application on           guinea-pigs: 0.5 ml,      spongiosis, acanthosis and
                                guinea-pig - 5 of each    shorn backs -            5 days/week (3 weeks)     parakeratosis in rabbits
                                sex/group                 uncovered                                          and guinea-pigs - some
                                                                                                             inflammation in the superficial
                                                                                                             dermis of rabbits exposed for 3
                                                                                                             weeks rabbits exposed for 3 weeks
                                                                                                                                              

    Table 20 (continued)
                                                                                                                                              

    Compound;                   Speciesa                  Routeb                   Dose                      Results
    Reference
                                                                                                                                              

    1,2,4-TCB                   rabbit                    application to the                                 irritation; pain, severe
      Brown et al. (1969)                                 eyes                                               conjunctivitis, chemosis and
                                                                                                             discharge, but without corneal
                                                                                                             involvement; swollen lids

    1,2,4-TCB                   New Zealand albino        dermal (topical          0, 30, 150, 450 mg/kg,    dermal irritation - fur matted by
     (70% + 30%                 rabbit - 5 of each        application on           5 days/week (4 weeks)     fine, white, bran-like scales
    1,2,3-TCB)                  sex/group                 shorn backs)                                       with variable degrees of
      Rao et al. (1982)                                                                                      erythema, fissures, erosions,
                                                                                                             and ulcers; inflammation and
                                                                                                             thickening of the epidermis; size
                                                                                                             of affected area varied with
                                                                                                             dose and increased
                                                                                                             severity at 450 mg/kg

    1,2,4-TCB                   ddY mouse -               dermal                   100, 70, 40, 1 or 0%      erythema with 100% TCB (4/8) and
      Yamamoto et al.           8 animals/group                                    TCB                       70% TCB (2/8); no remarkable
      (1978)                                                                                                 change in histology

    1,2-4-TCB                   New Zealand white         dermal (topical          0, 5, 25, 100%            dose-related dermal irritation;
      Powers et al.             rabbit - 12 of each       application on           (0.2 ml), 3 times         acanthosis and hyperkeratosis
      (1975)                    sex/group                 ventral surface          weekly (13 weeks)
                                                          of ear)
                                                                                                                                              

    Table 20 (continued)
                                                                                                                                              

    Compound;                   Speciesa                  Routeb                   Dose                      Results
    Reference
                                                                                                                                              

    Sensitization

    1,2,4-TCB                   guinea-pig                intradermal              1 day/week for            no overt signs of skin
      Brown et al. (1969)                                 injection or             3 successive weeks;       sensitization
                                                          topical application      challenge after
                                                          on shorn backs (0.1%     10 days
                                                          w/v in light liquid
                                                          paraffin)
                                                                                                                                              

    a    Strain and number of animals/group specified where available.
    b    Vehicle specified, where available.

    

    With the exception of 1,2,4,5-TeCB, administration by gavage (for
    periods of from 5 to 15 days) of all of the chlorinated (mono to
    penta-) benzene isomers examined caused hepatic porphyria,
    characterized by increased levels of porphyrins and porphyrin
    precursors in the liver and excreta. 1,3-DCB, 1,3,5-TCB, and
    1,2,3,5-TeCB were not examined (Rimington & Ziegler, 1963). The most
    active isomers in inducing porphyria were those with 2 chlorine
    atoms in a  para position to one another (1,4-DCB, 1,2,4-TCB, and
    1,2,3,4-TeCB). Liver damage was most severe (intense necrosis and
    fatty changes over large areas) in animals treated with high doses
    of MCB, 1,2-DCB, or 1,2,4-TCB (maximum doses ranged from 455 to 1140
    mg/kg body weight per day, by gavage, for the different isomers).
    The other chlorinated benzenes (1,4-DCB, 1,2,3-TCB, 1,2,3,4-TeCB,
    and 1,2,4,5-TeCB) produced degeneration of individual liver cells or
    focal necrosis in the central, midzonal, and periportal regions.
    Hepatomegaly was common in most porphyric rats.

    Hepatic porphyria was also observed in rats administered 800 mg
    1,3-DCB/kg body weight per day, by gavage, for 5 days (Poland et
    al., 1971). Rao et al. (1982) reported an increase in urinary
    coproporphyrin in male rabbits treated dermally with 450 mg
    1,2,4-TCB/kg body weight per day, for 5 days/week, over 4 weeks.
    Fatty degeneration of the liver and changes in blood cell counts
    indicative of bone marrow damage, were observed following inhalation
    by Swiss white mice of about 1250 mg MCB/m3 or 500 mg TCB/m3
    (isomer not specified) for 7 h/day, over 3 weeks (Zub, 1978).
    Necrotic foci in the liver were also observed following the dermal
    application to guinea-pigs of 0.5 ml undiluted 1,2,4-TCB, for 5
    days/ week, over 3 weeks (Brown et al., 1969).

    Effects on the adrenal glands and uterus have also been noted in a
    study in which 1,2,4-TCB at 250 or 500 mg/kg body weight per day was
    administered intraperitoneally for 3 days to immature female rats
    (Robinson et al., 1981). There was a decrease in uterine weight and
    hepatomegaly at both doses and a decrease in body weight and
    increase in adrenal weight at the high dose (500 mg/kg).

    The most extensive short-term study (28 days) completed to date on
    the toxicity of the higher chlorobenzenes was conducted by Chu
    et al. (1983) on 3 isomers of TeCB and PeCB. Levels administered in
    the diet of 0.5, 5.0, 50, or 500 mg/kg (ppm) for TeCB, and 5, 50, or
    500 mg/kg (ppm) for PeCB, did not cause effects on body weight gain
    or food consumption, or induce clinical signs of toxicity. No
    haematological aberrations were observed; however, dose-dependent
    effects were seen, principally, in the liver, but also in the
    thyroid, kidney, and lungs in Sprague-Dawley rats. While the results
    of acute toxicity studies indicated that the 1,2,4,5-isomer was the
    least toxic of the TeCBs, it was the most toxic congener in the
    28-day studies. This was well supported by the observation that it
    was present at highest concentrations in fat and liver. The order of
    toxicity for the TeCBs and PeCB, which was well correlated with

    tissue concentrations, was as follows: 1,2,4,5-TeCB>PeCB> 1,2,3,4-
    and 1,2,3,5-TeCB. Moderate to severe histopathological hepatic
    changes (e.g., cytoplasmic ballooning and anisokaryosis of
    hepatocytes) and increases in liver weight were observed in rats
    exposed to 1,2,4,5-TeCB or PeCB at levels of about 50 mg/kg body
    weight per day. Histopathological changes in the thyroid (i.e.,
    increase in epithelial height and angular collapse of thyroid
    follicles with a reduction in colloid density), kidney (i.e.,
    eosinophilic inclusions in proximal convoluted tubules), and lung
    (i.e., focal alveolar emphysema and inflammation) were mild, even at
    the highest dose levels.  Although all isomers of TeCB and PeCB
    induced hepatic enzymes, liver porphyrin concentrations were not
    affected. The data suggest that the position of the chlorine
    substituents in TeCBs affects the tissue accumulation and toxicity
    of these chemicals.

    The toxicity of 1,2,4,5-TeCB following short-term administration (14
    days) of 0, 30, 100, 1000, or 3000 mg/kg (ppm) in the diet to
    B6C3F1 mice or F344 rats was also investigated recently in an NTP
    bioassay (NTP, 1989a). In rats, there were no deaths in any dose
    group, though compound-related clinical signs were observed in the
    high-dose group. There were also decreases in food consumption and
    final mean body weights of both sexes at 3000 mg/kg, increases in
    liver weights in males at 1000 mg/kg or more and in females at
    3000 mg/kg, and abnormal hyaline droplets in the renal cortical
    epithelium of exposed males. In mice, all animals in the 3000 mg/kg
    dose group died before the end of exposure. There was also a
    significant increase in liver weights in males at 1000 mg/kg and in
    females at 300 or 1000 mg/kg. Depletion and necrosis of lymphoid
    tissue of the spleen, thymus, and lymph nodes in both sexes were
    also observed, particularly in moribund or early death animals.

    Concentrations of 0, 100, 330, 1000, 3300, or 10 000 PeCB mg/kg
    (ppm) in the diet have also been administered in short-term studies
    (15 days) to F344 rats and B6C3F1 mice (NTP, 1989b). All rats in
    the 10 000 mg/kg dose group died by day 7, and final mean body
    weights in both sexes were lower at 3300 mg/kg. There were also
    significant increases in liver weights at all doses except 100 mg/kg
    (females), and increases in kidney weights and abnormal hyaline
    droplet formation in the renal cortical epithelium in males at all
    doses. Centrilobular hepatocellular hypertrophy was observed in
    males at 330 and 1000 mg/kg and in females at 1000 and 3300 mg/kg.
    At 10 000 mg/kg, there was depletion of thymic lymphocytes and
    hyperkeratosis of the forestomach in both sexes, and forestomach
    acanthosis in females. In mice, all animals in the 2 highest dose
    groups (3300 and 10 000 mg/kg) died by day 10. There was a
    significant increase in liver weights in both sexes at 330 and 1000
    mg/kg, and mild to moderate depletion of thymic lymphocytes, due to
    lymphocyte necrosis, in moribund animals or those that died early. 


    
    Table 21.  Short-term toxicity of chlorobenzenes in experimental animals
                                                                                                                                              

    Compound;          Speciesa                Routeb             Dosec                      Resultsd
    Reference
                                                                                                                                              

    MCB                Fischer-344 rat;        oral (gavage in    rats: 0, 125, 250,         rats: prostration, reduced response to stimuli
      NTP (1983a);     B6C3F1 mouse -          corn oil)          500, 1000, or              and death of all animals at 1000 and 2000 mg/kg;
      Kluwe et al.     5 of each                                  2000 mg/kg per day         mice: no clinical signs of toxicity or deaths
      (1985)           sex/group                                  mice: 0, 30, 60,
                                                                  125, 250, or
                                                                  500 mg/kg per day
                                                                  (14 days)

    MCB                male albino rat         oral (gavage in    maximum dose -             hepatic porphyria and hepatomegaly in porphyric
      Rimington &      -                       paraffin)          1140 mg/kg per day         rats; severe liver damage (intense necrosis and
      Ziegler          3 animals/group                            (5 days)                   fatty change) at high doses; weight and appetite
      (1963)                                                                                 loss; decrease in haemoglobin levels

    MCB                Swiss white             inhalation         0, 2500 mg/m3              fatty degeneration of the liver with "acute
      Zub (1978)       mouse - 5 of                               (2.5 mg/litre)             yellow atrophy"; changes in blood cell counts
                       each sex/group                             reduced to 1250 mg/m3      indicative of bone marrow damage; loss of
                                                                  (7 h/day - 3 weeks)        appetite, general emaciation and marked
                                                                                             somnolence with death of the animals at the
                                                                                             higher dose

    1,2-DCB            Fischer-344 rat;        oral (gavage in    rats: 0, 60, 125, 500,     rats: dose-related decrease in weight gain (more
      NTP (1983b)      B6C3F1 mice -           corn oil)          or 1000 mg/kg per day      than 10% in males at highest dose); death of all
                       5 of each                                  mice: 0, 60, 125, or       animals at 1000 mg/kg; mice: death of 1 male and
                       sex/group                                  500 mg/kg per day          1 female in high dose (500 mg/kg) group
                                                                  (14 days)
                                                                                                                                              

    Table 21 (continued)
                                                                                                                                              

    Compound;          Speciesa                Routeb             Dosec                      Resultsd
    Reference
                                                                                                                                              

    1,2-DCB            male albino rat -       oral (gavage in    maximum dose -             results similar to those for MCB with exception
      Rimington &      3 animals/group         liquid paraffin)   455 mg/kg per              that there was no decrease in haemoglobin levels
      Ziegler                                                     day (15 days)
      (1963)

    1,3-DCB            Sherman male rat -      oral (gavage in    0, 800 mg/kg per day       hepatic porphyria; peak effect at 3 days
      Poland et al.    4 animals/group         peanut oil)        (9 days)
      (1971)

    1,4-DCB            male albino rat -       oral (gavage in    maximum dose -             hepatic porphyria; non-necrotic liver cell
      Rimington &      3 animals/group         liquid paraffin)   770 mg/kg per day          degeneration; weight and appetite loss
      Ziegler                                                     (5 days)
      (1963)

    1,4-DCB            Fischer-344 rat;        oral (gavage in    rats: 0, 500, 1000,        rats: death of all animals at 3 highest doses;
      NTP (1987)       B6C3F1 mouse -          corn oil)          2000, 4000, or             decrease in body weight gain at lower doses;
                       5 of each                                  8000 mg/kg per day         mice: no compound-related deaths or decreases in
                       sex/group                                  mice: 0, 60, 125, 250,     body weight gain
                                                                  500, or 1000 (14 days)

    1,2,3-TCB          male albino rat -       oral (gavage in    maximum dose -             hepatic porphyria; non-necrotic liver cell
      Rimington &      3 animals/group         1% cellofas)       785 mg/kg per day          degeneration; weight and appetite loss
      Ziegler                                                     (7 days)
      (1963)

    1,2,4-TCB          male albino rat -       oral (gavage in    maximum dose -             results similar to those for MCB with the
      Rimington &      3 animals/group         1% cellofas)       730 mg/kg per day          exception that there was no decrease in
      Ziegler                                                     (15 days)                  haemoglobin levels
      (1963)
                                                                                                                                              

    Table 21 (continued)
                                                                                                                                              

    Compound;          Speciesa                Routeb             Dosec                      Resultsd
    Reference
                                                                                                                                              

    1,2,4-TCB          rabbit (1 of each       percutaneous       rabbits - 1 ml/day         death of some guinea-pigs - necrotic foci in
      Brown et al.     sex) and                (applied on        guinea-pigs -              livers
      (1969)           guinea-pig (5 of        shaved backs)      0.5 ml/day
                       each sex)                                  (5 days/week for
                                                                  3 weeks)

    1,2,4-TCB          New Zealand albino      percutaneous       0, 30, 150, or             systemic effects only at 450 mg/kg - increase in
     (70% + 30%        rabbit - 5 of each      (applied on        450 mg/kg per day          urinary coproporphyrin in males and slight pallor
    1,2,3-TCB)         sex/group               shaved backs)      (5 days/week for           of liver in both sexes at necropsy; NOEL -
      Rao et al.                                                  4 weeks)                   150 mg/kg per day
      (1982)

    1,2,4-TCB          Charles River           intraperitoneal    0, 250 or 500 mg/kg        decrease in uterus weights and increase in liver
      Robinson et al.  immature female rat     (in corn oil)      per day (3 days)           weight at both doses; decrease in body weight and
      (1981)           - 9-10                                                                increase in adrenal weight at high dose
                       animals/group                                                         (500 mg/kg)

    1,2,4-TCB          Alderley Park SPF       inhalation         0, 148, 519, or            lethargy and retarded weight gain at 2 highest
      (up to 20%       rat - 2-4 of each                          1484 mg/m3 (0, 20, 70,     doses; lacrimation at 519 mg/m3; no observed
    1,2,3-TCB)         sex/group                                  or 200 ppm)                effects at 148 mg/m3
      Gage (1970)                                                 (6 h/day, 5 days/week
                                                                  for 3 or 4 weeks)

    1,3,5-TCB          CD (outbred             inhalation         0, 10, 100, or             increase in liver to body weight ratio at highest
      Sasmore et al.   albino) rat - 20                           1000 mg/m3 (6 h/day, 5     dose level (1000 mg/m3)
      (1983)           of each sex/group                          days/week for 4 weeks)

    TCB                Swiss white mouse -     inhalation         0, 500 mg/m3               fatty degeneration of the liver; changes in blood
      (isomer not      5 of each sex/group                        (0.5 mg/litre)             cell counts indicative of bone marrow damage;
      specified)                                                  (7 h/day for 3 weeks)      loss of appetite, hypoactive
      Zub (1978)
                                                                                                                                              

    Table 21 (continued)
                                                                                                                                              

    Compound;          Speciesa                Routeb             Dosec                      Resultsd
    Reference
                                                                                                                                              

    1,2,4,5-TeCB       albino rat (male) -     oral (gavage in    maximum dose -             no effect on urinary porphyrin levels, possibly
      Rimington &      3 animals/group         1% cellofas)       905 mg/kg per day          because of poor absorption
      Ziegler (1963)                                              (5 days)

    1,2,4,5-TeCB       F344/N rat -            oral (mixed in 1%  0, 30, 100, 300, 1000,     no deaths at any dose; compound-related clinical
      NTP (1989a)      5 of each               corn oil added to  or 3000 mg/kg (14 days)    signs included tremors, lethargy, thin appearance,
                       sex/group               feed)                                         rough coats, ataxia, and chromodacryorrhoea in
                                                                                             both sexes at 3000 mg/kg and rapid breathing in
                                                                                             females at 3000 mg/kg; decrease in final mean
                                                                                             body weights at 3000 mg/kg (18% in males; 15% in
                                                                                             females); 20% decrease in food consumption at
                                                                                             3000 mg/kg; at >300 mg/kg, increases in absolute
                                                                                             and relative kidney weights (males only); liver
                                                                                             congestion in males at >1000 mg/kg and in females
                                                                                             at 3000 mg/kg; abnormal hyaline droplets in the
                                                                                             renal cortical epithelium of exposed male rats
                                                                                             (doses unspecified)

    1,2,4,5-TeCB       B6C3F1 mouse -          oral (mixed in 1%  0, 30, 100, 300, 1000,     all animals in the 3000 mg/kg dose group died;
      NTP (1989a)      5 of each sex/group     corn oil added to  or 3000 mg/kg (14 days)    compound-related clinical signs included tremors,
                                               feed)                                         rapid breathing, lethargy, hunched posture, rough
                                                                                             coats, dyspnoea, and prostration in both sexes at
                                                                                             3000 mg/kg and thin appearance in females at
                                                                                             3000 mg/kg; significant increase in absolute and
                                                                                             relative liver weights in males at 1000 mg/kg and
                                                                                             in females at 300 or 1000 mg/kg; at 3000 mg/kg,
                                                                                             depletion and necrosis of lymphoid tissue of the
                                                                                             spleen, thymus, and lymph nodes in both sexes
                                                                                             (these changes frequently observed in moribund or
                                                                                             early-death animals)
                                                                                                                                              

    Table 21 (continued)
                                                                                                                                              

    Compound;          Speciesa                Routeb             Dosec                      Resultsd
    Reference
                                                                                                                                              

    1,2,3,4-TeCB       albino rat (male) -     oral (gavage in    maximum dose -             results similar to those for 1,2,3-TCB and hair
      Rimington &      3 animals/group         liquid paraffin)   660 mg/kg per day          loss
      Ziegler (1963)                                              (10 days)

    1,2,3,4-TeCB       Sprague-Dawley rat      oral (diet)        TeCBs: 0, 0.5, 5.0, 50,    no effect on body weight gain, food consumption;
    1,2,4,5-TeCB       - 10 of each                               or 500 mg/kg diet (28      no clinical signs of toxicity; no haematological
    1,2,3,5-TeCB       sex/group                                  days) PeCB: 0. 5.0, 50,    aberrations; increase in serum cholesterol for
    PeCB                                                          or 500 mg/kg diet          1,2,4,5-TeCB at 500 mg/kg; induction of hepatic
      Chu et al.                                                  (28 days)                  enzymes by all isomers; increase in liver weight
      (1983)                                                                                 for 1,2,4,5-TeCB and PeCB at 500 mg/kg;
                                                                                             dose-dependent histological changes (e.g.,
                                                                                             cytoplasmic vacuolation) in the liver (moderate to
                                                                                             severe) for 1,2,4,5-TeCB at 500 mg/kg, mild in all
                                                                                             other cases - PeCB > 1,2,3,4-TeCB and
                                                                                             1,2,3,5-TeCB; dose-dependent accumulation of
                                                                                             TeCBs in fat and liver - greatest for 1,2,4,5-TeCB
                                                                                             and PeCB; mild thyroid changes for 1,2,4,5-TeCB
                                                                                             and PeCB at 500 mg/kg, very mild in all other
                                                                                             cases; mild changes in kidney and lung

    PeCB               F344/N rat - 5 of       oral (in feed)     0, 100, 330, 1000,         all animals in the 10 000 mg/kg dose group died
      NTP (1989b)      each sex/group                             3300, or 10 000 mg/kg      by day 7; at 3300 mg/kg, final mean body weights
                                                                  (15 days)                  were 23% and 15% lower in males and females,
                                                                                             respectively; feed consumption lower in week 1
                                                                                             and higher in week 2; significant increase in
                                                                                             absolute and relative liver weights in all dose
                                                                                             groups except at 100 mg/kg (females); in males,
                                                                                             significant increases in absolute kidney weights
                                                                                             at 100, 330, and 1000 mg/kg and significant
                                                                                             increase in relative kidney weights at all doses;
                                                                                                                                              

    Table 21 (continued)
                                                                                                                                              

    Compound;          Speciesa                Routeb             Dosec                      Resultsd
    Reference
                                                                                                                                              

                                                                                             significant decrease in the absolute weights
                                                                                             of the kidney, thymus, heart, and lung of both
                                                                                             sexes at 3300 mg/kg possibly attributable to the
                                                                                             lower weight gain in these animals; excessive
                                                                                             abnormal hyaline droplets in the renal cortical
                                                                                             epithelium in males (0/5, 1/5, 5/5, 5/5, 2/5, 0/5
                                                                                             in control and increasing dose groups,
                                                                                             respectively); centrilobular hepatocellular
                                                                                             hypertrophy in males at 330 and 1000 mg/kg, and in
                                                                                             females at 1000 and 3300 mg/kg; at 10 000 mg/kg,
                                                                                             depletion of thymic lymphocytes and hyperkeratosis
                                                                                             (mild to moderate) of the forestomach in both
                                                                                             sexes and forestomach acanthosis in females

    PeCB               B6C3F1 mouse -          oral (in feed)     0, 100, 330, 1000,         all mice in 3300 or 10 000 mg/kg dose groups died
      NTP (1989b)      5 of each                                  3300, or 10 000 mg/kg      by day 10; clinical signs of toxicity in animals
                       sex/group                                  (15 days)                  exposed to 3300 mg/kg prior to death included
                                                                                             tremors, lethargy, hunched posture, and paralysis
                                                                                             (both sexes) and dyspnoea in females; significant
                                                                                             increase in absolute and relative liver weights
                                                                                             at 330 and 1000 mg/kg (both sexes); no
                                                                                             compound-related lesions in surviving animals, but
                                                                                             mild-to-moderate depletion of thymic lymphocytes,
                                                                                             due to lymphocyte necrosis, in moribund or
                                                                                             early-death animals
                                                                                                                                              

    a    Strain and number of animals/group specified, where available.
    b    Vehicle specified, where available.
    c    Doses given as mg/kg body weight, unless specified.

    

    8.4  Long-term Exposures

    The results of selected studies of the toxicity of the
    chlorobenzenes after long-term exposures are presented in Table 22.
    The data included in the table have been restricted to
    investigations for which analyses of, at least, body weight gain,
    survival, clinical signs of toxicity, clinical chemistry,
    haematology, and histopathology of major organs and tissues have
    been conducted.  No-observed-effect levels (NOEL),
    no-observed-adverse-effect levels (NOAEL), and lowest-observed-
    adverse-effect levels (LOAEL), determined on the basis of the
    results of these studies, are also presented in Table 22. Additional
    studies, in which analyses were more limited, are referenced in the
    text.

    As in the case of the single and short-term exposure studies, there
    are comparatively more data on the toxicity of the lower chlorinated
    congeners (i.e., mono- and dichlorobenzenes) after long-term
    exposure than there are for the tri-, tetra-, and
    pentachlorobenzenes.

    Because of the paucity of available data on some of the congeners
    and the wide variations in study design and duration, it is
    difficult to draw very specific conclusions about structure-activity
    relationships with respect to the toxicity of the chlorobenzenes
    after long-term exposures. However, on the basis of available data,
    it appears that, with the exception of 1,4-DCB, which has relatively
    low long-term toxicity, there is a trend for toxicity to increase
    with increased chlorination of the benzene ring for many of the
    endpoints examined. However, it should be noted that the variations
    in the long-term toxicity of different isomers of the same congener
    are, in some cases, considerable. The toxicity of the compounds also
    appears to be well correlated with the extent of accumulation in the
    body tissues, and, in general, female animals appear to be less
    sensitive to the chlorinated benzenes than males.

    Administration of MCB via inhalation or ingestion to rats, mice,
    rabbits, or dogs has caused reductions in both body weight gain and
    survival at high doses, and hepatic and renal toxicity, as indicated
    by increases in serum enzymes, liver and kidney weights,
    histo-pathological changes, and necrosis (Irish, 1963; Knapp et al.,
    1971; Dilley, 1977; NTP, 1983a).  At high doses, depression of bone
    marrow activity in mice (Zub, 1978) and myeloid depletion of the
    thymus, spleen, or bone marrow in rats and mice (NTP, 1983a) have
    also been observed. Inhibited chronaxia of antagonistic muscles, an
    increase in blood cholinesterase, and a decrease in serum
    alpha-globulin in rats have also been reported at considerably lower
    doses (0.1 mg/m3) (Tarkhova, 1965); however, it is difficult to
    assess the validity of these results on the basis of the published
    data.

    The no-observed-effect level for the long-term inhalation of MCB (32
    exposures of 7 h/day, over 44 days) was approximately 910 mg/m3 in
    rats (Irish, 1963).  For ingestion, the no-observed-effect level was
    50-125 mg/kg body weight in rats, and 125 mg/kg body weight in mice
    (Knapp et al., 1971; NTP, 1983a) (Table 22).

    The effects of long-term exposure of rats, guinea-pigs, rabbits, and
    mice to the DCBs, via inhalation or ingestion, have been similar to
    those of MCB. Reductions in body weight gain and reduced survival
    have resulted from exposures to high doses of DCBs. Hepatic and
    renal toxicity, as indicated by increases in liver and kidney
    weights, as well as histopathological changes and necrosis, have
    also been reported (Hollingsworth et al., 1956, 1958; NTP, 1983b,
    1987). Increases in porphyrin excretion, and lymphoid depletion of
    the thymus and spleen in rats, and multifocal mineralization of the
    myocardial fibres and skeletal muscles in mice have also been
    observed following administration of high doses of 1,2-DCB (NTP,
    1983b).

    As was observed in the acute and short-term studies, the 1,4-isomer
    appears to be considerably less toxic than 1,2-DCB. While the NOEL
    for the long-term inhalation of 1,2-DCB, derived from available
    studies, was 560 mg/m3 for rats, guinea-pigs, rabbits, and monkeys
    (Hollingsworth et al., 1958), the NOEL for the 1,4-isomer, was
    950 mg/m3 in mice, rabbits, and monkeys, and 580 mg/m3 in rats
    and guinea-pigs (Hollingsworth et al., 1956). The NOEL for ingestion
    of the 1,2-isomer in male mice was 125 mg/kg body weight (NTP,
    1983b) compared with values for the 1,4-isomer of 337.5 mg/kg body
    weight in mice and 300-600 mg/kg body weight in rats (NTP, 1987).

    Most of the data on the trichlorobenzenes are restricted to
    1,2,4-TCB, the most widely used isomer. Inhalation of 1,2,4-TCB in
    long-term studies on rabbits, rats, dogs, and monkeys resulted in
    liver and kidney damage, as indicated by increases in organ weight
    and transient histopathological changes (Coate et al., 1977; Kociba
    et al., 1981). The NOELs were 742 mg/m3 in rabbits and monkeys
    (Coate et al., 1977) and 223 mg/m3 in dogs (Kociba et al., 1981).
    Increases in porphyrin excretion have also been observed in various
    species following the inhalation of 1,2,4-TCB (Watanabe et al.,
    1978; Kociba et al., 1981); the no-observed-adverse-effect level
    (NOAEL) in rats for this effect was reported to be 22.3 mg/m3.

    On the basis of the results of one long-term inhalation study, the
    1,3,5-isomer appears to be somewhat less toxic than 1,2,4-TCB,
    possibly owing to low absorption of this relatively non-volatile
    chemical. The only notable effects resulting from the long-term
    administration of doses up to 1000 mg/m3 to rats were squamous
    metaplasia and hyperplasia of the respiratory epithelium of the
    nasal passages at the highest dose (NOEL - 100 mg/m3) (Sasmore
    et al., 1983).


    
    Table 22.  Toxicity of chlorobenzenes after long-term exposures
                                                                                                                                              

    Compound;         Speciesa         Doseb,c           Resultsd                                                   Effect Levelse
    Reference
                                                                                                                                              

    Inhalation

    MCB               Sprague-Dawley   0, 341,           increase in food intake (rats); reduction in SGOT;         341 mg/m3 "marginally
      Dilley (1977)   rat (male) and   1138 mg/m3,       increase in liver weight (both species) and                toxic concentration"
                      rabbit (male);   7 h/day,          congestion of liver (rabbits, 1138 mg/m3); increase
                      32 animals/      5 days/week       in kidney weight and tubular and interstitial
                      group            for 24 weeks      lesions (both species); lesions of the adrenal
                                                         cortex (rats); small changes in red cell parameters
                                                         (both species)

    MCB               rat, rabbit,     910, 2161,        at 4550 mg/m3, increase in mortality (guinea-pigs),        910 mg/m3 (NOEL)
      Irish (1963)    and guinea-pig   or 4550 mg/m3,    slight depression in growth, histopathological             2161 mg/m3 (LOAEL)
                                       7 h/day,          changes in the lungs, liver, and kidney; at 2161
                                       5 days/week       mg/m3, slight increase in liver weight and slight
                                       for 32            histopathological changes in the liver; no effects
                                       exposures         at 910 mg/m3
                                       over 44 days

    1,2-DCB           rat: 20 of       0, 290, or        decrease in spleen weight (M guinea-pigs) not              560 mg/m3 (NOEL)
      Hollingsworth   each             560 mg/m3,        believed to be treatment related; no other effects
      et al. (1958)   sex/group;       7 h/day,          on growth, mortality, organ weights, haematological
                      guinea-pig:      5 days/week       or urinalysis parameters; no histopathological
                      8 of each        for 6-7           changes
                      sex/group;       months
                      rabbit: 7 of
                      each
                      sex/group;
                      monkey:
                      2 females
                                                                                                                                              

    Table 22 (continued)
                                                                                                                                              

    Compound;         Speciesa         Doseb,c           Resultsd                                                   Effect Levelse
    Reference
                                                                                                                                              

    1,4-DCB           rat,             0, 580, or        growth depression (guinea-pig), increase in liver          580 mg/m3 (rats, (NOEL)
      Hollingsworth   guinea-pig,      950 mg/m3,        and kidney weight, cloudy swelling and granular            guinea-pigs);
      et al. (1956)   rabbit, mouse,   7 h/day,          degeneration of the liver in rats at 950 mg/m3             950 mg/m3 (monkeys,
                      and monkey;      5 days/week                                                                  (NOEL) rabbits, mice);
                      1-10             for 5-7                                                                      950 mg/m3 (rats,
                      animals/group    months                                                                       (LOAEL) guinea-pigs)

    1,3,5-TCB         CD rat - 20 of   0, 10, 100,       squamous metaplasia and hyperplasia in the                 100 mg/m3 (NOEL)
      Sasmore et al.  each sex/group   or 1000           respiratory epithelium of the nasal passages at
      (1983)                           mg/m3, 6 h/day,   1000 mg/m3
                                       5 days/week
                                       for 13 weeks

    1,2,4-TCB         Sprague-Dawley   0, 223, or        increased liver weight (rats and dogs) and kidney          742 mg/m3 (rabbits);
     (99.41%)         rat (male) -     742 mg/m3,        weight at 742 mg/m3; increased urinary excretion of        223 mg/m3 (dogs) (NOEL)
     Kociba et al.    20/group; New    (0, 30, or        porphyrins at >223 mg/m3 (rats), considered to
     (1981)           Zealand albino   100 ppm)          be physiological rather than toxic effect
                      rabbit (male)    7 h/day,
                      - 4/group;       5 days/week
                      beagle dogs      for 30
                      (male) -         exposures
                      2/group          (44 days)

    1,2,4-TCB         Sprague-Dawley   0, 22.3, or       slight reversible increase in urinary porphyrins           22.3 mg/m3 (M) (NOAEL)
      Watanabe        rat (male and    74.2 mg/m3        at 74.2 mg/m3
      et al. (1978)   female)          (0, 3, or
                                       10 ppm),
                                       6 h/day,
                                       5 days/week
                                       for 3 months
                                                                                                                                              

    Table 22 (continued)
                                                                                                                                              

    Compound;         Speciesa         Doseb,c           Resultsd                                                   Effect Levelse
    Reference
                                                                                                                                              

    1,2,4-TCB         Sprague-Dawley   0, 186, 371,      no effect on pulmonary function or operant behaviour       742 mg/m3 (NOEL)
     (99.07%)         albino rat       or 742 mg/m3      in monkeys; transient changes in the liver
      Coate et al.    (male) -         (0, 25, 50,       (hepatocytomegaly) and kidney (hyaline degeneration
      (1977)          30/group; New    or 100 ppm)       of the cortex) in rats, at all doses; no
                      Zealand white    7 h/day,          abnormal opthalmic changes in rabbits and monkeys
                      albino rabbit    5 days/week
                      (male) -         for 26 weeks
                      16/group;
                      cynomolgus
                      monkey (male)
                      - 9/group

    Ingestion

    MCB               Fischer-344      0, 60, 125,       reduced survival and reduction in body weight gain         125 mg/kg per day
      Kluwe et al.    rat; B6C3F1      250, 500, or      at >250 mg/kg; increase in SAP and SGGPT at >500           (NOEL);
      (1985)          mouse - 10 of    750 mg/kg         mg/kg (F rats); polyuria and porphyrinuria at >500         250 mg/kg per day
                      each sex/group   per day,          mg/kg (rats and F mice); increase in liver porphyrin       (LOAEL)
                                       5 days/week       at >500 mg/kg (F rats); dose-dependent increase in
                                       for 13 weeks;     liver weight, centrilobular hepato-cellular
                                       gavage in         degeneration and necrosis; slight increase in kidney
                                       corn oil          weight, degeneration and focal necrosis of the
                                                         proximal renal tubules; slight decrease in spleen
                                                         weight with lymphoid or myeloid depletion of the
                                                         thymus, spleen, or bone marrow at >250 mg/kg
                                                                                                                                              

    Table 22 (continued)
                                                                                                                                              

    Compound;         Speciesa         Doseb,c           Resultsd                                                   Effect Levelse
    Reference
                                                                                                                                              

    MCB               dog - 8          27.25, 54.5,      in high-dose group, 50% mortality, low blood sugar,        54.5 mg/kg per day
      Knapp et al.    animals/group    or 272.5 mg/kg    increase in SGPT and SAP, increase in total(NOAEL);
      (1971)                           per day,          bilirubin and cholesterol in some animals,                 272.5 mg/kg per day
                                       5 days/week       histopathological changes in liver, kidneys,               (LOAEL)
                                       for 93 days;      gastrointestinal mucosa, and haematopoietic tissue
                                       capsule           and increase in immature leukocytes; in
                                                         intermediate- and low-dose groups, no consistent
                                                         toxic effects

    MCB               rat              12.5, 50, or      in high-dose group, retarded growth in males;              50 mg/kg per day
      Knapp et al.                     250 mg/kg         increase in liver and kidney weight at >50 mg/kg; no       (NOEL);
      (1971)                           per day for       significant histopathological changes                      250 mg/kg per day
                                       93-99 days;                                                                  (LOAEL)
                                       diet

    1,2-DCB           Fischer-344      0, 30, 60,        reduced survival at 500 mg/kg (mice and F rats) and        125 mg/kg per day
      NTP (1983b)     rat; B6C3F1      125, 250, or      reduction in body weight gain at 500 mg/kg (F rats);       (NOEL);
                      mouse - 10 of    500 mg/kg         no increase in serum hepatic enzymes; increase in          250 mg/kg per day
                      each sex/group   per day,          urinary porphyrin at 500 mg/kg (rats and F mice),          (LOAEL)
                                       5 days/week       but no increase in hepatic porphyrin; increase in
                                       for 13            liver weight/body weight ratio (>125 mg/kg - rats,
                                       weeks;            500 mg/kg - F mice); centrilobular hepatic
                                       gavage in         degeneration and necrosis (>125 mg/kg - rats;
                                       corn oil          >250 mg/kg - M mice); renal tubular degeneration
                                                         (500 mg/kg - M rats); decrease in spleen/body weight
                                                         ratio (>30 mg/kg - F mice) and decrease in thymus/-
                                                         body weight ratio (500 mg/kg - M rats) and lymphoid
                                                         depletion of the thymus and spleen at 500 mg/kg in
                                                         mice; in rats, slight decrease in haemoglobin levels
                                                         and haematocrit and in red blood cell counts (M), at
                                                                                                                                              

    Table 22 (continued)
                                                                                                                                              

    Compound;         Speciesa         Doseb,c           Resultsd                                                   Effect Levelse
    Reference
                                                                                                                                              

    1,2-DCB                                              500 mg/kg; in mice, multifocal mineralization of
      NTP (1983b)                                        myocardial fibres of heart and skeletal muscle at
    cont'd                                               500 mg/kg

    1,4-DCB           Fischer 344/N    0, 37.5, 75,      no compound-related deaths or changes in body weight       600 mg/kg per day (F);
      NTP (1987)      rat - 10 of      150, 300, or      gain; increase in the incidence and severity of            300 mg/kg per day (M)
                      each sex/group   600 mg/kg         kidney cortical tubular degeneration at 600 mg/kg          (NOEL);
                                       per day,          (M)                                                        600 mg/kg per day (M)
                                       5 days/week                                                                  (LOAEL)
                                       for 13
                                       weeks;
                                       gavage in
                                       corn oil

    1,4-DCB           B6C3F1 mouse -   0, 84.4,          no compound-related deaths or change in body weight        337.5 mg/kg per day
      NTP (1987)      10 of each       168.8,            gain; mild to moderate centrilobular                       (NOEL);
                      sex/group        337.5, 675,       hepatocytomegaly at 900 mg/kg; minimal to                  675 mg/kg per day
                                       or 900 mg/kg      mild hepatocytomegaly at 675 mg/kg                         (LOAEL)
                                       per day,
                                       5 days/week
                                       for 13
                                       weeks;
                                       gavage in
                                       corn oil

    1,2,4-TCB         ICR-JCL mouse    600 mg/kg         no abnormal weight changes in organs; no macroscopic
      Goto et al.     (male)           diet (78          or histological lesions in liver
      (1972)          - 20 animals/-   œg/kg per
                      group            day for
                                       6 months;
                                       diet
                                                                                                                                              

    Table 22 (continued)
                                                                                                                                              

    Compound;         Speciesa         Doseb,c           Resultsd                                                   Effect Levelse
    Reference
                                                                                                                                              

    1,2,3-TCB         Sprague-Dawley   0, 1, 10,         no clinical signs of toxicity; deaths of one               1,2,3,-TCB:
    1,2,4-TCB         rat              100, 1000         high-dose female (not treatment related) and one           7.7 mg/kg per day;
    1,3,5-TCB         (weanling);      mg/kg diet        male control (no apparent cause); statistically            1,2,4-TCB:
     (>99%)           5 animals each   mixed with        significant growth suppression in males exposed to         7.8 mg/kg per day;
     Côté et al.      sex/group        corn oil in       10 or 1000 mg 1,2,3-TCB/kg; nephrosis in one male          1,3,5-TCB:
     (1988)                            the diet          exposed to 1000 mg 1,2,4-TCB/kg; significant               7.6 mg/kg per day
                                       (males: 0,        increase in liver/body weight ratios in males              (NOAEL)
                                       0.07-0.08,        exposed to high dose of all 3 TCBs; significant
                                       0.78-0.81,        increase in serum AH (males) and APDM (both sexes)
                                       7.6-7.8,          in animals exposed to 1000 mg 1,2,4-TCB/kg;
                                       78-82 mg/kg       "qualitatively similar" changes, mild to moderate
                                       per day;          (all TCB isomers) observed in the liver, thyroid,
                                       females: 0,       and kidney, significant at high-dose levels only and
                                       0.11-0.13,        more severe in males; histopathological changes
                                       1.3-1.5,          include: liver: mild to moderate increase in
                                       12-17,            cytoplasmic volume and anisokaryosis of hepatocytes;
                                       101-146           all isomers produced fatty infiltration-most severe
                                       mg/kg per         at 1000 mg 1,2,4-TCB/kg; thyroid: mild to moderate
                                       day)              changes (high-dose groups) including reduction in
                                                         follicular size, increased epithelial height and
                                                         reduced colloid density; kidney: moderate changes in
                                                         the convoluted tubules of males exposed to 1000 mg
                                                         1,3,5-TCB/kg

    1,2,4,5 TeCB      albino rat       0, 0.001,         increase in content of SH groups in serum, increases
      Fomenko                          0.005, or         in hemoglobin and reticulocytes of the peripheral
      (1965)                           0.05 mg/kg        blood at >0.005 mg/kg; disorders in the
                                       per day for       glycogen-forming function of the liver
                                       8 months
                                                                                                                                              

    Table 22 (continued)
                                                                                                                                              

    Compound;         Speciesa         Doseb,c           Resultsd                                                   Effect Levelse
    Reference
                                                                                                                                              

    1,2,4,5-TeCB      B6C3F1 mouse -   0, 30, 100,       compound-related clinical signs included tremors           300 mg/kg diet (NOEL);
      NTP (1989a)     10 of each       300, 1000,        (females), prostration, lethargy, hunched posture,         1000 mg/kg diet (LOAEL)
                      sex/group        or 2000           and rough hair coats (both sexes) at 2000 mg/kg;
                                       mg/kg diet        2/10 female mice in the 2000 mg/kg dose group were
                                       for 13            killed in moribound condition, before termination of
                                       weeks; mixed      the study; decrease in final mean body weights of
                                       in 1% corn        exposed mice (all doses in males; 30 mg/kg and >1000
                                       oil added to      mg/kg for females); decrease in food consumption in
                                       the diet          males (at 2000 mg/kg) and females (>1000 mg/kg); at
                                                         2000 mg/kg, absolute liver weights (both sexes)
                                                         approximately 3 times those of controls; absolute
                                                         liver weights increased in females at 30 mg/kg and
                                                         >1000 mg/kg and in males at 100 mg/kg and
                                                         >1000 mg/kg; relative liver weights increased in
                                                         females at >1000 mg/kg and in males at >100 mg/kg;
                                                         minimal to mild centrilobular hepatocellular
                                                         hypertrophy (both sexes) at 1000 mg/kg (7/10 M; 7/10
                                                         F) and 2000 mg/kg (10/10 M; 9/10 F); minimal to mild
                                                         individual hepatocyte degeneration at 1000 mg/kg
                                                         (9/10 M; 5/10 F); hepatocellular necrosis in males
                                                         at 2000 mg/kg (4/10) and in females at 30 mg/kg
                                                         (1/10) (not considered to be treatment-related),
                                                         1000 mg/kg (1/10) and 2000 mg/kg (1/10);
                                                         mineralization of the heart in males at 300 (2/10)
                                                         and 2000 (3/10) mg/kg with relationship to treatment
                                                         unclear; at doses >1000 mg/kg (both sexes),
                                                         increases in serum sorbitol dehydrogenase and
                                                         alanine aminotransferase activity; thyroid
                                                         follicular hypertrophy in males at >300 mg/kg and in
                                                                                                                                              

    Table 22 (continued)
                                                                                                                                              

    Compound;         Speciesa         Doseb,c           Resultsd                                                   Effect Levelse
    Reference
                                                                                                                                              

    1,2,4,5-TeCB                                         females at >100 mg/kg; at 2000 mg/kg in males and
      NTP (1989a)                                        >1000 mg/kg in females, decreased hemoglobin
                                                         concentrations, mean corpuscular hemoglobin,
                                                         haematocrit, and mean cell volume

    1,2,4,5-TeCB      F344/N rat -     0, 30, 100,       significant decrease in body weights of both sexes         30 mg/kg diet (F)
      NTP (1989a)     20 of each       300, 1000,        at >1000 mg/kg; compound-related clinical symptoms         (NOEL);
                      sex/group        or 2000           included hypoactivity and lethargy; significant            100 mg/kg diet (F)
                                       mg/kg diet        increases in absolute (>300 and >100 mg/kg) and            (LOAEL)
                                       for 13            relative (>300 and >30 mg/kg) liver weights for
                                       weeks; mixed      males and females, respectively; significant
                                       in 1% corn        increases in absolute (>300 mg/kg - both sexes) and
                                       oil and           relative kidney weights (M >100 mg/kg, F >300
                                       added to the      mg/kg); thyroid follicular cell hypertrophy
                                       feed              (M >300 mg/kg, F >100 mg/kg); "primary hypothyroid
                                                         state" (M >300 mg/kg, F >30 mg/kg); centrilobular
                                                         hypertrophy in both sexes (>1000 mg/kg); "hyaline
                                                         droplet nephropathy" particularly in males (>100
                                                         mg/kg); in females, renal cortical tubular
                                                         regeneration (>100 mg/kg) and renal tubular
                                                         epithelial accumulation of an unidentified
                                                         yellow-brown pigment (2000 mg/kg); in males,
                                                         decreases in haematocrit value, haemoglobin
                                                         concentrations, and erythrocyte counts at >1000
                                                         mg/kg and increases in platelet count and serum
                                                         albumin at >100 mg/kg; in females, increase in serum
                                                         albumin at 2000 mg/kg and decrease in mean cell
                                                         volume at >1000 mg/k3g
                                                                                                                                              

    Table 22 (continued)
                                                                                                                                              

    Compound;         Speciesa         Doseb,c           Resultsd                                                   Effect Levelse
    Reference
                                                                                                                                              

    1,2,3,4-TeCB      Sprague-Dawley   0, 0.5, 5.0,      for 1,2,4,5-TeCB - increase in hepatic AH and APDM         1,2,3,4-TeCB:
    1,2,3,5-TeCB      rat - 15 of      50, or            at >50 mg/kg (M) 500 mg/kg (F); at 500 mg/kg               3.4 mg/kg per day (M);
    1,2,4,5-TeCB      each sex/group   500 mg/kg         increase in serum cholesterol, haemoglobin levels,         42 mg/kg per day (F)
     (>99.5%)                          diet for 90       haematocrit, liver and kidney weights with                 (NOEL);
      Chu et al.                       days; in          dose-dependent changes in severity and prevalence of       34 mg/kg per day (M)
      (1984a)                          corn oil in       kidney and liver lesions; dose increase in serum           (LOAEL)
                                       diet              cholesterol, haemoglobin levels and haematocrit at
                                                         500 mg/kg; increase in liver and kidney weights at         1,2,3,5-TeCB:
                                                         500 mg/kg; dose-dependent changes in severity and          0.42 mg/kg per day (F);
                                                         prevalence of renal lesions - (extensive epithelial        3.4 mg/kg per day (M)
                                                         necrosis with large intratubular casts at 500 mg/kg)       (NOEL);
                                                         and of hepatic lesions (accentuation of zonation,          4.2 mg/kg per day (F);
                                                         increase in cytoplasmic homogeneity, aggravated            34 mg/kg per day (M)
                                                         basophilia, anisokaryosis and pyknotic                     (LOAEL)
                                                         hepatocellular nuclei); dose-dependent accumulation        1,2,4,5-TeCB:
                                                         in fat and liver; for the other isomers, changes in        0.034 mg/kg per
                                                         kidney and liver much milder, little accumulation in       day (M);
                                                         fat and liver; males more susceptible than females         4.2 mg/kg per day (F)
                                                                                                                    (NOEL);
                                                                                                                    0.34 mg/kg per
                                                                                                                    day (M);
                                                                                                                    42 mg/kg per day (F)
                                                                                                                    (LOAEL)
                                                                                                                                              

    Table 22 (continued)
                                                                                                                                              

    Compound;         Speciesa         Doseb,c           Resultsd                                                   Effect Levelse
    Reference
                                                                                                                                              

    PeCB              Sherman rat -    males: 6 -        dose-dependent accumulation in adipose tissue; no          16-31 mg/kg per day (F)
     (99.1%)          10 of each       140 mg/kg         evidence of porphyria; increase in liver weight at         (NOEL);
      Linder et al.   sex/group        per day (0,       >500 mg/kg; increase in adrenal (M) and kidney             27-63 mg/kg per day
      (1980)                           125, or 1000      weight at 1000 mg/kg (and increase in kidney weight        (LOAEL)
                                       mg/kg diet)       in M at 125 mg/kg); hypertrophy of hepatic cells at
                                       for 100           >500 mg/kg; dose-related increase in hyaline
                                       days;             droplets in kidney (M) at >125 mg/kg (at 1000 mg/kg,
                                       females: 7 -      focal areas of tubular atrophy and interstitial
                                       150 mg/kg         lymphocytic infiltration); decrease in haemoglobin
                                       per day (0,       levels, increase in WBC at 1000 mg/kg; decrease in
                                       125, 250,         RBC and haematocrit (M) at 1000 mg/kg
                                       500, or 1000
                                       mg/kg diet)
                                       for 180 days

    PeCB              F344/N rat -     0, 33, 100,       decrease in mean body weights of males (>1000 mg/kg)       33 mg/kg (M)
      NTP (1989b)     20 of each       330, 1000,        and females in all dose groups; increase in absolute       330 mg/kg (F) (NOEL);
                      sex/group        or 2000           liver weights in males at >100 mg/kg and in females        100 mg/kg (M)
                                       mg/kg for 13      at 100 and >1000 mg/kg; increase in relative liver         1000 mg/kg (F) (LOAEL)
                                       weeks in          weights in males at >33 mg/kg and in females at
                                       feed              >100 mg/kg; increase in
                                                         absolute kidney weights in males at >330 mg/kg and
                                                         in females at >1000 mg/kg; increase in relative
                                                         kidney weights in males >100 mg/kg and in females at
                                                         100 and >1000 mg/kg; at >1000 mg/kg, decreases in
                                                         hematocrit values, hemoglobin concentrations, mean
                                                         corpuscular hemoglobin, and mean cell volume in both
                                                         sexes; increases in serum albumin (males, >1000
                                                         mg/kg; females, >330 mg/kg); increase in
                                                         reticulocyte (males at 2000 mg/kg) and platelet
                                                         (males, >1000 mg/kg) counts and creatinine
                                                                                                                                              

    Table 22 (continued)
                                                                                                                                              

    Compound;         Speciesa         Doseb,c           Resultsd                                                   Effect Levelse
    Reference
                                                                                                                                              

    PeCB                                                 concentrations (males, >1000 mg/kg); lower platelet
      NTP (1989b)                                        counts in females at all doses but within normal
      (continued)                                        variation; significant increase in serum sorbitol
                                                         dehydrogenase activity in males (>1000 mg/kg) and
                                                         females (at concentrations as low as 100 mg/kg);
                                                         compound-related urinary effects included
                                                         significant increase in glucose concentrations
                                                         (males, >330 mg/kg; females >1000 mg/kg), increased
                                                         protein concentrations (both sexes >1000 mg/kg; more
                                                         pronounced in males) and significantly increased
                                                         urine volume (males, >1000 mg/kg; females at 2000
                                                         mg/kg on day 90); compound-related effects on the
                                                         thyroid included decreased free thyroxin and total
                                                         thyroxin at all doses in males and >100 mg/kg in
                                                         females; incidence of abnormal sperm increased in
                                                         males at 330 mg/kg (70%) and 2000 mg/kg (100%)
                                                         (sperm of males receiving 1000 mg/kg not examined);
                                                         dose-related renal lesions of males included
                                                         hyaline droplets of the cortical tubular epithelium
                                                         (>100 mg/kg), medullary tubular dilatation
                                                         (>100 mg/kg),
                                                         medullary collecting tubule mineralization (>330
                                                         mg/kg) and tubular cortex regeneration and cortex
                                                         chronic inflammation (>100 mg/kg) (also seen in some
                                                         control animals); tubular cortex regeneration in
                                                         females only at 2000 mg/kg; tubular cortex
                                                         pigmentation (males, 2000 mg/kg; females
                                                         >1000 mg/kg) and cortex protein casts (both sexes at
                                                                                                                                              

    Table 22 (continued)
                                                                                                                                              

    Compound;         Speciesa         Doseb,c           Resultsd                                                   Effect Levelse
    Reference
                                                                                                                                              

    PeCB                                                 2000 ppm); hepatic centrilobular hypertrophy in
      NTP (1989b)                                        males at >330 ppm and in females at >1000 ppm;
      (continued)                                        hepatic pigmentation and periportal cytoplasmic
                                                         vacuolization in females at >1000 ppm; follicular
                                                         cell hypertrophy in both sexes at >1000 ppm

    PeCB              B6C3F1 mouse -   0, 33, 100,       compound-related clinical signs included ventral           100 mg/kg (F) (NOEL);
      NTP (1989b)     20 of each       330, 1000,        body swelling and ruffled fur in both sexes at             330 mg/kg (F)
                      sex/group        or 2000 mg/kg,    2000 mg/kg; significant increase in males in               (LOAEL)
                                       for 13 weeks      absolute kidney weight at >330 mg/kg and relative
                                       in feed           kidney weights at >1000 mg/kg; increase in absolute
                                                         liver weights (males, >100 mg/kg; females,
                                                         >330 mg/kg); increase in relative liver weights
                                                         (both sexes, >330 mg/kg); increases in hemoglobin of
                                                         both sexes at >2000 mg/kg (although within normal
                                                         variation); increase in serum sorbitol dehydrogenase
                                                         activity (both sexes, >1000 mg/kg); decrease in
                                                         total thyroxin concentration in both sexes at
                                                         concentrations >33 mg/kg; at end of study, liver
                                                         porphyrin increased in both sexes at >1000 mg/kg;
                                                         minimal-to-moderate centrilobular hepatocellular
                                                         hypertrophy in males at all dose levels and in
                                                         females at >330 mg/kg; occasional necrosis of
                                                         hypertrophied hepatocytes (considered secondary to
                                                         the hypertrophy) observed in both sexes (males, 33
                                                         and 2000 mg/kg; females in control, 330 and
                                                         2000 mg/kg dose groups)
                                                                                                                                              

    Table 22 (continued)

    a  Strain and number of animals/group specified, where available.
    b  Vehicle specified, where available.
    c  Doses reported as mg/kg body weight, unless specified.
    d  M - male.
       F - female.
       WBC - white blood cells.
       RBC - red blood cells.
       ALH - microsomal aniline hydroxylase.
       SGOT - serum glutamic-oxaloacetic transaminase.
       SGPT - serum glutamic-pyruvic transaminase.
       SAP  - serum alkaline phosphatase.
       ALT - alanine aminotransferase.
       APDM - aminopyrine demethylase.
     e  NOEL - no-observed-effect level.
        NOAEL - no-observed-adverse-effect level.
        LOAEL - lowest-observed-adverse-effect level.
    

    Reports of investigations of the long-term toxicity of the
    tetra-chlorobenzenes following inhalation have not been found.
    However, in a 90-day study to compare the toxicities of TeCB isomers
    administered in the diet to rats, renal and hepatic toxicity were
    observed, as indicated by increases in organ weights and
    histopathological changes (Chu et al., 1984a). As was seen in a
    short-term study conducted by the same investigators, the
    1,2,4,5-isomer was the most toxic of the TeCBs; this may be
    attributable to its comparatively greater accumulation in fat and
    liver. The authors concluded that the observed changes were similar
    to those resulting from 28-day exposures to the same doses, but that
    renal lesions induced by the highest concentration of 1,2,4,5-TeCB
    (30-40 mg/kg) were more severe. The NOEL in male rats adminis-tered
    the 1,2,4,5-isomer was 0.034 mg/kg body weight; the value for
    females was considerably higher (4.2 mg/kg body weight). The NOEL
    for the other isomers in male rats was 3.4 mg/kg body weight; in
    females, these values were 42 and 0.42 mg/kg body weight for the
    1,2,3,4- and 1,2,3,5-isomers, respectively.

    In a 13-week study on F344 rats, which was completed recently by the
    US National Toxicology Program, 1,2,4,5-TeCB was mixed in corn oil
    (1%) and added to the diet at concentrations of 0, 30, 100, 300,
    1000, or 2000 mg/kg (NTP, 1989a). There were significant decreases
    in body weights, compound-related clinical symptoms,
    histopathological changes in the liver, and haematological effects
    at the highest doses; increases in the weights of both liver and
    kidney, renal histopathological effects, and effects on the thyroid
    were seen at lower doses. The NOEL for histopathological effects in
    females was considered by the investigators to be 30 mg/kg diet
    (approximately 1.95 mg/kg body weight); a NOEL in males could not be
    established.

    In a similar study, in which B6C3F1 mice were administered a diet
    containing 0, 30, 100, 300, 1000, or 2000 mg 1,2,4,5-TeCB/kg for 13
    weeks, there were significant decreases in body weights and food
    consumption, compound-related clinical signs, increases in liver
    weights and circulating hepatic enzymes, histopathological changes
    in the liver, and haematological effects, at the highest doses. The
    NOEL in both males and females was considered to be 300 mg/kg diet
    (approximately 48 mg/kg body weight) (NTP, 1989a).

    Only limited data are available on the long-term toxicity of
    penta-chlorobenzene. Ingestion of high doses by rats resulted in
    hepatic and renal toxicity, as indicated by increases in organ
    weights and histopathological changes (Linder et al., 1980),
    increases in adrenal weight (Linder et al., 1980), and increased
    excretion of porphyrins (Goerz et al., 1978). The NOEL in female
    rats, derived from the results of Linder et al. (1980), was
    16-31 mg/kg.

    In a recently completed 13-week study conducted by NTP (1989b), F344
    rats and B6C3F1 mice were fed diets containing 0, 33, 100, 330,
    1000, or 2000 mg PeCB/kg. Decreases were seen in the mean body
    weights of male rats at 1000 mg/kg or more and in females at all
    dose levels. Increased liver weights were seen at the lower doses
    and histopathological effects on the liver, at the higher doses. In
    males, there were increases in kidney weights and renal
    histo-pathological effects at lower doses; these effects were
    observed only at higher doses in females. Functional effects were
    observed in the kidney in both sexes at the highest doses and in the
    thyroid at all doses, with histopathological effects occurring only
    at the highest doses (1000 or 2000 mg/kg diet). There were also
    haematological effects at doses exceeding 1000 mg/kg in males and
    330 mg/kg in females. The incidence of abnormal sperm in males was
    also increased at the dose levels at which it was examined (330 and
    2000 mg/kg diet). On the basis of histopathological lesions, the
    authors considered the NOEL to be 33 mg/kg diet in male rats, and
    330 mg/kg diet in females (approximately 2.0 and 21.5 mg/kg body
    weight, respectively).

    In mice, there were compound-related clinical signs at the highest
    dose. Increased kidney weights were observed at the highest doses
    and functional effects on the thyroid at all doses.  There were
    increases in liver weights at lower doses and histopathological
    effects on the liver at all doses in males and at doses of 330 mg/kg
    diet or more in females. On the basis of the histopathological
    lesions, the authors considered the NOEL in female mice to be 100
    mg/kg diet (approximately 18.3 mg/kg body weight); no NOEL in males
    could be established.

    8.5  Chronic Toxicity and Carcinogenicity

    The protocols and results of the few studies on chronic toxicity and
    carcinogenicity of the chlorobenzenes are summarized in Table 23.
    The United States National Toxicology Program (NTP) has studied the
    chronic toxicity and carcinogenicity for rats and mice of MCB, and
    the 1,2- and 1,4-isomers of DCB (NTP, 1983a,b, 1987), following oral
    administration. The results of an additional investigations by
    Loeser & Litchfield (1983) on the chronic toxicity and
    carcino-genicity of 1,4-DCB for rats and mice have also been
    reported.

    Only one rather limited investigation on the chronic toxicity and
    carcinogenicity of the TCBs (1,2,4-isomer) following skin painting
    in mice has been identified (Yamamoto et al., 1982) and studies on
    the chronic toxicity of the TeCBs are confined to a very limited
    investigation involving the oral administration of the
    1,2,4,5-isomer to dogs (Braun et al., 1978). No data were found on
    the chronic toxicity and carcinogenicity of PeCB.


    
    Table 23.  Chronic toxicity and carcinogenicity of chlorobenzenes
                                                                                                                                              

    Compound;          Speciesa            Doseb,c                      Resultsd                                        Effect Levelse
    Reference
                                                                                                                                              

    Inhalation

    1,4-DCB            SPF Alderlely       0, 450, or 3000 mg/m3        increase in liver and kidney weights,           450 mg/m3
      Loeser &         Park Wistar         (0, 75 or 500 ppm); 5h       urinary protein, and coproporphyrin at            (NOEL)
      Litchfield       -derived rat        /day, 5 days/week for        3000 mg/m3; no treatment-related tumours        3000 mg/m3
      (1983)           - 76-79 of each     76 weeks; killed at 102                                                        (LOAEL)
                       sex/group           weeks

    1,4-DCB            SPF Swiss           0, 450, or 3000 mg/m3        no treatment-related toxic effects or           3000 mg/m3 (NOEL)
      Loeser &         (Alderley Park      (0, 75, or 500 ppm); 5h      tumours; one osteosarcoma in nasal sinus
      Litchfield       strain) mouse       /day, 5 days/week for 57     at 450 mg/m3
      (1983)           (female) -          weeks; killed at 75-76
                       75/group            weeks

    Ingestion

    MCB                Fischer 344 rat -   0, 60, or 120 mg/kg per      significant increase in hepatic                 60 mg/kg per day (M),
      (99%)            50 of each          day (5 days/week for 103     neoplastic nodules (M) at 120 mg/kg             120 mg/kg per day (F)
      NTP (1983a);     sex/group           weeks); gavage in corn       in comparison with vehicle and pooled             (NOEL);
      Kluwe et al.                         oil                          controls, but no carcinomas at this             120 mg/kg per day (M)
      (1985)                                                            dose; marginally significant                      (LOAEL)
                                                                        dose-response trend; rare tumours in 3
                                                                        exposed animals - 1 renal tubular cell
                                                                        adenocarcinoma (F) and 2 transitional
                                                                        cell papillomas of the bladder (M);
                                                                        decrease in pituitary tumours
                                                                                                                                              

    Table 23 (continued)
                                                                                                                                              

    Compound;          Speciesa            Doseb,c                      Resultsd                                        Effect Levelse
    Reference
                                                                                                                                              

    MCB                B6C3F1 mouse - 50   males: 0, 30, or 60 mg       no treatment-related toxic effects or           60 mg/kg per day (M),
      (99%)            of each sex/group   /kg per day; females: 0,     tumours                                         120 mg/kg per day (F)
      NTP (1983a)                          60, or 120 mg/kg per day                                                       (NOEL)
      Kluwe et al.                         (5 days/week for
      (1985)                               103 weeks); gavage in

    1,2-DCB            Fischer-344 rat -   0, 60, or 120 mg/kg per      decrease in survival and body weight            120 mg/kg per day (F)
      (>99%)           50 of each          day (5 days/week for         gain (M) at 120 mg/kg; increase in body           (NOEL)
      NTP (1983b)      sex/group           103 weeks); gavage in        weight gain (F) after 32 weeks; increase
                                           corn oil                     in adrenal phacochromocytomas at 60
                                                                        mg/kg - probably not compound-related

    1,2-DCB            B6C3F1 mouse -      0, 60, or 120 mg/kg per      dose-related trend for increase in              60 mg/kg per day (M),
      (>99%)           50 of each          day (5 days/week for         tubular regeneration in the kidney (M at        120 mg/kg per day (F)
      NTP (1983b)      sex/group           103 weeks); gavage in        120 mg/kg); positive trend for incidence          (NOEL);
                                           corn oil                     of malignant histiocytic lymphomas in           120 mg/kg per day (M)
                                                                        both sexes, but negative trend for                (LOAEL)
                                                                        malignant lymphocytic lymphomas;
                                                                        significant positive trend in
                                                                        alveolar/bronchiolar carcinomas in males
                                                                        not significant when combined with
                                                                        adenomas; dose-related decrease in
                                                                        hepatocellular adenomas (M)
                                                                                                                                              

    Table 23 (continued)
                                                                                                                                              

    Compound;          Speciesa            Doseb,c                      Resultsd                                        Effect Levelse
    Reference
                                                                                                                                              

    1,4-DCB            Fischer 344 rat -   males: 0, 150, or            reduced survival (M) and body weight
      (>99%)           50 of each          300 mg/kg per day            gain at 300 mg/kg; increased severity of
      NTP (1987)       sex/group           females:  0, 300, or         nephropathy and incidence of hyperplasia
                                           600 mg/kg per day            of the parathyroid at >150 mg/kg (M) and
                                           (5 days/week for             dose-related increase in nephropathy (F)
                                           103 weeks); gavage in        at >300 mg/kg; dose-related increase in
                                           corn oil                     renal tubular cell adenocarcinomas (M);
                                                                        tubular cell adenoma in high-dose groups
                                                                        (M); marginal increase in mononuclear
                                                                        leukaemias (M)

    1,4-DCB            B6C3F1 mouse -      0, 300,or 600 mg/kg per      increased incidence of hepatic lesions;
      (>99%)           50 of each          day (5 days/week for         nephropathy (M), renal tubular
      NTP (1987)       sex/group           103 weeks); gavage in        regeneration (F); thyroid gland
                                           corn oil                     follicular cell hyperplasia (M)
                                                                        (positive trend in F); adrenal medullary
                                                                        hyperplasia (M) and focal hyperplasia of
                                                                        the adrenal gland capsule (M); positive
                                                                        trend and increase in hepatocellular
                                                                        carcinomas at 600 mg/kg and
                                                                        hepatocellular adenomas
                                                                        (M >300 mg/kg; F >600 mg/kg);
                                                                        hepatoblastomas in 4 high-dose males;
                                                                        positive trend for phaeochromocytomas
                                                                        f adrenal gland with increased incidence
                                                                        at 600 mg/kg (M); marginal trend in
                                                                        follicular cell adenomas of the thyroid
                                                                        (F)
                                                                                                                                              

    Table 23 (continued)
                                                                                                                                              

    Compound;          Speciesa            Doseb,c                      Resultsd                                        Effect Levelse
    Reference
                                                                                                                                              

    1,2,4,5-TeCB       Beagle dog -        5 mg/kg per day (2           increases in SAP and total bilirubin at
      Braun et al.     2 of each           years; killed at 3 years     24 months returned to normal, 3 months
      (1978)           sex/group (no       8 months); diet              after exposure (no measurement of
                       concurrent                                       urinary, haematological, or clinical
                       control group)                                   chemistry, during exposure); no
                                                                        morphological changes after the 20-month
                                                                        recovery phase (no gross or histological
                                                                        examination during, or at the end of,
                                                                        exposure)

    Dermal

    1,2,4-TCB          Slc:ddY mouse -     0.03 ml of 0, 30%, or        clinical symptoms of toxicity including
      Yamamoto         75 of each          60% solution (twice/week     hysterical excitement, acceleration of
      et al. (1982)    sex/group (50 of    for 2 years); dissolved      spontaneous activity, and panting;
                       each sex/control    in acetone                   decreased survival (F-both doses, M-high
                       group)                                           dose); thickening and keratinization of
                                                                        epidermis followed by inflammation;
                                                                        increase in spleen weight at both doses
                                                                        (M-low dose, F-high dose); minor
                                                                        haematological changes at both doses;
                                                                        authors report no increase in tumour
                                                                        incidence attributable to TCB - however
                                                                        data inadequate for evaluation
                                                                                                                                              

    Table 23 (continued)

    a   Strain and number of animals/group specified, where available.
    b   Vehicle specified, where available.
    c   Doses given as mg/kg body weight, unless specified.
    d   SAP - serum alkaline phosphatase.
        M - male.
        F - female.
    e   NOEL - no-observed-effect level.
        NOAEL - no-observed-adverse-effect level.
        LOAEL - lowest-observed-adverse-effect level.

    

    In the NTP bioassays on MCB, there was no convincing evidence of
    compound-related toxicity in either rats or mice administered doses
    of up to 120 mg/kg body weight per day for 103 weeks. Evidence for
    mild hepatocellular necrosis in rats was equivocal and, though there
    was a significant decrease in the survival of male rats in the
    high-dose group (120 mg/kg), the absence of marked toxic lesions did
    not support a causal relationship with MCB. The doses administered
    in the long-term bioassay were not significantly less than those at
    which toxic effects were observed in the NTP 13-week studies (LOAEL
    = 250 mg/kg per day), indicating little potential for progressive
    toxicity with continued MCB administration for more than 13 weeks
    (NTP, 1983a; Kluwe et al., 1985).

    A significant increase in neoplastic nodules in the liver was noted
    in the high-dose group of male rats administered MCB (incidence,
    2/50, 4/49, and 8/49 at 0, 60, and 120 mg/kg body weight,
    respectively). However, no hepatocellular carcinomas were found and
    analysis of the combined data on neoplastic nodules and
    hepato-cellular carcinomas reduced the significance of the increase
    in tumour incidence. It was concluded that the NTP study provided
    some, but not clear, evidence of carcinogenicity in male Fischer 344
    rats, based on the increased incidence of hepatic nodules, but that
    there was no evidence of carcinogenicity in female Fischer 344 rats
    or in male or female B6C3F1 mice (NTP, 1983a).

    In the NTP bioassay for the carcinogenesis of 1,2-DCB, the only
    evidence of toxicity was a decrease in survival and body weight gain
    in male rats and an increase in tubular regeneration of the kidney
    in male mice, both of which occurred at the highest dose level (120
    mg/kg body weight per day for 103 weeks) (NTP, 1983b). The rates of
    survival until the end of the study in the 3 groups of male rats
    were 42/50 (84%), 36/50 (72%), and 19/50 (38%) for 0, 60 mg/kg, and
    120 mg/kg body weight, respectively. Although the survival rate in
    the high-dose group was significantly different from those in the
    low-dose and vehicle-control groups in the male rat, this may have
    been the result of accidents occurring during the dosing by gavage
    (NTP, 1983b). In mice administered 1,2-DCB, there was a dose-related
    trend in the tubular regeneration of the kidney in males only, with
    an increased incidence at the highest dose (120 mg/kg body weight)
    (control, 17%; 60 mg/kg, 24%; 120 mg/kg, 35%); otherwise, there was
    no other evidence of non-neoplastic toxicity (NTP, 1983b).

    In rats administered 1,2-DCB in the NTP study, the only tumours that
    occurred in excess were adrenal phaeochromocytomas in the low-dose
    group of male rats (incidence in controls, 9/50; low-dose, 16/50 and
    high-dose, 6/49), which were not considered to be treatment-related.
    In mice, there was a positive trend in the incidence of malignant
    histiocytic lymphomas in both sexes; however, the combined incidence
    of all types of lymphomas was not significantly greater than that in
    the controls for mice of either sex. Similarly, alveolar/bronchiolar

    carcinomas occurred in male mice with a statistically significant
    positive trend; there were, however, no significant trends when the
    incidences of alveolar/bronchiolar adenomas and carcinomas were
    combined. Thus, the NTP concluded that, under the conditions of
    these studies, there was no evidence for the carcinogenicity of
    1,2-DCB in male or female F344 rats or B6C3F1 mice.

    There are 2 bioassays that are relevant to the assessment of the
    chronic toxicity and carcinogenicity of 1,4-DCB: an inhalation study
    on rats and mice (Loeser & Litchfield, 1983) and an NTP bioassay
    involving ingestion by the same species (NTP, 1987).

    Loeser & Litchfield (1983) reported increases in liver and kidney
    weights, as well as in urinary protein and coproporphyrin, in the
    high-dose group when rats were administered 0, 450, or 3000 mg
    1,4-DCB/m3, for 5 h/day, 5 days/week, over 76 weeks, followed by
    36 weeks without exposure. There were also some statistically
    significant changes in blood biochemical and haematological
    parameters; however, there was no indication of a dose-response
    relationship in this regard. There was no evidence of toxicity in
    mice following administration of the same doses for a shorter period
    of 57 weeks, followed by 19 weeks without exposure. No
    treatment-related effects on the incidence, multiplicity, or
    malignancy of tumours were observed in either species. The
    relatively short exposure period (76 weeks in rats, 57 weeks in
    mice) and the high early mortality in mice may have decreased the
    sensitivity of this carcinogenicity bioassay.

    In the NTP (1987) study, 1,4-DCB was administered, by gavage, in
    corn oil, for 5 days/week, over 103 weeks. Groups of 50 male F344
    rats received 150 or 300 mg/kg body weight per day, while groups of
    50 female F344 rats and 50 male and 50 female B6C3F1 mice received
    300 or 600 mg/kg body weight per day. Under this regimen, there was
    an increased incidence of non-neoplastic liver lesions in male and
    female mice, including cytomegaly and karyomegaly, hepatocullular
    degeneration, and individual cell necrosis. Also, 1,4-DCB
    administration resulted in an increased incidence of nephropathy in
    male mice and renal tubular regeneration in female mice.
    Non-neoplastic lesions in male rats after 1,4-DCB administration
    included an increased incidence and severity of nephropathy, an
    increased incidence of epithelial hyperplasia of the renal pelvis,
    mineralization of the collecting tubules in the renal medulla, and
    focal hyperplasia of the renal tubular epithelium. An increased
    incidence of nephropathy was noted in both low- and high-dose female
    rats compared with the vehicle controls.

    As reported by NTP (1987), administration of 1,4-DCB resulted in a
    dose-related increase in the incidence of tubular cell
    adenocarcinomas of the kidney in male rats (1/50, 3/50, and 7/50 in
    the control, mid-, and high-dose groups, respectively); an uncommon
    malignant tumour was found in F344 rats, but only in 4/1098 of the
    NTP historical controls fed corn oil by gavage. An additional
    tubular cell adenoma was observed in a high-dose male rat. No
    tubular cell tumours were found in either treated or vehicle-control
    female rats. A marginal increase in the incidence of mono-nuclear
    cell leukaemia in treated male rats was noted compared with controls
    (5/50, 7/50, and 11/50 in control, mid- and high-dose groups,
    respectively).

    In mice, there were positive trends in the incidence of
    hepatocellular adenomas, hepatocellular carcinomas, and
    hepatocellular adenomas and carcinomas (combined) in males and
    females, the incidences in the high-dose groups being significantly
    greater than those in the vehicle controls. In low-dose male mice,
    the incidences of hepatocellular adenomas and adenomas or carcinomas
    (combined) were also significantly increased over those in the
    vehicle controls (combined incidence 17/50, 22/49, and 40/50 in
    control, low-, and high-dose groups of males; combined incidence
    15/50, 10/48, and 36/50 in control, low-, and high-dose groups of
    females) (NTP, 1987). Hepatoblastomas occurred in 4 high-dose male
    mice, each of which also bore hepatocellular carcinomas. This rare
    type of hepatocellular carcinoma had not been observed by NTP in
    1091 control (corn oil by gavage) male mice and had only been seen
    in 1/2080 untreated female mice. Marginal increases were observed in
    the incidences of pheochromocytomas of the adrenal gland in male
    mice (controls, 0/47; low-dose group, 2/48; and high-dose group,
    2/49) reaching statistical significance in the high-dose group
     (P=0.035), and in the incidence of follicular cell adenomas of the
    thyroid gland in female mice (controls, 0/48; low-dose group, 0/45;
    and high-dose group, 3/46).

    On the basis of these results, the NTP (1987) concluded that there
    was clear evidence of the carcinogenicity of 1,4-DCB in male F344/N
    rats, and clear evidence of carcinogenicity in both male and female
    B6C3F1 mice. There was no evidence of carcinogenicity in female
    F344/N rats.

    It is possible that the discrepancies between the results of Loeser
    & Litchfield (1983) and NTP (1987) are the result of differences in
    experimental design. Loeser & Litchfield (1983) administered
    approximately 390 mg/kg body weight per day via inhalation to rats
    and approximately 790 mg/kg to mice. Although these doses were
    higher than those used by NTP (1987), mice were exposed for only 57
    weeks and rats for only 76 weeks. The strains of animals used and
    the nature of administration also varied between the 2 studies
    (i.e., continuous inhalation for 5 h/day versus bolus dose by
    gavage).

    The induction of kidney tumours in the male rat is believed to be
    associated with hyaline droplet formation resulting in a
    characteristic alpha-2-microglobulin nephropathy (hyaline droplet
    nephropathy). Such effects, specific for the male rat, have been
    shown to occur with a number of chemicals, including 1,4-DCB,
    unleaded gasoline, isophorone, decalin, and limonene, and the
    mechanism has been established (Short et al., 1987; Goldsworthy et
    al., 1988; Murty et al., 1988; Charbonneau et al., 1989). It
    involves increased formation of protein droplets and crystalloid
    accumulation in the cytoplasm of the P2 segment of the proximal
    tubule with a marked increase in cell proliferation. The hyaline
    droplets formed are composed of lysosomes containing excess
    alpha-2-microglobulin and protein-bound chemical. Increased cell
    turnover in the P2 segment of the kidneys of male rats may be
    related to the slow catabolism of this accumulated protein within
    the lysosomes leading, in some cases, to renal tubular
    adenocarcinomas in the male rat. Alpha-2-microglobulin occurs in
    large amounts in the male Fisher 344 rat, but is not seen in
    significant amounts in the female rat, mouse, or man (Olson et al.,
    1990).

    For 1,4-DCB, there is much evidence to support the involvement of
    hyaline droplet accumulation in the induction of the tubular cell
    adenocarcinomas in the male rat. Bomhard et al. (1988) demonstrated
    hyaline droplet accumulation in male, but not in female, rats
    following exposure to 1,4-DCB. Charbonneau et al. (1989) reported
    that 1,4-DCB (single exposure of F344 rats to 300 or 500 mg/kg body
    weight in corn oil) increased protein droplet formation and cell
    proliferation in male but not female rat kidneys, whereas equimolar
    doses of 1,2-DCB did not have any effect. The maximum amount of
    radiolabel reversibly bound to alpha-2-microglobulin by
    C14-labelled 1,4-DCB was also twice that for an equimolar dose of
    C14-labelled 1,2-DCB.

    Available data are inadequate for the assessment of the chronic
    toxicity and carcinogenicity of the higher chlorinated benzenes
    (tri- to penta-). Clinical signs of toxicity, decreased survival,
    increased organ weights, keratinization of the epidermis, and minor
    haemato-logical effects were reported in Slc:ddy mice treated
    dermally with 0.03 ml of a 30 or 60% solution of 1,2,4-TCB, twice a
    week, over 2 years (Yamamoto et al., 1982). No increase in tumour
    incidence, attributable to TCB, was reported.

    An increase in serum alkaline phosphatase and total bilirubin
    following 24 months of exposure of beagle dogs to 5 mg
    1,2,4,5-TeCB/kg body weight per day in the diet has been reported
    (Braun et al., 1978). The values for these parameters returned to
    normal 3 months after cessation of exposure, and there were no
    morpho-logical changes after a 20-month recovery phase. However, the
    results of this study are inadequate for the assessment of chronic

    toxicity or carcinogenicity. No measurements were made of urinary,
    haematological, or clinical chemistry parameters during exposure,
    and no histopathological examination was carried out at the end of
    exposure. Moreover, there were only 2 animals of each sex in the
    exposed group, only 1 dose level was examined, there was no
    concurrent control group, and the period of administration (2 years)
    was short in relation to the life span of the dog.

    No data are available on the chronic toxicity or carcinogenicity of
    pentachlorobenzene.

    8.6  Mutagenicity and Related Endpoints

    8.6.1  In vitro systems

    When tested in  S. typhimurium strains TA98, TA100, TA1535, or
    TA1537, with, or without, the addition of an S9 fraction from the
    liver of Aroclor(R) 1254-treated rats, MCB did not show any
    mutagenic potential (Haworth et al., 1983). In another study in
     S. typhimurium using a slightly lower dose (1.28 µl/plate) and
    adding strain TA1538, Shimizu et al. (1983) reported that there was
    no evidence for the mutagenicity of MCB in this system.

    The dichlorobenzenes (1,2-, 1,3-, and 1,4-DCB) have been studied for
    mutagenic effects in  S. typhimurium , with, and without, metabolic
    activation. Haworth et al., (1983) studied a mixture of DCB isomers
    in 4 strains with, and without, activation with S9 supernatant from
    the livers of rats treated with Aroclor(R) 1254. No mutagenicity
    was noted. Using a similar protocol with 5 strains of
     S. typhimurium, at doses of up to approximately 1.3 µl/plate,
    Shimizu et al. (1983) reported that neither 1,2- nor 1,3-DCB was
    mutagenic. 1,4-DCB, at doses up to 6.6 mg/plate, was also found to
    be negative in  S. typhimurium, under the conditions outlined by
    Shimizu et al. (1983).

    No evidence was reported by Haworth et al. (1983) that mixed TeCBs
    and PeCB were mutagenic, when assayed in  S. typhimurium strains
    TA98, TA100, TA1535, and TA1537 with, and without, metabolic
    activation. Using a similar protocol, Schoeny et al. (1979) reported
    that 1,2,4-TCB was not mutagenic in  S. typhimurium.

    When tested for forward mutations in L5178Y/TK+/- mouse lymphoma
    cells, 1,4-DCB was negative when assayed without metabolic
    activation and the results were equivocal with activation with S9
    from Aroclor(R) 1254-induced rat liver (NTP, 1987). No evidence
    was reported by Perocco et al. (1983) for the induction by 1,4-DCB
    of unscheduled DNA synthesis in human lymphocytes  in vitro.

    The induction  in vitro of chromosomal aberrations and
    sister-chromatid exchanges in Chinese hamster ovary (CHO) cells by
    1,4-DCB was studied by Galloway et al. (1985). Experiments were
    carried out with, and without, S9 from the livers of male rats
    induced with Aroclor(R) 1254. No chromosomal effects were
    reported. Using cultured Chinese hamster lung fibroblast cells,
    with, and without, activation by S9 from livers of rats induced with
    the PCB KC-400, Sofuni et al. (1985) reported that treatment with
    1,4-DCB, 1,2,3-TCB, 1,2,4-TCB, or 1,3,5-TCB did not cause
    chromosomal aberrations.

    In unpublished studies reviewed by the Task Group, 1,4-DCB did not
    induce mutation at the HGPRT locus in CHO cells (Bayer, 1986a),
    unscheduled DNA synthesis in HeLa cells (Milone, 1986a), or
    chromosome aberrations in human lymphocytes (Milone, 1986b), in
    either the presence or absence of an exogenous metabolic activation
    system. 1,4-DCB did not induce cell transformation in the Balb/3T3
    assay (Bayer, 1986b).

    8.6.2  In vivo tests on experimental animals

    Very few studies have been reported on the  in vivo genotoxicity of
    chlorobenzenes.

    No increase in micronucleated red blood cells was reported after
    oral administration to male mice of 600, 900, 1000, 1500, or 1800 mg
    1,4-DCB/kg body weight, by gavage, for 5 days/week, over 13 weeks.
    Female mice were similarly treated with 1200, 1500, or 1800 mg/kg
    body weight (NTP, 1987). These results support those from a
    previously unpublished study, reviewed by Loeser & Litchfield
    (1983), in which treatment of rats, via inhalation with doses of
    1,4-DCB as high as 4092 mg/m3 (682 ppm) for 2 h/day, or 3000
    mg/m3 (500 ppm) for 5 h/day, over 3 months, did not result in any
    increase in chromosomal abnormalities in bone marrow cells.

    A study of the clastogenic activity of halogenated benzenes in mice
    has been published by Mohtashamipur et al. (1987). MCB, 1,2-, 1,3-,
    or 1,4-DCB, or 1,2,3-, 1,2,4-, or 1,3,5-TCB, administered by
    intraperitoneal injection in corn oil to groups of 5 mice, resulted
    in a dose-related increase in the formation of micronucleated
    poly-chromatic erythrocytes. The doses used were between
    approximately 15 and 70% of the respective LD50s, given in 2
    doses, separated by a 24-h period.  Bone marrow samples were taken
    30 h after the first injection. Doses were similar to those given by
    gavage for 13 weeks in other studies (NTP, 1987). However, this
    result was not confirmed in studies by other workers, also using the
    interperitoneal route (Heibold, 1988). Groups of mice were
    administered doses of 2 x 177.5 and 2 x 355 mg/kg in solution in
    corn oil, intraperitoneally (doses similar to those inducing an
    effect in the study by Mohtashamipur et al., 1987). The two doses
    were given 24 h apart, and the cells were harvested 6 h later.

    Evidence of a reduction in erythropoiesis was seen at both dose
    levels; however, there was no indication of micronuclei induction at
    either dose level. The ability of orally administered 1,4-DCB to
    produce micronuclei in bone marrow has also been investigated
    (Heibold, 1986). There was no evidence of any increase in
    micronuclei following the administration of a single oral dose of
    2500 mg/kg body weight and the harvesting of the bone marrow at 24,
    48, and 72 h.

    The ability of 1,4-DCB to produce unscheduled DNA synthesis (UDS) in
    the liver, or effects on DNA replication (S phase), was investigated
    following oral exposure of B6C3F1 mice to the compound (Steinmetz
    & Spanggord, 1987). Mice were given doses of 300, 600, or 1000 mg
    1,4-DCB/kg body weight in corn oil and hepatocytes were harvested 16
    and 48 h later. There was no evidence of any increase in UDS at any
    of the dose levels studied. The small increase in S-phase DNA
    replication seen was statistically significant in males only. These
    data indicate that 1,4-DCB does not produce DNA damage in the mouse
    liver following oral exposure.

    The production of chromosome damage in the bone marrow of mice by
    1,4-DCB has been investigated by a number of workers. Negative
    results were obtained in all except one case. In addition, negative
    results were obtained in an assay of DNA damage (UDS) in the liver
    of mice following oral exposure to 1,4-DCB. These results indicate
    that 1,4-DCB does not have any mutagenic potential in  in vivo
    studies.

    MCB and 1,4-DCB bind covalently to DNA in the mouse liver, kidney,
    and lung, while only MCB binds to the DNA in rat tissue (Grilli
    et al., 1985; Lattanzi et al., 1989). The levels of binding for both
    compounds are low.

    8.6.3  Human in vivo studies

    Workers in a pathology laboratory (8 male/18 female, average age 35
    years) were accidently exposed to vapours of 1,2-DCB, for 8 h/day,
    over 4 days. Chromosome analyses on peripheral leukocytes revealed a
    marked increase in chromosomal aberrations compared with controls.
    The controls (8 male/8 female, average age 34 years) were from other
    pathology laboratories where the occupational exposures to chemicals
    were similar to that of the DCB-exposed population. In the 1345
    cells studied in the exposed workers, 120 exhibited chromosomal
    alterations (84 single breaks and 86 double breaks) compared with 19
    cells with aberrations in the 942 cells examined in the control
    group. Analyses carried out 6 months after exposure indicated that
    the alterations were reversible (Zapata-Gayon et al., 1982).
    Although no air monitoring was carried out, the symptoms reported by
    22 out of the 26 subjects were consistent with those produced at
    exposure levels in excess of 600 mg/m3 (100 ppm), described by
    Hollingsworth et al. (1958).

    In workers (24 male/1 female) producing 1,2,4,5-TeCB in a chemical
    plant, in which several organochlorine and organophosphorus
    pesticides were also produced, there were increases (significance
    not reported) in the total number of chromatid gaps and breaks,
    labile chromosome-type aberrations (acentric fragment, ring
    chromosomes, and dicentric chromosomes), and stable chromosome-type
    aberrations (deletions, inversions, and translocations), compared
    with those in 14 workers from another type of factory and 49
    unexposed controls. No workplace monitoring for exposure levels was
    carried out and workers were exposed to several other compounds.
    Thus, it is difficult to assess the potential risks in other groups
    exposed to TeCB on the basis of these results (Kiraly et al., 1979).

    8.7  Developmental and Reproductive Effects

    The results of studies concerning the embryotoxicity, fetotoxicity,
    teratogenicity, and reproductive effects of the chlorobenzenes are
    presented in Table 24. Effect levels derived in these studies for
    both mothers and offspring are also presented in this table. In
    contrast to the lack of information on acute, short-term, long-term,
    and carcinogenic effects, comparatively more data are available on
    the potential embryotoxic, fetotoxic, and teratogenic effects of the
    higher chlorinated benzenes. Furthermore, the TCBs, TeCBs, and PeCB
    have been better studied in this regard than MCB and the isomers of
    DCB.

    There has been no evidence in any of the studies conducted to date
    that the chlorobenzenes (mono- to penta-) are teratogenic in animal
    species. Some relatively minor embryotoxic and fetotoxic effects
    have been observed for the lower chlorinated benzenes (MCB and
    DCBs), but only at dose levels that were toxic for the mother. For
    example, there was a slight delay in skeletal development
    (ossification) in the fetuses of pregnant rats exposed to 2864 mg
    MCB/m3, a dose that induced decreases in body weight gain in the
    mothers (John et al., 1984). Similarly, the ossification of cervical
    vertebrae in fetuses of pregnant rats exposed to 2400 mg
    1,2-DCB/m3 was delayed; this dose also induced decreases in body
    weight gain and food consumption in the mothers (Hayes et al.,
    1985). However, in both of these studies, there was no convincing
    evidence of embryotoxic, fetotoxic, or teratogenic effects in
    rabbits exposed to MCB or 1,2-DCB via inhalation, even at dose
    levels that were maternally toxic (John et al., 1984; Hayes et al.,
    1985). In fetuses of pregnant rabbits exposed to 4720 mg
    1,4-DCB/m3, there was an increase in the incidence of
    retro-oesophageal right subclavian artery, a minor variation in the
    circulatory system that is often observed in control litters; at
    this dose, the maternal body weight gain was also decreased (Hayes
    et al., 1985). In an additional study, Giavini et al. (1986)

    administered 1,4-DCB, in corn oil, by gavage, at doses of 250, 500,
    750, or 1000 mg/kg body weight per day, between days 6 and 15 of
    gestation. Effects were noted only at doses greater than 500 mg/kg
    per day. These included an increased frequency of extra ribs, a
    reduction in fetal weight, and an increase in skeletal
    abnormalities. These dose levels also induced decreases in body
    weight gain and food consumption in the mothers.

    There is some evidence that the higher chlorinated benzenes (TCBs,
    TeCBs, PeCB) are embryotoxic or fetotoxic at dose levels that are
    not maternally toxic. However, available data are not consistent and
    the toxicities of the various isomers of the TCBs and TeCBs for the
    mother and fetus vary considerably. For example, the 1,2,4-isomer
    was the most maternally toxic of the 3 TCB isomers administered by
    ingestion to pregnant rats in a study conducted by Black et al.
    (1988); changes in haematological parameters occurred at doses as
    low as 150 mg/kg per day. At a lower dose (75 mg/kg), there were
    mild histological changes in the lenses of pups of exposed mothers;
    however, these changes were not observed at higher doses (150 or
    300 mg/kg) and were unlikely, therefore, to be treatment-related.
    Kitchin & Ebron (1983a) observed growth retardation in the embryos
    of pregnant rats administered 360 mg 1,2,4-TCB/kg body weight on
    days 9-13, a dose that caused some lethality, reduced body weight
    gain, and produced moderate hepatocellular hypertrophy in mothers.

    Although less toxic for the mothers than 1,2,4-TCB, the 1,3,5-isomer
    of trichlorobenzene induced mild changes in the lenses of pups of
    pregnant rats administered doses as low as 150 mg/kg body weight by
    gavage; there was no significant maternal toxicity at this dose
    (Black et al., 1988). For the 1,2,3-isomer, there were no effects in
    offspring at any dose level (up to 600 mg/kg body weight), even
    though a level of 300 mg/kg was toxic to the mothers. The authors of
    this study did not discuss the significance of the observed
    histological changes in the lenses (areas of cellular disorientation
    and disaggregation with ballooning and granular degeneration) of the
    pups of mothers administered the 1,3,5-isomer, but concluded that
    there was no evidence that any of the TCB congeners were teratogenic
    or fetotoxic.

    Kacew et al. (1984) reported that the 1,2,4,5-isomer was the most
    toxic of the TeCBs for both mothers and fetuses, in a study in which
    all 3 isomers were administered to pregnant rats by gavage (death of
    9/10 animals at 200 mg/kg and increase in serum cholesterol at
    50 mg/kg body weight). The toxicity was well correlated with the
    greater accumulation of 1,2,4,5-TeCB in maternal and fetal tissues.
    There was a decrease in the number of live fetuses in pregnant rats
    administered 50 mg 1,2,4,5-TeCB/kg body weight, a dose that induced
    minor changes (increases in serum cholesterol) in exposed mothers.


    
    Table 24.  Developmental and reproductive studies on chlorobenzenes
                                                                                                                                              

    Compound;     Speciesa              Doseb,c                        Resultsd                                               Effect Levelse
    Reference
                                                                                                                                              

    Developmental Studies:
      Inhalation

    MCB           Fischer 344 rat       rats: 0, 341, 955, or          rats: maternal toxicity (decreased body weight gain    955 mg/m3 (F);
     (99.98%)     (pregnant),           2684 mg/m3 (0, 75, 210, or     and increased liver weight) at 2684 mg/m3 - slight     (NOEL);
     John et al.  32-33/group;          590 ppm), 6 h/day on days      delay in skeletal development (ossification) in        2684 mg/m3 (F)
     (1984)       New Zealand white     6-15 of gestation; rabbits:    fetuses at this dose; rabbits: maternal toxicity       *2684 mg/m3
                  rabbit, (pregnant),   0, 341, 955 or 2684 mg/m3      (increased liver weight) at >2684 mg/m3; significant   (O) (LOAEL)
                  30-32/group           (0, 75, 210, or 590 ppm)       increase in resorptions at 2684 mg/m3 (second
                                        6 h/day on days 6-18 of        study), but within historical range; no
                                        gestation; or rabbits: 0,      treatment-related effects on fetus
                                        45, 136, 341, or 2684 mg/m3
                                        (0, 10, 30, 75 or 590 ppm)
                                        6 h/day on days 6-18 of
                                        gestation

    1,2-DCB       Fischer 344 rat       rats: 0, 600, 1200, or         rats: maternal toxicity at all doses; increased        rats:
     (98.81%)     (pregnant),           2400 mg/m3, 6 h/day on days    liver weight at 2400 mg/m3; significant increase in    600 mg/m3 (F);
      Hayes       30-32/group;          6-15 of gestation; rabbits:    spurs on first lumbar vertebra and delayed             *2400 mg/m3
      et al.      New Zealand white     doses as above - on days 6-18  ossification of sternebrae in fetuses at 1200 mg/m3    (O) (LOAEL)
      (1985)      rabbit (pregnant),    of gestation                   not considered to be treatment related; delayed
                  28-30/group                                          ossification of cervical vertebra centra in fetuses    rabbits:
                                                                       at 2400 mg/m3; rabbits: maternal toxicity (decreased   *2400 mg/m3
                                                                       body weight gain) at all doses; ratio of male:female   (O) (NOEL);
                                                                       offspring significantly different from 50:50 at 1200   600 mg/m3 (F)
                                                                       mg/m3 not considered to be treatment related; no       (LOAEL)
                                                                       other embryotoxic, fetotoxic or teratogenic effects
                                                                                                                                              

    Table 24 (continued)
                                                                                                                                              

    Compound;     Speciesa              Doseb,c                        Resultsd                                               Effect Levelse
    Reference
                                                                                                                                              

    1,4-DCB       New Zealand white     0, 590, 1770, or               slight maternal toxicity (decreased body weight        1770 mg/m3 (F)
     (99.9%)      rabbit (pregnant),    4720 mg/m3, 6 h/day on days    gain) at 4720 mg/m3; significant increase in           (NOEL)
      Hayes       29-30/group           6-18 of gestation              retroesophageal right subclavian artery at 4720        4720 mg/m3 (F)
      et al.                                                           mg/m3, not considered to be a teratogenic response     *4720 mg/m3
      (1985)                                                                                                                  (O) (LOAEL)

    1,4-DCB       SPF rat (pregnant),   0, 450, 1200, or               no evidence of maternal toxicity, embryo-, or
      Loeser &    20/group              3000 mg/m3 (0, 75, 200 or 500  fetotoxicity or teratogenicity
      Litchfield                        ppm), 6 h/day on days 6-15
      (1983)                            of gestation

    Developmental Studies:
      Ingestion

    1,4-DCB       CD rat (pregnant),    0, 250, 500, 750, or           maternal toxicity (decreased body weight gain and      250 mg/kg per
      Giavini     11-16/group           1000 mg/kg per day on days     food consumption) at >500 mg/kg; reduction in fetal    day (F) (NOEL)
      et al.                            6-15 of gestation; gavage in   weight at 1000 mg/kg per day; fetotoxic effects        500 mg/kg per
      (1986)                            corn oil                       included increase in fetal skeletal variations at      day (F)
                                                                       >750 mg/kg, dose-related increase in the frequency     *500 mg/kg per
                                                                       of extra ribs at >500 mg/kg                            day (O)
                                                                                                                              (LOAEL)

    1,2,3-TCB     Sprague-Dawley rat    1,2,4-TCB: 0, 75, 150, or      maternal toxicity - reduced body weight gain at 600    1,2,3-TCB:
    1,2,4-TCB     (pregnant); 14/group  300 mg/kg per day; 1,2,3-TCB   mg/kg (1,3,5-TCB), increased liver weight at 600       300 mg/kg per
    1,3,5-TCB                           and 1,3,5-TCB: 0, 150, 300 or  mg/kg (1,2,3- and 1,3,5-TCB) and 300 mg/kg             day (F);
     (99.5%)                            600 mg/kg per day on days      (1,2,4-TCB), decreased haemoglobin levels and          *600 mg/kg per
      Ruddick                           6-15 of gestation; gavage in   haematocrit, generally at highest dose (all 3          day (O) (NOEL)
      et al.                            corn oil                       isomers), decreased RBC at 300 mg/kg (1,2,3-TCB),
      (1983);                                                          150 and 300 mg/kg (1,2,4-TCB), and 150 and             1,2,4-TCB:
                                                                                                                                              

    Table 24 (continued)
                                                                                                                                              

    Compound;     Speciesa              Doseb,c                        Resultsd                                               Effect Levelse
    Reference
                                                                                                                                              

      Black                                                            600 mg/kg (1,3,5-TCB), mild treatment-related          75 mg/kg per
      et al.                                                           histopathological changes in spleen, liver, and        day (F);
      (1988)                                                           thyroid, generally at highest dose (all three          *300 mg/kg per
                                                                       isomers); mild histological changes in the lenses of   day (O)
                                                                       pups at all doses (1,3,5-TCB) and 75 mg/kg             (NOEL);
                                                                       (1,2,4-TCB); no significant accumulation in maternal   150 mg/kg per
                                                                       or fetal tissue                                        day (F)
                                                                                                                              (LOAEL)
                                                                                                                              1,3,5-TCB:
                                                                                                                              300 mg/kg per
                                                                                                                              day (F)
                                                                                                                              (NOEL);
                                                                                                                              150 mg/kg per
                                                                                                                              day (O)
                                                                                                                              (LOEL);
                                                                                                                              600 mg/kg per
                                                                                                                              day (F)
                                                                                                                              (LOAEL)

    1,2,4-TCB     Sprague-Dawley CD     0, 36, 120, 360, or            maternal toxicity - all animals died at                120 mg/kg per
     (>99%)       rat (pregnant);       1200 mg/kg per day on days     1200 mg/kg, some lethality and reduced body weight     day (F)
     Kitchin      >6/group              9-13 of gestation; gavage in   gain at 360 mg/kg, moderate hepato- cellular           (NOEL);
     & Ebron                            corn oil                       hypertrophy at 360 mg/kg, and moderate to severe       360 mg/kg per
     (1983a)                                                           multifocal hepatic necrosis at 1200 mg/kg;             day (F);
                                                                       embryonic growth retardation at 360 mg/kg              *360 mg/kg per
                                                                                                                              day (O)
                                                                                                                              (LOAEL)
                                                                                                                                              

    Table 24 (continued)
                                                                                                                                              

    Compound;     Speciesa              Doseb,c                        Resultsd                                               Effect Levelse
    Reference
                                                                                                                                              

    1,2,3,4-TeCB  Sprague-Dawley        0, 50, 100, or 200 mg/kg per   maternal toxicity - death of 9/10 animals at           1,2,3,4-TeCB:
    1,2,3,5-TeCB  rat (pregnant);       day on days 6-15 of            200 mg/kg and increased serum cholesterol at >50       200 mg/kg per
    1,2,4,5-TeCB  10/group              gestation; gavage in corn oil  mg/kg (1,2,4,5-TeCB); greater toxicity of              day (F)
     (99.5%)                                                           1,2,4,5-TeCB correlated with its accumulation in       (NOEL);
     Kacew                                                             tissue; decrease in number of live fetuses at          200 mg/kg per
     et al.                                                            200 mg/kg (1,2,3,4-TeCB, 1,2,3,5-TeCB); decrease in    day (O)
     (1984)                                                            number of live fetuses at 50 mg/kg (1,2,4,5-TeCB),     (LOAEL)
                                                                       probably not treatment-related
                                                                                                                              1,2,3,5-TeCB:
                                                                                                                              200 mg/kg per
                                                                                                                              day (F)
                                                                                                                              (NOEL);
                                                                                                                              200 mg/kg per
                                                                                                                              day (O)
                                                                                                                              (LOAEL)

                                                                                                                              1,2,4,5-TeCB:
                                                                                                                              *50 mg/kg per
                                                                                                                              day (O)
                                                                                                                              (LOEL);
                                                                                                                              50 mg/kg per
                                                                                                                              day (F)
                                                                                                                              (LOAEL)

    1,2,4,5-TeCB  Sprague-Dawley CD     0, 30, 100, 300, or            maternal toxicity - decrease in body weight gain       300 mg/kg per
     (>98%)       rat (pregnant)        1000 mg/kg per day on days     and slight centrilobular hypertrophy (3/9) at          day (F);
     Kitchin &                          9-13 of gestation; gavage      1000 mg/kg; no embryo- or fetotoxic effects            *1000 mg/kg
     Ebron                              in 1.5% gum tragacanth         or evidence of teratogenicity                          per day (O)
     (1983c)                                                                                                                  (NOEL);
                                                                                                                                              

    Table 24 (continued)
                                                                                                                                              

    Compound;     Speciesa              Doseb,c                        Resultsd                                               Effect Levelse
    Reference
                                                                                                                                              

                                                                                                                              1000 mg/kg per
                                                                                                                              day (F)
                                                                                                                              (LOAEL)

    1,2,3,4-TeCB  Sprague-Dawley CD     0, 100, 300, or 1000 mg/kg     maternal toxicity - death of 7/19 animals, decrease    100 mg/kg per
     (>98%)       rat (pregnant)        per day on days 9-13 of        in body weight gain and liver weight, and minimal      day (F)
     Kitchin &                          gestation; gavage in 1.5% gum  to moderate hepatocellular hypertrophy (2/9) at        (NOEL);
     Ebron                              tragacanth                     1000 mg/kg, death of 1/10 and minimal                  300 mg/kg per
     (1983b)                                                           hepatocellular hypertrophy (2/9) at 300 mg/kg;         day (F);
                                                                       decrease in yolk sac diameter, embryonic crown-rump    *300 mg/kg per
                                                                       length and head length, at 300 mg/kg (not examined     day (O)
                                                                       at 1000 mg/kg because of maternal lethality)           (LOAEL)

    PeCB          Wistar rat            0, 50, 100, or 200 mg/kg per   maternal toxicity - non-significant reduction in       200 mg/kg per
      Villeneuve  (pregnant) 20/group   day on days 6-15 of            body weight gain at 200 mg/kg; increased incidence     day (F)
      & Khera                           gestation; gavage in corn oil  of extra ribs at >50 mg/kg, and sternal defects and    (NOAEL);
      (1975)                                                           decreased fetal weight at 200 mg/kg                    50 mg/kg per
                                                                                                                              day (O) (LOEL)

    PeCB          CD-1 mouse            0, 50, or 100 mg/kg per day on maternal toxicity - increase in liver weight (both     *100 mg/kg per
     (>97%)       (pregnant); 9-10      days 6-15 of gestation; oral - doses); no embryotoxic, fetotoxic, or teratogenic      day (O)
     Courtney     litters/group (6      gastric intubation in corn oil effects                                                (NOEL);
     et al.       litters - control                                                                                           50 mg/kg per
     (1977)       group)                                                                                                      day (F)
                                                                                                                              (LOAEL)
                                                                                                                                              

    Table 24 (continued)
                                                                                                                                              

    Compound;     Speciesa              Doseb,c                        Resultsd                                               Effect Levelse
    Reference
                                                                                                                                              

    Reproductive Studies:
       Inhalation

    MCB           Sprague-Dawley CD     0, 50, 150 or 450 ppm for 10   hepatocellular hypertrophy and renal changes in F0
      Nair        rat; 30 of each       weeks prior to mating through  and F1 males (>150 ppm); incidence of bilateral
      et al.      sex/group             weaning of the F2 generation   degeneration of the testicular germinal epithelium
      (1987)                                                           increased in F0 adults at 450 ppm but relation to
                                                                       MCB unclear since not observed in F1.

    Reproductive Studies:
       Ingestion

    1,2,4-TCB     Charles River rat     0, 25, 100, or 400 mg/kg       no effects on fertility, growth, viability,            approx.
      Robinson    (pregnant); 17-23     (during pregnancy through to   locomotor activity or blood chemical analyses;         50 mg/kg per
      et al.      litters/group         weaning of F2 generation). For decrease in water intake of some F0 groups at          day (F)
      (1981)                            F0, doses ranged from 8.3-134  400 mg/kg; enlarged adrenals in F0 and F1 at 95        (NOEL);
                                        mg/kg at day 29 and 2.5-54     days at 400 mg/kg                                      approx.
                                        mg/kg at day 83 (mating at day                                                        50 mg/kg per
                                        90); mixed with Tween 20 in                                                           day (O)
                                        drinking-water                                                                        (LOAEL)

    PeCB          Sherman rat; 10       females: 7-150 mg/kg per day   maternal toxicity - increased liver weight and         approx.
     (99.1%)      of each sex/group     (0, 125, 250, 500, or 1000     hypertrophy of hepatic cells at >500 mg/kg,            17-31 mg/kg
      Linder                            ppm), 180 days (from 4-5       decreased haemoglobin levels at 1000 mg/kg and         per day (F)
      et al.                            weeks of age to mating,        dose-dependent accumulation in adipose tissue;         (NOEL);
      (1980)                            through gestation and          pre-weaning growth rates decreased at higher           approx.
                                                                                                                                              

    Table 24 (continued)
                                                                                                                                              

    Compound;     Speciesa              Doseb,c                        Resultsd                                               Effect Levelse
    Reference
                                                                                                                                              

                                        lactation) males: 6-140        concentrations, tremors in suckling pups at            17-31 mg/kg
                                        mg/kg per day (0, 125, or      >250 mg/kg and significant mortality in pups at        per day (O);
                                        1000 ppm), 100 days (through   1000 mg/kg                                             approx.
                                        mating); diet                                                                         27-64 mg/kg
                                                                                                                              per day (F)
                                                                                                                              (LOAEL)
                                                                                                                                              

    a    and number of animals/group specified, where available.
    b    Vehicle specified, where available.
    c    Doses given as mg/kg body weight, unless specified otherwise.
    d    RBC - red blood cells.
         F - females.
         O - offspring.
    e    NOEL - no-observed-effect level.
         NOAEL - no-observed-adverse-effect level.
         LOEL - lowest-observed-effect level.
         * - maternally toxic dose.

    

    However, the decrease in the number of live fetuses was not observed
    at a higher concentration of 1,2,4,5-TeCB (100 mg/kg body weight)
    and, therefore, may not have been treatment-related. The only toxic
    effect observed in the mothers or fetuses, when pregnant rats
    ingested either the 1,2,3,4- or the 1,2,3,5-isomer, was a decrease
    in the number of live fetuses at the highest dose (200 mg/kg body
    weight).

    In contrast, Kitchin & Ebron (1983b) reported that the
    1,2,3,4-isomer of TeCB was more toxic for both mothers and fetuses
    than the 1,2,4,5-isomer (Kitchin & Ebron, 1983c). The LOAEL in
    mothers administered the 1,2,3,4-isomer by gavage, was 300 mg/kg
    body weight; the LOAEL for the 1,2,4,5-isomer was 1000 mg/kg
    (compared with 50 mg/kg in the study of Kacew et al., 1984).
    Embryonic growth retardation was observed in offspring administered
    the maternally toxic dose (300 mg/kg body weight) of the
    1,2,3,4-isomer, only.

    For pentachlorobenzene, Villeneuve & Khera (1975) reported an
    increased incidence of extra ribs in the fetuses of pregnant rats
    administered oral doses as low as 50 mg/kg body weight, and an
    increased incidence of sternal defects and decreased fetal weight
    following ingestion of 200 mg/kg; these doses did not induce
    significant toxic effects in the mothers. The results contrast with
    those of Courtney et al. (1977) in which increases in liver weights
    were observed in pregnant mice administered 50 or 100 mg PeCB/kg,
    but no embryotoxic, fetotoxic, or teratogenic effects.

    The possible reproductive effects of the chlorobenzenes have not
    been well studied; only 3 relevant studies have been conducted.
    There were no treatment-related adverse reproductive effects in a 2-
    generation study in which rats were exposed via inhalation to MCB at
    227.5, 682.5, or 2047.5 mg/m3 (50, 150, or 450 ppm), though there
    was evidence of hepatotoxicity and nephrotoxicity in male rats in
    the F0 and F1 generations (Nair et al., 1987). Robinson et al.
    (1981) did not find any significant effects on fertility, growth,
    viability,  locomotor activity,  or the chemical composition of the
    blood in rats administered 1,2,4-TCB, at levels of up to
    approximately 54 mg/kg, during pregnancy and through to weaning of
    the F2 generation. However, enlarged adrenal glands were observed
    in the F0 and F1 generations at 95 days in the highest dose
    group.

    When rats were administered PeCB in the diet from 4 to 5 weeks of
    age, and during gestation and lactation, Linder et al. (1980) noted
    maternal toxicity (LOAEL approx. 27-64 mg/kg per day), tremors in
    suckling pups (LOAEL approx. 17-31 mg/kg per day), and, at higher
    doses, decreases in pre-weaning growth rates, and mortality of pups.

    9. EFFECTS ON HUMANS

    9.1  Case Reports

    9.1.1  General population exposure

    Data on the health effects of exposure of the general population to
    chlorobenzenes are restricted to case reports mainly concerning
    accidental exposure to, or misuse of, products containing the lower
    chlorinated benzenes (MCB, 1,2- or 1,4-DCB, and an unspecified
    isomer of TCB). Many of these reports are from the early literature
    with no indication of the purity of the chlorobenzene or the actual
    dose/time relationship.

    Reversible acute effects on the central nervous system (loss of
    reflexes, cyanosis leading to unconsciousness, with head and neck
    twitching) were observed in a 2-year-old boy following the ingestion
    of 5-10 ml of MCB (Reich, 1934). An adult female showed nausea,
    shortness of breath, sleepiness, and haematuria, 1 week after an
    acute exposure to DCB used as a termiticide (Nill, 1936). Two cases
    of acute myeloblastic leukaemia were reported in females who had
    been repeatedly exposed (over 1 year) to DCBs (primarily 1,2-DCB)
    during its use as a cleaning solution (Girard et al., 1969). There
    have been numerous case reports of adverse effects of 1,4-DCB,
    because of its availability to the public as a moth repellent and
    air freshener. Reported effects of acute or short-term exposure (all
    of which were reversible) include acute haemolytic anaemia
    (Hallowell, 1959; Campbell & Davidson, 1970), respiratory irritation
    (rhinitis) (Cotter, 1953), and allergic purpura of the skin and
    glomerulonephritis (Nalbandian & Pearce, 1965). Effects on the lungs
    (pulmonary granulomatosis), (Weller & Crellin, 1953), blood
    (anaemia), central nervous system effects including dizziness,
    numbness, and incoordination, "mental sluggishness", tremor, and
    polyneuritis (Frank & Cohen, 1961), and liver damage, including
    yellow atrophy and jaundice (Berliner, 1939; Cotter, 1953) have been
    recorded in case reports of persons exposed to 1,4-DCB for prolonged
    periods (several months to 15 years) .  Limb and truncal ataxia,
    dysarthria, hyporeflexia, hypotonus, and mild proximal limb weakness
    were reported in a 25-year-old woman exposed to 1,4-DCB during a
    period of 6 years,  under very unusual circumstances, i.e., through
    extensive use of mothballs in her bedclothes and wardrobe. She
    developed difficulty in speech and gait. Exposure was not
    quantified, but was probably high, according to the observed effects
    and reported use (Miyai et al., 1988).

    There has also been a case report of aplastic anaemia in a
    68-year-old woman with long-term exposure through the soaking of her
    husband's work clothes in TCB (isomer not identified) (Girard
    et al., 1969).

    9.1.2  Occupational exposure

    Most of the available data on the adverse effects of occupational
    exposure to chlorobenzenes come from case reports. Many of these
    cases are poorly described with regard to chemical purity, dose/time
    relationships, and possible confounding factors, and thus provide
    very little information relevant to the assessment of human health
    risks.

    Case reports concerning MCB in occupationally exposed populations
    have been restricted to symptoms of effects on the central nervous
    system (headaches, numbness, and lethargy) and irritation of the
    eyes and upper respiratory tract (Girard et al., 1969) after
    exposures for periods of up to 6 years, in the presence of several
    other chemicals.

    In workers exposed to 1,2-DCB, or mixtures of chlorobenzenes
    containing mainly 1,2-DCB, there have been case reports of:
    haematological disorders, including anaemia in 1 male worker filling
    barrels for 8 years (Girard et al., 1969; US EPA, 1985); chronic
    lymphoid leukaemia (2 cases) after inhalation exposures of 10 and 16
    years, respectively (Girard et al., 1969); and myelocytic/
    myeloblastic leukaemia (1 case) after 22 years in a dyestuff plant
    (Tolot et al., 1969).

    In workers exposed to 1,4-DCB, probably often in combination with
    several other chemicals, there have been case reports of
    haemato-logical disorders, including anaemia (Petit & Champeix,
    1948; Cotter, 1953; Harden & Baetjer, 1978); splenomegaly (2 cases)
    (Sumers et al., 1952; Cotter, 1953); effects on the gastrointestinal
    tract (Sumers et al., 1952; Cotter, 1953; Wallgren, 1953); drying or
    hardening of the skin (Cotter, 1953; Harden & Baetjer, 1978); and
    symptoms of effects on the CNS, including finger tremors, stronger
    muscle reflexes, and ankle contractions (Wallgren, 1953).

    Only two case reports have been identified concerning
    trichloro-benzene. Ehrlicher (1968) reported massive haemoptysis in
    an adult male who had inhaled TCB vapours for several hours, during
    the repair of a pump, and Popovki et al. (1980) reported 7 cases of
    chloracne in 15 TCB production workers, exposed for 2-6 months.
    However, the isomer was not specified in either report, and no
    details of confounding factors and doses received were available for
    evaluation.

    9.2  Epidemiological Studies

    Only a few epidemiological studies have been carried out on workers
    exposed to chlorobenzenes other than hexachlorobenzene. Many of
    these studies have been carried out on groups of workers
    simultaneously exposed to other chemicals with known adverse effects
    on man (e.g., benzene, aromatic and/or chlorinated solvents).
    Furthermore, most of the studies have not been fully described with
    regard to methods and confounding factors, making them inadequate
    for use in risk assessments.

    In an early cross-sectional study, 3 groups of workers were examined
    for the general adverse effects of solvent vapours during the
    production of perchlorovinyl lacquer. Two health examinations were
    carried out in the course of 1 year. Group 1 included 28 workers (25
    of whom had been employed on the job for 1 year or more), reported
    to have been exposed only to chlorobenzene at levels ranging between
    0.034 and 1.44 mg/litre (Rozenbaum et al., 1947). Group 2 consisted
    of 12 workers in the central chemical laboratory working on
    long-term experiments with chlorobenzene. Group 3 included 14 female
    workers in the lacquer plant, who were exposed to benzene (0.02-0.4
    mg/litre) as well as to chlorobenzene (0.06-0.6 mg/litre). There was
    no unexposed control group. No significant adverse effects were
    reported for workers in Groups 2 and 3; however, workers in Group 1
    reported headaches, dizziness, drowsiness, and dyspeptic disorders.
    Numerical data concerning the prevalence of these disorders were not
    given.  No effects on "internal organs" that could be attributed to
    chlorobenzene exposure were noted; however, the first
    neuropathological examination indicated numbness and stiffness in
    the extremities of 8 workers, convulsive muscle contractions in the
    fingers of 9, and hypoaesthesia of the hand in 4. The deviations
    noted were reported to have returned to normal by the second
    examination.

    Workers producing enamel-insulated wire are exposed to both MCB and
    tricresol. An examination of 311 female workers for the possible
    effects of these chemicals on gynaecological and obstetrical
    functions was reported by Syrovadko & Malysheva (1977). Levels of
    exposure to MCB varied from 11 to 429 mg/m3 (mean, 72.3 mg/m3)
    and those to tricresol from 0.8 to 18.7 mg/m3 (mean, 4.3 mg/m3).
    Similar health parameters were examined in some 15 000 women in
    other occupations and the general population in the region. The
    frequency of various gynaecological dysfunctions was 2.6-9.4 times
    higher in the exposed workers than in women outside the plant, but
    was similar to that in the controls from within the enamel-wire
    plant. Lost-time was 2.5 times greater in the enamellers than in
    in-plant controls. The authors reported marked hormonal
    disturbances, but did not quantify these results. An analysis of 190
    births in the enameller group, and 152 from the in-plant controls,
    revealed an increase in birth anomalies (10 versus 3.9%) in the

    exposed group. Congenital heart defects (26.3%) were the most
    prevalent. Neonatal development appeared to be compromised in
    infants of exposed mothers, as evidenced by patterns of
    breast-feeding and body weight gain. These results are difficult to
    interpret, however, with respect to MCB, owing to concomitant
    exposure to another chemical and a lack of quantitative data.

    MCB was considered to be the causative agent in 26 out of 1951 cases 
    of  work-related  dermatosis observed  at  the  "Shanghai Institute
    for Occupational Disease Prevention in the Chemical Industry"
    between 1970 and 1982; reported manifestations were eczematous
    dermatitis, pigmentation, and neurodermatitis (Zong & Ma, 1985).

    In periodic medical examinations of 58 workers exposed to various
    concentrations of 1,4-DCB, there was no evidence of "organic injury
    or untoward haematological effects". It was concluded, however,
    that, at levels ranging between 300 and 480 mg/m3 (50 and 80 ppm),
    1,4-DCB was irritating to the eyes and nose, the irritation becoming
    severe at a level of 960 mg/m3 (160 ppm).  Details of the study
    design in this early investigation were incomplete (Hollingsworth et
    al., 1956).

    In the only identified cross-sectional epidemiological study of
    workers exposed to 1,2-DCB, there was no evidence of "organic injury
    or untoward haematological effects" in an unspecified number of
    workers exposed to mean levels of 90 mg/m3 (15 ppm) 1,2-DCB
    (Hollingsworth et al., 1958). However, details of the study design
    were not presented in the account of this early investigation.

    As described in section 8, there was an increase in the total number
    of chromosomal aberrations (primarily single and double breaks) in
    the peripheral leukocytes of 26 laboratory workers exposed for 4
    days, 8 h/day, to 1,2-DCB vapour compared with a control group of 11
    unexposed laboratory personnel (Zapata-Gayon et al., 1982). Of the
    white cells analysed (1345, exposed; 942, control), 8.92% of the
    exposed cells contained aberrations compared with 2.02% in the
    control group. In 15 exposed subjects examined at 6 months, only
    double breaks were significantly increased. Although mention was
    made of a strong odour of DCB in the room and all subjects suffered
    mucosal irritation, no determination of exposure levels was carried
    out.

    Only one study on workers exposed to TeCB was found. The peripheral
    lymphocytes of workers producing 1,2,4,5-TeCB in a
    pesticide-manufacturing complex were examined for chromosomal
    aberrations. Exposure levels were not reported; however, workers (24
    male and 1 female) were considered to be exposed to only TeCB and
    they were compared with 14 other workers, minimally exposed to
    chemicals, as well as a group from the local community. An increase

    (significance unspecified) in the total number of chromatid-type,
    labile (acentric fragment and dicentric chromosome), and stable
    (deletion, inversion, and translocation) chromosomal aberrations was
    reported. No follow-up studies of these findings have been reported.

    No case reports or epidemiological studies on workers exposed to
    PeCB were found.

    10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

    10.1  Evaluation of Human Health Risks

    10.1.1  Exposure of the general population

    Exposure to chlorobenzenes other than hexachlorobenzene may occur
    via ingestion, inhalation, or dermal contact (section 5.2.1). The
    general population is thought to be exposed to the lower chlorinated
    congeners mainly through inhalation, whereas a greater proportion of
    the total daily intake of the higher chlorinated compounds is
    ingested in food. Dermal exposure may occur if consumers use
    chlorobenzene-based products without appropriate care and
    protection.

    Exposure of the general population through the ingestion of
    drinking-water and food and via inhalation has been estimated (Table
    12). However, these estimates are based on few data from a limited
    number of countries and, therefore, must be considered tentative
    until further monitoring data become available.

    On the basis of the limited data available, the total daily intakes
    of MCB and the various DCB isomers are estimated to be less than 1
    µg/kg body weight. The intakes of the higher chlorinated benzenes
    are lower, probably, less than 0.05 µg/kg body weight per day.

    Dichlorobenzenes, TCBs, TeCBs, and PeCB have been detected in human
    milk, the DCBs (particularly the 1,4-isomer) being present in the
    highest concentrations. On the basis of the limited data available
    from a small number of countries, it is estimated that, on a body
    weight basis, the intake of chlorobenzenes in breast-fed infants is
    greater than that in the adult population,.

    10.1.2  Occupational exposure

    Very few data are available to serve as a basis for the estimation
    of occupational exposure. Air levels of MCB of up to 18.7 mg/m3
    have been detected in chemical plants, whereas levels of 1,4-DCB in
    one manufacturing plant averaged 204 mg/m3 (42-288 mg/m3). On
    the basis of established exposure limits, workers may be exposed
    daily to maximum concentrations of 350 mg/m3 for MCB, 450 mg/m3
    for 1,4-DCB, and 300 mg/m3 for 1,2-DCB.

    10.1.3  Toxic effects

    Acute lethal doses of the lower chlorinated benzenes (MCB and DCBs)
    in experimental animals cause narcosis and CNS depression, damage to
    the liver and kidneys, as well as respiratory paralysis. Inhalation
    LC50s for MCB have been reported to range from approximately
    9000 mg/m3 in mice to 13 000 mg/m3 in rats. Inhalation LC50
    values for 1,2-DCB are similar. With few exceptions, oral LD50
    values in the species examined to date have been >1000 mg/kg body
    weight for all congeners, and, according to the limited data
    available, dermal LD50s are higher.

    In general, effects following short-term and long-term exposures to
    chlorobenzenes are similar to those following acute exposure and
    include damage to the liver and kidneys, and, at higher doses,
    effects on the thyroid gland in rats and on the bone marrow in mice.

    Of the few chlorobenzenes tested, only 1,2,4-TCB has been shown to
    cause dermatitis after prolonged contact with skin.

    In a bioassay for the carcinogenicity of MCB, there was an increased
    incidence of hepatic neoplastic nodules in the high-dose group
    (120 mg/kg body weight) of male F344 rats, but no treatment-related
    increases in tumour incidence in female F344 rats or male and female
    B6C3F1 mice. There was no evidence for the carcino-genicity of
    1,2-DCB in male or female F344 rats or B6C3F1 mice (60 or
    120 mg/kg body weight).

    In a bioassay for the carcinogenicity of 1,4-DCB, there was a
    dose-related increase in renal tubular cell adenocarcinomas in male
    F344 rats and an increase in hepatocellular adenomas and carcinomas
    in both sexes of B6C3F1 mice. No evidence of carcinogenicity was
    reported in male and female Wistar rats or female Swiss mice
    following inhalation of slightly higher doses of 1,4-DCB (estimated
    to be 400 mg/kg per day for rats and 790 mg/kg per day for mice) for
    shorter periods of time. Available data indicate, however, that
    renal tumours in male F344 rats and the associated severe
    nephropathy and hyaline droplet formation, induced by 1,4-DCB, are
    species- and sex-specific responses associated with the
    re-absorption of alpha-2-microglobulin.

    Available data are inadequate to assess the carcinogenicity of the
    higher chlorinated benzenes (tri- to penta-).

    Although available data from  in vitro and  in vivo assays of
    isomers other than 1,4-DCB are limited, chlorobenzenes do not appear
    to be mutagenic. On the basis of a more extensive database for
    1,4-DCB, it can be concluded that this compound has no mutagenic
    potential, either  in vivo or  in vitro.

    In studies conducted to date, there has been no evidence that
    chlorobenzenes are teratogenic in animal species. Exposure of rats
    or rabbits to MCB or DCBs, via inhalation at levels exceeding
    2400 mg/m3, resulted in minor embryotoxic and fetotoxic effects.
    However, such doses were clearly toxic for the mother. Although
    there is some evidence that TCBs, TeCBs, and PeCB are embryo-toxic
    and fetotoxic at doses that are not toxic for the mother, available
    data are inconsistent.

    The lowest reported NOELs or LOAELs for each of the chlorobenzene
    isomers in long-term exposure studies and studies on chronic
    toxicity, teratogenicity, and developmental and reproductive
    toxicity, of acceptable design, are summarized in Table 25.

    Toxic effects in humans following acute exposures to MCB, 1,2-DCB,
    and 1,4-DCB include CNS depression, haematuria, haemolytic anaemia,
    rhinitis, tremor, ataxia, polyneuritis, and jaundice. No reports
    have been published on the possible health effects that might result
    from long-term exposures to low levels of chlorobenzenes in the
    general environment. Effects attributed to occupational exposures to
    chlorobenzenes have been confounded by exposures to several
    chemicals and the limitations of the epidemiological studies
    conducted to date; however, they include CNS depression, dermatitis,
    and eye and nose irritation. No dose-response data are available
    from these epidemiological studies.

    10.1.4  Risk evaluation

    The following is an example of a risk assessment procedure for
    setting Tolerable Daily Intakes (TDIs) for chlorobenzenes other than
    hexachlorobenzene. This is only an illustration and may need to be
    adjusted to take into account local considerations and any
    additional scientific data that are reported.

    10.1.4.1  General population

    The general population appears to be exposed to low levels of
    chlorinated benzenes (see Table 12, section 5). Exposure to the
    major chlorobenzenes other than hexachlorobenzene, for non-
    occupationally-exposed populations, is estimated to be less than 2
    µg/kg body weight per day. Over 90% of the total exposure is to MCB
    and DCBs, principally from air.

    For comparison with these estimated exposures, TDIs can be
    calculated from the no-observed-effect levels (NOELs) from
    long-term, chronic teratogenicity, and developmental reproductive
    toxicity studies on experimental animals.  TDIs, based on the lowest
    NOELs reported in studies of acceptable design, using uncertainty
    factors established on the basis of the principles outlined by WHO
    (1987), are listed in Table 26.

    Table 25. Summary of lowest reported NOELs (or LOAELs) for the
    inhalation and ingestion of chlorobenzenes other than
    hexachlorobenzene

    Inhalation
                                                                   
    Compound       Reported NOEL        Species          Exposure
                   (mg/m3)                               period
                                                                   
    MCB            341 (LOAEL)          rat, rabbit      24 weeks
    1,4-DCB        450                  rat; mousea      76 weeks
    1,3,5-TCB      100                  rat              13 weeks
    1,2,4-TCB      22.3                 rat              13 weeks
                                                                   

    Ingestion (dietary incorporation or gavage)
                                                                   
    Compound       Reported NOEL        Species          Exposure
                   (mg/kg body weight                    period
                   per day)
                                                                    
    MCB            60                   rat              103 weeks
    1,2-DCB        60                   mouse            103 weeks
    1,4-DCB        150 (LOAEL)          rat              103 weeks
    1,2,4-TCB      7.8                  rat              13 weeks
    1,2,3-TCB      7.7                  rat              13 weeks
    1,3,5-TCB      7.6                  rat              13 weeks
    1,2,4,5-TeCB   0.034                rat              13 weeks
    1,2,3,4-TeCB   3.4                  rat              13 weeks
    1,2,3,5-TeCB   0.42                 rat              13 weeks
    PeCB           3.3                  rat              13 weeks
                                                                   

    a = In this bioassay, only female mice were included.

    For most chlorobenzenes, the TDIs are based on non-neoplastic
    effects. Neoplastic effects were taken into consideration in the
    derivation of the uncertainty factors for MCB and 1,4-DCB. However,
    available data indicate that the observed increase in renal tumours
    in rats caused by 1,4-DCB is a species- and sex-specific response
    that is unlikely to be relevant to humans. It should be noted,
    however, that on the basis of evidence of increased DNA replication
    in the mouse liver, and the increased incidence of hepatocellular
    adenomas and carcinomas in mice in a bioassay for the
    carcinogenicity of 1,4-DCB, this compound may act as a non-genotoxic
    carcinogen in the rodent liver. On the basis of the increased
    incidence of hepatic neoplastic nodules observed in the high-dose
    group of male rats in a bioassay for the carcinogenicity of MCB,
    this may also be true for this compound.

    As stated above, with the exception of individuals who use
    chlorobenzene-based products without appropriate care and
    protection, non-occupationally exposed humans are exposed to levels
    of chlorobenzenes well below the derived TDIs, indicating that the
    anticipated health hazards for the general population from exposure
    to chlorobenzenes other than hexachlorobenzene are minimal. However,
    the odour thresholds of chlorobenzenes range between 0.1 and 3
    µg/litre in drinking-water, thus, necessitating continuous pollution
    control measures to ensure aesthetically acceptable water supplies.

    Table 26. Calculated Tolerable Daily Intakes for chlorobenzenes
    other than hexachlorobenzene

    Inhalation
                                                                 

    Compound       Reported NOEL        Uncertainty      Estimated
                   (mg/m3)              factor           TDIb
                                                                 
    MCB            341 (LOAEL)          1000             0.5
    1,4-DCB        450                  500              1
    1,3,5-TCB      100                  500              0.2
    1,2,4-TCB      22.3                 500              0.05
                                                                 

    Ingestion
                                                                 
    Compound       Reported NOEL        Uncertainty      Estimated
                   (mg/kg body weight   factor           TDIa
                   per day
                                                                 
    MCB            60                   500              0.1
    1,2-DCB        60                   100              0.60
    1,4-DCB        150 (LOAEL)          1000             0.1
    1,2,4-TCB      7.8                  500              0.02
    1,2,3-TCB      7.7                  500              0.02
    1,3,5-TCB      7.6                  500              0.02
    1,2,4,5-TeCB   0.034                500              0.0001
    1,2,3,4-TeCB   3.4                  500              0.01
    1,2,3,5-TeCB   0.42                 500              0.001
    PeCB           3.3                  500              0.01
                                                                 

    a = Values were rounded up according to the judgement of the
    panel.

    10.1.4.2  Occupationally exposed population

    Workers can be exposed to levels as high as 2.7 mg/kg body weight
    for MCB and 29.1 mg/kg body weight for 1,4-DCB. These estimates may
    not be representative, however, since they are based on only two
    reports.

    If good industrial hygiene practices are followed, the risks
    associated with occupational exposure to chlorobenzenes are
    considered to be minimal.

    10.2  Evaluation of Effects on the Environment

    10.2.1  Levels of exposure

    Chlorobenzene isomers have been found in air, surface water, ground
    water, drinking-water, municipal waste water, rain water, soils, and
    sediments. Most monitoring has been limited to levels in air and the
    aquatic environment.

    In surface waters,  levels of total chlorobenzenes are in the
    ng-µg/litre range; however, values as high as 0.1 mg/litre have been
    reported near industrial sources. Examples of levels in waste water
    average about 700 µg/litre for MCB and less than 170 µg/litre for
    the other congeners.

    10.2.2  Fate

    Chlorobenzenes released into the aquatic environment will become
    distributed preferentially to the air and to sediments (particularly
    organically rich sediments). Levels 1000 times those found in water
    have been detected in sediments, particularly those in highly
    industrialized regions, though available data are limited. The
    retention of chlorobenzenes in soil increases with the organic
    content of the soil; the degree of chlorination is positively
    correlated with adsorption.

    10.2.3  Bioavailability and bioaccumulation

    The bioavailability of chlorobenzenes is inversely correlated with
    the organic matter content of soil and sediment. Accumulation
    studies are limited, but organisms have been shown to accumulate
    chlorobenzenes from water, soil, and aquatic sediment. Adsorption on
    organic sediment increases with increasing level of chlorination,
    which may reduce bioavailability; however, uptake into, and
    retention by, organisms also increases with increasing level of
    chlorination.

    10.2.4  Degradation

    Chlorobenzenes are eliminated from the environment by both abiotic
    and biotic degradation, the latter appearing the more important. 
    Photolysis and hydrolytic reactions are possible processes, but
    aerobic degradation constitutes the major route of breakdown for the
    removal of chlorobenzene residues. Many microorganisms are capable
    of degrading chlorobenzenes (section 4.2.3, Table 6); however, the
    more highly chlorinated congeners are degraded microbiologically at
    a slower rate than the less chlorinated benzenes. This degradation
    does not appear to occur anaerobically.

    10.2.5  Persistence

    In water, chlorobenzenes are considered moderately persistent with
    half-times of approximately 1 day in rivers, 10 days in lakes, and
    more than 100 days in ground water. They are much more persistent
    under the anaerobic conditions usually found in sediment and ground
    water.

    10.2.6  Toxic effects on organisms

    The toxicities of chlorobenzenes for microorganisms, invertebrates,
    and fish are comparable; with a few exceptions, the EC50 and
    LC50 values fall within the several mg/litre range (Tables 16, 17,
    and 18). In general, toxicity increases with increased chlorination
    of the benzene ring. For example, in the bluegill sunfish
     (L. macrochirus), the following 96-h LC50 values were reported:
    MCB (>16 mg/litre); 1,2,4-TCB (3.4 mg/litre); 1,2,4,5-TeCB (1.6
    mg/litre) and PeCB (0.3 mg/litre).

    No data on the effects of chlorobenzenes on terrestrial biota were
    found; however, data from studies on laboratory mammals suggest a
    low risk for terrestrial mammals (see section 10.1.3).

    10.2.7  Risk evaluation

    There are insufficient data on  (a) the quantities of
    chlorobenzenes entering the environment and their subsequent
    dynamics, and  (b) toxicity studies on many chlorobenzene isomers,
    carried out under realistic environmental conditions. It is,
    therefore, impossible to predict quantitatively the impact on the
    environment of widespread low-level contamination by chlorobenzenes
    other than hexachlorobenzene.

    In virtually all instances within the aquatic ecosystem, the levels
    at which acute effects occur in experimental studies are many times
    higher than the environmental levels monitored at present (mg/litre
    range versus µg/litre range). Organisms will be exposed only
    transiently to chlorobenzenes in surface water (because of
    volatility and adsorption on sediment) and will be mainly exposed to
    chlorobenzenes in the interstitial water of sediments. Few studies
    on organisms living in sediments have been conducted, despite
    evidence for bioavailability. Similarly, there are no data on the
    transfer of chlorobenzenes in the food chain.

    Only in the case of accidental spills or uncontrolled industrial
    discharges would ambient concentrations approach toxic levels.
    However, the continued discharge of chlorobenzenes into the aquatic
    environment should be avoided, to prevent the build up of persistent
    residues in sediment and/or ground water.

    11.  CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH
         AND THE ENVIRONMENT

    11.1  Conclusions

    If good industrial practices are followed, the risks associated with
    occupational exposure to chlorobenzenes are considered to be
    minimal. The present risk assessment also indicates that current
    concentrations of chlorobenzenes in the environment pose a minimal
    risk for the general population, except in the case of the misuse of
    chlorobenzene-based products or uncontrolled discharge to the
    environment. However, this assessment is based on limited monitoring
    data; additional information is needed to substantiate this
    conclusion. The reduction of the widespread use and disposal of
    chlorobenzenes should, however, be considered because:

    *    Chlorobenzenes may act as precursors for the formation of
         PCDDs/PCDFs, e.g., in incineration processes;

    *    These chemicals can lead to taste and odour problems in
         drinking-water and fish;

    *    Residues persist in organically-rich anaerobic sediments and
         soils, and ground water.

    For most chlorobenzenes, the assessment of risk was based on
    non-neoplastic effects. However, neoplastic effects were taken into
    consideration in the risk assessments for MCB and 1,4-DCB. Available
    data indicate that the observed increase in renal tumours in rats
    caused by 1,4-DCB is a species- and sex-specific response that is
    unlikely to be relevant to humans. On the basis of evidence of
    increased DNA replication in the mouse liver and the increased
    incidence of hepatocellular adenomas and carcinomas in mice, 1,4-DCB
    may act as a non-genotoxic carcinogen in the rodent liver. MCB may
    also be a non-genotoxic carcinogen, in view of the increased
    incidence of hepatic neoplastic nodules observed in the high-dose
    group of male rats in a bioassay for carcinogenicity. 

    11.2.  Recommendations

    11.2.1  Public health measures

    The present risk assessment indicates that current concentrations of
    chlorobenzenes in the environment pose a minimal risk for humans.
    However, this assessment is based on limited monitoring data and
    additional information is needed to substantiate this conclusion.
    The reduction of the widespread use and disposal of chlorobenzenes
    should, however, be considered because:

    *    Chlorobenzenes may act as precursors for the formation of
         PCDDs/PCDFs, e.g., in incineration processes;

    *    These chemicals can lead to taste and odour problems in
         drinking-water and fish;

    *    Residues persist in organically-rich anaerobic sediments and
         soils, and ground water.

    More information is needed on the fate of chlorinated benzenes at
    high temperatures, in order to better assess the hazards associated
    with their disposal by incineration. 

    11.2.2  Human health risk evaluation

    In order to improve the database available for the assessment of the
    risks of chlorobenzenes for human health, it is recommended that:

    1.   The IPCS should coordinate the collection of industrial
         production data for chlorobenzenes.

    2.   Additional monitoring data should be collected so that a more
         accurate assessment of human exposure can be made. In
         particular, additional information is desirable on the
         concentrations in different geographical areas, especially with
         regard to the levels in food of the highly chlorinated
         congeners.

    3.   There is a lack of chronic toxicity data on the higher
         chlorinated benzenes. On the basis of subchronic toxicity data,
         it appears that 1,2,4,5-TeCB is the most toxic congener  and 
         should be examined in long-term bioassays or studied with
         regard to possible species-specific mechanisms.

    4.   Since ambient air is believed to be the major source of
         exposure to the chlorinated benzenes for humans, more
         information is required on the photoreactivity and
         photodegradation of these compounds.

    There is a lack of experimental data on the interaction between
    chlorobenzenes and other chemicals. As a general recommendation,
    research on the toxicity of chemical mixtures, and the consideration
    of toxicological interaction in the risk assessment process is
    encouraged.

    11.2.3  Environmental risk evaluation

    Persistent residues of chlorobenzenes have been reported in organic
    sediments and limited information indicates that these residues are
    bioavailable. The following recommendations are made to improve the
    understanding of the environmental distribution, fate, and impact of
    chlorobenzenes:

    1.   Residues of chlorobenzenes in sediment should be included in
         monitoring programmes.

    2.   The extent to which the presence of organic matter governs the
         distribution of chlorobenzenes between water, sediment, and air
         should be further studied.

    3.   Further research into the role of, and uptake from sediment
         (aquatic sediment and soil) by, biota is needed, together with
         studies on possible transfer in the food chains.

    4.   The capacity of a wider range of organisms to metabolize
         chlorobenzenes should be assessed.

    12. PREVIOUS EVALUATIONS BY INTERNATIONAL
    BODIES

    The carcinogenicity of 1,2-DCB and 1,4-DCB has been evaluated by the
    International Agency for Research on Cancer (IARC, 1982, 1987). Data
    on the carcinogenicity of both compounds for humans were considered
    inadequate. There was inadequate evidence for carcinogenicity to
    animals for 1,2-DCB and sufficient evidence for 1,4-DCB. 

    In the  Guidelines for drinking-water quality (WHO, 1984), the
    following guideline values were developed for chlorobenzenes: MCB, 3
    µg/litre; 1,2-DCB, 0.3 µg/litre; and 1,4-DCB, 0.1 µg/litre. All
    values represent 10% of the taste and odour threshold value. 

    Regulatory standards established by national bodies in different
    countries and the EEC are summarized in the Legal File of the
    International Register of Potentially Toxic Chemicals (IRPTC, 1986).


    REFERENCES

    ABERNATHY, S., BOBRA, R.M., SHIU, W.Y., WELLS, P.G., & MACKAY, D.
    (1986) Acute lethal toxicity of hydrocarbons and chlorinated
    hydrocarbons to two planktonic crustaceans: The key role of
    organism-water partitioning. Aquat. Toxicol., 8: 163-174.

    AHBORG, U.G. & VICTORIN, K. (1987) Impact on health of chlorinated
    dioxins and other trace organic emissions. Waste Manag. Res., 5:
    203-224.

    AHLING, B. (1987) Formation of chlorinated hydrocarbons during
    combustion of poly(vinyl chloride). Chemosphere, 10: 799-806.

    AMOORE, J.E. & HAVTALA, E. (1983) Odor as an aid to chemical safety:
    Odor thresholds compared with threshold limit values and
    volatilities for 214 industrial chemicals in air and water dilution.
    J. appl. Toxicol., 3(6):272-290.

    AKERMARK, B., BAECKSTROM, P., WESTLIN, U.E., GOTHE, R., &
    WACHTMEISTER, C.A. (1976) Photochemical dechlorination of
    1,2,4-trichlorobenzene. Acta chem. Scand., B30: 49-52.

    ANTOINE, S.R., DELEON, I., & O'DELL-SMITH, R.M. (1986)
    Environmentally significant volatile organic pollutants in human
    blood. Bull. environ. Contam. Toxicol., 36: 364-371.

    ARIYOSHI, T.M., IDEGUCHI, K., ISHIZUKA, Y., IWASAKI, K., & ARAKAKI,
    M. (1975) Relationship between chemical structure and activity. I.
    Effects of the number of chlorine atoms in chlorinated benzenes on
    the components of drug-metabolizing system and the hepatic
    constituents. Chem. Pharm. Bull., 23 (4): 817-823.

    ARIYOSHI, T., YASUMATSU, F., SUETSUGU, M., KOKUBA, Y., HAMASAKI, K.,
    & ARIZONO, K. (1981) Effects of halogenated compounds on the
    cytochrome P-450 content and the activities of enzymes in
    biosynthesis and degradation of heme. J. Pharmacobiodyn., 4(2):
    4-5.

    AZOUZ, W.M., PARKE, D.V., & WILLIAMS, R.T. (1955) Studies in
    detoxication: The metabolism of halogenobenzenes. ortho- and
    para-dichlorobenzenes. Biochem. J., 59(3): 410-415.

    BALKON, J. & LEARY, J.A. (1979) An initial report on a comprehensive
    quantitative, screening procedure for volatile compounds of forensic
    and environmental interest in human biofluids by GC/MS. J. anal.
    Toxicol., 3: 213-215.

    BALLSCHMITER, K. & SCHOLZ, C. (1980) Microbial decomposition of
    chlorinated aromatic substances. VI. Formation of dichlorophenols
    and dichloropyrocatechol from dichlorobenzenes in a micromolar
    solution by  Pseudomonas species. Chemosphere, 9 (7-8): 457-467.

    BARKLEY, J., BUNCH, J., BURSEY, J.T., CASTILLO, N., COOPER, S.D.,
    DAVIS, J.M., ERICKSON, M.D., HARRIS, B.S.H., KIRKPATRICK, M.,
    MICHEAL, L.C., PARKS, S.P., PELLIZZARI, E.D., RAY, M., SMITH, D.,
    TOMER, K.B., WAGNER, R., & ZWEIDINGER, R.A. (1980) Gas
    chromatography mass spectrometry computer analysis of volatile
    halogenated hydrocarbons in man and his environment-a multimedia
    environmental study. Biomed. mass Spectrom., 7(4): 139-147.

    BAUER, U. (1981) [Human exposure to environmental
    chemicals-investigations on volatile organic halogenated compounds
    in water air, food, and human tissues. III. Communication: results
    of investigations.] Zbl. Bakteriol. Hyg., I. Abt. Orig. B., 174:
    200-237 (in German).

    BAYER, A.G. (1986a)  Para-dichlorobenzene in the CHO HGPRT forward
    mutation assay. Report prepared by Litton Bionetics, USA, submitted
    to WHO by Bayer, A.G., Institute of Toxicology (Unpublished). 

    BAYER, A.G. (1986b)  Para-dichlorobenzene in the  in vitro
    transformation of Balb/3T3 cells assay. Report prepared by Litton
    Bionetics, USA, submitted to WHO by Bayer, A.G., Institute of
    Toxicology (Unpublished). 

    BECK, J. & HANSEN, K.E. (1974) The degradation of quintozene,
    pentachlorobenzene, hexachlorobenzene and pentachloroaniline in
    soil. Pestic. Sci., 5: 41-48.

    BERLINER, M.L. (1939) Cataract following the inhalation of
    paradichlorobenzene vapor. Arch. Ophthalmol., 22: 1023-1034.

    BIRGE, W.J., BLACK, J.A. & BRUSER, D.M. (1979) Toxicity of organic
    chemicals to embryo-larval stages of fish. Lexington, Kentucky, 69
    pp (EPA Report No. 560/11-79-007; NTIS Report No. PB80-101637).

    BLACK, W.D., VALLI, V.E.O., RUDDICK, J.A., & VILLENEUVE, D.C. (1988)
    Assessment of teratogenic potential of 1,2,3-, 1,2,4- and
    1,3,5-trichlorobenzenes in rats. Bull. environ. Contam. Toxicol.,
    41: 719-726.

    BLANCHARD, R.D. & HARDY, J.K. (1985) Use of a permeation sampler in
    the collection of 23 volatile organic priority pollutants. Anal.
    Chem., 57(12): 2349-2351.

    BOMHARD, E., LUCKHAUS, G., VOIGT, W.-H., & LOESER, E. (1988)
    Induction of light hydrocarbon nephropathy by  p-dichlorobenzene.
    Arch. Toxicol., 61: 433-439. 

    BONNET, P., RAOULT, G., & GRADISKI, D. (1979) Concentrations
    lethales 50 des principaux hydrocarbons aromatiques. Arch. Mal.
    prof., 40(8-9): 805-810. 

    BONNET, P., MORELE, Y., RAOULT, G., ZISSU, D., & GRADISKI, D. (1982)
    Determination de la concentration lethale 50 des hydrocarbones
    aromatiques chez le rat. Arch. Mal. prof., 63(4): 461-465. 

    BOUWER, E.J. & MCCARTY, P.L. (1983) Transformation of halogenated
    organic compounds under denitrification conditions. Appl. environ.
    Microbiol., 45(4): 13295-1299.

    BOUWER, E.J. & MCCARTY, P.L. (1984) Modeling of trace organics
    biotransformation in the subsurface. Ground Water, 22(4): 433-440.

    BOYLES, D.T. (1980) Toxicity of hydrocarbons and their halogenated
    derivatives in an aqueous environment. In: Afgan, B.K. & Mackay, D.,
    ed. Hydrocarbons and halogenated hydrocarbons in the aquatic
    environment, New York and London, Plenum Press, pp. 545-557. 

    BOY-MARCOTTE, J.L. (1980) 100-1000 kW(el) medium-power distributed-
    collector solar system. Electr. Power Syst. Res., 3: 41-51.

    BRAUN, W.H., SUNG, L.Y., KEYES, D.G., & KOCIBA, R.J. (1978)
    Pharmacokinetic and toxicological evaluation of dogs fed
    1,2,4,5-tetra-chlorobenzene in the diet for two years. J. environ.
    Pathol. Toxicol., 2: 225-233.

    BRINGMANN, G. & KUHN, R. (1980) Comparison of the toxicity
    thresholds of water pollutants to bacteria, algae, and protozoa in
    the cell multiplication inhibition test. Water Res., 14(3):
    231-241.

    BRINGMANN, G. & KUHN, R. (1982) [Results of toxic action of water
    pollutants on  Daphnia magna Straus tested by an improved
    standardized procedure.] Wasser abwasser Fors., 15(1): 1-6 (in
    German).

    BRISTOL, D.W., CRIST, H.L., LEWIS, R.G., MACLEOD, K.E., & SOVOCOOL,
    G.W. (1982) Chemical analysis of human blood for assessment of
    environmental exposure to semivolatile organochlorine chemical
    contaminants. J. anal. Toxicol., 6: 269-275.

    BRONDEAU, M.T., BONNET, P., GUENIER, J.P., & DECEAURRIZ, J. (1983)
    Short-inhalation test for evaluating industrial hepatotoxicants in
    rats. Toxicol. Lett., 19: 139-146.

    BROWN, V.K.H., MUIR, C., & THORPE, E. (1969) The acute toxicity and
    skin irritant properties of 1,2,4-trichlorobenzene. Ann. occup.
    Hyg., 12: 209-212.

    BUCCAFUSCO, R.J., ELLS, S.J. & LEBLANC, G.A. (1981) Acute toxicity
    of priority pollutants to bluegill  (Lepomis macrochirus). Bull.
    Environ. Contam. Toxicol., 26: 446-452.

    BUSER, H.R. (1979) Formation of polychlorinated dibenzofurans
    (PCDFs) from the pyrolysis of chlorobenzenes. Chemosphere, 6:
    415-424. 

    CALARMARI, D., GALASSI, S., SETTI, F. & VIGHI, M. (1983) Toxicity of
    selected chlorobenzenes to aquatic organisms. Chemosphere, 12(2):
    253-262. 

    CAMPBELL, D.M. & DAVIDSON, R.J.L. (1970) Toxic haemolytic anaemia in
    pregnancy due to a pica for paradichlorobenzene. J. Obstet.
    Gynaecol. Br. Commonw., 77: 657-659.

    CANTON, J.H., SLOOFF, W., KOOL, H.J. & STRUYS, J. (1985) Toxicity,
    biodegradability, and accumulation of a number of C/N-containing
    compounds for classification and establishing water quality
    criteria. Regulat. Toxicol. Pharmacol., 5: 123-131. 

    CARLSON, G.P. (1980) Effects of halogenated benzenes on arylesterase
    activity  in vivo and  in vitro. Res. Comm. chem. Pathol.
    Pharmacol., 30 (2): 361-364.

    CARLSON, G.P. & TARDIFF, R.G. (1976) Effect of chlorinated benzenes
    on the metabolism of foreign organic compounds. Toxicol. appl.
    Pharmacol., 36: 383-394.

    CARLSON, G.P., DZIEZAK, J.D., & JOHNSON, K.M. (l979) Effect of
    halogenated benzenes on acetanilide esterase, acetanilide
    hydroxilase and procaine esterase in rats. Res. Comm. chem. Pathol.
    Pharmacol., 25(1): 181-184.

    CARLSON, R.M., CARLSON, R.E., KOPPERMAN, H.L., & CAPLE, R. (1975)
    Facile incorporation of chlorine into aromatic systems during
    aqueous chlorination process. Environ. Sci. Technol., 9: 674-675.

    CHARBONNEAU, M., STRASSER, J., LOCK, E.A., TURNER, M.J., & SWENBERG,
    J.A. (1989) Involvement of reversible binding to a-2u-globulin in
    1,4-dichlorobenzene-induced nephrotoxicity. Toxicol. appl.
    Pharmacol., 99: 122-132. 

    CHOUDHRY, G.G. & WEBSTER, G.R.B. (1985) Photochemistry of
    halogenated benzene derivatives. V. Photolytic reductive
    dechlorination and and isomerization of tetrachlorobenzenes in
    acetonitrile-water mixtures. Toxicol. environ. Chem., 9: 291-308.

    CHOUDHRY, G.G., ROOF, A.A.M., & HUTZINGER, O. (1979) Photochemistry
    of halogenated benzene derivatives. I. Trichlorobenzenes: reductive
    dechlorination, isomerization and formation of polychlorobiphenyls.
    Tetrahed. Lett., 22: 2059-2062.

    CHU, I., VILLENEUVE, D., SECOURS, V., & VALLI, V.E. (1983)
    Comparative toxicity of 1,2,3,4-, 1,2,4,5-, and
    1,2,3,5-tetrachlorobenzene in the rat: results of acute and subacute
    studies. J. Toxicol. environ. Health, 11(5): 663-667.

    CHU, I., VILLENEUVE, D.C., VALLI, V.E., & SECOURS, V.E. (1984a)
    Toxicity of 1,2,3,4-, 1,2,3,5-, and 1,2,4,5-tetrachlorobenzene in
    the rat: results of a 90-day feeding study. Drug Chem. Toxicol.,
    7(2): 113-127.

    CHU, I., VILLENEUVE, D.C., VIAU, A., BARNES, C.R., BENOIT, F.M., &
    QIN, Y.H. (1984b) Metabolism of 1,2,3,4-, 1,2,3,5-, and
    1,2,4,5-tetrachlorobenzene in the rat. J. Toxicol. environ. Health,
    13(4-6): 777-786.

    CHU, I., MURDOCH, D.J., VILLENEUVE, D.C. & VIAU, A. (1987) Tissue
    distribution and elimination of trichlorobenzenes in the rat. J.
    environ. Sci. Health, B22(4): 439-453.

    CLARK, J.R., PATRICK, J.M. MOORE, J.C., & LORES, E.M. (1987)
    Waterborne and sediment-source toxicities of six organic chemicals
    to grass shrimp  (Palaemonetes pugio) and amphioxus  (Branchiostoma
     caribaeum). Arch. environ. Contam. Toxicol., 16: 401-407.

    COATE, W.B., SCHOENFISCH, W.H., LEWIS, T.R., & BUSEY, W.M. (1977)
    Chronic inhalation exposure of rats, rabbits, and monkeys to
    1,2,4-trichlorobenzene. Arch. environ. Health, 32(6): 249-255.

    COHEN, J.M., DAWSON, R., & KOKETSU, M. (l981) Extent-of-exposure
    survey of monochlorobenzene. Cincinnati, Ohio, National Institute of
    Occupational Safety and Health, Div. Surveillance, Hazard
    Evaluations and Field Studies, NIOSH (PB 82-183963).

    COTE, M., CHU, I., VILLENEUVE, D.C., SECOURS, V.E., & VALLI, V.E.
    (1988) Trichlorobenzenes: Results of a thirteen week feeding study
    in the rat. Drug chem. Toxicol., 11(1): 11-28.

    COTTER, L.H. (1953) Paradichlorobenzene poisoning from insecticides.
    N.Y. State J. Med., 53: 1690-1692.

    COURTNEY, K.D., ANDREWS, J.E., & EBRON, M.T. (1977) Teratology study
    of pentachlorobenzene in mice: no teratogenic effect at 50 or 100
    mg/kg/day from day 6 to day 15 of gestation. IRCS med. Sci.: Libr.
    Compend., 5: 587. 

    CROSBY, D.G. & HAMADMAD, N. (1971) The photoreduction of
    pentachlorobenzenes. J. agric. food Chem., 19(6): 1171-1174.

    CUPITT, L.T. (1980) Fate of toxic and hazardous materials in the air
    environment. Washington, US Environmental Protection Agency (Report
    EPA-600/3-80-084) (NTIS PB80-221948).

    CURRAN, H.M. (1981) Use of organic working fluids in Rancine
    engines. J. Energy, 5(4): 218-223.

    DALICH, G.M. & LARSON, R.E. (1985) Temporal and dose-response
    features of monochlorobenzene hepatotoxicity in rats. Fundam. appl.
    Toxicol., 5: 105-116.

    DALY, J.W., JERINA, D.M., & WITKOP, B. (1972) Arene oxides and the
    NIH shift: the metabolism, toxicity and carcinogenicity of aromatic
    compounds. Experimentia(Basel), 28: 1129-1149.

    DAVIS, H.C. & HIDU, H. (1969) Effects of pesticides on embryonic
    development of clams and oysters on survival and growth of the
    larvae. US Fish. Bull., 67: 393-404.

    DAVIS, E.M., MURRAY, H.E., LIEHR, J.G., & POWERS, E.L. (1981) Basic
    microbial degradation rates and chemical byproducts of selected
    organic compounds. Water Res., 15: 1125-1127.

    DAVIES, D. & MES, J. (1987) Comparison of the residue levels of some
    organochlorine compounds in breast milk of the general and
    indigenous Canadian populations. Bull. environ. Contam. Toxicol.,
    39: 743-749.

    DAWSON, G.W., JENNINGS, A.L., DROZDOWSKI, D., & RIDER, E. (1977) The
    acute toxicity of 47 industrial chemicals to fresh and saltwater
    fishes. J. hazard. Mat., 1: 303-318.

    DEBORTOLI, M., KNOPPEL, H., PECCHIO, E., PEIL, A., ROGORA, L.,
    SCHAUENBURG, H., SCHLITT, H., & VISSERS, H. (1985) Measurement of
    indoor air quality and comparison with ambient air: a study on 15
    homes in northern Italy. Luxembourg, Commission of the European
    Communities (EUR 9656 EN).

    DE CEAURRIZ, J.C., MICILLINO, J.C., BONNET, P., & GUENIER, J.P.
    (1981) Sensory irritation caused by various industrial airborne
    chemicals. Toxicol. Lett., 9: 137-143.

    DEN BESTEN, C., PETERS, M.M.C.G. & VAN BLADEREN, P.J. (1989) The
    metabolism of pentachlorobenzene by rat liver microsomes: The nature
    of the reactive intermediates formed. Biochem. biophys.Res. Comm.,
    163(3): 1275-1281.

    DILLEY, J.V. (1977) Toxic evaluation of inhaled chlorobenzene
    (monochlorobenzene). Springfield, Virginia, National Technical
    Information Service, US Department of Commerce (PB-276 623).

    DILLING, W.L., BREDEWEG, C.J., & TEFERTILLER, N.B. (1976) Organic
    photochemistry: simulated atmospheric photodecomposition rates of
    methylene chloride, 1,1,1-trichloroethane, trichloroethylene,
    tetrachloroethylene and other compounds. Environ. Sci. Technol.,
    10(4): 351-356.

    DURHAM, R.W. & OLIVER, B.G. (1983) History of Lake Ontario
    contamination from the Niagara River by sediment radiodating and
    chlorinated hydrocarbon analysis. J. Great Lakes Res., 9(2):
    160-168.

    DYCK, P.J., THOMAS, P.K., LAMBERT, E.H., & BUNGE, R. (1984)
    Peripheral, neuropathy, 2nd ed., Philadelphia, Pennsylvania, W.B.
    Saunders, Vol. 1. 

    EHRLICHER, H. (1968) [Observations and experiences in industry
    concerning the toxicity (physiopathologic effect) of chlorated
    benzene vapours (mono- to hexachlorobenzene).] Zentrabl.
    Arbeitsmed., 18: 204-205 (in German).

    EICEMAN, G.A., CLEMENT, R.E., & KASAREK, F.W. (1979) Analysis of fly
    ash from municipal incinerators for trace organic compounds. Anal.
    Chem., 51(14): 2343-2350.

    EICEMAN, G.A., CLEMENT, R.E., & KASAREK, F.W. (1981) Variations in
    concentrations of organic compounds including polychlorinated
    dibenzo- p-dioxins and polynuclear aromatic hydrocarbons in fly
    ash from a municipal incinerator. Anal. Chem., 53(7): 955-959.

    ELDER, V.A., PROCTOR, B.L., & HITES, R.A. (1981) Organic compounds
    found near dump sites in Niagara Falls, New York. Environ. Sci.
    Technol., 15(10): 1237-1243.

    ENGST, R., MACHOLZ, R.M., KUJAWA, M., LEWERENZ, H-J., & PLASS, R.
    (1976) The metabolism of lindane and its metabolites
    gamma-2,3,4,5,6-pentachlorocyclohexene, pentachlorobenzene and
    pentachlorophenol in rats and the pathways of lindane metabolism. J.
    environ. Sci. Health. Bull., B11(2): 905-117.

    ENVIRONMENT CANADA (1986) Ambient air concentrations of volatile
    organic compounds in Toronto and Montreal. Ottawa, Environment
    Canada, Pollution Measurement Division.

    EUROPEAN PATENT APPLICATION 36,270, September 23, 1981.

    FIELDING, M., GIBSON, T.M., & JAMES, H.A. (1981) Levels of
    trichloroethylene and  p-dichlorobenzene in groundwaters. Environ.
    Technol. Lett., 2(12): 545-550.

    FOMENKO, V.N. (1965) Determination of the maximum permissible
    concentration of tetrachlorobenzene in water basins. Hyg. Sanit.,
    30: 8-15.

    FRANK, S.B. & COHEN, H.J. (1961) Fixed drug eruption due to paradi-
    chlorobenzene. NY State J. Med., 61: 4079.

    GAFFNEY, P.E. (1976) Carpet and rug industry case study: I. Water
    and wastewater treatment plant operation. J. Water Pollut. Contr.
    Fed., 48: 2590-2598.

    GAGE, J.C. (1970) The subacute inhalation toxicity of 109 industrial
    chemicals. Br.ö òJ. industr. Med., 27: 1-18.

    GALLOWAY, S., BLOOM, A., RESNICK, M., MARGOLIN, B., NAKAMURA, F.,
    ARCHER, P., & ZEIGER, E. (1985) Development of a standard protocol
    for  in vitro cytogenetic testing with Chinese Hamster ovary cells:
    comparison of results for 22 compounds in two laboratories. Environ.
    Mutagen., 7: 1-51.

    GIAVINI, E., BOCCIA, M.L., PRATI, M., & VISMARA, C. (1986)
    Teratologic evaluation of  p-dichlorobenzene in the rat. Bull.
    environ. Contam. Toxicol., 37: 164-168. 

    GIBSON, D.T., KOCH, J.R., SCHULD, C.L., & KALLIO, R.E. (1968)
    Oxidative degradation of aromatic hydrocarbons by microorganisms.
    II. Metabolism of halogenated aromatic hydrocarbons. Biochemistry,
    7(11): 3795-3802.

    GIRARD, R., MARTIN, P., & BOURRET, J. (1969) [Haemopathies graves et
    exposition à des dérivés chlorés du benzène (a propos de 7 cas). J.
    Med. Lyon, 50(1164): 771-773. 

    GOERZ, G., VIZETHUM, W., BOLSEN, K., KRIEG, Th., & LISSNER, R.
    (1978) [Hexachlorobenzene (HBC) induced porphyria in rats. Influence
    of HBC-metabolites on the biosynthesis of heme.] Arch. dermatol.
    Res., 263: 189-196 (in German).

    GOLDSWORTHY, T.L., LYGHT, O., BURNETT, V.L., & POPP, J.A. (1988)
    Potential role of 2µ - globulin, protein droplet accumulation, and
    cell replication in the renal carcinogenicity of rats exposed to
    trichloroethylene, perchloroethylene, and pentachloroethane.
    Toxicol.appl. Pharmacol., 96: 367-379.

    GOTO, M., HATTORI, M., MIYAGAWA, T., & ENOMOTO, M. (1972)[Hepatoma
    generation in mice following application of high doses of HCH
    (hexachlorocyclohexane)-isomers.] Chemosphere, 6: 279-282. (in
    German).

    GREVE, P.A. (1973) Pentachlorobenzene as a contaminant of animal
    feed. Med. Fac. Landbouwwet. Rigksonio. Gent., 38: 775-784.

    GRILLI, S., ARFELLINI, G., COLACCI, A., MAZZULLO, M., & PRODI, G.
    (1985)  In vivo and  in vitro covalent binding of chlorobenzene to
    nucleic acids. Jpn. J. Cancer Res. (Gann)., 76: 745-751. 

    GROSCH, D.S. (1973) Reproduction tests: the toxicity for  Artemia
    of derivatives from non-persistent pesticides. Biol. Bull., 145:
    340-351. 

    HAIDER, K., JAGNOW, G., KOHNEN, R., & LIM, S.U. (1974) [Degradation
    of chlorinated benzenes, phenols, and cyclohexane derivatives by
    benzene and phenol utilizing soil bacteria under aerobic
    conditions.] Acta Microbiol., 96(3): 183-200 (in German).

    HALLOWELL, M. (1959) Acute haemolytic anaemia following the
    ingestion of paradichlorobenzene. Arch. Dis. Childhood (London),
    34: 74-75.

    HANAI, Y., KATOU, T., JIMMA, T., & NOMURA, K. (1985) [The movement
    of p-dichlorobenzene in the atmosphere.] Yokohama Kokuritsu Daigaku
    Kankyo Kagaku Kenkyu Senta Kiyo, 12: 31-39 (in Japanese).

    HARDEN., R.A. & BAETJER, A.M. (1978) Aplastic anemia following
    exposure to paradichlorobenzene and naphthalene. J. occup. Med.,
    20(12): 820-822.

    HARKOV, R., GIANTI, S.J.Jr., BOZZELLI, J.W., & LAREGINA, J.E. (1985)
    Monitoring volatile organic compounds at hazardous and sanitary
    landfills in New Jersey. J. environ. Sci. Health, A20(5): 491-501.

    HARKOV, R., KEBBEKUS, B., BOZZELLI, J.W., & LIOY, P.J. (1983)
    Measurement of selected volatile organic compounds at three
    locations in New Jersey during the summer season. J. Air Pollut.
    Contr. Assoc., 33(12): 1177-1183.

    HAWKINS, D.R., CHASSEAUD, L.F., WOODHOUSE, R.N., & CRESSWELL, D.G.
    (1980) The distribution, excretion and biotransformation of
     p-di-chloro[14]benzene in rats after repeated inhalation, oral
    and subcutaneous doses. Xenobiotica, 10(2): 81-95.

    HAWORTH, S., LAWLOR, T., MORTELMANS, K., SPECK, W., & ZEIGER, E.,
    (1983)  Salmonella mutagenicity test results for 250 chemicals.
    Environ. Mutag., Suppl. 1, 5: 3-142.

    HAYES, W.C., HANLEY, T.R., GUSHOW, T.S., JOHNSON, K.A., & JOHN, J.
    A. (1985) Teratogenic potential of inhaled dichlorobenzenes in rats
    and rabbits. Fundam. appl. Toxicol., 5(1): 190-202.

    HEIKES, D.L. (1980) Residues of pentachlorobenzene and related
    compounds in peanut butter. Bull. environ. Contam. Toxicol., 24:
    338-343.

    HEIKES, D.L., GRIFFITT, K.R., & CRAUN, J.C. (1979) Residues of
    tetrachloro-nitrobenzene and related compounds in potatoes. Bull.
    environ. Contam. Toxicol., 21: 563-568.

    HEITMULLER, P.T., HOLLISTAR, T.A., & PARRISH, P.R. (1981) Acute
    toxicity of 54 industrial chemicals to sheepshead minnows
     (Cyprinodon variegatus). Bull. environ. Contam. Toxicol., 27:
    596-604. 

    HERBOLD, B.A. (1986) Investigation of  p-dichlorobenzene
    1,4-dichlorobenzene for clastogenic effects in mice using the
    micronucleus test. Bayer, A.G., Institute of Toxicology (Unpublished
    report No. 14694 submitted to WHO) .

    HERBOLD, B.A. (1988)  p-Dichlorobenzene micronucleus test on the
    mouse to evaluate clastogenic effects. Bayer, A.G., Institute og
    Toxicology (Unpublished report no. 16902 submitted to WHO). 

    HERMENS, J., BROEKHUYZEN, E., CANTON, H., & WEGMAN, R. (1985)
    Quantitative structure activity relationships and mixture toxicity
    studies of alcohols and chlorohydrocarbons: effects on growth of
    Daphnia magna. Aquat. Toxicol., 6: 209-217.

    HIATT, M.H. (1981) Analysis of fish and sediment for volatile
    priority polutants. Anal. Chem., 53(9): 1541-1543.

    HITES, R.A. (1973) Analysis of trace organic compounds in New
    England rivers. J. Chromatogr. Sci., 11: 570-574.

    HOFLER, M., LAHANIATIS, E.S., BIENIEK, D., & KORTE, F. (1983)
    [Reactionbehaviour of benzene at ppm concentrations during
    chlorination withsodium hypochlorite in an aqueous solution.]
    Chemosphere, 12(2): 217-224 (in German).

    HOLLINGSWORTH, R.L., ROWE, V.K., OYEN, F., HOYLE, H.R., & SPENCER,
    H. (1956) Toxicity of paradichlorobenzene; determinants on
    experimental animals and human subjects. Arch. ind. Health, 14:
    138-147.

    HOLLINGSWORTH, R.L., ROWE, V.K., OYEN, F., TORKELSON, T.R., & ADAM,
    E.M. (1958) Toxicity of  o-dichlorobenzene; studies on animals and
    industrial experience. Arch. Ind. Health, 17: 180-187.

    IARC (1982) Ortho and para dichlorobenzenes. In: Some industrial
    chemicals and dyestuffs. Lyon, International Agency for Research on
    Cancer, pp. 213-238 (Monographs on the Evaluation of Carcinogenic
    Risk of Chemicals to Man, Vol. 29).

    IARC (1987) Overall evaluations of carcinogenicity: an update of
    IARC Monographs, Volumes 1 to 42, Lyon, International Agency for
    Research on Cancer, pp. 192-193 (IARC Monographs on the Evaluation
    of Carcinogenic Risks to Humans, Supplement 7). 

    IRISH, D.D. (1963) Halogenated hydrocarbons: II. Cyclic. In: Patty,
    F.A., ed. Industrial hygiene and toxicology, 2nd ed. New York,
    Inter-Science Publishers, pp. 1333-1340.

    IRPTC (1987) IRPTC Legal File 1986, Vol. 1. Geneva, International
    Register of Potentially Toxic Chemicals, United National Environment
    Programme. 

    JACOBS, A., BLANGETTI, M., & HELLMUND, E. (1974) Accumulation of
    noxious chlorinated substances from Rhine River water in the fatty
    tissue of rats. Vom Wass., 43: 259-274 (in German).

    JACOBS, A., HELLMUND, E., & EBERLE, S.H. (1977) [Accumulation of
    trace water pollutants in living organisms: time and dose dependence
    of the accumulation of hexachlorobenzene and tetrachlorobenzene
    derivatives in rats.] Vom Wass., 48: 255-272 (in German).

    JAN, J. (1980) Chlorinated benzene residues in some seeds.
    Chemosphere, 9: 165-167.

    JAN, J. (1983a) Chlorobenzene residues in human fat and milk. Bull.
    environ. Contam. Toxicol., 30: 595-599.

    JAN, J. (1983b) Chlorobenzene residues in market milk and meat.
    Mitt. Gebiete Lebensm. Hyg., 74(4): 420-425.

    JAN, J. & MALNERSIC, S. (1980) Chlorinated benzene residues in fish
    in Slovenia (Yugoslavia). Bull. environ. Contam. Toxicol., 24:824-827.

    JERINA, D.M. & DALY, J.W. (1974) Arene oxides: a new aspect of drug
    metabolism. Science, 185(4151): 573-582.

    JOHN, J.A., HAYES, W.C., HANLEY, T.R., Jr, JOHNSON, K.A., GUSHOW, T.
    S., & RAO, K.S. (1984) Inhalation teratology study on
    monochlorobenzene in rats and rabbits. Toxicol. appl. Pharmacol.,
    76: 365-373.

    JONDORF, W.R., PARKE, D.V., & WILLIAMS, R.T. (1955) Studies in
    detoxication: the metabolism of halogenobenzenes. 1,2,3-, 1,2,4-,
    and 1,3,5-tri-chlorobenzenes. Biochem. J., 61: 512-521.

    JONDORF, W.R., PARKE, D.V., & WILLIAMS, R.T. (1958) Studies in
    detoxication: the metabolism of halogenobenzenes 1,2,3,4-, 1,2,3,5-,
    and 1,2,4,5-tetrachlorobenzenes. Biochem. J., 69: 181-189.

    JUNGCLAUS, G.A., LOPEZ-AVILA, V., & HITES, R.A. (1978) Organic
    compounds in an industrial wastewater: a case study of their
    environmental impact. Environ. Sci. Technol., 12(1): 88-96.

    KACEW, S., RUDDICK, J.A., PARULEKAR, M., VALLI, V.E., CHU, I., &
    VILLENEUVE, D.C. (1984) A teratological evaluation and analysis of
    fetal tissue levels following administration of tetrachlorobenzene
    isomers to the rat. Teratology, 29: 21-27.

    KANNO, S. & NOJIMA, K. (1979) Studies on photochemistry of aromatic
    hydrocarbons. V. Photochemical reaction of chlorobenzene with
    nitrogen oxides in air. Chemosphere, 4: 225-232.

    KAO, C.I. & POFFENBERGER, N. (1979) Chlorinated benzenes. In:
    Kirk-Othmer encyclopedia of chemical technology, 3rd ed. Toronto,
    Ontario, John Wiley and Sons, Vol. 5, pp. 797-808.

    KARLOKOFF, S.W., BROWN, D.S., & SCOTT, T.S. (1979) Sorption of
    hydrophobic pollutants on natural sediments. Water Res., 13:
    241-249.

    KHERA, K.S. & VILLENEUVE, D.C. (1975) Teratogenicity studies on
    halogenated benzenes (pentachloro-, pentachloronitro- and
    hexabromo-) in rats. Toxicology, 5: 117-122.

    KIMURA, R., HAYASHI, T., SATO, M., AIMOTO, T., & MURATA, T. (1979)
    Identification of sulfur-containing metabolites of
     p-dichlorobenzene and their disposition in rats. J. Pharmacobio-
    Dyn., 2: 237-244.

    KIRALY, J., SZENTESI, I., RUZICSKA, M., & CZEIZE, A. (1979)
    Chromosome studies in workers producing organophosphate
    insecticides. Arch. environ. Contam. Toxicol., 8: 309-319.

    KITCHIN, K.T. & EBRON, M.T. (1983a) Maternal hepatic and embryonic
    effects of 1,2,4-trichlorobenzene in the rat. Environ. Res., 31:
    362-373.

    KITCHIN, K.T. & EBRON, M.T. (1983b) Maternal hepatic and embryonic
    effects of 1,2,3,4-tetrachlorobenzene in the rat. Toxicologist,
    26: 243-256.

    KITCHIN, K.T. & EBRON, M.T. (1983c) Maternal hepatic effects of
    1,2,4,5-tetrachlorobenzene in the rat. Environ. Res., 32:
    134-144.

    KLUWE, W.M., DILL, G., PERSING, A., & PETERS, A. (1985) Toxic
    response to acute, subchronic, and chronic oral administrations of
    monochlorobenzene to rodents. J. Toxicol. environ. Health, 15(6):
    745-767.

    KNAPP, W.K., Jr, BUSEY, W.M., & KUNDZINS, W. (1971) Subacute oral
    toxicity of monochlorobenzene in dogs and rats. Toxicol. appl.
    Pharmacol., 19(2): 393 (Abstract)

    KNEZOVICH, J.P. & HARRISON, F.L. (1988) The bioavailability of
    sediment-sorbed chlorobenzenes to larvae of the midge,  Chironomus
     decorus. Ecotoxicol. environ. Saf., 15: 226-241.

    KOBAYASHI, H. & RITTMAN, B.E. (1982) Microbial removal of hazardous
    organic compounds. Environ. Sci. Technol., 16(3): 170A-183A.

    KOCIBA, R.J., LEONG, B.J.K., & HEFNER, R.E. Jr (1981) Subchronic
    toxicity study of 1,2,4-trichlorobenzene in the rat, rabbit and
    beagle dog. Drug Chem. Toxicol., 4(3): 229-249.

    KOHLI, J., JONES, D., & SAFE, S. (1976) The metabolism of higher
    chlorinated benzene isomers. Can. J. Biochem., 54(3): 203-208.

    KONEMANN, H. & VAN LEEUWEN, K. (1980) Toxicokinetics in fish:
    accumulation and elimination of six chlorobenzenes by guppies.
    Chemosphere, 9: 3-19.

    KOSS, G. & KORANSKY, W. (1977) Pentachlorophenol in different
    species of vertebrates after administration of hexachlorobenzene and
    pentachlorobenzene. Environ. Sci. Res., 12: 131-137.

    KROST, K.J., PELLIZZARI, E.D., WALBURN, S.G., & HUBBARD, S.A. (1982)
    Collection and analysis of hazardous organic emissions. Anal. Chem.,
    54: 810-817.

    KUEHL, D.W., LEONARD, E.N., WELCH, K.J., & VEITH, G.D. (1980)
    Identification of hazardous organic chemicals in fish from the
    Ashtabula River, Ohio, and Wabash River, Indiana. J. Assoc. Off.
    Anal. Chem., 63(6): 1238-1244.

    KUHN, E.P., COLBERG, P.J., SCHNOOR, J.L., WANNER, O., ZEHNER, A.J.
    B., & SCHWARZENBACH, R.P. (1985) Microbial transformations of
    substituted benzenes during infiltration of river water to
    ground-water: laboratory column studies. Environ. Sci. Technol.,
    19: 961-968.

    LAHANIATIS, E.S., BIENIEK, D., VOLLNER, L., & KORTE, F. (1981a)
    [Formation of organochlorine compounds in the combustion of
    chlorine-containing polymers.] Chemosphere, 10(8): 935-943 (in
    German)

    LAHANIATIS, E.S., ROAS, R., BIENIEK, D., KLEIN, W., & KORTE, F.
    (1981b) [Formation of chlorinated organic compounds in combustion of
    polyethylenes in the presence of sodium chloride.] Chemosphere,
    10(11-12): 1321-1326 (in German).

    LAMPARSKI, L.L., LANGHORST, M.L., NESTRICK, T.J., & CUTIE, S. (1980)
    Gas-liquid chromatographic determination of chlorinated benzenes and
    phenols in selected biological matrices. J. Assoc. Off. Anal. Chem.,
    63(1): 27-32.

    LANGHORST, M.L. & NESTRICK, T.J. (1979) Determination of
    chlorobenzenes in air and biological samples by gas chromatography
    with photoionization detection. Anal. Chem., 51(12): 2018-2025.

    LATTANZI, G., BARTOLI, S., BONORA, B., COLACCI, A., GRILLI, S.,
    NIERO, A., & MAZZULLO, M. (1989) The different genotoxicity of
     p-dichlorobenzene in mouse and rat: Measurement of the  in vivo
    and  in vitro covalent interaction with nucleic acids. Tumori,
    75: 305-310.

    LAY, J.P., SCHAUERTE, W., MULLER, A., KLEIN, W., & KORTE, F. (1985)
    Long-term effects of 1,2,4-trichlorobenzene on freshwater plankton
    in an outdoor-model ecosystem. Bull. environ. Contam. Toxicol.,
    34: 761-769.

    LEBEL, G.L. & WILLIAMS, D.T. (1986) Determination of halogenated
    contaminants in human adipose tissue. J. Assoc. Off. Anal. Chem.,
    69(3): 451-458.

    LE BLANC, G.A. (1980) Acute toxicity of priority pollutants to water
    flea  (Daphnia magna). Bull. environ. Contam. Toxicol, 24:
    684-691.

    LEBRET, E. (1985) Air pollution in Dutch homes: an exploratory study
    in environmental epidemiology. Wageningen, The Netherlands,
    Department of Air Pollution, Department of Environmental and
    Tropical Health, Wageningen Agricultural University (Report R-138).

    LEE, R.P. & RYAN, C. (1979) Microbial degradation of organochlorine
    compounds in esturine waters and sediments. In: Proceedings of the
    Workshop: Microbial Degradation of Pollutants in Marine
    Environments, Pensacola Beach, Florida, April 9-14, 1978.
    Springfield, Virginia, US Environmental Protection Agency,
    pp.443-450 (Contract No., EPA-600/9-79-012. NTIS: PB298254).

    LEVINE, S.P., COSTELLO, R.J., GERACI, C.L., & CONLIN K.A. (1985) Air
    monitoring at the drum bulking process of a hazardous waste remedial
    action site. Am. Ind. Hyg. Assoc. J., 46(4): 192-196.

    LINDER, R., SCOTTI, T., GOLDSTEIN, J., MCELROY, K., & WALSH, D.
    (1980) Acute and subchronic toxicity of pentachlorobenzene. J.
    environ. Pathol. Toxicol., 4(5-6): 183-196.

    LINGG, R.D., KAYLOR, W.H., PYLE, S.M., KOPFLER, F.C., SMITH, C.C.,
    WOLFE, G.F., & CRAGG, S. (1982) Comparative metabolism of
    1,2,4-trichlorobenzene in the rat and rhesus monkey. Drug Metab.
    Disp., 10(2): 134-141.

    LOESER, E. & LITCHFIELD, M.H. (1983) Review of recent toxicology
    studies on  p- dichlorobenzene. Food.cChem. Toxicol., 21(6):
    825-832.

    LOPEZ-AVILA, V., NORTHCUTT, R., ONSTOT, J., WICKHAM, M., & BILLETS,
    S. (1983) Determination of 51 priority organic compounds after
    extraction from standard reference materials. Anal. Chem., 55(6):
    881-889.

    LOVEGREN, N.V., FISHER, G.S., LEGENDRE, M.G., & SCHULLER, W.H.
    (1979) Volatile constituents of dried legumes. J. agric. food Chem.,
    27(4): 851-853.

    LU, P-Y. & METCALF, R.L. (1975) Environmental fate and
    biodegradability of benzene derivatives as studied in a model
    aquatic ecosystem. Environ. Health Persp., 10: 269-284.

    LUNDE, G. & BJORSETH, A. (1977) Human blood samples as indicators of
    occupational exposure to persistent chlorinated hydrocarbons. Sci.
    total Environ., 8: 241-246.

    LUNDE, G. & OFSTAD, E.B. (1976) Determination of fat-soluble
    chlorinated compounds in fish. Z. anal. Chem., 282: 395-399.

    MACHOLZ, R.M. & KUJAWA, M. (1985) Recent state of lindane
    metabolism. Part III. Res. Rev., 94: 119-149.

    MACKAY, D., BOBRA, A., CHAN, D.W., & SHIU, W.Y. (1982) Vapour
    pressure correlations for low-volatility environmental chemicals.
    Environ. Sci. Technol., 16: 645-649.

    MACKAY, D. & SHIU, W.Y. (1981) A critical review of Henry's Law
    Constants for chemicals of environmental interest. J. phys. chem.
    Ref. Data, 10(4): 1175-1199.

    MACKAY, D. & WOLKOFF, A.W. (1973) Rate of evaporation of
    low-solubility contaminants from water bodies to atmosphere.
    Environ. Sci. Technol., 7(7): 611-614.

    MARINUCCI, A.C. & BARTHA, R. (1979) Biodegradation of 1,2,3- and
    1,2,4-trichlorobenzene in soil and in liquid enrichment culture.
    Appl. environ. Microbiol., 38(5): 8ll-817.

    MCKINNEY, J.D., FISHBEIN, C.E., FLETCHER, C.E., & BARTEL, W.F.,
    (1970) Electron-capture gas chromatography of paradichlorobenzene
    metabolites as a measure of exposure. Bull. environ. Contam.
    Toxicol., 5(4): 354-361.

    MES, J., DAVIES, D.J., & TURTON, D. (1982) Polychlorinated biphenyl
    and other chlorinated hydrocarbon residues in adipose tissue of
    Canadians.  Bull. environ. Contam. Toxicol., 28(1): 97-104.

    MES, J., DAVIES, D.J., TURTON, D., & SUN, W-F. (1986) Levels and
    trends of chlorinated hydrocarbon contaminants in the breast milk of
    Canadian women. Food Addit. Contam., 3(4): 313-322.

    MICHAEL, L.C., ERICKSON, M.D., PARKS, S.P., & PELLIZZARI, E.D.
    (1980) Volatile environmental pollutants in biological matrices with
    a headspace purge technique. Anal. Chem., 52(12): 1836-1841. 

    MILES, D.H., MODY, N.V., & MINYARD, J.P. (1973) Constituents of
    marsh grass: survey of the essential oils in Juncus roemerianus.
    Phyto-chemistry, 12: 1399-1404.

    MILLER, M.M., GHODBANE, S., WASIK, S.P., TEWARI, Y.B., & MARTIRE,
    D.E. (1984) Aqueous solubilities, octanol/water partition
    coefficients, and entropies of melting of chlorinated benzenes and
    biphenyls. J. chem. eng. Data, 29: 184-190.

    MILONE, M.F. (1986a) Capacity of para-dichlorobenzene to induce
    unscheduled DNA synthesis in cultured Hela cells, Bayer Chemical Co.
    (unpublished report submitted to WHO).

    MILONE, M.F. (1986b) Chromosome aberrations in human lymphocytes
    cultured  in vitro and treated with  p-dichlorobenzene, Bayer
    Chemical Co., (Unpublished report submitted to WHO ). 

    MIYAI, I., HIRONO, N., FUJITA, M., & KAMEYAMA, M. (1988) Reversible
    ataxia following chronic exposure to paradichlorobenzene. J. Neurol.
    Neurosurg. Psychiat., 51: 453-454.

    MOHTASHAMIPUR, E., TRIEBEL, R., STRAETER, H., & NORPOTH, K. (1987)
    The bone marrow clastogenicity of eight halogenated benzenes in male
    NMRI mice. Mutagenesis, 2(2): 111-113.

    MORITA, M. & OHI, G. (1975) Para-dichlorobenzene in human tissue and
    atmosphere in Tokyo metropolitan area. Environ. Pollut., 8:
    269-274.

    MORITA, M., MIMURA, S., OHI, G., YAGYU, H., & NISHIZAWA, T. (1975) A
    systematic determination of chlorinated benzenes in human adipose
    tissue. Environ. Pollut., 9: 175-179.

    MOTTRAM, D.S., PSOMAS, I.E., & PATTERSON, R.L.S. (1983) Chlorinated
    residues in the adipose tissue of pigs treated with
    hexachlorocyclohexane. J. Sci. Food Agric., 34: 378-387.

    MURTY, C.V.R., OLSON, M.J. GARG, B.D., & RAY, A.K. (1988)
    Hydrocarbon induced hyaline droplet nephropathy in male rats during
    senescence. Toxicol. appl. Pharmacol., y6: 380-392.

    NAIR, R.S., BARTER, J.A., SCHROEDER, R.E. KNEZEVICH, A., & STACK,
    C.R. (1987) A two-generation reproduction study with
    monochlorobenzene vapor in rats. Fund. appl. Toxicol., 9: 678-686.

    NALBANDIAN, R.M. & PEARCE, J.F. (1965) Allergic purpura induced by
    exposure to  p- dichlorobenzene. J. Am. Med. Assoc., 194(7):
    828-829.

    NAQUADAT (1987) National Water Quality Data Bank, Inland Waters
    Directorate, Water Quality Branch, Environment Canada, Ottawa.

    NEPTUNE, D. (1980) Descriptive statistic for detected priority
    pollutants and tabulation listings. Washington, DC, US EPA (Office
    of Water Planning and Standards, TRDB-0280-001).

    NILL, J.P. (1936) Effects of dichlorobenzene. J. Am. Med. Assoc.,
    107: 607-608.

    NOJIMA, K. & KANNO, S. (1980) Studies on photochemistry of aromatic
    hydrocarbons. VII. Photochemical reaction of  p-dichlorobenzene
    with nitrogen oxides in air. Chemosphere, 9: 437-440.

    NTP  (1985a) NTP technical report on the carcinogenesis studies of
    chlorobenzene (CAS No. 108-90-7) in F344/N rats and B6C3F1 mice
    (gavage studies). Research Triangle Park, North Carolina, National
    Toxicology Program, US Department of Health and Human Services,
    pp.228 (NTP TR 261).

    NTP (1985b) NTP technical report on the carcinogenesis studies of
    1,2-dichlorobenzene (CAS No. 95-50-1) in F344/N rats and B6C3F1
    mice (gavage studies). Research Triangle Park, North Carolina,
    National Toxicology Program, US Department of Health and Human
    Services, pp.192 (NTP TR 255) .

    NTP (1987) NTP technical report on the toxicology and
    carcinogenicity studies of 1,4-dichlorobenzene (CAS No. 106-46-7) in
    F344/N rats and B6C3F1 mice (gavage studies . Research Triangle
    Park, North Carolina, National Toxicology Program, US Department of
    Health and Human Services, pp.198 (NTP TR 319) .

    NTP (1989a) Draft NTP report on the toxicity studies of
    1,2,4,5-tetra-chlorobenzene in F344/N rats and B6C3F1 mice (feed
    studies). Research Triangle Park, North Carolina, National
    Toxicology Program, US Department of Health and Human Services (NTP
    Tox 7).

    NTP (1989b)  Draft NTP report on the toxicity studies of
    Pentachlorobenzene in F344/N rats and B6C3F1 mice (feed studies).
    Research Triangle Park, North Carolina, National Toxicology Program,
    US Department of Health and Human Services (NTP Tox 6) .

    OESCH, F., JERINA, D.M., DALY, J.W., & RICE, J.M. (1973) Induction,
    activation and inhibition of epoxide hydrase: an anomalous
    prevention of chlorobenzene-induced hepatotoxicity by an inhibitor
    of epoxide hydrase. Chem-Biol. Interact., 6(3): 189-202.

    OGATA, M. & SHIMADA, Y. (1983) Differences in urinary
    monochlorobenzene metabolites between rats and humans. Int. Arch.
    occup. Environ. Health, 53: 51-57.

    OLIVER, B.G. & BOTHEN, K.D. (1980) Determination of chlorobenzenes
    in water by capillary gas chromatography. Anal. Chem., 52:
    2066-2069.

    OLIVER, B.G. & BOTHEN, K.D. (1982) Extraction and clean-up
    procedures for measuring chlorobenzenes in sediments and fish by
    capillary gas chromatography. Int. J. environ. anal. Chem., 12:
    131-139.

    OLIVER, B.G. & NICOL, K.D. (1982) Chlorobenzenes in sediments,
    water, and selected fish from lakes Superior, Huron, Erie, and
    Ontario. Environ. Sci. Technol., 16: 532-536.

    OLIVER, B.G., & NICOL, K.D. (1984) Chlorinated contaminants in the
    Niagara River, 1981-1983. Sci. total Environ., 39: 57-70. 

    OLIVER, B.G., CHARLTON, M.N., & DURHAM, R.W. (1989) Distribution,
    redistribution and geochronology of polychlorinated biphenyl
    congeners and other chlorinated hydrocarbons in Lake Ontario
    Sediments. Environ. Sci. Technol., 23: 200-208. 

    OLSON, M.J., JOHNSON, J.T., & REIDY, C.A. (1990) A comparison of
    male rat & human urinary proteins: implications for human resistance
    to hyaline droplet nephropathy. Toxicol. appl. Pharmacol., 102:
    524-536. 

    ONUSKA, F.I. & TERRY, K.A. (1985) Determination of chlorinated
    benzenes in bottom sediment samples by WCOT column gas
    chromatography. Anal. Chem., 57: 801-805.

    OPPERHUIZEN, A. & STOKKEL, R.C.A.M. (1988) Influence of contaminated
    particles on the bioaccumulation of hydrophobic organic
    micropollutants in fish. Environ. Pollut., 51: 165-177.

    OTSON, R. (1987) Purgeable organics in Great Lakes raw and treated
    water. Int. J. environ. anal. Chem., 31: 43-53.

    OTSON, R. & BENOIT, F.M. (1986) Surveys of selected organics in
    residential air. In; Walkenshaw, D.S. ed. Transactions - Indoor air
    quality in cold climates - Hazards and abatement measures, April
    1985, Pittsburgh, PA, Air Pollution Control Association, pp 224-236.

    OTSON, R. & WILLIAMS, D.T. (1981) Evaluation of a liquid-liquid
    extraction technique for water pollutants. J. Chromatogr., 212:
    187-197.

    OTSON, R. & WILLIAMS, D.T. (1982) Headspace chromatographic
    determination of water pollutants. Anal. Chem., 54(6): 942-946.

    OTSON, R., WILLIAMS, D.T., & BIGGS, D.C. (1982a) Relationship
    between raw water quality, treatment, and occurence of organics in
    Canadian potable water. Bull. environ. Contam. Toxicol., 28:
    396-403.

    OTSON, R., WILLIAMS, D.T., & BOTHWELL, P.D. (1982b) Volatile organic
    compounds in water at thirty Canadian potable water treatment
    facilities. J. Assoc. Off. Anal. Chem., 65(6): 1370-1374.

    PAGNOTTO, L.D. & WALKLEY, J.E. (1965) Urinary dichlorophenol as an
    index of para-dichlorobenzene exposure. Am. Ind. Hyg. Assoc. J.,
    26: 137-142.

    PANKOW, J.F. & ISABELLE, L.M. (1982) Adsorption-thermal desorption
    as a method for the determination of low levels of aqueous organics.
    J. Chromatog., 237: 25-39. 

    PANKOW, J.F., ISABELLE, L.M., ASHER, W.E., KRISTENSEN, T.J., &
    PETERSON, M.E. (1983) Organic compounds in Los Angeles and Portland
    rain: identities, concentrations, and operative scavenging
    mechanisms. In: Pruppacher, H.R., Semonin, R.G., & Slinen, W.G.N.,
    ed. Precipitation Scavenging, Dry Deposition, and Resususpensions:
    Proceedings of the Fourth International Conference, Santa Monica,
    California, 29 November-3 December, 1982,. Elsevier, New York. Vol.
    1, 403-415.

    PARKE, D.V. & WILLIAMS, R.T. (1960) Studies in detoxication: the
    halogeno-benzenes  (a) penta- and hexa-chlorobenzenes,  (b)
    further observations on 1,3,5-trichlorobenzene. Biochem. J., 74:
    5-9.

    PELLIZZARI, E.D. (1982) Analysis for organic vapour emissions near
    industrial and chemical waste disposal sites. Environ. Sci.
    Technol., 16: 781-785.

    PELLIZZARI, E.D., HARTWELL, T.D., HARRIS, B.S.H., WADDELL, R.D.,
    WHITAKER, D.A., & ERIKSON, M.D. (1982) Purgeable organic compounds
    in mother's milk. Bull. environ. Contam. Toxicol., 28: 322-328.

    PELLIZZARI, E.D., HARTWELL, T.D., PERRITT, R.L., SPARACINO, C.M.,
    SHELDON, L.S., ZELON, H.S., WHITMORE, R.W., BREEN, J.J., & WALLACE,
    L. (1986) Comparison of indoor and outdoor residential levels of
    volatile organic chemicals in five U.S. geographical areas. Environ.
    Int., 12(6): 619-623.

    PEREIRA, W.E. & HUGHES, B.A. (1980) Determination of selected
    volatile organic priority pollutants in water by computerized
    spectrometry. J. Am. Water Works Assoc., 72(4): 220-230.

    PEROCCO, P., BOLOGNESI, S., & ALBERGHINI, W. (1983) Toxic activity
    of seventeen industrial solvents and halogenated compounds on human
    lymphocytes cultured  in vitro. Toxicol. Lett., 16: 69-75.

    PIET, G.J., SLINGERLAND, P., BIJLSMA, G.H., & MORRA, C. (1980) Fast
    quantitative analysis of a wide variety of halogenated compounds in
    surface-, drinking-, and groundwater. Environ. Sci. Res., 16:
    69-80

    PIKE, M.H. (1944) Ocular pathology due to organic compounds.
    Michigan State Med. Assoc. J., 43: 581-584.

    POLAND, A., GOLDSTEIN, J., HICKMAN, P., & BURSE, V.W. (1971) A
    reciprocal relationship between the induction of -aminolevulinic
    acid synthetase and drug metabolism produced by  m-dichlorobenzene.
    Biochem. Pharmacol., 2: 1281-1290.

    POPOVKI, P., ORUSEV, T., URUMOVA, E., BLAGOEVA, L., & TRPOVSKI, V.
    (1980) [Skin changes of workers employed in trichlorobenzene
    production.] Arh. Hig. Rada Toksikol., 31: 177-184 (in
    Serbo-Croat, with French abstract).

    POTENTA, E.J. & SAUNDERS, M.F. (1983) Indoor air quality
    investigation of chronic health problems in a Manhattan office
    space. In:Proceedings of the 76th Annual Meeting of the Air
    Pollution Control Association, Atlanta, Georgia, 19-24 June, 1983,
    Pittsburgh, Air Pollution Control Association, pp. 2-12.

    POWERS, M.B., COATE, W.B., & LEWIS, T.R. (1975) Repeated topical
    applications of 1,2,4-trichlorobenzene: effects on rabbit ears.
    Arch. environ. Health, 30: 165-167.

    RAO, K.S., JOHNSON, K.A., & HENCK, J.W. (1982) Subchronic dermal
    toxicity study of trichlorobenzene in the rabbit. Drug chem.
    Toxicol., 5(3): 249-263.

    RAUTAPAA, J., PYYSALO, H., & BLOMQVIST, H. (1977) Quintozene in some
    soils and plants in Finland. Ann. Agric. Fenn., 16: 277-282.

    REICH, H. (1934) [Puran(R) poisoning in a 2-year-old child].
    Schweizerische Medzinische Wochenschrift, 64: 223-224. (in German)

    REID, W.D. (1973) Mechanism of renal necrosis induced by
    bromobenzene or chlorobenzene. Exp. mol. Pathol., 19: 197-214.

    REID, W.D. & KRISHNA, G. (1973) Centrolobular hepatic necrosis
    related to covalent binding of metabolites of halogenated aromatic
    hydrocarbons. Exp. Mol. Path., 18: 80-99.

    REINEKE, W., KNACKMUSS, H-J. (1984) Microbial metabolism of
    haloaromatics: isolation and properties of chlorobenzene-degrading
    bacterium. Appl. environ. Microb., 47(2): 395-402.

    RENNER, G. & MUCKE, W. (1986) Transformation of pentachlorophenol.
    Part 1: metabolism in animals and man. Toxicol. environ. Chem.,
    11: 9-29.

    RIMINGTON, C. & ZIEGLER, G. (1963) Experimental porphyria in rats
    induced by chlorinated benzenes. Biochem. Pharmacol., 12:
    1387-1397.

    ROBINSON, K.S., KAVLOCK, R.J., CHERNOFF, N., & GRAY, L.E. (1981)
    Multigeneration study of 1,2,4-trichlorobenzene in rats. J. Toxicol.
    environ. Health, 8: 489-500.

    ROGERS, H.R, CAMPBELL, J.A., CRATHORNE, B. & DOBBS, A.J. (1989) The
    occurrence of chlorobenzenes and permethrins in twelve U.K. sewage
    sludges. Water Res., 23(7): 913-921.

    ROZENBAUM, N.D., BLOCK, R.S., KREMNAVA, S.N., GINZBURG, S.L., &
    POZHARISKII, I.V. (1947) [Use of chlorobenzene as a solvent from the
    standpoint of industrial hygiene.] Gig. i Sanit., 12(1): 21-24(in
    Russian).

    ROZMAN, K., WILLIAMS, J., MUELLER, W.F., COULSTON, F., & KORTE, F.
    (1979) Metabolism and pharmacokinetics of pentachlorobenzene in the
    rhesus monkey. Bull. environ. Contam. Toxicol., 22: 190-195.

    RUDDICK, J.A., BLACK, W.D., VILLENEUVE, D.C., & VALLI, V.E. (1983) A
    teratological evaluation following oral administration of trichloro-
    and dichlorobenzene isomers to the rat. Teratology, 27(2): 73A.

    RUDLING, L., AHLING, B. & LOFROTH, G. (1980) Chemical and biological
    characterization of emissions from combustion of wood and wood-chips
    in a small central heating furnace and from combustion of wood in
    closed fireplace stoves, Solna, Sweden, Swedish Environment
    Protection Board (SNV PM 1331) (in Swedish, with English summary). 

    SASMORE, D.P., MITOMA, C., TYSON, C.A., & JOHNSON, J.S. (1983)
    Subchronic inhalation toxicity of 1,3,5-trichlorobenzene. Drug chem.
    Toxicol., 6(3): 241-258.

    SATO, A. & NAKAJIMA, T. (1979) A structure-activity relationship of
    some chlorinated hydrocarbons. Arch. environ. Health, 34(2):
    69-75.

    SCHOENY, R.S., SMITH, C.C., & LOPER, J.C. (1979) Non-mutagenicity
    for  Salmonella of the chlorinatd hydrocarbons Aroclor 1254,
    1,2,4-tri-chlorobenzene, Mirex and Kepone. Mutat. Res., 68(2):
    125-132.

    SCHWARTZ, H., CHU, I., VILLENEUVE, D.C., VIAU, A., & BENOIT, F.M.
    (1985) Metabolites of 1,2,3,4-tetrachlorobenzene in monkey urine. J.
    Toxicol. environ. Health, 15(5): 603-607.

    SCHWARTZ, H., CHU, I., VILLENEUVE, D.C., & BENOIT, F.M. (1987)
    Metabolism of 1,2,3,4-, 1,2,3,5-, and 1,2,4,5-tetrachlorobenzene in
    the Squirrel monkey. J. Toxicol. environ. Health, 22: 341-350. 

    SCHWARZENBACH, R.P., MOLNAR-KUBICA, E., GIGER, W., & WAKEHAM, S.G.
    (1979) Distribution, residence time and fluxes of tetrachlorethylene
    and 1,4-dichlorobenzene in Lake Zurich, Switzerland. Environ. Sci.
    Technol., 13(11): 1367-1373.

    SCHWARZENBACH, R.P., GIGER, W., HOEHN, E., & SCHNEIDER, J.K. (1983)
    Behavior of organic compounds during infiltration of river water to
    groundwater. Field Stud.environ. Sci. Technol., 17: 472-479.

    SEARS, G.W. & HOPKE, E.R. (1949) Vapor pressures of the isomeric
    trichlorobenzenes in the low pressure region. J. Am. Chem. Soc.,
    71: 2575-2576.

    SELANDER, H. G., JERINA, D.M., & DALY, J.W. (1975) Metabolism of
    chlorobenzene with hepatic microsomes and solubilized cytochrome
    P-450 systems. Arch. Biochem. Biophys., 168: 309-321.

    SHELDON, L.S. & HITES, R.A. (1978) Organic compounds in the Delaware
    River. Environ, Sci. Technol., 12(10): 1188-1194.

    SHELTON, D.W. & WEBER, L.J. (1981) Quantification of the joint of
    effects of mixtures of hepatotoxic agents: evaluation of a
    theoretical model in mice. Environ. Res., 26: 33-41.

    SHIMIZU, M., YASUI, Y., & MATSUMOTO, N. (1983) Structural
    specificity of aromatic compounds with special reference to
    mutagenic activity in  Salmonella typhimurium: a series of
    chloro-or fluoro-nitrobenzene derivatives. Mutat. Res., 116:
    217-238.

    SHORT, B.G., BURNETT, V.L., COX, M.G., BUS, J.S., & SWENBERG, J.A.
    (1987) Site-specific renal cytotoxicity and cell proliferation in
    male rats exposed to petroleum hydrocarbons. Lab. Invest., 57(5):
    564-577.

    SIMMONS, P., BRANSON, D., & BAILEY, R. (1977)
    1,2,4-Trichlorobenzene: biodegradable or not. Text. Chem. Color.,
    9(9): 211-213.

    SIEVERS, R.E., BARKLEY, R.M., DENNEY, D.W., HARVEY, S.D., ROBERTS,
    J. M., & DELANY, A.C. (1980) Gas chromatographic and mass
    spectrometric analysis of volatile organics in the atmosphere. In:
    Sampling and analysis of toxic organics in the atmosphere.
    Philadelphia, American Society for Testing and Materials, pp. 3-21
    (ASTM STP 721).

    SINGH, H.B., SALAS, L.J., SMITH, A.J., & SHIGEISHI, M. (1981)
    Measurements of some potentially hazardous organic chemicals in
    urban environments. Atmos. Environ., 15: 601-612.

    SMITH, J.R.L., SHAW, B.A., & FOULKES, D.M. (1972) Mechanisms of
    mammalian hydroxylation: some novel metabolites of chlorobenzene.
    Xenobiotica, 2(3): 215-226.

    SMITH, E.N. & CARLSON, G.P. (1980) Various pharmacokinetic
    parameters in relation to enzyme-inducing abilities of
    1,3,4-trichlorobenzene and 1,2,4-tribromobenzene. J. Toxicol.
    environ. Health, 6(4): 737-749.

    SOFUNI, T., HAYASHI, M., MATSUOKA, A., SAWADA, M., HATANAKA, M., &
    ISHIDATE, M.JR. (1985) [Mutagenicity tests on organic chemical
    contaminants in city water and related compounds. II. Chromosome
    aberration tests in cultured mammalian cells.] Eisei Shikenjo
    Hokoku, 103: 64-75. (in Japanese).

    SPENCE, R-M.M. & TUCKNOTT, O.G. (1983) The examination of the
    headspace volatiles of watercress. J. Sci. Food Agric., 34:
    768-772.

    STATISTICS CANADA (1981) Apparent per capita food consumption in
    Canada. Ottawa, Queen's Printer (Cat. 32-229, Annual, Part II).

    STEINMETZ, K.L., SPANGGORD, R.J. (1987) Examination of the potential
    of  p- dichlorobenzene to induce unscheduled DNA synthesis or DNA
    replication in the  in vivo-in vitro mouse hepatocyte DNA repair
    assay (Task 1). (Unpublished report prepared by SRI International,
    USA, for US Chemical Manufacturers Association and submitted to WHO
    by ICI, Central Toxicology Laboratory ). 

    STULL, D.R. (1947) Vapor pressure of pure substances: organic
    compounds. Ind. Eng. Chem., 39: 517-539.

    SULLIVAN, T.M., BORN, G.S., CARLSON, G.P., & KESSLER, W.V. (1983)
    The pharmacokinetics of inhaled chlorobenzene in the rat. Toxicol.
    appl. Pharmacol., 71: 194-203.

    SUMERS, J. FUHRMAN, M. & KELMAN, A. (1952) Hepatitis with
    concomitant esophageal varices following exposure to mothball
    vapors. N.Y. State med. J., 52: 1048-1049.

    SYROVADKO, O.N. & MALYSHEVA, Z.V. (1977) [Working conditions and
    their effect on some specific functions of women engaged in the
    manufacture of enamel-insulated wires.] Gig. Tr. Prof. Zabol., 4:
    25-28 (in Russian)

    TAGATZ, M.E., PLAIA, G.R., & DEANS, C.H. (1985) Effects of 1,2,4-
    trichlorobenzene on estuarine macrobenthic communities exposed via
    water and sediment. Ecotoxicol. environ. Safety, 10: 351-360.

    TANAKA, A., SATO, M., TSUCHIYA, T., ADACHI, T., NIIMURA, T., &
    YAMAHA, T. (1986) Excretion, distribution and metabolism of
    1,2,4-trichlorobenzene in rats. Arch. Toxicol., 59: 82-88.

    TARKHOVA, L.P. (1965) [Materials for determining the maximum
    permissible concentration of chlorobensol in atmospheric air.] Gig.
    i Sanit., 30: 327-333 (in Russian).

    TOLOT, F., SOUBRIER, B., BRESSON, J.-R., & MARTIN, P. (1969) Myélose
    proliférative d'évolution rapide. Role étiologigue possible des
    dérivés chlorés du benzène. J. Med. Lyon, 50(164): 761-780.

    TOPP, E., SCHEUNERT, I., ATTAR, A,. & KORTE, F. (1986) Factors
    affecting the utake of 14C-labelled organic chemicals by plants
    from soil. Ecotoxicol. Environ. Safety, 11: 219-228.

    TOPP, E., SCHEUNERT, I., & KORTE, F. (1989) Kinetics of the uptake
    of 14C-labelled chlorinated benzenes from soil by plants.
    Ecotoxicol. environ. Safety, 17: 157-166.

    US EPA (1980a) Ambient water quality criteria for chlorinated
    benzenes.  Washington, DC, Office of Water Regulations and
    Standards, US Environmental Protection Agency (Report EPA
    440/5-80-028, PB81-117392).

    US EPA (1980b) Ambient water quality criteria for dichlorobenzenes.
    Washington, DC, Office of Water Regulations and Standards, US
    Environmental Protection Agency (Report EPA 440/5-80-039,
    PB81-117509). 

    US EPA (1985) Health assessment document for chlorinated benzenes.
    Final Report. Washington, DC, Office of Health and Environment
    Assessment, US Environmental Protection Agency ( Report
    EPA/600/8-84/015F).

    UYETA, M., TAUE, S., CHIKASAWA, K., & MAZAKI, M. (1976)
    Photoformation of polychlorinated biphenyls from chlorinated
    benzenes. Nature (Lond.), 264: 583-584.

    VAN HOOGEN, G. & OPPERHUIZEN, A. (1988) Toxicokinetics of
    chlorobenzenes in fish. Environ. Toxicol. Chem., 7: 213-219.

    VARSHAVSKAYA, S.P. (1968) Comparative toxicological characteristics
    of chlorobenzene and dichlorobenzene (ortho- and para-isomers) in
    relation to the sanitary protection of water bodies. Hyg. Sanit.,
    33(10-12): 17-23.

    VILLENEUVE, D.C. & KHERA, K.S. (1975) Placental transfer of
    halogenated benzenes (pentachloro- pentachloronitro-, and
    hexabromo-) in rats. Environ. Physiol. Biochem., 5(5): 328-331.

    WAKEHAM, S.G., DAVIS, A.C., & KARAS, J.L. (1983) Mesocosm
    experiments to determine the fate and persistence of volatile
    organic compounds in coastal seawater. Environ. Sci. Technol., 17:
    611-617.

    WALLACE, L.A. (1986) Personal exposures, indoor and outdoor air
    concentrations and exhaled breath concentrations of selected
    volatile organic compounds measured for 600 residents of New Jersey,
    North Dakota, North Carolina and California. Toxicol. environ.
    Chem., 12(3-4): 215-236.

    WALLACE, L.A., PELLIZZARI, E., HARTWELL, T., ROSENZWEIG, M.,
    ERIKSON, M., SPARACINO, C., & ZELON, H. (1984) Personal exposure to
    volatile organic compounds. I. Direct measurements in breathing-zone
    air, drinking water, food, and exhaled breath. Environ. Res., 35:
    293-319.

    WALLACE, L.A., PELLIZZARI, E.D., HARTWELL, T.D., SPARACINO, C.M.,
    SHELDON, L.S.,& ZELON, H. (1985) Personal exposures, indoor-outdoor
    relationships, and breath levels of toxic air pollutants measured
    for 355 persons in New Jersey. Atmos. Environ., 19(10): 1651-1661.

    WALLACE, L.A., PELLIZZARI, E., HARTWELL, T., ZELON, H., SPARACINO,
    C., PERRITT, R., & WHITMORE, R. (1986) Concentrations of 20 volatile
    organic compounds in the air and drinking water of 350 residents of
    New Jersey compared with concentrations in their exhaled breath. J.
    occup. Med., 28(8): 603-608.

    WALLGREN, K. (1953) [Chronic poisoning in the production of moth
    deterrents mainly composed of  p-dichlorobenzene]. Zentralbl.
    Arbeitsmed. Arbeitsschutz, 3: 14-15 (in German).

    WARE, S.A. & WEST, W.L. (1977) Investigation of selected potential
    environmental contaminants: halogenated benzenes. Washington, DC,
    297 pp. (US EPA Report, EPA 560/2-77-004, NTIS PB 273 206).

    WATANABE, P.G., KOCIBA, R.J., HEFNER, R.E. JR., YAKEL, H.O., &
    LEONG, B.K.J. (1978) Subchronic toxicity studies of
    1,2,4-trichlorobenzene in experimental animals. Toxicol. appl.
    Pharmacol., 45(1): 332-333 (Abstract).

    WATSON, A. & PATTERSON, R.L.S. (1982) Tainting of pork meat by 1,4-
    dichlorobenzene. J. Sci. Food Agric., 33: 103-105.

    WEAST, R.C., ed. (1986) CRC handbook of chemistry and physics, 67th
    ed., Boca Raton, Florida, The Chemical Rubber Company.

    WELLER, R.W. & CRELLIN, A.J. (1953) Pulmonary granulomatosis
    following extensive use of paradichlorobenzene. Arch. intern. Med.,
    91: 408-413.

    WHO (1984) Guidelines for drinking-water quality. Vol. 1:
    Recommendations, Geneva, World Health Organization, 130 pp.

    WHO (1987) Environmental Health Criteria 70: Principles for the
    safety assessment of food additives and contaminants in food.
    Geneva, World HealthOrganization, 174pp. 

    WILLIAMS, R.T. (1959) The metabolism of halogenated aromatic
    hydrocarbons, In: Detoxification mechanisms, 2nd ed., London,
    Chapman and Hall Ltd., pp. 237-258.

    WILLIAMS, R.T., HIROM, P.C., & RENWICK, A.G. (1975) Species
    variation in the metabolism of some organic halogen compounds, In:
    Mcintyre, A.D. & Mills, C.F., ed., Ecolical and toxicological
    Research, New York and London, Plenum Press, pp. 91-105.

    WILLIAMS, D.T., LEBEL, G.L., & JUNKINS, E. (1988) Organohalogen
    residues in human adipose autopsy samples from six Ontario
    municipalities. J. Assoc. Off. Anal. Chem., 71(2): 410-414. 

    WILSON, J.T., ENFIELD, C.G., DUNLAP, W.J., COSBY, R.L., FOSTER,
    D.A., & BASKIN, L.B. (1981) Transport and fate of selected organic
    pollutants in a sandy soil. J. environ. Qual., 10(4): 501-506.

    WONG, P.T.S., CHAU, Y.K., RHAMEY, J.S., & DOCKER, M. (1984)
    Relationship between water solubility of chlorobenzenes and their
    effects on a freshwater green alga. Chemosphere, 13(9): 991-996.

    YAMAMOTO, H., TANIGUCHI, Y., IMAI, S., OHNO, Y., & TSUBURA, Y.
    (1978) [Acute toxicity and local irritation tests of
    trichlorobenzene (TCB) on ddY mice.] J. Tara Med. Assoc., 29:
    569-573 (in Japanese).

    YAMAMOTO, H., OHNO, Y., NAKAMORI, K., OKUYAMA, T., IMAI, S., &
    TSUBURA, Y. (1982) [Chronic toxicity and carcinogenicity test of
    1,2,4-trichlorobenzene on mice by dermal painting.] J. Nara Med.
    Assoc., 33(2): 132-145 (in Japanese).

    YANG, K.H., PETERSON, R.E., & FUJIMOTO, J.M. (1979) Increased bile
    duct-pancreatic fluid flow in benzene-treated rats. Toxicol. appl.
    Pharmacol., 47(3): 505-514.

    YOSHIDA, M. & HARA, I. (1985) Composition of urinary metabolites and
    variation of urinary taurine levels in rats injected with
    chlorobenzene. Ind. Health, 23(3): 239-243.

    YOSHIOKA, Y., OSE, Y., & SATO, T. (1985) Testing for the toxicity of
    chemicals with  Tetrahymena pyriformis. Sci. tot. Environ., 43:
    149-157. 

    YOUNG, D.R. & HEESEN, T.C. (1978) DDT, PCB, and chlorinated benzenes
    in the marine ecosystem off Southern California. In: Jolley, R.L.,
    Gorshev, H., & Hamilton, D.H., Jr, ed., Water chlorination.
    Environmental impact and health effects, Ann Arbor, Michigan, Ann
    Arbor Science Publishers, Vol. 2, pp. 267-290.

    ZAPATA-GAYON, C., ZAPATA-GAYON, N., & GONZALEZ-ANGULO, A. (1982)
    Clastogenic chromosomal aberrations in 26 individuals accidentally
    exposed to ortho dichlorobenzene vapors in the National Medical
    Center in Mexico City. Arch. environ. Health, 37(4): 231-235.

    ZOETEMAN, B.C.J., HARMSEN, K., LINDERS, J.B.H.J., MORRA, C.F.H., &
    SLOOFF, W. (1980) Persistent organic pollutants in river water and
    ground water of the Netherlands. Chemosphere, 9: 231-249.

    ZONG, Z. & MA, A. (1985) [Statistical analysis of 1951 cases of
    occupational dermatosis in Shanghai chemical plants.,] Zhonghua
    Yufanguixue Zazhi, 19(2): 90-92 (in Chinese).

    ZUB, M. (1978) Reactivity of the white blood cell system to toxic
    action benzene and its derivatives. Acta biol. Cracoviensia, 21:
    163-174.

    RESUME

    La présente publication traite des risques pour la santé humaine et
    l'environnement qui découlent de l'exposition au monochloro-benzène
    (MCB), aux dichlorobenzènes (DCB), aux trichlorobenzènes (TCB), aux
    tétrachlorobenzènes (TeCB) et au pentachlorobenzène (PeCB). La
    substitution par le chlore est indiquée comme suit:
    1,2-dichlorobenzène (1,2-DCB); 1,2,3-trichlorobenzène (1,2,3-TCB),
    etc.

    1.  Identitée, proprietes physiques et chimiques, et methodes
    d'analyse

    Les chlorobenzènes sont des dérivés aromatiques cycliques formés par
    addition de 1 à 6 atomes de chlore au noyau benzénique. On obtient
    ainsi 12 composés: le monochlorobenzène, trois isomères pour chacun
    des di-, tri et tétrachlorobenzènes, ainsi que le penta- et
    l'hexachlorobenzène.

    Les chlorobenzènes sont des solides blancs cristallins à la
    température ambiante, sauf dans le cas du MCB, du 1,2-DCB, du
    1,3-DCB et du 1,2,4-TCB qui sont des liquides incolores. En général,
    ils sont peu solubles dans l'eau, leur solubilité diminuant à mesure
    que la substitution par le chlore augmente. Ils sont peu
    inflammables, leurs coéfficients de partage octanol/eau sont moyens
    à élevés et augmentent avec le nombre d'atomes de chlore; la tension
    de vapeur est basse à moyenne et diminue lorsque la substitution
    augmente. Les seuils gustatif et olfactif sont bas, en particulier
    dans le cas des dérivés les moins chlorés.

    Même lorsqu'ils sont purifiés, les chlorobenzènes du commerce
    contiennent en proportions diverses, des isomères très voisins. Par
    exemple, le MCB pur peut contenir jusqu'à 0,05% de benzène et 0,1%
    de DCB; le 1,2-DCB technique pouvant contenir jusqu'à 19 % des
    autres DCB, 1% de TCB et jusqu'à 0,05% de MCB. Rien n'indique qu'il
    puisse y avoir contamination par des dibenzo- p-dioxines
    polychlorées (PCDD) ni par des polychlorodibenzofuranes (PCDF).

    Un grand nombre de techniques de prélèvement ont été mises au point
    pour l'échantillonnage des chlorobenzènes, techniques qui sont
    fonction du milieu. Elles vont de l'extraction par solvant dans le
    cas des milieux aqueux à l'utilisation de substances absorbantes
    pour les composés en suspension dans l'air. La chromatographie
    gaz-liquide (GLC) est la technique de choix pour le dosage du
    chlorobenzène dans des échantillons provenant de l'environnement.

    2.  Sources d'exposition humaine et environnementale

    2.1  Chiffres de production

    D'après les données dont on dispose sur le volume de la production
    des chlorobenzènes et qui correspondent à la période 1980-83, la
    production mondiale serait de 568 x 106 kg; cependant,
    l'utilisation des chlorobenzènes a reculé dans certains pays depuis
    lors. Environ 50 % de cette quantité a été produite aux Etats-Unis
    d'Amérique et le reste, essentiellement en Europe occidentale et au
    Japon. Le MCB correspondait à 70% de la production mondiale, la
    production du 1,2-DCB, du 1,4-DCB et du 1,2,4-TCB étant
    respectivement de 22 x 106, 4 x 106, et 1,2-3,7 x 106 kg.

    Le MCB et les DCB sont obtenus par chloration directe du benzène en
    phase liquide en présence d'un catalyseur, alors que les TCB et les
    TeCB sont produits par chloration directe des chlorobenzènes
    isomères convenables, en présence d'un catalyseur métallique.

    2.2  Usages

    On utilise principalement les chlorobenzènes comme intermédiaires
    dans la synthèse des pesticides et d'autres produits chimiques; le
    1,4-DCB est utilisé dans les désodorisants d'ambiance et comme
    répulsif contre les mites. Les chlorobenzènes les plus substitués
    (TCB et 1,2,3,4-TeCB) entrent dans la composition des fluides
    diélectriques.

    2.3  Liberation de chlorobenzenes dans l'environnement

    Il peut y avoir libération de chlorobenzènes dans l'environnement,
    principalement lors de la production de ces substances, qu  i sont
    en outre amenées à être dispersées lors d'un certain nombre de leurs
    utilisations. Par exemple, aux Etats-Unis d'Amérique, entre 0,1 et
    0,2% de la production de 1983 (qui correspondait à 130 x 106
    tonnes de MCB a sans doute été dispersée dans l'environnement. Les
    quantités libérées lors du rejet de déchets, et notamment
    l'incinération de déchets municipaux, sont beaucoup plus faibles.
    Toutefois, l'incinération des chlorobenzènes peut conduire à
    l'émission de PCDD et de PCDF.

    3.  Transport, repartition et transformation dans l'environnement

    3.1  Degradation

    C'est principalement par voie biologique et, dans une moindre
    mesure, par des processus abiotiques que les chlorobenzènes
    disparaissent de l'environnement. Toutefois, on estime qu'ils sont
    moyennement persistants dans l'eau, l'air et les sédiments. On a
    fait état de temps de séjour dans l'eau allant d'une journée dans

    les rivières à plus de 100 jours dans les eaux souterraines. D ans
    l'air, la dégradation des chlorobenzènes s'effectue principalement,
    semble-t-il, par voie chimique et par photolyse, la durée de séjour
    se situant entre 13 et 116 jours pour le MCB, les DCB et un isomère
    du TCB non précisé.

    On a montré que nombre de microorganismes présents dans les
    sédiments et les boues d'effluents dégradaient les chlorobenzènes.
    Il semblerait que les composés les plus substitués soient les plus
    difficiles à dégrader, la dégradation s'effectuant uniquement en
    aérobiose. Dans les conditions d'anaérobiose du sol et les eaux
    souterraines, le DCB, les TCB et les PeCB résistent en général à la
    dégradation microbienne.

    3.2  Destinee

    Les chlorobenzènes qui sont libérés dans le milieu aquatique se
    redistribuent préférentiellement dans l'air et les sédiments (en
    particulier dans les sédiments riches en matières organiques).
    D'après les renseignements limités dont on dispose, il semble que
    l'on trouve dans les sédiments, notamment les sédiments des régions
    très industrialisées, des quantités 1000 fois plus élevées que
    celles qui sont présentes dans l'eau. La rétention dans le sol
    augmente avec la teneur de celui-ci en matières organiques; il
    existe une corrélation positive entre le degré de chloration du
    composé et son adsorption sur les matières organiques. Quelques
    données montrent que les résidus liés aux sédiments sont
    biodisponibles; c'est ainsi que les invertébrés aquatiques sont
    susceptibles de fixer les résidus présents sur les sédiments, les
    plantes et dans le sol.

    4.  Concentrations dans l'environnement et exposition humaine

    4.1  Les chlorobenzènes dans l'environnement

    Les concentrations moyennes en chlorobenzènes (mono- à tri-) dans
    l'air ambiant sont de l'ordre de 0,1 µg/m3, avec des valeurs
    maximales allant jusqu'à 100 µg/m3. On ne dispose d'aucune donnée
    sur les teneurs en TeCB et PeCB de l'air ambiant, encore que ces
    substances aient été décelées dans des cendres volantes provenant
    d'incinérateurs municipaux. Les concentrations de chlorobenzènes
    dans l'air intérieur sont analogues à celles que l'on trouve dans
    l'air extérieur; toutefois, on a fait état de valeurs beaucoup plus
    élevées que dans l'air ambiant dans des régions très polluées, ainsi
    que dans des espaces confinés où l'on avait utilisé des produits
    contenant du chlorobenzène.

    Des chlorobenzènes (mono- à penta-) ont été décelés dans des eaux
    superficielles à des concentrations de l'ordre du ng/litre-µg/litre,
    avec quelquefois des valeurs atteignant quelques dixièmes de
    mg/litre à proximité d'installations industrielles. La teneur en
    chlorobenzènes des eaux résiduaires industrielles peut être encore
    plus élevée et varier en fonction de la nature des procédés mis en
    oeuvre.

    Dans les échantillons d'eau de boisson analysés on a décelé la
    présence de tous les chlorobenzènes. Ce sont les composés les moins
    chlorés qui étaient le plus fréquemment présents et aux
    concentrations les plus fortes, avec prédominance de l'isomère
    1,4-DCB; toutefois, les concentrations moyennes étaient généralement
    inférieures à 1 µg/litre et ne dépassaient que rarement 50 µg/litre,
    quel que soit le composé.

    On n'a pas trouvé de données sur la teneur des aliments en
    chlorobenzènes qui proviennent de programmes de surveillance bien
    conçus; les renseignements disponibles se limitent principalement à
    la concentration dans le poisson à proximité d'installations
    industrielles ou à des incidents isolés de contamination de produits
    carnés. Tous les isomères du chlorobenzène (mono- à penta-) ont été
    décelés dans des truites d'eau douce, à des teneurs allant de 0,1 à
    16 µg/kg. Dans une autre étude, les teneurs des poissons d'eau douce
    en chlorobenzènes totaux variaient en moyenne de 0,2 mg/kg de
    graisse dans les régions peu polluées à 1,8 mg/kg dans une zone
    industrialisée. Il existe certains indices de l'augmentation de la
    concentration en chlorobenzènes dans le poisson d'eau douce avec le
    degré de chloration du composé. En ce qui concerne le poisson de
    mer, les quelques études disponibles donnent une teneur en 1,4-DCB
    de 0,05 mg/kg de poids humide.

    Les résultats dont on dispose au sujet des taux de chlorobenzène
    dans la viande et le lait et qui concernent principalement les
    régions contaminées, sont de l'ordre de 0,02 à 5 µg/kg.

    Lors de deux enquêtes sur le lait humain, on a procédé au dosage de
    la totalité des chlorobenzènes, sauf le MCB. Dans une des études,
    les concentrations de DCB étaient égales en moyenne à 25 µg/kg de
    lait alors qu'elles étaient inférieures à 5 µg/kg dans le cas du
    TCB, des isomères du TeCB et du PeCB. Dans la seconde enquête, les
    concentrations étaient beaucoup plus basses puisqu'en moyenne elles
    allaient de 1 µg/kg (1,2,3-TCB et PeCB) à un maximum de 6 µg/kg (1,3
    et 1,4-dichlorobenzène).

    4.2  Exposition humaine

    4.2.1  Population generale

    Sur la base des données limitées dont on dispose, il semble que
    c'est à partir de l'air que l'apport journalier de chlorobenzènes
    dans la population générale est le plus élevé, en particulier en ce
    qui concerne les dérivés les moins chlorés qui sont plus volatils
    (0,2-0,9 µg/kg de poids corporel). Par comparaison avec l'apport
    d'autres origines, l'apport d'origine alimentaire augmente à mesure
    qu'augmente le degré de chloration; ainsi, l'alimentation contribue
    davantage que l'air à la dose journalière de TeCB et de PeCB.
    Toutefois, les niveaux d'exposition dans ce cas restent
    vraisem-blablement au-dessous de 0,05 µg/kg de poids corporel.
    Quelques études, en nombre limité, ont montré que les enfants
    nourris au sein risquaient de recevoir une dose de chlorobenzène
    plus forte, rapportée au poids corporel, que les adultes.

    4.2.2  Contexte professionnel

    Il n'est pas possible de chiffrer avec précision l'exposition
    professionnelle au chlorobenzène sur la base des données
    disponibles. Toutefois, dans une unité de production, on a trouvé
    des teneurs en 1,4-DCB allant de 42 à 288 mg/m3 et dans d'autres
    usines chimiques, la concentration de MCB pouvait atteindre 18,7
    mg/m3.

    5.  Cinetique et metabolisme

    Tous les chlorobenzènes sont facilement résorbés dans les voies
    digestives et respiratoires chez l'homme et les animaux
    d'expérience, la résorption dépendant de la position de l'atome de
    chlore pour les différents isomères d'un même dérivé.

    Chez l'animal d'expérience, après une rapide répartition dans les
    organes très irrigués, les chlorobenzèn s'accumulent principalement
    dans les tissus adipeux, une quantité plus faible passant dans le
    foie et les autres organes. On a montré que les chlorobenzènes
    étaient capables de traverser la barrière placentaire et l'on en a
    trouvé dans le cerveau de foetus. En général, ces dérivés
    s'accumulent d'autant plus qu'ils sont plus chlorés. Toutefois, les
    variations sont considérables en ce qui concerne les différents
    isomères d'un même dérivé.

    Chez l'homme et l'animal d'expérience, le métabolisme des
    chlorobenzènes conduit au chlorophénol correspondant par oxydation
    microsomique. Ces chlorophénols peuvent être excrétés dans l'urine
    sous forme d'acides mercapturiques, d'acide glucuronique ou de

    sulfo-conjugués. Le TeCB et le PeCB sont métabolisés plus lentement
    et séjournent dans les tissus plus longtemps que les dérivés
    monochlorés, dichlorés et trichlorés. Certains des chlorobenzènes
    induisent toute une variété de systèmes enzymatiques et notamment
    ceux qui interviennent dans les processus d'oxydation, de réduction,
    de conjugaison et d'hydrolyse.

    En général, les dérivés les plus chlorés s'éliminent plus lentement
    que le MCB et le DCB, la proportion des dérivés tétra et
    pentachlorés éliminés tels quels dans les matières fécales étant
    plus importante. C'est ainsi que 17 % d'une dose 1,2,4-TCB a été
    éliminé dans les matières fécales au bout de sept jours alors que 91
    à 97 % d'une dose de 1,4 TCB était éliminé sous forme de métabolites
    dans les urines au bout de cinq jours. La position des atomes de
    chlore sur le noyau benzénique conditionne également de manière
    importante la vitesse de métabolisation et d'élimination, les
    isomères possédant deux atomes de carbone adjacents non substitués
    étant métabolisés et éliminés plus rapidement.

    6.  Effets sur les organismes aquatiques dans leur milieu naturel

    Les renseignements dont on dispose sur les effets des
    chloro-benzènes au niveau de l'environnement, portent principalement
    sur leur toxicité aiguë pour les organismes aquatiques. En général,
    la toxicité augmente avec le degré de chloration du noyau
    benzénique. Alors que le MCB, le 1,2-DCB, le 1,3-DCB, le 1,2,4-TCB,
    le 1,3,5-TCB et le 1,2,4,5-TeCB sont tous peu toxiques pour les
    micro-organismes, la toxicité du TCB et des TeCBs est, à l'exception
    du 1,2,4,5-TeCB, plus élevée que celle des autres composés; chez les
    algues unicellulaires, la CL50 à 96 heures (pour la croissance
    cellulaire ou la production de chlorophylle) allait de plus de 300
    mg/litre dans le cas du MCB à environ 1 mg/litre dans le cas du
    1,2,3,5-TeCB. Certains invertébrés aquatiques paraissent plus
    sensibles aux chlorobenzènes, toutefois les concentrations
    nécessaires pour entraîner une mortalité à 48 ou 96 heures restent
    encore proches de 1 mg/litre ou nettement supérieures (par exemple
    2,4 mg/litre dans le cas du 1,2-DCB pour
     Daphnia magna et jusqu'à 530 mg/litre dans le cas du
    1,2,4,5-TeCB).

    Les valeurs de la CL50 à 96 heures pour  Lepomis machrochirus
    allaient de 0,3 mg/litre dans le cas du TeCB à 24 mg/litre dans le
    cas du MCB. L'étude de la toxicité chronique sur des stades
    embryo-larvaires a donné des limites allant de 0,76 à 2,0 mg/litre
    dans le cas des DCBs pour  Pimephales promelas; de 0,22 et de 0,13
    mg/litre respectivement dans le cas du 1,2,4-TCB et du 1,2,4,5-TeCB
    pour un autre vairon des eaux estuarielles. Les stades les plus
    sensibles dans le cas du MCB sont les alevins nouvellements éclos de
    poissons rouges et de  Micropterus salmoides, avec une CL50 à 96
    heures respectivement égale à 1 et 0,05 mg/litre.

    On ne dispose d'aucune donnée concernant les effets des
    chlorobenzènes sur les organismes terrestres.

    7.  Effets sur les animaux d'experience et sur les systemes
     in vitro

    A quelques exceptions près, les chlorobenzènes ne présentent qu'une
    toxicité aiguë modérée pour les animaux d'expérience et en général
    la DL50 par voie orale est supérieure à 1000 mg/kg de poids
    corporel; la DL50 dermique est plus élevée mais les données
    disponibles à ce sujet sont limitées. L'ingestion de doses mortelles
    entraîne une paralysie respiratoire, l'inhalation de fortes doses
    entraînant une irritation locale et une dépression du système
    nerveux central. Une intoxication aiguë par des doses non mortelles
    de chlorobenzène entraîne des effets au niveau du foie, des reins,
    des surrénales, des muqueuses, du cerveau ainsi que sur les enzymes
    métabolisantes.

    On n'a étudié l'irritation cutanée et oculaire due au chlorobenzène
    que dans le cas du 1,2,4-TCB et du 1,2-DCB. Ces deux composés
    causent une gêne très importante mais on n'a pas constaté de lésion
    permanente après application directe dans l'oeil de lapins. Le
    1,2,4-TCB est légèrement irritant pour la peau et peut provoquer une
    dermatite par suite d'un contact répété ou prolongé. On n'a constaté
    aucun signe de sensibilisation.

    Des rats et des souris exposés pendant de courtes périodes (5 et 21
    jours) à du MCB et des DCBs, à doses de plusieurs centaines de mg/kg
    de poids corporel ont présenté des lésions hépatiques et des
    anomalies hématologiques indiquant une atteinte de la moelle
    osseuse. Après exposition de brève durée de rats et de lapins à
    d'autres chlorobenzènes (TCD et PeCB) à des doses légèrement plus
    faibles que celles de MCB et de DCB, ce sont les lésions hépatiques
    qui constituaient le principal effet nocif constaté. Plusieurs des
    isomères étudiés ont provoqué une porphyrie, les isomères porteurs
    d'atomes de chlore en  para, étant les plus actifs de ce point de
    vue (c'est-à-dire 1,4-DCB, 1,2,4-TCB, 1,2,3,4-TeCB et PeCB). L'ordre
    décroissant de toxicité générale dans le cas des TeCBs et du PeCB
    après exposition de brève durée était le suivant : 1,2,4,5-TeCB 
    PeCB  1,2,3,4- et 1,2,3,5-TeCB, en bonne corrélation avec les
    concentrations retrouvées dans les graisses et le foie.

    Des études d'exposition au long cours (jusqu'à six mois) portant sur
    plusieurs espèces d'animaux d'expérience ont fait ressortir une
    tendance à l'augmentation de la toxicité avec le degré de chloration
    du noyau benzénique. Toutefois pour un même dérivé on constatait des
    variations importantes de cette toxicité selon l'isomère en cause.
    Par exemple 1,4-DCB s'est révélé beaucoup moins toxique que le
    1,2-DCB.

    Il y avait une bonne corrélation entre la toxicité d'un composé
    donné et son degré d'accumulation dans les tissus, les femelles
    étant moins sensibles que les mâles. Les principaux organes cibles
    étaient le foie et le rein; à dose plus élevée, on a signalé des
    effets sur le système hématopoïetique et une toxicité thyroïdienne a
    été observée dans les études portant sur le 1,2,4,5-TeCB et le PeCB.

    Une étude de cancérogénicité portant sur le MCB a fait ressortir un
    accroissement de l'incidence des nodules néoplasiques du foie dans
    le groupe de rats mâles F344 soumis à la dose la plus élevée (120
    mg/kg de poids corporel); toutefois on n'a pas noté d'accroissement
    de l'incidence tumorale, lié au traitement, chez ces rats, mâles ou
    femelles ou chez des souris femelles B6C3F1. Du 1,2-DCB a été
    administré à des rats F344 mâles et femelles et à des souris B6C3F1
    (60 ou 120 mg/kg de poids corporel), sans qu'on puisse observer de
    signe de cancérogénicité.

    Lors d'une étude de cancérogénicité portant le 1,4-DCB, on a noté un
    accroissement, lié à la dose, de la fréquence des adénocar-cinomes
    des tubules rénaux chez des rats mâles F344 ainsi qu'une
    augmentation de celle des carcinomes et des adénomes
    hépatocellulaires chez des souris B6C3F1 des deux sexes. Chez des
    rats Wistar mâles et femelles ainsi que des souris Swiss femelles on
    n'a noté aucun signe de cancérogénicité après exposition de ces
    animaux par inhalation à des doses légèrement plus élevées de
    1,4-DCB (dose estimée à 400 mg/kg par jour pour les rats et à 790
    mg/kg par jour pour les souris) pendant des périodes plus courtes.
    Toutefois les données disponibles indiquent que l'induction de
    tumeurs rénales par le 1,4-DCB chez les rats F344 mâles et la
    néphropathie grave avec formation d'inclusions hyalines, qui lui
    sont associées, constituent des réactions spécifiques de l'espèce et
    du sexe, liées à la réabsorption de l'alpha-2-microglobuline.

    Les données disponibles sont insuffisantes pour qu'on puisse évaluer
    le pouvoir cancérogène des chlorobenzènes fortement chlorés (tri,
    tétra et pentachlorobenzènes).

    On ne dispose que de données limitées résultant d'expériences
     in vitro et  in vivo, à propos des isomères autres que le
    1,4-DCB, toutefois les chlorobenzènes ne semblent pas être
    mutagènes. Sur la base de données plus nombreuses concernant le
    1,4-DCB, on peut conclure que ce composé n'a aucun pouvoir mutagène
     in vivo ou  in vitro.

    Rien n'indique non plus que les chlorobenzènes soient tératogènes
    pour le rat ou le lapin. L'administration de MCB et de DCBs à des
    rats ou des lapins par la voie respiratoire à une concentration
    supérieure à 2000 mg/m3 (environ 550 mg/kg de poids corporel et
    par jour) et, par voie orale, à des concentrations supérieures à

    500 mg/kg de poids corporel, a entraîné des effets embryotoxiques et
    fétotoxiques minimes. Toutefois ces doses étaient nettement toxiques
    pour les femelles gravides. Selon certains indices, les TCBs, les
    TeCBs et le PeCB seraient embryotoxiques et fétotoxiques à des doses
    non toxiques pour les femelles gravides, cependant les données
    disponibles ne sont pas cohérentes.

    8.  Effets sur l'homme

    8.1  Population generale

    Les rapports dont on dispose sur les effets des chlorobenzènes dans
    la population générale se limitent à des rapports ponctuels sur
    des cas d'accidents ou d'erreurs de manipulations de composés
    contenant des chlorobenzènes peu substitués (MCB, 1,2-DCB, 1,4-DCB
    ainsi qu'un isomère non précisé du TCB). On n'a pratiquement aucun
    renseignement sur les doses, la pureté chimique, les relations
    doses/temps et les effets observés, tels qu'une leucémie
    myéloblastique, une rhinite, une glomérulonéphrite, une
    granulomatose pulmonaire, des sensations vébrieuses, des
    tremblements, de l'ataxie, une polynévrite et un ictère - tous
    effets qui ne peuvent être évalués quantitativement.

    Aucune étude épidémiologique concernant les effets des
    chlorobenzènes sur la santé au sein de la population générale n'a
    été rapportée.

    8.2  Exposition professionnelle

    Au cours de la fabrication et de l'utilisation du chlorobenzène, on
    peut observer la symptomatologie suivante qui résulte d'une
    exposition excessive : effets sur le système nerveux central et
    irritation des yeux et des voies respiratoires supérieures (MCB);
    troubles hématologiques (1,2-DCB); effets sur le système nerveux
    central, durcissement de l'épiderme et troubles hématologiques -
    notamment anémie (1,4-DCB). Toutefois ces symptômes n'ont été
    décrits que lors de cas d'intoxications et sont difficiles à évaluer
    quantitativement car on ne possède guère de renseignements sur les
    concentrations réelles, la pureté chimique ou les relations
    dose/temps.

    Peu d'études é pidémiologiques ont été consacrées à l'exposition des
    travailleurs aux chlorobenzènes; elles ne portent que sur le MCB,
    1,2-DCB, 1,4-DCB et le 1,2,4,5-TeCB. On a signalé des effets sur le
    système nerveux, sur le développement néonatal et sur la peau après
    exposition au MCB mais les trois études en cause ne permettaient pas
    d'évaluer le risque pour des raisons d'ordre méthodologique qui
    tenaient notamment à l'évaluation de l'exposition, au fait que
    l'exposition n'était pas uniforme et qu'il n'y avait pas de groupe

    témoin. On peut émettre des critiques analogues à l'encontre de
    l'étude consacrée au 1,4-DCB, étude au cours de laquelle on a
    observé une irritation des muqueuses oculaires et nasales ainsi que
    de l'étude faisant état d'aberrations chromosomiques à la suite
    d'une exposition à des doses non précisées de 1,2-DCB et
    1,2,4,5-TeCB.

    9.  Conclusions

    Dans la mesure où les opérations industrielles sont effectuées
    conformément aux normes de bonne pratique, les risques qu'impliq ue
    une exposition professionnelle au chlorobenzène peuvent être
    considérés comme minimes. A l'heure actuelle, les concentrations de
    chlorobenzène dans l'environnement ne font courir qu'un risque
    minimum à la population générale sauf dans le cas d'erreurs de
    manipulation de produits à base de chlorobenzène ou de leur rejet
    inconsidéré dans le milieu ambiant. Cependant cette évaluation se
    base sur des données de surveillance limitées et il faudrait
    disposer de renseignements complémentaires pour confirmer cette
    conclusion. Il faudrait cependant envisager de réduire l'usage et
    les rejets de chlorobenzène pour les raisons suivantes:

     a) Les chlorobenzènes peuvent servir de précurseurs dans la
    formation de dibenzodioxines polychlorés et de dibenzofuranes
    polychlorés, par exemple lors de l'incinération de déchets.

     b) Ces produits peuvent communiquer un goût ou une odeur
    déplaisants à l'eau de boisson et au poisson.

     c) Des résidus persistent en condition d'anaérobiose dans les
    sédiments, des sols et les eaux souterraines riches en matières
    organiques.

    Pour la plupart des chlorobenzènes, l'évaluation du risque repose
    sur leurs effets non tumorigènes. Toutefois, on a tenu compte des
    effets tumorigènes lors de l'évaluation du risque dans le cas du MCB
    et du 1,4-DCB. Les données disponibles montrent que la fréquence
    accrue de tumeurs rénales chez des rats exposés à du 1,4-DCB
    constituent une réaction typique de cette espèce, liée au sexe, qui
    ne saurait être extrapolée à l'homme. En se basant sur le fait
    qu'après exposition à du 1,4-DCB, il y a accroissement de la
    réplication de l'ADN dans le foie de souris et accroissement de la
    fréquence des adénomes et des carcinomes hépatocellulaires chez ces
    mêmes animaux, on peut penser que ce produit est susceptible de se
    comporter comme un cancérogène non génotoxique dans le foie des
    rongeurs. La fréquence accrue de nodules hépatiques néoplasiques
    observée dans un groupe de rats mâles soumis à une dose élevée de
    MCB lors d'une étude de cancérogénicité indique également que ce
    dernier produit peut se comporter comme un cancérogène non
    génotoxique.

    RESUMEN

    La presente publicación se centra en los riesgos que tiene para la
    salud humana y el medio ambiente la exposición a los siguientes
    compuestos: monoclorobenceno (MCB), diclorobencenos (DCB),
    triclorobencenos (TCB); tetraclorobencenos (TeCB) y
    pentacloro-benceno (PeCB). La sustitución del cloro se indica de la
    manera siguiente: 1,2-diclorobenceno (1,2-DCB);
    1,2,3-triclorobenceno (1,2,3-TCB), etc.

    1  Identidad, propiedades fisicas y quimicas y metodos analiticos

    Los clorobencenos son compuestos aromáticos cíclicos formados por la
    adición de 1 a 6 átomos de cloro al anillo de benceno. De esta
    manera se obtienen 12 compuestos: monoclorobenceno, tres formas
    isómeras de di-, tri- y tetraclorobencenos, así como penta- y
    hexaclorobencenos.

    Los clorobencenos son sólidos cristalinos de color blanco a
    temperatura ambiente, excepto el MCB, el 1,2-DCB, el 1,3-DCB y el
    1,2,4-TCB, que son líquidos incoloros. La solubilidad de los
    clorobencenos en agua es en general baja, disminuyendo al aumentar
    el número de átomes de cloro. La inflamabilidad es escasa, los
    coeficientes de reparto octanol/agua son de moderados a altos y
    aumentan con el número de átomes de cloro, y las presiones de vapor
    son de bajas a moderadas, disminuyendo al aumentar el grado de
    cloración. El umbral de sabor y olor son bajos, en particular para
    los compuestos menos clorados.

    Los clorobencenos comerciales, incluso los purificados, contienen
    distintas cantidades de isómeros estrechamente relacionados. Por
    ejemplo, el MCB puro puede contener hasta un 0,05% de benceno y un
    0,1% de DCB, mientras que el 1,2-DCB de calidad técnica puede
    contener hasta un 19% de los otros DCB, un 1% de TCB y hasta un
    0,05% de MCB. No se ha informado de la existencia de pruebas de
    contaminación por dibenzo- p-dioxinas policloradas (DDPC) y
    dibenzofuranos policlorados (DFPC).

    Se han puesto a punto, en función del medio, un gran número de
    técnicas de muestreo para clorobencenos. Abarcan desde los métodos
    de extracción con disolventes para los medios acuosos hasta el uso
    de absorbentes para los compuestos presentes en el aire. La técnica
    analítica de elección para la determinación de clorobencenos en
    muestras obtenidas del medio ambiente es la cromatografía
    gas-líquido (CGL).

    2  Fuentes de exposicion humana y ambiental

    2.1  Cifras de produccion

    Los datos disponibles sobre las cifras de producción de
    clorobencenos corresponden al período 1980-83, cuando la producción
    mundial se estimaba en 568 x 106 kg, aunque la utilización de
    clorobencenos ha disminuido posteriormente en algunos países.
    Alrededor del 50% de esta cantidad se fabricaba en los Estados
    Unidos, y la mayor parte del resto en Europa occidental y el Japón.
    El 70% de la producción mundial era de MCB, y de 1,2-DCB, 1,4-DCB y
    1,2,4-TCB se producían respectivamente 22 x 106, 4 x 106 y 1,2-3,7 x
    106 kg.

    El MCB y el DCB se obtienen por cloración directa del benceno en la
    fase líquida utilizando un catalizador, mientras que los TCB y los
    TeCB se producen mediante la cloración directa de los isómeros de
    clorobenceno apropiados en presencia de un catalizador metálico.

    2.2  Aplicaciones

    Los clorobencenos se utilizan sobre todo como intermediarios en la
    síntesis de plaguicidas y de otros productos químicos; el 1,4-DCB se
    usa en los desodorante para ambientes cerrados y como repelente de
    las polillas. Los bencenos con mayor número de átomos de cloro (TCB
    y 1,2,3,4-TeCB) se han empleado como componentes de fluidos
    dieléctricos.

    2.3  Liberacion de clorobencenos en el medio ambiente

    La liberación de clorobencenos en el medio ambiente tiene lugar
    fundamentalmente durante la fabricación y por la naturaleza
    dispersiva de sus aplicaciones. En los Estados Unidos, por ejemplo,
    se estima que de las 130 x 106 toneladas de MCB producidas en 1983
    se perdió en el medio ambiente el 0,1-0,2%. La liberación de
    clorobencenos a partir de la eliminación de residuos, inclusive la
    incineración de vertidos municipales, es mucho más baja. Sin
    embargo, la incineración de clorobencenos puede producir emisiones
    de DDPC y DFPC.

    3  Transporte, distribucion y transformacion en el medio
    ambiente

    3.1  Degradacion

    La eliminación de los clorobencenos del medio ambiente se efectúa
    principalmente mediante mecanismos biológicos y, en menor medida,
    por otros sistemas; sin embargo, se considera que su presencia es
    moderadamente persistente en el agua, el aire y los sedimentos. Se
    ha informado que su tiempo de permanencia en el agua es de un día en

    la de río y de más de 100 días en la subterránea. En el aire, parece
    que las vías predominantes de degradación del clorobenceno son las
    reacciones químicas y fotolíticas, con tiempos de permanencia que
    para el MCB, los DCB y un isómero sin especificar del TCB se ha
    informado que oscilan entre 13 y 116 días. Se ha demostrado que
    muchos microorganismos presentes en los sedimentos y los fangos
    cloacales degradan los clorobencenos. Parece ser que los compuestos
    con mayor número de átomos de cloro se descomponen menos fácilmente,
    y tal proceso sólo tiene lugar en condiciones aerobias. El DCB, los
    TCB y los PeCB presentes en el suelo y en el agua subterránea en
    condiciones anaerobias suelen resistir la degradación microbiana.

    3.2  Destino final

    Los clorobencenos que se liberan en el medio acuático se
    redistribuyen de manera preferente en el aire y en los sedimentos
    (sobre todo en los ricos en materia orgánica). Son limitadas las
    informaciones según las cuales en los sedimentos se han detectado
    niveles 1000 veces superiores a los del agua, en particular en
    regiones muy industrializadas. La retención de clorobencenos en el
    suelo aumenta con el contenido de éste en materia orgánica; existe
    una correlación positiva entre el grado de cloración del compuesto y
    su adsorción a la materia orgánica. Hay pruebas limitadas que
    indican que los residuos unidos a los sedimentos están
    biodisponibles para los organismos, es decir, que los invertebrados
    acuáticos pueden captar residuos de los sedimentos, y las plantas,
    del suelo.

    4  Niveles medio ambientales y exposicion humana

    4.1  Clorobencenos en el medio ambiente

    Los niveles medios de clorobencenos (de mono- a tri-) en el aire del
    medio ambiente son del orden de 0,1 µg/m3, con niveles máximos de
    hasta 100 µg/m3. No se dispone de datos sobre los niveles de TeCB
    y PeCB en el aire, aunque estos compuestos químicos se han detectado
    en cenizas volantes procedentes de incineradores municipales. Los
    niveles de clorobencenos en el aire de los espacios cerrados son
    similares a los presentes en el aire exterior; sin embargo, se han
    comunicado concentraciones muy superiores en zonas intensamente
    contaminadas y en espacios cerrados donde se habían utilizado
    productos con clorobenceno.

    Se han detectado clorobencenos (de mono- a penta-) en aguas
    superficiales con concentraciones del orden de ng/litro-µg/litro,
    con niveles ocasionales de hasta décimas de mg/litro en las
    cercanías de fuentes industriales. Los niveles de clorobencenos en
    las aguas residuales industriales pueden ser más elevados y varían
    en función de la naturaleza de los procesos utilizados.

    En los análisis de muestras de agua de bebida se han detectado todos
    los tipos de clorobencenos. Los compuestos menos clorados eran los
    que se encontraban con mayor frecuencia y en concentraciones más
    elevadas, con predominio del isómero 1,4-DCB; sin embargo, las
    concentraciones medias de todos los clorobencenos detectados han
    sido en general inferiores a 1 µg/litro y raramente han superado los
    50 µg/litro.

    No se han encontrado datos procedentes de programas de vigilancia
    bien formulados sobre los niveles de clorobencenos en los alimentos;
    la información disponible se ha limitado principalmente a las
    concentraciones en los peces de zonas cercanas a fuentes
    industriales y a casos aislados de contaminación de productos
    cárnicos. En truchas de agua dulce se detectaron todos los isómeros
    del clorobenceno (de mono- a penta-), en concentraciones que
    oscilaban entre 0,1 y 16 µg/kg. En otro estudio, los niveles totales
    de clorobencenos en peces de agua dulce variaron de una media de 0,2
    mg/kg de grasa en las zonas ligeramente contaminadas a 1,8 mg/kg de
    grasa en una industrializada. Existen algunos indicios de que las
    concentraciones de clorobencenos en los peces de agua dulce aumentan
    a medida que es mayor el grado de cloración del producto. En los
    escasos estudios disponibles de algunos peces marinos se señalan
    niveles de 1,4-DCB de 0,05 mg/kg (peso fresco).

    En los estudios conocidos sobre los niveles de clorobencenos en la
    carne y en la leche, limitados principalmente a muestras procedentes
    de zonas contaminadas, se han comunicado concentraciones de 0,02-5
    µg/kg.

    En dos estudios de la leche materna se determinaron
    cuantitativamente las concentraciones de todos los clorobencenos,
    excepto el MCB. En el primero, el promedio de los niveles de DBC era
    de 25 µg/kg de leche, mientras que los valores medios relativos a
    los isómeros del TCB y el TeCB y al PeCB fueron inferiores a 5 µg/kg
    de leche. Los niveles en el segundo estudio fueron mucho más bajos,
    con concentraciones medias que oscilaban entre 1 µg/kilo (1,2,3-TCB
    y PeCB) y un máximo de 6 µg/kg (1,3- y 1,4-diclorobenceno).

    4.2  Exposicion humana

    4.2.1  Poblacion general

    De acuerdo con los limitados datos disponibles, la ingestión diaria
    de clorobencenos por la población general procede en su mayor parte
    del aire, en particular de los compuestos inferiores, más volátiles
    (0,2-0,9 µg/kg de peso corporal). La ingestión a partir de los
    alimentos en comparación con otras fuentes aumenta al elevarse el
    grado de cloración; Los alimentos contribuyen a un porcentaje más
    alto de la ingestión diaria total de TeCB y PeCB que el aire. Sin

    embargo, los niveles de exposición para este tipo de compuestos son
    probablemente inferiores a 0,05 µg/kg de peso corporal. En un número
    limitado de estudios se ha puesto de manifiesto que, teniendo en
    cuenta el peso corporal, los lactantes alimentados con leche materna
    pueden recibir una dosis más alta de clorobencenos que las personas
    adultas.

    4.2.2  Profesional

    Con los datos de que se dispone no es posible cuantificar con
    exactitud la exposición profesional a los clorobencenos. Sin
    embargo, en una fábrica se encontraron niveles de 1,4-DCB que
    oscilaban entre 42 y 288 mg/m3, y en otras instalaciones químicas
    las concentraciones de MCB eran de hasta 18,7 mg/m3.

    5  Cinetica y metabolismo

    Parece que todos los clorobencenos se absorben fácilmente de los
    tractos gastrointestinal y respiratorio en el hombre y en los
    animales de experimentación; influye en la absorción la posición de
    los átomos de cloro en los distintos isómeros del mismo compuesto.
    Los clorobencenos se absorben menos fácilmente a través de la piel.

    En los animales de experimentación, tras una rápida distribución en
    órganos con elevada perfusión, los clorobencenos absorbidos se
    acumulan sobre todo en el tejido adiposo, con cantidades menores en
    el hígado y en otros órganos. Se ha demostrado que atraviesan la
    placenta, y se han detectado en el cerebro del feto. En general, la
    acumulación es mayor en el caso de los compuestos más clorados. Sin
    embargo, hay una considerable diferencia de acumulación entre los
    distintos isómeros del mismo compuesto.

    El metabolismo de los clorobencenos en la especie humana y en los
    animales de experimentación sigue la vía de la oxidación microsómica
    para formar el clorofenol correspondiente. Estos clorofenoles se
    pueden excretar en la orina en forma de ácidos mercaptúricos, o bien
    como ácido glucurónico o conjugados de sulfato. El TeCB y el PeCB se
    metabolizan a menor velocidad y permanecen en los tejidos durante
    más tiempo que el grupo de los monocloro- a los triclorobencenos.
    Algunos de estos clorobencenos inducen una amplia gama de sistemas
    enzimáticos, entre ellos los que participan en las vías de
    oxidación, reducción, conjugación e hidrólisis.

    En general, la eliminación de los bencenos con mayor grado de
    cloración es más lenta que la de los MCB y DCB, y es mayor la
    proporción de los compuestos tri-, tetra y pentaclorobencenos que se
    eliminan inalterados en las heces. Por ejemplo, el 17% de una dosis
    de 1,2,4-TCB se eliminó en las heces al cabo de 7 días, mientras que

    el 91-97% del 1,4-DCB se excretó en la orina en forma de metabolitos
    a los 5 días. La posición de los átomos de cloro en el anillo
    bencénico es también un factor importante del que depende la
    velocidad de metabolización y eliminación; los isómeros con dos
    átomos de carbono adyacentes sin sustituir se metabolizan y eliminan
    más rápidamente.

    6.  Efectos en los organismos acuaticos del medio ambiente

    La información disponible acerca de los efectos de los clorobencenos
    en el medio ambiente se centra principalmente en sus efectos agudos
    sobre los animales acuáticos. En general, la toxicidad aumenta con
    el grado de cloración del anillo bencénico. Mientras que los MCB,
    1,2-DCB, 1,3-DCB, 1,2,4-TCB, 1,3,5-TCB y 1,2,4,5-TeCB presentan una
    baja toxicidad para los microorganismos, la de los TCB y TeCB es, a
    excepción del 1,2,4,5-TeCB, ligeramente superior a la de los otros
    compuestos; en algas unicelulares acuáticas, los valores de la CE50
    para el crecimiento celular o la producción de clorofila a en 96
    horas variaron de más de 300 mg/litro para el MCB hasta
    aproximadamente 1 mg/litro para el 1,2,3,5-TeCB. Algunos
    invertebrados acuáticos muestran mayor sensibilidad a los
    clorobencenos, pero los niveles necesarios para la letalidad en 48 ó
    96 horas son todavía próximos, o muy superiores, a 1 mg/litro (por
    ejemplo, para  Daphnia magna son de 2,4 mg/litro en el caso del
    1,2-DCB y de hasta 530 mg/litro en el del 1,2,4,5-TeCB).

    La CL50 a las 96 horas para  Lepomis macrochirus osciló entre 0,3
    mg/litro para el PeCB y 24 mg/litro para el MCB. En ensayos con
    embriones-larvas, los límites de toxicidad crónica para los DCB
    oscilaron entre 0,76 y 2,0 mg/litro para  Pimephales promelas; en
    la variedad de  Aplodinotus grunniens de los estuarios, los límites
    de la toxicidad crónica para el 1,2,4-TCB y 1,2,4,5-TeCB fueron de
    0,22 y 0,13 mg/litro respectivamente. En el caso de Carassius
    auratus y de la perca atruchada, los alevines recién nacidos
    constituyeron la etapa vital m s sensible, con CL50 (a las 96 h)
    de 1 y 0,05 mg/litro, respectivamente, para el MCB.

    No se conocen datos sobre los clorobencenos en los sistemas
    terrestres.

    7.  Efectos en los animales de experimentacion y en los
    sistemas  in vitro

    Salvo algunas excepciones, los clorobencenos son sólo moderadamente
    tóxicos para los animales de experimentación en cuanto a la
    toxicidad aguda, y en general la DL50 por vía oral es superior a
    los 1000 mg/kg de peso corporal; según los limitados datos
    disponibles, la DL50 por vía cutánea es más alta. La ingestión de

    una dosis letal produce parálisis respiratoria, mientras que la
    inhalación de dosis elevadas causa irritación local y depresión del
    sistema nervioso central. La exposición aguda a dosis no letales de
    clorobencenos induce efectos tóxicos en el hígado, los riñones, las
    glándulas suprarrenales, las adrenales membranas mucosas y el
    cerebro, y tiene efectos sobre las enzimas metabolizantes.

    Los estudios sobre la irritación de la piel y de los ojos ocasionada
    por los clorobencenos se han limitado al 1,2,4-TCB y al 1,2-DCB.
    Ambos producen graves molestias, pero no se observaron lesiones
    permanentes tras su aplicación directa a los ojos de conejos. El
    1,2,4-TCB es ligeramente irritante para la piel, pudiendo ocasionar
    dermatitis por contacto repetido o prolongado. No se encontraron
    pruebas de sensibilización.

    La exposición breve (5-21 días) de ratas y ratones al MCB y a los
    DCB en concentraciones del orden de cientos de mg/kg de peso
    corporal se tradujo en lesiones hepáticas y en cambios hemáticos
    indicativos de lesiones en la médula ósea. Las lesiones hepáticas
    fueron también el principal efecto nocivo observado tras la
    exposición breve de ratas y ratones a otros clorobencenos
    (TCB-PeCB), en dosis ligeramente menores que las utilizadas con el
    MCB y los DCB. Varios de los isómeros estudiados indujeron porfiria,
    siendo los más activos los que tienen los átomos de cloro en
    posición para (es decir, 1,4-DCB, 1,2,4-TCB, 1,2,3,4-TeCB y PeCB).
    El orden general de toxicidad observado para los TeCB y el PeCB tras
    una exposición breve fue el siguiente: 1,2,4,5-TeCB PeCB 1,2,3,4- y
    1,2,3,5-TeCB, lo que guarda una correlación adecuada con los niveles
    encontrados en la grasa y en el hígado.

    Los estudios de exposición a largo plazo (hasta seis meses) en
    varias especies de animales de experimentación pusieron de
    manifiesto que la toxicidad de los clorobencenos tendía a aumentar
    con el grado de cloración del anillo. Sin embargo, fue considerable
    la variación de la toxicidad a largo plazo de los distintos isómeros
    de un mismo compuesto. Por ejemplo, el 1,4-DCB demostró ser mucho
    menos tóxico que el 1,2-DCB. Se observó una correlación positiva
    entre la toxicidad y el grado de acumulación del compuesto en los
    tejidos, siendo las hembras menos sensibles que los machos. Los
    órganos más afectados fueron el hígado y los riñones; con dosis más
    elevadas se describieron efectos en el sistema hematopoyético, y en
    estudios con el 1,2,4,5-TeCB y el PeCB se observó toxicidad en el
    tiroides.

    En un bioensayo para determinar la carcinogenicidad del MCB, aumentó
    la frecuencia de nódulos neoplásicos hepáticos en el grupo de dosis
    alta (120 mg/kg de peso corporal) de ratas macho F344, pero no hubo
    aumento de la incidencia de tumores asociada con el tratamiento en
    ratas hembra F344 o en ratones macho o hembra B6C3F1. No se
    obtuvieron pruebas de la carcinogenicidad del 1,2-DCB en ratas
    machos o hembras F344 ni en ratones B6C3F1 (60 ó 120 mg/kg de peso
    corporal).

    En un bioensayo para determinar la carcinogenicidad del 1,4-DCB, se
    registró un incremento de la formación de adenocarcinomas de las
    células de los túbulos renales relacionado con la dosis en ratas
    macho F344 y un aumento de los carcinomas y adenomas hepatocelulares
    en ambos sexos de ratones B6C3F1. No se comunicaron signos de
    carcinogenicidad en ratas Wistar macho y hembra, ni en hembras de
    raton suizo tras la inhalación de dosis ligeramente más altas de
    1,4-DCB (estimadas en 400 mg/kg al día para las ratas y 790 mg/kg al
    día para los ratones) durante períodos más cortos. Sin embargo, los
    datos disponibles indican que la inducción de tumores renales por el
    1,4-DCB en ratas macho F344 y la inducción asociada de nefropatia
    grave y de la formación de gotitas hialinas son respuestas
    específicas de la especie y del sexo, asociadas a la reabsorción de
    alfa-2-microglobulina.

    Los datos disponibles son insuficientes para valorar la
    carcinogenicidad de los bencenos con mayor grado de cloración (de
    tri- a penta-).

    Aunque los datos obtenidos en ensayos in vitro e in vivo para
    isómeros distintos del 1,4-DCB son limitados, los clorobencenos no
    parecen tener efectos mutagénicos. Teniendo en cuenta la base de
    datos más amplia del 1,4-DCB, se puede concluir que este compuesto
    carece de potencial mutagénico, tanto in vivo como in vitro.

    No hay pruebas de teratogenicidad de los clorobencenos en ratas y en
    conejos. La administración de MCB y de distintos DCB a ratas o
    conejos por vía respiratoria en concentraciones superiores a
    2000 mg/m3 (unos 550 mg/kg de peso corporal al día) y por vía oral
    a concentraciones de >500 mg/kg de peso corporal dio como resultado
    efectos embriotóxicos y fetotóxicos de poca consideración. Sin
    embargo, esas dosis fueron claramente tóxicas para la madre. Aunque
    hay algunas pruebas de embriotoxicidad y fetotoxicidad de los TCB,
    los TeCB y los PeCB en dosis que no son tóxicas para la madre, los
    datos disponibles son contradictorios.

    8.  Efectos en el ser humano

    8.1  Poblacion general

    Los informes acerca de los efectos de los clorobencenos en la
    población general se limitan a los casos notificados de accidentes
    y/o de uso indebido de productos con los bencenos menos clorados
    (MCB, 1,2-DCB, 1,4-DCB y un isómero de TCB sin especificar). Se
    dispone de información escasa o nula sobre las dosis, la pureza
    química o las relaciones dosis:tiempo y no es posible determinar
    cuantitativamente los efectos observados, como leucemia
    mieloblástica, rinitis, glomerulonefritis, granulomatosis pulmonar,
    mareo, temblor, ataxia, polineuritis e ictericia. 

    No se han comunicado de estudios epidemiológicos sobre los efectos
    de los clorobencenos en la salud de la población general.

    8.2  Exposicion profesional

    Entre los síntomas y los signos clínicos derivados de la exposición
    excesiva durante la fabricación y el uso de los clorobencenos cabe
    mencionar los siguientes: efectos en el sistema nervioso central
    (SNC) e irritación de los ojos y del tracto respiratorio superior
    (MCB); trastornos hematológicos (1,2-DCB); y efectos en el SNC,
    endurecimiento de la piel y trastornos hematológicos, incluso anemia
    (1,4-DCB). Sin embargo, tales síntomas proceden sólo de informes de
    casos aislados y son difíciles de determinar cuantitativamente,
    puesto que se dispone de escasa información relativa a los niveles
    reales, la pureza química o las relaciones dosis:tiempo.

    Los pocos estudios epidemiológicos sobre trabajadores expuestos a
    clorobencenos que se han publicado se refieren solamente al MCB, el
    1,2-DCB, el 1,4-DCB y el 1,2,4,5-TeCB. Aunque se ha informado de
    efectos en el sistema nervioso, en el desarrollo neonatal y en la
    piel tras la exposición al MCB, ninguno de los tres estudios fue
    suficiente para evaluar el riesgo, a causa de problemas
    metodo-lógicos, como la valoración de la exposición, las
    exposiciones mixtas y la ausencia de grupos testigo. Una crítica
    parecida merece el estudio sobre el 1,4-DCB, en el que se informó de
    irritación ocular y nasal, así como el estudio en el que se
    describieron aberraciones cromosómicas como consecuencia de la
    exposición a niveles no especificados de 1,2-DCB y 1,2,4,5-TeCB.

    9  Conclusiones

    Si se aplica una práctica industrial correcta, los riesgos asociados
    con la exposición profesional a los clorobencenos se pueden
    considerar mínimos. La evaluación del riesgo en la actualidad pone
    de manifiesto también que las concentraciones actuales de

    clorobencenos en el medio ambiente representan un riesgo
    insignificante para la población general, excepto en el caso de uso
    indebido de productos que contienen clorobencenos o de su liberación
    incontrolada en el medio ambiente. Sin embargo, esta valoración se
    basa en datos limitados de vigilancia, y se necesita más información
    para justificar esta conclusión. Se debería considerar, sin embargo,
    la posibilidad de reducir el uso y la eliminación generalizados de
    clorobencenos por los siguientes motivos:

     a) Los clorobencenos pueden actuar como precursores de la
    formación de dibenzodioxinas policloradas/dibenzofuranos
    policlorados (DDPC/DFPC), por ejemplo en los procesos de
    incineración.

     b) Estos productos químicos pueden ocasionar alteraciones del
    sabor y el olor del agua de bebida y del pescado.

     c) Los residuos persisten en los sedimentos y suelos anaerobios
    ricos en materia orgánica y en el agua subterránea.

    En la mayor parte de los clorobencenos, la evaluación del riesgo se
    ha basado en efectos no neoplásicos. Sin embargo, los efectos
    neoplásicos se tuvieron en cuenta en la valoración del riesgo del
    MCB y el 1,4-DCB. Los datos disponibles indican que el aumento
    observado de los tumores renales en ratas debido al 1,4-DCB es una
    respuesta específica de la especie y del sexo, probablemente sin
    importancia para la especie humana. De acuerdo con las pruebas de
    aumento de la replicación del ADN en el hígado de ratón y la mayor
    incidencia de adenomas y carcinomas hepato-celulares en ratones, el
    1,4-DCB puede actuar como agente carcinógeno no genotóxico en el
    hígado de los roedores. La mayor incidencia de nódulos neoplásicos
    hepáticos observada en el grupo de ratas macho que recibió dosis
    altas en un bioensayo de carcinogenicidad indica que también el MCB
    puede ser un agente carcinógeno no genotóxico.


    See Also:
       Toxicological Abbreviations