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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 176




    1,2-DICHLOROETHANE 
    (SECOND EDITION)











    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 K. Hughes, Environmental Health
    Directorate, Health Canada


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


    World Health Organization
    Geneva, 1995

       The International Programme on Chemical Safety (IPCS) is a joint
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    WHO Library Cataloguing in Publication Data

    1,2-Dichloroethane - 2nd ed.

    (Environmental health criteria ; 176)

    1.Ethylene dichlorides - toxicity   I.Series

    ISBN 92 4 157176 4        (NLM Classification: QV 633)
    ISSN 0250-863X

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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR 1,2-DICHLOROETHANE

    Preamble

    1. SUMMARY

         1.1. Identity, physical and chemical properties,
                and analytical methods
         1.2. Sources of human and environmental exposure
         1.3. Environmental transport, distribution and
                transformation
         1.4. Environmental levels and human exposure
         1.5. Kinetics and metabolism in laboratory animals
         1.6. Effects on laboratory mammals and in vitro
                test systems
         1.7. Effects on humans
         1.8. Effects on non-target organisms in the
                laboratory and field

    2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND
         ANALYTICAL METHODS

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

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1. Natural occurrence
         3.2. Anthropogenic sources
                3.2.1. Production levels and processes
                3.2.2. Uses

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND
         TRANSFORMATION

         4.1. Transport and fate in the environment

    5. ENVIRONMENTAL LEVELS AND POPULATION EXPOSURE

         5.1. Environmental levels
                5.1.1. Ambient air
                5.1.2. Indoor air
                5.1.3. Drinking-water
                5.1.4. Surface water
                5.1.5. Food
                5.1.6. Soils and sediments
                5.1.7. Consumer products
         5.2. General population exposure
                5.2.1. Ambient air
                5.2.2. Indoor air
                5.2.3. Drinking-water
                5.2.4. Food
                5.2.5. Other media
         5.3. Occupational exposure during manufacture,
                formulation or use

    6. KINETICS AND METABOLISM IN LABORATORY ANIMALS
         AND HUMANS

         6.1. Absorption
         6.2. Distribution
         6.3. Metabolic transformation
         6.4. Elimination and excretion
         6.5. Retention and bioaccumulation

    7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO
         TEST SYSTEMS

         7.1. Single exposure
         7.2. Skin and eye irritation
         7.3. Short-term exposure
         7.4. Subchronic exposure
                7.4.1. Inhalation
                7.4.2. Ingestion
         7.5. Chronic exposure and carcinogenicity
                7.5.1. Inhalation
                7.5.2. Ingestion
                7.5.3. Other routes of administration
                7.5.4. Initiation/promotion bioassays
         7.6. Mutagenicity and related end-points
         7.7. Reproductive toxicity, embryotoxicity and
                teratogenicity
         7.8. Immunological effects
         7.9. Toxicological interactions with other agents

    8. EFFECTS ON HUMANS

         8.1. Case reports
         8.2. Epidemiological studies

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY
         AND FIELD

         9.1. Aquatic organisms
                9.1.1. Microorganisms
                9.1.2. Invertebrates
                9.1.3. Vertebrates
         9.2. Terrestrial organisms
                9.2.1. Invertebrates
                9.2.2. Vertebrates
                9.2.3. Plants

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

         10.1. Evaluation of human health risks
         10.2. Environmental assessment

    11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF
         HUMAN HEALTH AND THE ENVIRONMENT

    12. FURTHER RESEARCH

    13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    RESUME

    RESUMEN
    

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS


         Every effort has been made to present information in the criteria
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         A detailed data profile and a legal file can be obtained from the
    International Register of Potentially Toxic Chemicals, Case postale
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                                    *     *     *



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

    Environmental Health Criteria

    PREAMBLE

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    FIGURE 01

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    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR 1,2-DICHLOROETHANE

     Members

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    Dr P. Sinhaseni, Chulalongkorn University, Bangkok, Thailand

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

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

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

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

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

     Secretariat

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

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

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

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

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

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

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

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

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

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

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

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

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

    ENVIRONMENTAL HEALTH CRITERIA FOR 1,2-DICHLOROETHANE


         The Core Assessment Group (CAG) of the Joint Meeting on
    Pesticides (JMP) met in Geneva from 25 October to 3 November 1994. 
    Dr W. Kreisel, Executive Director, welcomed the participants on behalf
    of WHO, and Dr M. Mercier, Director, IPCS, on behalf of the IPCS and
    its cooperating organizations (UNEP/ILO/WHO).  The Core Assessment
    Group reviewed and revised the draft monograph and made an evaluation
    of the risks for human health and the environment from exposure to
    1,2-dichloroethane (ethylene dichloride).

         The first draft of the monograph was prepared by Ms K. Hughes,
    Environmental Health Directorate, Health Canada.  The second draft,
    revised in the light of international comment, was also prepared by
    Ms K. Hughes.  Dr E. Smith and Dr P.G. Jenkins, both members of the IPCS
    Central Unit, were responsible for the scientific content and
    technical editing respectively.

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

                          *      *      *

         1,2-Dichloroethane was previously evaluated by a WHO Task Group
    in 1986 and published by WHO in 1987 as Environmental Health Criteria
    62.

    ABBREVIATIONS

    BCF          bioconcentration factor
    BUN          blood urea nitrogen
    ECD          electron capture detector
    FID          flame ionization detector
    GC           gas chromatography
    GSH          glutathione
    gamma-GT     gamma-glutamyltranspeptidase
    HECD         Hall electron capture detector
    LOEL         lowest-observed-effect level
    MS           mass spectrometry
    NOEL         no-observed-effect level
    PIB          piperonyl butoxide
    SGOT         serum glutamic-oxalic transaminase
    SGPT         serum glutamic-pyruvic transaminase
    TEAM         total exposure assessment methodology
    TWA          time-weighted average

    1.  Summary

    1.1  Identity, physical and chemical properties, and analytical
         methods

         1,2-Dichloroethane (ethylene dichloride) is a synthetic chemical
    which is a colourless liquid at room temperature.  It is also highly
    volatile, with a vapour pressure of 8.5 kPa (at 20°C), and is soluble
    in water, with a solubility of 8690 mg/litre (at 20°C).  The log
    octanol/water partition coefficient is 1.76.

         Analysis for 1,2-dichloroethane in environmental media is usually
    by gas chromatography, in combination with electron capture or flame
    ionization detection or mass spectrometry.  Detection limits range
    from 0.016 to > 4 µg/m3 in air, 0.001 to 4.7 µg/litre in water, and
    from 6 to 10 µg/kg in various foodstuffs.

    1.2  Sources of human and environmental exposure

         The principal use of 1,2-dichloroethane is in the synthesis of
    vinyl chloride monomer, and to a lesser extent in the manufacture of
    various chlorinated solvents.  It is also incorporated into anti-knock
    gasoline additives (although this use is declining with the phase-out
    of leaded gasoline in some countries), and has been used as a
    fumigant.  Total annual production of 1,2-dichloroethane in Canada in
    1990 and the USA in 1991 was 922 and 6318 kilotonnes, respectively.

    1.3  Environmental transport, distribution and transformation

         The majority of 1,2-dichloroethane released to the environment is
    in emissions to air.  It is moderately persistent in air; the
    estimated atmospheric lifetime is between 43 and 111 days.
    1,2-Dichloroethane is transported to the stratosphere, where
    photolysis may produce chlorine radicals which may in turn react with
    ozone.  Some 1,2-dichloroethane may be released in industrial
    effluents to the aquatic environment, from which it is removed rapidly
    by volatilization.  1,2-Dichloroethane may also leach to groundwater
    near industrial waste sites.  It is not expected to bioconcentrate in
    aquatic or terrestrial species.

    1.4  Environmental levels and human exposure

         Mean concentrations of 1,2-dichloroethane in recent surveys of
    ambient air in non-source-dominated areas of cities range from 0.07 to
    0.28 µg/m3, while mean levels in residential indoor air are reported
    to range from < 0.1 to 3.4 µg/m3. In drinking-water, mean
    concentrations are generally less than 0.5 µg/litre. 
    1,2-Dichloroethane has only rarely been detected in foodstuffs in
    recent surveys and, since it has low potential for bioaccumulation,
    food is unlikely to be a major source of exposure.

         Based on estimates of mean exposure from various media, the
    predominant source of exposure to 1,2-dichloroethane by the general
    population is indoor and outdoor air, only minor amounts being
    contributed by drinking-water. Intake of 1,2-dichloroethane from food
    is probably negligible.  The amount inhaled in ambient air may be
    greater in the vicinity of industrial sources.

    1.5  Kinetics and metabolism in laboratory animals

         1,2-Dichloroethane is readily absorbed following inhalation,
    ingestion or dermal exposure and is rapidly and widely distributed
    throughout the body.  It is rapidly and extensively metabolized in
    rats and mice, with principally sulfur-containing metabolites being
    eliminated in the urine in a dose-dependent manner.  Metabolism
    appears to be saturated or limited in rats at levels of exposure
    resulting in blood concentrations of 5 to 10 µg/ml.  Levels of DNA
    alkylation were higher following exposure to a bolus dose by gavage
    than in the case of inhalation over a 6-h period.

         1,2-Dichloroethane appears to be metabolized via two principal
    pathways; the first involves a saturable microsomal oxidation mediated
    by cytochrome P-450 to 2-chloroacetaldehyde and 2-chloroethanol
    followed by conjugation with glutathione.  The second pathway entails
    direct conjugation with glutathione to form  S-(2-chloroethyl)-
    glutathione, which may be non-enzymatically converted to a glutathione
    episulfonium ion; this ion can form adducts with DNA.  Although DNA
    damage has been induced by the P-450 pathway  in vitro, several lines
    of evidence indicate that the glutathione conjugation pathway is
    probably of greater significance than the P-450 pathway as the major
    route for DNA damage.

    1.6  Effects on laboratory mammals and in vitro test systems

         The acute toxicity of 1,2-dichloroethane is low in experimental
    animals.  For example, inhalation LC50s for rats exposed for 6 or
    7.25 h ranged from 4000 mg/m3 to 6600 mg/m3, while oral LD50s
    for rats, mice, dogs and rabbits ranged from 413 to 2500 mg/kg body
    weight.

         The results of short-term and subchronic studies in several
    species of experimental animals indicate that the liver and kidneys
    are the target organs;  reliable NOELs or LOELs were not attained in
    general due to inadequate documentation and the limited range of
    end-points examined in small groups of animals.  In a series of early
    limited studies, morphological changes in the liver were observed in
    several species following subchronic exposure to airborne
    concentrations as low as 800 mg/m3.  Increases in the relative liver
    weight have been observed in rats following subchronic oral
    administration of doses of 49 to 82 mg/kg body weight per day or more

    for 13 weeks.  Little information was presented on non-neoplastic
    effects in available chronic studies.  Changes in serum parameters
    indicative of liver and kidney toxicity were observed in rats exposed
    to airborne concentrations as low as 202 mg/m3 for 12 months,
    although histopathological examinations were not conducted in this
    study.

         The carcinogenicity of 1,2-dichloroethane has been investigated
    in a few limited bioassays on experimental animals (limitations
    include short duration of exposure and high mortality).  Significant
    increases were not reported in the incidence of any type of tumour in
    Sprague-Dawley rats or Swiss mice exposed to up to 607 mg/m3 for 78
    weeks and observed until spontaneous death.  Mortality was high in
    rats in this study, although it was not related to concentration, and
    the incidence rates were not adjusted for differential mortality among
    groups.  There was a nonsignificant increase in the incidence of
    mammary gland adenomas and fibroadenomas in female Sprague-Dawley rats
    exposed to 200 mg/m3 for 2 years in an assay in which no other
    compound-related toxicity was observed.

         In contrast, there was convincing evidence of increases in tumour
    incidence in two species following ingestion.  Significant increases
    in the incidence of tumours at several sites (including squamous cell
    carcinomas of the stomach (males), haemangiosarcomas (males and
    females), fibromas of the subcutaneous tissue (males), adenocarcinomas
    and fibroadenomas of the mammary gland (females)) were observed in
    Osborne-Mendel rats administered TWA daily doses of 47 or 95 mg/kg
    body weight per day by gavage for 78 weeks.  Similar increases in the
    incidences of tumours at multiple sites (including
    alveolar/bronchiolar adenomas (males and females), mammary gland
    adenocarcinomas (females) and endometrial stromal polyp or endometrial
    stromal sarcoma combined (females) and hepatocellular carcinomas
    (males)) occurred in B6C3F1 mice administered TWA daily doses of 97 or
    195 mg/kg body weight per day (males) or 149 or 299 mg/kg body weight
    per day (females) by gavage for 78 weeks.

         The incidence of lung tumours (benign papillomas) was
    significantly increased in female mice following repeated dermal
    application of 1,2-dichloroethane for 440 to 594 days.  Repeated
    intraperitoneal injections of 1,2-dichloroethane resulted in
    dose-related increases in the number of pulmonary adenomas per mouse
    in a susceptible strain, although none of these increases was
    significant.  Concomitant exposure to inhaled 1,2-dichloroethane and
    disulfiram in the diet resulted in an increased incidence of
    intrahepatic bile duct cholangiomas and cysts, subcutaneous fibromas,
    hepatic neoplastic nodules, interstitial cell tumours in the testes
    and mammary adenocarcinomas in rats, compared to rats administered
    either compound alone or untreated controls.  No potential to initiate
    or promote tumour development was evident in three bioassays, although
    the extent of histopathological examination was limited in these
    studies.

         In  in vitro assays, 1,2-dichloroethane has been consistently
    positive in mutagenicity bioassays in  Salmonella typhimurium.
    Responses have been greater in the presence of an exogenous activation
    system (possibly due to activation by the cytochrome system) than in
    its absence, and mutagenicity was more than doubled in  S. typhimurium
    expressing the human GSTA1-1 gene. In cultured mammalian cells,
    1,2-dichloroethane forms adducts with DNA.  It also induces
    unscheduled DNA synthesis in primary cultures of rodent and human
    cells and gene mutation in several cell lines.  Mutation frequency in
    human cell lines has been correlated with differences in
    glutathione- S-transferase activity.  In  in vivo studies,
    1,2-dichloroethane induced somatic cell and sex-linked recessive
    lethal mutations in  Drosophila melanogaster and the compound bound
    to DNA in all reported studies in rats and mice.  Although primary DNA
    damage in liver and sister chromatid exchange has been observed in
    studies in mice, there has been no evidence for micronucleus
    induction.

         Based on the results of a limited number of studies, there is no
    evidence that 1,2-dichloroethane is teratogenic in experimental
    animals.  There is also little convincing evidence that it induces
    reproductive or developmental effects at doses below those which cause
    other systemic effects. Available data on the immunotoxicity of
    1,2-dichloroethane are limited.

    1.7  Effects on humans

         Acute incidental exposure to 1,2-dichloroethane by inhalation or
    ingestion has resulted in a variety of effects in humans, including
    effects on the central nervous system, liver, kidney, lung and
    cardiovascular system.

         The potential carcinogenicity of 1,2-dichloroethane in exposed
    human populations has not been extensively investigated.  Mortality
    due to pancreatic cancer was significantly increased in a group of
    workers at a chemical production plant who had been exposed
    principally to 1,2-dichloroethane (in combination with other
    chemicals).  Mortality due to pancreatic cancer increased with
    duration of exposure.  In addition, although the number of cases was
    small, and the association with duration of exposure was less
    consistent, mortality due to leukaemia was also increased in these
    workers.  No association between occupational exposure to
    1,2-dichloroethane and brain cancer was noted in a small case-control
    study.  Although the incidence of colon and rectal cancer increased
    with the concentration of 1,2-dichloroethane in drinking-water in an
    inherently limited ecological study, concomitant exposure to other
    substances may have contributed to the observed effects.

    1.8  Effects on non-target organisms in the laboratory and field

         The effects of exposure to 1,2-dichloroethane on a number of
    other organisms in the laboratory and field have been investigated. 
    For aquatic microorganisms, IC50s or EC50s for various end-points
    have been reported to range from 25 to 770 mg/litre.  The lowest
    reported LC50 value for Daphnia was 220 mg/litre, while effects on
    reproductive success and growth were observed at 20.7 and
    71.7 mg/litre, respectively.  Based on available data, the most
    sensitive freshwater vertebrate species appears to be the northwestern
    salamander  (Ambystoma gracile), in which 9-day larval survival (4
    days post-hatch) was reduced at 2.54 mg/litre.  Only limited data are
    available on the toxicity of 1,2-dichloroethane to terrestrial
    organisms.

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS

    2.1  Identity

         The empirical formula for 1,2-dichloroethane (ethylene
    dichloride) is C2H4Cl2 and the molecular structure is as
    follows:

                                H     H
                                '     '
                          Cl -  C  -  C  -  Cl
                                '     '
                                H     H

         Synonyms include EDC, 1,2-DCE, 1,2-bichloroethane, 1,2-ethylene
    dichloride, acethylenchlorid, alpha, beta-dichloroethane, bichlorure
    d'ethelene, ethyleen dichloride, ethylene chloride, glycol dichloride,
    and sym-dichlorothane.  Trade names include: Borer sol, Brocide,
    Destruxo,l Di-chlor-mulson, Dichlor-mulsion, Dutch liquid, Dutch oil,
    ENT 1656, Freon 150, Gaze Olefiant and Granosan (which also contains
    carbon tetrachloride).

         The Chemical Abstract Service (CAS) registry number for
    1,2-dichloroethane is 107-06-2.

    2.2  Physical and chemical properties

         1,2-Dichloroethane is a clear, colourless liquid at room
    temperature.  It is a highly volatile and flammable synthetic chemical
    which absorbs infrared light at several wavelengths (7, 12 and 13 µm). 
    Other properties of 1,2-dichloroethane are presented in Table 1.

    2.3  Conversion factors

           1 ppm = 4 mg/m3
           1 mg/m3 = 0.25 ppm (at 25°C and 760 mmHg)

    Table 1.  Physical properties of 1,2-dichloroethanea
                                                                        

    Physical state                         liquid
    Colour                                 colourless
    Odour                                  sweet, chloroform-like
    Relative molecular mass                98.96
    Density d20                            1.253
    Refractive index r20                   1.4449
                       D
    Boiling point                          83°C
    Melting point                          -35°C
    Water solubility                       8690 mg/litre (20°C)
    Vapour pressure                        8.5 kPa (20°C)
    Saturation concentration in air        350 g/m3 (20°C)
                                           537 g/m3 (30°C)
    log Kow                                1.76
    log Koc                                1.28
    Henry's law constant                   111.5 Pa.m3/mol (25°C)
    Flash point                            12-15°C
    Limits of flammability in air          275-700 mg/litre
                                                                        

    a    From: Archer (1979); Chiou et al. (1979); Konemann (1981);
         Warner et al. (1987); Worthing & Hance (1991)

    2.4  Analytical methods

         Methods of analysis of 1,2-dichloroethane in various
    environmental media are described in Table 2.  Gas chromatography,
    coupled with electron capture or flame ionization detection or mass
    spectrometry, is commonly used for analysis of 1,2-dichloroethane in
    most media.


        Table 2.  Analytical methods for 1,2-dichloroethane in environmental mediaa
                                                                                                                                                

    Sample matrix      Preparation method                         Analytical method    Sample detection   Percentage       Reference
                                                                                       limit              recovery
                                                                                                                                                

    Air                collect sample on Tenax(R)-GC absorbent    GC/MS                100 ng/m3          not available    Wallace et al.
                                                                                                                           (1984)

                       not available                              GC/MS                < 20 ng/m3         ± 5% precision   Grimsrud &
                                                                                       (< 5 ppt)                           Rasmussen (1975)

                       collect in 6-litres canisters; direct      GC/ECD-MS            > 4 µg/m3          not available    Pleil et al.
                       injection                                                       (> 1 ppb)                           (1988)

                       collect air sample in tubes filled with    GC/MS                30 pg/sample       98-108%          Jonsson & Berg
                       solid absorbent; heat sample tubes;                                                                 (1980)
                       monitor for 1,2-dichloroethane using
                       selected ion monitoring

                       collect sample on Tenax(R) TA; thermal     GC/ECD               16 ng/m3           not available    Class &
                       desorption                                                      (4 ppt)                             Ballschmiter (1986)

                       charcoal-tube sampler; desorption with     GC/FID               10 µg/sample       not available    NIOSH (1984)
                       CS2 solvent

                       continuous monitoring and breath           infra-red            not available      not available    Baretta et al.
                       analysis                                   spectroscopy                                             (1969)

                       sampling on charcoal or Chromosorb         GC/FID               1.2 µg/m3          not available    Parkes et al.
                                                                                                                           (1976)
                                                                                                                                                

    Table 2. cont'd.
                                                                                                                                                

    Sample matrix      Preparation method                         Analytical method    Sample detection   Percentage       Reference
                                                                                       limit              recovery
                                                                                                                                                

                       collect sample on Tenax(R) polymeric       GC/MS                32 ng/m3           not available    Krost et al. (1982)
                       beads

    Water              purge-and-trap                             GC/MS                5 ng/litre         not available    Wallace et al.
                                                                                                                           (1984)

                       purge-and-trap                             GC/FID               0.1 µg/litre       99%              Warner & Beasley
                                                                                       (0.1 ppb)                           (1984)

                       headspace/cryogenic trapping               HR capillary         80 ng/litre        75%              Comba & Kaiser
                                                                  GC/ECD                                                   (1983)

    Water and          purge-and-trap                             GC                   30 ng/litre        1.04-1.06C       US EPA (1982b)
    wastewater                                                                                            97.8%            (method 601)

                       grab sample                                GC/MS                4.7 µg/litre       1.02 + 0.45C     US EPA (1982b)
                                                                                                          99%              (method 624)

                       modified purge-and-trap                    GD/HECD and FID      FID 0.1 µg/litre;  FID 78%;         Otson & Williams
                                                                  simultaneous         HECD <             HECD 79%         (1982)
                                                                                       0.1 µg/litre

                       stripping by helium adsorption on          GC/FID or MS         1 ng/litre         not available    Sauer (1981)
                       Tenax(R)

                       stripping by helium or nitrogen,           GC with              0.1-0.4 µg/litre   not available    Symons et al.
                       sorption on Tenax(R) or chromosorb         microcoulometric                                         (1975)
                                                                  detection

                       not available                              GC/MS                0.5 µg/litre       not available    Fujii (1977)
                                                                                                                                                

    Table 2. cont'd.
                                                                                                                                                

    Sample matrix      Preparation method                         Analytical method    Sample detection   Percentage       Reference
                                                                                       limit              recovery
                                                                                                                                                

    Grains, legumes,   acidified acetone-water extraction;        GC/ECD               not available      14-75%           Daft (1987, 1988,
    spices, citrus     isooctane back extraction; for liquids,                                                             1989, 1991, 1993)
    fruits,            isooctane extraction
    beverages,
    dairy
    products, meat

    Table-ready        stirred with water; purge-and-trap         GC/ECD               6 µg/kg            85-104%          Heikes (1987b);
    foods              on Tenax(R) GC; hexane desorption                               (6 ppb)                             Heikes & Hopper
                                                                                                                           (1986)

    Fish               add fish tissue to reagent grade water;    GC/MS                10 µg/kg           85 ± 11%         Easley et al.
                       disrupt cells ultrasonically; analyse                                                               (1981)
                       sample by purge-and-trap method

                       spiked samples of ground fish tissue;      GC/MS                not available      92 ± 5%c         Hiatt (1981)
                       vaporize VOCs from fish sample under
                       vacuum and condense in purge-and-trap

                       homogenize fish sample; remove residual    GC/MS-fused          not available      not available    Hiatt (1983)
                       moisture by vacuum distillation            silica capillary     column

    Sediment           spiked samples; vaporize VOCs under        GC/MS                not available      96 ± 17%c        Hiatt (1981)
                       vacuum and condense in purge-and-trap
                                                                                                                                                

    a    Modified from: ATSDR (1994); CS2 = carbon disulfide; ECD = electron capture detector; FID = flame ionization detector; GC = gas
         chromatography; HECD = Hall electron capture detector; MS = mass spectrometry;
    b    VOCs = volatile organic carbon compounds
    c    Reported as percentage spike recoveries for 25 µg/kg (ppb) spikes
    

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         1,2-Dichloroethane is a synthetic chemical which has no known
    natural sources.

    3.2  Anthropogenic sources

    3.2.1  Production levels and processes

         1,2-Dichloroethane, first produced in 1795, was the first
    chlorinated hydrocarbon to be synthesized (IARC, 1979).  It is
    manufactured by either the catalytic vapour-phase or liquid-phase
    chlorination of ethylene or by oxychlorination of ethylene
    (Archer, 1979).  Most commercial grade 1,2-dichloroethane is 97-99%
    pure (Drury & Hammons, 1979).

         The total annual production of 1,2-dichloroethane in Canada in
    1990 was estimated to be 922 000 tonnes (CPI, 1991), while the total
    production in the USA in 1991 was 6 318 000 tonnes (Chemical Marketing
    Reporter, 1992), increasing from a production value of 5 038 000
    tonnes in 1980 (Kirschmer & Ballschmiter, 1983).  More than 1 million
    tonnes of 1,2-dichloroethane was produced in the United Kingdom in
    1991 (UK HSE, 1992).  1,2-Dichloroethane is released to the
    environment principally through emissions to ambient air during its
    production and that of vinyl chloride monomer.  1,2-Dichloroethane is
    recovered from waste streams of manufacturing facilities in a
    two-stage distillation operation.  This waste stream is then
    incinerated (McPherson et al., 1979), the estimated destruction
    efficiency being 99.99% (US EPA, 1986).

         Release of 1,2-dichloroethane to the atmosphere from production
    facilities can occur from a number of sources. Incidental emissions
    usually comprise around 50% of the total, while releases from
    secondary sources, such as losses from process wastewater, valves and
    vents, such as thermal oxidizer vents, handling and storage, and other
    sources result in release of the balance.  The US EPA estimated that
    18 000 tonnes of 1,2-dichloroethane was released to the atmosphere in
    the USA in 1982 from fugitive sources (e.g., valves, etc.), storage
    tanks, secondary sources (e.g., emissions from wastewater treatment
    processes), process vents and shipping operations (US DHHS, 1994).

         1,2-Dichloroethane is also released to the atmosphere from
    automobile emissions due to its incorporation into anti-knock
    formulations for leaded petrol (gasoline).

         1,2-Dichloroethane may enter surface waters via effluents from
    industries that manufacture or use the substance.  In addition, it may
    enter the atmosphere or groundwater following disposal in waste sites.

    3.2.2  Uses

         The predominant uses of 1,2-dichloroethane is as an intermediate
    in the synthesis of vinyl chloride; 99% of total demand in Canada, 90%
    in Japan and 88% of total production in the USA is used for this
    purpose (CPI, 1991; Chemical Marketing Reporter, 1992).  It has also
    been used in the production of chlorinated solvents such as
    trichloroethylene, tetrachloroethylene, 1,1,1-trichloroethane,
    ethyleneamines and vinylidene chloride, and in the manufacture of
    anti-knock fluids containing tetraethyllead, although this latter use
    has declined with the phase-out of leaded petrol.  1,2-Dichloroethane
    has been used as a fumigant.  However, it is no longer registered for
    use on agricultural products in Canada, the USA, the United Kingdom
    and Belize.

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1  Transport and fate in the environment

         Due to the high vapour pressure of 1,2-dichloroethane, the
    atmosphere is expected to be the predominant environmental sink for
    the compound. The rate of reaction of 1,2-dichloroethane with hydroxyl
    radicals has been predicted to be 3.63 × 10-13 cm3/mol-sec at
    25°C (Atkinson, 1987) and 5.42 × 10-13 cm3/mol-sec at 4°C
    (Nimitz & Skaggs, 1992).  It was experimentally determined to be 2.09
    × 10-13 cm3/mol-sec at 19°C (Qiu et al., 1992).  Based on these
    values, and assuming an atmospheric hydroxyl radical concentration
    representative of a moderately polluted area (Finlayson-Pitts & 
    Pitts, 1986), the estimated atmospheric lifetime of 1,2-dichloroethane
    is between 43 and 111 days.  Due to the moderate persistence of
    1,2-dichloroethane in the troposphere, long-range transport is
    possible.  Indeed, 1,2-dichloroethane has been detected in the lower
    troposphere over the northern Atlantic Ocean and over the Pacific
    Ocean (Singh et al., 1983; Class & Ballschmiter, 1986).

         Once 1,2-dichloroethane reaches the troposphere, it undergoes
    photo-oxidation to produce formyl chloride, chloroacetyl chloride,
    hydrochloric acid, carbon monoxide and carbon dioxide (Spence & 
    Hanst, 1978).  Any 1,2-dichloroethane that reaches the stratosphere
    may be photolysed to produce chlorine radicals that may, in turn,
    react with ozone (Spence & Hanst, 1978; Callahan et al., 1979). 
    However, 1,2-dichloroethane is not expected to contribute
    significantly to the depletion of the stratospheric ozone layer,
    since, based on either the experimental or predicted rates of reaction
    between hydroxyl radicals and 1,2-dichloroethane, its ozone depletion
    potential is very much less than 0.001 relative to the
    chlorofluorocarbon, CFC-11.  1,2-Dichloroethane was not included as a
    controlled substance in the "Montreal Protocol on Substances that
    Deplete the Ozone Layer".

         Volatilization is the major removal process of 1,2-dichloroethane
    from the aquatic environment (Dilling et al., 1975).  The half-life in
    a stirred aqueous solution, at varying depths and surface areas,
    ranged between 5 and 29 min (Dilling et al., 1975; Chiou et al.,
    1980).  Based on fate modelling (EXAMS), the predicted half-life of
    1,2-dichloroethane was 9 days in a eutrophic lake and one day in a
    300-km stretch of a river system (assuming a loading rate of 0.1 kg
    1,2-dichloroethane in both cases) (US EPA, 1982a).

         Although hydrolysis of 1,2-dichloroethane may also occur in the
    aquatic environment, this is not a significant removal process, since
    the half-life for hydrolysis has been estimated to be 72 years at
    neutral pH and 25°C (Barbash & Reinhard, 1989). In conditions similar
    to those of groundwater (i.e. in the presence of sodium sulfide, a pH
    of 7, and a temperature of 15°C), the estimated half-life of

    1,2-dichloroethane was 23 years (Barbash & Reinhard, 1989).  The
    primary products of hydrolysis are vinyl chloride and 2-chloroethanol
    (Jeffers et al., 1989); vinyl chloride can be further degraded to
    acetylene and acetaldehyde (Hill et al., 1976), while 2-chloroethanol
    may be degraded to ethylene glycol (Ellington et al., 1988).

         Microbial degradation of 1,2-dichloroethane in water has been
    observed, but it is a slow process, probably due to the insufficient
    time before volatilization of the substance to allow for microbial
    adaptation (US EPA, 1982a).  In a static flask study with initial
    1,2-dichloroethane concentrations of 5 and 10 mg/litre, there was a
    loss due to aerobic degradation of 20 to 63% within 7 days following
    an acclimation period.  However, 5 to 27% of the total loss was
    attributed to volatilization (Tabak et al., 1981).  The methanotrophic
    bacterium Methylosinus trichosporium (Oldenhuis et al., 1989),
    methylotrophic bacterium Ancylobacter aquaticus (van den Wijngaard et
    al., 1992) and a nitrogen-fixing bacterium Xanthobacter autotrophicus
    (Janssen et al., 1985) have been identified as microorganisms capable
    of biodegrading 1,2-dichloroethane under aerobic conditions.  In a
    batch experiment under anaerobic conditions, Bouwer & McCarty (1983)
    reported a 63% reduction in 25 days, but were unable to induce
    transformation in a flow-through system when initial concentrations of
    1,2-dichloroethane were 174 and 22 µg/litre, respectively.

         No biodegradation was observed after 35 days of incubation in an
    anoxic sediment-water system in which the initial concentration of
    1,2-dichloroethane was 1.0 mg/litre (pH not reported) (Jafvert &
    Wolfe, 1987).

         Based on its low sorption coefficient, 1,2-dichloroethane is not
    expected to adsorb appreciably to soil, suspended solids or sediments. 
    In one study, 1,2-dichloroethane rapidly percolated through sandy soil
    with a low organic matter content; no degradation was observed, and
    72-74% of the initial amount was reported to have volatilized (Wilson
    et al., 1981). 1,2-Dichloroethane may leach to groundwater, based on
    its solubility in water, low Koc value and high mobility in soil. 
    Reductive dechlorination of 1,2-dichloroethane in leachates under
    anaerobic conditions has been demonstrated (Lesage et al., 1993).

         1,2-Dichloroethane has low potential for bioaccumulation, based
    on experimental data and modelling predictions.  The bioconcentration
    factor (BCF) was determined to be 2, with a clearance half-life in
    tissues of less than 2 days, in freshwater bluegill  (Lepomis
     macrochirus) exposed to 95.6 µg 1,2-dichloroethane/litre for 14 days
    (Barrows et al., 1980).  This is identical to the value predicted by
    Isnard & Lambert (1988).  Accumulation and loss of radiolabelled
    1,2-dichloroethane was studied in the dab  (Limanda limanda) liver
    and in the oyster  (Ostrea edulis). Following exposure to 3 mg/litre
    for 20 days, the level in the dab liver rose rapidly to approximately
    80 mg/kg and then remained stable.  Following cessation of exposure,

    1,2-dichloroethane levels decreased to about 12 mg/kg at 40 days.  In
    the oyster, the level rose to approximately 9 mg/kg in 4 days, reached
    a plateau, and decreased to 3 mg/kg by 40 days after cessation of
    exposure (Pearson & McConnell, 1975).

    5.  ENVIRONMENTAL LEVELS AND POPULATION EXPOSURE

    5.1  Environmental levels

    5.1.1  Ambient air

         The mean concentrations of 1,2-dichloroethane in 1412 samples of
    ambient air from 23 sites in 12 cities across Canada taken between
    1988 to 1990 ranged from 0.07 to 0.28 µg/m3, with an overall mean of
    0.13 µg/m3 and a maximum single value of 2.78 µg/m3 (Dann, 1992). 
    1,2-Dichloroethane was detected in 55 out of 62 samples of ambient air
    from 19 out of 21 areas of Japan surveyed in 1992 at concentrations
    ranging from non-detectable (i.e. < 0.004 µg/m3) to 3.8 µg/m3
    (Environment Agency Japan, 1993).  In the United Kingdom and the
    Netherlands, average levels of 1,2-dichloroethane in rural areas were
    0.08 and 0.2 µg/m3, respectively (Clark et al., 1984a,b; Guicherit &
    Schulting, 1985).  In both of these countries, the average
    concentration in urban air was 1.2 µg/m3 (Clark et al., 1984a,b;
    Guicherit & Schulting, 1985).

         The US Environmental Protection Agency (US EPA, 1987) reported
    levels of 1,2-dichloroethane in urban/suburban air to be generally
    < 0.8 µg/m3 (< 0.2 ppb).  Concentrations of 1,2-dichloroethane in
    ambient air reported in several early studies conducted in 10 cities
    in the USA between 1980 and 1982 were somewhat higher, mean
    concentrations ranging from 0.33 µg/m3 (83 ppt) to 6.05 µg/m3
    (1512 ppt) (Singh et al., 1980, 1981, 1982).  Median concentrations of
    1,2-dichloroethane in air of rural/remote areas, urban/suburban areas
    and source-dominated areas in the USA were 0 µg/m3, 0.49 µg/m3 and
    4.9 µg/m3, respectively; the maximum level was 240 µg/m3
    (Brodzinsky & Singh, 1982).

         Concentrations of 1,2-dichloroethane in air near areas where
    chemicals are manufactured or used in the USA were found to be as high
    as 736 µg/m3 (184 ppb), with an average of 110 µg/m3 (27.5 ppb)
    (US EPA, 1985a).  Concentrations were also high (300 µg/m3) near a
    vinyl chloride manufacturing plant in the Netherlands (Kretzschmar et
    al., 1976).  The annual mean concentrations of 1,2-dichloroethane in
    250 samples of ambient air from 12 sites in Hamburg, Germany, surveyed
    in 1986-1987 ranged from 0.2 to 119 µg/m3, the highest levels being
    detected in an industrial region where lubrication oil was produced
    (Bruckmann et al., 1988).  Levels of 1,2-dichloroethane ranged from
    0.09 to 3.5 µg/m3 in heavily industrialized areas in Japan in
    1980/1981 (Environment Agency, Japan, 1983).  In New Jersey, USA,
    where several petrochemical industries were located and there had been
    substantial chemical dumping activity in the past, the mean and

    maximum values for five hazardous waste sites (14 to 24 samples each)
    ranged up to 1.12 µg/m3 (0.28 ppb) and 20.6 µg/m3 (5.15 ppb),
    respectively (LaRegina & Bozzelli, 1986).  1,2-Dichloroethane was also
    detected in air at a waste disposal site in New Jersey at levels
    ranging from trace to 27 µg/m3 (6.8 ppb) (detection limit not
    specified) (Pellizzari, 1982).

    5.1.2  Indoor air

         In a pilot study of samples taken for 1 year beginning in
    mid-January 1991, indoor air of approximately 750 residences from 10
    provinces across Canada was analysed.  The mean concentration of
    1,2-dichloroethane was < 0.1 µg/m3, and the maximum value
    1.7 µg/m3 (detection limit not specified) (Fellin et al., 1992).

         In the US EPA Total Exposure Assessment Methodology
    (TEAM) study, samples of "personal" and outdoor air were taken in 600
    residences of New Jersey, North Carolina, North Dakota and California. 
    1,2-Dichloroethane was detected only occasionally at low
    concentrations,  and the levels in personal air (range of mean values,
    0.1 to 0.5 µg/m3) were higher than those in outdoor air (range of
    mean values, 0.05 to 0.2 µg/m3) (quantifiable limit approximately
    1 µg/m3) (Wallace, 1986).  Based on a recent review of available
    literature, mean concentrations of 1,2-dichloroethane in indoor air in
    the USA ranged from 1.49 to 2.21 µg/m3 in hospitals and 4.51 µg/m3
    in office buildings (US EPA, 1992).

         The mean concentration of 1,2-dichloroethane in the air of 20
    homes in areas in the Netherlands with "non-contaminated" soil was
    3.4 µg/m3, compared to a mean outdoor level of 4.9 µg/m3.  In the
    crawl space or cellar of these homes, the mean concentration was
    2.5 µg/m3 (Kliest et al., 1989).

         1,2-Dichloroethane was also detected in the indoor air of two out
    of nine residences from the Love Canal area of Niagara, New York
    (0.100 µg/m3 and 0.130 µg/m3), while only trace levels were
    detected in samples of outdoor air (detection limit not specified)
    (Barkley et al., 1980).

    5.1.3  Drinking-water

         In Ontario, Canada, 1,2-dichloroethane was detected in 15 out of
    > 2000 samples of drinking-water from 85 sites surveyed between 1988
    and 1991; mean concentrations ranged from nondetectable (detection
    limit 0.050 µg/litre) to 0.139 µg/litre, with a maximum single value
    of 0.850 µg/litre, in treated water (it was not detected in untreated
    water) (Ministry of Environment, 1991).  1,2-Dichloroethane was not
    detected in 237 samples of drinking-water taken from 171 sites across
    New Brunswick during the summer months of 1990 (detection limit
    0.2 µg/litre) (Ecobichon & Allen, 1990).

         In a survey of untreated and treated water from 10 potable water
    treatment plants along the Great Lakes system in Ontario in 1982-1983,
    1,2-dichloroethane was detected (< 0.1 µg/litre) in one sample each
    for untreated and treated water in the summer, not at all in the
    winter, and in two samples of each (<0.1 µg/litre) in the spring
    (Otson, 1987).  In an earlier survey of 30 potable water treatment
    facilities serving major population centres across Canada sampled in
    1979, 1,2-dichloroethane was detected frequently in both untreated and
    treated water at mean concentrations of up to 2 µg/litre and
    5 µg/litre, respectively (Otson et al., 1982).

         Based on a summary of data on levels of 1,2-dichloroethane in
    groundwater and surface water supplies from six US Federal surveys,
    1,2-dichloroethane was detected in 24 out of 1973 samples of
    groundwater at concentrations up to 18 µg/litre and in 12 of 589
    samples of surface water at concentrations up to 19 µg/litre
    (detection limits not specified) (Letkiewicz et al., 1982).

         The US EPA (1987) estimated that 0.3% of groundwater and 3% of
    surface water supplies contain concentrations of 1,2-dichloroethane in
    the range of 0.5 to 5 µg/litre and 0.5 to 20 µg/litre, respectively
    (the basis for these estimates was not specified).  1,2-Dichloroethane
    was detected (detection limit not clearly specified) in 7 out of 1792
    wells in Wisconsin, USA in the early 1980s; in two of the wells,
    concentrations exceeded 7 µg/litre) (Krill & Sonzongni, 1986).  In the
    Love Canal district of Niagara, New York, 1,2-dichloroethane was
    detected in the drinking-water in three out of nine residences
    surveyed, at a concentration of 50 ng/litre (Barkley et al., 1980).

         Concentrations of 1,2-dichloroethane in drinking-water from five
    locations in Japan ranged from non-detectable (i.e. < 0.5 µg/litre)
    to 0.9 µg/litre (Fujii, 1977).  It was not detected in the
    drinking-water samples from 100 cities in Germany (detection limit,
    1.0 µg/litre) (Bauer, 1981).  1,2-Dichloroethane was not detected
    (detection limit, 0.5 µg/litre) in 229 out of 232 groundwater stations
    in the Netherlands surveyed from 1976 to 1978; in the other three
    stations concentrations ranged from 0.8 to 1.7 µg/litre (Zoetman et
    al., 1979).  Concentrations of 1,2-dichloroethane ranged from 2 to
    22 µg/litre in 400 samples of drinking-water from six cities in Spain
    in 1987 (Freiria-Gandara et al., 1992).

    5.1.4  Surface water

         1,2-Dichloroethane was detected in 2% of samples in surveys in
    the early 1980s of Canadian surface waters (Government of Canada,
    1994), but it was not detected (detection limit of 0.08 µg/litre) in
    351 samples from several lakes and rivers in Ontario (Kaiser et al.,
    1983; Comba & Kaiser, 1985; Kaiser & Comba, 1986; Lum & Kaiser, 1986). 
    It was detected 300 m downstream of a plant manufacturing
    1,2-dichloroethane in Ontario, with a maximum concentration of
    16 µg/litre (Environment Canada, 1986).

         1,2-Dichloroethane was detected (detection limit not specified)
    in 53 of 204 sites from six river basins in the USA surveyed before
    1977 at concentrations ranging from 1 to 15 µg/litre and one site
    containing 90 µg/litre (HSDB, 1993).  It was detected (detection limit
    not specified) in 7% of 4972 samples of surface water from the Ohio
    River basin in the USA in 1980-1981; concentrations ranged from 1 to
    10 µg/litre in 44 samples (HSDB, 1993).

         1,2-Dichloroethane was detected in 39 of 102 samples of surface
    water from 14 of 34 sites in Japan in 1992 at concentrations ranging
    from non-detectable (i.e., < 0.01 µg/litre) to 3.4 µg/litre
    (Environment Agency Japan, 1993).

         Concentrations of 1,2-dichloroethane in the influent of six
    wastewater treatment plants in the Netherlands ranged from < 2 to
    400 µg/litre, while levels in the effluents ranged from < 2 to
    74 µg/litre.  The variation was determined to be due to industrial
    discharges (van Luin & van Starkenburg, 1984).

    5.1.5  Food

         1,2-Dichloroethane was not detected in any samples of 34 food
    groups (consisting of dairy products, meats, eggs, fish, soup, bread,
    cereal, pasta, fruit, vegetables, cooking oil, peanut butter,
    sugar/jam, coffee/tea, soft drinks, wine/beer and tap water) collected
    in Calgary, Canada, in 1991 (detection limit 50 µg/kg for solids and
    1.0 µg/litre for liquids) (Enviro-Test Laboratories, 1991).  In
    January 1992, the study was repeated for the same 34 food groups
    collected in Windsor, Canada, using more sensitive analytical
    methodology (detection limit 5 µg/kg for solids and 1 µg/litre for
    liquids).  Based on preliminary results, 1,2-dichloroethane was not
    detected in any of the samples analysed (Enviro-Test Laboratories,
    1992).

         In a Total Diet Study conducted by the US Food and Drug
    Administration (FDA), 1,2-dichloroethane was not detected in 11
    decaffeinated instant coffees or in 14 decaffeinated ground coffees
    (detection limit not specified) (Heikes, 1987a).

         1,2-Dichloroethane was detected only in one ready-to-eat cereal
    (mean 0.31 µg/kg) out of 19 table-ready food items, including butter,
    margarine, ready-to-eat cereals, cheese, peanut butter, processed
    foods and drinking-water, which were selected to be representative of
    the 234 table-ready food items examined in the Total Diet Study
    (Heikes, 1987b, 1990).  In further analysis of these foodstuffs,
    1,2-dichloroethane was detected only in plain granola and shredded
    wheat cereal at concentrations of 12 and 8.2 µg/kg, respectively
    (Heikes, 1987b).

         1,2-Dichloroethane was detected only in one item (whisky, at a
    concentration of 30 µg/kg) in an additional Total Diet Study in the
    USA of 231 different table-ready foods (quantification limit 9 µg/kg). 
    The food types examined included off-the-shelf cooked and uncooked
    grain-based items, dairy products, fresh and canned fruits and
    vegetables, meats and meat dishes, infant and junior blends, baked
    goods, nuts and nut products, clear beverages, sugars, jams, and
    candies (Daft, 1988).  1,2-Dichloroethane was not detected in four
    earlier composite market basket surveys of dairy products, meats, oils
    and fats, and beverage products (detection limit not specified) in the
    USA (Entz et al., 1982).

         In Germany, the mean concentrations of 1,2-dichloroethane in 12
    samples of milk-products containing fruits (i.e. ice-cream, yoghurt,
    curds and buttermilk) was 0.8 µg/kg fresh weight, with a maximum
    concentration of 3.5 µg/kg fresh weight (detection limit not
    specified) (Bauer, 1981).

         Prior to 1984, 1,2-dichloroethane was used in Canada as a grain
    fumigant (Lange, personal communication to the IPCS). In an early
    survey, 1,2-dichloroethane concentrations ranged from 23 to 38 mg/kg
    in wheat which had been treated with a fumigant containing
    1,2-dichloroethane (Wit et al., 1969).  1,2-Dichloroethane could not
    be "determined satisfactorily" in wheat which had been fumigated with
    a mixture containing 30% of the compound (limit of detection specified
    as 1.5 ng); similarly, it was not detected or determined only at trace
    levels (not further specified) in samples of cereals (Berck, 1974).

         1,2-Dichloroethane is currently not registered for use in
    agricultural products in the USA.  It was detected in wheat and
    bleached flour samples at concentrations of 110 and 180 µg/kg and 6.1
    and 6.5 µg/kg, respectively (limit of quantification 6 µg/kg), in a
    survey of compounds used as fumigants in whole grains, milled grain
    products and intermediate grain-based foods (Heikes & Hopper, 1986). 
    In 1979, it was detected at a concentration of 290 mg/kg in 1 out of
    71 samples of wheat grown in the USA, but was not detected in 61
    samples of wheat exported from England to the USA (Bailey et al.,
    1982).  Cooking (steaming, baking, etc.) tends to reduce levels of
    1,2-dichloroethane in most foods contaminated during fumigation (Bond,
    1984).

         The use of 1,2-dichloroethane in agricultural products in the
    United Kingdom has been discontinued.  In earlier surveys, it was
    detected in one out of 155 samples of wheat grown in the United
    Kingdom in 1978-1979 at a concentration of 290 mg/kg and in none of
    126 samples of imported wheat (MAFF, 1982); in 1981 and 1982,

    1,2-dichloroethane was not detected in 47 and 59 samples of wheat,
    respectively (MAFF, 1984).  It was also not detected in 84 samples of
    brown rice, 107 samples of rye products and 71 samples of processed
    oats collected in 1985-1986 (MAFF, 1989).  More recently,
    1,2-dichloroethane was not detected (detection limit 0.4 mg/kg) in 24
    samples of rice analysed in 1992 (UK HSE, 1992; MAFF/HSE, 1993).

         No information on concentrations of 1,2-dichloroethane in breast
    milk of women in the general population is available.

    5.1.6  Soils and sediments

         1,2-Dichloroethane was not detected (detection limit 0.01 mg/kg)
    in 30 samples of soil taken from "typical" urban residential and
    parkland locations in southern Ontario, Canada in 1987 (Golder
    Associates, 1987).  The mean concentration of 1,2-dichloroethane in
    soil near 20 homes in areas of the Netherlands with "uncontaminated"
    soil was 11 mg/kg, while samples of soil in the vicinity of a garage
    and a waste site contained < 5 and 30 mg/kg, respectively (Kliest et
    al., 1989).  The US EPA (1988) reported that 1,2-dichloroethane has
    been detected in soil samples from 1.5% of 2783 hazardous waste sites
    sampled in the USA (concentrations and detection limits were not
    reported).

         1,2-Dichloroethane was not detected (detection limit, 0.01 µg/kg)
    in sediments downstream of two facilities in Canada which manufactured
    the compound (Oliver & Pugsley, 1986; AEC, 1989).  It was detected in
    11 out of 99 samples of sediment from 5 out of 33 areas surveyed in
    Japan in 1992 at concentrations ranging from non-detectable (i.e.,
    < 0.4 µg/kg) to 0.7 µg/kg (dry weight) (Environment Agency Japan,
    1993).

    5.1.7  Consumer products

         In studies conducted in the USA, 1,2-dichloroethane was released
    from cleaning agents and pesticides, glued wallpaper and glued carpets
    in environmental chambers, while it was not emitted by painted
    sheetrock (detection limit not specified) (Wallace et al., 1987). 
    More recently, 1,2-dichloroethane was detected in 5 out of 1043
    household products tested in the USA; concentrations ranged up to 0.1%
    (by weight) in automotive products, oils, greases and lubricants, and
    miscellaneous products (Sack et al., 1992). It should be noted that
    the use of 1,2-dichloroethane in products such as upholstery and
    carpet fumigants, soap and scouring compound ingredients, wetting and
    penetrating agents and degreasing fluid has been largely discontinued
    in the USA.  In addition it is not used in any registered drug
    products in the USA (Drury & Hammons, 1979).

         In a survey in Germany, 1,2-dichloroethane was not detected in
    facial soap, mouthwash or toothpaste (detection limit not specified).
    However, it was detected in shampoo and shaving cream at levels
    ranging up to 7.6 µg/litre and 122 µg/litre, respectively, and in 1
    out of 7 cough-syrups at a concentration of 12.9 µg/kg (Bauer, 1981).

         No data on concentrations of 1,2-dichloroethane in cigarettes are
    available.  No difference was reported between the median air
    concentrations of 1,2-dichloroethane in air in the offices of smokers
    and those in the offices of non-smokers in southern England (Proctor
    et al., 1989).

    5.2  General population exposure

         Based on estimates of mean exposure from various media, the
    principal source of exposure to 1,2-dichloroethane by the general
    population is indoor and outdoor air (< 0.03 to 0.1 µg/kg body weight
    per day and 0.004 to 0.02 µg/kg body weight per day, respectively),
    with only minor amounts being contributed by drinking-water (< 0.001
    to 0.003 µg/kg body weight per day).  Intake of 1,2-dichloroethane
    from food is probably negligible.  For some individuals residing in
    the vicinity of industrial sources of airborne 1,2-dichloroethane,
    intake from ambient air may be substantially greater than that for the
    general population.

    5.2.1  Ambient air

         Based on a daily inhalation volume for adults of 22 m3, a mean
    body weight for males and females of 64 kg, the assumption that 4 out
    of 24 h are spent outdoors (IPCS, 1994), and the range of mean
    1,2-dichloroethane levels found in a recent survey of cities across
    Canada (0.07-0.28 µg/m3 as presented in section 5.1.1), mean intake
    of 1,2-dichloroethane from ambient air for the general population is
    estimated to range from 0.004 to 0.02 µg/kg body weight per day.

    5.2.2  Indoor air

         Based on a daily inhalation volume for adults of 22 m3, a mean
    body weight for males and females of 64 kg, the assumption that 20 out
    of 24 h are spent indoors (IPCS, 1993), and the range of
    1,2-dichloroethane concentrations in indoor air or "personal" air in
    surveys in Canada and the USA (< 0.1 to 0.5 µg/m3 as presented in
    section 5.1.2), mean intake of 1,2-dichloroethane from indoor air for
    the general population is estimated to range from < 0.03 to 0.1 µg/kg
    body weight per day.

    5.2.3  Drinking-water

         Based on a daily volume of water consumption for adults of 1.4
    litres, a mean body weight for males and females of 64 kg (IPCS,
    1993), and the mean levels of 1,2-dichloroethane in provincial surveys
    in Canada (< 0.05 to 0.139 µg/litre as presented in section 5.1.3),
    mean intake of 1,2-dichloroethane from drinking-water for the general
    population is estimated to range from < 0.001 to 0.003 µg/kg body
    weight per day.

    5.2.4  Food

         Based on its low octanol/water partition coefficient,
    1,2-dichloroethane is unlikely to bioaccumulate, and therefore it is
    considered that food does not represent a significant source of
    exposure for the general population.  It has only rarely been detected
    in individual samples of foodstuffs in North America (see section
    5.1.5).  Even if the compound was assumed to be present in foods at
    concentrations up to the limit of detection in the surveys with the
    more sensitive analytical methodology, the daily intake of
    1,2-dichloroethane from food would still be negligible compared to
    that from air.

    5.2.5  Other media

         Available data were considered insufficient to estimate intake of
    1,2-dichloroethane from soil or consumer products.

    5.3  Occupational exposure during manufacture, formulation or use

         Based on a review of available information, current occupational
    exposure to 1,2-dichloroethane in North America occurs predominantly
    during the manufacture of other chemicals, such as vinyl chloride,
    where 1,2-dichloroethane is used as an intermediate. In a 1982
    National Occupational Exposure Survey by the US National Institute for
    Occupational Safety and Health (NIOSH), 28% of employees working with
    adhesives and solvents were exposed to 1,2-dichloroethane, while
    between 5 and 9% of workers were exposed to the substance in the
    medicinals and botanicals, biological products, petroleum refining and
    organic chemicals industries, and in museums and art galleries (US
    Department of Labour, 1989).

         Mean concentrations of 1,2-dichloroethane at three production
    plants in the United Kingdom in 1990 were 2.8, 3.2 and 6.8 mg/m3
    (0.7, 0.8 and 1.7 ppm); 95% of samples contained less than 20 mg/m3
    (5 ppm), while maximum values at the plants were 18, 80 and
    160 mg/m3 (4.5, 20 and 40 ppm) (UK HSE, 1992).

         The time-weighted average concentration of 1,2-dichloroethane in
    an electron microscopy preparation laboratory in Hong Kong, in which
    the chemical was used as a solvent, was 19.8 mg/m3 (4.9 ppm).  The
    concentration in the breathing zone of the operator was 52.87 mg/m3
    (13.06 ppm) while the average concentration in the preparation room
    was 35.1 mg/m3 (8.67 ppm) (Li & Cheng, 1991).

    6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

    6.1  Absorption

         Case reports of acute effects following inhalation exposure to
    1,2-dichloroethane in the workplace indicate that it is readily
    absorbed (Nouchi et al., 1984).

         In experimental animals, absorption following ingestion of
    1,2-dichloroethane is rapid and complete.  Spreafico et al. (1980) and
    Reitz et al. (1982) reported that peak levels in blood (13 to
    67 mg/litre) occurred within 10 or 15 min in rats administered single
    oral doses of 25, 50 or 150 mg/kg body weight in corn oil.  A plot of
    administered dose against peak blood level appeared linear up to
    50 mg/kg, with a perceptible decrease in steepness thereafter,
    possibly indicating a relative saturation in gastrointestinal
    absorption at doses of 100 to 150 mg/kg body weight. (The authors
    noted that there were no significant differences in kinetic parameters
    following single and 10 daily administrations of 50 mg/kg body
    weight).  Gastrointestinal absorption in rats was more rapid and
    efficient following administration in water, compared to corn oil
    (Withey et al., 1983).

         Absorption following inhalation in experimental animals is also
    rapid.  In rats, levels of 1,2-dichloroethane in the blood peaked (8
    to 10 mg/litre) within 1-2 h of continuous inhalation of 600 mg/m3
    (150 ppm) for 6 h (Reitz et al., 1982).

         The rate of dermal absorption of 1,2-dichloroethane by mice was
    479.3 ± 38.3 nmol/min per cm2 following covered application of 0.5 ml
    of the undiluted solvent (Tsuruta, 1975), while the rate of absorption
    of 1,2-dichloroethane in 0.9% NaCl  in vitro in excised skin of rats
    was 169 ± 0.44 nmoles/min per cm2 (Tsuruta, 1977).  Dermal
    absorption of 1,2-dichloroethane in aqueous solution (1000 mg/litre)
    was found to be similar in human and rat epidermis  in vitro within
    one hour of occluded application (20.3 µg/cm2 per h versus 33.1 µg/cm2
    per h), whereas when the substance was applied neat (uncovered),
    absorption within the first 15 min was approximately four to ten-fold
    greater in the rat epidermis than in the human epidermis.  In
    addition, absorption increased with applied dose in the rat epidermis,
    whereas absorption was not dependent upon dose in the human epidermis
    (Ward, 1992).

         The concentration of 1,2-dichloroethane in the blood of
    guinea-pigs increased rapidly (up to approximately 7 mg/litre) during
    the first 30 min following covered application of 1.0 ml of the
    undiluted compound to shaved skin; the level in blood then began to
    decrease abruptly to a minimum (approximately 5 mg/litre) after one

    hour, at which point it began to gradually increase again (up to about
    17 mg/litre after 12 h) (Jakobson et al., 1982).  1,2-Dichloroethane
    was also rapidly absorbed when applied in aqueous solution to the skin
    of rats  in vivo, with the levels in blood being directly related to
    the concentration of the solution (Morgan et al., 1991).

    6.2  Distribution

         Absorbed 1,2-dichloroethane is widely distributed throughout the
    human body, based on analysis of several tissues of humans who died
    following acute oral poisonings with the substance.  Concentrations
    ranged from 1 to 50 mg/kg in the spleen and 100 to 1000 mg/kg in the
    stomach; levels in the liver and kidney were approximately 10 times
    less than those in the stomach (Luznikov et al., 1985).  The
    metabolite 2-chloroacetaldehyde was not detected; detectable
    quantities of 2-chloroethanol and monochloroacetic acid were reported,
    though levels were too low to compare among tissues. 
    1,2-Dichloroethane has been detected in the breast milk of women
    occupationally exposed via inhalation and dermal contact (Urusova,
    1953).

         Similarly, 1,2-dichloroethane is widely distributed throughout
    the body in experimental animals exposed via inhalation or ingestion. 
    The highest concentrations were usually found in adipose tissue,
    although it was also detected in blood, liver, kidney, brain and
    spleen.  1,2-Dichloroethane accumulated most rapidly in the liver of
    rats administered single oral doses of 25, 50 or 150 mg/kg body weight
    in corn oil, although concentrations were greatest in adipose tissue. 
    Peak levels in adipose tissue, at 45 to 60 min, exceeded those in
    blood by 3.9 to 8.3 times, whereas peak levels in the liver, 10 min
    after exposure, exceeded those in the blood by 1.3 to 2.2 times
    (Spreafico et al., 1980).  Accumulation was less than expected at the
    two higher exposure levels, indicating saturation of the tissues. 
    Similar accumulation in adipose tissue in rats was noted following
    inhalation of 200 or 1000 mg/m3 (50 or 250 ppm) for up to 6 h. 
    During inhalation, steady state levels were reached within 2 to 3 h
    and increased 20-to 30-fold when the exposure increased from 202 to
    1012 mg/m3, suggesting saturable metabolic capacity.  Levels of
    1,2-dichloroethane in the spleen, brain and kidney were similar to
    those in the blood, irrespective of the route of exposure (Spreafico
    et al., 1980).

         Reitz et al. (1982) reported that the relative distribution of
    radioactivity at 48 h (assumed to be primarily in the form of
    metabolites) was similar in rats administered [14C]-labelled
    1,2-dichloroethane orally (single dose of 150 mg/kg body weight) or by
    inhalation (600 mg/m3 or 150 ppm for 6 h).  Residual reactivity in
    selected tissues was 1.5 to 2 times higher after oral exposure than
    following inhalation.  There was also a higher residual activity in
    the forestomach after the oral exposure.  The distribution pattern for
    macromolecular binding was similar, as determined 4 h after oral
    ingestion or directly after inhalation.  Oral exposure produced lower
    (i.e. 1.5 to 2 times less) levels of total macromolecular binding but
    higher (i.e. 3 to 5 times more) levels of DNA alkylation than
    inhalation, though the absolute levels were considered low.

         Arfellini et al. (1984) reported a greater degree of binding to
    DNA in organs (liver, kidneys, lung and stomach) of mice than in those
    of rats (1.45 to 2.26 fold) 22 h after intraperitoneal administration
    of equivalent single doses of 8.7 µmoles/kg body weight.

         In periods from 1 min to 4 days following intravenous
    administration of a single dose (0.73 mg/kg body weight) of
    radiolabelled 1,2-dichloroethane to mice, the highest levels of
    radioactivity (non-volatile and bound metabolites) determined by whole
    body autoradiography were present in the nasal olfactory mucosa and
    the tracheo-bronchial epithelium.  Low levels of metabolites were also
    present in the epithelium of the upper alimentary tract, vagina and
    eyelid and in the liver and kidney.  Mucosal and epithelial binding
    was decreased by pretreatment with metapyrone, indicating that binding
    might be due to oxidative metabolism.  In  in vitro studies in
    tissues from the same strain of mice, reactive products of
    1,2-dichloroethane were irreversibly bound to the nasal mucosa, lung
    and liver but not to the oesophagus, forestomach or vagina.  The level
    of binding in the nasal mucosa was twice that in the lung and 1.4
    times that in the liver.  On the basis of their results, the authors
    suggested that the epithelium of the respiratory tract may be a
    potential target for the toxic effects of 1,2-dichloroethane due to in
    situ metabolism to reactive intermediates (Brittebo et al., 1989).

         1,2-Dichloroethane was detected in fetal tissue of rats following
    maternal exposure to airborne concentrations ranging from 612-
    7996 mg/m3 (153-1999 ppm) on day 17 of gestation, the detected
    concentrations in fetal tissues being related to the level of exposure
    as well as the position on the uterine horn (Withey & Karpinski,
    1985).

    6.3  Metabolic transformation

         1,2-Dichloroethane is metabolized extensively in rats and mice. 
    It is principally sulfur-containing metabolites that are eliminated in
    the urine.  Mitoma et al. (1985) reported slightly more complete
    metabolism in mice than in rats, based on 100% recovery of metabolites
    as expired CO2 and in the excreta and carcasses of mice administered
    an oral dose of 150 mg/kg body weight [14C]-labelled
    1,2-dichloroethane, compared to about 85% in rats administered
    100 mg/kg body weight.  This difference may have been due to
    experimental variation or error.  Reitz et al. (1982) reported 70 and
    91% transformation of 1,2-dichloroethane in the rat following oral
    (150 mg/kg body weight) and inhalation (607 mg/m3, 6 h) exposures,
    respectively, with 85% of the metabolites appearing in the urine.

         Proposed metabolic pathways for 1,2-dichloroethane are
    illustrated in Fig. 1.  Metabolism appears to occur via two principal
    pathways for which the reactions and subsequent metabolism of the
    products can account for all of the identified sulfur-containing
    metabolites in the urine of 1,2-dichloroethane-exposed animals.  One
    pathway begins with cytochrome P-450-mediated oxidation, and the other
    with glutathione conjugation.  In the first pathway, cytochrome P-450
    enzymes catalyse an oxidative transformation of 1,2-dichloroethane to
    form reactive intermediates, which result in the formation of
    2-chloroacetal-dehyde and 2-chloroethanol (Guengerich et al., 1980),
    which are conjugated both enzymatically and non-enzymatically with
    glutathione (GSH) and excreted in the urine.  Guengerich et al. (1991)
    concluded that cytochrome P-450 IIE1 is a major catalyst in the
    oxidation of 1,2-dichloroethane in human microsomes.

         The other pathway involves direct conjugation with glutathione to
    form  S-(2-chloroethyl)-glutathione, which is a half mustard with a
    half-life of 69 min at 20°C (Schasteen & Reed, 1983) and less than 15
    min at 37°C (Foureman & Reed, 1985).  Non-enzymic conversion of the
    half mustard to the corresponding episulfonium ion gives a putative
    alkylating agent (episulfonium ion) that has several fates.  Reaction
    can occur with water to form  S-(2hydroxyethyl) glutathione, with
    thiols such as GSH to form ethene bis-glutathione, or with DNA to form
    adducts.  With the exception of the precursors which form DNA adducts,
    the reaction products are considered non-toxic and undergo further
    metabolism.

    FIGURE 1

         Although some DNA damage has been induced via the P-450 pathway
     in vitro (Banerjee et al., 1980; Guengerich et al., 1980; Lin et
    al., 1985), several lines of evidence suggest that the GSH conjugation
    pathway is probably of greater significance than the P-450 pathway as
    the major route for DNA damage (Guengerich et al., 1980; Rannug, 1980;
    Sundheimer et al., 1982; Inskeep et al., 1986; Koga et al., 1986).

         The P-450-dependent pathway can, however, presumably form
    considerable quantities of 2-haloacetaldehydes, which readily bind to
    protein and non-protein thiols, as shown for vinyl bromide and vinyl
    chloride (Guengerich et al., 1981) and dibromoethane (DBE) (van
    Bladeren et al., 1981).  However, these authors concluded that 2H
    and 18O studies on the formation of 2-haloethanols and
    2-haloacetaldehydes from 1,2-dihaloethanes are inconsistent with a
    major role of such a mechanism for DNA damage (Guengerich et al.,
    1986; Koga et al., 1986).

         The 1,2-dichloroethane-induced mutation frequency of two human
    cell lines has been correlated with the difference in levels of
    glutathione- S-transferase activities.  AHH-1 cell line mutation
    frequency was 25 times that in the TK6 cell line in the presence of
    1,2-dichloroethane.  The difference was attributed to the fact that
    the AHH-1 cell line possesses 5 times more glutathione- S-transferase
    activity than the TK6 cell line (Crespi et al., 1985).

         Moreover, although the significance of the reported results is
    uncertain, the results of an additional study by Storer & Conolly
    (1985) are not inconsistent with the hypothesis that reduction of GSH
    levels is associated with a reduction in DNA damage.  Male B6C3F1
    mice pretreated with piperonyl butoxide (PIB), a P-450 inhibitor, were
    examined for the extent of hepatic DNA damage produced 4 h after
    1,2-dichloroethane administration.  Hepatic DNA damage, as measured by
    alkali-labile lesions, was potentiated by PIB.  Treatment of mice with
    high doses of 2-chloroethanol failed to produce DNA damage, as
    measured by this assay. Diethylmaleate, a GSH depletor, potentiated
    the hepatotoxicity of 2-chloroethanol but not DNA damage.

         In addition, Cheever et al. (1990) reported that although the
    levels of hepatic DNA covalent binding of metabolites of
    14C-1,2-dichloroethane injected (single dose) to rats which had been
    exposed by inhalation to 1,2-dichloroethane in a long-term bioassay
    were significant (p < 0.05), these levels were not different in rats
    with concomitant exposure to disulfiram in the diet over two years.

         Evidence suggests that the putative episulfonium ion, resulting
    from non-enzymatic conversion of  S-(2-chloroethyl) glutathione, is a
    major intermediate in the formation of DNA adducts  in vivo from
    1,2-dichloroethane exposure (Inskeep et al., 1986).  When rats were

    administered single does of 14C-1,2-dichloroethane  in vivo and the
    liver was analysed 8 h later, 78% of the DNA adducts (0.25 nmol/mg
    DNA) could be released by neutral thermal hydrolysis.  A major adduct
    and several minor adducts were present; the major adduct
    co-chromatographed with  S-[2-(N7-guanyl)ethyl] glutathione.  The
    postulated adduct of liver DNA after 14C-1,2-dichloroethane
    exposure,  S-[2-(N7-guanyl)ethyl] glutathione, appears to be
    chromatographically identical to the major adduct in rats after
    exposure to 1,2-dibromoethane (Koga et al., 1986).  This
    1,2-dibromoethane adduct, which has been isolated and characterized by
    NMR and mass spectrometry, gives strong support to an identical adduct
    being the principal DNA adduct from exposure to 1,2-dihaloethanes.

         Reitz et al. (1982) found (based on consideration of results of
    their own work as well as that of Spreafico et al., 1980) that
    metabolism of 1,2-dichloroethane appears to be saturated or limited in
    rats at levels of exposure resulting in blood concentrations of 5 to
    10 mg/litre, based on an observed non-linear relationship between
    levels in blood and administered doses or concentrations. 
    Administration by gavage resulted in the formation of about twice the
    amount of "total" metabolites as did exposure by inhalation, based on
    recovery in excreta, expired air and the carcass.  Oral exposure
    produced 1.5- to 2-fold lower levels of total macromolecular binding
    but 3- to 5-fold higher levels of DNA alkylation than inhalation,
    though the absolute levels of DNA alkylation were considered low.

         Based on examination of DNA binding in the liver and lung of rats
    exposed by inhalation to a low constant concentration (0.3 mg/litre)
    of 1,2-dichloroethane for 12 h or to a peak concentration (up to
    18 mg/litre) for a few minutes, Baertsch et al. (1991) concluded that
    DNA damage by 1,2-dichloroethane depends upon the concentration time
    profile, with bolus doses causing disproportionately greater damage.

    6.4  Elimination and excretion

         Unmetabolized 1,2-dichloroethane is eliminated in expired air,
    while its metabolites are largely excreted in the urine.  Unchanged
    1,2-dichloroethane was detected in the exhaled breath of women exposed
    dermally and to airborne concentrations of 0.252 mg/m3 (0.063 ppm)
    in the workplace; the amount of 1,2-dichloroethane expired was greater
    immediately following exposure and decreased over time (Urusova,
    1953).

         A single dose of 150 mg/kg body weight radiolabelled
    1,2-dichloroethane was injected into rats that had been exposed via
    inhalation at a concentration of 200 mg/m3 (50 ppm) for 2 years. The
    proportion of radioactivity present in the urine within 24 h was 42.5
    and 33.9% (in males and females, respectively), while 27.3 and 40.3%
    were eliminated as the unchanged parent compound in the breath. Only a

    very small amount of radioactivity was detected as 14CO2 or in the
    faeces.  In rats that had been concomitantly exposed to disulfiram
    during the 2-year period, the proportion of unchanged
    1,2-dichloroethane eliminated in the breath increased significantly
    (i.e. 57.6 and 57.7%; p < 0.05), while the proportion eliminated in
    the urine decreased correspondingly (27.6 and 24.9%).  Levels of
    unchanged 1,2-dichloroethane in blood were significantly (p < 0.05)
    increased in rats exposed to 1,2-dichloroethane and disulfiram
    compared to those exposed to 1,2-dichloroethane alone (see section
    7.10) (Cheever et al., 1990).

         The pattern of elimination of metabolites was similar in rats and
    mice 48 h after administration of oral doses of radiolabelled
    1,2-dichloroethane (100 and 150 mg/kg body weight, respectively).  In
    rats, 8.2 and 69.51% of the radiolabelled dose was recovered as CO2
    and in the excreta (principally urine), respectively, compared to
    18.21 and 81.11% in mice.  The overall recovery was less in rats than
    in mice (96.26 versus 110.12%) (Mitoma et al., 1985).

         In rats exposed to 600 mg/m3 (150 ppm) 1,2-dichloroethane for
    6 h or administered 150 mg/kg body weight by gavage, there was no
    significant difference in the route of excretion of non-volatile
    metabolites.  After 48 h, in each case, more than 84% of total
    metabolites was eliminated in the urine, 7-8% was excreted as carbon
    dioxide in expired air, 2% was excreted unchanged in the faeces, and
    4% remained in the carcass (Reitz et al., 1982).  The major urinary
    metabolites identified following exposure of rats by either route were
    thiodiacetic acid (70%) and thiodiacetic acid sulfoxide (26 to 28%). 
    The rate of elimination following oral (gavage) administration or
    inhalation was such that 1,2-dichloroethane was not detected in the
    blood a few hours after exposure and only small amounts were detected
    in tissues (liver, kidney, lung, spleen, forestomach, stomach and
    carcass) 48 h after exposure (Reitz et al., 1982).  The rate of
    elimination from blood and tissues appeared to depend on the exposure
    level; the higher the exposure level, the lower the elimination rate
    of 1,2-dichloroethane, after both oral and inhalation exposure. 
    Elimination from the liver was reported to be biphasic, a higher
    elimination rate occurring just after the peak levels of
    1,2-dichloroethane were reached.  Elimination from other organs was
    monophasic. Following inhalation up to an exposure level of
    1012 mg/m3, elimination was slowest in adipose tissue and most rapid
    in the lung (Spreafico et al., 1980).

         Withey & Collins (1980) also reported that the elimination of
    1,2-dichloroethane was dose-dependent.  After intravenous
    administration of from 3 to 15 mg/kg body weight to male Wistar rats,
    the authors found that the elimination fitted a twocompartment model
    at a low dose level and a three-compartment model at high dose levels.

         The percentage of administered radioactivity excreted in the
    urine over a 24-h period in rats decreased with increasing single
    doses (0.25 to 8.08 mmol 1,2-dichloroethane/kg body weight)
    administered by gavage in mineral oil (Payan et al., 1993).  The
    authors attributed these results to saturation of metabolism rather
    than kidney damage, as there were no variations in biochemical
    parameters of nephrotoxicity between the controls and groups exposed
    to doses up to 4.04 mmol/kg body weight.  Urinary thiodiglycolic acid
    increased as a linear function of the dose of 1,2-dichloroethane until
    at least 1.01 mmol/kg body weight; it accounted for 63% of the total
    metabolites in urine at this dose.

    6.5  Retention and bioaccumulation

         Although 1,2-dichloroethane is eliminated more slowly from
    adipose tissue than from blood or other tissues (lung and liver)
    following exposure, it is unlikely to bioaccumulate significantly, as
    no difference was observed between levels in blood or tissues (data
    not presented) following single or repeated (10 days) oral doses of
    50 mg/kg body weight in rats (Spreafico et al., 1980).  Only 71 and
    75%, respectively, of an administered oral dose of radiolabelled
    1,2-dichloroethane was recovered in the excreta and exhaled breath of
    rats administered 150 mg/kg body weight by gavage following 2 years of
    exposure via inhalation (200 mg/m3 or 50 ppm); the authors
    speculated that the remainder may have been sequestered in the body
    fat.  Recovery in the excreta and exhaled breath was complete in
    younger rats (4 months old) receiving the same oral dose (Cheever et
    al., 1990).

    7.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

    7.1  Single exposure

         Data on the acute toxicity of 1,2-dichloroethane in experimental
    animals are summarized in Table 3.  These data indicate that
    1,2-dichloroethane is of relatively low acute toxicity.

         LC50 values in rats exposed to 1,2-dichloroethane for 6 or
    7.25 h ranged from 4000 mg/m3 (1000 ppm) (Spencer et al., 1951) to
    6600 mg/m3 (1650 ppm) (Bonnet et al., 1980).  The 6-h LC50 in mice
    was 1050 mg/m3 (Gradiski et al., 1978).  LC50 values decreased
    with increasing duration of exposure in rats exposed to concentrations
    ranging from 1200 to 80 000 mg/m3 (300 to 20 000 ppm)
    1,2-dichloroethane for 1 to 8 h (Spencer et al., 1951).  Various
    non-lethal effects have been reported in animals following acute
    exposure to 1,2-dichloroethane, including central nervous system
    depression, cardiovascular collapse, altered behaviour, pulmonary
    congestion and oedema, histological damage in the liver, kidneys and
    adrenal glands and myocardial failure, at concentrations ranging from
    4000 mg/m3 for 1.5 or 4 h to 80 000 mg/m3 (20 000 ppm) for 30 min
    (Heppel et al., 1945; Spencer et al., 1951; Alumot et al., 1976a;
    Wolff et al., 1979; ATSDR, 1989).  Central nervous system depression
    occurred at much higher concentrations than those which induce effects
    in other organs.

         Oral LD50 values for rats, mice, dogs and rabbits ranged from
    413 mg/kg body weight in female mice to 2500 mg/kg body weight in dogs
    (Barsoum & Saad, 1934; McCollister et al., 1956; Smyth, 1969; Larionov
    & Kokarovtseva, 1976; Munson et al., 1982; NIOSH, 1994).  Non-lethal
    effects observed in rats and rabbits following single oral doses of
    1,2-dichloroethane ranging from 615 to 1476 mg/kg body weight include
    hepatic effects (fatty degeneration, cloudy swelling, congestion,
    haemorrhagic lesions, dystrophy in the cytoplasm and hyperchromatosis
    in the nuclei of hepatocytes), degeneration of the renal tubular
    epithelium, altered levels of enzymes in the serum and liver, oedema
    and haemorrhaging in the walls of the coronary vessels, stasis and
    thrombi in the myocardium, altered fibrinolytic activity in the blood,
    and altered haematological parameters.  A single dose of 0.5 ml
    altered the ratio of the oxidized and reduced forms of nicotinamide
    coenzymes in the liver and myocardium of rats (Natsyuk & Chekman,
    1975).  Electrocardiographic changes were reported at doses of 1, 1.5
    and 2 mg/kg body weight, although these effects have not been
    confirmed in other studies (Saitanov & Arsenieva, 1969).

         The LD50 for dermal exposure in rabbits was estimated to be
    between 2.8 and 4.9 g/kg (Torkelson & Rowe, 1981; NIOSH,
    1994).


        Table 3.  Acute toxicity of 1,2-dichloroethane in experimental animals
                                                                                                                                                

    Species                                       Numbers/sex   Duration/vehicle       LC50 or LD50                 Reference
                                                                                                                                                

    Inhalation

    Rats (Wistar equal no. of m & f)              10-54         0.53 h                 48 000 mg/m3 (12 000 ppm)    Spencer et al. (1951)
                                                  20-51         2.75 h                 12 000 mg/m3 (3000 ppm)
                                                  31-32         7.20 h                 4000 mg/m3 (1000 ppm)

    Rats (albino, strain, number and sex not                    not specified          30 000 mg/m3                 Nevrotsky et al. (1971)
    specified)

    Rats (Sprague-Dawley, 12 per group, sex not                 6 h                    6600 mg/m3 (1646 ppm)        Bonnet et al. (1980)
    specified)

    Mice (OF1, 20 f per group)                                  6 h                    1050 mg/m3 (262 ppm)         Gradiski et al. (1978)

    Ingestion

    Rats (strain, number and sex not specified)                 not specified          850 mg/kg body weight        Larionov &
                                                                                                                    Kokarovtseva (1976)

    Rats (6 per group, strain and sex not                       not specified          770 mg/kg body weight        Smyth (1969)
    specified)

    Rats (young adult albino, 80 m & f)                         corn oil               680 mg/kg body weight        McCollister et al. (1956)

    Mice, 6-week old (CD-1, number not            male          water                  489 mg/kg body weight        Munson et al. (1982)
    specified)                                    female                               413 mg/kg body weight
                                                                                                                                                

    Table 3. (cont'd).
                                                                                                                                                

    Species                                       Numbers/sex   Duration/vehicle       LC50 or LD50                 Reference
                                                                                                                                                

    Dogs (strain, number and sex not specified)                 acacia gum             2500 mg/kg body weight       Barsoum & Saad (1934)

    Rabbits (strain, number and sex not                         not specified          860 mg/kg body weight        NIOSH (1994)
    specified)

    Dermal

    Rabbits (strain, number and sex not                         not specified          2800 mg/kg body weight       NIOSH (1994)
    specified)

    Rabbits (strain, number and sex not                         olive oil; duration    2800-4900 mg/kg body weight  Torkelson & Rowe
    specified)                                                  and area of skin                                    (1981)
                                                                exposed not
                                                                specified
                                                                                                                                               
    

    7.2  Skin and eye irritation

         When 1.0 ml undiluted 1,2-dichloroethane was applied directly to
    the clipped skin of guinea-pigs for up to 12 h in occluded patch
    tests, no gross skin reactions were visible (Jakobson et al., 1982). 
    Microscopic changes appeared 4 h after application, comprising
    karyopyknosis, perinuclear oedema, spongiosis and junctional
    separation (Kronevi et al., 1981).  In Draize tests on rabbits,
    moderate erythema and oedema were observed 24 h after
    application (dose not specified).  Microscopy on the third day
    revealed necrosis and other lesions such as ulcerations and
    acanthosis.  The severity of the changes was not indicated (Duprat et
    al., 1976).

         Instillation of 0.1 ml undiluted 1,2-dichloroethane into the
    conjunctival sac of the eye of rabbits generated reversible, mild
    irritation characterized by conjunctivitis and epithelial abrasion. 
    Epithelial keratitis, described as being "in a state of repair", was
    observed microscopically 7 days after application (Duprat et al.,
    1976).  Reversible clouding of the cornea was observed in dogs within
    10 h of subcutaneous administration of undiluted 1,2-dichloroethane at
    0.9 mg/kg body weight.  The clouding continued up to 48 h, but the
    corneas appeared clear after 5 days.  Histological changes, including
    necrosis of the corneal endothelium, partially denuded Descemet's
    membrane, formation of excess basement membrane, and swelling of the
    corneal stroma, were also observed in dogs, cats and rabbits after
    ocular injection of 1.8 mg 1,2-dichloroethane (0.15 ml of a 1%
    solution) into the anterior chamber (Kuwabara et al., 1968).

    7.3  Short-term exposure

         Small groups of Wistar rats, rabbits, guinea-pigs, dogs and pigs
    (n = 1 to 21) were exposed to 6000 mg/m3 (1500 ppm)
    1,2-dichloroethane, 7 h/day for 6 days.  Sections of the liver, heart,
    lungs, kidney adrenal glands and spleen were examined microscopically. 
    In most animals, degeneration or necrosis of the kidney and liver,
    along with congestion and haemorrhage of the lungs and adrenal glands,
    were observed (Heppel et al., 1945).

         No significant changes in organ or body weights, histology or
    clinical chemistry and haematological parameters were observed in rats
    administered 1,2-dichloroethane doses of up to 150 mg/kg body weight
    per day in corn oil by gavage, 5 times/week for 2 weeks (van Esch et
    al., 1977; Reitz et al., 1982).

    7.4  Subchronic exposure

    7.4.1  Inhalation

         The subchronic toxicity of inhaled 1,2-dichloroethane was
    investigated in three early limited studies in multiple species, as
    presented in Table 4.  Heppel et al. (1946) exposed groups of rats,
    mice, rabbits, guinea-pigs, dogs, cats and monkeys to 4000 mg/m3
    (1000 ppm) for up to 66 days.  Mice, rats, rabbits and guinea-pigs
    were the most sensitive species, based on mortality after only one or
    a few exposures.  Various effects were noted in these animals,
    including pulmonary congestion (guinea-pigs, cats and rats), fatty
    changes in the kidney (rats and monkeys), fatty changes in the
    livera (cats, dogs and monkeys) and clouded corneas (dogs).  At
    1600 mg/m3 (400 ppm), observed effects included fatty degeneration
    of the liver, kidney or heart (guinea-pigs and one rat), fatty changes
    in the liver (dogs) and pulmonary congestion (rats), while at
    800 mg/m3 (200 ppm), rats and guinea-pigs had mild pulmonary
    congestion and one rat had fatty degeneration in the kidneys.  No
    effects on growth were noted in mice and rats exposed to 400 mg/m3
    (100 ppm).

         In a similar study, rats, guinea-pigs, rabbits and monkeys were
    exposed to 400, 800 or 1600 mg/m3 (100, 200 or 400 ppm)
    1,2-dichloroethane for 6 to 9 months (Spencer et al., 1951).  Severe
    effects, including hepatotoxicity, and deaths were observed in rats
    and guinea-pigs exposed at the highest level, while monkeys also
    showed degeneration of the liver and kidneys at this concentration. 
    No effects were noted in rabbits.  At 800 mg/m3 (200 ppm) no adverse
    effects were observed in rats, but slight degeneration of the liver
    was noted in guinea-pigs.  At 400 mg/m3 (100 ppm), no adverse
    effects were observed in any of the four species.  The authors
    considered the "maximum concentrations without adverse effects" to be
    1600 mg/m3 (400 ppm)  in the rabbit, 800 mg/m3 (200 ppm) in the
    rat, and 400 mg/m3 (100 ppm) in the monkey and guinea-pig, based on
    a limited range of end-points.

                 

    a  It has been suggested, on the basis of in vitro investigations,
       that fatty accumulation in the liver may be due to the ability of
       1,2-dichloroethane to block the secretion of hepatocellular
       (Cotalasso et al., 1994).


        Table 4.  Subchronic toxicity of 1,2-dichloroethane in experimental animals
                                                                                                                                                

    Species                     Protocol                         Results                                                                Reference
                                                                                                                                                

    Inhalation
    Rats (26, strain and        animals were exposed to 0 or     There was high mortality in exposed rats (20/26), rabbits (5/6) and    Heppel
    sex not specified)          4000 mg/m3 (0 or 1000 ppm),      guinea-pigs (36/41) after a few exposures. All mice died after one     et al.
    Mice (22, strain and        7 h/day, 5 days/week for up      exposure. Survival was higher among cats and dogs (4/6 of either       (1946)
    sex not specified)          to 66 exposures; sections of     species survived more than 23 exposures). One monkey died after 2
    Rabbits (5 m & 1 f,         liver, heart, lungs, kidney,     days and the other after 32 exposures. Pulmonary congestion was
    strain not specified)       adrenal glands and spleen        noted in guinea-pigs, cats and rats. Rats and monkeys had fatty
    Guinea-pigs (10-16, strain  were examined                    changes in the kidney. Cats and monkeys had fatty changes in the
    and sex not specified)      microscopically; haematological  liver. Dogs had cloudy corneas; one dog had fatty degeneration of
    Dogs (3 f, strain not       and urinary parameters were      the liver. No effects on haematological or urinary parameters were
    specified)                  assessed in dogs                 observed in dogs. Rabbits had no obvious effects on postmortem.
    Cats (6 f, strain not
    specified)
    Monkeys (Rhesus, 2,
    sex not specified)

    Rats (15 m & 1 f,           animals were exposed to 0 or     All dogs and puppies survived 177 exposures. All rabbits died, after   Heppel
    strain not specified)       1600 mg/m3 (0 or 400 ppm),       1 to 97 exposures; 14/20 and 9/16 guinea-pigs and rats died by the     et al.
    Rabbits (2 m & 3 f,         7 h/day, 5 days/week for up to   60th exposure. Rats had pulmonary congestion and 1 rat and 6           (1946)
    strain not specified)       177 exposures; sections of       guinea-pigs had fatty degeneration of the liver, kidney and heart.
    Guinea-pigs (8-10 m &       liver, heart, lungs, kidney,     Dogs had slight fatty changes in the liver. No effects were noted in
    2 f, strain not specified)  adrenal glands and spleen were   rabbits on postmortem. There were no significant differences in
    Dogs (6 f, strain not       examined microscopically;        haematological parameters in exposed dogs and rabbits compared
    specified) and puppies      haematological parameters        to controls.
    (3 m, strain not            were also assessed in dogs
    specified)                  and rabbits
                                                                                                                                                

    Table 4. (cont'd).
                                                                                                                                                

    Species                     Protocol                         Results                                                                Reference
                                                                                                                                                

    Rats (Wistar 1 m & 11 f)    animals were exposed to 0 or     5/14 guinea-pigs, 7/12 rats and 8/12 rats died after 1 to 115          Heppel
    Osborne-Mendel rats (12 m)  800 mg/m3 (0 or 200 ppm), 7 h/   exposures. Rats and guinea-pigs had mild pulmonary congestion,         et al.
    Rabbits (5  m, strain       day, 5 days/week, for up to      and 1 rat had fatty degeneration in the kidneys. There were no         (1946)
    not specified)              125 exposures; sections of       significant differences in haematological parameters in exposed
    Guinea-pigs (12 m & 2 f,    liver, heart, lungs, kidney,     rats and rabbits, compared to controls.
    strain not specified)       adrenal glands and spleen
    Monkeys (2 m, strain        were examined microscopically;
    not specified)              haematological parameters were
                                assessed in rats and rabbits

    Rats (23 m & 16 f,          animals were exposed to 0 or     All animals survived. There were no differences in the rate of         Heppel
    strain not specified)       400 mg/m3 (0 or 100 ppm), 7 h/   growth in rats or mice.                                                et al.
    Mice (19, strain and        day, 5 days/week for 74 (rats)                                                                          (1946)
    sex not specified)          and 19 (mice) exposures;
                                sections of liver, heart,
                                lungs, kidney, adrenal glands
                                and spleen were examined
                                microscopically

    Rats (Wistar, 15-20  m &    animals were exposed to 0, 400,  1600 mg/m3: All female rats and male guinea-pigs died by 10            Spencer
    15-20 f)                    800 or 1600 mg/m3 (0, 100, 200,  exposures; all male rats died by 40 exposures. All female              et al.
    Guinea-pigs (2-8 m &        or 400 ppm), 7 h/day, 5 days/    guinea-pigs died by 24 exposures. Rats and guinea-pigs had rapid body  (1951)
    8 m, strain not specified)  week for 6 to 9 months; animals  weight loss, slight increases in liver and kidney weights, and
    Rabbits (albino, number     were killed at various times     some fatty changes in the liver. Guinea-pigs had swelling of the
    and sex not specified)      throughout the study;            tubular epithelium of the kidneys and alterations in levels of
    Monkeys (Rhesus, number     haematological parameters were   non-protein nitrogen urea nitrogen in the blood. Monkeys had
    and sex not specified)      assessed and histopathological   degeneration of the liver and kidneys and increased fat content
                                examinations of several tissues  of the liver. No effects were noted in rabbits.
                                were conducted
                                                                                                                                                

    Table 4. (cont'd).
                                                                                                                                                

    Species                     Protocol                         Results                                                                Reference
                                                                                                                                                

                                                                 800 mg/m3: Guinea-pigs tolerated up to 180 exposures (246 days).
                                                                 Male guinea-pigs had significantly (p=0.001) decreased body
                                                                 weight gain; both sexes of guinea-pigs had slight degeneration
                                                                 and fatty accumulation in the liver. Rats tolerated up to 151
                                                                 exposures (212 days) with no observed adverse effects.

                                                                 400 mg/m3: No effects were noted in rats, guinea-pigs, rabbits
                                                                 or monkeys.

    Rats (Sprague-Dawley,       were exposed to 400              At the higher concentration, rats were dyspnoeic and guinea-pigs       Hofman
    10, sex not specified)      or 2000 mg/m3 (100 or 500        were "apathetic". 3/4 rabbits died after 10-17 exposures; 9/10         et al.
    Guinea-pigs (10, strain     ppm), 6 h/day, 5 days/week       guinea-pigs died after 4-14 exposures. Rats died after 1-5 exposures,  (1971)
    and sex not specified)      for up to 17 weeks;              while all cats survived 30 exposures. Rats had pulmonary hyperaemia
    Rabbits (4, strain and      histological examinations were   and oedema, fatty liver and adrenal and myocardial necrosis. Cats and
    sex not specified)          conducted, and several           rabbits had heart lesions, and guinea-pigs had fatty changes in the
    Cats (2 per group, strain   bio-chemical parameters were     myocardium, liver and adrenals, and necrosis in the myocardium and
    and sex not specified)      assessed                         liver. At 400 mg/m3, there were no clinical or histological
                                                                 changes after exposure for 17 weeks.
                                                                                                                                                

    Table 4. (cont'd).
                                                                                                                                                

    Species                  Protocol                          Results                                                                  Reference
                                                                                                                                                

    Ingestion
    Rats F344/N,             animals were administered 0,      Drinking-water: F344/N rats: Body weight was significantly decreased     NTP
    Sprague-Dawley and       500, 1000, 2000, 4000 and         in males at 4000 and 8000 mg/litre (>8%, p<0.001).  Relative kidney      (1991)
    Osborne Mendel, mice,    8000 mg/litre in the              weight was significantly increased at >1000 mg/litre in both sexes
    B6C3F1 (10 or 20 m & f   drinking-water (equivalent to     (>11%, p<0.001).  Relative liver weight was significantly increased at
    per group)               doses of of 49-82, 86-126,        >2000 mg/litre in males (>14%, p<0.05) and 4000 mg/litre in females
                             146-213, 259-428, and             (>9%, p<0.001). Alterations in haematological and serum parameters
                             492-727 mg/kg body weight per     at the higher concentrations reflected dehydration caused by
                             day in rats and 244-249,          decreased water consumption. Renal tubular "regeneration" observed
                             448-647, 781-1182, 2478-2710      in all groups of males at similar frequencies and severity, but
                             and 4207-4926 mg/kg body          frequency was related to dose in females (0/10, 0/10, 1/10, 2/10
                             weight per day in mice) for       3/10 and 9/10 with increasing concentration).
                             13 weeks

    Rats F344/N (10 or       rats were administered 0, 30,     Sprague-Dawley rats: Body weight was significantly decreased in
    20 m & f per group)      60, 120, 240 or 480 mg/kg body    males at 8000 ppm (9%, p<0.05). Relative kidney weight was
                             per day (males) or 0, 18, 37,     significantly increased at >1000 mg/litre in males (>7%, p<0.05)
                             75, 150 or 300 mg/kg body         and at >500 mg/litre in females (>8%, p<0.05).  Relative liver
                             weight per day (females) in       weight was increased in males at >500 mg/litre (>6%, p<0.05)
                             corn oil by gavage,               and at 8000 mg/litre in females (13%, p<0.001). Alterations in
                             5 days/week for 13 weeks          haematological and serum parameters at the higher
                                                               concentrations reflected dehydration caused by decreased water
                                                               consumption. Renal tubular "regeneration" was observed in all
                                                               groups at similar frequencies and severity.
                                                                                                                                                

    Table 4. (cont'd).
                                                                                                                                                

    Species               Protocol                            Results                                                                   Reference
                                                                                                                                                

                          haematological and serum            Osborne-Mendel rats: Body weight was significantly decreased
                          chemistry parameters were           at 8000 mg/litre in males (15%, p<0.05).  Relative kidney weight
                          examined at several times           was increased at 4000 and 8000 mg/litre in males (>8%, p<0.05)
                          during the course of the study.     and >500 mg/litre in females (>12%, p<0.001).  Relative liver weight
                          Extensive histopathological         was increased in males at 1000 and 2000 mg/litre (>14%, p<0.05).
                          examinations were conducted         Alterations in haematological and serum parameters at the higher
                          for controls and all animals        concentrations reflected dehydration caused by decreased water
                          at the highest concentration        consumption. Although the incidence of renal tubular "regeneration"
                          in drinking-water and in female     was increased at the higher concentrations, the increases were

                          mice at 4000 ppm, as well as in     not related to dose, and severity was similar in all groups.
                          male rats receiving doses of
                          120 or 240 mg/kg body weight        B6C3F1 mice: 9/10 females exposed to 8000 mg/litre died. Body
                          per day by gavage and in            weight was significantly decreased in males at 8000 mg/litre
                          female rats at 150 mg/kg body       (17.5%, p<0.001). Relative kidney weight was significantly increased
                          weight per day                      in males at >1000 mg/litre (>12%, p<0.001) and in females at >500
                                                              mg/litre (>16%, p<0.001). Relative liver weight was significantly
                                                              increased in males at 500 mg/litre and above and in females at 1000
                                                              mg/litre or more. The incidence of renal tubular cell regeneration
                                                              was significantly increased in males at 4000 and 8000 mg/litre;
                                                              karyomegaly was observed in all males at 8000 mg/litre.

                                                              Gavage: F344/N rats: All males receiving 240 or 480 mg/kg body
                                                              weight per day and 9/10 female receiving 300 mg/kg body weight per
                                                              day died before the end of the study. The incidence of hyperplasia
                                                              and inflammation of the forestomach was significantly increased in
                                                              males at 240 mg/kg body weight per day; necrosis of the thymus was
                                                              observed in 10/10 males at 480 mg/kg body weight per day and 5/10
                                                              females at 300 mg/kg body weight per day, compared to none
                                                              in controls.
                                                                                                                                                

    Table 4. (cont'd).
                                                                                                                                                

    Species                 Protocol                            Results                                                               Reference
                                                                                                                                                

    Rats (Osborne-Mendel,   animals were administered           At the highest dose, three males and one female died. In males,       NCI
    5 m & 5 f per group)    doses of 0, 40, 63, 100, 159 or     mean body weight was only significantly decreased (by 50%) at         (1978)
                            251 mg/kg body weight per day       251 mg/kg body weight per day. In females mean body weight was
                            in corn oil by gavage, 5 days       depressed (10% at 40 mg/kg body weight per day to 17% at 100
                            week for 6 weeks followed by a      mg/kg body weight per day and 32% at 159 mg/kg body weight
                            2-week observation period           per day). No other parameters were investigated.

    Mice (B6C3F1 5 m &      animals were administered           All males receiving 398 mg/kg body weight per day and all females     NCI
    5 f per group)          doses of 0, 159, 251, 398,          receiving 631 mg/kg body weight per day died. Mean body weight        (1978)
                            631 or 1000 mg/kg body weight       depression was only observed in females receiving 398 mg/kg body
                            per day in corn oil by              weight per day, in which "drastic weight loss" was reported. No
                            gavage, 5 days/week for             other parameters were investigated.
                            6 weeks followed by a 2-week
                            observation period

    Rats (6 per group,      rats were fed mash fumigated        The only effect noted, based on examination of lipid content          Alumot
    strain and sex not      with 1,2-dichloroethane,            of the liver and liver weight, was an increase in liver fat at        et al.
    specified)              resulting in initial                1600 mg/kg. Chronic respiratory disease was evident in all exposure   (1976a)
                            concentrations of 200 or            groups (incidence data not presented, but the disease was not
                            600 mg/kg (approximately            believed to be associated with exposure); mortality was higher in
                            equivalent to doses of 10 and       males than females, with the number of rats surviving after 21
                            30 mg/kg body weight per day,       months ranging from 3 to 14.
                            respectively) for 5 weeks, or
                            1600 mg/kg (approximately
                            equivalent to a dose of
                            80 mg/kg body weight per day)
                            for 7 weeks; the authors
                            noted that the dose ingested
                            was approximately 60 to 70% of
                            the initial amount after loss
                                                                                                                                                

    Table 4. (cont'd).
                                                                                                                                                

    Species                   Protocol                           Results                                                              Reference
                                                                                                                                                

                              to volatilization was
                              considered; lipid content of
                              liver and liver weight were
                              measured, and hepatic
                              triglycerides were measured at
                              the highest dose; no
                              histopathological examinations
                              were conducted

    Rats (m & f, strain and   rats were administered doses       Decreased weight gain was observed at the two highest doses.         Van Esch
    number not specified      of 0, 10, 30 or 90 mg/kg body      Males and females had increased relative kidney weight at 90         et al.
    in secondary account)     weight per day (method of oral     mg/kg body weight per day. Females also had increased relative       (1977)
                              administration not specified       weights of liver and brain at this dose. No effects on histology
                              in secondary account), 5 times     or clinical chemistry were noted. Alterations in some
                              per week for 90 days;              haematological parameters observed, although these did not occur
                              histopathological examinations     in a dose-related manner.
                              were conducted, along with
                              assessment of haematological
                              and clinical chemistry
                              parameters, although the
                              extent of the examinations
                              was not specified in the
                              secondary account

    Rats (m, strain and       rats were orally                   There was a statistically significant (p < 0.02) increase in the     Apostolov
    number not specified)     administered doses                 activity of the serum lysosome enzyme,                               &
                              equivalent to 1/5000, 1/1000       beta-N-acetylglucosa-minidase at the two highest doses.              Mihaylova
                              or 1/200 the LD50 (not further                                                                          (1975)
                              specified) for 3 months                                                                                 (abstract
                                                                                                                                      only)
                                                                                                                                                
    
         Hofmann et al. (1971) exposed rats, guinea-pigs, rabbits and cats
    to 400 or 2000 mg/m3 (100 or 500 ppm) for up to 17 weeks.  Mortality
    was high in rats, guinea-pigs and rabbits exposed to the higher
    concentration.  At 2000 mg/m3 (500 ppm) pulmonary hyperaemia and
    oedema, fatty liver and adrenal and myocardial necrosis were noted in
    rats, while heart lesions were observed in cats and rabbits. 
    Guinea-pigs had fatty changes in the myocardium, liver and adrenals
    and necrosis in the myocardium and liver at the higher concentration. 
    No clinical or histological effects were noted at 400 mg/m3
    (100 ppm).

    7.4.2  Ingestion

         Available data on the subchronic toxicity of ingested
    1,2-dichloroethane are presented in Table 4.  In a recent study
    conducted by the National Toxicology Program (NTP, 1991) and partially
    reported by Morgan et al. (1990), the relative susceptibility of three
    strains of rats (F344/N, Sprague-Dawley and Osborne-Mendel) and one
    strain of mice (B6C3F1) exposed to 1,2-dichloroethane in
    drinking-water at concentrations of up to 8000 mg/litre for 13 weeks,
    and one of the same strains of rats (F344/N) exposed to doses of up to
    480 mg/kg body weight per day by gavage in corn oil for 13 weeks, was
    investigated.  Based on increased relative organ weights, the liver
    and kidneys were the target organs in both rats and mice, although
    treatment-related microscopic lesions were noted only in female F344/N
    rats and male B6C3F1 mice.  Administration of 1,2-dichloroethane to
    F344/N rats by gavage resulted in more severe toxic effects (including
    death) than administration of similar doses in drinking-water,
    probably due to greater peak levels of the compound in the blood and
    saturation of elimination mechanisms.  The authors considered the
    no-observed-effect levels (NOEL) for 1,2-dichloroethane administered
    to F344/N rats by gavage to be 120 and 150 mg/kg body weight per day
    in males and females, respectively, based on mortality and chemically
    related lesions in the forestomach.  The NOEL of B6C3F1 mice exposed
    via drinking-water was considered to be 780 mg/kg body weight per day)
    (2000 ppm) in males, based on kidney lesions, and (2500 mg/kg body
    weight per day) (4000 ppm) in females, based on mortality.  The
    authors did not consider the doses to which the three strains of rats
    were exposed in the drinking-water to be high enough to result in
    biologically significant toxic effect, although increases in organ
    weights without accompanying histopathological alterations were
    observed at doses as low as 49 to 82 mg/kg body weight per day in some
    strains (i.e. Sprague-Dawley and Osborne-Mendel).

         In limited subchronic studies preliminary to long-term
    carcinogenesis bioassays, groups of Osborne-Mendel rats and B6C3F1
    mice were administered doses of up to 251 and 1000 mg/kg body weight
    per day, respectively, by gavage for 6 weeks.  Significant mean body
    weight loss was noted in male rats at 251 mg/kg body weight per day
    and in female rats at > 40 mg/kg body weight per day.  In mice,
    mean body weight was decreased only in females receiving 398 mg/kg
    body weight per day.  No other parameters were investigated in this
    study (NCI, 1978).

         Decreased body weight gain was observed in rats orally
    administered doses of 30 or 90 mg/kg body weight per day for 90 days,
    but not in those receiving 10 mg/kg body weight per day.  Increased
    relative weights of kidneys (both sexes), liver and brain (females
    only) were noted at the highest dose, although no histopathological
    effects or alterations in clinical chemistry parameters were noted. 
    Changes in some haematological parameters were noted, but these were
    not related to dose (Van Esch et al., 1977).

         A slight increase in the fat content of the livers was reported
    in rats consuming feed which had been fumigated with
    1,2-dichloroethane, resulting in an initial concentration of
    1600 mg/kg (approximately equivalent to a dose of 80 mg/kg body weight
    per day) for 7 weeks, while no effects were observed at 600 mg/kg
    (approximately equivalent to a dose of 30 mg/kg body weight per day)
    after 5 weeks (Alumot et al., 1976a).  The parameters examined were
    limited to hepatic lipid content and liver weight.  The activity of
    the serum lysosome enzyme, ß- N-acetylglucosaminidase, was
    significantly increased in rats administered oral doses equivalent to
    1/1000 and 1/200 the LD50 (not further specified in abstract)
    (Apostolov & Mihaylova, 1975).

    7.5  Chronic exposure and carcinogenicity

    7.5.1  Inhalation

         Groups of 90 Sprague-Dawley rats of each sex were exposed by
    inhalation to 1,2-dichloroethane (99.92% pure) at concentrations of 0,
    20, 40, 202 and 1012 mg/m3 (0, 5, 10, 50 and 250 ppm), 7 h/day, 5
    days/week for 78 weeks, and observed until spontaneous death (due to
    severe toxicity, the highest concentration was reduced to 607 mg/m3
    or 150 ppm after several days).  "Incidence" was reported as the
    number of animals developing specific tumours over the number of
    animals alive at the time the first tumour of that type was detected
    (i.e. incidences have not been adjusted for differential survival (see
    Table 5)).  The only tumour types for which the authors reported an
    increase in incidence (when compared with controls kept in exposure
    chambers, but not when compared with those not kept in chambers) were
    fibromas and fibroadenomas (combined) of the mammary gland, which the
    authors attributed to the differential survival among the groups
    (Maltoni et al., 1980).

         Groups of 50 male and 50 female Sprague-Dawley rats were exposed
    to 0 or 200 mg/m3 (50 ppm) 1,2-dichloroethane 7 h/day, 5 days/week
    for 2 years.  No effects on body weight gain or mortality were noted. 
    There was no significant difference in the incidence of tumours at any
    site, although there was a nonsignificant increase in the incidence of
    mammary gland adenomas (4 in exposed group versus 2 in control group)
    and fibroadenomas (21/50 in exposed group versus 15/50 in control
    group) in females.  There was an increased incidence of testicular
    lesions (not further specified) in males (24% versus 10% in controls,
    significance not reported) (Cheever et al., 1990).  However, the
    sensitivity of this investigation to detect any carcinogenic potential
    may have been compromised (the study was designed to investigate the
    interaction between 1,2-dichloroethane and other substances), based on
    the lack of convincing evidence of compound-related toxicity at the
    only concentration to which animals were exposed.

         Clinical chemistry and haematological parameters were
    investigated in groups of 8 to 10 male or female Sprague-Dawley rats
    exposed to 0, 20, 40, 202 or 1012 mg/m3 (decreased to 607 mg/m3
    after several days) (0, 5, 10, 50 or 250/150 ppm), 7 h/day, 5
    days/week for 3, 6, and 18 months, beginning at 3 months of age.  In
    addition, groups of 8 to 10 rats were also exposed to these same
    concentrations beginning at 14 months of age for 12 months.  Although
    values were occasionally significantly (p < 0.05) different from
    those of controls, no consistent dose-related effects on various
    haematological parameters, circulating protein levels or clinical
    chemistry parameters were reported in rats exposed from 3 months of
    age.  In animals exposed for 12 months beginning at 14 months of age,
    there were no consistent dose-related effects on haematological
    parameters.  There were significant (p < 0.05) changes in serum
    parameters indicative of effects on liver and kidney function,
    including levels of glutamic-pyruvic transaminase (SGPT),
    gamma-glutamyltranspeptidase (gamma-GT), glutamic-oxalic transaminase
    (SGOT) and cholesterol, and levels of uric acid in the blood and blood
    urea nitrogen (BUN) at 202 and 607 mg/m3. Histopathological
    examinations were not conducted (Spreafico et al., 1980).

         No increase in the incidence of any type of tumour was reported
    in groups of 90 male or female Swiss mice exposed to 20, 40, 202 or
    1012 (decreased to 607 mg/m3 after a few days) mg/m3 (5, 10, 50 or
    250/150 ppm), 7 h/day, 5 days/week for 78 weeks, and observed until
    spontaneous death (Maltoni et al., 1980).  However, it should be noted
    that survival was poor (especially among males).


        Table 5.  Chronic toxicity and carcinogenicity of 1,2-dichloroethane in experimental animals
                                                                                                                                                

    Species            Protocol                               Results                                                                 Reference
                                                                                                                                                

    Inhalation
    Rats               Rats were exposed to 0, 20, 40, 202    After several days of exposure to 1012 mg/m3, severe toxic effects,     Maltoni
    (Sprague-Dawley,   and 1012/607 mg/m3 (0, 5, 10, 50       including death were observed and the level of exposure was reduced     et al.
    90 m & 90 f per    and 250/150 ppm) 1,2-dichloroethane    to 607 mg/m3. Survival varied among the groups, but was not related     (1980)
    group, 180 m &     (99.92% pure), 7 h/day, 5 days/week    to concentration; most rats died by week 140. Survival at 104 weeks
    180 f controls)    for 78 weeks and observed until        of age in controls, chamber controls, and groups exposed to 20, 40,
                       spontaneous death. One group of        202 and 1012/607 mg/m3 was 17.8, 13.3, 50.0, 14.4, 18.9 and 11.1%
                       controls was kept in a nearby room,    (males) and 40.0, 24.4, 53.3, 28.9, 32.2, and 23.3% (females).
                       while the other was kept in an         "Incidence" was reported as the number of animals developing specific
                       exposure chamber under the same        tumours over the number of animals alive at the time the first tumour
                       conditions as the exposed groups.      of that type was detected (i.e. incidences have not been adjusted for
                       A complete autopsy was performed       differential survival). With the exception of benign mammary tumours,
                       on each animal, regardless of time     there were no significant increases in the incidence of any types of
                       of death. Several organs were          (combined) tumours in exposed rats.  The incidence of all mammary
                       routinely histopathologically          tumours (number of animals alive at the time of appearance of the
                       examined, along with any organs        first mammary tumour (12 weeks) was 90 in each exposure group) was
                       with pathological lesions.             52/90 (57.8%), 38/90 (42.2%), 65/90 (72.2%), 43/90 (47.8%), 58/90
                                                              (64.4%) and 52/90 (57.5%) in non-chamber controls, chamber controls,
                                                              and groups exposed to 20, 40, 202 and 1012/607 mg/m3, respectively.
                                                              The numbers (denominators not specified) of fibromas and
                                                              fibroadenomas (combined) of the mammary gland were 47, 27, 56, 33, 49
                                                              and 47 in non-chamber controls, chamber controls, and groups exposed
                                                              to 20, 40, 202 and 1012/607 mg/m3, respectively.  The "incidence"
                                                              of these tumours at 20, 40, 202 and 1012/607 mg/m3, was
                                                              significantly (p<0.01 or 0.001) different from the incidence in
                                                              chamber controls.  The "incidences" of benign mammary tumours in the
                                                              two control groups were also significantly (p<0.01) different.
                                                                                                                                                

    Table 5. (cont'd).
                                                                                                                                                

    Species            Protocol                               Results                                                                 Reference
                                                                                                                                                

    Rats               Rats were exposed to 0, 20, 40, 202    There were no consistent, exposure-related changes in various           Spreafico
    (Sprague-Dawley,   or 1012-607 mg/m3 (0, 5, 10, 50 or     haematological parameters, circulating protein levels or clinical       et al.
    8-10 or f per      250/150 ppm) 7 h/day, 5 days/week      chemistry parameters in animals exposed from 3 months of age,           (1980)
    group)             for 3, 6 or 18 months, beginning at    although values occasionally differed significantly from controls.
                       3 months of age. In addition, groups   In animals exposed for 12 months from 14 months of age, there were no
                       of rats were exposed to 0, 20, 40,     consistent exposure-related alterations in haematological parameters.
                       202 or 1012-607 mg/m3 (0, 5, 10, 50    Levels of serum glutamic-pyruvic transaminase (SGPT) were
                       or 250/150 ppm) 7 h/day, 5 days/       significantly elevated in both males and females at 202 and 607 mg/m3
                       week for 12 months, beginning at 14    (p<0.05), and gamma-glutamil transpeptidase (gamma-GT) levels were
                       months of age. Histopathological       also significantly greater in females at the two highest
                       examinations were not conducted.       concentrations (p<0.05). Levels of serum glutamic-oxalic transaminase
                                                              (SGOT) were significantly increased in both sexes at 20 and 40 mg/m3
                                                              (p<0.05), but significantly decreased in males and females at 202 and
                                                              607 mg/m3 (p<0.05). Levels of cholesterol were significantly lower
                                                              in males and females at 202 and 607 mg/m3 (p<0.05). Levels of uric
                                                              acid in the blood were significantly higher in both sexes at 202 and
                                                              607 mg/m3 (p<0.05), while blood urea nitrogen (BUN) values were
                                                              significantly elevated at 607 mg/m3 (p<0.05), although there were
                                                              no effects on urinary parameters.

    Rats               Rats were exposed to 200 mg/m3 (0      There were no compound-related effects on body weight gain or           Cheever
    (Sprague-Dawley,   or 50 ppm) 7 h/day, 5 days/week for    mortality. There were no significant increases in the incidence of      et al.
    50 m & 50 f        2 years. Extensive histopathological   any type of tumours, although there was a non-significant increase      (1990)
    per group)         examinations were conducted.           in the incidence of mammary gland adenomas (4 versus 2 in controls)
                                                              and fibroadenomas (21/50 versus 15/50) in females.  The incidence of
                                                              testicular lesions (not further specified) was increased in exposed
                                                              animals (24% versus 10% in controls, significance not reported).
                                                                                                                                                

    Table 5. (cont'd).
                                                                                                                                                

    Species            Protocol                               Results                                                                 Reference
                                                                                                                                                

    Mice (Swiss,       Mice were exposed to 20, 40, 202 or    Survival of mice was poor, especially in males, as only 43.4 to 65.6%   Maltoni
    90 m & 90 f        1012-607 mg/m3 (5, 10, 50 or 250/      of exposed males survived for 52 weeks after exposure commenced.        et al.
    per group,         150 ppm), 7 h/day, 5 days/week for     There were no significant increases in the incidence of any type of     (1980)
    115 m & 134 f      78 weeks and observed until            tumours.
    controls)          spontaneous death. Controls were
                       kept in a nearby room. A complete
                       autopsy was performed on each
                       animal, regardless of time of death.
                       Several organs were routinely
                       histopathologically examined, along
                       with any organs with pathological
                       lesions.

    Ingestion

    Rats               Animals were administered time         There were no effects on body weight gain in either sex. Mortality      NCI
    (Osborne-Mendel,   weighted average doses of 47 or 95     was significantly higher in both males and females in the high dose     (1978)
    50 50 m & f per    mg/kg body weight per day (initial     group, as 50% of exposed rats had died by week 55 (males) and 57
    group, 20 m &      doses of 50 and 100 mg/kg body         (females), compared to week 72 (males) and 88 (females) in controls.
    20 f controls;     weight per day were increased to 75    Signs of toxicity, including wheezing, nasal discharge, ulcerations,
    60 m & 60 f        and 150 mg/kg body weight per day      localized alopecia, discoloured or stained fur, bloated appearance
    pooled controls    after 7 weeks then decreased to        and swollen areas, occurred at a greater frequency in exposed
    from concurrent    original doses after 17 weeks) in      animals than in controls. Chronic murine pneumonia was present in 60
    experiments)       corn oil by gavage, 5 days/week, for   to 94% of rats in each group (incidence not related to dose).
                       78 weeks followed by 32 weeks of       Acanthosis and hyperkeratosis of the forestomach was present in a
                       observation. Complete                  greater proportion of exposed females than controls (1/20, 6/50 and
                       histopathological examinations were    7/50 in vehicle controls, low and high dose, respectively,
                       conducted.                             significance not reported). Other non-neoplastic lesions occurred
                                                              at similar frequencies in control and exposed rats.  The incidence
                                                              of squamous cell carcinomas of the forestomach in males was 0/60,
                                                                                                                                                

    Table 5. (cont'd).
                                                                                                                                                

    Species            Protocol                               Results                                                                 Reference
                                                                                                                                                

                                                              0/20, 3/50 and 9/50 in pooled controls, matched controls, low and
                                                              high dose groups, respectively, significant at the high dose
                                                              (p=0.01); only 2/50 females in the low dose group had this tumour.
                                                              There were also one leiomyosarcoma of the stomach and one
                                                              adenocarcinoma of the small intestine in high dose males (not
                                                              significant). The incidence of hemangiosarcomas (mostly in the
                                                              spleen) in males was 1/60, 0/20, 9/50 and 7/50 in pooled vehicle
                                                              controls, matched vehicle controls, low and high dose groups,
                                                              respectively (significant in both exposed groups, p=0.03 (low) and
                                                              p=0.016 (high)), and in females was 0/59, 0/20, 4/50 and 4/50 in
                                                              pooled vehicle controls, matched vehicle controls, low and high dose
                                                              groups, respectively (significant in both exposed groups (p=0.041 in
                                                              both)). Both groups of exposed males had an increased incidence of
                                                              fibromas of the subcutaneous tissue (0/60, 0/20, 5/50 and 6/50 in
                                                              pooled vehicle controls, matched vehicle controls, low and high dose
                                                              groups, respectively); no such increase was noted in females. In
                                                              females, there was an increased incidence of adenocarcinomas and
                                                              fibroadenomas of the mammary gland (1/59, 0/20, 1/50 and 18/50
                                                              (adenocarcinoma), 5/59, 0/20, 14/50 and 8/50 (fibroadenoma) and 6/59,
                                                              0/20, 15/50 and 24/50 (adenocarcinoma or fibroadenoma)) in pooled
                                                              vehicle controls, matched vehicle controls, low and high dose groups,
                                                              respectively). Renal tubular cell adenocarcinomas were noted in one
                                                              male and one female at the highest dose, while tubular cell adenomas
                                                              were present in one male and two females at this dose, and none was
                                                              observed in controls (significance not reported).

    Rats (18 m &       Animals were fed mash fumigated        Chronic respiratory disease was reported in all groups in the second    Alumot
    18 f per group,    with 1,2-dichloroethane for 2 years.   year of exposure. The number of rats surviving after 21 months ranged   et al.
    strain not         Resulting concentrations were 250      from 2 to 14 per group. No effects on growth or the biochemical         (1976a)
    specified)         and 600 mg/kg. Due to loss of the      parameters investigated were observed.
                                                                                                                                                

    Table 5. (cont'd).
                                                                                                                                                

    Species            Protocol                               Results                                                                 Reference
                                                                                                                                                

                       compound through volatilization,
                       the mash actually consumed was
                       estimated to contain 60 to 70% of
                       the initial concentration (estimated
                       to result in doses of approximately
                       7.5 to 8.75 and 15 to 17.5 mg/kg
                       body weight per day). The liver was
                       analysed for total fat triglyceride
                       content. Levels of total protein,
                       albumin, glucose, urea, uric acid
                       and cholesterol in the serum were
                       determined.  Histopathological
                       examinations do not appear to have
                       been conducted on surviving rats
                       at the end of the exposure period.

    Mice (B6C3F1,      Animals were administered              Mortality in females was related to dose (36 animals in the high dose   NCI
    50 m & 50 f        time-weighted average doses of 97      group died between weeks 60 and 80, which may have been related to      (1978)
    per group; 20      or 195 mg/kg body weight per day       the appearance of tumours as 25 of these animals had tumours); no
    m & 20 f           (males) or 149 or 299 (females) in     similar dose-related trend in mortality was observed in males. Body
    controls; 60 m     corn oil by gavage, 5 days/week, for   weight in females in the high dose group was depressed as early as
    & 60 f pooled      78 weeks followed by 13 weeks of       week 15 (>10%). The incidence of non-neoplastic lesions was
    controls from      observation (initial doses in males    comparable in exposed and control mice. There was an increased
    concurrent         of 75 and 150 mg/kg body weight        incidence of hepatocellular carcinomas in male mice at the highest
    experiments)       per day were increased to 100 and      dose (4/59, 1/19, 6/47 and 12/48 in pooled vehicle controls, matched
                       200 mg/kg body weight per day after    vehicle controls, low and high dose groups, respectively), but not in
                       8 weeks; initial doses in females      females. The incidence of alveolar/bronchiolar adenomas in males was
                                                                                                                                                

    Table 5. (cont'd).
                                                                                                                                                

    Species            Protocol                               Results                                                                 Reference
                                                                                                                                                

                       of 125 and 250 mg/kg body weight per   0/59, 0/19, 1/47 and 15/48 in pooled vehicle controls, matched
                       day were increased to 200 and          vehicle controls, low and high dose groups, respectively
                       400 mg/kg body weight per day after    (significant at the highest dose (p<0.001)); the incidence of this
                       8 weeks, then decreased to 150 and     tumour in females was 2/60, 1/20, 7/50 and 15/48 in pooled vehicle
                       300 mg/kg body weight per day after    controls, matched vehicle controls, low and high dose groups,
                       11 weeks). Complete                    respectively (significant in both exposed groups(p=0.046 (low) and
                       histopathological examinations were    p<0.001 (high)). There was also one alveolar/bronchiolar carcinoma in
                       conducted.                             females at 299 mg/kg body weight per day. There was a non-significant
                                                              increase in the incidence of squamous cell carcinoma of the
                                                              forestomach in females at 299 mg/kg body weight per day (5/48 versus
                                                              1/60 or 1/20 in controls). There was a significantly increased
                                                              incidence of mammary gland adenocarcinomas in both groups of exposed
                                                              females (0/60, 0/20, 9/50 and 7/48 in pooled vehicle controls,
                                                              matched vehicle controls, low and high dose groups, respectively
                                                              (p=0.001 (low) and p=0.003 (high)).
                                                              Uterine adenocarcinomas occurred in 3/49 low dose and 4/47 high
                                                              dose females, compared to none in controls; however, this increase
                                                              was not statistically significant. The incidence of endometrial
                                                              stromal polyp or endometrial stromal sarcoma (combined) was 0/60,
                                                              0/20, 5/49 and 5/47 in pooled vehicle controls, matched vehicle
                                                              controls, low and high dose groups, respectively (significant at
                                                              both doses, p=0.016 (low) and p=0.014 (high)).
                                                                                                                                                

    Table 5. (cont'd).
                                                                                                                                                

    Species            Protocol                               Results                                                                 Reference
                                                                                                                                                

    Dermal
    application

    Swiss mice         Doses of 0, 42 or 126 mg/application   The incidence of benign lung papillomas was significantly (p<0.0005)    van Duuren
    (Ha:ICR, 30 f;     per mouse in 0.2 ml acetone were       increased at the higher dose (26/30 compared to 17/30, 11/30 and        et al.
    30 vehicle         applied 3 times per week to the        30/100 in low dose group, vehicle controls and untreated controls,      (1979)
    controls and       shaved dorsal skin (area of skin       respectively). The incidence of stomach tumours was 3/30, 1/30, 2/30
    100 naive          exposed not specified) of mice for     and 5/100 in high dose group, low dose group, vehicle controls and
    controls)          440 to 594 days. The skin, liver,      untreated controls, respectively (not significant).
                       kidney and any tissues or
                       organs appearing abnormal were
                       examined histopathologically.
                                                                                                                                                
    

    7.5.2  Ingestion

         In a study conducted by the National Cancer Institute (NCI,
    1978), time-weighted average daily doses of 47 or 95 mg/kg body weight
    per day of 1,2-dichloroethanea in corn oil were administered by
    gavage 5 days/week for 78 weeks to 50 Osborne-Mendel rats of each sex,
    followed by 32 weeks of observation.   Mortality was significantly
    (p < 0.001) higher in both males and females in the high dose group. 
    Clinical signs of general toxicity occurred at a greater frequency in
    exposed animals than in controls.  In each group 60-94% of rats had
    chronic murine pneumonia, but the incidence was not related to dose. 
    The incidence of acanthosis and hyperkeratosis of the forestomach was
    greater in exposed females than controls.

         The incidence of a variety of tumours was increased in exposed
    animals compared with controls.  The incidence of squamous cell
    carcinomas of the stomach was significantly increased in males (3/50
    and 9/50 in low and high dose groups, respectively), compared to none
    in either group of controls; in females, there were only 2/50 in the
    low dose group.  The incidence of haemangiosarcoma was significantly
    increased in males (1/60, 0/20, 9/50 and 7/50 in pooled vehicle
    controls, matched vehicle controls, low and high dose groups,
    respectively) and females (0/59, 0/20, 4/50 and 4/50 in pooled vehicle
    controls, matched vehicle controls, low and high dose groups,
    respectively).  The incidence of fibromas of the subcutaneous tissue
    was significantly increased in males (0/60, 0/20, 5/50 and 6/50 in
    pooled vehicle controls, matched vehicle controls, low and high dose
    groups, respectively), but not in females.  There was a significant
    increase in the incidence of adenocarcinomas and fibroadenomas of the
    mammary gland in females (1/59, 0/20, 1/50 and 18/50 (adenocarcinoma),
    5/59, 0/20, 14/50 and 8/50 (fibroadenoma) and 6/59, 0/20, 15/50 and
    24/50 (adenocarcinoma or fibroadenoma)) in pooled vehicle controls,
    matched vehicle controls, low and high dose groups, respectively). It
    was concluded that 1,2-dichloroethane was carcinogenic in this strain
    of rats, under the conditions of this study.

         No effects on growth or biochemical parameters were observed in a
    limited study on rats fed mash that had been fumigated with
    1,2-dichloroethane, which resulted in doses of approximately 7.5-8.75
    and 15-17.5 mg/kg body weight per day.  Chronic respiratory disease
    was evident in all groups in the second year, the number of rats
    surviving after 21 months ranging from 2 to 14 in each of the groups. 
    The occurrence of respiratory disease and mortality did not appear to
    be exposure-related (Alumot et al., 1976a).

                 

    a  Technical grade with reported purity of > 90% containing 11 minor
       contaminants; subsequent analysis indicated a purity of about
       98-99% (Hooper et al., 1980 and Ward, 1980).

         The National Cancer Institute (NCI, 1978) also conducted a
    bioassay in which groups of 50 B6C3F1 mice were administered
    time-weighted average daily doses of 97 or 195 mg/kg body weight per
    day (males) and 149 or 299 mg/kg body weight per day (females)
    1,2-dichloroethane in corn oil by gavage, 5 days/week for 78 weeks,
    followed by 13 weeks of observation.  A doserelated increase in
    mortality was noted in female mice, but not in males.  Body weight was
    also decreased in females at 299 mg/kg body weight per day.

         As in rats, there was a significant increase in the incidence of
    several types of tumours in exposed mice.  The incidence of
    hepatocellular carcinomas was significantly increased in males in the
    high dose group (4/59, 1/19, 6/47 and 12/48 in pooled vehicle
    controls, matched vehicle controls, low and high dose groups,
    respectively); no such increase was noted in females.  However, the
    authors noted that, due to the high variability of incidence of
    hepatocellular neoplasms in historical controls (data not presented),
    this increase, although statistically significant, was not considered
    to be convincing evidence that these tumours were attributable to the
    test chemical.  The incidence of alveolar/bronchiolar adenomas was
    significantly increased in males in the high dose group (0/59, 0/19,
    1/47 and 15/48 in pooled vehicle controls, matched vehicle controls,
    low and high dose groups, respectively), and in both groups of exposed
    females (2/60, 1/20, 7/50 and 15/48 in pooled vehicle controls,
    matched vehicle controls, low and high dose groups, respectively); one
    alveolar/bronchiolar carcinoma was noted in a high-dose female mouse. 
    There was a non-significant increase in the incidence of squamous cell
    carcinoma of the forestomach in females in the high dose group.  The
    incidence of mammary gland adenocarcinomas was significantly increased
    in females at both doses (0/60, 0/20, 9/50 and 7/48 in pooled vehicle
    controls, matched vehicle controls, low and high dose groups,
    respectively).  The incidence of endometrial stromal polyp or
    endometrial stromal sarcoma (combined) was significantly elevated at
    both doses (0/60, 0/20, 5/49 and 5/47 in pooled vehicle
    controls, matched vehicle controls, low and high dose groups,
    respectively).  It was concluded that 1,2-dichloroethane was
    carcinogenic in this strain of mice, under the conditions of this
    study.

         It should be noted that the data on tumour incidence presented in
    the bioassays by the NCI (1978) do not take into account the increased
    early mortality in the high exposure groups; the incidences of several
    tumours (and thus the carcinogenic potency of 1,2-dichloroethane) may
    have been higher had all animals survived for a long enough period of
    time to develop tumours (Ward, 1980; Hooper et al., 1980).

    7.5.3  Other routes of administration

         1,2-Dichloroethane in acetone was applied to the shaved dorsal
    skin of groups of 30 female non-inbred Ha:ICR Swiss mice, 3 times/week
    for 440 to 594 days at doses of 0, 42, and 126 mg/application per
    mouse.  The incidence of lung tumours (benign lung papillomas) was
    significantly increased at the higher dose (26/30 compared to 11/30 in
    vehicle controls and 30/100 in naive controls, p < 0.0005). 
    Histopathological examination was limited to the skin, liver, kidney
    and any "abnormal-appearing tissues" (van Duuren et al., 1979).

         In a bioassay designed to screen the potential of numerous
    chemicals to induce pulmonary tumours in a susceptible strain of mice
    (A/St), groups of 20 males were administered 24 intraperitoneal
    injections of 1,2-dichloroethane (20, 40 or 100 mg/kg body weight) in
    tricaprylin, 3 times/week for 8 weeks (total doses of 480, 920 or
    2400 mg/kg body weight).  All surviving mice were killed 24 weeks
    after the first injection.  Although there was a dose-related increase
    in the number of pulmonary adenomas per mouse (0.39, 0.21, 0.44 and
    0.75 in the control, low, mid and high dose groups, respectively),
    none of these increases was statistically significant (Theiss et al.,
    1977).  It should be noted, however, that the duration of the period
    of observation may have been insufficient to allow for the development
    of most types of tumours.

    7.5.4  Initiation/promotion bioassays

         In a dermal initiation/promotion protocol, 126 mg
    1,2-dichloroethane was applied once to the skin (area exposed not
    specified) of 30 female non-inbred Ha:ICR Swiss mice, followed 14 days
    later by 5 µg (0.005 mg) of phorbol myristate acetate (PMA) (a
    promoter) in 0.2 ml acetone, 3 times/week for 428 to 576 days.  Two
    PMA control groups of 120 and 90 mice were administered 0.0025 mg and
    0.0050 mg PMA/application permouse (number of applications not
    specified), respectively.  Treatment with 1,2,-dichloroethane did not
    significantly increase the incidence of skin papillomas (3/30 versus
    9/120 and 6/90 in PMA controls).  There were three squamous cell
    carcinomas in the control groups, while none was observed in the
    exposed group (van Duuren et al., 1979).

         In a hepatic initiation/promotion assay, groups of 10
    Osborne-Mendel rats were partially hepatectomized and then
    administered 1,2-dichloroethane (100 mg/kg body weight) in corn oil by
    gavage, followed 5 days later by diets containing phenobarbital for 7
    weeks and a control diet for 1 week (initiation protocol).  Livers
    were examined histopathologically for GGT-positive foci (a putative
    preneoplastic indicator).  Additional groups of 10 rats were initiated
    with an intraperitoneal injection of diethyl-nitrosamine or water

    (control) following partial hepatectomy, then administered
    1,2-dichloroethane (100 mg/kg body weight) in corn oil by gavage, 5
    days/week for 7 weeks (promotion protocol).  In rats administered
    1,2-dichloroethane in the initiation protocol, there was no increase
    in the number of GGT-positive foci.

    Similarly, in rats administered 1,2-dichloroethane in the promotion
    protocol, there was no significant increase in the number of
    GGT-positive foci, either with or without the initiator, when compared
    to controls (Story et al., 1986; Milman et al., 1988).

         Groups of 35 male B6C3F1 mice were administered
    diethylnitrosamine in the drinking-water for 4 weeks, followed by
    exposure to 1,2-dichloroethane (835 or 2500 mg/litre) in
    drinking-water for 24 or 52 weeks.  Only the liver, kidneys and lungs
    were examined histopathologically.  Drinking-water intake was reduced
    at the highest concentration.  No significant differences in body
    weight gain were noted.  However, three mice consuming the highest
    concentration of 1,2-dichloroethane died within 52 weeks.  There was
    no increase in the incidence of liver or lung tumours in exposed mice
    either with or without diethylnitrosamine initiation (Klaunig et al.,
    1986).

    7.6  Mutagenicity and related end-points

         The genotoxicity of 1,2-dichloroethane has been extensively
    investigated in non-mammalian and mammalian test systems.  Data from
     in vitro and  in vivo studies are summarized in Tables 6 and 7; a
    summary of the weight of available evidence is presented here.

         1,2-Dichloroethane induced differential toxicity in Escherichia
    coli, but it had no effect in a  Bacillus subtilis rec assay.  It
    consistently induced positive responses in mutagenicity assays with
     Salmonella typhimurium, whereas it has not produced consistent
    responses in mutation assays with E. coli and was negative in a mouse
    peritoneal host-mediated assay with  E. coli.

         In the fungus  Aspergillus nidulans, 1,2-dichloroethane induced
    errors of mitotic segregation and aneuploidy, but did not induce gene
    mutation.


        Table 6.  Genotoxicity of 1,2-dichloroethane in vitro (modified from ATSDR, 1994)
                                                                                                                                                

    Species (test system)         End-point                               Resulta                            Reference
                                                                                                  
                                                             With activation     Without activation
                                                                                                                                                

    Bacterial systems

    Salmonella typhimurium        Gene mutation                   +                       +                 Milman et al. (1988)
                                                                  +                       +                 Barber et al. (1981)
                                                                  +                       +                 Kanada & Uyeta (1978)
                                                                  +                       +                 Nestmann et al. (1980)
                                                                  +                       +                 Rannug et al. (1978)
                                                                  +                       +                 Van Bladeren et al. (1981)
                                                                  +                       NT                Rannug & Beije (1979)
                                                                  +                       -                 Cheh et al. (1980)
                                                                  +                       -                 Moriya et al. (1983)
                                                                  -                       -                 King et al. (1979)
                                                                  +                       +                 Strobel & Grummt (1987)
                                                                  NT                      +b                Simula et al. (1993)

    S. typhimurium/spot test                                      NT                      (+)               Brem et al. (1974)
                                                                  (+)                     -                 Principe et al. (1981)
                                                                  NT                      -                 Buijs et al. (1984)
                                                                                                                                                

    Table 6 (contd).
                                                                                                                                                

    Species (test system)              End-point                             Resulta                        Reference
                                                                                                   
                                                               With activation    Without activation
                                                                                                                                                

    S. typhimurium/Ara test                                          +                    -                 Roldan-Arjona et al. (1991)
    (standard)

    S. typhimurium/Ara test                                          (+)                  (+)               Roldan-Arjona et al. (1991)
    (liquid)

    Streptomyces coelicolor            Gene mutation                 NT                   -                 Principe et al. (1981)

    Escherichia coli/K12/343/113       Gene mutation                 -                    -                 King et al. (1979)

    E. coli/wp2                                                      NT                   (+)               Hemminki et al. (1980)
                                                                     -                    -                 Moriya et al. (1983)

    E. coli Pol A                      DNA damage                    NT                   (+)               Brem et al. (1974)

    Bacillus subtilis/rec-assay        DNA damage                    NT                   -                 Kanada & Uyeta (1978)

    Fungal systems

    Aspergillus nidulans               Gene mutation                 NT                   -                 Crebelli & Carere (1988)
                                                                     NT                   -                 Principe et al. (1981)
                                                                                                                                                

    Table 6 (contd).
                                                                                                                                                

    Species (test system)            End-point                                    Resulta                        Reference
                                                                                                        
                                                                    With activation    Without activation
                                                                                                                                                

    A. nidulans                      Mitotic segregation                  NT                   +              Crebelli et al. (1984)
                                     aberrations

    A. nidulans                      Aneuploidy induction                 NT                   +              Crebelli et al. (1988)

    Saccharomyces cerevisiae         Mitotic recombination                NT                   (+)            Simmon (1980)

    Animal systems

    Hamster CHO/HGPRT                Gene mutation                        +                    (+)            Tan & Hsie (1981)
                                                                          +                    (+)            Zamora et al. (1983)

    Rat hepatocytes                  Unscheduled DNA synthesis            NT                   +              Williams et al. (1989)

    Mouse hepatocytes                                                     NT                   +              Milman et al. (1988)

    Mouse liver DNA                  DNA binding                          +                    NT             Banerjee (1988)

    Calf thymus DNA                                                       +                    NT             Prodi et al. (1986)

    Salmon sperm DNA                                                      +                    -              Banerjee & Van Duuren (1979);
                                                                                                              Banerjee et al. (1980)

    Mouse BALBc/3T3                  Cell transformation                  NT                   -              Milman et al. (1988)
                                                                          NT                   -              Tu et al. (1985)
                                                                                                                                                

    Table 6 (contd).
                                                                                                                                                

    Species (test system)            End-point                                    Resulta                        Reference
                                                                                                        
                                                                    With activation    Without activation
                                                                                                                                                

    Mouse C3H1OT´                    Cell transformation                  NT                   +c             Schultz et al. (1992)

    Syrian hamster embryo cells      Cell transformation                  NT                   +              Hatch et al. (1983)

    Human cells

    Human lymphoblasts AHH-1         Gene mutation                        NT                   +              Crespi et al. (1985)

    Human lymphoblasts TK6                                                NT                   +              Crespi et al. (1985)

    Human embryo epithelial-like                                          NT                   +              Ferreri et al. (1983)
    EUE cells

    Human peripheral lymphocytes     Unscheduled DNA synthesis            +                    -              Perocco & Prodi (1981)
                                                                                                                                                

    a   NT = not tested; - = negative result; + = positive result; (+) = weakly positive or marginal result
    b   increase in cells expressing GSTA1-1
    c   transformed cells induced tumours in nude mice

    Table 7.  Genotoxicity of 1,2-dichloroethane in vivo (modified from ATSDR, 1994)
                                                                                                                           

    Species (test system)                       End-point                      Resultsa      Reference
                                                                                                                           

    Mammalian assays

    Mouse                                       Dominant lethal mutations         -          Lane et al. (1982)

    Mouse/spot test                             Gene mutation                     (+)        Gocke et al. (1983)

    Mouse bone marrow                           Sister-chromatid exchange         +          Giri & Que Hee (1988)

    Mouse bone marrow                           Micronuclei                       -          Jenssen & Ramel (1980);
                                                                                             King et al. (1979)

    Mouse peripheral erythrocytes                                                 -          Armstrong & Galloway (1993)

    Mouse liver, kidney, lung and stomach       DNA binding                       +          Prodi et al. (1986)

    Mouse liver, kidney, lung and stomach                                         +          Arfellini et al. (1984)

    Mouse forestomach and kidney                                                  +          Hellman & Brandt (1986)

    Mouse liver                                                                   +          Banerjee (1988)
                                                                                                                           

    Table 7 (contd).
                                                                                                                           

    Species (test system)                       End-point                      Resultsa      Reference
                                                                                                                                                

    Rat liver, kidney, spleen, lung,                                              +          Reitz et al. (1982)
    forestomach and stomach

    Rat liver, kidney, lung and stomach                                           +          Arfellini et al. (1984)

    Rat liver, kidney, lung and stomach                                           +          Prodi et al. (1986)

    Rat liver and kidney                                                          +          Inskeep et al. (1986)

    Rat liver and lung                                                            +          Baertsch et al. (1991)

    Rat liver                                                                     +          Banerjee (1988)

    Rat liver                                                                     +          Cheever et al. (1990)

    Mouse liver                                 DNA damage                        +          Storer & Conolly 1983, 1985;
                                                                                             Storer et al. (1984)

    Mouse liver                                                                   +          Taningher et al. (1991)

    Insect assays

    Drosophila melanogaster/somatic mutation    Gene mutation                     +          Nylander et al. (1978)
                                                                                                                                                

    Table 7 (contd).
                                                                                                                                                

    Species (test system)                       End-point                      Resultsa      Reference
                                                                                                                                                

    D. melanogaster/somatic mutation                                              +          Romert et al. (1990)

    D. melanogaster/somatic mutation                                              +          Kramers et al. (1991)

    D. melanogaster/somatic mutation                                              (+)        Ballering et al. (1993)

    D. melanogaster/recessive lethal                                              +          Ballering et al. (1993)

    D. melanogaster/vermilion locus                                               +          Ballering et al. (1993)

    D. melanogaster/sex-linked recessive                                          +          King et al. (1979)

    D. melanogaster/sex-linked recessive                                          +          Kramers et al. (1991)

    D. melanogaster                             Chromosomal loss/gain             +/+        Valencia et al. (1984)

    Host-mediated assays

    Escherichia coli K12/343/113 mouse          Gene mutation                     -          King et al. (1979)
    host-mediated assay
                                                                                                                                                

    a   - = negative result; + = positive result; (+) = weakly positive or marginal result
    

         In cultured mammalian cells, 1,2-dichloroethane formed
    adducts with DNA. It also induced unscheduled DNA synthesis in primary
    cultures of mouse and rat hepatocytes, and human peripheral
    lymphocytes (the last in the presence of an exogenous metabolic
    activation system), and gene mutation in several cell lines.  Mutation
    frequency of two human cell lines has been correlated with the
    difference in levels of glutathione- S-transferase activities (Crespi
    et al., 1985; section 6.3).  Cell transformation was induced in
    studies with C3H10T´ cells, but not with BALBc/3T3 cells. 
    1,2-Dichloroethane enhanced SV40 virus transformation of Syrian
    hamster embryo cells.

          In vivo, both somatic cell and sex-linked recessive lethal
    mutations have been consistently induced in  Drosophila melanogaster by
    1,2-dichloroethane.  1,2-Dichloroethane has been found to bind to DNA
    in all reported studies in mice and rats.  In other studies with mice,
    clearly positive responses have been restricted to primary DNA damage
    in liver and sister-chromatid exchange induction in bone marrow.  No
    evidence for micronucleus induction has emerged from bone marrow
    micronucleus studies or for a dominant lethal effect in one study
    (although this study may have been insufficiently sensitive), and only
    a weak but significant (p < 0.03) response was observed in a single
    spot test.

         It has been noted that stronger responses were obtained in the
    bacterial mutation assay in the presence of an exogenous metabolic
    system than in its absence.  This could imply the formation of
    additional mutagenic metabolites, through either the cytochrome P450
    or glutathione-S-transferase pathway.  In these  in vitro assays with
    liver homogenates, activation by the cytochrome system is more likely,
    and 2-chloroacetaldehyde, which is a possible metabolite, is known to
    be mutagenic (McCann et al., 1975).  The mutagenicity of
    1,2-dichloroethane in S. typhimurium TA100, in the absence of S9 mix,
    was more than doubled if the bacterium expressed the human GSTA1-1
    gene, but there was no change in the mutagenic response if the SSTP1-1
    gene was expressed (Simula et al., 1993).

    7.7  Reproductive toxicity, embryotoxicity and teratogenicity

       The reproductive and developmental effects of 1,2-dichloro-ethane
    have not been extensively investigated in experimental animals (see
    Table 8), although the compound has been detected in fetal tissues in
    rats and mice following maternal exposure to 600 mg/m3 for 5 h
    (Withey & Karpinski, 1985) and 1000 mg/m3 for 3 days (Vozovaya,
    1977).


        Table 8.  Reproductive and developmental toxicity of 1,2-dichloroethane in experimental animals
                                                                                                                                                

    Species                         Protocol                                            Results                                         Reference
                                                                                                                                                

    Inhalation

    Rats                Animals were exposed to 0, 101, 304, or    No exposure-related histopathological effects in the parents nor     Rao
    (Sprague-Dawley,    607 mg/m3 (0, 25, 75, or 150 ppm)          any alterations in the fertility index and gestation periods were    et al.
    20 m & 20 f per     6 h/day, 5 days/week for 60 days prior     observed compared to controls. There was a significant decrease      (1980)
    exposed group,      to mating, and for an additional 116       in the number of pups per litter in the F1A pups at 304 mg/m3
    30 m & 30 f         days (7 days/week) after mating. Dams      (13%, p<0.05), but not at 607 mg/m3; there was significantly
    controls)           were not exposed from gestation day 21     increased kidney weight in the F1B male pups at 101 mg/m3
                        through to day 4 postpartum. The pups      (29%, p<0.05), although the authors did not consider this effect
                        (F1A) were removed after 21 days, and      to be related to exposure.  There were no significant differences
                        the females were remated to exposed        in growth, sex ratios, survival indices, organ or neonatal body
                        males following removal of the last        weights, or histology in pups.
                        litter to produce F1B litters. Liver,
                        kidneys, ovaries , uterus and testes
                        of parental animals in control and
                        high exposure group (and other groups
                        if any changes were noted in high
                        exposure group) were examined
                        histopathologically

    Rats (Albino, f,    Rats were exposed to 57 mg/m3, 4 h/day,    Exposed rats had reduced fertility (6.5 fetuses per dam compared     Vozovaya
    strain and          6 days/week, for 6 or 9 months. The        to 9.7 per dam in controls). Newborn pups had reduced body           (1974)
    number              animals were apparently then mated, but    weight (5.06 g versus 6.44 g in controls). Perinatal mortality
    unspecified         it is not clearly stated whether the       was increased in the exposed group (data not presented). No
    in secondary        exposure period extended beyond            information was available on maternal effects.
    account)            mating.
                                                                                                                                                

    Table 8 (contd).
                                                                                                                                                

    Species                         Protocol                                            Results                                         Reference
                                                                                                                                                

    Rats (f, strain     Rats were exposed to 15 mg/m3, 4 h/day,    The estrous cycle was longer in exposed rats than in controls. No    Vozovaya
    and number          6 days/week for 4 months prior to and      information on the effects on fertility was presented. Embryonal     (1977)
    unspecified         after mating.                              mortality increased from approximately 11% in controls to 27% in
    in secondary                                                   exposed dams. Pre-implantation losses were 5-fold greater in
    account)                                                       exposed animals than in controls. No fetal abnormalities were
                                                                   observed, except for haematomas in the region of the head, neck
                                                                   and anterior extremities (presumably only in pups of exposed
                                                                   animals, although not clearly stated). No information was
                                                                   available on maternal effects.

    Rats                Rats were exposed to 0, 405 or 1215        10/16 dams at 1215 mg/m3 died. At 405 mg/m3, there were no           Rao
    (Sprague-Dawley,    mg/m3 (0, 100 or 300 ppm) for 7 h/day      effects on mean litter size, incidence of resorptions, or fetal      et al.
    16 to 30 pregnant   on days 6 to 15 of gestation.              body measurements; no significant increase in the incidence of       (1980)
    f per group)                                                   major malformations was observed at this concentration.

    Rabbits (New        Rabbits were exposed to 0, 405, or         4/21 and 3/19 dams died at 405 and 1215 mg/m3, respectively,         Rao
    Zealand White,      1215 mg/m3 (0, 100 or 300 ppm) for         compared to none in 20 controls. There were no effects on mean       et al.
    19 to 21            7 h/day on days 6 to 18 of gestation.      litter size, incidence of resorptions or fetal body measurements     (1980)
    pregnant f                                                     at either concentration, and there were no significant differences
    per group)                                                     in the incidence of major malformations.
                                                                                                                                                

    Table 8 (contd).
                                                                                                                                                

    Species                         Protocol                                            Results                                         Reference
                                                                                                                                                

    Ingestion

    Rats (45 m &        Animals were fed mash fumigated with       There were no significant differences in various reproductive        Alumot
    90 f, strain        1,2-dichloroethane for 2 years.            parameters, including number of dams pregnant, number of dams        et al.
    unspecified)        Resulting concentrations were 250 and      with litters, mean litter size, mortality or body weight of young    (1976a)
                        600 mg/kg. Due to loss of the compound     at birth and at weaning.
                        through volatilization, the mash
                        actually consumed was estimated to
                        contain 60 to 70% of the initial
                        concentration (estimated to result in
                        doses of approximately 7.5 to 8.75 and
                        15 to 17.5 mg/kg body weight per day).
                        Exposed females were mated with
                        exposed males at 2 month intervals.

    Mice (ICR Swiss,    F0 mice were administered                  There were no differences in body weight in adults, and there        Lane
    (10 m & 30 f        concentrations of 0, 0.03, 0.09 or 0.29    were no effects on fertility or gestation indices. There were no     et al.
    per exposed         mg/litre drinking-water (equivalent        effects on survival, litter size, postnatal body weight or gross     (1982)
    group, 20 m &       to nominal doses of approximately          pathology of pups. The incidence of fetal visceral or skeletal
    60 f controls)      0, 5, 15 or 50 mg/kg body weight           malformations was not increased in exposed animals. F1C litters
                        per day) for 35 days prior to              were not examined for skeletal malformations.
                        mating. Three sets of offspring
                        (F1A, F1B and F1C) were produced.
                                                                                                                                                

    Table 8 (contd).
                                                                                                                                                

    Species                         Protocol                                            Results                                         Reference
                                                                                                                                                

                        After weaning and 11 weeks of
                        exposure to the same concentrations,
                        the F1B mice were mated (30 female,
                        10 male) to produce a second generation
                        of offspring (F2A and F2B). Teratology
                        screening tests were performed using
                        F1C and F2B matings where the females
                        were co-housed with unexposed males.

    Mice (f, number     Pregnant mice were administered            There were no developmental effects and "few discernible effects"    Kavlock
    and strain not      1,2-dichloroethane in the drinking-water   on maternal health. There were no skeletal or visceral anomalies     et al.
    specified in        at a concentration equivalent to a         which could be attributed to exposure.                               (1979)
    secondary           dose of 510 mg/kg body weight per
    account)            day on days 7 to 14 of gestation.
                                                                                                                                                

    

         No effects on reproductive parameters, including fertility index,
    gestation period or histological changes, were reported in a
    two-generation study on Sprague-Dawley rats exposed to 0, 101, 304 or
    607 mg/m3 (0, 25, 75 or 150 ppm) 1,2-dichloroethane 6 h/day, for 60
    days prior to mating and 116 days after mating (except during the
    delivery period).  There were also no effects on growth, sex ratios,
    survival indices, organ or neonatal body weights, or histology in pups
    (Rao et al., 1980).

         Exposure to 1,2-dichloroethane (15 mg/m3), 4 h/day, for 4
    months prior to mating and after mating resulted in a
    longer-than-normal estrous cycle in female rats (strain not
    specified).  Although embryonal mortality and preimplantation losses
    were greater in exposed animals than in controls, no fetal
    abnormalities were reported, except for haematomas in the area of the
    head, neck and anterior extremities (Vozovaya, 1977).  Similarly,
    increased perinatal mortality and reduced body weight of newborn pups
    were observed in the offspring of female albino rats exposed to 57
    (± 10) mg/m3 for 6 and 9 months.  Exposed females also produced a
    lower number of fetuses per dam (Vozovaya, 1974).  Information from
    these studies was insufficient for evaluation.

         Rao et al. (1980) also conducted a developmental study in which
    pregnant Sprague-Dawley rats were exposed to 0, 405 or 1215 mg/m3
    (0, 100 or 300 ppm) 1,2-dichloroethane, 7 h/day, during gestation. 
    Mortality was high in dams at 1215 mg/m3 (10/16 rats died); thus the
    developmental effects could not be ascertained at this concentration. 
    No fetotoxic or teratogenic effects were observed at 405 mg/m3.  In
    pregnant rabbits exposed to the same concentrations, 7 h/day, during
    gestation, mortality was increased in exposed animals (4/21 and 3/19
    dams died at 405 and 1215 mg/m3, respectively, compared to none in
    20 controls).  However, no fetotoxic or teratogenic effects were
    reported at either concentration.  The authors concluded that
    1,2-dichloroethane was not teratogenic or fetotoxic in rats at
    405 mg/m3 or in rabbits at 405 or 1215 mg/m3.

         No effects on male fertility or various reproductive parameters
    were noted in rats consuming mash which had been fumigated with
    1,2-dichloroethane, the resultant concentrations being 250 and
    500 mg/kg (approximately equivalent to doses of 7.5 to 8.75 and 15 to
    17.5 mg/kg body weight per day when loss due to volatilization was
    taken into account), for up to 2 years (Alumot et al., 1976a).  No
    effects on reproduction (in terms of fertility and gestation indices)
    were reported in a two-generation study on Swiss ICR mice exposed to
    1,2-dichloroethane in the drinking-water at concentrations of 0, 0.03,
    0.09 or 0.29 g/litre (approximately equivalent to doses of 0, 5, 15 or
    50 mg/kg body weight per day).  In addition, no fetotoxic or
    teratogenic effects were noted in either generation of offspring of

    F1C and F2B litters sacrificed on day 18 (Lane et al., 1982). No
    developmental effects were reported in a study in which groups of 30
    pregnant CD-1 mice were administered drinking-water containing a
    mixture of organic compounds, including 0.01% 1,2-dichloroethane
    (equivalent to a dose of 5.1 mg/kg body weight per day), during days 7
    to 14 of gestation (Kavlock et al., 1979).

    7.8  Immunological effects

         Groups of 140 female CD1 mice were exposed to airborne
    concentrations of 0, 10, 20 and 40 mg/m3 (0, 2.5, 5 and 10 ppm)
    1,2-dichloroethane for a 3-h period or to 0 or 10 mg/m3, 3 h/day for
    5 consecutive days.  After acute exposure to 20 and 40 mg/m3, there
    was a significant increase in mortality in mice from streptococcal
    challenge (p < 0.05 and p < 0.001, respectively), while no effects
    were noted following acute or repeated exposure to 10 mg/m3.  In
    similarly exposed groups of 18 to 36 mice, significantly (p < 0.01)
    decreased pulmonary bactericidal activity to inhaled  Klebsiella
     pneumoniae was noted only at 40 mg/m3.  Single exposure to 40 or
    400 mg/m3 (10 or 100 ppm) did not affect the  in vitro phagocytic
    or cytostatic ability of alveolar macrophages to red blood cells and
    tumour target cells, respectively (Sherwood et al., 1987).

         Male Sprague-Dawley rats (16 per group) were exposed to 0, 400 or
    800 mg/m3 (0, 100 or 200 ppm) 1,2-dichloroethane for 3 h, or to 0,
    40, 80, 200 or 400 mg/m3 (0, 10, 20, 50 or 100 ppm), 5 h/day, 5
    days/week for 12 days.  Pulmonary bactericidal activity was not
    affected at any concentration.  No effects were noted on  in vitro
    phagocytic activity to red blood cells,  in vitro cytostatis and
    cytolysis of tumour target cells, or levels of ectoenzymes in alveolar
    macrophages.  Blastogenesis of mitogen-stimulated T- and B-lymphocytes
    from popliteal and mesenteric lymph nodes was not affected (Sherwood
    et al., 1987).

         Chinchilla rabbits (number per group not specified but
    probably less than 10) were exposed to 2, 10 or 100 mg/m3
    1,2-dichloroethane for 3 h/day, 6 days/week, for 7.5 to 8 months.  At
    the two highest concentrations production of antibodies against
    typhoid vaccine was increased, while total antibody production was
    reduced at 100 mg/m3 (Shmuter, 1977).

         Groups of 10 male CD1 mice (12 per group) (Munson et al., 1982)
    were administered 1,2-dichloroethane (4.9 and 49 mg/kg body weight per
    day) in water by gavage for 14 days. A significant (p < 0.05)
    reduction of 25 and 40% in IgM antibody-forming cells to sheep RBCs
    was observed at 4.9 and 49 mg/kg body weight per day, respectively.  A
    significant (p < 0.05) reduction of cell-mediated responses to sheep
    erythrocytes was also observed at both levels, which was not related
    to dose, while a significant (p < 0.05) reduction in leucocyte count

    was observed at the highest dose.  In the same study, groups of 16 to
    32 male CD1 mice were administered time-weighted average
    1,2-dichloroethane doses of 0, 3, 24 and 189 mg/kg body weight per day
    (0, 0.02, 0.2 and 2.0 g/litre) for 90 days in drinking-water; controls
    consisted of 24 to 48 mice.  The fluid consumption of exposed mice was
    decreased in a dose-related manner, which corresponded to a
    dosedependent reduction in body weight.  No effects on organ weights,
    haematology, B-cell mitogen lipopolysaccharide response, spleen cell
    response to the T-cell mitogen concanavalin A or cellmediated immunity
    (assessed by measuring the delayed-type hypersensitivity responses to
    sheep erythrocytes) were noted.  There was a tendency towards a
    reduction in the serum antibody level after immunization with sheep
    erythrocytes, and in the immunoglobulin spleen antibody-forming cells
    at all exposure levels (not significant) (Munson et al., 1982).

    7.9  Toxicological interactions with other agents

         In a recent bioassay designed to determine the influence of
    disulfiram or ethanol on the carcinogenicity, metabolism and covalent
    binding to DNA of 1,2-dichloroethane, male and female Sprague-Dawley
    rats were exposed to 200 mg/m3 (50 ppm) 1,2-dichloroethane for 7 h
    per day, 5 days a week, for 2 years.  Additional rats were similarly
    exposed and administered either 0.05% disulfiram in the diet or 5%
    ethanol in the drinking-water, either alone or in combination with
    1,2-dichloroethane.  The incidence of any type of tumour was not
    elevated compared to controls in any groups exposed to these compounds
    individually, nor was the incidence of any type of tumour increased in
    rats exposed to 1,2-dichloroethane and ethanol in combination compared
    to unexposed controls or rats exposed to these compounds alone. 
    Exposure to disulfiram in combination with 1,2-dichloroethane resulted
    in a significant (p<0.05) increase in the incidence of intrahepatic
    bile duct cholangiomas (males: 9/49 versus 0/50, females: 17/50 versus
    0/50) and cysts (males: 12/49 versus 0/50, females: 24/50 versus 0/50)
    in both male and female rats compared to that in rats exposed to
    1,2-dichloroethane only.  Male rats exposed to this combination also
    had a significantly (p<0.05) increased incidence of subcutaneous
    fibromas (10/50 versus 0/50), hepatic neoplastic nodules (6/49 versus
    2/50) and interstitial cell tumours in the testes (11/50 versus 3/50)
    compared to rats exposed to 1,2-dichloroethane alone.  Female rats
    similarly exposed had a significantly (p<0.05) higher incidence of
    mammary adenocarcinomas compared with rats exposed to
    1,2-dichloroethane only (12/48 versus 5/50).  Combined exposure to
    1,2-dichloroethane and disulfiram did not increase the level of
    covalent binding to hepatic DNA compared to that found in rats exposed
    to 1,2-dichloroethane alone.  The profile of urinary metabolites of a
    single radiolabelled oral dose of 1,2-dichloroethane in rats
    simultaneously exposed to disulfiram and 1,2-dichloroethane for 2

    years indicated that the metabolism of 1,2-dichloroethane was
    qualitatively similar to that of rats exposed to 1,2-dichloroethane
    alone for 2 years.  However, a reduced rate of elimination, and
    sustained blood levels of unchanged 1,2-dichloroethane were observed
    (see section 6.4), which, the authors stated, could be related to the
    carcinogenic effects noted following simultaneous exposure (Cheever et
    al., 1990).

         In addition, concomitant exposure to disulfiram (as may occur in
    the rubber industry or in persons undergoing therapy for alcoholism)
    in the diet resulted in a synergistic increase in the hepatotoxicity
    (as determined by levels of enzymes in serum and increased relative
    liver weight (> 30%)) of 1,2-dichloroethane inhaled at
    concentrations of 600, 1200 or 1800 mg/m3 (150, 300 and 450 ppm) for
    30 days by male Sprague-Dawley rats. However, rats administered
    1,2-dichloroethane alone had evidence of liver damage only at the
    highest concentration.  The enhanced effects were hypothesized to be
    due to the inhibition of mixed-function oxidase-mediated metabolism of
    1,2-dichloroethane and a compensatory increase in metabolism of
    1,2-dichloroethane to reactive metabolites via cytosolic pathways
    mediated by glutathione  S-transferase, since hepatic cytochrome
    P-450 content decreased with increasing concentration of
    1,2-dichloroethane only in the presence of disulfiram (Igwe et al.,
    1986a). Concomitant exposure to 1,2-dichloroethane by inhalation
    (> 1216 mg/m3 or 304 ppm) or intraperitoneal injection
    (150 mg/kg body weight per day) and disulfiram administered in the
    diet (0.15%) resulted in testicular atrophy in Sprague-Dawley rats
    compared to rats exposed to either compound alone (Igwe et al.,
    1986b).

         The acute toxicity of carbon tetrachloride was potentiated by
    1,2-dichloroethane in rats administered single doses of each of 60 and
    125 µl/kg body weight perorally, based on determination of serum
    hepatic enzymes and indicators of lipid peroxidation at 24 h after
    exposure.  Pre-treatment with vitamin E prevented hepatotoxicity. 
    Based on the observation that the hepatic GSH level in the group
    concomitantly exposed to both compounds was not significantly
    different from that in the group exposed to carbon tetrachloride
    alone, the authors concluded that GSH depletion did not play an
    important role in the potentiation (Aragno et al., 1992).  Concomitant
    exposure to oral doses of 1,2-dichloroethane and 1,2-dibromoethane (60
    and 20 µl/kg body weight, respectively) did not result in liver
    toxicity in rats, based on levels of serum hepatic enzymes and
    indicators of lipid peroxidation, although the compounds alone and in
    combination resulted in a decrease in hepatic GSH level 2 h after
    exposure, which subsequently returned to control values (Danni et al.,
    1992).

         The  in vitro metabolism of 1,2-dichloroethane by liver
    homogenates of rats administered ethanol increased with the dose of
    ethanol up to 4 g/kg body weight, but declined sharply at 5 g/kg body
    weight (Sato et al., 1981).

         High doses (1000 to 2000 mg/kg body weight) of several chemicals,
    including methionine,  p-aminobenzoic acid, sulfanilamide and
    aniline, administered orally to mice were protective against the
    lethal effects caused by inhalation of 1600 mg/m3 (400 ppm)
    1,2-dichloroethane (Heppel et al., 1945).

         The acute and subacute toxicity of dichloroethane increased when
    it was administered under conditions of high temperature (species and
    exposure protocol not specified in abstract) (Mihaylova, 1976).

    8.  EFFECTS ON HUMANS

    8.1  Case reports

         The lethal oral dose of 1,2-dichloroethane in humans has been
    estimated to be between 20 and 50 ml.  Death due to cardiac arrhythmia
    has been reported following ingestion of large, single doses
    (50-75.2 g) of 1,2-dichloroethane (Hueper & Smith, 1935; Garrison &
    Leadingham, 1954; Martin et al., 1969).  Effects identified following
    ingestion of 1,2-dichloroethane include central nervous system
    depression, gastroenteritis, liver, kidney and lung damage,
    cardiovascular disorders and haematological effects (Weiss, 1957;
    Morozov, 1958; Hinkel, 1965; Bogoyavlenski et al., 1968; Martin et
    al., 1969; Schönborn et al., 1970; Yodaiken & Babcock, 1973; Natsyuk &
    Mudritsky, 1974; Dorndorf et al., 1975; Andriukin, 1979).

         Effects reported following exposure to 1,2-dichloroethane via
    inhalation are very similar to those observed after ingestion but are
    usually less pronounced.  Inhalation of 1,2-dichloroethane vapour
    first affects the central nervous system and causes irritation and
    inflammation of the respiratory tract.  Damage to the liver, kidneys
    and lungs (Wirtschafter & Schwartz, 1939; Hadengue & Martin, 1953;
    Menschick, 1957; Troisi & Cavallazzi, 1961; Suveev & Babichenko, 1969;
    Nouchi et al., 1984) and changes in the heart rhythm (Suveev &
    Babichenko, 1969) have been reported in several cases.  Death due to
    cardiac toxicity has been reported following a 30-min exposure to an
    unknown concentration of 1,2-dichloroethane (Nouchi et al., 1984).

         Effects on the eyes were observed in several early case reports
    (Weiss, 1957; Menschick, 1957; Troisi & Cavallazzi, 1961), while
    severe dermatitis has been reported following dermal contact with
    1,2-dichloroethane (Wirtschafter & Schwartz, 1939).

    8.2  Epidemiological studies

         In a study of 278 men working in the chlorohydrin unit of a
    chemical production plant between 1940 and 1967 and followed up to
    1988, there was a significant (p < 0.01) excess of deaths due to
    pancreatic cancer compared to the USA national rates [Standardized
    Mortality Ratio (SMR) = 492 (95% CI = 158 - 1140); Observed:Expected
    (O:E) = 8:1.6].  The excess was greater when confined to men who
    worked in the unit for more than 2 years (SMR = 800).  Based on
    comparison with two groups of workers in nearby plants, there were
    pronounced increases in mortality due to pancreatic cancer as exposure
    duration increased.  Though an excess of deaths due to "lymphatic and
    haemopoietic cancers" was also observed, it appeared to be
    attributable principally to leukaemia, for which numbers of observed

    cases were small (O=4) and associations with duration of exposure were
    less consistent.  Although quantitative data were not available, the
    authors concluded on the basis of considerable qualitative information
    that workers in this unit had been exposed primarily to
    1,2-dichloroethane in combination with bis-chloroethyl ether, ethylene
    oxide and ethylene chlorohydrin (Benson & Teta, 1993).

         In a case-control study, the exposure of 21 male employees at a
    petrochemical plant in Texas, USA, whose deaths were
    attributed to cancer of the brain, was compared to that of two groups
    of 80 controls from the same plant.  One control group consisted of
    male employees who had died from non-neoplastic causes, while the
    second group of controls consisted of those men whose deaths were due
    all other causes.  Employees were classified as having been exposed to
    1,2-dichloroethane if they had ever worked in a department in which
    the compound had been used; unexposed workers had never worked in
    these departments and the exposure of others was considered to be
    unknown (47.6% of cases, 58.8 and 61.3% of the first and second group
    of controls, respectively).  When those with unknown exposure were
    excluded from the analyses, the proportion of cases (all cases or
    glioma cases specifically) who were exposed (n = 11 and 10, or 45.5
    and 50.0%, respectively) did not differ significantly from the
    proportion of controls who had been exposed to 1,2-dichloroethane
    (42.4 and 45.2% for the two control groups).  When a 15-year latency
    period was considered in the analysis, the proportion of cases and
    controls exposed still did not differ significantly (40.0 and 44.4%
    for cases versus 32.3 and 34.6% for the two control groups) (Austin &
    Schnatter, 1983a).

         In an accompanying historical cohort study of 6588 workers at
    this plant, there was no significant excess in malignant brain tumours
    in the overall population of the plant compared to national rates,
    although there was a borderline significant (p < 0.05) increase in
    hourly employees with more than 6 months of employment (O/E = 10/5). 
    However, exposure to 1,2-dichloroethane was not specifically
    considered in this study, and employees were also exposed to a number
    of potentially confounding substances, including benzene, diethyl
    sulfate, ethylene oxide and vinyl chloride (Austin & Schnatter,
    1983b).

         Deschamps & Band (1993) conducted a small case-control study to
    investigate a possible association between a spill of
    1,2-dichloroethane in 1982 into a river supplying drinking-water to
    parts of the city of Vancouver, Canada, and an identified cluster of
    childhood leukaemia cases in the city.  It was determined that none of
    the 15 cases diagnosed between 1975 and 1988 had lived in areas of the
    city serviced by the contaminated supply.

         In an ecological study in which potential associations between
    contamination of drinking-water from groundwater supplies by
    particular substances (including 10 volatile organic compounds and 43
    inorganic elements) and cancer were investigated, the average annual
    age-adjusted incidence (1969 to 1981) of colon and rectal cancer was
    statistically significantly greater in men aged > 55 years whose
    drinking-water contained > 0.1 µg 1,2-dichloroethane/litre than in
    those whose drinking-water contained < 0.1 µg/litre (222.8 per
    100 000 versus 170.3 per 100 000 (193 and 633 cases, p = 0.02) and
    126.5 per 100 000 versus 92.9 per 100 000 (106 and 337 cases,
    p = 0.009), respectively).  Rectal cancer in males was also associated
    with chlorination of drinking-water.  Of the study population over 55
    years of age, 50% had lived at the same address for 20 years or more. 
    There were no significant differences between groups of towns with
    respect to eight socioeconomic factors examined, except that the
    percentage change in population between 1970 and 1980 was
    significantly less in those towns with > 0.1 µg
    1,2-dichloroethane/litre.  The authors did not suggest that the result
    indicated a causal relationship between 1,2-dichloroethane and cancer,
    but that cancer incidence may be elevated in populations consuming
    water from wells subject to anthropogenic contamination (Isacson et
    al., 1985).

         The prevalence of subjective symptoms was higher in a group of 10
    male oil refinery workers exposed to between 250 and 800 mg/m3 than
    in those exposed to lower concentrations (40 to 150 mg/m3); a
    "general reduction in body weight" was also noted in both groups. 
    "Abnormalities" of the liver, central nervous system, gastrointestinal
    tract and haematological parameters were reported in some workers
    (n = 1 to 8) in the group exposed to the higher concentration,
    presumably based upon clinical examination, although this was not
    specified in the previous account of this early study.  There were no
    unexposed controls, and workers were also exposed to benzene (10 to
    25 mg/m3) (Cetnarowicz, 1959).

         The morbidity during a 5-year period (1951 to 1955) was increased
    for all disease categories (not further specified) in a group of
    workers (number not specified) at an aircraft factory exposed to
    5 mg/m3 or less for 70 to 75% of the working time and 80 to
    150 mg/m3 for the remainder, when compared to workers in the entire
    factory.  Of 83 workers examined further, 19 had disease of the liver
    and bile duct, 13 had neurotic conditions, 11 had autonomous dystonia
    and 10 had hyperthyroidism and goitre (there were no controls for
    comparison) (Kozik, 1957).

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    9.1  Aquatic organisms

    9.1.1  Microorganisms

         Blum & Speece (1991) investigated the toxicity of
    1,2-dichloroethane to three groups of aquatic bacteria: methanogens,
    aerobic heterotrophs and  Nitrosomonas.  The end-points assessed
    included inhibition of gas production (methanogens), oxygen uptake
    (aerobic heterotrophs), and ammonia consumption  (Nitrosomonas).  The
    IC50 values for Nitrosomonas and methanogens (29 and 25 mg/litre,
    respectively) were considerably lower than that for aerobic
    heterotrophs (470 mg/litre).  For the bacteria  Pseudomonas putida,
    the nominal 16-h toxicity threshold for the onset of cell
    multiplication inhibition was 135 mg/litre (Bringmann & Kühn, 1981). 
    Tang et al. (1990) determined the IC50 values based on inhibition of
    respiration rate for activated sewage sludge using open and closed
    serum bottle methods to be 35 500 mg/litre and 2780 mg/litre,
    respectively.  The difference was attributed to the volatility of
    1,2-dichloroethane which was stripped from the substrate in the open
    method.

         The freshwater cyanobacterium (blue-green alga)  Microcystis
     aeruginosa was seven times more sensitive to 1,2-dichloroethane than
    the green alga  Scenedesmus quadricauda, the nominal 7-day EC50
    values for inhibition of cell multiplication at 27°C being 105 and
    710 mg/litre, respectively (Bringmann & Kühn, 1978).  The 72-h EC50
    for inhibition of growth was 189 mg/litre (Freitag et al., 1994). 
    Bringmann & Kühn (1980) determined the toxicity thresholds for
    Scendesmus quadricauda and the protozoan  Entosiphon sulcatum to be
    710 mg/litre and 1127 mg/litre, respectively.  Knie et al. (1983)
    reported the acute EC50 for the alga  Haematococcus pluvialis to be
    130 mg/litre.  Based on bioluminescence, the 5-min IC50 was
    700 mg/litre in a Microtox test with  Photobacterium phosphoreum
    (Blum & Speece, 1991).  Freitag et al. (1994) reported the 15-min EC50
    for inhibition of bioluminescence in this species to be 770 mg/litre.

         Bringmann & Kühn (1981) determined the toxicity thresholds in the
    holozoic bacteriovorous flagellate protozoan  Entosiphon sulcatum, the
    holozoic bacteriovorous ciliate protozoan  Uronema parduczi, and the
    saprozoic flagellate protozoan  Chilomonas paramecium to be > 8000
    mg/litre, > 16 000 mg/litre and > 800 mg/litre, respectively, using
    the cell multiplication inhibition test.

         Pearson & McConnell (1975) determined the EC50 (based on carbon
    uptake from CO2 during photosynthesis) in the marine unicellular
    alga  Phaeodactylum tricorhutum to be 340 mg/litre.

    9.1.2  Invertebrates

         Based on a review of identified acute and chronic toxicity
    studies in freshwater invertebrates, Daphnia magna appears to be the
    species most sensitive to 1,2-dichloroethane.  Under static test
    conditions, the measured 48-h LC50 values for fed and unfed first
    instar  D. magna were 320 and 270 mg/litre, respectively; the 48-h
    EC50 values, based on complete immobilization, were 180 and
    160 mg/litre for fed and unfed organisms, respectively (Richter et
    al., 1983).  Leblanc (1980) reported the 24-h and 48-h LC50 values
    in  D. magna to be 250 and 220 mg/litre, respectively, while the "no
    discernible effect concentration" (apparently based on mortality only)
    was < 68 mg/litre.  Using the Probit method, Ahmad et al. (1984)
    determined the 48-h LC50 in unfed D. magna to be 268 mg/litre (95%
    CL: 246-293), while the EC50, based on reproductive effects was
    155 mg/litre (95% CL: 137-188).  Freitag et al. (1994) determined the
    24-h EC50 for 10% immobilization of D. magna to be 150 mg/litre. 
    Knie et al. (1983) reported the EC0, EC50 and EC100 in  D. magna
    to be 67, 600 and 1075 mg/litre, respectively.  Richter et al. (1983)
    also examined the effect of 1,2-dichloroethane on reproductive success
    and length of first instar  D. magna in a 28-day flow-through test. 
    For reproductive success, the measured lowest-observed-effect level
    (LOEL) and no-observed-effect level (NOEL) were 20.7 and
    10.6 mg/litre, respectively, while the measured LOEL and NOEL for
    growth were 71.7 and 41.6 mg/litre, respectively.

         Ahmad et al. (1984) also conducted chronic toxicity studies in
    which  D. magna were exposed to 0, 10.6, 20.6, 41.6, 71.7, 94.4 and
    137 mg 1,2-dichloroethane/litre for 28 days.  There was a
    concentration-related decrease (as low as 12% of control values) in
    the number of young produced (significant (p < 0.05 or 0.01) at
    41.6 mg/litre or more) as well as a decrease (as low as 59% of control
    values) in the length of adults (significant (p < 0.01) at
    71.7 mg/litre or more).  Few acute toxicity studies in marine
    invertebrates were identified.  Under static test conditions, the
    nominal 24-h EC50 for immobilization of 30-h posthatch larvae of the
    brine shrimp  Artemia salina was 93.6 mg/litre (Foster & Tullis,
    1984).  For marine adult shrimp (Crangon crangon), the measured 24-h
    LC50 was 170 mg/litre under static test conditions (Rosenberg et
    al., 1975).  The 48-h LC50 for barnacle nauplii  (Elminuis modestus)
    was 186 mg/litre (Pearson & McConnell, 1975). Teratogenic effects
    (expressed as surviving larvae with gross debilitating abnormalities)
    were observed in the nauplii of the marine brine shrimp  (Artemia
     salina) at concentrations between 0.25 and 25 mg/litre (Kerster &
    Schaeffer, 1983).

    9.1.3  Vertebrates

      The embryos and larvae of the northwestern salamander  (Ambystoma
     gracile) and the leopard frog  (Rana pipiens) were continuously
    exposed to 1,2-dichloroethane from within 30 min of fertilization
    (embryos) and maintained for 4 days after hatching (larvae).  The
    LC50 values for the salamander at the day of hatching (day 5) and 4
    days after hatching (day 9) were 6.53 and 2.54 mg/litre, respectively;
    the measured LOEL for 23% reduction in egg hatchability was
    0.99 mg/litre.  The measured 5-day and 9-day LC50 values for the
    frog were 4.52 and 4.40 mg/litre, respectively, while the 5-day
    posthatch LOEL was 1.07 mg/litre (Black et al., 1982).

         Acute toxicity studies have been conducted on several species of
    freshwater fish.  The most sensitive species was the guppy  (Poecilia
     reticulata, 2-3 months old), with a nominal 7-day LC50 of
    106 mg/litre under static renewal test conditions (Konemann, 1981).
    In three studies on 30-day-old fathead minnows  (Pimephales promelas),
    measured 96-h LC50 values ranged from 116 to 136 mg/litre under
    flow-through conditions (Veith et al., 1983; Walbridge et al., 1983;
    Geiger et al., 1985).  LC50 values after 24, 48, 72 and 96 h in
    rainbow trout  (Salmo gairdneri) were 362, 340, 337 and 336 mg/litre,
    respectively, using the static test method (Bartlett, 1979).  Knie et
    al. (1983) reported the EC0, EC50 and EC100 in golden orfe
     (Leuciscus idus) to be 67, 600 and 1075 mg/litre, respectively.

         In marine fish, a nominal 96-h LC50 of 480 mg/litre was
    reported in tidewater silversides  (Minidia beryllina) under static
    test conditions (Dawson et al., 1975/77).  Heitmuller et al. (1981)
    reported the static test LC50 at 24, 48, 72 and 96 h in sheepshead
    minnows  (Cyprinodon variegatus) to be between 130 and 230 mg/litre. 
    The 96-h LC50 for dab  (Limanda limanda) was 115 mg/litre (Pearson
    & McConnell, 1975).

         In a long-term, flow-through study of the early life stages of
    fathead minnows  (Pimephales promelas), there were no effects on egg
    hatchability or larval survival and deformity at 29 mg/litre (NOEL);
    however, larval growth was significantly (p < 0.05) reduced by 62% at
    59 mg/litre (LOEL) (Benoit et al., 1982).  Black et al. (1982) exposed
    the embryos and larvae of the rainbow trout  (Oncorhynchus mykiss)
    continuously to 1,2-dichloroethane under flow-through conditions from
    within 30 min of fertilization (embryos) and maintained them until 4
    days after hatching.  The resulting EC50 for hatchability and 27-day
    LC50 for post-hatch survival were both 34 mg/litre, and the LOEL for
    a 24% reduction in egg hatchability was 3.49 mg/litre.  After 21 days
    of continuous exposure to 150 mg 1,2-dichloroethane/litre, the
    mortality of coho salmon  (Oncorhynchus kisutch) eggs was 46%, while
    in alevins, 100% mortality occurred 9 days after hatching at

    320 mg/litre (Reid et al., 1982).  In addition, premature hatching was
    observed at 56 mg/litre, and, within one week of hatching, sublethal
    effects, including lethargy and loss of equilibrium, were observed in
    alevins exposed to 56 mg/litre; 100% mortality occurred 9 days after
    hatching.

         Ahmad et al. (1984) conducted chronic toxicity studies in which
    fathead minnows were exposed to 300, 4000, 7000, 14 000, 29 000 or
    39 000 µg/litre for 32 days.  There were no significant effects on
    survival, although there was a significant (p < 0.05) decrease in
    mean individual net weight at the highest concentration (38% of
    control values).  The MATC was determined to be 49 000 to
    59 000 µg/litre.

         Teratogenic effects (expressed as surviving larvae with gross,
    debilitating abnormalities) were observed in the larvae of
    northwestern salamanders  (Ambystoma gracile), leopard frogs
     (Rana pipiens) and rainbow trout  (Oncorhynchus mykiss) at 21.4,
    21.9 and 34.4 mg/litre, respectively (Black et al., 1982).

    9.2  Terrestrial organisms

    9.2.1  Invertebrates

         In an acute contact test, the 48-h LC50 for earthworms  (Eisenia
     fetida) exposed to 1,2-dichloroethane-treated filter-paper was
    60 µg/m2 (Neuhauser et al., 1985).

    9.2.2  Vertebrates

         Male and female white leghorn chickens were fed mash which had
    been fumigated with 1,2-dichloroethane, resulting in concen-trations
    in the feed of 250 and 500 mg/kg, for 2 years.  The end-points
    examined included serum composition, growth, semen characteristics and
    fertility.  The weight of eggs was significantly reduced at 250 mg/kg
    (5 to 10% (p < 0.01)), while both the number and weight of eggs were
    reduced at 500 mg/kg (5 to 48% (p < 0.05) and 5 to 13% (p < 0.01),
    respectively) (Alumot et al., 1976b).

    9.2.3  Plants

         1,2-Dichloroethane vapour was both lethal and mutagenic to barley
    kernels (two-rowed variety, Bonus) following exposure to 3 mg/m3 for
    24 h (Ehrenberg et al., 1974).

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

    10.1  Evaluation of human health risks

         Available data on the carcinogenicity of 1,2-dichloroethane in
    humans are limited.  There is convincing evidence of increases in the
    incidence of both common and rare tumours in experimental animals at
    several sites (including squamous cell carcinomas of the stomach,
    haemangiosarcomas, fibromas of the subcutaneous tissue and
    adenocarcinomas and fibroadenomas of the mammary gland in rats; and
    alveolar/bronchiolar adenomas, mammary gland adenocarcinomas,
    endometrial stromal polyp or endometrial stromal sarcoma combined and
    hepatocellular carcinomas in mice) following administration by gavage
    for 78 weeks.

         The incidence of benign lung papillomas was significantly
    increased in mice following long-term dermal application of
    1,2-dichloroethane, while a non-significant increase in the number of
    pulmonary adenomas per animal was reported in a screening bioassay on
    mice and in the incidence of benign mammary gland tumours in rats
    exposed by inhalation for 2 years.

         1,2-Dichloroethane is genotoxic in  in vitro and  in vivo
    assays, and binds to DNA in rodents  in vivo.

         Based on the induction of both rare and common tumours in rats
    and mice exposed by ingestion and supporting evidence in other limited
    bioassays, the production of a reactive intermediate that alkylates
    DNA and positive results in a range of  in vitro assays for
    genotoxicity, 1,2-dichloroethane is considered to be a probable human
    carcinogen.

    10.2  Environmental assessment

         The high volatility of 1,2-dichloroethane makes the atmosphere
    the predominant environmental sink. Consequently, measured
    concentrations in surface waters are low (around 1 to 10 µg/litre).
    Air concentrations are highest around manufacturing plants where they
    may reach 300 µg/m3; concentrations in urban air average
    < 1 µg/m3.  Low adsorption to soil leads to potential leaching to
    groundwater; some measurements of low concentrations in drinking-water
    (< 0.2 µg/litre) confirm this.

         Both hydrolysis and microbial degradation are slow; the
    volatility of the compound means that it has low residence time in
    media where these processes occur and they are not considered to be of
    environmental significance.

         The estimated atmospheric lifetime of 1,2-dichloroethane is
    between 40 and 110 days. Stratospheric photolysis may produce chlorine
    radicals which may in turn react with ozone. However, the
    ozone-depleting potential is low (0.001 relative to CFC-11) and the
    compound is not listed in the Montreal Convention.

         Various toxicity tests have shown LC50s for organisms in the
    environment to be generally greater than 10 mg/litre.  The difference
    (at least 7 orders of magnitude) between measured water concentrations
    and these toxic concentrations indicate that 1,2-dichloroethane poses
    no risk to organisms since exposure will not occur.

    11.  CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN
         HEALTH AND THE ENVIRONMENT

         Considering the toxicological characteristics of
    1,2-dichloroethane, both qualitatively and quantitatively, an exposure
    that would not cause adverse effects in humans by any route of
    exposure cannot be estimated.  Consequently, all appropriate measures
    should be taken to eliminate or minimize human exposure to
    1,2-dichloroethane.

    12.  FURTHER RESEARCH

         Although specific studies were not recommended for
    1,2-dichloroethane, additional analytical epidemiological studies are
    desirable.

    13.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         The International Agency for Research on Cancer (IARC, 1979) has
    classified 1,2-dichloroethane in group 2B (possibly carcinogenic to
    humans), based on sufficient evidence of carcinogenicity in
    experimental animals.

         The International Programme on Chemical Safety has previously
    evaluated 1,2-dichloroethane (IPCS, 1987).  It concluded that
    1,2-dichloroethane produces central nervous system depression, and
    gastrointestinal and liver abnormalities in humans.  The same effects
    occur in experimental animals, in addition to possible kidney
    abnormalities, lung oedema and cardiovascular disorders.
    1,2-Dichloroethane, administered by gavage, is carcinogenic in rats
    and mice, and should be regarded, for practical purposes, as if it
    presented a carcinogenic risk for humans. 1,2-Dichloroethane was not
    considered to accumulate in the environment.  In the atmosphere, it is
    removed by photo-chemical degradation via hydroxyl radicals and is
    eliminated from water by evaporation. It has a low octanol/water
    partition coefficient and bioconcentration is unlikely. It was not
    considered to pose a hazard to the aquatic environment except in the
    case of accidents and inappropriate disposal.  Data were insufficient
    to evaluate the effects of 1,2-dichloroethane on the terrestrial
    environment.

         The Joint FAO/WHO Expert Committee on Food Additives
    (JECFA) has evaluated 1,2-dichloroethane on three occasions (WHO,
    1971, 1980, 1992).  When last evaluated, the Committee concluded that
    this compound is genotoxic in both  in vitro and  in vivo test
    systems and carcinogenic in mice and rats when administered by the
    oral route.  No ADI was therefore allocated.  The Committee expressed
    the opinion that 1,2-dichloroethane should not be used in food.

         In the WHO Guidelines for drinking-water quality (WHO, 1993), the
    concentrations of 1,2-dichloroethane in drinking-water estimated to be
    associated with excess risks of 10-4, 10-5 and 10-6 are 300, 30 and
    3 µg/litre, respectively, based on linearized multistage modelling of
    the incidence of haemangiosarcomas in male rats in the NCI (1978)
    study.

         The European Commission published a directive in 1990 in which
    limit values for emission of 1,2-dichloroethane were specified for
    various types of industrial plants.  These limits ranged from
    0.1 mg/litre (monthly) for plants using 1,2-dichloroethane for
    degreasing metals away from an industrial site to 12 mg/litre (daily)
    for plants producing 1,2-dichloroethane and processing or using the
    substance at the site (CEC, 1990).

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    RESUME

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

         Le 1,2-Dichloréthane (ou dichlorure d'éthylène) est un produit
    chimique de synthèse qui se présente sous la forme d'un liquide
    incolore à la température ambiante.  Il est extrêmement volatil, avec
    une tension de vapeur de 8,5 kPa à 20°C et il est soluble dans l'eau,
    sa solubilité étant de 8690 mg/litre à 20°C.  Son coefficient de
    partage octanol/eau (log Kow) est égal à 1,76.

         Le dosage du dichloréthane dans les différents compartiments de
    l'environnement s'effectue généralement par chromatographie en phase
    gazeuse, avec détection par capture d'électrons, ionisation de flamme
    ou spectrométrie de masse.  Les limites de détection vont de 0,016 à
    > 4 µg/m3 dans l'air, de 0,001 à 4,7 µg/litre dans l'eau et de 6 à
    10 µg/kg dans différentes denrées alimentaires.

    2.  Sources d'exposition humaine et environnementale

         On utilise principalement le 1,2-dichloréthane pour la synthèse
    du chlorure de vinyle monomère et dans une moindre mesure pour la
    production de divers solvants chlorés.  Il entre également dans la
    composition des additifs antidétonants de l'essence (encore que cet
    usage soit en déclin avec l'élimination progressive de l'essence au
    plomb dans certains pays) et on l'utilise aussi pour des fumigations. 
    La production annuelle totale de 1,2-dichloréthane a été de 922
    kilotonnes au Canada en 1990 et de 6318 kilotonnes aux Etats-Unis
    d'Amérique en 1991.

    3.  Transport, distribution et transformation dans l'environnement

         La majeure partie du 1,2-dichloréthane rejeté dans
    l'environnement provient d'émissions dans l'atmosphère.  Il
    estmoyennement persistant dans l'air; sa durée de vie estimative dans
    l'atmosphère est comprise entre 43 et 111 jours.  Le dichloréthane est
    transporté vers la stratosphère où, par photolyse, il peut donner
    naissance à du chlore radicalaire qui peut à son tour réagir sur
    l'ozone.  Une partie du 1,2-dichloréthane rejeté dans les effluents
    industriels peut passer dans le milieu aquatique dont il s'échappe
    rapidement par volatilisation.  Il peut également s'infiltrer
    jusqu'aux nappes d'eau souterraines à proximité des zones de décharges
    industrielles.  On ne pense pas qu'il puisse subir une
    bioconcentration chez les espèces aquatiques ou terrestres.

    4.  Concentrations dans l'environnement et exposition humaine

         Des enquêtes récentes portant sur l'air ambiant de zones urbaines
    non dominées par des sources polluantes ont permis de relever des
    concentrations moyennes de 1,2-dichloréthane allant de 0,07 à
    0,28 µg/m3, alors que dans l'air intérieur aux habitations des zones
    résidentielles, ces valeurs moyennes vont de < 0,1 à 3,4 µg/m3.
    Dans l'eau destinée à la consommation, les concentrations moyennes
    sont généralement inférieures à 0,5 µg/litre.  Lors de récentes
    enquêtes, on a rarement décelé du 1,2-dichloréthane dans les denrées
    alimentaires et comme il ne présente qu'un faible potentiel de
    bioaccumulation, il est peu probable que la nourriture constitue une
    source importante d'exposition à ce composé.

         La valeur estimative de l'exposition moyenne au 1,2-dichloréthane
    à partir de divers milieux montre que la source principale
    d'exposition est constituée par l'air intérieur et extérieur, l'eau de
    consommation n'y contribuant que pour une très faible part.  L'apport
    de 1,2-dichloréthane par la voie alimentaire est probablement
    négligeable.  Les quantités inhalées dans l'air ambiant pourraient
    être plus importantes à proximité des sources industrielles.

    5.  Cinétique et métabolisme chez les animaux de laboratoire

         Après inhalation, ingestion ou exposition par voie cutanée, le
    1,2-dichloréthane est rapidement absorbé et il se répartit rapidement
    et largement dans l'ensemble de l'organisme.  Il est rapidement et
    largement métabolisé chez le rat et la souris, principalement sous
    forme de métabolites soufrés dont l'excrétion s'effectue par la voie
    urinaire et dépend de la dose.  A des niveaux d'exposition qui
    entraînent des concentrations sanguines de 5 à 10 µg/ml, il semble
    qu'il y ait saturation ou limitation du métabolisme chez le rat. 
    Après administration d'une dose unique de dichloréthane par gavage, on
    a constaté que le taux d'alkylation de l'ADN était plus important que
    lorsque le produit était inhalé sur une période de six heures.

         Il existe semble-t-il deux voies principales de métabolisation. 
    La première est une oxydation saturable qui s'effectue au niveau des
    microsomes par l'intermédiaire du cytochrome P-450 et aboutit au
    2-chloracétaldéhyde et au 2-chloréthanol, pour s'achever sur une
    conjugaison avec le glutathion.  La deuxième voie métabolique comporte
    une conjugaison directe avec le glutathion pour former du
     S-(2-chloréthyl)-glutathion, qui est peut-être ensuite transformé
    par voie non enzymatique en un ion glutathion-épitsulfonium
    susceptible de former des adduits avec l'ADN.  Bien qu'on ait pu
    observer  in vitro que la voie du P-450 conduisait à des lésions de
    l'ADN, il semble bien qu'à cet égard, la voie impliquant la
    conjugaison du glutathion soit la plus importante.

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

         Le 1,2-dichloréthane présente une faible toxicité aiguë pour les
    animaux de laboratoire.  Ainsi, la CL50 par inhalation pour des rats
    exposés soit 6 soit 7,25 heures à ce composé allait de 4000 mg/m3 à
    6600 mg/m3, la DL50 par voie orale pour le rat, la souris, le
    chien et le lapin allant de 413 à 2500 mg/kg de poids corporel.

         D'après les résultats d'études à court terme et d'études
    subchroniques menées sur différentes espèces d'animaux de laboratoire,
    c'est le foie et les reins qui sont les organes cibles; il n'a pas été
    possible d'obtenir de valeurs pour la dose sans effets observables
    (NOEL) ou La dose la plus faible provoquant un effet (LOEL),
    généralement en raison d'une documentation insuffisante et du nombre
    trop limité de paramètres biologiques examinés sur un trop petit
    nombre d'animaux.  Une série d'études limitées anciennes a révélé la
    présence de modifications morphologiques au niveau du foie chez
    plusieurs espèces après exposition subchronique à des concentrations
    atmosphériques ne dépassant pas 800 mg/m3.  Après administration
    subchronique par voie orale de 1,2-dichloréthane à des doses
    quotidiennes allant de 49 à 82 mg/kg de poids corporel ou davantage
    pendant 13 semaines, on a observé chez des rats un accroissement du
    poids relatif du foie.  Les études de toxicité chronique dont on
    possède les résultats ne donnent guère d'information sur les effets
    non néoplasiques.  Chez des rats exposés pendant 12 mois à des
    concentrations atmosphériques de 1,2-dichloréthane ne dépassant pas
    202 mg/m3, on a observé, au niveau des paramètres sériques, des
    modifications indiquant une toxicité hépatique et rénale; toutefois,
    aucun examen histopathologique n'a été pratiqué lors de cette étude.


         Quelques épreuves limitées ont été effectuées sur des animaux de
    laboratoire à la recherche d'une cancérogénicité éventuelle du
    1,2-dichloréthane (ces études souffraient d'une trop faible durée
    d'exposition et d'une forte mortalité parmi les animaux).  Chez des
    rats Sprague-Dawley et des souris Swiss exposés pendant 78 semaines à
    des concentrations allant jusqu'à 607 mg/m3 et observés jusqu'à ce
    qu'ils meurent spontanément, on n'a pas observé d'augmentation
    significative dans l'incidence des tumeurs quel qu'en soit le type. 
    La mortalité était forte parmi les rats, mais sans rapport avec la
    concentration du produit et on n'a pas tenu compte des différences de
    mortalité entre les groupes pour corriger les taux d'incidence.  Des
    rattes Sprague-Dawley ont été exposées pendant deux ans à 200 mg/m3
    de 1,2-dichloréthane et on a observé à cette occasion une augmentation
    de l'incidence des adénomes et des fibroadénomes de la mère, qui
    n'était toutefois pas significative;  aucun autre effet toxique
    attribuable au composé n'a été observé.

         En revanche, on a observé, après ingestion, chez deux espèces,
    des signes convaincants d'un accroissement de l'incidence tumorale. 
    Chez des rats Osborne-Mendel à qui l'on avait administré
    quotidiennement par gavage pendant 78 semaines des doses de 47 ou
    95 mg/kg (en moyenne pondérée par rapport au temps), on a observé une
    augmentation significative de l'incidence des tumeurs de différentes
    localisations (notamment des carcinomes spinocellulaires de l'estomac
    (chez les mâles), des hémangiosarcomes (chez les mâles et les
    femelles), des fibromes du tissu sous-cutané (chez les mâles) ainsi
    que des adénocarcinomes et des fibroadénomes mammaires chez les
    femelles.  Chez des souris B6C3F1 à qui l'on avait administré
    quotidiennement des doses de 97 ou 195 mg/kg de produit (en moyenne
    pondérée par rapport au temps) (mâles) ou de 149 et 299 mg/kg
    (femelles) par gavage sur 78 semaines, on a observé une augmentation
    similaire de l'incidence des tumeurs de diverses localisations
    (notamment des adénomes alvéolaires/bronchiolaires chez les mâles et
    les femelles, des adénocarcinomes mammaires chez les femelles, des
    polypes ou des sarcomes du stroma de l'endomètre (femelles) et des
    carcinomes hépatocellulaires (mâles)).

         Chez des souris femelles qui avaient été soumises respectivement
    pendant 440 et 594 jours à des applications cutanées répétées de
    1,2-dichloréthane, on a observé une incidence sensiblement accrue des
    tumeurs pulmonaires (papillomes bénins).  Chez une souche sensible de
    souris, des injections intrapéritonéales répétées de 1,2-dichloréthane
    ont déterminé un accroissement, lié à la dose, du nombre des adénomes
    pulmonaires, mais cet accroissement n'était en aucun cas significatif. 
    Chez des rats à qui l'on faisait simultanément respirer du
    1,2-dichloréthane et ingérer du disulfirame avec leur nourriture, on a
    observé une incidence accrue des cholangiomes et des kystes dans la
    partie intrahépatique des canaux biliaires, et davantage de fibromes
    sous-cutanés, de nodules hépatiques malins, de tumeurs du tissu
    testiculaire interstitiel et d'adénocarcinomes mammaires, que chez des
    rats qui avaient reçu soit l'un, soit l'autre des composés ou aucun
    des deux.  Trois épreuves biologiques n'ont pas permis de mettre en
    évidence une aptitude quelconque de ce composé à se comporter comme un
    initiateur ou un promoteur tumoral, encore que l'examen
    histopathologique effectué à la suite de ces études ait été de portée
    limitée.

         Lors d'épreuves de mutagénicité  in vitro sur  Salmonella
     typhimurium, le 1,2-dichloréthane a toujours donné des résultats
    positifs.  L'effet était plus important en présence d'un système
    d'activation exogène (sans doute du fait d'une activation par le
    cytochrome) et on constatait que le pouvoir mutagène était plus que
    doublé chez  S. typhimurium exprimant le gène humain GSTA1-1.  Le
    1,2-dichloréthane forme des adduits avec l'ADN en cultures de cellules
    mammaliennes.  Il provoque également une synthèse non programmée de

    l'ADN dans des cultures primaires de cellules murines et humaines
    ainsi que des mutations géniques dans certaines lignées cellulaires. 
    On a trouvé une corrélation entre la fréquence des mutations observées
    dans des lignées cellulaires humaines et la modification de l'activité
    de la glutathion-S-transférase.  Des études  in vivo ont montré que
    le 1,2-dichloréthane produisait des mutations létales récessives dans
    les cellules somatiques et germinales de  Drosophila melanogaster et
    selon toutes les études publiées portant sur des rats et des souris,
    il y a liaison du 1,2-dichloréthane à l'ADN.  Des lésions directes de
    l'ADN des cellules hépatiques ainsi que des échanges entre chromatides
    soeurs ont été observés lors d'études sur la souris mais rien
    n'indique que le 1,2-dichloréthane provoque la formation de
    micronoyaux.

         Rien n'indique, à en juger par les résultats d'un nombre limité
    d'études, que le 1,2-dichloréthane soit tératogène pour les animaux de
    laboratoire.  Il n'y a également guère d'éléments en faveur d'effets
    sur la reproduction ou le développement à des doses inférieures à
    celles qui provoquent d'autres effets généraux.  On ne dispose que de
    données limitées sur l'immunotoxicité du 1,2-dichloréthane.

    7.  Effets sur l'homme

         Des effets divers ont été observés à la suite d'expositions
    accidentelles aiguës à du 1,2-dichloréthane par inhalation ou
    ingestion: au niveau du système nerveux central, du foie, des reins,
    des poumons et de l'appareil cardio-vasculaire.

         On n'a pas beaucoup étudié le pouvoir cancérogène du
    1,2-dichloréthane dans les populations humaines exposées.  Chez un
    groupe d'ouvriers d'un atelier de production de produits chimiques qui
    avaient été exposés principalement à du 1,2-dichloréthane, à côté
    d'autres substances, on a observé une augmentation significative de la
    mortalité par cancer du pancréas.  Cette mortalité augmentait avec la
    durée de l'exposition.  En outre, malgré un nombre limité de cas et
    une association moins systématique avec la durée de l'exposition, il y
    avait également accroissement de la mortalité par leucémie chez ces
    travailleurs.  Une petite étude cas-témoins, portant sur l'exposition
    à du 1,2-dichloréthane n'a pas permis de mettre en évidence une
    corrélation avec l'apparition de tumeurs cérébrales.  Une étude
    écologique intrinsèquement limitée, portant sur la présence de
    1,2-dichloréthane dans de l'eau de consommation, a mis en évidence une
    augmentation de l'incidence des cancers colo-rectaux mais il est
    possible qu'une exposition simultanée à d'autres substances explique
    pour une part les effets observés.

    8.  Effets sur les organismes non visés au laboratoire et dans leur
        milieu naturel

         On a étudié les effets d'une exposition au 1,2-dichloréthane sur
    un certain nombre d'autres organismes tant au laboratoire que dans
    leur milieu naturel.  En ce qui concerne les microorganismes
    aquatiques, les valeurs de la CI50 et de la CE50 correspondant à
    divers paramètres biotoxicologiques vont de 25 à 770 mg/litre.  La
    valeur de la CL50 la plus faible qui ait été observée pour les
    daphnies était de 220 mg/litre, des effets ayant été toutefois
    observés sur la fécondité et la croissance aux concentrations
    respectives de 20,7 et 71,7 mg/litre.  En s'appuyant sur les données
    disponibles, on constate que le vertébré d'eau douce le plus sensible
    au 1,2-dichloréthane est une espèce de salamandre  (Ambystoma gracile),
    chez laquelle la survie des larves à neuf jours (quatre jours après
    l'éclosion) a accusé une chute à 2,54 mg/litre.  On ne possède que des
    données limitées sur la toxicité du 1,2-dichloréthane pour les
    organismes terrestres.

    Resumen

    1.  Identidad, propiedades físicas y químicas y métodos analíticos

         El 1,2-dicloroetano (dicloruro de etileno), producto químico
    sintético, es un líquido incoloro a temperatura ambiente.  Es también
    muy volátil, con una presión de vapor de 8,5 kPa (a 20°C), y soluble
    en agua, con una solubilidad de 8690 mg/litro (a 20°C).  El log del
    coeficiente de reparto octanol/agua es de 1,76.

         El análisis del 1,2-dicloroetano en el medio ambiente se realiza
    habitualmente por cromatografía de gases, en combinación con la
    captura de electrones, la detección de ionización por conductor o bien
    la espectrometría de masas.  Los límites de la detección oscilan entre
    0,016 y > 4 µg/m3 en el aire, entre 0,001 y 4,7 µg/litro en el agua
    y entre 6 y 10 µg/kg en diversos productos alimenticios.

    2.  Fuentes de exposición humana y ambiental

         El 1,2-dicloroetano se utiliza principalmente en la síntesis del
    monómero cloruro de vinilo y, en menor grado, en la fabricación de
    diversos disolventes clorados.  Se incorpora también a los aditivos
    antidetonantes de la gasolina (aunque este empleo está disminuyendo
    con la reducción progresiva en muchos países de la gasolina con plomo)
    y se ha usado como fumigante.  La producción anual total de
    1,2-dicloroetano en el Canadá en 1990 y en los Estados Unidos en 1991
    fue de 922 000 y 6 318 000 toneladas, respectivamente.

    3.  Transporte, distribución y transformación en el medio ambiente

         La mayor parte del 1,2-dicloroetano liberado en el medio ambiente
    ha sido emitido en el aire.  En este medio es moderadamente
    persistente; su permanencia en la atmósfera se estima entre 43 y 111
    días.  Es transportado a la estratosfera, donde, por fotólisis, pueden
    producirse radicales de cloro que a su vez pueden reaccionar con el
    ozono.  Cierta cantidad de 1,2-dicloroetano puede escapar a los
    efluentes industriales y de allí pasar al medio ambiente acuático, de
    donde desaparece rápidamente por volatilización.  También puede
    alcanzar por lixiviación las aguas subterráneas próximas a los
    vertederos de desechos industriales.  No se prevé su bioconcentración
    en especies acuáticas o terrestres.

    4.  Niveles medioambientales y exposición humana

         Según estudios recientes del aire ambiental, las concentraciones
    medias de 1,2-dicloroetano detectadas en zonas urbanas donde no
    abundan sus fuentes de emisión oscilan entre 0,07 y 0,28 µg/m3,
    mientras que los niveles medios notificados como presentes en el aire
    del interior de las viviendas oscilan entre < 0,1 y 3,4 µg/m3.  En

    el agua potable, la concentración media suele ser menor de
    0,5 µg/litro.  En estudios recientes rara vez se ha detectado la
    presencia de 1,2-dicloroetano en alimentos y, puesto que el potencial
    de bioacumulación de esta sustancia es bajo, los alimentos
    probablemente no representen una fuente de exposición importante.

         Teniendo en cuenta las estimaciones de la exposición media en
    diversos entornos, la principal fuente de exposición de la población
    general al 1,2-dicloroetano es el aire de locales cerrados y el aire
    exterior, mientras que el agua de bebida contribuye sólo en cantidades
    muy pequeñas.  La ingestión de 1,2-dicloroetano con los alimentos
    probablemente sea insignificante.  La cantidad inhalada con el aire
    ambiental puede ser más grande en las proximidades de fuentes de
    emisión industriales.

    5.  Cinética y metabolismo en animales de laboratorio

         El 1,2-dicloroetano se absorbe fácilmente tras la inhalación, la
    ingestión o la exposición cutánea y se distribuye rápida y ampliamente
    por todo el organismo.  En la rata y el ratón se metaboliza de forma
    rápida y completa y por orina se eliminan principalmente metabolitos
    azufrados en concentraciones que dependen de la dosis.  En la rata, el
    metabolismo parece saturado o limitado cuando la exposición alcanza
    niveles que dan lugar a concentraciones sanguíneas de 5 a 10 µg/ml. 
    Después de la administración por sonda de una dosis única, los niveles
    de alquilación del ADN eran más elevados que después de la inhalación
    durante un periodo de seis horas.

         El 1,2-dicloroetano parece metabolizarse siguiendo dos vías
    principales: la primera comporta una oxidación microsómica saturable
    mediada por el citocromo P-450, que produce 2-cloroacetaldehído y
    2-cloroetanol, seguida de conjugación con el glutatión.  La segunda
    vía entraña la conjugación directa con el glutatión para formar
     S-(2-cloroetil)-glutatión, que puede convertirse mediante un proceso
    no enzimático en un ion glutatión episulfonio; este ion puede formar
    aductos con el ADN.  Aunque se han inducido daños en el ADN por la
    ruta del P-450  in vitro, hay varias pruebas de que la vía de la
    conjugación del glutatión probablemente sea más importante que la otra
    en cuanto a los daños que causa en el ADN.

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

         La toxicidad aguda del 1,2-cicloroetano en animales de
    experimentación es baja.  Por ejemplo, la CL50 por inhalación en
    ratas expuestas durante 6 ó 7,25 horas oscilaba entre 4000 mg/m3 y
    6600 mg/m3, mientras que la DL50 por vía oral en ratas, ratones,
    perros y conejos variaba entre 413 y 2500 mg/kg de peso corporal.

         Los resultados de estudios de corta duración y subcrónicos
    realizados en varias especies de animales de experimentación indican
    que los órganos afectados son el hígado y los riñones; en general no
    se obtuvieron NOEL ni LOEL fidedignos debido a la documentación
    insuficiente y a la gama limitada de puntos finales examinados en
    pequeños grupos de animales.  En una serie de estudios iniciales
    limitados, se observaron cambios morfológicos en el hígado de varias
    especies tras la exposición subcrónica a concentraciones de
    1,2-dicloroetano en el aire de sólo 800 mg/m3.  Tras la
    administración subcrónica a ratas por vía oral de dosis comprendidas
    entre 49 y 82 mg/kg de peso corporal por día durante más de 13 semanas
    se observó un incremento del peso relativo del hígado.  En los
    estudios crónicos disponibles se ha presentado poca información sobre
    efectos no neoplásicos.  Las ratas expuestas a concentraciones de sólo
    202 mg/m3 en el aire durante 12 meses acusaron en los parámetros del
    suero cambios indicativos de toxicidad hepática y renal, pero en ese
    estudio no se realizaron exámenes histopatológicos.

         La carcinogenicidad del 1,2-dicloroetano se ha investigado en un
    pequeño número de biovaloraciones limitadas sobre animales de
    experimentación (las limitaciones comprenden una exposición de corta
    duración y una mortalidad alta).  No se notificaron aumentos
    significativos en la incidencia de ningún tipo de tumor en ratas
    Sprague-Dawley o en ratones suizos expuestos a concentraciones de
    hasta 607 mg/m3 durante 78 semanas; los animales se observaron hasta
    que se produjo su muerte espontánea.  En este estudio, la mortalidad
    de las ratas fue elevada, pero no guardaba relación con la
    concentración, y no se realizó un ajuste de la incidencia en función
    de la mortalidad diferencial entre los grupos.  En un ensayo con ratas
    Sprague-Dawley hembra expuestas durante dos años a 200 mg/m3, se
    produjo un aumento no significativo de la incidencia de adenomas y
    fibroadenomas en las glándulas mamarias, y no se observó otra forma de
    toxicidad relacionada con el compuesto.

         En cambio, hay pruebas convincentes de un aumento de la
    incidencia de tumores en dos especies tras la ingestión del producto. 
    Las ratas Osborne-Mendel que habían recibido mediante sonda durante 78
    semanas dosis diarias de 47 ó 95 mg/kg de peso corporal (promedio
    ponderado en función del tiempo) mostraron un aumento significativo de
    la incidencia de tumores en diversos lugares (por ejemplo, carcinomas
    escamosos del estómago en machos, hemangiosarcomas en machos y
    hembras, fibromas del tejido subcutáneo en machos, adenocarcinomas y
    fibroadenomas de las glándulas mamarias en hembras.  En ratones
    B6C3F1 que habían recibido, como promedio ponderado en función del
    tiempo, dosis diarias de 97 ó 195 mg/kg de peso corporal (machos) y
    149 ó 299 mg/kg de peso corporal (hembras) mediante sonda durante 78
    semanas se observaron aumentos semejantes de la incidencia de tumores
    en múltiples lugares (adenomas alveolares/bronquiolares en machos y
    hembras, adenocarcinomas de las glándulas mamarias en hembras y pólipo
    estromal endometrial o sarcoma estromal endometrial combinados en
    hembras y carcinomas hepatocelulares en machos).

         La incidencia de tumores pulmonares (papilomas benignos)
    aumentó significativamente en ratones hembra tras la aplicación
    cutánea repetida de 1,2-dicloroetano durante 440 a 594 días. La
    administración intraperitoneal repetida produjo en una raza
    susceptible aumentos en el número de adenomas pulmonares por ratón;
    dichos aumentos estaban relacionados con la dosis, pero ninguno de
    ellos fue significativo.  En comparación con las ratas que recibieron
    el compuesto solo y con el grupo testigo, que no recibió ningún
    tratamiento, las ratas expuestas simultáneamente a 1,2-dicloroetano
    por inhalación y a disulfiram en los alimentos acusaron una mayor
    incidencia de colangiomas y de quistes en el conducto biliar
    intrahepático, de fibromas subcutáneos, de nódulos neoplásicos en el
    hígado, de tumores de las células intersticiales de los testículos y
    de adenocarcinomas mamarios.  En tres biovaloraciones realizadas no se
    observaron indicios de potencial iniciador o facilitador del
    desarrollo de tumores, pero el alcance del examen histopatológico de
    esos estudios fue limitado.

          In vitro, el 1,2-dicloroetano ha dado constantemente resultados
    positivos en biovaloraciones de mutagenicidad en  Salmonella
     typhimurium.  Las respuestas han sido mayores en presencia de un
    sistema de activación exógeno (posiblemente debido a la activación por
    el sistema del citocromo) que en su ausencia; la mutagenicidad se
    duplicó con creces en la cepa de S. typhimurium que contenía el gen
    humano GSTA1-1.  En cultivos de células mamarias, el 1,2-dicloroetano
    forma aductos con el ADN.  También induce síntesis no programada del
    ADN en cultivos primarios de células de roedores y humanas y mutación
    génica en varias líneas celulares.  La frecuencia de las mutaciones en
    las líneas celulares humanas se ha correlacionado con diferencias en
    la actividad de la glutatión-S-transferasa.  En estudios  in vivo,
    el 1,2-dicloroetano indujo mutaciones en células somáticas y
    mutaciones letales recesivas ligadas al sexo en  Drosophila
     melanogaster y, según todos los estudios realizados en ratas y
    ratones, el compuesto se había unido al ADN.  Aunque en estudios
    efectuados en ratones se han observado lesiones primarias del ADN en
    el hígado e intercambio de cromátides hermanas, no hay indicaciones de
    inducción de micronúcleos.

         Teniendo en cuenta los resultados de un número limitado de
    estudios, no hay pruebas de que el 1,2-dicloroetano sea teratogénico
    en animales de experimentación.  Además, hay pocas pruebas
    convincentes de que tenga efectos sobre la reproducción o el
    desarrollo con dosis inferiores a las que causan otros efectos
    sistémicos.  Los datos disponibles sobre la inmunotoxicidad del
    1,2-dicloroetano son limitados.

    7.  Efectos en el ser humano

         La exposición accidental aguda al 1,2-dicloroetano por inhalación
    o por ingestión ha producido diversos efectos en el ser humano, por
    ejemplo en el sistema nervioso central, el hígado, el riñón, el pulmón
    y el sistema cardiovascular.

         No se ha estudiado con detenimiento la carcinogenicidad potencial
    del 1,2-dicloroetano en poblaciones humanas expuestas.  La mortalidad
    por cáncer pancreático aumentó de forma significativa en un grupo de
    trabajadores de una planta de producción química que había estado
    expuesto sobre todo a 1,2-dicloroetano (en combinación con otros
    productos químicos).  La mortalidad por cáncer pancreático aumentó con
    la duración de la exposición.  Además, aunque el número de casos fue
    pequeño y la relación con la duración de la exposición menos
    constante, en estos trabajadores también aumentó la mortalidad por
    leucemia.  No se observó relación entre la exposición ocupacional al
    1,2-dicloroetano y el cáncer cerebral en un pequeño estudio de casos y
    controles.  Si bien en un estudio ecológico con limitaciones
    inherentes se observó que la incidencia de cáncer de colon y de recto
    aumentaba con la concentración del producto en el agua de bebida, la
    exposición simultánea a otras sustancias podría haber contribuido a
    producir los efectos observados.

    8.  Efectos en organismos no destinatarios en el laboratorio y
        sobre el terreno

         Se han investigado los efectos de la exposición al
    1,2-dicloroetano en varios otros organismos en el laboratorio y en el
    medio ambiente.  Con respecto a los microorganismos acuáticos, se ha
    informado de que las CI50 y CE50 correspondientes a diversos
    puntos finales oscilan entre 25 y 770 mg/litro.  La CL50 más baja
    notificada para  Daphnia fue de 220 mg/litro, mientras que se
    detectaron efectos en el éxito reproductivo y el crecimiento a 20,7 y
    71,7 mg/litro, respectivamente.  Teniendo en cuenta los datos
    disponibles, la especie de vertebrados de agua dulce más sensible
    parece ser la salamandra noroccidental  (Ambystoma gracile), cuyas
    larvas de nueve días (cuatro días después de la eclosión) vieron
    reducida su supervivencia a concentraciones de 2,54 mg/litro.  Se
    dispone sólo de datos limitados sobre la toxicidad del
    1,2-dicloroetano en organismos terrestres.
    



    See Also:
       Toxicological Abbreviations
       Dichloroethane, 1,2- (EHC 62, 1987, 1st edition)
       Dichloroethane, 1,2- (FAO Nutrition Meetings Report Series 48a)
       Dichloroethane, 1,2- (WHO Food Additives Series 30)
       Dichloroethane, 1,2-  (WHO Pesticide Residues Series 1)
       Dichloroethane, 1,2- (Pesticide residues in food: 1979 evaluations)
       Dichloroethane, 1,2- (CICADS 1, 1998)
       Dichloroethane, 1,2- (IARC Summary & Evaluation, Volume 71, 1999)