INTOX Home Page



    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 185





    CHLORENDIC ACID AND ANHYDRIDE












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


    First draft prepared by Dr. G.J. van Esch,
    Bilthoven, Netherlands



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


    World Health Organization
    Geneva, 1996

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

    WHO Library Cataloguing in Publication Data

    Chlorendic acid and anhydride

    (Environmental health criteria ; 185)

    1.Insecticides, Organochlorine     2. Environmental exposure
    I.Series

    ISBN 92 4 157185 3                      (NLM Classification: WA 240)
    ISSN 0250-863X

         The World Health Organization welcomes requests for permission to
    reproduce or translate its publications, in part or in full.
    Applications and enquiries should be addressed to the Office of
    Publications, World Health Organization, Geneva, Switzerland, which
    will be glad to provide the latest information on any changes made to
    the text, plans for new editions, and reprints and translations
    already available.

    (c) World Health Organization 1996

         Publications of the World Health Organization enjoy copyright
    protection in accordance with the provisions of Protocol 2 of the
    Universal Copyright Convention. All rights reserved. The designations
    employed and the presentation of the material in this publication do
    not imply the expression of any opinion whatsoever on the part of the
    Secretariat of the World Health Organization concerning the legal
    status of any country, territory, city or area or of its authorities,
    or concerning the delimitation of its frontiers or boundaries. The
    mention of specific companies or of certain manufacturers' products
    does not imply that they are endorsed or recommended by the World
    Health Organization in preference to others of a similar nature that
    are not mentioned. Errors and omissions excepted, the names of
    proprietary products are distinguished by initial capital letters.

    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR CHLORENDIC ACID AND ANHYDRIDE

    INTRODUCTION

    1. SUMMARY AND EVALUATION; CONCLUSIONS
         AND RECOMMENDATIONS
         1.1. Summary and evaluation
               1.1.1. Physical and chemical properties
               1.1.2. Production and use
               1.1.3. Environmental transport, distribution
                       and transformation
               1.1.4. Environmental levels and human exposure
               1.1.5. Kinetics and metabolism in laboratory animals
               1.1.6. Effects on laboratory mammals and  in vitro
                       test systems
               1.1.7. Effects on humans
               1.1.8. Effects on other organisms in the laboratory
                       and field
         1.2. Conclusions
         1.3. Recommendations
               1.3.1. Protection of human health and the environment
               1.3.2. Further research

    2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
         METHODS
         2.1. Chlorendic acid
               2.1.1. Identity
                       2.1.1.1  Primary constituent
                       2.1.1.2  Technical product
         2.2. Chlorendic anhydride
               2.2.1. Identity
                       2.2.1.1  Primary constituent
                       2.2.1.2  Technical product
         2.3. Physical and chemical properties
               2.3.1. Chlorendic acid
               2.3.2. Chlorendic anhydride
         2.4. Analytical methods
               2.4.1. Air sampling

    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
               3.2.3. Contamination of the environment

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSPORTATION
         4.1. Transport and distribution between media
         4.2. Transformation

               4.2.1. Biodegradation
               4.2.2. Abiotic degradation
                       4.2.2.1  Chlorendic acid
                       4.2.2.2  Chlorendic anhydride
               4.2.3. Bioaccumulation and biomagnification
         4.3. Ultimate fate following use

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    6. KINETICS AND METABOLISM IN LABORATORY ANIMALS
         6.1. Chlorendic acid
               6.1.1. Absorption, distribution and elimination
                       6.1.1.1  Oral administration
                       6.1.1.2  Intravenous administration
         6.2. Chlorendic anhydride
               6.2.1. Absorption, distribution and elimination

    7. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS
         7.1. Single exposure
               7.1.1. Oral exposure
                       7.1.1.1  Chlorendic acid
                       7.1.1.2  Chlorendic anhydride
               7.1.2. Dermal exposure
                       7.1.2.1  Chlorendic anhydride
               7.1.3. Inhalation exposure
                       7.1.3.1  Chlorendic acid
                       7.1.3.2  Chlorendic anhydride
         7.2. Short-term exposures
               7.2.1. Oral
                       7.2.1.1  Mice
                       7.2.1.2  Rats
               7.2.2. Dermal
                       7.2.2.1  Chlorendic anhydride
               7.2.3. Inhalation
                       7.2.3.1  Chlorendic anhydride
         7.3. Long-term exposure
         7.4. Skin and eye irritation; sensitization
               7.4.1. Chlorendic acid
               7.4.2. Chlorendic anhydride
         7.5. Reproductive toxicity, embryotoxicity and
               teratogenicity
               7.5.1. Chlorendic anhydride
         7.6. Mutagenicity and related end-points
               7.6.1. Chlorendic acid
               7.6.2. Chlorendic anhydride
         7.7. Carcinogenicity
               7.7.1. Chlorendic acid
                       7.7.1.1  Mice
                       7.7.1.2  Rats
                       7.7.1.3  Special studies
               7.7.2. Chlorendic anhydride

    8. EFFECTS ON HUMANS

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         9.1. Chlorendic acid
         9.2. Chlorendic anhydride

    10. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    RESUME ET EVALUATION; CONCLUSIONS ET RECOMMANDATIONS

    RESUMEN Y EVALUACION; CONCLUSIONES Y RECOMENDACIONES
    

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

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

                                 *     *     *

         A detailed data profile and a legal file can be obtained from the
    International Register of Potentially Toxic Chemicals, Case postale
    356, 1219 Châtelaine, Geneva, Switzerland (Telephone No. 9799111).

                                 *     *     *

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

    Environmental Health Criteria

    PREAMBLE

    Objectives

         In 1973 the WHO Environmental Health Criteria Programme was
    initiated with the following objectives:

    (i)     to assess information on the relationship between exposure to
            environmental pollutants and human health, and to provide
            guidelines for setting exposure limits;

    (ii)    to identify new or potential pollutants;

    (iii)   to identify gaps in knowledge concerning the health effects of
            pollutants;

    (iv)    to promote the harmonization of toxicological and
            epidemiological methods in order to have internationally
            comparable results.

         The first Environmental Health Criteria (EHC) monograph, on
    mercury, was published in 1976 and since that time an ever-
    increasing number of assessments of chemicals and of physical effects
    have been produced.  In addition, many EHC monographs have been
    devoted to evaluating toxicological methodology, e.g., for genetic,
    neurotoxic, teratogenic and nephrotoxic effects.  Other publications
    have been concerned with epidemiological guidelines, evaluation of
    short-term tests for carcinogens, biomarkers, effects on the elderly
    and so forth.

         Since its inauguration the EHC Programme has widened its scope,
    and the importance of environmental effects, in addition to health
    effects, has been increasingly emphasized in the total evaluation of
    chemicals.

         The original impetus for the Programme came from World Health
    Assembly resolutions and the recommendations of the 1972 UN Conference
    on the Human Environment.  Subsequently the work became an integral
    part of the International Programme on Chemical Safety (IPCS), a
    cooperative programme of UNEP, ILO and WHO.  In this manner, with the
    strong support of the new 14  partners, the importance of occupational
    health and environmental effects was fully recognized. The EHC
    monographs have become widely established, used and recognized
    throughout the world.

         The recommendations of the 1992 UN Conference on Environment and
    Development and the subsequent establishment of the Intergovernmental
    Forum on Chemical Safety with the priorities for action in the six
    programme areas of Chapter 19, Agenda 21, all lend further weight to
    the need for EHC assessments of the risks of chemicals.

    Scope

         The criteria monographs are intended to provide critical reviews
    on the effect on human health and the environment of chemicals and of
    combinations of chemicals and physical and biological agents.  As
    such, they include and review studies that are of direct relevance for
    the evaluation.  However, they do not describe every study carried
    out.  Worldwide data are used and are quoted from original studies,
    not from abstracts or reviews.  Both published and unpublished reports
    are considered and it is incumbent on the authors to assess all the
    articles cited in the references.  Preference is always given to
    published data.  Unpublished data are only used when relevant
    published data are absent or when they are pivotal to the risk
    assessment.  A detailed policy statement is available that describes
    the procedures used for unpublished proprietary data so that this
    information can be used in the evaluation without compromising its
    confidential nature (WHO (1990) Revised Guidelines for the Preparation
    of Environmental Health Criteria Monographs. PCS/90.69, Geneva, World
    Health Organization).

         In the evaluation of human health risks, sound human data,
    whenever available, are preferred to animal data.  Animal and
     in vitro studies provide support and are used mainly to supply
    evidence missing from human studies.  It is mandatory that research on
    human subjects is conducted in full accord with ethical principles,
    including the provisions of the Helsinki Declaration.

         The EHC monographs are intended to assist national and
    international authorities in making risk assessments and subsequent
    risk management decisions.  They represent a thorough evaluation of
    risks and are not, in any sense, recommendations for regulation or
    standard setting.  These latter are the exclusive purview of national
    and regional governments.

    Content

         The layout of EHC monographs for chemicals is outlined below.

    *    Summary - a review of the salient facts and the risk evaluation
         of the chemical
    *    Identity - physical and chemical properties, analytical methods
    *    Sources of exposure
    *    Environmental transport, distribution and transformation
    *    Environmental levels and human exposure
    *    Kinetics and metabolism in laboratory animals and humans
    *    Effects on laboratory mammals and  in vitro test systems
    *    Effects on humans
    *    Effects on other organisms in the laboratory and field
    *    Evaluation of human health risks and effects on the environment
    *    Conclusions and recommendations for protection of human health
         and the environment

    *    Further research
    *    Previous evaluations by international bodies, e.g., IARC, JECFA,
         JMPR

    Selection of chemicals

         Since the inception of the EHC Programme, the IPCS has organized
    meetings of scientists to establish lists of priority chemicals for
    subsequent evaluation.  Such meetings have been held in: Ispra, Italy,
    1980; Oxford, United Kingdom, 1984; Berlin, Germany, 1987; and North
    Carolina, USA, 1995. The selection of chemicals has been based on the
    following criteria: the existence of scientific evidence that the
    substance presents a hazard to human health and/or the environment;
    the possible use, persistence, accumulation or degradation of the
    substance shows that there may be significant human or environmental
    exposure; the size and nature of populations at risk (both human and
    other species) and risks for environment; international concern, i.e.
    the substance is of major interest to several countries; adequate data
    on the hazards are available.

         If an EHC monograph is proposed for a chemical not on the
    priority list, the IPCS Secretariat consults with the Cooperating
    Organizations and all the Participating Institutions before embarking
    on the preparation of the monograph.

    Procedures

         The order of procedures that result in the publication of an EHC
    monograph is shown in the flow chart.  A designated staff member of
    IPCS, responsible for the scientific quality of the document, serves
    as Responsible Officer (RO).  The IPCS Editor is responsible for
    layout and language.  The first draft, prepared by consultants or,
    more usually, staff from an IPCS Participating Institution, is based
    initially on data provided from the International Register of
    Potentially Toxic Chemicals, and reference databases such as Medline
    and Toxline.

         The draft document, when received by the RO, may require an
    initial review by a small panel of experts to determine its scientific
    quality and objectivity.  Once the RO finds the document acceptable as
    a first draft, it is distributed, in its unedited form, to well over
    150 EHC contact points throughout the world who are asked to comment
    on its completeness and accuracy and, where necessary, provide
    additional material.  The contact points, usually designated by
    governments, may be Participating Institutions, IPCS Focal Points, or
    individual scientists known for their particular expertise.  Generally
    some four months are allowed before the comments are considered by the
    RO and author(s).  A second draft incorporating comments received and
    approved by the Director, IPCS, is then distributed to Task Group
    members, who carry out the peer review, at least six weeks before
    their meeting.

         The Task Group members serve as individual scientists, not as
    representatives of any organization, government or industry.  Their
    function is to evaluate the accuracy, significance and relevance of
    the information in the document and to assess the health and
    environmental risks from exposure to the chemical.  A summary and
    recommendations for further research and improved safety  aspects  are 
    also  required.  The composition of the Task Group is dictated by the
    range of expertise required for the subject of the meeting and by the
    need for a balanced geographical distribution.

         The three cooperating organizations of the IPCS recognize the
    important role played by nongovernmental organizations.
    Representatives from relevant national and international associations
    may be invited to join the Task Group as observers.  While observers
    may provide a valuable contribution to the process, they can only
    speak at the invitation of the Chairperson. Observers do not
    participate in the final evaluation of the chemical; this is the sole
    responsibility of the Task Group members.  When the Task Group
    considers it to be appropriate, it may meet  in camera.

         All individuals who as authors, consultants or advisers
    participate in the preparation of the EHC monograph must, in addition
    to serving in their personal capacity as scientists, inform the RO if
    at any time a conflict of interest, whether actual or potential, could
    be perceived in their work.  They are required to sign a conflict of
    interest statement. Such a procedure ensures the transparency and
    probity of the process.

         When the Task Group has completed its review and the RO is
    satisfied as to the scientific correctness and completeness of the
    document, it then goes for language editing, reference checking, and
    preparation of camera-ready copy.  After approval by the Director,
    IPCS, the monograph is submitted to the WHO Office of Publications for
    printing.  At this time a copy of the final draft is sent to the
    Chairperson and Rapporteur of the Task Group to check for any errors.

         It is accepted that the following criteria should initiate the
    updating of an EHC monograph: new data are available that would
    substantially change the evaluation; there is public concern for
    health or environmental effects of the agent because of greater
    exposure; an appreciable time period has elapsed since the last
    evaluation.

         All Participating Institutions are informed, through the EHC
    progress report, of the authors and institutions proposed for the
    drafting of the documents.  A comprehensive file of all comments
    received on drafts of each EHC monograph is maintained and is
    available on request.  The Chairpersons of Task Groups are briefed
    before each meeting on their role and responsibility in ensuring
    that these rules are followed.

    FIGURE 1

    IPCS TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR
    CHLORENDIC ACID AND ANHYDRIDE

     Members

    Dr L.A. Albert, Xalapa, Veracruz, Mexico  (Vice-Chairman)

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

    Mr H. Malcolm, Institute of Terrestrial Ecology, Monks Wood
       Experimental Station, Huntingdon, United Kingdom (part-time)

    Dr K. Peltonen, Institute of Occupational Health, Helsinki,
       Finland

    Professor Wai-On Phoon, Worksafe Australia and Department of
       Occupational Health, University of Sydney, Sydney, Australia
        (Chairman)

    Mr D.J. Reisman, US Environmental Protection Agency,
       Cincinnati, USA

    Dr E. Soderlund, National Institute of Public Health, Oslo,
       Norway

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

     Observers

    Mr P.C. Schreiber, Occidental Chemical, Genk, Belgium

     Secretariat

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

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

    ENVIRONMENTAL HEALTH CRITERIA FOR CHLORENDIC ACID AND ANHYDRIDE

         A WHO Task Group on Environmental Health Criteria for Chlorendic
    Acid and Anhydride met at the World Health Organization, Geneva, from
    12 to 16 December 1994.  Dr K.W. Jager, IPCS, welcomed the
    participants on behalf of Dr M. Mercier, Director of the IPCS, and the
    three IPCS cooperating organizations (UNEP/ILO/WHO).  The Group
    reviewed and revised the draft monograph and made an evaluation of the
    risks for human health and the environment from exposure to chlorendic
    acid and anhydride.

         The first draft of the monograph was prepared by Dr G.J. van
    Esch, Bilthoven, Netherlands.  The second draft, incorporating
    comments received following circulation of the first draft to the IPCS
    contact points for Environmental Health Criteria monographs, was
    prepared by the IPCS Secretariat.

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

         The fact that industry made available to the IPCS and the Task
    Group their proprietary toxicological information on the products
    under discussion is gratefully acknowledged.  This allowed the Task
    Group to make its evaluation on a more complete database.

         The effort of all who helped in the preparation and the
    finalization of the document is gratefully acknowledged.

    INTRODUCTION

         Chlorendic acid and anhydride are important flame retardants. 
    However, it should be noted that the IPCS is preparing several other
    EHC monographs on flame retardants, which will provide additional
    information relevant to chlorendic acid and anhydride.

         There will be one monograph,  Flame Retardants - A General
     Introduction (in preparation), giving a general introduction to the
    use, the mode of action, and the potential risks of flame retardants. 
    It will list the substances used as flame retardants and give a
    general indication of the data available on them.

         Some flame retardants in wide use have been discussed in separate
    monographs, e.g., EHC 162:  Brominated diphenyl ethers (IPCS, 1994a)
    and EHC 172:  Tetrabromobisphenol-A and derivatives (IPCS, 1995a).

         Certain flame retardants considered hazardous for humans and the
    environment have also been reviewed in separate monographs e.g., EHC
    152:  Polybrominated biphenyls (IPCS, 1994b), and EHC 173:  Tris-
     and bis(2,3-dibromopropyl) phosphate (IPCS, 1995b).

         Because of the possibility of the formation of halogenated
    dibenzodioxins and dibenzofurans under certain circumstances, such as
    pyrolysis, the following monographs have been developed:  EHC 88:
     Polychlorinated dibenzodioxins and dibenzofurans (IPCS, 1989) and
     Polybrominated dibenzodioxins and dibenzofurans (in preparation).

         The reader should consult these monographs for further
    information.

         Whatever their use, flame retardants will ultimately end up in
    the environment, either as such or as breakdown products.  The
    ultimate breakdown products and their levels will differ according to
    whether they have been used as reactives or as additive flame
    retardants.

         In order to make a proper hazard assessment for humans and the
    environment, it is essential that, apart from toxicity and ecotoxicity
    data, the following are available:

    -    data on the ultimate fate of the substance under various use and
         disposal conditions, including incineration, and on its breakdown
         products; and

    -    adequate data on the persistence and bioaccumulation/
         biomagnification of the substance and its breakdown products.

    1. SUMMARY AND EVALUATION; CONCLUSIONS AND RECOMMENDATIONS

    1.1  Summary and evaluation

    1.1.1  Physical and chemical properties

         Chlorendic acid (commercial grade 99.5%) and chlorendic anhydride
    (technical grade 97%) are closely related white crystalline materials. 
    Structurally they are closely related to the chlorinated cyclodiene
    insecticides.  When chlorendic acid is heated in an open system it
    loses water, forming chlorendic anhydride.  Chlorendic anhydride can
    be hydrolysed rapidly to chlorendic acid.  The melting points range
    from 208°C (acid) to 235°C (anhydride). 

    1.1.2  Production and use

         Chlorendic acid and chlorendic anhydride are mostly used as
    reactive flame retardants in polyester resins and plasticizers for
    electrical systems and paints, and in fibreglass-reinforced resins for
    chemical process equipment.  In the textile industry they have been
    used in the past as finishing treatment for wool fabrics and carpets.

         The combined worldwide production for chlorendic acid and
    anhydride is at present around 4000 tonnes per year.

    1.1.3  Environmental transport, distribution and transformation

         Chlorendic acid may be released via hydrolytic degradation of
    polyesters and as an oxidation product of chlorinated cyclodiene
    insecticides.

         Ultraviolet light degrades chlorendic acid with a half-life of 16
    days in a solid thin layer and 5 days in an aqueous solution.  In soil
    the half-life ranges from 140 to 280 days.  Chlorendic acid is fairly
    persistent in soil, although the data available on this subject are
    inadequate.

         No data are available on bioaccumulation and biomagnification
    potential or on ultimate fate following use.

         Exposure to chlorendic anhydride is likely to lead to exposure to
    chlorendic acid due to hydrolysis of the former.

    1.1.4  Environmental levels and human exposure

         Chlorendic acid has been found in landfill leachate at
    concentrations up to 455 mg/litre.

    1.1.5  Kinetics and metabolism in laboratory animals

         After oral and intravenous administration of radiolabelled
    chlorendic acid to rats, the substance was rapidly distributed

    throughout the body and rapidly metabolized.  More than 90% of the
    radiolabel was excreted within 24 h in the faeces, mainly in a
    conjugated form.  Only 3-6% was excreted in urine.  The highest
    concentrations of radiolabel were found in adipose tissue, liver,
    kidneys, whole blood and lung.

         A similar pattern was found in the rat in a gavage study with
    chlorendic anhydride.  The half-life of the radiolabel in this latter
    study was less than 2 days, except for fat, where it was 22.5 days.

         No data on kinetics following the dermal or inhalation routes are
    available.

    1.1.6  Effects on laboratory mammals and  in vitro test systems

         The acute oral toxicity of chlorendic acid is low; the LD50 for
    the rat is 1770 mg/kg body weight.  In the case of chlorendic
    anhydride, the oral LD50 for rats is 2480 mg/kg body weight.

         The acute dermal LD50 of crude chlorendic anhydride in rabbits
    is > 3000 mg/kg body weight.

         The 4-h dust inhalation LC50 of chlorendic acid in rats is >
    0.79 mg/litre.

         Chlorendic acid and anhydride are skin irritants and severe eye
    and respiratory tract irritants in the rabbit.  Chlorendic anhydride
    is a skin sensitizer in guinea-pigs, but one test with chlorendic acid
    gave a negative result.

         A no-observed-effect level (NOEL) of 2500 mg/kg diet (equivalent
    to 250 mg/kg body weight) was found in a 13-week feeding study using
    chlorendic acid in mice; in rats the NOEL in a similar feeding study
    was 1250 mg/kg diet (equivalent to 62.5 mg/kg body weight).  At higher
    doses growth depression was significant and microscopic changes were
    seen in the liver.

         In a 90-day feeding study on rats with chlorendic anhydride, the
    NOEL was 125 mg/kg body weight per day, and in a 3-week dermal study
    it was 100 mg/kg body weight/day (apart from skin irritation).  No
    NOEL could be established in a 28-day dust inhalation study on rats.

         A teratogenicity study on rats with chlorendic anhydride,
    administered orally by gavage at dose levels of up to 400 mg/kg body
    weight on gestational days 6-15, showed maternal toxicity but no
    teratogenic effects.

         Chlorendic acid was tested for mutagenic potential in five
    strains of  Salmonella typhimurium in the presence and absence of an
    exogenous metabolism system.  Negative results were obtained at dose
    levels up to 7690 µg/plate.  A mouse lymphoma mutation assay in the

    absence of an exogenous metabolism system was positive.  The dose
    levels tested were 1300 to 1700 µg/ml.  The highest dose level was
    cytotoxic.

         Chlorendic acid was positive in a transformation assay using
    BALB/c3T3 cells without metabolic activation, and was negative in a
    test for sex-linked recessive lethal mutations in male  Drosophila
     melanogaster.  Chlorendic acid did not give an increase of
    replicative DNA synthesis after oral or subcutaneous application of
    450 or 900 mg/kg body weight to F-344 rats.

         In tests of chlorendic anhydride with five strains of  Salmonella
     typhimurium and one strain of the yeast Saccharomyces cerevisiae, at
    dose levels of up to 7500 µg/plate, no mutagenic potential was found. 
    It did not induce forward mutation in a mouse lymphoma test and was
    negative in a transformation assay in BALB/c3T3 cells.  It produced
    significant unscheduled DNA synthesis in human WI-38 cells.  In a
    dominant lethal assay, mice were exposed to single doses of up to
    223 mg chlorendic anhydride/kg body weight, followed by a breeding
    period of 7 weeks.  Only a statistically significant decrease in the
    fertility index, relative to controls, for all females mated to
    treated males during week 5, and for females mated to mid-dose level
    males during week 4, was observed.  No effects were seen on the number
    of implantations, resorptions or  dead implants.  It was concluded
    that this test yielded negative results, although the study design was
    inadequate.

         Chlorendic acid was tested for carcinogenic potential in F- 344/N
    rats at dose levels of 620 and 1250 mg/kg diet (equivalent to 31 and
    62.5 mg/kg body weight).  In addition to significant non-neoplastic
    changes in a number of organs, such as cystic degeneration and focal
    cellular changes, and bile duct hyperplasia in the liver, increases in
    the incidence of hepatocellular adenomas in treated males and
    hepatocellular adenomas and carcinomas, significant at the highest
    dose level, in females were found.  Furthermore, slight increases in
    acinar cell adenomas of the pancreas and alveolar/bronchiolar adenomas
    in the lung were found in the males.

         Chlorendic acid tested in B6C3F1 mice fed diets containing 620
    and 1250 mg/kg diet (equivalent to 62 and 125 mg/kg body weight)
    showed an increased incidence of necrosis and mitotic alteration in
    the liver.  An increase in the incidence of hepatocellular adenomas
    and carcinomas was found in males at both dose levels.  An increased
    incidence of alveolar/bronchiolar adenomas or carcinomas was found in
    females.

         Studies were carried out to investigate the mechanisms of
    carcinogenesis using an initiation/promotion assay, the partial
    hepatectomy model and the neonatal model.  The tests showed that
    chlorendic acid has promoting activity.

    1.1.7  Effects on humans

         No data concerning effects on humans are available.

    1.1.8  Effects on other organisms in the laboratory and field

         Chlorendic acid has been reported to exert toxic effects on algae
    at 250 mg/litre.  Effects reported include inhibition of microfaunal
    activity, decreased production of oxygen and decreased respiration. 
    Toxic effects were not reported in algae exposed to 125 mg chlorendic
    acid/litre or in algae exposed to chlorendic anhydride.  The toxic
    effects reported in algae have been attributed to pH change rather
    than direct toxicity of chlorendic acid.  At low pH values, chlorendic
    acid exists in the non-ionized form, which may exert direct toxic
    effects.

         Effects of chlorendic acid have been reported for a single
    species of terrestrial plant.  Inhibition of both growth and seed
    germination was reported following exposure to 0.1 mg/litre or more,
    but no effects were reported following exposure to 0.01 mg/litre.

         The 48-h LC50 for  Daphnia magna was 110.7 mg chlorendic
    anhydride/litre, and the 96-h LC50 for both rainbow trout and
    bluegill sunfish was 422.7 mg/litre.

         The potential effects of chlorendic anhydride on organisms in the
    environment cannot be evaluated without data on the concentrations and
    fate processes of this compound in environmental compartments.

    1.2  Conclusions

         The database on chlorendic acid and chlorendic anhydride is far
    from being complete.  For several studies no full reports (only
    abstracts) were available to the Task Group.  In particular, no data
    are available on the ultimate fate of the substances as such or in
    their reacted form, nor are data available on the bioaccumulation and
    biomagnification potential.  Moreover, data on the exposure of humans
    and of organisms in the environment are lacking.

         Both substances seem to have low acute and subacute oral
    toxicity, but they are dermal, eye and respiratory irritants.  From
    the results of long-term toxicity/carcinogenicity studies with
    chlorendic acid on rats and mice, it is concluded that chlorendic acid
    induces tumours in rats and mice and is, therefore, considered to have
    a carcinogenic potential.  However, a full hazard assessment for
    humans and the environment cannot be made in view of the lack of data.

         The present database is inadequate to support the commercial use
    of chlorendic acid and anhydride.

    1.3  Recommendations

    1.3.1  Protection of human health and the environment

    a)   Exposure of the general population to chlorendic acid, chlorendic
         anhydride and products derived from them should be minimized.

    b)   Chlorendic acid and anhydride must be used only in closed systems
         to prevent exposure to the vapour and dust.  Workers producing
         and handling these substances should be properly trained in
         safety procedures.  They should be protected from exposure with
         adequate engineering controls and appropriate industrial hygiene
         measures.

    c)   Disposal of chlorendic acid and anhydride and their waste
         products must be by methods which ensure that the general
         population cannot be exposed and that exposure of the environment
         is minimized.

    1.3.2  Further research

    a)   The database should be completed with adequate data on:

         i)   the ultimate fate of these substances as such or in their
              reacted form;

         ii)  bioaccumulation and biomagnification potential;

         iii) human and environmental exposure data;

    b)   Studies should be carried out on the combustion products of
         materials prepared or treated with the acid or the anhydride, on
         their toxicity by inhalation, and on the potential of these
         combustion products for environmental contamination.

    c)   The concentrations of chlorendic acid and anhydride in
         environmental compartments should be measured, or at least
         predicted, using available models.

    d)   Data on the presence of chromosomal aberrations in a metaphase
         analysis study should be generated.  Some  in vivo mutagenicity
         data will be required before a full hazard assessment can be
         made.

    e)   A three-generation reproduction study should be conducted.

    f)   The carcinogenic mechanism for both substances should be
         clarified.

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

         Chlorendic acid and chlorendic anhydride are closely related
    compounds.  When chlorendic acid is heated in an open system it loses
    water and forms chlorendic anhydride.  Chlorendic anhydride can be
    hydrolysed to chlorendic acid (Yu & Atallah, 1977a; Antonov, 1980;
    Larsen, 1980).

         Exposure to chlorendic anhydride is likely to lead to exposure to
    chlorendic acid due to hydrolysis of the former (IARC, 1990).

    2.1  Chlorendic acid

    2.1.1  Identity

    2.1.1.1  Primary constituent

    Chemical formula:             C9 H4 Cl6 O4

    Chemical structure:           CHEMICAL STRUCTURE 1

    Chemical names:               -   1,4,5,6,7,7,-hexachloro-
                                      bicyclo[2,2,1]hept-5-ene- endo
                                       cis-2,3-dicarboxylic acid (CAS);

                                  -   1,4,5,6,7,7-hexachloro-5
                                      norbornene- endo-cis-2,3-
                                      dicarboxylic acid (IUPAC);

                                  -   1,4,5,6,7,7,-hexachloro-bicyclo
                                      [2,2,1]-5-heptene-2,3-dicarboxylic
                                      acid;

                                  -   hexachloro- endo-methylene-
                                      tetrahydrophthalic acid.

    Common name:                  chlorendic acid

    Trade name:                   HET acid

    Relative molecular mass:      388.87

    CAS number:                   115-28-6

    2.1.1.2  Technical product

         Both chlorendic acid and chlorendic anhydride have similar
    chemical structure, using the same building blocks (hexachloro-
    cyclopentadiene and maleic anhydride) in their production processes.
    Both products are manufactured in a closed system by a Diels-Alder
    reaction.  The solvent used in the two processes differs.  Chlorendic
    anhydride will form chlorendic acid in the presence of water (Yu &
    Atallah, 1977a; Occidental Chemical, 1988).

         Chlorendic acid has only one commercial grade of high purity
    (99.5%).  Common impurities are as follows:

         unreacted maleic anhydride         < 0.25%

         Fe                                 < 1 ppm

         hexachlorocyclopentadiene          < 50 ppm

         moisture                           < 1%

         other volatiles                    < 0.25%
         (Occidental Chemical, 1988).

    2.2  Chlorendic anhydride

    2.2.1  Identity

    2.2.1.1  Primary constituent

    Chemical formula:             C9H2Cl6O3

    Chemical structure:           CHEMICAL STRUCTURE 2

    Chemical names:               -   4,5,6,7,8,8-hexachloro-3a,4,7,7a-
                                      tetrahydro-4,7-methano
                                      isobenzofuran-1,3-dione (CAS);

                                  -   1,4,5,6,7,7-hexachloro- endo-5-
                                      norbornene-2,3-dicarboxylic
                                      anhydride;

                                  -   hexachloro- endo-methylene
                                      tetrahydrophthalic anhydride;

                                  -   1,4,5,6,7,7-hexachloro- endo-
                                      bicyclo[2,2,1]-hept-5-ene-2,3
                                      dicarboxylic anhydride.

    Common names:                 chlorendic anhydride

    Trade name:                   HET anhydride (this name is no longer
                                  used)

    Relative molecular mass:      370.86

    CAS number:                   115-27-5

    RTECS number:                 RB 9080000


    2.2.1.2  Technical product

         Chlorendic anhydride is available in two main grades "Refined"
    and "Technical", the latter being more commonly used.

         Depending on the grade, the purity varies from 95% to 97%. 
    Therefore, common impurities and volatile compounds are higher in
    chlorendic anhydride than in chlorendic acid (Velsicol Chemical Corp.,
    1982).

    2.3  Physical and chemical properties

    2.3.1  Chlorendic acid

         Chlorendic acid is a hexachloro-norbornene compound, structurally
    related to the chlorinated cyclodiene insecticides such as aldrin,
    dieldrin, endrin, isodrin, endosulfan, chlordane and heptachlor.  It
    is a fine white anhydrous non-dusting crystalline powder that is
    slightly soluble in water (0.35% by weight at 22.8°C) and non-polar
    organic solvents (benzene (0.81%), carbon tetrachloride (0.21%),
     n-hexane (0.2%) and linseed oil (9.65%)) and is readily soluble in
    more polar organic solvents (e.g., methanol, ethanol and acetone). 
    The chlorine content is 54.7% (US NTP, 1987; Occidental Chemical,
    1988).

    Melting point:         208-210°C (sealed tube); 230-235°C (open
                           tube); conversion to the anhydride occurs prior
                           to melting (Gupta et al., 1978; Occidental
                           Chemical, 1987).

    Stability:             The acid loses water in a heated open system,
                           tends to discolour and forms the anhydride,
                           which melts at 230-235°C (Gupta et al., 1978). 
                           It emits chlorine when heated to decomposition
                           at temperatures above 200°C (Occidental
                           Chemical, 1987). Chlorendic acid is very
                           resistant to hydrolytic dechlorination, readily
                           forms salts with a variety of metals, forms
                           esters by heating with or without azeotropic
                           solvent (e.g., chlorobenzene) and readily forms
                           alkyl-type polyester resins by reaction with
                           glycols and other polyols (Kirk-Othmer, 1981).

     n-Octanol/water        2.30 (Chemical Information Systems, 1988)
    partition co-          2.21 (Yu & Atallah, 1977b)
    efficient (log Poct/w):


    2.3.2  Chlorendic anhydride

         Chlorendic anhydride is a white crystalline substance with a
    melting point of 230-235°C (US NTP, 1987).  Commercial chlorendic
    anhydride contains 1-3% chlorendic acid (Velsicol Chemical Corp.,
    1982).

         In aqueous solution, chlorendic anhydride is rapidly hydrolysed
    to chlorendic acid, with a half-life of approximately one hour (Yu &
    Atallah, 1977a).

         Chlorendic anhydride will react almost quantitatively with excess
    methanol to form monomethyl chlorendate (Yu & Atallah, 1977a).

         The partition coefficient for 1,2-dichlorobenzenea/water is
    0.49  (Yu & Atallah, 1977b).

    2.4  Analytical methods

         Chlorendic acid may be determined by extraction with methanol and
    methylation with either 20% BF3/methanol (Occidental Chemical, 1986)
    or diazomethane (Pilenkova & Fatyanova, 1980).  The dimethyl ether is
    then determined by gas chromatography with electron capture detection
    after separation in packed columns (3% OV-1 on Chromosorb WHP, 80/100)
    or in capillary columns (Occidental Chemical, 1986).

         The acid may also be analysed directly by C18 reverse phase
    HPLC elution with water/acetonitrile/acetic acid and ultraviolet
    detection at 222 nm (Dietz et al., 1993).  The detection limit for
    this method is 200 µg/litre with an average recovery of over 95%.

         The earlier gas chromatography methods for direct analysis of the
    acid are not to be recommended.

         The anhydride may be analysed by extraction and hydrolysis to the
    acid (Pilenkova & Fatyanova, 1980).  The acid can then be analysed by
    any of the methods described above.

             

    a    1,2-dichlorobenzene and  n-octanol have similar dielectric
         constants; chlorendic anhydride would react with  n-octanol to
         form a chlorendate.

    2.4.1  Air sampling

         Air concentrations of chlorendic acid and chlorendic anhydride
    can be measured by trapping the compounds on a glass-fibre filter.  A
    portable pump is used to suck the air at a flow rate of 1 to 2
    litre/min for 8 h.  The samples are desorbed into methanol and can be
    analysed as described above (Occidental Chemical, 1986).


    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         Chlorendic acid and chlorendic anhydride are not known to occur
    as natural products.

    3.2  Anthropogenic sources

    3.2.1  Production levels and processes

         Chlorendic acid and chlorendic anhydride production levels peaked
    in 1984 at an estimated annual volume of 6000 tonnes (US ITC, 1988). 
    Since then, production levels have continuously declined, the 1993
    estimated worldwide volume being 4000 tonnes.

         Both products are prepared in a closed system, using the
    Diels-Alder reaction of hexachlorocyclopentadiene with maleic
    anhydride.  The solvent used in the production process of the two
    products differs.  The hydrolysis of the anhydride will lead to
    chlorendic acid having a higher purity than the anhydride form.

         Chlorendic acid is currently manufactured in Belgium, and this is
    the sole production source in the world.

         Chlorendic anhydride is produced only by one supplier located in
    the USA.

    3.2.2  Uses

         Chlorendic acid and chlorendic anhydride are reactive chemical
    intermediates used primarily in the preparation of flame-retardant
    polyester resins and plasticizers.  They are among the most reactive
    flame retardants in use.  Both are used as chemical intermediates in
    the manufacture of corrosion-resistant (unsaturated) polyester resins
    with special applications in electrical systems, panelling,
    engineering, plastics and paints (Makhoulf, 1982). A major market is
    in fibreglass-reinforced resins for process equipment in the chemical
    industry.  Chlorendic acid is also used to impart flame resistance to
    polyurethane foams when reacted with non-halogenated glycols to form
    halogenated polyols.  In addition, it can be used in the manufacture
    of alkyl resins for special paints and inks.  As an additive, it is
    used in acrylonitrile-butadiene-styrene copolymer (ABS) and
    polypropylene, but only in very limited amounts (Gupta et al., 1978;
    Larsen, 1980; Talbot, 1984; Occidental Chemical, 1988).

         The double bond in chlorendic acid is not reactive as a
    cross-linkage site.  Hence, reactive chemicals, such as maleic
    anhydride, glycols and styrene monomers, must be included in the
    polyester backbone to achieve cross-linkage (Gupta et al., 1978;
    Larsen, 1980; Talbot, 1984).

         In Europe, 80% of chlorendic acid is used in composites for the
    building or transportation market where flame retardancy is required.
    The remainder is used in composites for the manufacture of
    anti-corrosion equipment such as tanks, piping and scrubbers. In the
    USA, Latin America and S.E. Asia, the usage pattern is reversed:
    70-80% is for the anti-corrosion market and 20-30% is for flame
    retardant applications (Occidental Chemical, 1988).

    3.2.3  Contamination of the environment

         Chlorendic acid may be released, via hydrolytic degradation of
    polyesters, to the environment (soil and water) after their disposal
    (US NTP, 1987).

         Chlorendic acid is also an oxidation product of endosulfan,
    chlordane, heptachlor, aldrin, dieldrin, isodrin and endrin, and their
    metabolites (Martens, 1972; Cochrane & Forbes, 1974; Menzie, 1978); it
    could, therefore, appear in the environment from sources other than
    direct fugitive emissions.  It may also enter the environment after
    oxidation of other hexachlorocyclopentadiene-derived products.

         Chlorendic acid may also enter the aquatic environment in
    wastewater from flame-proofing processes in the textile industry
    (Friedman et al., 1973, 1974).

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    4.1  Transport and distribution between media

         No data on transport and distribution between media are
    available.

    4.2  Transformation

    4.2.1  Biodegradation

         Studies on  Clostridium butyricum indicate that chlorendic acid
    is resistant to hydrolytic dechlorination and that it is not easily
    degradable (Schuphan & Ballschmiter, 1972).

    4.2.2  Abiotic degradation

    4.2.2.1  Chlorendic acid

         From a comparison of the characteristics of the cyclodiene
    derivatives, chlorendic acid would be expected, on theoretical
    grounds, to degrade by direct photolysis or by reactions with hydroxyl
    radicals and ozone (Parlar & Korte, 1977).

         An experimental study was conducted to investigate the use of
    ozone to dechlorinate chlorendic acid.  The dechlorination and
    subsequent degradation of chlorendic acid by ozonation was influenced
    by the pH, applied ozone dose and bicarbonate concentration.  A change
    in the initial chlorendic acid concentration to 50, 100 and
    200 mg/litre did not influence the rate of degradation of chlorendic
    acid.  Ultraviolet (UV) radiation alone dechlorinates chlorendic acid. 
    UV radiation was also shown to greatly enhance the oxidation of
    chlorendic acid in the presence of ozone.  In a typical case, 80%
    dechlorination of chlorendic acid was obtained in 60 min when using an
    ozone dose of 125 mg/min ozone at pH 7.4. Conditions favouring
    radicals in solution, such as high pH and exposure to UV light,
    resulted in much faster dechlorination.  The conditions which did not
    favour radicals, such as low pH and the addition of bicarbonate,
    resulted in slower dechlorination (Stowell & Jensen, 1991).

         The photolysis of chlorendic acid by UV light and sunlight has
    been determined on solid surface and in aqueous solution.  On a solid
    surface, chlorendic acid was degraded by UV light (half-life = 16
    days) to a number of unknown products.  The irradiation of chlorendic
    acid in aqueous solution with UV light showed that the half-life in
    this system was 5 days (Yu & Atallah, 1978).

         In soil, the half-life of 14C-chlorendic acid was found to be
    140 ± 37 days at a soil concentration of 1 mg/kg and 280 ± 35 days at
    10 mg/kg.  However, it should be noted that the labelled carbon atoms
    were those in the chlorinated bicycloheptene ring and that these

    half-lives are more representative of that moiety than of chlorendic
    acid itself.  Chlorendic acid can thus be considered fairly persistent
    in soil (Butz & Atallah, 1979a).

    4.2.2.2  Chlorendic anhydride

         In aqueous solution, chlorendic anhydride is rapidly hydrolysed
    to chlorendic acid, with a half-life of approximately one hour (Yu &
    Atallah, 1977a).

         The photolysis of chlorendic anhydride by UV light and sunlight
    has been investigated.  On a solid surface, chlorendic anhydride
    rapidly absorbed water and was hydrolysed to chlorendic acid. 
    Irradiation of chlorendic anhydride with sunlight on a thin-layer
    plate resulted in the formation of chlorendic acid and an unknown
    compound (Yu & Atallah, 1978).

    4.2.3  Bioaccumulation and biomagnification

         The octanol/water partition coefficient of chlorendic acid was
    found to be 2.21, and the 1,2-dichlorobenzene/water partition
    coefficient for chlorendic anhydride was found to be 0.49.  Chlorendic
    anhydride rapidly converts to chlorendic acid and, as a result, will
    not bioconcentrate (Yu & Atallah, 1977a).  The results indicate that
    neither chemical is likely to bioconcentrate in the environment (Yu &
    Atallah, 1977a,b).

         No actual measured levels are available.

    4.3  Ultimate fate following use

         No data on ultimate fate following use are available.

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         Chlorendic acid has been found in landfill leachate in the USA 
    at concentrations up to 455 mg/litre.  After treatment by powdered
    activated charcoal in sequencing batch reactors, the concentration of
    chlorendic acid was reduced to 51 mg/litre in the effluent (Ying et
    al., 1987).

    6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS

    6.1  Chlorendic acid

    6.1.1  Absorption, distribution and elimination

    6.1.1.1  Oral administration

         After oral administration of 14C-chlorendic acid (99%), in a
    solution of "Emulphor", ethanol and water, at 3 mg/kg body weight to
    male F-344/N rats, the compound was rapidly distributed, metabolized
    and eliminated.  Approximately 78% of a single oral dose was excreted
    as conjugates in faeces within 24 h.  The conjugates were resistant to
    beta-glucuronidase or arylsulfatase.  Biliary excretion was the
    primary route of removal of the radioactivity from the liver.  Only
    3-6% was eliminated in the urine (Decad & Fields, 1982).

         14C-Chlorendic acid was administered orally (0.5-56 mg/kg body
    weight) to male rats to study the distribution and elimination.  A
    mean total of 90% of the dose was recovered in excreta over 48 h and
    no major changes in the routes of elimination were observed over the
    dose range investigated.  The major route of elimination was via
    faeces (87%), while 3% was excreted in urine.  Expired air accounted
    for less than 0.5% of the radioactivity.  After 48 h, the
    radioactivity in the liver increased in proportion to the dose, but
    there was no evidence of accumulation over the dose range studied.  In
    general the concentrations in the other organs and tissues showed the
    same tendency, but the concentrations of radioactivity were about 4 to
    5 times lower in the kidneys, whole blood and plasma, and lung than
    they were in the liver.  The other organs contained at least 10 times
    lower concentrations.

         Liver extracts of the animals exposed to 3 and 56 mg/kg showed
    unchanged chlorendic acid and at least one unidentified metabolite
    (Gurba et al., 1990).

    6.1.1.2  Intravenous administration

         After intravenous administration of 14C-chlorendic acid (99%)
    in a solution of "Emulphor", ethanol and water, at 3 mg/kg body weight
    to male F-344 rats, the compound was rapidly distributed, metabolized
    and eliminated.  The main route of elimination was via the faeces. 
    The liver, blood, muscle, skin and kidneys were the most important
    depots for chlorendic acid, especially during the first hours.  More
    than 50% of the total dose was found in the liver within 15 min. 
    Radioactivity was rapidly removed from this organ and, by 7 h after
    the administration, less than 4% was present.  Biliary excretion was
    the primary route of removal of the radioactivity from the liver. 
    This decrease followed a single-component exponential curve. The
    half-life of chlorendic-acid-derived radioactivity from liver into

    bile was 1.19 h. The half-life for blood was 0.84 h, for muscle tissue
    0.57 h and for skin 0.6 h. Other organs had only low levels of
    radioactivity, except for the adrenals. These organs had a greater
    specific activity than the liver for the first 3 h (Decad & Fields,
    1982).

    6.2  Chlorendic anhydride

    6.2.1  Absorption, distribution and elimination

         The pharmacokinetics of chlorendic anhydride was evaluated in
    four male and eight female Holzman's albino rats that ingested 
    14C-chlorendic anhydride via gavage in a single dose of 3.65 (Group
    1: 2 females), 4.00 (Group 2: 4 females), 5.55 (Group 3: 2 females) or
    3.62 mg/kg (Group 4: 4 males).  Blood was drawn from females treated
    with 4 mg/kg at 1, 4, 8, 17, 24, 48, 72 and 96 h after dosing.  Urine
    and faeces were collected daily in the Group 1, 3 and 4 rats.  Animals
    were sacrificed 17, 96, 192 and 192 h, respectively, after treatment,
    and selected tissues were excised.  Regardless of sex, the primary
    route of excretion was the faeces, 70% of the administered dose being
    eliminated within the first 72 h.  Only 10% of the administered dose
    was eliminated in the urine.  After 192 h, the maximum residues
    present in any tissue were less than 0.1 mg/kg, with the exception of
    the fat (0.121 mg/kg) and liver (0.296 mg/kg).  The blood
    concentration of chlorendic anhydride peaked one hour after dosing and
    was significantly decreased by 96 h.  The absorption of chlorendic
    anhydride followed the two-compartment open model.  The first
    compartment was suggested to consist of the blood and selected tissues
    which equilibrated rapidly, while the second compartment consisted of
    the fat which was slow in equilibrating and considered a deep
    reservoir.  The half-life of the radiocarbon was less than 2 days
    except in fat (22.5 days) (Diaz & Atallah, 1978).

    7.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

    7.1  Single exposure

    7.1.1  Oral exposure

    7.1.1.1  Chlorendic acid

         The acute oral LD50 of chlorendic acid in rats (strain
    unspecified) was found to be 1770 mg/kg body weight (US NTP, 1987). 
    The acute oral toxicity was evaluated in Charles River-CD male rats
    (number not reported) administered single doses of chlorendic acid, as
    a solution in acetone-peanut oil (1+9), by oral gavage at levels of
    1.5, 2, 12, 130, 670, 1000, 1500, 2250, 3400 and 5000 mg/kg body
    weight.  Mortality was observed at 2250 mg/kg or more.  Clinical
    observations included discomfort, inactivity, irregular respiration,
    and weight loss.  Gross necropsy was not reported (personal
    communication from E.I. du Pont de Nemours and Co. to the IPCS).

    7.1.1.2  Chlorendic anhydride

         The acute oral LD50 of crude chlorendic anhydride in albino
    rats was found to be 2480 mg/kg body weight (Trzyna & Paa, 1975).

    7.1.2  Dermal exposure

    7.1.2.1  Chlorendic anhydride

         The acute dermal LD50 of crude chlorendic anhydride in albino
    rabbits was found to be > 3000 mg/kg body weight (Trzyna & Paa,
    1975).

    7.1.3  Inhalation exposure

    7.1.3.1  Chlorendic acid

         The acute inhalation toxicity of chlorendic acid was evaluated in
    groups of six male Charles River-CD rats exposed to chlorendic acid at
    chloride concentrations of 0.064, 0.066 or 0.102 mg/litre under
    nitrogen, and at chloride concentrations of 0.065 or 0.095 mg/litre
    under air for 4 h.  The test atmosphere was generated by passing
    metered houseline air or nitrogen through a three-neck flask
    containing the test material heated to 100°C.  Mortality was observed
    in one animal in the 0.066-mg/litre group, all six in the
    0.102-mg/litre group, three in the 0.065-mg/litre group, and all six
    in the 0.095-mg/litre group.  The approximate lethal concentration was
    reported to be 0.066 mg/litre under nitrogen and 0.095 mg/litre under
    air.  Clinical observations included lacrimation, irregular breathing,
    paleness, gasping, congestion, bloody nose, hyperaemia and weight
    loss.  Histopathological examination revealed severe pulmonary

    irritation (personal communication from E.I. du Pont de Nemours and
    Co. to the IPCS).

         An acute inhalation toxicity study was conducted with five female
    and five male Charles River-CD rats administered chlorendic acid dust
    at a maximum attainable concentration of 0.79 mg/litre of air in a
    80-litre dynamic air flow chamber for 4 h.  No deaths or toxic signs
    were observed during the exposure or during the 14-day observation
    period.  The average 2-week body weight gains were within normal
    limits.  Necropsy of animals did not reveal any gross pathological
    alterations (Kinert & Goode, 1975).

    7.1.3.2  Chlorendic anhydride

         In a 4-h vapour inhalation study with crude chlorendic anhydride
    in albino rats, the acute LC50 was found to be > 5.27 mg/litre. 
    The observation period was 14 days (Myers & Goode, 1975).

         An acute inhalation toxicity study was conducted with five male
    and five female Charles River CD rats given whole body exposure to the
    dust of chlorendic anhydride in a dynamic air flow chamber for 1 h. 
    The chamber dust concentration was calculated to be 203 mg/litre.  All
    animals survived the exposure and subsequent 14-day observation
    period.  After 30 min of exposure, six rats exhibited salivation, and
    by the end of the exposure all animals exhibited salivation and one
    animal exhibited nasal discharge.  After exposure, all animals
    appeared normal (Leong et al., 1978).

    7.2  Short-term exposures

    7.2.1  Oral

    7.2.1.1  Mice

         Four or five male and five female B6C3F1 mice (6-7 weeks old)
    were fed diets containing 0, 3100, 6200, 12 500, 25 000 or 50 000
    mg/kg diet (equivalent to 0, 310, 620, 1250, 2500 or 5000 mg/kg body
    weight) chlorendic acid for 14 days.  With the highest dose, the mice
    lost weight and four out of five males died.  Mice receiving diets
    with 6200 mg/kg diet or more gained less weight than the controls.  No
    treatment-related gross lesions were observed at necropsy (US NTP,
    1987).

         Four-week-old male and female B6C3F1 mice were administered a
    diet containing 0, 1250, 2500, 5000, 10 000 or 20 000 mg/kg diet
    (equivalent to 0, 125, 250, 500, 1000 or 2000 mg/kg body weight)
    chlorendic acid for 13 weeks. Groups of 10 mice of each sex were used. 
    Growth depression was seen in all groups, but with 5000 mg/kg diet or
    more this effect was significant.  Feed consumption was not notably
    affected.  No evidence of other compound-related effects was seen,
    except centrilobular hyperplasia, mitotic alterations and coagulative

    necrosis in the liver, especially in the animals given the two highest
    dose levels.  The NOEL level was established at 250 mg/kg body weight
    (US NTP, 1987).

    7.2.1.2  Rats

     a)  Chlorendic acid

         Five male and five female F-344/N rats (6-7 weeks old) were fed
    diets containing 0, 3100, 6200, 12 500, 25 000 or 50 000 mg/kg diet
    (equivalent to 0, 155, 310, 625, 1250 or 2500 mg/kg body weight)
    chlorendic acid for 14 days.  With the highest dose, three out of five
    males and two out of five females died, and with 6200 mg/kg or more
    decreased growth was observed.  No treatment-related gross
    observations were reported (US NTP, 1987).

         Four-week-old male and female F-344/N rats (groups of 10 animals
    of each sex) were administered diets containing 0, 620, 1250, 2500,
    5000 or 10 000 mg/kg diet (equivalent to 0, 31, 62.5, 125, 250 or
    500 mg/kg body weight) chlorendic acid for 13 weeks. Growth depression
    was seen in both sexes with dose levels of 1250 mg/kg diet or more. 
    In addition, the food intake was lower, especially in the groups fed
    with 2500 mg/kg or more.  No abnormalities were seen except changes in
    the liver. The changes were hepatocytomegaly, mitosis alteration
    (increase in mitotic figures/field and abnormal mitotic figures) and
    bile duct hyperplasia in rats with 5000 and 10 000 mg/kg diet
    (equivalent to 250 and 500 mg/kg body weight, respectively) (US NTP,
    1987).

     b)  Chlorendic anhydride

         Four groups of Charles River CD rats, 15 rats of each sex per
    group, were fed diets containing 0, 100, 500 or 2500 mg/kg (equivalent
    to 0, 5, 25 or 125 mg/kg body weight per day) chlorendic anhydride for
    90 days.  They were observed twice daily.  Haematological and
    biochemical tests and urinalyses were performed at 1, 2 and 3 months
    of the study for five rats of each sex per group.  Three high-dosed
    females died between the fifth and thirteenth week of the study.  Mid-
    and high-dose males and high-dose females had a decreased food
    consumption, and the mean body weight of mid- and high-dose males and
    all three treated female groups was decreased, compared to controls. 
    Treated males and females had elevated serum alkaline phosphatase
    activities at 1, 2 and 3 months of the study.  The mean absolute heart
    weight of male rats and the mean absolute and relative liver weight of
    male and female rats were statistically significantly decreased at all
    treatment levels.  No compound-related gross lesions were seen in any
    of the treated rats, and no compound-related microscopic lesions were
    seen in 10 males and 10 females from the 2500-mg/kg group (Jefferson &
    Goldenthal, 1980).

    7.2.2  Dermal

    7.2.2.1  Chlorendic anhydride

         Four groups of New Zealand White rabbits (4 of each sex per
    group) were administered chlorendic anhydride at 0, 100, 500 or
    2500 mg/kg body weight per day onto their clipped and/or abraded
    backs, 5 days/week for 3 weeks.  The compound was wetted with
    physiological saline prior to dosing.  All rabbits survived the
    treatment period.  No compound-related changes were seen in urinalysis
    and haematological and biochemical investigations.  All rabbits in the
    high-dose group had decreased body weight.  Incidental findings,
    mainly in the high-dose group, were diarrhoea, nasal or ocular
    discharge, hypoactivity, anorexia and dehydration.  One or more signs
    of dermal irritation, such as erythema, oedema, atonia, desquamation,
    coriaceousness and fissuring, were seen in all groups in a
    dose-related matter.  Stomach mucosal erosions and ulcerations were
    found at necropsy in the two highest exposure groups.  Apart from the
    skin irritation found at all dosages, the NOEL in this study was
    100 mg/kg body weight per day (Goldenthal et al., 1979).

    7.2.3  Inhalation

    7.2.3.1  Chlorendic anhydride

         Four groups of Charles River CD rats (10 of each sex per group)
    were exposed to chlorendic anhydride dust for 6 h per day, 5 days/week
    during a 28-day experimental period.  The average nominal exposure
    concentrations were 0, 0.11, 0.99 or 9.97 mg/litre.  The median dust
    diameter was 6.0 (± 3.16) µm.  All animals survived.  All animals
    exhibited dose-related ocular and nasal irritation as well as
    salivation, following the daily exposures. They also exhibited a
    dose-related alopecia.  Male rats at the highest dose level had
    decreased weight gains. Statistical differences were seen in
    haematocrit and erythrocyte values (males and females), haemoglobin
    (males), leukocytes (females), alkaline phosphatase levels (males and
    females) and glucose and serum glutamic pyruvic transaminase levels
    (males).  Dark red foci and dark red discolouration in the lungs and
    dark red or brown foci in the glandular part of the stomach were seen
    at necropsy in the treated groups.  Relative liver weights of males
    were decreased in all treated groups.  The absolute and relative
    weight of the thyroid glands were decreased in females of the two
    highest dose groups.  Compound-related microscopic changes of a
    haemorrhagic inflammatory nature in the lungs and of an inflammatory
    nature in the trachea, nasal turbinates and stomach mucosa occurred in
    rats from all treated groups.  A NOEL was not established in this
    study (Ulrich, 1980).

    7.3  Long-term exposure

         Data from long-term exposure studies are given in section 7.7.

    7.4  Skin and eye irritation; sensitization

    7.4.1  Chlorendic acid

         Repeated application of chlorendic acid (as a powder or as a
    solution in dimethyl phthalate) to the skin of New Zealand rabbits
    caused local skin irritation (Witherup et al., 1965).

         Repeated application of chlorendic acid (as a powder or as a 5,
    10 or 20% solution in dimethyl phthalate) beneath the eyelids of New
    Zealand rabbits caused severe eye irritation (Witherup et al., 1965).

         In a skin sensitization test in albino guinea-pigs, chlorendic
    acid gave a negative response (Brett, 1975).

    7.4.2  Chlorendic anhydride

         In a 3-week dermal toxicity study with chlorendic anhydride in
    New Zealand White rabbits, it was considered to be a mild skin
    irritant (see section 7.2.2) (Goldenthal et al., 1979).

         Chlorendic anhydride was severely irritating to the eyes of
    albino rabbits (Trzyna & Paa, 1975).

         In a dermal sensitization study in albino guinea-pigs, chlorendic
    anhydride produced a positive response, and it has to be considered as
    a possible dermal sensitizing agent in humans (Dean & Jessup, 1978).

    7.5  Reproductive toxicity, embryotoxicity and teratogenicity

    7.5.1  Chlorendic anhydride

         The teratogenicity of chlorendic anhydride was evaluated in
    pregnant Charles River CD rats (25 per group) exposed orally by gavage
    at dose levels of 0, 25, 100 or 400 mg/kg chlorendic anhydride per day
    on gestational days 6-15.  Cesarean sections were performed on day 20. 
    Significant differences were observed between treated and control
    animals in the following: decreased maternal body weight and weight
    gain (high-dose group), fetal sex ratio (low-dose level), and
    increased mean number of post-implantation losses (mid- and high-dose
    groups).  No significant differences were observed between treated and
    control animals in the following: mean number of  corpora lutea,
    viable or non-viable fetuses, mean fetal body weights and fetal
    malformations (Goldenthal et al., 1978).

    7.6  Mutagenicity and related end-points

    7.6.1  Chlorendic acid

         Chlorendic acid was not mutagenic in  Salmonella typhimurium
    strains TA100, TA98, TA1535 and TA1537, in the presence or absence of
    an exogenous metabolism system (liver S9 mix induced by Aroclor 1254
    in male Sprague-Dawley rats or male Syrian hamsters). Dose levels
    tested were 100 to 7690 µg/plate (Haworth et al., 1983; Zeiger, 1990).

         The mutagenicity of chlorendic acid was evaluated in  S.
     typhimurium strains TA1537, TA1538, TA98, TA1535 and TA100, both in
    the presence and absence of metabolic activation by rat liver S9
    fraction (inducer not reported).  Following preliminary toxicity
    tests, assays using activation were performed at concentrations of
    500, 1000, 1500, 2500, 5000 and 7500 µg/plate and with no activation
    at 50, 100, 250, 500 and 750 µg/plate.  The test material did not
    produce a positive mutagenic response in any bacterial strain, either
    with or without activation (Dupont-deNemours, proprietary information
    (US EPA, 1982).

         Chlorendic acid was tested in the Microscreen prophage-induction
    assay in  Escherichia coli at seven dose levels ranging from 0.4 to
    25.7 mM, with and without metabolic activation.  In the repeat study
    only, a dubious positive reaction was found at the highest dose level
    with activation.  In the first test this dose level was toxic
    (DeMarini & Brooks, 1992).

         Chlorendic acid was mutagenic in the L5178Y/TK+/- mouse lymphoma
    assay in the absence of S9 activation.  The assay was performed twice
    with the same results.  Dose levels were 1300 to 1700 µg/ml. The
    highest (cytotoxic) dose showed a positive effect; an increase of
    total mutant clones, relative total growth depression and increase in
    mutation frequency (US NTP, 1987).  Similar finding were reported by
    McGregor et al., (1988).

         Chlorendic acid was positive in a standard transformation assay
    using BALB/c-3T3 cells without exogenous activation at concentrations
    of 2-4 mM (Matthews et al., 1993).

         Chlorendic acid was tested for its ability to induce sex-linked
    recessive lethal mutations in post-meiotic and meiotic germ cells of
    male  Drosophila melanogaster.  Chlorendic acid was negative at 2000
    and 15 000 mg/kg administered by injection (Foureman et al., 1994).

    7.6.2  Chlorendic anhydride

         The mutagenicity of chlorendic anhydride was evaluated in
     Salmonella tester strains TA98, TA100, TA1535, TA1537 and TA1538,
    and the yeast  Saccharomyces cerevisiae tester strain D4, both in the
    presence and absence of metabolic activation by Aroclor-induced rat

    liver S9 fraction.  Chlorendic anhydride dimethylsulfoxide (DMSO), at
    doses up to 500 µg/plate, did not cause a positive response in any of
    the bacterial strains or the yeast strain, either with or without
    metabolic activation (Jagannath & Brusick, 1977).

         Chlorendic anhydride did not induce forward mutations at the TK
    locus in L5178Y mouse lymphoma cells at concentrations up to
    0.24 mg/ml without, and up to 0.32 mg/ml with, an S9 activation
    system.  Toxicity was observed with higher concentrations (Matheson &
    Brusick, 1978a).

         Chlorendic anhydride was negative in an  in vitro malignant
    transformation assay in BALB/3T3 cells without exogenous activation at
    concentrations of 0.005-0.078 mg/ml.  Only at 0.010 mg/ml was a
    significant, but non-dose-related, increase in transformation
    frequency found (Matheson & Brusick, 1978b).

         Chlorendic anhydride produced significant increases in
    unscheduled DNA synthesis assay in human WI-38 cells at dose levels up
    to 0.5 mg/ml (Matheson & Brusick, 1978c).

         The mutagenicity of chlorendic anhydride was evaluated in a
    dominant lethal assay using four groups of 20 male CD-1 mice exposed
    orally by gavage at dose levels of 0, 22, 74 or 223 mg/kg in a single
    exposure (in DMSO vehicle).  Following exposure, each male was rested
    for 2 days and then mated for 5 days/week with two untreated females
    each week for 7 consecutive weeks.  Mated females were sacrificed 14
    days after the  midweek of the mating period. Pregnant females were
    scored for dominant lethal indices at mid-pregnancy.  A statistically
    significant decrease was observed in the fertility index, relative to
    controls, for all females mated to treated males during week 5 and
    females mated to mid-dose level males during week 4.  There were no
    differences between females mated to treated and control males with
    respect to average number of implantations per pregnant female,
    average resorptions per pregnant female, proportions of dead
    implants/implants, proportions of females with one or more
    resorptions, or proportions of females with two or more resorptions
    (Matheson & Brusick, 1978d).  Although the study was reported as
    giving negative results, there were some statistically non-significant
    increases in dead implants per pregnant mouse in females mated at
    weeks 2 and 8 at the high dose and at week 5 in the low- and mid-dose
    treated mice.  However, the study was found to be inadequately
    designed.

    7.7  Carcinogenicity

    7.7.1  Chlorendic acid

    7.7.1.1  Mice

         Diets containing 0, 620 or 1250 mg chlorendic acid (> 98%)/kg
    diet (equivalent to 0, 62 and 125 mg/kg body weight per day) were fed
    to groups of 50 male and 50 female B6C3F1 mice for 103 weeks.  The
    estimated daily intake of chlorendic acid was 89 and 185 mg/kg body
    weight for low- and high-dose males and 100 and 207 mg/kg body weight
    for low- and high-dose female mice.  All survivors were killed at week
    112.  The mice were 8 weeks old when placed on the diets.  Survival
    and feed consumption of treated mice of both sexes were similar to
    those of controls, although mean body weights of high-dose males and
    females were lower than those of the controls. In the liver an
    increased incidence of necrosis was observed in dosed male mice
    (coagulative necrosis), and mitotic alterations were found in
    high-dose female mice.  The incidence of hepatocellular adenomas was
    increased in males (see Table 1; controls 5/50 (10%), low-dose 9/49
    (18%) and high-dose 10/50 (20%) (statistically significant)) and so
    was the incidence of hepatocellular carcinomas (male controls 9/50
    (18%), low-dose 17/49 (35%) and high-dose 20/50 (40%) (statistically
    significant)). Hepatocellular carcinomas metastasized to the lung in
    males (controls 2/50 (4%), low-dose 4/49 (8%) and high-dose 7/50
    (14%)). The incidence of alveolar/bronchiolar adenomas and carcinomas
    (combined) in females was controls 1/50 (2%), low-dose 5/50 (10%) and
    high-dose 6/50 (12%).  However, the incidence in the concurrent
    controls compared with the historical control average was low and the
    biological significance of these results is unclear.  On the basis of
    the results from this study, it was concluded that there was clear
    evidence of carcinogenic potential of chlorendic acid in male B6C3F1
    mice, as demonstrated by an increase in hepatocellular carcinomas (US
    NTP, 1987; Huff et al., 1989; IARC, 1990).

    
    Table 1.  Incidence of tumours in B6C3F1 mice (from: US NTP, 1987)

                                                                                                                     
                                                 Males                                     Females
    Type of tumour                                                                                                   
                              Control          620 mg/kg       1250 mg/kg     Control     620 mg/kg      1250 mg/kg
                                                 diet             diet                      diet            diet
                                                                                                                     

    Liver

    Hepatocellular adenoma      5/50 (10%)     9/49 (18%)     10/50 (20%)

    Hepatocellular carcinoma    9/50 (18%)     17/49 (35%)    20/50 (40%)

    Hepatocellular adenoma      13/50 (26%)    23/49 (47%)    27/50 (54%)    3/50 (6%)    7/49 (14%)    7/50 (14%)
    or carcinoma

    Lung

    Alveolar/bronchiolar                                                     1/50 (2%)    5/50 (10%)    6/50 (12%)
    adenoma or carcinoma

    Thyroid

    Follicular cell adenoma     0/50 (0%)      0/47 (0%)      3/50 (6%)
                                                                                                                     
    

    7.7.1.2  Rats

         Diets containing 0, 620 or 1250 mg chlorendic acid (> 98%)/kg
    diet (equivalent to 0, 31 and 62.5 mg/kg body weight per day) were fed
    to groups of 50 male and 50 female F-344/N rats for 103 weeks.  The
    estimated daily intake of chlorendic acid was 27 and 56 mg/kg body
    weight for low- and high-dose males, and 39 and 66 mg/kg body weight
    for low- and high-dose female rats.  All survivors were killed in week
    112.  The rats were 8 weeks old when placed on the diets. Survival and
    feed consumption of treated rats were similar to those of the
    controls, although mean body weight of high-dose males and females
    were lower.  Significant changes were observed in the incidence of
    rats with neoplastic or non-neoplastic lesions of the liver, pancreas,
    lung, preputial gland, uterus, salivary gland, urinary system, mammary
    gland, adrenals, testes and pituitary gland.  In the liver of male
    rats, increases in the incidence of cystic degeneration and focal
    cellular changes were found.  An increase in the incidence of
    granulomatous inflammation was observed in females.  Bile duct
    hyperplasia incidence was increased in both sexes.

         From Table 2, it is clear that an increase in tumour incidence
    was found in the liver, pancreas, preputial gland and lung. The
    incidence of neoplastic nodules of the liver (adenomas) was
    significantly increased in treated males (controls 2/50 (4%), low-dose
    21/50 (42%) and high-dose 23/50 (46%) (statistically significant)) and
    in females (controls 1/50 (2%), low-dose 3/49 (6%) and high-dose 11/50
    (22%) (statistically significant)).  The values for hepatocellular
    carcinomas in females were controls 0/50 (0%), low-dose 3/49 (6%) and
    high-dose 5/50 (10%) (statistically significant).  Those for the
    acinar cell adenomas of the pancreas in males were controls 0/49 (0%),
    low-dose 4/50 (8%) and high-dose 6/50 (12%).  The incidence of
    alveolar/bronchiolar adenomas was significantly increased in high-dose
    males (controls 0/50 (0%), low-dose 3/50 (6%) and high-dose 5/50
    (10%)) and that of carcinomas of the preputial gland in males
    (controls 1/50 (2%), low-dose 8/50 (16%) and high-dose 4/50 (8%)). 
    Slight increases in the incidences of salivary gland tumours in males
    and endometrial stromal polyps in females were noted.  Under the
    conditions of the experiment, it was concluded that chlorendic acid
    showed carcinogenic properties in F-344/N rats, demonstrated by
    increased incidence of adenomas of the liver in both sexes and of 
    hepatocellular carcinomas in females.  An increase in the incidence of
    acinar cell adenomas of the pancreas was found in males (US NTP, 1987;
    Huff et al., 1989; IARC, 1990).

    
    Table 2.  Incidence of tumours in F-344/N rats (from: US NTP, 1987)

                                                                                                                     
                                                 Males                                     Females
    Type of tumour                                                                                                   
                              Control          620 mg/kg       1250 mg/kg     Control     620 mg/kg      1250 mg/kg
                                                 diet             diet                      diet            diet
                                                                                                                     

    Liver

    Hepatocellular adenoma      2/50 (4%)       21/50 (42%)   23/50 (46%)    1/50 (2%)    3/49 (6%)     11/50 (22%)

    Hepatocellular carcinoma                                                 0/50 (0%)    3/49 (6%)     5/50 (10%)

    Pancreas

    Acinar cell adenoma         0/49 (0%)      4/50 (8%)      6/50 (12%)

    Lungs

    Alveolar/bronchiolar        0/50 (0%)      3/50 (6%)      5/50 (10%)
    adenoma

    Preputial gland

    Squamous cell papilloma,    1/50 (2%)      8/50 (16%)     4/50 (8%)
    adenoma or carcinoma

    Uterus/endometrium

    Endometrial stromal polyp                                                5/50 (10%)   15/49 (31%)   10/50 (20%)

    Salivery gland

    Fibrosarcoma/               1/50 (2%)      2/49 (4%)      4/50 (8%)
    neurofibrosarcoma
                                                                                                                     
    
         In an initiation-promotion assay in rat liver designed as a
    complement to the 2-year bioassay, groups of male and female
    Fischer-344 rats were given a single oral dose of 10 mg/kg body weight
    diethylnitrosamine followed 24 h later by 70% partial hepatectomy. 
    After a 2-week recovery period, animals were fed a basal diet
    containing 0, 620 or 1250 mg/kg diet (equivalent to 0, 31 and
    62.5 mg/kg body weight per day) chlorendic acid for 6 months, at which
    time all surviving animals were killed.  Altered hepatic foci (AHF)
    were measured using four markers: placental glutathione- S-
    transferase (PGST), gamma-glutamyl transpeptidase, adenosine
    triphosphate and glucose-6-phosphatase.  The number of AHF/liver and
    the volume percentage of liver as AHF were significantly increased by
    chlorendic acid at both dose levels.  Placental GST was the best
    single marker for hepatic promoting activity in both sexes (Dragan et
    al., 1991).

         Partial hepatectomy and neonatal rat short-term liver focus
    models were used to examine the potential of chlorendic acid for
    initiating and promoting activity.  Chlorendic acid showed clear
    evidence of hepatocarcinogenicity.  While it showed no initiating
    activity, promoting activity, as indicated by increased number, size
    or volume fraction of histochemically detected hepatic foci of
    cellular alteration, was evident (Maronpot et al., 1989).

    7.7.1.3  Special studies

         Chlorendic acid was administered in single doses of 0, 450 or
    900 mg/kg body weight to 9-week-old male F-344 rats by oral
    application or subcutaneous injection.  Replicative DNA synthesis was
    measured in primary hepatocyte  in vitro cultures prepared from the
    livers of the treated animals at 24, 39 or 48 h after treatment. 
    Chlorendic acid did not increase replicative DNA synthesis in this
    test (Uno et al., 1994).

         Nine female Sprague-Dawley (CD) rats (90-days old; 200-230 g)
    were administered two doses of chlorendic acid (159 mg/kg body weight)
    in corn oil by gavage, 21 and 4 h before sacrifice, and compared with
    corn oil controls.  Hepatic DNA damage was indicated as an increased
    hepatic ornithine decarboxylase activity.  However, there was no DNA
    damage (Kitchin et al., 1993).

    7.7.2  Chlorendic anhydride

         Chlorendic anhydride rapidly converts to chlorendic acid on
    contact with water.

         A separate carcinogenicity study with chlorendic anhydride has
    not been conducted and seems not to be necessary, since chlorendic
    anhydride is metabolically transformed into chlorendic acid.

    8.  EFFECTS ON HUMANS

         No data concerning the effects of chlorendic acid or anhydride on
    humans are available.

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    9.1  Chlorendic acid

         Studies were conducted to estimate the effects of 125, 250 and
    500 mg/litre chlorendic acid (99.5%) on an aquatic microcosm.  To
    account for the pH effect of the acid, two additional flask
    experiments were conducted in which the solutions of chlorendic acid
    were titrated with 50% (w/w) NaOH to pH 7.4 or with HCl to create a
    working solution of pH 6.2, 4.6 and 3.5 (equivalent to the initial pH
    of the 125, 250 and 500 mg/litre chlorendic acid treatments,
    respectively).  The experiments were carried out with naturally
    derived laboratory microcosms containing bacteria, fungi, unicellular
    and colonial green algae, filamentous blue-green algae, diatoms,
    protozoans, rotifers, copepods and ostracods.  In 6- day flask
    studies, chlorendic acid concentrations of 500 mg/litre (pH 3.5)
    completely inhibited algal growth and microfaunal activity,
    250 mg/litre (pH 4.1) inhibited microfaunal activity and reduced the
    abundance of all but one algal species, and 125 mg/litre (pH 6.2) had
    no observable effects.  Similar results occurred in longer term
    microcosm studies where, in addition, 500 and 250 mg/litre chlorendic
    acid (no pH specified) resulted in decreased oxygen production and
    respiration, altered chlorophyll  a concentrations and bacterial
    populations, and increased concentrations of dissolved NO3-N,
    NH3-N and PO4-P.  In contrast, few distinct effects were observed
    in flasks or microcosms treated with the non-ionized form of
    chlorendic acid.  Results indicate that the observed effects at lower
    pH values were due primarily to increases in hydrogen ion
    concentration; direct toxicity also may have occurred at low pH, where
    chlorendic acid existed as the non-ionized species (Hendrix et al.,
    1983).

         Chlorendic acid caused a dose-related inhibition of seed
    germination and early growth of garden cress ( Lepidium sativum L).
    It inhibited growth by 0, 20, 60 and approximately 90% during exposure
    for 7 days to 0, 0.1, 1.0 and 10.0 mg/litre (concentrations of
    chlorendic acid in aquatic test solutions), respectively.  At 0.001
    and 0.01 mg/litre, no influence was found (Koch, 1970).

         Butz & Atallah (1979b) studied the effect of chlorendic acid on
    soil microorganisms.  A silty clay soil was treated with 0, 1 or
    10 mg/kg chlorendic acid in Erlenmeyer flasks and incubated at 30°C
    for 28 days.  A significant increase in the number of soil fungi was
    reported for the 10-mg/kg group, but no effects on soil fungi were
    reported at 1 mg/kg.  A non-significant increase in the number of
    bacteria was reported for both treated soils.

    9.2  Chlorendic anhydride

         The 48-h LC50 of chlorendic anhydride for  Daphnia magna is
    110.7 mg/litre; the 48-h NOEL is 56 mg/litre (Vilkas & Hutchinson,
    1977).

         The 96-h LC50 of chlorendic anhydride for rainbow trout  (Salmo
     gairdneri) is 422.7 mg/litre nominal concentration in a static
    system.  Above 100 mg/litre the trout become excitable (Calmbacher et
    al., 1977a).

         The 96-h LC50 of chlorendic acid for bluegill sunfish  (Lepomis
     macrochirus) is 422.7 mg/litre (nominal concentration) in a static
    system.  Below 320 mg/litre no abnormal behaviour is observed
    (Calmbacher et al., 1977b).

    10.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         Chlorendic acid has been evaluated by the International Agency
    for Research on Cancer in its series of IARC Monographs on the
    Evaluation of Carcinogenic Risks to Humans.  The evaluation was that
    there is sufficient evidence for the carcinogenicity of chlorendic
    acid in experimental animals.  No data were available from human
    studies on the carcinogenicity of chlorendic acid.  The overall
    evaluation was that chlorendic acid is possibly carcinogenic to humans
    (Group 2B) (IARC, 1989, 1990).

    REFERENCES

         Antonov LT (1980) [Selection of structural materials in chemical
    engineering.] Khim Prom-st (Moscow), 3: 167-168 (in Russian).

         Brett B (1975) Skin sensitization test with five samples in
    albino guinea-pigs. Northbrook, Illinois, Industrial Biotest
    Laboratories Inc. (Proprietary report submitted to WHO by Velsicol
    Chemical Corporation, Chicago, USA).

         Butz RG & Atallah YH (1979a) Persistence of chlorendic acid in
    soil at 1 and 10 µg/g. Chicago, Illinois, Velsicol Chemical
    Corporation (Proprietary report).

         Butz RG & Atallah YH (1979b) Effects of chlorendic acid at 1 and
    10 µg/g on soil microflora. Chicago, Illinois, Velsicol Chemical
    Corporation (Proprietary report).

         Calmbacher CW, Vilkas AG, & Hutchinson CH (1977a) The acute
    toxicity of chlorendic anhydride to the rainbow trout,  salmo
     gairdneri Richardson. Tarrytown, New York, Union Carbide
    Environmental Services (Proprietary report No. 11506-03-07a, submitted
    to WHO by Velsicol Chemical Corporation, Chicago, USA).

         Calmbacher CW, Vilkas AG, & Hutchinson CH (1977b) The acute
    toxicity of chlorendic anhydride to the Bluegill sunfish,  Lepomis
     macrochirus Rafinesque. Tarrytown, New York, Union Carbide
    Environmental Services (Proprietary report No. 11506-03-07b, submitted
    to WHO by Velsicol Chemical Corporation, Chicago, USA).

         Chemical Information Systems (1988) Information system for
    hazardous organics in water (ISHOW). Baltimore, Maryland, Infrared
    Search System (IRSS), Mass Spectral Search System (MSSS).

         Cochrane WP & Forbes MA (1974) Oxidation products of heptachlor
    and its metabolites - a chemical study. Chemosphere, 3: 41-46.

         Dean WP & Jessup DC (1978) Dermal sensitization study in the
    albino guinea-pig with chlorendic anhydride. Mattawan, Michigan,
    International Research and Development Corporation (Proprietary report
    No. 163-529 to Velsicol Chemical Corporation, Chicago, USA).

         Decad GM & Fields MT (1982) Disposition and excretion of
    chlorendic acid in Fischer 344 rats. J Toxicol Environ Health, 9(5-6):
    911-920.

         Demarini DM & Brooks HG (1992) Induction of prophage lambda by
    chlorinated organics: detection of some single-species/single site
    carcinogens. Environ Mol Mutagen, 19: 98-111.

         Diaz L & Atallah YH (1978) Pharmacokinetics of chlorendic
    anhydride in rats. Chicago, Illinois, Velsicol Chemical Corporation
    (Proprietary report No. 482348).

         Dietz EA, Cortellucci NJ, & Singley KL (1993) Determination of
    benzoic acid, chlorobenzoic acids and chlorendic acid in water. J Liq
    Chromatogr, 16(15): 3331-3347.

         Dragan YP, Rizvi T, Xu Y-H, Hully JR, Bawa N, Campbell HA,
    Maronpot RR, & Pitot HC (1991) An initiation-promotion assay in rat
    liver as a potential complement to the 2-year carcinogenesis bioassay.
    Fundam Appl Toxicol, 16(3): 525/547.

         Foureman P, Mason JM, Valencia R, & Zimmering S (1994) Chemical
    mutagenesis testing in Drosophila: X. Results of 70 coded chemicals
    tested for the National Toxicology Program. Environ Mol Mutagen,
    23(3): 208-227.

         Friedman M, Whitefield RE, & Tillin S (1973) Enhancement of the
    natural flame-resistance of wool. Text Res J, 43: 212-217.

         Friedman M, Ash JF, & Fox W (1974) Dye bath application of
    chlorendic acid for flame-resistant wool. Text Res J, 44: 555-556.

         Goldenthal EI, Jessup DC, & Rodwell DE (1978) Chlorendic
    anhydride, teratology study in rats. Mattawan, Michigan, International
    Research and Development Corporation (Proprietary report No. 163.535,
    submitted to WHO by Velsicol Chemical Corporation, Chicago, USA).

         Goldenthal EI, Jessup DC, Geil RG, & Dean WP (1979) Chlorendic
    anhydride. Three-week dermal toxicity study in rabbits. Mattawan,
    Michigan, International Research and Development Corporation
    (Proprietary report No. 163.530, submitted to WHO by Velsicol Chemical
    Corporation, Chicago, USA).

         Gupta SK, Krishman M, & Thampy RT (1978) Preparation of
    chlorendic acid based polyester resins. Ind J Text Res, 3: 124-128.

         Gurba PE, Smith LW, & Cameron BD (1990) Disposition of chlorendic
    acid in the rat. Toxicologist, 10(1): 237 (Abstract No. 948).

         Haworth S, Lawlor T, Mortelmans K, Speck W, & Zeiger E (1983)
     Salmonella mutagenicity test results for 250 chemicals. Environ
    Mutagen, 1(suppl): 3-142.

         Hendrix PF, Hamala JA, Langner CL, & Kollig HP (1983) Effects of
    chlorendic acid, a priority substance, on laboratory aquatic
    ecosystems. Chemosphere, 12(7/8): 1083-1099.

         Huff JA, Eustis SL, & Haseman JK (1989) Occurrence and relevance
    of chemically induced benign neoplasms in long-term carcinogenicity
    studies. Cancer Metastasis, 8: 1-21.

         IARC (1989) Some organic solvents, resin monomers and related
    compounds, pigments and occupational exposures in paint manufacture
    and painting. Lyon,  International Agency for Research on Cancer,
    535 pp (IARC Monographs on the Evaluation of Carcinogenic Risks to
    Humans, Volume 47).

         IARC (1990) Chlorendic acid. In: Some flame retardants and
    textile chemicals, and exposures in the textile manufacturing
    industry. Lyon, International Agency for Research on Cancer, pp 45-53
    (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans,
    Volume 48).

         IPCS (1989) Environmental Health Criteria 88: Polychlorinated
    dibenzo- para-dioxins and dibenzofurans.  Geneva, World Health
    Organization, 409 pp.

         IPCS (1994a) Environmental Health Criteria 162: Brominated
    diphenyl ethers.  Geneva, World Health Organization, 347 pp.

         IPCS (1994b) Environmental Health Criteria 152: Polybrominated
    biphenyls.  Geneva, World Health Organization, 577 pp.

         IPCS (1995a) Environmental Health Criteria 172:
    Tetrabromobisphenol-A and derivatives.  Geneva, World Health
    Organization, 139 pp.

         IPCS (1995b) Environmental Health Criteria 173: Tris- and
    bis(2,3-dibromopropyl) phosphate.  Geneva, World Health Organization,
    129 pp.

         Jagannath DR & Brusick DJ (1977) Mutagenicity evaluation of
    chlorendic anhydride: Final report. Kensington, Maryland, Litton
    Bionetics Inc. (Proprietary report No. 20838, submitted to WHO by
    Velsicol Chemical Corporation, Chicago, USA).

         Jefferson ND & Goldenthal EI (1980) Chlorendic anhydride:  90-day
    subacute renal toxicity study in rats. Mattawan, Michigan,
    International Research and Development Corporation (Proprietary report
    No. 163.533, submitted to WHO by Velsicol Chemical Corporation,
    Chicago, USA).

         Kinert JC & Goode JW (1975) Acute dust inhalation study in rats
    with Het acid. Northbrook, Illinois, Industrial Biotest Laboratories
    Inc. (Proprietary report No. 663-06279 to Hooker Chemical Corporation,
    Niagara Falls, USA).

         Kirk-Othmer (1981) Encyclopedia of chemical technology, 3rd ed.
    New York, John Wiley and Sons, vol 10, pp 387-389.

         Kitchin KT, Brown JL, & Kulkarni AP (1993) Predicting rodent
    carcinogenicity of halogenated hydrocarbons by  in vivo biochemical
    parameters. Teratogen Carcinogen Mutagen, 13(4): 167-184.

         Koch H (1970) [Phytotoxic substances and their possible mechanism
    of action.]  Sci Pharm, 38(2): 79-98 (in German).

         Larsen ER (1980) Flame retardants: Phosphorous compounds. In:
    Mark HF, Othmer DF, Overberger CG, Seaborg GT, & Grayson M ed.
    Encyclopedia of chemical technology, 3rd ed. New York, John Wiley &
    Sons, vol 10, pp 388-389.

         Leong KJ, Cavender FL, Branch JW, & Sabaitis CP (1978) Chlorendic
    anhydride: Acute inhalation toxicity study in rats. Mattawan,
    Michigan, International Research and Development Corporation
    (Proprietary report No. 163.512, submitted to WHO by Velsicol Chemical
    Corporation, Chicago, USA).

         McGregor DB, Brown A, Cattanach P, Edwards I, McBride D, &
    Caspary WJ (1988) Response of the L5178Y tk+/tk- mouse lymphoma cell
    forward mutation assay.II: 18 Coded chemicals. Environ Mol Mutagen,
    11(1): 91-118.

         Makhoulf J (1982) Polyesters unsaturated. In: Mark HF, Othmer DF,
    Overberger CG, Seaborg GT, & Grayson M ed. Encyclopedia of chemical
    technology, 3rd ed. New York, John Wiley & Sons, vol 18, pp 579-594.

         Maronpot RR, Pitot HC, & Peraino C (1989) Use of rat liver
    altered focus models for testing chemicals that have completed
    two-year carcinogenicity studies. Toxicol Pathol, 17(4): 651-662.

         Martens R (1972) [Degradation of endosulfan by soil
    microorganisms.] Schr.reihe Ver Wasser Boden Lufthyg (Berlin-Dahlem),
    37: 167-173 (in German).

         Matheson DW & Brusick DJ (1978a) Mutagenicity evaluation of
    chlorendic anhydride in the mouse lymphoma forward mutation assay.
    Kensington, Maryland, Litton Bionetics Inc. (Proprietary report
    No. 20839, submitted to WHO by Velsicol Chemical Corporation, Chicago,
    USA).

         Matheson DW & Brusick DJ (1978b) Evaluation of chlorendic
    anhydride:  in vitro malignant transformation in BALB/3T3 cells.
    Kensington, Maryland, Litton Bionetics Inc. (Proprietary report,
    project no. 20840, submitted to WHO by Velsicol Chemical Corporation,
    Chicago, USA).

         Matheson DW & Brusick DJ (1978c) Mutagenicity evaluation of
    chlorendic anhydride in the unscheduled DNA synthesis in human WI-38
    cells assay. Kensington, Maryland, Litton Bionetics Inc. (Proprietary
    report, project no. 20840, submitted to WHO by Velsicol Chemical
    Corporation, Chicago, USA).

         Matheson DW & Brusick DJ (1978d) Mutagenicity evaluation of
    chlorendic anhydride in the mouse dominant lethal assay. Kensington,
    Maryland, Litton Bionetics Inc. (Proprietary report No. 20862,
    submitted to WHO by Velsicol Chemical Corporation, Chicago, USA).

         Mathews EJ, Spalding JW, & Tennant RW (1993) Transformation of
    BALB/c-3T3 cells: V. Transformation responses of 168 chemicals
    compared with mutagenicity in  Salmonella and carcinogenicity in
    rodent bioassays. Environ Health Perspect, 101(suppl 2): 347-482.

         Menzie CM (1978) Metabolism of pesticides: update II to special
    scientific report No. 212. Washington, DC, US Department of Interior,
    Fish and Wildlife Service, pp 131-133.

         Myers TW & Googe JW (1975) Acute vapor inhalation toxicity study
    with crude Het anhydride. Northbrook, Illinois, Industrial Biotest
    Laboratories Inc. (Proprietary report No. 663-06667).

         Occidental Chemical (1986) Analytical procedure for the
    determination of HET acid trapped on glass fibre filters. Brussels,
    Occidental Chemical.

         Occidental Chemical (1987) Material safety data sheet M8584: HET
    acid. Niagara Falls, New York, Occidental Chemical.

         Occidental Chemical (1988) HET acid. Brussels, Occidental
    Chemical.

         Parlar H & Korte F (1977) Photoreactions of cyclodiene
    insecticides under simulated environmental conditions - A review.
    Chemosphere, 10: 665-705.

         Pilenkova II & Fatyanova AD (1980) [Determination of chlorendic
    anhydride in the air of working environments.] Zh Anal Khim, 35:
    2047-2049 (in Russian).

         Schuphan I & Ballschmiter K (1972) Metabolism of polychlorinated
    norborenes by  Clostridium butyricum. Nature (Lond), 237(5350):
    100-101.

         Stowell JP & Jensen JN (1991) Dechlorination of chlorendic acid
    with ozone.  Water Res, 25(1): 83-90.

         Talbot RC (1984) Using fiberglass-reinforced plastics. Chem Eng,
    91: 76-82.

         Tryzna GE & Paa H (1975) Acute toxicity studies with crude Het
    anhydride. Northbrook, Illinois, Industrial Biotest Laboratories Inc.
    (Proprietary report No. 601.06668 to Hooker Chemical Corporation,
    Niagara Falls, USA).

         Ulrich CE (1980) Chlorendic anhydride, subacute inhalation
    toxicity study in rats: 20 exposures in 28 days. Mattawan, Michigan,
    International Research and Development Corporation (Proprietary report
    No. 163.531, submitted to WHO by Velsicol Chemical Corporation,
    Chicago, USA).

         Uno Y, Takasawa H, Miyagawa M, Inoue Y, Murata T, & Yoshikawa K
    (1994) An  in vivo-in vitro replicative DNA synthesis (RDS) test
    using rat hepatocytes as an early prediction assay for non-genotoxic
    hepatocarcinogens screening of 22 known positives and 25 non
    carcinogens. Mutat Res, 320(3): 189-205.

         US EPA (1982) Final technical support document: Chlorendic acid
    (Contract No. 68-01-6530). Washington, DC, US Environmental Protection
    Agency, Office of Pesticides and Toxic Substances.

         US ITC (1988) Synthetic organic chemicals - US production and
    sales, 1987. Washington, DC, US International Trade Commission, pp 3-9
    (USITC Publication No. 2118).

         US NTP (1987) Toxicology and carcinogenesis studies of chlorendic
    acid (CAS No. 115-28-6) in F344/N rats and B6C3F1 mice (Feed studies).
    Research Triangle Park, North Carolina, US Department of Health and
    Human Services, National Toxicology Program (NTP Technical Report
    Series No. 304).

         Velsicol Chemical Corporation (1982) Product information bulletin
    - Speciality chemicals: Velsicol chlorendic anhydride. Rosemont,
    Illinois, Velsicol Chemical Corporation.

         Vilkas AG & Hutchinson CH (1977) Acute toxicity of chlorendic
    anhydride to the water flea,  Daphnia magna straus. Tarrytown, New
    York, Union Carbide Environmental Services (Proprietary report No.
    11506-03-06, submitted to WHO by Velsicol Chemical Corporation,
    Chicago, USA).

         Witherup S, Stemmer KL, & Schlecht H (1965) The toxicity of
    chlorendic acid and chlorendic anhydride. Cincinnati, Ohio, University
    of Cincinnati, Department of Preventive Medicine and Industrial
    Health, Kethering Laboratory (Proprietary report submitted to WHO by
    Velsicol Chemical Corporation, Chicago, USA).

         Ying WC, Bonk RR, & Sojka SA (1987) Treatment of a landfill
    leachate in powdered activated carbon enhanced sequencing batch
    bioreactors. Environ Prog, 6(1): 1-8.

         Yu CC & Atallah YH (1977a) Hydrolysis of chlorendic anhydride in
    aqueous solutions and stability on TLC plates. Chicago, Illinois,
    Velsicol Chemical Corporation (Proprietary report).

         Yu CC & Atallah YH (1977b) Partition coefficients of MC-680,
    chlorendic anhydride and chlorendic acid. Chicago, Illinois, Velsicol
    Chemical Corporation (Proprietary report).

         Yu CC & Atallah YH (1978) Photolysis of chlorendic anhydride and
    chlorendic acid. Chicago, Illinois, Velsicol Chemical Corporation
    (Proprietary report).

         Zeiger E (1990) Mutagenicity of 42 chemicals in  Salmonella.
    Environ Mol Mutagen, 16 (suppl 18): 32-54.

    RESUME ET EVALUATION; CONCLUSIONS ET RECOMMANDATIONS

    1.  Résumé et évaluation

    1.1  Propriétés physiques et chimiques

         L'acide chlorendique (qualité commerciale 99,5%) et l'anhydride
    du même nom (qualité technique 97%) sont des substances cristallines
    voisines de couleur blanche.  De par leur structure, ils sont
    apparentés aux insecticides diéniques chlorés.  Par chauffage de
    l'acide chlorendique dans un système ouvert, on obtient l'anhydride
    correspondant.  Inversement on peut rapidement revenir à l'acide par
    hydrolyse. Le point de fusion varie de 208°C pour l'acide à 235°C pour
    l'anhydride.

    1.2  Production et usages

         L'acide et l'anhydride chlorendiques sont surtout utilisés comme
    retardateurs de flamme dans les résines polyester et les plastifiants
    destinés aux installations électriques et aux peintures ainsi que dans
    les résines renforcées par des fibres de verre qui servent à la
    fabrication d'équipements pour l'industrie chimique. L'industrie
    textile les a aussi utilisés pour le finissage des tissus de laine et
    des tapis.

         La production mondiale totale d'acide et d'anhydride
    chlorendiques tourne actuellement autour de 4 000 tonnes par an.

    1.3  Transport, distribution et transformation
         dans l'environnement

         Il peut y avoir libération d'acide chlorendique par suite d'une
    décomposition hydrolytique de polyesters ou de l'oxydation
    d'insecticides cyclodiéniques chlorés.

         Le rayonnement ultraviolet décompose l'acide chlorendique avec
    une demi-vie de 16 jours lorsque ce dernier se trouve sous la forme
    d'une fine couche solide.  La demi-vie tombe à 5 jours en solution
    aqueuse.  Dans le sol,la demi-vie oscille entre 140 et 280 jours.  Le
    composé est assez persistant dans le sol, mais on manque de données à
    ce sujet.

         On ne sait rien non plus de son potentiel de bioaccumulation et
    de bioamplification.  Par ailleurs, il n'y a aucune donnée sur la
    destinée finale des produits de la réaction de ce composé avec
    d'autres substances présentes dans les décharges et les incinérateurs.

         L'exposition à l'anhydride chlorendique risque de conduire à une
    exposition à l'acide correspondant par suite de l'hydrolyse de
    l'anhydride.

    1.4  Concentrations dans l'environnement et exposition humaine

         On a trouvé de l'acide chlorendique à des concentrations
    atteignant 455 mg/litre dans l'eau de lessivage de certaines
    décharges.

    1.5  Cinétique et métabolisme chez les animaux de laboratoire

         Après administration d'acide chlorendique radiomarqué par voie
    orale à des rats, on a constaté que le composé se répartissait
    rapidement dans tout l'organisme et qu'il était métabolisé sans délai. 
    Le marqueur radioactif a été excrété à plus de 90% dans les matières
    fécales en l'espace de 24 h, principalement sous forme de conjugué. 
    Dans les urines, il n'a été excrété qu'à hauteur de  3 à 6%.  C'est
    dans les tissus adipeux, le foie, les reins,le sang total et les
    poumons que l'on a mesuré les plus fortes teneurs en marqueur
    radioactif.

         Des résultats analogues ont été obtenus lors d'une étude au cours
    de laquelle des rats ont reçu de l'anhydride chlorendique par gavage. 
    Dans cette étude, on a obtenu une demi-vie de moins de 2 jours, sauf
    dans de cas du tissu adipeux où elle a atteint 22,5 jours.

         On ne dispose d'aucune donnée sur la cinétique de ce composé
    après administration par la voie percutanée ou respiratoire.

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

         L'acide chorendique a une faible toxicité aiguë par voie orale;
    chez le rat, la DL50 est égale à 1770 mg/kg de poids corporel.  Dans
    le cas de l'anhydride, la DL50 orale est de 2480 mg/kg de poids
    corporel.

         La DL50 aiguë par la voie percutanée est > 3000 mg/kg de poids
    corporel pour le lapin dans le cas de l'anhydride.

         Pour l'acide chlorendique, la CL50 à 4h en cas d'inhalation de
    poussières est > 0,79 mg/litre chez le rat.

         Des tests sur des lapins ont montré que l'anhydride et l'acide
    chlorendiques ont un effet irritant cutané qui peut être sévère au
    niveau des yeux et des voies respiratoires.L'anhydride a un effet
    sensibilisateur sur la peau du cobaye, mais il est vrai que le même
    test effectué avec l'acide a donné un résultat négatif.

         Lors d'une étude de 13 semaines sur des souris au cours de
    laquelle les animaux ont reçu de l'acide chlorendique mélangé à leur
    nourriture, on a obtenu la valeur de 2500 mg par kg de nourriture pour
    la dose sans effet observable, soit l'équivalent de 250 mg/kg de poids
    corporel.  Chez des rats ayant fait l'objet d'une étude analogue, la

    valeur obtenue a été de 1250 mg par kg de nourriture, soit 62,5 mg/kg
    de poids corporel.  Aux doses élevées, on a noté une diminution
    sensible de la croissance et l'examen microscopique a révélé des
    anomalies au niveau du foie.

         Une étude d'alimentation de 90 jours, au cours de laquelle des
    rats ont reçu de l'anhydride chlorendique dans leur nourriture, a
    donné une valeur de 125 mg/kg de poids corporel par jour pour la dose
    sans effet observable.  Dans une autre étude, qui a duré 3 semaines et
    a consisté à exposer les animaux par la voie cutanée, on a obtenu la
    valeur de 100 mg/kg de poids corporel par jour pour la dose en
    question (indépendamment de l'effet irritant pour la peau).  En
    revanche, on n'a pas pu établir la dose sans effet observable lors
    d'une étude de 28 jours consistant à faire inhaler de la poussière à
    des rats.

         Lors d'une étude de tératogénicité effectuée sur des rats, on a
    administré aux animaux de l'anhydride chlorendique par gavage à des
    doses allant jusqu'à 400 mg/kg de poids corporel du 6ème au 15ème jour
    de la gestation; le composé s'est révélé toxique pour les mères mais
    il n'y a pas eu d'effets tératogènes.

         On a étudié le pouvoir mutagène de l'acide chlorendique sur cinq
    souches de  Salmonella typhimurium en présence ou en l'absence d'un
    système métabolique exogène.  Des résultats négatifs ont été obtenus
    avec des doses allant jusqu'à 7690 µg/boîte.  Une épreuve de mutation
    sur lymphome murin s'est par contre révélée positive, en l'absence de
    système métabolique exogène.  Les doses utilisées étaient
    respectivement égales à 1300 µg et 1700 µg/ml.  La plus élevée des
    deux doses s'est révélée cytotoxique.

         L'acide chlorendique a donné un résultat positif dans une épreuve
    de transformation sur des cellules BALB/c-3T3 en l'absence
    d'activation métabolique et un résultat négatif lors d'une épreuve sur
    des mâles de  Drosophila melanogaster, pour la mise en évidence de
    mutations létales récessives liées au sexe.  Le composé n'a pas
    provoqué d'augmentation de la synthèse réplicative de l'ADN après
    administration par voie orale ou sous-cutanée à des rats F-344 de
    doses respectivement égales à 450 ou 900 mg/kg de poids corporel.

         Lors d'épreuves au cours desquelles de l'anhydride chlorendique a
    été testé sur cinq souches de  Salmonella typhimurium et une souche
    de la levure  Saccharomyces cerevisiae à des doses allant jusqu'à
    7500 µg/boîte, on n'a pas constaté d'activité mutagène.  Il n'a pas
    induit de mutations directes dans l'épreuve sur lymphome murin et a
    donné un résultat négatif lors d'une épreuve de transformation sur
    cellules BALB/3T3. L'anhydride chlorendique a également produit une
    synthèse non programmée de l'ADN en proportion non négligeable dans
    des cellules humaines WI-38.  Lors d'une épreuve de létalité
    dominante, des souris ont été exposées à des doses uniques d'anhydride
    chlorendique allant jusqu'à 223 mg par kg de poids corporel, après une

    période de reproduction de 7 semaines.  Le seul effet observé a été
    une réduction statistiquement significative de l'indice de fécondité,
    par rapport aux témoins, chez toutes les femelles accouplées avec des
    mâles traités, au cours de la 5ème semaine, ainsi que chez les
    femelles accouplées avec des mâles traités par une demi-dose, au cours
    de la 4ème semaine.  Aucun autre effet n'a été observé, qu'il s'agisse
    du nombre des implantations, viables ou non viables, et des
    résorptions.  Malgré les défauts de conception de cette étude, on en a
    conclu que les résultats de l'épreuve étaient négatifs.

         On a étudié le pouvoir cancérogène de l'acide chlorendique sur
    des rats F-344/N à des doses respectivement égales à 620 et 1250 mg/kg
    de nourriture (soit l'équivalent de 31 et 62,5 mg/kg de poids
    corporel).  Outre les anomalies non malignes observées dans un certain
    nombre d'organes-dégénérescence kystique et altérations focales au
    niveau cellulaire ou encore hyperplasie des canaux biliaires, on a
    noté une augmentation, significative à la dose maximale, de
    l'incidence des tumeurs chez les animaux traités: adénomes
    hépatocellulaires chez les mâles et adénomes ou carcinomes
    hépatocellulaires chez les femelles.  De plus, il y avait chez les
    mâles une légère augmentation des cancers acineux du pancréas et des
    adénomes alvéolaires et bronchiolaires.

         Chez des souris B6C3F1 qui avaient reçu une alimentation
    contenant soit 620, soit 1250 mg d'acide chlorendique par kg de
    nourriture (c'est-à-dire l'équivalent de 62 ET 125 mg/kg de poids
    corporel, respectivement), on a constaté une plus grande incidence des
    nécroses et des altérations mitotiques au niveau du foie.  Chez les
    mâles, il y a eu, aux deux doses, augmentation de l'incidence des
    adénomes et des carcinomes hépatocellulaires.  Chez les femelles,
    c'est l'incidence des adénomes et des carcinomes alvéolaires et
    bronchiolaires qui était en augmentation.

         On a cherché à élucider le mécanisme de la cancérogénèse en
    faisant appel à plusieurs modèles ou épreuves: l'épreuve
    d'initiation/promotion, le modèle avec hépatectomie partielle et le
    modèle néonatal.  La conclusion a été que l'acide chlorendique se
    comporte comme un promoteur.

    1.7  Effets chez l'homme

         On ne dispose d'aucune donnée concernant d'éventuels effets sur
    l'homme.

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

         L'acide chlorendique aurait des effets toxiques sur les algues à
    la dose de 250 mg/litre.  Il s'agit notamment d'une inhibition de
    l'activité de la microfaune, d'une baisse de la production d'oxygène
    et d'une réduction de la respiration.  On n'a en revanche signalé

    aucun effet toxique chez les algues exposées à 125 mg d'acide
    chlorendique par litre ou à de l'anhydride chlorendique.  Les effets
    toxiques observés sont attribués à la modification du pH plutôt qu'à
    une toxicité directe de l'acide chlorendique.  Aux faibles valeurs du
    pH, l'acide chorendique se trouve sous sa forme non ionisée, qui peut
    avoir un effet toxique direct.

         Il n'y a qu'une seule espèce végétale terrestre pour laquelle on
    ait signalé des effets toxiques imputables à l'acide chlorendique. 
    Après exposition à 0,1 mg/litre ou davantage, il y a eu inhibition de
    la croissance et de la germination, mais à la dose de 0,01 mg/litre,
    aucun effet n'a été signalé.

         La CL50 d'anhydride chlorendique pour  Daphnia magna est de
    110,7 mg/litre à 48h; elle est de 422,7 mg/litre à 96h pour la truite
    arc-en-ciel et  Lepomis macrochirus.

         Il est impossible d'évaluer les effets de l'anhydride
    chlorendique sur les êtres vivants dans leur milieu naturel sans
    connaître la concentration et la destinée de ce composé dans les
    différents compartiments de l'environnement.

    2.  Conclusions

         La base de données relative à l'acide et à l'anhydride
    chlorendiques est loin d'être complète.  Pour beaucoup d'études, le
    Groupe de travail ne disposait pas de rapports  in extenso, mais
    seulement de résumés.  En particulier, il n'y a aucune donnée sur la
    destinée ultime de ces composés, soit tels quels, soit après réaction
    avec d'autres substances et l'on ne sait pas non plus ce qu'il en est
    de leur potentiel de bioaccumulation et de bioamplification.  Par
    ailleurs, on ne possède pas de données sur l'exposition de l'homme et
    des autres êtres vivants dans leur milieu naturel.

         Les deux composés semblent n'avoir qu'une faible toxicité aiguë
    et subaiguë par voie orale, mais ils sont irritants pour l'oeil, la
    peau et les voies respiratoires.  D'après les résultats des études de
    toxicité et de cancérogénicité à long terme, l'acide et l'anhydride
    chlorendiques provoquent la formation de tumeurs chez le rat et la
    souris, ce qui permet de les considérer comme potentiellement
    cancérogènes.  On ne peut cependant pas évaluer le risque qu'ils
    représentent pour l'homme et son environnement, faute de données
    suffisantes.

         La base de données actuelle n'est pas suffisamment étoffée pour
    que l'on puisse se prononcer en faveur d'une utilisation commerciale
    de l'acide et de l'anhydride chlorendiques.

    3.  Recommandations

    3.1  Protection de la santé humaine et de l'environnement

    a)   L'exposition de la population générale à l'acide et à  
         l'anhydride chlorendiques ainsi qu'à leurs dérivés doit être  
         réduite au minimum.

    b)   Il ne faut utiliser l'acide et l'anhydride chlorendiques qu'en  
         vase clos afin d'éviter une exposition aux vapeurs ou aux  
         poussières.  Les travailleurs qui produisent ou manipulent ces  
         composés doivent être suffisamment familiarisés avec les  
         mesures de sécurité.  Des dispositifs techniques appropriés et  
         des mesures relevant de l'hygiène et de la sécurité du travail  
         doivent assurer leur protection.

    c)   L'évacuation de l'acide et de l'anhydride chlorendiques ou des
         déchets qui en contiennent doivent se faire selon des méthodes
         permettant d'éviter l'exposition de la population et de réduire
         au minimum la pollution de l'environnement.

    3.2  Recherches futures

    a)   Il conviendrait de compléter la base de données par des  
         renseignements suffisants sur:

         i)   la destinée finale de ces composés, soit tels quels, soit  
              après réaction;

         ii)  leur potentiel de bioaccumulation et de bioamplification;

         iii) l'exposition humaine et la pollution de l'environnement;

    b)   Il faudrait étudier les produits de combustion de matériaux
         préparés ou traités avec de l'acide ou de l'anhydride
         chlorendiques et, en particulier, leur toxicité par la voie
         respiratoire ainsi que le risque de pollution de l'environnement
         par ces produits.

    c)   Il conviendrait de mesurer la concentration de l'acide et de
         l'anhydride chlorendiques dans les différents compartiments de
         l'environnement ou de s'efforcer tout au moins de les calculer à
         l'avance à l'aide des modèles existants.

    d)   Il faudrait obtenir des données sur la présence éventuelle
         d'aberrations chromosomiques en procédant à une analyse de la
         métaphase.  Il faudra également obtenir des données de
         mutagénicité  in vivo avant de pouvoir procéder à une analyse
         complète du risque.

    e)   Une étude de reproduction portant sur trois générations serait  
         à effectuer.

    f)   Il faudrait élucider le mécanisme qui est à la base de la  
         cancérogénicité de ces deux substances.

    RESUMEN Y EVALUACION; CONCLUSIONES Y RECOMENDACIONES

    1.  Resumen y evaluación

    1.1  Propiedades físicas y químicas

         El ácido cloréndico (calidad comercial, 99,5%) y el anhídrido
    cloréndico (calidad técnica, 97%) son productos cristalinos blancos
    estrechamente relacionados entre sí.  Estructuralmente son muy
    parecidos a los insecticidas clorados derivados del ciclodieno. 
    Calentado en un sistema abierto, el ácido cloréndico pierde agua y
    forma anhídrido cloréndico.  Este puede hidrolizarse rápidamente y
    transformarse en ácido cloréndico.  Los puntos de fusión van de 208°C
    (para el ácido) a 235°C (para el anhídrido).

    1.2  Producción y uso

         El ácido cloréndico y el anhídrido cloréndico se utilizan
    principalmente como reactivos pirorretardantes en resinas
    poliestéricas y agentes ablandantes para sistemas eléctricos y
    pinturas, y en resinas reforzadas con fibra de vidrio para equipo de
    procesos químicos.  En la industria textil se utilizaron en el pasado
    en el acabado de alfombras y tejidos de lana.

         La producción mundial total de ácido cloréndico y anhídrido
    cloréndico se sitúa actualmente en torno a las 4000 toneladas por año.

    1.3  Transporte, distribución y transformación en el medio ambiente

         El ácido cloréndico puede liberarse por degradación hidrolítica
    de poliésteres y como producto de la oxidación de los insecticidas
    clorados derivados del ciclodieno.

         La radiación ultravioleta degrada el ácido cloréndico, cuya
    semivida es de 16 días en una capa sólida fina y de 5 días en solución
    acuosa.  En el suelo la semivida oscila entre 140 y 280 días.  El
    ácido cloréndico es bastante persistente en el suelo, aunque los datos
    disponibles a este respecto son insuficientes.

         No se dispone de datos sobre el potencial de bioacumulación y
    bioamplificación.  Asimismo, se carece de datos sobre el destino final
    de los productos de reacción entre otros en la eliminación de desechos
    y la incineración.

         La exposición al anhídrido cloréndico entraña probablemente
    también la exposición al ácido cloréndico, debido a la hidrólisis del
    primero.

    1.4  Niveles medioambientales y exposición humana

         En el lixiviado de vertederos se ha encontrado ácido cloréndico a
    concentraciones de hasta 455 mg/litro.

    1.5  Cinética y metabolismo en animales de laboratorio

         Tras la administración a ratas de ácido cloréndico radiomarcado
    por vía oral e intravenosa, la sustancia se distribuyó velozmente por
    todo el organismo y se metabolizó con rapidez.  Más del 90% se excretó
    en las primeras 24 horas en las heces, principalmente en forma
    conjugada.  Sólo entre el 3% y el 6% se excretó en la orina.  Las
    concentraciones más altas de la sustancia radiomarcada se hallaron en
    el tejido adiposo, el hígado, los riñones, la sangre entera y los
    pulmones.

         En un estudio de alimentación con sonda en ratas se obtuvieron
    resultados parecidos con el anhídrido cloréndico.  La semivida del
    compuesto marcado en este estudio fue inferior a dos días, salvo en la
    grasa, donde ascendió a 22,5 días.

         No se dispone de datos sobre la cinética tras la exposición
    cutánea o respiratoria.

    1.6  Efectos en mamíferos de laboratorio y en sistemas de pruebas
         in vitro

         La toxicidad oral aguda del ácido cloréndico es baja; la DL50
    en la rata es de 1770 mg/kg de peso corporal.  Para el anhídrido
    cloréndico, la DL50 por vía oral en las ratas es de 2480 mg/kg de
    peso corporal.

         La DL50 aguda por vía cutánea del anhídrido cloréndico crudo en
    el conejo es de > 3000 mg/kg de peso corporal.

         En las ratas, la CL50 del ácido cloréndico por inhalación de
    polvo durante cuatro horas es de > 0,79 mg/litro.

         El ácido y el anhídrido cloréndico provocan irritación cutánea y
    grave irritación de los ojos y de las vías respiratorias en el conejo. 
    El anhídrido cloréndico produce sensibilización de la piel en el
    cobayo, mientras que una prueba con ácido cloréndico fue negativa.

         En un estudio de alimentación de ratones de 13 semanas de
    duración en el que se utilizó ácido cloréndico se halló un nivel sin
    efectos observados (NOEL) de 2500 mg/kg de alimento (equivalente a
    250 mg/kg de peso corporal); en un estudio de alimentación análogo
    realizado con ratas el NOEL fue de 1250 mg/kg de alimento (equivalente
    a 62,5 mg/kg de peso corporal).  A dosis más altas la disminución del
    crecimiento fue significativa y se observaron cambios microscópicos en
    el hígado.

         En un estudio de alimentación de 90 días en ratas con anhídrido
    cloréndico, el NOEL fue de 125 mg/kg de peso corporal por día, y en
    otro estudio de tres semanas con administración por vía cutánea el
    NOEL ascendió a 100 mg/kg de peso corporal por día (aparte de la
    irritación de la piel).  En un estudio de inhalación de polvo en ratas
    durante 28 días no se pudo establecer ningún NOEL.

         Un estudio de teratogenicidad en la rata con anhídrido
    cloréndico, administrado mediante alimentación con sonda a dosis de
    hasta 400 mg/kg de peso corporal en los días 6 a 15 de la gestación,
    reveló toxicidad materna pero no efectos teratógenos.

         Se determinó el potencial mutagénico del ácido cloréndico en
    cinco cepas de  Salmonella typhimurium en presencia y ausencia de un
    sistema de metabolismo exógeno.  Con dosis de hasta 7690 µg/placa se
    obtuvieron resultados negativos.  Una prueba de mutación en células de
    linfoma de ratón en ausencia de un sistema de metabolismo exógeno fue
    positiva.  Las dosis utilizadas fueron de 1300 a 1700 µg/ml.  La dosis
    más alta resultó ser citotóxica.

         El ácido cloréndico dio resultados positivos en una prueba de
    transformación con células BALB/c-3T3 sin activación metabólica, y
    negativo en una prueba de mutaciones letales recesivas ligadas al sexo
    en machos de  Drosophila melanogaster.  El ácido cloréndico no
    estimuló la síntesis replicativa del ADN tras la aplicación oral o
    subcutánea de 450 ó 900 mg/kg de peso corporal a ratas F-344.

         En pruebas realizadas en cinco cepas de  Salmonella typhimurium
    y una de la levadura  Saccharomyces cerevisiae con dosis de hasta
    7500 µg/placa, el anhídrido cloréndico no resultó potencialmente
    mutagénico.  El compuesto no indujo mutaciones directas en un ensayo
    con células de linfoma de ratón, y no tuvo efectos en una prueba de
    transformación con células BALB/3T3.  En células humanas WI-38 produjo
    un grado significativo de síntesis no programada de ADN.  En una
    prueba de dominancia letal en ratones, se les expuso a dosis únicas de
    hasta 223 mg de anhídrido cloréndico/kg de peso corporal, seguidas de
    un periodo de reproducción de siete semanas.  Sólo se observó una
    disminución estadísticamente significativa del índice de fecundidad,
    respecto de los testigos, en todas las hembras que se aparearon con
    machos tratados durante la semana 5, y en las que se aparearon con
    machos tratados una dosis media durante la semana 4.  No se detectaron
    efectos en el número de implantaciones, resorciones o huevos muertos. 
    Se concluyó que esta prueba daba resultados negativos, si bien el
    diseño del estudio era inadecuado.

         El potencial carcinogénico del ácido cloréndico se determinó en
    ratas F-344/N a dosis de 620 y 1250 mg/kg de alimento (equivalentes a
    31 y 62,5 mg/kg de peso corporal).  Además de algunas modificaciones
    no neoplásicas significativas en varios órganos, como la degeneración
    quística y alteraciones celulares focales, y de una hiperplasia del
    conducto biliar en el hígado, se observaron aumentos de la incidencia

    de adenomas hepatocelulares en los machos tratados, y de adenomas y
    carcinomas hepatocelulares, significativos a las dosis más altas, en
    las hembras.  Además, en los machos se detectaron ligeros aumentos de
    los adenomas de células acinosas del páncreas y de los adenomas de
    alveolos/bronquiolos en el pulmón.

         En ratones B6C3F1 alimentados con dietas que contenían 620 y
    1250 mg de ácido cloréndico por kg de alimento (equivalentes a 62 y
    125 mg/kg de peso corporal) se observó una mayor incidencia de
    necrosis y alteraciones mitóticas en el hígado.  Con ambas dosis se
    observó un aumento de los adenomas y carcinomas hepatocelulares en los
    machos.  En las hembras se halló una mayor incidencia de adenomas o
    carcinomas de los alveolos/bronquiolos.

         Se realizaron estudios para investigar los mecanismos de
    carcinogénesis mediante una valoración del potencial
    iniciador/facilitador, el modelo de hepatectomía parcial y el modelo
    neonatal.  Las pruebas indicaron que el ácido cloréndico tiene
    actividad facilitadora.

    1.7  Efectos en el ser humano

         No se dispone de datos sobre los efectos en el ser humano.

    1.8  Efectos en otros organismos en el laboratorio y en el medio ambiente

         Se ha notificado que a 250 mg/litro el ácido cloréndico tiene
    efectos tóxicos sobre las algas.  Entre los efectos señalados figuran
    la inhibición de la actividad de la microfauna, la menor producción de
    oxígeno y la merma de la respiración.  Para las algas expuestas a
    125 mg de ácido cloréndico/litro y para las expuestas al anhídrido
    cloréndico no se han notificado efectos tóxicos.  Los efectos tóxicos
    observados en las algas se han atribuido a la modificación del pH más
    que a la toxicidad directa del ácido cloréndico.  A valores de pH
    bajos el ácido cloréndico está en forma no ionizada, forma que puede
    tener efectos tóxicos directos.

         Se han señalado efectos del ácido cloréndico sólo sobre una
    especie de planta terrestre.  Tras la exposición a 0,1 mg/litro o más,
    se observó una inhibición tanto del crecimiento como de la germinación
    de las semillas, mientras que la exposición a 0,01 mg/litro no produjo
    ningún efecto.

         La CL50 a las 48 horas para Daphnia magna fue de 110,7 mg de
    anhídrido cloréndico/litro, y la CL50 a las 96 horas para la trucha
    arco iris y para  Lepomis machrochirus fue de 422,7 mg/litro.

         Los efectos potenciales del anhídrido cloréndico sobre los
    organismos en el medio ambiente no pueden evaluarse en ausencia de
    datos sobre las concentraciones y los procesos que determinan el
    destino de este compuesto en los compartimientos ambientales.

    2.  Conclusiones

         La base de datos sobre el ácido cloréndico y el anhídrido
    cloréndico dista mucho de ser completa.  Para varios estudios el Grupo
    de Trabajo no dispuso de la versión integral de los informes (sino
    sólo de resúmenes).  En particular, no hay datos sobre el destino
    final de las sustancias en sí ni de los productos a que dan lugar, ni
    tampoco sobre el potencial de bioacumulación y bioamplificación. 
    Además, se carece de datos sobre la exposición de seres humanos y de
    organismos en el medio ambiente.

         Las dos sustancias parecen tener una toxicidad aguda y subaguda
    baja por vía oral, pero son irritantes de la piel, los ojos y las vías
    respiratorias.  Los resultados de estudios de toxicidad/
    carcinogenicidad de larga duración con administración de ácido
    cloréndico a ratas y ratones llevan a concluir que el ácido cloréndico
    provoca tumores en ambos, por lo que se considera que tiene un
    potencial carcinógeno.  Sin embargo, vista la falta de datos, no es
    posible hacer una evaluación cabal de la peligrosidad para el ser
    humano y el medio ambiente.

         La base de datos actual es insuficiente para respaldar el uso
    comercial del ácido cloréndico y del anhídrido cloréndico.

    3.  Recomendaciones

    3.1  Protección de la salud humana y del medio ambiente

    a)   La exposición de la población general al ácido cloréndico, al  
         anhídrido cloréndico y a los productos de ellos derivados debe  
         reducirse al mínimo.

    b)   El ácido cloréndico y el anhídrido cloréndico deben utilizarse  
         sólo en sistemas cerrados para evitar la exposición al vapor y  
         al polvo.  Los trabajadores que producen y manipulan estas  
         sustancias deben estar debidamente adiestrados en los  
         procedimientos de seguridad, y se les debe proteger de la  
         exposición con los adecuados medios técnicos de control y con  
         medidas apropiadas de higiene industrial.

    c)   La eliminación del ácido y el anhídrido cloréndico y de sus  
         productos residuales debe efectuarse por métodos que aseguren  
         que la población general no quede expuesta y que la exposición  
         del medio ambiente sea mínima. 

    3.2  Nuevas investigaciones

    a)   La base de datos debería completarse con información adecuada
         sobre:

         i)   el destino final de estas sustancias como tales y de sus
              productos de reacción;

         ii)  el potencial de bioacumulación y de bioamplificación;

         iii) la exposición humana y ambiental.

    b)   Deberían realizarse estudios sobre los productos de combustión  
         de los materiales preparados o tratados con el ácido o el  
         anhídrido, su toxicidad por inhalación, y su potencial de  
         contaminación del medio ambiente.

    c)   Las concentraciones de ácido y anhídrido cloréndico en los  
         compartimientos ambientales deberían medirse, o por lo menos  
         predecirse con ayuda de los modelos disponibles.

    d)   Deberían obtenerse datos sobre la presencia de aberraciones
         cromosómicas mediante un estudio de análisis de la metafase.  Se
         necesitarán algunos datos sobre la mutagenicidad  in vivo antes
         de poder efectuar una evaluación cabal de la peligrosidad.

    e)   Debería realizarse un estudio de reproducción de tres  
         generaciones.

    f)   Debería clarificarse el mecanismo carcinogénico de ambas  
         sustancias.
    


See Also:
        Chlorendic acid (IARC Summary & Evaluation, Volume 48, 1990)