IPCS INCHEM Home


    UNITED NATIONS ENVIRONMENT PROGRAMME
    INTERNATIONAL LABOUR ORGANISATION
    WORLD HEALTH ORGANIZATION


    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 201





    SELECTED CHLOROALKYL ETHERS














    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. R. Liteplo and Ms R. Gomes, Health Canada,
    Canada

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

    World Health Organization
    Geneva, 1998

         The International Programme on Chemical Safety (IPCS),
    established in 1980, is a joint venture of the United Nations
    Environment Programme (UNEP), the International Labour Organisation
    (ILO), and the World Health Organization (WHO). The overall objectives
    of the IPCS are to establish the scientific basis for assessment of
    the risk to human health and the environment from exposure to
    chemicals, through international peer-review processes, as a
    prerequisite for the promotion of chemical safety, and to provide
    technical assistance in strengthening national capacities for the
    sound management of chemicals.

         The Inter-Organization Programme for the Sound Management of
    Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and
    Agriculture Organization of the United Nations, WHO, the United
    Nations Industrial Development Organization, the United Nations
    Institute for Training and Research, and the Organisation for Economic
    Co-operation and Development (Participating Organizations), following
    recommendations made by the 1992 UN Conference on Environment and
    Development to strengthen cooperation and increase coordination in the
    field of chemical safety.  The purpose of the IOMC is to promote
    coordination of the policies and activities pursued by the
    Participating Organizations, jointly or separately, to achieve the
    sound management of chemicals in relation to human health and the
    environment.

    WHO Library Cataloguing in Publication Data

    Selected chloroalkyl ethers.

       (Environmental health criteria ; 201)

       1. Bis(Chloromethyl) ether - toxicity
       2. Bis(Chloromethyl) ether - adverse effects
       3. Environmental exposure    4. Occupational exposure
       I. International Programme on Chemical Safety        II.Series

       ISBN 92 4 157201 9       (NLM Classification: QZ 202)
       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 1998

         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 SELECTED CHLOROALKYL ETHERS

    PREAMBLE

    ABBREVIATIONS

    1. SUMMARY AND CONCLUSIONS

         1.1. Identity, physical and chemical properties, analytical
              methods
         1.2. Sources of human exposure
         1.3. Environmental transport, distribution and transformation
         1.4. Environmental levels and human exposure
         1.5. Kinetics and metabolism
         1.6. Effects on laboratory animals and  in vitro test systems
         1.7. Effects on humans
         1.8. Effects on other organisms in the laboratory and field
         1.9. Conclusions
              1.9.1. BCEE
              1.9.2. BCME and CMME

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

         2.1. Identity
         2.2. Physical and chemical properties
         2.3. Conversion factors
         2.4. Analytical methods
              2.4.1. BCEE
              2.4.2. BCME
              2.4.3. CMME

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1. Natural occurrence
         3.2. Anthropogenic sources
              3.2.1. Production
                    3.2.1.1  BCEE
                    3.2.1.2  BCME
                    3.2.1.3  CMME
              3.2.2. Uses
                    3.2.2.1  BCEE
                    3.2.2.2  BCME
                    3.2.2.3  CMME
              3.2.3. Sources in the environment
                    3.2.3.1  BCEE
                    3.2.3.2  BCME and CMME

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         4.1. Transport and distribution between media
              4.1.1. BCEE
              4.1.2. BCME and CMME
         4.2. Abiotic degradation
              4.2.1. BCEE
              4.2.2. BCME and CMME
         4.3. Biodegradation, biotransformation and bioaccumulation
              4.3.1. BCEE
              4.3.2. BCME and CMME
         4.4. Ultimate fate following use

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1. Environmental levels
              5.1.1. BCEE
              5.1.2. BCME and CMME
         5.2. General population exposure
         5.3. Occupational exposure
              5.3.1. BCEE
              5.3.2. BCME and CMME

    6. KINETICS AND METABOLISM IN LABORATORY ANIMALS

         6.1. Absorption and distribution
         6.2. Metabolism
         6.3. Elimination

    7. EFFECTS ON EXPERIMENTAL MAMMALS AND  IN VITRO TEST SYSTEMS

         7.1. Single exposure
              7.1.1. BCEE
              7.1.2. BCME and CMME
         7.2. Short-term exposure
              7.2.1. BCEE
              7.2.2. BCME
              7.2.3. CMME
         7.3. Long-term exposure/carcinogenicity
              7.3.1. BCEE
              7.3.2. BCME
              7.3.3. CMME
         7.4. Mutagenicity and related end-points
              7.4.1. BCEE
              7.4.2. BCME
              7.4.3. CMME
         7.5. Other toxicity studies

    8. EFFECTS ON HUMANS

         8.1. General population exposure
              8.1.1. Human exposure studies
         8.2. Occupational exposure
              8.2.1. Case reports
              8.2.2. Epidemiological studies

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

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

         10.1. Evaluation of human health risks
              10.1.1. BCEE
              10.1.2. BCME and CMME
              10.1.3. Guidance values
         10.2. Evaluation of effects on the environment
              10.2.1. BCEE
              10.2.2. BCME and CMME

    11. RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH AND THE
         ENVIRONMENT

    12. FURTHER RESEARCH

    13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         REFERENCES

    RÉSUMÉ ET CONCLUSIONS

    RESUMEN Y CONCLUSIONES
    

    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. + 41 22 -
    9799111, fax no. + 41 22 - 7973460, E-mail irptc@unep.ch).

                                 *     *     *

         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 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 data bases 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

    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR SELECTED
    CHLOROALKYL ETHERS

     Members

    Dr D. Anderson, BIBRA Toxicology International, Carshalton,
         Surrey, United Kingdom

    Dr R. Chhabra, Division of Intramural Research, Environmental

         Toxicology Program, Toxicology Branch, National Institute of
         Environmental Health Sciences, Research Triangle Park, North
         Carolina, USA  (Chairman)

    Dr H. Ellisa, Epidemiology Department, Rohm & Haas, Bristol,
         Pennsylvania, USA

    Dr B. Gilbert, FarManguinhos, FIOCRUZ, Institute of
         Pharmaceutical Technology, Ministry of Health, Rio de Janeiro,
         Brazil

    Professor M. Jakubowski, Occupational and Environmental
         Hygiene Division, Nofer Institute of Occupational Medicine, Lodz,
         Poland

    Dr S.K. Kashyap, National Institute of Occupational Health,
         Meghani Nagar, Ahmedabad, India  (Vice-chairman)

    Dr R. Liteplo, Environmental Health Directorate, Health Protection
         Branch, Environmental Health Centre, Ottawa, Ontario, Canada
          (Co-rapporteur)

    Dr E.E. McConnell, Laurdane Estates, Raleigh, North Carolina,
         USA

    Dr H. Naito, Ibaraki Prefecture University of Health Sciences,
         Amimachi, Inashikigun, Japan

    Dr W. Popp, Universitätsklinikum Essen, Institut für Hygiene und 
         Arbeitsmedizin, Essen, Germany

    Dr R. Sram, Laboratory of Genetic Ecotoxicology, c/o Institute of
         Experimental Medicine, Prague, Czech Republic



                         

    a Invited, but unable to attend.

    Dr Shou-Zheng Xue, Toxicology Programme, Shanghai Medical
         University, Shanghai, China

     Secretariat

    Dr G.C. Becking, IPCS/IRRU, World Health Organization,
         Research Triangle Park, North Carolina, USA

    Ms R. Gomes, Health Canada, Environmental Health Directorate,
         Tunney's Pasture, Ottawa, Ontario, Canada  (Co-rapporteur)

    IPCS TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR SELECTED
    CHLOROALKYL ETHERS

         A WHO Task Group on Environmental Health Criteria for Selected
    Chloroalkyl Ethers met at the British Industrial Biological Research
    Association (BIBRA) Toxicology International, Carshalton, Surrey,
    United Kingdom, from 18 to 23 March 1996.  Dr D. Anderson opened the
    meeting and welcomed the participants on behalf of the host institute. 
    Dr G.C. Becking, IPCS, welcomed the participants on behalf of Dr M.
    Mercier, Director of the IPCS and the three cooperating organizations
    (UNEP/ILO/WHO).  The Task Group reviewed and revised the draft
    criteria monograph and made an evaluation of the risks to human health
    and the environment from exposure to selected chloroalkyl ethers.

         Financial support for this Task Group was provided by the United
    Kingdom Department of Health as part of its contribution to the IPCS.

         The first and second drafts of this monograph were prepared by Dr
    R. Liteplo and Ms R. Gomes, Health Canada, Ottawa.  The second draft
    incorporated the comments received following circulation of the first
    draft to the IPCS contact points for environmental health criteria
    monographs.

         Dr G.C. Becking (IPCS Central Unit, Interregional Research Unit)
    and Dr P.G. Jenkins (IPCS Central Unit, Geneva) were responsible for
    the overall scientific content and technical editing, respectively.

         The efforts of all who helped in the preparation of the document
    are gratefully acknowledged.

    ABBREVIATIONS

              BCEE      bis(2-chloroethyl) ether

              BCME      bis(chloromethyl) ether 

              CMME      chloromethyl methyl ether

              MTD       maximum tolerated dose 

              PMA       phorbol myristate acetate

              TDGA      thiodiglycolic acid

    1.  SUMMARY AND CONCLUSIONS

    1.1  Identity, physical and chemical properties, analytical methods

         Bis(2-chloroethyl) ether (BCEE), bis(chloromethyl) ether (BCME)
    and chloromethyl methyl ether (CMME) are chemicals from a large class
    known as chloroalkyl ethers. The three ethers are colourless volatile
    liquids at room temperature having characteristic odours. The vapour
    pressure of these three compounds is high. The solubility of BCEE is
    1.7% in water and its octanol/water partition coefficient is 1.46. The
    alpha-chloroalkyl ethers BCME and CMME are reactive compounds,
    hydrolysing rapidly in aqueous media (with half-lives of approximately
    38 seconds and <0.007 seconds, respectively); hydrolysis of the more
    stable ß-chloroether BCEE is slower (with a half-life in water of
    about 20 years).

         Sampling and analytical methods have been described for BCEE in
    water and for BCME and CMME in air.  Typically, determination is by
    gas chromatography (GC-electron capture) or GC mass spectrometry.

    1.2  Sources of human exposure

         Natural sources of BCEE, BCME or CMME in the environment have not
    been identified. The recent production data available are limited and
    confined to the USA and Canada. Approximately 104 tonnes of BCEE were
    produced in the USA in 1986 for use as a solvent and in the production
    of polymers and several industrial processes. Industrial uses of BCME
    are currently restricted in the USA to specific intermediate chemical
    reactions. BCME has also been produced for use in the production of
    ion exchange resins, manufacture of other polymers, and as a solvent
    in polymerization reactions. In China, some 200 tonnes of BCME are
    produced annually as an intermediate in the manufacture of the
    insecticide synergist, octachlorodipropyl ether. Technical grade CMME
    contains from 1 to 8% BCME.

    1.3  Environmental transport, distribution and transformation

         The mobility and distribution of the selected chloroalkyl ethers
    is influenced by the high reactivity of BCME and CMME and the water
    solubility and stability of BCEE. The alpha-chloroalkyl ethers BCME
    and CMME are hydrolysed rapidly in aqueous media and degraded quickly
    by photolysis. In aqueous media, the hydrolytic products of BCME and
    CMME are formaldehyde and hydrochloric acid, and methanol,
    formaldehyde and hydrochloric acid, respectively. The decomposition
    products of BCME and CMME in air include hydrogen chloride,
    formaldehyde and chloromethylformate, and chloromethyl and methyl
    formate, respectively. BCEE is soluble in water; rainfall removes it
    from the atmosphere and it tends to remain in water with very slow
    hydrolysis. BCEE evaporates from surface water within a week and is
    degraded in a little more than a day in the atmosphere by abiotic
    processes.

         Owing to the highly reactive nature of the alpha-chloroalkyl
    ethers in water and air, CMME and BCME are not expected to be present
    in the environment; however BCEE may be persistent due to the relative
    stability of ß-chloroalkyl ethers.

    1.4  Environmental levels and human exposure

         Only limited data on levels of BCEE in environmental media are
    available. It has been identified in air but not quantified; levels up
    to 0.42 µg/litre have been found in drinking-water in the USA.
    Reported levels of BCEE in groundwater have ranged from 0.001 µg/litre
    at an industrial gypsum waste disposal site in Belgium to 840 µg/litre
    near a waste disposal site in the USA. Higher concentrations have been
    measured in landfill leachates. Information on levels of BCEE in
    foodstuffs is not available, but bioaccumulation is not expected to
    occur.

         Quantitative data on levels of BCME or CMME in environmental
    media are not available.

         Based on the maximum reported level of BCEE in drinking-water,
    i.e., 0.42 µg/litre, the average human (64 kg) consuming 1.4
    litres/day would have an intake of about 0.01 µg/kg body weight per
    day from this source, with unknown amounts from other environmental
    sources. No estimates can be made on the daily intake of BCME and CMME
    from environmental sources. However, based upon the lack of
    persistence of BCME and CMME in the environment, average human
    exposure to these compounds is likely to be very low.

         Based on limited older data, workers in industries related to
    plastics and textile production could have been exposed to between 1.2
    and 72.9 µg BCME/m3 in workroom air. However, a recent study of a
    resin-manufacturing plant reported average occupational exposures
    ranging from 2.4 to 20.6 µg/m3. Data from other studies reported
    levels of BCME as low as 0.01 µg/m3. Higher occupational exposure to
    BCME occurred in China up until 1975 and still occurs on a lower level
    in the manufacture of octachlorodipropyl ether. General population
    exposure to BCME and CMME occurs where they are produced by the
    widespread burning of this synergist in mosquito coils.

         The highest reported concentrations of BCEE in the USA for
    industrial effluents are 8 to 170 µg/litre and for municipal and
    industrial waste landfill leachates 12 400 µg/litre.

    1.5  Kinetics and metabolism

         Quantitative information on the kinetics and metabolism of BCEE,
    BCME and CMME in humans is not available. However, it is anticipated
    that although  in vivo BCME and CMME would be rapidly hydrolysed in
    tissues to formaldehyde and hydrogen chloride, and methanol,
    formaldehyde and hydrogen chloride, respectively, there should be
    alkylation activity.

         Limited data show that radioactive BCEE administered to rats by
    inhalation or gavage is rapidly absorbed. Less than 3% of the
    radioactivity was retained 48 h after gavage dosing.

         BCEE is readily metabolized in rats. The principal metabolite is
    thiodiglycolic acid (TDGA). After rats were given a single gavage dose
    of [14C]-BCEE, approximately 12% of the administered radioactivity
    was present as 14CO2.

         BCEE is eliminated quickly in both rats and rhesus monkeys. Less
    than 2% of the radioactivity was recovered in the faeces of monkeys 72
    h after oral administration of [14C]-BCEE; approximately 2.3% of the
    administered radioactivity was found in rat tissues or faeces 48 h
    after dosing. Over 50% of the radioactivity was recovered in the urine
    and exhaled air 12 h after a gavage dose of [14C]-BCEE was
    administered to rats. Less than 2% of the radioactivity expired
    through the lungs was exhaled as the parent compound.

    1.6  Effects on laboratory animals and  in vitro test systems

         BCEE is acutely toxic by the oral, inhalation or dermal routes of
    exposure. Reported LD50 values for the oral exposure of animal
    species to BCEE range from 75 to 215 mg/kg body weight. BCME and CMME
    are acutely toxic by inhalation or ingestion. Reported LC50 values
    for the inhalation exposure of laboratory animals to BCME or CMME
    range from 25 to 48 mg/m3, and from 182 to 215 mg/m3, respectively.

         Exposure of laboratory animals by inhalation to high single
    concentrations of BCEE (>320 mg/m3) resulted in eye irritation as
    well as congestion, oedema, and haemorrhage in the lungs. During
    inhalation of BCME, irritation of the eyes and respiratory tract were
    noted as well as necrotizing bronchitis. Skin application resulted in
    erythema and necrosis, and application to the eye resulted in corneal
    necrosis. Similar effects were noted after exposure to CMME.

         Increased mortality and tracheal hyperplasia were observed in
    rats and hamsters following multiple inhalation exposure to 4.7 mg
    BCME/m3. Similar results were observed in rats repeatedly exposed by
    inhalation to 3.3 or 33 mg CMME/m3.

         In general, positive results were obtained when BCEE, BCME and
    CMME were tested for mutagenicity  in vitro. However, interpretation
    of the results is difficult given the lack of details in the reports
    available. BCME and CMME have been reported to increase unscheduled
    DNA synthesis  in vitro, and BCME increased the level of transformed
    cells in  in vitro assays.

         In small groups of males from two strains of hybrid F1 mice (and
    in females from one F1 strain) treated orally with BCEE
    (time-weighted dose 41.3 mg/kg body weight over 18 months), there was
    a significant increase in the incidence of hepatomas (combined benign
    hepatomas and malignant tumours) compared to unexposed controls. Four

    other limited studies in rats and mice using oral gavage, subcutaneous
    or intraperitoneal injection and skin painting failed to confirm these
    findings.

         Carcinogenicity studies in experimental animals (mice and rats)
    exposed to BCME showed significantly elevated incidence of pulmonary
    adenomas and respiratory tumours. In mice, inhalation exposure also
    showed evidence of an elevated incidence of lung tumours.

         Studies with CMME have shown an increased incidence of tracheal
    metaplasia and bronchial hyperplasia in a dose-dependent manner in
    rats. However, results of carcinogenicity bioassays are inconclusive
    in animal studies.

         Information regarding the reproductive, developmental,
    immunological or neurological toxicity of BCEE, BCME or CMME is not
    available.

    1.7  Effects on humans

         BCEE was found to be irritating to the eyes and nasal passages of
    humans at levels >150 mg/m3 following short-term exposure.

         No epidemiological studies on the effects of long-term exposure
    to BCEE have been reported.

         In eight epidemiological studies, exposure of workers to BCME
    (CMME) was associated with increased risk of lung cancer. Workers
    exposed to commercial grade CMME were probably also exposed to BCME.
    The predominant tumours in exposed workers were small cell carcinomas,
    quite distinct from the chiefly squamous cell carcinomas usually found
    in smokers. The association between exposure to BCME (CMME) and lung
    cancer was strong, with standardized mortality ratios ranging up to
    21. The type of lung cancer, latency period and average age of
    appearance of lung tumours in workers exposed to BCME (CMME) have been
    remarkably consistent. For CMME, there is also evidence of a positive
    relationship between a qualitative measure of exposure and mortality
    due to lung cancer.

         Even concentrations of 0.01 µg BCME/m3 and 20 µg CMME/m3, in
    the course of occupational exposure, increased the frequency of
    chromosomal aberrations in the peripheral lymphocytes of exposed
    workers.

         Information has not been reported regarding the neurological,
    immunological, developmental or reproductive effects of BCME or CMME
    in humans.

    1.8  Effects on other organisms in the laboratory and field

         There have been few studies on the effects of BCEE on
    environmental organisms; most are restricted to aquatic species. For
    BCEE a 7-day LC50 concentration in the guppy of 56.9 mg/litre, a 96-h
    LC50 in fish of 600 mg/litre and a 48-h LC50 in  Daphnia magna of
    240 mg/litre have been reported.

         Anaerobic microbial activity was not inhibited at concentrations
    of BCEE up to 100 mg/litre and an LC10 of 600 µg/litre has been
    reported for microbes indigenous to waste stabilization ponds.

         No information on the toxicological effects of BCME and CMME on
    environmental organisms has been reported.

    1.9  Conclusions

    1.9.1  BCEE

    -    Exposure of terrestrial organisms to BCEE is considered to be
         negligible because of the low rate of release and its short
         persistence in the atmosphere.

    -    Although it is more persistent in water, the highest reported
         concentration of BCEE in surface water is approximately five
         orders of magnitude lower than the concentration found to induce
         adverse effects in the guppy, the most sensitive aquatic species
         identified among existing toxicity studies.

    -    Owing to the lack of available information on concentrations of
         BCEE in several environmental media to which humans are exposed,
         it is not possible to estimate quantitatively the total daily
         intake of BCEE.

    -    Available data on the toxicity of BCEE in humans are limited.
         Information on the developmental and reproductive effects of BCEE
         in laboratory animals has not been identified, and none of the
         long-term studies in laboratory animals is of sufficient quality
         to provide quantitative information on either the potential of
         BCEE to cause cancer or the toxicological effects produced by
         long-term exposure to this substance.

    -    In the absence of adequate toxicological and carcinogenicity
         data, it is prudent to minimize human exposure to BCEE.

    1.9.2  BCME and CMME

    -    If these substances were to enter the environment, they would
         both be rapidly broken down by hydrolysis and photo-oxidation.
         Data concerning concentrations of BCME and CMME in the ambient
         environment have not been reported.

    -    BCME and technical grade CMME (which contains BCME) are proven
         human carcinogens. In addition, both of these chemicals are
         carcinogens in laboratory animals. Both chemicals cause
         chromosomal aberrations in occupationally exposed workers.
         Occupational and general population exposure to these compounds
         should be eliminated.

    -    Based on the fate of these substances in the environment and the
         lack of exposure, there is no reason to suspect that adverse
         effects on aquatic and terrestrial organisms would occur.

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

    2.1  Identity

         Bis(2-chloroethyl) ether (BCEE), bis(chloromethyl) ether (BCME)
    and chloromethyl methyl ether (CMME) are included in a large class of
    chemical substances known as the chloroalkyl ethers. Identifying
    features of BCEE, BCME and CMME are summarized in Table 1.

    2.2  Physical and chemical properties

         BCEE, a ß-chloroalkyl ether, is a colourless, volatile liquid
    with a "chlorinated solvent-like" odour (Sittig, 1981). BCME and CMME,
    both alpha-chloroalkyl ethers, are also colourless, volatile liquids
    with characteristic odours. The odour of BCME has been described as
    "suffocating" (Sittig, 1981; Verschueren, 1983), while that of CMME
    has been described as "irritating" (Verschueren, 1983). Technical
    grade CMME contains from 1 to 8% BCME (Travenius, 1982) and, unless
    otherwise indicated in this monograph, CMME refers to the technical
    grade material. In general, the vapour pressure and water solubility
    of these compounds are high, and the log octanol/water partition
    coefficients (log Kow) are low. The ß-chloroalkylethers like BCEE are
    only slightly reactive towards water, but the alpha-chloroalkyl ethers
    like BCME and CMME are rapidly hydrolysed by water, and their
    solubility, Kow, Koc and Henry's Law constant cannot be
    experimentally determined. The physical and chemical properties of the
    selected chloroalkyl ethers are presented in Table 2.

    2.3  Conversion factors

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

         BCEE:     1 ppm (v/v) = 5.85 mg/m3; 1 mg/m3 = 0.17 ppm
         BCME:     1 ppm (v/v) = 4.7 mg/m3; 1 mg/m3 = 0.21 ppm
         CMME:     1 ppm (v/v) = 3.3 mg/m3; 1 mg/m3 = 0.30 ppm


    2.4  Analytical methods

    2.4.1  BCEE

         One method for the analysis of BCEE in water involves solvent
    extraction (using diethyl ether in pentane, methylene chloride, or
    ethyl ether in hexane), concentration with a Kuderna-Danish (K-D)
    apparatus, and separation and analysis by gas chromatography with
    electron capture detection (GC/EC) or gas chromatography mass
    spectrometry (GC/MS) (Dressman et al., 1977; Quaghebeur et al., 1986).
    This method has been expanded to include clean-up with Florisil and
    K-D concentration of the sorbed fraction prior to analysis by GC/EC
    (McMillin et al., 1984). Vapour stripping using helium or nitrogen gas
    has also been used to extract BCEE from samples of ground and surface


        Table 1.  Information on the identity of BCEE, BCME and CMME (US NLM, 1996)

                                                                                                                                               

    Compound                     Identification   Molecular   Chemical structure     Relative         Synonyms
    (CAS number)a                                 formula                            molecular mass
                                                                                                                                               

    Bis(2-chloroethyl) ether     BCEE             C4H8Cl2O    Cl-(CH2)2-O-(CH2)2-Cl  143.02           dichloroethyl ether,
    (111-44-4)                                                                                        dichloroethyl oxide,
                                                                                                      bis (ß-chloroethyl) ether,
                                                                                                      dichloroether,
                                                                                                      1,1'-oxybis(2-chloro)ethane,
                                                                                                      1,5-dichloro-3-oxapentane,
                                                                                                      1-chloro-2-(ß-chloroethoxy)-
                                                                                                      ethane,
                                                                                                      2,2'-dichloroethyl ether,
                                                                                                      ß,ß'-dichlorodiethyl ether,
                                                                                                      bis(chloro-2-ethyl) oxide,
                                                                                                      di(ß-chloroethyl) ether,
                                                                                                      di(2-chloroethyl) ether,
                                                                                                      ether, bis(2-chloroethyl),
                                                                                                      sym-dichloroethyl ether,
                                                                                                      diethylene glycol dichloride.

    Bis(chloromethyl) ether      BCME             C2H4Cl2O    Cl-CH2-O-CH2-Cl        114.97           chloro(chloromethoxy) methane,
    (542-88-1)                                                                                        sym-dichloro-dimethyl ether,
                                                                                                      oxybis(chloromethane),
                                                                                                      dichloromethyl ether,
                                                                                                      bichloromethyl ether,
                                                                                                      dichlorodimethyl ether,
                                                                                                      1,1'-dichlorodimethyl ether.
                                                                                                                                               

    Table 1.  (continued)

                                                                                                                                               

    Compound                     Identification   Molecular   Chemical structure     Relative         Synonyms
    (CAS number)a                                 formula                            molecular mass
                                                                                                                                               

    Chloromethyl methyl ether    CMME             C2H5ClO     Cl-CH2-O-CH3           80.52            chloromethoxymethane,
    (107-30-2)                                                                                        monochlorodimethyl ether,
                                                                                                      methoxymethyl chloride,
                                                                                                      chlorodimethyl ether,
                                                                                                      methyl chloromethyl ether,
                                                                                                      monochloromethyl methyl ether.
                                                                                                                                               

    a  Chemical Abstracts Services registry number.

    Table 2.  Physical and chemical properties of BCEE, BCME and CMME

                                                                                                                                           

    Physical/chemical property     BCEE                                        BCME                           CMME
                                                                                                                                           

    Melting point (°C)             -50a                                        -41.5a                         -103.5b
    Boiling point (°C)             178.67a                                     104a                           59.5b
    Vapour pressure (mmHg)         0.71 at 20°Cb                               30 at 22°Cc                    122 at 20°Cd
    Vapour density                 4.93b                                       3.97b                          2.8d
    Water solubility (mg/litre)    10 200b                                     NA                             NA
    Log octanol/water partition
      coefficient (log Kow)        1.46c                                       NA                             NA
    Henry's Law constant
      (atm.m3/mol)                 1.31 x 10-5c                                NA                             NA
    Soil sorption coefficient 
      (log Koc)                    1.1c                                        NA                             NA
    Hydrolysis rate constant
       in water                    4 x 10-6 h-1 at 25°Cc                       0.05 sec-1h                    >90 sec-1 at 25°Ce
       in air                      not available                               1.7 x 10-1 sec-1 at 45°Ci      0.0018 min-1 at 29°Ck

    Photolysis rate constant
      in water                     24 to <360 mol-1.h-1c                       3 to <360 mol-1.h-1c           not available
      in air                       1.79 x 10-11 cm3.mol-1.sec-1f               not available                  1.0 x 10-10 mol-1.sec-1e

    Half-life
      in water                     20 years at 25°C (hydrolysis)c              38 sec at 20°C (hydrolysis)j   <0.007 sec at 25°Ce
      in air                       13.44 h at 25°C (indirect photolysis)f      >25 h at 25°C (hydrolysis)k    3.5 to 6 min at 25°C
                                                                                                              (hydrolysis)i 

      in soil                      1 to 6 months (estimate)g                   not available                  not available
                                                                                                                                           

    Table 2 (continued)

    a  Weast & Astle (1985)        g  Howard et al. (1991)
    b  Verschueren (1983)          h  Tou & Kallos (1974a)
    c  Mabey et al. (1982)         i  Nichols & Merritt (1973)
    d  CCINFO (1991)               j  US EPA (1980)
    e  Radding et al. (1977)       k  Tou & Kallos (1974b)
    f  US EPA (1987b)

    NA = not applicable. Due to the extremely rapid hydrolysis of this substance in water, it is not possible to obtain an experimental 
         value, and calculated values are meaningless.
    
    water. Typically, this step is followed by concentration of the
    extract with a cold or lipophilic vapour trap, and analysis by GC/MS
    (Hites et al., 1979; DeWalle & Chian, 1981). An additional technique
    has been described by Kleopfer & Fairless (1972), in which samples of
    water are passed through an activated carbon filter, followed by
    Soxhlet extraction of the carbon, drying of the extract with sodium
    sulfate, K-D concentration, Shriner-Fuson separation of the acidic,
    basic and neutral fractions, and analysis of the last by GC/MS.
    Determination of BCEE in air involves passing air samples through a
    sorbent, followed by elution and analysis by gas chromatography
    (NIOSH, 1984).

         Reported detection limits for these methodologies differ by up to
    two orders of magnitude. Detection limits for the procedure described
    by Dressman et al. (1977) and Quaghebeur et al. (1986) range from
    0.005 to 0.04 µg/litre, respectively. Limits of detection for the
    methods described by McMillin et al. (1984) and Kleopfer & Fairless
    (1972) are 0.3 and 0.2 µg/litre, respectively.

    2.4.2  BCME

         While information concerning the sampling and analysis of BCME in
    water, soil or foodstuffs was not available, considerable data on
    techniques for the analysis of low levels (µg/m3) of BCME in air have
    been identified (Collier, 1972; Evans et al., 1975; Frankel & Black,
    1976; Parkes et al., 1976; Kallos, 1981; Muller et al., 1981; Galvin &
    House, 1988; Blease et al., 1989). Typically, air samples are drawn
    into a (Poropak or Tenax) sorption tube, thermally eluted, and
    analysed by GC/MS or GC/EC. Two additional methods have been described
    which involve the direct derivatization of BCME (with
    2,4,6-trichlorophenol or sodium pentafluorophenolate), and subsequent
    analysis by GC/EC (Sawicki et al., 1976; Langelaan & Nielen, 1989).
    Norpoth et al. (1981) reported a spectrophotometric method for the
    determination of BCME. 

         Collier (1972), Frankel & Black (1976) and Galvin & House (1988)
    reported a detection limit of 470 ng/m3 for BCME in air, while Evans
    et al. (1975) and Langelaan & Nielen (1989) achieved detection limits
    as low as 50 and 14 ng/m3, respectively. Muller et al. (1981) did not
    report a detection limit, but quantified BCME at a concentration of
    2.35 µg/m3 in air. A detection limit of 0.94 µg/m3 was reported for
    the spectrophotometric quantification method described by Norpoth et
    al. (1981). The methods described by Sawicki et al. (1976) and Parkes
    et al. (1976) have a detection limit of 2.35 µg/m3, while a detection
    limit of approximately 4.7 ng/m3 was established for the method
    described by Blease et al. (1989), in which high resolution was
    achieved with the combined use of gas chromatography and tandem mass
    spectrometry (GC/MS/MS).

    2.4.3  CMME

         Identified methods for the sampling and analysis of CMME in
    environmental media are limited to techniques developed for monitoring
    low levels (µg/m3) in air. Several methods have been described which
    involve the derivatization of CMME (with 2,4,6-trichlorophenol or
    sodium pentafluorophenolate) and subsequent analysis by GC/EC (Sawicki
    et al., 1976; Kallos et al., 1977; Langhorst et al., 1981; Langhorst,
    1985; Langelaan & Nielen, 1989). The limits of detection for these
    methodologies are 49 ng/m3 (Langelaan & Nielen, 1989), 1.65 µg/m3
    (Sawicki et al., 1976; Langhorst et al., 1981) and 3.29 µg/m3 (Kallos
    et al., 1977).

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         Natural sources of BCEE, BCME or CMME in the environment have not
    been identified. While BCME could be formed spontaneously from the
    reaction of formaldehyde and chloride ions in an acidic atmosphere,
    this reaction is unlikely in the general environment, although it may
    be important in occupational settings (Durkin et al., 1975; Tou &
    Kallos, 1976; Kallos & Tou, 1977; Travenius, 1982).

    3.2  Anthropogenic sources

    3.2.1  Production

         Only limited information on the production of BCEE, BCME or CMME
    has been reported.

    3.2.1.1  BCEE

         BCEE used to be prepared commercially in the USA as a by-product
    in the manufacture of ethylene oxide by the chlorohydrin process, but
    this process went out of use in the USA in 1973 (IARC, 1975). Other
    methods of production also involving ethylene glycol or ethylene,
    ethylene chlorohydrin and chlorine as reagents have been mentioned
    (Durkin et al., 1975; IARC, 1975; ATSDR, 1989a). In 1975, two US
    companies, one German and one Japanese company manufactured BCEE for
    captive use as a solvent or chemical intermediate (IARC, 1975).

    3.2.1.2  BCME

         BCME is formed when formaldehyde reacts with chloride ions in an
    acidic medium (Travenius, 1982). In China, BCME is produced by the
    reaction of paraformaldehyde and hydrogen chloride gas as an
    intermediate in the synthesis of the insecticide synergist S-2,
    octachlorodipropyl ether [bis(1,2,3,3-tetrachloropropyl)ether] to
    which it is converted in a one-part process. The scale of S-2
    production is believed to be around 700 tonnes/year, which would
    require over 200 tonnes of BCME. Specific synthesis reactions include
    the reaction between paraformaldehyde and chlorosulfonic acid (Durkin
    et al., 1975) and the saturation of a paraformaldehyde solution in
    cold sulfuric acid with hydrogen chloride (US EPA, 1980). Small
    amounts (several percent) of BCME are also produced during the
    synthesis of CMME from gaseous hydrogen chloride and heated methanol
    and formaldehyde (Durkin et al., 1975). In addition, the decomposition
    products of commercial forms of CMME can combine to produce 1 to 8%
    BCME as an impurity (Travenius, 1982). While BCME is not produced in
    commercial quantities in Canada or the USA, it has been produced in
    small quantities for use as a chemical intermediate in laboratory
    applications (IARC, 1974).

    3.2.1.3  CMME

         CMME is produced by the reaction of anhydrous hydrogen chloride,
    methanol and formaldehyde (Fishbein, 1979) or by the direct
    chlorination of dimethyl ether (Durkin et al., 1975). An additional
    method, which is designed to produce CMME that is free of BCME
    impurities, involves the addition of actinium chloride to a slight
    excess of anhydrous dimethoxymethane at room temperature (CCINFO,
    1991). Production of CMME in the USA was estimated to be at least 4590
    tonnes in 1977 and about 2.27 tonnes in 1982 (HSDB, 1996).

    3.2.2  Uses

         Only information concerning the use of BCEE, BCME or CMME in
    Canada and the USA is available.

    3.2.2.1  BCEE

         In the USA, BCEE was formerly used in the process for the
    manufacture of methyldithiocarbamic acid fungicide commonly known as
    metham-sodium. Besides this use, approximately 20% of the BCEE sold in
    the USA was used in the production of polymers, and 7% was either used
    to synthesize a derivative of diquat or recycled for use as a
    co-solvent (S. Helmhout, personal communication to the IPCS, 1992).
    Other applications have included its use as a solvent for fats, waxes,
    greases and esters; as a constituent of paints, varnishes and
    lacquers; as a solvent for the removal of fatty substances from
    various textiles, and as a penetrant and wetting agent in the textile
    industry. It has also been used in the purification of oils and
    gasoline, as a soil fumigant, insecticide and acaricide, and as an
    intermediate in the manufacture of pharmaceuticals and other chemicals
    (Durkin et al., 1975; IARC, 1975; US EPA, 1987a; ATSDR, 1989a).

    3.2.2.2  BCME

         In the USA, industrial use of BCME has been restricted since the
    early 1980s to specific intermediate chemical reactions (Travenius,
    1982). In China, BCME is an intermediate in the production of the
    insecticide synergist S-2, octachlorodipropylether (see section
    3.2.1.2). In the past, BCME has been used as a chloromethylating agent
    in the production of ion exchange resins, water repellents and other
    textile-treating agents, the manufacture of polymers, and a solvent
    for polymerization reactions (Fishbein, 1979). Specific minor uses of
    BCME have included the crosslinking of cellulose, the preparation of
    three-block styrene-butadiene-styrene polymers, and the surface
    treatment of vulcanized rubber to increase adhesion of epoxy resin and
    polyurethane elastomers (Durkin et al., 1975).

         Available data indicate that there is currently no commercial
    activity involving more than one kilogram of BCME in Canada
    (Government of Canada, 1993b).

    3.2.2.3  CMME

         In the USA, industrial use of CMME has been restricted since the
    early 1980s to specific intermediate chemical reactions (Travenius,
    1982). Based on available data, there is currently no commercial
    activity in Canada involving more than one kilogram of CMME
    (Government of Canada, 1993b).

         In the past, CMME has been used as a chloromethylating agent in
    many synthetic processes, most notably in the production of anion
    exchange resins (Durkin et al., 1975). It has also been used as a
    solvent for polymerization reactions (Fishbein, 1979), in the
    synthesis of methoxymethyl ethers of phenols, the crosslinking of
    polystyrene, and the surface treatment of vulcanized rubber (Durkin et
    al., 1975).

    3.2.3  Sources in the environment

         Information on the release of BCEE, BCME and CMME in countries
    other than the USA and Canada has not been reported.

    3.2.3.1  BCEE

         BCEE may enter the environment as a by-product from the
    chlorination of waste streams containing ethylene or propylene, and as
    a contaminant in the fungicide metam-sodium. It has been estimated,
    based on the quantities imported and the known level of contamination,
    that less than 100 g of BCEE would have been released into the
    Canadian environment in 1990 from metam-sodium (Government of Canada,
    1993a). In the USA, a total of 2700 kg/year was estimated to be
    released into the environment from chemical plants in 1989. Seventy
    percent of this amount was reported to be emitted to the air, while
    the remaining 30% was released in water (US EPA, 1990). The
    chlorination of drinking-water containing diethyl ether can result in
    the formation of BCEE (NRC, 1977); however, quantitative data have not
    been identified. 

    3.2.3.2  BCME and CMME

         It was reported in the Toxic Release Inventory Database (US EPA,
    1990) that less than 1 kg of BCME and 50 kg of CMME were released into
    the atmosphere in the USA from industrial producers and users during
    1989. However, release occurred in the two-step production of
    octachlorodipropyl ether in China (Chen et al., 1996). This process
    ceased in 1975, but manufacture of octachlorodipropyl ether was
    revived in 1987 using a one-step process, from which gas releases and
    accidental liquid spills occur. There is no information on the amount
    of BCME that may remain as a contaminant of the product, which
    contains formaldehyde and hydrogen chloride (BCME's precursors). There
    is, however, gas-chromatographic evidence that CMME and BCME are
    released into the air by the burning of octachlorodipropyl ether in
    mosquito coils. No information is available from these sources

    concerning the release of BCME or CMME into other media (water, soil,
    underground injection), but, owing to their rapid rate of hydrolysis,
    these compounds are not expected to remain as such for prolonged
    periods in waste streams from plants where they are produced or used
    (IARC, 1974).

         The spontaneous formation of BCME or CMME in drinking-water from
    the chlorination of ethers has not been investigated. However, in view
    of their rapid rate of hydrolysis (see section 4.2.2), it is unlikely
    that BCME or CMME would be present as contaminants in drinking-water
    (Durkin et al., 1975).

         No information has been identified concerning the quantities of
    BCME or CMME released into the environment during storage or
    transportation. However, these amounts are likely to be insignificant
    since BCME and CMME have been usually produced and used in "closed
    system" operations where containment prevents the release of these
    chemicals into the environment (Durkin et al., 1975).

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    4.1  Transport and distribution between media

    4.1.1  BCEE

         Based on the low-to-moderate Henry's Law constant (1.3 × 10-5
    atm.m3/mol), BCEE would tend to remain in water. The air/water ratio,
    as well as the Henry's Law constant, will determine the amounts of
    BCEE distributed between the two compartments. Rainfall would probably
    result in the removal of BCEE from the atmosphere (Durkin et al.,
    1975). Using the approach of Mackay & Wolkoff (1973), Durkin et al.
    (1975) calculated the half-life with respect to volatilization of BCEE
    from a body of water to be 5.78 days at 25°C. Similarly, a
    volatilization half-life of 3.4 days (from water) was calculated by
    the US EPA (1987b). Thus the removal of BCEE from surface water will
    probably occur within a week, although it will persist in bottom
    water. Based upon its low log Koc (organic carbon partition
    coefficient) and high water solubility, BCEE is not expected to adsorb
    to soil or sediment and is therefore considered to be mobile in these
    media (US EPA, 1987b). The US EPA (1987b) reported that, because of
    its vapour pressure, BCEE should volatilize relatively rapidly from
    dry surfaces. In the only study dealing with soil volatilization (a
    7-day microcosm study by Piwoni et al. (1986) in which the soil was
    kept moist), an insignificant amount (3%) of applied BCEE was
    calculated to have volatilized.

    4.1.2  BCME and CMME

         Information regarding the mobility and distribution of BCME and
    CMME in environmental media is limited. Callahan et al. (1979)
    suggested that BCME could volatilize rapidly from an aquatic system
    only if it were discharged in a water-immiscible solvent with a high
    vapour pressure. Once in the atmosphere, these substances would be
    rapidly degraded by photo-oxidation or hydrolysis. Very little
    information was identified concerning the behaviour of BCME or CMME in
    soil. It is unlikely that BCME and CMME are mobile in soil as both
    compounds hydrolyse rapidly in an aqueous environment.

    4.2  Abiotic degradation

    4.2.1  BCEE

         At a temperature of 20°C in water, a hydrolysis half-life of 20
    to 22 years was estimated for BCEE (Mabey et al., 1982; Milano et al.,
    1989). The US EPA estimated the half-life for the reaction of BCEE
    with hydroxyl radicals in the atmosphere to be approximately 2.8 days
    (A. Leifer, Office of Toxic Substances, US EPA, personal
    communication, 1992). A half-life of 13.4 h has been reported for the
    indirect photolysis of BCEE in the gaseous phase (US EPA, 1987b).
    Photolysis products of BCEE include 2-chloroethanol, ethyl alcohol,
    methyl alcohol, 2-chloroethyl ethyl ether, peracetic acetic acid,

    1-(2-chloroethoxy)-1,2-epoxyethane, acetaldehyde and chloracetaldehyde
    (Milano et al., 1989).

    4.2.2  BCME and CMME

         BCME and CMME are removed from environmental media via abiotic
    processes. In the atmosphere, these substances are degraded by
    photo-oxidation or hydrolysis. Cuppit (1980) reported atmospheric
    half-lives of < 2.9 days for BCME and < 3.9 days for CMME. Tou &
    Kallos (1974a) reported half-lives for atmospheric hydrolysis of
    > 1 day for BCME and between 0.0024 (Nichols & Merritt, 1973) and
    0.27 days for CMME, in humid air. At low humidity levels, however,
    BCME may be degraded by oxidative as well as hydrolytic pathways. In
    air, the decomposition products for BCME include hydrogen chloride,
    formaldehyde and chloromethylformate, while those of CMME include
    chloromethyl and methyl formate (Cupitt, 1980).

         BCME and CMME hydrolyse rapidly in water. At 20°C, half-lives in
    water of 38 seconds for BCME and < 1 second for CMME have been
    reported (Tou et al., 1974; Radding et al., 1977; US EPA, 1980).
    Although BCME may be degraded by oxidation, the extremely rapid
    hydrolysis of BCME in aqueous media precludes any significant
    oxidative degradation of this substance in aquatic systems (Callahan
    et al., 1979). BCME is hydrolysed to formaldehyde and hydrogen
    chloride (ATSDR, 1989b), while CMME is hydrolysed to hydrogen
    chloride, methanol and formaldehyde (Travenius, 1982).

    4.3  Biodegradation, biotransformation and bioaccumulation

    4.3.1  BCEE

         In the only study identified, Tabak et al. (1981) reported that
    BCEE was completely biodegraded within 7 days in an aqueous medium
    inoculated with sewage sludge. Although data on the biodegradation of
    BCEE in soil are limited, this process may play some role in the fate
    of this substance in soil. Kincannon & Lin (1986) reported a half-life
    of BCEE in soil of approximately 16.7 days, based on the results of a
    97-day soil column study in which the degradation of BCEE mixed with
    hexachloroethane (as a constituent of a hazardous waste sludge) was
    quantified.

         For biota, Barrows et al. (1978) reported a bioconcentration
    factor (BCF) of 11 and a biological half-life of between 4 and 7 days
    for BCEE in bluegill sunfish  (Lepomis marochirus) based on the
    results of a study in which the fish were exposed to BCEE (under
    flow-through conditions) for 14 days at a mean water concentration of
    10 µg/litre.

    4.3.2  BCME and CMME

         No information on the biodegradation of either BCME or CMME in
    soil was identified. However, their high rates of hydrolysis in
    aqueous media preclude any possibility of BCME or CMME bioaccumulating
    in organisms.

    4.4  Ultimate fate following use

         Owing to the highly reactive nature of the
    alpha-chloroalkylethers in water and air, CMME and BCME are not
    expected to be present in the general environment (Durkin et al.,
    1975). However, owing to the relative stability of ß-chloroalkylethers
    in environmental media, BCEE may be persistent in the general
    environment (Durkin et al., 1975).

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  BCEE

         Quantitative information on the levels of BCEE in air is limited
    to a single study in the USA in which this substance was detected (but
    not quantified) in the atmosphere above two landfill sites in New
    Jersey (US NLM, 1996).

         Available data concerning the levels of BCEE detected in surface
    water and drinking-water are summarized in Tables 3 and 4,
    respectively. BCEE has been detected in samples of municipal
    drinking-water at mean concentrations of up to 0.42 µg/litre in the
    USA (Kraybill, 1977). The highest concentration reported for selected
    surface waters was 58 µg/litre in Belgium, in the vicinity of
    industrial discharges (Quaghebeur et al., 1986).

         Identified studies concerning the levels of BCEE in groundwater
    were limited to surveys conducted in the vicinity of contaminated
    areas; concentrations of BCEE ranged from 0.001 µg/litre in samples
    collected at an industrial gypsum waste disposal site in Belgium
    (Quaghebeur et al., 1986) to 840 µg/litre in samples collected near a
    municipal and industrial waste landfill site in the USA (DeWalle &
    Chian, 1981).

         Identified studies on the levels of BCEE in soil were limited to
    two investigations in which this compound was detected in samples
    collected from contaminated areas in the USA. BCEE was monitored (but
    not quantified) in samples of soil collected at Love Canal, New York
    (Hauser & Bromberg, 1982), and measured at a mean concentration of 140
    mg/kg in samples of soil from waste disposal sites in the USA (ATSDR,
    1989a).

         No information is available on the levels of BCEE in foodstuffs.
    Based on its high water solubility and low Kow, BCEE is not expected
    to bioaccumulate in fish or other aquatic species (ATSDR, 1989a).

         The concentration of BCEE in in-plant effluents in Canada has
    been reported to range from 6.1 to 1057 µg/litre (Government of
    Canada, 1993a). These effluents are diluted with cooling water before
    being discharged to the environment and, although levels of BCEE at
    the outflow pipe were not monitored, they were probably below the
    limit of detection.

         The highest concentrations of BCEE in the USA were reported for
    industrial effluents (8 to 170 µg/litre), and municipal and industrial
    waste landfill leachates (12 400 µg/litre) (DeWalle & Chian, 1981).


        Table 3.  Bis(2-chloroethyl) ether levels in surface water

                                                                                                                                          
    Location             Number of       Concentrationb     Remarks                                              Reference
                         samplesa        mean (range)
                                         (µg/litre)
                                                                                                                                          

    Philadelphia, USA    NR              ND                 samples collected from April 1975 to July 1975       Manwaring et al. (1977)
                                                            from the Delaware River, upstream from a 
                                                            water treatment plant

                         NR              trace              samples collected in April 1975 from the 
                                                            Delaware River, upstream from a chemical plant       Manwaring et al. (1977)

                         2               trace              samples collected in October 1976 from the 
                                                            Delaware River                                       Sheldon & Hites (1978)

                         5               (ND - trace)       samples collected in March 1977 from the 
                                                            Delaware River                                       Sheldon & Hites (1978);
                                                                                                                 US EPA (1980)
    New Orleans and
    Baton Rouge, USA     3               0.11 (0.04 - 0.16)                                                      Pellizzari et al. (1979)

    Houston, USA         1 (1)           1.4                                                                     Pellizzari et al. (1979)

    Nitro, USA           NR              0.041              samples collected from the Kanawha River             Rosen et al. (1963);
                                                                                                                 Durkin et al. (1975)

    USAc                 808 (3)         < 10.0  median     limit of detection, 10.0 µg/litre                    Staples et al. (1985) 

    Belgiumc             NR              (7 - 58)           samples collected from Haine River adjacent to 
                                                            industrial discharges                                Quaghebeur et al. (1986)

    Belgiumc             NR              (trace - 7.9)      samples collected from Durme River, Scheldt 
                                                            River and Gheut-Terneuzen Channel 
                                                            downstream from industrial discharges                Quaghebeur et al. (1986)
                                                                                                                                          

    a  Value in parenthesis indicates the number of samples with detectable levels of bis(2-chloroethyl) ether.
    b  Mean and/or (range) of concentrations, unless otherwise indicated; detection limits were reported, when possible. 
    c  Locations were not specified.
    NR = not reported;  ND = not detected


    Table 4.  Bis(2-chloroethyl) ether levels in drinking water

                                                                                                                                           

    Location             Number of     Concentrationb         Detection       Remarks                         Reference
                         samplesa      mean (range)           limit
                                       (µg/litre)             (µg/litre)
                                                                                                                                           

    Toronto, Canada      50 (0)        ND                     0.00003         finished drinking-water         Kendall (1990)

    Toronto, Canada      8 (0)         ND                     0.001           bottled spring water            Kendall (1990)

    Alberta, Canadac     1512 (1)      ND (ND - trace)        1               samples of treated (from 215    Alberta Ministry of the
                                                                              sites) and raw (from 14 sites)  Environment (1991)
                                                                              drinking-water 
                                                                              collected from January 1986 
                                                                              to June 1991 

    Nitro, USA           1 (1)         0.2                    NR              tap water                       DeWalle & Chian (1981)

    Evansville, USA      1             NQ                     NR              finished drinking-water         Kleopfer & Fairless (1972)

    Philadelphia, USA    NR            NQ                     NR              finished drinking-water         Suffet et al. (1980)
                                                                              collected between 1975 
                                                                              and 1977

    Philadelphia, USA    NR            < 0.1 (0.04 - 0.6)     NR              finished drinking-water         Manwaring et al. (1977)
                                                                              collected between February 
                                                                              1975 and July 1975

    New Orleans, USA     NR            (0.04 - 0.16)          NR              finished drinking-water         Keith et al. (1976)
                                                                              collected in August 1974

    Philadelphia, USA    NR            (0.03 - < 1)           NR              raw drinking-water collected    Manwaring et al. (1977)
                                                                              between April 1975 and 
                                                                              July 1975

    Philadelphia, USA    NR            (0.4 - 0.5)            NR              raw drinking-water              Durkin et al. (1975)
                                                                                                                                           

    Table 4.  (continued)

                                                                                                                                           

    Location             Number of     Concentrationb         Detection       Remarks                         Reference
                         samplesa      mean (range)           limit
                                       (µg/litre)             (µg/litre)
                                                                                                                                           

    USAc                 NR            0.42                   NR              finished drinking-water         Kraybill (1977)

                         NR            ND                     5               finished drinking-water         US EPA (1980)
                                                                              collected (between March 
                                                                              1976 and April 1976) from 
                                                                              112 cities during the 
                                                                              National Organics Monitoring 
                                                                              Survey (NOMS) (Phase I)

                         NR            0.0115 (ND - 0.36)     0.005           finished drinking-water         Dressman et al. (1977)
                                                                              collected (between May 1976 
                                                                              and June 1976) from 113 
                                                                              cities during the NOMS 
                                                                              (Phase II); BCEE was detected 
                                                                              in drinking-water from 13 
                                                                              cities at a mean concentration 
                                                                              of 0.10 µg/litre

    USAc                 NR            0.0017                 NR              finished drinking-water         US EPA (1980)
                                                                              collected (between November 
                                                                              1976 and June 1977) from 110 
                                                                              cities during the NOMS (Phase 
                                                                              III); BCEE was detected in 
                                                                              drinking-water from 8 cities 
                                                                              at a mean concentration of 
                                                                              0.024 µg/litre

                         NR            (0.02 - 0.12)          NR              drinking-water from 80 cities   Fishbein (1979)

    Netherlandsc         NR            0.1  maximum           NR                                              Kraybill (1977)
                                                                                                                                           

    Table 4 (continued)

    a Values in parenthesis indicate the number of samples with detectable levels of bis(2-chloroethyl) ether.
    b Mean and/or (range) of concentrations, unless otherwise indicated.
    c Locations were not specified
    ND = not detected
    NR = not reported
    NQ = not quantified
    
    5.1.2  BCME and CMME

         No information has been reported on levels of BCME or CMME in
    ambient air or the indoor air of homes or offices. In a small survey
    of outdoor air in the Netherlands, BCME and CMME were not detected
    (detection limits, 14.1 µg/m3 and 49.5 µg/m3, respectively) in
    samples collected in the neighbourhood of a potential emission source
    (distance and source were not specified) (Langelaan & Nielen, 1989).

         Available data on the levels of BCME or CMME in drinking-water,
    surface water or ground water are limited to one investigation in
    which BCME was not detected (detection limit, 10 µg/litre) in a total
    of 317 samples of surface and groundwater from unspecified locations
    in the USA (Staples et al., 1985).

         Quantitative data concerning the levels of BCME or CMME in soil
    have not been reported. However, in view of their rapid rate of
    hydrolysis, these compounds are not expected to persist as
    contaminants in moist soil (US NLM, 1996). Similarly, while no studies
    on the levels of BCME or CMME in foodstuffs have been reported, the
    high rates of hydrolysis reduce the likelihood of BCME or CMME
    bioaccumulating in the food chain (US NLM, 1996).

         No reliable data on levels of either BCME or CMME in industrial
    effluents have been reported.

    5.2  General population exposure

         Quantitative data concerning the levels of BCEE in the general
    environment are restricted to the results of studies in which the
    levels of this substance in surface water and drinking-water have been
    assessed. Based on a daily volume of ingestion for adults of 1.4
    litres, a mean body weight for males and females of 64 kg (IPCS,
    1994), and the highest mean concentration of BCEE in drinking-water
    presented in Table 4 (0.42 µg/litre), the estimated intake of BCEE
    from drinking-water for adults would be approximately 0.01 µg/kg body
    weight per day.

         Adequate information on the concentrations of BCME and CMME in
    air, drinking-water, soil, or foodstuffs have not been reported, and
    therefore it is not possible to estimate the intake of these
    substances. No quantitative data are available for the exposure of
    populations that use mosquito coils containing octachlorodipropyl
    ether (see section 3.2.3.2), but the number of users of such coils is
    of the order of millions in China.

    5.3  Occupational exposure

    5.3.1  BCEE

         Occupational exposure to BCEE (via inhalation or dermal contact)
    may occur in individuals involved in the dry cleaning and textile
    industries, or in the processing of gum, lacquer, oil, paint, soap and
    tar (Tabershaw et al., 1977). However, no investigations concerning
    quantitative levels of exposure to BCEE in the workplace have been
    reported.

    5.3.2  BCME and CMME

         Occupational exposure to BCME or CMME may occur in laboratory and
    textile workers, and in individuals involved in the production of
    anion-exchange resins, organic chemicals and polymers (Lemen et al.,
    1976; US EPA, 1980). In China, occupational exposure to BCME occurs in
    the manufacture of octachlorodipropyl ether. Under conditions where
    vapours of formaldehyde and hydrochloric acid co-exist, BCME may form
    spontaneously in air. Available quantitative data concerning
    occupational exposure to either BCME or CMME are limited to
    investigations of the levels of BCME in workroom air (Table 5).

         BCME may be produced in solution from a variety of sources of
    formaldehyde and chloride ions, and has been detected in the vapours
    above these solutions (Frankel et al., 1974). In one study, the
    concentration of BCME in the headspace above formalin slurries
    containing Freidel-Crafts (chloride) salts ranged from 0.99 to
    7.1 mg/m3 (210 to 1500 ppb) (Frankel et al., 1974).

         While no recent studies have been identified where levels of
    occupational exposure to CMME have been reported, it has been
    estimated that in the past, concentrations of CMME in workroom air may
    have ranged from 4.7 to 47 mg/m3 (1-10 ppm) (Travenius, 1982).


        Table 5.  Concentrations of bis(chloromethyl) ether in workroom air

                                                                                                                                         

    Industry                                  Sampling period            Concentrationa      Detection limit     Reference
                                                                         (µg/m3)             (µg/m3)
                                                                                                                                         

    Dye auxiliaries (resin) production;       Jan. 1976 - Aug. 1976      ND                  0.5 or 0.9          Yao & Miller (1979)
    dye manufacture; fertilizer 
    production; textile finishing on 
    woven goods; hospital procedures; 
    foundry products (research plant); 
    foundry products (full-scale plant) 
    (USA)

    Plastics industryb (USA)                  Jan. 1973                  <4.7 - 72.9         NR                  Eisner (1974)

    Textile finishing plants (4) (USA)        Nov. 1974 - Dec. 1974      <0.5 - 37.6         0.5                 Marceleno (1974)

    Chemical plant (UK)                       1978                       <4.7                NR                  Travenius (1982)

    Chemical plant (Netherlands)              NR                         1.2 - 3.8           0.5                 van der Ven & Venema 
                                                                                                                 (1979)

    Resin manufacturing plantd (France)       1979 - 1984                2.8 - 20.6          NR                  Gowers et al. (1993)
                                                                                                                                         

    a  Concentrations of bis(chloromethyl) ether measured in workroom air
    b  Samples of air collected at the Diamond Shamrock Chemical Company in California, in the vicinity of reactors used to condense 
       phenol and formaldehyde
    c  Unspecified industrial operations; location of sample acquisition was not reported
    d  Range of average concentrations from various areas in the plant
    ND - not detected
    NR - not reported
    
    6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS

         Quantitative information on the absorption, distribution,
    elimination and metabolism of BCEE, BCME or CMME in humans is not
    available.

    6.1  Absorption and distribution

         Gwinner et al. (1983) reported that more than 95% of the total
    [14C]-BCEE vapour (calculated to be approximately 75 mg) introduced
    into an inhalation chamber containing three male Wistar rats was
    absorbed by the animals after an 18-h exposure. When the tissue
    (protein)-associated radioactivity (per gram of tissue) was examined
    after this exposure period, approximately 0.32% of the administered
    radioactivity was present in the liver, while 0.17 and 0.12% were
    found in the kidney and small intestine, respectively. Only 0.07% of
    the administered radioactivity was present in the lungs. Lingg et al.
    (1982) administered by gavage a single dose of [14C]-BCEE (40 mg/kg
    body weight, dissolved in corn oil) to male Sprague-Dawley rats and
    monitored the amount of radioactivity present in a limited number of
    tissues during the subsequent 48-h period. After 48 h, the percentage
    of administered 14C was found to be 11.5 in expired CO2, 64.7 in
    urine, 2.4 in faeces, and 2.3 in organs and tissues. In tissues,
    approximately 1, 0.56, 0.49 and 0.19% of the radioactivity was
    retained in muscle, kidney, blood and liver, respectively.
    Quantitative data on the absorption and distribution of BCME or CMME
    in animal species have not been reported.

    6.2  Metabolism

         BCEE is readily metabolized following absorption. Thiodiglycolic
    acid (TDGA) was the principal metabolic product (representing 50 to
    80% of the total metabolites) in the urine of rats administered BCEE
    either orally, by intraperitoneal injection or by inhalation (Lingg et
    al., 1979, 1982; Muller et al., 1979; Norpoth et al., 1986).
    2-Chloroethoxy-acetic acid, N-acetyl-S-[2-(2-chloroethoxy)-ethyl]-L-
    cysteine, 1-(2-chloroethyl)-ß-D-glucopyranosiduronic acid and
    S-carboxymethyl-L-cysteine have been reported to be minor metabolites
    (each comprising less than 10% of the total) in the urine of rats
    administered BCEE (Lingg et al., 1979, 1982; Muller et al., 1979).
    Lingg et al. (1982) reported that in male Sprague-Dawley rats
    administered (by gavage) a single dose of [14C]-BCEE (40 mg/kg body
    weight, dissolved in corn oil), approximately 12% of the radioactivity
    was metabolized to 14CO2.

         The formation of TDGA from BCEE involves a number of steps (Lingg
    et al., 1979, 1982; Muller et al., 1979; Gwinner et al., 1983; Norpoth
    et al., 1986). BCEE is believed to undergo oxidative degradation
    (involving ether cleavage) to produce chloroacetaldehyde and
    chloroethanol (which itself is rapidly converted to
    chloroacetaldehyde) (Gwinner et al., 1983). It is believed that
    chloroacetaldehyde is subsequently converted to chloroacetic acid,
    which after conjugation with glutathione and further modification,

    produces TDGA. The formation of N-acetyl-S-[2-(2-chloroethoxy)ethyl]-
    L-cysteine is believed to involve the direct substitution of one of
    the chlorine atoms in BCEE with cysteine (Lingg et al., 1982).
    S-Carboxymethyl-L-cysteine, although not detected in all studies in
    which the metabolism of BCEE was examined, has been postulated to be
    an intermediate in the synthesis of TDGA (Lingg et al., 1982).
    1-(2-Chloroethyl)-ß-D-glucopyranosiduronic acid is evidence of the
    occurence of 2-chloroethanol among metabolic products, while
    S-carboxymethyl- n-cysteine may be produced by alkylation of
    glutathione by chloroacetaldehyde (Lingg et al., 1982), and
    2-chloroethoxy-acetic acid is believed to be produced via the
    oxidative dehalogenation of BCEE (Lingg et al., 1982).

         Information on the metabolism of BCME or CMME in laboratory
    animals has not been reported; however it is anticipated that BCME and
    CMME would be rapidly hydrolysed in the aqueous environment of
    tissues, forming formaldehyde and hydrogen chloride, and methanol,
    formaldehyde and hydrogen chloride, respectively. However, the effects
    of BCME (CMME) are most likely attributable to their direct alkylating
    activity (van Duuren, 1989).

    6.3  Elimination

         Although quantitative information on the elimination of BCME or
    CMME in laboratory animals is not available, limited quantitative data
    concerning the elimination of BCEE (administered orally) in laboratory
    animals have been reported. Lingg et al. (1982) administered (by
    gavage) a single dose of [14C]-BCEE (40 mg/kg body weight, dissolved
    in corn oil) to male Sprague-Dawley rats and monitored the amount of
    radioactivity appearing in the faeces, urine and expired air during
    the subsequent 48-h period. Twelve hours after the administration of
    [14C]-BCEE, 50% of the radioactivity had been lost in the urine and
    exhaled air (as 14CO2). Lingg et al. (1979) estimated that less than
    2% of the administered radioactivity that was expired through the
    lungs was exhaled as the parent compound. Forty-eight hours after the
    oral administration of [14C]-BCEE, approximately 65% of the
    radioactivity was excreted in the urine and 11.5% exhaled from the
    lungs (total loss of 76%); approximately 2.3 and 2.4% of the
    administered radioactivity remained in the organs (and tissues) and
    faeces, respectively.

         Smith et al. (1985) reported that 24, 48 and 72 h after the oral
    administration (by gavage) of [14C]-BCEE (10 mg/kg body weight, in a
    solution containing ethanol, Emulphor and distilled water) to two
    female Rhesus monkeys, approximately 43, 56 and 58% of the
    administered radioactivity had been eliminated in the urine.
    Seventy-two hours after the administration of [14C]-BCEE, less than
    2% of the radioactivity was recovered in the faeces.

    7.  EFFECTS ON EXPERIMENTAL MAMMALS AND  IN VITRO TEST SYSTEMS

    7.1  Single exposure

         Information on the acute toxicity of BCEE, BCME and CMME is
    summarized in Table 6.

    7.1.1  BCEE

         Although the acute toxicity of BCEE has been examined in a number
    of studies, complete experimental details were not always provided.
    Reported LD50 values for the oral exposure of animal species to BCEE
    range from 75 to 215 mg/kg body weight. An LC50 of 5850 mg/m3 (1000
    ppm) was estimated from studies in which Sherman strain rats were
    exposed to BCEE for 0.75 h (Smyth & Carpenter, 1948). The exposure of
    guinea-pigs to 5850 mg/m3 for 3.8 to 5.5 h resulted in the death of
    the animals (Schrenk et al., 1933). Exposure to 1521 mg/m3 (260 ppm)
    resulted in the death of the animals after 7.5 to 12.3 h of continuous
    exposure. No deaths were observed after exposure to 205 mg/m3 (35
    ppm) for up to 13.5 h, although slight nasal irritation was observed
    within 3 to 10 min of exposure to this concentration. Acute exposure
    of guinea-pigs to BCEE vapour (320 mg/m3) caused eye irritation (as
    indicated by squinting and lacrimation) as well as congestion, oedema
    and haemorrhage in the lungs; liver, kidney and brain congestion was
    also noted (Schrenk et al., 1933). The severity of the toxicological
    effects produced by exposure to the higher concentrations of BCEE was
    also related to the length of the exposure period. Effects in
    Sprague-Dawley rats or CD-1 mice administered a single oral dose of
    BCEE (dissolved in cottonseed oil) included ptosis, increased
    salivation, diarrhoea, decreased activity and ataxia (Drake & Myer,
    1992).

         Smyth & Carpenter (1948) reported that the dermal exposure of
    guinea-pigs to BCEE caused skin irritation; the LD50 was 366 mg/kg
    body weight.

    7.1.2  BCME and CMME

         Reported LC50 values for the exposure (by inhalation) of
    laboratory animals to BCME range from 25 to 48 mg/m3 (5.3 to 10.3
    ppm). The acute exposure (by inhalation) of animals to BCME produced
    severe irritation of the eyes and respiratory tract (congestion,
    oedema and haemorrhage (mainly of the lungs) and acute necrotizing
    bronchitis (Union Carbide, 1968; Drew et al., 1975). The median life
    span of rats exposed (by inhalation) to 0, 3.3, 9.9, 32.4 or 44.7
    mg/m3 (0, 0.7, 2.1, 6.9 or 9.5 ppm) was 462, 420, 36, 2 and 2 days,
    respectively. For hamsters exposed (by inhalation) to these
    concentrations of BCME, the median life span was 675, 657, 68, 16 and
    4 days, respectively (Drew et al., 1975). Exposure to 9.9 mg/m3 
    (2.1 ppm) for 7 h increased the incidence of tracheal and bronchial
    hyperplasia 2- to 3-fold in rats and 4- to 5-fold in hamsters,
    compared to unexposed controls (Drew et al., 1975).


        Table 6.  Acute toxicity of BCEE, BCME and CMME

                                                                                                                                      

    Speciesa                    Route                         LC50 or LD50                             Reference
                                                              (duration)
                                                                                                                                      

    BCEE
    Rat (Sherman)               inhalation (0.75 h)           LC50: 5850 mg/m3 (1000 ppm)              Smyth & Carpenter (1948)
    Rat (Sherman)               oral                          LD50: 75 mg/kg bw                        Smyth & Carpenter (1948)
    Rat                         oral                          LD50: 105 mg/kg bw                       Spector (1956)
    Rat (Sprague-Dawley)        oral                          LD50: 175 mg/kg bw                       Drake & Myer (1992)
    Mouse                       oral                          LD50: 136 mg/kg bw                       Spector (1956)
    Mouse (CD-1)                oral                          LD50: 215 mg/kg bw                       Drake & Myer (1992)
    Rabbit                      oral                          LD50: 126 mg/kg bw                       Spector (1956)
    Guinea-pig                  dermal (poultice;  24 h)      LD50: 366 mg/kg bw                       Smyth & Carpenter (1948)

    BCME
    Rat (Sprague-Dawley)        inhalation (7 h)              LC50: 33 mg/m3  (7 ppm)                  Drew et al. (1975)
    Rat                         inhalationb                   LC50: 48 mg/m3  (10.3 ppm)               Union Carbide (1968)
    Mouse (A/Heston)            inhalation (6 h)              LC50: 25 mg/m3  (5.3 ppm)                Leong et al. (1971)
    Hamster (Syrian)            inhalation (7 h)              LC50: 33 mg/m3  (7 ppm)                  Drew et al. (1975)
    Rat (Wistar)                oral (undiluted)              LD50: 0.21 ml/kg bw  (278 mg/kg bw)      Union Carbide (1968)
    Rabbit  (New Zealand)       dermal (undiluted; 24 h)      LD50: 0.28 ml/kg bw (370 mg/kg bw)       Union Carbide (1968)

    CMMEc
    Rat                         inhalation (7 h)              LC50: 182 mg/m3  (55 ppm)                Drew et al. (1975)
    Hamster                     inhalation (7 h)              LC50: 215 mg/m3  (65 ppm)                Drew et al. (1975)
    Rat                         oral                          LD50: 817 mg/kg bw                       NIOSH (1974)
                                                                                                                                      

    a Data on strain presented if reported in study.
    b Duration not specified.
    c Containing BCME.
    
         Reported LC50 values for the exposure (by inhalation) of
    laboratory animals to CMME range from 182 to 215 mg/m3 (55 to 65
    ppm). Exposure to CMME produced pulmonary congestion, oedema,
    haemorrhage and acute necrotizing bronchitis (Drew et al., 1975);
    however the toxic effects produced by CMME may be due, at least in
    part, to contaminating BCME.

         Application of BCME to the skin of rabbits produced erythema and
    necrosis, while exposure of the eye to this substance produced severe
    corneal necrosis (Union Carbide, 1968).

    7.2  Short-term exposure

    7.2.1  BCEE

         Information on the effects of short-term or subchronic exposure
    of animals to BCEE is limited primarily to range-finding studies for
    carcinogenicity bioassays. Theiss et al. (1977) reported that the
    maximum tolerated dose (MTD) of BCEE in A/St male mice (receiving 6
    intraperitoneal injections over a 2-week period) was 40 mg/kg body
    weight. The administration (route not clearly specified) of 19 daily
    doses (100 mg/kg body weight) of BCEE (deemed to be the MTD) to two
    strains of hybrid F1 mice [strain (C57BL/6 × C3H/Anf)F1 and strain
    (C57BL/6 × AKR)F1] had no effect on mortality, although other
    toxicological effects were not reported (Innes et al., 1969).

    7.2.2  BCME

         In one study (Drew et al., 1975) on the short-term toxicity of
    BCME, groups of 50 male Sprague-Dawley rats and Syrian hamsters were
    exposed by inhalation to 0 or 4.7 mg/m3 (0 or 1 ppm) for 1, 3, 10 or
    30 multiple 6-h exposures (duration between exposures not specified),
    after which time the animals were observed for their entire life span
    and the trachea and bronchi examined histopathologically. In groups of
    rats exposed to BCME for 0, 1, 3, 10 or 30 occasions, 50% mortality
    was observed after 66, 66, 20, 4 and 4 weeks, respectively. The
    incidence of tracheal hyperplasia, with and without atypias, increased
    from 27% after 1 exposure to 89% after 30 exposures to BCME. The
    incidence of tracheal squamous metaplasia increased after 3 to 30
    exposures. The incidence of bronchial hyperplasia and squamous
    metaplasia increased with greater exposure to BCME. In hamsters
    subjected to 0, 1, 3, 10 or 30 exposures (6-h) to BCME, 50% mortality
    was observed after 95, 95, 70, 22 and 8 weeks, respectively. The
    incidence of tracheal hyperplasia, with and without atypias, tracheal
    squamous metaplasia and alveolar metaplasia with atypia increased with
    more frequent exposure to BCME. Exposure to BCME also produced
    bronchoalveolar metaplasia, squamous metaplasia with atypia and
    atypical alveolar epithelium. Evidence of subarachnoid haemorrhage was
    observed in 24% of the rats and 8% of the hamsters that received 30
    exposures (6-h) to 4.7 mg/m3 (1 ppm) (Drew et al., 1975).

    7.2.3  CMME

         In one study on the short-term toxicity of CMME, groups of 25
    male Sprague-Dawley rats were exposed (by inhalation) to 3.3 or 33
    mg/m3 (1 or 10 ppm) for 30 days (duration and frequency of exposure
    not specified) (Drew et al., 1975). Exposure to 3.3 mg/m3 resulted in
    8% mortality, but no effect on body weight, within 30 days (data for
    unexposed controls were not presented). Regenerative hyperplasia and
    squamous metaplasia in bronchial epithelium were observed in rats
    killed 2 weeks after the last exposure. Exposure to 33 mg/m3 resulted
    in 88% mortality within 30 days (data for controls not presented);
    marked (not quantified) weight decrease was observed with some
    recovery towards the end of exposure. Significant (not quantified)
    increases in lung/body weight ratios were observed in rats that died
    after exposure to CMME; regenerative hyperplasia of bronchial
    epithelium was also observed.

    7.3  Long-term exposure/carcinogenicity

         Studies on long-term exposure and carcinogenicity are given in
    Table 7.

    7.3.1  BCEE

         Studies on the toxicological effects produced by the long-term
    exposure of laboratory animals to BCEE have focused on its
    carcinogenic potential. However there are numerous deficiencies in all
    of these studies, compared to the more stringent protocols used in
    current carcinogenicity bioassays.

         Innes et al. (1969) assessed the carcinogenicity of BCEE in mice
    following ingestion. Groups of 18 males and 18 females from two
    strains of hybrid F1 mice [(C57BL/6 × C3H/Anf) and (C57BL/6 × AKR)]
    were administered by stomach tube approximately 100 mg/kg body weight
    BCEE (dissolved in distilled water) from the age of 7 to 28 days
    (although the amount of BCEE was not adjusted during this period to
    account for weight gain). Once the mice had reached four weeks of age,
    the BCEE was then provided in the diet at a concentration of 300 mg/kg
    diet until the mice were 18 months of age, after which time they were
    killed and necropsied. The time-weighted average dose for these
    studies was calculated to be 41.3 mg/kg body weight per day (US EPA,
    1987a). There were multiple groups of controls consisting of animals
    of both strains and sexes. "Hepatomas" (representing benign hepatomas
    and malignant tumours), tumours of the pulmonary system (adenomas and
    adenocarcinomas) and lymphomas (Type-B reticulum cell sarcomas and
    leukaemias) were the predominant types of tumours observed in these
    animals. Compared to unexposed controls, the incidence of "hepatomas"
    was significantly (p = 0.01) increased in the treated (C57BL/6 ×
    C3H/Anf)F1 mice (in males, 8/79 versus 14/16; in females, 0/87 versus
    4/18; in control and exposed animals, respectively) and in (C57BL/6 ×
    AKR)F1 males (5/90 versus 9/17 in control and exposed animals,
    respectively). However the incidence of pulmonary tumours or lymphomas
    was not significantly increased in the BCEE-exposed animals of either


        Table 7. Long-term exposure/carcinogenicity of BCEE, BCME and CMME

                                                                                                                                           
    Protocol                                        Result                                         Comments                Reference
                                                                                                                                           

    BCEE

    Groups of 18 males and 18 females from          The incidence of "hepatomas" (benign           Evidence of             Innes et al.
    two strains of F1 hybrid mice [(C57BL/6 x       and malignant tumours), "pulmonary             increased incidence     (1969)
    C3H/Anf) and (C57BL/6 x AKR)] were              tumours" and lymphomas in the male             of liver tumours. 
    given (by gavage) approximately 100             control and BCEE-exposed (C57BL/6 x            However, study 
    mg/kg bw BCEE (dissolved in distilled           C3H/Anf)F1 mice was 8/79 and 14/16             limited owing to 
    water) from the age of 7 to 28 days. Once       (p = 0.01), 5/79 and 0/16 and 5/79             small number of 
    the mice had reached four weeks of age,         and 2/16, respectively; the incidence          BCEE-exposed 
    BCEE was then provided in the diet at a         of these tumours in the female control         animals, use of 
    concentration of 300 mg/kg until the mice       and (C57BL/6 x C3H/Anf)F1 mice was             single dose level 
    were 18 months of age, after which time         0/87 and 4/18 (p = 0.01), 3/87 and             and inadequate 
    they were sacrificed and necropsied.  The       0/18 and 4/87 and 0/18, respectively.          reporting of tumour 
    time-weighted-average dose for these            The incidence of "hepatomas" (benign           pathology. Amount 
    studies was calculated to be 41.3 mg/kg         and malignant tumours), "pulmonary             of BCEE was not 
    bw/day (US EPA, 1987a). Controls                tumours" and lymphomas in the male             adjusted during 
    consisted of multiple groups of animals of      control and BCEE-exposed (C57BL/6 x            initial period to 
    both strains and sexes.                         C3H/AKR)F1 mice was 5/90 and 9/17              account for weight 
                                                    (p = 0.01), 10/90 and 2/17 and 1/90            gain.
                                                    and 0/17, respectively; the incidence 
                                                    of these tumours in the female control
                                                    and BCEE-exposed mice was 1/82 and 
                                                    0/18, 3/82 and 0/18 and 4/82 and 1/18, 
                                                    respectively.
                                                                                                                                           

    Table 7.  (continued)

                                                                                                                                           
    Protocol                                        Result                                         Comments                Reference
                                                                                                                                           

    BCME (dissolved in a solution containing        The authors reported that BCEE was not         No reported             Weisburger et 
    sodium chloride, Polysorbate 80,                carcinogenic in these male or female           evidence of             al., 1981
    carboxy-methylcellulose and benzyl              rats; however, there was a "substantial        carcinogenicity. 
    alcohol) was administered by gavage to          difference" between the mean weight of         However, study 
    groups of 26 male and 26 female Charles         the females administered BCEE and              limited due to 
    River CD rats (at doses of 50 and               corresponding controls, as well as "a          small number of 
    25 mg/kg bw) twice weekly for 78 weeks,         reduction" in the mean weight of the           BCEE-exposed 
    after which time the animals were               high-dose male rats, compared to the           animals and 
    observed for a further 26-week period.          controls.  Notably, survival after 52          relatively short 
    The animals were necropsied and tissues         weeks on the study was only 65% for the        exposure period. 
    examined histopathologically, either at         high-dose females and 96-100% for the          The size of 
    the end of the study or when the animals        other BCEE-exposed animals.  The survival      control groups 
    became moribund.  Groups of controls of         for the control animals at 52 weeks was        was not clearly 
    each sex were administered vehicle alone.       97% and 99% for males and females,             stated, and 
                                                    respectively.                                  quantitative data 
                                                                                                   on tumour 
                                                                                                   incidence were 
                                                                                                   not presented. 

    Groups of 20 male A/St mice were injected       The incidence of lung tumours (expressed       No evidence of          Theiss et al.,
    intraperitoneally three times a week with       as the number of lung tumours/mouse) in        carcinogenicity         1977
    8, 20 or 40 mg/kg bw BCEE (dissolved in         the BCEE-exposed animals (approximately        in a limited 
    tricaprylin).  Mice injected with 8 and         0.13 lung tumours/mouse) was lower than        study of 
    20 mg/kg bw BCEE received a total of 24         that observed in animals injected with         carcinogenic 
    injections while animals administered           vehicle alone (0.39 lung tumours/mouse).       potential.
    40 mg/kg bw BCEE only received 4 injections.
    Controls (n = 20) were injected with 
    vehicle alone.  The mice were sacrificed 
    24 weeks after the initial injection and 
    the number of surface lung tumours 
    (adenomas) determined.
                                                                                                                                           

    Table 7.  (continued)

                                                                                                                                           
    Protocol                                        Result                                         Comments                Reference
                                                                                                                                           

    Thirty female ICR/Ha Swiss mice were            Compared to animals injected with vehicle      Inconclusive            van Duuren et 
    injected subcutaneously with 1 mg BCEE          alone, where no tumours developed at the       evidence of             al., 1972
    (suspended in 0.05 ml mineral oil) once         site of injection, 2/30 animals injected       carcinogenicity 
    a week for life (median survival time           with BCEE developed sarcomas at the site       in a limited study 
    of animals was 656 days). Controls              of injection.                                  involving small 
    (n = 30) were administered vehicle alone.                                                      numbers of animals 
                                                                                                   administered one 
                                                                                                   dose-level with 
                                                                                                   inadequate 
                                                                                                   reporting of data 
                                                                                                   on other effects.

    Groups of 50 male and 50 female                 The incidence of all malignant and             No evidence of          Norpoth et al., 
    Sprague-Dawley rats were injected               benign tumours (e.g., mesenchymal,             carcinogenicity         1986
    subcutaneously with either 4.36 µmole           epithelial, sarcomas, carcinomas,              in a study 
    (0.62 mg) or 13.1 µmole(1.87 mg) BCEE           unclassified) in the untreated controls,       involving limited 
    (dissolved in 0.25 ml DMSO) once a              vehicle-treated controls, low- and             exposure to 
    week for two years.  Controls were              high-dose males and females was 2/35,          BCEE with limited 
    administered DMSO or left untreated.            4/35, 4/50 and 6/50, and 24/50, 24/50,         reporting of 
                                                    23/50 and 22/50, respectively. The             toxicological 
                                                    median survival time of the untreated          effects.
                                                    control, vehicle-treated control, low- 
                                                    and high-dose groups was 696, 605, 590 
                                                    and 643 (for males), and 639, 668, 629 
                                                    and 654 days (for females), respectively.
                                                                                                                                           

    Table 7.  (continued)

                                                                                                                                           
    Protocol                                        Result                                         Comments                Reference
                                                                                                                                           

    One milligram of BCEE (in 0.1 ml                The incidence of skin papillomas at            No evidence of          Van Duuren et 
    benzene) was applied to the skin of 20          the site of application was 2/20 and           skin tumour             al., 1972
    female ICR/Ha Swiss mice.  Two weeks            3/20 in the control and BCEE-initiated         initiating 
    later the secondary (promotion)                 animals, respectively.                         activity by 
    treatment (2.5 µg phorbol myristate                                                            BCEE.
    acetate (PMA) in 0.1 ml acetone, three 
    times weekly) commenced and was 
    maintained for the lifespan of the 
    animals. Controls were administered 
    PMA alone. 

    BCME

    Fifty A/Heston male mice were exposed           Exposure to BCME produced loss of body         Limited evidence        Leong et al., 
    (by inhalation) to 0 or 5 mg/m3 BCME            weight, respiratory distress and death.        of increased            1971
    (industrial grade) for 6 h/day,                 Survival of control and BCME-exposed           pulmonary tumour 
    5 days/week for 82 days, after which            mice was 90% and 28%, respectively.            burden in mice 
    exposure was terminated and survivors           The incidence of pulmonary adenomas was        exposed to one 
    observed for a further 10 weeks.  The           20/49 and 26/47 in control and                 concentration of 
    animals were necropsied and lungs               BCME-exposed mice respectively                 BCME for a 
    examined pathologically.                        (statistical significance not specified).      relatively short 
                                                    The average number of pulmonary                period.
                                                    adenomas/animal among tumour-bearing 
                                                    mice was 2.2 for controls and 5.2 for 
                                                    the BCME-exposed group.
                                                                                                                                           

    Table 7.  (continued)

                                                                                                                                           
    Protocol                                        Result                                         Comments                Reference
                                                                                                                                           

    Groups of 120 male Sprague-Dawley rats          Six-month survival was greater than            Increased incidence     Leong et 
    were exposed (by inhalation) to 0, 1, 10        97% for control and BCME-exposed rats.         of respiratory          al., 1981
    or 100 ppb (0, 0.0047, 0.047, 0.47 mg/m3)       Nineteen-month survival for animals            tract tumours in 
    BCME 6 h/day, 5 days/week for 6 months,         exposed to 0, 0.0047 or 0.047 mg/m3 was        rats exposed to 
    after which exposure was terminated and         approximately 45%, while no animals            BCME.
    the rats observed for a further 22 months.      exposed to 0.47 mg/m3 survived. After 6 
    Eight rats from each group were sacrificed      months there was no significant 
    after 6 months for haematological,              difference in the weights of the total 
    cytological, cytogenetic and                    body, liver, kidneys, brain, heart and 
    histopathological analyses.                     testes; exposure to BCME produced no 
                                                    adverse haematological or cytogenetic 
                                                    effects. The incidence of "respiratory 
                                                    tract" tumours was 0/112, 0/113, 0/111 
                                                    and 102/111, respectively; in the 
                                                    highest-concentration group, there were 
                                                    96 esthesioneuroepitheliomas 
                                                    (significantly different [p < 0.05] 
                                                    than controls), four pulmonary adenomas, 
                                                    one carcinoma of the nasal passage and 
                                                    an esthesio-neuroepithelioma metastasis 
                                                    in the lung.
                                                                                                                                           

    Table 7.  (continued)

                                                                                                                                           
    Protocol                                        Result                                         Comments                Reference
                                                                                                                                           

    Groups of 20 to 50 male Sprague-Dawley          Sixty exposures to BCME had no effect          Increased incidence     Kuschner et 
    rats were exposed (by inhalation) to 0 or       upon mortality, although the time at           of respiratory          al., 1975
    0.1 ppm (0 or  0.47 mg/m3) BCME 6 h/day,        which 50% mortality was reached was            tract tumours 
    5 days/week for 2, 4, 8, 12, 16 and 20          reduced by approximately 24% in animals        in rats exposed 
    weeks (10, 20, 40, 60, 80 or 100 exposures),    receiving 80 or 100 exposures to BCME.         to BCME.
    after which the rats were necropsied and        Animals surviving 30 weeks had                 
    examined histopathologically.                   "respiratory tract  cancers" (26 in            
                                                    the nasal cavity and 13 in the lung).          
                                                    The incidence of "respiratory tract            
                                                    cancer" in animals surviving for more          
                                                    than 210 days and receiving 10, 20, 
                                                    40, 60, 80 or 100 exposures of BCME 
                                                    was, 1/41 (2.4%), 3/46 (6.5%), 4/18 
                                                    (22.2%), 4/18 (22.2%), 15/34 (44.1%) 
                                                    and 12/20 (60.0%), respectively 
                                                    (statistical significance not specified).  
                                                    No lung tumours were observed following 
                                                    up to 40 exposures to BCME.  The 
                                                    incidence of squamous cell carcinomas 
                                                    of the lung was 2/20, 3/50 and 8/30, 
                                                    after 60, 80 and 100 exposures, 
                                                    respectively.

    Groups of 20 female Sprague-Dawley rats         The incidence of malignant tumours at          Limited evidence        van Duuren 
    were injected subcutaneously once per           the site of injection (i.e., fibrosarcoma)     of carcinogenicity      et al., 1969
    week with 3 mg BCME (dissolved in 0.1 ml        and in the breast (i.e., adenocarcinoma)       in rats injected 
    mineral oil) or vehicle alone for               in the control and BCME-exposed animals        subcutaneously 
    approximately 300 days. (Because of the         was 0/20 and 1/20, and 5/20 and 0/20,          with BCME.
    corrosive effects produced by BCME, after       respectively.
    114 days the dose was reduced to 1 mg, 
    and injections performed only three times 
    per month; however because of severe 
    weight loss of the animals, the injections 
    were terminated after 300 days).
                                                                                                                                           

    Table 7.  (continued)

                                                                                                                                           
    Protocol                                        Result                                         Comments                Reference
                                                                                                                                           

    Fifty female and 50 male newborn ICR            Exposure to BCME had no effect upon growth     Increased incidence     Gargus et 
    Swiss mice received a single subcutaneous       or survival of the mice. The incidence of      of lung tumours         al., 1969
    injection of 12.5 µl/kg bw (16.6 mg/kg bw)      pulmonary adenomas in the control and          in mice injected 
    BCME (dissolved in peanut oil) and the          BCME-exposed males was 2/30 and 25/50,         subcutaneously 
    animals were observed for a period of six       respectively; 5/20 controls and 20/50 of       with BCME.
    months, after which the survivors were          the BCME-exposed females had lung adenomas.
    necropsied and the number of lung tumours 
    (adenomas, based on histopathological 
    analysis) quantified.  Controls (20 females 
    and 30 males) received a single 
    subcutaneous injection of vehicle alone.

    Thirty male and 30 female XVIInc/Z mice         Approximately 0%, 44% and 42% of the male      Evidence of            Zajdela et 
    received 32 subcutaneous injections of          controls and male and female BCME-exposed      carcinogenicity        al., 1980
    0.3 mg BCME (dissolved in mineral oil)          mice, respectively, had tumours (e.g.,         in mice injected 
    over a period of 42 weeks. Controls             fibrosarcomas and squamous carcinomas)         subcutaneously 
    consisted of 30 XVIInc/Z male mice injected     at the site of injection.                      with BCME.
    with vehicle alone.

    Groups of 20 female ICR/Ha mice which           The incidence of squamous cell carcinomas      Evidence of             van Duuren 
    received 2 mg BCME (applied dermally) or        of the skin in the controls and                carcinogenicity         et al., 1969
    solvent (i.e., benzene) alone (controls)        BCME-exposed animals was 0/20 and 12/20,       in mice exposed 
    thrice weekly for 325 days.                     respectively.                                  dermally to BCME.
                                                                                                                                           

    Table 7.  (continued)

                                                                                                                                           
    Protocol                                        Result                                         Comments                Reference
                                                                                                                                           

    CMME

    Fifty A/Heston male mice were exposed           The incidence of pulmonary tumours in          Suggestion of           Leong et 
    (by inhalation) to 0 or 2 ppm (0 or             CMME-exposed mice (25/50) was not              increased               al., 1971
    6.6 mg/m3) (industrial grade) CMME for          significantly (i.e., p > 0.05) different       pulmonary tumour 
    6 h/day, 5 days/week for 101 days, after        from that in the unexposed controls            burden in mice 
    which time exposure was terminated and          (20/49). The average number of pulmonary       exposed to one 
    survivors observed for a further 7 weeks.       tumours/animal among tumour-bearing mice       concentration 
    The animals were necropsied and lungs           was 2.2 and 3.1 for the control and            of CMME for a 
    examined histopathologically.                   CMME-exposed group, respectively.              relatively short 
                                                                                                   period.

    Seventy-four male Sprague-Dawley rats           Exposure to CMME had no effect upon            No clear                Laskin et 
    were exposed (by inhalation) to 0 or            mortality or body weight gain. The             evidence of             al., 1975
    1 ppm (0 or 3.3 mg/m3) (industrial grade)       incidence of tracheal squamous metaplasia      carcinogenicity 
    CMME for 6 h/day, 5 days/week for their         and bronchial hyperplasia was 3% and 10%,      in a limited 
    entire lifespan (up to 852 days). The           and 35% and 59%, in the control and            study.
    rats were necropsied and tissues examined       BCME-exposed animals respectively 
    histopathologically.                            (statistical significance not stated). 
                                                    Two respiratory tract cancers (lung 
                                                    squamous cell carcinoma and an 
                                                    esthesioneuroepithelioma of olfactory 
                                                    epithelium) were found in animals 
                                                    exposed to CMME (but presumably not 
                                                    in unexposed controls).
                                                                                                                                           

    Table 7.  (continued)

                                                                                                                                           
    Protocol                                        Result                                         Comments                Reference
                                                                                                                                           

    Ninety male Syrian hamsters were exposed        Exposure to CMME had no effect upon            No clear                Laskin et
    (by inhalation) to 1 ppm (3.3 mg/m3)            mortality or body weight gain. The             evidence of             al., 1975
    (industrial grade) CMME for 6 h/day,            incidence of tracheal squamous metaplasia      carcinogenicity 
    5 days/week for their entire lifespan           was 0% and 2%, and incidence of bronchial      in a limited 
    (up to 852 days). The hamsters were             hyperplasia was 5% and 8%, in the control      study.
    necropsied and tissues examined                 and BCME-exposed animals respectively 
    histopathologically. Eighty-eight unexposed     (statistical significance not stated). 
    animals served as controls.                     One lung adenocarcinoma and a tracheal 
                                                    squamous papilloma were observed in two 
                                                    animals exposed to CMME.

    Groups of 20 female Sprague-Dawley rats         The incidence of malignant tumours at          No evidence of          van Duuren 
    were injected subcutaneously once per           the site of injection (i.e., fibrosarcoma)     carcinogenicity         et al., 1969
    week with 3 mg laboratory purified CMME         and in the breast (adenocarcinoma) in the      in rats injected 
    (dissolved in 0.1 ml mineral oil) or            control and CMME-exposed animals               subcutaneously 
    vehicle alone for approximately 300 days.       was 0/20 and 1/20, and 1/20 and 0/20,          with laboratory 
    Because of moderate corrosive effects,          respectively.                                  purified CMME.
    the injections were terminated after 
    this time.

    Thirty female ICR/Ha Swiss mice were            Compared to the animals injected with          Evidence of             van Duuren 
    injected (subcutaneously) with 0.3 mg of        vehicle alone, where no tumours developed      carcinogenicity         et al., 1972
    laboratory purified CMME (suspended in          at the site of injection, 10/30 animals        in mice 
    0.05 ml mineral oil) once a week for            injected with CMME developed sarcomas at       injected 
    life. Controls (n = 30) received                the site of injection.                         subcutaneously 
    vehicle alone.                                                                                 with CMME.
                                                                                                                                           

    Table 7.  (continued)

                                                                                                                                           
    Protocol                                        Result                                         Comments                Reference
                                                                                                                                           

    Forty-eight female and 51 male newborn          The numbers of female mice with lung           No increase in          Gargus et 
    ICR Swiss mice received a single                adenomas in the control (vehicle) and          the incidence           al., 1969
    subcutaneous injection of 125 µl/kg bw          CMME-exposed groups were 5/20 and 8/48,        of lung 
    (132.5 mg/kg bw) CMME dissolved in peanut       respectively.  The numbers of male mice        tumours in 
    oil; the animals were observed for a            with lung adenomas in the control              mice injected 
    period of six months, after which time          (vehicle) and CMME-exposed groups were         subcutaneously 
    the survivors were necropsied and the           2/30 and 9/51, respectively.                   with CMME.
    number of lung tumours (adenomas, based 
    on histopathological analysis) quantified.  
    Controls (20 females and 30 males) 
    received a single subcutaneous injection 
    of vehicle alone. 

    Groups of 20 female ICR/Ha mice received        No squamous cell carcinomas of the             No evidence of          van Duuren 
    2 mg CMME (applied dermally) or solvent         skin were observed in either the               carcinogenicity         et al., 1969
    (i.e., benzene) alone (controls) thrice         control or CMME-exposed animals.               in mice exposed 
    weekly for 325 days.                                                                           dermally to 
                                                                                                   CMME.
                                                                                                                                           
    
    sex. Clinical, biochemical or haematological effects were not
    addressed in the published account of this study.

         Weisburger et al. (1981) reported that the oral administration of
    BCEE to rats had no significant carcinogenic effect. BCEE (dissolved
    in a solution containing sodium chloride, Polysorbate 80,
    carboxy-methylcellulose and benzyl alcohol) was administered (by
    gavage) to groups of 26 male and 26 female Charles River CD rats (at
    doses of 50 and 25 mg/kg body weight) twice weekly for 78 weeks, after
    which time the animals were observed for a further 26-week period.
    Control groups of each sex (the size of which was not clearly stated)
    were administered vehicle alone. The authors reported (although no
    data on tumour incidence were presented) that BCEE was not
    carcinogenic in these male or female rats. However, the authors
    indicated (but results were not quantified) that there was a
    "substantial difference" between the mean body weight of the females
    administered both doses of BCEE and that of the corresponding
    controls, as well as "a reduction" in the mean body weight of the
    high-dose male rats, compared to controls. Notably, survival after 52
    weeks on the study was only 65% for the high-dose females and 96 to
    100% for the other BCEE-exposed animals. The survival for the control
    animals at 52 weeks was 97 and 99% for males and females,
    respectively. Clinical, biochemical or haematological effects were not
    addressed in the published account of this study.

         Theiss et al. (1977) assessed the potential of BCEE to produce
    lung tumours in groups of 20 male A/St mice injected intraperitoneally
    three times per week with 8, 20 or 40 mg/kg body weight BCEE
    (dissolved in tricaprylin). Mice injected with 8 and 20 mg/kg received
    a total of 24 injections while animals administered 40 mg/kg only
    received 4 injections. Controls (n = 20) were injected with vehicle
    (tricaprylin) alone. The mice were killed 24 weeks after the initial
    injection and the number of surface lung tumours (adenomas)
    determined. The incidence of lung tumours (expressed as the number of
    lung tumours/mouse) in the BCEE-exposed animals was less than that
    observed in animals injected with vehicle alone.

         The potential of BCEE to induce tumours was also investigated in
    a study in which groups of 30 female ICR/Ha Swiss mice were injected
    subcutaneously with 1 mg BCEE (suspended in 0.05 ml mineral oil) once
    per week for life (the median survival time of animals was 656 days)
    (van Duuren et al., 1972). Compared to animals injected with vehicle
    alone, where no tumours developed at the site of injection, 2/30
    animals injected with BCEE developed sarcomas at the site of
    injection. Norpoth et al. (1986) also examined the carcinogenicity of
    BCEE in a study in which groups of 50 male and 50 female
    Sprague-Dawley rats were injected subcutaneously with either 4.36
    µmole (0.62 mg) or 13.1 µmole BCEE (1.87 mg) (dissolved in 0.25 ml
    DMSO) once per week over a 2-year period. Controls were injected with
    DMSO (alone) or left untreated. The incidence of all malignant and
    benign tumours (e.g., mesenchymal, epithelial, sarcomas, carcinomas
    and unclassified) in the BCEE-exposed animals was not significantly 

    different from that in the controls. The median survival time of the
    untreated control, vehicle-treated control, and low- and high-dose
    groups was 696, 605, 590 and 643 (for males), and 639, 668, 629 and
    654 days (for females), respectively.

         Van Duuren et al. (1972) assessed the skin-tumour-initiating
    potential of BCEE. One milligram BCEE (in 0.1 ml benzene) was applied
    to the skin of 20 female ICR/Ha Swiss mice. Two weeks later the
    secondary (promotion) treatment (2.5 µg PMA in 0.1 ml acetone, three
    times weekly) commenced and was maintained for the life span of the
    animals. Compared to controls (administered PMA alone) where 2/20
    animals developed papillomas, 3/20 of the BCEE-initiated animals
    developed papillomas at the site of application.

    7.3.2  BCME

         Studies on the toxicological effects produced by long-term
    exposure (by inhalation) to BCME have been restricted primarily to
    limited carcinogenesis bioassays. The exposure (by inhalation) of male
    A/Heston mice to 5 mg/m3 for 6 h/day, 5 days/week for a period of 82
    days, followed by a 10-week observation period, produced a marked
    reduction in survival (90 and 28% in control and BCME-exposed mice,
    respectively) and an increase in the number of pulmonary adenomas
    (20/49 and 26/47 in control and BCME-exposed mice, respectively),
    although the statistical significance was not specified (Leong et al.,
    1971). The average number of pulmonary adenomas per animal among
    tumour-bearing mice was 2.2 for controls and 5.2 for the BCME-exposed
    group.

         The exposure (by inhalation) of groups of 144 to 157 male ICR/Ha
    mice to concentrations of BCME from 0.0047 to 0.47 mg/m3 (1 to 100
    ppb) for 6 h/day, 5 days/week for a period of 6 months, followed by an
    18-month observation period, produced a reduction in survival (55, 35,
    25 and 18% in mice exposed to 0, 0.0047, 0.047 or 0.47 mg/m3 [0, 1,
    10 or 100 ppb], respectively), although no difference in survival 
    (> 90%) was observed between the control and BCME-exposed groups
    after 24 months (Leong et al., 1981). All mice developed an ascending
    urinary tract infection. After 6 months, the incidence of pulmonary
    adenomas in surviving mice exposed to 0, 0.0047, 0.047 and 0.47 mg/m3
    was 9/86, 5/45, 3/37 and 8/27 (p < 0.05), respectively. Exposure to
    these concentrations of BCME had no adverse effect on body weight and
    produced no nasal or eye irritation.

         Groups of 120 male Sprague-Dawley rats were exposed (by
    inhalation) to BCME concentrations of 0, 0.0047, 0.047 or 0.47 mg/m3
    (0, 1, 10 or 100 ppb) 6 h/day, 5 days/week for 6 months, after which
    time exposure was terminated and the animals observed for a further 22
    months (Leong et al., 1981). Although 6-month survival was greater
    than 97% for control and BCME-exposed rats, 19-month survival for
    animals exposed to 0, 0.0047 or 0.047 mg/m3 was approximately 45%,
    while none of the animals exposed to 0.47 mg/m3 survived. After 6
    months there was no significant difference in the weights of the total

    body, liver, kidneys, brain, heart and testes, and no adverse
    haematological or cytogenetic effects were observed. The incidence of
    "respiratory tract" tumours in animals exposed to 0, 0.0047, 0.047 or
    0.47 mg/m3 was 0/112, 0/113, 0/111 and 102/111, respectively; in the
    highest-concentration group, there were 96 esthesioneuroepitheliomas
    (significantly different [p < 0.05] from controls), 1 carcinoma of
    the nasal passage and an esthesioneuroepithelioma metastasis in the
    lung, and 4 pulmonary adenomas.

         Kuschner et al. (1975) exposed (by inhalation) groups of 20 to 50
    male Sprague-Dawley rats to 0.47 mg BCME/m3 (0.1 ppm) for 6 h/day, 
    5 days/week for 2, 4, 8, 12, 16 or 20 weeks (10, 20, 40, 60, 80 or 100
    exposures). Sixty exposures to BCME had no effect on mortality,
    although the time at which 50% mortality was reached was reduced by
    approximately 24% in animals receiving 80 or 100 exposures to BCME.
    The incidence of "respiratory tract cancer" in animals surviving for
    more than 210 days and receiving 10, 20, 40, 60, 80 or 100 exposures
    of BCME was 1/41 (2.4%), 3/46 (6.5%), 4/18 (22.2%), 4/18 (22.2%),
    15/34 (44.1%) and 12/20 (60.0%), respectively. No lung tumours were
    observed following up to 40 exposures to BCME; however, the incidence
    of squamous cell carcinomas of the lung was 2/20, 3/50 and 8/30 after
    60, 80 and 100 exposures, respectively.

         The carcinogenicity of BCME has also been examined following
    subcutaneous injection in rats and mice. Groups of 20 female
    Sprague-Dawley rats (weighing between 120 and 125 g) were injected
    subcutaneously once per week with 3 mg BCME (dissolved in 0.1 ml
    mineral oil) or vehicle alone for approximately 300 days (van Duuren
    et al., 1969). Because of the corrosive effects produced by BCME,
    after 114 days the dose was reduced to 1 mg, and injections were
    performed only three times per month; however, because of severe
    weight loss of the animals, the injections were terminated after 300
    days. In the controls administered vehicle alone, no tumours were
    observed at the site of injection; however a fibroadenoma and an
    adenocarcinoma (of the breast) were observed elsewhere. In the group
    of animals administered BCME, two fibromas and five fibrosarcomas were
    observed at the site of injection, and one fibroadenoma (of the
    breast) was found elsewhere (van Duuren et al., 1969).

         The potential of BCME to increase the incidence of spontaneous
    lung tumours in mice was assessed by Gargus et al. (1969). A group of
    50 female and 50 male newborn ICR Swiss mice received a single
    subcutaneous injection of 12.5 µl/kg body weight (16.6 mg/kg body
    weight) BCME (dissolved in peanut oil) and the animals were observed
    for a period of 6 months, after which time the survivors were
    necropsied and the number of lung tumours (adenomas, based on
    histopathological analysis) quantified. A group of control animals (20
    females and 30 males) received a single subcutaneous injection of
    vehicle alone. The numbers of female mice with pulmonary adenomas in
    the control (vehicle) and BCME-exposed groups were 5/20 and 20/50,
    respectively. The numbers of male mice with pulmonary adenomas in the
    control (vehicle) and BCME-exposed groups were 2/30 and 25/50,

    respectively. The administration of BCME had no effect upon the growth
    or survival of the mice.

         Zajdela et al. (1980) assessed the carcinogenicity of BCME
    following repeated subcutaneous injection in male and female XVIInc/Z
    mice. Groups of 30 males and 30 females received 32 injections of 0.3
    mg BCME (dissolved in mineral oil) over a period of 42 weeks. The
    control group consisted of 30 male mice injected with vehicle alone.
    After 110 days (when the first sarcoma was observed), survival in the
    control and male and female BCME-exposed groups was 100, 90 and 80%,
    respectively. The number of animals with tumours (mainly
    fibrosarcomas) at the site of injection was 0/30, 12/27 and 10/24,
    respectively (p < 0.0001). The incidence of tumours at locations
    other than the site of injection was the same in the control and
    BCME-exposed groups. The incidence of pulmonary adenomas in the
    control and BCME-exposed groups was 2/30 and 7/30, respectively; this
    difference was not statistically significant (Zajdela et al., 1980).

         The incidence of squamous cell carcinomas of the skin in female
    ICR/Ha mice that received 2 mg BCME (applied dermally) or solvent
    (i.e., benzene) alone thrice weekly for 325 days was 12/20 and 0/20,
    respectively (van Duuren et al., 1969). A two-stage skin tumour
    carcinogenesis bioassay was conducted in which the primary treatment
    involved the application of 1 mg BCME (dissolved in 80 µl benzene) to
    the dorsal skin of 28 male XVIInc/Z mice and the secondary treatment,
    commencing 14 days later, involved the application three times per
    week of 2 µg PMA (dissolved in acetone) to the dorsal skin of these
    animals for 42 weeks. The incidence of mice with squamous cell
    carcinomas was 0/28 and 3/28 in unexposed and BCME-initiated animals,
    respectively (Zajdela et al., 1980).

    7.3.3  CMME

         Studies on the toxicological effects produced by long-term
    inhalational exposure to CMME have been restricted primarily to
    limited carcinogenesis bioassays in mice, rats and hamsters.

         A study was conducted in which 50 A/Heston male mice were exposed
    (by inhalation) to 0 or 6.6 mg CMME/m3 (0 or 2 ppm) for 6 h/day, 
    5 days/week for 101 days, followed by an observation period of 
    7 weeks. Although there was no significant effect upon the incidence
    of pulmonary tumours, the average number of pulmonary tumours per
    animal among tumour-bearing mice was 3.1 and 2.2 for the CMME-exposed
    and control groups, respectively (Leong et al., 1971).

         In a study in which 74 male Sprague-Dawley rats were exposed (by
    inhalation) to 0 or 3.3 mg CMME/m3 (0 or 1 ppm) for 6 h/day,
    5 days/week for their entire life span (up to 852 days), the incidence
    of tracheal squamous metaplasia and bronchial hyperplasia was 3 and
    10%, and 35 and 59%, in the control and CMME-exposed animals,
    respectively. Two respiratory tract cancers (lung squamous cell
    carcinoma and an esthesioneuroepithelioma of the olfactory epithelium)

    were found in animals exposed to CMME (but presumably not in unexposed
    controls) (Laskin et al., 1975). Exposure to CMME had no effect upon
    mortality or body weight gain.

         The exposure (6 h/day, 5 days/week) of 90 male hamsters to 3.3 mg
    CMME/m3 (1 ppm) for virtually their entire lives increased the
    incidence of tracheal metaplasia and bronchial hyperplasia compared to
    88 unexposed controls. The incidence of tracheal squamous meta-plasia
    was 0 and 2%, and the incidence of bronchial hyperplasia was 5 and 8%,
    in the control and CMME-exposed animals, respectively (statistical
    significance not stated). One lung adenocarcinoma and a tracheal
    squamous papilloma were observed in two animals exposed to CMME;
    presumably none was found in unexposed controls (Laskin et al., 1975).

         The carcinogenicity of purified CMME has also been examined
    following subcutaneous injection of this substance in rats and mice.
    Groups of 20 female Sprague-Dawley rats (weighing between 120 and 125
    g) were injected once per week with 3 mg (laboratory purified) CMME
    (dissolved in 0.1 ml mineral oil) or vehicle alone for approximately
    300 days; because of moderate corrosive effects, the injections were
    terminated after this time (van Duuren et al., 1969). In controls
    administered the vehicle alone, no tumours were observed at the site
    of injection; however a fibroadenoma and an adenocarcinoma (of the
    breast) were found elsewhere. In animals administered (laboratory
    purified) CMME, a fibrosarcoma (at the site of injection) in one
    animal was the only tumour described.

         Van Duuren et al. (1972) subcutaneously injected (laboratory
    purified) CMME (dissolved in 0.05 ml mineral oil, 300 µg/animal, once
    per week) to a group of 30 female ICR/Ha Swiss mice for their entire
    lives, and a similarly sized group of controls received vehicle alone.
    Median survival time was 643 days and 496 days, and the numbers of
    mice with sarcomas at the site of injection were 0 and 10 in the
    control and purified CMME-exposed groups, respectively.

         The potential of CMME to increase the incidence of spontaneous
    lung tumours in mice was assessed by Gargus et al. (1969). A group of
    48 female and 51 male newborn ICR Swiss mice received a single
    subcutaneous injection of 125 µl/kg body weight (132.5 mg/kg body
    weight) CMME dissolved in peanut oil, and subsequently observed for a
    period of 6 months, after which time the survivors were necropsied and
    the number of lung tumours (adenomas, based on histopathological
    analysis) quantified. Controls (20 females and 30 males) received a
    single subcutaneous injection of vehicle alone. The numbers of female
    mice with adenomas in the control (vehicle) and CMME-exposed groups
    were 5/20 and 8/48, respectively. The numbers of male mice with
    adenomas in the control (vehicle) and CMME-exposed groups were 2/30
    and 9/51, respectively.

         Purified CMME was not carcinogenic when applied thrice weekly 
    (2 mg/animal for 325 days) to the skin of female ICR/Ha Swiss mice
    (van Duuren et al., 1969).

    7.4  Mutagenicity and related end-points

    7.4.1  BCEE

         A small number of investigations have been performed to assess
    the genotoxic potential of BCEE. The  in vitro studies have yielded
    somewhat equivocal results. However it should be noted that, in
    general, detailed descriptions of the laboratory conditions were not
    provided, making interpretation of the findings difficult. The
    mutagenic activity of BCEE in bacteria has been examined in a number
    of strains, in the presence and absence of metabolic activating
    systems. Simmon et al. (1977a,b) reported BCEE (vapour) to be strongly
    mutagenic in  Salmonella typhimurium TA100 in the absence of a
    metabolic activating system, with the number of revertants increasing
    with the duration of exposure. Simmon et al. (1977a,b) also reported
    that in suspension assays BCEE was mutagenic in  S. typhimurium 
    strains TA1535 and TA100, as well as in  Saccharomyces cerevisiae 
    D3. Norpoth et al. (1986) reported "weak" mutagenic activity in 
     S. typhimurium TA100 (in the presence of a metabolic activating
    system) when BCEE (up to 40 µg/dish) was added directly to culture
    plates. Mortelmans et al. (1986) reported BCEE (up to 10 mg/plate) had
    "weak" mutagenic activity in a number of  S. typhimurium strains
    (TA100, TA1535, TA1537, TA98), either in the presence or absence of a
    metabolic activating system. Shirasu et al. (1975) reported that BCEE
    was mutagenic in various strains of  Escherichia coli, Bacillus 
     subtilis and  S. typhimurium, although experimental details were
    not provided in the published account of this study. In contrast,
    Quinto & Radman (1987) reported that BCEE was not mutagenic in the MT
    103, MT 119 and MT 126 tester strains of  E. coli, although complete
    experimental details were not provided in this published account.

         Foureman et al. (1994) considered BCEE mutagenic, based upon the
    results of a sex-linked recessive lethal assay in which male
     Drosophila were injected with the compound. However the response was
    negative when the males were fed BCEE. To examine the genotoxicity of
    BCEE in mammals, Jorgenson et al. (1977) performed heritable
    translocation assays in mice administered BCEE orally. These authors
    concluded that BCEE did not promote heritable translocations. However,
    few experimental details were provided in this published account.
    Gwinner et al. (1983) did not detect radioactivity bound to liver DNA
    or RNA isolated from male Sprague-Dawley rats exposed (by inhalation)
    to [1-14C]-BCEE (amount not clearly specified) for 18 h.

    7.4.2  BCME

         The genotoxicity of BCME has been examined in a variety of
    limited and generally poorly documented studies. BCME (at a maximum
    concentration of 20 µg/plate) was mutagenic in the presence of an
    exogenous metabolic activating system in  S. typhimurium strain
    TA100, based on a 3-fold increase in the frequency of revertants above
    control levels. However, similar results were not observed in 
     S. typhimurium strains TA1535, TA1538 and TA98 (Anderson & Styles,
    1978). BCME was also reported to be mutagenic in various strains of
     E. coli and  S. typhimurium, but experimental details and results
    were not provided (Mukai & Hawryluk, 1973).

         BCME (at concentrations as low as 0.16 µg/ml) was reported to
    increase DNA repair (unscheduled DNA synthesis) in human skin
    fibroblasts, although quantitative results were not provided (Agrelo &
    Severin, 1981). In  in vitro assays with BHK-21 and human lung WI-38
    cells, concentrations of BCME between 0.008 and 25 mg/ml (in the
    presence of an exogenous metabolic activating system) increased the
    frequency of transformed cells approximately 6.6- and 11-fold,
    respectively (Styles, 1978). The exposure  (in vitro) of human
    neonatal foreskin fibroblasts to concentrations of BCME between 0.1
    and 8 µg/ml produced a 3- to 14-fold increase in the frequency of
    anchorage-independent cells (Kurian et al., 1990).

         BCME was reported to directly alkylate DNA (at guanine and
    adenine residues) when the two substances were incubated together in
    an  in vitro assay (Goldschmidt et al., 1975). It was reported to
    damage RNA within bacteriophage R17 (Shooter, 1975).

    7.4.3  CMME

         CMME was reported to be mutagenic in various strains of  E. coli
    and  S. typhimurium. However, experimental details or results were
    not provided in this published account (Mukai & Hawryluk, 1973). In
    the presence of an exogenous metabolic activating system, CMME (1 and
    10 mmol/litre) increased unscheduled DNA synthesis in human
    lymphocytes approximately 30 and 100%, respectively (Perocco et al.,
    1983).

    7.5  Other toxicity studies

         The exposure (by inhalation) of male Sprague-Dawley rats to 0.47
    mg BCME/m3 (100 ppb) for 6 h/day, 5 days/week, for a period of six
    months had no observable effect upon the nervous or reproductive
    systems, based on gross and microscopic analysis (Leong et al., 1981).
    No other relevant information regarding the reproductive,
    developmental, immunological or neurological toxicity of BCEE, BCME or
    CMME was identified.

    8.  EFFECTS ON HUMANS

    8.1  General population exposure

    8.1.1  Human exposure studies

         Schrenk et al. (1933) reported that the "brief" (time not stated)
    exposure of men to concentrations of BCEE ranging from 3218 to 5850
    mg/m3 (550 to 1000 ppm) caused irritation to the eyes (lacrimation)
    and nasal passages, such that exposure was considered intolerable.
    Inhalation of BCEE also caused nausea. The intensity of such effects
    gradually declined as the concentration of BCEE was lowered from 1521
    mg/m3 (260 ppm) to 585 mg/m3 (100 ppm); exposure to 205 mg/m3 (35
    ppm) was reported to be "only slightly offensive and practically free
    from irritation". No clinical studies on BCME and CMME were
    identified.

    8.2  Occupational exposure

    8.2.1  Case reports

         The death of a worker in a fulling mill (textile factory) was
    attributed to the inhalation of BCEE, but details were not provided
    (Elkins, 1959). One anecdotal report on the occurrence of dermatitis
    in textile workers exposed to resins containing BCEE was identified
    (Kirwin & Sandmeyer, 1981).

         Sakabe (1973) reported that 5 out of 32 Japanese males employed
    in dyestuffs factories who had been exposed to BCME died of "lung
    cancer" (between 1963 and 1969). Small (oat) cell carcinoma was
    identified in one of the cases. Quantitative information on exposure
    was not provided in this published account and these individuals were
    exposed to a number of chemical substances in addition to BCME
    (smoking habits could not be confirmed). However, because a large
    proportion (approximately 16%) of the individuals exposed to BCME
    developed lung cancer, and those exposed to chemicals other than BCME
    did not, the authors attributed the occurrence of these pulmonary
    tumours to exposure to BCME.

         Reznick et al. (1977) reported the case of a 45-year-old male
    chemist who had died of a slightly differentiated adenocarcinoma of
    the lung. Twelve years earlier this individual had been exposed to
    BCME and CMME over a period of two years. Although quantitative
    information on exposure was not presented (and the individual was also
    exposed to vinyl chloride), the lung adenocarcinoma was attributed to
    his exposure to BCME and CMME.

         Roe (1985) reported the case of three males (between 35 and 40
    years of age) who had died of lung cancer (small (oat) cell and
    squamous cell carcinomas) after having been occupationally exposed to
    BCME. Although quantitative or qualitative information on exposure was

    not provided and the individuals had been smokers, the relatively
    young age at which these individuals died was attributed to their
    exposure to BCME.

    8.2.2  Epidemiological studies

         Data on the effects of long-term exposure to BCEE on human health
    were not identified. In a number of epidemiological studies, mortality
    and morbidity due to cancer in workers occupationally exposed to BCME
    and CMME have been examined. Lemen et al. (1976) examined the
    incidence of lung cancer in a group of workers employed at a chemical
    plant in California, USA, where BCME was used in the production of
    ion-exchange resins. The authors identified 136 individuals who had
    been employed for at least 5 years between 1955 and 1972. The number
    of cases of lung cancer (5) was significantly greater (p < 0.01) than
    the number expected (0.54), based on age-respiratory cancer-specific
    incidence rates for white males in the state of Connecticut in
    1960-1962. Notably, 80% of the tumours were small cell
    undifferentiated cancers. Importantly, lung tumours in persons
    occupationally exposed to BCME and CMME are predominantly small (oat)
    cell carcinomas (Weiss, 1976; Pasternack et al., 1977). The occurrence
    of this type of lung cancer in these individuals is quite distinct
    from that caused by tobacco, one of the potential confounders in such
    studies, where the lung tumours are predominantly squamous cell
    carcinomas (Weiss, 1976; Pasternack et al., 1977). Individuals (80%
    were smokers) with cancer averaged 47 years of age, and the average
    latency period was approximately 10 years. Quantitative or qualitative
    information on exposure was not provided in this published account.
    The incidence of metaplastic and atypical cells in the sputum of
    workers exposed to BCME was greater than in controls (uranium miners),
    based on cytological analysis.

         Nishimura et al. (1990) examined the incidence of lung cancer in
    a group of Japanese workers employed in two dyestuff factories where
    BCME was used. The study group consisted of 35 males employed at these
    plants between 1955 and 1970. The number of cases (13) of lung cancer
    (11 cases were in smokers) was significantly (p < 0.001) higher than
    the number expected (0.62). Tumours from eight of the individuals were
    examined histopathologically; four were diagnosed as small cell
    undifferentiated carcinomas, two were adenocarcinomas and one a large
    cell carcinoma; in one individual, both a small cell carcinoma and an
    adenocarcinoma were found. The average age at which individuals with
    lung cancer died was 46 years, and the latency period was
    approximately 13.5 years. The average duration of exposure to BCME was
    approximately 7.2 years, although no other quantitative or qualitative
    information on exposure was provided.

         Since technical grade CMME contains between 1 and 8% BCME
    (Travenius, 1982), in epidemiological studies in which mortality and
    the incidence of cancer in workers exposed to CMME were examined, the
    effects may have been due (at least in part) to BCME. Weiss (1976)
    reported the results of a 10-year prospective study (1963-1973) in
    which 125 male employees of a chemical plant in the USA who had been

    occupationally exposed to CMME(BCME), were examined with respect to
    the "incidence" of pulmonary cancer. No quantitative or qualitative
    information on exposure was provided. However, an exposure index (low,
    medium and high) based on type and duration of job associated with
    potential exposure to CMME(BCME) was developed. Eleven cases of lung
    cancer were reported in 49 individuals with medium or high exposure to
    CMME(BCME); no "incidence" of lung cancer was reported in 76 workers
    with no or low exposure to CMME(BCME). The number of deaths (16)
    during this period was 2.7-fold greater than the number expected
    (5.9), based on a comparison with death rates for white males in the
    USA. All of the excess deaths (10) were attributable to lung cancer,
    100% of which were small cell carcinomas that developed in individuals
    less than 55 years of age. The latency period for these cancers ranged
    from 10 to 24 years. Among individuals exposed to CMME(BCME) the
    "incidence" of pulmonary tumours was inversely related to their use of
    tobacco (Weiss, 1980). In a follow-up study of these workers, the
    number of deaths (13) due to lung cancer (which were attributable to
    either moderate or heavy exposure to CMME[BCME]) was 19.5-fold greater
    than the number (0.66) expected, based on lung cancer mortality rates
    in the surrounding municipality (Philadelphia) (Weiss, 1982). The
    standardized mortality ratio for deaths due to lung cancer which
    peaked 15 to 19 years from the onset of exposure, declined during the
    subsequent 20- to 29-year period. Subsequently, Weiss (1989) indicated
    that over-representation of workers with moderate to high exposure
    within the cohort led to some over-estimation of the risk of lung
    cancer. However, even when such selection bias was accounted for, an
    increased risk of lung cancer remained associated with exposure to
    CMME(BCME).

         Maher & DeFonso (1987) examined mortality in a group of workers
    exposed to CMME(BCME). [This report represented an update and
    extension of a previous investigation on death due to lung cancer
    performed by these authors (DeFonso & Kelton, 1976)]. The study
    population consisted of a group of 737 "exposed" and 2120 "unexposed"
    white male workers (who comprised 97% of the labour force) employed
    for any length of time at a chemical plant in the USA between 1948 and
    1971. The vital status of 90% of the group was determined up to 1982.
    No quantitative information on exposure was provided, but an exposure
    rating (from 0-6) was developed based on the type of work, proximity
    of exposure to CMME(BCME) and production methods. Cumulative exposure
    was calculated based on the exposure rating and duration of employment
    at a particular job. The expected number of deaths for each type of
    cancer was calculated using cause-specific death rates for white males
    residing in the surrounding municipality (Philadelphia). Information
    on smoking habits was incomplete but "no marked differences between
    smoking habits of exposed and unexposed workers were noted" (Maher &
    DeFonso, 1987). Among the workers exposed to CMME(BCME), the number of
    deaths (32) due to cancer of the "respiratory tract" was significantly
    (P < 0.01) higher than the number expected (11.5). For individuals
    not exposed to CMME(BCME), the number of deaths (25) due to
    respiratory tract cancer was similar to those expected (23.8). In the
    CMME(BCME)-exposed group, the number of deaths due to cancer of the
    digestive, genito-urinary, haematopoietic, lymphatic and central

    nervous systems was not significantly greater than expected. The
    greatest increase in deaths due to cancer of the respiratory tract
    occurred approximately 10 to 20 years after the first exposure to
    CMME(BCME). Among workers exposed to CMME(BCME), the ratio of
    observed/expected number of deaths due to lung cancer was lower
    between 1975 and 1981 than for the period between 1960 and 1974, this
    being attributed to a reduction in the level of exposure to CMME(BCME)
    in 1971 as a result of the implementation of stringent engineering
    controls on the use of this substance (Maher & DeFonso, 1987).

         Collingwood et al. (1987) assessed mortality due to respiratory
    cancer in a group of workers employed at seven industrial facilities
    in which CMME(BCME) was produced or utilized. This report represented
    a follow-up and extension of a previous study by two of these authors
    (Pasternack et al., 1977). The study group (97% white, 96% male)
    comprised 2460 CMME(BCME)-exposed and 3692 unexposed workers employed
    between 1948 and 1980. Only limited information on smoking habits was
    available. No quantitative or qualitative information on exposure was
    provided, but an exposure index (taking into account type of job,
    frequency of work and potential exposure to CMME(BCME)) was developed.
    Cumulative exposure was calculated on the basis of the exposure index
    and duration of employment at a particular job. The number of expected
    deaths was calculated from death rates in the USA specific for age,
    cause, sex, race and calendar year. Among workers exposed to
    CMME(BCME), the standardized mortality ratio for death due to
    respiratory cancer was significantly increased (SMR = 3.01; 
    95% CI = 2.24-3.98); this was attributed to excess deaths at two
    companies (where the ratio of observed to expected deaths due to lung
    cancer among exposed workers was 32/7.4 and 9/1.5). In the entire
    study group, there were 90 deaths due to respiratory cancer, 52 and 38
    in the CMME(BCME)-exposed and unexposed groups, respectively. In those
    cases with verifiable histology, 12/32 (38%) cases in the exposed
    group had small (oat) cell carcinomas while 6/20 (30%) cases in the
    unexposed group had adenocarcinomas. The relative risk of death due to
    lung cancer was found to be related to total cumulative exposure based
    on a regression model.

         Gowers et al. (1993) examined the incidence of lung cancer among
    1203 males employed at an ion-exchange resin manufacturing plant in
    France between 1958 and 1986; of the total study cohort, 258 were
    exposed to technical grade CMME (i.e., containing BCME), the remainder
    were considered to be unexposed. Data on the incidence of lung cancer
    among these workers was obtained from a local registry; the expected
    number of lung cancer cases was calculated, based upon incidence rates
    for males provided by a registry serving an area some 250 km distant
    from the plant (i.e., external population). There were 8 (one small
    cell carcinoma) and 11 (10 small cell carcinomas) cases of lung cancer
    among the unexposed and CMME(BCME)-exposed workers, respectively.
    Reductions in occupational exposure to CMME(BCME) were instituted in
    1972 and 1984. Potential exposure to CMME(BCME) was rated according to
    employment experience; cumulative exposure was based upon the job
    exposure rating and length of employment at a particular job. Based
    upon limited monitoring studies, conducted between 1979 and 1984, the

    average level of BCME in the plant ranged from 3.3 to 20.7 µg/m3 
    (0.7 to 4.4 ppb); after 1984 the average level in the plant was
    reportedly < 2.4 µg/m3 (0.5 ppb). The rate ratio for lung cancer
    among the CMME(BCME)-exposed workers, compared to the rate for the
    unexposed workers or external population, was 5.5 (95% CI = 2.0-12.3)
    and 7.6 (95% CI = 4.3-13.5), respectively. The rate ratio for lung
    cancer among the unexposed workers, compared to the rate for the
    external population, was 1.6 (95% CI = 0.8-3.12). Linear regression
    analysis revealed an increased rate of lung cancer with increasing
    cumulative exposure. The ratio of observed/expected cases of lung
    cancer for the CMME(BCME)-exposed workers (based upon comparison with
    the external population) generally increased with increasing
    cumulative exposure. The mean age at diagnosis for the unexposed and
    CMME(BCME)-exposed workers was 56.5 and 46 years, respectively; the
    mean induction period for lung cancer among the CMME(BCME)-exposed
    workers was approximately 13 years.

         Excess deaths due to lung cancer have also been reported for
    Chinese (Xue et al., 1988) chemical workers exposed to
    "chloromethylether"; latency as low as 2 years was reported. In a
    follow-up study of one of the cohorts examined by Xue et al. (1988),
    exposed to both CMME and BCME, there was an increased rate of lung
    markings similar to asbestosis as well as evidence of reduced
    pulmonary function (Xue et al., 1996). The magnitude of these changes
    was higher among workers exposed before 1975 to CMME levels of 0.096
    µg/m3 than to those exposed after 1981 to approximately 0.013 µg/m3.
    Sram et al. (1983, 1985) reported the increased frequency of
    chromosomal aberrations in peripheral lymphocytes of workers (1.64 to
    3.75% in controls, and 5.06 to 5.49% in subjects employed from 1-10
    years) exposed in the production of ion exchange resins to levels of
    0.01 to 0.1 µg BCME/m3 and 20 to > 200 µg CMME/m3.

         No relevant studies are available concerning the neurological,
    immunological, developmental or reproductive effects of BCME or CMME
    in humans.

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         For aquatic species, the 7-day LC50 for exposure of the guppy
     (Poecilia reticulata) to BCEE was 56.9 mg/litre (Konemann, 1981).
    Buccafusco et al. (1981) reported a 96-h LC50 of 600 mg BCEE/litre
    for the bluegill sunfish  (Lepomis macrochirus). LeBlanc (1980)
    reported a 48-h LC50 of 240 mg BCEE/litre for  Daphnia magna. In all
    three of the above studies, organisms were exposed to nominal
    concentrations of BCEE in closed containers, under static or
    static-with-renewal conditions.

         Anaerobic activity was not inhibited when microorganisms were
    exposed to BCEE at concentrations up to 100 mg/litre in a nutrient
    buffer solution (Johnson & Young, 1983). Cho et al. (1989) reported an
    LC50 and an LC10 of 2160 and 600 µg BCEE/litre, respectively, for
    microbes indigenous to industrial waste stabilization ponds and that
    required a supply of organic material for food.

         No relevant data are available to assess toxicity of BCEE to
    species of wildlife, and no studies have been identified in which the
    toxicity of either BCME or CMME to aquatic or terrestrial organisms
    was investigated.

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

    10.1  Evaluation of human health risks

    10.1.1  BCEE

         The lack of available information on concentrations of BCEE in
    several environmental media to which humans are exposed precludes
    quantitative estimation of the total daily intake of this substance
    from the general environment. Based upon extremely limited data, the
    estimated intake of BCEE from drinking-water for adults would be
    approximately 0.01 µg/kg body weight per day. Quantitative information
    on the extent of potential workplace exposure to this substance was
    not identified.

         Available data on the toxicity of BCEE in humans are extremely
    limited. Irritation to the eyes, nasal passages and respiratory tract
    could result from acute inhalation exposure to moderate levels of
    BCEE. Data were considered inadequate to assess the human health risks
    of non-neoplastic effects arising from longer-term exposure to this
    substance.

         Studies on the toxicological effects produced by the long-term
    exposure of laboratory animals to BCEE have focused on its
    carcinogenic potential. Some very limited evidence of carcinogenicity
    in hybrid F1 mice was reported in one study (Innes et al., 1969).
    However, none of the long-term (subchronic or chronic/
    carcinogenicity) studies in laboratory animals is considered to be of
    sufficient quality to provide useful quantitative information on the
    carcinogenic potential of BCEE or the toxicological effects produced
    by long-term exposure to this substance. Moreover, studies of
    developmental and reproductive effects of BCEE in laboratory animals
    have not been identified. Available data were, therefore, considered
    inadequate to assess the risks to human health associated with
    exposure to BCEE in the general or occupational environments.

    10.1.2  BCME and CMME

         Information on the concentrations of BCME and CMME in air,
    drinking-water, soil or foodstuffs were not identified, and therefore
    it was not possible to estimate the intake of these substances by the
    general population. However, owing to the extremely rapid hydrolysis
    of these compounds in aqueous media, exposure of non-occupationally
    exposed individuals is likely to be negligible. However, in some
    countries exposure of the general population to chloromethyl ethers
    may occur through the use of mosquito coils. Information on
    occupational exposure to BCME and CMME is also limited, although a
    recent study of a resin manufacturing plant reported lower levels of
    BCME than had been observed in previous, older investigations of
    plastics, textile and chemical manufacturing plants.

         Based upon the results of studies conducted with animals,
    inhalation of BCME or CMME may produce severe irritation of the eyes
    and respiratory tract as well as necrotizing bronchitis. Dermal
    exposure to BCME and CMME can result in erythema and necrosis.

         In all of the cohort studies of occupationally exposed workers
    conducted to date, an association between lung cancer and exposure to
    either BCME or CMME has been observed. The type of lung cancer, the
    standardized mortality ratios, the latency periods and average age of
    appearance of lung cancer in groups of workers exposed to either BCME
    or CMME have been remarkably consistent. The type and incidence of
    lung cancer in individuals exposed to BCME or CMME, predominantly
    small (oat) cell carcinomas, occurring in relatively young individuals
    after short latency periods (as low as 2 years), is distinct from that
    caused by tobacco, one of the potential confounders in such studies,
    where lung tumours are predominantly squamous cell carcinomas,
    occurring after long latency periods in individuals greater than 60
    years of age. The association between exposure to either BCME or CMME
    and lung cancer is strong, with standardized mortality ratios ranging
    up to 21.

         For CMME, there is also evidence of a positive relationship
    between a qualitative measure of exposure and mortality due to lung
    cancer. In two studies of occupationally exposed individuals, the
    standardized mortality ratios for deaths due to lung cancer peaked 10
    to 20 years following the onset of exposure. Furthermore, observation
    of an association between occupational exposure to BCME or CMME and
    the development of lung cancer is plausible. This observation is based
    on the results of early, rather limited carcinogenesis bioassays in
    exposed animal species, in which increases in the incidence of
    tumours, predominantly of the respiratory tract, have been observed,
    as well as on available data on the genotoxicity of BCME and CMME.

         The observed association of lung cancer and occupational exposure
    to either BCME or CMME fulfil traditional criteria for assessment of
    causality in epidemiological studies, i.e. consistency, strength,
    specificity, temporal relationship, exposure-response relationship,
    plausibility and supporting data on chromosomal effects in workers
    exposed to 0.01 µg BCME/m3 and 20 µg CMME/m3. Clearly, BCME and
    technical grade CMME are carcinogenic to humans, and, therefore,
    exposure to these substances should be eliminated.

    10.1.3  Guidance values

         Available data on BCEE were considered inadequate to derive a
    meaningful guidance value for this substance.

         Inhalation is the principal route of exposure to these
    substances. Data available in epidemiological studies of workers
    exposed to BCME and CMME are inadequate to characterize quantitatively
    the exposure-response relationship for carcinogenicity. There is
    evidence that the general population may be exposed to BCME and CMME
    through the use of mosquito coils, but there are no quantitative

    exposure data available. However, in humans there is an increase in
    cancer incidence (latency period as short as 2 years) with cumulative
    exposure to BCME and an increase in chromosomal aberrations in workers
    at levels as low as 0.01 µg BCME/m3 and 20 µg CMME/m3. Based on
    multistage modelling of the incidence of esthesioneuro-epitheliomas in
    rats exposed to BCME (Leong et al., 1981), the estimated concentration
    of this substance associated with a 5% increase in tumour incidence
    (TD05), corrected for intermittent (6 of 24 h, 5 days/week) versus
    continuous exposure, is 6 µg/m3. Data on CMME were insufficient to
    derive a TD50. Limitations of the critical study including the
    relatively short period of exposure (6 months followed by 22-month
    observation period) and sharp increase in the incidence of these
    tumours between the mid- and high-concentration groups, should,
    however, be borne in mind in the interpretation of this value.

         The above analysis of data further strengthens the recommendation
    to eliminate human exposure to BCME and CMME.

    10.2  Evaluation of effects on the environment

    10.2.1  BCEE

         BCEE is highly soluble in water and tends to remain there,
    although some volatilization from soil and water to the atmosphere
    occurs. Owing to lack of adsorption, BCEE is mobile in soils,
    especially those with low organic carbon content, and therefore it has
    the potential to reach groundwater. BCEE does not bioaccumulate or
    biomagnify to any significant extent.

         Exposure of terrestrial organisms to BCEE is considered to be
    negligible because of its extremely low rate of release and short
    persistence in the atmosphere. For aquatic biota, a 7-day LC50 of
    56.9 mg/litre (nominal concentration) for the guppy  (Poecilia 
     reticulata) has been reported. The lowest LC50 reported for acute
    toxicity (48-h) is 240 mg/litre (nominal concentration) for  Daphnia 
     magna. The highest concentration of BCEE reported for surface water
    in the USA (1.4 µg/litre) is approximately 40 000 times lower than the
    reported 7-day LC50 for the guppy  (Poecilia reticulata).

         Although it is relatively persistent in water, the highest
    reported concentration of BCEE in surface water is approximately five
    orders of magnitude lower than the concentration found to induce
    adverse effects in the guppy, the most sensitive aquatic species
    identified among existing toxicity studies. Therefore, BCEE is not
    expected to pose a significant risk to environmental organisms.

    10.2.2  BCME and CMME

         Both substances are readily hydrolysed in aqueous media or
    photo-oxidized in the atmosphere and, therefore, are not likely to
    accumulate. Because of their extremely short residence times, levels 
    in the environment (if any) are likely to be extremely low. Thus,

    despite the lack of data concerning the environmental toxicity of BCME
    and CMME, there is no reason to suspect that adverse effects could
    occur to organisms living in the ambient environment.

    11.  RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH AND THE
         ENVIRONMENT

    a)   Exposure to BCME and technical CMME should be eliminated.

    b)   Levels of BCEE in environmental media to which humans are exposed
         should be determined. 

    12.  FURTHER RESEARCH

    a)   Workers previously exposed to BCME and technical grade CMME
         should be followed using all available methods, including markers
         of biological effect for the detection of lung cancer at an early
         stage.

    b)   The degree of exposure of the general public to BCME and CMME
         through the use of mosquito coils containing the S-2 synergist
         octachlorodipropyl ether should be measured. In this study the
         degree of possible contamination of the S-2 synergist by BCME and
         CMME should also be taken into account.

    c)   If it is still used, the toxicological profile for BCEE should be
         determined in well-designed toxicological studies.

    13.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         BCEE has been evaluated by the International Agency for Research
    on Cancer (IARC) and placed in Group 3 - "not classifiable as to its
    carcinogenicity in humans" (IARC, 1987). BCME and CMME are considered
    by IARC to be carcinogenic to humans (Group 1) (IARC, 1987).

    REFERENCES

    Agrelo CE & Severin BJ  (1981) A simplified method for measuring
    scheduled and unscheduled DNA synthesis in human fibroblasts.
    Toxicology, 21: 151-158.

    Albert RE, Sellakumar AR, Laskin S, Kuschner M, Nelson N, & Snyder CA
    (1982) Gaseous formaldehyde and hydrogen chloride induction of nasal
    cancer in the rat.  J Natl Cancer Inst, 68: 597-603.

    Anderson D & Styles JA (1978) The bacterial mutation test. Br J
    Cancer, 37: 924-930.

    ATSDR (1989a) Toxicological profile for bis(2-chloroethyl)ether.
    Atlanta, Georgia, Agency for Toxic Substances and Disease Registry
    (Report PB90-168683). 

    ATSDR (1989b) Toxicological profile for bis(chloromethyl) ether.
    Atlanta, Georgia,  Agency for Toxic Substances and Disease Registry 
    (Report PB90-168691).  

    Barrows M, Petrocelli S, Macek K, & Carrol J (1978) Bioconcentration
    and elimination of selected water pollutants by bluegill sunfish
     (Leptomis macrochirus). In: Haque R ed.  Dynamics, exposure and
    hazard assessment of toxic chemicals.  Ann Arbor, Michigan, Ann Arbor
    Science Publishers, Inc., pp 379-392.

    Blease T, Scrivens J, & Morden W  (1989) The determination of
    atmospheric bis(chloromethyl) ether by gas chromatography/ tandem mass
    spectrometry.  Biomed Environ Mass Spectrom, 18: 775-779.

    Buccafusco RJ, Ells SJ, & LeBlanc GA (1981) Acute toxicity of priority
    pollutants to bluegill  (Lepomis macrochirus). Bull Environ Contam
    Toxicol, 26: 446-452. 

    Callahan M, Slimak M, Gabel N, May I, Fowler C, Freed J, Durfee R,
    Whitmore F, Maestri B, Mabey W, Holt B, & Gould C (1979) Water-related
    environmental fate of 129 priority pollutants: Volume II - Halogenated
    aliphatic hydrocarbons, halogenated ethers, monocyclic aromatics,
    phthalate esters, polycyclic aromatic hydrocarbons, nitrosamines, and
    miscellaneous compounds.  Washington, DC, US Environmental Protection
    Agency, Office of Water Planning and Standards, Office of Water and
    Waste Management (EPA-440/4-79-029b, PB80-204381).

    CCINFO (1991) Canadian Centre for Occupational Health and Safety
    database: Data for chloromethyl methyl ether. Hamilton, Ontario,
    Canadian Centre for Occupational Health and Safety. 

    Chen BI, Sun FG, & Xue SZ (1997)The occurrence of a cluster of lung
    cancer among the workers in the synthesis of octachloropropanyl ether.
    Chin J Ind Med, 10(5): 305-306.

    Cho Y-H, Davis EM, & Ramey GD  (1989) Assessing microbial toxicity of
    2-ethoxyethanol and bis(2-chloroethyl)ether by a modified spread plate
    method. Environ Technol Lett, 10: 875-886.

    Collier L (1972) Determination of bis(chloromethyl) ether at the ppb
    level in air samples by high-resolution mass spectroscopy. Environ Sci
    Technol, 6: 930-932.

    Collingwood KW, Pasternack BS, & Shore RE (1987) An industry-wide
    survey of respiratory cancer in chemical workers exposed to
    chloromethyl ethers. J Natl Cancer Inst, 78: 1127-1136.

    Cuppit L  (1980) Fate of toxic and hazardous materials in the air
    environment. Research Triangle Park, US Environmental Protection
    Agency, Atmospheric Chemistry and Physics Laboratory
    (EPA-600/3-80-084, PB80-221948).

    DeFonso LR & Kelton SC (1976) Lung cancer following exposure to
    chloromethyl methyl ether.  Arch Environ Health, 31: 125-130.

    DeWalle FB & Chian ES (1981) Detection of trace organics in well water
    near a solid waste landfill. J Am Water Works Assoc, 73: 206-211.

    Drake KD & Myer JR (1992) Acute oral toxicity of DCEE (dichloroethyl
    ether) in rats and mice. Acute Toxicol Data, 1: 163-164.

    Dressman RC, Fair J, & McFarren EF (1977) Determinative method of
    analysis of aqueous sample extracts for bis(2-chloro) ethers and
    dichlorobenzenes. Environ Sci Technol, 11: 719-721.  

    Drew RT, Laskin S, Kuschner M, & Nelson N (1975) Inhalation
    carcinogenicity of haloethers: I. The acute inhalation toxicity of
    chloromethyl methyl ether and bis(chloromethyl)ether. Arch Environ
    Health, 30: 61-69.

    Durkin P, Howard P, & Saxena J  (1975)  Investigation of selected
    environmental contaminants:  Haloethers. Washington, DC, US
    Environmental Protection Agency, Office of Toxic Substances 
    (EPA 68-1-2996, PB-246 356).

    Eisner D (1974) Formation of bis-chloromethylether from hydrogen
    chloride and formaldehyde.  Redwood City, California, Diamond Shamrock
    Chemical Co., Nopco Chemical Division (Report No. EQR-7412).  

    Elkins HB (1959) Chemistry of industrial toxicology. New York,  John
    Wiley and Sons.

    Evans K, Mathias A, Mellor N, Silvester R, & Williams A (1975)
    Detection and estimation of bis(chloromethyl) ether in air by
    gas-chromatography high-resolution mass spectrometry. Anal Chem, 47:
    821-824.

    Fishbein L (1979) Potential halogenated industrial carcinogenic and
    mutagenic chemicals: III.  Alkane halides, alkanols and ethers. Sci
    Total Environ, 11: 223-257.

    Foureman P, Mason JM, Valencia R, & Zimmering S (1994) Chemical
    mutagenesis testing in  Drosophila: IX. Results of 50 coded compounds
    tested for the National Toxicology Program. Environ Mol Mutagen, 23:
    51-63.

    Frankel L & Black R (1976) Automatic gas chromatographic monitor for
    the determination of parts-per-billion levels of bis(chloromethyl)
    ether. Anal Chem, 48: 732-737.  

    Frankel LS, McCallum K, & Collier L (1974) Formation of
    bis(chloromethyl) ether from formaldehyde and hydrogen chloride.
    Environ Sci Technol, 8: 356-359.

    Galvin R & House M (1988) Atmospheric monitoring of bis(chloromethyl)
    ether at low ppb levels using an automated system. Environ Technol
    Lett, 9: 563-570.  

    Gargus JL, Reese WH, & Rutter HA (1969) Induction of lung adenomas in
    newborn mice by bis(chloromethyl)ether. Toxicol Appl Pharmacol, 15:
    92-96.

    Goldschmidt BM, van Duuren BL, & Frenkel K (1975) The reaction of
    14C-labelled bis(chloromethyl)ether with DNA. Proc Am Assoc Cancer
    Res, 16: 66.

    Government of Canada (1993a) Canadian Environmental Protection Act -
    Priority substances list assessment report: Bis(2-chloroethyl) ether.
    Ottawa, Government of Canada.

    Government of Canada (1993b) Canadian Environmental Protection Act -
    Priority substances list assessment report: Bis(chloromethyl)ether and
    chloromethyl methyl ether. Ottawa, Government of Canada.

    Gowers DS, DeFonso LR, Schaffer P, Karli A, Monroe CB, Bernabeu L, &
    Renshaw FM (1993) Incidence of respiratory cancer among workers
    exposed to chloromethyl-ethers. Am J Epidemiol, 137: 31-42.

    Gwinner LM, Laib RJ, Filser JG, & Bolt HM (1983) Evidence of
    chloroethylene oxide being the reactive metabolite of vinyl chloride
    toward DNA: Comparative studies with 2,2'-dichloro-diethylether.
    Carcinogenesis, 4: 1483-1486.  

    Hauser T & Bromberg S (1982)  EPA's program at Love Canal. Environ
    Monit Assess, 2: 249-272.

    Hites RA, Jungclaus GA, & Lopez-Avila V (1979) Potentially toxic
    organic compounds in industrial waste-waters and river systems: Two
    case studies. In: Monitoring toxic substances. Washington, DC,
    American Chemical Society, pp 63-90 (American Chemical Symposium
    Series 94).

    Howard P, Boething R, Jarvis W, Meylan W, & Michalenko E (1991)
    Handbook of environmental degradation rates.  Chelsea, Michigan, Lewis
    Publishers, Inc.

    IARC (1974) Bis(chloromethyl)ether. Some aromatic amines, hydrazines,
    and related substances, N-nitroso compounds and miscellaneous
    alkylating agents. Lyon, International Agency for Research on Cancer,
    pp 231-245 (Monographs on the Evaluation of the Carcinogenic Risk of
    Chemicals to Man, Volume 4). 

    IARC (1975) Bis(2-chloroethyl) ether. In: Some aziridines, N-, S- and
    O-mustards and selenium.  Lyon, France, International Agency for
    Research on Cancer, pp 117-123 (Monographs on the Evaluation of the
    Carcinogenic Risk of Chemicals to Man, Volume 9). 

    IARC  (1987) Overall evaluations of carcinogenicity: An updating of
    IARC monographs, volums 1 to 42. Lyon, International Agency for
    Research on Cancer, p 58 (Monographs on the Evaluation of Carcinogenic
    Risks to Humans, Supplement 7).

    Innes JRM, Ulland BM, Valerio MG, Petrucelli L, Fishbein L, Pallotta
    AJ, Bates RR, Falk HL, Gart JJ, Klein M, Mitchell I, & Peters J 
    (1969) Bioassay of pesticides and industrial chemicals for
    tumorigenicity in mice: a preliminary note. J Natl Cancer Inst, 
    42: 1101-1114.

    IPCS (1994) Environmental health criteria 170: Assessing human health
    risks of chemicals: Derivation of guidance values for health-based
    exposure limits. Geneva, World Health Organization, International
    Programme on Chemical Safety, 71 pp.

    Johnson LD & Young JC (1983) Inhibition of anaerobic digestion by
    organic priority pollutants.  J Water Pollut Control Fed, 
    55: 1441-1449. 

    Jorgenson TA, Rushbrook CJ, Newell GW, & Tardiff RG (1977) Study of
    the mutagenic potential of bis(2-chloroethyl) and
    bis(2-chloroisopropyl) ethers in mice by the heritable translocation
    test. Toxicol Appl Pharmacol, 41: 196-197.  

    Kallos G  (1981) Oxygen induced response enhancement of determination
    of bis(chloromethyl) ether by gas chromatography with nickel-63
    electron capture detection. Anal Chem, 53: 963-965.  

    Kallos G & Tou J (1977) Study of photolytic oxidation and chlorination
    reactions of dimethyl ether and chlorine in ambient air. Environ Sci
    Technol, 11: 1101-1105.

    Kallos G, Albe W, & Solomon R (1977) On-column reaction gas
    chromatography for determination of chloromethyl methyl ether at the
    one part-per-billion level in ambient air. Anal Chem, 49: 1817-1820.

    Keith L, Garrison A, Allen F, Carter M, Floyd T, Pope J, & Thruston A
    (1976) Identification of organic compounds in drinking-water from
    thirteen U.S. cities.  In: Keith LH ed.  Identification and analysis
    of organic pollutants in water. Ann Arbor, Michigan, Ann Arbor Science
    Publishers, Inc., p 356.  

    Kendall PR (1990) The quality of drinking-water in Toronto: A review
    of  tapwater, bottled water and water treated by a point-of-use device
    - Summary report. Toronto, Canada, Department of Public Health,
    Environmental Protection Office, 41 pp.  

    Kincannon D & Lin Y  (1986) Microbial degradation of hazardous wastes
    by land treatment.  In: Proceedings of the 40th Industrial Waste
    Conference, Purdue University, West Lafayette, IN,  14-16 May 1985. 
    Boston, Ann Arbor Science Publishers, Inc., pp 607-619.  

    Kirwin CJ & Sandmeyer EE (1981) Ethers. In: Clayton GD & Clayton FE
    ed.  Patty's industrial hygiene and toxicology: Volume IIA, 3rd ed.
    New York, John Wiley and Sons, pp 2491-2565.

    Kleopfer RD & Fairless BJ  (1972) Characterization of organic
    components in a municipal water supply. Environ Sci Technol, 
    6: 1036-1037.   

    Konemann H  (1981) Quantitative structure-activity relationships in
    fish toxicity studies - Part 1:  Relationship for 50 industrial
    pollutants. Toxicology, 19: 209-221.  

    Kraybill HF (1977) Global distribution of carcinogenic pollutants in
    water. Ann NY Acad Sci, 298: 80-89.  

    Kurian P, Nesnow S, & Milo GE (1990) Quantitative evaluation of the
    effects of human carcinogens and related chemicals on human foreskin
    fibroblasts. Cell Biol Toxicol, 6: 171-184.

    Kuschner M, Laskin S, Drew RT, Cappiello V, & Nelson N (1975)
    Inhalation carcinogenicity of alpha haloethers: III. Lifetime and
    limited period inhalation studies with bis(chloromethyl)ether at 0.1
    ppm. Arch Environ Health, 30: 73-77.

    Langelaan F & Nielen M  (1989) Determination of trace levels of
    chloromethyl methyl ether and bis(chloromethyl) ether in air. Int J
    Environ Anal Chem, 36: 27-34.

    Langhorst M (1985) Monitoring chloromethyl methyl ether in air. In:
    Fishbein L & O'Neill KI ed. Environmental carcinogens. Selected
    methods of analysis - Volume 7: Some volatile halogenated
    hydrocarbons. Lyon, International Agency for Research on Cancer, pp
    235-246 (IARC Scientific Publications No. 68).

    Langhorst M, Melcher R, & Kallos G (1981) Reactive adsorbent
    derivative collection and gas chromatographic determination of
    chloromethyl methyl ether in air. Am Ind Hyg Assoc J, 42: 47-55.

    Laskin S, Drew RT, Cappiello V, Kuschner M, & Nelson N (1975)
    Inhalation carcinogenicity of alpha halo ethers: II. Chronic
    inhalation studies with chloromethyl methyl ether. Arch Environ
    Health, 30: 70-73.

    LeBlanc GA  (1980) Acute toxicity of priority pollutants to water
    fleas  (Daphnia magna). Bull Environ Contam Toxicol, 24: 684-691.  

    Lemen R, Johnson W, Wagoner J, Archer V, & Saccomanno G (1976)
    Cytologic observations and incidence following exposure to BCME. Ann
    NY Acad Sci, 271: 71-80.

    Leong BKJ, MacFarland HN, & Reese WH (1971) Induction of lung adenomas
    by chronic inhalation of bis (chloromethyl) ether. Arch Environ
    Health, 22: 663-666.

    Leong BKJ, Kociba RJ, & Jersey GC (1981) A lifetime study of rats and
    mice exposed to vapors of bis(chloromethyl)ether. Toxicol Appl
    Pharmacol, 58: 269-281.

    Lingg RD, Kaylor WH, Pyle SM, & Tardiff RG  (1979) Thiodiglycolic
    acid: a major metabolite of bis(2-chloroethyl) ether. Toxicol Appl
    Pharmacol, 47: 23-34.

    Lingg RD, Kaylor WH, Pyle SM, & Domino MM  (1982) Metabolism of
    bis(2-chloroethyl)ether and bis(2-chloroisopropyl)ether in the rat.
    Arch Environ Contam Toxicol, 11: 173-183.  

    Mabey W, Smith J, Podoll R, Johnson H, Mil T, Chou T, Gates J,
    Partridge I, Jaber H, & Vandenberg D (1982) Aquatic fate processes
    data for organic priority pollutants. Washington, DC, US Environmental
    Protection Agency, Office of Water Regulations and Standards,
    Monitoring and Data Support Division (EPA 440/4-81-014).  

    Mackay D & Wolkoff A  (1973) Rate of evaporation of low-solubility
    contaminants from water bodies to the atmosphere. Environ Sci Technol,
    7: 611-614.  

    McMillin CR, Gable RC, Kyne JM, Quill RP, Snyder AD, & Thomas JA 
    (1984) EPA method study 21, method 611: Haloethers. Cincinnati, Ohio,
    US Environmental Protection Agency, Environmental and Support
    Laboratory, Office of Research and Development (EPA-600/4-84-052,
    PB84-205939).

    Maher KV & DeFonso LR (1987) Respiratory cancer among
    chloromethylether workers.  J Natl Cancer Inst, 78: 839-843.

    Manwaring J, Blankenship W, Miller L, & Voigt F (1977) 
    Bis(2-chloroethyl) ether removal from drinking-water by source
    protection.  In: Pojasek RB ed.  Drinking-water quality enhancement
    through source protection.  Ann Arbor, Michigan, Ann Arbor Science
    Publishers, Inc., pp 417-429.  

    Marceleno T (1974)  Survey of Burlington Industries, Inc.,  Burlington
    House Finishing Plant, Form Fabrics Plant, Durham Domestics Plant,
    Brookneal Finishing Plant. Cincinnati,Ohio, National Institute for
    Occupational Safety and Health, Environmental Investigations Branch,
    Division of Field Studies and Clinical Investigations (Report 
    PB82-151077). 

    Milano J, Bernat-Escallon C, & Vernet J (1989) Dégradations dans l'eau
    par hydrolyse et photolyse du bis-2 chloroéthyl éther. Environ Technol
    Lett, 10: 291-300.  

    Mortelmans K, Haworth S, Lawlor T, Speck W, Tainer B, & Zeiger E
    (1986)  Salmonella mutagenicity tests: II. Results from the testing
    of 270 chemicals. Environ Mutagen, 7: 1-119.

    Mukai FH & Hawryluk I (1973) Mutagenicity of some halo-ethers and
    halo-ketones. Mutat Res, 21: 228.

    Muller G, Norpoth K, & Eckard R (1979) Identification of
    S-(carboxymethyl)-L-cysteine and thiodiglycollic acid, urinary
    metabolites of 2,2'-bis-(chloroethyl)-ether in the rat. Cancer Lett,
    7: 299-305.

    Muller G, Norpoth K, & Travenius S (1981) Quantitative determination
    of bis(chloromethyl) ether (BCME) in the ppb range by using portable
    air sample collectors. Int Arch Occup Environ Health, 48: 325-329.

    National Research Council (NRC)  (1977)  Drinking-water and health - 
    Volume 1.  Washington, DC, National Academy Press, p 711. 

    Nichols RW & Merritt RF (1973) Brief communication: relative
    solvolytic reactivities of chloromethyl ether and bis(chloromethyl)
    ether. J Natl Cancer Inst, 50: 1373-1374.

    NIOSH (1974) The toxic substances list, 1974 edition. Cincinnati,
    Ohio, National Institute for Occupational Safety and Health, p 134 (US
    Department of Health, Education and Welfare Publication No. 74). 

    NIOSH (1984) Method 1004: Dichloroethyl ether. In: NIOSH manual of
    analytical methods, 3rd ed. Cincinnati, Ohio, National Institute for
    Occupational Health and Safety,  pp 1004/1-1004/3. 

    Nishimura K, Miyashita K, Yoshida Y, Kuroda M, Matsumoto M, Matsumoto
    K, Takeda S, & Hara I (1990) An epidemiological study of lung cancer
    among workers exposed to bis(chloromethyl)ether. Jpn J Ind Health, 32:
    448-453.

    Norpoth K, Muller G, Zilius Z, Ulynec U, & Travenius SZM (1981)
    Sensitive spectrophotometric determination of carcinogenic alpha
    chloro ethers. Int Arch Occup Environ Health, 49: 151-155.

    Norpoth K, Heger M, Muller G, Mohtashamipur E, Kemena A, & Witting C
    (1986)  Investigations of metabolism, genotoxic effects, and
    carcinogenicity of 2,2-dichlorodiethyl ether.  J Cancer Res Clin
    Oncol, 112: 125-130.  

    Parkes D, Ganz C, Polinsky A, & Schultze J (1976) A simple gas
    chromatographic method for the analysis of trace organics in ambient
    air. Am Ind Hyg Assoc J, 37: 165-173.

    Pasternack BS, Shore RE, & Albert RE (1977) Occupational exposure to
    chloromethylethers.  J Occup Med, 19: 741-746.

    Pellizzari E, Erickson M, & Zweidinger R (1979) Formulation of a
    preliminary assessment of halogenated compounds in man and
    environmental media. Washington, DC, US Environmental Protection
    Agency, Office of Toxic Substances (EPA-560/13-79-006, PB 80-112170).

    Perocco P, Bolognesi S, & Alberghini W (1983) Toxic activity of 17
    industrial compounds on human lymphocytes cultured  in vitro. Toxicol
    Lett, 16: 69-76.

    Piwoni M, Wilson J, Walters D, Wilson B, & Enfield C (1986) Behaviour
    of organic pollutants during rapid infiltration of wastewater into
    soil: I. Processes, definition, and characterization using a
    microcosm. Hazard Waste Hazard Mater, 3: 43-55.

    Quaghebeur DG, Hierneaux G, & DeWulf E (1986) Tracing a source of
    pollution by determination of specific pollutants in surface- and
    groundwater. Proceedings of the 4th European Symposium, Vienna,
    Austria, 1985, pp 142-146.

    Quinto I & Radman M  (1987) Carcinogenic potency in rodents versus
    genotoxic potency in  E. coli: a correlation analysis for
    bifunctional alkylating agents. Mutat Res, 181: 235-242.  

    Radding S, Holt B, Jones J, Jiu D, Mill T, & Hendry D (1977) Review of
    the environmental fate of selected chemicals. Washington, DC, US
    Environmental Protection Agency, Office of Toxic Substances (EPA
    560/5-77/003).  

    Reznick G, Wagner WW, & Atay Z (1977) Lung cancer following exposure
    to bis(chloromethyl)ether: A case report. J Environ Pathol Toxicol, 1:
    105-111.

    Roe FJC (1985) Chloromethylation: Three lung cancer deaths in young
    men. Lancet, 2: 268.

    Rosen A, Skeel R, & Ettinger M (1963) Relationship of river water
    odour to specific organic contaminants. J Water Pollut Control Fed,
    35(6): 777-782.  

    Sakabe H  (1973) Lung cancer due to exposure to
    bis(chloromethyl)ether. Ind Health, 11: 145-148.

    Sawicki E, Belsky T, Friedel R, Hyde D, Monkman J, Rasmussen R,
    Ripperton L, & White L  (1976) Analytical method for chloromethyl
    methyl ether (CMME) and bis(chloromethyl) ether (BCME) in air. Health
    Lab Sci, 13: 78-81.

    Schrenk HH, Patty FA, & Yant WP (1933) Acute response of guinea pigs
    to vapors of some new commercial organic compounds. Public Health Rep,
    48: 1389-1398.

    Sellakumar AR, Snyder CA, Soloman JJ, & Albert RE (1985)
    Carcinogenicity of formaldehyde and hydrogen chloride in rats. Toxicol
    Appl Pharmacol, 81: 401-406.

    Sheldon L & Hites R (1978) Organic compounds in the Delaware River.
    Environ Sci Technol, 12(10): 1188-1194.

    Shirasu Y, Moriya M, Kato K, & Kada T (1975) Mutagenicity screening of
    pesticides in microbial systems: II. Mutat Res, 31: 268-269.

    Shooter KV (1975) Assays for phosphotriester formation in the reaction
    of bacteriophage R17 with a group of alkylating agents. Chem-Biol
    Interact, 11: 575-588.

    Simmon VF, Kauhanen K, & Tardiff RG (1977a) Mutagenic activity of
    chemicals identified in drinking water. In: Scott D, Bridges BA, &
    Sobels FH ed. Progress in genetic toxicology. Amsterdam,
    Elsevier/North-Holland, pp 249-258.

    Simmon VF, Kauhanen K, & Tardiff RG (1977b) Mutagenic assays with
    bis-(2-chloroethyl) ether.  In : Plaa GL & Duncan WAM ed. Proceedings
    of the First International Congress on Toxicology. New York, London,
    San Francisco, Academic Press, p 31.

    Sittig M  (1981) Handbook of toxic and hazardous chemicals. Park
    Ridge, New Jersey, Noyes Publications, 729 pp.

    Smith CC, Cragg ST, Wolfe GF, & Weigel WW (1985) Investigation of the
    metabolism of chlorinated hydrocarbons in sub-human species.  Research
    Triangle Park, North Carolina, US Environmental Protection Agency,
    Health Effects Research Laboratory (PB85-152387).

    Smyth HF Jr & Carpenter CP (1948) Further experience with the range
    finding test in the industrial toxicology laboratory. J Ind Hyg
    Toxicol, 30: 63-68.

    Spector WS ed. (1956) Handbook of toxicology. Philadelphia,
    Pennsylvania, W.B. Saunders Co., 671 pp.

    Sram RJ, Samkova I, & Hola N (1983) High-dose ascorbic acid
    prophylaxis in workers occupationally exposed to halogenated ethers. J
    Hyg Epidemiol Microbiol Immunol, 27: 305-318.

    Sram RJ, Landa K, & Roznickova I (1985) The use of cytogenetic
    analysis of peripheral lymphocytes as a method for checking the level
    of MAC in Czechoslovakia. Mutat Res, 147: 322. 

    Staples CA, Werner A, & Hoogheem TJ  (1985) Assessment of priority
    pollutant concentrations in the United States using STORET database.
    Environ Toxicol Chem, 4: 131-142. 

    Styles JA (1978) Mammalian cell transformation  in vitro. Br J
    Cancer, 37: 931-936.

    Suffet I, Brenner L, & Cairo P (1980) GC/MS identification of trace
    organics in Philadelphia drinking-water during a 2-year period. Water
    Res, 14: 853-867.

    Tabak H, Quave S, Mashni C, & Barth E (1981) Biodegradability studies
    with organic priority pollutant compounds. J Water Pollut Control Fed,
    53: 1503-1518.  

    Tabershaw IR, Utidjian HMD, & Kawahara BL (1977) Chemical hazards. In:
    Occupational diseases: A guide to their recognition.  Washington, DC,
    United States Department of Health, Education and Welfare, p 131
    (Publication DHEW (NIOSH) 77-181).

    Theiss WC, Stoner GD, Shimkin MB, & Weisburger EK (1977) Test for
    carcinogenicity of organic contaminants of United States
    drinking-waters by pulmonary tumor response in strain A mice. Cancer
    Res, 37: 2717-2720.

    Tou J & Kallos G (1974a) Study of aqueous HCl and formaldehyde
    mixtures for formation of bis(chloromethyl) ether. Am Ind Hyg Assoc J,
    35: 419-422.

    Tou J & Kallos G (1974b) Kinetic study of the stabilities of
    chloromethyl methyl ether and bis(chloromethyl) ether in humid air.
    Anal Chem, 46: 1866-1869.  

    Tou J & Kallos G (1976) Possible formation of bis(chloromethyl) ether
    from the reactions of formaldehyde and chloride ion. Anal Chem, 48:
    958-963.

    Tou J, Westover L, & Sonnabend L  (1974) Kinetic studies of
    bis(chloromethyl) ether hydrolysis by mass spectrometry. J Phys Chem,
    78: 1096-1098.  

    Travenius S  (1982) Formation and occurrence of bis(chloromethyl)
    ether and its prevention in the chemical industry. Scand J Work
    Environ Health, 8(suppl 3): 1-86.  

    Union Carbide (1968) Bis(chloromethyl)ether: Range finding toxicity
    studies. Danbury, Connecticut, Union Carbide Corporation, 5 pp (Report
    No. 31-85).

    US EPA (1980) Ambient water quality criteria for chloroalkyl ethers.
    Washington, DC, US Environmental Protection Agency, Environmental
    Criteria Assessment Office, Office of Water Regulations and Standards,
    Criteria and Standards Division (EPA-440/5-80-03, PB81-117418). 

    US EPA (1987a) Health and environmental effects document for
    haloethers. Cincinnati, Ohio, US Environmental Protection Agency,
    Environmental Criteria and Assessment Office  (ECAO-CIN-G014).

    US EPA  (1987b) Health effects assessment for bis(2-chloroethyl)
    ether. Cincinnati, Ohio,  US Environmental Protection Agency,
    Environmental Criteria and Assessment Office (EPA/600/8-88023,
    PB88-179486).  

    US EPA (1990) Toxic chemical release inventory database for 1989. 
    Washington, DC, US Environmental Protection Agency and National
    Library of Medicine

    US NLM (1996) Hazardous substances database: Records for
    bis(chloromethyl)ether, bis(2-chloroethyl)ether and chloromethyl
    methyl ether. Bethesda, Maryland, National Library of Medicine. 

    van der Ven LGJ & Venema A (1979) Determination of
    bis(chloromethyl)ether in air. Anal Chem, 51: 1016-1019.

    van Duuren BL (1989) Comparison of potency of human carcinogens: vinyl
    chloride, chloromethylmethyl ether and bis(chloromethyl)ether. Environ
    Res, 49: 143-151.

    van Duuren BL, Sivak A, Goldschmidt BM, Katz C, & Melchionne S (1969)
    Carcinogenicity of halo-ethers. J Natl Cancer Inst, 43: 481-486.

    van Duuren BL, Katz C, Goldschmidt BM, Frenkel K, & Sivak A (1972)
    Carcinogenicity of halo-ethers: II. Structure-activity relationships
    of analogues of bis(chloromethyl)ether. J Natl Cancer Inst, 48:
    1431-1439.

    Verschueren K  (1983) Handbook of environmental data on organic
    chemicals, 2nd ed.  Toronto, Canada, Van Nostrand Reinhold Co., 1310
    pp.  

    Weast RC & Astle M ed. (1985) CRC handbook of data on organic
    compounds - Volume 1.  Boca Raton, Florida, CRC Press.  

    Weisburger EK, Ulland BM, Nam J-M, Gart JJ, & Weisburger JH  (1981)
    Carcinogenicity tests of certain environmental and industrial
    chemicals. J Natl Cancer Inst, 67: 75-88.

    Weiss W (1976) Chloromethyl ethers, cigarettes, cough and cancer. J
    Occup Med, 18: 194-199.

    Weiss W (1980) The cigarette factor in lung cancer due to chloromethyl
    ethers. J Occup Med, 22: 527-529.

    Weiss W (1982) Epidemic curve of respiratory cancer due to
    chloromethylethers.  J Natl Cancer Inst, 69: 1265-1270.

    Weiss W (1989) Lung cancer due to chloromethyl ethers: bias in cohort
    definition. J Occup Med, 31: 102-105.

    Xue SZ, Quian C, Tang GF, Wang ZQ, Zhou DH, Deng J, Zhao JZ, & He YP
    (1988)  Epidemiological investigations on the lung cancer among
    chloro-methyl-ether exposures. In: Xue SZ & Liang Y. ed. Occupational
    health in industrialization and modernization. Shanghai, Shanghai
    Medical University Press, pp 75-80 (Bulletin of WHO Collaborating
    Centre for Occupational Health, Shanghai, Volume 2).

    Xue MI, Tang GF, Diao WX, & Cai MD (1996) Follow-up study on the
    cohorts exposed to chloro-methyl ethers. Chin J Ind Med, 9(4) 225-227.

    Yao CC & Miller GC (1979) Research study on bis(chloromethyl) ether
    formation and detection in selected work environments. Cincinnati,
    Ohio,  National Institute for Occupational Safety and Health, Division
    of Surveillance, Hazard Evaluations and Field Studies (Report
    PB83-174102).  

    Zajdela F, Croisy A, Barbin A, Malaveille C, Tomatis L, & Bartsch H
    (1980) Carcinogenicity of chloroethylene oxide, an ultimate reactive
    metabolite of vinyl chloride, and bis(chloromethyl)ether after
    subcutaneous administration and in initiation promotion experiments in
    mice. Cancer Res, 40: 352-356.

    RÉSUMÉ ET CONCLUSIONS

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

         Le bis (2-chloroéthyl) éther (BCEE), le bis (chlorométhyl) éther
    (BCME) et le chlorométhylméthyléther (CMME) sont des composés
    chimiques qui appartiennent à un vaste groupe de produits connus sous
    le nom de chloroalkyléthers. A la température ambiante, ces trois
    éthers se présentent sous la forme de liquides volatils incolores à
    l'odeur caractéristique. Ils sont dotés d'une forte tension de vapeur.
    La solubilité dans l'eau du BCEE est de 1,7% et son coefficient de
    partage entre l'octanol et l'eau est égal à 1,46. Le BCME et le CMME,
    qui sont des alpha-chloroalkyléthers, sont des composés réactifs. Ils
    subissent une hydrolyse rapide en milieu aqueux (avec une demi-vie ou
    temps de demi-hydrolyse respectivement égale à 38 secondes et < 0,007
    secondes); le BCEE, qui est un ß-chloroéthyléther, s'hydrolyse plus
    lentement (demi-vie dans l'eau approximativement égale à 20 ans).

         Les méthodes d'échantillonnage et d'analyse applicables au BCEE
    dans l'eau et au CMME dans l'air sont décrites dans la littérature. On
    peut citer comme exemples caractéristiques la chromatographie en phase
    gazeuse (détection par capture d'électrons) ou le couplage
    chromatographie en phase gazeuse-spectrométrie de masse.

    2.  Sources d'exposition humaine

         On n'a pas trouvé dans l'environnement de BCEE, de BCME ou de
    CMME qui soient d'origine naturelle. Les données de production
    récentes se limitent aux Etats-Unis et au Canada. On a produit environ
    10 000 tonnes de BCEE aux Etats-Unis en 1986 en vue d'une utilisation
    comme solvant, pour la production de polymères ou encore dans un
    certain nombre de processus industriels. Dans ce même pays, l'usage du
    BCME est actuellement limité à certaines réactions chimiques
    intermédiaires bien déterminées. On produit également du BCME en vue
    de la fabrication de résines échangeuses d'ions ou autres types de
    polymères ou encore comme solvant dans les réactions de
    polymérisation. En Chine, on produit chaque année, environ 200 tonnes
    de BCME comme intermédiaire dans la préparation d'un synergisant
    d'insecticide, l'octachlorodipropyléther. Le CMME de qualité technique
    contient de 1 à 8% de BCME.

    3.  Transport, distribution et transformation dans l'environnement

         La mobilité et la distribution de ces chloroalkyléthers sont,
    dans le cas du BCME et du CMME, déterminées par la grande réactivité
    de ces composés et, dans le cas du BCEE, par la grande solubilité et
    stabilité dans l'eau de cet éther. Le BCME et le CMME, des éthers
    alpha-chloroalkylés, subissent une hydrolyse rapide en milieu aqueux
    et sont rapidement décomposés par photolyse. En milieu aqueux, les
    produits d'hydrolyse du BCME et du CMME sont constitués de
    formaldéhyde et d'acide chlorhydrique dans le cas du premier et de
    méthanol, de formaldéhyde et d'acide chlorhydrique dans le cas du

    second. Parmi les produits de décomposition du BCME et du CMME,
    figurent le chlorure d'hydrogène, le formaldéhyde et le
    chlorométhylformiate, pour le premier, et le chlorométhyl- ainsi que
    le méthylformiate, pour le second. Le BCEE est soluble dans l'eau; les
    précipitations l'éliminent de l'atmosphère et il a tendance à rester
    dans l'eau où il subit une très lente hydrolyse. En l'espace d'une
    semaine, il s'évapore de la surface et se décompose en un peu moins
    d'une journée sous l'action de processus abiotiques.

         En raison du caractère extrêmement réactif des
    alpha-chloroalkyléthers dans l'eau et dans l'air, on ne peut guère
    s'attendre à trouver du CMME et du BCME dans l'environnement.
    Toutefois, le BCEE peut présenter une plus grande persistance en
    raison de la meilleure stabilité relative des ß-chloroalkyléthers.

    4.  Niveaux d'exposition dans l'environnement et exposition humaine

         On ne dispose que de données limitées sur la concentration du
    BCEE dans les divers compartiments de l'environnement. On l'a mis en
    évidence dans l'air, mais sans procéder à un dosage; aux Etats-Unis,
    on en a trouvé jusqu'à 42 µg/litre dans de l'eau de boisson. Les
    concentrations rapportées dans la littérature en ce qui concerne les
    eaux de surface vont de 0,001 µg/litre dans une décharge industrielle
    de gypse en Belgique, à 840 µg/litre dans une autre décharge située
    aux Etats-Unis. On a mesuré des concentrations encore plus élevées
    dans les eaux de lessivage d'une décharge contrôlée. On n'a pas
    connaissance de la teneur des denrées alimentaires en BCEE, mais on ne
    pense pas qu'il puisse y avoir bioaccumulation.

         On ne dispose d'aucune donnée sur la concentration du BCME et du
    CMME dans les divers compartiments de l'environnement.

         Si l'on se base sur la concentration maximale de BCEE rapportée
    pour l'eau de boisson, soit 42 µg/litre, un être humain moyen pesant
    64 kg et consommant 1,4 litres d'eau par jour ingérerait
    quotidiennement environ 0,01 µg de ce produit par kg de poids
    corporel, plus une quantité indéterminée provenant de sources
    inconnues. Il est impossible d'évaluer la dose quotidienne de BCME et
    de CMME ingérée à partir de sources environnementales. Toutefois,
    comme ces deux composés ne persistent pas dans l'environnement, il est
    probable que l'exposition humaine à ces produits est très faible.

         En s'appuyant sur des données limitées et assez anciennes, on
    pense que les ouvriers travaillant à la production de plastiques et de
    fibres textiles ont pu être exposés, dans l'air des lieux de travail,
    à des concentrations de BCME comprises entre 1,2 et 72,9 µg/m3.
    Cependant, une récente étude, effectuée dans une usine de production
    de résines plastiques, fait état d'une exposition professionnelle
    moyenne allant de 2,4 à 20,6 µg/m3. Selon d'autres travaux, la
    concentration de BCME ne dépasserait pas 0,01 µg/m3.En Chine,
    l'exposition au BCME a été plus élevée que ces chiffres jusqu'en 1975
    et alle persiste encore, quoiqu'à un niveau moindre, dans les usines
    qui produisent de l'octachlorodipropyléther. Il y exposition de la

    population générale au BCME et au CMME là où l'on fait beaucoup brûler
    de serpentins anti-moustiques qui en contiennent comme synergisants.

         La concentration la plus élevée de BCEE signalée aux Etats-Unis
    dans les effluents industriels se situe entre 8 et 170 µg/litre; dans
    le cas d'eaux provenant du lessivage de décharges contrôlées
    industrielles et municipales, la concentration était de 12 400
    µg/litre.

    5.  Cinétique et métabolisme

         On ne dispose pas de données quantitatives sur la cinétique et le
    métabolisme du BCEE, du BCME et du CMME chez l'homme. On estime
    toutefois que, même si le BCME et le CMME doivent, en principe, être
    rapidement hydrolysés  in vivo, pour donner, le premier, du
    formaldéhyde et de l'acide chlorhydrique et le second, du
    formaldéhyde, du méthanol et de l'acide chlorhydrique, il se produit
    sans doute une alkylation.

         D'après des données limitées, du BCEE radiomarqué administré à
    des rats par inhalation ou gavage subit une résorption rapide. Après
    administration par gavage, on a constaté que l'organisme des rats
    n'avait retenu que moins de 3% de la dose initiale au bout de 24
    heures.

         Chez le rat, le BCEE est rapidement métabolisé. Son principal
    métabolite est l'acide thiodiglycolique (TDGA). Chez des rats qui
    avaient reçu par gavage une dose unique de 14C-BCEE, on a constaté
    que 12% environ de la radioactivité absorbée se trouvait sous la forme
    de 14CO2.

         Chez le rhésus comme chez le rat, le BCEE est rapidement éliminé.
    Chez des rhésus auxquels on avait administré du 14C-BCEE par la voie
    orale, on a retrouvé moins de 2% de la radioactivité initiale dans les
    matières fécales 72 h après l'administration. Chez des rats, c'est
    approximativement 2,3% de la radioactivité initiale qui ont été
    retrouvés dans les tissus et les matières fécales, 48 h après
    l'administration. Après avoir administré par gavage du 14C-BCEE à des
    rats, on a retrouvé plus de 50% de la radioactivité dans les urines et
    dans l'air expiré 12 heures après l'administration. Moins de 2% de la
    radioactivité présente dans l'air expiré correspondaient au composé
    initial.

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

         Absorbé par la voie orale, par inhalation ou par voie
    transcutanée, le BCEE peut provoquer des intoxications aiguës. Les
    valeurs de la DL50 dont il est fait état dans la littérature en cas
    d'exposition d'animaux par la voie orale, vont de 75 à 215 mg/kg de
    poids corporel. Le BCME et le CMME provoquent également des
    intoxications aiguës lorsqu'ils sont absorbés par voie orale ou par
    inhalation. Les valeurs de la CL50 pour des animaux de laboratoire

    exposés par la voie respiratoire à du BCME ou à du CMME, vont de 25 à
    48 mg/m3 dans le cas du premier composé et de 182 à 215 mg/m3 dans
    le cas du second.

         L'exposition d'animaux de laboratoire par la voie respiratoire à
    une seule mais forte concentration de BCEE (>320 mg/m3), a provoqué
    une irritation oculaire ainsi qu'une congestion, un oedème et des
    hémorragies pulmonaires. Pendant l'inhalation de BCME, on a noté une
    irritation des yeux et des voies respiratoires ainsi qu'une bronchite
    nécrosante. L'application du produit sur la peau a donné lieu à un
    érythème et à une nécrose. L'instillation dans les yeux provoque une
    nécrose cornéenne. On a observé des effets analogues après exposition
    au CMME.

         On a constaté un accroissement de la mortalité et une hyperplasie
    trachéenne chez des rats et des hamsters exposés par la voie
    respiratoire à du BCME à la dose de 4,7 mg/m3. Des résultats
    analogues ont été obtenus à plusieurs reprises chez des rats exposés à
    du CMME par la voie respiratoire à raison de 3,3 ou de 33 mg de
    composé par m3.

         En général, les épreuves de mutagénicité  in vitro ont donné des
    résultats positifs avec le BCEE, le BCME et le CMME. Toutefois, les
    résultats sont difficiles à interpréter en raison de l'absence de
    détails dans les comptes rendus de ces expériences. Selon la
    littérature, le BCME et le CMME provoquent  in vitro un accroissement
    de la synthèse non programmée de l'ADN et le BCME augmente la
    proportion de cellules transformées, également  in vitro. Dans de
    petits groupes de souris mâles appartenant à deux souches de souris
    hybrides F1 (de même que chez les femelles d'une des souches F1),
    qui avaient reçu du BCEE par voie orale (dose pondérée par rapport au
    temps égale à 41,3 mg/kg p.c. sur une période de 18 mois), on a
    observé une augmentation significative de l'incidence des tumeurs
    hépatiques (bénignes et malignes) par rapport aux animaux témoins non
    exposés. Quatre autres études de portée plus limitée effectuées sur
    des rats et des souris qui recevaient le composé par gavage, en
    injections sous-cutanées ou intrapéritonéales ou par badigeonnage
    cutané, n'ont pas permis de confirmer ces résultats.

         Les études de cancérogénicité effectuées sur des animaux de
    laboratoire (souris ou rats) exposés à du BCME, ont révélé un
    accroissement significatif de l'incidence des adénomes pulmonaires et
    autres tumeurs des voies respiratoires. Chez la souris, on a également
    obtenu des indices d'une élévation de l'incidence des tumeurs
    pulmonaires.

         Les études effectuées sur le CMME ont révélé, chez le rat, un
    accroissement de l'incidence des métaplasies trachéennes et des
    hyperplasies bronchiques qui dépendait de la dose. Toutefois, les
    résultats des épreuves de cancérogénicité menées sur l'animal n'ont
    pas donné de résultats concluants.

         On ne dispose d'aucun renseignement concernant les effets
    toxiques éventuels du BCEE, du BCME et du CMME sur la fonction de
    reproduction, le développement, le système immunitaire et le système
    nerveux.

    7.  Effets sur l'homme

         On a constaté que le BCEE avait un effet irritant sur l'oeil et
    les fosses nasales aux concentrations supérieures à 150 mg/m3 après
    exposition de courte durée.

         On n'a pas trace d'études épidémiologiques sur les effets à long
    terme d'une exposition au BCEE.

         Une association entre l'exposition d'ouvriers à du BCME ou du
    CMME et un risque accru de cancer du poumon a été mise en évidence
    dans 8 études épidémiologiques. Les travailleurs exposés à du CMME de
    qualité technique l'étaient probablement aussi à du BCME. Les tumeurs
    prédominantes observées chez les ouvriers exposés étaient des
    carcinomes à petites cellules, tout à fait distincts des carcinomes
    essentiellement spinocellulaires qui s'observent. chez les fumeurs. Il
    s'agissait d'une forte association, avec des rapports comparatifs de
    mortalité qui allaient jusqu'à 2,1. Le type de cancer pulmonaire, la
    période de latence et l'âge moyen d'apparition de la tumeur chez les
    ouvriers exposés au BCME ou au CMME présentaient une cohérence
    remarquable. Dans le cas du CMME, on est également fondé à penser
    qu'il y a une relation positive entre l'expression qualitative de
    l'exposition et la mortalité par cancer du poumon.

         Lors d'une exposition professionnelle, et même à des
    concentrations de 0,01 µg/m3 de BCME ou de 20 µg/m3 de CMME, on a
    constaté une augmentation de la fréquence des aberrations
    chromosomiques dans les lymphocytes du sang périphérique des ouvriers
    exposés.

         On ne dispose d'aucun renseignement concernant les effets du BCME
    ou du CMME sur la fonction de reproduction, le développement, le
    système nerveux et le système immunitaire chez l'homme.

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

         Peu d'études ont été consacrées aux effets du BCEE sur les êtres
    vivants dans leur milieu naturel; la plupart des travaux se limitent
    aux espèces aquatiques. Ainsi la CL50 à 7 jours pour le guppy est
    égale à 56,9 mg/litre; pour d'autres poissons on a trouvé une CL50 à
    96 h de 600 mg/litre et en ce qui concerne les invertébrés, on a fait
    état d'une CL50 à 48 h égale à 240 mg/litre pour  Daphnia magna.

         Il n'y a pas eu d'inhibition de l'activité microbienne anaérobie
    en présence de BCEE à des concentrations allant jusqu'à 100 mg/litre
    et on a trouvé une CL10 de 600 µg/litre pour des microorganismes
    colonisant des bassins de stabilisation.

         On ne dispose d'aucune donnée concernant les effets toxiques que
    le BCME ou le CMME pourraient exercer sur les êtres vivants dans leur
    milieu naturel.

    9.  Conclusions

    9.1  BCEE

    -    L'exposition des organismes terrestres au BCEE est jugée
         négligeable du fait que ce composé n'est que lentement libéré
         dans l'environnement et qu'il ne subsiste que peu de temps dans
         l'atmosphère.

    -    Le BCEE persiste davantage dans l'eau, mais la concentration la
         plus élevée mesurée dans les eaux de surface est beaucoup plus
         faible (environ cinq ordres de grandeur) que celle qui se révèle
         toxique pour le guppy, l'espèce la plus sensible selon les études
         toxicologiques.

    -    En raison de l'absence de données concernant la concentration du
         BCEE dans un certain nombre de compartiments de l'environnement
         auxquels l'homme est exposé, il n'est pas possible de donner une
         estimation quantitative de la dose totale de ce composé absorbée
         au cours d'une journée.

    -    On ne dispose que de données limitées sur la toxicité du BCEE
         pour l'homme. On ne trouve pas de relation des effets sur la
         reproduction et le développement qui auraient pu être observés
         chez des animaux de laboratoire. Par ailleurs, aucune des études
         à long terme effectuées sur les animaux de laboratoire n'est
         d'une qualité suffisante pour que l'on puisse en tirer des
         données quantitatives sur la cancérogénicité du BCEE ou sur les
         effets toxiques à longue échéance que ce composé pourrait
         produire.

    -    Faute de données toxicologiques et cancérogénétiques suffisantes,
         la prudence commande de faire en sorte que l'exposition humaine
         soit réduite au minimum.

    9.2  BCME et CMME

    -    Au cas ou ces composés pénétreraient dans l'environnement, ils
         subiraient rapidement une hydrolyse et une photo-oxydation. On ne
         possède pas de données sur la concentration du BCME et du CMME
         dans l'environnement.

    -    Le BCME et le CMME de qualité technique (qui contient du BCME)
         sont des substances dont la cancérogénicité pour l'homme est
         prouvée. Ils se sont d'ailleurs tous les deux révélés
         cancérogènes pour les animaux de laboratoire. Ces deux composés
         provoquent des aberrations chromosomiques chez les travailleurs

         qui leur sont exposés de par leur profession. Il faut éviter
         toute exposition professionnelle et toute exposition de la
         population générale à ces composés.

    -    Compte tenu de la destinée de ces composés dans l'environnement
         et de l'absence d'exposition, il n'y aucune raison de craindre
         des effets nocifs sur les organismes terrestres ou aquatiques.

    RESUMEN Y CONCLUSIONES

    1.  Identidad, propiedades físicas y químicas y métodos analíticos

         El bis(2-cloroetil)éter (BCEE), el bis(clorometil)éter (BCME) y
    el clorometilmetiléter (CMME) son sustancias químicas de una clase
    amplia conocida como cloroalquiléteres. Los tres éteres son líquidos
    volátiles incoloros a temperatura ambiente con olores característicos.
    La presión de vapor de estos tres compuestos es alta. La solubilidad
    del BCEE es del 1,7% en agua, y su coeficiente de reparto octanol/
    agua es de 1,46. Los alpha-cloroalquiléteres BCME y CMME son
    compuestos reactivos, que se hidrolizan con rapidez en medios acuosos
    (con semividas de alrededor de 38 segundos y <0,007 segundos,
    respectivamente); la hidrólisis del ß-cloroéter BCEE, más estable, es
    más lenta (con una semivida en agua de unos 20 años).

         Se han descrito métodos de muestreo y analíticos para el BCEE en
    el agua y para el BCME y el CMME en el aire. Normalmente la
    determinación se efectúa por cromatografía de gases (CG-captura de
    electrones) o CG-espectrometría de masas.

    2.  Fuentes de exposición humana

         No se han identificado fuentes naturales de BCEE, BCME o CMME en
    el medio ambiente. Los datos recientes de producción disponible son
    limitados y corresponden solamente a los Estados Unidos y el Canadá.
    En 1986 se produjeron en los Estados Unidos alrededor de 104
    toneladas de BCEE para utilizarlo como disolvente y en la producción
    de polímeros y en varios procesos industriales. Las aplicaciones
    industriales del BCME están actualmente limitadas en los Estados
    Unidos a reacciones químicas intermedias específicas. También se ha
    producido BCME para utilizarlo en la obtención de resinas de
    intercambio iónico, en la fabricación de otros polímeros y como
    disolvente en reacciones de polimerización. En China se producen unas
    200 toneladas al año de BCME como producto intermedio en la
    fabricación de octaclorodipropiléter, un insecticida sinérgico. El
    CMME de calidad técnica contiene del 1% al 8% de BCME.

    3.  Transporte, distribución y transformación en el medio ambiente

         En la movilidad y distribución de los cloroalquiléteres
    seleccionados influyen tanto la elevada radiactividad del BCME y del
    CMME como la solubilidad en agua y la estabilidad del BCEE. Los
    alpha-cloroalquiléteres BCME y CMME se hidrolizan con rapidez en
    medios acuosos y se degradan en poco tiempo por fotolisis. En medios
    acuosos, los productos hidrolíticos del BCME y del CMME son
    formaldehído y ácido clorhídrico, y metanol, formaldehído y ácido
    clorhídrico, respectivamente. Los productos de descomposición del BCME
    y el CMME en el aire son ácido clorhídrico, formaldehído y formato de
    clorometilo, y formato de clorometilo y de metilo, respectivamente. El
    BCEE es soluble en agua; la lluvia lo elimina de la atmósfera y tiende
    a mantenerse en el agua, con una hidrólisis muy lenta. El BCEE se 

    evapora del agua superficial en una semana y se degrada en poco más de
    un día en la atmósfera mediante procesos abióticos.

         Debido al carácter muy reactivo de los alpha-cloroalquiléteres en
    el agua y en el aire, no es previsible la presencia de CMME y BCME en
    el medio ambiente; sin embargo, el BCEE puede ser persistente, debido
    a la estabilidad relativa de los ß-cloroalquiléteres.

    4.  Niveles ambientales y exposición humana

         Los datos disponibles sobre los niveles de BCEE en medios
    ambientales son limitados. Se ha identificado en el aire, pero sin
    determinación cuantitativa; se han encontrado niveles de hasta 0,42
    µg/litro en el agua potable en los Estados Unidos. Los niveles
    notificados de BCEE en el agua fréatica han oscilado entre 0,001
    µg/litro en un vertedero de yeso industrial en Bélgica y 840 µg/litro
    cerca de un vertedero en los Estados Unidos. Se han medido
    concentraciones más elevadas en productos de lixiviación de
    vertederos. No se dispone de información sobre los niveles de BCEE en
    los productos alimenticios, pero se supone que no se produce
    bioacumulación.

         No se dispone de datos cuantitativos sobre los niveles de BCME o
    CMME en el medio ambiente.

         Tomando como base el nivel máximo notificado de BCEE en el agua
    potable, es decir, 0,42 µg/litro, la persona de tipo medio (64 kg) que
    consuma 1,4 litros/día tendrá una ingesta aproximada de 0,01 µg/kg de
    peso corporal al día de esta procedencia, con cantidades desconocidas
    de otras fuentes del medio ambiente. No se puede hacer ninguna
    estimación de la ingesta diaria de BCME y CMME a partir de fuentes del
    medio ambiente. Sin embargo, considerando la falta de persistencia del
    BCME y del CMME en el medio ambiente es probable que la exposición
    humana media a estos compuestos sea muy baja.

         En función de datos limitados más antiguos, los trabajadores de
    industrias relacionadas con los plásticos y la producción textil
    podrían haber estado expuestos a cantidades comprendidas entre 1,2 y
    72,9 µg de BCME/m3 en el aire del lugar de trabajo. Sin embargo, en
    un estudio reciente de una fábrica de resina se señalaron exposiciones
    medias en el trabajo comprendidas entre 2,4 y 20,6 µg/m3. En los
    datos de otros estudios se indicaron niveles de BCME muy bajos de 0,01
    µg/m3. En China se producía hasta 1975 una exposición más alta en el
    trabajo al BCME, y sigue existiendo con un nivel menor en la
    fabricación de octaclorodipropiléter. La población general está
    expuesta al BCME y al CMME cuando se producen en la quema generalizada
    de este producto sinérgico en serpentines fumigantes de mosquitos.

         Las concentraciones más elevadas notificadas de BCEE en los
    Estados Unidos en efluentes industriales son de 8 a 170 µg/litro, y en
    los productos de lixiviación de vertederos municipales e industriales
    de 12 400 µg/litro.

    5.  Cinética y metabolismo

         No se dispone de información cuantitativa sobre la cinética y el
    metabolismo del BCEE, del BCME y del CMME en el ser humano. Sin
    embargo, se supone que, aunque el BCME y el CMME se hidrolicen con
    rapidez  in vivo en los tejidos a formaldehído y ácido clorhídrico, y
    a metanol, formaldehído y ácido clorhídrico respectivamente, debe
    haber actividad de alquilación.

         Los datos limitados que se conocen indican que el BCEE radiactivo
    administrado a ratas por inhalación o con sonda se absorbe con
    rapidez. A las 48 horas de la administración por sonda se retenía
    menos del 3% de la radiactividad.

         El BCEE se metaboliza fácilmente en ratas. El principal
    metabolito es el ácido tiodiglicólico. Después de administrar una
    dosis única por sonda de [14C]-BCEE, alrededor del 12% de la
    radiactividad administrada estaba presente en forma de 14CO2.

         El BCEE se elimina con rapidez tanto en ratas como en monos
    resus. A las 72 horas de la administración oral de [14C]-BCEE se
    recuperó menos del 2% de la radiactividad en las heces de los monos; a
    las 48 horas de la administración, se encontró alrededor del 2,3% de
    la radiactividad administrada en los tejidos o las heces de ratas; más
    del 50% de la radiactividad se recuperó en la orina y en el aire
    exhalado a las 12 horas de la administración a ratas con sonda de una
    dosis de [14C]-BCEE. De la radiactividad expirada a través de los
    pulmones, correspondió al compuesto original menos del 2%.

    6.  Efectos en animales de laboratorio y en sistemas de prueba 
         in vitro

         El BCEE tiene toxicidad aguda por vías de exposición oral,
    inhalación o cutánea. Los valores notificados de la DL50 para la
    exposición oral de especies animales al BCEE oscilan entre 75 y 215
    mg/kg de peso corporal. El BCME y el CMME tienen toxicidad aguda por
    inhalación o ingestión. Los valores de la CL50 notificados para la
    exposición de animales de laboratorio por inhalación al BCME o al CMME
    oscila entre 25 y 48 mg/m3 y entre 182 y 215 mg/m3, respectivamente.

         La exposición de animales de laboratorio por inhalación a una
    dosis elevada única de BCEE (>320 mg/m3) provocó irritación ocular,
    además de congestión, edema y hemorragia pulmonar. Durante la
    inhalación de BCME, se observó irritación ocular y de las vías
    respiratorias, así como bronquitis necrosante. La aplicación cutánea
    dio lugar a la aparición de eritema y necrosis, y la aplicación en el
    ojo indujo necrosis corneal. Tras la exposición al CMME se observaron
    efectos análogos.

         En ratas y hámsteres se observó un aumento de la mortalidad y la
    hiperplasia traqueal después de la exposición por inhalación múltiple
    a 4,7 mg de BCME/m3. Se observaron efectos análogos en ratas
    expuestas repetidamente por inhalación a 3,3 o 33 mg de CMME/m3.

         En general, se obtuvieron resultados positivos en las pruebas de
    mutagenicidad del BCEE, del BCME y del CMME  in vitro. Sin embargo,
    la interpretación de los resultados resulta difícil, debido a la falta
    de detalles en los informes disponibles. Se ha notificado que el BCME
    y el CMME aumentan la síntesis no programada de ADN  in vitro, y el
    BCME elevó el nivel de células transformadas en pruebas  in vitro.

         En pequeños grupos de machos pertenecientes a dos estirpes de
    ratones F1 híbridos (y en hembras de una estirpe F1) tratados por
    vía oral con BCEE (dosis media ponderada por el tiempo de 41,3 mg/kg
    de peso corporal durante 18 meses), se registró un aumento
    significativo de la incidencia de hepatomas (hepatomas benignos y
    tumores malignos combinados) en comparación con los testigos no
    tratados. En otros cuatro estudios limitados con ratas y ratones en
    los que se utilizó la administración oral con sonda, la inyección
    subcutánea o intraperitoneal y la aplicación sobre la piel no se
    confirmaron esos resultados.

         Los estudios de carcinogenicidad en animales experimentales
    (ratones y ratas) expuestos a BCME pusieron de manifiesto una
    incidencia significativamente elevada de adenomas pulmonares y tumores
    de las vías respiratorias. En ratones, tras la exposición por
    inhalación también se observaron pruebas de una incidencia elevada de
    tumores pulmonares.

         Los estudios realizados con CMME han puesto de manifiesto una
    mayor incidencia de metaplasia traqueal e hiperplasia bronquial
    dependiente de la dosis en ratas. Sin embargo, los resultados de las
    biovaloraciones de carcinogenicidad en estudios con animales no han
    sido concluyentes.

         No hay información disponible relativa a la toxicidad
    reproductiva, en el desarrollo, inmunológica o neurológica del BCEE,
    del BCME o del CMME.

    7.  Efectos en el ser humano

         Se ha comprobado que el BCEE irrita los ojos y los orificios
    nasales de las personas en concentraciones >150 mg/m3 tras una
    exposición breve.

         No se tienen noticias de estudios epidemiológicos sobre los
    efectos de la exposición prolongada al BCEE.

         En ocho estudios epidemiológicos, la exposición de los
    trabajadores al BCME (CMME) se relacionó con un aumento del riesgo de
    cáncer de pulmón. Los trabajadores expuestos al CMME de calidad
    comercial probablemente también estuvieron expuestos al BCME. Los
    tumores predominantes en los trabajadores expuestos fueron carcinomas
    de células pequeñas, bastante distintos de los que son principalmente
    de células escamosas y que suelen aparecer en los fumadores. Hubo una
    relación clara entre la exposición al BCME (CMME) y el cáncer de 

    pulmón, con unas razones de mortalidad normalizada que llegaban hasta
    21. El tipo de cáncer de pulmón, el período de latencia y la edad
    media de aparición de los tumores de pulmón en los trabajadores
    expuestos al BCME (CMME) han sido básicamente invariables. Para el
    CMME hay también pruebas de una relación positiva entre una medida
    cualitativa de la exposición y la mortalidad debida a cáncer de
    pulmón.

         En el curso de una exposición en el trabajo, incluso
    concentraciones de 0,01 µg de BCME/m3 y de 20 µg de CMME/m3
    aumentaron la frecuencia de aberraciones cromosómicas en los
    linfocitos periféricos de los trabajadores expuestos.

         No se dispone de información relativa a los efectos neurológicos,
    inmunológicos, en el desarrollo o reproductivos del BCME o del CMME en
    el ser humano.

    8.  Efectos en otros organismos en el laboratorio y en condiciones
        naturales

         Son pocos los estudios que se han realizado sobre los efectos del
    BCEE en los organismos del medio ambiente; la mayoría se limitan a
    especies acuáticas. Para el BCEE, se ha notificado un valor de la
    CL50 en siete días en  Lebistes reticulatus de 56,9 mg/litro, una
    CL50 en peces en 96 horas de 600 mg/litro y una CL50 en 48 horas en
     Daphnia magna de 240 mg/litro.

         La actividad microbiana anaerobia no se vio inhibida en
    concentraciones de BCEE de hasta 100 mg/litro, y se ha notificado una
    CL10 de 600 µg/litro en el caso de microorganismos indígenas en
    estanques de estabilización de desechos.

         No hay información sobre los efectos toxicológicos del BCME y del
    CMME en los organismos del medio ambiente.

    9.  Conclusiones

    9.1  BCEE

    -    Se considera que la exposición de los organismos terrestres al
         BCEE es insignificante, debido a la escasa tasa de liberación y
         su breve persistencia en la atmósfera.

    -    Aunque es más persistente en el agua, la concentración más
         elevada notificada de BCEE en agua superficial es aproximadamente
         cinco veces inferior a la concentración con la que se ha
         comprobado que induce efectos adversos en  Lebistes reticulatus,
         que es la especie acuática más sensible identificada en los
         estudios de toxicidad realizados.

    -    Debido a la falta de información disponible sobre las
         concentraciones de BCEE en varios tipos de medios a los cuales
         está expuesto el ser humano, no es posible estimar
         cuantitativamente la ingesta diaria total de BCEE.

    -    Los datos disponibles sobre la toxicidad del BCEE en el ser
         humano son limitados. No se ha encontrado información sobre los
         efectos del BCEE en el desarrollo y la reproducción en animales
         de laboratorio, y ninguno de los estudios de larga duración en
         animales de laboratorio tiene suficiente calidad para
         proporcionar información cuantitativa acerca del potencial del
         BCEE para provocar cáncer o sobre los efectos toxicológicos
         producidos por la exposición prolongada a esta sustancia.

    -    En ausencia de datos toxicológicos y de carcinogenicidad
         adecuados, es conveniente reducir al mínimo la exposición humana
         al BCEE.

    9.2  BCME y CMME

    -    En el caso de que estas sustancias se incorporaran al medio
         ambiente, se degradarían con rapidez por hidrólisis y
         fotooxidación. No se han identificado datos relativos a las
         concentraciones de BCME y CMME en el medio ambiente natural.

    -    Está demostrado que el BCME y el CMME de calidad técnica (que
         contiene BCME) son carcinógenos para el ser humano. Además, ambos
         productos químicos son carcinógenos en animales de laboratorio.
         Los dos provocan aberraciones cromosómicas en los trabajadores
         expuestos en el trabajo. Se debe eliminar la exposición en el
         trabajo y de la población general a estos compuestos.

    -    Tomando como base el destino de estas sustancias en el medio
         ambiente y la falta de exposición, no hay motivo para suponer que
         se produzcan efectos adversos en organismos acuáticos y
         terrestres.

    


    See Also:
       Toxicological Abbreviations