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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT NO. 4


    METHYL METHACRYLATE

    INTER-ORGANIZATION PROGRAMME FOR THE SOUND MANAGEMENT OF CHEMICALS
    A cooperative agreement among UNEP, ILO, FAO, WHO, UNIDO, UNITAR and
    OECD

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

    First draft prepared by Ms W. Dormer, Ms R. Gomes, and Ms M.E. Meek,
    Environmental Health Directorate,
    Health Canada


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

    Methyl methacrylate.

         (Concise international chemical assessment document ; 4)

         1.Methacrylates - toxicity  2.Environmental exposure
         3.Occupational exposure  I.International Programme on Chemical
         Safety  II.Series

         ISBN 92 4 153004 9  (NLM Classification: QV 50)
         ISSN 1020-6167

         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
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    (c) World Health Organization 1998

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    protection in accordance with the provisions of Protocol 2 of the
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    TABLE OF CONTENTS

         FOREWORD

    1. EXECUTIVE SUMMARY

    2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

    3. ANALYTICAL METHODS

    4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         6.1. Environmental levels
         6.2. Human exposure

    7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS


    8. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         8.1. Single exposure
         8.2. Irritation and sensitization
         8.3. Short-term exposure
         8.4. Long-term exposure
              8.4.1. Subchronic exposure
              8.4.2. Chronic exposure and carcinogenicity
         8.5. Genotoxicity and related end-points
         8.6. Reproductive and developmental toxicity
         8.7. Immunological and neurological effects

    9. EFFECTS ON HUMANS

         9.1. Case reports
         9.2. Epidemiological studies

    10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         10.1. Aquatic environment
         10.2. Terrestrial environment

    11. EFFECTS EVALUATION

         11.1. Evaluation of health effects
              11.1.1. Hazard identification and dose-response assessment

              11.1.2. Criteria for setting guidance values for methyl methacrylate

              11.1.3. Sample risk characterization
         11.2. Evaluation of environmental effects

    12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION

         13.1. Human health hazards
         13.2. Advice to physicians
         13.3. Health surveillance advice
         13.4. Explosion and fire hazards
              13.4.1. Explosion hazards
              13.4.2. Fire hazards
              13.4.3. Fire-extinguishing agents
         13.5. Storage
         13.6. Transport
         13.7. Spillage

    14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

         INTERNATIONAL CHEMICAL SAFETY CARD

         REFERENCES

         APPENDIX 1 - SOURCE DOCUMENTS

         APPENDIX 2 - CICAD PEER REVIEW

         APPENDIX 3 - CICAD FINAL REVIEW BOARD

         RÉSUMÉ D'ORIENTATION

         RESUMEN DE ORIENTACION
    

    FOREWORD

         Concise International Chemical Assessment Documents (CICADs) are
    the latest in a family of publications from the International
    Programme on Chemical Safety (IPCS) - a cooperative programme of the
    World Health Organization (WHO), the International Labour Organisation
    (ILO), and the United Nations Environment Programme (UNEP).  CICADs
    join the Environmental Health Criteria documents (EHCs) as
    authoritative documents on the risk assessment of chemicals.

         CICADs are concise documents that provide summaries of the
    relevant scientific information concerning the potential effects of
    chemicals upon human health and/or the environment.  They are based on
    selected national or regional evaluation documents or on existing
    EHCs.  Before acceptance for publication as CICADs by IPCS, these
    documents have undergone extensive peer review by internationally
    selected experts to ensure their completeness, accuracy in the way in
    which the original data are represented, and the validity of the
    conclusions drawn.

         The primary objective of CICADs is characterization of hazard and
    dose-response from exposure to a chemical.  CICADs are not a summary
    of all available data on a particular chemical; rather, they include
    only that information considered critical for characterization of the
    risk posed by the chemical.  The critical studies are, however,
    presented in sufficient detail to support the conclusions drawn.  For
    additional information, the reader should consult the identified
    source documents upon which the CICAD has been based.

         Risks to human health and the environment will vary considerably
    depending upon the type and extent of exposure.  Responsible
    authorities are strongly encouraged to characterize risk on the basis
    of locally measured or predicted exposure scenarios.  To assist the
    reader, examples of exposure estimation and risk characterization are
    provided in CICADs, whenever possible.  These examples cannot be
    considered as representing all possible exposure situations, but are
    provided as guidance only.  The reader is referred to EHC 1701 for
    advice on the derivation of health-based guidance values.

              

    1 International Programme on Chemical Safety (1994)  Assessing 
     human health risks of chemicals: derivation of guidance values 
     for health-based exposure limits. Geneva, World Health Organization
    (Environmental Health Criteria 170).

         While every effort is made to ensure that CICADs represent the
    current status of knowledge, new information is being developed
    constantly.  Unless otherwise stated, CICADs are based on a search of
    the scientific literature to the date shown in the executive summary.
    In the event that a reader becomes aware of new information that would
    change the conclusions drawn in a CICAD, the reader is requested to
    contact the IPCS to inform it of the new information.

    Procedures

         The flow chart shows the procedures followed to produce a CICAD.
    These procedures are designed to take advantage of the expertise that
    exists around the world - expertise that is required to produce the
    high-quality evaluations of toxicological, exposure, and other data
    that are necessary for assessing risks to human health and/or the
    environment.

         The first draft is based on an existing national, regional, or
    international review.  Authors of the first draft are usually, but not
    necessarily, from the institution that developed the original review.
    A standard outline has been developed to encourage consistency in
    form.  The first draft undergoes primary review by IPCS and one or
    more experienced authors of criteria documents to ensure that it meets
    the specified criteria for CICADs.

         The second stage involves international peer review by scientists
    known for their particular expertise and by scientists selected from
    an international roster compiled by IPCS through recommendations from
    IPCS national Contact Points and from IPCS Participating Institutions.
    Adequate time is allowed for the selected experts to undertake a
    thorough review.  Authors are required to take reviewers' comments
    into account and revise their draft, if necessary.  The resulting
    second draft is submitted to a Final Review Board together with the
    reviewers' comments.

         The CICAD Final Review Board has several important functions:

    -    to ensure that each CICAD has been subjected to an appropriate
         and thorough peer review;
    -    to verify that the peer reviewers' comments have been addressed
         appropriately;
    -    to provide guidance to those responsible for the preparation of
         CICADs on how to resolve any remaining issues if, in the opinion
         of the Board, the author has not adequately addressed all
         comments of the reviewers; and
    -    to approve CICADs as international assessments.

    Board members serve in their personal capacity, not as representatives
    of any organization, government, or industry.  They are selected
    because of their expertise in human and environmental toxicology or
    because of their experience in the regulation of chemicals.  Boards
    are chosen according to the range of expertise required for a meeting
    and the need for balanced geographic representation.

         Board members, authors, reviewers, consultants, and advisers who
    participate in the preparation of a CICAD are required to declare any
    real or potential conflict of interest in relation to the subjects
    under discussion at any stage of the process.  Representatives of
    nongovernmental organizations may be invited to observe the
    proceedings of the Final Review Board.  Observers may participate in
    Board discussions only at the invitation of the Chairperson, and they
    may not participate in the final decision-making process.

    FIGURE 1

    1.  EXECUTIVE SUMMARY

         This CICAD on methyl methacrylate was prepared by the
    Environmental Health Directorate of Health Canada and was based
    principally on a Government of Canada (1993) review to assess the
    potential effects on human health of indirect exposure to methyl
    methacrylate in the general environment as well as the chemical's
    environmental effects and an International Agency for Research on
    Cancer review (IARC, 1994) concerning primarily hazard identification
    for carcinogenicity.  Data identified as of March 1992 were considered
    in the Government of Canada (1993) review and were subsequently
    updated, based on a comprehensive literature search conducted in
    September 1995 of on-line databases and the International Register of
    Potentially Toxic Chemicals.  Information on the nature of peer review
    and the availability of the Government of Canada (1993) and IARC
    (1994) reviews is presented in Appendix 1.  During the peer review
    phase for this CICAD, additional draft reviews of the United Kingdom
    Health and Safety Executive (Cary et al., 1995) and the European Union
    (Draft Assessment on Methyl Methacrylate) and published reviews of
    ECETOC (1995) and the Finnish Advisory Board of Chemicals (1992) were
    considered, primarily for identification of relevant additional
    information for review.  Additional information identified during
    review by Contact Points and consideration by the Final Review Board
    has also been incorporated.  Information on the peer review of this
    CICAD is presented in Appendix 2.  This CICAD was approved for
    publication at a meeting of the Final Review Board, held in Brussels,
    Belgium, on 18-20 November 1996.  Participants at the Final Review
    Board meeting are listed in Appendix 3.  The International Chemical
    Safety Card for methyl methacrylate (ICSC 0300), produced by the
    International Programme on Chemical Safety (IPCS, 1993), has also been
    reproduced in this document.

         Methyl methacrylate (CAS no. 80-62-6) is a volatile synthetic
    chemical that is used principally in the production of cast acrylic
    sheet, acrylic emulsions, and moulding and extrusion resins.  Polymers
    and copolymers of methyl methacrylate are also used in waterborne,
    solvent, and undissolved surface coatings, adhesives, sealants,
    leather and paper coatings, inks, floor polishes, textile finishes,
    dental prostheses, surgical bone cements, and leaded acrylic radiation
    shields and in the preparation of synthetic fingernails and orthotic
    shoe inserts.  The majority of methyl methacrylate is predicted to be
    emitted to air, with very small amounts being released into water and
    soil.  The persistence of methyl methacrylate in the atmosphere is
    short, and the chemical is not considered to contribute directly to
    depletion of the ozone layer.  Methyl methacrylate is not expected to
    bioconcentrate in the environment, and inhalation from air is likely
    the primary route of human exposure.

         Methyl methacrylate is rapidly absorbed and distributed following
    inhalation or oral administration to experimental animals.  Data on
    absorption following dermal exposure are limited.  In both
    experimental animals and humans, methyl methacrylate is rapidly
    metabolized to methacrylic acid.  Following inhalation, 16-20% of the
    chemical is deposited in the upper respiratory tract of rats, where it
    is primarily metabolized by local tissue esterases.

         The acute toxicity of methyl methacrylate is low.  Irritation of
    the skin, eye, and nasal cavity has been observed in rodents and
    rabbits exposed to relatively high concentrations of methyl
    methacrylate.  The chemical is a mild skin sensitizer in animals.  The
    effect observed most frequently at lowest concentration after repeated
    inhalation exposure to methyl methacrylate is irritation of the nasal
    cavity.  Effects on the kidney and liver at higher concentrations have
    also been reported.  The lowest reported effect level for inhalation
    was 410 mg/m3 in rats exposed to methyl methacrylate for 2 years
    (based upon inflammatory degeneration of the nasal epithelium); the
    no-observed-effect level (NOEL) in this investigation was
    approximately 100 mg/m3.

         In a well conducted study in rats, there were no developmental
    effects, although there were decreases in maternal body weight
    following inhalation of concentrations up to 8315 mg/m3.  Other
    available data on developmental toxicity are restricted to results of
    limited early or poorly documented studies in which fetotoxic effects
    were observed at concentrations that (where reported) were toxic to
    the mothers.  Available data on reproductive effects of methyl
    methacrylate are limited.  There was no reduction in fertility in a
    dominant lethal assay in mice exposed to methyl methacrylate
    concentrations up to 36 900 mg/m3 and no adverse effects on
    reproductive organs in repeated-dose studies conducted to date.
    Available data on the neurotoxicity of methyl methacrylate are
    limited; impairment of locomotor activity and learning and behavioural
    and biochemical effects on the brain were observed in rats exposed
    orally to 500 mg/kg body weight per day for 21 days.

         Methyl methacrylate was not carcinogenic in an extensive, well
    documented 2-year bioassay in rats and mice exposed by inhalation and
    in additional chronic inhalation studies in rats and hamsters.
    Although not mutagenic  in vitro in bacterial systems, methyl
    methacrylate has been mutagenic and clastogenic in mammalian cells
     in vitro. In  in vivo studies (primarily by the inhalation route)
    in which there has been clear evidence of toxicity within the target
    tissue, there has been limited evidence of the genotoxicity of methyl
    methacrylate.

          Methyl methacrylate is a mild skin irritant in humans and has
    the potential to induce skin sensitization in susceptible individuals.
    Although occupational asthma associated with methyl methacrylate has
    also been reported, there is no conclusive evidence that methyl
    methacrylate is a respiratory sensitizer.  As a whole, the available
    epidemiological studies do not provide strong or consistent evidence
    of a carcinogenic effect of methyl methacrylate on any target organ in
    humans, nor can it be inferred with any degree of confidence that the
    possibility of an excess risk has been disproved.

         The toxicity of methyl methacrylate to aquatic organisms is low.
    Although no chronic studies on aquatic organisms were identified,
    acute tests have been conducted on fish,  Daphnia magna, and algae.
    The most sensitive effect was the onset of inhibition of cell
    multiplication by the green alga  Scenedesmus quadricauda at 37
    mg/litre following 8 days of exposure.  The lowest reported 24-hour
    EC50 for immobilization in  Daphnia is 720 mg/litre.  The 96-hour
    LC50 in juvenile bluegill sunfish  (Lepomis macrochirus) under
    flow-through conditions was 191 mg/litre, whereas LC50 values for
    durations of 1-24 hours ranged from 420 to 356 mg/litre, respectively.
    The 96-hour LC50 for rainbow trout  (Oncorhynchus mykiss) under
    flow-through conditions was >79 mg/litre, the highest concentration
    tested.  Sublethal/behavioural responses were noted among the fish at
    40 mg/litre.

         The available studies in humans are considered inadequate as the
    principal basis for derivation of a guidance value; therefore, in
    order to provide guidance, a tolerable concentration has been
    established on the basis of inflammatory degeneration of the nasal
    epithelium of rats exposed to methyl methacrylate at a concentration
    of 410 mg/m3 for 2 years.  The NOEL in this investigation was
    approximately 100 mg/m3.  Data available to serve as a basis for
    estimation of indirect exposure in the general environment or consumer
    exposure are extremely limited.  The derived (likely conservative)
    tolerable concentration of approximately 0.2 mg/m3 is many orders of
    magnitude higher than the sample predicted concentrations of methyl
    methacrylate in ambient air of the general environment.  Inhalation
    exposure predicted from the use of dispersion and oil-based paints
    containing methyl methacrylate may be up to an order of magnitude
    higher than the tolerable intake associated with exposure at the level
    of the tolerable concentration, although it has been reported that in
    some countries these products are not supplied to the general public.
    Information on use patterns of these products in other countries was
    not identified.  Based on a chronic study by the oral route of
    administration, a tolerable daily intake (TDI) of 1.2 mg/kg body
    weight per day has been derived.

         Although available data on the environmental effects of methyl
    methacrylate are limited and predicted values in various media are
    highly uncertain, a wide margin exists between observed effect levels
    and uncertain predicted environmental concentrations of methyl
    methacrylate.

    2.  IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

         Methyl methacrylate (CAS no. 80-62-6) is a colourless, volatile
    liquid with an acrid fruity odour.  It has a relatively high vapour
    pressure (4 kPa at 20°C), moderate water solubility (15.8 g/litre),
    and a low log octanol/water partition coefficient ( Kow = 1.38)
    (Government of Canada, 1993).  The empirical formula for methyl
    methacrylate is C5H8O2.  The structural formula for methyl
    methacrylate is given below.  Additional physical/chemical properties
    are presented in the International Chemical Safety Card reproduced in
    this document.

                       O
                       "
             H2C = C - C - O - CH3
                   '
                   CH3

         The purity of commercial methyl methacrylate is typically 99.9%.
    It contains traces of acidity as methacrylic acid (0.003% max.;
    specification, 0.005% max.) and water (0.03% max.; specification,
    0.05% max.).  Inhibitors added for storage and transportation are
    usually 2-100 ppm methyl ether of hydroquinone and 25-100 ppm
    hydroquinone, although other phenolic inhibitors, such as dimethyl
     tert-butylphenol, may also be used (IARC, 1994; M. Pemberton,
    personal communication, 1996).

    3.  ANALYTICAL METHODS

           Methods commonly used for the analysis of acrylic compounds
    include gas chromatography (GC), mass spectrometry (MS), GC/MS,
    nuclear magnetic resonance, and infrared spectroscopy (Government of
    Canada, 1993).  Methyl methacrylate can be determined in air by gas
    chromatography with flame ionization detection; the sample is adsorbed
    on fused silica (XAD-2 resin) or charcoal coated with
    4- tert-butylcatechol and desorbed with carbon disulfide or toluene.
    The estimated limit of detection for this method is 0.01 mg per
    sample.  A detection limit of 0.8 mg/m3 is obtained with a method
    involving desorption with 5% isopropanol in carbon disulfide from
    charcoal (IARC, 1994).

    4.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         Methyl methacrylate is not known to occur naturally (IARC, 1994).
    It is used principally in the production of cast acrylic sheet,
    acrylic emulsions, and moulding and extrusion resins (IARC, 1994).
    Polymers and copolymers of methyl methacrylate are used in waterborne,
    solvent, and undissolved surface coatings (exterior latex paint based
    on emulsions containing methyl methacrylate is the surface coating in
    which it is used most widely).  Solvent reducible polymers containing
    methyl methacrylate are used for industrial finishes, metal and foil
    coatings, and a variety of overlays for special purposes.  Solvent and
    emulsion polymers containing methyl methacrylate are also used in
    adhesives, sealants, leather and paper coatings, inks, floor polishes,
    and textile finishes (IARC, 1994).  Methyl methacrylate and polymers
    of methyl methacrylate are also used for dental prostheses, surgical
    bone cements, and leaded acrylic radiation shields and in the
    preparation of synthetic fingernails and orthotic shoe inserts (IARC,
    1994).

         Global production of methyl methacrylate was estimated to be 1.4
    million tonnes in 1988 (IARC, 1994).  In the USA and Japan, production
    of methyl methacrylate ranged from 380 000 to 536 000 t and from
    384 000 to 403 000 t, respectively, between 1990 and 1992 (IARC,
    1994).  Total production volume within the European Union was
    447 000 t in 1993 (CEFIC, 1994).

         Methyl methacrylate can enter the environment during its
    transport, bulk storage, and use.  Based on data from the US Toxic
    Chemical Release Inventory, emissions to air, water, and soil from
    industries in the USA are estimated to be about 0.46% of
    production.1  Most of the released methyl methacrylate (i.e. 98%) is
    estimated to be emitted to air, with very small amounts being released
    into water and soil.  Data on emissions of methyl methacrylate in
    other countries have not been identified.  Assuming a production in
    the USA in 1992 of approximately 500 000 t (IARC, 1994), approximately
    2300 t are estimated to have been released to the environment.

              

    1 Source: Toxic Chemical Release Inventory (TRI), databank produced
    by the National Library of Medicine and the US Environmental
    Protection Agency (1989).

    5.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         As methyl methacrylate is highly reactive with hydroxyl radicals,
    its estimated half-life in the troposphere is short: from <5 hours in
    summer to a few days in winter at a latitude such as that of Toronto,
    Canada.  The reported photooxidation half-life of methyl methacrylate
    is 1.1-9.7 hours.  Methyl methacrylate is readily polymerized by light
    and heat but is not expected to photolyze (Government of Canada,
    1993).

         In neutral or acidic aquatic environments, hydrolysis of methyl
    methacrylate is not significant.  Based upon its measured second-order
    hydrolysis rate constant of 200 (mol/litre)-1 h-1 at 25°C, the
    hydrolysis half-life of methyl methacrylate is estimated to be 3.9
    years at pH 7 and 14.4 days at pH 9 (Howard, 1989).

         No data were identified on the rate of volatilization of methyl
    methacrylate; however, the half-life for evaporation from a river 1 m
    deep with a 1 m/s current and 3 m/s wind has been calculated as 6.3
    hours.  Evaporation of methyl methacrylate from soil is expected to be
    rapid, owing to its high vapour pressure and weak adsorption to soil.

         A Level I fugacity model in an evaluative environment predicts
    the following equilibrium partitioning of methyl methacrylate: air,
    86.6%; water, 13.1%; and soil/sediment, <0.4% (Mackay et al., 1995).

         Biodegradation contributes significantly to removal of methyl
    methacrylate from the environment.  The aqueous aerobic degradation
    half-life is estimated to be 1-4 weeks, and the anaerobic degradation
    half-life is estimated to be 4-16 weeks (Howard, 1989).

         Although no studies have been conducted to measure
    bioconcentration factors for methyl methacrylate, a bioconcentration
    factor of 3 has been estimated from the log  Kow; based on this
    value, methyl methacrylate is not expected to bioconcentrate or
    biomagnify in food-chains (Government of Canada, 1993).

    6.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    6.1  Environmental levels

          In an analysis of 204 samples of water collected from 14 heavily
    industrialized river basins in the USA (Ewing & Chian, 1977), methyl
    methacrylate was detected (detection limit 1.0 µg/litre) only once at
    a concentration of 10 µg/litre in final tap-water after chlorination
    in Chicago, Illinois, in 1976.  No additional information was
    provided.  Methyl methacrylate was not detected in 24 water samples
    (limit of determination 0.005-1 µg/litre) or in 24 sediment samples
    (limit of determination 0.000 11-0.01 µg/g dry weight) taken in Japan
    in eight locations (harbour or estuarine areas) in 1979 (no further
    information provided) (S. Tsuda, personal communication, 1996).
    Methyl methacrylate was not detected (detection limit 0.01 µg/g wet
    weight) in 30 samples of (edible) shellfish collected from various
    locations in Atlantic Canada (Environment Canada, 1989).  Methyl
    methacrylate may be present in food as a result of migration of the
    monomer from food containers made from polymethyl methacrylate (IARC,
    1994); for example, concentrations ranged from 180 to 275 ppb (ng/g)
    in maple syrup that had been packaged in plastic containers
    (Hollifield et al., 1980).  The migration of methyl methacrylate from
    commercial plastic wrap into 20% ethanol at 25°C was 1 ppm in 1 day
    and 10 ppm in 90 days.  Migration into water and acetic acid was not
    detected (detection limit 0.05 ppm) (Inoue et al., 1981).

         In view of the limited available monitoring data, estimates of
    the fate and concentrations of methyl methacrylate in the Canadian
    environment were generated by a Level III fugacity model (Mackay &
    Paterson, 1981, 1982, 1991; Mackay et al., 1985) developed for
    southern Ontario, incorporating data on the physical and chemical
    properties of the chemical (Government of Canada, 1993),
    transformation half-lives (Howard et al., 1991), and proportion of
    production in the USA emitted to environmental media (see section 4)
    applied to the volume imported into Canada.  Methyl methacrylate is
    not produced in Canada; approximately 22 000 t are imported (CPI,
    1989).  The model assumed emissions of 95% to air, 4.5% to water, and
    0.5% to soil.  The estimated relative proportions of methyl
    methacrylate predicted for air, water, soil, and sediment at steady
    state were 26.6%, 60.8%, 12.6%, and 0.03%, respectively.  The amount
    of methyl methacrylate estimated to partition to fish was negligible.
    The relatively longer half-life for methyl methacrylate in water
    compared with air accounts for the higher estimated relative
    proportion predicted for the water compartment.  Although such models
    are useful primarily for identification of the relative proportions of
    exposure from various media rather than for quantitative estimates of
    concentrations, the latter are presented here primarily as a baseline
    for comparison with measured concentrations.  It should also be noted
    that such predicted values will vary in different countries depending
    upon production and releases of methyl methacrylate.  The average
    concentrations estimated on the basis of the model were 2.44 × 10-4
    µg/m3 in air, 0.13 ng/litre in surface water, 1.2 × 10-6 µg/g in
    soil, 8.7 × 10-8 µg/g in sediment, and 1.5 × 10-7 µg/g in fish
    (Government of Canada, 1993).

    6.2  Human exposure

         Examples of estimated indirect exposure in the general
    environment and during use of consumer products are presented here.
    Levels determined in various occupational settings are also
    summarized.  Estimates of indirect exposure in the general environment
    are based in Canada owing to the availability of relevant data for
    input; however, predicted levels will vary considerably as a function
    of production and use patterns in various countries.  Consumer
    exposure estimates are based on data on the percent composition of
    methyl methacrylate in products provided by European manufacturers.
    Levels in occupational environments are those reported from various
    countries.  Countries are strongly encouraged, however, to estimate
    exposure on the basis of local data, possibly in a manner similar to
    that outlined here.

         Adequate data on measured concentrations of methyl methacrylate
    in air, drinking-water, foodstuffs, and soil have not been identified;
    indeed, they are limited to non-detectable values in a limited number
    of small surveys.  Although predicted concentrations in environmental
    media based on fugacity modelling are uncertain, they are helpful in
    estimating proportions of exposure from various media.  Based on a
    daily inhalation volume for adults of 22 m3, a mean body weight for
    males and females of 64 kg, and a predicted concentration (by fugacity
    modelling; see section 6.1) of methyl methacrylate in ambient air in
    Canada of 2.44 × 10-4 µg/m3, the estimated intake of methyl
    methacrylate from air for the general population represents
    approximately 97% of the total intake from air, drinking-water, fish,
    and soil.  Based on a daily volume of water consumption for adults of
    1.4 litres, a mean body weight of 64 kg, and a predicted concentration
    of methyl methacrylate in surface water in Canada of 0.13 ng/litre
    (see section 6.1), the estimated intake of methyl methacrylate from
    drinking-water for the general population represents approximately
    3.3% of total intake.  Available data were inadequate to estimate the
    intake of methyl methacrylate from food, with the exception of intake
    from fish.  Based on a daily amount of fish ingested for adults of 23
    g/day, a mean body weight for adults of 64 kg, and the predicted
    concentration of methyl methacrylate in fish in Canada of 1.5 × 10-7
    µg/g (see section 6.1), the estimated intake of methyl methacrylate
    from fish represents 0.06% of total intake.  Based on a daily amount
    of soil ingested for adults of 20 mg, a mean body weight for adults of
    64 kg, and a predicted concentration of methyl methacrylate in soil in
    Canada of 1.2 × 10-6 µg/g (see section 6.1), the estimated intake of
    methyl methacrylate from soil, as a proportion of total intake, is
    negligible (0.0004%).  Therefore, based on predicted concentrations in
    the Canadian environment, the overwhelmingly principal source of
    indirect exposure to methyl methacrylate for most of the general
    population is air.

         Inhalation exposure to methyl methacrylate from the use of
    consumer products containing methyl methacrylate (e.g. dispersion
    paints and oil-based paints) was modelled using the US EPA Screening
    Consumers Inhalation Exposure Software (SCIES) computer model.  All
    scenarios were based on the assumption that the percent composition of
    methyl methacrylate-based polymers in formulations of dispersion
    paints, varnishes, or lacquers is 15%, although residual monomer
    content is much less (European Union Draft Assessment on Methyl
    Methacrylate), and that 100% is absorbed.  Although it has been
    reported that in some countries these products are not supplied to the
    general public, information on use patterns of these products in other
    countries was not available.

         For the use of dispersion paints, the standard default values of
    the SCIES model were assumed for the following parameters: frequency
    of use, six events per year; mass of product, 13.6 kg; room size, 40
    m3; duration of use, 4.9 hours; house air exchange rate, 0.2 room air
    exchanges per hour; and user inhalation rate, 1.3 m3/hour.  The
    vapour pressure of methyl methacrylate was considered to be 38.4 torr
    (5.12 kPa) (Howard, 1989).  Resulting estimated consumer exposure from
    inhalation was in the range of 10-100 mg/kg body weight per day.
    However, as the residual methyl methacrylate monomer content in
    dispersion paints is specified to be 0.1% (ECETOC, 1995), consumer
    exposure to methyl methacrylate would fall within the range of 10-100
    µg/kg body weight per day.

         For the estimation of consumer exposure from the use of oil-based
    (solvent-based) paints, the standard default values of the SCIES model
    were assumed as above, with the exception of the following parameters,
    for which default values were: mass of product, 6.71 kg; and duration
    of use, 3.2 hours.  The vapour pressure of methyl methacrylate and
    absorption were the same as those for the scenario mentioned above.
    The resulting estimated consumer exposure from inhalation was again in
    the range of 10-100 mg/kg body weight per day.  However, as the
    residual methyl methacrylate monomer content in solvent-based paints
    is assumed to be 1.5% by the producer (European Union Draft Assessment
    on Methyl Methacrylate), consumer exposure to methyl methacrylate
    would fall within the range of 100-1000 µg/kg body weight per day.

         Occupations in which there is potential exposure to methyl
    methacrylate include those in the medical, dental, and beauty
    professions, such as chemical process operators, surgeons and surgical
    assistants, operating room nurses, dental technicians and hygienists,
    and beauty technicians applying synthetic fingernails (IARC, 1994).
    Exposure to methyl methacrylate in the workplace could be
    substantially greater than that in the general environment.  Based on
    experience in the United Kingdom, for example, long-term personal
    exposures during monomer production average about 2 ppm (8.2 mg/m3)
    and are less than 60 ppm (246 mg/m3) (Cary et al., 1995).  In open
    system industries such as cast sheet production, long-term exposures

    are higher, averaging 22.2 ppm (91 mg/m3) and ranging from 0.5 to 165
    ppm (2-677 mg/m3).  For various end uses of methyl methacrylate,
    including aerospace manufacture, plastics processing, and artificial
    teeth production, the mean long-term value for personal exposure was
    13.4 ppm (55 mg/m3), with a range of 0.8-109 ppm (3.3-447 mg/m3).
    In medical and dental applications, peak concentrations up to 374 ppm
    (1533 mg/m3) have been recorded, although short-term
    time-weighted-average exposures are likely to be less than 100 ppm
    (410 mg/m3).

         Mean levels (time period often unspecified) of methyl
    methacrylate in the air of various chemical manufacturing and
    processing plants (located in Europe, the USA, Canada, Russia, Japan,
    and China) vary widely, ranging from not detectable (detection limit
    not reported) to 1500 mg/m3 (CEFIC, 1993; Mizunuma et al., 1993;
    IARC, 1994; M. Baril, personal communication, 1996).  Peak values as
    high as 7900 mg/m3 have been reported for some manufacturing
    facilities (M. Baril, personal communication, 1996).  Mean
    concentrations of methyl methacrylate in the air of dental clinics and
    dental laboratories (in the USA, Norway, Denmark, and the United
    Kingdom) have ranged from not detectable (detection limit not
    reported) to 273 mg/m3 during denture prosthesis manufacture and
    repair (IARC, 1994).  Mean concentrations of methyl methacrylate in
    the air of beauty salons (in the USA) have ranged from 21.7 to 87.5
    mg/m3 during the application of artificial fingernails (IARC, 1994).
    It should be noted that in some cases these values reflect
    shorter-term peak exposures rather than time-weighted averages.
    Elevated levels (above 1500 mg/m3) during floor coating with methyl
    methacrylate-containing resins have been reported, although these
    levels were measured during activities that normally do not cover a
    full shift; hence, time-weighted-average concentrations would be
    less.1


              

    1 Source: Excerpts from the (1995) BIA file provided by BG Chemie
    containing measurement data of occupational exposures to methyl
    methacrylate in industry and trade.  Communication to Bundesinstitut
    für Gesundheitlichen Verbraucherschutz und Veterinarmedizin (BgVV).

    7.  COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS
        AND HUMANS

         Methyl methacrylate is rapidly absorbed and distributed following
    inhalation or oral administration to rats.  On the basis of available
    data, methyl methacrylate appears to be rapidly metabolized to
    methacrylic acid, which is subsequently converted to carbon dioxide
    via the tricarboxylic acid cycle in both experimental animals and
    humans.  Adequate studies on the dermal absorption of methyl
    methacrylate were not identified.  Methyl methacrylate is rapidly
    eliminated, primarily via the lungs in expired air.  After oral or
    intravenous administration to rats, approximately 65% of the dose was
    exhaled in the expired air as 14CO2 within 2 hours (Bratt & Hathway,
    1977).  Lesser amounts are eliminated in the urine, and an even
    smaller fraction in the faeces.  Owing to its rapid metabolism and
    excretion, there appears to be little potential for accumulation of
    methyl methacrylate within tissues (Government of Canada, 1993;
    ECETOC, 1995).

         Deposition in the surgically isolated upper respiratory tract of
    urethane-anaesthetized male F344 rats exposed to methyl methacrylate
    at 90, 437, or 2262 mg/m3 under cyclic flow conditions was 16-20%
    (Morris & Frederick, 1995).  Deposition was 3% less on average in the
    unidirectional flow groups than in the cyclic flow groups.  Deposition
    was less efficient at the high than at the low and middle
    concentrations, although the mechanism is unknown.  (The deposition
    efficiency of inhaled methacrylic acid under similar conditions was
    much greater, averaging 95% under unidirectional flow.)  Pretreatment
    with a carboxylesterase inhibitor (bis-nitrophenylphosphate) decreased
    uptake of methyl methacrylate by one-third, suggesting that methyl
    methacrylate is hydrolysed by carboxylesterase in nasal tissues and
    that such metabolism serves to enhance its deposition efficiency.
    Methyl methacrylate decreased nasal non-protein content by
    approximately 25% at the highest concentration, but not at lower
    concentrations.  Nasal non-protein content was not decreased by
    exposure to methacrylic acid even at delivered dose rates twofold more
    than that for methyl methacrylate, suggesting that this effect is
    attributable to the ester itself and not to the acid metabolite
    (Morris & Frederick, 1995).

    8.  EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

    8.1  Single exposure

         The acute toxicity of methyl methacrylate is consistently low,
    although unconfirmed effects on the lungs were reported at relatively
    low concentrations in one study of poor design (Raje et al., 1985).
    The 4-hour LC50s for methyl methacrylate in rats ranged from 3750 to
    7093 ppm (15 375-29 080 mg/m3).  The oral LD50s ranged from 5.0
    ml/kg body weight (4.7 g/kg body weight) in dogs to 10.0 ml/kg body
    weight (9.44 g/kg body weight) in rats (Government of Canada, 1993).

    8.2  Irritation and sensitization

         Irritation of the skin, eye, and mucosa of the respiratory tract
    has been observed in rodents and rabbits exposed to relatively high
    concentrations of methyl methacrylate (dermal application of
    approximately 2-38 g/kg body weight; inhalation of 100-17 600 ppm
    [410-72 160 mg/m3]; or instillation of approximately 0.1 ml into the
    cornea) (Spealman et al., 1945; Castellino & Colicchio, 1969; Rohm &
    Haas, 1982; Raje et al., 1985; Kanerva & Verkkala, 1986; NTP, 1986;
    Ouyang et al., 1990).

         The weight of evidence is that methyl methacrylate is a skin
    sensitizer in animals (Cary et al., 1995; ECETOC, 1995).

    8.3  Short-term exposure

         Death, decreases in body weight, changes in respiration rate,
    increases in level of blood urea nitrogen, and pulmonary damage were
    observed after exposure to high concentrations in short-term
    repeated-dose studies in rats and mice in which inhaled concentrations
    of methyl methacrylate ranged up to 5000 ppm (20 500 mg/m3)
    (Government of Canada, 1993).  Cardiovascular effects (irregular ECG,
    changes in blood pressure) were also observed in rats exposed to
    undocumented concentrations of vaporized methyl methacrylate for 20
    minutes/day for 21 or 42 days in a limited study (Blanchet et al.,
    1982).

         In short-term studies, mice were more susceptible than rats, with
    effects on the respiratory tract (redness and swelling of the nasal
    region) observed after exposure to 500 ppm (2050 mg/m3; the lowest
    tested concentration in the study) for 10 days (NTP, 1986).  No
    systemic histopathological effects were observed after inhalation of
    concentrations up to 5000 ppm (20 500 mg/m3).

    8.4  Long-term exposure

         The protocols and results of available long-term studies on
    methyl methacrylate are summarized in Table 1.



        Table 1:  Summary of effect levels in long-term studies.

                                                                                                                                                

    Species         Study design                      Effects                            Effect levels    Comments             Reference
                                                                                                                                                

    INHALATION
                                                                                                                                                

    Rats,           Exposed to 0 or 116 ppm           Rats exposed for 3 months lacked   Effects at 116   One dose group only  Tansy et al.,
    Sprague-Dawley, (476 mg/m3) methyl methacrylate,  visceral and subcutaneous fat      ppm (476                              1976
    50 males per    8 hours/day, for 5 days/week.     deposits, had significantly lower  mg/m3)
    group           Approximately half of the rats    body, lung, and spleen weights,
                    in each group were sacrificed     and had significantly higher mean
                    after 3 months; blood and         serum alkaline phosphatase
                    tissue samples were taken. The    concentration. Rats exposed for
                    remainder of the rats were        6 months had less subcutaneous
                    exposed for 6 months.             fat, significantly lower mean body
                                                      weights, popliteal fat pad
                                                      weights, and mean intestinal transit
                                                      time, and significantly higher mean
                                                      alkaline phosphatase and inorganic
                                                      phosphate concentrations compared
                                                      with controls.

    Rats,           Exposure to 0 or 116 ppm          Exposed rats had significantly     Effects at 116   One dose group only  Tansy et al.,
    Sprague-Dawley, (476 mg/m3) methyl methacrylate,  lower total bilirubin and higher   ppm (476                              1980a
    23 males per    5 days/week, averaging 7          total cholesterol levels; possible mg/m3)
    group           hours/day, for 542 hours (3       liver damage in the exposed group,
                    months). Excretion studies in     but details not reported.
                    nine rats from each group;
                    histopathological examinations
                    of heart, lung, kidneys, spleen,
                    stomach, small bowel, liver,
                    and adrenal.

                                                                                                                                                

    Table 1 (continued)

                                                                                                                                                

    Species         Study design                      Effects                            Effect levels    Comments             Reference
                                                                                                                                                

    Rats,           Exposure to 0 or 116 ppm          Mild lung damage in some of the    Effects at 116   One dose group only; Tansy et al.,
    Sprague-Dawley, (476 mg/m3) methyl methacrylate,  rats exposed for 3 and 6 months    ppm (476 mg/m3)  statistical          1980b
    23 males per    7 hours/day, 5 days/week, for     and the sham-exposed controls.                      significance not
    group for 3     3 or 6 months. Histopathological  Rats exposed for 6 months had                       reported; similar
    months and      examinations of heart, lung,      damaged tracheal mucosa. The                        effects in
    unspecified     kidneys, spleen, stomach, small   epithelium was denuded of cilia,                    sham-exposed controls
    number for      bowel, liver, and adrenal.        and the cellular covering of
    6 months                                          microvilli was reduced in rats
                                                      exposed for 3 months.

    Rats, F344,     Exposure to 0, 63, 125, 250,      Some clinical signs and one death  NOEL = 1000                           Rohm & Haas,
    10 per sex      500, or 1000 ppm (0, 258, 512,    each in groups exposed to 63 ppm   ppm (4100                             1977
    per group       1025, 2050, or 4100 mg/m3)        and controls, but not              mg/m3)
                    methyl methacrylate, 6 hrs/day,   dose-related.
                    for 65 days. Complete gross
                    pathological and histopathological
                    examinations.

    Rats, F344/N,   Inhalation of 0, 63, 125, 250,    No methyl methacrylate-related     NOEL = 1000                           NTP, 1986
    10 per sex      500, or 1000 ppm (0, 258, 512,    effects.                           ppm (4100
    per group       1025, 2050, or 4100 mg/m3)                                           mg/m3)
                    methyl methacrylate, 6 hours/day,
                    5 days/week, for 14 weeks (65
                    exposures). Histological
                    examinations were conducted of
                    an unspecified range of tissues
                    from all high-dose and control
                    rats, those that died before
                    the end of the study, and some
                    of the rats from the other
                    groups.

                                                                                                                                                

    Table 1 (continued)

                                                                                                                                                

    Species         Study design                      Effects                            Effect levels    Comments             Reference
                                                                                                                                                

    Rats, F344/N,   Exposure to 0, 500, 1000, 2000,   At 1000 ppm, a low incidence of    LOEL = 1000                           NTP, 1986
    10 per sex      3000, or 5000 ppm (0, 2050,       mild effects on the brain and      ppm (4100
    per group       4100, 8200, 12 300, or 20 500     nasal turbinates in females was    mg/m3)
                    mg/m3) methyl methacrylate, 6     observed. At 2000-5000 ppm,
                    hours/day, 5 days/week, for 14    death, effects on body weight,     NOEL = 500
                    weeks (65 exposures).             and lesions of nasal turbinates    ppm (2050
                    Histological examinations were    and brain were observed; changes   mg/m3)
                    performed on the controls, the    in spleen were observed at 3000
                    two highest dose groups, and      ppm and above. Also, follicular
                    rats that died before the end     atrophy of the spleen in 4/10
                    of the study. Tissues from the    males, bone marrow atrophy in
                    nasal turbinates, larynx,         8/10 males (5000 ppm exposure
                    trachea, lungs, and brain for     group), and cerebellar congestion
                    all rats exposed at 1000 ppm      and penducle haemorrhage in the
                    and survivors of the 2000 ppm     females exposed to 3000 and 5000
                    groups were also examined         ppm that died early. At 5000 ppm,
                    histopathologically.              listlessness, nasal and serous
                                                      ocular discharge, and prostration
                                                      during the first 2 days, nasal
                                                      cavity inflammation with necrosis
                                                      and loss of epithelium, follicular
                                                      atrophy of the spleen, and bone
                                                      marrow atrophy in the males.
                                                      Cerebellar congestion and
                                                      penducle haemorrhage in the
                                                      early-death females exposed to
                                                      3000 and 5000 ppm, and malacia and
                                                      gliosis in 5/9 females exposed to
                                                      2000 ppm and 1/8 females exposed
                                                      to 1000 ppm.

                                                                                                                                                

    Table 1 (continued)

                                                                                                                                                

    Species         Study design                      Effects                            Effect levels    Comments             Reference
                                                                                                                                                

    Rats, albino    Exposure to 0, 25, 100, or 400    Decreased body weights; slight     NOEL = 25 ppm                         Rohm & Haas,
    F344, 70 per    ppm (0, 102.5, 410, or 1640       increase in the incidence of mild  (102.5 mg/m3)                         1979a; Lomax,
    sex per group   mg/m3) methyl methacrylate, 6     rhinitis in the nasal mucosal                                            1992; Lomax et
                    hours/day, 5 days/week, for up    lining of the turbinates.                                                al., 1997
                    to 104 weeks. Histopathological
                    examination of a wide range of    The re-examination revealed that   LOEL =
                    tissues from controls and         rats exposed to 100 or 400 ppm     100 ppm (410
                    high-dose groups, as well as      methyl methacrylate had            mg/m3)
                    selected tissues from other       exposure-related and
                    dose groups (ovaries or testes    concentration-dependent
                    and nasal turbinates).            microscopic changes in the
                                                      olfactory epithelium lining
                                                      the dorsal meatus in the anterior
                    A re-examination of the nasal     region of the nasal cavity.
                    tissues from the rats of the      The microscopic changes consisted
                    Rohm & Haas (1979a) study was     of degeneration/atrophy of the
                    conducted. The review consisted   olfactory epithelium and
                    of microscopic examination of     underlying Bowman's glands,
                    nasal tissue from at least 10%    hyperplasia of basal (reserve)
                    of randomly selected rats from    cells, replacement of olfactory
                    each group, and the slides        epithelium by ciliated
                    evaluated included the original   (respiratory-like) epithelium,
                    study slides plus slides from     and inflammation of the mucosa
                    tissue sections taken deeper      and/or submucosa. The squamous
                    into the block.                   epithelium of the nasal cavity
                                                      was not affected. The lesions
                                                      tended to be bilateral in
                                                      distribution in rats exposed to
                                                      both 100 and 400 ppm methyl
                                                      methacrylate. A small nasal
                                                      polypoid adenoma was observed in
                                                      one male from both the 100 and
                                                      400 ppm exposure groups.

                                                                                                                                                

    Table 1 (continued)

                                                                                                                                                

    Species         Study design                      Effects                            Effect levels    Comments             Reference
                                                                                                                                                

    Rats, F344/N,   Rats exposed to methyl            Inflammation and degeneration of   LOEL = 250                            NTP, 1986; Chan
    50 per sex      methacrylate at 0, 2050, or       the olfactory epithelium           ppm (1025                             et al., 1988
    per group       4100 mg/m3 (males) or 0, 1025,    (accompanied by variable atrophy   mg/m3)
                    or 2050 mg/m3 (females), 6        of the nerve bundles in the
                    hours/day, 5 days/week, for       submucosa and, in the most
                    102 weeks. Histological           severely affected areas,
                    examination of a comprehensive    replacement of sensory
                    range of tissues.                 neuroepithelial cells with
                                                      respiratory epithelium) and
                                                      minimal increases in the numbers
                                                      of alveolar macrophages in the
                                                      nasal cavity at all dose levels.
                                                      The incidence of focal or
                                                      multifocal fibrosis of the lung
                                                      was increased in the females
                                                      exposed to 2050 mg/m3.

    Rats, Fischer   Exposure to 0, 25, 100, or 400    Mild rhinitis was observed                          Abstract only        Smith et al.,
    344, male and   ppm (0, 102.5, 410, or 1640       (dose level not specified).                                              1979
    female (number  mg/m3) methyl methacrylate, 6
    not specified)  hours/day, 5 days/week, for 24
                    months. Evaluation of haemograms,
                    clinical chemistries, and urine,
                    as well as gross histopathological
                    examination.

                                                                                                                                                

    Table 1 (continued)

                                                                                                                                                

    Species         Study design                      Effects                            Effect levels    Comments             Reference
                                                                                                                                                

    Mice, B6C3F1,   Exposure to 0, 63, 125, 250,      Final mean body weight of the      NOEL = 500                            NTP, 1986
    10 per sex      500, or 1000 ppm (0, 258, 512,    highest-dose males was 7% lower    ppm (2050
    per group       1025, 2050, or 4100 mg/m3)        than controls.                     mg/m3)
                    methyl methacrylate, 6 hours/day,
                    5 days/week, for 14 weeks (64                                        LOEL = 1000
                    exposures). Histological                                             ppm (4100
                    examination of an unspecified                                        mg/m3)
                    range of tissues in all mice of
                    the highest-dose and control
                    groups, all animals that died
                    before the end of the study, and
                    some mice in the other groups.

    Mice, B6C3F1,   Exposure to 0, 63, 125, 250,      Some clinical signs and one        NOEL = 250                            Rohm & Haas,
    10 per sex      500, or 1000 ppm (0, 258, 512,    death in the group exposed to      ppm (1025                             1977
    per group       1025, 2050, or 4100 mg/m3)        500 ppm, but not dose-related.     mg/m3)
                    methyl methacrylate, 6            Body weights of males receiving
                    hours/day, for 64 days. Complete  the two highest doses were         LOEL = 500
                    gross pathological and            significantly decreased during     ppm (2050
                    histopathological examinations.   weeks 11-13 (500 ppm) and weeks    mg/m3)

                                                      6, 11, and 12 (1000 ppm). In
                                                      female mice, the total body
                                                      weight changes were statistically
                                                      significantly lower in animals
                                                      exposed to 500 ppm but not to 1000
                                                      ppm.

                                                                                                                                                

    Table 1 (continued)

                                                                                                                                                

    Species         Study design                      Effects                            Effect levels    Comments             Reference
                                                                                                                                                

    Mice, B6C3F1,   Exposure to 0, 500, 1000, 2000,   The final mean body weights of     LOEL = 500                            NTP, 1986
    10 per sex      3000, or 5000 ppm (0, 2050,       all groups of exposed mice were    ppm (2050
    per group       4100, 8200, 12 300, or 20 500     lower than controls. Deaths at     mg/m3)
                    mg/m3) methyl methacrylate, 6     2000 ppm and above. Renal
                    hours/day, 5 days/week, for 14    cortical necrosis, cortical
                    weeks. Histological examinations  tubular degeneration and/or focal
                    of tissues from the major organs  mineralization, nasal cavity
                    of all mice in the highest-dose   inflammation with necrosis, and
                    and control groups and mice that  loss of olfactory epithelium at
                    died before the end of the        2000-5000 ppm in males and extensive
                    study, of the lung and nasal      liver necrosis in males exposed
                    turbinates of the males and the   to 5000 ppm. Inflammation of the
                    nasal membranes of all females    nasal turbinates in females
                    in the 2000 and 3000 ppm groups,  exposed to 2000 ppm and above.
                    and of the liver of the males     Metaplasia of the nasal epithelium
                    in the 2000 ppm group. At 1000    in all exposed mice.
                    ppm, the nasal turbinates from
                    both sexes and brain from the
                    males were also histologically
                    examined.

    Mice, B6C3F1,   Exposure to 0, 2050, or 4100      Decrease in mean body weights;     LOEL = 500                            NTP, 1986; Chan
    50 per sex      mg/m3 methyl methacrylate, 6      localized histopathological        ppm (2050                             et al., 1988
    per group       hours/day, 5 days/week, for       effects (inflammation and          mg/m3)
                    102 weeks. Histological           degeneration of the olfactory
                    examination of a comprehensive    epithelium) in the nasal
                    range of tissues.                 epithelium.

                                                                                                                                                

    Table 1 (continued)

                                                                                                                                                

    Species         Study design                      Effects                            Effect levels    Comments             Reference
                                                                                                                                                

    Golden          Exposure to 0, 25, 100, or 400    Decreased body weights; increased  LOEL = 400                            Rohm & Haas,
    hamsters, 56    ppm (0, 102.5, 410, or 1640       mortality.                         ppm (1640                             1979b
    per sex per     mg/m3) methyl methacrylate, 6                                        mg/m3)
    group           hours/day, 5 days/week, for 18
                    months. Haematological analysis                                      NOEL = 100
                    and gross and microscopic                                            ppm (410
                    examination of a comprehensive                                       mg/m3)
                    range of tissues.

    Golden          Exposure to 0, 25, 100, or 400    No exposure-related toxic          NOEL =  400      Abstract only        Smith et al.,
    hamsters,       ppm (0, 102.5, 410, or 1640       effects were observed.             ppm (1640                             1979
    male and        mg/m3) methyl methacrylate, 6                                        mg/m3)
    female (number  hours/day, 5 days/week, for 18
    not specified)  months. Evaluation of haemograms,
                    clinical chemistries, and urine,
                    as well as gross
                    histopathological examination.

    Dogs, beagles,  Exposure to 0, 100, or 400 ppm    No significant differences in      NOEL = 400                            Tansy & Drees,
    6 per group,    (0, 410, or 1640 mg/m3) methyl    systolic and diastolic blood       ppm (1640                             1979
    sex             methacrylate vapour, 6            pressure, ECG, heart and           mg/m3)
    unspecified     hours/day, 5 days/week, for 3     respiratory rates, haematology,
                    months. Each dog had an external  clinical chemistries, and
                    iliac artery catheter. Two dogs   urinalysis; histopathological
                    from each group sacrificed at     examination of the major organs
                    the end of the 3-month period;    was unremarkable.
                    remaining dogs observed for
                    another month.

                                                                                                                                                

    Table 1 (continued)

                                                                                                                                                

    Species         Study design                      Effects                            Effect levels    Comments             Reference
                                                                                                                                                

    Dogs,           Exposure to 0, 100, or 400 ppm    No exposure-related toxic          NOEL = 400       Abstract only        Smith et al.,
    beagles, male   (0, 410, or 1640 mg/m3) methyl    effects were observed.             ppm (1640                             1979
    (number not     methacrylate vapour, 6                                               mg/m3)
    specified)      hours/day, 5 days/week, for 3
                    months. Gross and
                    histopathological evaluations
                    in addition to evaluation of
                    haemograms, clinical chemistries
                    and urine, ECGs, and blood
                    pressure.
                                                                                                                                                

    INGESTION
                                                                                                                                                

    Rats (sex and   Ingestion of 0, 1, 3, or 5        Rats in mid-dose group did not     NOAEL = 3        Small group sizes;   Deichmann-Gruebler
    strain          ml/kg body weight (0, 0.9, 2.8,   gain as much weight as those in    ml/kg body       histopathological    & Read, undated
    unspecified,    or 4.7 mg/kg body weight)         low-dose group; animals in         weight (2832     examination
    groups of 5)    orally by gavage, every second    high-dose group died before the    mg/kg body       unspecified
                    day for 70 days. Urine samples    4th treatment. All high-dose rats  weight)
                    from rats of all groups were      had distended bladders filled
                    periodically collected and        with blood; a moderate degree of
                    examined for blood.               cellular degeneration in the
                    Histopathological examinations    liver, but without necrosis or
                    unspecified.                      fibrosis; renal effects
                                                      (haemorrhages in the tubules,
                                                      marked hyperaemia, and
                                                      degeneration of the tubular
                                                      epithelium).

                                                                                                                                                

    Table 1 (continued)

                                                                                                                                                

    Species         Study design                      Effects                            Effect levels    Comments             Reference
                                                                                                                                                

    Rats, Wistar,   Ingestion of 0, 6, 60, or 2000    Increase in relative kidney        NOEL = 60 ppm                         Borzelleca et
    25 per sex      ppm (mg/litre) (equivalent to     weight in females only.            (5 mg/kg body                         al., 1964
    per group       0, 0.4, 4, and 121 mg/kg body                                        weight per day)
                    weight per day for males; and
                    0, 0.5, 5, and 146 mg/kg body                                        NOAEL = 2000
                    weight per day for females)                                          ppm (146 mg/kg
                    methyl methacrylate in                                               body weight per
                    drinking-water for 2 years.                                          day)
                    (Groups received 6 and 60 ppm
                    for 5 months, then the
                    concentrations were increased
                    to 7 and 70 ppm for the remainder
                    of the 2 years.)
                    Histopathological examination of
                    a wide range of tissues from
                    mid- and high-dose groups.
                    Limited haematological and urine
                    analyses conducted.

    Dogs,           Ingestion of 0, 10, 100, or       No treatment-related effects.      NOEL = 1500      Extremely small      Borzelleca et
    beagles, 2      1000 ppm (mg/kg) methyl                                              ppm (38 mg/kg    number of animals    al., 1964
    per sex per     methacrylate in corn oil in                                          body weight
    group           the diet (high dose gradually                                        per day)
                    increased to 1500 ppm
                    [equivalent to about 38 mg/kg
                    body weight per day] at week
                    9) for 2 years.
                    Histopathological examination
                    of a wide range of tissues.
                    Limited haematological and
                    urine analyses conducted.
                                                                                                                                                


    8.4.1  Subchronic exposure

         In most subchronic studies conducted to date, rats and mice have
    been exposed to methyl methacrylate by inhalation.  Effects observed
    most commonly in these investigations were decreases in body weight
    gain and irritation of the skin, nasal cavity, and eye at high
    concentrations (generally >500 ppm [2050 mg/m3]) (Rohm & Haas,
    1977; NTP, 1986).  At higher concentrations, other effects, such as
    renal cortical necrosis and tubular degeneration (rats and mice) and
    hepatic necrosis (mice), have also been reported (Tansy et al., 1980a;
    NTP, 1986; Deichmann-Gruebler & Read, undated).

         On the basis of decreases in final mean body weight and squamous
    metaplasia at the site of entry (i.e. nasal epithelium), the lowest
    reported NOEL and lowest-observed-effect level (LOEL) in a subchronic
    inhalation bioassay in which several concentration levels were
    administered were 250 and 500 ppm (1025 and 2050 mg/m3),
    respectively, in mice exposed to methyl methacrylate for 64 days or 14
    weeks (Rohm & Haas, 1977; NTP, 1986).  Except for effects at the site
    of entry, histopathological changes have not been observed in the two
    most extensive subchronic bioassays in rats exposed to methyl
    methacrylate for 65 days or 14 weeks, at concentrations up to 1000 ppm
    (4100 mg/m3) (Rohm & Haas, 1977; NTP, 1986).

         In less extensive and less well documented studies conducted by
    Tansy et al. (1976, 1980a,b), effects on the trachea and some
    indications of liver damage in rats were observed at the only tested
    concentration of 116 ppm (476 mg/m3), administered for 7 hours/day
    for 3 or 6 months, although the statistical significance of the
    pulmonary changes was not specified, and similar effects were observed
    in some of the sham-exposed control animals.  In a supplementary
    study, there was weak evidence of an effect on liver function
    (barbiturate sleeping time) in male rats administered "intermittent
    daily exposures" of 100 ppm (410 mg/m3) methyl methacrylate for a
    total of 160 hours (Tansy et al., 1980b).  Initial reports of reduced
    fat deposits after exposure for 3 months were not confirmed in later
    studies of similar protocol by the same investigators (Tansy et al.,
    1980a,b).

    8.4.2  Chronic exposure and carcinogenicity

         In the few studies identified in which the chronic toxicity and
    carcinogenicity of methyl methacrylate were investigated, the observed
    effects were, in general, similar to those reported in short-term and
    subchronic studies and included inflammation and epithelial
    hyperplasia of the nasal cavity and degeneration of the olfactory
    sensory epithelium.  Based on the results of a well documented
    inhalation study in F344/N rats and B6C3F1 mice reported by the NTP
    (1986) and Chan et al. (1988), there was no evidence of
    carcinogenicity of methyl methacrylate for groups of 50 male F344/N
    rats and 50 male and 50 female B6C3F1 mice exposed to 500 or 1000 ppm

    (2050 or 4100 mg/m3) and groups of 50 female rats exposed to 250 or
    500 ppm (1025 or 2050 mg/m3) for 2 years.  Based on inflammation and
    degeneration of the olfactory epithelium in the nasal cavity
    (accompanied by variable atrophy of the nerve bundles in the submucosa
    and, in the most severely affected areas, replacement of sensory
    neuroepithelial cells with respiratory epithelium) and minimal
    increases in the numbers of alveolar macrophages in the nasal cavity
    at all dose levels, the LOEL in rats was considered to be 250 ppm
    (1025 mg/m3).  In mice, the LOEL was considered to be 500 ppm (2050
    mg/m3) on the basis of lower mean body weights in exposed animals and
    localized histopathological effects at the site of entry (including
    inflammation and degeneration of the olfactory epithelium).

         In earlier studies conducted for Rohm & Haas (1979a,b), no
    treatment-related increases in tumour incidence occurred in either
    groups of 56 male and 56 female golden hamsters or groups of 70 male
    and 70 female albino F344 rats exposed to 0, 25, 100, or 400 ppm (0,
    102.5, 410, or 1640 mg/m3) methyl methacrylate 6 hours/day, 5
    days/week, for 18 months and 2 years, respectively.  At the highest
    concentration, body weight decreased significantly in both species,
    mortality increased in hamsters, and the incidence of mild rhinitis in
    the nasal mucosa increased slightly in rats.

         A histopathological review of the nasal tissues from the rats in
    the above-mentioned Rohm & Haas (1979a) study was commissioned by the
    US Methacrylate Producers Association (Lomax, 1992; Lomax et al.,
    1997).  The review consisted of microscopic examination of nasal
    tissue from at least 10% of randomly selected rats from each group,
    and the slides evaluated included the original study slides plus
    slides from tissue sections taken deeper into the block.  The tissues
    from male and female rats that had been exposed to 25 ppm (102.5
    mg/m3) methyl methacrylate for 2 years were morphologically similar
    to those of controls.  Rats exposed to 100 or 400 ppm (410 or 1640
    mg/m3) methyl methacrylate had exposure-related and concentration-
    dependent microscopic changes in the olfactory epithelium lining the
    dorsal meatus in the anterior region of the nasal cavity.  The
    microscopic changes consisted of degeneration/atrophy of the olfactory
    epithelium and underlying Bowman's glands, hyperplasia of basal
    (reserve) cells, replacement of olfactory epithelium by ciliated
    (respiratory-like) epithelium, and inflammation of the mucosa and/or
    submucosa (Lomax et al., 1997).  Changes in the respiratory epithelium
    were observed only at the high concentration (400 ppm [1640 mg/m3])
    and were limited to hyperplasia of the submucosal gland and/or goblet
    cells in the anterior region of the nasal cavity.  The squamous
    epithelium of the nasal cavity was not affected.  The lesions tended
    to be bilateral in distribution in rats exposed to both 100 and 400
    ppm (410 and 1640 mg/m3) methyl methacrylate.  A small nasal polypoid
    adenoma was observed in one male from both the 100 and 400 ppm (410
    and 1640 mg/m3) exposure groups.  Based on this re-examination, the
    NOEL and LOEL are considered to be 25 ppm (102.5 mg/m3) and 100 ppm
    (410 mg/m3), respectively.

         Data available on the effects of methyl methacrylate following
    ingestion are limited.  In an early study (Borzelleca et al., 1964) in
    which organ to body weight ratios were determined and
    histopathological examination of a wide range of tissues as well as
    limited haematological and urine analyses were conducted, the relative
    kidney weight was increased in a small group of female rats  (n = 25)
    exposed to 2000 ppm (mg/litre) methyl methacrylate in drinking-water
    for 2 years.  This effect was not observed in the males, and
    histopathological examination revealed no damage.  The authors also
    reported a decrease in fluid consumption in rats exposed to 2000 ppm.
    The no-observed-adverse-effect level (NOAEL) was therefore considered
    to be 2000 ppm (equivalent to a dose of about 146 mg/kg body weight
    per day for females and 121 mg/kg body weight per day for males, based
    on intake and body weight data presented by the authors).  There were
    no treatmentrelated effects, based upon gross or histopathological
    examination, in extremely small groups of beagle dogs  (n = 2)
    exposed to concentrations of up to 1500 ppm (mg/kg) methyl
    methacrylate (equivalent to a dose of about 38 mg/kg body weight per
    day) in their feed for 2 years (Borzelleca et al., 1964).

    8.5  Genotoxicity and related end-points

         Results of available genotoxicity studies on methyl methacrylate
    are summarized in Table 2.  In a number of well conducted  in vitro 
    studies with precautions taken to limit evaporation, methyl
    methacrylate was not mutagenic in  Salmonella typhimurium with or
    without metabolic activation.  In a single study (Poss et al., 1979),
    results were positive at clearly cytotoxic concentrations in the
    presence of metabolic activation in a poorly validated forward
    mutation assay in  S. typhimurium TM677; results were negative in the
    absence of metabolic activation.

         Methyl methacrylate has been mutagenic and clastogenic in
    mammalian cells in culture.  It induced gene mutation in mouse
    lymphoma L5178Y cells without metabolic activation in five
    investigations and was positive with metabolic activation in all of
    the three investigations in which it was examined.  Results for
    chromosomal aberrations and micronucleus formation were also positive
    in this cell line without metabolic activation at concentrations at
    which there was poor cell survival (Doerr et al., 1989).  An increase
    in chromosomal aberrations and sister chromatid exchanges in Chinese
    hamster ovary cells has also been observed in the presence and absence
    of metabolic activation in assays conducted in two laboratories (NTP,
    1986; Anderson et al., 1990).

         In  in vivo studies conducted to date, there has been limited
    evidence of genotoxicity.  In an early study in which rats were
    exposed to methyl methacrylate as either a single 2-hour exposure or
    for 5 hours/day for 5 days at concentrations up to 9000 ppm (36 900
    mg/m3), there were small but significant increases in chromosomal
    aberrations in bone marrow cells from rats exposed to the highest
    concentration in the multiple-exposure study (Anderson & Richardson,
    1976).  Although of questionable biological significance, small
    increases in gaps were also noted at the two highest concentrations.

    In a follow-up study with a larger number of intermediate dose levels,
    there were significant increases in chromosomal aberrations following
    both single and repeated exposures (Anderson et al., 1979); although
    there was no clear dose-response, the pattern of effect may have been
    attributable to chemically induced cell cycle delay (Anderson et al.,
    1979).  The maximum concentration tested in the follow-up study (1000
    ppm [4100 mg/m3]) caused significant reductions in the mitotic
    activity in the bone marrow of all exposed animals.  Results were
    negative in a well conducted dominant lethal assay in which mice were
    exposed to concentrations of methyl methacrylate up to 9000 ppm
    (36 900 mg/m3) 6 hours/day for 5 days (Anderson & Hodge, 1976).

         No significant increase in the incidence of micronuclei was
    observed in the bone marrow of mice following a single administration
    of methyl methacrylate by gavage at doses up to 4.52 g/kg body weight
    or in an additional investigation with one dose group that was exposed
    to 1.13 g/kg body weight per day for 4 days; however, cells were
    harvested at one time point (24 hours) only, and there was no evidence
    of toxicity in the target tissue (Hachitani et al., 1981).  Negative
    results of an additional  in vivo micronucleus assay in mice do not
    contribute to an assessment of the weight of evidence of genotoxicity
    owing to inadequate dose levels (Jensen et al., 1991).  Available data
    in the published accounts were inadequate to allow the assessment of
    the mixed results of two additional studies in which chromosomal
    aberrations in bone marrow cells of rats were examined following
    intraperitoneal administration of methyl methacrylate (Fedyukovich et
    al., 1988; Fedyukovich & Egorova, 1991).

         Although not mutagenic in bacterial systems  in vitro, methyl
    methacrylate has induced mutation and chromosomal aberrations in
    mammalian cells  in vitro. In  in vivo inhalation studies in which
    there has been clear evidence of toxicity within the target tissue,
    there has been limited evidence of genotoxicity of methyl
    methacrylate.

    8.6  Reproductive and developmental toxicity

         In a well conducted study in Crl:CDBR rats, there was no
    embryotoxicity or fetotoxicity and no increase in the incidence of
    malformations or variations following exposure for 6 hours/day on days
    6-15 of gestation to concentrations of methyl methacrylate that ranged
    from 99 to 2028 ppm (406-8315 mg/m3; NOEL = 8315 mg/m3).  However,
    there were treatment-related effects on maternal body weight at all
    concentrations (Solomon et al., 1993).  In an earlier study in which
    pregnant ICR mice were exposed to 1330 ppm (5450 mg/m3) methyl
    methacrylate for 2 hours twice daily during days 6-15 of pregnancy,
    there were no developmental effects.  Maternal toxicity was not
    addressed in the report (McLaughlin et al., 1978).



        Table 2:  Genetic effects (adapted from IARC, 1994).

                                                                                                                                          
                                                                                           Resultsb
                                                                                                           
                                                                                     Without     With
                                                                                     exogenous   exogenous
                                                                             Dosea    metabolic   metabolic
    Test system                     End-point                           (LED/HID)    system      system      Reference
                                                                                                                                          

    Salmonella typhimurium TM677    Forward mutation                         5000    -           +           Poss et al., 1979

    Salmonella typhimurium TA100    Reverse mutation                          500    -           -           Lijinsky & Andrews, 1980
                                                                             5000    -           -           Hachitani et al., 1981
                                                                             2300    -           -           Waegemaekers & Bensink, 1984
                                                                             5000    -           -           Zeiger et al., 1987
                                                                      25 mg/plate    -           -           Schweikl et al., 1994

    Salmonella typhimurium TA1535   Reverse mutation                          500    -           -           Lijinsky & Andrews, 1980
                                                                             2300    -           -           Hachitani et al., 1981
                                                                             5000    -           -           Waegemaekers & Bensink, 1984
                                                                             1700    -           -           Zeiger et al., 1987

    Salmonella typhimurium TA1537   Reverse mutation                          500    -           -           Lijinsky & Andrews, 1980
                                                                             2300    -           -           Hachitani et al., 1981
                                                                             5000    -           -           Waegemaekers & Bensink, 1984
                                                                             5000    -           -           Zeiger et al., 1987

    Salmonella typhimurium TA1538   Reverse mutation                          500    -           -           Lijinsky & Andrews, 1980
                                                                             2300    -           -           Hachitani et al., 1981
                                                                             5000    -           -           Waegemaekers & Bensink, 1984

    Salmonella typhimurium TA98     Reverse mutation                          500    -           -           Lijinsky & Andrews, 1980
                                                                             2300    -           -           Hachitani et al., 1981
                                                                             5000    -           -           Waegemaekers & Bensink, 1984
                                                                             5000    -           -           Zeiger et al., 1987
                                                                      25 mg/plate    -           -           Schweikl et al., 1994

                                                                                                                                          

    Table 2 (continued)

                                                                                                                                          
                                                                                           Resultsb
                                                                                                           
                                                                                     Without     With
                                                                                     exogenous   exogenous
                                                                             Dose    metabolic   metabolic
    Test system                     End-point                           (LED/HID)    system      system      Reference
                                                                                                                                          

    Salmonella typhimurium TA97     Reverse mutation                         1700    -           -           Zeiger et al., 1987
    Salmonella typhimurium TA97a                                      25 mg/plate    -           -           Schweikl et al., 1994
    Salmonella typhimurium TA102                                      25 mg/plate    -           -           Schweikl et al., 1994
    Salmonella typhimurium TA104                                      25 mg/plate    -           -           Schweikl et al., 1994

    Mouse lymphoma L5178Y cells     Gene mutation (tk locus)                 2200    +           0           Doerr et al., 1989
      in vitro                                                               2000    +           0           Moore et al., 1988
                                                                              250                +           Myhr et al., 1990
                                                                              500    +                       Myhr et al., 1990
                                                                              500    +           +           Dearfield et al., 1991
                                                              117.5 (0.125 µl/ml)    +           +           NTP, 1986

    Mouse lymphoma L5178Y cells     Micronucleus formation                   2200    (+)         0           Doerr et al., 1989
      in vitro

    Chinese hamster ovary cells     Sister chromatid exchange                  16    +           +           Anderson et al., 1990
      in vitro                                                                750    +                       NTP, 1986
                                                                              500                +           NTP, 1986

    Chinese hamster ovary cells     Chromosomal aberrations                  1600    +           (+)         Anderson et al., 1990
      in vitro                                                               5000                +c          NTP, 1986
                                                                             1600    +c                      NTP, 1986

    Mouse lymphoma L5178Y cells     Chromosomal aberrations                  2200    (+)         0           Doerr et al., 1989
      in vitro

    Human lymphocytes in vitro      Sister chromatid exchange                 0.1    ?           0           Cannas et al., 1987

                                                                                                                                          

    Table 2 (continued)

                                                                                                                                          
                                                                                           Resultsb
                                                                                                           
                                                                                     Without     With
                                                                                     exogenous   exogenous
                                                                             Dose    metabolic   metabolic
    Test system                     End-point                           (LED/HID)    system      system      Reference
                                                                                                                                          

    Mouse bone marrow cells         Micronucleus formation        <4.52 g/kg body    -                       Hachitani et al., 1981
    in vivo                                                      weight x 1 p.o.d
                                                                   1.13 g/kg body    -                       Hachitani et al., 1981
                                                                 weight x 4 p.o.d

    Rat bone marrow cells in vivo   Chromosomal aberrations         36 900 mg/m3,    -                       Anderson & Richardson, 1976
                                                                2 hour x 1 inhal.

                                                                    36 900 mg/m3,    +                       Anderson & Richardson, 1976
                                                                     5 hours/day,
                                                                    5 days inhal.

                                                               4100 mg/m3, 2 hour    Equivocal               Anderson et al., 1979
                                                                       x 1 inhal.

                                                                      4100 mg/m3,
                                                                     5 hours/day,    Equivocal               Anderson et al., 1979
                                                                    5 days inhal.

    Male mice in vivo               Dominant lethal assay          <36 900 mg/m3,    -                       Anderson & Hodge, 1976
                                                                     6 hours/day,
                                                                    5 days inhal.
                                                                                                                                          

    Table 2 (continued)

    a    In vitro tests, µg/ml; in vivo tests, mg/kg body weight; LED = lowest effective dose; HID = highest ineffective dose.
    b    +, positive; (+), weak positive; -, negative; 0, not tested; ?, inconclusive (variable response within several experiments
         within an adequate study).  Negative results of an additional in vivo micronucleus assay in mice do not contribute to an assessment
         of the weight of evidence of genotoxicity owing to inadequate dose levels (Jensen et al., 1991).  Available data in the published
         accounts were inadequate to permit an assessment of the mixed results of two additional studies in which chromosomal aberrations
         in bone marrow cells of rats were examined following intraperitoneal administration (Fedyukovich et al., 1988; Fedyukovich &
         Egorova, 1991).
    c    5% of cells affected without exogenous metabolic system; 30% of cells affected with exogenous metabolic system.
    d    No toxicity in target tissue. p.o. = per os.



         In a study reported only in the form of an abstract, a number of
    effects, including intrauterine deaths, an increase in the number of
    fetuses with vascular pathology, and an increase in the frequency of
    "functional immaturity," were observed in the offspring of rat dams
    exposed to concentrations of methyl methacrylate as low as 0.01 mg/m3
    (Farmakovskaya & Tikhomirov, 1993).  The information presented in the
    published account of this study is inadequate to permit assessment of
    the protocol and results.

         In early studies, developmental effects, including decreases in
    fetal weights, embryo-fetal deaths, and skeletal abnormalities, were
    observed in rats following inhalation of concentrations of methyl
    methacrylate that were toxic to the dams (Hodge & Palmer, 1977;
    Nicholas et al., 1979).  Similar effects were reported in studies in
    mice in which maternal toxicity was not addressed (Tansy, 1975) and in
    studies in rats in which the protocol and results were not well
    documented (Luo et al., 1986).

         Data on reproductive effects are limited to a dominant lethal
    assay and examination of gonads in repeated-dose toxicity studies.
    There was no reduction in fertility as measured by the number and
    percentage of successful matings each week or the percentage of female
    mice that become pregnant in a dominant lethal assay in mice exposed
    to 100, 1000, or 9000 ppm (410, 4100, or 36 900 mg/m3) methyl
    methacrylate by inhalation for 6 hours/day for 5 days (Anderson &
    Hodge, 1976).

         Adverse effects on the reproductive organs of experimental
    animals have not been observed in repeated-dose studies in animals
    exposed to methyl methacrylate (see sections 8.3 and 8.4).

    8.7  Immunological and neurological effects

         In a study in which the leukocyte migration inhibition method was
    employed to determine if methyl methacrylate was potentially a
    causative agent in denture stomatitis, three groups of five albino
    rabbits of both sexes were injected intramuscularly with 1 ml of
    methyl methacrylate on days 1, 5, and 14 (Zafiropoulos et al., 1985).
    On the 36th day, blood was drawn to test the inhibition of leukocyte
    migration.  The results indicated that methyl methacrylate was a
    specific antigen that was capable of inducing cellular immune
    reaction.

         Methyl methacrylate markedly impaired locomotor activity and
    learning while significantly increasing aggressive behaviour in male
    rats orally administered the chemical at 500 mg/kg body weight for 21
    days (Husain et al., 1985).  There was an overall increase in levels
    of biogenic amine in the pons-medulla and hippocampus.  Levels of
    noradrenaline in the cerebral cortex and 5-hydroxytryptamine in the
    mid-brain and the hypothalamus were increased, whereas there was a
    slight decrease in dopamine levels in the corpus striatum (Husain et

    al., 1985).  In a separate study under the same experimental
    conditions, a significant increase in cholesterol (26%) and
    triglycerides (65%) and a slight decrease in the total phospholipid
    content of the sciatic nerve were noted (Husain et al., 1989).

         In a study investigating the neurotoxic effects of acrylamide, no
    evidence of neurotoxicity (evaluated as observation of ataxia) or
    enhancement of acrylamide neuropathy was observed in male rats fed a
    diet containing 18 800 ppm (mg/kg) methyl methacrylate for 5 weeks
    (the intake of methyl methacrylate was estimated to be 410 mg/day)
    (Edwards, 1975).  Other limited studies that have been identified do
    not contribute to our understanding of the neurotoxicity of methyl
    methacrylate (Innes & Tansy, 1981; Wynkoop et al., 1982; Kanerva &
    Verkkala, 1986).

    9.  EFFECTS ON HUMANS

         Data on effects of methyl methacrylate on humans are informative
    primarily with respect to irritation and sensitization (for exposure
    both dermally and by inhalation), respiratory effects, and
    carcinogenicity; however, in cross-sectional epidemiological studies
    conducted to date, effects on the nervous (Seppalainen & Rajaniemi,
    1984; Schwartz et al., 1989) and cardiac (Cromer & Kronoveter, 1976;
    NIOSH, 1976) systems have also been examined.

         Hypotension, changes in pulse rate, and cardiac arrest have been
    reported following bone replacement surgery with polymethyl
    methacrylate cemented prostheses; however, the significance of these
    observations with respect to methyl methacrylate exposure is
    questionable owing to lack of correlation between peak plasma
    concentrations of methyl methacrylate and reported effects and the
    absence of similar effects in younger patients (Government of Canada,
    1993; Cary et al., 1995; ECETOC, 1995).

    9.1  Case reports

         There are reports of skin irritation and sensitization in human
    volunteers and in patients suspected of occupational sensitization to
    acrylates from exposure to dental materials or anaerobic sealants
    (Spealman et al., 1945; Estlander et al., 1984; Kassis et al., 1984;
    Rajaniemi & Tola, 1985; Conde-Salazar et al., 1988; Kanerva et al.,
    1988, 1989; Farli et al., 1990; Guerra et al., 1993).  Occupational
    asthma associated with methyl methacrylate has also been reported
    (Lozewicz et al., 1985; Pickering et al., 1986, 1993); however, there
    is no conclusive evidence that methyl methacrylate is a respiratory
    sensitizer, and the possibility of a non-specific response due to
    respiratory tract irritation cannot be excluded.

    9.2  Epidemiological studies

         Protocols and results of cross-sectional studies in which
    respiratory effects of methyl methacrylate have been investigated in
    occupationally exposed populations are presented in Table 3.  For
    example, in a study in which smoking was taken into account, an
    increase in the prevalence of chronic cough (as evaluated by
    questionnaire) was observed in a small group of workers  (n = 40)
    exposed exclusively to methyl methacrylate for at least 5 years in two
    factories (mean atmospheric levels of methyl methacrylate in the two
    factories were 18.5 and 21.6 ppm [75.8 and 88.6 mg/m3]) compared with
    controls engaged in similar job categories, but without exposure to
    methyl methacrylate (Marez et al., 1993).  Spirometric values did not
    differ before the work shift, but two of nine parameters decreased
    during the work shift.  Information concerning exposure to other
    respiratory irritants was not provided; although increased cough and
    mild airway resistance correlated with exposure to methyl
    methacrylate, peak versus mean exposures were not examined.  In other
    studies in which there was some quantitative information on exposure,
    results have varied, with effects on respiratory function being
    observed in some cases at mean concentrations as low as 11 mg/m3
    (Jedrychowski, 1982) and no effects in other investigations at
    time-weighted-average concentrations up to 40-50 ppm (164-205 mg/m3)
    (Cromer & Kronoveter, 1976; NIOSH, 1976; Röhm, 1994).  It is
    difficult, however, to draw meaningful conclusions concerning levels
    of exposure that induced effects in these studies, as there was little
    attempt to assess mean versus peak exposures.  Moreover,
    interpretation of several of the investigations is complicated by
    concomitant exposure of the examined populations to other substances.
    In other investigations reported to date, quantitative data on
    exposure of workers to methyl methacrylate were not included (Andrews
    et al., 1979; Schwartz et al., 1989).  An additional cross-sectional
    study of the prevalence of disorders of smell in methyl
    methacrylate-exposed workers is under way (A. Muttray, personal
    communication, 1997).

    Table 3: Cross-sectional epidemiological studies - respiratory effects

                                                                                                                                              
    Protocol                                                            Results                                              Reference
                                                                                                                                              

    Study population composed of 40 workers from two factories who      An increase in the prevalence of chronic cough       Marez et al., 1993
    were exposed to methyl methacrylate for >5 years and 45 controls    observed in exposed workers compared with controls
    engaged in similar job categories but without exposure to methyl    (p = 0.04). This difference remained significant
    methacrylate. Mean atmospheric concentrations of methyl             after adjustment for smoking (p = 0.03). Airway
    methacrylate at the two factories were 18.5 ppm (75.9 mg/m3)        resistance increased during the 8-hour work shift
    (range 9-32 ppm [36.9-131.2 mg/m3]) and 21.6 ppm                    in workers exposed to methyl methacrylate (as
    (88.6 mg/m3) (range 11.9-38.5 ppm [48.8-157.9 mg/m3]).              measured by MEF50 [p = 0.04] and MEF50/MEF
    Smoking history and information on the presence of respiratory      [p = 0.0)). The obstruction was mild, and forced
    symptoms were gathered by means of a questionnaire. Respiratory     expiratory volume in one second (FEV,) did not
    measurements (maximum expiratory flow volume [MEFV],                decrease during the work shift.
    forced vital capacity [FVC], forced expiratory volume [FEV])
    were performed by means of a spirometer: one before the
    working shift, and the second in the last 2 hours of the 8-hour
    shift.
                                                                                                                                              

    Ninety-one exposed and 43 non-exposed workers were evaluated at     No significant differences were observed for         Cromer & Kronoveter,
    five plants manufacturing polymethyl methacrylate sheets. For       respiratory function, chronic liver and              1976
    exposed workers, 8-hour time-weighted-average concentrations of     gastrointestinal effects, skin and allergic
    methyl methacrylate were between 4 and 49 ppm (16.4-200.9           problems, blood pressure and pulse rate, white
    mg/m3). Evaluation of chronic effects was conducted through an      blood cell count, and haemoglobin values. The
    extensive questionnaire, a comparison of mean blood pressure        only parameters for which effects were observed
    values with predicted values from the 1971-1972 US National         were serum glucose, blood urea nitrogen, cholesterol,
    Health Survey, and results of pulmonary function tests,             albumin, and total bilirubin values, although the
    haemoglobin and white blood cell counts, urinalysis, and blood      implication of these effects remains unclear.
    chemistry.                                                          Although not statistically significant, the data also
                                                                        "suggested possible alterations in skin and nervous
                                                                        system symptomatology, urinalysis findings, and
                                                                        serum triglycerides."
                                                                                                                                              

    Employees of the Rohm & Haas Co. (which manufactures acrylic        Upon cross-sectional analysis, when the age, ethnic  Schwartz et al., 1989
    acid, acrylates, and methacrylates) - 618 males and 113 females     group, and smoking status were considered, the mean
    (mean age 42.9 years), out of  the total number of 909 short- and   UPSIT scores in the four exposure groups did not
    long-term employees - were asked to complete a University of        differ. For the "no significant chemical exposures,"
    Pennsylvania Smell Identification Test (UPSIT) and                  "exposure to other chemicals," "exposure to low
    questionnaires on job histories as well as personal and medical     levels of acrylate/methacrylate," and "exposure to
    information. Employees were grouped into four exposure              higher levels of acrylate/methacrylate" groups, the
    categories: no significant chemical exposures (n = 319), exposure   scores were 37.8, 37.4, 37.0, and 37.6, respectively.
    to other chemicals (n = 193), exposure to low levels of             Based on logistic regression analysis, adjusting for
    acrylate/methacrylate (n = 164), and exposure to higher levels of   multiple confounders, in the nested case-control
    acrylate/methacrylate (n = 55). In a nested case-control study, 77  study, the odds ratios for the association of UPSIT
    workers who scored below the 10th percentile in their age group     score with exposure to methyl methacrylate for all
    on the UPSIT were matched with controls (scored at or above the     workers was 2.8 (95% CI 1.1-7.0) and for those who
    50th percentile). Exposure was classified in terms of whether       never smoked was 13.5 (95% CI 2.1-87.6); the crude
    workers had been exposed to methyl methacrylate for at least 6      odds ratios were 2.0 and 6.0, respectively. There
    weeks, the total time of employment at the plant, and a cumulative  was a dose-response relationship between olfactory
    exposure score - a semi-quantitative index of lifetime exposure     dysfunction and the cumulative exposure. The odds
    to the acrylates - for each worker.                                 ratios increased with the cumulative exposure scores,
                                                                        except for a decrease in the highest exposure
                                                                        category. The olfactory dysfunction may be
                                                                        reversible, as the odds ratios decreased with the
                                                                        length of time since the last exposure.
                                                                                                                                              

    Four hundred and fifty-four males from a plant (Plant A)            There was a non-significantly lower occurrence of    Jedrychowski, 1982
    producing styrene and methyl methacrylate were compared with        bronchitis and/or asthma in the exposed (17.8%)
    683 males from a plant producing carbon derivatives who served      compared with the control (19.5%) group. There was
    as controls (jobs were similar in both plants, but there was no     no significant difference in the incidence of
    exposure to styrene or methyl methacrylate in the latter plant).    chronic chest symptoms between the two groups.
    Standardized interviews on chest symptoms, measured heights,        However, the frequency of lung obstruction was over
    lung function tests, and examinations for chronic bronchitis and    twice as high in the exposed workers (45.4% vs
    asthmatic syndrome were conducted. The workers were divided         18.0%); this percentage was higher for smokers than
    into the following groups: non-smokers, ex-smokers, and current     for non-smokers (20.9% vs 13.6%). Within the
    smokers. Styrene and methyl methacrylate concentrations were        exposed group, the occurrence of lung obstruction
    determined in 18 workplaces in Plant A. For methyl methacrylate,    in smokers and in non-smokers did not differ
    the mean concentration in Plant A was 11 mg/m3.                     significantly. Fifty-six per cent of the controls and
                                                                        76% of the exposed workers with lung obstruction
                                                                        did not have any chronic chest symptoms. The lung
                                                                        function of the exposed group was significantly
                                                                        poorer than that of the controls; the effects were
                                                                        slightly worse among smokers in both groups. The
                                                                        relative risk of lung obstruction (compared with
                                                                        non-exposed ex- and non-smokers) was 1.7 for non-
                                                                        exposed smokers, 4.7 for exposed ex- and
                                                                        non-smokers, and 5.5 for exposed smokers.
                                                                                                                                              

    Five hundred and two dental students (who handled methyl            In exposed students, 6% reported respiratory         Andrews et al., 1979
    methacrylate in their laboratories) completed self-administered     symptoms associated with exposure to methyl
    multiple-choice questionnaires concerning their past histories      methacrylate (88% had histories of asthma or
    and any symptoms (not specified) associated with activities in the  allergic rhinitis), and 5% when using high-speed
    lab. Spirometric tests were performed before and after exposure to  drills. Among the 77 students who underwent
    unreported amounts of methyl methacrylate for 77 students who       spirometric tests, there was no significant change
    had allergic rhinitis, smoked, or had symptoms upon usual           in symptoms or spirometry.
    exposure.
                                                                                                                                              

    A study of 91 exposed and 43 non-exposed workers from five          Some significant differences in terms of coughing    NIOSH, 1976
    methyl methacrylate cast sheet manufacturing plants in the USA.     and expectoration, but these were likely due to
    The survey included a medical questionnaire, measurement of         differences in smoking habits. When smoking
    clinical symptoms, blood pressure, and pulse rate, testing of       histories were taken into consideration, there was
    pulmonary function and blood chemistry, urinalysis, and white       no significant change in pulmonary function among
    blood cell counts. Based on 8-hour time-weighted-average            the exposure groups. No significant differences in
    exposures to methyl methacrylate, workers were divided into five    blood pressure or in white blood cell count were
    categories: <5 ppm (20.5 mg/m3) (n = 13), 5-25 ppm (20.5-102.5      found. There were several significant differences
    mg/m3) (n = 20), 25-50 ppm (102.5-205 mg/m3) (n = 33), no           in the blood chemistry tests of the "no current
    current exposure but past exposure >1 year (n = 25), and the        exposure" group, but this was likely due to the
    control group with no exposure (n = 43). The ages and smoking       fact that they were significantly older than the
    histories of exposure groups were not matched very well because     controls.
    of the low number of volunteers.
                                                                                                                                              

    A cross-sectional study involving 211 workers at a polymethyl       There were no significant respiratory effects        Röhm, 1994
    methacrylate sheet producing factory in Germany. The study          associated with exposure in any of the groups.
    report period was 1991-1993. Working areas were classified into     There were some observations of eye and respiratory
    the following exposure ranges: 3-10 ppm (12.3-41 mg/m3), 10-20      tract irritation, which were reported to be
    ppm (41-82 mg/m3), 20-30 ppm (82-123 mg/m3), and 30-40 ppm          transient and were limited to short-term exposures
    (123-164 mg/m3) (8-hour time-weighted averages; ranges              (5-15 minutes in duration) at concentrations
    represent geometric means). The numbers of persons in each          exceeding 100 ppm (410 mg/m3).
    exposure group were 7, 128, 20, and 56, respectively. The
    examination of the workers consisted of a self-administered
    questionnaire (concerning lifestyle, occupation, and medical
    history, with emphasis on complaints of nose, throat, and
    respiratory system failures and allergic reactions, including
    skin and asthmatic reactions) as well as a visual examination
    of the nasal cavity.
                                                                                                                                              


         Owing to an excess of mortality from colon cancer observed in
    early investigations in exposed workers, several historical cohort
    studies have been conducted to examine the mortality rate from cancer
    of the colon or rectum among male workers employed at two plastics
    manufacturing plants in Bristol, Pennsylvania, and Knoxville,
    Tennessee (DeFonso & Maher, 1981, 1986; Maher & DeFonso, 1987a,b;
    Walker et al., 1991).  An additional cohort study of workers at a
    small number of polymethyl methacrylate sheet production factories in
    the United Kingdom has also been identified (Tomenson & Bonner, 1994;
    Cary et al., 1995); however, documentation available at this time is
    inadequate for evaluation.  In the most recent and extensive follow-up
    by Walker et al. (1991) in the above-mentioned plastics manufacturing
    plants, data were reanalysed as a function of the period of employment
    of the workers.  In this investigation, the two cohorts were composed
    of 10 482 men who had worked during the period 1933-1982 in the
    Bristol plant and 3381 men hired between 1943 and 1982 in the
    Knoxville plant.  The population of workers at the Bristol plant was
    further divided into an early cohort (men employed at some time
    between 1933 and 1945, inclusive) and late cohort (1946-1982,
    inclusive).  The early cohort worked in conditions that are thought to
    have involved high exposures to the vapour phase of ethyl acrylate and
    methyl methacrylate monomer, as well as to a variety of volatile
    by-products of the ethyl acrylate/methyl methacrylate polymerization
    process.

         In the two cohorts with later dates of first hire (Knoxville and
    late Bristol), there was no excess mortality due to cancer of the
    colon or rectum.  In the early (Bristol) cohort, there was an apparent
    excess of deaths due to colon cancer (38 cases observed overall in
    those persons who accumulated a dose of >0 units, compared with an
    expected number of 25.4).  Although the highest risk was in the
    subgroup of workers with the highest cumulative exposure, there was no
    trend of increasing risk with increasing exposure after allowing for a
    long latency period.  There was no systematic pattern of excess risk
    of cancer at any other site.  For respiratory cancer, however, there

    was a significantly high standardized mortality ratio (of 1.44) in the
    Knoxville cohort, with no excess in either of the Bristol cohorts.
    Owing to the large number of statistical estimates in this study and
    the absence of a clear dose-response trend, the association of methyl
    methacrylate with respiratory cancer is unclear.  The apparent excess
    may have been due to statistical fluctuation or to confounding by
    other occupational exposures in the environment at the time.

         Collins et al. (1989) reported a limited study of a much smaller
    cohort of workers exposed for considerably shorter periods to methyl
    methacrylate at two plants that either manufactured methyl
    methacrylate or used methyl methacrylate in other product manufacture
    between 1951 and 1983.  There was no excess mortality for any type of
    cancer examined (Collins et al., 1989).  There was a very weak
    indication of an excess of rectal cancer (two cases in exposed workers
    with the expected number much less than 1.0) and weak to moderate
    indication of an excess risk of lung cancer (odds ratios of 4-5) in a
    population-based study of a small number of workers exposed to methyl
    methacrylate in Montreal, Canada (Siemiatycki, 1991).

         Identified studies on the potential genotoxicity of methyl
    methacrylate in occupationally exposed populations contribute limited
    information.  There was no increase in the number of sister chromatid
    exchanges in the peripheral lymphocytes of 31 male workers
    occupationally exposed to methyl methacrylate (mean value per 8 hours
    ranged from 0.70 to 21.6 ppm [2.9-88.6 mg/m3]) in four factories
    compared with that of 31 unexposed male workers of similar mean age
    and smoking habits (Marez et al., 1991).  The distribution frequency
    of sister chromatid exchange, however, was significantly higher in the
    group exposed to methyl methacrylate at peak concentrations ranging
    from 114 to 400 ppm (467-1640 mg/m3), although the number of
    individuals in this exposure subgroup was small  (n = 6).  Similarly,
    no increase in the frequency of chromosomal aberrations was observed
    in the peripheral lymphocytes of 38 male workers who were engaged in
    organic glass production (polymethyl methacrylate plates) and exposed
    to 8-hour, time-weighted-average concentrations of methyl methacrylate
    of 0.9-71.9 ppm (3.7-295 mg/m3) (Seiji et al., 1994).  The frequency
    of sister chromatid exchange was higher in the exposed group than in
    controls; however, this was considered to be due to a higher age
    distribution in the exposed workers.

    10.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    10.1  Aquatic environment

         Bailey et al. (1985) studied the toxicity of methyl methacrylate
    in juvenile bluegill sunfish at 22°C under static and flow-through
    conditions of various durations (1-96 hours).  The 96-hour LC50 under
    flow-through conditions was 191 mg/litre, whereas LC50 values for
    durations of 1-24 hours ranged from 420 to 356 mg/litre, respectively.
    The 96-hour LC50 for rainbow trout under flow-through conditions was
    >79 mg/litre, the highest concentration tested.
    Sublethal/behavioural responses were noted among the fish in the 40
    and 79 mg/litre concentration groups (Bowman, 1990).

         The 24-hour EC50 for immobilization of  Daphnia magna was 720
    mg/litre, with extrapolated EC0 and EC100 values of 502 and 1042
    mg/litre, respectively (Bringmann & Kuhn, 1982).  The 24-hour LC50
    was 1760 mg/litre, with extrapolated values for the LC0 and LC100 of
    875 and 2500 mg/litre, respectively (Bringmann & Kuhn, 1977).  The
    threshold for onset of inhibition of cell multiplication was 447
    mg/litre for the flagellate protozoan  Entosiphon sulcatum after 72
    hours of exposure (Bringmann, 1978).  These studies were done in
    static, open systems, with only nominal concentrations reported.

         Thresholds for onset of inhibition of cell multiplication
    following 8 days of exposure to methyl methacrylate were 120 mg/litre
    for the blue-green alga  Microcystis aeruginosa and 37 mg/litre for
    the green alga  Scenedesmus quadricauda at pH 7 (Bringmann & Kuhn,
    1976, 1978a,b).  The 96-hour LC50 for  Selenastrum capricornutum was
    170 mg/litre, with a NOEL of 100 mg/litre (Forbis, 1990).  No studies
    were identified on the effects of methyl methacrylate on higher
    aquatic plants.

    10.2  Terrestrial environment

         Data on the toxicity of methyl methacrylate to terrestrial
    animals are limited to a single study on soil microflora in which no
    effects of biological significance were observed (Hossack & Thomas,
    1992).

    11.  EFFECTS EVALUATION

    11.1  Evaluation of health effects

    11.1.1  Hazard identification and dose-response assessment

         Data on effects of methyl methacrylate in humans are informative
    primarily with respect to irritation and sensitization (for exposure
    both dermally and by inhalation) and carcinogenicity.  Although there
    are some quantitative data on exposure to methyl methacrylate in
    available cross-sectional investigations of other end-points (NIOSH,
    1976; Jedrychowski, 1982; Marez et al., 1993), they are considered
    inadequate as the principal basis for hazard identification and
    dose-response assessment owing to limitations of design and the
    potential role of confounding factors.  Data on hazard identification
    and dose-response assessment for effects other than
    irritation/sensitization and carcinogenicity are derived primarily,
    therefore, from investigations in experimental animals.

         The acute toxicity of methyl methacrylate is low.  Irritation of
    the skin, eye, and nasal cavity has been observed in rodents and
    rabbits exposed to relatively high concentrations of methyl
    methacrylate.  This substance is a mild skin sensitizer in animals.
    Methyl methacrylate is a mild skin irritant in humans and has the
    potential to induce skin sensitization in susceptible individuals.
    Although occupational asthma associated with methyl methacrylate has
    also been reported, there is no conclusive evidence that methyl
    methacrylate is a respiratory sensitizer.

         The effect observed most frequently at lowest concentration after
    repeated inhalation exposure of experimental animals to methyl
    methacrylate is irritation of the nasal cavity.  Effects on the kidney
    and liver at higher concentrations have also been reported.

         Limited available data indicate that methyl methacrylate is
    unlikely to induce fetotoxic effects in the absence of maternal
    toxicity.  There has been no evidence of reproductive toxicity, based
    on limited available data (a dominant lethal assay in mice and
    examination of the gonads in repeated-dose toxicity studies).  Based
    on limited available data, neurological effects have been observed
    following ingestion of doses greater than those that induce minimal
    renal effects.

         As a whole, the available epidemiological studies do not provide
    strong or consistent evidence of a carcinogenic effect of methyl
    methacrylate on any target organ in humans, nor can it be inferred
    with any degree of confidence that the possibility of an excess risk
    has been disproved.  Methyl methacrylate has not been carcinogenic in
    an extensive, well documented 2-year bioassay in rats and mice exposed
    by inhalation and in additional chronic inhalation studies in rats and
    hamsters.  Although not mutagenic  in vitro in bacterial systems,
    methyl methacrylate has been mutagenic and clastogenic in mammalian

    cells  in vitro. In  in vivo studies (primarily by the inhalation
    route) in which there has been clear evidence of toxicity within the
    target tissue, there has been limited evidence of genotoxicity of
    methyl methacrylate.  On the basis of these observations, methyl
    methacrylate is considered unclassifiable with respect to
    carcinogenicity in humans.

           Owing to the limitations of the available studies in humans on
    effects associated with longer-term exposure to methyl methacrylate,
    it is necessary to rely primarily on information obtained from the
    studies in animals for determination of critical effect levels.  The
    lowest reported effect level for inhalation was 100 ppm (410 mg/m3)
    in rats exposed to methyl methacrylate for 2 years (based upon
    inflammatory degeneration of the nasal epithelium); the NOEL in this
    investigation was 25 ppm (102.5 mg/m3) (Rohm & Haas, 1979a; Lomax,
    1992; Lomax et al., 1997).

    11.1.2   Criteria for setting guidance values for methyl methacrylate

         The following quantitative guidance is provided as an example of
    a possible basis for derivation of limits of exposure and judgement of
    the quality of environmental media by relevant authorities.  As methyl
    methacrylate is considered to be "unclassifiable with respect to
    carcinogenicity in humans," guidance values are derived on the basis
    of a lowest-observed-(adverse)-effect level [LO(A)EL] or a
    no-observed-(adverse)-effect level [NO(A)EL] for non-neoplastic
    effects. For methyl methacrylate, the route of exposure most relevant
    to the general population is likely inhalation.

         The value considered most appropriate as a basis for development
    of a tolerable concentration in air is the NOEL of 25 ppm (102.5
    mg/m3) in rats exposed to methyl methacrylate for 2 years (Rohm &
    Haas, 1979a; Lomax, 1992; Lomax et al., 1997).  Effects at the next
    higher concentration were degenerative changes in the olfactory
    epithelium.

         There is some debate currently about extrapolation of data on
    nasal irritation of the olfactory epithelium observed in rodents in
    risk assessment for humans.  There are significant morphological
    differences between species in the structure of the nasal cavity,
    which result in differences in concentrations of inhaled materials at
    the nasal tissue.  These are reflected in differences in surface area
    normalized to minute ventilation, being fivefold greater in rodents
    than in humans (DeSesso, 1993).  A much greater percentage of the
    nasal cavity is lined by olfactory epithelium in rats than in humans.
    In addition, rodents are obligate nose breathers, whereas humans can
    also breathe through their mouths, which is expected to reduce
    exposure of the nasal epithelium for much of the population.  There
    are also differing nasal flow patterns, with the greater airflow
    across the human olfactory epithelium during the expiratory phase when
    the vapour concentration would be considerably reduced as a result of
    absorption in the lower respiratory tract.

         The pattern of the critical effects of inhalation of methyl
    methacrylate in animal studies (i.e. the olfactory epithelium being
    affected at lowest concentration) is consistent with toxicity
    resulting from metabolism of the inhaled material in the olfactory
    tissue by carboxylic esterases to methacrylic acid.  Data on species
    differences in olfactory tissue carboxylesterase activity have not
    been identified; however, based on limited data from human tissue
    samples that may not have been morphologically normal taken at polyp
    biopsy, the activity of alpha-naphthylbutyrate carboxylesterase in
    human nasal respiratory tissue is less than that in the rat (Mattes &
    Mattes, 1992).

         Although it is possible that humans may be less sensitive than
    rodents to lesions of the nasal epithelium caused by methyl
    methacrylate, currently available data are inadequate to account
    quantitatively for potential interspecies variation in sensitivity.
    However, studies that are currently under way may shed some additional
    light on this aspect (T. Green, personal communication, 1997; P.J.
    Pinto, personal communication, 1997).  Therefore, on the basis of the
    available data, a tolerable concentration (TC) has been derived on the
    basis of a commonly adopted default value of 10-fold for interspecies
    variation as follows:

    TC   = (102.5 mg/m3/100) × (6/24) × (5/7)
         = 0.2 mg/m3 (rounded to one significant figure)

    where:

    *    102.5 mg/m3 (25 ppm) is the lowest NOEL reported in inhalation
         bioassays of adequate quality in animal species (rats) conducted
         to date (exposure-related and concentration-dependent microscopic
         changes [degeneration/atrophy of the olfactory epithelium and
         underlying Bowman's glands, hyperplasia of basal (reserve) cells,
         replacement of olfactory epithelium by ciliated
         (respiratory-like) epithelium, and inflammation of the mucosa
         and/or submucosa] were observed in anterior portions of the nasal
         cavity in rats exposed to the next higher concentration) (Rohm &
         Haas, 1979a; Lomax, 1992; Lomax et al., 1997);

    *    6/24 and 5/7 are the conversion of intermittent exposure of rats
         (i.e. 6 hours/day, 5 days/week) to continuous exposure of humans;
         this is appropriate in view of data that suggest that continuous
         exposure to methyl methacrylate could result in effects at
         concentrations below the NOAEL for intermittent exposure (Lomax
         et al., 1994); no scaling factor for inhalation volume to body
         weight was used, as effects at the next higher dose level are
         limited to the site of entry; and

    *    100 is the uncertainty factor (×10 for intraspecies variation;
         ×10 for interspecies variation).

         Based on the results of limited available cross-sectional studies
    on respiratory effects in human populations, this value is likely to
    be protective.

         A TDI can be derived for the oral route of exposure based on a
    2-year drinking-water study in rats in which the NOAEL in females was
    considered to be 146 mg/kg body weight per day; the NOEL in males was
    121 mg/kg body weight per day, the highest dose level tested
    (Borzelleca et al., 1964).  Incorporating an uncertainty factor of 100
    (×10 for intraspecies variation; ×10 for interspecies variation), the
    TDI would be 1.2 mg/kg body weight per day.

    11.1.3  Sample risk characterization

         The extremely limited nature of the available data as a basis for
    estimation of exposure should be borne in mind in interpreting the
    comparisons presented here for predicted indirect population exposure
    in the general environment and estimated exposure from the use of
    consumer products containing methyl methacrylate.  Moreover, the
    sample exposure estimates presented in section 6.2 will vary
    considerably as a function of production and use patterns and control
    measures in various countries.

         Based upon the sample predicted concentration (based on fugacity
    modelling) of methyl methacrylate in air of 2.44 × 10-4 µg/m3,
    presented in section 6.1, levels of methyl methacrylate in ambient air
    are many orders of magnitude less than the calculated tolerable
    concentration of 200 µg/m3.  Estimated intakes associated with
    inhalation exposure (predicted by computer modelling) during the use
    of consumer products containing methyl methacrylate, such as
    dispersion paints (estimated to be in the 10-100 µg/kg body weight per
    day range) and oil-based paints (predicted exposure in the 100-1000
    µg/kg body weight per day range) (see section 6.2), may be up to an
    order of magnitude higher than the tolerable intake associated with
    exposure at the level of the tolerable concentration.  Although it has
    been reported that in some countries these products are not supplied
    to the general public, information on use patterns of these products
    in other countries was not available.

         With respect to occupational exposure, mean levels of methyl
    methacrylate in the air of production and manufacturing facilities and
    dental facilities range up to several hundred mg/m3, whereas levels
    in beauty salons are generally less than 100 mg/m3 (IARC, 1994).
    Elevated levels (greater than 1500 mg/m3) during floor coating with
    methyl methacrylate-containing resins have been reported, although
    time-weighted-average concentrations would be less.

    11.2  Evaluation of environmental effects

         Because of its release principally in emissions from industrial
    sources and its relatively high volatility, the atmosphere is the
    predominant environmental sink for methyl methacrylate.  It is highly
    reactive with hydroxyl radicals; thus, its lifetime in the atmosphere

    is short.  Substances whose atmospheric half-lives do not exceed 1
    year are not considered to contribute to global warming; therefore,
    methyl methacrylate is not considered to be a greenhouse gas, nor
    would it contribute directly to depletion of the ozone layer.  Methyl
    methacrylate is not expected to bioconcentrate in the environment.

         Terrestrial organisms will have the greatest potential for
    exposure to methyl methacrylate in ambient air.  However, as no field
    or laboratory studies on birds, terrestrial invertebrates, or
    terrestrial plants were identified, the toxicity of methyl
    methacrylate to these organisms could not be assessed.  Chronic
    studies on laboratory mammals are available, however, as well as data
    on levels of exposure of aquatic-based mammals to methyl methacrylate,
    thus permitting the comparison between effects and environmental
    exposure for these organisms.  The mink was chosen as the model
    species, with aquatic organisms comprising up to 100% of its diet.
    Based on the concentrations of methyl methacrylate in air, water, and
    fish predicted by fugacity modelling and assuming daily consumption
    rates for mink of 0.55 m3 of air, 0.1 litre of water, and 158 g of
    fish, the estimated total daily intake of methyl methacrylate by mink
    in southern Ontario, Canada, is 0.17 ng/kg body weight per day, with
    approximately 80% of the exposure being attributable to inhalation
    (Government of Canada, 1993).  The lowest NOEL observed in chronic
    inhalation studies in laboratory animals is 102.5 mg/m3, based on
    exposure-related and concentration-dependent microscopic changes in
    anterior portions of the nasal cavity (degeneration/atrophy of the
    olfactory epithelium and underlying Bowman's glands, hyperplasia of
    basal cells, replacement of olfactory epithelium by respiratory
    epithelium, and inflammation of the mucosa and/or submucosa) (Rohm &
    Haas, 1979a; Lomax, 1992; Lomax et al., 1997).  Using a factor of 10
    to account for interspecies variability in sensitivity, the NOEL is
    108 times higher than levels predicted to occur in the environment in
    Canada (i.e. 0.24 ng/m3).

         No chronic studies on aquatic organisms were identified; however,
    acute tests have been conducted on fish,  Daphnia magna, and algae.
    The most sensitive effect was the onset of inhibition of cell
    multiplication by the green alga  Scenedesmus quadricauda at 37
    mg/litre following 8 days of exposure.  This is similar to the
    concentration (i.e. 40 mg/litre) at which sublethal/ behavioural
    responses were noted in rainbow trout following 96 hours of exposure.
    Using a factor of 20 to convert from an acute to a chronic end-point
    and another factor of 10 to account for interspecies variability in
    sensitivity, the estimated effects threshold is approximately
    106-fold higher than the concentration predicted to occur in surface
    water in Canada (i.e. 0.13 ng/litre).

         Therefore, although available data on the environmental effects
    of methyl methacrylate are limited and predicted concentrations in
    various media are highly uncertain, a wide margin exists between
    observed effect levels and uncertain predicted environmental

    concentrations of methyl methacrylate.  As such, the concentrations of
    methyl methacrylate predicted to be in the environment are unlikely to
    pose a risk to aquatic or terrestrial organisms.

    12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         The International Agency for Research on Cancer (IARC, 1994) has
    classified methyl methacrylate in Group 3 (not classifiable as to its
    carcinogenicity to humans) based on inadequate evidence for
    carcinogenicity in humans and evidence suggesting a lack of
    carcinogenicity in experimental animals.

         Information on international hazard classification and labelling
    is included in the International Chemical Safety Card reproduced in
    this document.

    13.  HUMAN HEALTH PROTECTION AND EMERGENCY ACTION

         Human health hazards together with preventative and protective
    measures and first aid recommendations are presented in the
    International Chemical Safety Card (ICSC 0300) reproduced in this
    document.

    13.1  Human health hazards

         Methyl methacrylate is highly flammable.  After long-term or
    repeated exposure, it may cause skin sensitization and asthma and may
    have effects on the nervous system.

    13.2   Advice to physicians

         In the event of poisoning, the treatment is supportive.  Owing to
    reports of systemic vasodilation and transient hypotension in patients
    following use of methyl methacrylate as a bone cement in total hip
    replacement procedures, monitoring for hypotension and respiratory
    depression is recommended.  Because a stabilizer or inhibitor is
    always a part of the formulation, toxicological properties may be
    different.

    13.3  Health surveillance advice

         Periodic medical examination of the area of the skin exposed to
    methyl methacrylate, tests to determine any disturbances of the
    nervous system, and surveillance of the respiratory system should be
    included in the health surveillance programme.

    13.4  Explosion and fire hazards

    13.4.1  Explosion hazards

         Methyl methacrylate is explosive in the form of vapour when
    exposed to heat, sparks, or flame.  Vapours may travel to a source of
    ignition and flash back.  Methyl methacrylate may undergo spontaneous,
    explosive polymerization.  It reacts in air to form a heat-sensitive
    explosive product.  Containers of methyl methacrylate may explode in
    the heat of a fire.  Runoff to sewers may create a fire or explosion
    hazard.

    13.4.2  Fire hazards

         Methyl methacrylate is highly flammable material.  When heated to
    decomposition, methyl methacrylate emits acrid smoke and irritating
    fumes.

    13.4.3  Fire-extinguishing agents

         Water may not be effective, except to absorb heat, keep
    containers cool, and protect exposed materials.

    13.5  Storage

         Store in a cool, dry, well ventilated area, out of direct
    sunlight.  Store away from heat and ignition sources and incompatible
    materials, such as flammable/combustible materials, materials that
    support combustion (oxidizing materials), and corrosive materials
    (strong acids or bases).  If storing small quantities under
    refrigeration, use an approved, explosion-proof refrigerator.  Methyl
    methacrylate monomer should not be stored for longer than 1 year.

    13.6  Transport

         Methyl methacrylate cannot be carried on passenger or cargo
    aircraft.

    13.7  Spillage

          Methyl methacrylate is highly flammable.  In the event of
    spillage, eliminate all sources of ignition in the vicinity.  Because
    the chemical is absorbed through the skin, do not touch or walk
    through the spilled material without proper equipment.  To avoid the
    flammability hazard, remove clothing immediately if wet or
    contaminated, and use non-sparking tools to clean up.  Do not let the
    chemical enter drains or watercourses.

    14.  CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

         Information on national regulations, guidelines, and standards is
    available from the International Register of Potentially Toxic
    Chemicals (IRPTC) legal file.

         The reader should be aware that regulatory decisions about
    chemicals taken in a certain country can be fully understood only in
    the framework of the legislation of that country.  The regulations and
    guidelines of all countries are subject to change and should always be
    verified with appropriate regulatory authorities before application.



        INTERNATIONAL CHEMICAL SAFETY CARD
    METHYL METHACRYLATE MONOMER, INHIBITED                                                                           ICSC:0300

                                                    METHYL METHACRYLATE MONOMER, INHIBITED
                                                         Methacrylic acid methyl ester
                                                           Methyl 2-methylpropenoate
                                                                CH2C(CH3)COOCH3
                                                             Molecular mass: 100.1
    CAS #       80-62-6
    RTECS #     0Z5075000
    ICSC #      0300
    UN #        1247
    EC #        607-035-00-6

                                                                                                                                        

    TYPES OF                   ACUTE HAZARDS/                  PREVENTION                      FIRST AID/
    HAZARD/                    SYMPTOMS                                                        FIRE FIGHTING
    EXPOSURE
                                                                                                                                        

    FIRE                       Highly flammable.               No open flames, NO sparks,      Foam, powder, carbon dioxide.
                                                               and NO smoking.

    EXPLOSION                  Vapour/air mixtures are         Closed system, ventilation,     In case of fire: keep drums,
                               explosive.                      explosion-proof electrical      etc., cool by spraying with
                                                               equipment and lighting. Do      water.
                                                               NOT use compressed air for
                                                               filling, discharging, or
                                                               handling.

    EXPOSURE                                                   PREVENT GENERATION OF MISTS!

    * INHALATION               Cough. Drowsiness. Headache.    Ventilation, local exhaust,     Fresh air, rest. Refer for
                               Shortness of breath. Sore       or breathing protection.        medical attention.
                               throat. Unconsciousness.

                                                                                                                                        

    INTERNATIONAL CHEMICAL SAFETY CARD (continued)

                                                                                                                                        

    TYPES OF                   ACUTE HAZARDS/                  PREVENTION                      FIRST AID/
    HAZARD/                    SYMPTOMS                                                        FIRE FIGHTING
    EXPOSURE
                                                                                                                                        

    * SKIN                     Redness.                        Protective gloves. Protective   Remove contaminated clothes.
                                                               clothing.                       Rinse and then wash skin with
                                                                                               water and soap.

    * EYES                     Redness. Pain.                  Safety goggles or eye           First rinse with plenty of
                                                               protection in combination       water for several minutes
                                                               with breathing protection.      (remove contact lenses if
                                                                                               easily possible), then take
                                                                                               to a doctor.

    * INGESTION                Nausea. Vomiting.               Do not eat, drink, or smoke     Rinse mouth. Refer for
                                                               during work.                    medical attention.

                                                                                                                                        

    SPILLAGE DISPOSAL                             STORAGE                                   PACKAGING & LABELLING
                                                                                                                                        

    Collect leaking and spilled liquid in         Fireproof. Separated from strong          F symbol
    sealable containers as far as                 oxidants, strong bases, strong acids.     Xi symbol
    possible. Absorb remaining liquid in          Cool. Keep in the dark. Keep in a
    sand or inert absorbent and remove to         well-ventilated room. Store only if       R: 11-36/37/38-43
    safe place. Do NOT wash away into             stabilized.                               S: (2-)9-16-29-33
    sewer.
                                                                                            Note: D

                                                                                            UN Hazard Class: 3
                                                                                            UN Packing Group: II

                                                                                                                                        

    INTERNATIONAL CHEMICAL SAFETY CARD (continued)

                                                                                                                                        

    IMPORTANT DATA      PHYSICAL STATE; APPEARANCE:                          EFFECTS OF SHORT-TERM EXPOSURE:
                        COLOURLESS LIQUID, WITH CHARACTERISTIC ODOUR.        A harmful contamination of the air can be
                                                                             reached rather quickly on evaporation of this
                                                                             substance at 20°C.

                        PHYSICAL DANGERS:                                    EFFECTS OF SHORT-TERM EXPOSURE:
                        The vapour is heavier than air and may travel        The substance irritates the eyes, the skin and
                        along the ground; distant ignition possible.         the respiratory tract.
                        The vapour mixes well with air, explosive
                        mixtures are easily formed. Vapours are not
                        inhibited, they may polymerize and block the
                        vents.

                        CHEMICAL DANGERS:                                    EFFECTS OF LONG-TERM OR REPEATED EXPOSURE:
                        The substance may polymerize due to warming or       Repeated or prolonged contact may cause skin
                        due to heating under the influence of light,         sensitization. Repeated or prolonged
                        polymerization catalysts and strong oxidants         inhalation exposure may cause asthma. The
                        with fire or explosion hazard. Reacts with           substance may have effects on the central
                        strong acids, strong bases and oxidants.             nervous system and the peripheral nervous
                                                                             system.

                        OCCUPATIONAL EXPOSURE LIMITS (OELs):
                        TLV: 100 ppm; 410 mg/m3 (as TWA)
                             (ACGIH 1994-1995).
                        MAK: 50 ppm; 210 mg/m3; I, A II (1993).

                        ROUTES OF EXPOSURE:
                        The substance can be absorbed into the body by
                        inhalation of its vapour, through the skin and
                        by ingestion.

                                                                                                                                        

    INTERNATIONAL CHEMICAL SAFETY CARD (continued)

                                                                                                                                        

    PHYSICAL            Boiling point:                         100-101°C     Relative density of the vapour/
    PROPERTIES          Melting                               -48°C          air-mixture at 20°C (air = 1):           1.1
                        Relative density (water = 1):          0.94          Flash point:                             10°C o.c.
                        Solubility in water, g/100 ml                        Auto-ignition temperature:               421°C
                        at 20°C                                1.6           Explosive limits, vol% in air:           1.7-12.5
                        Vapour pressure, kPa at 20°C:          3.9           Octanol/water partition coefficient
                        Relative vapour density (air = 1):     4.16          as log Pow:                              1.38
                        Vapour pressure, kPa at 20°C:          0.647
                        Vapour pressure, Pa at 25°C:           780
                                                                                                                                        

    ENVIRONMENTAL       This substance may be hazardous to the environment; special attention should be given to water.
    DATA

                                                                                                                                        

    NOTES
    Usually contains hydroquinone, hydroquinone methyl ether and dimethyl t-butylphenol as inhibitors of polymerization. An added
    stabilizer or inhibitor can influence the toxicological properties of this substance, consult an expert.

    ICSC: 0300 1.1                                                                                 Transport Emergency Card: TEC (R)-196
                                                                                                                   NFPA Code: H2; F3; R2
                                                                                                                                        


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    Raje RR, Ahmad S, Weisbroth SH (1985) Methyl methacrylate: tissue
    distribution and pulmonary damage in rats following acute inhalation.
     Research communications in chemical pathology and pharmacology, 
    50:151-154.

    Röhm (1994)  Medical examination of workers in acrylic sheet 
     production exposed to methyl methacrylate. Pausch, Höffer, Claus,
    Lehr, Jacobi, 15.03.1994. Darmstadt, Röhm [cited in ECETOC, 1995].

    Rohm and Haas (1977)  Subchronic vapor inhalation study with methyl 
     methacrylate (C50680) in F344 rats and B6C3F1 mice. Report to
    Tracor Jitco, Inc., submitted by IBT Laboratories Inc.

    Rohm and Haas (1979a)  A two-year vapor inhalation safety evaluation 
     study in rats. Methyl methacrylate. Final report. Submitted by
    Hazleton Laboratories America Inc., 217 pp.

    Rohm and Haas (1979b)  18-month vapor inhalation safety evaluation 
     study in hamsters. Methyl methacrylate vapor. Final report. 
    Submitted by Hazleton Laboratories America Inc., 85 pp. (Project No.
    417-354).

    Rohm and Haas (1982)  Acute oral LD50 range finding rat, acute 
     dermal LD50 range finding rabbit, acute skin irritation range 
     finding rabbit 4-hr contact, acute eye irritation range finding 
     rabbit. Test substance methyl methacrylate - 10 ppm Topanol A [cited
    in ECETOC, 1995].

    Schwartz BS, Doty RL, Monroe C, Frye R, Baker S (1989) Olfactory
    function in chemical workers exposed to acrylate and methacrylate
    vapours.  American journal of public health, 79:613-618.

    Schweikl H, Schmalz G, Bey B (1994) Mutagenicity of dentin bonding
    agents.  Journal of biomedical materials research, 28:1061-1067.

    Seiji K, Inoue O, Kawai T, Mizunuma K, Yasugi T, Moon C, Takeda S,
    Ikeda M (1994) Absence of mutagenicity in peripheral lymphocytes of
    workers occupationally exposed to methyl methacrylate.  Industrial 
     health, 32:97-105.

    Seppalainen AM, Rajaniemi TC (1984) Local neurotoxicity of methyl
    methacrylate among dental technicians.  American journal of 
     industrial medicine, 5:471-478.

    Siemiatycki J (1991)  Risk factors for cancer in the workplace. Boca
    Raton, FL, CRC Press, 310 pp.

    Smith JM, Cruzan G, Drees JA, Tansy MF, Coate WB, Reno FE (1979)
    Methyl methacrylate: subchronic, chronic and oncogenic inhalation
    safety evaluation studies.  Toxicology and applied pharmacology, 
    48:A30.

    Solomon HM, McLaughlin JE, Swenson RE, Hagan JV, Wanner FJ, O'Hara GP,
    Krivanek ND (1993) Methyl methacrylate: inhalation developmental
    toxicity study in rats.  Teratology, 48:115-125.

    Spealman CR, Main RJ, Haag HB, Larson PS (1945) Monomeric methyl
    methacrylate - Studies on toxicity.  Industrial medicine, 14:292-298.

    Tansy MF (1975)  Progress report on teratology studies of mice 
     exposed to methyl methacrylate monomer vapour. Submitted to Rohm and
    Haas Company, 5 pp.

    Tansy MF, Drees JA (1979)  Methyl methacrylate, three month 
     subchronic vapour inhalation safety evaluation study, beagle dogs. 
    Prepared for Rohm and Haas Company, 239 pp.

    Tansy MF, Kendall FM, Benhayem S, Hohenleitner FJ, Landin WE, Gold M
    (1976) Chronic biological effects of methyl methacrylate vapor. 1.
    Body and tissue weights, blood chemistries, and intestinal transit in
    the rat.  Environmental research, 11:66-77.

    Tansy MF, Hohenleitner FJ, Landin WE, Kendall FM (1980a) Chronic
    biological effects of methyl methacrylate vapor. II. Body and tissue
    weights, blood chemistries and gross metabolic performance in the rat.
     Environmental research, 21:108-116.

    Tansy M, Hohenleitner F, White D, Oberly R, Landin W, Kendall F
    (1980b) Chronic biological effects of methyl methacrylate vapour. III.
    Histopathology, blood chemistries and hepatic and ciliary function in
    the rat.  Environmental research, 21:117-125.

    Tomenson JA, Bonner SM (1994)  A cohort study of employees in 
     Perspex plants. Northwich, Cheshire, ICI Epidemiology Unit, 15
    December.

    Waegemaekers THJM, Bensink MPM (1984) Nonmutagenicity of 27 aliphatic
    acrylate esters in the  Salmonella microsome test.  Mutation 
     research, 137:95-102.

    Walker AM, Cohen AJ, Loughlin JE, Rothman KJ, DeFonso LR (1991)
    Mortality from cancer of the colon or rectum among workers exposed to
    ethyl acrylate and methyl methacrylate.  Scandinavian journal of 
     work, environment & health, 17:7-19.

    Wynkoop JR, Miller RA, Cheong V, Lorton L (1982) Levels of neuroactive
    substances following exposure to methyl methacrylate monomer.
     Journal of dental research, 61:202 (abstract no. 213).

    Zafiropoulos GG, Apostolopoulos AX, Patramani I (1985) Study of the
    antigenic properties of methyl methacrylate using the
    leukocyte-migration inhibition test.  Dental materials, 1:200-204.

    Zeiger E, Anderson B, Haworth S, Lawlor T, Mortelmans K, Speck W
    (1987)  Salmonella mutagenicity tests: III. Results from the testing
    of 255 chemicals.  Environmental mutagenesis, 9 (Suppl. 9):1-110
    [cited in IARC, 1994].

    APPENDIX 1 - SOURCE DOCUMENTS

    Government of Canada (1993)

         Copies of the  Canadian Environmental Protection Act Priority
    Substances List Assessment Report (Government of Canada, 1993) and
    unpublished Supporting Documentation for methyl methacrylate may be
    obtained from the:

         Commercial Chemicals Branch
         Environment Canada
         14th Floor, Place Vincent Massey
         351 St. Joseph Blvd.
         Hull, Quebec
         Canada  K1A 0H3

         Environmental Health Centre
         Health Canada
         Address Locator: 0801A
         Tunney's Pasture
         Ottawa, Ontario
         Canada  K1A 0L2

         Initial drafts of the Assessment Report and unpublished
    Supporting Documentation for methyl methacrylate were prepared by
    staff of Health Canada and Environment Canada.  The human health-
    related sections of this document were reviewed externally by Dr J.
    Siemiatycki (University of Quebec), Dr N. Krivanek (E.I. duPont de
    Nemours) (Supporting Documentation only), and the Information
    Department of BIBRA Toxicology International.  These sections were
    approved by the Standards and Guidelines Rulings Committee of the
    Bureau of Chemical Hazards of Health Canada.  The environmental
    sections were reviewed externally by Dr N. Bunce (University of
    Waterloo) and Dr N. Krivanek (E.I. duPont de Nemours).

    IARC (1994)

         Copies of  Some industrial chemicals (IARC Monographs on the
    Evaluation of Carcinogenic Risks to Humans, Vol. 60) (IARC, 1994) may
    be obtained from the:

         International Agency for Research on Cancer
         150 cours Albert Thomas
         69372 Lyon  Cedex 08
         France

         The members of the Working Group on the Evaluation of
    Carcinogenic Risks to Humans of Some Industrial Chemicals (including
    methyl methacrylate), which met in Lyon on 15-22 February 1994, were:

         P.A. Bertazzi, Institute of Occupational Health, Clinica del
         Lavoro "Luigi Devoto," University of Milan, via S. Barnaba 8,
         20122 Milan, Italy

         C.J. Calleman, School of Public Health and Community Medicine,
         Department of Environmental Health, SC-34, University of
         Washington, Seattle, WA 98195, USA

         D. Coggon, MRC Environmental Epidemiology Unit, Southampton
         General Hospital, Southampton, SO9 4XY, United Kingdom

         T.A. Dragani, Division of Experimental Oncology A, National
         Institute for the Study and Treatment of Tumours, via Venezian 1,
         20133 Milan, Italy

         M.R. Elwell, Toxicology Research and Testing Program, National
         Institute of Environmental Health Sciences, PO Box 12233,
         Research Triangle Park, NC 27709, USA

         H.J. Evans, MRC Human Genetic Unit, Western General Hospital,
         Crewe Road, Edinburgh EH4 2XU, United Kingdom  (Chairperson)

         J.G. Filser, GSF Institute of Toxicology, Neuherberg, PO Box
         1129, 85758 Oberschleissheim, Germany

         M. Gérin, University of Montréal, Department of Occupational and
         Environmental Health, Faculty of Medicine, CP 6128, Station A,
         Montréal, Québec, Canada  H3C 3J7

         K. Hemminki, Centre for Nutrition and Toxicology, Karolinska
         Institute, Novum, 141 57 Huddinge, Sweden

         C. Hogstedt, National Institute of Occupational Health, 171 84
         Solna, Sweden

         M. Kirsch-Volders, Laboratorium Antropogenetica, Free University
         of Brussels, Pleinlaan 2, 1050 Brussels, Belgium

         W. Lutz, Institute of Toxicology, Swiss Federal Institute of
         Technology, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland

         S.S. Olin, International Life Sciences Institute, Risk Science
         Institute, 1126 Sixteenth Street NW, Washington, DC 20036, USA

         A. Pintér, "Johan Béla" National Institute of Hygiene, Gyáli ut.
         2-6, 1966 Budapest, Hungary

         P. Schulte, Screening and Notification Section, National
         Institute for Occupational Safety and Health, Robert A Taft
         Laboratories, 4676 Columbia Parkway, R-42, Cincinnati, OH
         45226-1998, USA

         T. Sofuni, Division of Genetics and Mutagenesis, Biological
         Safety Research Centre, National Institute of Hygienic Sciences,
         1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158, Japan

         M. Sorsa, Institute of Occupational Health, Topeliuksenkatu 41 a
         A, 00250 Helsinki, Finland  (Vice-Chairperson)

         F.M. Sullivan, Division of Pharmacology and Toxicology, UMDS, St.
         Thomas's Hospital, Lambeth Palace Road, London SE17EH, United
         Kingdom

         V.S. Turusov, Cancer Research Centre, Russian Academy of Medical
         Sciences, Kashirskoye Shosse 24, 115478 Moscow, Russia

         M.A. Waters, National Institute for Occupational Safety and
         Health, 4676 Columbia Parkway, R-14, Cincinnati, OH 45226-1998,
         USA

         M.D. Waters, International Programs, MD-51A, Health Effects
         Research Laboratory, US Environmental Protection Agency, Research
         Triangle Park, NC 27711, USA

    APPENDIX 2 - CICAD PEER REVIEW

         The draft CICAD on methyl methacrylate was sent for review to
    institutions and organizations identified by IPCS after contact with
    IPCS national Contact Points and Participating Institutions, as well
    as to identified experts.  Comments were received from:

         Bundesinstitut für Gesundheitlichen Verbraucherschutz und
         Veterinarmedizin, Berlin, Germany

         CEFIC, Brussels, Belgium

         Department of Health, London, United Kingdom

         Department of Public Health, Albert Szent-Gyorgyi University
         Medical School, Szeged, Hungary

         Direccion General de Salud Ambiental, Subsecretario de Regulacion
         y Fomento Sanitario, San Luis Potosi, Mexico

         ECETOC, Brussels, Belgium

         Guy's & St. Thomas' Hospital Trust, Medical Toxicology Unit,
         London, United Kingdom

         International Agency for Research on Cancer, Lyon, France

         Ministry of Health, National Centre of Hygiene, Medical Ecology
         and Nutrition, Sofia, Bulgaria

         Ministry of Health and Welfare, International Affairs Division,
         Government of Japan, Tokyo, Japan

         National Institute for Working Life, Solna, Sweden

         National Institute of Public Health, Oslo, Norway

         Russian Register of Potentially Hazardous Chemical and Biological
         Substances, Moscow, Russia

         United States Department of Health and Human Services  (National
         Institute of Environmental Health Sciences)

         United States Environmental Protection Agency (Office of
         Pollution Prevention and Toxics; National Center for
         Environmental Assessment, Office of Research and Development;
         Office of Drinking Water)

    APPENDIX 3 - CICAD FINAL REVIEW BOARD

    Brussels, Belgium, 18-20 November 1996

    Members

    Dr A. Aitio, Institute of Occupational Health, Helsinki, Finland

    Dr K. Bentley, Director, Environment Policy Section, Commonwealth
    Department of Human Services and Health, Canberra, Australia

    Mr R. Cary, Toxicology and Existing Substances Regulation Unit, Health
    and Safety Executive, Merseyside, United Kingdom

    Dr J. de Fouw, National Institute of Public Health and Environmental
    Protection, Bilthoven, The Netherlands

    Dr C. DeRosa, Director, Division of Toxicology, Agency for Toxic
    Substances and Disease Registry, Atlanta, GA, USA

    Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood, Abbots
    Ripton, Huntingdon, Cambridgeshire, United Kingdom

    Dr W. Farland, Director, National Center for Environmental Assessment,
    Office of Research and Development, US Environmental Protection
    Agency, Washington, DC, USA  (Chairperson)

    Dr T.I. Fortoul, Depto. Biologia Celular y Tisular, National
    University of Mexico and Environmental Health Directorate of the
    Health Ministry, Mexico D.F., Mexico

    Dr H. Gibb, National Center for Environmental Assessment, US
    Environmental Protection Agency, Washington, DC, USA

    Dr R.F. Hertel, Federal Institute for Health Protection of Consumers &
    Veterinary Medicine, Berlin, Germany

    Mr J.R. Hickman, Environmental Health Directorate, Health Canada,
    Ottawa, Ontario, Canada

    Dr T. Lakhanisky, Head, Division of Toxicology, Institute of Hygiene
    and Epidemiology, Brussels, Belgium  (Vice-Chairperson)

    Dr I. Mangelsdorf, Documentation and Assessment of Chemicals,
    Fraunhofer Institute for Toxicology and Aerosol Sciences, Hanover,
    Germany

    Ms E. Meek, Head, Priority Substances Section, Environmental Health
    Directorate, Health Canada, Ottawa, Ontario, Canada

    Dr K. Paksy, National Institute of Occupational Health, Budapest,
    Hungary

    Mr D. Renshaw, Department of Health, London, United Kingdom

    Dr J. Sekizawa, Division of Chemo-Bio Informatics, National Institute
    of Hygienic Sciences, Tokyo, Japan

    Dr H. Sterzl-Eckert, GSF-Forschungszentrum für Umwelt und Gesundheit
    GmbH, Institut für Toxikologie, Oberschleissheim, Germany

    Professor S. Tarkowski, Department of Environmental Health Hazards,
    The Nofer Institute of Occupational Medicine, Lodz, Poland

    Dr M. Wallen, National Chemicals Inspectorate (KEMI), Solna, Sweden

    Observers

    Professor F.M.C. Carpanini,1 Director, Centre for Ecotoxicology and
    Toxicology of Chemicals (ECETOC), Brussels, Belgium

    Mr R. Haigh,1 Head of Unit, Health and Safety Directorate,  European
    Commission, Luxembourg

    Mr B.U. Hildebrandt, Federal Ministry for the Environment, Nature
    Conservation and Nuclear Safety, Bonn, Germany

    Mr P. Hurst,1 Chemical and Consumer Policy Officer, Conservation
    Policy Division, World Wide Fund for Nature, Gland, Switzerland

    Dr A. Lombard (Representative of CEFIC), ELF-ATOCHEM, Paris, France

    Dr P. McCutcheon,1 Environment, Consumer Protection and Nuclear
    Safety, European Commission, Brussels, Belgium

    Dr R. Montaigne, Counsellor, Technical Affairs Department, European
    Chemical Industry Council (CEFIC), Brussels, Belgium

    Dr M. Pemberton, ICI Acrylics, Lancashire, United Kingdom

    Dr A. Smith, Organisation for Economic Co-operation and Development,
    Environment Division, Paris, France


              

    1 Invited but unable to attend.

    Secretariat

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

    Dr L. Harrison, International Programme on Chemical Safety, World
    Health Organization, Geneva, Switzerland

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

    Dr P. Toft, Associate Director, International Programme on Chemical
    Safety, World Health Organization, Geneva, Switzerland

    RÉSUMÉ D'ORIENTATION

         La Direction de l'Hygiène du Milieu de Santé Canada a rédigé ce
    CICAD (document international succinct sur l'évaluation des risques
    chimiques) relatif au méthacrylate de méthyle en s'inspirant
    principalement d'une étude menée par le Gouvernement du Canada (1993)
    pour évaluer les effets potentiels d'une exposition indirecte au
    méthacrylate de méthyle dans l'environnement général et les effets de
    cette substance sur l'environnement, ainsi que d'une étude du Centre
    international de Recherche sur le Cancer (CIRC, 1994), visant
    principalement à déterminer les risques de cancérogénicité.  L'étude
    du Gouvernement du Canada (1993) a pris en compte les données qui
    étaient disponibles en mars 1992; ces données ont été mises à jour
    ultérieurement à la suite d'une recherche bibliographique approfondie
    menée en septembre 1995 dans des bases de données en ligne et dans le
    Registre international des substances chimiques potentiellement
    toxiques.  Des informations concernant la nature de l'évaluation par
    les pairs et la disponibilité des études du Gouvernement du Canada
    (1993) et du CIRC (1994) figurent à l'appendice 1.  Au cours de la
    phase d'évaluation par les pairs du présent CICAD, d'autres travaux
    ont été pris en compte, à savoir des projets d'études du United
    Kingdom Health Safety Executive (Cary et al., 1995) et de l'Union
    européenne (Draft Assessment on Methyl Methacrylate), ainsi que des
    études publiées par l'ECETOC (1995) et le Bureau consultatif
    finlandais des substances chimiques (1992), principalement en vue de
    rechercher des informations supplémentaires pertinentes.  Des
    informations supplémentaires identifiées lors des examens pratiqués
    par les correspondants et par le Comité d'évaluation finale ont
    également été incorporées.  L'appendice 2 contient des informations
    sur le processus d'évaluation par les pairs du présent CICAD.  Ce
    CICAD a été approuvé pour publication à une réunion du Comité
    d'évaluation finale qui s'est tenue à Bruxelles (Belgique) du 18 au
    20 novembre 1996.  La liste des participants à cette réunion figure à
    l'appendice 3.  La fiche d'information sur la sécurité chimique du
    méthacrylate de méthyle (ICSC 0300), préparée par le Programme
    international sur la Sécurité chimique (IPCS, 1993), est également
    reproduite dans le présent document.

         Le méthacrylate de méthyle (CAS N° 80-62-6) est un produit
    chimique de synthèse volatil, utilisé principalement dans la
    production de feuilles acryliques moulées, d'émulsions acryliques et
    de résines pour moulage et extrusion.  Des polymères et copolymères de
    méthacrylate de méthyle entrent dans la composition de nombreux
    produits: revêtements de surfaces, adhésifs, produits d'étanchéité,
    enduits pour cuirs et papiers, encres, encaustiques, apprêts pour
    textiles, prothèses dentaires, ciments pour chirurgie osseuse, écrans
    antiradiations au plomb, ongles artificiels, semelles orthopédiques,
    etc.  Selon les calculs, la plus grande partie du méthacrylate de
    méthyle devrait être émis dans l'atmosphère, les quantités émises dans
    l'eau et le sol étant minimes.  Le méthacrylate de méthyle ne persiste
    pas longtemps dans l'atmosphère et il est admis qu'il ne contribue pas

    directement à la destruction de la couche d'ozone.  Il ne devrait pas
    subir de bioconcentration dans l'environnement et l'inhalation est
    probablement la principale voie d'exposition pour l'homme.

         Le méthacrylate de méthyle est rapidement absorbé et distribué
    dans l'organisme après inhalation ou administration par voie orale aux
    animaux d'expérience.  Les données concernant l'absorption après
    exposition cutanée sont limitées.  Le méthacrylate de méthyle est
    rapidement métabolisé en acide méthacrylique, aussi bien chez l'animal
    que chez l'homme.  Chez le rat, 16 à 20 % du produit inhalé se dépose
    dans les voies respiratoires supérieures, où il est surtout métabolisé
    par les estérases tissulaires locales.

         La toxicité aiguë du méthacrylate de méthyle est faible.  On a
    observé une irritation de la peau, des yeux et des fosses nasales chez
    des rongeurs et des lapins exposés à des concentrations relativement
    élevées.  Il se révèle légèrement sensibilisant pour la peau des
    animaux.  L'effet le plus souvent observé après inhalation répétée de
    faibles doses est une irritation des fosses nasales.  Des effets ont
    également été signalés sur les reins et le foie à des concentrations
    plus élevées.  La plus faible concentration suivie d'effet
    (dégénérescence inflammatoire de l'épithélium nasal) a été de
    410 mg/m3 chez des rats exposés pendant 2 ans; dans cette étude, la
    dose sans effet observé (NOEL) a été évaluée à 100 mg/m3 environ.

         Une étude de qualité menée sur des rats n'a révélé aucun effet
    sur le développement, malgré une diminution du poids des mères après
    inhalation de concentrations allant jusqu'à 8315 mg/m3.  Les seules
    autres données disponibles en ce qui concerne les effets sur le
    développement sont les résultats d'études limitées, anciennes ou peu
    documentées, faisant état d'une foetotoxicité à des concentrations qui,
    lorsqu'elles étaient mentionnées, étaient toxiques pour la mère.  Les
    données relatives aux effets du méthacrylate de méthyle sur la
    reproduction sont limitées.  Il n'y a pas eu de baisse de la fécondité
    dans un test de létalité dominante chez des souris exposées à des
    concentrations atteignant 36 900 mg/m3 et aucun effet indésirable n'a
    été observé sur les organes de la reproduction dans les études menées
    jusqu'ici avec des doses répétées.  Les données disponibles sur la
    neurotoxicité du méthacrylate de méthyle sont également limitées; on a
    observé une dégradation de l'activité locomotrice, de la capacité
    d'apprentissage et du comportement, ainsi que des effets biochimiques
    sur le cerveau de rats exposés par voie orale à une dose de 500 mg/kg
    de poids corporel par jour pendant 21 jours.

         Le méthacrylate de méthyle ne s'est pas révélé cancérogène dans
    une étude approfondie et bien documentée de 2 ans au cours de laquelle
    des rats et des souris ont été exposés par inhalation, ni dans une
    autre étude d'inhalation chronique menée sur des rats et des hamsters.
     In vitro, le méthacrylate de méthyle n'est pas mutagène dans les
    systèmes bactériens, mais il s'est révélé mutagène et clastogène dans
    des cellules mammaliennes.  Dans les études  in vivo (principalement

    les études d'inhalation) qui ont clairement démontré la toxicité du
    méthacrylate de méthyle pour les tissus cibles, on trouve également
    quelques indices de génotoxicité.

         Le méthacrylate de méthyle est légèrement irritant pour la peau
    de l'homme et il peut induire une sensibilisation cutanée chez des
    individus prédisposés.  Bien que l'on ait également signalé des cas
    d'asthme professionnel liés au méthacrylate de méthyle, il n'est pas
    prouvé de façon concluante que cette substance soit un sensibilisant
    des voies respiratoires.  Dans l'ensemble, les études épidémiologiques
    disponibles n'apportent pas de preuve convaincante d'un effet
    cancérogène chez l'homme, mais on ne peut pas en déduire non plus avec
    quelque certitude que l'exposition au méthacrylate de méthyle
    n'entraîne aucun risque supplémentaire.

         Le méthacrylate de méthyle est peu toxique pour les organismes
    aquatiques.  Aucune étude de toxicité chronique portant sur ce type
    d'organismes n'a été retrouvée, mais des épreuves de toxicité aiguë
    ont été effectuées sur des poissons, sur  Daphnia magna et sur des
    algues.  L'effet le plus sensible a été l'inhibition de la
    multiplication cellulaire chez l'algue verte  Scenedesmus 
     quadricauda après 8 jours d'exposition à la concentration de
    37 mg/litre.  La valeur la plus faible de CE50 à 24 heures pour
    l'immobilisation des  Daphnia est de 720 mg/litre.  La CL50 à
    96 heures pour le poisson  Lepomis macrochirus, en conditions de
    renouvellement continu, était de 191 mg/litre, tandis que les CL50
    pour des durées de 1 à 24 heures allaient de 420 à 356 mg/litre.  La
    CL50 à 96 heures pour la truite arc-en-ciel  (Oncorhynchus mykiss) 
    en conditions de renouvellement continu était supérieure à la plus
    forte concentration testée, soit 79 mg/litre.  Des réactions
    sublétales/comportementales ont été notées chez des poissons à
    40 mg/litre.

         Les données disponibles chez l'homme sont jugées insuffisantes
    pour servir de base principale au calcul d'une valeur guide; on a donc
    établi une concentration tolérable sur la base de la dégénérescence
    inflammatoire de l'épithélium nasal observée chez des rats exposés
    pendant 2 ans à une concentration de 410 mg/m3.  Dans cette étude, la
    NOEL était d'approximativement 100 mg/m3.  Les données pouvant servir
    à évaluer l'exposition indirecte dans l'environnement général ou
    l'exposition des consommateurs sont extrêmement limitées.  La
    concentration tolérable calculée (probablement avec une certaine marge
    de sécurité), qui est d'environ 0,2 mg/m3, est supérieure de
    plusieurs ordres de grandeur aux quelques prédictions qui ont été
    faites des concentrations atmosphériques de méthacrylate de méthyle
    dans l'environnement général.  Le niveau d'exposition par inhalation
    auquel on peut s'attendre du fait de l'utilisation de peintures
    dispersables ou de peintures à l'huile contenant du méthacrylate de
    méthyle est peut-être supérieur d'un ordre de grandeur à la dose
    qu'entraînerait une exposition à la concentration tolérable, encore
    que dans certains pays ces produits ne soient pas destinés au grand
    public.  Aucun renseignement n'a été trouvé sur leurs conditions

    d'utilisation dans d'autres pays.  Une dose journalière tolérable
    (DJT) de 1,2 mg/kg de poids corporel par jour a été calculée sur la
    base d'une étude de toxicité chronique par voie orale.

         Bien que les données disponibles au sujet des effets du
    méthacrylate de méthyle sur l'environnement soient limitées et que les
    concentrations prévues dans divers milieux soient très incertaines, il
    existe une marge considérable entre les concentrations suivies
    d'effets avérés et les concentrations prévues de façon approximative
    dans l'environnement.

    RESUMEN DE ORIENTACION

         Esta reseña de la evaluación química internacional del
    metacrilato de metilo fue preparada por la Dirección de Higiene del
    Medio de Health Canada y se basó principalmente en un examen realizado
    por el Gobierno del Canadá (1993) para evaluar los efectos potenciales
    sobre la salud humana de la exposición indirecta a dicha sustancia en
    el medio ambiente general, así como sus efectos ambientales, y en un
    examen del Centro Internacional de Investigaciones sobre el Cáncer
    (CIIC, 1994) centrado principalmente en la identificación de riesgos
    de carcinogenicidad.  En el examen del Gobierno del Canadá (1993) se
    tuvieron presentes los datos obtenidos en marzo de 1992, actualizados
    posteriormente sobre la base de una amplia búsqueda bibliográfica
    realizada en septiembre de 1995 en las bases de datos en línea y el
    Registro Internacional de Productos Químicos Potencialmente Tóxicos.
    En el apéndice 1 se presenta información sobre la naturaleza de la
    revisión científica y sobre los exámenes del Gobierno del Canadá
    (1993) y del CIIC (1994).  Durante la fase de revisión científica de
    esta reseña se tomaron en consideración otros exámenes provisionales
    de la Dirección de Salud y Seguridad del Reino Unido (Cary et al.,
    1995) y de la Unión Europea (Evaluación Provisional del Metacrilato de
    Metilo), así como exámenes ya publicados del ECETOC (1995) y de la
    Junta Consultiva Finlandesa de Sustancias Químicas (1992), con miras
    principalmente a obtener información adicional pertinente para la
    revisión. También se ha incorporado la información adicional
    identificada durante la revisión efectuada por los puntos de contacto
    y el examen realizado por el Comité de Revisión Final.  La información
    relativa a la revisión científica de la presente reseña figura en el
    apéndice 2.  La publicación de esta reseña fue aprobada en una reunión
    del Comité de Revisión Final celebrada en Bruselas (Bélgica) del 18 al
    20 de noviembre de 1996.  La lista de participantes en la reunión del
    Comité de Revisión Final figura en el apéndice 3.  También se ha
    reproducido en este documento la ficha internacional de seguridad
    química para el metacrilato de metilo (ICSC 0300), emitida por el
    Programa Internacional de Seguridad de las Sustancias Químicas (IPCS,
    1993).

         El metacrilato de metilo (N° CAS 80-62-6) es una sustancia
    química sintética y volátil que se utiliza principalmente en la
    producción de hojas acrílicas fraguadas, emulsiones acrílicas y
    resinas moldeadas y extruidas.  Los polímeros y copolímeros de
    metacrilato de metilo también se utilizan en los revestimientos de
    exterior con base acuosa, con base disolvente y sin diluir, en
    adhesivos, selladores, revestimientos de cuero y de papel, tintas,
    ceras para suelos, aprestos textiles, prótesis dentales, cementos
    quirúrgicos fosfatados y pantallas acrílicas emplomadas contra la
    radiación, así como en la preparación de uñas sintéticas y separadores
    ortéticos para zapatos.  La mayor parte de las emisiones del
    metacrilato de metilo se producen en el aire, liberándose en muy
    pequeñas cantidades en el agua y en el suelo.  Su persistencia en la
    atmósfera es corta y no se considera que contribuya directamente al

    agotamiento de la capa de ozono.  No parece que se bioconcentre en el
    medio ambiente y su inhalación con el aire probablemente sea la
    principal vía de exposición humana.

         El metacrilato de metilo tiene una absorción y distribución
    rápidas en animales de experimentación, tras su inhalación o
    administración por vía oral.  Los datos de que se dispone sobre su
    absorción tras una exposición cutánea son limitados.  Tanto en
    animales de experimentación como en seres humanos, el metacrilato de
    metilo se metaboliza rápidamente en ácido metacrílico.  Tras su
    inhalación, el 16-20% de la sustancia química se deposita en las vías
    respiratorias altas de las ratas, donde principalmente es metabolizada
    por las esterasas del tejido local.

         El metacrilato de metilo tiene una toxicidad aguda baja.  En los
    roedores y conejos expuestos a concentraciones relativamente altas se
    han observado irritaciones cutáneas, oculares y de la cavidad nasal.
    Esta sustancia química es un sensibilizador cutáneo ligero en los
    animales.  El efecto observado con mayor frecuencia tras una
    exposición repetida por inhalación en su concentración más baja es la
    irritación de la cavidad nasal.  También se han señalado efectos en el
    riñón y el hígado con concentraciones más altas.  El nivel mínimo de
    inhalación con efectos comunicados fue de 410 mg/m3 en las ratas
    expuestas a metacrilato de metilo durante dos años (basado en la
    degeneración inflamatoria del epitelio nasal); el nivel sin efectos
    observados (NOEL) en esta investigación fue de aproximadamente 100
    mg/m3.

         En un estudio bien llevado sobre ratas no se observaron efectos
    en el desarrollo, aunque se produjeron disminuciones en el peso
    corporal materno tras la inhalación de concentraciones de hasta 8315
    mg/m3.  Los demás datos de que se dispone sobre la toxicidad para el
    desarrollo se limitan a los resultados de un número reducido de
    estudios precoces o mal documentados en los que se observaron efectos
    fetotóxicos con concentraciones (cuando se comunicaron) que resultaron
    tóxicas para las madres.  Se dispone de pocos datos sobre los efectos
    del metacrilato de metilo en la reproducción.  No hubo disminución de
    la fecundidad en una valoración de dominancia letal en ratones
    expuestos a concentraciones de hasta 36 900 mg/m3 ni se observaron
    efectos negativos sobre los órganos reproductores en los estudios de
    administración repetida realizados hasta la fecha.  Se dispone de
    pocos datos sobre la neurotoxicidad del metacrilato de metilo; se
    observaron una disminución de la actividad locomotora y efectos a
    nivel de aprendizaje, de comportamiento y bioquímico en el cerebro, en
    ratas expuestas por vía oral a 500 mg/kg de peso corporal al día
    durante 21 días.

         El metacrilato de metilo no resultó carcinógeno en una amplia
    biovaloración bien documentada de dos años realizada en ratas y
    ratones expuestos por inhalación, ni en otros estudios de inhalación
    crónica realizados en ratas y hámsters.  Aunque no es mutagénico en
    los sistemas bacterianos  in vitro, ha resultado mutagénico y
    clastogénico en las células de mamíferos  in vitro. En los estudios

     in vivo (principalmente por inhalación) en los que ha habido pruebas
    claras de toxicidad en el tejido diana, ha habido pocos indicios de la
    genotoxicidad del metacrilato de metilo.

         En los seres humanos, el metacrilato de metilo es un irritante
    cutáneo ligero y puede inducir sensibilización cutánea en las personas
    con predisposición.  Aunque también se han señalado casos de asma
    profesional asociados a dicha sustancia, no existen pruebas
    concluyentes de que el metacrilato de metilo sea un sensibilizador
    respiratorio.  En general, los estudios epidemiológicos disponibles no
    ofrecen indicios firmes ni sistemáticos de un efecto carcinogénico del
    metacrilato de metilo en ningún órgano diana en los seres humanos,
    pero tampoco se puede inferir con algún grado de confianza que se haya
    descartado la posibilidad de un exceso de riesgo.

         El metacrilato de metilo tiene una toxicidad baja en organismos
    acuáticos.  Aunque no se identificaron estudios de toxicidad crónica
    en organismos acuáticos, se han realizado pruebas de toxicidad aguda
    en  Daphnia magna y en algas.  El efecto más sensible fue el comienzo
    de la inhibición de la multiplicación celular en el alga verde
     Scenedesmus quadricauda, con niveles de 37 mg/litro tras ocho días
    de exposición.  La CE50 de inmovilización más baja notificada a las
    24 horas para  Daphnia es de 720 mg/litro.  La CL50 a las 96 horas
    en juveniles de  Lepomis macrochirus en condiciones de flujo continuo
    fue de 191 mg/litro, mientras que los valores de la CL50 para
    periodos de 1 a 24 horas oscilaron entre 420 y 356 mg/litro,
    respectivamente.  La CL50 a las 96 horas para la trucha arco iris
     (Oncorhynchus mykiss) en condiciones de flujo continuo fue >79
    mg/litro, la concentración más alta probada.  Se observaron respuestas
    subletales/comportamentales en los peces, con niveles de 40 mg/litro.

         Los estudios de que se dispone en seres humanos se consideran
    inadecuados como base principal para establecer un valor orientativo;
    por consiguiente, a modo de orientación, se ha establecido una
    concentración tolerable sobre la base de la degeneración inflamatoria
    del epitelio nasal de las ratas expuestas a concentraciones de 410
    mg/m3 durante dos años.  La concentración sin efectos observados en
    esta investigación fue de aproximadamente 100 mg/m3.  Los datos de
    que se dispone para establecer una base para la estimación de la
    exposición indirecta en el medio ambiente general y de la exposición
    en los usuarios son muy limitados.  La concentración tolerable
    obtenida (probablemente moderada) de aproximadamente 0,2 mg/m3 es
    muchos órdenes de magnitud más elevada que las concentraciones
    previstas de la muestra de metacrilato de metilo en el aire ambiente
    del medio ambiente general.  La exposición por inhalación prevista por
    el uso de pinturas de dispersión y al aceite que contienen metacrilato
    de metilo puede ascender a un orden de magnitud superior a la ingesta
    tolerable asociada con la exposición al nivel de concentración
    tolerable, si bien se ha notificado que en algunos países esos
    productos no se suministran al público en general.  No se obtuvo
    información sobre las modalidades de utilización de estos productos en

    otros países.  Sobre la base de un estudio de toxicidad crónica
    realizado por vía oral, se ha determinado una ingesta diaria tolerable
    (IDT) de 1,2 mg/kg de peso corporal al día.

         Si bien los datos de que se dispone sobre los efectos ambientales
    del metacrilato de metilo son limitados y los valores pronosticados en
    distintos medios son muy inciertos, existe un amplio margen entre los
    niveles con efectos observados y las concentraciones ambientales de
    pronóstico incierto.




    See Also:
       Toxicological Abbreviations
       Methyl methacrylate (ICSC)
       Methyl Methacrylate (IARC Summary & Evaluation, Volume 60, 1994)