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    Concise International Chemical Assessment Document 16








    AZODICARBONAMIDE









    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.



    Concise International Chemical Assessment Document 16



    AZODICARBONAMIDE



    First draft prepared by
    Mr R. Cary, Health and Safety Executive, Merseyside, United Kingdom,
    Dr S. Dobson, Institute of Terrestrial Ecology, Cambridgeshire, United
    Kingdom, and
    Mrs E. Ball, Health and Safety Executive, Merseyside, United Kingdom



    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, 1999

         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
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    the risk to human health and the environment from exposure to
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    technical assistance in strengthening national capacities for the
    sound management of chemicals.

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    Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and
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    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

    Azodicarbonamide.

         (Concise international chemical assessment document ; 16)

         1.Azo compounds  2.Occupational exposure  3.Risk assessment
         I.International Programme on Chemical Safety  II.Series

         ISBN 92 4 153016 2        (NLM classification: QV 235)
         ISSN 1020-6167

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    reproduce or translate its publications, in part or in full.
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    (c) World Health Organization 1999

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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

    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 azodicarbonamide
                   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. Health surveillance advice

    14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

    INTERNATIONAL CHEMICAL SAFETY CARD

    REFERENCES

    APPENDIX 1 -- SOURCE DOCUMENT

    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 undergo 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.

         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 IPCS to inform it of the new information.
                 
    1 International Programme on Chemical Safety (1994)
       Assessing human health risks of chemicals: deriviation of
       guidance values for health-based exposure limits. Geneva, World
      Health Organization (Environmental Health Criteria 170).


    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 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.  EXECUTIVE SUMMARY

         This CICAD on azodicarbonamide was based on a review of human
    health (primarily occupational) concerns prepared by the United
    Kingdom's Health and Safety Executive (Ball et al., 1996). Hence,
    although this CICAD includes an assessment of the available
    environmental data, the main focus is on risks to human health in the
    working environment, including an emphasis on information from routes
    that are relevant to occupational settings. Data identified up to June
    1994 were covered in the review. A further literature search was
    performed, up to July 1997, to identify any new information published
    since this review was completed. The original source document did not
    address environmental concerns; as literature searches have failed to
    identify relevant studies in this area, an environmental risk
    assessment has not been attempted. Information on the nature of the
    peer review and availability of the source document is presented in
    Appendix 1. Information on the peer review of this CICAD is presented
    in Appendix 2. This CICAD was approved as an international assessment
    at a meeting of the Final Review Board, held in Tokyo, Japan, on 30
    June - 2 July 1998. Participants at the Final Review Board meeting are
    listed in Appendix 3. The International Chemical Safety Card (ICSC
    0380) for azodicarbonamide, produced by the International Programme on
    Chemical Safety (IPCS, 1993), has also been reproduced in this
    document.

         Toxicokinetic data on azodicarbonamide (CAS No. 123-77-3) are
    limited, but the chemical appears to be well absorbed by the
    inhalation and oral routes in rodents. Substantial quantities of the
    substance remain unabsorbed from the gastrointestinal tract and are
    passed out in the faeces. Azodicarbonamide is readily converted to
    biurea, the only breakdown product identified, and it is likely that
    systemic exposure is principally to this derivative rather than to the
    parent compound. Elimination of absorbed azodicarbonamide/biurea is
    rapid, occurring predominantly via the urine, and there is very little
    systemic retention of biurea.

         Azodicarbonamide is of low acute toxicity and does not cause
    skin, eye, or respiratory tract irritation in experimental animals.
    Results from a poorly conducted skin sensitization study were
    negative, and there was no evidence of an asthmatic-type response in
    guinea-pigs in one study. No adverse effects were observed in
    experimental animals inhaling up to 200 mg/m3 for up to 13 weeks.
    Repeated oral exposures resulted in the appearance of pyelonephritis
    with casts and crystalline deposits in renal tubuli in several
    species. However, the dose levels required to induce these effects
    were high (>200; mg/kg body weight per day in studies of up to
    1 year's duration). Although azodicarbonamide was found to be a
    mutagen in bacterial systems, there is no evidence that this effect
    would be expressed  in vivo. The carcinogenicity and reproductive
    toxicity of azodicarbonamide have not been examined in detail, but no
    tumorigenic or antifertility effects were observed in early studies in
    which animals were treated with the breakdown product biurea.
    Developmental toxicity has not been studied.

         Studies in humans have concentrated solely on the ability of
    azodicarbonamide to induce asthma and skin sensitization. Evidence
    that azodicarbonamide can induce asthma in humans has been found from
    bronchial challenge studies with symptomatic individuals and from
    health evaluations of employees at workplaces where azodicarbonamide
    is manufactured or used. There are also indications that
    azodicarbonamide may induce skin sensitization.

         On the basis that azodicarbonamide is a human asthmagen and that
    the concentrations required to induce asthma in a non-sensitive
    individual or to provoke a response in a sensitive individual are
    unknown, it is concluded that there is a risk to human health under
    present occupational exposure conditions. The level of risk is
    uncertain; hence, exposure levels should be reduced as much as
    possible.

         Data have been identified that indicate ethyl carbamate formation
    in consumer products such as bread and beer following the addition of
    azodicarbonamide. Exposure of the general public to azodicarbonamide
    could not be evaluated because of the lack of available data.

         Azodicarbonamide released to surface waters would partition to
    the hydrosphere with no significant sorption to particulates. The
    half-life for reaction with hydroxyl radicals in the atmosphere is
    calculated to be 0.4 days. Azodicarbonamide was readily biodegradable
    in two out of three tests with sewage sludge and was degraded in soil
    by 20-70% over 14 days. No-observed-effect concentrations (NOECs) for
    fish and the water flea have been reported at >50 and 5 mg/litre,
    respectively. Lack of information on release to the environment
    precludes a quantitative risk assessment.
    

    2.  IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

         Azodicarbonamide (CAS No. 123-77-3) is a synthetic chemical that
    exists at ambient temperature as a yellow-orange crystalline solid. It
    is poorly soluble in water at 20°C (<50; mg/litre), although it is
    slightly soluble in hot water. It is insoluble in many organic
    solvents, but it is soluble in  N, N-dimethyl formamide and dimethyl
    sulfoxide. It has a very low vapour pressure (2.53 × 10-11 kPa at
    20°C). Additional physical/chemical properties are presented in the
    International Chemical Safety Card reproduced in this document.

         Common synonyms for azodicarbonamide are ADA, ADC,
    azobiscarbonamide, azobiscarboxamide, azodicarbodiamide,
    azodicarboxamide, azodiformamide, azobisformamide,
    1,1'-azobisformamide, diazenedicarboxamide, and diazenedicarbonic acid
    amide. Trade names are listed in the International Chemical Safety
    Card appended to this document.

         Azodicarbonamide's structural formula is shown below:

    CHEMICAL STRUCTURE 


         The conversion factors for azodicarbonamide at 20°C and 101.3 kPa
    are as follows:

         1 mg/m3 = 0.21 ppm
         1 ppm = 4.8 mg/m3
    

    3.  ANALYTICAL METHODS

         Two methods can be used to measure levels of azodicarbonamide in
    workplace air. In the first, samples are collected on 37-mm Teflon
    filters backed with polyethylene, which in turn is backed with a
    cellulose pad (Ahrenholz & Neumeister, 1987). Sampling takes place at
    2 litres/min for periods from 7 to 486 min. After sampling,
    azodicarbonamide is recovered from the filter with dimethyl sulfoxide
    and analysed by high-performance liquid chromatography. The limit of
    quantification is given as 5 µg per sample. For a 15-min sample at 2
    litres/min, this is equivalent to a quantification limit in air of
    0.167 mg/m3; over 8 h, it is equivalent to 0.005 mg/m3.

         In the second method, azodicarbonamide is collected on 37-mm
    glass fibre filters at 15-20 litres/min (Vainiotalo & Pfaffli, 1988).
    It is then eluted from the filter with dimethyl sulfoxide. Following
    the addition of sodium hydroxide and glucose solutions, the
    azodicarbonamide is reduced to hydrazine. This is reacted with
    4-dimethylaminobenzaldehyde, and the resulting aldazine is measured
    spectrophotometrically at 460 nm. The lower detection limit is given
    as 0.001 mg/m3 for a 4-m3 air sample (equivalent to 4 µg per
    sample). This is a considerably larger volume than would normally be
    collected for assessing personal exposure samples. At a more typical
    flow rate of 2 litres/min for 8 h, 960 litres of air would be sampled,
    resulting in a detection limit of about 0.005 mg/m3. Sampling over 15
    min at the same rate would give a detection limit of about 0.16
    mg/m3.

         Although there are published methods for measuring
    azodicarbonamide and its metabolite biurea in rats (Bechtold et al.,
    1989; see also Mewhinney et al., 1987), there are no reports
    describing their measurement in human body fluids.
    

    4.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         The principal end use of azodicarbonamide is as a blowing agent
    in the rubber and plastics industries. It is used in the expansion of
    a wide range of polymers, including polyvinyl chloride, polyolefins,
    and natural and synthetic rubbers. The blowing action occurs when the
    azodicarbonamide decomposes on heating (process temperatures
    approx. 190-230°C) to yield gases (nitrogen, carbon monoxide, carbon 
    dioxide, and ammonia), solid residues, and sublimated substances. 
    Decomposition accelerators, in the form of metal salts and oxides, may 
    also be added to bring about decomposition at lower temperatures.

         Azodicarbonamide has in the past been used in the United Kingdom
    and Eire (but not other European Union member states) as a flour
    improver in the bread-making industry, but this use is no longer
    permitted. It is not known how common this practice is worldwide.
    Azodicarbonamide is not used in other consumer products.

         Azodicarbonamide is manufactured by the reaction of dihydrazine
    sulfate and urea under high temperature and pressure. The product of
    this reaction is then oxidized using sodium chlorate and centrifuged
    to yield a slurry containing azodicarbonamide. The slurry is washed to
    remove impurities and dried to obtain the azodicarbonamide powder.
    This is then micronized to a fine powder (95% of particles <10; µm,
    which is in the respirable range for humans) before packaging.

         Very limited information is available on production volumes. The
    Hazardous Substances Data Bank (HSDB, 1996) gives US production
    figures of "greater than 4.54 tonnes." Until recently,
    azodicarbonamide was produced in the United Kingdom; however, this
    production has now stopped, and all azodicarbonamide used in the
    United Kingdom is imported, predominantly through one large company.
    Approximately 2500 tonnes are supplied to the United Kingdom market
    each year. Both pure azodicarbonamide (approximately 2200 tonnes) and
    pre-mixed formulations (300 tonnes) are supplied, the latter
    containing between 10 and 95% azodicarbonamide, depending on the end
    use application. "Masterbatch" products, in which the azodicarbonamide
    is pelletized with polyolefins, and blended pastes (azodicarbonamide
    and plasticizer) are also supplied to the rubber and plastics
    industries. In addition to the main importer, there are some firms
    that process azodicarbonamide into dust-suppressed powders, pastes,
    and "Masterbatch" formulations before selling the processed
    azodicarbonamide to the end users.

         Recent studies have examined the contribution of azodicarbonamide
    to the levels of ethyl carbamate in bread and beer (Canas et al.,
    1997; Dennis et al., 1997a,b). It is not clear if unreacted
    azodicarbonamide is present in these products; therefore, it is not
    possible to assess the contribution that consumption of such products
    might make to the overall body burden of azodicarbonamide.
    

    5.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         A calculated half-life of 0.4 days for reaction with hydroxyl
    radicals in air has been reported.1

         Azodicarbonamide added to five different soil types at 200 mg
    nitrogen/kg soil (dry weight) was degraded (measured as recovery of
    inorganic nitrogen) by between 21.1% and 66.1% over 14 days
    (Frankenberger & Tabatabai, 1982).

         Degradation of azodicarbonamide by sewage sludge organisms has
    been investigated in three modified Sturm tests (Organisation for
    Economic Co-operation and Development [OECD] Guideline 301B). The
    compound was "readily biodegradable" in two out of the three tests and
    was degraded by 21% over 30 days in the third test (Uniroyal,
    1992).2

         According to Mackay Level I fugacity modelling, azodicarbonamide
    released to surface waters will partition to the hydrosphere with no
    significant sorption to particulates.3

                  
    1 Bayer, unpublished calculated value (1988) based on the method of
      Atkinson; value presented in IUCLID (European Union database), 
      version dated 7 February 1996.

    2 Bayer, unpublished value (1991) presented in IUCLID (European
      Union database), version dated 7 February 1996; no details 
      available.

    3 Bayer remark in IUCLID (European Union database), version dated 7
      February 1996.
    

    6.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    6.1  Environmental levels

         There are no data available on levels of azodicarbonamide in
    ambient air, water, soils, or sediment.

    6.2  Human exposure

         The data available to the authors of this CICAD are restricted to
    the occupational environment. It is estimated that several thousand
    persons are exposed to azodicarbonamide in the workplace in the United
    Kingdom. Of this total, it is estimated that only a few hundred
    persons are exposed as part of their main work activity (i.e., those
    involved in compounding, mixing, or raw material handling).

         Data obtained by the United Kingdom's Health and Safety Executive
    at a plant milling azodicarbonamide powder in micronizing mills (four
    samples were collected in total) showed average personal exposures
    during the day shift to be 11.8 and 9.8 mg/m3 and during the night
    shift to be 2.3 and 2.8 mg/m3 because of the lower throughput at
    night. Samples were collected over 4 h. The operators' tasks involved
    bagging, weighing, and packaging the milled product.

         In the published literature, Slovak (1981) reported time-weighted
    average total dust levels in the range 2-5 mg/m3 for azodicarbonamide
    manufacturing operations. However, no details were given concerning
    occupational groups or tasks. A US National Institute for Occupational
    Safety and Health study (Ahrenholz et al., 1985) examined personal
    exposures of workers handling azodicarbonamide in a flooring factory.
    The work involved the formulation of pastes or paints and required the
    blending of azodicarbonamide powder with plasticizers, resins,
    pigments, and other additives. Exposures to azodicarbonamide occurred
    primarily while the workers were weighing and tipping the powder.
    Short-term (sample duration <70; min) personal exposures were in the
    range 0.15-12 mg/m3 (median 2.7 mg/m3). A second study (Ahrenholz &
    Anderson, 1985) focused on the use of azodicarbonamide in the
    injection moulding of plastics. The process involved blending
    azodicarbonamide powder with resins. Two sets of full-shift
    measurements were reported, with median 8-h time-weighted average
    levels of 6.2 µg/m3 (range, not detectable to 280 µg/m3) and 25
    µg/m3 (range, trace to 752 µg/m3), respectively.

         No data are available relating to dermal exposure levels.
    

    7.  COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

         No information is available on the toxicokinetics of
    azodicarbonamide in humans.

         Most of the toxicokinetic data available for azodicarbonamide
    come from animal studies (Mewhinney et al., 1987). Absorption of
    azodicarbonamide has been demonstrated following both a single
    inhalation exposure of up to 6 h (34% of dose) and a single oral
    administration (10-33% of dose) of radiolabelled azodicarbonamide to
    rats. In contrast, approximately 90% of a single intratracheally
    instilled dose was apparently absorbed. The difference in absorption
    between inhaled and intratracheally instilled azodicarbonamide could
    be related to the fact that much of the inhaled azodicarbonamide did
    not reach the lower respiratory tract. Half an hour after a 6-h
    nose-only exposure of rats to 25 mg/m3 of a dry aerosol (average
    mass aerodynamic diameter 3.4 µm), 78% of the calculated total intake
    was located in the gastrointestinal tract.

         Following exposure by both inhalation and oral routes,
    substantial quantities of the substance remain unabsorbed from the
    gastrointestinal tract and are passed out in the faeces.
    Azodicarbonamide is readily converted to biurea, the only breakdown
    product identified, and it is likely that systemic exposure is
    principally to this derivative rather than to the parent compound.
    Elimination of absorbed azodicarbonamide/biurea is rapid, occurring
    predominantly via the urine, and there is very little systemic
    retention of biurea.
    

    8.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

          It is noted that some of the available toxicological studies
    were conducted using biurea. Azodicarbonamide readily undergoes
    reduction in the presence of thiol groups to form the stable compound
    biurea. Given that thiol groups are also present in many biological
    molecules, there is the potential for this reaction to take place
    wherever azodicarbonamide encounters thiol groups in biological
    systems. This has been demonstrated in an experiment in which
    radiolabelled azodicarbonamide was added to fresh rat blood (Mewhinney
    et al., 1987). All radioactivity was in the form of biurea within 5
    min when untreated blood was used. Radioactivity associated with
    azodicarbonamide was detected only in blood to which 5 mg unlabelled
    azodicarbonamide/ml blood was added. This level is very much greater
    than the levels that humans are likely to encounter.

    8.1  Single exposure

         Azodicarbonamide is of low acute toxicity by all relevant routes
    of exposure. The LC50 was greater than 6100 mg/m3 in rats and mice
    exposed to a dry aerosol (median mass aerodynamic diameter
    5.8 ± 2.25 µm [geometric standard deviation]) of azodicarbonamide for
    4 h (IRDC, 1982a,b). No mortality was observed in rats given oral
    doses of up to 5000 mg/kg body weight (Loeser, 1976). The dermal LD50
    was >2000; mg/kg body weight in rabbits following application of this
    substance under an occlusive dressing for 24 h (MB Research
    Laboratories Inc., 1986). Few specific toxic effects were observed in
    any single exposure study.

    8.2  Irritation and sensitization

         Although most studies were of uncertain quality and in many cases
    would not comply with modern regulatory standards, results of several
    skin and eye irritation studies indicate that azodicarbonamide should
    not be regarded as a skin or eye irritant (Kimmerle, 1965; Conning,
    1966; Mihail, 1977; MB Research Laboratories Inc., 1986). In a study
    of respiratory irritation, in which guinea-pigs were exposed head only
    to azodicarbonamide in plethysmography tubes, either no changes or
    effects of doubtful significance were reported for various lung
    function parameters, indicating that irritation was minimal at
    concentrations up to 97 mg/m3 for 1 h (Shopp et al., 1987).

         Owing to the poor quality of the only available skin
    sensitization study (the concentration used for induction and
    challenge -- a 1% solution in dimethyl formamide -- was very low; only
    four guinea-pigs were used in the test group; and test sites were not
    occluded), it was not possible to draw any conclusions regarding the
    ability of azodicarbonamide to induce skin sensitization in animals
    (Stevens, 1967). No evidence of pulmonary irritation or
    asthmatic-type-reactions (no changes in specific airways conductance,
    no evidence of histopathological effects on the upper or lower
    respiratory tract, and no evidence of circulating antibodies) was

    obtained in one study in which groups of 10 guinea-pigs were
    repeatedly exposed by inhalation to unconjugated azodicarbonamide at
    0, 51, or 200 mg/m3 for 6 h/day, 5 days/week, for 4 weeks (Gerlach et
    al., 1989).


    8.3  Short-term exposure

         Azodicarbonamide is of relatively low toxicity to animals
    repeatedly exposed by the inhalation or oral routes. In well-conducted
    2-week inhalation studies, groups of 10 male and 10 female F344/N rats
    or B6C3F1 mice were exposed to dry aerosols (median mass aerodynamic
    diameter 2 µm) at 0, 2, 10, 50, 100, or 200 mg/m3 for 6 h/day, 5
    days/week (Medinsky et al., 1990). Investigations included analyses of
    methaemoglobin and blood cholinesterase and extensive macroscopic and
    microscopic pathology; no changes of toxicological significance were
    seen.

         Groups of five male and five female mice received 0, 625, 1250,
    5000, or 10 000 mg azodicarbonamide/kg body weight per day by oral
    gavage in corn oil, 5 days/week for 2 weeks.1 Mortalities were
    observed at 1250 mg/kg body weight per day and above (presumably
    treatment related). Histopathologically, at 1250 mg/kg body weight per
    day and above, pyelonephritis with casts was seen in renal tubuli, and
    crystalline deposits were observed in renal tubuli and the urinary
    bladder.

         A similar study was conducted in rats; again, there was a
    dose-related increase in mortality at 1250 mg/kg body weight per day
    and above and a similar profile of renal lesions, although effects
    were seen at 1250 mg/kg body weight per day and above in males and at
    2500 mg/kg body weight per day and above in females.1

         In one early and very briefly reported study, signs of toxicity,
    the nature of which was not reported, were seen in male rats given 300
    mg azodicarbonamide/kg body weight per day for 5 days but not in rats
    given 200 mg/kg body weight per day (Kimmerle, 1965).

         In another study designed to look for adverse effects in the
    thyroid (but only investigating the uptake of iodine in the thyroid
    gland and serum protein-bound iodine), no clear evidence of thyroid
    toxicity was found in rats given low-iodine diets containing 1, 5, or
    10% azodicarbonamide or 5 or 10% biurea for periods ranging between 1
    and 4 weeks (Gafford et al., 1971).

         There are no data relating to the effects of repeated dermal
    exposures.

                  
    1 IRDC, unpublished data; cited in BG Chemie (1995).

    8.4  Long-term exposure

    8.4.1  Subchronic exposure

         Groups of 10 male and 10 female F344/N rats or B6C3F1 mice were
    exposed to dry aerosols (median mass aerodynamic diameter 2 µm) at 0,
    50, 100, or 200 mg/m3 for 6 h/day, 5 days/week, for 13 weeks
    (Medinsky et al., 1990). Investigations included analyses of various
    enzyme activities in urine, haematology, blood cholinesterase, serum
    triiodothyronine and thyroxine, vaginal cytology, sperm morphology,
    levels of azodicarbonamide and biurea in lungs and kidneys (Mewhinney
    et al., 1987), and extensive macroscopic and microscopic pathology; no
    changes of toxicological significance were seen.

         Groups of 10 male mice received 1, 78, 156, 312, 625, or 1250 mg
    azodicarbonamide/kg body weight per day and groups of 10 female mice
    received 0, 156, 312, 625, 1250, or 2500 mg azodicarbonamide/kg body
    weight per day by oral gavage in corn oil, 5 days/week for 13 weeks.1
    In contrast to the 2-week study (see section 8.3), there were no
    mortalities and no histopathological abnormalities.

         Groups of 10 male rats received 1, 100, 500, or 2500 mg
    azodicarbonamide/kg body weight per day and groups of 10 female mice
    received 0, 200, 1000, or 5000 mg azodicarbonamide/kg body weight per
    day by oral gavage in corn oil, 5 days/week for 13 weeks.1 Mortality
    was observed only at 2500 mg/kg body weight per day in males and at
    5000 mg/kg body weight per day in females. Histopathologically,
    pyelonephritis and crystalline deposits were observed in males at 2500
    mg/kg body weight per day and in females at 5000 mg/kg body weight per
    day only.

    8.4.2  Chronic exposure and carcinogenicity

         The effects of long-term exposure to azodicarbonamide have not
    been well studied, and no conventional carcinogenicity studies are
    available. The only data come from 1- and 2-year studies in which rats
    and dogs received diets containing various amounts of biurea. In the
    1-year study, rats and dogs ate diets containing 5 or 10% biurea (Oser
    et al., 1965). One high-dose rat died, and body weight gain was
    slightly depressed in high-dose males. No other signs of toxicity were
    observed in rats at necropsy. Most dogs from both dose groups died.
    Necropsy revealed massive, multiple renal calculi, bladder calculi,
    and chronic pyelonephritis. However, the dogs that were selected for
    this study were of uncertain and variable origin; hence, no useful
    results could be obtained from them. The main constituent (comprising
    80-100%) of the calculi was identified as biurea.

         In the 2-year study, rats and dogs ate diets containing either
    bread baked with untreated flour but supplemented with 750, 2370, or
    7500 mg biurea/kg or bread baked with flour containing 100 mg
                  
    1 IRDC, unpublished data; cited in BG Chemie (1995).

    azodicarbonamide/kg (Oser et al., 1965). Controls received diets
    containing bread baked with untreated flour. Given that
    azodicarbonamide is readily converted to biurea (Joiner et al., 1963),
    it is likely that the animals receiving the bread baked with
    azodicarbonamide-treated flour were actually exposed to biurea. As
    with the previous investigations, the dogs that were selected for this
    study were of uncertain and variable origin; hence, no useful results
    could be obtained from them. For rats, no treatment-related deaths
    occurred, and no adverse effects were observed that were considered to
    be treatment related. Assuming food consumption of 20 g/day and a mean
    body weight of 350 g, the dietary inclusion levels correspond to
    approximately 45, 140, and 450 mg biurea/kg body weight per day.

    8.5  Genotoxicity and related end-points

         Azodicarbonamide is mutagenic  in vitro, inducing base-pair
    mutations in bacteria with and without metabolic activation (Pharmakon
    Research International, 1984a; Mortelmans et al., 1986; Hachiya,
    1987).1 In contrast, several standard  in vitro assays in mammalian
    cell systems have yielded negative results; gene mutation assays in
    Chinese hamster ovary cells, using the hypoxanthine guanine
    phosphoribosyl transferase locus, and in mouse lymphoma cells, using
    the thymidine kinase locus, have been conducted, along with an  in
     vitro liver unscheduled DNA synthesis assay and a sister chromatid
    exchange assay in Chinese hamster ovary cells (Pharmakon Research
    International, 1984b,c).1,2 A positive result was obtained in a
    chromosomal aberration assay in Chinese hamster ovary cells, but the
    result was not reproducible.2 Negative results were obtained in a
    sex-linked recessive lethal assay in  Drosophila (Yoon et al., 1985).
    Two  in vivo bone marrow micronucleus assays in mice conducted by the
    intraperitoneal route (0 or 150 mg azodicarbonamide/kg body weight)
    were available, both giving negative results (Pharmakon Research
    International, 1984d; Hachiya, 1987).

                  
    1 T. Cameron, unpublished Ames and mouse lymphoma test results
      (1990) from the short-term program sponsored by the Division of 
      Cancer Aetiology, National Cancer Institute (cited in Chemical 
      Carcinogenesis Research Information System [CCRIS] database, 
      US National Cancer Institute).

    2 NTP, unpublished data on chromosome aberration and sister
      chromatid exchange assays in Chinese hamster ovary cells for
      azodicarbonamide, submitted to the National Toxicology Program,
      National Institutes of Health, US Department of Health and Human
      Services, Research Triangle Park, NC.

    8.6  Reproductive and developmental toxicity

         The only study that has been conducted1 is a three-generation
    study in which rats were given diets containing up to 7500 mg
    biurea/kg (equivalent to approximately 450 mg/kg body weight per day)
    (Oser & Oser, 1963; Oser et al., 1965). For each generation, rats were
    mated twice, and the first litter was sacrificed at weaning. From the
    second litter, 10 males and 10 females were chosen at random to form
    the parents for the next generation. The study finished with the
    weaning of the F3 generation. For each generation, fertility index
    (percentage of matings resulting in pregnancy), gestation index
    (number of pregnancies resulting in live litters), viability index
    (numbers of pups surviving 4 or more days), and lactation index
    (numbers of pups alive at 4 days surviving to weaning) were
    determined. No reproductive effects were observed.

         The only other information available is that no organ weight or
    histological changes were observed in the reproductive organs of rats
    and mice repeatedly exposed for 13 weeks to up to 200 mg
    azodicarbonamide/m3 by inhalation (see section 8.4.1, Medinsky et
    al., 1990).

         The developmental toxicity of azodicarbonamide has not been
    studied.

    8.7  Immunological and neurological effects

         No studies are available that specifically investigate these
    endpoints, and there is no relevant information from toxicity studies
    in animals.

                  
    1 The authors of this CICAD have been informed that a reproductive
      toxicity screening test is being conducted according to OECD test
      method 421.
    

    9.  EFFECTS ON HUMANS

         The effects of exposure to azodicarbonamide in humans have not
    been fully evaluated. There are no data detailing the effects of
    single exposures by any route. The most frequently reported effects of
    repeated exposure to azodicarbonamide are respiratory symptoms as well
    as, to a lesser extent, skin sensitization reactions. There are no
    reports relating to the potential for azodicarbonamide to produce
    other systemic adverse effects. The potential genotoxic, carcinogenic,
    and reproductive effects of azodicarbonamide in exposed humans have
    not been studied.

    9.1  Case reports

         A number of reports have been published of individual
    azodicarbonamide workers alleging asthma induced by exposure to
    azodicarbonamide. The strongest evidence comes from a study of two
    individuals (one atopic and one non-atopic) who worked at the same
    plastics factory for about 4 years (Malo et al., 1985; Pineau et al.,
    1985). Both were intermittently exposed (1-2 weeks' duration, 3-4
    times per year) to azodicarbonamide at work. A few months after their
    first encounter with azodicarbonamide, both developed symptoms
    described as "eye/nose irritation" at work, followed a few hours later
    by nocturnal asthmatic symptoms. After a 1-month period free from
    exposure, both subjects underwent lung provocation studies. Baseline
    values for forced expiratory volume in 1 s (FEV1), forced vital
    capacity (FVC), and the concentration of histamine required to produce
    a 20% drop in FEV1 (PC20H) were obtained by spirometry. Both
    subjects performed a control challenge using lactose and then a 50:50
    mixture of lactose and azodicarbonamide for 15 s on the next day. On
    both days, lung function was monitored to follow the time course of
    any response. It was reported that the trial was not carried out
    blind.

         No effects on lung function were observed following challenge
    with lactose alone. After the azodicarbonamide challenge, however, the
    atopic individual developed a late respiratory response starting 3 h
    after challenge and reaching a maximum 24% drop in FEV1 6 h after
    challenge. A drop in PC20H was also reported, demonstrating increased
    airway hyperreactivity, and this parameter did not return to the
    baseline value until 6 weeks after challenge. The non-atopic
    individual showed a dual response to azodicarbonamide. Peak reductions
    in FEV1 of greater than 20% were recorded 30 min and 5-6 h after
    exposure. No significant reduction in PC20H was reported for the
    second individual. A control atopic subject with underlying asthma who
    worked in the same industry but did not experience work-related
    respiratory effects was also tested. His baseline PC20H was similar
    to that of the atopic subject, but no change in lung function was
    observed following a 15-min exposure to azodicarbonamide under similar
    conditions (as this subject had less reactive airways, a much longer
    exposure duration was utilized). Owing to the insolubility of
    azodicarbonamide, skin prick tests were not performed.

         Six other cases have been reported in the literature, but in each
    case the evidence that azodicarbonamide was the cause of the
    respiratory symptoms is less strong. In some cases, there had been
    previous exposure in industries associated with potential exposure to
    other asthmagenic substances; for others, the bronchial challenge test
    was either poorly conducted or not conducted at all (Valentino &
    Comai, 1985; Alt & Diller, 1988; Normand et al., 1989).

         Three case reports on skin sensitization have been published. In
    the most recently reported investigation, a male textile worker
    exposed to azodicarbonamide in foam ear-plugs was patch tested to
    discover the cause of a recurrent dermatitis of the ear (Nava et al.,
    1983; Bonsall, 1984; Yates & Dixon, 1988). No response was elicited
    with a number of standard (International Contact Dermatitis Research
    Group standard series) allergens. However, the individual gave a
    strong positive reaction to the ear-plugs at 48 and 96 h and also to
    azodicarbonamide (a component of the ear-plugs) at a concentration of
    1 and 5% in petrolatum but not at 0.1% in petrolatum. Ten control
    subjects patch tested with 1 and 5% azodicarbonamide in petrolatum did
    not respond, and the individual reported no further symptoms upon
    discarding the ear-plugs.

    9.2  Epidemiological studies

         Workplace health surveys have also been carried out where
    azodicarbonamide was either manufactured or used to investigate the
    presence of respiratory symptoms in azodicarbonamide workers.

         A prevalence study of occupational asthma was carried out among a
    group of 151 workers at a factory manufacturing azodicarbonamide
    (Slovak, 1981). Diagnosis of asthma was made on the basis of an
    administered questionnaire and a detailed occupational history taken
    by the author. The population was divided into three groups: those
    classified as potentially sensitized, on the basis of questionnaire
    results; those with daily exposure but without symptoms; and those
    with no exposure to azodicarbonamide or any other known sensitizer. On
    one day, pre- and post-shift spirometry was performed, and FEV1, FVC,
    and the FEV1/FVC ratio were determined. Skin prick tests were also
    attempted using both common allergens to determine atopic status and
    azodicarbonamide at concentrations of 0.1, 1, and 5% in dimethyl
    sulfoxide. Concurrent personal sampling measurements were made to
    determine the levels of airborne azodicarbonamide to which individuals
    were exposed.

         Personal sampling indicated that, at the time of the
    investigation, airborne concentrations of azodicarbonamide ranged
    between 2 and 5 mg/m3, as 8-h time-weighted averages. From the
    questionnaires and occupational histories, 28 individuals (18.5%) were
    diagnosed as having asthma apparently related to azodicarbonamide
    exposure. Twelve further cases of occupational asthma were identified
    from company records of past employees. Skin prick tests with
    azodicarbonamide could not be adequately performed owing to the
    insolubility of the substance.

         Of the 28 current workers classified as sensitized, over half
    developed symptoms within 3 months of first exposure and 21/28 (75%)
    within 1 year. Symptoms and signs included shortness of breath, chest
    tightness, wheezing, cough, rhinitis, conjunctivitis, and rash.
    Reactions were of an immediate type for 6/28 (21%) individuals, late
    onset for 16/28 (57%), and dual onset for 6/28 workers. Of those
    showing a dual response, all but one had initially shown a late onset
    pattern. A total of 13/28 (46%) workers reported worsening of symptoms
    with continuing exposure to azodicarbonamide and a shortening of the
    time between returning to work and reappearance of symptoms. Eight out
    of 13 workers exposed to azodicarbonamide for more than 3 months after
    development of symptoms also developed sensitivity to previously
    well-tolerated irritants (e.g., sulfur dioxide and tobacco smoke),
    which persisted for over a month after removal from exposure to
    azodicarbonamide. In five individuals, this airway hyperreactivity
    persisted for over 3 years. There were no changes in FEV1 or FVC over
    the work shift in any group. In view of the latency in development of
    effects, late or dual onset of symptoms in 12/28 (43%) symptomatic
    workers, increase in sensitivity with repeated exposure, and the
    persisting lung hyperreactivity in workers with prolonged exposure
    after developing symptoms, it seems likely that these individuals had
    become sensitized to azodicarbonamide.

         Ahrenholz & Anderson (1985) and Whitehead et al. (1987) conducted
    detailed investigations of the workforce at a plastics factory
    employing about 325 workers. Lung function tests and interviews to
    gather information on occupational history, smoking habits, past
    illnesses, and respiratory, nasal, eye, and skin irritation, including
    the time course of any symptoms, were carried out with a large
    percentage of the workforce. There were no clear differences in the
    results of lung function studies between those exposed to
    azodicarbonamide and non-exposed individuals. However, responses to
    the questionnaire revealed a significant association between symptoms
    of irritation, cough, wheezing, shortness of breath, and headache and
    present or previous employment as an injection mould operator. There
    was also a slight but not statistically significant increase in the
    reporting of skin rash among those with current or previous work in
    the injection moulding department. The prevalence of all the above
    symptoms was reduced among those whose employment in this department
    was limited to the period before azodicarbonamide was introduced or
    after a change in the process significantly reduced the use of
    azodicarbonamide at the plant.

         Personal sampling showed that concentrations of airborne
    azodicarbonamide ranged from below the limit of detection (0.001
    mg/m3) to 0.32 mg/m3 (median 0.006 mg/m3; geometric mean 0.004
    mg/m3) averaged over the full shift. The highest concentration of
    azodicarbonamide recorded (for an injection mould operator) was 0.01
    mg/m3. Toluene, styrene, phenols, and triphenyl phosphate were also
    detected at concentrations at or below the odour threshold for each
    substance.

         Other personal sampling data for a group of 17 individuals
    revealed levels of azodicarbonamide ranging from traces to 0.8 mg/m3
    (median 0.03 mg/m3; geometric mean 0.02 mg/m3) averaged over the
    full shift. The second highest value recorded was 0.4 mg/m3, and the
    next highest, 0.06 mg/m3. A moderate although statistically
    significant reduction in FEV1 (mean reduction of 64 ml) and FVC (mean
    reduction of 77 ml) occurred following shifts in which workers were
    exposed to azodicarbonamide. Coughing at work, wheeze, and chest
    tightness were also reported, and symptoms were apparently worse
    during the week than on Sunday.

         A detailed investigation of the workforce at a plant making floor
    coverings was conducted after nosebleeds, mucous membrane irritation,
    and skin rashes were reported in workers handling azodicarbonamide
    (Ahrenholz et al., 1985). Two surveys were carried out. The initial
    survey revealed, in decreasing order of prevalence, symptoms of eye
    irritation, nose irritation, cough, nocturnal cough, shortness of
    breath, wheeze, and chest tightness. The more extensive follow-up
    survey was conducted 6 weeks later. Pre- and post-shift auscultation,
    lung function tests, and respiratory symptoms (recorded by
    questionnaire) were recorded. Blood samples were also taken for
    immunological investigations.

         Responses to the questionnaire revealed 15/30 regularly exposed
    workers experiencing occupationally related lower respiratory tract
    symptoms (cough, wheeze, and shortness of breath) compared with 1/16
    never-exposed workers. No significant differences in pre- and
    post-shift FEV1 and FVC measurements were found. For those workers
    apparently not exposed to azodicarbonamide or exposed indirectly
    (working in the vicinity but not directly handling azodicarbonamide),
    levels (8-h time-weighted average) ranged from <0.001; to 0.1 mg/m3.
    However, during weighing and charging operations, peaks of between
    0.15 and 12 mg/m3 (median 2.7 mg/m3) were measured for individuals
    directly involved.
    

    10.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         Azodicarbonamide has been tested under OECD Guideline protocols
    in one species of fish and in the water flea ( Daphnia magna);
    results are in an unpublished industry report, which has not been
    peer-reviewed (see Table 1). A second study, not conducted to a
    protocol or under Good Laboratory Practices, showed no effect of an
    azodicarbonamide solution analysed at 8 mg/litre on the zebra fish
    ( Brachydanio rerio).1 There was no effect on oxygen consumption of
    sewage sludge organisms exposed over 3 h to azodicarbonamide at
    >10; 000 mg/litre (this is substantially greater than the solubility
    of the compound, and no information is available on how this
    concentration was achieved).2 Overall, it is not possible to draw
    firm conclusions from these studies.

                  
    1 IUCLID (European Union database), version dated 7 February 1996.

    2 Bayer, unpublished value (1988) presented in IUCLID (European
      Union database), version dated 7 February 1996; no details
      available.


        Table 1: Acute studies on toxicity to aquatic organisms.
                                                                                                 

    Organism                   Protocol        End-point         Concentration     Reference
                                                                 (mg/litre)
                                                                                                 

    Fathead minnow             OECD 203        96-h NOEC         >50               Uniroyal (1992)
    (Pimephales promelas)

    Water flea                 OECD 202        48-h NOEC         4.8 (measured)    Uniroyal (1992)
    (Daphnia magna)                                              ~16 (nominal)

                                               48-h EC50         11 (measured)
                                               immobilization    29 (nominal)
                                                                                                 
        


    11.  EFFECTS EVALUATION

    11.1  Evaluation of health effects

    11.1.1  Hazard identification and dose-response assessment

         Some of the available toxicological studies have been conducted
    using biurea rather than azodicarbonamide. However, azodicarbonamide
    is readily converted to biurea  in vivo. Hence, similar toxicological
    properties would be expected.

         Azodicarbonamide is of low acute toxicity by all routes, and,
    although the animal studies are of uncertain quality, solid
    azodicarbonamide would not be regarded as a skin or eye irritant. With
    respect to respiratory tract irritation, no changes of toxicological
    significance were seen in guinea-pigs exposed to azodicarbonamide
    aerosol at concentrations up to 97 mg/m3 for 1 h.

         No conclusions could be drawn regarding skin sensitization
    potential from the available, poor-quality animal studies. Although
    there are currently no validated animal studies investigating
    asthmagenic potential, there was no evidence of pulmonary irritation
    or asthmatic-type reactions in guinea-pigs exposed to up to 200 mg
    azodicarbonamide aerosol/m3 for 6 h/day, 5 days/week, for 4 weeks.

         Similarly, there were no changes of toxicological significance
    seen among rats or mice exposed by inhalation to up to 200 mg
    azodicarbonamide aerosol/m3 for 6 h/day, 5 days/week, for up to 13
    weeks.

         For repeated-dose studies using the oral route, data were
    inconsistent. In 2-year studies in which rats received up to 450 mg
    biurea/kg body weight per day, there were no adverse effects seen.
    Unpublished information suggests that no adverse effects were seen in
    male mice exposed to up to 1250 mg azodicarbonamide/kg body weight per
    day and in female mice exposed to up to 2500 mg/kg body weight per day
    for 13 weeks. However, shorter-term studies (2 weeks, also
    unpublished) indicated histological lesions in the kidneys of rats and
    mice of both sexes at 1250 mg/kg body weight per day or more. A
    13-week study in rats indicated kidney lesions in males at 2500 mg/kg
    body weight per day, with no adverse effects observed at the next
    lowest exposure level, 500 mg/kg body weight per day. For female rats,
    kidney lesions were observed at 5000 mg/kg body weight per day, and no
    adverse effects were observed at 1000 mg/kg body weight per day. There
    were no data in relation to repeated dermal exposure.

         Azodicarbonamide has been identified as a mutagen in bacterial
    systems, but it was not mutagenic in mammalian cell  in vitro test
    systems or in two mammalian assays  in vivo using bone marrow. It is
    therefore unlikely that the mutagenic properties displayed by
    azodicarbonamide in bacterial systems will be expressed  in vivo.
    However, it is considered that a confirmatory  in vivo study in a
    second tissue is desirable.

         There are no adequate data available relating to carcinogenic,
    reproductive, or developmental effects; hence, it is not possible to
    evaluate the risk to human health for these end-points.

         Several bronchial challenge studies have been reported, but only
    one provides reasonable evidence that the work-related asthmatic
    symptoms were due specifically to azodicarbonamide. This report is
    considered to show an asthmatic response and not an irritant response
    to azodicarbonamide on challenge. Animal studies suggest that airborne
    concentrations of up to 200 mg/m3 can be tolerated with little or no
    pulmonary irritation, and it is unlikely that the levels used in the
    bronchial challenge tests approached those used in animal studies. The
    delay in response to azodicarbonamide challenge, the magnitude of
    reduction in FEV1 accompanied by an increase in airway
    hyperreactivity in one individual, and the fact that a control
    individual with mildly hyperreactive airways did not respond to a much
    more prolonged exposure under similar challenge conditions provide
    further evidence for asthmagenicity. Further evidence of a link
    between azodicarbonamide and respiratory problems is provided by the
    results of workplace health evaluations. Although criticisms can be
    levelled at individual studies, weight of evidence suggests that
    azodicarbonamide can induce asthma in a significant proportion of
    exposed people.

         There are some case reports of individuals with skin reactions to
    topically applied azodicarbonamide. For some of these, results are
    questionable. However, in workplace health surveys, the incidence of
    skin rash was found to be greater among workers regularly exposed to
    azodicarbonamide. Although no firm conclusions could be drawn from the
    poorly reported animal study, clear evidence of skin sensitization to
    azodicarbonamide in one individual and supporting evidence of skin
    problems from workplace health surveys lead to the conclusion that
    azodicarbonamide should be considered as a human skin sensitizer.

         In conclusion, the key toxic effect of azodicarbonamide in humans
    is asthmagenicity. Evidence of this effect has been found from
    bronchial challenge studies and workplace health evaluations. From the
    information available, azodicarbonamide is considered to have a low
    potential for irritancy; thus, it is considered that the respiratory
    symptoms observed in these studies are most likely due to an
    asthmatic-type response rather than respiratory tract irritancy. There
    is no clear information on the levels that may have induced or
    provoked the state of asthma.

         There is also information to indicate that azodicarbonamide can
    cause skin sensitization in humans.

    11.1.2  Criteria for setting guidance values for azodicarbonamide

         The main cause for concern relates to the risk of developing
    occupational asthma. There is no information available relating to
    dose-response relationships or levels associated with the induction of
    a hypersensitive state or provocation of an asthmatic response. Hence,
    it is not possible to reliably quantify the risk of developing
    occupational asthma.

    11.1.3  Sample risk characterization

         Using data obtained from a factory in the United Kingdom and
    published exposure data as an example (section 6.2), levels of
    airborne azodicarbonamide measured over periods of <70; min to 4 h of
    up to 12 mg/m3 have been observed. Short-term peak exposures could be
    higher than this level.

         In the United Kingdom occupational setting, it is recommended
    that a maximum exposure limit (MEL) be assigned to substances for
    which it has not been possible to identify a level of exposure that is
    without adverse effects on health. This is a non-health-based
    standard, and, in determining the most appropriate level for a MEL,
    consideration is taken of the level of control that it is reasonably
    practicable for industry to achieve. The MEL of 1 mg/m3 
    (8-h time-weighted average) was based on a level of control that was 
    deemed by tripartite agreement to be reasonably practicable under 
    workplace conditions within the United Kingdom. There is also a 
    continuing remit for industry to keep on reducing exposure levels as 
    advances in technology make this possible. For substances that are 
    asthmagens, it is also advisable to have a short-term exposure limit 
    (STEL) to restrict peak exposures, as they may have a role in the 
    induction and triggering of asthmatic phenomena. In the absence of any 
    specific data that might advise adequately on the numerical value of 
    the STEL, 3 mg/m3 (15-min reference period) has been established.

         As azodicarbonamide is a skin sensitizer, where skin contact can
    occur, there may be a risk of developing allergic dermatitis if
    suitable personal protective equipment is not used.

         There is evidence to suggest that azodicarbonamide has been added
    to consumer products such as bread and beer. The limited toxicology
    database and lack of exposure data make it difficult to adequately
    assess the risk to humans potentially exposed; hence, there is a need
    for further information.

    11.2  Evaluation of environmental effects

         Lack of information on release to the environment precludes a
    quantitative risk assessment.
    

    12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         Previous evaluations by international bodies were not identified.
    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 preventive and protective
    measures and first aid recommendations, are presented in the
    International Chemical Safety Card (ICSC 0380) reproduced in this
    document.

    13.1  Human health hazards

         Azodicarbonamide is of low acute toxicity, but repeated or
    prolonged contact may cause asthma and skin sensitization.

    13.2  Health surveillance advice

         Physicians involved in worker health surveillance programmes
    should be aware of the potential of azodicarbonamide as a human
    asthmagen.
    

    14.  CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

         Information on national regulations, guidelines, and standards
    may be obtained from UNEP Chemicals (IRPTC), Geneva.

         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
                                                                                                                           

    AZODICARBONAMIDE                                             ICSC:0380
                                                                 October 1997
                                                                                                                           
    CAS#      123-77-3                      Diazenedicarboxamide
    RTECS #   LQ1040000                     1,1'-Azobisformamide
    UN #      3242                          C2H2N4O2/NH2CON=NCONH2
    EC3       611-028-00-3
                                            Molecular mass: 116.1
                                                                                                                           
    TYPES OF HAZARD/        ACUTE HAZARDS/                  PREVENTION                     FIRST AID/
    EXPOSURE                SYMPTOMS                                                       FIRE FIGHTING
                                                                                                                           
    FIRE                    Flammable. Gives off            NO open flames, NO sparks,     Foam, powder.
                            irritating or toxic fumes       and NO smoking.
                            (or gases) in a fire.
                                                                                                                           
    EXPLOSION
                                                                                                                           
    EXPOSURE                                                PREVENT DISPERSION OF
                                                            DUST! STRICT HYGIENE!
                                                                                                                           
    Inhalation              Cough. Headache. Shortness of   Local exhaust or breathing     Fresh air, rest.
                            breath. Sore throat. Wheezing.  protection.                    Refer for medical
                            Fatigue. Cramps.                                               attention.
                                                                                                                           
    Skin                    Redness.                        Protective clothing.           Remove contaminated clothes.
                                                                                           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                                               Do not eat, drink, or smoke    Rinse mouth. Give
                                                            during work.                   plenty of water to drink.
                                                                                           Rest.
                                                                                                                           
    SPILLAGE DISPOSAL                                       PACKAGING & LABELLING
                                                                                                                           
    Sweep spilled substance into sealable containers;       EU Classification
    if appropriate, moisten first to prevent dusting.       Symbol: Xn
    Carefully collect remainder, then remove to safe        R: 42-44
    place (extra personal protection; P2 filter             S: (2-)22-24-37
    respirator for harmful particles).                      UN Classification
                                                            UN Hazard Class: 4.1
                                                            UN Pack Group: II
                                                                                                                           

    EMERGENCY RESPONSE                                      STORAGE
                                                                                                                           
    Transport Emergency Card: TEC (R)-41G19

                                                                                                                           
                                         IMPORTANT DATA
                                                                                                                           
    PHYSICAL STATE; APPEARANCE:                             ROUTES OF EXPOSURE:
    ORANGE RED CRYSTALS OR YELLOW POWDER.                   The substance can be absorbed into the body by
                                                            inhalation of its aerosol.

    CHEMICAL DANGERS:                                       INHALATION RISK:
    The substance decomposes on heating or on burning       Evaporation at 20°C is negligible;
    producing toxic fumes (nitrogen oxides).                a harmful concentration of airborne particles
                                                            can, however, be reached quickly.

    OCCUPATIONAL EXPOSURE LIMITS:                           EFFECTS OF SHORT-TERM EXPOSURE:
    TLV not established.                                    The substance irritates the eyes and the respiratory
                                                            tract. Inhalation of dust may cause asthmatic
                                                            reactions (see Notes).

                                                            EFFECTS OF LONG-TERM OR REPEATED EXPOSURE:
                                                            Repeated or prolonged contact with skin may cause
                                                            dermatitis. Repeated or prolonged contact may cause
                                                            skin sensitazation. Repeated or prolonged inhalation
                                                            exposure may cause asthma.
                                                                                                                           

                                         PHYSICAL PROPERTIES
                                                                                                                           
    Melting point (decomposed):    225°C
    Relative density (water = 1):  1.65
    Solubility in water:           none
                                                                                                                           
                                         ENVIRONMENTAL DATA
                                                                                                                           

                                                                                                                           
                                                NOTES
                                                                                                                           
    The symptoms of asthma often do not become manifest until a few hours have passed and they are aggravated
    by physical effort. Rest and medical observation are therefore essential. Anyone who has shown symptoms
    of asthma due to this substance should avoid all further contact with this substance. Genitron AC,
    Kempore 125, Porofor LK 1074 and Unifoam AZ are trade names.
                                                                                                                           

                                         ADDITIONAL INFORMATION
                                                                                                                           



                                                                                                                           

    LEGAL NOTICE    Neither the CEC nor the IPCS nor any person acting on behalf of the CEC or the IPCS is
                    responsible for the use which might be made of this information.
    

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    Malo J, Pineau L, Cartier A (1985) Occupational asthma due to
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    MB Research Laboratories Inc. (1986)  Acute dermal toxicity in
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    Medinsky M, Bechtold W, Birnbaurn L, Bond J, Burt D, Cheng Y, Gillett
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    Mewhinney J, Ayres P, Bechtold W, Dutcher J, Cheng Y, Bond J, Medinsky
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    Normand J, Grange F, Hernandez C, Ganay A, Davezies P, Bergeret A,
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    Oser B, Oser M, Morgareidge K, Stemberg S (1965) Studies of the safety
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    Pineau L, Cartier A, Malo J-L (1985) Occupational asthma due to
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    Shopp G, Cheng Y, Gillet N, Bechtold W, Medinsky M, Hobbs C, Birnbaum
    L, Mauderly J (1987) Acute inhalation exposure of azodicarbonamide in
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    Uniroyal (1992) Unpublished report from the Uniroyal Chemical Company
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    Vainiotalo S, Pfaffli P (1988) Measurement of azodicarbonamide in
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     occupational hygiene, 43:203-208.

    Valentino M, Comai M (1985) Occupational asthma from azodicarbonamide:
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    Whitehead L, Robins T, Fine L, Hansen D (1987) Respiratory symptoms
    associated with the use of azodicarbonamide foaming agent in a
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    Yates V, Dixon J (1988) Contact dermatitis from azodicarbonamide in
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    APPENDIX 1 -- SOURCE DOCUMENT

    Ball et al. (1996):  Azodicarbonamide; Criteria document for an
     occupational exposure limit

         The authors' first draft was initially reviewed internally by a
    group of approximately 10 United Kingdom Health and Safety Executive
    experts (mainly toxicologists, but also scientists involved in other
    relevant disciplines, such as epidemiology and occupational hygiene).
    The toxicology section of the amended draft was then reviewed by
    toxicologists from the United Kingdom Department of Health.
    Subsequently, the entire criteria document was reviewed by a
    tripartite advisory committee to the United Kingdom Health and Safety
    Commission, the Working Group for the Assessment of Toxic Chemicals
    (WATCH). This committee is composed of experts in toxicology and
    occupational health and hygiene from industry, trade unions, and
    academia.

         The members of the WATCH committee at the time of the peer review
    were Mr S.R. Bailey, Independent Consultant; Professor J. Bridges,
    University of Surrey; Dr H. Cross, Trade Unions Congress; Dr A
    Fletcher, Trade Unions Congress; Dr I.G. Guest, Chemical Industries
    Association; Dr A. Hay, Trade Unions Congress; Dr J. Leeser, Chemical
    Industries Association; Dr L. Levy, Institute of Occupational Hygiene,
    Birmingham; Mr A. Moses, Chemical Industries Association; Dr R. Owen,
    Trade Unions Congress; and Dr M. Sharratt, University of Surrey.
    

    APPENDIX 2 -- CICAD PEER REVIEW

         The draft CICAD on azodicarbonamide 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:

         Department of Health, London, United Kingdom

         Health Canada, Ottawa, Canada

         International Agency for Research on Cancer, Lyon, France

         József Fodor National Center of Public Health, Budapest, Hungary

         National Chemicals Inspectorate (KEMI), Solna, Sweden

         National Institute of Public Health, Prague, Czech Republic

         National Institute of Public Health and Environmental Protection,
         Bilthoven, The Netherlands

         United States Department of Health and Human Services (National
         Institute for Occupational Safety and Health, Cincinnati, USA;
         National Institute of Environmental Health Sciences, Research
         Triangle Park, USA)

         United States Environmental Protection Agency (Drinking Water
         Program, Denver, USA)
    

    APPENDIX 3 -- CICAD FINAL REVIEW BOARD

    Tokyo, Japan, 30 June - 2 July 1998

    Members

    Dr R. Benson, Drinking Water Program, United States Environmental
    Protection Agency, Denver, CO, USA

    Dr T. Berzins, National Chemicals Inspectorate (KEMI), Solna, Sweden

    Mr R. Cary, Health Directorate, Health and Safety Executive,
    Merseyside, United Kingdom

    Dr C. DeRosa, Agency for Toxic Substances and Disease Registry, Center
    for Disease Control and Prevention, Atlanta, GA, USA

    Dr S. Dobson, Institute of Terrestrial Ecology, Cambridgeshire, United
    Kingdom

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

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

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

    Ms M.E. Meek, Environmental Health Directorate, Health Canada, Ottawa,
    Ontario, Canada ( Chairperson)

    Dr J. Sekizawa, Division of Chem-Bio Informatics, National Institute
    of Health Sciences, Tokyo, Japan ( Vice-Chairperson)

    Professor S.A. Soliman, Department of Pesticide Chemistry, Alexandria
    University, Alexandria, Egypt

    Ms D. Willcocks, Chemical Assessment Division, Worksafe Australia,
    Camperdown, Australia ( Rapporteur)

    Professor P. Yao, Chinese Academy of Preventive Medicine, Institute of
    Occupational Medicine, Beijing, People's Republic of China

    Observers

    Professor F.M.C. Carpanini,1 Secretary-General, ECETOC (European
    Centre for Ecotoxicology and Toxicology of Chemicals), Brussels,
    Belgium
                 
    1 Invited but unable to attend.
    Dr M. Ema, Division of Biological Evaluation, National Institute of
    Health Sciences, Osakai, Japan 

    Mr R. Green,1 International Federation of Chemical, Energy, Mine and
    General Workers' Unions, Brussels, Belgium

    Dr B. Hansen,1 European Chemicals Bureau, European Commission, Ispra,
    Italy

    Mr T. Jacob,1 Dupont, Washington, DC, USA

    Dr H. Koeter, Organisation for Economic Co-operation and Development,
    Paris, France

    Mr H. Kondo, Chemical Safety Policy Office, Ministry of International
    Trade and Industry, Tokyo, Japan

    Ms J. Matsui, Chemical Safety Policy Office, Ministry of International
    Trade and Industry, Tokyo, Japan

    Mr R. Montaigne,1 European Chemical Industry Council (CEFIC),
    Brussels, Belgium

    Dr A. Nishikawa, Division of Pathology, National Institute of Health
    Sciences, Tokyo, Japan

    Dr H. Nishimura, Environmental Health Science Laboratory, National
    Institute of Health Sciences, Osaka, Japan

    Ms C. Ohtake, Chem-Bio Informatics, National Institute of Health
    Sciences, Tokyo, Japan

    Dr T. Suzuki, Division of Food, National Institute of Health Sciences,
    Tokyo, Japan

    Dr K. Takeda, Mitsubishikasei Institute of Toxicological and
    Environmental Sciences, Yokohama, Japan

    Dr K. Tasaka, Department of Chemistry, International Christian
    University, Tokyo, Japan

    Dr H. Yamada, Environment Conservation Division, National Research
    Institute of Fisheries Science, Kanagawa, Japan

    Dr M. Yamamoto, Chem-Bio Informatics, National Institute of Health
    Sciences, Tokyo, Japan

                  
    1 Invited but unable to attend.

    Dr M. Yasuno, School of Environmental Science, The University of Shiga
    Prefecture, Hikone, Japan

    Dr K. Ziegler-Skylakakis, GSF-Forschungszentrum für Umwelt und
    Gesundheit GmbH, Institut für Toxikologie, Oberschleissheim, Germany

    Secretariat

    Ms L. Regis, International Programme on Chemical Safety, World Health
    Organization, Geneva, Switzerland

    Mr A. Strawson, Health and Safety Executive, London, United Kingdom

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

    RÉSUMÉ D'ORIENTATION

         Ce CICAD relatif à l'azodicarbonamide a été préparé à partir
    d'une étude du Health and Safety Executive du Royaume-Uni sur les
    risques pour la santé humaine (risques professionnels pour
    l'essentiel) (Ball et al., 1996). De ce fait, bien qu'il comporte un
    volet sur l'évaluation des données écologiques disponibles, il est
    principalement centré sur les risques pour la santé humaine sur les
    lieux de travail et tout particulièrement sur les voies d'exposition
    professionnelle à prendre en considération. L'analyse des données sur
    lesquelles repose l'étude a été arrêtée à juin 1994. Un dépouillement
    de la littérature a été ensuite effectué jusqu'à juillet 1997, à la
    recherche de données qui auraient pu être publiées depuis la fin de
    l'étude. Le document original ne prend pas en considérations les
    problèmes d'ordre écologique et comme le dépouillement de la
    littérature n'a pas permis de trouver trace de travaux qui leur soit
    consacrés, on n'a pas cherché à procéder à une évaluation des risques
    pour l'environnement. On trouvera à l'appendice 1 des indications sur
    les sources documentaires utilisées et sur leur mode de dépouillement.
    Les renseignements concernant l'examen du CICAD par des pairs font
    l'objet de l'appendice 2. Ce CICAD a été approuvé en tant
    qu'évaluation internationale lors d'une réunion du Comité d'évaluation
    finale qui s'est tenue à Tokyo (Japon) du 30 juin au 2 juillet 1998.
    La liste des participants à cette réunion figure à l'appendice 3. La
    fiche d'information internationale sur la sécurité chimique (ICSC No
    0380) établie par le Programme international sur la Sécurité chimique
    (IPCS, 1993) est également reproduite dans ce document.

         Les données toxicocinétiques sur l'azodicarbonamide (No CAS
    123-77-3) sont limitées, mais ce composé se révèle être bien absorbé
    chez les rongeurs après inhalation ou ingestion. Une fraction notable
    de l'azocarbonamide traverse cependant les voies digestives sans être
    résorbé et se retrouve dans les matières fécales. L'azodicarbonamide
    est facilement transformé en biurée ou dicarbamylhydrazine, le seul
    métabolite qui ait été identifié et il est probable que l'exposition
    par la voie générale concerne ce dernier dérivé plutôt que la molécule
    initiale. Après absorption, l'élimination de l'azocarbonamide ou de la
    biurée est rapide et s'effectue principalement par la voie urinaire,
    la biurée étant très peu retenue dans l'organisme.

         L'azocarbonamide présente une faible toxicité aiguë et il ne
    provoque pas d'irritation cutanée, oculaire ou respiratoire chez les
    animaux d'expérience. Des résultats négatifs ont été obtenu lors d'une
    étude de la sensibilisation cutanée, d'ailleurs mal conduite, et une
    autre étude, effectuée sur des cobayes, n'a pas révélé de réaction de
    nature asthmatiforme. Aucun effet indésirable n'a été observé chez des
    animaux de laboratoire à qui on en avait fait inhaler pendant des
    durées allant jusqu'à 13 semaines à des doses pouvant atteindre
    200 mg/m3. Une exposition répétée par la voie orale a entraîné des
    lésions évocatrices de pyélonéphrite avec présence intratubulaire de

    cylindres et de dépôts cristallins chez plusieurs espèces. Cependant,
    il a fallu une dose élevée pour provoquer ces effets (>200; mg/kg de
    poids corporel par jour sur une durée pouvant aller jusqu'à 1 an).
    L'azodicarbonamide s'est révélé mutagène sur des systèmes bactériens,
    mais il n'est pas certain que cet effet se produise  in vivo. On n'a
    pas examiné en détail la cancérogénicité de l'azodicarbonamide, ni sa
    toxicité génésique, mais des études anciennes au cours desquelles des
    animaux avaient reçu son métabolite, la biurée, n'ont pas mis en
    évidence d'effets tumorigènes ou stérilisants. On n'a pas étudié son
    action toxique éventuelle sur le développement.

         Les études relatives à la santé humaine portent uniquement sur
    l'aptitude de l'azodicarbonamide à provoquer de l'asthme ou une
    sensibilisation cutanée. Des épreuves d'exposition bronchique
    effectuées sur des sujets symptomatiques de même que l'examen médical
    de personnes employées à la fabrication d'azodicarbonamide ou sur des
    lieux ou on en utilisait, ont révélé que le composé pouvait provoquer
    de l'asthme chez l'Homme. Certains indices permettent également de
    penser qu'il peut provoquer une sensibilisation cutanée.

         En se basant sur le fait que l'azodicarbonamide peut provoquer un
    asthme chez l'Homme et que l'on ignore à partir de quelle
    concentration cet asthme risque d'apparaître chez un sujet non
    sensible ou une réaction se manifester chez un sujet sensible, on est
    arrivé à la conclusion que dans les conditions actuelles d'exposition
    professionnelles, il y avait un risque pour la santé humaine. Compte
    tenu de l'incertitude sur la concentration à partir de laquelle il y a
    effectivement risque, il convient de réduire l'exposition le plus
    possible.

         On possède des données indiquant qu'il se forme du carbamate
    d'éthyle dans certains produits de consommation comme le pain ou la
    bière après addition d'azodicarbonamide. Faute de données, il n'a pas
    été possible d'évaluer le degré d'exposition de la population générale
    à l'azodicarbonamide.

         En cas de décharge dans les eaux superficielles, l'azocarbonamide
    se répartirait dans l'hydrosphère sans sorption importante aux
    matières particulaires. Dans le cas d'une réaction sur les radicaux
    hydroxyles de l'atmosphère, la demi-vie calculée est de 0,4 jour. Dans
    deux essais sur trois effectués avec des boues d'égout, on a constaté
    que l'azodicarbonamide se révélait facilement biodégradable et on
    observé une décomposition à 20-70 % dans le sol en 14 jours. La
    concentration sans effet observable pour les poissons et la puce d'eau
    a été trouvée respectivement égale à >50 et 5 mg/litre. En
    l'absence de renseignements sur la décharge d'azodicarbonamide dans
    l'environnement, on ne peut procéder à une évaluation quantitative du
    risque.
    

    RESUMEN DE ORIENTACION

         Este CICAD sobre la azodicarbonamida se basa en un examen de los
    problemas relativos a la salud humana (fundamentalmente ocupacionales)
    preparado por la Dirección de Salud y Seguridad del Reino Unido (Ball
    et al., 1996). Por consiguiente, aunque el presente CICAD incluye una
    evaluación de los datos ecológicos disponibles, se concentra sobre
    todo en el riesgo para la salud humana en las condiciones del trabajo,
    con particular atención a la información acerca de las rutas que son
    de interés para el entorno ocupacional. En este examen se han
    incorporado los datos identificados hasta junio de 1994. Se realizó
    una ulterior búsqueda bibliográfica hasta julio de 1997 para localizar
    la información nueva que se hubiera publicado desde la terminación del
    examen. En el documento original no se abordaban los problemas
    relativos al medio ambiente; dado que en la búsqueda bibliográfica no
    se han encontrado estudios de interés de este sector, no se ha
    intentado realizar una evaluación del riesgo para el medio ambiente.
    La información acerca del carácter del examen colegiado del documento
    original y su disponibilidad figura en el apéndice 1. La información
    sobre el examen colegiado de este CICAD aparece en el apéndice 2. Este
    CICAD se aprobó como evaluación internacional en una reunión de la
    Junta de Evaluación Final celebrada en Tokio, Japón, del 30 de junio
    al 2 de julio de 1998. La lista de participantes en esta reunión
    figura en el apéndice 3. La Ficha internacional de seguridad química
    (ICSC 0380) para la azodicarbonamida, preparada por el Programa
    Internacional de Seguridad de las Sustancias Químicas (IPCS, 1993),
    también se reproduce en el presente documento.

         Los datos toxicocinéticos sobre la azodicarbonamida 
    (CAS No 123-77-3) son limitados, pero parece que se absorbe bien en
    roedores por inhalación y por vía oral. Quedan sin absorber cantidades
    importantes de la sustancia en el sistema gastrointestinal, que se
    eliminan en las heces. La azodicarbonamida se convierte fácilmente en
    biurea, único producto de la biodegradación identificado, y es
    probable que haya exposición sistémica fundamentalmente a este
    derivado y no al compuesto original. La eliminación de la
    azodicarbonamida/biurea absorbida es rápida, sobre todo a través de la
    orina, y hay una retención sistémica de biurea muy escasa.

         La toxicidad aguda de la azodicarbonamida es baja y en los
    animales de experimentación no produce irritación cutánea, ocular o
    del aparato respiratorio. Los resultados de un estudio de
    sensibilización cutáneo poco fidedigno fueron negativos y en otro
    estudio no se obtuvieron pruebas de una respuesta de tipo asmático en
    cobayas. No se detectaron efectos adversos en animales de
    experimentación que inhalaron hasta 200 mg/m3 durante 13 semanas. La
    exposición oral repetida provocó pielonefritis con cilindros y
    depósitos cristalinos en los túbulos renales en varias especies. Sin
    embargo, las dosis necesarias para inducir estos efectos fueron altas
    (>200; mg/kg de peso corporal al día en estudios de hasta un año de
    duración). Si bien se observó que la azodicarbonamida era mutagénica

    en sistemas bacterianos, no hay pruebas de que este efecto aparezca
     in vivo. No se han examinado con detalle la carcinogenicidad y la
    toxicidad reproductiva de la azodicarbonamida, pero en estudios
    iniciales en los cuales se trataron animales con el producto de
    degradación, la biurea, no se detectaron efectos tumorígenos o
    anticonceptivos. No se ha estudiado la toxicidad en el desarrollo.

         Los estudios en el ser humano se han concentrado exclusivamente
    en la capacidad de la azodicarbonamida para inducir asma y
    sensibilización cutánea. En estudios de estímulo bronquial de personas
    sintomáticas y en evaluaciones de la salud de los empleados en lugares
    donde se fabrica o utiliza azodicarbonamida se ha comprobado que este
    producto puede inducir asma en el ser humano. Existen asimismo
    indicios de que la azodicarbonamida puede inducir sensibilización
    cutánea.

         A partir de la base de que la azodicarbonamida es un asmógeno
    humano y de que no se conocen las concentraciones que se requieren
    para inducir el asma en una persona no sensible o provocar una
    respuesta en una persona sensible, se llega a la conclusión de que
    existe un riesgo para la salud humana en las condiciones actuales de
    exposición ocupacional. El nivel del riesgo es incierto; por
    consiguiente, se deben reducir al máximo los niveles de exposición.

         Se conocen datos que indican que se forma etilcarbamato en
    productos de consumo como el pan y la cerveza después de la adición de
    azodicarbonamida. La exposición del público general no se pudo evaluar
    debido a la falta de datos disponibles.

         La azodicarbonamida liberada en las aguas superficiales se
    distribuiría en la hidrosfera con una sorción no significativa en
    partículas. La semivida para la reacción en la atmósfera con los
    radicales hidroxilo se calcula que es de 0,4 días. La biodegradación
    de la azodicarbonamida fue fácil en dos de las tres pruebas realizadas
    con lodos cloacales y la degradación en el suelo fue del 20%-70% en un
    período de 14 días. No se han notificado concentraciones sin efectos
    observados (NOEC) para peces y pulgas de agua a >50 y 5 mg/litro,
    respectivamente. La falta de información sobre la liberación en el
    medio ambiente impide una evaluación cuantitativa del riesgo.
    


    See Also:
       Toxicological Abbreviations
       Azodicarbonamide (ICSC)
       Azodicarbonamide (FAO Nutrition Meetings Report Series 40abc)
       AZODICARBONAMIDE (JECFA Evaluation)