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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 126



    PARTIALLY HALOGENATED CHLOROFLUROCARBONS
    (METHANE DERIVATIVES)









    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.

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

    Draft prepared by Professor D. Beritic-Stahuljak and
    Professor F. Valic, University of Zagreb, Yugoslavia,
    using texts made available by Dr. D.S. Mayer, Hoechst AG,
    Frankfurt am Main, Germany and by Dr. I.C. Peterson
    and Dr. G.D. Wade, ICI Central Toxicological Laboratory,
    Macclesfield, United Kingdom

    World Health Organization
    Geneva, 1991

          The International Programme on Chemical Safety (IPCS) is a joint
    venture of the United Nations Environment Programme, the International
    Labour Organisation, and the World Health Organization.  The main
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    the effects of chemicals on human health and the quality of the
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    with chemical accidents, coordination of laboratory testing and
    epidemiological studies, and promotion of research on the mechanisms
    of the biological action of chemicals.

    WHO Library Cataloguing in Publication Data

    Partially halogenated chlorofluorocarbons (methane derivatives).

          Environmental health criteria: 126)

          1. Freons - adverse effects   2. Freons - toxicity

          3. Environmental exposure     I. Series

          ISBN 92 4 157126 8         (NLM Classification QV 633)
          ISSN 0250-863X

    (c) World Health Organization 1991

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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR PARTIALLY
    HALOGENATED CHLOROFLUOROCARBONS (METHANE DERIVATIVES)

    INTRODUCTION

    1. SUMMARY

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

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

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

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1. Natural occurrence
         3.2. Anthropogenic sources
                3.2.1. Production levels
                3.2.2. Manufacturing processes
                3.2.3. Loss during disposal, transport, storage,
                        and accidents
         3.3. Use patterns
                3.3.1. Major uses
                3.3.2. Releases during use: controlled or
                        uncontrolled

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         4.1. Biodegradation and bioaccumulation
         4.2. Environmental transformation and interaction with
                other environmental factors

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1. Environmental levels
                5.1.1. Air
                5.1.2. Water
                5.1.3. Food and other edible products
         5.2. General population exposure
         5.3. Occupational exposure

    6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

         6.1. Animal studies
                6.1.1. Absorption
                6.1.2. Distribution
                6.1.3. Metabolic transformation
                6.1.4. Elimination
         6.2. Human studies
                6.2.1. Absorption and elimination
                6.2.2. Distribution

    7. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         7.1. Single exposure
                7.1.1. Acute oral toxicity
                7.1.2. Acute inhalation toxicity
         7.2. Short-term inhalation exposure
                7.2.1. HCFC 21
                7.2.2. HCFC 22
                7.2.3. Mixed exposure
         7.3. Skin and eye irritation; sensitization
                7.3.1. Skin irritation
                7.3.2. Eye irritation
                7.3.3. Skin sensitization
         7.4. Long-term inhalation exposure
         7.5. Reproduction, embryotoxicity, and teratogenicity
                7.5.1. Reproduction
                7.5.2. Embryotoxicity and teratogenicity
                        7.5.2.1   HCFC 21
                        7.5.2.2   HCFC 22
         7.6. Mutagenicity
                7.6.1. HCFC 21
                7.6.2. HCFC 22
         7.7. Carcinogenicity
         7.8. Special studies - cardiovascular and respiratory
                effects
                7.8.1. HCFC 21
                7.8.2. HCFC 22

    8. EFFECTS ON HUMANS

         8.1. General population exposure
                8.1.1. Accidents
                8.1.2. Controlled human studies
         8.2. Occupational exposure

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

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

         10.1. Evaluation of human health risks
                10.1.1. Direct health effects resulting from
                        exposure to partially halogenated
                        chlorofluorocarbons
                10.1.2. Health effects expected from a depletion of
                        stratospheric ozone by partially halogenated
                        chlorofluorocarbons
         10.2. Effects on the environment

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

         11.1. Conclusions
         11.2. Recommendations for protection of human health
                and the environment

    12. FURTHER RESEARCH

    13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    RESUME

    RESUMEN
    
    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR PARTIALLY
    HALOGENATED CHLOROFLUOROCARBONS (METHANE DERIVATIVES)

     Members

    Professor D. Beritic-Stahuljak, Andrija Stampar School of Public
         Health, University of Zagreb, Zagreb, Yugoslavia

    Dr B. Gilbert, Technology Development Company (CODETEC), Cidade
         Universitaria, Campinas, Brazil  (Joint Rapporteur)

    Professor H.A. Greim, Institute of Toxicology, Association for
         Radiation and Environmental Research, Neuherberg, Germany
          (Chairman)

    Dr H. Illing, Health and Safety Executive, Merseyside, United
         Kingdom

    Dr W. Jameson, Office of the Senior Scientific Advisor to the
         Director, National Institute of Environmental Health Sciences,
         Research Triangle Park, North Carolina, USA

    Dr H. Kraus, Chemicals Hazardous to the Environment, Federal
         Ministry for the Environment, Nature Conservation and Nuclear
         Safety, Bonn, Germany

    Dr J. Sokal, Department of Toxicity Evaluation, Institute of
         Occupational Medicine, Lodz, Poland

    Dr V. Vu, Oncology Branch, Office of Toxic Substances, US
         Environmental Protection Agency, Washington, DC, USA 

     Observers

    Dr D.S. Mayer, Department of Toxicology, Hoechst AG, Frankfurt am
         Main, Germany

    Dr H. Trochimowicz, E.I. Du Pont de Nemours & Co., Haskell
         Laboratory for Toxicology and Industrial Medicine, Newark,
         Delaware, USA

     Secretariat

    Professor F. Valic, Consultant, IPCS, World Health Organization,
         Geneva, Switzerland,  also Vice-Rector, University of Zagreb,
         Zagreb, Yugoslavia  (Responsible Officer and Secretary)

    Dr S. Swierenga, Health and Welfare Canada, Ottawa, Canada,  also
         Representative of the International Agency for Research on
         Cancer, Lyon, France  (Joint Rapporteur)

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

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

                                  * * *

         A detailed data profile and a legal file can be obtained from
    the International Register of Potentially Toxic Chemicals, Palais
    des Nations, 1211 Geneva 10, Switzerland (Telephone No. 7988400 or
    7985850).

    ENVIRONMENTAL HEALTH CRITERIA FOR PARTIALLY HALOGENATED
    CHLOROFLUOROCARBONS (METHANE DERIVATIVES)

         A Task Group on Environmental Health Criteria for Partially
    Halogenated Chlorofluorocarbons (Methane Derivatives) met at the
    Institute of Toxicology, Neuherberg, Germany, from 17 to 21 December
    1990. Professor H.A. Greim opened the meeting on behalf of the host
    institute. Dr H. Kraus spoke on behalf of the Federal Government,
    which sponsored the meeting. Professor F. Valic welcomed the members
    on behalf of the three cooperating organizations of the IPCS
    (UNEP/ILO/WHO). The Task Group reviewed and revised the draft
    criteria document, made an evaluation of the direct and indirect
    risks for human health from exposure to the partially halogenated
    chlorofluorocarbons reviewed, and made recommendations for health
    protection and further research.

         The first draft on HCFC 21 was prepared by Dr D.S. Mayer
    (Department of Toxicology, Hoechst AG, Frankfurt am Main, Germany)
    and on HCFC 22 by Dr I.C. Peterson and Dr J.D. Wade (ICI Central
    Toxicology Laboratory, Macclesfield, United Kingdom). The second
    draft of the monograph was prepared by Professors D. Beritic-
    Stahuljak and F. Valic. 

         Professor F. Valic was responsible for the overall scientific
    content, and Dr P.G. Jenkins, IPCS, for the technical editing of the
    monograph.

                                  *  *  *

         Financial support for the Task Group meeting was provided by
    the Ministry for the Environment, Nature Conservation and Nuclear
    Safety, Germany, which also generously supported the cost of
    printing this monograph.

    ABBREVIATIONS

    ALAT      alanine aminotransferase
    ASAT      aspartate aminotransferase
    CNS       central nervous system
    ECG       electrocardiogram
    EEC       European Economic Community
    FSH       follicle stimulating hormone
    GWP       global-warming potential
    HCFC      hydrochlorofluorocarbon
    ip        intraperitoneal
    LH        luteinizing hormone
    ODP       ozone-depletion potential
    TLV       threshold limit value
    UNEP      United Nations Environment Programme

    INTRODUCTION

         Chlorofluorocarbons were developed as refrigerants some 60
    years ago. However, their application soon significantly
    diversified, owing to their properties of non-flammability, chemical
    and thermal stability, and generally low toxicity. They are now used
    as blowing agents in foam insulation production, as propellants in
    aerosols, as cleaning agents of metals and electronic components,
    and to a lesser extent as chemical intermediates. Their current
    production is more than 1 000 000 tonnes per year with a market
    value estimated to be close to US$ l.5 billion. 

         Chlorofluorocarbons are very stable compounds, which remain
    intact in the air, releasing chlorine only when they reach the
    stratosphere. The active chlorine destroys ozone molecules, thus
    depleting the ozone layer, which is a natural barrier to ultraviolet
    radiation potentially harmful to human health and the environment.

         The growing global concern over this effect resulted in the
    development of the Vienna Convention for the Protection of the Ozone
    Layer, adopted in March 1985, and its "Montreal Protocol on
    Substances that Deplete the Ozone Layer", signed by 24 countries in
    September 1987. The agreement required a freeze in the production
    and use of the fully halogenated chlorofluorocarbons 11, 12, 113,
    114, and 115 at 1986 levels by mid-1989, a 20% reduction in their
    use from 1 July 1993, and a further 30% reduction from 1 July 1998.
    The Protocol has been in effect since January 1989; 67 countries and
    the European Economic Community had signed the Protocol by July
    1989. As a further development, the Helsinki Declaration, a non-
    binding agreement of April 1989, called for a total phase-out of the
    fully halogenated chlorofluorocarbons. The European Economic
    Community, the Nordic countries, Canada, the USA, and certain other
    countries have called for this complete phase-out, rather than a
    mere reduction in use of the fully halogenated chlorofluorocarbons.
    Adjustments of the Protocol were agreed by the Parties to the
    Protocol in June 1990. A total phase-out of 15 fully halogenated
    chlorofluorocarbons, halons 1211, 1301, and 2402, and carbon
    tetrachloride is to be effected by the year 2000. In addition,
    methyl chloroform must be phased out by the year 2005.

         These developments have created an urgent need for acceptable
    substitute chemicals. These should have similar physical and
    chemical properties and safety characteristics to the
    chlorofluorocarbons included in the Montreal Protocol. There should
    be a realistic anticipation that their commercial-scale production
    will be technologically and economically feasible, and their ozone-
    depleting potential and possible global-warming potential should be
    considerably lower.

         The phase-out of chlorofluorocarbons can also be accomplished
    by employing alternative technologies.

         The chemical industry worldwide is already engaged in efforts
    to develop substitutes for the chlorofluorocarbons included in the
    Montreal Protocol. In order to avoid the risk of introducing
    chemicals that could prove to be either health or environmental
    hazards, the toxicological and environmental evaluation of the
    potential substitutes is of utmost importance and urgence. There are
    already two international industry-supported efforts underway: the
    Programme for Alternative Fluorocarbon Toxicity Testing (PAFT), and
    the Alternative Fluorocarbon Environmental Acceptability Studies
    (AFEAS).

         There is a need to help prevent the use of harmful
    chlorofluorocarbons and of any substitutes for the harmful
    chlorofluorocarbons that would pose an unreasonable risk to human
    health or the environment. There is also a need for producers to
    make decisions about the manufacture of acceptable substitutes in
    time. Environmental Health Criteria 113: Fully Halogenated
    Chloroflurocarbons (WHO, 1990) evaluated ten fully halogenated
    chlorofluorocarbons. Among these are the five compounds included in
    the Montreal Protocol mainly on the basis of their high ozone-
    depleting potential and long residence times in the atmosphere. The
    ozone-depleting and global-warming potentials of the partially
    halogenated chlorofluorocarbons are considerably lower and their
    atmospheric residence times are shorter. Thus certain of these
    partially halogenated chlorofluorocarbons, i.e. those for which the
    toxicity evaluation suggests no unreasonable health or environmental
    risk and which are likely to be technologically and economically
    feasible, could be possible substitutes for the fully halogenated
    derivatives. In this monograph, the evaluation of two partially
    halogenated chlorofluorocarbons (methane derivatives) is presented.
    The evaluation of six other partially halogenated
    chlorofluorocarbons (ethane derivatives) has already started and
    will shortly be published in the Environmental Health Criteria
    series. The mere selection of a chemical for the evaluation
    programme of the IPCS does not mean its endorsement as a substitute
    chemical. Only a full toxicological and environmental evaluation can
    be a basis for such a conclusion.

    1.  SUMMARY

    1.1  Identity, physical and chemical properties, and analytical
         methods

         The two chlorofluorocarbons reviewed in this monograph
    (dichlorofluoromethane, HCFC 21, and chlorodifluoromethane, HCFC 22)
    are hydrochlorofluorocarbons (HCFCs), i.e. compounds derived by the
    partial substitution of the hydrogen atoms in methane with both
    fluorine and chlorine atoms. Only HCFC 22 has commercial
    significance. Both HCFC 21 and HCFC 22 are non-flammable gases (at
    normal temperatures and pressures), colourless, and practically
    odourless. HCFC 21 is slightly soluble and HCFC 22 moderately
    soluble in water, and both are miscible with organic solvents. HCFC
    22 is available as a liquified gas.

         There are several analytical methods for determining these two
    HCFCs. These include gas chromatography with electron capture and
    flame ionization detection, gas chromatography/mass spectrometry,
    and photothermal deflection spectrophotometry.

    1.2  Sources of human and environmental exposure

         The two HCFCs reviewed in this monograph are not known to occur
    as natural products. HCFC 21 is only produced in small quantities
    for non-occupational purposes. The total annual worldwide production
    of HCFC 22 was estimated in 1987 to be 246 000 tonnes.

         The main loss of HCFC 22 is due to its release during the
    repair, use, and disposal of refrigerators and air-conditioning
    units. The estimated maximum current world-wide loss is around 120
    000 tonnes per year. There have been reports of accidental release
    of HCFC 22 on fishing vessels.

         HCFC 22 is used as a refrigerant, as an intermediate in the
    production of tetrafluoroethylene, and as a blowing agent for
    polystyrene. A small quantity is used as an aerosol propellant.

    1.3  Environmental transport, distribution, and transformation

         The log octanol/water partition coefficient for HCFC 22 is
    l.08, which makes bioaccumulation unlikely. The estimated
    tropospheric lifetime of HCFC 21 is about 2 years and that of HCFC
    22 about 17 years. Reaction with hydroxy radicals in the troposphere
    is likely to be the primary route of degradation. Only a small
    fraction of HCFCs 21 and 22 reach the stratosphere, where, mainly by
    reaction with oxygen radicals, they release ozone-depleting
    chlorine. However, it is estimated that HCFC 22 is responsible for
    less than 1% of the ozone-depleting chlorine in the stratosphere.
    The ozone-depleting potential (ODP) of HCFC 22 has been estimated to
    be 0.05, while that of HCFC 21 is assumed to be lower.

         The global-warming potential (GWP), relative to CFC 11 (taken
    as 1.0), has been estimated to be lower by a factor of about 3-4 for
    HCFC 22 and lower still for HCFC 21.

    1.4  Environmental levels and human exposure

         There are no data available on concentrations in water or on
    the presence of these compounds in food, although HCFC 22 is used in
    the manufacture of expanded polystyrene food containers. There are
    no data on human exposure to HCFC 21, but two studies on the use of
    experimental sprays containing 17-65% HCFC 22 have shown that short
    (l0-20 secs) exposures might result in peak concentrations ranging
    from 5000 to 8000 mg/m3. Workers in beauty parlours could be
    exposed to 8-h time-weighted average levels of 90-125 mg/m3, but
    these are well below the currently regulatory MAK or LTV levels of
    1800-3540 mg/m3 for Germany, USA, and the Netherlands.

         HCFC 22 mixes rapidly in the atmosphere. Concentrations of
    about 326 mg/m3ere reported in 1986 and the level is believed to
    be increasing by about 11% annually.

    1.5  Kinetics and metabolism in laboratory animals and humans

         There are limited data on the absorption, distribution,
    metabolism, and excretion of HCFC 21. That HCFC 21 is absorbed
    following inhalation can be inferred from systemic effects and the
    elevated urinary fluoride levels seen in toxicity studies in rats.
    HCFC 21 is exhaled by rats following intraperitoneal injection, and
    both kinetic data and evidence from fluoride excretion suggest that
    HCFC 21 is metabolized. However, the extent of metabolism is unknown
    and, apart from fluoride, the products have not been identified.

         HCFC 22 is rapidly and well absorbed following inhalation in
    rat, rabbit, and humans and is distributed widely. High levels of
    HCFC 22 have been found in the blood, brain, heart, lung, liver,
    kidney, and visceral fat of rabbits dying during exposure and in
    postmortem samples of brain, lung, liver, and kidney from accidental
    victims of HCFC 22 exposure. Elimination is rapid, most of the HCFC
    being eliminated with a half-life of 1 min in the rabbit and 3 min
    in the rat. In humans, a limited amount of material is eliminated in
    three phases (half-lives of 3 min, l2 min, and 2.7 h).

         Inhaled or intraperitoneally administered HCFC 22 is almost
    entirely exhaled unchanged in both rats and humans. There is good
    evidence that no significant metabolism occurs  in vivo in rats or
    in rat liver preparations.

    1.6  Effects on laboratory mammals and in vitro test systems

         There are no satisfactory data on the acute oral toxicity of
    HCFC 21 or HCFC 22.

         The principal effects of a single inhalation exposure to HCFC
    21 or HCFC 22 are essentially similar in a variety of animal
    species. Both substances have low toxicity by this route. Effects
    seen are typical of those of chlorofluorocarbons, i.e. loss of
    coordination and narcosis. Cardiac arrhythmias and pulmonary effects
    may occur at high concentrations (106.7 g/m3 or more).

         It has been claimed that both HCFC 21 and HCFC 22 cause skin
    and eye irritation, although these effects may have been related to
    the consequences of heat loss due to evaporation rather than to the
    chemical properties of the HCFCs. Neither substance caused skin
    sensitization.

         The only studies conducted on the short-term toxicity of HCFC
    21 have investigated the inhalation route. Liver damage was the
    principal effect noted in the rat, guinea-pig, dog, and cat; a no-
    observed-effect level was not determined. Histopathological lesions
    of the liver were seen in rats at levels as low as 0.213 g/m3
    given 6 h/day, 5 days/week, for 90 days. Pancreatic interstitial
    oedema and seminiferous tubule epithelial degeneration also occurred
    at this level. Lesions were essentially absent in studies with HCFC
    22 at exposure levels between 17.5 g/m3 (for 13 weeks) and l75
    g/m3 (for 4 or 8 weeks). 

         There have been no long-term studies on HCFC 21 in animals. The
    only consistent non-tumorigenic finding in long-term studies with
    HCFC 22 was hyperactivity seen in male mice given 175 g/m3, 5
    h/day, 5 days/week in a lifetime inhalation study.

         No conventional studies have investigated the effects of HCFC
    21 on fertility. In an embryotoxicity study on rats (42.7 g/m3, 6
    h/day on days 6-15 of gestation) no teratogenic effect was observed,
    but a high rate of implantation loss was found. HCFC 22 (l75 g/m3
    per day, 5 h/day, 5 days/week for 8 weeks) had no effect on the
    reproductive capacity of male rats. As a consequence of a small,
    non-significant excess of eye defects seen in three teratology
    studies in rats, an extensive study was conducted on the potential
    ability of HCFC 22 to cause eye defects. In this study a small, but
    statistically significant, increase in the number of litters
    containing fetuses with microphthalmia or anophthalmia was found
    following maternal exposure to 175 g/m3, 6 h/day on days 6-15 of
    gestation. This exposure level gave slight maternal toxicity (lower
    body weight compared to controls). No other effects were seen, and
    3.5 g/m3 was the no-observed-effect level in this study. HCFC 22
    was not teratogenic in a conventional study on rabbits at similar
    exposure regimens.

         HCFC 21 was found to be non-mutagenic in two bacterial and one
    yeast assay (no further data was available). HCFC 22 was mutagenic
    in bacterial assays using  S. typhimurium, but did not show
    activity in tests on other micro-organisms or in mammalian systems,
    either  in vitro or  in vivo. These tests covered gene mutation
    and unscheduled DNA synthesis  in vitro, in vivo bone marrow
    cytogenetic assays, and dominant lethal assays in both rat and
    mouse. 

         Carcinogenicity assays  in vivo have only been conducted with
    HCFC 22. Two groups of investigators have conducted lifetime
    inhalation studies on both rats and mice. The only evidence of
    excess tumours occurred in the one study in which male rats were
    given 175 g/m3, 5 days per week, for up to 131 weeks. Small
    excesses of fibrosarcomas of the salivary gland region and of
    Zymbal's gland were noted. These effects were not seen at lower
    doses (up to 35 g/m3), and this high dose was not used in the
    second study. Although it was not an adequate demonstration of the
    absence of tumorigenic effects, no excess of tumours was seen in an
    oral gavage study on rats. These animals were given HCFC 22 at a
    level of 300 mg/kg per day, 5 days/week, for 52 weeks, and the study
    terminated at l25 weeks.

    1.7  Effects on humans

         Only very limited data are available on the effects of HCFC 21
    and HCFC 22 in humans.

         Death has occurred following accidental or intentional exposure
    to high levels of HCFC 22. Histopathological examination of the
    tissues of some of these victims revealed oedematous lungs and
    cytoplasmic fatty droplets mainly in the peripheral liver
    hepatocytes.

         Although an increase in the incidence of palpitations has been
    claimed in a questionnaire study on people occupationally exposed to
    HCFC 22, there is no good evidence that volunteer or occupational
    exposure to HCFC 21 or HCFC 22 leads to ill health effects. No
    conclusions can be drawn from a very small mortality study on people
    occupationally exposed to several chlorofluorocarbons including HCFC
    22.

    1.8  Effects on other organisms in the laboratory and field

         There are no data available on the effects of HCFCs 21 and 22
    on organisms in the environment.

    1.9  Evaluation and conclusions

         Environmental exposure levels of both HCFC 21 and HCFC 22 are
    extremely low and are not considered likely to cause direct effects
    on human health. Controlled occupational exposures are also unlikely
    to represent a significant risk to humans.

         Both HCFC 21 and HCFC 22 have a lower ozone-depleting potential
    and a shorter atmospheric residence time than the fully halogenated
    chlorofluorocarbons and should therefore pose a lower indirect
    health risk. Their global-warming potentials are considerably lower
    than those of the fully halogenated chlorofluorocarbons suggesting a
    lower environmental effect.

         Since the toxicity of HCFC 22 is low, the ozone-depleting and
    global-warming potentials lower, and the atmospheric residence time
    shorter than those of the fully halogenated chlorofluorocarbons, it
    can be considered as a transient substitute for the CFCs included in
    the Montreal Protocol. Although HCFC 21 poses a low environmental
    and indirect health risk, it is not recommended as a substitute for
    the chlorofluorocarbons included in the Montreal Protocol because of
    possible direct health risk due to its liver toxicity.

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

    2.1  Identity

         The chlorofluorocarbons reviewed in this monograph are
    dichlorofluoromethane (HCFC 21) and chlorodifluoromethane (HCFC 22).
    These are hydrochlorofluorocarbons (HCFCs), i.e. compounds derived
    by the partial substitution of the hydrogen atoms in methane with
    both fluorine and chlorine atoms. The chemical formulae, chemical
    structures, common names, common synonyms, trade names and CAS
    registry numbers are presented in Table 1.

    2.2  Physical and chemical properties

         The physical and chemical properties of HCFCs 21 and 22 are
    summarized in Table 2. They are non-flammable gases at normal
    temperatures and pressures, colourless, and practically odourless.
    They are slightly or moderately soluble in water and miscible with
    organic solvents (Horrath, 1982; Weast, 1985).

         Generally, hydrochlorofluorocarbons of low relative molecular
    mass are characterized by high vapour pressure, density, and
    refractive index, and low viscosity and surface tension (Bower,
    1973).

         HCFC 22 is available as a liquified gas with a minimum purity
    of 99.9% or in a variety of blends and azeotropic mixtures.

    2.3  Conversion factors

         Conversion factors for HCFCs 21 and 22 are given in Table 1.

    2.4  Analytical methods

         Analytical procedures for the determination of HCFCs 21 and 22
    are summarized in Table 3. By far the most frequently applied
    methods use gas chromatography with various detection techniques.

         A number of methods have been described for the determination
    of HCFC 21. These include gas chromatography with dual flame
    detection (Lindberg, 1979) and with electron capture detection
    (Vidal-Madjar et al., 1981; Rasmussen et al., 1983 and Höfler et
    al., 1986). Similarly, a number of methods have been described for
    the determination of HCFC 22. These include gas chromatography/mass
    spectrometry (Brunner et al., 1981), gas chromatography with
    electron capture detection (Shimohara et al., 1979), and
    photothermal deflection spectrophotometry (Long & Bialkowski, 1985).

        Table 1. Identity of HCFC 21 and HCFC 22a
                                                                                               
                                        HCFC 21                         HCFC 22
                                                                                               

    Chemical structure

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

    Chemical formula              CHCl2F                        CHClF2

    Common name                   dichlorofluoromethane         chlorodifluoromethane

    Common synonyms               methane, dichlorofluoro-;     Algeon 22; Arcton 22; 
     and trade names              fluorodichloromethane;        Chlorofluorocarbon 22; 
                                  F-21; R-21; Freon 21;         difluorochloromethane; 
                                  Genetron 21;                  difluoromonochloromethane; 
                                  dichloromonofluoromethane;    Electro-CF 22; Eskimon 22; 
                                  monofluorodichloromethane     F-22; FC-22; Flugene 22; 
                                                                Fluorocarbon 22; Forane 22;
                                                                Freon 22; Frigen 22; 
                                                                Genetron 22; HFA 22; 
                                                                Hydrochlorofluorocarbon 22; 
                                                                Hydrofluoroalkane 22; Isceon 22;
                                                                Osotron 22; Khladon 22; methane,
                                                                chlorodifluoro-;
                                                                monochlorodifluoromethane;
                                                                Propellant 22; R-22; 
                                                                Refrigerant 22; UCON 22

    CAS registry number           75-43-4                       75-45-6

    Conversion factors (20 °C)

      ppm --> mg/m3               4.276                         3.54

      mg/m3 --> ppm               0.234                         0.282

                                                                                               

    a    Chlorofluorocarbons are numbered as follows:
         the first digit = number of C atoms minus 1 
         for methane derivatives it is therefore zero);
         second digit = number of H atoms plus 1; 
         third digit = number of F atoms.
    
    Table 2. Physical and chemical properties of HCFC 21 and HCFC 22a
                                                                     
                                            HCFC 21        HCFC 22
                                                                     

    Physical state                          gas            gas

    Colour                                  colourless     colourless

    Relative molecular mass                 102.92         86.47

    Boiling point (°C) at 103 kPa           8.9            - 40.8

    Freezing point (°C)                     -135.0         -146.0

    Liquid density (g/ml)                   1.405          1.49
                                            (at 9 °C)      (at -68 °C)

    Vapour density (g/litre)                4.57           4.82
     at boiling point

    Vapour pressure (atm) at 21 °C          1.57           9.33

    Surface tension (dynes/cm) at -41 °C    -              15

    Refractive index at 9 °C                1.3724         -

                                                                     

    a    From: Grasselli & Richey (1975); Hawley (1981);
         Horrath (1982); Sax (1984); Weast (1985).

        Table 3. Analytical methods for the determination of partially
             halogenated methane derivatives
                                                                                               
    Medium         Analytical method               Detection limit    Reference
                                                                                               

    HCFC 21

    Air            gas chromatography with                            Lindberg (1979)
                   dual flame ionization
                   detection

                   gas chromatography with                            NIOSH (1985)
                   flame ionization detection

                   gas chromatography with                            Höfler et al. (1986)
                   electron capture detection

                   gas chromatography with         0.009µg/m3         Rasmussen et al. (1983)
                   electron capture detection

                   gas chromatography with         0.08µg/m3          Vidal-Madjar et al. (1981)
                   electron capture detection

    HCFC 22

    Air            gas chromatography with         0.14-0.46µg/m3     Shimohara et al. (1979)
                   electron capture detection

                   gas chromatography/             0.4µg/m3           Brunner et al. (1981)
                   mass spectrometry

                   photothermal deflection         0.6µg/m3           Long & Bialkowski (1985)
                   spectrophotometry

    Blood and      head space method, gas          0.1µl/g            Sakata et al. (1981)
    tissues        chromatography with flame
                   ionization detection

                   head space method, gas                             Morita et al. (1977)
                   chromatography with flame
                   ionization detection

                                                                                               
    
    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         HCFC 21 and HCFC 22 are not known to occur as natural products.

         Stoibe et al. (1971) reported the presence of HCFC 22 in
    volcanic emissions, but Rasmussen et al. (1980) did not observe any
    excess of this compound, compared with normal atmospheric levels, in
    their studies of volcanic emissions. In their analyses of air
    samples collected over the State of Washington, USA, Leifer et al.
    (1981) found that the concentrations of HCFC 22 (110-195 ng/m3)
    after the eruption of the Mount St. Helens volcano were no higher
    than normal.

    3.2  Anthropogenic sources

    3.2.1  Production levels

         HCFC 21 has been manufactured by one company in the USA, but
    only in very small quantities, and is no longer produced (personal
    communication by H. Trochimowicz to IPCS, 1990).

         HCFC 22 is produced by companies in the USA, Western Europe,
    Japan, Latin America, and elsewhere, the total annual world-wide
    production in 1987 being estimated to be 246 000 tonnes (personal
    communication by E.I. Du Pont de Nemours & Co. Inc., 1989).

    3.2.2  Manufacturing processes

         Both HCFC 21 and HCFC 22 are manufactured by the liquid phase
    reaction of chloroform with anhydrous hydrofluoric acid in the
    presence of an antimony halide catalyst (Hawley, 1981) at various
    reaction temperatures and pressures (SRI, 1985). This process is
    being replaced by a continuous vapour-phase process employing
    gaseous hydrogen fluoride in the presence of chromium oxide or
    halide, ferric chloride, or thorium tetrafluoride catalysts
    (Grayson, 1978).

    3.2.3  Loss during disposal, transport, storage, and accidents

         The source of the main loss of HCFC 22 during disposal is
    discarded refrigerators and air conditioners. Trace quantities of
    HCFCs 21 and 22 have been detected in landfill gas (Höfler et al.,
    1986).

         Equipment for the transport and storage of HCFC 22 is designed
    to withstand high pressure and is fitted with safety valves,
    bursting discs, and fusible plugs. Losses of product during normal
    transport and storage should, therefore, be relatively small because
    of the completely closed systems used.

         The main release of HCFC 22 occurs in the form of leakages from
    refrigeration and air-conditioning units (see section 3.3.2). Two
    accidental releases with fatal consequences on fishing vessels have
    been described by Morita et al. (1977) and Haba & Yamamoto (1985).
    In general, some fugitive losses during manufacturing are likely.

    3.3  Use patterns

    3.3.1  Major uses

         HCFC 21 has been reported to be used as a refrigerant for
    centrifugal machines, as a solvent (where its high Kauri-butanol
    number is desirable), in combinations with Freon 12 in aerosol
    products (National Library of Medicine, 1990), in fire extinguishers
    (Hawley, 1981), as a propellant gas (Sittig, 1985), and as a heat
    exchange fluid in geothermal energy applications (Grayson, 1978).
    However, it is no longer manufactured for any commercial purpose
    (personal communication by H. Trochimowicz, 1990). 

         HCFC 22 is used as a refrigerant in residential, commercial,
    and mobile air-conditioning units. An azeotropic mixture (HCFC 502)
    of HCFC 22 and CFC 115 (48.8:51.2 wt.%) is used as a refrigerant in
    food display cases, ice makers, home freezers, and heat pumps
    (American Chemical Society, 1985). It is also used as an
    intermediate in the production of tetrafluoroethylene by pyrolysis
    at 650-700 °C (Smart, 1980). It is estimated that approximately 34%
    of the total amount is currently used for this latter purpose. HCFC
    22 is used as a blowing agent, especially for polystyrene (see
    section 5.1.3) and as a propellant in aerosols (Hanhoff-Stemping,
    1989). It is not used to any significant extent as an industrial
    solvent but has been in the past (US EPA, 1981).

    3.3.2  Releases during use: controlled or uncontrolled

         Data are only available for HCFC 22. The major loss to the
    environment results from equipment and system leaks during use,
    repair, servicing, and after scrapping (Salzburger et al., 1989).
    Assuming no significant loss from its use as a polymer intermediate,
    it has been estimated that the maximum current worldwide release of
    HCFC 22 is around 120 000 tonnes per year (personal communication by
    E.I. Du Pont de Nemours & Co. Inc., 1988). 

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         Environmental Health Criteria 113: Fully Halogenated
    Chlorofluorocarbons considered the transport between media,
    environmental transformation processes, interaction with other
    physical, chemical or biological factors, and bioconcentration and
    bioaccumulation of fully halogenated chlorofluorocarbons (WHO,
    1990). Much more information has been published on fully halogenated
    than on partially halogenated chlorofluorocarbons.

    4.1  Biodegradation and bioaccumulation

         There is practically no information on the biodegradation in
    the environment of HCFC 21 and HCFC 22. The log octanol/water
    partition coefficient of HCFC 22 is 1.08, which makes
    bioaccumulation of this hydrochlorofluorocarbon unlikely (Hansch &
    Leo, 1979).

    4.2  Environmental transformation and interaction with other
         environmental factors

         The physical and chemical properties of the partially
    halogenated chlorofluorocarbons suggest that they would mix rapidly
    within the lower region of the troposphere. Mixing would be expected
    to be complete in the hemisphere of the emission (northern or
    southern) within months and in the entire troposphere possibly
    within about three years. The tropospheric concentration of HCFC 22
    is rapidly increasing (Hanhoff-Stemping, 1989). Reaction with
    naturally occurring hydroxy radicals in the troposphere is thought
    to be the primary degradation route. The estimated tropospheric rate
    of this reaction is such that the average lifetime is about 2 years
    for HCFC 21 (UNEP/WMO, 1989) and 13-25 years for HCFC 22 (Makide &
    Rowland, 1981; WMO, 1986; UNEP/WMO, 1989; Zurer, 1989). It should be
    noted that the lifetimes of fully halogenated chlorofluorocarbons
    are much longer (75 years for CFC 11 and 111 years for CFC 12). The
    mechanism of decomposition of HCFC 22 following the initial reaction
    with hydroxy radicals has been studied but not fully elucidated. The
    most likely product of the gas-phase reaction in the atmosphere is
    carbonyl fluoride (COF2) (Atkinson, 1985), which would be
    hydrolysed rapidly by atmospheric water to carbon dioxide and
    hydrogen fluoride, the latter being removed by precipitation.

         The small fraction of HCFC 22 not destroyed in the troposphere
    slowly enters and mixes with the upper layer of the atmosphere, the
    stratosphere. Seigneur et al. (1977), in their discussion of the
    photochemical and chemical processes of HCFCs 21 and 22 in the
    atmosphere, used a one-dimensional model at steady state to estimate
    the upward diffusion of these HCFCs in the atmosphere from ground
    level to 60 km. Their models of diffusion and reaction predict that,
    at steady state, the amounts of these chemicals reaching the

    stratosphere would be, relative to the amount released at ground
    level, between 1 and 3% for HCFC 21 and between 4 and 12% for HCFC
    22. The major destruction mechanisms are reactions with hydroxy
    radicals and excited oxygen atoms (Seigneur et al., 1977). Photo-
    decomposition by solar ultraviolet radiation, which is a major
    process for the fully halogenated chlorofluorocarbons, does not play
    a significant role in the destruction of HCFC 22 in the stratosphere
    (Molina et al., 1976).

         The major part of the ozone-depleting chlorine in the
    stratosphere comes from fully halogenated chlorofluorocarbons. The
    above model indicates that the partially halogenated
    chlorofluorocarbons are not expected to have high ozone-depleting
    potential (ODP). The ODP is defined as the calculated ozone
    depletion due to the emission of a unit mass of the
    chlorofluorocarbon divided by the ozone depletion calculated to be
    due to the emission of CFC 11; calculations are based on steady-
    state conditions (UNEP/WMO, 1989).

         No ODP value has been determined for HCFC 21 although Seigneur
    et al. (1977) stated that the compound is  "50-100 times less
    hazardous than CFC 11" to the stratospheric ozone level, based on
    calculations by Molina et al. (1976). The ODP for HCFC 22 has been
    estimated to be 0.05 (Hammitt et al., 1987; UNEP, 1988). Solomon &
    Tuck (1990) believe that reaction on ice particles in the Antarctic
    stratosphere may raise this figure by a factor of two or more, but
    Fisher et al. (1990b) do not completely agree with this supposition.
    A value of 0.05 means that continuous emissions of HCFC 22 would
    have to be 20 times as large as continuous emissions of CFC 11 to
    have the same effect on ozone. A 5% annual increase in HCFC 22
    emissions has been estimated by Ramanathan et al. (1985), but the
    11-12% figure calculated by Khalil & Rasmussen (1981, 1983) agrees
    better with the published data. The 16% yearly increase assumed by
    Krüger & Fabian (1986) is probably too high. The transitional use of
    HCFC 22 as a substitute for the highly ozone-depleting fully
    halogenated CFC 12 has been agreed, but the phase-out of HCFC 22 is
    also foreseen (Zurer, 1990; UNEP, 1990; FRG, 1990).

         Current assessment of the global-warming potential (GWP)
    ("greenhouse effect") of HCFC 22, based on the comparison with CFC
    11 (the reference compound with a GWP of 1.0), indicates that it is
    lower by a factor of about 3-4 (Garber, 1989; Fisher et al., 1990a).
    The GWP of HCFC 21 is lower still (Garber, 1989).

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Air

         Penkett et al. (1980) reported that extremely low background
    concentrations of HCFC 21, ranging from 4.3 to 8.6 ng/m3 (1-2
    ppt), have been found in the atmosphere. However, other
    investigators have determined much higher concentrations ranging
    from 43 to 86 ng/m3 (10-20 ppt) (Crescentini & Bruner, 1979).
    Rasmussen et al. (1983) concluded that this difference in the
    reported concentrations of HCFC 21 in the troposphere cannot be
    reconciled on the basis of difficulties in identification or
    differences in absolute accuracy.

         Rasmussen et al. (1980) determined an average global HCFC 22
    concentration of 159 ng/m3 (45 ppt) in mid-1979. The average
    concentrations were 177 ng/m3 (50 ppt) and 149 ng/m3 (42 ppt) in
    the northern and southern hemispheres, respectively. These values
    are considerably higher than the value of 89-106 ng/m3 (25-30 ppt)
    calculated from estimates of emissions. Leifer et al. (1981) found
    values (110-190 ng/m3) over the State of Washington, USA, in 1980.

         Khalil & Rasmussen (1981) determined concentrations of HCFC 22
    in 100 atmospheric samples collected between April 1978 and January
    1981 at a latitude of 45 °N in the north-west Pacific. The
    concentration of HCFC 22 increased at an average rate of 11.7% per
    year over the two and a half years of the study, and in January 1981
    was about 230 ng/m3 (65 ppt). The same authors calculated the
    concentrations expected from the estimated industrial release of
    HCFC 22 since 1950. The observed concentrations were, on average, 60
    ng/m3 (17 ppt) higher than the estimated concentrations. The
    authors considered the difference to be the consequence of an
    underestimation of past industrial release.

         Rasmussen & Khalil (1983) measured an average HCFC 22
    concentration of 259 ng/m3 (73 ppt) in the lower Arctic atmosphere
    (0-4 km) at 70 °N in May 1982. This concentration was 1.3 times
    greater than that found at 30-40 °S in November 1981 (Rasmussen et
    al., 1982), a difference which the authors considered significant.

         In the Arctic (72 °N in Alaska), the winter concentrations of
    HCFC 22, as well as those of other halocarbons, carbon monoxide, and
    soot from combustion, are higher than at other times of the year.
    This is attributable to faster transport of anthropogenic emissions
    in winter. The average winter concentration of HCFC 22 in the years
    1980 and 1981 was 217 ng/m3 (61 ppt), whereas the average during
    the summer was 198 ng/m3 (56 ppt). The rate of increase from
    August 1980 to February 1982 was 11.9% per year (Khalil & Rasmussen,

    1983). The most recent studies reported a concentration of 326
    ng/m3 (92 ppt) in 1986 (NASA, 1988), which corresponds
    approximately to the expected value based on an average annual
    increase of 11% since 1979. The rate of increase is somewhat
    uncertain due to the limited number of measurements, and lower
    values have been assumed by other authors (Ramanathan et al., 1985).
    These authors pointed out that, at an estimated increase of 5% per
    year, the average concentration in the global atmosphere would reach
    3200 ng/m3 by the year 2030.

    5.1.2  Water

         No data are available on the concentrations in water of the
    HCFCs 21 and 22.

    5.1.3  Food and other edible products

         No information is available on the possible content of
    partially halogenated chlorofluorocarbons in food or other edible
    products.

         HCFC 22 is used in the USA, the United Kingdom, and several
    other countries as a blowing agent for polystyrene foam, an
    authorized food contact plastic.

    5.2  General population exposure

         There are no data on human exposure to HCFC 21. The maximum
    workplace concentration (MAK) is limited to 45 mg/m3 in Germany
    (DFG, 1990) and to 42 mg/m3 in the USA (ACGIH, 1990). 

         Simulated-use studies have been carried out to assess the
    potential human exposure to HCFC 22 arising from its assumed use as
    an aerosol propellant. After a single spray (5 or 10 seconds
    duration) of an aerosol containing 17% HCFC in a closed room of 22
    m3, the air concentration was determined at various positions
    relative to the spray cone. When the spray was directed towards the
    sampling tube, peak concentrations were 5075 and 8050 mg/m3 after
    5 and 10 seconds spraying, respectively. The concentrations declined
    after about 10 or 20 seconds, respectively, stabilizing at levels of
    25 or 45 mg/m3. In all other spray positions the concentration did
    not exceed the level calculated for homogeneous distribution in the
    air of the room (Bouraly & Lemoine, 1988).

         Hartop & Adams (1989) reported a series of similar studies in
    which the concentrations of HCFC 22 were measured during simulated
    human use using experimental manikins representing adult and child.
    They examined hair sprays containing 20-40% HCFC 22, whole body
    deodorants containing 20-65%, and antiperspirants containing 20-40%.
    The peak concentrations found in a closed room of 21 m3 ranged

    from 53 mg/m3 (for a 4-second spray of an anti-perspirant
    containing 18.8% HCFC 22) to 5000 mg/m3 (for a 20-second spray of
    a deodorant containing 65%). This corresponds to 10-min weighted
    average concentrations of about 50 mg/m3 and 1440 mg/m3,
    respectively. In the same study, simulated use of a hair spray in a
    beauty parlour gave 10-min weighted average values of 160-225
    mg/m3 for the "customer" and 8-h weighted average values of 90-125
    mg/m3 for the "beautician", based on the assumption that the
    latter would use one 10-second spray every 15 min with the door of
    the beauty parlour open. This latter value is well below the MAK
    (Maximale Arbeitsplatzkonzentration, maximum working place
    concentration) of 1800 mg/m3 in Germany (DFG, 1990) and the TLV of
    3540 mg/m3 in the USA (ACGIH, 1990).

    5.3  Occupational exposure

         Bales (1978) reported HCFC 22 exposure levels of 17-48 mg/m3
    for workers in a fluorocarbon packaging and shipping plant.

    6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

    6.1  Animal studies

    6.1.1  Absorption

         There are no quantitative data on the absorption of HCFC 21,
    but the increase in fluoride levels observed in 90-day inhalation
    toxicity studies (section 7.2) and the data on metabolic
    transformation (section 6.1.3) suggest that inhaled HCFC 21 is
    absorbed.

         Carney (1977) studied the relationship between exposure to HCFC
    22 and blood levels in anaesthetized rats. The gas in air was
    applied through a canula inserted into the trachea. After 15 min of
    exposure, a blood sample was withdrawn from the carotid artery, and
    further blood samples were taken at intervals up to 30 min. Male and
    female rats were exposed to nominal air concentrations of 35 or 175
    g/m3. At 35 g/m3 the mean blood concentration was 31 mg/litre,
    while at 175 g/m3 it was 155 mg/litre, showing a relationship
    between the inhaled air and blood concentrations of HCFC 22. The
    clearance was rapid with a half-life of 3 min.

         Similar results have been reported by Sakata et al. (1981) in
    experiments with rabbits. Animals, anaesthetized with phenobarbitone
    (25 mg/kg ip), received HCFC 22/air mixtures via a plastic mask, and
    blood samples were taken through a catheter in a femoral artery. The
    concentration of HCFC 22 inhaled ranged from 175 g/m3 (5%) to 1400
    g/m3 (40%). At every air concentration, blood concentrations
    increased rapidly from the beginning of inhalation, and saturation
    was reached in about 5 min. The blood concentration was related to
    the concentration in inhaled air: at 175 g/m3 it was 148 mg/litre
    (similar to the blood level found by Carney (1977) in rats under the
    same conditions), and at 700 g/m3 it was 583 mg/litre. Clearance
    was rapid with a half-life of 1 min; no HCFC 22 could be detected
    one hour following cessation of exposure. 

         Woollen (1988) exposed pregnant rats to atmospheric HCFC 22
    concentrations of between 1239 and 609 g/m3 (350 and 175 000 ppm).
    Blood samples taken at various intervals showed that the compound
    rapidly reached equilibrium with the blood. At the highest exposure
    level, the blood level reached 118.5 mg/litre after 30 min and there
    was no significant increase after a further 5.5 h of exposure (121
    mg/litre).

    6.1.2  Distribution

         No information is available on the distribution of HCFC 21.

         Sakata et al. (1981) determined the amount of HCFC 22 in the
    tissues of rabbits exposed by inhalation to concentrations of up to
    1400 g/m3 (see section 6.1.1). The results are presented in Table
    4. No major differences were found in the tissues examined except
    for fat tissue, where there was a difference after long and short
    inhalation times at high concentrations. The authors postulated that
    the effect was related to the poor vascular blood supply of adipose
    tissue and that the distribution depended on partial pressures.
    Those tissues with a good blood supply would reach equilibrium
    quickly, whereas fat would equilibrate only slowly. Komoriya et al.
    (1980) found HCFC 22 to be widely distributed in rats after a
    variety of lethal exposures.

    6.1.3  Metabolic transformation

         A saturable dose-related increase in urinary fluoride was
    observed in both sexes of Charles River albino rats in a 90-day
    inhalation study with HCFC 21 (Lindberg, 1979). Details are given in
    section 7.2.

         The pharmacokinetics of HCFC 21 has been investigated in male
    Wistar rats. Animals were injected intraperitoneally with a dose of
    3.25 ml gas/kg body weight and placed in a closed chamber. Exhaled
    HCFC 21 was monitored for 7 h by gas chromatography. Only part of
    the injected compound was exhaled and it was assumed that the
    remainder was metabolized (Peter et al., 1986).

         Peter et al. (1986) found that HCFC 22 was not metabolized by
    Wistar rats after intraperitoneal exposure (3.08 ml gas/kg body
    weight). In their first experiment, rats received a single ip
    injection of HCFC 22, after which they were placed in a closed
    desiccator with a gas sample loop connected to a gas chromatograph.
    The injected HCFC 22 was almost completely exhaled. Pretreatment of
    the animals with phenobarbital (80 mg/kg ip followed by 3 days with
    0.1% phenobarbital in the drinking-water) or DDT (200 mg/kg, one
    week prior to the experiment) did not alter the observation. The
    authors concluded that there was no detectable metabolism of HCFC
    22. From these studies, it seems that HCFC 22, unlike HCFC 21, is
    not metabolized.

         The findings of Peter et al. (1986) support the earlier, more
    comprehensive, studies of Salmon et al. (1979) who carried out
     in vivo studies using 14C- and 36Cl-labelled HCFC 22. Alderley
    Park Wistar-derived rats were exposed to 14C-labelled HCFC 22 at
    levels of 1.75 g/m3 in three experiments and 35 g/m3 in three
    others. The exposure durations were 15-24 h. Exhaled carbon dioxide
    was collected by absorption on barium hydroxide and radioactivity
    was subsequently measured. Separate collection of urine and faeces 


        Table 4. Tissue levels of HCFC 22 in rabbits following lethal inhalation exposurea
                                                                                                           
                                                            Rabbit no.
                                 1         2         3         4         5         6         7         8
                                                                                                           

    HCFC 22 concentration
    (%, v/v)c                 0-32      0-29      0-33      0-42        30        30        40        40

    O2concentration
    (%, v/v)                 20-14     20-14     20-13     20-14        20        20        20        20

    Time of death
    after start of
    inhalation (min)            67        31        25        19        15        92         7        10

    Amount of HCFC 22b

    Brain                      145       138        76       156       137       148       140       159
    Heart                      145       150       100       158       135       140       125       129
    Lung                       167       128       187       231       139       136       121       186
    Liver                      143        95        72        78       101       153        44        60
    Kidney                     160        90        81        89       102       142        82        56
    Visceral fat               327        93        48        33        38       196        23        27
    Blood                      219       193       140       161       131       219       147       199

                                                                                                           

    a    From: Sakata et al. (1981).
    b    Values are µl/g at 20-25 °C, 1 atmosphere
    c    Animals 1-4 were exposed to increasing concentrations of HCFC 22.
         Values are inhaled concentrations; highest concentrations in rabbits
         1-4 indicate those at the time of death.
    

    into containers cooled to 0 °C was followed by measuring
    radioactivity, directly in the case of urine and after appropriate
    oxidation in the case of faeces. Similar exposure and collection
    conditions were used for the experiments with 36Cl-labelled HCFC
    22, in which the exposure applied was 35 g/m3 for 17.5 h. The
    study showed that metabolism of HCFC 22 in the rat was minimal. The
    amount of 14CO2 released was equivalent to approximately 0.1% of
    the inhaled HCFC 22 at the exposure level of 1.75 g/m3 and 0.06%
    at 35 g/m3. The amounts of 14C in the urine were also small,
    equivalent to approximately 0.03 and 0.01% of the inhaled dose at
    1.750 and 35 g/m3, respectively. Insignificant quantities were
    found in the faeces. The results of the experiment with 36Cl
    supported those obtained with 14C; only 0.01% of the inhaled dose
    was detected in urine. It is not quite clear whether the minimal
    metabolism observed was of HCFC 22 or of an impurity present in the
    test compound (Salmon et al., 1979).

         Salmon et al. (1979) also conducted  in vitro studies, using a
    microsomal preparation derived from liver homogenates of the same
    rat strain induced with Aroclor 1254. Microsomes, NADPH, and 36Cl-
    labelled HCFC 22 were incubated in a repeat-dosing syringe, and
    samples were taken for analysis at 2-min intervals. Released
    36Cl- was isolated as silver chloride and estimated by
    scintillation counting. Under the test conditions, there was no
    release of chloride ion from HCFC 22 (studied over the concentration
    range 0.2-1.3 mmol/litre). This was a further indication of the
    resistance of HCFC 22 to breakdown in biological systems and
    suggested that any potential biological activity of the compound was
    unlikely to be due to the formation of reactive intermediates.

    6.1.4  Elimination

         Peter et al. (1986), in their pharmacokinetic studies of HCFC
    21 and HCFC 22 (details in section 6.1.3), calculated the total
    clearance values of these compounds to be 4400 and 120 ml/h per kg,
    respectively.

         Carney (1977) showed that the clearance of HCFC 22 from the
    blood of rats was rapid, the half-life being approximately 3 min
    (details given in section 6.1.1). In studies by Sakata et al. (1981)
    on rabbits, using exposure concentrations of 175 and 1400 g/m3, it
    was found that the blood concentration decreased rapidly after
    cessation of exposure, the maximum half-life being 1 min. After
    15-30 min, blood concentrations were 27-31 mg/litre irrespective of
    the concentration inhaled. Once the exposure ceased, HCFC 22 was
    rapidly cleared from the blood and alveolar air, this being followed
    by slower elimination from poorly perfused tissues.

         Studies of Salmon et al. (1979) demonstrated that only minimal
    amounts of the dose were excreted in the urine of rats following
    exposure to a HCFC 22 concentration of 35 g/m3. Peter et al.
    (1986) demonstrated that after ip injection the compound was exhaled
    unchanged almost completely (see section 6.1.3).

    6.2  Human studies

         Data are available on the absorption and elimination of HCFC 22
    only.

    6.2.1  Absorption and elimination

         In studies by Woollen et al. (1989), two groups of three male
    subjects were exposed to average air HCFC 22 concentrations of 0.32
    or 1.81 g/m3 for 4 h. Blood and expired air samples were collected
    during the exposure period and for up to 26 h after exposure, and
    were analysed for HCFC 22. Urine samples were collected for up to 22
    h after exposure and analysed for HCFC 22 and fluorides. During the
    exposure period blood concentrations approached a plateau, the
    maximum blood concentrations of 0.25 and 1.36 µg/ml being related to
    the exposure level. The concentrations of HCFC 22 in the expired air
    were similar to the air concentrations during the exposure period.
    The ratio between blood and expired air concentrations towards the
    end of the exposure period was, on average, 0.77. This is consistent
    with  in vitro measurements of the solubility of HCFC 22 in human
    blood (blood/air partition coefficient: 0.79). In the post-exposure
    period, three phases of elimination were apparent with half-lifes of
    3 min, 12 min, and 2.7 h. The first phase, identified only from
    expired air analyses, probably represented elimination from alveolar
    air and/or lung tissues. The second and third phases may correspond
    to elimination from better and more poorly perfused tissues,
    respectively. HCFC 22 was detected in urine samples collected in the
    post-exposure period at both exposure levels, and the rate of
    decline was consistent with the terminal rate of elimination
    determined by blood and breath analyses. Fluoride concentrations in
    urine did not increase significantly following exposure, indicating
    that no detectable HCFC 22 metabolism occurs at these exposure
    levels.

    6.2.2  Distribution

         Three days after a fatal accident on board a fishing vessel
    (for details see section 8.2), samples of major tissues taken from
    two of the deceased people were analysed for HCFC 22 by gas
    chromatography (Morita et al., 1977). The findings are presented in
    Table 5. The concentrations were similar to those found in two
    rabbits examined three days after death by asphyxiation with HCFC 22
    (Sakata et al., 1981; see section 6.1.2, Table 4). 

    Table 5. Concentration (µg/g) of HCFC 22 in major human tissues
             after fatal poisoninga
                                                                  
                      Brain     Lung      Liver    Kidney    Blood
                                                                  

    Subject A           68       18        71        18        69

    Subject B          100       20        92         8       130

                                                                  

    a    From: Morita et al. (1977).

         In a survey of organic compounds in human milk, HCFC 22 was
    detected in one of twelve samples as one of 184 compounds
    (Pellizzari et al., 1982). No information on exposure or
    quantification of the amount found was given in the report.

    7.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

    7.1  Single exposure

    7.1.1  Acute oral toxicity

         No published data on the oral toxicity of HCFC 21 or HCFC 22
    are available except for a study by Anatova et al. (1983), in which
    no signs of toxicity were noted in rats administered 4 ml of an
    aqueous HCFC 22 solution at a concentration of 2700 mg/litre.

    7.1.2  Acute inhalation toxicity

         Detailed information on the acute effects of HCFC 21 in various
    animal species is given in Table 6.

         The signs of acute intoxication indicate that the CNS is the
    major target organ when animals are exposed to high concentrations
    of HCFC 21. Levels higher than 400 g per m3 were lethal to the rat
    and guinea-pig within a few minutes to two hours. The 4-h LC50 in
    rats was 213.07 g per m3 (Tappan & Waritz, 1964). Animals exposed
    to concentrations above 42.7 g/m3 for 5 min or more exhibited
    signs typical of various stages of anaesthesia. Dyspnoea was
    observed at exposure levels above 50 g/m3.

         In addition to central nervous system depression, increased
    lacrimation, piloerection, and mydriasis were observed.

         The concentrations and durations of exposure at which HCFC 22
    proved lethal to a variety of animal species are given in Table 7.
    These data show that HCFC 22 has a low order of acute toxicity to
    several laboratory animal species. Deaths have been reported in
    rats, mice, and guinea-pigs exposed to HCFC 22 concentrations of
    775-1295 g/m3 (220 000 to 365 000 ppm) of HCFC 22 for periods of
    15-240 min (Table 7). The signs of toxicity in rats were tremor of
    the limbs and head, convulsions, narcosis, shallow respiration, and
    death from respiratory depression. Death always occurred during
    exposure, never after. Recovery from non-lethal exposure was rapid.
    Rats appeared normal within 10 min and showed no delayed after-
    effects. 

         The 10-min EC50 for the CNS effects described was 490 g/m3
    for rats (Clark & Tinston, 1982). Signs in rabbits were similar to
    those in rats, namely incoordination and other signs of CNS
    depression, followed by respiratory depression and asphyxiation
    (Sakata et al., 1981). The primary toxic effect of the single
    inhalation exposure was central nervous system depression, which
    occurred at very high exposure levels.

         Cardiac and pulmonary effects are described in section 7.8.


        Table 6. Acute effects of HCFC 21 in various animal species
                                                                                                       
    Species        Concentration     Time of         Symptoms                     Reference
                   (g/m3)            exposure
                                                                                                       

    Mouse            42.7            30-100 min      hyperactivity                Booth & Bixby (1932)

    Rat             213.07            4 h            (LC50); central              Tappan & Waritz (1964)
                                                      nervous system 
                                                      depression, lacrimation,
                                                      piloerection, mydriasis

    Rat and         427              15-50 min       deep narcosis,               Weigand (1971)
     guinea-pig                                       death
                    213.5             2 h            loss of balance,             Weigand (1971)
                                                      narcosis
                    106.75            2 h            loss of balance,             Weigand (1971)
                                                      tremors, excitation
                     10               2 h            no changes                   Weigand (1971)

    Guinea-pig     1708               6 min          tremors, death               Booth & Bixby (1932)
                    854              11 min          tremors, death               Booth & Bixby (1932)
                    435.54           35-65 min       death                        Nuckolls (1935)
                    256               5 min          deep narcosis                Booth & Bixby (1932)
                    213.5             2 h            loss of coordination,        Nuckolls (1935)
                                                      unconsciousness
                    213.5             2 h            death within 2 h             Caujolle (1964)
                    106.75            2 h            seizures,                    Nuckolls (1935)
                     98.21                            loss of balance
                     51.24            2 h            dyspnoea, stupor             Nuckolls (1935)

                                                                                                       

    Table 7.  Acute inhalation toxicity of HCFC 22
                                                                                                           
    Species        Concentration   Exposure    Effects observed                Reference
                   (g/m3)          period
                                   (min)
                                                                                                           

    Mouse          1295            120         death (MLC)                     Karpov (1963)
                    970             30         incoordination, deep            Sakata et al. (1981)
                                                narcosis, death (LC50)

    Rabbit         1050             30         incoordination, cyanosis,       Sakata et al. (1981)
                                                death (MLC)

    Rat            2100              2         depressed heart rate            Pantaleoni & Luzi (1975a,b)
                                                and blood pressure,
                                                ECG changes
                   1225             15         deep narcosis, death            Clark & Tinston (1982)
                                                (LC50)
                   1050            120         incoordination,                 Weigand (1971)
                                                accelerated respiration,
                                                deep narcosis, death (MLC)
                    875            240         death (MLC)                     NIOSH (1976)
                    775            240         death (LC50)                    Litchfield & Longstaff (1984)
                    700            120         incoordination, accelerated     Weigand (1971)
                                               respiration, narcosis

    Rat and        1400            120         incoordination, narcosis        Weigand (1971)
     guinea-pig

    Guinea-pig     1050            120         narcosis                        Weigand (1971)
                    700              2         lacrimation, stupor,            Nuckolls (1940)
                                                tremor

    Dog            2450             90         partial narcosis,               Poznak & Artusio (1960)
                                               depressed respiration,
                                               death
                                                                                                           

    Table 7 (contd)
                                                                                                           
    Species        Concentration   Exposure    Effects observed                Reference
                   (g/m3)          period
                                   (min)
                                                                                                           

    Dog (contd)    1400             90         incoordination, partial         Poznak & Artusio (1960)
                                               narcosis

    Monkey          700              5         depressed respiration,          Aviado & Smith (1975)
                                                heart rate, and blood
                                                pressure

                                                                                                           

    MLC = Minimum lethal concentration.
    

    7.2  Short-term inhalation exposure

         In this monograph, short-term exposures are defined as those
    involving repeated daily exposures for up to 90 days and long-term
    exposures as those lasting more than 90 days. 

         Cardiac and pulmonary effects are described in section 7.8.

    7.2.1  HCFC 21

         Weigand (1971) exposed five rats, five guinea-pigs, two beagle
    dogs, and two cats to HCFC 21 (42.7 g/m3) for 3.5 h/day, 5
    days/week, for 4 weeks. The behaviour of all animals remained normal
    throughout the experiment. The increase in body weight of rats was
    somewhat retarded and the guinea-pigs lost weight. The blood and
    urine analyses were normal. Gross pathological examination revealed
    alterations in the livers of all the guinea-pigs and cats, and one
    of the dogs, but not of the rats. Histopathological examination
    showed hepatic single cell necrosis and fatty degeneration in all
    exposed animals.

         Kelly (1976, 1977) and Trochimowicz et al. (1977) exposed a
    group of 10 male rats to HCFC 21 (42.7 g/m3) 6 h per day, 5
    days/week, for 2 weeks. There were no deaths but the rats lost
    weight and exhibited marked anaemia and increased serum transaminase
    levels, indicating liver damage. Pathological examination
    immediately after the last exposure showed liver necrosis; this
    necrosis was still present in a recovery group examined 14 days
    later. 

         In a further study (Kelly, 1977) groups of 27 male and 27
    female Charles River albino rats and 4 male beagle dogs were exposed
    to HCFC 21 levels of 4.27 or 21.35 g/m3 6 h per day, 5 days/week,
    for 90 days. Rats were severely affected; between days 59 and 90,
    37% of the rats exposed to the low and 29% exposed to the high
    concentration died. Standard clinical chemistry investigations
    showed alterations in liver function. Histopathological examination
    revealed extensive liver cirrhosis. Neither the mortality nor the
    histopathological damage was related to the dosage. None of the dogs
    died; the only significant effects occurred at 21.35 g/m3 and
    consisted of slight weight loss during exposure and minimal
    unspecified morphological changes in the liver.

         Lindberg (1979) exposed four groups of Charles River albino
    rats (35 males and 35 females in each group) to HCFC 21
    concentrations of 0, 0.213, 0.64, and 2.13 g/m3 for 6 h/day, 5
    days/week, for 90 days. At a level of 2.13 g/m3 the average body
    weight gain was lower than in controls during the early phase of the
    experiment. Leucocyte counts were elevated in animals exposed to the
    highest concentration, as were serum alkaline phosphatase and

    alanine aminotransferase activities. Urine volumes showed a tendency
    to increase. At this exposure level an increase in urine fluoride
    concentration was observed in both sexes after 45 days of treatment.
    There was a similar increase in urinary fluoride concentration at 90
    days, with essentially no difference between rats exposed to 0.64
    and 2.13 g/m3. This suggests that saturation of the metabolic
    transformations occurs at exposure levels at or below 0.64 g/m3.
    Histopathological evaluation revealed portal cirrhosis of the liver,
    interstitial oedema of the pancreas, and degeneration of the
    seminiferous epithelium at all dose levels. The liver toxicity and
    indications for metabolism suggest a similar mechanism of toxicity
    to that demonstrated for trichloromethane (DFG, 1986). Thus, a
    reactive metabolite may be responsible for the induction of liver
    effects.

    7.2.2  HCFC 22

         No effects were seen on body weight, haematological parameters,
    urine analysis, organ weights or macroscopic and microscopic
    appearance of the tissues in rats, guinea-pigs, dogs or cats exposed
    to HCFC 22 (175 g/m3) 3.5 h per day, 5 days/week, for 4 weeks
    (Weigand, 1971).

         Lee & Suzuki (1981) exposed two groups of 16 male Sprague-
    Dawley rats to HCFC 22 (0 or 175 g/m3), 5 h/day for 8 weeks, after
    which 6 rats in each group were killed and blood and tissue samples
    taken for haematological and biochemical assays and for
    histopathological examination. The remaining animals were retained
    for a fertility study, the results of which are presented in section
    7.5. No signs of toxicity were apparent in the exposed animals, and
    body weight was not affected. Prostate weight was decreased slightly
    but not the weights of other organs. No histopathological lesion was
    related to exposure in any of the organs examined. Plasma glucose
    and triglyceride levels were reduced and plasma cholesterol slightly
    raised, but no haematological parameter was affected.

         Leuschner et al. (1983) exposed Sprague-Dawley rats (35 and
    17.5 g/m3) and beagle dogs (17.5 g/m3 only) to HCFC 22 6 h/day
    for 13 weeks. The treatment and control groups consisted of 20 male
    and 20 female rats and 3 male and 3 female dogs. Investigations of
    behaviour, body weight, haematology, clinical biochemistry, and
    organ weights were carried out in both species, and dogs were also
    subjected to ECG measurements and to an examination of circulatory
    function. The clinical biochemistry examinations included assays for
    serum alanine transaminase, aspartate transaminase, and alkaline
    phosphatase activities, as well as liver function tests.
    Histopathological examinations were undertaken on a wide variety of
    tissues. No changes were found in any of these examinations. It was
    therefore concluded that the no-observed-effect level for HCFC 22
    was in excess of 35 g/m3 in the rat and in excess of 17.5 g/m3
    in the dog.

         In a limited experiment on rabbits that also received sodium
    barbital in the drinking-water, Van Stee & McConnell (1977) found
    that exposure to HCFC 22 (210 g per m3, 5 h/day, 5 days/week for
    8-12 weeks) induced cardiac arrhythmia in one of 14 rabbits. In
    addition, some rabbits (number unknown) showed slight
    histopathological liver damage and a modest elevation in the level
    of unspecified serum enzymes. The lack of detail and the fact that
    no controls were used make meaningful conclusions impossible.

    7.2.3  Mixed exposure

         Two unweaned beagle puppies (one male, one female) weighing
    1.5-3 kg inhaled a mixture of HCFC 22 and HCFC 21 (60% : 40%) for 5
    min, twice daily, 5 days a week for 2 weeks, at a concentration of
    1714 mg/kg body weight. After 1-2 min the puppies became sedated and
    ataxic, but they recovered a few minutes after removal from
    exposure. No other effects were noted during investigations that
    included blood chemistry and urine analyses, and gross and
    microscopic examinations of the lungs (Knox-Smith & Case, 1973).

    7.3  Skin and eye irritation; sensitization

    7.3.1  Skin irritation

         HCFC 21 produced mild irritation when applied at concentrations
    higher than 25% in propylene glycol to the shaved, intact skin of
    guinea-pigs. No irritation was observed at a concentration of 2.5%
    (Goodman, 1975).

         Quevauvillier et al. (1964) reported that a 10-second spray of
    HCFC 22 on the shaved belly of the rat twice a day, 5 days/week, for
    6 weeks caused reddening of the skin and slight swelling of the
    surface. There was also a delay in hair regrowth. A more recent
    report (Atochem, 1986) classified the compound as a skin irritant
    but this effect was only observed following the application of 0.5
    ml in liquified form under occlusion to the intact and abraded skin
    of rabbits.

         The irritation induced by a chemical with a boiling point at or
    near room temperature appears to be related to rapid evaporation,
    resulting in a drying effect on the skin or mucous membrane.

    7.3.2  Eye irritation

         Undiluted liquid HCFC 21, chilled to the temperature of dry
    ice, was placed into the right conjunctival sacs of two rabbits.
    After 20 seconds, the treated eye of one rabbit was washed with 0.9%
    saline for 1 min. Slight corneal opacity, transient congestion of
    the iris and moderate conjunctival irritation in the unwashed eye
    was seen. There was slight corneal opacity and moderate conjunctival

    irritation but no iris involvement in the washed eye. Both eyes were
    normal within 5 days (Brittelli, 1975). This report did not
    distinguish between the effects of cold, including that caused by
    evaporation, and the intrinsic properties of HCFC 21. In another
    study, HCFC 21 was sprayed directly into the eyes of each of six
    rabbits from a distance of 5 cms. No corneal or iris injury was seen
    but lacrimation was observed in four of the rabbits examined 1 and 4
    h after exposure (Hood, 1964a). Two additional studies on rabbits
    evaluated the eye irritation potential of diluted HCFC 21 in various
    solvents (Hood, 1964b; Eddy, 1970). In both studies, 0.1 ml of the
    test solution was instilled in one eye of each of six albino
    rabbits. The other eye, which was treated with vehicle, served as a
    control. The eyes were not washed after treatment. HCFC 21, as
    either a 50% solution in mineral oil or a 40% solution in propylene
    glycol or dimethyl phthalate, produced varying degrees of injuries
    to the cornea, iris, and conjunctivae. Milder irritant effects were
    seen with a 15% solution. All these effects disappeared within 7 to
    10 days.

         HCFC 22 was reported to be a slight irritant when the corneas
    of albino rabbits were exposed to the gas for 5 or 30 seconds
    (Atochem, 1986).

    7.3.3  Skin sensitization

         No evidence of skin sensitization with HCFC 21 was found in
    guinea-pigs by Hood (1964b) or Goodman (1975). 

         The skin-sensitizing potential of HCFC 22 was tested in 10 male
    and 10 female Hartley albino guinea-pigs using a modification of the
    Magnusson-Kligman maximization text. On day 0, Freund Complete
    Adjuvant was injected intradermally and 0.25 ml of liquified
    compound was applied topically to the skin under a capsule for 28 h.
    On days 2, 4, 7, 9, 11, and 14, 0.5 ml of liquified HCFC 22 was
    applied topically at the same place for 48 h under occlusion. After
    a period of 2 weeks, the challenge exposure was performed on day 28
    at the opposite side of the body: 0.25 ml of liquified HCFC 22
    (maximum non-irritating dose as determined in the previous
    experiment) was applied under a capsule for 48 h. No cutaneous
    sensitizing reaction was observed during a macroscopic or
    histological evaluation of the skin 1, 6, 24, and 48 h after removal
    of the occlusive patch (Atochem, 1986).

    7.4  Long-term inhalation exposure

         No data are available on the chronic toxicity of HCFC 21 based
    on exposures longer than 90 days.

         Karpov (1963) exposed rats, mice, and rabbits to HCFC 22 (50
    g/m3), as well as rats and mice to 7 g per m3, for 6 h/day, 6

    days/week, over a 10-month period. Body weights, oxygen consumption,
    CNS function, and biochemical and haematological parameters were
    recorded, and histopathological examinations of some tissues were
    undertaken at the end of the test. Depressed body weight gain in
    mice after 4-6 months, depressed oxygen consumption in rats, CNS
    function changes in rats and mice, decreased haemoglobin
    concentration in rabbits, and histopathological (dystrophic) changes
    in the liver, lungs, and nervous tissue were observed at 50 g/m3.
    No effect was seen at the lower exposure level (7 g/m3).

         In a life-time study, Tinston et al. (1981a) exposed Alderley
    Park Swiss-derived mice (80 male and 80 female per group) to HCFC 22
    (0, 3.5, 35, and 175 g/m3) 5 h per day, 5 days/week, for up to 83
    weeks (females) and 94 weeks (males), at which time there was 80%
    mortality. At week 38, 10 mice per group were killed in order to
    perform blood assays, including red and white blood cell counts,
    platelet counts, prothrombin and kaolin-cephalin times, and bone
    marrow examination. Measurements of plasma ASAT (EC 2.6.1.1) and
    ALAT (2.6.1.2) activities and urine analyses were also undertaken.
    The only consistent finding was hyperactivity observed in the male
    mice exposed to 175 g/m3. There were no treatment-related effects
    on mortality or body weight gain. No abnormalities were observed
    during haematological, biochemical or histopathological
    investigations, with the exception of the neoplasia described in
    section 7.7.

         Tinston et al. (1981b) performed a similar lifetime study on
    Alderley Park Wistar-derived rats using the same group sizes and
    exposure levels. The study lasted 118 weeks in females and 131 weeks
    in males (80% mortality). Some animals were killed at week 52. The
    same investigations were carried out as in the case of the mouse
    study. No clinical abnormalities, increased mortality, or
    haematological or biochemical changes could be attributed to HCFC 22
    at any exposure level. At the highest level (175 g/m3), there was
    a decrease in body weight gain in males and increased liver, kidney,
    and adrenal and pituitary gland weights in the females. A number of
    non-neoplastic lesions were observed histologically in all the
    groups but there was no evidence of exposure-relatedness.

    7.5  Reproduction, embryotoxicity, and teratogenicity

    7.5.1  Reproduction

         No data are available on the effects of HCFC 21 on
    reproduction, except for a limited study by Aranjina (1972) who
    claimed a decrease in the levels of DNA and total nucleic acids in
    the liver, brain, ovaries, and placenta of female rats exposed to
    0.153 or 0.303 g/m3 for the whole gestation period. The biological
    significance of this finding cannot be evaluated due to the lack of
    adequate reporting.

         Lee & Suzuki (1981) tested HCFC 22 for effects on male
    reproduction in Sprague-Dawley rats. A group of 16 male rats was
    exposed to a concentration of 175 g/m3, 5 h per day, for 8 weeks,
    and a control group of the same size was exposed to filtered air.
    The animals were examined and weighed weekly. At the end of the 8-
    week period, six rats from each group were killed, organ weights
    determined, and histopathological, clinical, chemical, and
    haematological examinations were carried out. The prostate glands
    were assayed for fructose and acid phosphatase (EC 3.1.3.2)
    activity. Immediately after the final exposure, blood was collected
    from the remaining 10 rats in each group, and the plasma was assayed
    for follicle stimulating hormone (FSH) and luteinizing hormone (LH).
    These animals were then used for serial mating, each male being
    housed with a virgin female for 7 days, after which time the female
    was replaced with another virgin female; this regime was followed
    for 10 weeks. Nine days after removal, each female was killed, and
    the numbers of corpora lutea, total implants, live implants,
    resorption sites, and dead implants were determined. There was no
    sign of any overt toxicity. The major organs of treated animals,
    including testes and epididymes, did not differ in weight from those
    of the controls. There was a slight decrease in weight of the
    prostate and coagulating gland in the treated rats but there were no
    accompanying histological changes. Prostatic fructose and acid
    phosphatase (EC 3.1.3.2) levels, as well as FSH and LH levels, were
    not different from those in controls. Serum cholesterol levels were
    slightly higher, and glucose and triglyceride levels were slightly
    lower in treated rats than in controls. Overall, there was no
    significant effect upon the fertility of male rats.

    7.5.2  Embryotoxicity and teratogenicity

    7.5.2.1  HCFC 21

         When Kelly et al. (1978) exposed pregnant rats to 42.7 g/m3
    (6 h/day on days 6-15 of gestation), no clinical signs of toxicity
    were observed but the rats gained substantially less weight than the
    control animals. HCFC 21 interfered with the process of
    implantation: 15 of 25 mated rats had no implants or viable fetuses.
    The outcome of pregnancy and the fetal development in the other 10
    rats were not affected. No teratogenic activity was observed.

    7.5.2.2  HCFC 22

         Three inhalation teratology studies with HCFC 22 were carried
    out in 1977 and 1978 (Culik et al., 1976; Culik & Crowe, 1978).
    Groups of 20-40 pregnant Charles River CD rats were exposed to
    several concentrations ranging from 0.35 to 70 g/m3 for 6 h/day on
    days 4-13 or 6-15 of gestation. There was no evidence of maternal or
    overt fetal toxicity. The only teratogenic abnormalities observed

    were small statistically insignificant increases in microphthalmia
    or anophthalmia. The incidence of microphthalmia/anophthalmia in the
    three studies is presented in Table 8.

        Table 8. Incidence (fetuses/litters) of microphthalmia or anophthalmia in
             three preliminary studies of HCFC 22 in Charles River CD ratsa
                                                                                 

                                        Exposure levels (g/m3)
                                                                                 

    Study          0       0.350     1.05      1.75       3.5       35        70

      1          0/21                                    1A/22     2A/21

      2          0/34                          1M/33   (2M+/33)              1A/35

      3          0/38      1M/40     0/35                          2M/34

                                                                                 

    a   From: Culik et al. (1976) and Culik & Crowe (1978)
    A = anophthalmia; M = microphthalmia
        (no quantitative procedures were applied to the assessment of microphthalmia);
        + = two fetuses were affected in the same litter.
    
         The comparatively low incidence of microphthalmia or
    anophthalmia in the above study led Palmer et al. (1978a) to conduct
    a large study designed to improve the sensitivity of the
    investigation of these infrequent malformations. Female CD rats were
    exposed to concentrations of 0, 0.35, 3.5 or 175 g/m3 for 6 h/day
    on days 6-15 of gestation. Nineteen batches of time-mated females
    were used, each batch consisting of 34 control rats and 22 rats in
    each of the three test groups; more than 6000 control fetuses and
    4000 fetuses from exposed animals were examined. The animals were
    killed on day 20 of pregnancy and examined macroscopically. The
    ovaries were examined for numbers of corpora lutea and the uteri for
    live young and embryonic fetal death; litter and mean pup weights
    were recorded. The heads of all fetuses were sectioned and examined
    with particular reference to microphthalmia, anophthalmia, and
    associated anomalies. Maternal body weights in the group exposed to
    175 g/m3 were slightly lower than in controls in most batches; the
    body weight gain was consistently lower in this group than in the
    controls during the first day of exposure. No other change in the
    dams was observed. Overall, there was no effect on litter size,
    post-implantation loss or litter weight. Mean fetal weight was
    slightly but consistently lower in the group exposed to 175 g/m3
    than in controls, but not at the two lower levels of exposure. The
    number of fetuses and the incidence of litters with anophthalmia or

    microphthalmia are shown in Table 9. There was no significant
    difference from controls with respect to the incidence of
    anophthalmia/microphthalmia at low or intermediate exposure levels.
    At the highest exposure level, there was a small but significant 
    (P < 0.05) increase in the incidence of litters containing fetuses
    with total eye malformations and anophthalmia. No other gross fetal
    abnormality was found.

         Palmer et al. (1978b) also carried out a teratology study in
    rabbits. New Zealand white rabbits were exposed to 0, 0.35, 3.5, or
    175 g/m3 for 6 h/day on days 6-18 of pregnancy. There were 14-16
    pregnant females per group. The animals were killed on day 29 of
    pregnancy for an assessment of litter data and an examination of
    fetuses for major malformations, minor anomalies, and variants.
    There were no significant treatment-related effects in females, and
    pregnancies were normal. Maternal body weight gain was slightly but
    consistently lower in the animals exposed to 175 g/m3 during the
    first 4 days of exposure but, thereafter, weight gain was comparable
    to that in the controls. Litter size, post-implantation loss, and
    litter and mean fetal weights were unaffected. There was no
    significant increase in the incidence of major or minor fetal
    abnormalities.

    7.6  Mutagenicity

    7.6.1  HCFC 21

         HCFC 21 was not mutagenic when incubated for 72 h with
     Salmonella typhimurium (TA98, TA100, TA1535, TA1537, TA1538) with
    or without metabolic activation. The compound was not mutagenic to
     Saccharomyces cerevisiae D4 (Brusick, 1976).

    7.6.2  HCFC 22

         The data from  in vitro and  in vivo studies are summarized
    in Table 10. HCFC 22 induced mutations in  Salmonella typhimurium 
    base-pair substitution strains TA1535 and TA100 but not strains
    TA98, TA1537 or TA1538 after gaseous exposure.

         The response was independent of the presence or absence of a
    metabolizing system, as would be expected from the lack of
    metabolism in animals. Negative responses were reported in mutation
    assays using  Schizosaccharomyces pombe and  Saccharomyces
     cerevisiae (Loprieno & Abbondandolo, 1980), plant cells (Van't
    Hoft & Schairer, 1982), Chinese hamster cells (McCooey, 1980;
    Loprieno & Abbondandolo, 1980), and in a cell transformation assay
    (BHK21; Loprieno & Abbondandolo, 1980).


        Table 9. The number and incidence of fetuses with eye malformations (anophthalmia and microphthalmia)
             in rats exposed to HCFC 22a
                                                                                                             
                           Eye malformations                Anophthalmia                 Microphthalmia
         HCFC 22        No. of         Incidence      No. of         Incidence      No. of         Incidence
      concentration     fetuses        per 1000       fetuses        per 1000       fetuses        per 1000
         (g/m3)         affected       litters        affected       litters        affected       litters
                                                                                                             

           0               3             4.94            1             1.65            2              3.29

           0.35            5            12.66            1             2.53            4             10.13

           3.5             3             7.69            1             2.56            2              5.13

         175              10            26.11b           6            15.67a           4             10.44

                                                                                                             

    a    From: Palmer et al. (1978a).
    b    Statistically significant (P < 0.05) by a one-sided stratified contingency chi-square test

    Table 10.  The genetic toxicity of HCFC 22
                                                                                                                                              
    Assay            Organism    Species/strain/cell type     Metabolic     Testing conditions        Results           Reference
                                                              activationa
                                                                                                                                              

    Reverse          bacteria    Salmonella typhimurium            ±        20 & 40% gas for 6 h      negative          Barsky (1976)
     mutation                    TA1535; TA1537; TA1538;
                                 TA98; TA100

    Reverse          bacteria    Salmonella typhimurium            ±        up to 40% gas for 48 h    positive for      Koops (1977)
     mutation                    TA1535; TA1537; TA98; TA100                                          TA1535 only,
                                                                                                      activation 
                                                                                                      independent

    Reverse          bacteria    Salmonella typhimurium            ±        incubated with 50% gas    positive for      Longstaff & McGregor
     mutation                    TA1535; TA1538; TA98; TA100                for 24 h                  TA1535, (TA100    (1978)
                                                                                                      positive in 1 of
                                                                                                      3 experiments),
                                                                                                      activation 
                                                                                                      independent

    Reverse          bacteria    Salmonella typhimurium            ±        50% gas for 24 h          positive          Bartsch et al. (1980)
     mutation                    TA100

    Reverse          bacteria    Salmonella typhimurium            ±        50% for 24 h              positive for      Longstaff et al. (1984)
     mutation                    TA1535; TA1538; TA98; TA100                                          TA1535 and 
                                                                                                      TA100, 
                                                                                                      activation
                                                                                                      independent

    Forward          yeast       Schizosaccharomyces pombe         ±        20 mM solution generated  negative          Loprieno & Abbondandolo
     mutation                                                               at 500 ml/min of                            (1980)
                                                                            50% gas

                                                                                                                                              

    Table 10 (contd)
                                                                                                                                              
    Assay            Organism    Species/strain/cell type     Metabolic     Testing conditions        Results           Reference
                                                              activationa
                                                                                                                                              

    Cell mutation    plant       Tradescantia                     N/A       closed chamber, highest   negative          Van't Hoft & Schairer
                                                                            ineffective dose                            (1982)
                                                                            1.16 g/m3

    Cell mutation    hamster     Chinese hamster ovary cells       ±        tested at 20-92% gas      negative          McCooey (1980)

    Cell mutation    hamster     Chinese hamster lung              ±        20 mM solution generated  negative          Loprieno & Abbondandolo
                                  V 79 cells                                at 500 ml/min of                            (1980)
                                                                            50% gas

    Cell mutation    yeast       Schizosaccharomyces pombe        N/A       816 mg/kg body weight     negative          Loprieno & Abbondandolo
     (host                       or Saccharomyces cerevisiae                in corn oil by gavage                       (1980)
     mediated)                   in CD-1 mice

    Gene             yeast       Saccharomyces cerevisiae          ±        20 mM solution generated  negative          Loprieno & Abbondandolo
     conversion                                                             at 500 ml/min of                            (1980)
                                                                            50% gas

    Unscheduled      human       heteroploid EUE cell line         ±        20 mM solution generated  negative          Loprieno & Abbondandolo
     DNA                                                                    at 500 ml/min of                            (1980)
     synthesis                                                              50% gas

    Cell             hamster     BHK-21 cells                      -        20 mM solution generated  negative          Loprieno & Abbondandolo
     transformation                                                         at 500 ml/min of                            (1980)
                                                                            50% gas

    Chromosome       mouse       CD-1, bone marrow cells          N/A       816 mg/kg body weight     negative          Loprieno & Abbondandolo
     aberrations                                                            in corn oil by gavage                       (1980)
     in vivo

                                                                                                                                              

    Table 10 (contd)
                                                                                                                                              
    Assay            Organism    Species/strain/cell type     Metabolic     Testing conditions        Results           Reference
                                                              activationa
                                                                                                                                              

    Chromosome       rats        bone marrow cells               N/A        inhalation for 2 h at     dose/related      Anderson et al. (1977a)
     aberrations     8/group                                                3.5, 35, or 525 g/m3      increase of 
     in vivo                                                                                          chromosome 
                                                                                                      damage, 
                                                                                                      significant only
                                                                                                      at high dose

    Chromosome       rats        bone marrow cells                N/A       inhalation at 3.5, 35,    significant       Anderson et al. (1977)
     aberrations     8/group                                                or 525 g/m3, 6 h/day      increase of 
     in vivo                                                                for 5 days                chromosome 
                                                                                                      aberrations at
                                                                                                      low and mid-dose
                                                                                                      but not at high
                                                                                                      dose

    Chromosome       mouse       CD-1, bone marrow cells          N/A       816 mg/kg body weight     negative          Loprieno & Abbondandolo
     aberrations                                                            in corn oil by gavage                       (1980)
     in vivo

    Dominant         mouse       CD-1                             N/A       inhalation for 6 h/day,   positive in some  Hodge et al. (1979)
     lethal          20/group                                               5 days, at 3.5, 35, or    parameters, not
                                                                            350 g/m3                  time or dose 
                                                                                                      related

    Dominant         mouse       CD-1                             N/A       inhalation for 6 h/day,   positive in some  Hodge et al. (1979)
     lethal          20/group                                               5 days, at 0.035, 0.35,   parameters, not
                                                                            1.75, 3.5, 35, 175 g/m3   time or dose 
                                                                                                      dependent

    Dominant         rat         Sprague-Dawley                   N/A       175 g/m3, 5 h/day, for    negative          Lee & Suzuki (1981)
     lethal                                                                 8 weeks

                                                                                                                                              

    Table 10 (contd)
                                                                                                                                              
    Assay            Organism    Species/strain/cell type     Metabolic     Testing conditions        Results           Reference
                                                              activationa
                                                                                                                                              

    Micronucleus     mouse       bone marrow cells                N/A       175 and 525 g/m3          negative          Howard et al. (1989)
     in vivo                                                                for 6 h

                                                                                                                                              

    a   ± indicates that separate experiments were carried out with and without metabolic activation; NA = not applicable
    

         Anderson et al. (1977a) found an increase in chromosomal damage
    in rats exposed to 3.5 g/m3, 6 h/day, for 5 days. However, there
    was less evidence of chromosomal damage at exposures of 35 and 525
    g/m3. Similar results were observed following a single 2-h
    exposure using the same concentrations. Anderson & Richardson (1979)
    repeated the experiment using lower exposure levels (0.035, 0.35,
    1.75, and 3.5 g/m3). There was an increase in chromosomal damage,
    but again it was not dose related. Both of these studies were
    reviewed by Litchfield & Longstaff (1984) and Longstaff (1988).
    Loprieno & Abbondandolo (1980) did not find chromosomal changes in
    the bone marrow of mice in a study in which HCFC 22 was administered
    by gavage.

         There was no evidence for dominant lethality in a study on male
    Sprague-Dawley rats exposed to 177 g/m3, 5 h/day, for 8 weeks (Lee
    & Suzuki, 1981). In two dominant lethal assays on mice at exposure
    levels of 0.035-350 g/m3, there were statistically significant
    differences from control values in certain parameters (e.g., early
    fetal death, reduction of fertility) at various points (Anderson et
    al., 1977b; Hodge et al., 1979). However, there was no time or
    exposure-relatedness. In addition, results were not reproducible.

         In an inhalation study in mice, Howard et al. (1989) found no
    evidence of micronucleus induction at exposure levels at 175 and 525
    g/m3.

         Most of these studies have been reviewed by Litchfield &
    Longstaff (1984) and Longstaff (1988). With the exception of
    positive findings in mutation assays using specific strains of
     Salmonella (TA1535 and TA100), HCFC 22 did not show activity in
    microorganisms or in mammalian  in vitro and  in vivo systems.
    These included mutation, unscheduled DNA synthesis assays  in vitro,
    and cytogenetic and dominant lethal assays in two species of
    rodents. Overall, the available information does not indicate a
    genotoxic effect of HCFC 22 in mammalian systems.

    7.7  Carcinogenicity

         No data are available on the carcinogenicity of HCFC 21.

         In a life-time study, Tinston et al. (1981b) exposed groups of
    80 male and 80 female Alderley Park Wistar-derived rats to HCFC 22
    (0, 3.5, 35, or 175 g/m3, 5 h per day, 5 days/week) for 118 weeks
    in females and 131 weeks in males (the period by which mortality had
    reached approximately 80%). No treatment-related clinical
    abnormalities, increased mortality, or haematological or biochemical
    changes were observed. The only effects were a body weight reduction
    in males exposed to 175 g/m3 and increased weight of liver,
    kidney, and adrenal and pituitary glands in females. In males there
    was no increase in the number of benign tumours, but there was a

    slight increase in the number of rats with malignant tumours at the
    highest exposure level (Table 11). This increase was primarily due
    to the increased incidence of rats with fibbrosarcoma. The only
    organ that was consistently associated with this increase was the
    salivary gland, but, according to Litchfield & Longstaff (1984),
    this may have been the consequence of generalized subcutaneous
    fibrosarcomas developing in a submandibular site and involving the
    salivary gland only by chance. The increase in fibrosarcomas was
    observed only in the late stages of the study (between 105 and 130
    weeks). No significant increase was found at lower exposure levels.
    Four male rats in the group exposed to 175 g/m3 were found to have
    Zymbal gland tumours at the highest exposure level. Female rats did
    not exhibit such changes at any of the exposure levels.

        Table 11.  Tumour incidence in male rats exposed to HCFC 22
               in a lifetime inhalation studya
                                                                                

                                         HCFC concentrations (g/m3)
                            0b             3.5            35             175
                                                                                

    Total malignant        16/80          27/80          22/80          33/80
     tumours               18/80

    Selected sites

     Fibrosarcomas         5/80           8/80           5/80          18/80c
                           7/80

     Salivary gland        1/80           1/80           0/80           7/80c
      fibrosarcomas        0/80

     Zymbal's gland        0/80           0/80           0/80           4/80c
      tumours              0/80

                                                                                

    a    From: Tinston et al. (1981b).
    b    Two control groups were used.
    c    Statistically significant difference in relation to the control group
         (P < 0.05)
    
         In a further study, Tinston et al. (1981a) exposed groups of 80
    male and 80 female Alderley Park Swiss-derived mice to HCFC 22 (0,
    3.5, 35, or 175 g/m3, 5 h per day, 5 days/week) for up to 83 weeks
    in males and 94 weeks in females (approximately 80% mortality). The
    only finding was hyperactivity. There was no significant increase in
    the incidences of benign or malignant tumours in treated male or
    female mice compared to the controls, with the exception of a small

    increase in the incidence of hepatocellular carcinomas in the males
    at the highest exposure level. However, the incidences of both
    benign and malignant nodules were within the range of historical
    control values for this strain of mouse.

         There have been two well-documented and well-conducted lifetime
    inhalation studies by Tinston et al. (1981a,b) in rats and mice.
    These did not indicate any increased tumour incidence except for
    fibrosarcomas in male rats at the highest exposure level of 175
    g/m3. The lack of tumour response was also seen in another
    inhalation study using a different mouse strain and a maximum
    exposure level of 17.5 g/m3, and in a limited gavage study in
    rats.

         The overall results of these studies indicate no tumorigenic
    effect up to exposure levels of 35 g/m3. It has been suggested
    that the increased tumorigenic response in male rats at the high
    exposure level may be due to the presence of HCFC 31, a known
    mutagen and animal carcinogen, as an impurity (DFG, 1986), but more
    evidence is needed to confirm this suggestion.

         Maltoni et al. (1982, 1988) exposed groups of 60 male and 60
    female Sprague-Dawley rats and Swiss mice by inhalation to HCFC 22
    (concentrations of 0, 3.5, and 17.5 g/m3, for 6 h/day, 5
    days/week) for 104 weeks (rats) or 78 weeks (mice). There were no
    differences in body weights or survival between treated and control
    animals (details not given). No increases in tumour incidence were
    observed.

         Longstaff et al. (1984) administered to a group of 36 male and
    a group of 36 female Alderley Park Wistar-derived rats HCFC 22 (300
    mg/kg body weight) in corn oil by gavage daily (on 5 days/week) for
    52 weeks. One similarly sized control group received no treatment
    and two control groups were dosed with corn oil. The study was
    terminated at week 125. The treatment had no effect on body weight
    gain or mortality. No increased incidence of tumours was observed in
    any of the organs in the treated groups compared either with
    untreated controls or those given corn oil.

    7.8  Special studies - cardiovascular and respiratory effects

         Chlorofluorocarbons have long been known to sensitize the heart
    to adrenaline-induced arrhythmias (Reinhardt et al., 1971; Zakhari &
    Aviado, 1982). Respiratory effects have also been noted.

    7.8.1  HCFC 21

         A summary of data on the effects of HCFC 21 on cardiovascular
    and respiratory function is given in Table 12. 

        Table 12.  Cardiovascular and respiratory function studies on HCFC 21
               in different animal species
                                                                                              
    Species    Concentration                 Effect                            Reference
                    (g/m3)
                                                                                              

    Mouse          427          arrhythmia (with and without exogenous         Aviado & Belej
                                adrenaline)                                    (1974)

    Rat            811.3        apnoea, cardiac arrest                         Friedman et al.
                                                                               (1973)

    Cat           1700          sensitization to exogenous adrenaline,         Branch et al.
                                cardiac arrhythmia                             (1990)

    Dog             42.7        lowest concentration causing cardiac           Mullin (1975)
                                sensitization (with exogenous adrenaline)

                   106.75       EC50 for cardiac sensitization (with           Clark & Tinston
                                exogenous adrenaline)                          (1973)

                   106.75       tachycardia, bronchoconstriction               Aviado (1975a,b)

                   106.75       rise in pulmonary resistance, decrease in      Belej & Aviado
                                pulmonary compliance                           (1975)

                   427          hypotension

    Monkey         106.75       minimal concentration for induction of         Aviado (1975);
                                cardiac arrhythmia, tachycardia, myocardial    Belej et al.
                                depression, and hypotension                    (1974)

                   106.75       reduction in respiratory minute volume         Aviado & Smith
                                                                               (1975)

                   213.5        bronchodilation with depression of             Aviado (1973,
                                respiration                                    1975)

                                                                                              
    
         In non-anaesthetized dogs, the concentration of HCFC 21 leading
    to cardiac arrhythmias in 50% of catecholamine-treated dogs (EC50
    value) was calculated to be 107 g/m3 for a 5-min exposure period
    (Clark & Tinston, 1973). In a separate study, the lowest dose
    causing this effect was 43 g/m3 (Mullin, 1975). Tachycardia,
    broncho-constriction, and loss of pulmonary compliance were also
    found at exposure levels of 107 g/m3 when anaesthetized dogs were
    given a 7-min exposure (Aviado, 1975a,b; Belej & Aviado, 1975).

         In anaesthetized monkeys (species not further defined),
    spontaneous cardiac arrhythmias, tachycardia, and hypertension, as
    well as reduced respiratory minute volume, were found following
    exposure to 107 g/m3 for 7 min (Belej et al., 1974; Aviado &
    Smith, 1975). In contrast to dogs, bronchodilation and early
    respiratory depression were found in monkeys exposed to 214 g/m3
    (Aviado, 1975a,b).

         Spontaneous arrhythmias occurred in mice exposed to 425 g/m3
    for 7 min (Aviado & Belej, 1974). Brachycardia, apnoea, and cardiac
    arrest, accompanied by lowered respiratory rates and raised lung
    tidal volumes, were apparent in rats exposed to 811 g/m3 (Friedman
    et al., 1973). 

         These effects of HCFC 21 are also characteristic of the fully
    halogenated chlorofluorocarbons (see WHO, 1990).

    7.8.2  HCFC 22

         A summary of data on the cardiovascular and respiratory effects
    of HCFC 22 in experimental animals is presented in Table 13.

         Belej et al. (1974) evaluated the cardiotoxic potential of HCFC
    22 in three Rhesus monkeys anaesthetized with sodium pentobarbitone.
    The trachea of each animal was canulated and the chest was open for
    direct measurement of cardiac function. Following exposure to 350 or
    700 g/m3 for 5 min, various indices of cardiac function were
    measured, i.e. heart rate, myocardial force, aortic blood pressure,
    and left atrial pressure. The only changes found were a slight but
    significant depression of myocardial contractility and a drop in
    aortic blood pressure in monkeys exposed to either concentration.

         The effect of HCFC 22 on respiratory function was studied by
    Aviado & Smith (1975) in three Rhesus monkeys anaesthetized by
    intravenous application of sodium phenobarbital (30 mg/kg) and
    exposed for 5 min to 350 g/m3 through a canulated trachea.
    Electrocardiograms and femoral arterial blood pressures were
    recorded, and pulmonary airway resistance and compliance were
    estimated from measurements of tracheal airflow and transpulmonary
    pressure. No significant change was recorded at 350 g/m3, but a
    slight, yet significant, elevation in pulmonary resistance was
    observed at 700 g/m3.

         Arrhythmias were also noted in cats given 1700 g per m3 of
    40% HCFC 22 for 10 minutes (Branch et al., 1990).


        Table 13.  Cardiovascular and respiratory function studies of HCFC 22 in different animal species
                                                                                                          
    Species    Concentration    Duration       Effects                                     Reference
                  (g/m3)           of
                                exposure
                                                                                                          

    Rat           525-2100      2 min          decreased heart rate and changes            Pantaleoni &
                                               in ECG                                      Luzi (1975a)

                 1050-2100      2 min          decreased myocardiac contractility,         Pantaleoni &
                                               ECG changes, arterial hypotension           Luzi (1975b)

    Mouse           700         6 min          no arrhythmias with or without              Aviado & Belej
                                               exogenous adrenaline;                       (1974)

                   1400         6 min          arrhythmias seen only with exogenous
                                               exogenous adrenaline

    Rabbit          210         5 h/day        one of 14 rabbits developed                 Van Stee &
                                for 8-12       arrhythmias; also received phenobarbital    McConnell (1977)
                                weeks          (no controls were used)

    Dog            1750         5 min          lowest concentration causing cardiac        Mullin (1975)
                                               sensitization (with exogenous adrenaline)

                   87.5         5 min          no effects (with exogenous adrenaline)      Reinhart et al.

                    175         5 min          cardiac sensitization (with exogenous       (1971)
                                               adrenaline)

                    490         5 min          EC50 for cardiac sensitization (with        Clark & Tinston
                                               exogenous adrenaline)                       (1982)

                                                                                                          

    Table 13 (contd)
                                                                                                          
    Species    Concentration    Duration       Effects                                     Reference
                  (g/m3)           of
                                exposure
                                                                                                          

    Dog            17.5         6 h/day        no effect on ECG and circulatory            Leuschner et al.
     (contd)                      for          functions                                   (1983)
                                90 days

    Monkey          350         5 min          depression of myocardial contractility;     Belej et al.

                    700         5 min          decreased aortic blood pressure             (1974)
                    350         5 min          no effect on pulmonary measurement          Aviado & Smith

                    700         5 min          slightly increased pulmonary resistance     (1975)

                                                                                                          
    

         Reinhardt et al. (1971) assessed the ability of HCFC 22 to
    induce cardiac sensitization to adrenaline in male beagle dogs
    exposed to 87.5 or 175 g/m3 via a face mask, using 12 dogs at each
    exposure level. After 5 min of exposure, a challenge injection of
    adrenaline (0.008 mg/kg) was given. At 87.5 g/m3 no effect was
    noted, but at 175 g/m3 two animals displayed cardiac sensitization
    as demonstrated by serious arrhythmias. The authors classified HCFC
    22 as a weak cardiac sensitizing agent. This is consistent with the
    finding of Mullin (1975) that the minimum concentration of HCFC 22
    at which cardiac sensitization occurs in dogs injected with
    adrenaline is 175 g/m3.

         Leuschner et al. (1983) did not observe any effect on ECG and
    circulatory functions in dogs exposed to 17.5 g per m3 (6 h/day, 7
    days/week) for 90 days.

         Clark & Tinston (1982) determined the exposure levels of HCFC
    22 causing acute cardiac sensitization after adrenaline treatment in
    dogs and mice. The concentration affecting 50% of the animals
    (EC50) was 490 g/m3 for both species.

         Aviado & Belej (1974) exposed anaesthetized Swiss mice to 700
    or 1400 g/m3 for 6 min via a face mask. In the first experiment no
    adrenaline was given, whereas in the second 6 µg/kg was administered
    intravenously. Only at the higher exposure level with adrenaline
    were arrhythmias recorded.

         Pantaleoni & Luzi (1975a,b) found a decreasing heart rate and
    ECG changes in rats exposed to 525-2100 g/m3 for 2 min. In a
    second study, rats exposed to 1050-2100 g/m3 for 2 min showed a
    decrease in cardiac contractile strength, followed by a decrease in
    carotid pressure, ECG changes, and arterial hypotension. Vagotomy
    partially inhibited the appearance of the ECG changes. In both
    experiments the modified parameters returned to normal within 2 min
    of breathing normal air.

         When Van Stee & McConnell (1977) exposed 7 male and 7 female
    rabbits to 210 g/m3 for 5 h/day (5 days/week, for 8-12 weeks), 1
    female rabbit, which was also receiving phenobarbital, developed
    arrhythmia, probably of supraventricular origin. No controls were
    used in this limited study.

    8.  EFFECTS ON HUMANS

    8.1  General population exposure

    8.1.1  Accidents

         One case of acute poisoning has been reported. A young boy was
    found dead in a small room with his mouth around the nozzle of a
    tank containing HCFC 22. No details were provided (Garriot & Petty,
    1980).

    8.1.2  Controlled human studies

         Ten healthy volunteers and ten patients suffering from a
    pronounced arterial hypoxaemia due to broncho-pulmonary disease were
    exposed by inhalation to an aerosol mixture containing 60% HCFC 21
    and 40% CFC 11. They inhaled 202 ml of the aerosol within 2.5 h or
    126 ml during 10 successive breaths. No ECG changes were observed in
    either group (Fabel et al., 1972).

         A group of eleven subjects, of whom seven were maintenance
    technicians of large cooling and refrigerating systems, were exposed
    to chlorofluorocarbons at weighted exposure levels similar to their
    usual occupational exposures. They were also exposed experimentally
    for 130 min to HCFC 22 concentrations of 0.71 or 1.89 g/m3, to a
    mixture of HCFC 115 (4 g/m3) and HCFC 22 (1.4 g/m3), or to HCFC
    115 (23.4 g/m3) and HCFC 22 (10.5 g/m3). No significant changes
    in ventilatory lung function or cardiac function were observed
    (Valic et al., 1982).

    8.2  Occupational exposure

         A fisherman working in the hold of a fishing boat, and another
    man who attempted to rescue him, died when the hold was filled with
    HCFC 22 from a broken refrigerant pipe. A judicial autopsy,
    performed 5 days after the accident, revealed that the blood of both
    cadavers was dark red. The lungs showed remarkable congestion,
    oedema, haemorrhage, emphysema and pigment-laden macrophages in the
    alveoli, which were detected histologically. Fine fatty droplets
    were observed in the cytoplasm of liver cells. No other signs that
    might have caused injury or sudden death were noted. HCFC 22 was
    detected by gas chromatography in samples of various tissues, blood,
    urine, and pericardial fluid. From these results, the cause of death
    was concluded to be oxygen deficiency resulting from the filling of
    the ship's hold with HCFC 22 from the broken refrigerant pipe (Haba
    & Yamamoto, 1985). 

         Speizer et al. (1975) carried out a questionnaire survey on the
    incidence of palpitations in a group of hospital pathology
    laboratory workers (118 people, 94% of total staff in the pathology

    department) who used HCFC 22 in the preparation of frozen sections.
    This study was triggered by the death of one of the workers from
    myocardial infarction. A 3.5-fold excess of palpitations was
    reported amongst exposed workers compared to an unexposed control
    group from the radiology department (85 people, 93% of total staff
    in the department). Using the number of slides produced as an
    indicator of HCFC 22 exposure, the authors reported a dose-response
    relationship. The only exposure data provided were breathing-zone
    samples collected from two subjects during a 2-min period of HCFC 22
    use; these revealed concentrations of 1062 mg per m3. The possible
    role of exposure to other substances was not taken into
    consideration, the control group was not adequate, and the validity
    of making estimates of exposure on the basis of the number of frozen
    sections prepared is questionable.

         Antti-Poika et al. (1990) did not find a clear connection
    between cardiac arrhythmia and exposure to a mixture of HCFC 22 and
    CFC 12 (average concentrations were 170-815 ppm HCFC 22 and 202 ppm
    CFC 12). One subject, however, had several ventricular ectopic
    beats; his average level of exposure was 170 ppm but the peak
    concentration was as high as 3200 ppm.

         A case of peripheral neuropathy in a commercial refrigeration
    repair worker prompted a survey of a group of 27 refrigeration
    workers (Gunter et al., 1982; Campbell et al., 1986). No case of
    peripheral neuropathy was identified, and chest radiograms,
    pulmonary function tests, electrocardiograms, and blood and urine
    analysis results were all within normal limits. A questionnaire
    completed by all subjects indicated that light-headedness and
    palpitations were more common in the refrigeration workers than in
    the control group of 14 unexposed workers. Personal air samples
    collected over a "typical" shift showed levels of HCFC 22 of 5.1
    mg/m3, and co-exposure to CFC 115 and CFC 12 was assumed.

         In a survey by Edling & Ohlson (1988), 89 workers with
    intermittent exposure to chlorofluorocarbons were examined during
    their work with refrigerant equipment. The refrigerants used were
    mainly CFC 12 (in 56% of the cases) and HCFC 22 (in 32% of cases),
    the rest being CFC 11, CFC 500, and CFC 502 (a mixture of CFC 115
    and HCFC 22). There was no statistically significant difference in
    ECG results between periods with and without exposure nor was there
    any exposure-related trend when workers were grouped in exposure
    groups. No effect on the central nervous system was found. Edling et
    al. (1990) confirmed that the data did not indicate that these
    fluorocarbons induced cardiac arrhythmia among occupationally
    exposed refrigerator repair workers.

         In a preliminary report, death rates were investigated in 539
    workers occupationally exposed to chlorofluorocarbons CFC 12, HCFC
    22, and CFC 502. No increase in total deaths (18 cases) was found

    among those employed for more than 6 months when compared with the
    expected number (26) derived from national statistics. There were
    five deaths due to heart disorders (compared to 9.6 expected), six
    deaths due to cancer (versus 5.7 expected), and two deaths from lung
    cancer (versus 1.0 expected). No significant increase was found even
    in those exposed for more than 3 or 10 years (Szmidt et al., 1981).
    In view of the limited data, no conclusions could be drawn from this
    study.

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         No information is available on the effects of HCFCs 21 or 22 on
    organisms in the environment.

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

    10.1  Evaluation of human health risks

    10.1.1  Direct health effects resulting from exposure to partially
            halogenated chlorofluorocarbons

         No information on exposure levels for the general population
    has been reported. Tropospheric concentration measurements range
    from 4.3 to 86 ng/m3 (1-20 ppt) for HCFC 21 and from 110 to 326
    ng/m3 (31-92 ppt) for HCFC 22.

         Information on simulated aerosol propellant use indicates peak
    HCFC 22 exposures ranging from 5 to 8 g/m3. These levels rapidly
    (in 10-20 seconds) decline to back-ground values of 0.025 to 0.045
    g/m3. No information is available regarding exposure
    concentrations at the work-place, but in a simulated beauty-salon
    model an 8-h time-weighted average HCFC 22 exposure level of
    0.09-0.125 g per m3 was measured.

         The recommended occupational exposure limits in different
    countries range from 1800 to 3540 mg/m3 (500-1000 ppm) for HCFC 22
    and from 40 to 45 mg/m3 (approximately 10 ppm) for HCFC 21.

         On the basis of available information, the kinetics and
    metabolism of HCFC 21 and HCFC 22 are characterized by rapid
    pulmonary absorption and distribution throughout the body. After
    cessation of exposure these chemicals are cleared from the blood
    within minutes. Metabolic transformation of HCFC 22 is minimal, if
    it occurs at all. Therefore, toxic effects of metabolites are
    extremely unlikely. However, there is evidence for some metabolism
    of HCFC 21, based on increased urinary excretion of fluoride after
    exposure of animals.

         The acute toxicity of both chemicals is very low. As with the
    fully halogenated chlorofluorocarbons, it is characterized in
    animals by effects on the central nervous and cardiopulmonary
    systems at inhalation concentrations of 175 g/m3 or more.

         In animal studies with repeated inhalation exposure, HCFC 21 is
    more toxic than HCFC 22. The latter causes little or no toxicity at
    exposure levels likely to be of any practical significance to
    humans. In various animal species HCFC 21 induces liver damage,
    which might be due to the formation of one or more reactive
    metabolites.

         The carcinogenicity of HCFC 21 has not been studied. However,
    the substance is not genotoxic in bacterial and yeast systems. In
    one lifetime study, exposure to HCFC 22 led to small, but
    statistically significant, increases in the incidence of

    fibrosarcomas in the salivary gland region and Zymbal's gland, but
    only in male rats at high exposure levels (175 g/m3). Other
    lifetime studies in rat and mouse did not produce any indication of
    carcinogenicity, and HCFC 22 was not genotoxic in mammalian systems.
    Thus, HCFC 22 is unlikely to constitute a carcinogenic risk to
    humans at environmental or controlled occupational exposure levels.

         An embryotoxicity study with HCFC 21 in rats revealed
    implantation losses at maternally toxic doses (42.7 g per m3), but
    there were no teratogenic effects. No further information is
    available on the potential effects of HCFC 21 on reproduction. At
    the maternally toxic high HCFC 22 exposure concentration of 175
    g/m3, a small increase in the incidence of eye malformations was
    reported in rats. In view of these findings and the absence of any
    effects in rabbits at similar exposure levels, HCFC 22 is considered
    unlikely to pose a risk to developmental processes in humans at
    environmental or controlled occupational exposure levels. No effects
    were observed in a one-generation reproduction study on rats exposed
    to HCFC 22 at a concentration of 175 g/m3 (5 h/day for 8 weeks).

         In summary, the toxic potency of HCFC 21 is greater than that
    of HCFC 22. This is reflected in the 50- to 100-fold lower
    occupational exposure limits for HCFC 21 than for HCFC 22.
    Controlled occupational exposures are unlikely to represent a
    significant risk to humans. Although high peak exposure levels may
    occur during consumer use of products containing HCFC 22 as a
    propellant, the exposure period is short and so adverse health
    effects are unlikely. Environmental exposure levels are extremely
    low and are not considered likely to cause direct effects to human
    health.

    10.1.2  Health effects expected from a depletion of stratospheric
            ozone by partially halogenated chlorofluorocarbons

         The possible indirect health effects (e.g., an increase in the
    incidence of skin cancer and immunotoxic and ocular effects) of
    fully halogenated chlorofluorocarbons, resulting from an increase in
    UV-B radiation due to a depletion of the ozone layer, have been
    discussed in Environmental Health Criteria 113. The ozone-depleting
    potential (ODP) of HCFC 22 is about 20 times lower than for CFC 11
    and that of HCFC 21 is estimated to be lower still. Based on this
    information, the indirect health effects of these chemicals are
    expected to be considerably lower than those of the fully
    halogenated chlorofluorocarbons.

    10.2  Effects on the environment

         No information is available to evaluate the direct ecological
    effects posed by HCFC 21 and HCFC 22. With respect to the indirect
    "greenhouse" effect, HCFC 22 is calculated to have a third to a
    quarter of the "global-warming potential" of the fully halogenated
    CFC 11, while that of HCFC 21 is lower still.

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

    11.1  Conclusions

         The available toxicological data on HCFC 21 and HCFC 22
    reviewed in this monograph show differences in their toxicological
    potential. HCFC 22 exhibits a low acute and chronic toxicity and the
    data indicate no mutagenic and only a low carcinogenic potential in
    animals. Developmental effects only occur at high and maternally
    toxic exposure concentrations. Although HCFC 21 also has a low acute
    toxicity potential, it appears to be more toxic than HCFC 22,
    causing damage mainly to the liver following repeated exposure.

         Owing to the observed differences in the toxicity profiles,
    different occupational exposure limits have been recommended for
    these two chemicals. Based on available exposure information, it is
    concluded that these chemicals are unlikely to elicit adverse health
    effects in humans associated with consumer and environmental
    exposures and workplace exposures at or below current occupational
    limits. The human health risks are mainly confined to those
    following accidental exposures and might also result from
    occupational exposure if this is not properly controlled.

         HCFC 21 and HCFC 22 have a lower ozone-depleting potential than
    the fully halogenated chlorofluorocarbons and should therefore pose
    a lower indirect health risk. 

         The global-warming potentials of HCFC 21 and HCFC 22 are
    considerably lower than those of the fully halogenated
    chlorofluorocarbons.

    11.2  Recommendations for protection of human health and the 
          environment

    1.   Since the toxicity of HCFC 22 is low and the ozone-depleting
         and global-warming potentials are lower than those of the fully
         halogenated chlorofluorocarbons, it can be considered as a
         transient substitute for the chlorofluorocarbons included in
         the Montreal Protocol. However, in line with the conclusions of
         the 1990 London Meeting of the Montreal Protocol Parties,
         efforts should be maintained to develop substitutes that would
         pose negligible or no risk to the environment and to develop
         alternative technologies.

    2.   Although HCFC 21 poses a low risk to the environment,  it is
         not recommended as a substitute for the chlorofluorocarbons
         included in the Montreal Protocol  because of its liver
         toxicity.

    12. FURTHER RESEARCH

    1.   In order to fill in gaps in the available information on
         general population exposure and global environmental effects,
         it is recommended that:

         *    the concentrations of HCFCs in food packaging materials
              and in packaged food should be measured;

         *    monitoring of atmospheric levels of HCFCs in different
              parts of the world should be maintained;

         *    more studies of heterogeneous atmospheric phenomena over
              polar regions should be conducted in order to substantiate
              the values for the ozone-depleting potential of HCFCs.

    2.   HCFC 21 is used on a very limited scale and it is not likely to
         become a substitute for the chlorofluorocarbons included in the
         Montreal Protocol. If its use is expected to increase
         substantially in the future, more information on potential
         health effects are needed, such as:

         *    chronic toxicity in animals, with special reference to
              hepatotoxicity;

         *    the mechanism of action in relation to liver toxicity;

         *    genotoxic and carcinogenic potential;

         *    results of targeted health surveillance in populations
              under exposure.

    3.   In view of the interim use of HCFC 22, the existing gaps in
         knowledge concerning its effects on human health and the
         environment should be filled. The following areas of research
         are recommended:

         *    a study of the mechanism of action in order to clarify the
              genotoxic and carcinogenic effects;

         *    targeted health surveillance in populations subject to
              elevated levels of exposure to this substance.

    13.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         An evaluation of the carcinogenicity of HCFC 22 by the
    International Agency for Research on Cancer (IARC, 1987) was
    reported as follows:

         "There is inadequate evidence of carcinogenicity in humans;
    there is limited evidence of carcinogenicity in experimental
    animals. The agent cannot be classified as to its carcinogenicity to
    humans (group 3)."

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    RESUME

    1.  Identité, propriétés physiques et méthodes d'analysew

         Les deux chlorofluorocarbures étudiés dans la présente
    monographie (le dichlorofluorométhane, HCFC 21, et le
    chlorodifluorométhane, HCFC 22) sont des hydrofluorocarbures (HCFC),
    c'est-à-dire des composés obtenus par substitution partielle des
    atomes d'hydrogène du méthane par des atomes de fluor et de chlore.
    Seul le HCFC 22 a une importance commerciale. Le HCFC 21 et le HCFC
    22 sont des gaz ininflammables (dans des conditions normales de
    température et de pression). Ils sont incolores et pratiquement
    inodores. Le HCFC 21 est légèrement et le HCFC 22 moyennement
    soluble dans l'eau. Tous deux sont miscibles aux solvants
    organiques. Le HCFC existe sous forme de gaz liquéfié.

         Il existe plusieurs méthodes pour doser ces deux composés,
    notamment la chromatographie en phase gazeuse avec détection par
    capture d'électrons ou ionisation de flamme, la chromatographie en
    phase gazeuse couplée à la spectrométrie de masse ou encore la
    spectrométrie par déflection photothermique.

    2.  Sources d'exposition humaine et environnementale

         Ces deux HCFC n'existent pas dans la nature. Le HCFC 21 n'est
    produit qu'en petites quantités sans application professionnelle. On
    estime qu'en 1987, la production mondiale de HCFC 22 était de 246
    000 tonnes.

         Le HCFC 22 est essentiellement dissipé dans l'environnement
    lors de la réparation, de l'utilisation et de la mise au rebut de
    réfrigérateurs ou de climatiseurs. On estime qu'à l'heure actuelle,
    il se perd chaque année dans le monde environ 120 000 tonnes de HCFC
    22. On a également fait état d'émissions accidentelles par des
    bateaux de pêche.

         Le HCFC est utilisé comme réfrigérant, comme intermédiaire dans
    la production de tétrafluoréthylène et comme agent de soufflage dans
    la fabrication du polystyrène. On l'utilise également en petites
    quantités comme gaz propulseur dans les bombes aérosols.

    3.  Transport, répartition et transformation dans l'environnement

         Le logarithme du coefficient de partage octanol/eau du HCFC 22
    est de 1,08, ce qui rend la bioaccumulation improbable. On estime
    que la durée de séjour du HCFC 21 dans la troposphère est d'environ
    2 ans et celle du HCFC 22 d'environ 17 ans. Dans la troposphère, la
    principale voie de dégradation consiste sans doute dans la réaction
    avec les radicaux OH. Seule une petite fraction de ces deux composés
    pénètre dans la stratosphère, où, par suite de leur réaction avec

    des radicaux oxygénés, ils libèrent du chlore qui attaque la couche
    d'ozone. Toutefois, on pense que le HCFC 22 produit moins de 1% du
    chlore qui s'attaque à la couche d'ozone. On estime que le potentiel
    de destruction de l'ozone du HCFC 22 est de 0,05, celui du HCFC 21
    étant sans doute plus faible. Quant au potentiel de réchauffement de
    la planète, calculé par rapport à celui du CFC 11 pris comme unité,
    on estime qu'il est de 1/3 à 1/4, celui du HCFC 21 étant encore plus
    faible.

    4.  Concentrations dans l'environnement et exposition humaine

         On ne dispose d'aucune donnée sur les concentrations dans l'eau
    ni sur la présence de ces composés dans des denrées alimentaires,
    encore que le HCFC 22 soit utilisé pour la fabrication de récipients
    en polystyrène expansé destinés au conditionnement de produits
    alimentaires. Il n'existe pas non plus de données sur l'exposition
    humaine au HCFC 21, mais deux études relatives à l'utilisation
    d'aérosols contenant 17-65% de HCFC 22 ont montré que lors
    d'expositions de courte durée (10-20 s), des concentrations
    maximales de l'ordre de 5000 à 8000 mg/m3 pouvaient être
    atteintes. Les employés d'instituts de beauté pourraient être
    exposés à des concentrations de 90-125 mg/m3 (moyenne pondérée par
    rapport au temps sur 8 h). Cependant, il s'agit là de valeurs qui
    sont bien inférieures aux limites fixées par la réglementation en
    vigueur en Allemagne, aux Etats-Unis et aux Pays-Bas.

         Le HCFC 22 se dissipe rapidement dans l'atmosphère. On a fait
    état de concentrations de l'ordre de 326 mg/m3 en 1986 et il
    semble que cette valeur augmente de 11% par an. 

    5.  Cinétique et métabolisme chez l'animal de laboratoire et chez
        l'homme

         Il existe quelques données concernant l'absorption, la
    distribution, le métabolisme et l'excrétion du HCFC 21. Ce composé
    est très probablement absorbé après inhalation, à en juger d'après
    les effets généraux et les taux élevés de fluorures dans l'urine que
    l'on a observés lors d'études toxicologiques sur le rat. Après
    injection intrapéritonéale à des rats, le HCFC 21 est exhalé et les
    données cinétiques, de même que l'excrétion des fluorures indiquent
    que le composé est effectivement métabolisé. Toutefois, on ignore
    dans quelle proportion le HCFC 21 est transformé et aucun autre
    métabolite que le fluorure n'a été identifié.

         Après inhalation, le HCFC 22 est rapidement et bien absorbé
    chez le rat, le lapin, et l'homme et il se répartit largement dans
    l'organisme. De fortes concentrations de HCFC 22 ont été retrouvées
    dans le sang, le cerveau, le coeur, le foie, les reins et la graisse
    des viscères chez des lapins morts des suites d'une exposition à ce
    composé ainsi que dans des échantillons nécropsiques prélevés sur le

    cerveau, les poumons, le foie et les reins de victimes d'une
    intoxication par le HCFC 22. L'élimination est rapide, la majeure
    partie du composé étant excrétée avec une demi-vie de 1 min chez le
    lapin et de 3 min chez le rat. Chez l'homme, le produit est éliminé
    en quantité limitée selon un processus triphasique (demi-vie de 3
    min, 12 min et 2,7 h respectivement).

         Le HCFC 22 réapparaît presque entièrement et sans modification
    dans l'air exhalé, après avoir été inhalé ou injecté par voie
    intrapéritonéale à des rats ou à des sujets humains. Il y a de
    bonnes raisons de penser qu'il ne subit pas de transformation
    métabolique notable chez le rat  in vivo ni en présence de
    préparations de foie de rat.

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

         On ne possède pas de données satisfaisantes sur les effets
    toxiques aigus par voie orale de ces deux composés. 

         Les principaux effets d'une seule inhalation de HCFC 21 ou de
    HCFC 22 sont en gros les mêmes chez nombre d'espèces animales. Par
    cette voie, leur toxicité est faible. Les manifestations toxiques
    observées sont caractéristiques des chlorofluorocarbures, c'est-à-
    dire qu'elles consistent en une perte de coordination et une
    narcose. A forte concentration, on voit quelquefois des arythmies
    cardiaques et des effets pulmonaires (concentrations supérieures ou
    égales à 106,7 g/m3).

         On a rapporté des cas d'irritation cutanée ou oculaire dus à
    ces deux composés. On peut toutefois penser que ces effets étaient
    dus davantage à des pertes thermiques par évaporation qu'aux
    propriétés chimiques des produits en cause. D'ailleurs, aucun d'eux
    n'a provoqué de sensibilisation cutanée.

         Les seules études consacrées à ces deux composés ne portaient
    que sur une seule voie d'administration, la voie respiratoire. Les
    principaux effets observés chez le rat, le cobaye, le chien et le
    chat consistaient en lésions au niveau du foie. On n'en a pas tiré
    de valeur pour la dose sans effet observable. Des lésions
    histopathologiques du foie ont été notées à des doses ne dépassant
    pas 0,213 g/m3 administrées 6 h par jour, 5 jours par semaine
    pendant 90 jours. A ces doses on a également observé un oedème
    interstitiel du pancréas et une dégénérescence des cellules
    épithéliales au niveau des tubes séminifères. Ces lésions
    n'apparaissaient pas lors des études où le HCFC 22 était administré
    à des doses comprises entre 17,5 g/m3 (13 semaines) et 175 g/m3
    (4 ou 8 semaines).

         Aucune étude de longue durée n'a été consacrée au HCFC 21 chez
    l'animal. Le seul effet non cancérogène qui ait été systématiquement
    relevé dans le cas du HCFC 22, consistait dans l'hyperactivité
    manifestée par des souris mâles exposées à des doses de 175 g/m3
    de ce produit 5 h par jour, 5 jours par semaine pendant toute leur
    existence. 

         Il n'y a pas eu d'étude toxicologique classique consacrée aux
    effets du HCFC 21 sur la fécondité. Lors d'une étude
    d'embryotoxicité effectuée sur des rats, on n'a pas observé d'effets
    tératogènes, mais dans un grand nombre de cas, la nidation n'a pas
    pu s'effectuer. Le HCFC 22 (175 g/m3, 5 h par jour, 5 jours par
    semaine pendant 8 semaines) n'a eu aucun effet sur la capacité de
    reproduction des rats mâles. Un léger surnombre de malformations
    oculaires sans signification véritable ayant été observé lors de
    trois études tératologiques chez le rat, on a entrepris une étude de
    grande envergure afin de voir si le HCFC 22 avait effectivement
    tendance à provoquer des lésions oculaires. On a ainsi constaté une
    augmentation faible, mais néanmoins statistiquement significative,
    du nombre de portées dans lesquelles des foetus présentaient une
    microphtalmie ou une anophtalmie lorsque les mères étaient exposées
    à une dose de 175 g/m3, 6 h par jour, du 6ème au 15ème jour de la
    gestation. Cette dose était légèrement toxique pour les mères
    (réduction du poids corporel par rapport aux témoins).

         Le HCFC 21 s'est révélé non mutagène dans trois tests de
    mutagénicité, l'un sur levure et les deux autres sur bactéries.
    Aucune autre donnée sur ce point n'a pu être obtenue. Le HCFC 22 a
    présenté une activité mutagène sur modèle bactérien  (S.
     typhimurium) mais cette activité ne s'est pas confirmée sur
    d'autres systèmes bactériens ni sur cellules mammaliennes, que ce
    soit  in vivo ou  in vitro. Ces épreuves portaient sur les
    mutations géniques, la synthèse non programmée de l'ADN, la
    cytogénétique des cellules de moelle osseuse et les mutations
    léthales dominantes (rat et souris).

         Seul le HCFC 22 a fait l'objet d'épreuves de cancérogénicité
     in vivo. Deux groupes de chercheurs ont fait inhaler du HCFC 22 à
    des rats et à des souris pendant toute la durée de leur existence.
    On n'a observé une surfréquence des tumeurs cancéreuses que dans une
    seule étude au cours de laquelle des rats mâles avaient été soumis à
    175 g/m3, 5 jours par semaine, pendant des périodes allant jusqu'à
    131 semaines. Un léger excès de fibrosarcomes a été noté dans la
    région des glandes salivaires et de la glande de Zymbal. Ces effets
    n'apparaissaient pas à dose plus faible (jusqu'à 35 g/m3) et la
    dose la plus élevée n'a pas été utilisée lors de la seconde étude.
    Même si cela ne constitue pas une véritable démonstration de
    l'absence d'effets oncogènes, il n'y a pas eu d'augmentation de la
    fréquence des tumeurs après administration du composé par gavage à

    des rats. Ces animaux ont reçu le HCFC 22 à raison de 300 mg/kg par
    jour, 5 jours par semaine, pendant 52 semaines et l'étude s'est
    achevée au bout de 125 semaines.

    7.  Effets sur l'homme

         On ne dispose que de données très limitées à propos des effets
    du HCFC 21 et du HCFC 22 sur l'homme.

         Dans certains cas d'exposition accidentelle ou délibérée à de
    fortes concentrations de HCFC 22, les intéressés sont décédés.
    L'examen histopathologique d'échantillons de tissus prélevés sur
    quelques-unes de ces victimes a révélé la présence d'un oedème du
    poumon et d'inclusions lipidiques dans le cytoplasme, surtout dans
    les hépatocytes périphériques.

         Un questionnaire que l'on a fait remplir par des personnes
    professionnellement exposées à du HCFC 22, a révélé une augmentation
    de l'incidence des palpitations, mais rien ne prouve avec certitude
    que l'exposition à l'un ou à l'autre des deux produits ait des
    effets nocifs. Une étude de mortalité a été effectuée sur des
    chlorofluorocarbures, dont le HCFC 22, mais elle portait sur un
    effectif trop faible pour qu'on puisse en tirer des conclusions.

    8.  Effets sur d'autres organismes au laboratoire et dans leur
        milieu naturel

         On ne possède aucune donnée concernant les effets que le HCFC
    21 ou le HCFC 22 pourraient exercer sur les êtres vivants dans leur
    milieu naturel.

    RESUMEN

    1.  Identidad, propiedades físicas y químicas y métodos analíticos

         Los dos clorofluorocarburos examinados en la presente
    monografía (diclorofluorometano, HCFC 21 y clorodifluorometano, HCFC
    22) son hidroclorofluorocarburos (HCFC), es decir, compuestos
    obtenidos por la sustitución parcial de los átomos de hidrógeno del
    metano por átomos de flúor y cloro. Sólo el HCFC 22 tiene
    importancia comercial. El HCFC 21 y el HCFC 22 son gases no
    inflamables (a temperaturas y presiones normales), incoloros y
    prácticamente inodoros. El HCFC 21 es ligeramente soluble y el HCFC
    22 moderadamente soluble en agua, y ambos son miscibles con
    disolventes orgánicos. El HCFC 22 puede encontrarse en forma de gas
    licuado.

         Existen varios métodos analíticos para determinar esos dos
    compuestos. Entre ellos figuran la cromatografía de gases con
    captura electrónica y detección por ionización de llama, la
    cromatografía de gases/espectrometría de masas, y la
    espectrofotometría de deflección fototérmica.

    2.  Fuentes de exposición humana y ambiental

         No se tiene noticia de que los dos HCFC estudiados en esta
    monografía existan como tales en la naturaleza. El HCFC 21 sólo se
    produce en pequeñas cantidades con fines no ocupacionales. Se
    calcula que la producción mundial total de HCFC 22 en 1987 ascendió
    a 246 000 toneladas. 

         La principal pérdida de HCFC 22 se produce durante la
    reparación, el uso y el desecho de frigoríficos y aparatos
    acondicionadores de aire. Actualmente se calcula que la pérdida
    mundial máxima está en torno a las 120 000 toneladas. Se han
    comunicado casos de liberación accidental de HCFC 22 en
    embarcaciones de pesca.

         El HCFC 22 se utiliza como refrigerante como intermedio en la
    producción de tetrafluoroetileno, y como agente expansor del
    poliestireno. Una pequeña cantidad se utiliza como propulsor de
    aerosoles.

    3.  Transporte, distribución y transformación en el medio ambiente

         El coeficiente de partición log octanol/agua del  HCFC 22 es
    1,08, lo que hace poco probable que se bioacumule. Se ha calculado
    que la persistencia del HCFC 21 en la troposfera es de unos 2 años y
    la del HCFC 22 de unos 17 años. Es probable que la reacción con
    radicales hidroxilo en la troposfera sea la principal vía de
    degradación. Sólo una pequeña fracción de los HCFC 21 y 22 alcanza

    la estratosfera donde, principalmente por reacción con radicales de
    oxígeno, liberan cloro que ataca al ozono. No obstante, se calcula
    que el HCFC 22 produce menos del 1% del cloro que ataca al ozono en
    la estratosfera. El potencial de destrucción de ozono (PDO) del HCFC
    22 se ha calculado en 0,05 y se supone que el del HCFC 21 es aún
    menor.

         Se estima que el potencial de calentamiento de la tierra (PCT),
    en relación con el del CFC 11, al que se asigna el valor 1,0, es
    inferior por un factor de 3 ó 4 el el caso del HCFC 22 y aún menor
    en el HCFC 21.

    4.  Niveles en el medio ambiente y exposición humana

         No se dispone de datos sobre las concentraciones en el agua ni
    sobre la presencia de estos compuestos en los alimentos, aunque el
    HCFC 22 se utiliza en la fabricación de recipientes alimentarios de
    poliestireno expandido. No se tienen datos sobre la exposición
    humana al HCFC 21, pero en dos estudios sobre el uso de
    vaporizadores experimentales con un 17-65% de HCFC 22 se ha
    demostrado que las exposiciones breves (10-20 segundos) pueden
    originar concentraciones máximas que van desde 5000 hasta 8000
    mg/m3. Los trabajadores de peluquerías pueden estar expuestos a
    niveles medios ponderados en un tiempo de 8 horas de 90-125 mg/m3,
    pero esos niveles se encuentran muy por debajo de los niveles
    reglamentarios MAK o LTV de 1800-3540 mg/m3 en Alemania, EE.UU. y
    los Países Bajos. 

         El HCFC 22 se mezcla rápidamente en la atmósfera. En 1986 se
    comunicaron concentraciones de unos 326 mg/m3 y se cree que el
    nivel aumenta en un 11% al año, aproximadamente.

    5.  Cinética y metabolismo en animales de laboratorio y en el ser 
        humano

         Se cuenta con datos limitados sobre la absorción, la
    distribución, el metabolismo y la excreción de HCFC 21. Puede
    inferirse que este compuesto se absorbe tras la inhalación a partir
    de los efectos sistémicos y de los elevados niveles de fluoruros en
    la orina observados en estudios de toxicidad en ratas. Las ratas
    exhalan HCFC 21 tras la inyección intraperitoneal y tanto los datos
    cinéticos como las pruebas de excreción de fluoruro sugieren que el
    HCFC 21 es metabolizado. No obstante, no se sabe hasta qué punto se
    metaboliza y, aparte del fluoruro, los productos no se han
    identificado.

         En la rata, el conejo y el ser humano el HCFC 22 se absorbe
    rápidamente y sin dificultad tras la inhalación y se distribuye por
    todo el organismo. Se han encontrado niveles elevados de HCFC 22 en
    la sangre, el cerebro, el corazón, el pulmón, el hígado, el riñón y

    la grasa visceral de conejos moribundos durante la exposición y en
    muestras postmortem de cerebro, pulmón, hígado y riñón de víctimas
    accidentales de la exposición a HCFC 22. La eliminación es rápida;
    la mayor parte del HCFC se elimina con una semivida de 1 minuto en
    el conejo y 3 minutos en la rata. En el ser humano, una cantidad
    limitada de material se elimina en tres fases (semividas de 3
    minutos, 12 minutos y 2,7 h).

         El HCFC 22 inhalado o administrado por vía intraperitoneal se
    exhala casi por completo sin alteraciones tanto en la rata como en
    el hombre. Existen pruebas convincentes de que en la rata no se
    metaboliza en grado significativo ni  in vivo ni en preparaciones
    de hígado.

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

         No se dispone de datos satisfactorios sobre la toxicidad aguda
    por vía oral del HCFC 21 ni del HCFC 22. 

         Los efectos principales de una sola exposición por inhalación
    de HCFC 21 o HCFC 22 son esencialmente similares en diversas
    especies animales. Ambas sustancias tienen baja toxicidad por esta
    vía. Los efectos observados son característicos de los
    clorofluorocarburos, a saber, pérdida de coordinación y narcosis.
    Con elevadas concentraciones (106,7 g/m3 o más) pueden producirse
    arritmias cardiacas y efectos pulmonares.

         Aunque se ha indicado que tanto el HCFC 21 como el HCFC 22
    causan irritación cutánea y ocular, esos efectos pueden haber
    guardado relación con las consecuencias de la pérdida de calor por
    evaporación antes que con las propiedades químicas de los HCFC.
    Ninguna de las dos sustancias provocó sensibilización cutánea.

         Los únicos estudios realizados sobre la toxicidad a corto plazo
    del HCFC 21 han investigado la vía de inhalación. El principal
    efecto observado en la rata, el cobayo, el perro y el gato fueron
    las lesiones hepáticas; no se determinó el nivel sin efectos
    observados. Con niveles tan bajos como 0,213 g/m3 administrados 6
    h/día, 5 días por semana, durante 90 días, se observaron lesiones
    histopatológicas en el hígado. Con esa concentración también se
    observó edema pancreático intersticial y degeneración del epitelio
    de los túbulos seminíferos. En estudios realizados con el HCFC 22 a
    niveles de exposición entre 17,5 g por m3 (durante 13 semanas) y
    175 g/m3 (durante 4 u 8 semanas) no se observaron lesiones.

         No se han hecho estudios a largo plazo sobre el HCFC 21 en
    animales. La única conclusión coherente no tumorigénica observada en
    estudios a largo plazo con HCFC 22 fue la hiperactividad observada

    en ratones machos a los que se administraron 175 g/m3, 5 h/día, 5
    días por semana en un estudio de inhalación durante un lapso de vida
    entera.

         No se han hecho estudios convencionales sobre los efectos del
    HCFC 21 en la fecundidad. En un estudio de la embriotoxicidad en
    ratas (42,7 g/m3, 6 h/día los días 6-15 de la gestación) no se
    observaron efectos teratogénicos, pero se encontró una tasa elevada
    de pérdida de la implantación. El HCFC 22 (175 g/m3 al día, 5
    h/día, 5 días/semana durante 8 semanas) no tuvo efecto alguno en la
    capacidad de reproducción de las ratas macho. Al observarse un
    exceso pequeño, no significativo, de defectos oculares en tres
    estudios de teratología en ratas, se realizó un amplio estudio sobre
    la posible capacidad del HCFC 22 de provocar defectos oculares. En
    ese estudio, se observó un aumento pequeño, aunque estadísticamente
    significativo, del número de camadas con fetos afectados de
    microftalmía o anoftalmía tras la exposición de la madre a 175
    g/m3, 6 h/día durante los días 6-15 de la gestación. Ese nivel de
    exposición produjo ligera toxicidad materna (peso corporal inferior
    en comparación con los testigos). No se observaron otros efectos; el
    nivel sin efectos observados en ese estudio fue de 3,5 g/m3. El
    HCFC 22 no resultó teratogénico en un estudio convencional realizado
    en ratones con regímenes de exposición similares.

         Se encontró que el HCFC 21 no era mutagénico en dos ensayos en
    bacterias y uno en levaduras (no se obtuvieron otros datos). El HCFC
    22 fue mutagénico en ensayos bacterianos con  S. typhimurium, pero
    no mostró actividad en ensayos con otros microorganismos ni en
    sistemas de mamíferos, ni  in vitro ni  in vivo. En esos ensayos
    se hicieron pruebas de mutación génica y de síntesis no programada
    del ADN  in vitro, pruebas citogenéticas en médula ósea  in vivo, 
    y pruebas de letalidad dominante en la rata y en el ratón.

         Sólo se han realizado ensayos de carcinogenicidad  in vivo con
    el HCFC 22. Dos grupos de investigadores han realizado estudios de
    inhalación durante un lapso de vida entera tanto en ratas como en
    ratones. Tan sólo se observó excedente de tumores en el único
    estudio en el que se administraron a ratas macho 175 g/m3, 5 días
    a la semana, durante hasta 131 semanas. Se observaron pequeños
    excedentes de fibrosarcomas en la región de las glándulas salivares
    y de la glándula de Zymbal. Esos efectos no se observaron con dosis
    inferiores (hasta 35 g/m3), y esa dosis elevada no se utilizó en
    el segundo estudio. Aunque no sirva como demostración adecuada de la
    ausencia de efectos tumorigénicos, no se observó excedente de
    tumores en un estudio de alimentación forzada por vía oral en ratas.
    Se administró a esos animales HCFC 22 en dosis de 300 mg/kg al día,
    5 días/semana, durante 52 semanas, y el estudio terminó a las 125
    semanas.

    7.  Efectos en el ser humano

         Se dispone de datos muy limitados sobre los efectos del HCFC 21
    y el HCFC 22 en el ser humano.

         Se han producido casos de muerte por exposición accidental o
    intencionada a niveles elevados de HCFC 22. El examen
    histopatológico de los tejidos de algunas de esas víctimas reveló la
    existencia de edema pulmonar y gotitas grasas citoplásmicas
    principalmente en los hepatocitos periféricos.

         Aunque se ha indicado un aumento de la incidencia de
    palpitaciones en un estudio realizado con cuestionarios entre
    individuos expuestos al HCFC 22 en el trabajo, no existen pruebas
    sólidas de que la exposición de volunarios o de trabajadores al HCFC
    21 o al HCFC 22 produzca efectos nocivos en la salud. Nada puede
    concluirse a partir de un estudio de mortalidad sumamente reducido
    en personas expuestas por su profesión a varios clorofluorocarburos,
    entre ellos el HCFC 22.

    8.  Efectos en otros organismos en el laboratorio y sobre el terreno

         No se dispone de datos sobre los efectos de los HCFC 21 y 22 en
    los organismos del medio ambiente.


    See Also:
       Toxicological Abbreviations