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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 139





    PARTIALLY HALOGENATED CHLOROFLUOROCARBONS
    (ETHANE 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. Beritc-Stahuljak and Professor
    F. Valic (University of Azgreb, Croatia) using texts made
    available by Dr R. Millischer (ATOCHEM, Paris, France), 
    Dr. S. Magda (Kali-Chemie, Hanover, Germany), Mr D.J. Tinston
    (ICI Central Toxicology Laboratory, United Kingdom), Dr. H.J.
    Trochimowicz (E.I. Du Pont de Nemours, Newark, Delaware, USA)
    and Dr G.M. Rusch (Engineered Materials Sector, Allied-Signal Inc.,
    Morristown, New Jersey, USA).

    World Health Orgnization
    Geneva, 1992


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    WHO Library Cataloguing in Publication Data

    Partially halogenated chlorofluorocarbons (ethane derivatives).

        (Environmental health criteria ; 139)

        1.Freons - adverse effects 2.Freons - toxicity 
        I.Series

        ISBN 92 4 157139 X        (NLM Classification: QV 633)
        ISSN 0250-863X

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    letters.







    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR PARTIALLY HALOGENATED
    CHLOROFLUOROCARBONS (ETHANE DERIVATIVES)

    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
               2.1.1. Technical products
         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

    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, food and other edible products
         5.2. Human exposure

    6. KINETICS AND METABOLISM


         6.1. Animal studies
               6.1.1. Absorption
               6.1.2. Distribution
               6.1.3. Metabolic transformation
                       6.1.3.1  General considerations
               6.1.4. Covalent binding to macromolecules
               6.1.5. Elimination
         6.2. Human studies

    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
               7.1.3. Acute dermal toxicity
         7.2. Short-term inhalation exposure
         7.3. Skin and eye irritation; sensitization
               7.3.1. Skin and eye irritation
               7.3.2. Skin sensitization
         7.4. Long-term exposure
         7.5. Reproduction, embryotoxicity, and teratogenicity
               7.5.1. Reproduction
               7.5.2. Embryotoxicity and teratogenicity
         7.6. Mutagenicity
         7.7. Carcinogenicity
         7.8. Special studies - cardiovascular and respiratory effects

    8. EFFECTS ON HUMANS

         8.1. General population exposure
         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. Direct health effects
               10.1.1. HCFC 141b
               10.1.2. HCFC 142b
               10.1.3. HCFC 132b
               10.1.4. HCFC 133a
               10.1.5. HCFC 123
               10.1.6. HCFC 124
         10.2. Health effects expected from a depletion of stratospheric
               ozone
         10.3. 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

    REFERENCES

    RESUME

    RESUMEN
    

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

     Members

    Dr U. Andrae, Genetic Toxicology Group, Research Centre for
         Environment and Health, Neuherberg, Germany

    Professor D. Beritic-Stahuljak, Medical School, University of Zagreb,
         Zagreb, Croatia

    Dr J. Delic, Toxicology Unit, Health and Safety Executive, Bootle,
         United Kingdom

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

    Ms G. Hodson-Walker, Cell Biology Department, Life Science Research
         Ltd., Eye, United Kingdom

    Dr W. Jameson, National Institute of Environmental Health Sciences,
         Research Triangle Park, North Carolina, USA

    Dr J. Kojima, Division of Environmental Chemistry, National Institute
         of Hygienic Sciences, Tokyo, Japan

    Dr J. Sokal, Institute of Occupational Medicine, Sosnowiec, Poland

    Dr S. Swierenga, Health and Welfare Canada, Ottawa, Canada ( Joint
          Rapporteur)

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

     Observers

    Dr R. Millischer, Department of Toxicology, ATOCHEM, Paris, France

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

     Secretariat

    Dr D. McGregor, Unit of Carcinogen Identification and Evaluation,
         International Agency for Research on Cancer, Lyon, France

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

    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 Director of the International
    Programme on Chemical Safety, World Health Organization, Geneva,
    Switzerland, in order that they may be included in corrigenda.

                                    * * *

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

    ENVIRONMENTAL HEALTH CRITERIA FOR PARTIALLY HALOGENATED
    CHLOROFLUOROCARBONS (ETHANE DERIVATIVES)

    A Task Group on Environmental Health Criteria for Partially
    Halogenated Chlorofluorocarbons (Ethane Derivatives) met at the
    British Industrial and Biological Research Association (BIBRA),
    Carshalton, Surrey, United Kingdom, from 30 September to 5 October
    1991. Dr S.D. Gangolli opened the meeting on behalf of the host
    institute and greeted the participants on behalf of the Department of
    Health. Professor F. Valic welcomed the participants on behalf of the
    heads of the three cooperating organizations of the IPCS
    (UNEP/ILO/WHO). The Task Group reviewed and revised the draft
    monograph, 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 draft was prepared by Professor D. Beritic-Stahuljak and Professor
    F. Valic, using the texts made available by Dr R. Millischer, ATOCHEM,
    Paris, France (HCFC 141b), Dr S. Magda, Kali-Chemie, Hanover, Germany
    (HCFC 142b), Mr D.J. Tinston, Central Toxicology Laboratory, ICI,
    Alderley Park, United Kingdom (HCFC 133a), Dr H.J. Trochimowicz, E.I.
    Du Pont de Nemours, Newark, Delaware, USA (HCFC 132b), and Dr G.M.
    Rusch, Engineered Materials Sector, Allied-Signal Inc., Morristown,
    New Jersey, USA (HCFC 123 and HCFC 124).

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

    INTRODUCTION

    The global concern over the depletion of the stratospheric ozone layer
    by active chlorine from fully halogenated chlorofluorocarbons 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 in 1987. The agreement
    required a freeze in the production and use of the fully halogenated
    chlorofluorocarbons 11, 12, 113, 114 and 115 at l986 levels by
    mid-1989, a 20% reduction from 1 July 1993 and a further 30% reduction
    from 1 July 1998. Sixty-seven countries and the European Economic
    Community have signed the Protocol. A total phase-out of 15 fully
    halogenated chlorofluorocarbons by the year 2000 was agreed by the
    Parties to the Protocol in June 1990.

    This phase-out has created an urgent need for acceptable substitute
    chemicals. These should have similar properties to the
    chlorofluorocarbons included in the Protocol, but their
    ozone-depleting potentials and possibly global-warming potentials
    should be lower, and their atmospheric residence times shorter. In
    addition, the substitute chemicals should not pose an unreasonable
    risk to human health or the environment.

    The hydrogenated partially halogenated chlorofluorocarbons constitute
    a class of chemicals being considered as substitutes. The
    ozone-depleting potentials and the global-warming potentials of the
    partially halogenated chlorofluorocarbons are considerably lower than
    those of the fully halogenated chlorofluorocarbons, and their
    atmospheric residence times are shorter. Therefore, the partially
    halogenated chlorofluorocarbons for which the toxicity evaluations
    suggest no unreasonable health risks could be considered as possible
    substitutes for the unacceptable fully halogenated
    chlorofluorocarbons, particularly in the case of those for which the
    production should be technologically feasible. The evaluation of two
    partially halogenated methane derivatives of chlorofluorocarbons
    (hydrochlorofluorocarbons 21 and 22) has been completed and published
    as monograph No. 126 in the WHO Environmental Health Criteria series
    (WHO, 1991). The present monograph evaluates six partially halogenated
    ethane derivatives of chlorofluorocarbons (hydrochlorofluorocarbons
    141b, 142b, 132b, 133a, 123 and 124).

    1.  SUMMARY

    1.1  Identity, physical and chemical properties, and analytical
         methods

         This monograph concerns six hydrochlorofluorocarbons (HCFCs)
    derived from the partial substitution of the hydrogen atoms in ethane
    with both fluorine and chlorine atoms. The compounds considered in
    this report are 1,1-dichloro-1-fluoroethane (HCFC 141b), 1-chloro-1,1-
    difluoroethane (HCFC 142b), 1,2-dichloro-1,1-difluoroethane (HCFC
    132b), 1-chloro-2,2,2-trifluoroethane (HCFC 133a), 1,1-dichloro-2,2,2-
    trifluoroethane (HCFC 123) and 1-chloro-1,2,2,2-tetrafluoroethane
    (HCFC 124).

         Under normal temperatures and pressures these compounds are
    flammable (HCFC 142b) or non-flammable gases (HCFC 133a, HCFC 124) or
    non-flammable volatile liquids (HCFC 141b, HCFC 132b, HCFC 123). They
    are colourless and the majority are practically odourless or have a
    faint ethereal odour (HCFC 141b and HCFC 123). They are slightly or
    moderately soluble in water and miscible with many organic solvents.

         Analytical methods available for the determination of these
    hydrochlorofluorocarbons include gas chromatography with flame
    ionization and electron capture detection. Relatively high
    concentrations in air can be monitored by single-beam photometry.

    1.2  Sources of human and environmental exposure

         The hydrochlorofluorocarbons reviewed in this monograph are not
    known to occur as natural products. Due to the fact that these
    compounds are not produced commercially on a large scale for end use,
    there is little human exposure or release to the environment. Some of
    these compounds may be used in the future as substitutes for fully
    halogenated chlorofluorocarbons (e.g., CFC 11, CFC 12, and CFC 113).
    HCFCs 133a and 142b are intermediates in the manufacture of other
    fluorinated products. HCFC 133a is an  in vivo metabolite of the
    anaesthetic halothane.

    1.3  Environmental transport, distribution and transformation

         Data on biodegradation in the environment is limited to studies
    of HCFCs 141b and 142b, which have been shown to be not readily
    biodegradable by microorganisms. Little information on log
    octanol/water partition coefficients is available, but that for HCFC
    141b is 2.3 and so bioaccumulation of this hydrochlorofluorocarbon is
    unlikely. In the troposphere these compounds are mainly decomposed by
    reactions with hydroxy radicals. Their atmospheric lifetimes (relative
    to an atmospheric lifetime of methyl chloroform of 6.3 years) lie
    between 1.6 years (HCFC 123) and 19.1 years (HCFC 142b). (The
    atmospheric lifetime of CFC 11 is 75, CFC 12 is 110, and

    CFC 113 is 90 years). With the exception of HCFC 133a, for which there
    are no values, the ozone-depleting and global-warming potentials of
    these compounds are less than or equal to one-tenth of that of CFC 11,
    the fully halogenated chlorofluorocarbon with the highest
    ozone-depleting and global-warming potential (HCFC 142b, for which the
    global-warming potential is approximately one-third that of CFC 11, is
    an exception).

    1.4  Environmental levels and human exposure

         As HCFCs 141b, 132b, 133a, 123 and 124 are not yet in large-scale
    commercial production and HCFC 142b is only used as an intermediate,
    these substances are not released significantly into the environment.
    There are therefore no data on environmental levels or human exposure.

    1.5  Kinetics and metabolism in laboratory animals and humans

         No data are available on the toxicokinetics in humans of any of
    the HCFCs reviewed.

    1.5.1  HCFC 141b

         Results from toxicity studies suggest that absorption of HCFC
    141b takes place across the respiratory epithelium. No information is
    available on the distribution of HCFC 141b in mammals. In recent
     in vitro single-exposure studies in rats, 2,2-dichloro-2-fluoro-
    ethyl glucuronide and 2,2-dichloro-2-fluoroacetic acid were identified
    in the urine.

         A pilot study for absorption and metabolism of HCFC 141b in rats
    exposed to its vapour suggested that metabolic transformation occurs
    only to a very small extent.

         An  in vitro study indicated that HCFC 141b is dechlorinated to
    a limited extent by hepatic microsomes.

    1.5.2  HCFC 142b

         There is no information on toxicokinetics for HCFC 142b. From
    animal toxicity studies it can be inferred that absorption takes
    place. An  in vitro study suggested that dechlorination may occur.

    1.5.3  HCFC 132b

         In a metabolism study using intraperitoneal administration of
    HCFC 132b to rats, 2-chloro-2,2-difluoroethylglucuronide,
    chlorodifluoroacetaldehyde (hydrated and conjugated) and
    chlorodifluoroacetic acid were identified in the urine. Formation and
    excretion of chlorodifluoroacetic acid were increased after repeated
    injection of the animals with HCFC 132b.  In vitro experiments using

    rat liver microsomes suggested the involvement of cytochrome P-450
    IIEI in the initial hydroxylation step. No evidence for covalent
    binding of fluorinated metabolites to liver proteins has been
    observed.

    1.5.4  HCFC 133a

         No information is available on the toxicokinetics of HCFC 133a.
    That absorption occurs following exposure of animals can be inferred
    from the toxic effects seen in various studies. Dechlorination of HCFC
    133a has been observed  in vitro.

    1.5.5 HCFC 123

         There are no toxicokinetic data on HCFC 123. Absorption, however,
    can be inferred from systemic effects and the elevated urinary
    fluoride levels seen in toxicity studies in rats. HCFC 123 has been
    shown to undergo metabolic transformation in rats. The extent of
    metabolism is not known, but trifluoroacetic acid (TFA) has been
    identified as a major urinary metabolite, in addition to fluoride.
    Covalent binding to liver protein has been demonstrated for HCFC 123.

    1.5.6  HCFC 124

         There are no data on the kinetics and metabolism of HCFC 124. It
    may be inferred from inhalation toxicity studies that absorption of
    HCFC 124 occurs in the respiratory tract.

    1.6  Effects on laboratory mammals and in vitro test systems

    1.6.1  HCFC 141b

         The acute oral toxicity of HCFC 141b is low. No signs of toxicity
    were observed after rats were dosed with 5 g/kg.

         In acute inhalation studies in rats and mice, central nervous
    system (CNS) depression, anaesthesia and death were observed at high
    exposure levels. No treatment-related macroscopic or histopathological
    effects were observed. The 4-h LC50 reported for rats in one study
    was 295 g/m3, and the 2-h LC50 in mice was reported to be 151
    g/m3 in another study. In rats, the lowest concentration inducing
    lethality was reported to be 242 g/m3 for 6 h.

         No mortality in rats or rabbits was observed after dermal
    exposure to 2 g/kg.

         No marked toxicity was observed in short-term inhalation studies
    at exposures ranging from 10 to 97 g/m3 and lasting up to 90 days.
    Effects seen included reduced body weight gain, "slight

    biochemical changes" and CNS depression. A no-observed-effect level
    was not achieved in the 90-day study.

         HCFC 141b did not produce signs of dermal irritation in rabbits,
    or eye irritation in one of the two studies performed. In the second
    study, a "mild" irritant response in the eye was observed. No skin
    sensitization was observed in guinea-pigs.

         A 2-generation reproduction study with HCFC 141b is currently in
    progress. In developmental studies, increased incidences of
    subcutaneous oedema and haemorrhaging in the fetuses and of embryonal
    deaths were observed, but only at the maternally toxic concentration
    of 97 g/m3 in a rat study. There were no teratogenic effects. No
    treatment-related effects on embryo or fetal development were observed
    in a rabbit study.

         HCFC 141b was not mutagenic in a bacterial DNA repair assay and
    produced conflicting results in other bacterial mutation tests. It had
    no effect on V79 cells in the  hprt locus assay. Chromosome
    aberrations were observed after  in vitro treatment of Chinese
    hamster ovary (CHO) cells, but this was not reflected in an  in vitro
    human lymphocyte study. Two  in vivo micronucleus assays in mice were
    also negative.

         A combined chronic inhalation toxicity/carcinogenicity study on
    rats is in progress.

         HCFC 141b exhibits cardiac sensitization potential to exogenous
    adrenaline in dogs. The lowest concentrations of HCFC 141b inducing
    responses were 24 and 48 g/m3 in dogs and monkeys, respectively.

    1.6.2  HCFC 142b

         Orally administered HCFC 142b produced only slight signs of
    toxicity in rats at single doses of up to 5 g/kg.

         Single inhalation exposure of rats to 525 g/m3 for 4 h killed
    approximately 50% of the animals. Other studies with shorter duration
    exposures yielded LC50 values in excess of 1000 g/m3.

         Repeated inhalation exposure studies did not produce any adverse
    responses in rats at a concentration of 41 g/m3 (6 h/day, 5 days per
    week for 90 days). At much higher dose levels, death in rats was
    associated with severe pulmonary irritation.

         There are no reports of studies with HCFC 142b on skin and eye
    irritation or skin sensitization. In cardiac sensitization experiments
    (using exogenous adrenaline), mice, dogs and monkeys were tested. Dogs
    were most sensitive; the NOEL was 102.5 g/m3 for a 5-min exposure,
    while 205 g/m3 (also a 5-min exposure) induced cardiac arrhythmia.

         There has been a single long-term study reported, in which rats
    (130 males and 110 females per group) were exposed to HCFC 142b at 4,
    41 and 82 g/m3 for 6 h/day, 5 days/week, for up to 104 weeks.  No
    treatment-related effects were observed in any of the parameters
    studied, which included haematology, blood and urine chemistry and
    histopathology. No significant treatment-related changes in tumour
    incidence were reported.

         No conventional studies have investigated the effect of HCFC 142b
    on reproduction, but no effect on male fertility was observed in a
    dominant lethal study. Two rat teratogenicity tests have been
    performed. In one teratogenicity study, Sprague-Dawley rats were
    exposed to 4 and 41 g/m3 (6 h/day from day 3 to day 15 of
    pregnancy), while in the other study, Sprague-Dawley rats were exposed
    to 13 and 39 g/m3 (6 h/day from day 6 to day 15 of pregnancy). No
    teratogenic effects were noted. Reduced ossification was observed in
    small numbers of fetuses at both dose levels in the latter study, but
    not in the former.

         HCFC 142b induces mutations in bacteria, but there is a lack of
    data from genotoxicity assays with cultured mammalian cells.  In vivo
    assays did not show any increases in chromosomal aberrations in bone
    marrow or dominant lethal effects in male rats.

    1.6.3  HCFC 132b

         The acute oral toxicity of HCFC 132b in the rat is low. The
    lowest dose at which mortality was observed was 25 g/kg. After oral
    dosing with 2 g/kg, depression of the autonomic and the central
    nervous system was observed, together with effects on motor
    coordination, motor activity and muscle tone. In males, swollen livers
    and reduced liver weights were noted.

         The acute inhalation toxicity of HCFC 132b is characterized by
    anaesthesia at high exposure levels. The lowest dose at which
    mortality was observed in rats during a 4-h exposure was 110 g/m3.
    In mice, the LC50 for a 30-min exposure was 269 g/m3; anaesthesia
    occurred at 71 g/m3. In one study, decreases in the weight of
    testis, and increases in the weight of liver and lungs of male rats
    were observed following exposure to 33 g/m3 for 6 h.

         Dermal application of HCFC 132b (2 g/kg) in rats resulted in
    clinical signs of CNS effects and swollen livers in some of the
    animals. The undiluted compound produced "mild" skin irritation in
    guinea-pigs and "mild to moderate" eye irritation in rabbits. No
    evidence for skin sensitization in guinea-pigs was obtained. Cardiac
    sensitization of dogs to adrenaline by inhaled HCFC 132b occurred at
    exposure levels of 27 g/m3 or more.

         The predominant consequences of short-term inhalation exposures
    of male rats to HCFC 132b, besides CNS depression, were thymic atrophy
    and effects on spermatogenesis. Disruption of spermatogenesis was
    observed after treatment with 3 g/m3 or more for 13 weeks. Other
    effects included bile duct proliferation and increased liver/body
    weight ratio in males, even at the lowest exposure level applied (3
    g/m3). Female rats appeared to be less sensitive than males to the
    liver effects.

         HCFC 132b induced embryotoxicity in rats after inhalation
    exposure to 3-28 g/m3 during days 6-15 of gestation, this resulting
    in increased numbers of resorptions (at 11 and 28 g/m3) and in
    decreased fetal weight at all exposure levels. Maternal toxicity was
    observed at all dose levels tested.

         Based on the limited data available, there is no evidence for
     in vitro mutagenicity of HCFC 132b. The carcinogenicity of the
    compound has not been studied.

    1.6.4  HCFC 133a

         No data are available on the acute oral toxicity of HCFC 133a. It
    is of low acute toxicity by the inhalation route (the 30-min LC50 in
    mice is 738 g/m3), and the principal toxic effects seen are those
    associated with anaesthesia. No information is available on cardiac
    sensitization, skin or eye irritation or skin sensitization.

         Repeated exposures (90 days) of rats to 49 g/m3 produced
    chronic inflammation of the nasal passages, pulmonary emphysema and
    oedema, bronchitis and pneumonia. Atrophy of the thymus, testis, ovary
    and spleen was also observed. No effects were seen in rats or dogs
    repeatedly exposed to HCFC 133a for 7 (rats) or 90 (dogs) days at a
    concentration of about 25 g/m3, although deaths were observed in
    mice exposed for 5 days to 0.5 g/m3 or more (excepting 2.5 g/m3).

         Although no conventional studies on the effects of HCFC 133a on
    reproduction are available, effects on male fertility and testicular
    histopathology were observed in three dominant lethal studies in mice.
    Exposures at concentrations of 2.5 g/m3 or more for 5 days resulted
    in a reduced number of pregnant females and an increase in the
    proportion of abnormal sperm, while exposure at a concentration of 5
    g/m3 resulted in histopathological damage to the seminiferous
    epithelium.

         Studies on rats (treated on days 6-16 of gestation), at exposure
    concentrations producing signs of only slight maternal toxicity, have
    demonstrated that HCFC 133a is embryotoxic at concentrations of 2
    g/m3 or more and embryolethal at 10 g/m3 or more. Progesterone
    pretreatment of the pregnant females did not influence the
    embryotoxic/lethal effects. Indications of teratogenic effects
    (external anomalies of limb and tail) were seen in one study. HCFC

    133a produced spontaneous abortions and total embryolethality in
    rabbits exposed to 25 g/m3 on days 7-19 of gestation, a
    concentration that produced only slight maternal toxicity.

         From the studies available, there is no evidence of mutagenic
    potential in bacteria. No increase was seen in the proportion of
    hamster kidney cells producing transformed colonies in one study.
    Dominant lethal effects were observed in two out of three studies
    after exposure of male mice to 12 g/m3 or more for 5 days. The
    proportion of bone marrow cells with chromosomal aberrations was
    unaffected in rats exposed to 98 g/m3 (6 h/day for up to 5 days). In
    the single carcinogenicity study, an increase in the incidence of
    adenocarcinomas of the uterus and of benign interstitial cell tumours
    of the testis was observed in rats that received 300 mg/kg in corn oil
    by gavage for 52 weeks (this being followed by an observation period
    of 73 weeks).

    1.6.5  HCFC 123

         HCFC 123 has low acute oral and dermal toxicity. The reported
    lowest oral dose of HCFC 123 producing lethality in rats is 9 g/kg. No
    mortality was found at a dose level of 2 g/kg in either rats or
    rabbits.

         The acute inhalation toxicity of HCFC 123 is also low. Effects
    seen are similar to those of chlorofluorocarbons, i.e. loss of
    coordination and narcosis. The 4-h LC50 is 178 g/m3 in hamsters,
    463 g/m3 in mice and ranges from 200 to 329 g/m3 in rats. Cardiac
    sensitization after a challenge with injected adrenaline occurred in
    dogs at concentrations of 119 g/m3 or more. Liquid HCFC 123 produces
    "mild" irritation of the skin and eye in rabbits. It does not cause
    skin sensitization in guinea-pigs.

         Several short-term toxicity studies have been conducted on HCFC
    123 using the inhalation route. Signs of CNS depression are
    consistently observed in rats at concentrations of 31 g/m3 or more.
    HCFC 123 also caused some liver effects in rats at exposure
    concentrations of 31 g/m3 or more. Long-term exposure (4 weeks or
    longer) to HCFC 123 also affects lipid and carbohydrate metabolism as
    reflected by consistent reduction of serum triglyceride cholesterol
    and glucose levels in rats. Interim results from an ongoing chronic
    inhalation toxicity/oncogenicity study in rats indicate that HCFC 123
    induces effects following long-term exposure to 2, 6 or 31 g/m3. The
    no-observed-effect level (NOEL) was not recorded in this study, based
    on the effects on lipid metabolism and increased hepatic peroxisomal
    activity.

         A 2-generation reproduction study in rats exposed by the
    inhalation route is currently being conducted on HCFC 123. No evidence
    of embryotoxicity was seen in two limited studies in rats at
    concentration producing slight maternal toxicity. There is evidence of

    embryotoxicity only at high maternally toxic concentrations (more than
    62.5 g/m3) in rabbits. Maternal toxicity (lower body weight, CNS
    depression) was seen in rats at exposure levels of 31 g/m3 or more,
    and in rabbits at 3 g/m3 or more. No evidence of teratogenicity was
    seen in either rats or rabbits.

         HCFC 123 shows no evidence of mutagenic activity in bacterial and
    yeast assays. However, there is evidence of clastogenic activity in
    human lymphocytes  in vitro, but this finding was not supported by
    data from an  in vivo mouse micronucleus assay.

         A combined chronic inhalation toxicity/carcinogenicity study on
    rats is in progress. A preliminary communication indicated that HCFC
    123 produces increased incidences of benign tumours of the testis and
    exocrine pancreas in male rats. However, an evaluation of the
    potential carcinogenicity of HCFC 123 cannot be made until complete
    results become available.

    1.6.6  HCFC 124

         The acute inhalation toxicity of HCFC 124 in animals is low.
    Death occurred in rats at 1674 g/m3 (240-min exposure) and in mice
    at 2460 g/m3 (10-min exposure). The effects seen are typical of
    those of chlorofluorocarbons, i.e. loss of coordination and narcosis.
    Cardiac sensitization after a challenge injection of adrenaline
    occurred in dogs at concentrations of 140 g/m3 or more. No
    information on skin or eye irritation or skin sensitization is
    available for this compound.

         Short-term inhalation toxicity has been investigated in five
    experiments on rats with exposure durations ranging from 14 to 90
    days. Histopathological changes in the organs were not observed even
    at the highest exposure levels studied (560 g/m3 in a 14-day
    experiment, 279 g/m3 in a 90-day study). The NOEL of 28 g/m3 was
    reported on the basis of functional observations and blood chemistry
    determinations in the 90-day study.

    A chronic inhalation toxicity study on HCFC 124 is in progress.

    In three limited teratogenicity studies on rats, in which HCFC 124 was
    tested at 30 g/m3 or in the range 3-279 g/m3, there was no
    evidence of embryotoxicity or teratogenic effects. Maternal toxicity
    was demonstrated at 84 g/m3. No information is available on the
    effects of HCFC 124 on reproductive potential. Full teratogenicity
    studies are in progress.

         Available data from several bacterial studies and a single
    mammalian cell study, show no evidence of mutagenic potential of HCFC
    124. An inhalation carcinogenicity study is in progress.

    1.7  Effects on humans

         No data are available on the effects of HCFC 141b, HCFC 132b,
    HCFC 133a, HCFC 123 or HCFC 124 on humans.

         The data from a single study on humans occupationally exposed to
    HCFC 142b do not allow the effects of HCFC 142b upon humans to be
    evaluated independently of many other exposures.

    1.8  Effects on other organisms in the laboratory and field

         No information is available on the effects on environmental
    organisms of the hydrochlorofluorocarbons reviewed, except for limited
    data on HCFC 141b and HCFC 142b. The 96-h LC50 of HCFC 141b for
    zebra fish is 126 mg/litre and the 48-h EC50 for the immobilization
    of  Daphnia magna is 31 mg/litre, both observations having been made
    in closed vessels. In the case of HCFC 142b, the 96-h EC50 for
    guppies is 220 mg/litre while the 48-h EC50 for the immobilization
    of  D. magna varies from 160 to > 190 mg/litre. The 96-h LC50 of
    HCFC 142b for rainbow trout is 36 mg/litre.

    1.9  Evaluation and conclusions

         Environmental levels for the six HCFCs reviewed are unknown, but
    are considered to be low based on current use patterns.

         HCFC 142b has a low toxic potential and is not considered to pose
    a significant risk to human health under non-accidental exposure
    conditions. The toxicological information on HCFC 141b, HCFC 123 and
    HCFC 124 are incomplete and more data are required before an
    evaluation of the human health hazard can be made. Both HCFC 133a and
    HCFC 132b pose a hazard to human health.

         All the six hydrochlorofluorocarbons reviewed either have, or are
    expected to have, lower ozone-depleting potentials and have
    considerably lower atmospheric residence times than the fully
    halogenated chlorofluorocarbons. They should, therefore, pose a lower
    indirect health risk. The global-warming potentials are, or are
    expected to be, lower than those of the fully halogenated
    chlorofluorocarbons and should not contribute significantly to global
    warming.

         Since the toxicity of HCFC 142b 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.

         No recommendations can be made for HCFC 141b, HCFC 123 or HCFC
    124 until more toxicity data become available. Although HCFC 133a and
    HCFC 132b pose low environmental and indirect health risks, they are

    not recommended as substitutes for the chlorofluorocarbons included in
    the Montreal Protocol because of their toxic potential.

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

    2.1  Identity

         The hydrochlorofluorocarbons (HCFCs) considered in this monograph
    are compounds derived by the partial substitution of the hydrogen
    atoms in ethane with both fluorine and chlorine atoms. The chemical
    formulae, chemical structures, common names, common synonyms, CAS
    registry numbers and conversion factors of the compounds reviewed
    (HCFC 141b, HCFC 142b, HCFC 132b, HCFC 133a, HCFC 123 and HCFC 124)
    are presented in Table 1.

         The individual chemical substances have many different trade
    names and are characterized by code numbers which are explained in
    Table 1.

    2.1.1  Technical products

         The HCFCs are being developed in part as substitutes for fully
    halogenated chlorofluorocarbons: HCFCs 123 and 141b for CFC-11 and in
    admixture for CFC-113; HCFCs 124 and 142b for CFC-12 (Hoffmann, 1990).
    HCFCs 133a and 142b are chemical intermediates, and one of the
    compounds reviewed, HCFC 132b, is still essentially experimental (see
    section 3.3.1). When marketed they are usually available at 99.8% (or
    more) purity. Impurities in HCFC 142b have been reported at levels of
    0.06% HCFC 141b, very much smaller levels of HCFC-22, CFC-11,
    HFC-152a, CFC-113 and traces of other compounds (Hutton & Lieder,
    1989a).

    2.2  Physical and chemical properties

         Some physical and chemical properties of the
    hydrochlorofluorocarbons reviewed in this monograph are summarized in
    Table 2. Under normal temperatures and pressures, they are flammable
    (HCFC 142b) or non-flammable gases (HCFC 133a, HCFC 124) or
    non-flammable volatile liquids (HCFC 141b, HCFC 132b and HCFC 123).
    They are colourless, and the majority of them are practically
    odourless or have a faint ethereal odour (HCFC 141b and HCFC 123).
    They are slightly or moderately soluble in water and miscible with
    many organic solvents. On heating to decomposition, HCFCs 124, 132a
    and 142b produce toxic fumes of fluorine- or chlorine-containing
    compounds (Sax, 1984) and this is probably true also of the other
    hydrochlorofluorocarbons reviewed. HCFC 142b can react vigorously with
    oxidizing materials (Sax, 1984).


    
    Table 1.  Identity of hydrochlorofluorocarbonsa
                                                                                                                                         
                                  HCFC 141b                          HCFC 142b                          HCFC 132b
                                                                                                                                         

    Chemical structure                Cl  H                               F   H                             Cl  Cl
                                      '   '                               '   '                             '   '
                                  F - C - C - H                      Cl - C - C - H                     F - C - C - H
                                      '   '                               '   '                             '   '
                                      Cl  H                               F   H                             F   H

    Chemical formula              CCl2F-CH3                          CClF2CH3                           CClF2-CH2Cl

    Common names                  dichlorofluoroethane               chlorodifluoroethane               dichlorodifluoroethane

    Common synonyms               1,1-dichloro-1-fluoroethane;       1-chloro-1,1-difluoroethane;       1,2-dichloro-1,1-difluoroethane;
                                  1-fluoro-1,1-dichloroethane;       1,1-difluoro-1-chloroethane;       HCFC 132b
                                  ethane, 1,1-dichloro-1-fluoro;     difluoromonochloroethane;
                                  HCFC 141b; Propellant 141b;        HCFC 142b;
                                  R-141b

    CAS Registry number           1717-00-6                          75-68-3                            1649-08-7

    Conversion factors (20 °C)
      ppm -> mg/m3                4.85                               4.1                                5.5
      mg/m3 -> ppm                0.206                              0.243                              0.181
                                                                                                                                         

    Table 1 (contd).
                                                                                                                                              
                                  HCFC 133a                          HCFC 123                              HCFC 124
                                                                                                                                              

    Chemical structure                H   F                               H   F                                 F   F
                                      '   '                               '   '                                 '   '
                                  H - C - C - F                      Cl - C - C - F                        Cl - C - C - F
                                      '   '                               '   '                                 '   '
                                      Cl  F                               Cl  F                                 H   F

    Chemical formula              CH2Cl-CF3                          CHCl2-CF3                             CHClF-CF3

    Common names                  chlorotrifluoroethane              dichlorotrifluoroethane               chlorotetrafluoroethane

    Common synonymsb              1-chloro-2,2,2-trifluoroethane;    1,1-dichloro-2,2,2-trifluoroethane;   1-chloro-1,2,2,2-tetrafluoroethane;
                                  1,1,1-trifluoro-2-chloroethane;    2,2-dichloro-1,1,1-trifluoroethane;   1,1,1,2-tetrafluoro-2-chloroethane;
                                  2,2,2-trifluorochloroethane;       ethane, dichlorotrifluoro-; Fluoro-   Fluorocarbon 124; HCFC 124
                                  1,1,1-trifluoroethyl chloride;     carbon 123; HCFC 123; Propellant
                                  CFC 133a; HCFC 133a; R-133a        123; Refrigerant 123; R-123

    CAS Registry number           75-88-7                            306-83-2                              2837-89-0

    Conversion factors (20 °C)
      ppm -> mg/m3                4.92                               6.25                                  5.58
      mg/m3 -> ppm                0.203                              0.160                                 0.179
                                                                                                                                              

    a Chlorofluorocarbons are numbered as follows: the first digit = number of C atoms minus 1 (for ethane derivatives it is therefore
      1); second digit = number of H atoms plus 1; third digit = number of F atoms
    b The trade names Arcton, Freon, Genetron and Isotron are used with the corresponding numbers by different manufacturers

    Table 2.  Physical and chemical properties of the hydrochlorofluorocarbonsa

                                                                                                                           
                             HCFC 141b       HCFC 142b       HCFC 132b       HCFC 133a       HCFC 123        HCFC 124
                                                                                                                           

    Physical state           liquid          gas             liquid          gas             liquid          gas

    Colour                   colourless      colourless      colourless      colourless      colourless      colourless

    Relative molecular mass  116.95          100.47          134.92          118.49          152.91          136.48

    Boiling point (°C)       32.0            -9.2            46.8            6.93            27.97           -11.0

    Freezing point (°C)      -103.5          -131.0          -101.2          -105.5          -107.0          -199.0

    Liquid density (g/ml)    1.24c           1.123c          1.42c           1.389c          1.46b           1.4d

    Vapour pressure
    (25 °C, psia)            11.5            49.2            6.1             29.7            14              61

    Density of saturated
    vapour at boiling
    point (g/litre)          4.82            4.72            5.15            5.17            6.38            6.88

    Flammability             non-flammablee  flammable       non-flammable   non-flammable   non-flammable   non-flammable

    Auto-ignition
    temperature (°C)         -               632             -               -               -               -

    Flammability limits in
    air (% vol)              -               6.0-14.8        -               -               -               -
                                                                                                                           
    Table 2 (contd).

                                                                                                                           
                             HCFC 141b       HCFC 142b       HCFC 132b       HCFC 133a       HCFC 123        HCFC 124
                                                                                                                           

    Solubility in water
    (g/litre)                4-13b           1.9b            4.9c            8.9b            2.1b            17.1c

    Octanol/water partition
    coefficient (log Pow)    2.3             1.60f           -               -               -               -
                                                                                                                           

    a From: Graselli & Ritchey (1975), Hawley (1981), Horrath (1982), Sax (1984), Weast (1985), Solvay et Cie (1989)
    b At 25 °C
    c At 20 °C
    d At 11.3 °C
    e No flash point between 21 °C and 33 °C; no explosive properties, but can become flammable as a vapour (personal communication by
      Solvay et Cie, 1989). Millischer (1990) lists HCFC 141b as non-flammable.
    f Log Kow cited in SRC (personal communication by H. Trochimowicz (1991), C-57 file Haskell Laboratories).
    

    2.3  Conversion factors

         Conversion factors for the hydrochlorofluorocarbons reviewed in
    this monograph are given in Table 1.

    2.4  Analytical methods

         Of the analytical procedures described for the determination of
    the hydrochlorofluorocarbons reviewed, by far the most frequently
    applied methods use gas chromatography with various detection
    techniques. For measuring the relatively high chamber concentrations
    in toxicology experiments, single beam photometry has been used.
    Examples are listed in Table 3.


    
    Table 3.  Analytical methods for the determination of hydrochlorofluorocarbons
                                                                                                                                               
    Hydrochlorofluorocarbons  Medium    Analytical method                                        Detection limit    Reference
                                                                                                                                               

    HCFC 141b                 air       absorption on silica gel, thermal desorption and         -                  Coombs et al. (1988)
                                        gas chromatography with flame ionization detection

                              corn oil  gas chromatography with electron capture detection       -                  Liggett et al. (1989)

    HCFC 142b                 air       gas chromatography with flame ionization detection       -                  Seckar et al. (1986)

                              water     head space analysis using gas chromatography with        -                  Hutton & Lieder (1989)
                                        electron capture detection

    HCFC 132b                 air       gas chromatography with thermal conductivity             -                  Hall (1976)
                                        detection

    HCFC 133a                 air       gas chromatography with flame ionization detection       0.2 ppm            Plummer et al. (1987)
                              air       gas chromatography with flame ionization detection       -                  Kilmartin et al. (1980)
                              air       gas chromatography with thermal conductivity detection   -                  Leuschner et al. (1977)
                              air       gas chromatography with flame ionization detection                          Hodge et al. (1980)

                              tissue    head space analysis using gas chromatography with        -                  Chapman et al. (1967)
                                        flame ionization detection

                              tissue    head space analysis using gas chromatography with        2.5 pmol/ml blood  Maiorino et al. (1979)
                                        flame ionization detection                               10 pmol/g liver

    HCFC 123                  air       single beam photometry                                   -                  Müller & Hofmann (1988)
                              air       gas chromatography with flame ionization detection       -                  Deleba-Crowe (1978)
                              air       gas chromatography with thermal conductivity detection   -                  Trochimowicz & Mullin (1973)

    HCFC 124                  air       gas chromatography with thermal conductivity detection   -                  Hall (1976)
                              air       gas chromatography with dual flame ionization detection  -                  Brewer (1977)
                                                                                                                                              
    

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         The hydrochlorofluorocarbons reviewed in this monograph are not
    known to occur in nature.

    3.2  Anthropogenic sources

    3.2.1  Production levels

         The manufacturing process for HCFC 124 is still in the
    developmental stage, since it is not produced for commercial use but
    only in research quantities. HCFC 133a is produced in small quantities
    as a chemical intermediate in the manufacture of the anaesthetic
    halothane (1-bromo-1-chloro-2,2,2-trifluoroethane) (McNeill, 1979),
    and HCFC 142b is produced at the rate of several thousand tonnes per
    year as an intermediate in the production of vinylidene fluoride for
    the manufacture of fluoropolymers (Seckar et al., 1986). Commercial
    quantities of HCFCs 123 and 141b were produced in 1991 (Anon., 1991;
    personal communication by R. Millischer, 1991). HCFC 132b does not
    appear to be envisaged as a commercial product but it occurs, as do
    HCFCs 133a and 141b, as a by-product in the manufacture of other
    halogenated ethanes. Others of the hydrochlorofluorocarbons reviewed
    probably also occur in this way.

    3.2.2  Manufacturing processes

         HCFC 133a is produced from trichloroethene and anhydrous hydrogen
    fluoride in the presence of an antimony trifluoride catalyst (McNeill,
    1979). Similarly, HCFC 142b is produced by hydrofluorination of
    methylchloroform or vinylidene chloride in the liquid phase (Seckar et
    al., 1986).

    3.2.3  Loss during disposal, transport, storage and accidents

         Since two of the hydrochlorofluorocarbons reviewed which are
    produced in commercial quantities (HCFC 142b and HCFC 133a) are used
    as intermediates for subsequent conversions into other fluoro
    compounds, the current release into the environment is expected to be
    low. There are no published data on losses of any of the
    hydrochlorofluorocarbons reviewed.

         No information is available on accidental release.

    3.3  Use patterns

    3.3.1  Major uses

         HCFC 133a has a limited use as a chemical intermediate in the
    manufacture of the anaesthetic halothane, 1-bromo-1-chloro-2,2,2-
    trifluoroethane (McNeill, 1979).

         HCFC 123 is used in large industrial chillers.

         HCFCs 123 and 141b were developed as substitutes for CFC-11, i.e.
    as foam-blowing agents in the plastics industry, aerosol propellants
    and, to a lesser degree, refrigerants, but their use requires
    equipment changes and they have a slightly poorer performance than the
    fully halogenated compounds (Hoffmann, 1990; Prinn & Golombek, 1990;
    Ahmadzai & Hedlund, 1990).

         A mixture of HCFCs 123 and 141b can substitute for CFC-113, a
    washing fluid in the electronic industry (Montague & Perrine, 1990).

         HCFCs 124 and 142b have been reported, in admixture with other
    compounds, as substitutes for fully halogenated chlorofluorocarbons,
    particularly as foam blowing agents and refrigerants. However, the
    mixtures developed which contained HCFC 142b were flammable (Hoffmann,
    1990; Shankland, 1990). HCFC 142b in admixture with CFC-22 has a small
    application as an aerosol propellant.

         HCFC 132b appears to be an experimental chemical with no
    commercial application at the present time.

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    4.1  Biodegradation and bioaccumulation

         Information on biodegradation in the environment is limited to
    studies on HCFCs 141b and 142b. Oyama (1990) tested the
    biodegradability of HFA 141b by microorganisms (closed bottle method)
    at test substance concentrations of 2.0 and 9.0 mg/litre and reported
    a biodegradation of 2-10% after 28 days. The biodegradability values
    of HCFC 142b at concentrations of 52 and 105 mg/litre were 5.6 and
    4.4%, respectively, after 28 days (Matla & Blom, 1991). In both cases
    the authors concluded that these compounds are not readily
    biodegradable.

         The log octanol/water partition coefficient of HCFC 141b is 2.3
    and therefore bioaccumulation of this hydrochlorofluorocarbon is
    unlikely.

         A study on the biodegradation of HCFC 142b is in progress
    (personal communication by Ch. de Rooij, Solvay et Cie, 1990).

    4.2  Environmental transformation and interaction with other
         environmental factors

         The scaled atmospheric lifetimes, ozone-depleting potentials and
    global-warming potentials of the hydrochlorofluorocarbons reviewed are
    shown in Table 4, where they are compared to those of methylchloroform
    (1,1,1-trichloroethane). The physical and chemical properties suggest
    that these hydrochlorofluorocarbons would be rapidly mixed 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. Reaction with naturally occurring hydroxy radicals (OH€)
    in the troposphere is expected to be the primary degradation route
    (Makide & Rowland, 1981; Prinn & Golombek, 1990).

         The hydrochlorofluorocarbons reviewed do not have high
    ozone-depleting potentials. This is defined as the calculated
    depletion due to the emission of a unit mass of the
    hydrochlorofluorocarbon divided by the ozone depletion calculated to
    be due to the emission of a unit mass of CFC 11 (the ozone-depleting
    potential of CFC 11 is 1.0); calculations are based on steady-state
    conditions.

         However, if the ozone-depleting potentials listed are compared
    with those of methylchloroform (1,1,1-trichloroethane), it can be seen
    that those of HCFCs 141b and 142b are of a similar order. The parties
    to the Montreal Protocol decided in June 1990 to phase out
    methylchloroform manufacture by the year 2005 (Ahmadzai & Hedlund,
    1990).

         When the global-warming potentials are similarly compared, three
    of the compounds reviewed, HCFCs 141b, 142b, and 124, have higher
    values than that of methylchloroform and HCFC 123 is only slightly
    lower. This effect however, is considered less critical (Montague &
    Perrine, 1990).

         The possible impact of HCFCs 141b, 142b, 123 and 124 on
    tropospheric ozone formation has been estimated to be extremely low
    (UNEP/WMO, 1989).


    
    Table 4.  Tropospheric lifetime, ozone-depleting potential and global-warming potential
              of hydrochlorofluorocarbonsa,b
                                                                                                                 
    Hydrochlorofluorocarbon   Scaled atmospheric          Ozone-depleting potential         Global-warming
                              lifetime                                                      potential
                              (years)c            1-dimensional model  2-dimensional model  (1-dimensional model)
                                                                                                                 

    HCFC 141b                 7.8                 0.066-0.092          0.065-0.14           0.087-0.097

    HCFC 142b                 19.1                0.05-0.06            0.05-0.08            0.34-0.39

    HCFC 132b                 4.2                 0.025                -                    -

    HCFC 133a                 4.8                 -                    -                    -

    HCFC 123                  1.6                 0.013-0.019          0.013-0.027          0.017-0.020

    HCFC 124                  6.6                 0.016-0.021          0.013-0.030          0.092-0.10

    Cl3C CH3                  6.3                 0.092-0.14           0.11-0.20            0.022-0.026
                                                                                                                 

    a From: Fisher et al. (1990a,b) and Freemantle (1991). See also Prinn & Golombek (1990).
    b The ozone-depleting and global-warming potential values for CFC-11 are defined as 1.0. The values reported
      in the table refer to this standard and the ranges are scaled assuming a methylchloroform atmospheric
      lifetime of 6.3 years (UNEP/WMO, 1989).
    c Other atmospheric lifetimes are: CFC 11 - 75 years, CFC 12 - 110 years and CFC 113 - 90 years.
    

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Air

         HCFCs 141b, 132b, 133a, 123 and 124 are not yet in large-scale
    commercial production. HCFC 142b is used as an intermediate and is not
    released significantly to the atmosphere. There are, therefore, no
    data on environmental levels but these compounds are unlikely to be
    present at detectable levels.

    5.1.2  Water, food and other edible products

         For the reasons cited above (section 5.1.1), no data are
    available on the concentrations in environmental water, food or other
    edible products of the partially halogenated chlorofluorocarbons
    reviewed in this monograph.

    5.2  Human exposure

         There are no data on human exposure to any of the
    hydrochlorofluorocarbons reviewed.

         As HCFC 133a is a major metabolite of the anaesthetic halothane,
    the use of this anaesthetic may constitute an exposure to this
    hydrochlorofluorocarbon.

    6.  KINETICS AND METABOLISM

    6.1  Animal studies

    6.1.1  Absorption

         No data are available concerning direct measurements of the
    absorption of the hydrochlorofluorocarbons reviewed, but it may be
    inferred from toxicity studies that absorption occurs (see chapter 7).

         The increased urinary fluoride levels observed in inhalation
    toxicity studies of HCFC 141b (Doleba-Crowe, 1977), HCFC 132b, HCFC
    123 (Doleba-Crowe, 1978; Trochimowicz, 1989; Malley, 1990a) and HCFC
    124 (Brewer, 1977; Malley, 1991) also indicate that absorption takes
    place (see section 7.1).

    6.1.2  Distribution

         No data are available on the distribution in animals of the
    hydrochlorofluorocarbons reviewed.

    6.1.3  Metabolic transformation

    6.1.3.1  General considerations

         The compounds reviewed in this monograph fit into three
    generalized structural classes: 1,1,1-trihaloethanes (HCFC 141b and
    142b), 1,1,1-trihalo-2-monohaloethanes (HCFC 132b and 133a) and
    1,1,1-trihalo-2,2-dihaloethanes (HCFC 123 and 124). Metabolic studies
    have been conducted on a representative from each class and have
    demonstrated similar metabolic pathways for each one as shown in
    Fig. 1.

         Based on the available literature (Harris & Anders, 1991a,b;
    Harris et al., 1991), it is expected that all six chemicals reviewed
    would be metabolized by a cytochrome P-450-dependent monooxygenase
    liver enzyme to give reactive metabolic products including
    1,1,1-trihaloacetic acid and 1,1,1-trihaloethanol. The
    1,1,1-trihalo-2,2-dihaloethanes are the only ones that go through the
    electrophilic acid chloride in their metabolic pathway. This may
    explain why HCFC 123 is the only one, of the three compounds for which
    there are data, that shows covalent binding to macromolecules. Salmon
    et al. (1981) reported on microsomal dechlorination of chloroethanes
    and structure-activity relationships and observed that the
    reactivities of the various structural types are markedly different:
    RCHCl2 >> RCH2Cl > RCCl3 (in the case of polyhalogenated
    ethanes where a less reactive group is linked to the one under
    consideration, the contribution of the less reactive group is
    ignored). The authors concluded that the dechlorination process shows
    the structural specificity commonly seen in enzyme-catalysed
    reactions.

    FIGURE 1

    6.1.3.2  HCFC 141b

         Harris & Anders (1991a) studied the  in vivo metabolism of HCFC
    141b. A single fluorinated urinary metabolite, identified as
    2,2-dichloro-2-fluoro-ethyl glucuronide, was found in rats exposed to
    HCFC 141b (56 g/m3) in air for 2 h. The metabolism was reported to
    be similar to that of its chlorinated analogue 1,1,1-trichloroethane,
    which is metabolized to 2,2,2-trichloroethanol and excreted as its
    glucuronate conjugate (Hake et al., 1960) and as trichloroacetic acid
    (Koizumi et al., 1982). It was claimed (although no data were given)
    that 2,2-dichlorofluoroacetic acid was also detected in the urine of
    rats exposed to a concentration of 194 g/m3 for 4 h, but not to 56
    g/m3 for 2 h (Harris & Anders, 1991a).

         In a pilot study for absorption and metabolism of HCFC 141b,
    seven groups of five male rats were exposed to the vapour by
    inhalation in a closed loop exposure system (concentrations ranging
    from 0.4 to 12 g/m3). No metabolism was detected but the sensitivity
    of the method is such that it will not detect metabolism below 0.15%.
    The results suggested that absorption did not take place, but that if
    any metabolism occurred it was at a low level (Zwart, 1989).

         Evidence of dechlorination was observed when rat hepatic
    microsomes were incubated with about 1% HCFC 141b  in vitro (Van
    Dyke, 1977).

    6.1.3.3  HCFC 142b

         No  in vivo studies on the metabolism of HCFC 142b have been
    reported. One  in vitro study provided evidence for dechlorination
    when rat hepatic microsomes were incubated with 0.6% HCFC 142b (Van
    Dyke, 1977).

    6.1.3.4  HCFC 132b

         Harris & Anders (1991) identified a number of metabolites in the
    urine of male Fischer-344 rats given one or four doses of 10 mmol/kg
    dissolved in corn oil by intraperitoneal injection. Approximately 1.8%
    of the single administered dose was recovered in the urine. The
    metabolites excreted in urine during the first 6 h were
    2-chloro-2,2-difluoroethyl glucuronide, chlorodifluoroacetic acid and
    chlorodifluoroacetaldehyde hydrate (free and conjugated). Repeated
    injection of rats with HCFC 132b significantly increased both the rate
    of chlorodifluoroacetic acid excretion and the relative fraction of
    the HCFC 132b dose excreted as chlorodifluoroacetic acid. The
    incubation of HCFC 132b with rat hepatic microsomes yielded
    chlorodifluoroacetaldehyde hydrate as the only fluorinated product.
    The  in vitro metabolism of HCFC 132b was increased in microsomes
    from pyridine-treated rats and inhibited by  p-nitrophenol. This
    inhibition by  p-nitrophenol led the authors to suggest an

    involvement of cytochrome P-450 IIE1 in the initial hydroxylation of
    HCFC 132b.

    6.1.3.5  HCFC 133a

         Evidence for dechlorination of HCFC 133a was provided by an
     in vitro study using a microsomal preparation derived from
    Aroclor-1254a-induced rat liver homogenates (Salmon et al., 1981).

    6.1.3.6  HCFC 123

         Harris et al. (1991) exposed adult male Fischer-344 rats to HCFC
    123 (43 g/m3 or 68 g/m3) or to halothane (2-bromo-2-2
    chloro-1,1,1-trifluoroethane) (1.05 g/m3) in air for 2 h. The
    pattern of proteins immunoreactive with haptens-specific
    anti-trifluoroacetylprotein antibodies was found to be identical in
    livers of the rats exposed to HCFC 123 and halothane. Trifluoroacetic
    acid was detected in urine of rats exposed to HCFC 123 or halothane by
    nuclear magnetic resonance (NMR) and by gas chromatography with mass
    spectrometry (GCMS), as had been reported previously (Maiorino et al.,
    1980; Trochimowicz, 1989).

    6.1.4  Covalent binding to macromolecules

    6.1.4.1  HCFC 141b

         19F-NMR analysis of microsomal and cytosolic proteins isolated
    from the livers of rats killed 15 h after a 2-h exposure to HCFC 141b
    (56 g/m3) did not yield any evidence for covalent binding of
    fluorinated metabolites (Harris & Anders, 1991a).

    6.1.4.2  HCFC 132b

         19F-NMR analysis of microsomal and cytosol proteins isolated
    from the livers of rats killed 15 h after a single intraperitoneal
    dose of HCFC 132b (10 mmol/kg) did not yield evidence for covalent
    binding of fluorinated metabolites (Harris & Anders, 1991a).

    6.1.4.3  HCFC 123

         Harris et al. (1991) exposed adult male Fischer-344 rats to HCFC
    123 (43 or 68 g/m3) or to halothane (105 g/m3) in air for 2 h.
    19F-NMR analysis of cytosolic protein and immunoblotting of
    microsomal and cytosolic hepatic protein using antibodies against
    trifluoroacetylprotein at 15 h after the exposure demonstrated
    covalent binding of fluorinated metabolites.

                             

    a Aroclor-1254 is a polychlorinated biphenyl mixture.

    6.1.5  Elimination

         No data are available from animal studies on the elimination of
    the hydrochlorofluorocarbons reviewed. However, based on the
    information on chlorofluorocarbons, it is likely that the main route
    of excretion for hydrochlorofluorocarbons is through the respiratory
    tract. Increased urinary inorganic fluoride has been observed in some
    inhalation toxicity studies with HCFCs 141b, 132b, 123, and 124
    (Doleba-Crowe, 1977, 1978; Brewer, 1977; Trochimowicz, 1989; Malley,
    1990a, 1991).

    6.2  Human studies

         No data are available on the absorption, distribution, metabolic
    transformation or elimination of the hydrochlorofluorocarbons
    reviewed.

    7.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

    7.1  Single exposure

    7.1.1  Acute oral toxicity

         Available data indicate low toxicity following single oral
    exposure associated with four hydrochlorofluorocarbons, i.e. HCFC
    141b, 142b, 132b and 123.

    7.1.1.1  HCFC 141b

         No mortality was observed in rats given a single oral dose of
    HCFC 141b (5 g/kg body weight) dissolved in corn oil (Sarver, 1988).

    7.1.1.2  HCFC 142b

         Other than piloerection, oral dosing with HCFC 142b (up to 5 g/kg
    body weight) dissolved in corn oil resulted in no signs of toxicity
    (Liggett et al., 1989).

    7.1.1.3  HCFC 132b

         According to Henry (1975), the lowest dose at which mortality was
    observed in rats treated with HCFC 132b was 25 g/kg.

         A 2-g/kg dose of HCFC 132b in corn oil was applied by stomach
    tubes to five male and five female Wistar rats, and the animals were
    observed for 14 days. The clinical signs were indicative of an effect
    on the autonomic nervous system (ptosis), on the central nervous
    system (diminished alertness and startle response, and positional
    passivity), on motor coordination (abnormal body posture and gait, and
    loss of righting reflex), on motor activity and on muscle tone
    (paralysis). Macroscopic examination showed swollen livers in some
    males, and a decrease in absolute and relative liver weights. However,
    no treatment-related effects were found during microscopic
    examinations (Janssen & Pot, 1989b).

    7.1.1.4  HCFC 123

         The lowest dose of HCFC 123 producing lethality in rats was
    reported to be 9 g/kg when it was administered as a corn oil solution
    by intragastric intubation (Henry, 1975a).

    7.1.2  Acute inhalation toxicity

    7.1.2.1  HCFC 141b

         The effects of a single inhalation exposure of rodents to HCFC
    141b are shown in Table 5. The main effects at high exposure
    concentrations include central nervous system depression, anaesthesia
    and death.

    7.1.2.2  HCFC 142b

         Table 6 summarizes the effects of single inhalation exposure to
    HCFC 142b in mice and rats. At high exposure levels, HCFC 142b induces
    anaesthesia and death.

    7.1.2.3  HCFC 132b

         Table 7 summarizes the effects of single inhalation exposures of
    mice and rats to HCFC 132b.

    7.1.2.4  HCFC 133a

         Inhalation of high concentrations of HCFC 133a is characterized
    by signs of anaesthesia followed by death, but recovery from nonlethal
    exposure is rapid. The effects of inhalation exposure to HCFC 133a are
    summarized in Table 8.

    7.1.2.5  HCFC 123

         The results of studies on the acute inhalation toxicity of HCFC
    123 are summarized in Table 9. Anaesthesia and death at higher
    exposures were reported for rats and hamsters. No gross morphological
    changes were observed in animals that died during exposure. Survivors
    recovered within several minutes without showing any observable
    clinical signs.

    7.1.2.6  HCFC 124

         Table 10 summarizes the effects of single inhalation exposure to
    high concentrations of HCFC 124. As with other
    hydrochlorofluorocarbons, the main effects observed were anaesthesia
    and death.

    7.1.3  Acute dermal toxicity

         There is information only on the hydrochlorofluorocarbons that
    are liquid at ambient temperatures, i.e. HCFC 141b, HCFC 132b and HCFC
    123.


    
    Table 5.  Effects of a single inhalation exposure to HCFC 141b in mice and rats
                                                                                                                                    
    Species            Exposure       Exposure  Effects                                                       Reference
    (strain)           concentration  duration
                       (g/m3)         (h)
                                                                                                                                    

    Rat                142-366        4         LC50 = 295 g/m3                                               Hardy et al. (1989a)
    (Sprague-Dawley)                            No deaths were observed at 142 or 217 g/m3. All deaths
                                                at higher concentrations (323 and 366 g/m3) occurred
                                                during exposure, and were preceded by disturbed breathing.
                                                Reduced motor activity, abnormal body carriage, restless
                                                behaviour and exaggerated respiratory movements were seen
                                                at all concentrations during exposure. No treatment-related
                                                macroscopic findings were seen. Focal basophilic staining
                                                was observed in the renal cortical tubules of 4 out of 10
                                                rats at 217 g/m3 and 2 out of 10 rats at 142 g/m3. No
                                                histopathological effects were seen in decedents.

    Rat (strain        unspecified    6         The lowest concentration producing lethality was 242 g/m3.    Doleba-Crowe (1977)
    unspecified)       range

    Mouse              17-388         6         Deaths preceded by signs of narcosis in 6 out of 10) animals  Vlachos (1989)
    (Crl: CD-1)                                 occurred within 30 min of exposure to 388 g/m3. No deaths
                                                occurred at the next highest (199 g/m3) concentration. Signs
                                                of CNS depression (lethargy, abnormal gait, partially closed
                                                eyes) were seen at 165 and 199 g/m3. No effects were seen at
                                                concentrations of 145 g/m3 or less.

    Mouse (strain      unspecified    2         LC16 = 115 g/m3; LC50 = 151 g/m3; LC84 = 200 g/m3. Signs of   Nikitenko & Tolgskaja
    unspecified)       range                    CNS depression and anaesthesia were observed. Death was       (1965)
                                                preceded by laboured breathing.

    Mouse (Schofield   unspecified    0.5       LC50 = 115 g/m3; concentration producing anaesthesia in       Davies et al. (1976)
    strain)            range                    50% of animals = 62 g/m3. No other information was given.
                                                                                                                                    

    Table 6.  Effects of single inhalation exposure to HCFC 142b in mice and rats
                                                                                                                               
    Species   Strain    Exposure         Exposure  Effects                                         Reference
                        concentration    duration
                        (g/m3)           (h)
                                                                                                                               

    Mouse     "white"   up to 2050       2         death; LC50 = 1514 g/m3                         Nikitenko & Tolgskaja (1965)

    Mouse     AP        unspecified      0.5       death; LC50 = 1228 g/m3                         Davies et al. (1976)
                        range

    Rat       "white"   615-3280         0.5       death at 2050 g/m3 and unconsciousness at       Lester & Greenberg (1950)
                                                   1230 g/m3; postural, righting and corneal
                                                   reflexes were lost at 820 g/m3

    Rat       Sherman   525              4         death (approx 50%) at 525 g/m3                  Carpenter et al. (1949)
                                                                                                                               

    Table 7.  Effects of single inhalation exposure to HCFC 132b in mice and rats
                                                                                                                                      
    Species   Strain          Exposure         Exposure   Effects                                              Reference
                              concentration    duration
                              (g/m3)           (h)
                                                                                                                                      

    Mouse     unspecified     range not given  0.5        LC50 = 269 g/m3; AC50 (anaesthesia) = 71 g/m3        Raventós & Lemon (1965)

    Rat       Wistar derived  55 and 110       4          lethalities at 110 g/m3; rats unsteady, weak and     Torkelson (1971)
                                                          drowsy at 55 g/m3

    Rat       Wistar derived  33-72            6          anaesthesia at 82 g/m3; kidney swelling at autopsy;  Janssen (1988)
              CPB-WU                                      at all dose levels, males showed decreased growth
                                                          and testis weight, and increased liver and lung
                                                          weights

    Rat       Wistar derived  55               0.4        decreased respiratory rate with rapid recovery       Janssen (1989b)
              CPB-WU                                      after exposure
                                                                                                                                      

    Table 8.  Effects of single inhalation exposure to HCFC 133a
                                                                                                                                         
    Species              Exposure       Exposure  Effectsa                                                       Reference
    (strain)             concentration  duration
                         (g/m3)         (min)
                                                                                                                                         

    Mice, male           unspecified    10        anaesthesia and death; convulsions on recovery; AC50 and       Robbins (1946)
    (white)              range                    LC50 were 394 and 1230 g/m3, respectively

    Mice (strain         unspecified    30        anaesthesia, convulsions and death; AC50 and LC50 were         Raventós & Lemon (1965)
    unspecified)         range                    212 and 738 g/m3, respectively

    Mice (strain         123-1230       10        rapid onset of anaesthesia, rapid recovery after cessation of  Shulman & Sadove (1965)
    unspecified)                                  exposure but no convulsions; AC50 and LC50 were 397 and
                                                  1033 g/m3, respectively

    Rats, female         2500           -         lack of muscular coordination in 3 min, anaesthesia in 4 min   Diggle & Gage (1956)
    (strain unspecified)                          and death within 8 min

    Dogs                 unspecified    -         anaesthesia at 492 g/m3, respiratory depression and arrest     Shulman & Sadove (1965)
                         range                    occurred at 1131 and 1427 g/m3, and circulatory arrest at
                                                  2902 g/m3
                                                                                                                                         

    a AC50 = calculated concentration expected to produce anaesthesia in 50% of the test group

    Table 9.  Acute inhalation toxicity of HCFC 123
                                                                                                                                              
    Species           Exposure         Exposure   Effects                                                        Reference
    (strain)          concentration    duration
                                       (g/m3)
                                                                                                                                              

    Mouse (strain     not given        30 min     LC50 = 463 g/m3                                                Raventós & Lemon (1965)
    unspecified)

    Rat (Charles      129-344          4 h        LC50 = 200 g/m3; loss of mobility, lethargy, prostration       Hall & Moore (1975)
    River CD)                                     at all concentrations; full recovery of survivors within
                                                  30 min post exposure

    Rat (Charles      49-767           6 h        LC50 = 329 g/m3; anaesthesia at 145 g/m3 and higher            Coate (1976a)
    River CD)                                     concentrations; discoloration of lungs in most animals that
                                                  died, discoloration of liver in some of them

    Rat (strain       6, 16, 31, 62    15 min     unconditioned reflexes, locomotor activity, coordination       Trochimowicz (1989)
    unspecified)                                  affected at 31 and 62 g/m3; full recovery within 30 min
                                                  post exposure

    Hamster           63-194           4 h        LC50 = 178 g/m3; incoordination, prostration at all            Darr (1981)
    (Chinese)                                     concentrations; full recovery of survivors after exposure;
                                                  0% mortality at 163 g/m3, 100 mortality at 194 g/m3
                                                                                                                                              

    Table 10.  Acute inhalation toxicity of HCFC 124
                                                                                                                                    
    Species   Strain                Exposure        Exposure    Effects                                 Reference
                                    concentration   duration
                                    (g/m3)          (min)
                                                                                                                                    

    Mouse     unspecified           594             10          no effect                               Wada (1977)a
                                    837             10          narcosis                                Wada (1977)a
                                    2230            10          no mortality                            Wada (1977)a
                                    2460            10          death                                   Wada (1977)a

    Rat       Sprague-Dawley        268             240         no effect                               Kelly (1990)
              Charles River COBS    558             300         reduced activity                        Coate (1976b)
              Sprague-Dawley        893             240         prostration, lethargy, incoordination   Kelly (1990)
              Sprague-Dawley        1283            240         prostration, lethargy, incoordination   Kelly (1990)
              Sprague-Dawley        1674            240         death                                   Kelly (1990)
              Charles River COBS    2009            300         narcosis, no mortality                  Coate (1976b)

    Dog                             2230-3910       10          narcosis                                Van Poznak & Artusio (1960)
                                                                                                                                    

    a Attachment to correspondence from H. Wada, Daikon Kogyo Company Ltd. to M.B. Berenbaum, Allied Chemical Corporation,
      entitled Anaesthetic activity and fatality (F-123, 123a, 124 and 11)
    

    7.1.3.1  HCFC 141b

         No deaths occurred at dermal doses of 2 g/kg body weight either
    among rats (Janssen & Pot, 1988; Gardner, 1988) or rabbits (Brock,
    1988a).

    7.1.3.2  HCFC 132b

         When Janssen & Pot (1989a) applied a single dose of HCFC l32b (2
    g/kg) under an occluding dressing to the shaved skin of five male and
    five female Wistar rats, there were no deaths. The clinical signs
    observed were decreased respiratory rate, decreased startle response,
    altered locomotor activity, restlessness and vocalization. Three male
    and four female rats had swollen or slightly swollen livers on
    autopsy.

    7.1.3.3  HCFC 123

         Several limit tests for dermal toxicity of HCFC 123 were
    conducted. No mortality was observed at the limit dose of 2 g/kg body
    weight in rats (Brock, 1988d; Trochimowicz, 1989) or rabbits (Brock,
    1988e,f; Trochimowicz, 1989). The only clinical signs of toxicity were
    red nasal or ocular discharges in one of five male and one of five
    female rats, and slight to moderate body weight losses (up to 12% of
    initial body weight). No gross pathological abnormality was observed
    (Trochimowicz, 1989). In rabbits, only slight to moderate erythema was
    observed (Trochimowicz, 1989).

    7.2  Short-term inhalation exposure

    7.2.1  HCFC 141b

         Nikitenko & Tolgskaja (1965) reported a reduction in body weight
    gain, a slight decrease in haemoglobin level and moderate
    leucocytosis, some "minor changes" in blood parameters related to
    liver and kidney function, and histopathological effects in the
    respiratory tract of rats and guinea-pigs (number and strains
    unspecified) that had been exposed to 40-50 g/m3 (2 h/day, 6
    days/week) for 4 weeks. The purity of the substance and the specific
    isomer were not indicated.

         No adverse clinical signs and only "slight biochemical changes"
    (no details given) were reported in rats (number and strain
    unspecified) exposed to 48.5 g/m3 (6 h/day, 5 days/week) for 2 weeks
    (Pennwalt Corporation, 1987).

         In a 2-week inhalation toxicity study, Doleba-Crowe (1977)
    exposed groups of 10 male rats to 0 or 48 g/m3 for 6 h/day, 5
    days/week. The animals were observed for 14 days after exposure. No
    adverse clinical signs were observed, and there were no differences in
    body weights between treated and control animals. After the tenth

    exposure, elevated red blood cell counts, plasma bilirubin level and
    increased urinary fluoride concentrations were found, but all these
    parameters returned to normal after 14 days. The treated animals
    showed a more severe focal interstitial pneumonitis than controls 14
    days after exposure, but no other treatment-related change was
    observed.

         Coombs et al. (1988) exposed five groups of 10 male and 10 female
    Sprague-Dawley rats to 0, 24, 42, 68 and 97 g/m3 (6 h/day for 9
    days, i.e. 5 days of exposure followed by 1 day without exposure and
    then 4 days with exposure). Signs of central nervous system (CNS)
    depression were seen during exposure to concentrations of 42 g/m3 or
    more. At 97 g/m3, these signs were accompanied by a decrease in body
    weight gain in males and a slightly reduced food intake in both sexes.
    Glucose and aspartate serum transaminase (AST) levels were increased
    at 97 g/m3, protein, cholesterol and sodium from 68 g/m3,
    phosphate from 42 g/m3 and calcium from 24 g/m3. No
    treatment-related histopathological changes were observed at any dose
    level.

         In a 13-week inhalation study (some animals were killed after 4
    weeks), four groups each of 15 male and 15 female Fischer-344 rats
    were exposed to 0, 10, 39 or 97 g/m3 (6 h/day, 5 days/week) as
    described in two reports (Yano et al., 1989; Landry et al., 1989).
    Alertness was reduced at 97 g/m3, and body weight gain and food
    consumption were slightly reduced in all exposed groups. After both 4
    and 13 weeks of exposure, plasma cholesterol, triglycerides and
    glucose were slightly elevated in the rats exposed to 97 g/m3. No
    changes in haematological or histopathological parameters were found.

    7.2.2  HCFC 142b

         Rats and guinea-pigs (numbers and strains not specified) were
    exposed to a concentration of 448 g/m3 (isomer not specified), 2
    h/day, 6 days/week, for 4 weeks (Nikitenko & Tolgskaja, 1965). A
    decrease in the rate of body weight gain was observed at the end of
    the study, as well as a reduction in haemoglobin concentration and the
    number of erythrocytes, and an increase in the number of leucocytes.
    Swelling of the alveolar septa and peribronchitis were the
    histopathological changes observed in the lungs.

         In a study in which 10 adult white rats were exposed to 410
    g/m3 for 16 h/day, all animals died within 9 exposures. All of them
    showed severe signs of pulmonary irritation at autopsy (consolidation
    and hepatization of the lungs). The other organs appeared normal. No
    signs of ill health were apparent in five rats exposed to a
    concentration of 41 g/m3 (16 h/day for 2 months). Gross examination
    of the organs on autopsy revealed no pathological changes, but
    microscopic examination of the lungs showed round cell infiltration in
    the lung of two animals. The appearance of sections of the livers was
    normal (Lester & Greenberg, 1950).

         No clinical, haematological, blood chemical, urine analytical or
    histopathological evidence of effects attributable to repeated
    exposure to HCFC 142b was found in 10 male Charles River CD rats
    exposed to a concentration of 82 g/m3 (6 h/day, 5 days/week) for 2
    weeks (Moore & Trochimowicz, 1976).

         Kelly (1976) did not find any adverse clinical, haematological,
    blood chemical, urine analytical or histopathological effects
    attributable to HCFC 142b at exposure levels of either 4.1 g/m3 or
    41 g/m3 (6 h/day, 5 days/week for 90 days) in groups of male and
    female Charles River CD rats (27 of each sex at each treatment level)
    or groups of male dogs (4 at each treatment level).

    7.2.3  HCFC 132b

         When 20 male Crl:CDRBR rats were exposed to 55 g/m3 (6 h/day,
    5 days/week) for 2 weeks, reduction in body weight gain, irregular
    respiration and CNS depression (lethargy, poor coordination,
    occasional tremors and prostration) were seen. The CNS effects
    disappeared within 30 min after each exposure. Pathological
    examinations of rats sacrificed immediately after the tenth exposure
    showed thymic atrophy and spermatogenesis arrest, but these changes
    were not present in rats sacrificed 14 days after exposure ceased
    (Hall, 1976).

         Groups of 20 male and 20 female Crl:CDRBR rats were exposed to
    0, 3, 11 and 27 g/m3 (6 h/day, 5 days/week) for 13 weeks (Kelly,
    1988). Male rats exposed at all the concentrations of HCFC 132b showed
    bile duct proliferation and disruption of spermatogenesis with cell
    debris in the epididymides at the two higher concentrations. Other
    effects included increases in liver/body weight ratio in males at all
    concentrations and in females at the two higher concentrations.
    Elevation of serum alkaline phosphatase activity was found in both
    sexes exposed to 11 or 27 g/m3. During the study, all groups exposed
    to HCFC 132b showed reduced food consumption and body weight gain. In
    the two highest exposure groups there were depressions in the absolute
    but not relative brain and testes weights. Other organ weight changes
    were also seen (slight increases in heart, lung and kidney weights).
    The biological significance of these weight changes is not clear since
    there were no accompanying histological findings. During exposure to
    27 g/m3, rats showed CNS depression as indicated by decreased
    activity and low responsiveness to sound.

    7.2.4  HCFC 133a

         Shulman & Sadove (1965) exposed mice to anaesthetic
    concentrations (the actual concentration was not specified) of HCFC
    133a for 30 min per day on 12 consecutive days, and the animals were
    killed for pathological evaluation after the last exposure by
    overdosage of HCFC 133a. None of the mice showed any treatment-related

    clinical effects, and no pathological changes were found in the organs
    (heart, lung, liver, kidney, adrenal gland, spleen and pancreas)
    examined microscopically.

         Diggle & Gage (1956) investigated the effects of repeated
    exposure (up to 8 days) of groups of 2-3 female rats. Concentrations
    of HCFC 133a between 50 and 125 g/m3 caused incoordination and
    lethargy, while at 250 or 500 g/m3 rats become comatose. They
    recovered between each exposure and no dose-related pathological
    changes were found on histological examination. No effect was seen at
    25 g/m3 during seven exposures lasting 6 h/day.

         In a study by Leuschner et al. (1977), 20 male and 20 female
    Sprague-Dawley rats were exposed to 49 g/m3 (6 h/day, every day) for
    90 days. Corresponding groups of 20 male and 20 female rats were used
    as controls. Observations for overt clinical signs of toxicity and
    investigations on body weight, food consumption, haematology, blood
    and urine biochemistry, urine sediments, ophthalmology, auditory
    reflex, organ weights, and histopathology were performed. There were
    no treatment-related deaths. The rats were sedated during each
    exposure but appeared normal before and after. Seventeen out of 40
    rats developed bloody and inflamed noses; this was associated with
    histological evidence of inflammatory changes of the mucosa. Body
    weight gain was reduced, so that the terminal average body weights
    were approximately 28 and 17% lower than those of male and female
    controls, respectively. Food consumption in the treated groups was
    also lower than in the controls. Haemoglobin concentration,
    haematocrit, red blood cell counts and platelet counts were all
    slightly reduced. Reduction in leucocyte counts of approximately 30%
    and increase in reticulocyte counts of approximately 40% were seen.
    There were reductions in plasma glucose levels of approximately 15%
    and in protein levels of approximately 10%. Bromosulfophthalein
    retention time was increased by approximately 35% and 62% in males and
    females, respectively. There was no change in plasma enzyme
    glutamic-pyruvic transaminase (GPT), alkaline phosphatase (AP) or
    glutamicoxalacetic transaminase (GOT) activity. The thymus to body
    weight ratio was reduced by approximately 50% and the testis and ovary
    to body weight ratios by approximately 60 and 35%, respectively.
    Histologically, these organs showed atrophy. Thyroid to body weight
    ratio was increased by approximately 45% in males only. Atrophy of the
    spleen was also observed. The exposure induced emphysema and oedema of
    the lungs as well as bronchitis and pneumonia. The testicular atrophy
    was consistent with the findings in three dominant lethal studies in
    mice (Hodge et al., 1979, 1980; Kilmartin et al., 1980) and a
    carcinogenicity study in rats (Longstaff et al., 1984) (see section
    7.6 and 7.7).

         Six beagle dogs were exposed by Leuschner (1977) to 24 g/m3
    (6 h/day, daily) for 3 months and six control dogs were used. No
    effects were seen on external appearance, faeces, food and water
    consumption, body weight gain, haematology, blood and urine

    biochemistry, urine sediments, electrocardiography, blood pressure,
    ophthalmology, hearing or dentition. There was no effect on organ
    weight at autopsy. No treatment-related histopathological changes were
    seen on microscopic examination of a standard range of 24 tissues.

         In two dominant lethal studies (for experimental details see
    section 7.5.1.4), male mice were exposed to between 0.5 and 49 g/m3,
    6 h/day, for 5 days (Hodge et al., 1980; Kilmartin et al., l980). The
    mice were subdued at exposure concentrations of 2 g/m3 or more.
    Deaths occurred as follows: in the first study 0/60 mice died at 0
    g/m3, l7/60 at l2 g/m3, and 28/80 at 49 g/m3; in the second
    study 0/80 died at 0 g/m3, 2/59 at 0.5 g/m3, 0/60 at 2.5 g/m3,
    5/60 at 5 g/m3, and 20/60 at 12 g/m3.

    7.2.5  HCFC 123

         In a study by Doleba-Crowe (1978), Sprague-Dawley rats and beagle
    dogs were exposed to concentrations of 0, 6 and 62 g/m3 (6 h/day, 5
    days/week) for 90 days. At the high exposure level, both species
    exhibited lack of motor coordination soon after the start of exposure.
    This was followed by reduced motor activity and reduction in
    responsiveness to noise. After removal from exposure, coordination and
    activity returned to normal within 20 min. Other than final body
    weight reductions and increased urinary fluoride level at both
    exposure levels, no significant exposure-related effects were observed
    in rats. At the high exposure level, dogs exhibited histopathological
    changes in the liver and clinical chemistry changes including
    increased levels of serum GOT and GPT, which might indicate slight
    liver damage. No exposure-related effect was noted at the lower
    exposure level.

         In a 90-day inhalation study, albino rats obtained from Charles
    River Breeding Laboratory were exposed to nominal levels of 0, 3, 6,
    and 31 g/m3, 6 h/day, 5 days/week (Rusch, 1985). No
    treatment-related deaths occurred in the study and mean body weight
    reductions observed in the males at the highest exposure level and in
    females at the two highest exposure levels were significant only at
    the end of the study. Slight depression was observed in heart weight
    in both male and female rats exposed to 31 g/m3. While depressions
    of the kidney weights and kidney/brain weight ratio (but not kidney to
    body weight ratio) were observed in male rats in all the three
    exposure groups, these effects were outside the normal range only at
    the highest exposure level. A similar depression in kidney weight and
    kidney/body weight ratio (but not in kidney/brain ratio) occurred in
    females at the highest exposure level. Increased liver/body weight
    ratios (but not liver weight or liver/brain weight ratios) were
    observed in all three exposure groups of females, but in males only at
    the highest exposure level. No significant difference was found in
    organ weights or ratios in animals sacrificed at the end of a 30-day
    recovery period. The absence of histopathological findings and of

    effects at the end of the recovery period indicates that the
    toxicological significance of the organ weight changes in this study
    is unclear.

         In a 4-week inhalation toxicity study (Kelly, 1989; Trochimowicz,
    1989), rats (10 of each sex at each exposure level) were exposed to 0,
    6, 31, 62 or 125 g/m3 (6 h/day, 5 days/week) for 4 weeks.
    Statistically significant body weight depression occurred in all
    female groups and in the two highest male groups, but was dose-related
    only in the male rats. At concentrations of 31 mg/m3 or more, rats
    exhibited dose-related anaesthesia. At 62 and 125 g/m3, rats became
    lethargic during exposure but were normal when they were examined
    again 16 to 18 h after exposure. A dose-related increase in liver/body
    weight ratio was observed in all female groups (a 27% increase at the
    highest level) and in the two highest-exposure male groups (an 18%
    increase at the highest level). Decreased cytochrome P-450 activity in
    the liver was also found in all female exposure groups and in the male
    groups exposed at the two highest levels. Histopathological
    examination showed no adverse effects attributable to HCFC 123 in
    liver or in any other organ at any exposure level. Microscopic
    examination revealed that testicular degeneration and hypospermia
    occurred in two out of four male exposure groups, but this was
    believed to be due to reduced body weight (because of an increase in
    relative testicular weight without a corresponding increase in
    absolute testicular weight) or may have resulted from spontaneous
    lesions. The fact that the incidence of testicular degeneration was
    highest in the 31- and 125-g/m3 exposure groups (5 out of 10 and 6
    out of 10 animals, respectively), and lower in the 0-, 6-, and
    62-g/m3 exposure groups (2 out of 10, 1 out of 10 and 2 out of 10
    animals, respectively) is consistent with the sporadic nature of this
    lesion in this strain of rat. However, it is not possible to evaluate
    the significance of this testicular effect from the information
    available.

         Another 28-day inhalation toxicity study in rats was conducted to
    characterize further the potential effects of HCFC 123 on the liver
    (Lewis, 1990). In addition, urine samples were examined to identify
    metabolites of HCFC 123. Groups of six male Charles River CD rats were
    exposed to 0, 6, 31 or 125 g/m3 (6 h/day, 5 days/week) for 4 weeks.
    Body weights were statistically significantly reduced in all treated
    groups compared to controls, the greatest reduction occurring in the
    high-dose group. A concentration-related decrease in serum cholesterol
    levels was found in all test groups. This reduction was statistically
    significant compared to controls at the medium and high
    concentrations. Serum triglyceride levels were significantly reduced
    to a similar extent in all treated groups. A statistically significant
    increase in absolute and relative liver weights compared to controls
    was seen in the high-dose rats. Hepatocyte hypertrophy and mild fatty
    vacuolation was found at all concentrations tested but the severity
    was greatly reduced at the low exposure level. Electron microscopic
    examination revealed a treatment-related induction of peroxisome

    proliferation at the medium and high exposure concentrations. A
    statistically significant concentration-related increase in relative
    testes weight was observed in all treated groups (11-30% above
    control), but no compound-related morphological or microscopic changes
    were observed. Urine analysis indicated the presence of
    trifluoroacetic acid as a major metabolite.

         In a study by Malley (1990a), groups of 10 male and 10 female
    Crl:CDRBR rats were exposed to concentrations of 0, 2, 6 or 31
    g/m3 (6 h/day, 5 days/week) for 90 days. No effect on food
    consumption or body weight was observed. At the highest exposure level
    the animals exhibited anaesthesia and a decreased response to auditory
    stimuli. Serum triglyceride and glucose levels were significantly
    decreased at all exposure levels, while serum cholesterol was
    significantly lower in females exposed to the two highest
    concentrations. The mean lymphocyte and white blood cell counts in
    female rats were decreased at the highest exposure level. Male rats
    had significantly higher alanine aminotransferase and alkaline
    phosphatase activity at the two highest exposure levels. In female
    rats alanine aminotransferase activity was elevated at the highest
    exposure level. Urine fluoride concentrations were increased in
    females at all exposure levels, but in males only at the highest
    exposure level. Absolute liver weights were significantly higher in
    male rats at the highest exposure level and in female rats at the two
    highest exposure levels, while relative liver weights in both male and
    female rats were higher at the two highest exposure levels. Hepatic
    peroxisomal beta-oxidation activity in both male and female rats was
    1.9 to 3.8 times higher than in controls, indicating an induction of
    hepatic peroxisome proliferation. No treatment-related gross or
    microscopic liver changes were observed.

    7.2.6  HCFC 124

         When ten male rats were exposed to approximately 560 g/m3 (6
    h/day, 5 days/week) for 14 days, no adverse haematology, clinical
    chemistry, urine analysis or histopathological changes were observed.
    Rats showed irregular respiration, lethargy and poor coordination
    (Hall, 1976).

         Trochimowicz et al. (1977) reported no adverse effect following
    the clinical and histopathological evaluation of rats exposed to
    concentrations of 560 g/m3 (6 h/day, 5 days/week) for 2 weeks.
    Brewer (1977) exposed groups of 60 Sprague-Dawley rats (35 males and
    25 females) to concentrations of 0, 3, 5 or 28 g/m3 (6 h/day, 5
    days/week) for 3 months. Ten male and ten female rats were examined
    and sacrificed after 45 days and a similar number after 92 days. Ten
    male and five female rats of each group were maintained without
    further exposure for an additional 30-day period after exposure.
    Clinical signs were observed, body and organ weights determined, and
    haematological, biochemical and histopathological examinations carried
    out on all animals. No statistically significant differences in body

    weight gain were noted. Haematology, clinical chemistry, and urine
    analysis in treated rats were normal and comparable to findings in
    control animals. Urinary fluoride excretion was increased after 45
    days of exposure in both males and females (4.0 and 3.5 times,
    respectively) at an exposure level of 28 g/m3; at the two lower
    levels, determinations were not made. After 95 days of exposure, the
    urinary fluoride level was elevated only in males at all three
    exposure levels (by 1.5, 1.7 and 1.8 times, respectively), and this
    effect persisted throughout the 30-day period after exposure. Gross
    and histopathological examinations did not reveal any
    treatment-related changes in any group of animals. Statistically
    significant difference in organ weights between treated and control
    rats were found. Liver weights were increased significantly in males
    at 5 and 28 g/m3, while the lung and adrenal gland weights were
    significantly decreased in males at all three exposure levels. In the
    absence of any histopathological change, the biological significance
    of these organ weight changes is unclear.

         Malley (1990b) exposed groups of ten male and ten female rats to
    HCFC 124 concentrations of 0, 3, 11, 56 or 279 g/m3 (6 h/day, 5
    days/week) for 4 weeks. Treatment-related effects on body weight, food
    consumption, mortality, clinical laboratory parameters, organ weights,
    and tissue morphology changes were not found at any exposure level.
    During exposure, rats exposed to 279 g/m3 were lethargic and
    uncoordinated. However, no evidence of lethargy and incoordination was
    observed shortly after exposure. The author considered the exposure
    concentration of 56 g/m3 the no-observed-adverse-effect level
    (NOAEL) based on the clinical observation of lethargic and
    uncoordinated movement during exposure to 279 g/m3, which was not
    observed at 56 g/m3.

         Malley (1991) exposed Crl:CDRBR rats (20 rats of each sex at
    each exposure level) to HCFC 124 at concentrations of 0, 28, 84 and
    279 g/m3 (6 h/day, 5 days/week) for 90 days. As part of this study,
    a functional observation battery (FOB) was conducted on 10 rats of
    each sex at each exposure level at various intervals during the course
    of exposure. There were no compound-related effects relative to body
    weight, food consumption, mortality, haematology, organ weights or
    histopathology at any exposure concentration. However, male rats, at
    a level of 84 and 279 g/m3, had lower serum triglyceride
    concentrations and a decreased arousal (4 of 10 and 6 of 10 rats,
    respectively). Persistent decrease of forelimb grip strength was found
    in high-dose females. However, there was no associated decrease in
    hindlimb grip strength or change in gait or footplay. Females at the
    highest concentration showed an increase in alkaline phosphatase. Both
    sexes at 279 g/m3 were less responsive to auditory stimuli, as
    demonstrated by a decreased reaction to a sharp knock on the chamber
    wall. Plasma fluoride, urinary fluoride and fractional clearance of
    free fluoride were also increased at all exposure levels in both
    sexes. The author concluded that the no-observed-effect level (NOEL)
    was 28 g/m3 for male rats and 84 g/m3 for female rats.

    7.3  Skin and eye irritation; sensitization

    7.3.1  Skin and eye irritation

    7.3.1.1  HCFC 141b

         Treatment of the intact skin of New Zealand albino rabbits with
    0.5 ml of undiluted HCFC 141b under occlusive patch (during 4 and 24
    h in the two respective studies) did not produce signs of dermal
    irritation during a 3-day observation period (Liggett, 1988a; Brock,
    1988b).

         Two studies were conducted with HCFC 141b on groups of six New
    Zealand albino rabbits where the undiluted compound (0.1 ml) was
    instilled into the eyes. No signs of irritation occurred within 3 days
    in one study (Liggett, 1988b), but the compound was found to be a
    "mild" irritant in the other study (Brock, 1988c). The majority of
    rabbits in the latter study showed conjunctival redness (5/6), mild
    chaemosis (3/8) and blood-tinged discharge (4/6).

    7.3.1.2  HCFC 142b

         Brittelli (1976a) observed no effects on the cornea or iris but
    slight conjunctival swelling with some discharge in an eye irritation
    test with HCFC 142b.

    7.3.1.3  HCFC 132b

         One drop (approximately 0.05 ml) each of 100% HCFC 132b and a 10%
    solution in propylene glycol was applied and slightly rubbed into the
    shaved intact shoulder skin of 10 male albino guinea-pigs, but the
    area was not occluded. The pure compound produced only mild irritation
    in one animal only. No irritation was induced by the 10% solution
    (Goodman, 1976).

         Undiluted HCFC 132b (0.1 ml) was placed into the right
    conjunctival sac of two albino rabbits, and after 20 seconds one
    treated eye was washed with water for 1 min. Observations of the
    cornea, iris and conjunctiva were made after 1 and 4 h, and 1, 2, 3
    and 7 days later. Slight corneal opacity and "mild" to "moderate"
    conjunctival irritation were seen in both rabbits up to 3 days after
    dosing, but had disappeared by 7 days after dosing (Brittelli, 1976b).

    7.3.1.4  HCFC 123

         Minimal dermal irritation with HCFC 123 was observed in rabbits
    (Brock, 1988e,f). HCFC 123 (purity 99.0%) produced no skin irritation
    when 0.5 ml/6 cm2 was applied to the clipped intact skin of four
    male and two female New Zealand rabbits for 4 h (Trochimowicz, 1989).

         Brittelli (1976c) reported HCFC 123 to be a "mild" ocular
    irritant causing reversible corneal opacity in rabbits. In another
    study by Daly (1979)a, HCFC 123, when instilled undiluted (0.1 ml)
    into the conjunctival sac of the rabbit eye without subsequent
    washing, produced "mild" to "moderate" conjunctival irritation. With
    washing, "mild" transient corneal opacity and "mild" to "moderate"
    conjunctival irritation were observed. With or without washing,
    complete recovery occurred within 3-7 days.

    7.3.2  Skin sensitization

    7.3.2.1  HCFC 141b

         No delayed contact hypersensitivity was found in any of the 20
    Hartley Dunkin guinea-pigs in a Magnusson-Kligman maximisation test
    with HCFC 141b (Kynoch & Parcell, 1989).

    7.3.2.2  HCFC 132b

         A series of four sacral intradermal injections of HCFC 132b was
    given (once per week at 7-day intervals) over a 3-week period to
    groups of nine male albino guinea-pigs (0.1 ml of a 1% solution in
    dimethyl phthalate). Fourteen days after the last application, the
    animals were challenged with either 1 drop (0.05 ml) of undiluted
    liquid or a 19% solution of test material in propylene glycol on the
    shaved skin. No evidence of sensitization was observed (Goodman,
    1976).

    7.3.2.3  HCFC 123

         When applied topically to the back of male guinea-pigs as 10% or
    50% solutions in propylene glycol, HCFC 123 produced no sensitization
    at challenge (Goodman, 1975; Daly, 1979).

    7.4  Long-term exposure

         Combined chronic inhalation toxicity/carcinogenicity studies on
    HCFC 141b, HCFC 123 and HCFC 124 are in progress within the Programme
    for Alternative Fluorocarbon Toxicity Testing (Rusch, 1989) sponsored
    by an international industry consortium. An interim report after the
    first year of the study is available on HCFC 123 (Malley, 1990b).

                             
    a Personal communication entitled "Toxicity testing summary for
      alternative fluorocarbons" by J.J. Daly to CFTA Interindustry
      Safety Committee, Wilmington, Delaware, USA, E.I. Du Pont de
      Nemours and Co.

    7.4.1  HCFC 142b

         Four groups each containing 130 male and 110 female Sprague-
    Dawley CD rats were exposed by inhalation to concentrations of 4.1, 41
    and 82 g/m3 (6 h/day, 5 days/week) for 104 weeks. No exposure-
    related effects were found on mortality, body weight, haematology,
    clinical chemistry, urine analysis, histopathological or
    ophthalmological findings (Seckar et al., 1986). However, high
    mortality (more than 50% by the end of the study) was seen in all
    groups including controls.

    7.4.2  HCFC 123

         Findings associated with the first year of the PAFT-supported
    study were provided by Malley (1990c). Following 12 months of
    inhalation exposure to 0, 2, 6 or 31 g/m3, 10 rats (Crl:CDRBR) of
    each sex at each concentration were sacrificed, selected organs were
    weighed, and tissues were examined for gross and microscopic lesions.
    Body weight and body weight gain were significantly lower in high-dose
    males and in mid- and high-dose females. Food consumption was higher
    and food efficiency was lower in high-dose males and females over the
    course of the l year of exposure. The lower food efficiency appeared
    to be directly related to the lower body weight gain at the high
    concentration (31 g/m3). High-dose males and females exhibited
    anaesthesia-like behaviour (e.g., less responsiveness to auditory
    stimuli compared to control rats). No compound-related effects on
    mortality or survival time were found in any treated group. Clinical
    chemistry parameters measured at 6 months and 1 year revealed several
    compound-related changes. The most noteworthy findings were the effect
    on lipid and carbohydrate metabolism. Significant decreases of serum
    triglyceride and glucose concentrations were found in males and
    females at all dose levels. Serum cholesterol was significantly lower
    in females at all dose levels and in high-dose males. Urine analysis
    indicated significant increases of urinary fluoride concentration in
    both sexes at all dose levels. High-dose (31 g/m3) males and females
    had significantly higher mean relative liver weights, but no
    compound-related gross or histopathological changes were found in the
    livers of exposed animals. Dose-related increases in hepatic
    beta-oxidation enzyme activity were found for males (2.3, 3.1 and 4.0
    fold increases at 2, 6 and 31 g/m3, respectively) and females (1.7
    and 3.1 fold increase at 6 and 31 g/m3). The higher enzyme activity
    indicated an induction of hepatic peroxisome proliferation. However,
    compound-related differences in the rate of cell proliferation, as
    measured by changes in labelling index, were not found at any exposure
    concentration. These data indicate that during the first year of
    exposure, HCFC 123 did not induce an increase in regenerative repair
    of the liver, which is consistent with the absence of morphological or
    microscopic changes in the liver of exposed animals. A
    no-observed-effect level (NOEL) was not achieved in this study based
    on the effects on clinical chemistry parameters and higher hepatic
    peroxisomal activity.

    7.5  Reproduction, embryotoxicity, and teratogenicity

    7.5.1  Reproduction

    7.5.1.1  HCFC 141b

         A 2-generation reproduction study on HCFC 141b is currently in
    progress (Rusch, 1989).

    7.5.1.2  HCFC 142b

         In a dominant lethal study on rats, no effect on male
    reproduction was found (Seckar et al., 1986). No other studies on
    reproductive effects are available.

    7.5.1.3  HCFC 132b

         No data are available on the effects of HCFC 132b.

    7.5.1.4  HCFC 133a

         No studies are available in which the effects of HCFC 133a on
    reproduction were investigated. Some information is available,
    however, on the effects on male fertility from a series of dominant
    lethal and "combined dominant lethal fertility" studies in mice (Hodge
    et al., 1979, 1980; Kilmartin, 1980). In these studies groups of male
    mice were exposed to between 0 and 98 g/m3, 6 h/day, for 5
    consecutive days. At the end of the treatment, dominant lethal and
    fertility effects were assessed in 15 males (30 controls) from each
    treatment group, which were each housed with two virgin females for
    four consecutive nights. This 4-nightly mating procedure was continued
    for 8-9 consecutive weeks. In the two later studies, satellite group
    males (at least two from each group per week) were killed, their
    epididymal sperm assessed for abnormalities and their testes examined
    histopathologically. A reduction in male fertility (seen as
    exposure-related decreases in the proportion of pregnant females:
    e.g., 0-60% of pregnant females in treatment groups compared to
    90-100% in controls) was seen between weeks 2-8 following exposure.
    The severity of the effects were related to time, the maximum
    reductions in pregnancies being seen at around 3-6 weeks after
    exposure. No effect on fertility was seen at 0.5 g/m3. Reduced
    fertility was observed at concentrations of 2.5 g/m3 or more, and
    histopathological evidence of degeneration of spermatogenic cells was
    seen at concentrations of 5 g/m3 or more. There was a slight and
    transient increase in the percentage of abnormal sperm at 2.5 g/m3
    or more.

    7.5.1.5  HCFC 123

         A 2-generation inhalation reproduction study on rats sponsored by
    PAFT is currently in progress (Rusch, 1989).

    7.5.2  Embryotoxicity and teratogenicity

    7.5.2.1  HCFC 141b

         Hughes et al. (1988) exposed three groups of 25 pregnant female
    Sprague-Dawley rats to 15, 39 or 97 g/m3 for 6 h/day from days 6 to
    15 of pregnancy. Some signs of maternal toxicity (prenarcotic signs,
    piloerection and reduced alertness) were observed at all exposure
    levels. At the highest level, salivation, hunched posture, and
    diaphragmatic breathing, a marked increase in water consumption, a
    transient reduction in food intake, and a marginal reduction in body
    weight gain were observed. At the highest exposure level, incidences
    of subcutaneous oedema and haemorrhaging and embryonal death were
    significantly increased. Reduced litter and mean fetal weights and
    retarded ossification were observed. However, no teratogenic effect
    occurred in any group.

         In a further study (Hughes et al., 1989), 16 pregnant female New
    Zealand rabbits were exposed to 7, 20 or 61 g/m3 for 6 h/day from
    days 7 to 19 of pregnancy. Signs of maternal toxicity (prenarcotic
    signs, palpebral ptosis, respiratory disturbances and body weight
    loss) were observed at the two highest exposure levels. There was no
    indication of any treatment-related effect on embryo or fetal
    development or evidence of teratogenicity at any exposure level.

    7.5.2.2  HCFC 142b

         Groups of 25 pregnant Sprague-Dawley rats were exposed to 4 or 41
    g/m3 for 6 h/day from day 3 to day 15 of gestation (Culik & Kelly,
    1976). The exposure had no effect on the body weight gain of the
    mothers, and no clinical signs of toxicity were observed in any of the
    animals. The number of early or late resorptions or number of live
    fetuses per litter was not affected by the exposure. Exposure also had
    no effect on embryonic development, as measured by the weight and
    crown-rump length of the fetuses, and there was no evidence of a
    teratogenic effect.

         Damske et al. (1978) exposed groups of 20 pregnant female
    Sprague-Dawley CD rats to concentrations of 0, 13 and 39 g/m3 for 6
    h/day on days 6-15 of gestation. There were no treatment-related
    effects in the dams or evidence of exposure-induced terata, variations
    in sex ratio, embryotoxicity or inhibition of fetal growth and
    development. There was an increase in the incidence of delayed
    ossification of the supraoccipital bone in both exposure groups; this
    effect was not observed in the control group.

    7.5.2.3  HCFC 132b

         In a pilot study, groups of seven or eight pregnant rats were
    exposed to 3, 11 or 28 g/m3 for 6 h/day on days 6-15 of gestation.
    Maternal and fetal body weights were reduced at all exposure levels.

    The number of resorptions was increased in the 11- and 27-g/m3
    exposure groups (Alvarez, 1988).

         In a development screening test using Hydra (Johnson et al.,
    1986), embryotoxicity was observed at paternally toxic doses.

    7.5.2.4  HCFC 133a

         Weigand et al. (1977) investigated the potential embryotoxic or
    teratogenic effects of HCFC 133a in Wistar rats and Himalayan rabbits.
    They also examined the effects of pre-treatment with progesterone to
    determine whether any of the adverse effects of HCFC 133a could be
    explained by its interaction with and depletion of progesterone in
    early pregnancy, since this hormone is responsible for the electrical
    and mechanical quiescence of the myometrium. Twenty-four pregnant
    Wistar rats, of which 12 were injected subcutaneously with
    progesterone (6 mg/day) prior to HCFC 133a exposure, were exposed to
    25 g/m3 for 6 h/day on days 7-16 of gestation (the day on which
    sperm was found in the vaginal smear was taken as day 1 of gestation).
    Twelve pregnant Himalayan rabbits were exposed to the same
    concentration on days 7-19 of gestation (the day of mating being taken
    as day 0 of gestation). No controls were used and data were compared
    with historical control data. Mild transient sedation, piloerection,
    reduced body weight gain and reduced food consumption were observed in
    the rats. At autopsy on day 21 of gestation, no macroscopic change was
    observed. There was a prenatal mortality of 77% in the dams with no
    pre-treatment with progesterone and 82% in the pre-treated dams.
    Placental weight, fetal weight and crown-rump length were reduced and
    some of the surviving fetuses showed generalized oedema (8/53) and
    external anomalies of the limbs and tail (5/53). There was no
    significant difference between the rats pre-treated with progesterone
    and those without pre-treatment. In rabbits, there were reductions in
    body weight gain and food consumption. All animals showed vaginal
    bleeding during the last three days of the exposure, and 4 out of 12
    aborted. By autopsy on day 29 all fetuses had died.

         Culik & Kelly (1979) exposed Charler River CD rats to approximate
    concentrations of 0, 2.5, 10, 25 or 98 g/m3 for 6 h/day on days 6-15
    of gestation, and the rats were subjected to autopsy on day 21 of
    gestation. There was no clear evidence of maternal toxicity. Evidence
    of embryotoxicity was observed at all exposure levels. In the control
    and the 2.5-g/m3 exposure groups, there was neither fetal death nor
    total litter resorption. Fetal weights and crown-rump lengths were
    lower in all the groups exposed to HCFC 133a than in controls. At 10
    g/m3, 4/21 pregnant females had total resorptions and only 67
    fetuses were alive in the other females. At 25 g/m3, 37/41 pregnant
    females had total resorptions and only 7 fetuses were alive in the
    other females. At 98 g/m3, 22/23 pregnant females had total
    resorptions and only one fetus was alive in the other female.
    Treatment-related increases in the incidence of runts and delayed
    ossification in several bone structures were also observed at all

    exposure levels. An increased incidence of hydronephrosis was reported
    in all treated groups. Thus, the no-observed-effect level for
    embryolethality was 2 g/m3 but, in view of the reduced fetal size
    and weight at this exposure level, the no-observed-effect level for
    embryotoxicity was not established from this study.

    7.5.2.5  HCFC 123

         Kelly et al. (1978) exposed 25 pregnant female rats to 62 g/m3
    for 6 h/day on days 6-15 of gestation. Dams and fetuses were
    sacrificed on day 21 and examined for gross changes. No embryotoxicity
    or teratogenic effects were seen.

         Two groups of 20 pregnant female rats were exposed to 0 and 31
    g/m3 for 6 h/day on days 6-15 of gestation (Rusch, 1985). The
    animals were sacrificed on day 20 and all dams and fetuses examined.
    The maternal mean body weight in the exposed group was depressed to a
    statistically significant degree on days 12 and 15 of the gestation
    period. At termination, maternal mean body weights were still
    depressed but not to a statistically significant degree. The numbers
    of corpora lutea, implantation sites, resorption sites and fetuses
    were similar in control and treated dams.

         In a range-finding study, groups of six pregnant rabbits were
    exposed to HCFC 123 concentrations of 0, 6, 31, 62 and 125 g/m3 for
    6 h/day on days 6-18 of gestation (Schroeder, 1989a). All treated
    rabbits lost weight during the study and food consumption was markedly
    reduced, particularly at the two highest exposure levels. At these two
    levels an increased number of resorption was also observed. In the
    final study (Schroeder, 1989b; Trochimowicz, 1989), 24 mated females
    per exposure group were exposed to 3, 9 or 31 g/m3 for 6 h/day
    during days 6-18 of gestation. No mortality was observed in the
    control or the low or medium exposure groups. The death of one rabbit
    in the high exposure group was not considered by the author to be
    treatment-related. There was evidence of maternal toxicity during days
    6-18 of gestation at all exposure levels. Statistically significant
    treatment-related mean body weight losses were observed in all the
    test groups during the exposure period, compared to the control group
    which showed a slight mean body weight gain. Mean daily food
    consumption was also statistically lower in test groups than in
    controls on most exposure days. There was no evidence of embryotoxic,
    fetotoxic or teratogenic effects.

    7.5.2.6  HCFC 124

         Brewer & Smith (1977) exposed a group of 20 pregnant Charles
    River CD rats to 30 g/m3 for 6 h/day during days 6-15 of gestation.
    Maternal body weight measurements and clinical observations did not
    reveal any difference between exposed and control groups, and no
    maternal deaths occurred. The incidence of resorption sites in the
    treated group was higher than in controls but within the range

    commonly experienced with the strain of rats employed. The numbers of
    corpora lutea, implantation sites, and fetuses in the treated groups
    were similar to those in the controls. Fetal body weights were not
    altered by treatment.

         In a recent range-findings study, Rickard (1990b) exposed
    Sprague-Dawley rats (4-6 per group) to minimal HCFC 124 concentrations
    of 0, 3, 11, 56 or 279 g/m3 for 6 h/day on days 6-15 of gestation.
    No change in mean body weight gain or evidence of embryotoxic effects
    was observed. Internal and skeletal examinations were not conducted;
    only external examination of fetuses was performed.

         Schroeder (1991), in a range-finding study, exposed New Zealand
    white rabbits (7 per group) to nominal HCFC 124 concentrations of 0,
    28, 84 and 279 g/m3 for 6 h/day on days 6-18 of gestation. The only
    sign of maternal toxicity was decreased activity during exposure at
    the two highest concentrations. There was no evidence of
    embryotoxicity, fetotoxicity or teratogenicity at any exposure
    concentration.

    7.6  Mutagenicity

    7.6.1  HCFC 141b

         The data from  in vitro and  in vivo studies are summarized in
    Table 11.

         HCFC 141b did not appear to damage bacterial DNA in a repair
    assay, but produced conflicting evidence for mutagenicity in other
    bacterial assays. Although sample purities differed in the two assays,
    this alone may not account for the difference in response.

         No significant response was obtained in the  in vitro V79 cell
    hprt locus assay.

         Chromosomal aberrations were induced in two  in vitro studies
    with CHO (Chinese hamster ovary) cells, but this activity was not
    apparent either in one assay with cultured human lymphocytes or in two
     in vivo studies for micronucleus induction in mouse bone marrow
    cells.

    7.6.2  HCFC 142b

         The data from  in vitro and  in vivo studies are summarized in
    Table 12.

         There was evidence of induction of base substitution mutations by
    HCFC 142b in four of the five bacterial tests conducted. In two of
    these studies this effect was apparent only in the presence of
    exogenous metabolic activation.

         A positive response, but without supporting data, was reported in
    a single BHK (baby hamster kidney) 21 cell transformation assay.

         No evidence of mutagenic activity of HCFC 142b was seen in a bone
    marrow cytogenetic test or a dominant lethal study in rats.

    7.6.3  HCFC 132b

         The data from  in vitro studies are summarized in Table 13.

         HCFC 132b was tested in bacterial assays (three studies) and in
    an  in vitro chromosomal aberration test using a CHO cell line.

         There was no evidence of mutagenic potential of HCFC 132b in
    these studies.

    7.6.4  HCFC 133a

         The data from  in vitro and  in vivo studies are summarized in
    Table 14.

         HCFC 133a did not induce mutations in bacteria and did not
    increase the proportion of BHK 21 cells forming colonies in soft agar.

         Chromosomal aberrations were not induced in a single rat bone
    marrow test using high concentrations. There were small, statistically
    significant increases in the incidences of early deaths in two of
    three male mouse dominant lethal assays. These increases occurred in
    mating weeks 6-8 in one study and in mating week 7 in the other, in
    which the lowest effective dose was 12.3 g/m3. No increases in early
    deaths were observed in the third study, in which the highest
    concentration tested was 12.3 g/m3.

    7.6.5  HCFC 123

         The data from  in vitro genotoxicity studies are summarized in
    Table 15.

         HCFC 123 showed no evidence of mutagenic potential when tested in
    suspension and plate assays using bacteria or yeasts.

          In vitro cytogenetic tests were performed using cultured human
    lymphocytes, in which HCFC 123 was tested both in the liquid and
    gaseous phase. There was evidence of clastogenic activity in both the
    presence and absence of exogenous activation systems, when HCFC 123
    was tested in the gaseous phase; in the liquid phase study, an
    increase in chromosomal aberrations was seen in the absence of
    exogenous activation.


    
    Table 11.  Genetic toxicity of HCFC 141b
                                                                                                                                       
    Test system                                   Resultsa           Dose         Remarks                  References
                                                                     LED/HEDb
                                             Without     With
                                             exogenous   exogenous
                                             metabolic   metabolic
                                             activation  activation
                                                                                                                                       

     Escherichia coli, DNA repair             -           -           10 mg/ml,                             Hodson-Walker & May (1988b)
                                                                      18 hc
     
     Salmonella typhimurium, reverse          +           +           1455 g/m3,   99.6% purity, positive   Hodson-Walker & May (1988a)
     mutation with TA98, TA100, TA1535,                               48 hc        in TA1535, negative
     TA1537, TA1538                                                               in other strains

     S. typhimurium, reverse mutation with    -           -           1455 g/m3,   99.95% purity            May (1989)
     TA98, TA100, TA1535, TA1537, TA1538                              48 hc

     E. coli, reverse mutation with WP2 uvrA  -           -           1455 g/m3,   99.95% purity            May (1989)
                                                                      48 hc

    Gene mutation  in vitro, V79 cells, hprt  -           -           1430 g/m3,   99.6% purity             Bootman et al. (1988a)
     locus                                                            3 hc

    Chromosomal aberrations  in vitro, CHO    ±           -           1 mg/ml      liquid phase; increase   Wilmer & De Vogel (1988)
     cells                                                                        in gaps only

    Chromosomal aberrations  in vitro, CHO    +           +           485 g/m3,    99.6% purity             Bootman & Hodson-Walker
     cells                                                            3 hc         (1988)

    Chromosomal aberrations  in vitro, CHO    +           +           485 g/m3,    99.83% purity            Hodson-Walker (1990a)
     cells                                                            4 hc
                                                                                                                                       
    Table 11 (contd).
                                                                                                                                       
    Test system                                   Resultsa           Dose         Remarks                  References
                                                                     LED/HEDb
                                             Without     With
                                             exogenous   exogenous
                                             metabolic   metabolic
                                             activation  activation
                                                                                                                                       

    Chromosomal aberrations  in vitro, human  -           -           1700 g/m3,   99.83% purity            Hodson-Walker (1990b)
     lymphocytes                                                      3 h (+ema)c
                                                                      243 g/m3,
                                                                      24 h (-ema)

    Micronucleus test  in vivo, mouse bone    -           NA          165 g/m3,    99.98% purity; marrow    Vlachos (1989)
     marrow                                                           6 h          sampled at 24, 48 and
                                                                                  72 h

    Micronucleus test  in vivo, mouse bone    -           NA          95 g/m3,     marrow sampled at 24,    Bootman et al. (1988b)
     marrow                                                           6 h          48 and 72 h
                                                                                                                                       

    a NA = not applicable; ± = inconclusive
    b LED = lowest effective dose; HED = highest effective dose; +ema = with exogenous metabolic activation; -ema = without exogenous
      metabolic activation
    c  in vitro assay in an enclosed system

    Table 12.  Genetic toxicity of HCFC 142b

                                                                                                                                               

    Test system                                   Resultsa           Dose               Remarksc                   References
                                                                     LED/HEDb
                                             Without     With
                                             exogenous   exogenous
                                             metabolic   metabolic
                                             activation  activation
                                                                                                                                               

     Salmonella typhimurium, reverse           -           -           1640 g/m3,         negative in all            Barsky (1976)
     mutation with TA98, TA100, TA1535,                                6 hd               strains
     TA1537

     S. typhimurium, reverse mutation with     +           +           2050 g/m3,         weakly positive only       Koops (1977)
     TA98, TA100, TA1535, TA1537, TA1538                               48 hd              in TA1535 (2-8 fold
                                                                                        increase at 2050 g/m3)

     S. typhimurium, reverse mutation with     +           +           not specifiedd     single gaseous conc.       Jagannath (1977)
     TA98, TA100, TA1535, TA1537, TA1538                                                (not specified), exposure
                                                                                        for 1-72 h, positive in
                                                                                        TA100 and TA1535

     S. typhimurium, reverse mutation with     -           +           2050 g/m3,         positive in TA100 and      McGregor (1976)
     TA98, TA100, TA1535, TA1538                                       48 hd              TA1535, experimental
                                                                                        data not reported

     S. typhimurium, reverse mutation with     -           +           2050 g/m3,         positive in TA100 and      Longstaff et al. (1984)
     TA98, TA100, TA1535, TA1538                                       48 hd              TA1535, experimental
                                                                                        data not reported

    Cell transformation,  in vitro BHK 21     ND          +           not specified      liquid phase, concs.       Longstaff et al. (1984)
     cell growth in soft agar assay                                                     not specified, exposure
                                                                                        for 1-24 h, experimental
                                                                                        data not reported
                                                                                                                                               
    Table 12 (contd).

                                                                                                                                               

    Test system                                   Resultsa           Dose               Remarksc                   References
                                                                     LED/HEDb
                                             Without     With
                                             exogenous   exogenous
                                             metabolic   metabolic
                                             activation  activation
                                                                                                                                               

    Chromosomal aberrations,  in vivo rat      -           NA          82 g/m3,                                      Seckar et al. (1986)
     bone marrow                                                       6 h/day, 5 days/
                                                                       week for 13 weeks

    Dominant lethal assay, male CD-1 rat       -           NA          82 g/m3,                                      Seckar et al. (1986)
                                                                       6 h/day, 5 days/
                                                                       week for 15 weeks
                                                                                                                                               

    a NA = not applicable; ND = not determined
    b LED = lowest effective dose; HED = highest effective dose
    c purity not specified for these studies
    d  in vitro assay in an enclosed system

    Table 13.  Genetic toxicity of HCFC 132b
                                                                                                                             
    Test system                                   Results            Dose           Remarks          References
                                                                     LED/HEDa
                                             Without     With
                                             exogenous   exogenous
                                             metabolic   metabolic
                                             activation  activation
                                                                                                                             

     Salmonella typhimurium, reverse           -           -           4 mg/plate     liquid phase     Russell (1976)
     mutation with TA98, TA100, TA1535,
     TA1537, TA1538

     S. typhimurium, reverse mutation with     -           -           550 g/m3b                       Waskell (1979)
     TA98, TA100, TA1535, TA1537

     S. typhimurium, reverse mutation with     -           -           578 g/m3b      99.9% purity     Koorn (1988)
     TA98, TA100, TA1535, TA1537, TA1538

    Chromosomal aberrations,  in vitro CHO     -           -           14.2 mg/ml,    liquid phase     Wilmer & de Vogel (1988)
     cells                                                             3 h (+ema)b
                                                                       3.0 mg/ml,
                                                                       21 h (-ema)b
                                                                                                                             

    a +ema = with exogenous metabolic activation; -ema = without exogenous metabolic activation; LED = lowest effective dose;
      HED = highest effective dose
    b  in vitro assay in an enclosed system

    Table 14.  Genetic toxicity of HCFC 133a
                                                                                                                                         
    Test system                                   Resultsa           Dose              Remarksc                   References
                                                                     LED/HEDb
                                             Without     With
                                             exogenous   exogenous
                                             metabolic   metabolic
                                             activation  activation
                                                                                                                                         

     Salmonella typhimurium, reverse           -           -           2460 g/m3,                                   McGregor (1976)
     mutation with TA98, TA100, TA1535,                                24 hd
     TA1538

     S. typhimurium, reverse mutation with     -           -           172 g/m3,                                    Waskell (1979)
     TA98, TA100                                                       48 hd

     S. typhimurium, reverse mutation with     -           -           49 g/m3,                                     Edmunds et al. (1979)
     TA98, TA100                                                       8 hd

    Cell transformation,  in vitro BHK 21      -           -           gas, 3 h          concentrations not         Longstaff et al. (1984)
     cell growth in soft agar assay                                                    specified, experimental
                                                                                       data not provided

    Chromosomal aberrations,  in vivo,         -           NA          98 g/m3, 6 h,     marrow sampled 24 h        Anderson & Richardson
     male AP rat bone marrow                                           and 6 h/day       after single and 6 h       (1979)
                                                                       5 days/week       after multiple exposure

    Dominant lethal assay, male CD-1           +           NA          49 g/m3, 6 h/     early deaths increased     Hodge et al. (1979)
     mouse                                                             day, 5 days/week  in mating weeks 6-8

    Dominant lethal assay, male CD-1           +           NA          12 g/m3, 6 h/     early deaths increased     Hodge et al. (1980)
     mouse                                                             day, 5 days/week  in mating week 7, no
                                                                                       dose response
                                                                                                                                         

    Table 14 (contd).
                                                                                                                                         
    Test system                                   Resultsa           Dose              Remarksc                   References
                                                                     LED/HEDb
                                             Without     With
                                             exogenous   exogenous
                                             metabolic   metabolic
                                             activation  activation
                                                                                                                                         

    Dominant lethal assay, male CD-1         -           NA          12 g/m3, 6 h/                                Kilmartin et al. (1980)
     mouse                                                           day, 5 days/week
                                                                                                                                         

    a NA = not applicable
    b HED = highest effective dose; LED = lowest effective dose
    c purity not provided for these studies
    d  in vitro assay in an enclosed system

    Table 15.  Genetic toxicity of HCFC 123
                                                                                                                                          
    Test system                                   Resultsa           Dose              Remarks                    References
                                                                     LED/HEDb
                                             Without     With
                                             exogenous   exogenous
                                             metabolic   metabolic
                                             activation  activation
                                                                                                                                          

     Salmonella typhimurium, reverse           -           -           937 g/m3, 6 h                                Barsky (1976)
     mutation with TA98, TA100, TA1535,
     TA1537, TA1538

     S. typhimurium, reverse mutation with     -           -           not specifiedc    single gaseous conc.       Brusick (1976)
     TA98, TA100, TA1535, TA1537, TA1538                                                 (not specified), exposure
                                                                                         for 5 or 24 h

     S. typhimurium, reverse mutation with     -           -           625 g/m3, 72 h    experimental data not      Longstaff et al. (1984)
     TA98, TA100, TA1535, TA1538                                                         provided

     S. typhimurium, reverse mutation with     -           -           not specifiedc    gaseous exposure,          Callander (1989)
     TA98, TA100, TA1535, TA1537, TA1538                                                 concs. not specified

     Sacharomyces cerevisiae: D4, forward      -           -           not specified     concs. not specified,      Brusick (1976)
     mutation                                                                            exposure for 4-72 mins

    Chromosomal aberrations,  in vitro,        +           -           75 µg/ml,         purity 99.95%              Dance (1991)
     human lymphocytes                                                 24 h

    Chromosomal aberrations,  in vitro,        +           +           1875 g/m3,        purity 99.95%              Edwards (1991a)
     human lymphocytes                                                3 h (+ema)c
                                                                      156 g/m3,
                                                                      24 h (-ema)c

    Cell transformation,  in vitro, BHK 21    ND          -           not specified     liquid phase, concs.       Longstaff et al. (1984)
     cell growth in soft agar assay                                                     not specified,
                                                                                        experimental data
                                                                                        not provided
                                                                                                                                          

    Table 15 (contd).
                                                                                                                                          
    Test system                                   Resultsa           Dose              Remarks                    References
                                                                     LED/HEDb
                                             Without     With
                                             exogenous   exogenous
                                             metabolic   metabolic
                                             activation  activation
                                                                                                                                          

    Micronucleus test,  in vitro, mouse        -           NA          112 g/m3, 6 h     marrow sampled 24,         Müller & Hoffman (1988)
     bone marrow                                                                         48 and 72 h after
                                                                                         exposure
                                                                                                                                          

    a ND = not determined; NA = not applicable
    b LED = lowest effective dose; HED = highest effective dose; +ema = with exogenous metabolic activation; -ema = without exogenous metabolic
      activation
    c  in vitro assay in an enclosed system
    

         A negative response was reported in a BHK transformation assay,
    but no supporting data were provided.

         There was no evidence of induction of micronuclei in a single
    mouse bone marrow assay.

    7.6.6  HCFC 124

         The data from the small number of  in vitro studies are
    summarized in Table 16.

         HCFC 124 did not induce mutations in bacteria or chromosomal
    aberrations in CHO cells.

    7.7  Carcinogenicity

         Combined chronic inhalation toxicity/carcinogenicity studies on
    HCFC 141b, HCFC 123 and HCFC 124 are in progress within the Programme
    for Alternate Fluorocarbon Toxicity Testing (Rusch, 1989).

    7.7.1  HCFC 142b

         Seckar et al. (1986) conducted a combined chronic
    toxicity/carcinogenicity study of HCFC 142b with Sprague-Dawley CD
    rats (details of exposure regimen are given in section 7.4).
    Neoplasmic findings in animals that died were similar in the control
    and treated animals, and predominantly comprised tumours of the
    mammary and subcutaneous tissues in females, and pituitary and adrenal
    adenomas in both sexes. A similar pattern existed in surviving
    animals.

    7.7.2  HCFC 133a

         The carcinogenic potential of HCFC 133a has been evaluated by
    Longstaff et al. (1984) in a limited study in Alpk/Ap Wistar- derived
    rats. The study included one undosed control group of 32 male and 32
    female rats and two vehicle-dosed control groups, one consisting of 40
    male and 40 female and the other of 36 male and 36 female rats. The
    HCFC 133a was dissolved in corn oil to give a 3% solution and dosed by
    gavage at 300 mg/kg body weight, 5 days/week until week 52, and the
    study was terminated at week 125. Dosed controls were given corn oil
    only. Reductions of body weight gain and decreased testicular size
    were observed in treated males. Aggressive behaviour occurred,
    particularly in males. Body weight gain in females was similar to that
    of controls. Mortality was not affected by treatment in either sex.
    The treated females had an increased incidence of uterine carcinomas
    (15/35) in comparison with controls (1/104). The first of these
    carcinomas was seen at week 84. The carcinomas metastasized
    transcoelomically to the abdomen in a large proportion of animals. A
    small proportion also had lung metastases. Histologically, the
    neoplasms were actively infiltrating adenocarcinomas.


    
    Table 16.  Genetic toxicity of HCFC 124
                                                                                                                                         
    Test system                                   Results            Dose              Remarks                    References
                                                                     LED/HEDa
                                             Without     With
                                             exogenous   exogenous
                                             metabolic   metabolic
                                             activation  activation
                                                                                                                                         

     Salmonella typhimurium, reverse           -           -           2230 g/m3,                                   Barsky (1976)
     mutation with TA98, TA100, TA1535,                                6 hb
     TA1537, TA1538

     S. typhimurium, reverse mutation with     -           -           2790 g/m3,        purity > 99%               May (1991)
     TA98, TA100, TA1535, TA1537, TA1538                               48 hb

     S. typhimurium, reverse mutation with     -           -           2790 g/m3,        experimental data          Longstaff et al. (1984)
     TA98, TA100                                                       48 hb             not reported

     Escherichia coli, reverse mutation with   -           -           2790 g/m3,        purity > 99%               May (1991)
     WP2 uvrA                                                          48 hb

    Chromosomal aberrations,  in vitro,        -           -           3348 g/m3,        purity > 99%               Edwards (1991b)
     CHO cells                                                         48 h (-ema)b
                                                                       3348 g/m3,
                                                                       4 h (+ema)b
                                                                                                                                         

    a LED = lowest effective dose; HED = highest effective dose; +ema = with exogenous metabolic activation; -ema = without exogenous
      metabolic activation
    b  In vitro assay in an enclosed system
    

         The treated males had an increased incidence of benign
    interstitial cell neoplasms of the testis (29/36) compared with
    controls (16/104). In many animals the neoplasms were bilateral. The
    first interstitial cell tumour was seen at week 64. The testes of all
    treated males, including those with no evidence of neoplasms,
    exhibited arrest of spermatogenesis and atrophy of the seminiferous
    tubules. These changes were first seen in the first rat to die in this
    study, which was in week 37.

    7.7.3  HCFC 123

         As discussed in section 7.4.2, a 2-year inhalation toxicity/
    carcinogenicity study in rats is being conducted. Groups of 80 male
    and 80 female Crl:CDRBR rats were exposed to HCFC 123 at 0, 2, 6 or
    31 g/m3 (6 h/day, 5 days/week) for 2 years. No histological lesions
    were found in 10 rats of each sex in each exposure group, which were
    sacrificed at the end of 1 year of exposure (Malley, 1990c).
    Preliminary findings from the histopathological examination of tissues
    of male rats at the end of the 2-year exposure period indicated an
    exposure-related increase in benign tumours of the testis and exocrine
    pancreas (US EPA, 1991). A full report is needed before these results
    can be evaluated.

    7.8  Special studies - cardiovascular and respiratory effects

         Chlorofluorocarbons have long been known to sensitize the heart
    to adrenaline-induced arrhythmias. Zakhari & Aviado (1982) reviewed
    the literature on this subject. Several studies have been conducted to
    evaluate the cardiac sensitization and respiratory effect potential of
    the alternative HCFC compounds.

    7.8.1  HCFC 141b

         Mullin (1977) exposed male dogs, which were pretreated with an
    intravenous injection of adrenaline (0.008 mg/kg), to HCFC 141b
    concentrations of 12, 24, 48 and 97 mg/m3. A challenge dose
    (intravenous injection with adrenaline) given during exposure elicited
    serious cardiac arrhythmias at the three highest concentrations but no
    response was noted at the lowest concentration.

         Hardy et al. (1989b) studied cardiac sensitization to adrenaline
    in two Cynomolgus monkeys and four beagle dogs and found that the
    lowest HCFC 141b concentrations inducing responses were about 24 and
    48 g/m3, respectively.

         No effect on respiratory rate was observed when three groups of
    three male Wistar rats were exposed to approximately 45 g/m3 for 25
    min. However, there was a small change in respiratory amplitude
    suggesting a decrease in tidal volume (Janssen, 1989a).

    7.8.2  HCFC 142b

         Adrenaline-induced cardiac arrhythmias were observed in 5 out of
    12 dogs exposed to 205 mg/m3. No such effect was noted in monkeys or
    mice at concentrations of up to 410 g/m3 (Mullin, 1969). It was also
    found that dogs exposed to 3280 g/m3 (80% by volume; 20% oxygen
    added) for 30 seconds, followed by a loud noise (to stimulate
    endogenous adrenaline), developed cardiac sensitization (Mullin,
    1970).

         Reinhardt et al. (1971) studied the ability of HCFC 142b to
    induce cardiac sensitization to exogenous and endogenous adrenaline in
    beagle dogs. No response was noted in six animals exposed to a
    concentration of 102.5 g/m3 for 5 min and then challenged with
    adrenaline. Five out of 12 dogs exposed to 205 g/m3 showed marked
    responses (arrhythmias considered to pose a serious threat to life or
    ventricular fibrillation), and all 12 dogs exposed to 410 g/m3
    showed such responses. When a group of 12 beagle dogs was exposed to
    3280 g/m3 for 30 seconds, without injected adrenaline, one out of 12
    showed a marked response. With simultaneous noise stimulation five
    dogs showed a marked response. No dogs showed the response when
    exposed to noise alone.

         No arrhythmia or tachycardia was observed when groups of three
    Rhesus monkeys ( Macaca mulatta) were anaesthetised with sodium
    pentobarbital and exposed to 205 or 410 g/m3 for 5 min (Belej et
    al., 1974). There was no effect on pulmonary resistance or compliance
    but respiratory stimulation was observed when three anaesthetised
    Rhesus monkeys ( M. mulatta) were exposed to 205 g/m3 and four
    monkeys to 410 g/m3 for 5 min (Aviado & Smith, 1975). When dogs were
    exposed to four different concentrations between 102.5 and 820 g/m3
    for 5 min, hypotension, tachycardia, an increase in pulmonary
    resistance, and a decrease in pulmonary compliance were found at the
    highest exposure level (Belej & Aviado, 1975).

    7.8.3  HCFC 132b

         HCFC 132b was reported to produce cardiac sensitization in beagle
    dogs in response to an intravenous adrenaline challenge at exposure
    levels of 27 g/m3 or more (Mullin, 1976).

    7.8.4  HCFC 123

         Trochimowicz & Mullin (1973) reported the EC50 (concentration
    producing an effect in 50% of the test group) in dogs for cardiac
    sensitization to adrenaline challenge to be 119 g/m3 and the NOEL to
    be 62 g/m3. At the latter concentration (the lowest one tested) CNS
    depression was observed.

    7.8.5  HCFC 124

         Van Poznak & Artusio (1960) found that HCFC 124 caused
    anaesthesia in dogs at concentrations ranging from 2230 to 3910
    g/m3; blood pressure was lowered in a dose-dependent fashion.
    Although ventilation was adequate even at the highest exposure level,
    the femoral arterial systolic pressure fell to as low as 40 mmHg (5.33
    kPa). Little or no anaesthetic effect was observed at exposure levels
    that did not depress blood pressure. Atropine had little effect on
    hypotension. Phenylephrine partially reversed the hypotension and
    caused several premature ventricular contractions but no ventricular
    fibrillation. Similar effects were produced by intravenously
    administered adrenaline. Mullin (1976) reported that the NOEL of HCFC
    124 for cardiac sensitization after a challenge injection of
    adrenaline in the dog was 56 g/m3, while the next exposure level
    tested (140 g/m3) induced sensitization, as did higher
    concentrations.

    8.  EFFECTS ON HUMANS

    8.1  General population exposure

         No effects on human health of the hydrochlorofluorocarbons
    reviewed in this monograph have been reported.

    8.2  Occupational exposure

         Filicheva (1975) examined 98 male and 98 female workers, 20-40
    years of age, reportedly exposed to chlorofluorocarbons 22, 113 and
    142 and to some other chlorofluoro and fluoro compounds. The
    concentrations were claimed to exceed the threshold limit values but
    were not specified. Functional disorders of the nervous system were
    reported in 67% of the workers. These included symptoms of
    neurovegetative system disturbances, and, in a few cases, polyneuritis
    of the upper extremities. Reduced haemoglobin content, moderate
    leucocytosis and reduced erythrocyte sedimentation rate were also
    reported. Exposure levels were not given, and the workers were exposed
    to a number of chemicals in addition to HCFC 142 (isomer not
    specified). The information provided in this study could not be used
    to evaluate the potential health effects on workers exposed to HCFC
    142b alone.

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         No information is available on the effects on environmental
    organisms of the hydrochlorofluorocarbons reviewed except for limited
    data on HCFC 141b and HCFC 142b. However, an ecotoxicology programme
    is being developed within the industry-sponsored Programme for
    Alternative Fluorocarbon Toxicity Testing (Rusch, 1989).

         The 96-h LC50 of HCFC 141b for zebra fish  (Brachidario rerio)
    was reported to be 126 mg/litre in a static test using a sealed vessel
    (Bazzon & Hervouet, 1989). The 48-h EC50 for the immobilization of
     Daphnia magna, also using a sealed vessel, was 31.2 mg/litre
    (Brinard & Hervouet, 1989).

         The 96-h EC50 of HCFC 142b for guppies ( Poecilia
     reticulata), tested in a static system in accordance with OECD
    Guidelines, was reported to be 220 mg/litre (Groenevald & Kuijpers,
    1990a). Groenevald & Kuijpers (1990b) found a 48-h EC50 for  Daphnia
     magna of 160 mg/litre. No immobilization of  Daphnia magna at 190
    mg/litre in 48 h was found (Hutton & Lieder, 1989a).

         Acute toxicity values of HCFC 142b have also been determined for
    rainbow trout. The 96-h LC50 was found to be 36 mg/litre (with a 95%
    confidence interval of 28-45 mg/litre). The authors concluded that,
    under the conditions of the test, HCFC 142b exhibited moderate acute
    toxicity to rainbow trout (Hutton & Lieder, 1989b).

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

    10.1  Direct health effects

    10.1.1  HCFC 141b

         HCFC 141b has only recently become available for commercial and
    industrial use. There is no information on exposure levels for the
    general population or in the environment. Available information
    indicates a low level of metabolism of HCFC 141b. It is of low acute
    toxicity. At high sublethal exposure concentrations, it induces signs
    of CNS depression and can sensitize the heart to adrenaline, as do
    other hydrochlorofluorocarbons. Such effects can appear at
    concentrations ranging from 24 to 48 g/m3 in the inhaled air.

         HCFC 141b has low irritant potential to the eye and skin. Skin
    sensitization has not been demonstrated.

         Short-term repeated inhalation exposure (2 to 13 weeks) did not
    induce serious toxic effects at concentrations below 97 g/m3.

         Effects of HCFC 141b on reproduction cannot be evaluated until
    the data from an ongoing two-generation study become available. It has
    not demonstrated teratogenic potential in rats or rabbits, although
    embryotoxicity was observed, but only at the highest maternally toxic
    concentration (97 g/m3) in rats. The no-observed-effect level (NOEL)
    for maternal toxicity (excepting minor clinical signs) is 7 g/m3 in
    rabbits and 15 g/m3 in rats.

         Mutagenicity testing of HCFC 141b yielded conflicting results.
     In vitro studies with CHO cells indicated clastogenic potential, but
    this was not reflected in a single human lymphocyte test or two
     in vivo mouse studies.

         A carcinogenicity study in rats is in progress for HCFC 141b.

         In summary, based on the toxicological information available at
    the time of the Task Group meeting, the toxicity of HCFC 141b is
    considered to be low. The present data base does not indicate any
    significant direct health effects on humans under non-accidental
    exposure conditions. However, studies to evaluate carcinogenicity and
    reproduction are still in progress. Consequently, these study results
    and any future changes in use pattern may require further evaluation.

    10.1.2  HCFC 142b

         HCFC 142b is produced in commercial quantities for use as an
    intermediate in the synthesis of vinylidene fluoride. Its current
    release to the environment has not been quantified and no information
    is available on accidental release. No study is available which
    permits the assessment of human health responses to HCFC 142b alone.

         No information is available from  in vivo studies on metabolism
    and kinetics, but an  in vitro study suggests that dechlorination may
    occur.

         The acute toxicity is very low after oral or inhalation exposure.
    The no-observed-effect level (NOEL) for cardiac sensitization using
    exogenous adrenaline in dogs is 102.5 g/m3 for 5 min.

         In rat and dog studies, repeated inhalation exposure at
    concentrations of up to 41 g/m3 for 90 days caused no adverse
    responses. No carcinogenic or other toxicological responses were
    reported in a single long-term inhalation study in rats exposed to up
    to 82 g/m3 for 104 week.

         HCFC 142b has mutagenic potential in bacterial systems. Data from
     in vitro mammalian cell systems are lacking. No mutagenic activity
    was seen in two  in vivo rat studies.

         Although no conventional reproductive toxicity studies are
    available, two rat teratogenicity tests have been conducted in which
    neither teratogenicity nor reproducible signs of embryotoxicity were
    observed. In addition, no effect on male fertility was observed in a
    dominant lethal study in rats.

         In summary, information on human exposures is lacking, but these
    are unlikely to approach the sustained high concentrations required to
    produce adverse effects in experimental animals. Future usage
    patterns, possibly resulting in higher occupational exposure
    concentrations and exposure for shorter periods among the general
    population, may require further evaluation.

    10.1.3  HCFC 132b

         HCFC 132b is only produced in small quantities for research
    purposes but it occurs as a by-product in the manufacture of some
    halogenated ethanes. Release into the environment is expected to be
    very low. There appears to be no commercial application for HCFC 132b
    at the present time. There are no data on human exposure and on the
    effects of HCFC 132b on human health.

         Data on the metabolism of HCFC 132b are only available for rats.
    They show that the compound can be metabolized to potentially
    cytotoxic metabolites and suggest that the compound can induce its own
    metabolism. The acute toxicity of the compound is low, the predominant
    effects being central nervous system (CNS) depression, anaesthesia
    and, at high concentrations, death. The compound has low irritation
    potential to the skin and eye. HCFC 132b can sensitize the heart to
    adrenaline, as do many other hydrochlorofluorocarbons.  Repeated
    exposure to HCFC 132b has been shown to cause CNS depression, signs of
    hepatotoxicity (at concentrations of 3 g/m3 or more) and effects on
    spermatogenesis (at 11 g/m3). HCFC 132b is also embryotoxic and was

    maternally toxic at the lowest dose tested (3 g/m3). NOEL values
    have not been established for systemic toxicity or for embryotoxicity.
    The available mutagenicity studies, which are limited to a few
     in vitro experiments, did not suggest that HCFC 132b is genotoxic.
    Long-term and carcinogenicity studies have not been performed.

         In summary, from the available information, exposure to HCFC 132b
    would appear to present a hazard to human health following repeated
    exposure. Current use restricts its exposure to research personnel.
    Therefore there is no expected health risk to the general population.

    10.1.4  HCFC 133a

         HCFC 133a is produced in small quantities for use as an
    intermediate in the manufacture of the anaesthetic halothane. Although
    it has not been quantified, release into the environment is expected
    to be low.

         No data are available on the toxicokinetics of HCFC 133a,
    although absorption can be assumed to occur from the toxic effects it
    induces. It is of low acute toxicity, the principal toxic effects
    being anaesthesia and death at high concentrations. Although no
    information is available, this compound is also expected to induce
    cardiac sensitization at high concentrations. In animal studies
    repeated exposure to HCFC 133a has induced death (in mice), and nasal
    and lung damage changes in clinical chemistry parameters (in rats).
    Atrophy of the thymus, testis, ovary and spleen have also been
    reported in rats. Reduced fertility and damage to the seminiferous
    epithelium have been observed in male mice at exposure concentrations
    of 2.5 g/m3 and 5 g/m3, respectively.

         HCFC 133a has been clearly demonstrated to be embryotoxic at
    exposure concentrations that did not produce clear evidence of
    maternal toxicity (2.5 g/m3); there was also indication of a
    teratogenic potential in rats. The NOEL for embryolethality was 2.5
    g/m3.

         HCFC 133a is non-mutagenic in bacterial assays. It gave positive
    results in two out of three dominant lethal assays in mice, but these
    results are difficult to interpret in view of the negative result in
    a single rat bone-marrow cytogenetic assay. From the limited evidence
    available, HCFC 133a is a carcinogen in rats inducing adenocarcinomas
    of the uterus; it also produces benign interstitial cell tumours of
    the testis.

         In summary, from the information available, exposure to HCFC 133a
    would appear to present a hazard to human health following repeated
    exposure and has the potential to cause serious effects in developing
    offspring. In the absence of exposure information the potential risk
    cannot be determined.

    10.1.5  HCFC 123

         HCFC 123 has only recently become available for commercial and
    industrial use. There is no information on exposure levels for the
    general population or the environment.

         There is limited information on the kinetics and metabolism of
    HCFC 123. It can be absorbed, the inference coming from observed
    systemic effects and elevated urinary fluoride levels in toxicity
    studies. There is evidence for some metabolism of HCFC 123, based on
    the detection of urinary trifluoroacetic acid, elevated urinary
    fluoride levels, and the detection of covalent binding to liver
    protein.

         The acute toxicity of HCFC l23 is low. As with the fully
    halogenated chlorofluorocarbons, it is characterized in animals by CNS
    depression at high inhalation exposure concentrations. Exposure to
    high concentrations of HCFC 123 can sensitize the heart to adrenaline
    (the EC50 for dogs is 119 g/m3).

         Effects associated with short-term and long-term inhalation
    exposure to HCFC 123 in rats include CNS depression, modulation of
    lipid and carbohydrate metabolism and mild liver toxicity. The
    lowest-observed-effect level (LOEL) for lipid and carbohydrate
    metabolism effects and increased hepatic enzyme activity is 2 g/m3
    following a 1-year exposure period to HCFC 123.

         There is no evidence of teratogenicity in rats and rabbits but
    there is evidence of embryotoxicity in rabbits at high inhalation
    exposure concentrations (62 g/m3). Maternal toxicity is seen at
    exposure concentration of 3 g/m3 or more in rabbits and 31 g/m3 or
    more in rats. The potential effect of HCFC 123 on reproduction is
    being investigated in a rat study.

         There is evidence of clastogenic effects in human lymphocytes
     in vitro, although this was not supported by an  in vivo mouse
    micronucleus study. HCFC 123 is not mutagenic in microorganisms. The
    carcinogenicity of HCFC 123 is being investigated in rats and thus
    cannot be evaluated at present.

         On the basis of available information, HCFC 123 does not appear
    to exhibit marked toxicity following short-term or long-term exposure.
    However, in the light of some evidence of clastogenicity and the
    reported increased incidences of benign tumours of the testes and
    exocrine pancreas communicated in an interim report, the potential
    health effects of HCFC 123 cannot be fully evaluated until more
    information becomes available.

    10.1.6  HCFC 124

         HCFC 124 is not yet in large scale commercial production.
    Therefore, there are no data on environmental levels and human
    exposure.

         The acute toxicity of HCFC 124 is low and is characterized in
    animals by effects on the central nervous system. Subchronic toxicity
    studies in rats did not reveal any histopathological changes of
    internal organs at concentration of HCFC 124 as high as 279 g/m3.
    Based on functional observations and clinical chemistry, the NOEL was
    reported to be 28 g/m3 for male rats, and 84 g/m3 for females. In
    three limited teratogenicity studies in rats, no indication of
    developmental toxicity of HCFC 124 was evident, even at a maternally
    toxic concentration. Based on the data available from bacterial and
    mammalian cell studies there is no evidence that HCFC 124 has a
    mutagenic potential.

         The available information indicates that HCFC 124 exhibits low
    toxicity, and it is not anticipated to pose significant health risk to
    humans at potential environmental or controlled occupational
    exposures. However, a firm conclusion on the potential health risk
    cannot be made until data from the ongoing teratogenicity and
    carcinogenicity studies are available.

    10.2  Health effects expected from a depletion of stratospheric
          ozone

         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 the Environmental Health Criteria 113: Fully Halogenated
    Chlorofluorocarbons (WHO, 1990).

         The ozone-depleting potentials of five of the six HCFCs for which
    data are available are lower than that of CFC 11 by 33-77 times (HCFCs
    123 and 124), 40 times (HCFC 132b), 12-20 times (HCFC 142b), and 7-15
    times (HCFC 141b). If the levels of release of the HCFCs reviewed are
    adequately controlled their indirect health effects should not be
    significant.

    10.3  Effects on the environment

         Insufficient information is available to evaluate adequately the
    direct ecological effects posed by the hydrochlorofluorocarbons
    reviewed. With respect to the indirect "greenhouse" effect, the HCFCs
    for which data are available have global-warming potentials lower than
    that of CFC 11 by about 50 times (HCFC 123), about 10 times (HCFCs 124
    and 141b), and about 3 times (HCFC 142b). These compounds are not
    expected to contribute significantly to global warming.

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

    11.1  Conclusions

         Based on the available information the Task Group reached the
    following conclusions:

    1.   All six hydrochlorofluorocarbons reviewed have low acute
         toxicity, the main toxic signs being those of CNS depression.
         However, accidental overexposure could result in acute poisoning
         or even lethality.

    2.   These chemicals exhibit different toxicity potentials following
         repeated exposure.

    3.   HCFC 141b has a low toxic potential on repeated exposure,
         produces no consistent developmental effects and has not been
         shown to be mutagenic in animals. The mutagenic status of HCFC
         141b tested  in vitro is unclear. No information is yet
         available to evaluate chronic toxicity/carcinogenicity.

    4.   HCFC 142b also has a low toxic potential on repeated exposure.
         The small data base indicates that HCFC 142b does not produce
         developmental effects or affect male fertility. HCFC 142b is
         mutagenic in bacteria. It has not been shown to be mutagenic or
         carcinogenic in rats.

    5.   HCFC 132b is toxic following repeated exposure in animals. It
         affects development in animals, but has only been tested at
         maternally toxic doses. No study on reproduction has been
         performed, but damage to spermatogenesis has been noted
         histopathologically following repeated exposure. It is not
         mutagenic  in vitro and no test has been performed  in vivo.
         There are no data on the carcinogenic potential.

    6.   HCFC 133a is toxic following repeated exposure in animals,
         producing a range of effects. It also induces serious effects on
         reproduction and development in animals.  In vivo data regarding
         mutagenicity are unclear. It is a carcinogen in rats.

    7.   On repeated exposure, HCFC 123 induces liver toxicity and effects
         on lipid and carbohydrate metabolism in rats. Developmental
         effects only occur at high maternally toxic exposure
         concentrations. No information is available on reproduction
         effects. HCFC 123 is clastogenic  in vitro, but has not been
         shown to be clastogenic in animals. Complete information on the
         carcinogenicity in rats is not yet available.

    8.   HCFC 124 has low toxic potential on repeated exposure. Based on
         a small data base, there is no evidence of developmental effects.
         No information is available on the reproduction toxicity
         potential or carcinogenicity. It is not mutagenic  in vitro and
         no test has yet been performed  in vivo.

    9.   The hydrochlorofluorocarbons reviewed (with the exception of HCFC
         133a for which there is no value but which is expected to have a
         value similar to the others reviewed) have a lower
         ozone-depleting potential than the fully halogenated
         chlorofluorocarbons and should therefore pose a lower indirect
         health risk.

    10.  The global-warming potentials of HCFC 141b, HCFC 142b, HCFC 123
         and HCFC 124 are similarly lower than those of the fully
         halogenated chlorofluorocarbons. No data are available for HCFC
         132b or HCFC 133a, but they would be expected to have similar
         values to the other hydrochlorofluorocarbons reviewed. These
         compounds are not expected to contribute significantly to global
         warming.

    11.2  Recommendations for protection of human health and the
          environment

    1.   Since the toxicity of HCFC 142b is low, and the ozone-depleting
         and global-warming potentials are considerably lower than those
         of the fully halogenated chlorofluorocarbons, HCFC 142b 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 no risk to the environment and to develop alternative
         technologies. Care should be exercised in the use of HCFC 142b
         because of its flammability.

    2.   Since more information regarding the toxicological potential of
         HCFC 141b, HCFC 123 and HCFC 124 is required before an evaluation
         of their hazard to human health can be made, no recommendation
         can be made at present regarding their use as potential transient
         substitutes for the fully halogenated chlorofluorocarbons
         included in the Montreal Protocol.

    3.   Although HCFC 133a and HCFC 132b pose low risk to the
         environment, they are not recommended as substitutes for the
         chlorofluorocarbons included in the Montreal Protocol because of
         their toxicity.

    4.   Since all the hydrochlorofluorocarbons reviewed have some
         ozone-depleting potential, their release to the environment
         should be minimized.

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    RESUME

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

         La présente monographie porte sur six hydrochlorofluorocarbures
    (HCFC) qui dérivent de l'éthane par substitution partielle des atomes
    d'hydrogène par des atomes de fluor et de chlore. Les composés étudiés
    dans le présent rapport sont le 1,1-dichloro-1-fluoréthane (HCFC
    141b), le 1-chloro-1,1-difluoréthane (HCFC 142b), le
    1,2-dichloro-1,1-difluoréthane (HCFC 132b), le 1-chloro-2,2,2-
    trifluoréthane (HCFC 133a), le 1,1-dichloro-2,2,2-trifluoréthane (HCFC
    123) et enfin le 1-chloro-1,2,2,2-tétrafluoréthane (HCFC 124).

         A la température et sous la pression normales ces composés se
    présentent sous la forme de gaz inflammable (HCFC 142b),
    non-inflammables (HCFC 133a, HCFC 124), ou encore de liquides volatils
    ininflammables (HCFC 141b, HCFC 132b, HCFC 123). Ils sont incolores
    et, pour la majorité d'entre eux, pratiquement inodores ou dégagent
    une odeur éthérée très légère (HCFC 141b et HCFC 123). Ils sont
    légèrement ou modérément solubles dans l'eau et miscibles à de
    nombreux solvants organiques.

         Parmi les méthodes d'analyse utilisables pour le dosage de ces
    hydrochlorofluorocarbures, on peut citer la chromatographie en phase
    gazeuse avec détection par ionisation en flamme ou capture
    d'électrons. La surveillance des HCFC présents dans l'air à fortes
    concentrations peut s'effectuer par spectrophotométrie monofaisceau.

    2.  Sources d'exposition humaine et environnementale

         Autant qu'on sache, les hydrochlorofluorocarbures qui font
    l'objet de la présente monographie n'existent pas à l'état naturel.
    Comme ces composés ne sont pas préparés industriellement pour être
    utilisés en tant que tels, il n'y a guère d'exposition humaine ou
    d'émissions dans l'environnement. Certains d'entre eux pourraient être
    utilisés dans l'avenir pour remplacer les chlorofluorocarbures
    totalement halogénés (CFC 11, CFC 12 et CFC 113). Le HCFC 133a et le
    HCFC 142b servent d'intermédiaires dans la préparation d'autres
    produits fluorés.  In vivo, le HCFC 133a est un métabolite de
    l'halothane, un anesthésique.

    3.  Transport, distribution et transformation dans l'environnement

         Les données dont on dispose sur la biodégradation de ces composés
    dans l'environnement se limitent aux résultats des études consacrées
    aux HCFC 141b et 142b qui ne sont pas spontanément dégradés par les
    microorganismes. On dispose de peu d'informations sur les coefficients
    de partage octanol/eau; toutefois sous sa forme logarithmique, celui
    du HCFC 141b est de 2,3 de sorte que la bioaccumulation de cet
    hydrochlorofluorocarbure est improbable. Dans la troposphère, ces

    composés sont principalement décomposés par réaction avec les radicaux
    hydroxyles. Leur durée de séjour dans l'atmosphère (comparée à la
    durée de séjour du méthylchloroforme qui est de 6,3 ans) se situe
    entre 1,6 an (HCFC 123) et 19,1 ans (HCFC 142b). (La durée de séjour
    dans l'atmosphère du CFC 11 est de 74 ans, celle du CFC 12 de 110 ans
    et celle du CFC 13 de 90 ans.) A l'exception du HCFC 133a pour lequel
    on ne possède pas de chiffres, l'agressivité de ces composés pour la
    couche d'ozone et leur effet de serre sont inférieurs ou égaux au
    dixième de ceux du CFC 11, le chlorofluorocarbure totalement halogéné
    le plus actif à cet égard. (Le HCFC 142b dont l'effet de serre
    potentiel est environ égal au tiers de celui du CFC 11 constitue une
    exception).

    4.  Concentrations dans l'environnement et exposition humaine

         Comme le HCFC 141b, 132b, 133a, 123 et 124 ne sont pas encore
    produits à l'échelle industrielle et que le HCFC 142b n'est utilisé
    que comme intermédiaire, ces substances ne sont pas libérées dans
    l'environnement en quantité importante. On ne dispose donc d'aucune
    donnée sur leur concentration dans l'environnement ni sur l'exposition
    humaine.

    5.  Cinétique et métabolisme chez les animaux de laboratoire
        et l'homme

         Il n'existe pas de données relatives à la toxicocinétique chez
    l'homme de l'un quelconque des HCFCs étudiés.

    5.1  HCFC 141b

         Les résultats des études toxicologiques incitent à penser que
    l'absorbtion du HCFC 141b s'effectue au travers de l'épithélium
    respiratoire. Aucune donnée n'est disponible quant à la distribution
    de ce composé chez les mammifères. Des études récentes au cours
    desquelles des rats ont été soumis à une seule exposition  in vivo
    ont permis de retrouver dans les urines du 2,2-dichloro-2-fluoréthyl-
    glucuronide et de l'acide 2,2,-dichloro-2-fluoracétique.

         D'après une étude pilote portant sur l'absorption et le
    métabolisme du HCFC 141b chez des rats exposés à des vapeurs de ce
    composé, il semblerait que le HCFC 141b ne soit que très faiblement
    métabolisé.

         Une étude  in vitro a montré que le HCFC 141b subissait une
    déchloration limitée au niveau des microsomes hépatiques.

    5.2  HCFC 142b

         On ne dispose d'aucune information sur la toxicocinétique du HCFC
    142b. D'après les études toxicologiques qui ont été effectuées sur
    l'animal on peut penser que ce composé est effectivement absorbé.
    D'après une étude  in vitro, il pourrait y avoir déchloration.

    5.3  HCFC 132b

         Lors d'une étude de métabolisme au cours de laquelle on a
    administré du HCFC 132b par voie intrapéritonéale à des rats, on a
    retrouvé dans les urines du 2-chloro-2,2-difluoréthylglucuronide, du
    chlorodifluoracétaldéhyde (hydraté et conjugué) et de l'acide
    chlorodifluoracétique. Lorsqu'on répétait les injections de HCFC 132b
    aux animaux, la formation et l'excrétion d'acide chlorodifluoracétique
    s'accroissait. Des expériences  in vitro sur des microsomes de foie
    de rats ont montré qu'il y avait probablement participation du
    cytochrome P-450 IIEI à la phase initiale de l'hydroxylation. On n'a
    pas observé de signes d'une liaison covalente des métabolites fluorés
    aux protéines du foie.

    5.4  HCFC 133a

         On ne dispose d'aucune donnée sur la toxicocinétique de l'HCFC
    133a. On peut néanmoins penser, d'après les effets toxiques observés
    lors d'un certain nombre d'études après exposition des animaux, que le
    composé est effectivement absorbé.  In vitro, on a observé une
    déchloration de l'HCFC 133a.

    5.5  HCFC 123

         On ne dispose d'aucune donnée toxicocinétique sur l'HCFC 123.
    Toutefois on peut penser qu'il y a absorption d'après les effets
    généraux et les taux élevés de fluorures urinaires observés lors
    d'études toxicologiques chez le rat. On a montré que l'HCFC 123 était
    métabolisé par l'organisme du rat. On ne sait pas quelle peut être
    l'ampleur de cette métabolisation mais, à côté des fluorures, l'acide
    trifluoracétique (TFA) apparaît comme un des principaux métabolites
    urinaires. On a mis en évidence dans le cas du HCFC 123 une liaison
    covalente aux protéines du foie.

    5.6  HCFC 124

         On ne dispose d'aucune donnée sur la cinétique et le métabolisme
    de l'HCFC 124. On peut penser, d'après les résultats des études
    toxicologiques par inhalation, qu'il y a absorption de ce composé au
    niveau des voies respiratoires.

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

    6.1  HCFC 141b

         Le HCFC 141b présente une faible toxicité aiguë par voie orale.
    Après administration de cette substance à des rats à raison de 5 g/kg,
    on n'a observé aucun signe de toxicité.

         Des études d'inhalation effectuées sur des rats et des souris ont
    montré qu'il y avait dépression du système nerveux central, anesthésie
    et mort en cas d'exposition intense. On n'a pas observé d'effets
    macroscopiques ou histopathologiques imputables au traitement. Dans
    une étude, on fait état d'une CL50 à 4 h chez le rat égale à 295
    g/m3 et dans une autre étude, d'une CL50 à 2 h chez la souris
    égale à 150 g/m3. Chez le rat, la concentration la plus faible
    entraînant la mort serait de 242 g/m3 sur 6 h.

         Après exposition cutanée (à raison de 2 g/kg) de rats ou de
    lapins on n'a pas observé de mortalité.

         Lors d'études d'inhalation à court terme où l'exposition allait
    de 10 à 97 g/m3 et durait jusqu'à 90 jours, on n'a pas observé
    d'effets toxiques marqués. Les effets observés consistaient en une
    réduction du gain de poids, "de légères modifications biochimiques",
    et une dépression du système nerveux central. L'étude de 90 jours n'a
    pas permis de dégager une valeur pour la dose sans effet observable.

         Le HCFC 141b n'a pas produit de signes d'irritation cutanée chez
    des lapins ni d'irritation oculaire lors de l'une des deux études
    effectuées. Dans la seconde étude, on a observé une légère réaction
    d'irritation au niveau de l'oeil. Aucune sensibilisation cutanée n'a
    été relevée chez des cobayes.

         Une étude de reproduction portant sur deux générations est
    actuellement en cours. Les études relatives au développement de
    l'embryon font ressortir un accroissement de l'incidence des oedèmes
    sous-cutanés et des hémorragies chez les foetus ainsi que des cas de
    mort embryonnaire, mais ce, uniquement à la concentration de 97 g/m3
    chez le rat, concentration par ailleurs toxique pour la mère. Aucun
    effet tératogène n'a été observé. Lors d'une étude sur des lapins,
    aucun effet imputable au traitement n'a été observé sur le
    développement des embryons ou des foetus.

         Le HCFC 141b ne s'est pas révélé mutagène lors d'une épreuve de
    réparation de l'ADN bactérien, en revanche il a produit des résultats
    contradictoires lors d'autres épreuves de mutation chez des bactéries.
    L'épreuve du locus  hprt n'a pas permis de relever d'effets sur les
    cellules V79. Des aberrations chromosomiques ont été observées après
    traitement  in vitro de cellules ovariennes d'hamsters chinois, mais
    ce phénomène n'a pas été observé lors d'une étude  in vitro sur des

    lymphocytes humains. Chez la souris, deux épreuves  in vivo en vue de
    mettre en évidence la formation de micronoyaux se sont révélées
    négatives.

         Une étude combinée de toxicité et cancérogénicité par inhalation
    chronique est en cours sur des rats.

         Le HCFC 141b est capable de provoquer une sensibilisation
    cardiaque à l'adrénaline exogène chez le chien. Les concentrations de
    HCFC 141b les plus faibles qui produisent des réponses sont
    respectivement de 24 et de 48 g/m3 chez le chien et le singe.

    6.2  HCFC 142b

         Après avoir été administré par voie orale, le HCFC 142b n'a
    produit que de légers signes de toxicité chez des rats en dose unique
    allant jusqu'à 5 g/kg.

         Des rats exposés une seule fois par inhalation à 525 g/m3 de
    HCFC 142b pendant 4 heures ont présenté une mortalité d'environ 50%.
    D'après d'autres études comportant une exposition plus courte, on
    évalue la CL50 à plus de 1000 g/m3.

         Des études au cours desquelles on a fait respirer à plusieurs
    reprises du HCFC 142b à des rats n'ont pas révélé d'effets
    indésirables à une concentration de 41 g/m3 (6 heures par jour, 5
    jours par semaine pendant 90 jours). En revanche, lorsque la dose
    était beaucoup plus élevée, on a observé une très forte irritation
    pulmonaire entraînant la mort.

         Il ne semble pas que des études aient été consacrées à
    l'irritation cutanée ou oculaire ou à la sensibilisation cutanée par
    le HCFC 142b. Des études de sensibilisation cardiaque à l'adrénaline
    exogène ont été effectuées sur des souris, des chiens et des singes.
    Ce sont les chiens qui étaient les plus sensibles; la dose sans effet
    observable était de 102,5 g/m3 pour une exposition de 5 minutes et
    une dose de 205 g/m3 (également pendant 5 minutes) a provoqué une
    arythmie.

         Une seule étude à long terme a été rapportée, au cours de
    laquelle des rats (130 mâles et 110 femelles par groupe) ont été
    exposés à du HCFC 142b aux doses respectives de 4, 41 et 82 g/m3, 6
    heures par jour, 5 jours par semaine pendant des périodes pouvant
    atteindre 104 semaines. Aucun effet imputable au traitement n'a été
    observé en ce qui concerne la NFS, la biochimie du sang et des urines
    et l'histopathologie. Aucune modification imputable au traitement n'a
    été observée dans l'incidence tumorale.

         Aucune étude classique n'a été consacrée aux effets du HCFC 142b
    sur la reproduction, toutefois, une étude de létalité dominante n'a
    fait ressortir aucun effet sur la fertilité des mâles. Deux études de

    tératogénicité ont été effectuées sur des rats. Dans la première, des
    rats Sprague-Dawley ont été exposés respectivement à 4 et 41 g/m3 (6
    heures par jour du troisième au quinzième jour de la grossesse), alors
    que dans l'autre étude, des rats de la même espèce ont été exposés
    respectivement à 13 et 39 g/m3 (6 heures par jour du sixième au
    quinzième jour de la grossesse). Aucun effet tératogène n'a été noté.
    On a observé une réduction de l'ossification chez un petit nombre de
    foetus à ces deux doses lors de cette dernière étude mais pas dans la
    première.

         Le HCFC 142b produit des mutations chez les bactéries mais on ne
    dispose pas de données tirées d'épreuves de génotoxicité sur des
    cellules mammaliennes en culture. Les tests  in vivo qui ont été
    pratiqués ne font ressortir aucune augmentation du nombre
    d'aberrations chromosomiques dans la moelle osseuse ni d'effets létaux
    dominants chez les rats mâles.

    6.3  HCFC 132b

         Chez le rat, la toxicité aiguë par voie orale du HCFC 132b est
    faible. La dose la plus faible à laquelle on ait observé une mortalité
    était égale à 25 g/kg. Après administration par voie orale à raison de
    2 g/kg, on a observé une dépression du système nerveux autonome et du
    système nerveux central, accompagnée d'effets sur la coordination et
    l'activité motrice ainsi que sur le tonus musculaire. Chez les mâles,
    on a observé une hypertrophie du foie dont le poids était cependant
    diminué.

         Lorsqu'il est inhalé à fortes doses, le HCFC 132b détermine des
    effets aigus caractérisés par une anesthésie. La dose la plus faible
    à laquelle on ait observé une mortalité chez des rats exposés de cette
    manière pendant 4 heures à du HCFC 132b était égale à 110 g/m3. Chez
    la souris, la CL50 à 30 minutes était de 269 g/m3 et l'anesthésie
    s'est produite dès 71 g/m3. Dans une étude, on a observé une
    réduction du poids des testicules et une augmentation de celui du foie
    et des poumons chez les rats mâles après exposition à une dose de 33
    g/m3 pendant 6 heures.

         L'application cutanée de HCFC 132b à raison de 2 g/kg à des rats
    a fait apparaître les signes cliniques d'une action au niveau du
    système nerveux central et produit une hypertrophie hépatique chez
    certains des animaux. Non dilué, le composé a provoqué une "légère"
    irritation de la peau chez des cobayes et une irritation oculaire
    "légère à modérée" chez des lapins. On n'a pas pu mettre en évidence
    de sensibilisation cutanée chez les cobayes. A partir de 27 g/m3 on
    a observé, chez des chiens exposés au HCFC 132b par voie respiratoire,
    une sensibilisation cardiaque à l'adrénaline.

         A côté de la dépression du système nerveux central, les
    principales conséquences d'une inhalation de brève durée de HCFC 132b
    par des rats mâles ont été une atrophie du thymus et des effets sur la

    spermatogénèse. Après un traitement de 13 semaines à raison de 3
    g/m3 on a observé une interruption de la spermatogénèse. Parmi les
    autres effets on pouvait noter une prolifération des canaux biliaires
    et un accroissement du rapport poids du foie/poids du corps chez les
    mâles, même à la dose la plus faible employée (3 g/m3). Les rattes
    ont paru moins sensibles que les rats aux effets hépatiques.

         Le HCFC 132b a déterminé des réactions d'embryotoxicité chez des
    rats après exposition par la voie respiratoire à des doses allant de
    3 à 28 g/m3 du sixième au quinzième jour de la gestation. On a
    observé un accroissement du nombre de résorptions (aux doses de 11 et
    28 g/m3) et une diminution du poids des foetus à toutes les doses.
    Toutes les doses utilisées étaient toxiques pour la mère.

         En se fondant sur les données limitées dont on dispose, on peut
    dire qu'il n'existe aucune preuve d'une mutagénicité  in vitro du
    HCFC 132b. La cancérogénicité de ce produit n'a pas été étudiée.

    6.4  HCFC 133a

         Il n'existe pas de données sur la toxicité aiguë par voie orale
    du HCFC 133a. Par inhalation, sa toxicité aiguë est faible (la CL50
    à 30 minutes chez la souris est de 738 g/m3) et ses principaux
    effets toxiques sont ceux d'une anesthésie. On ne dispose d'aucune
    donnée sur la sensibilisation cutanée ou cardiaque ni sur l'irritation
    de la peau ou des yeux.

         L'exposition réitérée (90 jours) de rats à la dose de 49 g/m3
    a produit une inflammation chronique des fosses nasales, un emphysème
    et un oedème pulmonaire, une bronchite et une pneumopathie. On a
    également observé une atrophie du thymus, des testicules, des ovaires
    et de la rate. Aucun effet n'a été observé chez des rats et des chiens
    exposés à plusieurs reprises à du HCFC 133a pendant 7 jours (rats) ou
    90 jours (chiens) à une concentration d'environ 25 g/m3; cependant
    une mortalité a été observée chez des souris exposées pendant cinq
    jours à une dose de 0,5 g/m3 ou davantage (sauf 2,5 g/m3).

         Bien qu'aucune étude de type classique n'ait été consacrée aux
    effets du HCFC 133a sur la reproduction, on a observé, au cours de
    trois études de létalité dominante chez des souris, un certain nombre
    d'effets sur la fertilité des mâles et l'histologie des testicules.
    L'exposition à des concentrations de 2,5 g/m3 ou davantage pendant
    cinq jours a entraîné une diminution du nombre de souris gravides et
    une augmentation de la proportion des spermatozoïdes anormaux, tandis
    qu'une exposition à la concentration de 5 g/m3 provoquait des
    lésions histopathologiques de l'épithélium des tubes séminifères.

         Des études sur des rats (traités du sixième au seizième jour de
    la gestation), à des concentrations qui ne produisaient que de légers
    signes de toxicité maternelle, ont montré que le HCFC 133a est
    embryotoxique aux concentrations supérieures ou égales à 2 g/m3 et

    mortel pour l'embryon à partir de 10 g/m3. Une prémédication des
    femelles gravides par la progestérone n'a pas eu d'effet sur les
    effets embryotoxiques ou létaux. Une autre étude a permis de relever
    les indices d'effets tératogènes (anomalies externes des membres et de
    la queue). Le HCFC 133a a produit des avortements spontanés et s'est
    révélé absolument mortel pour les embryons après exposition de lapines
    gravides à la dose de 25 g/m3 du septième au dix-neuvième jour de la
    gestation, alors que cette concentration ne produisait que de légers
    signes de toxicité maternelle.

         D'après les résultats disponibles, rien n'indique que ce composé
    soit mutagène chez la bactérie. Une étude, portant sur des cellules de
    reins de hamsters n'a pas permis de mettre en évidence d'augmentation
    dans la proportion des cellules produisant des colonies transformées.
    Sur trois études de mutagénicité, deux ont fait ressortir l'existence
    d'effets létaux dominants après exposition de souris mâles à 12 g/m3
    ou davantage pendant cinq jours. La proportion des cellules de moelle
    osseuse porteuses d'aberrations chromosomiques n'était pas augmentée
    chez les rats exposés à 98 g/m3 (6 heures par jour pendant des
    durées allant jusqu'à 5 jours). La seule étude de cancérogénicité qui
    ait été effectuée a permis de mettre en évidence une augmentation de
    l'incidence des adénocarcinomes de l'utérus et des tumeurs du tissu
    interstitiel des testicules chez des rats ayant reçu 300 mg/kg de
    composé dans de l'huile de maïs par gavage pendant 52 semaines (après
    quoi ils ont été placés en observation pendant 73 semaines).

    6.5  HCFC 123

         Le HCFC 123 présente une faible toxicité aiguë par voie orale et
    cutanée. La dose orale la plus faible qui soit mortelle pour le rat
    est de 9 g/kg. Administré à raison de 2 g/kg à des rats ou à des
    lapins, ce composé n'a entraîné aucune mortalité.

         Par la voie respiratoire, le HCFC 123 est également peu toxique.
    Ses effets sont analogues à ceux des chlorofluorocarbures,
    c'est-à-dire une perte de coordination et une narcose. La CL50 à 4
    h est de 178 g/m3 chez le hamster, de 463 g/m3 chez la souris et
    varie de 200 à 329 g/m3 chez le rat. Chez le chien, on a obtenu une
    sensibilisation cardiaque à des doses supérieures ou égales à 119
    g/m3 après une injection d'épreuve d'adrénaline. Le HCFC 123 liquide
    provoque une "légère" irritation de la peau et de l'oeil chez le
    lapin. Chez le cobaye, il ne provoque pas de sensibilisation cutanée.

         Plusieurs études toxicologiques à court terme ont été effectuées
    sur le HCFC 123 en utilisant la voie respiratoire. On observe
    systématiquement des signes de dépression du système nerveux central
    chez le rat à des concentrations de 31 g/m3 ou davantage. On a
    également observé certains effets sur le foie de ces animaux. Une
    exposition de longue durée (4 semaines ou davantage) au HCFC 123
    affecte également le métabolisme des lipides et des glucides comme le
    montre la réduction systématique des triglycérides, du cholestérol et

    du glucose sériques chez les rats. D'après les résultats provisoires
    d'une étude en cours sur la toxicité et l'oncogénicité de ce composé,
    il apparaît qu'il exerce un certain nombre d'effets sur des rats
    exposés pendant de longues durées à des doses de 2,6 ou de 31 g/m3.
    Les effets observés, perturbation du métabolisme lipidique et
    accroissement de l'activité des peroxysomes hépatiques, ont servi de
    base à l'établissement de la dose sans effet observable, dont la
    valeur n'est toutefois pas mentionnée.

         Une étude de reproduction portant sur deux générations de rats
    exposés par la voie respiratoire à du HCFC 123 est en cours. Deux
    autres études de portée limitée n'ont pas permis de mettre en évidence
    d'effets embryotoxiques sur des rats à des concentrations qui étaient
    légèrement toxiques pour la mère. Les seuls signes d'embryotoxicité
    relevés l'ont été chez des lapins et, là encore, seulement lorsque les
    concentrations étaient fortement toxiques pour les lapines gravides
    (plus de 62,5 g/m3). Cette toxicité maternelle (réduction du poids,
    dépression du système nerveux central) s'observe chez des rattes
    exposées à des doses supérieures ou égales à 31 g/m3 et chez des
    lapines à partir de 3 g/m3. Aucun signe de tératogénicité n'a été
    relevé, ni chez les rats ni chez les lapins.

         Le HCFC 123 ne paraît avoir aucune activité mutagène sur les
    bactéries ou les levures. Toutefois des signes d'une activité
    clastogène ont été observés dans des lymphocytes humains  in vitro,
    encore que cette observation ne soit pas corroborée par les résultats
    d'une étude  in vivo portant sur la présence de micronoyaux dans des
    cellules murines.

         Une étude combinée de toxicité et de cancérogénicité par
    inhalation chronique de HCFC 123 est en cours sur des rats. Une
    communication préliminaire fait état d'une augmentation de l'incidence
    des tumeurs bénignes au niveau des testicules et du pancréas exocrine
    chez les rats mâles. Toutefois, on ne pourra pas évaluer la
    cancérogénicité potentielle du HCFC 123 avant de disposer de
    l'ensemble des résultats.

    6.6  HCFC 124

         Chez l'animal, le HCFC 124 n'a qu'une faible toxicité aiguë par
    la voie respiratoire. Une mortalité a été observée chez des rats à la
    dose de 1674 g/m3 (exposition de 240 minutes) et chez des souris à
    la dose de 2460 g/m3 (exposition de 10 minutes). Les effets observés
    sont caractéristiques des chlorofluorocarbures, c'est-à-dire perte de
    coordination et narcose. A des doses supérieures ou égales à 140
    g/m3, on a observé chez des chiens une sensibilisation cardiaque
    après une injection d'épreuve d'adrénaline. On ne dispose d'aucune
    donnée sur l'irritation oculaire ni sur l'irritation ou la
    sensibilisation cutanée que ce composé pourrait provoquer.

         Cinq expériences ont permis d'étudier la toxicité à court terme
    de ce composé lorsqu'il est inhalé par des rats pendant des périodes
    de 14 à 90 jours. Aux doses les plus fortes étudiées (500 g/m3 sur
    14 jours et 279 g/m3 sur 90 jours) on n'a observé aucune
    modification histopathologique au niveau des organes. Une dose sans
    effet observable de 28 g/m3 a été établie d'après les résultats
    concernant les troubles fonctionnels et la biochimie sanguine, fournis
    par l'étude de 90 jours.

         Une étude toxicologique à long terme utilisant la voie
    drespiratoire est en cours sur le HCFC 124.

         Lors de trois études de tératogénicité de portée limitée
    effectuées sur des rats, au cours desquelles on a fait inhaler du HCFC
    124 à raison de 30 g/m3 ou à des doses allant de 3 à 279 g/m3, on
    n'a pas relevé de signes d'embryotoxicité ni de tératogénicité. Des
    signes d'intoxication maternelle étaient visibles dès 84 g/m3. On ne
    dispose d'aucune donnée sur les effets que le HCFC 124 pourrait
    exercer sur la fonction de reproduction. Des études de tératogénicité
    complètes sont en cours.

         Les données fournies par un certain nombre d'études sur des
    bactéries ainsi que par une seule et unique étude portant sur des
    cellules mammaliennes, n'attribuent aucun pouvoir mutagène au HCFC
    124. Une étude de cancérogénicité utilisant la voie respiratoire est
    en cours.

    7.  Effets sur l'homme

         On ne dispose d'aucune donnée sur les effets que le HCFC 141b, le
    HCFC 132b, le HCFC 133a, le HCFC 123 ou le HCFC 124 pourraient exercer
    sur l'homme.

         Les données fournies par une seule et unique étude consacrée à
    des personnes exposées de par leur profession au HCFC 142b ne
    permettent pas d'évaluer les effets de ce composé indépendamment des
    autres types d'exposition auxquelles ces personnes avaient été
    soumises.

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

         On ne dispose d'aucune donnée sur les effets que les
    hydrochlorofluorocarbures en cause pourraient avoir sur les êtres
    vivants dans leur milieu naturel, si ce n'est quelques données
    concernant le HCFC 141b et le HCFC 142b. La CL50 à 96 h du HCFC 141b
    pour les poissons de l'espèce  Melambaphes zebra est de 126 mg/litre
    et la CL50 à 48 h pour l'immobilisation de la daphnie est de 31
    mg/litre. Ces deux observations ont été faites dans des aquariums
    clos. Dans le cas du HCFC 142b, la CE50 à 96 h pour le guppy est 220
    mg/litre alors que la CL50 à 48 h pour l'immobilisation de la

    daphnie varie de 160 à < de 190 mg/litre. La CL50 à 96 h du HCFC
    142b pour la truite arc-en-ciel est de 36 mg/litre.

    9.  Evaluation et conclusions

         On ignore qu'elle est la concentration dans l'environnement des
    six HCFC étudiés mais, compte tenu de leurs modalités actuelles
    d'utilisation, on peut penser qu'elle est faible.

         Le HCFC 142b ne présente qu'une faible toxicité potentielle et
    l'on estime qu'il ne constitue pas un risque important pour la santé
    humaine lorsqu'il n'y a pas d'exposition accidentelle. Les données
    toxicologiques concernant le HCFC 141b, le HCFC 123 et le HCFC 124
    sont incomplètes et il faudra en obtenir davantage avant qu'on puisse
    évaluer les dangers qu'ils représentent pour la santé humaine. En
    revanche le HCFC 133a et le HCFC 132b sont dangereux pour la santé.

         Par rapport aux chlorofluorocarbures complètement halogénés, ces
    six hydrochlorofluorocarbures sont ou devraient être beaucoup moins
    agressifs vis-à-vis de la couche d'ozone et leur temps de séjour dans
    l'atmosphère est beaucoup plus faible. Ils constituent donc un risque
    indirect. Leur contribution potentielle à l'effet de serre est ou
    devrait également être plus faible que celle des chlorofluorocarbures
    complètement halogénés et ils ne devraient donc pas contribuer de
    façon sensible au réchauffement de la planète.

         Etant donné que la toxicité du HCFC 142b est faible et qu'il est
    moins agressif vis-à-vis de la couche d'ozone et contribue moins à
    l'effet de serre que les chlorofluorocarbures complètement halogénés,
    on peut considérer qu'il est susceptible d'être provisoirement
    substitué aux chlorofluorocarbures visés par le Protocole de Montréal.

         Aucune recommandation ne peut être faite concernant le HCFC 141b,
    le HCFC 123 ou le HCFC 124 tant qu'on ne disposera pas de données
    toxicologiques plus complètes. Bien que le HCFC 133a et le HCFC 132b
    ne menacent guère l'environnement et que les risques qu'ils
    constituent pour la santé ne soient qu'indirects, il n'est pas
    recommandé de les substituer aux chlorofluorocarbures visés par le
    Protocole de Montréal en raison de leur toxicité potentielle.

    RESUMEN

    1.  Identidad, propiedades físicas y químicas y métodos analíticos

         La presente monografía se ocupa de seis hidroclorofluorocarburos
    (HCFCs) derivados de la sustitución parcial de los átomos de hidrógeno
    del etano por átomos de flúor y de cloro. En este informe se estudian
    los siguientes compuestos: 1,1-dicloro-1-fluoroetano (HCFC 141b),
    1-cloro-1,1-difluoroetano (HCFC 142b), 1,2-dicloro-1,1-difluoroetano
    (HCFC 132b), 1-cloro-2,2,2-trifluoroetano (HCFC 133a),
    1,1-dicloro-2,2,2-trifluoroetano (HCFC 123) y
    1-cloro-1,2,2,2-tetrafluoroetano (HCFC 124).

         En condiciones normales de presión y temperatura, estos
    compuestos son gases inflamables (HCFC 142b) o ininflamables (HCFC
    133a, HCFC 124) o líquidos volátiles ininflamables (HCFC 141b, HCFC
    132b, HCFC 123). Son incoloros y la mayoría prácticamente inodoros o
    con un débil olor a éter (HCFC 141b y HCFC 123). Su solubilidad en
    agua es escasa o moderada y son miscibles con muchos disolventes
    orgánicos.

         Entre los métodos analíticos utilizados para la determinación de
    estos hidroclorofluorocarburos figuran la cromatografía de gases con
    ionización de llama y la detección con captura de electrones. Se
    pueden medir concentraciones relativamente altas en el aire mediante
    fotometría de un solo haz.

    2.  Fuentes de exposición humana y ambiental

         Los hidroclorofluorocarburos que se estudian en la presente
    monografía no se conocen como productos naturales. Dado que estos
    compuestos no se producen comercialmente en gran escala para
    utilizarlos como tales, la exposición humana o la liberación al medio
    ambiente son muy pequeñas. Algunos de estos compuestos se podrían
    utilizar en el futuro como sustitutivos de clorofluorocarburos
    completamente halogenados (por ejemplo, CFC 11, CFC 12 y CFC 113). Los
    HCFCs 133a y 142b son compuestos intermedios en la fabricación de
    otros productos fluorados. El HCFC 133a es un metabolito  in vivo del
    anestésico halotano.

    3.  Transporte, distribución y transformación en el medio ambiente

         Los datos sobre la biodegradación en el medio ambiente se limitan
    a unos estudios sobre los HCFCs 141b y 142b, que han demostrado no ser
    fácilmente biodegradables por los microorganismos. Apenas se dispone
    de información sobre los logaritmos de los coeficientes de reparto
    octanol/agua; en el caso del HCFC 141b es 2,3, por lo que no es
    probable que se bioacumule. En la troposfera, estas sustancias se
    descomponen principalmente por reacciones con radicales hidroxilo. Su
    permanencia en la atmósfera (en relación con los 6,3 años de
    permanencia del metilcloroformo) oscila entre 1,6 años (HCFC 123) y

    19,1 años (HCFC 142b). (La permanencia en la atmósfera del CFC 11 es
    de 75 años, la del CFC 12 de 110 y la del CFC 113 de 90). A excepción
    del HCFC 133a, del que no se tienen datos, su contribución potencial
    a la destrucción de ozono y al calentamiento del planeta es inferior
    o igual al 10 por ciento de la del CFC 11, el clorofluorocarburo
    completamente halogenado con la mayor influencia potencial en esos
    fenómenos (el HCFC 142b, cuya contribución al calentanierto del
    planeta es aproximadamente un tercio de la del CFC 11, es una
    excepción).

    4.  Niveles ambientales y exposición humana

         Como los HCFCs 141b, 132b, 133a, 123 y 124 no se producen todavía
    comercialmente en gran escala y el HCFC 142b se utiliza sólo como
    producto intermedio, no se libera al medio ambiente en cantidades
    apreciables. No se dispone, por consiguiente, de datos sobre los
    niveles ambientales ni la exposición humana.

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

         No hay datos acerca de la toxicocinética en el ser humano de
    ninguno de los HCFCs examinados.

    5.1  HCFC 141b

         Los resultados obtenidos de los estudios de toxicidad sugieren
    que la absorción del HCFC 141b tiene lugar a través del epitelio
    respiratorio. No se dispone de información acerca de su distribución
    en mamíferos. En estudios recientes de exposición única  in vitro
    en ratas se detectaron en la orina 2,2-dicloro-2-fluoroetilglucurónido
    y ácido 2,2-dicloro-2-fluoroacético. En un estudio piloto sobre la
    absorción y el metabolismo del HCFC 141b en ratas expuestas a sus
    vapores se puso de manifiesto que sólo se produce transformación
    metabólica en muy pequeña medida.

         Un estudio  in vitro indicó que los microsomas hepáticos
    decloran el HCFC 141b en grado limitado.

    5.2  HCFC 142b

         No se dispone de información sobre la toxicocinética del HCFC
    142b. De los estudios de toxicidad en animales se deduce que se
    produce absorción. Un estudio  in vitro sugirió que puede producirse
    decloración.

    5.3  HCFC 132b

         En un estudio de metabolismo con administración intraperitoneal
    de HCFC 132b a ratas se detectaron en la orina 2-cloro-2,2-
    difluoroetilglucurónido, clorodifluoroacetaldehído (hidratado y

    conjugado) y ácido clorodifluoroacético. La formación y excreción de
    este último aumentó al volver a inyectar a los animales HCFC 132b. 
    Los experimentos  in vitro con microsomas hepáticos de rata sugieren
    la participación del citocromo P-450 IIEI en el paso inicial de
    hidroxilación. No hay pruebas experimentales de la unión covalente de
    metabolitos fluorados a las proteínas hepáticas.

    5.4  HCFC 133a

         Se carece de información sobre la toxicocinética del HCFC 133a.
    De los efectos tóxicos observados en diversos estudios puede deducirse
    que se produce absorción tras la exposición de animales. Se ha
    advertido  in vitro la decloración del HCFC 133a.

    5.5  HCFC 123

         No hay datos acerca de la toxicocinética del HCFC 123. Sin
    embargo, de los efectos sistémicos y de los elevados niveles de flúor
    en la orina observados en los estudios de toxicidad en ratas se puede
    deducir que hay absorción. Se ha demostrado que el HCFC 123
    experimenta una transformación metabólica en ratas. No se conoce el
    alcance del metabolismo, pero se ha identificado el ácido
    trifluoroacético (TFA) como principal metabolito urinario, además del
    fluoruro. Se ha demostrado que el HCFC 123 forma enlaces covalentes
    con las proteínas hepáticas.

    5.6  HCFC 124

         Se carece de datos acerca de la cinética y el metabolismo del
    HCFC 124. De los estudios de toxicidad por inhalación se puede deducir
    que la absorción del HCFC 124 se produce en el tracto respiratorio.

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

    6.1  HCFC 141b

         La toxicidad aguda del HCFC 141b por vía oral es baja. No se
    observaron signos de toxicidad tras suministrar a ratas dosis de 5
    g/kg.

         En estudios de inhalación aguda en ratas y ratones, con altos
    niveles de exposición se observó depresión del sistema nervioso
    central, anestesia y muerte. No se advirtieron efectos macroscópicos
    o histopatológicos relacionados con el tratamiento. En un estudio, la
    CL50 a las 4 h en ratas fue de 295 g/m3, y en otro estudio en
    ratones la CL50 a las 2 h fue de 151 g/m3. Se informó que la
    concentración letal más baja en ratas era de 242 g/m3 en 6 h.

         Tras la exposición cutánea a 2 g/kg no se observó mortalidad en
    ratas ni en conejos.

         En estudios de inhalación de corta duración con exposiciones que
    oscilaron entre 10 y 97 g/m3 y que se prolongaron hasta 90 días no
    se advirtió toxicidad pronunciada. Entre otros efectos, se observó
    menor aumento del peso corporal, "ligeros cambios bioquímicos" y
    depresión del sistema nervioso central. En los 90 días del estudio no
    se alcanzó un nivel sin efecto observado.

         El HCFC 141b no produjo signos de irritación cutánea en conejos,
    ni de irritación ocular en uno de los dos estudios realizados. En el
    segundo estudio se observó una respuesta de irritación ocular
    "ligera". No se advirtió sensibilización cutánea en cobayos.

         Actualmente hay un estudio en curso acerca del efecto del HCFC
    141b sobre la reproducción en dos generaciones. En estudios sobre el
    desarrollo se observaron frecuencias superiores de edema subcutáneo y
    hemorragias en los fetos y de muerte de embriones, pero sólo con la
    concentración tóxica para la madre de 97 g/m3 en un estudio en
    ratas. No se observaron efectos teratogénicos. En un estudio con
    conejos no se advirtieron efectos en el desarrollo embrionario o fetal
    a causa del tratamiento.

         El HCFC 141b no resultó mutagénico en un ensayo de reparación del
    ADN bacteriano y los resultados fueron contradictorios en otras
    pruebas de mutación de bacterias. No tuvo ningún efecto sobre las
    células V79 en el ensayo sobre el locus  hprt. Se detectaron
    aberraciones cromosómicas tras el tratamiento  in vitro de células de
    ovario de hámster chino, pero no aparecieron en un estudio  in vitro
    con linfocitos humanos. También fueron negativos dos ensayos  in vivo
    efectuados con micronúcleos de ratones.

         Está en marcha un estudio combinado de toxicidad crónica por
    inhalación/carcinogenicidad en ratas.

         El HCFC 141b muestra en perros un efecto potencial de
    sensibilización cardíaca a la adrenalina exógena. Las concentraciones
    más bajas de HCFC 141b que indujeron respuesta en perros y monos
    fueron respectivamente de 24 y 48 g/m3.

    6.2  HCFC 142b

         El HCFC 142b administrado por vía oral a dosis únicas de hasta 5
    g/kg sólo produjo signos leves de toxicidad en ratas.

         La exposición de ratas a una inhalación única de 525 g/m3
    durante 4 h produjo la muerte de alrededor del 50% de los animales. En
    otros estudios con exposiciones de menor duración se obtuvieron
    valores de la CL50 superiores a 1000 g/m3.

         En los estudios de exposiciones repetidas por inhalación en ratas
    con dosis de 41 g/m3 (6 h/día, 5 días a la semana durante 90 días)
    no se observaron respuestos adversas. Con dosis mucho más elevadas se

    producía la muerte de las ratas relacionada con una irritación
    pulmonar grave.

         No se han comunicado estudios sobre el HCFC 142b en relación con
    la irritación cutánea u ocular o la sensibilización cutánea. Se
    realizaron experimentos de sensibilización cardíaca (utilizando
    adrenalina exógena) en ratones, perros y monos. Los perros fueron los
    más sensibles; el NOEL fue de 102,5 g/m3 con una exposición de 5
    minutos, mientras que 205 g/m3 (también con 5 minutos de exposición)
    inducían arritmia cardíaca.

         Sólo hay datos de un estudio prolongado, en el que se expusieron
    ratas (130 machos y 110 hembras por grupo) a concentraciones de HCFC
    142b de 4, 41 y 82 g/m3, 6 h/día, 5 días/semana, hasta un máximo de
    104 semanas. No se observaron efectos relacionados con el tratamiento
    en ninguno de los parámetros estudiados, que comprendían hematología,
    química sanguínea y urinaria e histopatología. No se notificaron
    cambios de importancia dependientes del tratamiento en relación con la
    aparición de tumores.

         No se han hecho estudios convencionales sobre el efecto del HCFC
    142b en la reproducción, pero en un estudio de letalidad dominante no
    se observaron efectos en la fertilidad de los machos. Se han realizado
    dos pruebas de teratogenicidad en ratas. En una de éstas, se expuso a
    ratas Sprague-Dawley a concentraciones de 4 y 41 g/m3 (6 h/día desde
    el 3 al 15 día de gestación), mientras que en el otro estudio se
    expuso a ratas Sprague-Dawley a 13 y 39 g/m3 (6 h/día del 6 al 15
    día de gestación). No se observaron efectos teratogénicos. En el
    segundo estudio se advirtió para ambas dosis osificación reducida en
    un pequeño número de fetos, pero no en el primero.

         El HCFC 142b induce mutaciones en bacterias, pero no se dispone
    de datos de ensayos de genotoxicidad en cultivos de células de
    mamíferos. En los ensayos  in vivo no se produjo aumento de las
    aberraciones cromosómicas en la médula ósea ni efectos letales
    dominantes en las ratas machos.

    6.3  HCFC 132b

         La toxicidad aguda oral del HCFC 132b en la rata es escasa. La
    dosis más baja a la que se ha observado mortalidad es 25 g/kg. Tras la
    administración oral de 2 g/kg se advirtió una depresión del sistema
    nervioso autónomo y del central, además de otros efectos en la
    coordinación motora, la actividad motora y el tono muscular. En los
    machos se advirtieron inflamación hepática y disminución del peso del
    hígado.

         La toxicidad aguda por inhalación del HCFC 132b con niveles de
    exposición elevados se caracteriza por un efecto anestésico. La dosis
    más baja que produjo mortalidad en ratas tras 4 horas de exposición
    fue de 110 g/m3. En ratones, la CL50 en 30 minutos de exposición

    fue de 269 g/m3, y se produjo anestesia con 71 g/m3. En un estudio
    se advirtió una disminución del peso de los testículos y un aumento
    del peso del hígado y los pulmones en ratas macho tras la exposición
    a 33 g/m3 durante 6 horas.

         La aplicación cutánea de HCFC 132b a ratas se tradujo en algunos
    animales en síntomas clínicos de efectos en el SNC e inflamación
    hepática. El compuesto sin diluir produjo una "ligera" irritación
    cutánea en cobayos y una irritación ocular "de ligera a moderada" en
    conejos. No se obtuvieron pruebas de sensibilización cutánea en
    cobayos. En los perros se produjo sensibilización cardíaca a la
    adrenalina por inhalación de HCFC 132b con niveles de exposición de 27
    g/m3 o superiores.

         Las consecuencias principales de la exposición de ratas macho a
    la inhalación de HCFC 132b durante un breve período fueron, además de
    la depresión del SNC, atrofia del timo y efectos en la
    espermatogénesis. Se observó alteración de la espermatogénesis tras un
    tratamiento con dosis de 3 g/m3 o superiores durante 13 semanas.
    Otros efectos que se detectaron fueron una proliferación del conducto
    biliar y un aumento de la relación ponderal hígado/cuerpo en machos,
    incluso con la aplicación de los niveles más bajos de exposición (3
    g/m3). Las ratas hembras resultaron menos sensibles que los machos
    a los efectos hepáticos.

         El HCFC 132b indujo embriotoxicidad en ratas tras la exposición
    por inhalación a 3-28 g/m3 durante los días 6-15 de gestación, dando
    lugar a un aumento del número de resorciones (a 11 y 28 g/m3) y a la
    disminución del peso fetal en todos los niveles de exposición. Se
    observó toxicidad materna con todos los niveles de dosificación que se
    probaron.

         De acuerdo con los limitados datos disponibles, no hay pruebas de
    mutagenicidad  in vitro del HCFC 132b. No se ha estudiado la
    carcinogenicidad del compuesto.

    6.4  HCFC 133a

         No se dispone de datos sobre la toxicidad aguda oral del HCFC
    133a. Su toxicidad aguda por inhalación es baja (la CL50 a los 30
    min en ratones es de 738 g/m3), y los principales efectos observados
    están en relación con su acción anestésica. Se carece de información
    sobre sensibilización cardíaca, irritación cutánea u ocular o
    sensibilización cutánea.

         Exposiciones repetidas de ratas (90 días) a 49 g/m3 produjeron
    una inflamación crónica del conducto nasal, enfisema y edema pulmonar,
    bronquitis y neumonía. También se observaron atrofia del timo, los
    testículos, los ovarios y el bazo. No se advirtieron efectos en ratas
    ni en perros repetidamente expuestos a concentraciones de HCFC 133a de
    unos 25 g/m3 durante siete días (ratas) o 90 días (perros), aunque

    se observaron muertes en ratones expuestos a concentraciones iguales
    o superiores a 0,5 g/m3 durante 5 días (a excepción de 2,5 g/m3).

         Aunque no se conocen estudios convencionales de los efectos del
    HCFC 133a en la reproduccción, en tres estudios de letalidad dominante
    en ratones se observaron efectos en la fertilidad del macho y la
    histopatología testicular. Las exposiciones a concentraciones de 2,5
    g/m3 o superiores durante 5 días dieron lugar a una reducción del
    número de hembras gestantes y a un aumento de la proporción de esperma
    anormal, mientras que la exposición a una concentración de 5 g/m3
    produjo lesiones histopatológicas en el epitelio seminífero.

         Los estudios en ratas (tratadas del 6 al 16 día de la gestación)
    con exposición a concentraciones que producen sólo síntomas de ligera
    toxicidad materna han demostrado que el HCFC 133a es embriotóxico en
    concentraciones de 2 g/m3 o superiores y embrioletal a 10 g/m3 o
    más. El tratamiento previo con progesterona de las hembras preñadas no
    tuvo influencia en los efectos embriotóxicos/letales. En un estudio se
    observaron síntomas de efectos teratogénicos (anomalías externas de
    las extremidades y la cola). El HCFC 133a produjo abortos espontáneos
    y embrioletalidad total en conejos expuestos a 25 g/m3 en los días
    7 a 19 de la gestación, concentración que produjo sólo una ligera
    toxicidad materna.

         En los estudios disponibles no hay pruebas de su capacidad
    mutagénica en bacterias. En un estudio no se observó aumento en la
    proporción de células renales de hámster que producían colonias
    transformadas. Se detectaron efectos letales dominantes en dos de tres
    estudios tras la exposición de ratones machos a concentraciones de 12
    g/m3 o superiores durante 5 días la proporción de células de la
    médula ósea con aberraciones cromosómicas se mantuvo inalterada en
    ratas expuestas a 98 g/m3 (6 h al día durante 5 días como máximo).
    En el único estudio de carcinogenicidad se observó un aumento de la
    incidencia de adenocarcinomas del útero y de tumores benignos de las
    células intersticiales de los testículos en ratas que recibieron 300
    mg/kg de aceite de maíz administrados por sonda durante 52 semanas
    (seguidas de un período de observación de 73 semanas).

    6.5  HCFC 123

         El HCFC 123 tiene una toxicidad aguda oral y cutánea baja. La
    dosis oral más baja de HCFC 123 con la que se han observado efectos
    letales en ratas es de 9 g/kg. Con dosis de 2 g/kg no se produjo
    mortalidad en ratas ni en conejos.

         La toxicidad aguda por inhalación de HCFC 123 es también baja.
    Los efectos observados son similares a los de los clorofluorocarburos,
    es decir, pérdida de coordinación y narcosis. La CL50 a las 4 h es
    de 178 g/m3 en el hámster, 463 g/m3 en el ratón y oscila entre 200
    y 329 g/m3 en la rata. En el perro, se produjo sensibilización
    cardíaca tras la exposición, con inyección de insulina, a

    concentraciones de 119 g/m3 o superiores. El HCFC 123 líquido
    produce en conejos una irritación "ligera" de la piel y los ojos. No
    provoca sensibilización cutánea en los cobayos.

         Se han realizado varios estudios de toxicidad de corta duración
    con el HCFC 123 por vía respiratoria. En ratas se observan síntomas
    invariables de depresión del SNC a concentraciones de 31 g/m3 o
    superiores. El HCFC 123 causó también algunos efectos hepáticos en
    ratas expuestas a dosis de 31 g/m3 o más. La exposición prolongada
    (4 semanas o más) al HCFC 123 afecta también al metabolismo de los
    lípidos y los glúcidos, como puso de manifiesto la reducción
    invariable de los niveles de triglicéridos, colesterol y glucosa en el
    suero. Los resultados provisionales de un estudio en curso de
    toxicidad crónica/oncogenicidad por inhalación en ratas indican que el
    HCFC 123 induce efectos tras la exposición prolongada a dosis de 2, 6
    ó 31 g/m3. En este estudio no se registró el nivel sin efectos
    observados (NOEL), basado en los efectos sobre el metabolismo lipídico
    y en el aumento de la actividad de los peroxisomas hepáticos.

         Actualmente se está llevando a cabo un estudio de reproducción de
    dos generaciones de ratas expuestas al HCFC 123 por vía respiratoria.
    En dos estudios limitados en ratas, con concentraciones capaces de
    producir una ligera toxicidad materna, no se obtuvieron pruebas de
    embriotoxicidad. Hay pruebas de toxicidad sólo a concentraciones muy
    tóxicas para la madre (superiores a 62,5 g/m3) en conejos. En ratas
    expuestas a concentraciones de 31 g/m3 o más y en conejos a niveles
    de 3 g/m3 o superiores se observó toxicidad materna (disminución del
    peso corporal y depresión del SNC). No aparecieron pruebas de
    teratogenicidad en ratas ni en conejos.

         El HCFC 123 no demuestra actividad mutagénica en los ensayos
    efectuados con bacterias y levaduras. Sin embargo, sí hay pruebas de
    actividad clastogénica en linfocitos humanos  in vitro, pero los
    datos procedentes de un ensayo  in vivo en micronúcleos de ratón no
    confirmaron ese resultado.

         Está en curso un estudio combinado de toxicidad crónica/
    carcinogenicidad por inhalación en ratas. En una comunicación
    preliminar se ha indicado que el HCFC 123 produce una mayor frecuencia
    de tumores benignos en los testículos y en el páncreas exócrino de
    ratas macho. Sin embargo, no es posible realizar una evaluación de la
    carcinogenicidad potencial del HCFC 123 hasta que no se disponga de
    los resultados completos.

    6.6  HCFC 124

         La toxicidad aguda por inhalación del HCFC 124 en animales es
    baja. Se produjo la muerte en ratas expuestas a concentraciones de
    1674 g/m3 (durante 240 minutos) y en ratones a 2460 g/m3 (durante
    10 minutos). Se observaron los efectos típicos de los
    clorofluorocarburos, es decir, pérdida de coordinación y narcosis. Se

    produjo sensibilización cardíaca tras la prueba de una inyección de
    adrenalina en perros a concentraciones de 140 g/m3 o superiores. Se
    carece de información sobre la irritación cutánea u ocular o la
    sensibilización cutánea con este compuesto.

         Se ha investigado la toxicidad por inhalación durante un breve
    período en cinco experimentos en ratas con exposiciones que oscilaron
    entre 14 y 90 días. No se observaron cambios histopatológicos en los
    órganos, ni siquiera con los niveles de exposición más altos de los
    estudiados (560 g/m3 en un experimento de 14 días, 279 g/m3 en un
    estudio de 90 días). Se comunicó un NOEL de 28 g/m3 sobre la base de
    las observaciones funcionales y los análisis de sangre efectuados en
    el estudio de 90 días.

         Está en curso un estudio sobre la toxicidad crónica por
    inhalación del HCFC 124.

         En tres estudios limitados de teratogenicidad en ratas, en los
    que se probaron concentraciones de HCFC 124 de 30 g/m3 o
    comprendidas entre 3 y 279 g/m3, no se encontraron pruebas de
    efectos embriotóxicos o teratogénicos. Con 84 g/m3 apareció
    toxicidad materna. No se dispone de información acerca de los efectos
    del HCFC 124 en el potencial de reproducción. Se están realizando
    estudios completos de teratogenicidad.

         Los datos disponibles de varios estudios en bacterias y de un
    único estudio en células de mamíferos no demuestran efecto mutagénico
    del HCFC 124. Está en marcha un estudio de carcinogenicidad por
    inhalación.

    7.  Efectos en el ser humano

         Se carece de datos sobre los efectos del HCFC 151b, el HCFC 132b,
    el HCFC 133b, el HCFC 123 y el HCFC 124 en el ser humano.

         Los datos de un solo estudio en el ser humano expuesto en el
    lugar de trabajo al HCFC 142b no permiten evaluar sus efectos en la
    especie humana independientemente de otras muchas exposiciones.

    8.  Efectos en otros organismos en el laboratorio y en el medio
        ambiente

         No se dispone de información acerca de los efectos de los
    hidroclorofluorocarburos estudiados sobre los organismos presentes en
    el medio ambiente, excepto algunos datos limitados de los HCFC 141b y
    142b. La CL50 a las 96 h del HCFC 141b para  Brachydanio rerio es
    de 126 mg/litro y la CE50 a las 48 h para la inmovilización de
     Daphnia magna de 31 mg/litro, habiéndose realizado ambas
    observaciones en recipientes cerrados. En el caso del HCFC 142b, la
    CE50 a las 96 h para  Lebistes reticulatus es de 220 mg/litro,
    mientras que la CE50 a las 48 h para la inmovilización de  Daphnia

     magna varía de 160 a > 190 mg/litro. La CL50 a las 96 h del HCFC
    142b para la trucha arco irís es de 36 mg/litro.

    9.  Evaluación y conclusiones

         Se desconocen los niveles de los seis HCFCs estudiados presentes
    en el medio ambiente, pero se consideran bajos, dado su grado actual
    de utilización.

         El HCFC 142b tiene un potencial tóxico bajo y se estima que no
    supone un riesgo para el ser humano en condiciones de exposición no
    debidas a un accidente. La información toxicológica acerca del HCFC
    141b, el HCFC 123 y el HCFC 124 es incompleta y se necesitan más datos
    para poder evaluar su riesgo para la salud humana. Tanto el HCFC 133a
    como el HCFC 132b representan un riesgo para ésta.

         Los seis hidroclorofluorocarburos estudiados tienen, o se les
    supone, una capacidad de destrucción del ozono más baja y tiempos de
    permanencia en la atmósfera considerablemente inferiores a los de los
    clorofluorocarburos completamente halogenados. Por consiguiente,
    deberían representar un riesgo indirecto menor para la salud. Su
    efecto sobre el calentamiento del planeta es, o se supone, inferior al
    de los clorofluorocarburos completamente halogenados y no se cree que
    contribuyan a él de manera apreciable.

         Puesto que la toxicidad del HCFC 142b es baja y su contribución
    al agotamiento del ozono y al calentamiento del planeta son inferiores
    a los de los clorofluorocarburos completamente halogenados, se lo
    puede considerar como un sustitutivo transitorio de los
    clorofluorocarburos que figuran en el Protocolo de Montreal.

         Hasta que no se disponga de más datos toxicológicos no se pueden
    hacer recomendaciones en relación con el HCFC 141b, el HCFC 123 y el
    HCFC 124. Debido a su potencial tóxico, no se recomiendan el HCFC 133a
    y el HCFC 132b como sustitutivos de los clorofluorocarburos que
    figuran en el Protocolo de Montreal, a pesar de representar un riesgo
    bajo para el medio ambiente e indirecto para la salud.


    See Also:
       Toxicological Abbreviations