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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT NO. 23



    2,2-DICHLORO-1,1,1-TRIFLUOROETHANE (HCFC-123)



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

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

    First draft prepared by

    Dr S. Kristensen, Mr S. Batt, and Ms D. Willcocks, Existing Chemicals
    Section, National Industrial Chemicals Notification and Assessment
    Scheme, Australia, and Mr C. Lee-Steere, Environment Australia


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


    World Health Organization
    Geneva, 2000


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

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

    WHO Library Cataloguing-in-Publication Data

    2,2-Dichloro-1,1,1-trifluoroethane (HCFC 123).

         (Concise international chemical assessment document ; 23)

         1.Chlorofluorocarbons - toxicity  2.Risk assessment
         3.Occupational exposure  4.Environmental exposure
         I.Programme on Chemical Safety  II.Series

         ISBN 92 4 153023 5      (NLM Classification: QV 633)
         ISSN 1020-6167

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              (c) World Health Organization 2000

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         The Federal Ministry for the Environment, Nature Conservation and
    Nuclear Safety, Germany, provided financial support for the printing
    of this publication.

    TABLE OF CONTENTS

         FOREWORD

    1. EXECUTIVE SUMMARY

    2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

    3. ANALYTICAL METHODS

    4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         6.1. Environmental levels

         6.2. Human exposure

    7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

    8. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

         8.1. Single exposure

         8.2. Irritation and sensitization

         8.3. Short-term exposure

         8.4. Long-term exposure

              8.4.1. Subchronic exposure

              8.4.2. Chronic exposure and carcinogenicity

         8.5. Genotoxicity and related end-points

         8.6. Reproductive and developmental toxicity

    9. EFFECTS ON HUMANS

    10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    11. EFFECTS EVALUATION

         11.1. Evaluation of health effects

              11.1.1. Hazard identification and dose-response assessment

              11.1.2. Criteria for setting tolerable intakes or guidance values for HCFC-123

              11.1.3. Sample risk characterization

         11.2. Evaluation of environmental effects

    12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         REFERENCES

         APPENDIX 1 -- SOURCE DOCUMENTS

         APPENDIX 2 -- CICAD PEER REVIEW

         APPENDIX 3 -- CICAD FINAL REVIEW BOARD

         APPENDIX 4 -- INTERNATIONAL CHEMICAL SAFETY CARD

         RÉSUMÉ D'ORIENTATION

         RESUMEN DE ORIENTACI²N
    

    FOREWORD

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

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

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

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

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

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

    Procedures

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

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

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

         The CICAD Final Review Board has several important functions:

    -    to ensure that each CICAD has been subjected to an appropriate
         and thorough peer review;

    -    to verify that the peer reviewers' comments have been addressed
         appropriately;

    -    to provide guidance to those responsible for the preparation of
         CICADs on how to resolve any remaining issues if, in the opinion
         of the Board, the author has not adequately addressed all
         comments of the reviewers; and

    -    to approve CICADs as international assessments.

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


    FIGURE 1

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

    1.  EXECUTIVE SUMMARY

         This CICAD was based principally on the assessments of the
    occupational health and environmental effects of
    2,2-dichloro-1,1,1-trifluoroethane (HCFC-123) completed under the
    Australian National Industrial Chemicals Notification and Assessment
    Scheme (NICNAS) and published in March 1996 (NICNAS, 1996) and July
    1999 (NICNAS, 1999). Relevant information that has become available
    since completion of the NICNAS reports or that was identified in a
    comprehensive search of several on-line databases up to August 1999
    has also been assessed and included in this CICAD. This CICAD is an
    update of the review of HCFC-123 in the monograph Environmental Health
    Criteria 139 (IPCS, 1992), prompted by the advent of new and
    significant data. Information on the nature of the peer review and the
    availability of the source documents is presented in Appendix 1.
    Information on the peer review of this CICAD is presented in Appendix
    2. The CICAD was approved for publication at a meeting of the Final
    Review Board, held in Sydney, Australia, on 21-24 November 1999.
    Participants at the Final Review Board meeting are listed in Appendix
    3. The International Chemical Safety Card (ICSC 1343) for
    2,2-dichloro-1,1,1-trifluoroethane, produced by the International
    Programme on Chemical Safety, has been reproduced in Appendix 4 (IPCS,
    1998).

         HCFC-123 (CAS No. 306-83-2) is a synthetic, non-combustible,
    volatile liquid that is used as a refrigerant in commercial and
    industrial air-conditioning installations, in gaseous fire
    extinguishants, as a foam-blowing agent, and in metal and electronics
    cleaning. Its ozone-depleting potential is only 2% of that of CFC-11
    (trichlorofluoromethane). It has a global warming potential of 300
    over a 20-year time horizon relative to carbon dioxide. As such,
    HCFC-123 is currently used as a transitional replacement for
    chlorofluorocarbons and bromofluorocarbons phased out pursuant to the
    1987 Montreal Protocol on Substances that Deplete the Ozone Layer. The
    1992 Copenhagen Amendment to the Montreal Protocol requires that
    HCFC-123 and other hydrochlorofluorocarbons be phased out by 2020.

         Releases of HCFC-123 to the environment are primarily to ambient
    air. Although slightly toxic to fish,  Daphnia, and algae, HCFC-123
    is unlikely to pose a significant hazard to the aquatic environment,
    as it is not persistent in water, even at concentrations below the
    solubility limit. In the atmosphere, HCFC-123 has an estimated
    lifetime of less than 2 years. The main atmospheric breakdown product
    of HCFC-123 (and other, more widely used fluorocarbons) is
    trifluoroacetic acid, which will partition into aqueous phases in the
    environment. Although trifluoroacetic acid is resistant to degradation
    and may accumulate in certain closed aquatic systems, current and
    predicted concentrations from HCFC-123 emissions are below toxic
    thresholds.

         Exposure of the general public to HCFC-123 is expected to be
    minimal. However, there is the potential for occupational exposure
    during the manufacture of HCFC-123 and the manufacture and use of
    products containing the chemical.

         Limited information is available on the effects of HCFC-123 on
    humans. Cases of dizziness, headache, and nausea following a single
    exposure to unknown levels of airborne HCFC-123 have been reported, as
    well as cases of manifest or subclinical liver disease associated with
    repeated occupational exposures to HCFC-123 vapours at 5-1125 ppm
    (31.3-7030 mg/m3) for 1-4 months.

         The acute toxicity of HCFC-123 in laboratory animals is low.
    Inhalation for a few minutes to a few hours causes liver lesions in
    guinea-pigs at 1000 ppm (6.25 g/m3), central nervous system (CNS)
    depression in all species examined at 5000 ppm (31.3 g/m3), and
    adrenaline-induced cardiac arrhythmia in dogs at 20 000 ppm (125
    g/m3). In the rat and hamster, inhalation of more than 30 000 ppm
    (188 g/m3) for 4 h causes severe CNS depression and death. HCFC-123
    is not a skin irritant or sensitizer, but it can cause eye irritation
    in liquid form. In repeated-exposure inhalation toxicity studies
    lasting 2-39 weeks in rats, guinea-pigs, dogs, and monkeys, the main
    target organs were the liver, the hypothalamic-pituitary-gonadal
    endocrine system, and the CNS. The lowest-observed-adverse-effect
    level (LOAEL) based on liver effects was 30 ppm (188 mg/m3). The
    no-observed-adverse-effect level (NOAEL) was 100 ppm (625 mg/m3)
    based on endocrine effects and 300 ppm (1880 mg/m3) based on CNS
    effects. There was no evidence that HCFC-123 is teratogenic in
    laboratory animals or induces reproductive or fetal toxicity at levels
    of exposure lower than those that cause other systemic effects. Growth
    was retarded in neonatal rats and monkeys reared by dams exposed to
    HCFC-123, with a LOAEL of 30 ppm (188 mg/m3). The main metabolite of
    HCFC-123, trifluoroacetic acid, was found in the milk of the dams.

         Although there was evidence of clastogenic activity in human
    lymphocytes exposed to HCFC-123 at high, cytotoxic concentrations
     in vitro, all other  in vitro and  in vivo tests for genetic
    toxicity were negative. Therefore, the evidence suggests that the
    chemical is unlikely to be genotoxic  in vivo. 

         In a 2-year inhalation study in rats, there was an increased
    incidence of pre-cancerous lesions and benign tumours in the liver,
    pancreas, and testes, but no exposure-related increase in the
    incidence of malignant tumours. It is likely that these tumours
    involve one or more non-genotoxic mechanisms, including peroxisome
    proliferation, hepatocellular damage, necrosis and regenerative
    proliferation, and disturbance of the
    hypothalamic-pituitary-testicular axis. Although humans may be less
    sensitive to tumours arising from some of these mechanisms, overall it
    is not possible to discount the tumours in an evaluation of the
    potential risk for humans.

         The most relevant critical effects for a single, brief exposure
    to HCFC-123, such as from the discharge of a fire extinguishant, are
    CNS depression and an increased likelihood of adrenaline-induced
    cardiac arrhythmia. The most relevant critical effect from repeated
    exposure is liver lesions, which have been reported in workers exposed
    to air levels above 5 ppm (31.3 mg/m3) for 1-4 months.
    

    2.  IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

         HCFC-123 (CAS No. 306-83-2; C2HCl2F3;
    2,2-dichloro-1,1,1-trifluoroethane,
    1,1,1-trifluoro-2,2-dichloroethane; see structural diagram in Figure
    1) is a synthetic chemical that is a clear, colourless,
    non-combustible liquid with a slight ethereal odour. Other common
    names or abbreviations are FC 123, Fluorocarbon 123, Forane-123, Freon
    123, Frigen, G 123, Genetron 123, R-123, and SUVA 123. HCFC-123 boils
    at 27.6°C and is highly volatile, with a vapour pressure of 89.3 kPa
    at 25°C. Its molecular weight is 152.93 g/mol. The solubility of
    HCFC-123 in water is 2.1 g/litre at 25°C. The estimated log
    octanol/water partition coefficient is 2.3-2.9 (NICNAS, 1996). Its
    Henry's law constant has been measured at 2.6 m3.kPa/mol at 22°C
    (Chang & Criddle, 1995), corresponding to a dimensionless constant of
    1.057. Additional physical/chemical properties are presented in the
    International Chemical Safety Card, reproduced in this document
    (Appendix 4).

         The conversion factors for airborne HCFC-123 at 101.3 kPa and 
    25°C are 1 ppm = 6.25 mg/m3 and 1 mg/m3 = 0.16 ppm.
    

    3.  ANALYTICAL METHODS

         Methods of automated vapour detection include infrared
    absorption, infrared photo-acoustic, halide ion, and metallic oxide
    resistance sensors, with most systems having a detection limit of 1-2
    ppm (6.25-12.5 mg/m3) (Trane Company, 1991). Analysis for HCFC-123
    in environmental media is usually by gas chromatography with flame
    ionization detection (Du Pont, 1993). This method has a detection
    limit of less than 0.94 ppm (5.88 mg/m3).

         There are no validated methods for biological monitoring of
    HCFC-123, although urinary excretion of trifluoroacetic acid has been
    used as an indicator of exposure (Tanaka et al., 1998).
    

    4.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         There are no known natural sources of HCFC-123. The principal use
    for HCFC-123 is as a refrigerant in commercial and industrial
    air-conditioning installations, in gaseous fire extinguishants, as a
    foam-blowing agent, and in metal and electronics cleaning. These uses
    are primarily as a temporary replacement for chlorofluorocarbons and
    bromofluorocarbons phased out pursuant to the 1987 Montreal Protocol
    on Substances that Deplete the Ozone Layer. Worldwide, commercially
    available volumes of the chemical may reach 10 000 tonnes per year
    (AIHA, 1998). In countries that have ratified the Copenhagen Amendment
    to the Montreal Protocol, the manufacture, import, and export of
    HCFC-123 and other hydrochlorofluorocarbons will be phased out by
    2020, although very small amounts will continue to be available until
    2030 to service existing equipment. For information on the Montreal
    Protocol and subsequent amendments, see UNEP (1999).
    

    5.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         The majority of HCFC-123 released to the environment is in
    emissions to air -- for example, from loss during normal running or
    maintenance of air-conditioning installations, from the discharge of
    fire extinguishants containing HCFC-123, or from the evaporation of
    solvents used in metal or electronics cleaning. Because of the limited
    solubility and high volatility of HCFC-123, only small amounts will
    enter aquatic environments. In a 28-day closed bottle test conducted
    according to Organisation for Economic Co-operation and Development
    (OECD) guidelines, oxygen consumption at a concentration of 12.5 mg
    HCFC-123/litre amounted to 24% of theoretical (Jenkins, 1992a); that
    is, HCFC-123 is not readily biodegradable, and spills to water would
    largely evaporate. HCFC-123 has been shown to undergo biodegradation
    in the presence of methanotrophic bacteria (Chang & Criddle, 1995).
    Microbial transformation involving reductive dechlorination to
    2-chloro-1,1,1-trifluoroethane was observed in anoxic freshwater and
    salt-marsh sediments, whereas no degradation was observed in aerobic
    soils (Oremland et al., 1996). Although methanotrophic and anaerobic
    biodegradation may occur, they are unlikely to be effective removal
    mechanisms for this highly volatile chemical.

         The estimated atmospheric lifetime of HCFC-123 is 1.4 years (WMO,
    1995). HCFC-123 has an ozone-depleting potential of 0.02 relative to
    CFC-11 (trichlorofluoromethane). The global warming potential relative
    to carbon dioxide is 300, 93, and 29 over time horizons of 20, 100,
    and 500 years, respectively (WMO, 1995). 

         In the troposphere, HCFC-123 is attacked by hydroxyl radicals to
    form hydrogen chloride and trifluoroacetyl chloride (Hayman et al.,
    1994). The latter may undergo photolysis to carbon monoxide, carbon
    dioxide, hydrogen fluoride, and hydrogen chloride, but the major loss
    process is hydrolysis to trifluoroacetic acid by cloud water and
    precipitation in rain. Trifluoroacetic acid is also an atmospheric
    degradation product of other, more widely used fluorocarbons
    (Kotamarthi et al., 1998). It is very stable and may accumulate in
    certain closed aquatic systems. Reported environmental levels range
    from 30 to 3800 ng/litre in rain, snow, and fog and from 40 to 5400
    ng/litre in most surface waters, with maximum concentrations of 6400
    and 40 000 ng/litre in two desert lakes (Frank et al., 1996; Wujcik et
    al., 1998). The environmental fate of trifluoroacetic acid was
    reviewed by Boutonnet et al. (1999). The available evidence indicated
    that soil retention of trifluoroacetic acid is poor, particularly in
    soils with low levels of organic matter. Although biodegradation was
    observed under specific anaerobic conditions, the relevance of these
    findings was considered to be doubtful. Trifluoroacetic acid did not
    accumulate in lower aquatic life forms, such as bacteria, small
    invertebrates, oligochaete worms, and some aquatic plants, including
    duckweed. In terrestrial higher plants, trifluoroacetic acid appeared
    to be taken up with water and concentrated due to transpiration water
    loss. The highest measured bioconcentration factor of 43 based on
    fresh weight was found in shoot/leaf from hydroponic wheat.

    FIGURE 2

    

    6.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    6.1  Environmental levels

         HCFC-123 was detected in non-urban ambient air in Australia at
    levels less than 0.01 ppt (62.5 pg/m3) (Fraser, 1994). Assuming that
    worldwide emissions will increase to 45 000 tonnes in 2010, the global
    average concentration of airborne HCFC-123 is projected to reach 1.1
    ppt (7 ng/m3) in that year, with levels being 2-4 times higher than
    the average near major sources of emissions in eastern North America
    and central Europe (Kotamarthi et al., 1998).

         Information on levels of HCFC-123 in water, wildlife or food was
    not available.

    6.2  Human exposure

         HCFC-123 is not used in consumer products. Indirect exposure via
    the environment would be low, as the concentration in ambient air is
    less than 0.01 ppt (62.5 pg/m3) and HCFC-123 is unlikely to persist
    in other media because of its limited solubility and high volatility.
    Therefore, exposure of the general population to HCFC-123 is expected
    to be minimal.

         There is potential for occupational exposure, predominantly via
    inhalation, during the manufacture of HCFC-123 and the manufacture and
    use of products containing HCFC-123, such as the operation and
    maintenance of air-conditioning installations running on HCFC-123, the
    discharge of HCFC-123 from fire protection systems, and the use of
    liquid HCFC-123 in metal and electronics cleaning.

         In an HCFC-123 manufacturing plant in Canada, two operators
    monitored over 165-480 min on 4 separate days had time-weighted
    breathing-zone levels of HCFC-123 ranging from 1.16 to 8.94 ppm (7.25
    to 55.9 mg/m3). On one occasion, a drum-filling lance failure
    resulted in a level in excess of 33 ppm (206 mg/m3) (Du Pont,
    personal communication, 1999). No monitoring data were available for
    the manufacture of products containing HCFC-123.

         Several studies have measured HCFC-123 levels in chiller
    machinery rooms during normal operations as well as maintenance and
    repair activities. In 4 of 12 unmanned machinery rooms containing
    air-conditioning equipment running on HCFC-123, air levels were below
    1 ppm (6.25 mg/m3) (4-h time-weighted average) at three sites (Trane
    Company, 1991). At one site, where samples were taken near a leak and
    a half-empty HCFC-123 drum, levels of 5.9-13.6 ppm (36.9-85.0 mg/m3)
    (20-min time-weighted average) were recorded. At the rest of the
    sites, machinery room air levels were below the limit of detection
    (0.2-0.4 ppm [1.25-2.50 mg/m3]). Breathing-zone levels of HCFC-123
    during routine chiller maintenance operations, including refrigerant

    transfer, were measured at nine US installations. Two-hour to 12-h
    time-weighted average concentrations were less than 1 ppm (6.25
    mg/m3) in five cases, less than 2 ppm (12.5 mg/m3) in three cases,
    and in the range of 2-5 ppm (12.5-31.3 mg/m3) in one case (MRI,
    1991; Sibley, 1992; Trane Company, 1992). In Australia, 4- to 6-h
    time-weighted average concentrations were less than 1 ppm (6.25
    mg/m3) during repair work at a single installation (NICNAS, 1996).
    In these studies, continuous area monitoring showed time-weighted
    average air concentrations below 1 ppm (6.25 mg/m3), with
    activity-related instantaneous peaks ranging from 30 to 500 ppm (188
    to 3130 mg/m3). 

         Air levels resulting from the use of a fire extinguishant
    containing 93% HCFC-123 were measured during fire control exercises in
    which the firefighters wore a self-contained breathing apparatus (MRI,
    1993a,b). Outdoor discharge resulted in maximum breathing-zone levels
    ranging from 7 to 870 ppm (43.8 to 5440 mg/m3), depending on the
    type of fire hazard. Inside an aircraft hangar, the discharge of
    hand-held extinguishers resulted in a breathing-zone concentration of
    20 ppm (125 mg/m3) during discharge, with average static air levels
    ranging from 29 to 141 ppm (181 to 881 mg/m3) over the next 30 min.
    With a large semi-portable fire extinguisher, breathing-zone
    concentrations during discharge reached 180-300 ppm (1130-1880
    mg/m3), whereas average static air levels ranged from 165 to 557 ppm
    (1030 to 3480 mg/m3) over the next 30 min.

         In a US factory converted to using HCFC-123 in its degreaser,
    personal air monitoring during normal degreaser operations showed
    5.5-h time-weighted average levels of HCFC-123 that ranged from 5.3 to
    12.0 ppm (33.1 to 75.0 mg/m3) throughout the facility.1 Charging
    and unloading the degreaser resulted in short-term breathing-zone
    levels ranging from 160 to 460 ppm (1000 to 2880 mg/m3).

                

    1 AlliedSignal Inc., personal communication, 1998 [cited in 
      NICNAS, 1999].
    

    7.  COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS
        AND HUMANS

         HCFC-123 is readily absorbed by inhalation and distributed
    throughout the body, where it reaches levels in body fat up to 25
    times higher than those in blood (Vinegar et al., 1994). Following
    exposure to an initial concentration of 2000 ppm (12.5 g/m3)
    radiolabelled HCFC-123 over two consecutive 3-h periods in a
    closed-chamber system, total uptake was 50-60% in rats and 90-100% in
    guinea-pigs (Urban & Dekant, 1994). In rats exposed to initial
    concentrations of 120-11 000 ppm (0.75-68.8 g/m3) HCFC-123 for 6 h,
    the inhalation uptake showed a rapid distribution phase lasting 
    30-45 min followed by a slow linear uptake phase (Vinegar et al., 
    1994). Blood levels declined rapidly once exposure was terminated. In 
    rats exposed to 1000 ppm (6.25 g/m3), blood concentrations fell 
    from 15.0 mg/litre at the end of a 4-h exposure period to 4.5 
    mg/litre at 4 min post-exposure and 1.5 mg/litre at 1 h post-exposure 
    (Vinegar et al., 1994). After the initial decline, HCFC-123 
    concentrations in both blood and fat decreased log-linearly with 
    a half-life of approximately 80 min, indicating fat as the main 
    depository for unmetabolized HCFC-123. Experimentally determined 
    tissue to air partition coefficients were 2-3 for gut and muscle, 
    3-4 for blood, 3-5 for liver, and 60-70 for fat (Dekant, 1993; 
    Vinegar et al., 1994). Data on oral or dermal absorption were not
    available.

         In the rat, 26-32% of the uptake of HCFC-123 is metabolized,
    predominantly by oxidation to trifluoroacetyl chloride, which is
    hydrolysed to trifluoroacetic acid or reacts with lysine residues in
    proteins or with low-molecular-weight amines to form
     N-trifluoroacetyl amides (Harris et al., 1992; Dodd et al., 1993;
    Urban & Dekant, 1994). Minor, reductive pathways lead to the formation
    of very small amounts of 2-chloro-1,1,1-trifluoroethane,
    2-chloro-1,1-difluoroethene, and 2,2-dichloro-1,1-difluoroethene. The
    latter reacts with glutathione to form
     N-acetyl- S-(2,2-dichloro-1,1-difluoroethyl)-L-cysteine. The
    structures of these metabolites are shown in Figure 1. Both oxidation
    and reduction of HCFC-123 are catalysed by cytochrome P450 2E1
    (CYP2E1). In human liver microsomes, the major biotransformation
    product is trifluoroacetic acid (Urban et al., 1994). Its rate of
    formation was directly related to the amount of CYP2E1 present and
    1.5-16 times faster than the rate in rat microsomes.

         In experimental animals, the major metabolite in blood, urine,
    and milk is trifluoroacetic acid. In rats exposed by inhalation to
    1000 ppm (6.25 g/m3) HCFC-123 for 4 h, blood levels of parent
    compound and trifluoroacetic acid amounted to 15.0 and 93.1 mg/litre,
    respectively (Vinegar et al., 1994). At 10 000 ppm (62.5 g/m3), the
    corresponding concentrations were 93.5 and 37.8 mg/litre,

    respectively. Trifluoroacetic acid blood levels rebounded and peaked
    12-26 h post-exposure, indicating that the metabolism of HCFC-123
    is subject to substrate inhibition at exposures above 1000 ppm (6.25
    g/m3). For exposure levels below 2000 ppm (12.5 g/m3), the
    metabolic rate constants developed for HCFC-123 were  Km = 1.2
    mg/litre and  Vmax = 7.20 mg/kg body weight per hour for male rats
    and  Km = 1.2 mg/litre and  Vmax = 7.97 mg/kg body weight per
    hour for female rats (Loizou et al., 1994). Generally, HCFC-123 was
    not detected in blood samples collected within 1 h post-exposure from
    lactating rhesus monkeys exposed by inhalation to 1000 ppm (6.25
    g/m3) for 6 h per day, whereas trifluoroacetic acid concentrations
    reached 150-190 µg/ml after 2-3 weeks of exposure. Based on data from
    a single monkey, the half-life of trifluoroacetic acid in blood was
    approximately 24 h (Slauter, 1997). In rats and guinea-pigs exposed to
    14C-labelled HCFC-123 vapours for 6 h and sacrificed 48 h
    post-exposure, only low amounts of radioactivity remained in the
    organs examined (Urban & Dekant, 1994). The liver contained most of
    the radiolabel, followed by testes and kidneys, lungs, brain,
    pancreas, and spleen. Covalent binding of labelled material was
    highest in liver tissue (0.4-0.7 nmol/mg protein), followed by lungs,
    kidneys, and plasma (0.1-0.3 nmol/mg protein). Trifluoroacetylated
    tissue proteins have been detected by immunological techniques in the
    liver and at 20- to 200-fold lower levels in the kidney and heart of
    rats 6-12 h after exposure to HCFC-123 by inhalation or
    intraperitoneal injection (Harris et al., 1992; Huwyler & Gut, 1992;
    Huwyler et al., 1992).

         The available data indicate that the predominant routes of
    HCFC-123 elimination are exhalation of the parent compound and urinary
    excretion of trifluoroacetic acid. In rats exposed to an initial
    concentration of 2000 ppm (12.5 g/m3) radiolabelled HCFC-123 for two
    consecutive 3-h periods and sacrificed 48 h post-exposure, 23-28% of
    the radioactive uptake was eliminated in the urine, predominantly as
    trifluoroacetic acid, whereas 3-4% was recovered from the body (Urban
    & Dekant, 1994). Small amounts of minor metabolites, such as
     N-acetyl- S-(2,2-dichloro-1,1-difluoroethyl)-L-cysteine,
     N-trifluoroacetyl-2-aminoethanol, and fluoride ion, were recovered
    from urine, and trace amounts of 2-chloro-1,1,1-trifluoroethane were
    detected in expired air (Urban & Dekant, 1994; Vinegar et al., 1994).
    In lactating rats and monkeys exposed to 1000 ppm (6.25 g/m3)
    HCFC-123 for 6 h per day for 3 weeks, trifluoroacetic acid was found
    in milk at a maximum concentration of 65 and 30 µg/ml, respectively
    (Buschman, 1996; Slauter, 1997). In monkeys, the milk also contained
    small amounts (up to 5 µg/ml) of HCFC-123. Rat milk was not analysed
    for HCFC-123, and neither monkey nor rat milk was analysed for
    metabolites other than trifluoroacetic acid.

         An analogue of HCFC-123, the common inhalation anaesthetic
    halothane (2-bromo-2-chloro-1,1,1-trifluoroethane), is also
    metabolized by hepatic CYP2E1 to trifluoroacetyl chloride, causing
    trifluoroacetylation of liver proteins (Harris et al., 1992; Urban et
    al., 1994). These include cytochrome P450 itself and other enzymes,

    many of which have been identified as residing in the lumen of the
    endoplasmic reticulum and involved in the maturation of newly
    synthesized proteins (Cohen et al., 1997). Both halothane and HCFC-123
    induce peroxisome proliferation and increased ß-oxidation in rat liver
    cells (Keller et al., 1998). They are also highly effective in
    inducing excess uncoupled cytochrome P450 activity in rabbit liver
    microsomes, thus increasing hepatic oxygen consumption and
    facilitating the oxidation of other cytochrome P450 substrates (Wang
    et al., 1993).

         Only limited information was available on the kinetics and
    metabolism of HCFC-123 in humans  in vivo. In four volunteers exposed
    by inhalation to 60-73 ppm (375-460 mg/m3) HCFC-123 for 6 h, the
    concentration of trifluoroacetic acid in the urine peaked at 10-27
    mg/litre by 20-30 h and returned to zero by 96 h post-exposure,
    indicating an elimination half-life of 25 h (Tanaka et al., 1998).
    Physiologically based pharmacokinetic models for halothane in humans
    and for halothane and HCFC-123 in rats have been used to deduce a
    human model for HCFC-123 and its main metabolite, trifluoroacetic acid
    (Williams et al., 1996). As the model has not been validated, its
    usefulness as a predictive tool is unknown at this time.
    

    8.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

         Unless otherwise indicated, only effects that were statistically
    different ( P < 0.05) from controls have been considered. All
    inhalation studies were performed by whole-body exposure, unless
    otherwise mentioned.

    8.1  Single exposure

         When HCFC-123 was administered in corn oil by oral gavage to rats
    at doses ranging from 2.25 to 11 g/kg body weight, rapid respiration
    and prostration were recorded at and above 3.4 g/kg body weight. An
    LD50 was not determined. The lowest dose causing mortality was 9
    g/kg body weight (Henry, 1975).

         In the rat and the hamster, inhalation of more than 30 000 ppm
    (188 g/m3) caused severe CNS depression and death (Clayton, 1966;
    Hall & Moore, 1975; Coate, 1976; Darr, 1981). The 4-h LC50 ranged
    from 28 400 to 52 600 ppm (178-329 g/m3). Clinical signs of toxicity
    included sedation, loss of muscle coordination and balance,
    prostration, and dyspnoea. Gross pathological findings were either
    negative or limited to congestion or discoloration of the lungs,
    kidneys, liver, thymus, or small intestine. The lowest concentration
    causing reversible CNS depression (failures in unconditioned reflexes)
    in rats was 5000 ppm (31.3 g/m3) (Mullin, 1976). In a study of
    cardiac sensitization to adrenaline, life-threatening or fatal
    arrhythmias occurred in 0 of 3, 4 of 6, and 3 of 3 dogs exposed
    nose-only to 10 000, 20 000, or 40 000 ppm (62.5, 125, or 250 g/m3).
    The dogs were pretreated with intravenous adrenaline (8 µg/kg body
    weight) prior to exposure and challenged with an identical adrenaline
    dose after breathing the compound for 5 min. Based on these findings,
    an EC50 (5 min) of 19 000 ppm (119 g/m3) and a NOAEL of 10 000 ppm
    (62.5 g/m3) were determined (Trochimowicz & Mullin, 1973). Exposure
    of guinea-pigs to 1000-30 000 ppm (6.25-188 g/m3) HCFC-123 for 4 h
    produced non-fatal liver damage in all exposure groups (Marit et al.,
    1994). At 48 h post-exposure, the liver effects included centrilobular
    vacuolar (fatty) change, multifocal random and centrilobular
    hepatocellular degeneration and necrosis, and increased levels of
    plasma isocitrate dehydrogenase, alanine transaminase (ALT), and
    aspartate transaminase (AST). In another study in guinea-pigs exposed
    to 10 000 ppm (62.5 g/m3) for 4 h, liver injury was minimal unless
    the animals had been glutathione depleted prior to exposure (Lind et
    al., 1995).

         In a rat and rabbit test for dermal toxicity carried out
    according to OECD guidelines, the only effect observed after a dose of
    2000 mg liquid HCFC-123/kg body weight was applied under occlusion for
    24 h was a slight to moderate erythema in 6 of 10 rabbits up to 5 days
    post-treatment. As such, the dermal LD50 for rats and rabbits was
    greater than 2000 mg/kg body weight (Brock, 1988a,b).

    8.2  Irritation and sensitization

         Application under occlusion of 0.5 ml liquid HCFC-123 for 4 h
    caused no erythema or oedema in a test for skin irritation potential
    in rabbits conducted according to OECD guidelines (Brock, 1988c). In
    rabbits, 0.1 ml undiluted HCFC-123 or 0.2 ml of a 50% solution in
    propylene glycol caused mild to moderate, reversible eye damage,
    including conjunctival irritation and corneal opacity (scoring not
    reported) (Britelli, 1975). HCFC-123 did not produce skin
    sensitization in guinea-pigs when 0.1 ml of a 1% solution in dimethyl
    phthalate was administered intradermally once a week for 3 weeks,
    followed by challenge 2 weeks later with 7 or 35 mg HCFC-123 dissolved
    in propylene glycol (Goodman, 1975).

    8.3  Short-term exposure

         In rats exposed to 1000, 5000, 10 000, or 20 000 ppm (6.25, 31.3,
    62.5, or 125 g/m3) HCFC-123 for 6 h per day, 5 days per week, in a
    28-day inhalation toxicity study conducted in accordance with OECD
    guidelines, exposures to 5000 ppm (31.3 g/m3) and above resulted in
    dose-related narcotic effects, which were reversible overnight (Kelly,
    1989; Rusch et al., 1994). Body weight was reduced at all dose levels
    in females (8-10%) and at the two highest dose levels in males
    (14-15%). There was a dose-related increase in relative liver weight
    at all exposure levels in females (14-27%) and at the highest level in
    males (18%). Plasma levels of ALT and AST were increased by 35% and
    71%, respectively, at the highest level in males. Except for isolated
    cases of fatty change at all dose levels, gross or microscopic liver
    lesions were not observed. A NOAEL was not established in this study.

         In a study in male rats exposed to approximately 1000, 5000, or
    20 000 ppm (6.25, 31.3, or 125 g/m3) HCFC-123 for 6 h per day, 5
    days per week, for 28 days, there was a decrease in body weight
    (6-11%) and an increase in relative testis weight (12-30%) in all dose
    groups and a 25% increase in relative liver weight in the highest dose
    group (Lewis, 1990). Microscopic liver lesions including dose-related
    hepatocyte hypertrophy and centrilobular fatty change were seen at all
    exposure levels, with proliferation of peroxisomes and mitochondria in
    liver cells of animals exposed to 5000 ppm (31.3 g/m3) and above.
    Plasma levels of ALT, AST, and alkaline phosphatase (ALP) were
    increased by up to 79%, whereas plasma triglycerides and cholesterol
    were decreased by up to 70%, with AST and triglycerides being the most
    sensitive markers of hepatic injury. 

         Similar findings accompanied by a 3-fold increase in hepatocyte
    mitotic activity were reported from a study in which male rats were
    exposed to 18 200 ppm (114 g/m3) HCFC-123 for 6 h per day, 5 days
    per week, for 28 days (Warheit, 1993). This study also found
    exposure-related testicular lesions, including germinal cell necrosis

    and atrophy of the seminiferous tubules. In male guinea-pigs exposed
    to 9400 ppm (58.8 g/m3) HCFC-123 for 6 h per day, 5 days per week,
    for 28 days, there was evidence of microscopic liver lesions,
    including centrilobular vacuolar (fatty) change and hepatocellular
    necrosis, but no testicular effects were observed (Warheit, 1993).

    8.4  Long-term exposure

    8.4.1  Subchronic exposure

         A number of subchronic inhalation studies have been carried out
    in rats and dogs and are summarized in Table 1. In each case, HCFC-123
    was administered for 6 h per day, 5 days per week. The main effects
    were liver injury, with changes in liver-related clinical chemistry
    parameters occurring at 300 ppm (1.88 g/m3) in rats and at 1000 ppm
    (6.25 g/m3) in dogs, and CNS depression, with a reduction in arousal
    occurring at 1000 ppm (6.25 g/m3) in rats.

    8.4.2  Chronic exposure and carcinogenicity

         In a 2-year inhalation study, groups of 80 male and female
    Sprague-Dawley rats were exposed for 6 h per day for 5 days per week
    to 300, 1000, or 5000 ppm (1.88, 6.25, or 31.3 g/m3) HCFC-123
    (Malley, 1992; Malley et al., 1995). 

         During the first year, rats exposed to 5000 ppm (31.3 g/m3)
    appeared sedated, but quickly recovered after the daily exposures
    ended. Female rats exposed to 1000 ppm (6.25 g/m3) and males and
    females exposed to 5000 ppm (31.3 g/m3) had lower body weight and
    body weight gain. At the 12-month sacrifice, the relative liver weight
    in male and female rats exposed to 5000 ppm (31.3 g/m3) was
    increased by 12% and 24%, respectively. No exposure-related gross or
    histopathological changes were observed. In both sexes, serum
    triglycerides and glucose were decreased at all exposure levels in a
    dose-related manner, by 65-100% and 15-31% for males and females,
    respectively. Serum cholesterol was decreased by approximately 30% in
    all exposed females and by 43% in males exposed to 5000 ppm 
    (31.3 g/m3).

         During the second year of exposure, slight, reversible CNS
    depression continued to be observed at 5000 ppm (31.3 g/m3). At the
    end of the 2-year period, there was a dose-related increase in
    survival rate, which reached a statistically significant level of 47%
    and 59% in females exposed to 1000 or 5000 ppm (6.25 or 31.3 g/m3),
    respectively. This is an expected effect of chemicals that reduce body
    fat and blood lipids. Compared with the controls, body weight was
    decreased by 8% in females exposed to 1000 ppm (6.25 g/m3) and by
    12% in males and 21% in females exposed to 5000 ppm (31.3 g/m3). At
    5000 ppm (31.3 g/m3), relative liver weight and the incidence of
    enlarged and discoloured livers were increased in males, as were
    grossly observed liver masses in females.

         There were no exposure-related effects on the incidence of
    malignant tumours. There was an increase in hepatocellular adenomas in
    females and males, an increase in cholangiofibromas in high-dose
    females, a dose-related increase in pancreatic acinar cell adenomas in
    males, and an increase in Leydig (interstitial) cell adenomas in males
    at all dose levels (Table 2). Except for hepatocellular adenomas in
    males, the increase in the incidence of these tumours remained
    statistically significant when corrected for mortality. Historical
    data on tumour incidence in the strain used for this study were not
    available. Other exposure-related lesions included hepatic foci of
    cellular alteration and focal pancreatic acinar cell hyperplasia
    (lesions less than 3 mm in diameter) in males and females at 1000 and
    5000 ppm (6.25 and 31.3 g/m3), in addition to hepatic focal necrosis
    in males, cholangiofibrosis in females, and hepatic centrilobular
    fatty change in both sexes at 5000 ppm (31.3 g/m3). Dose-related
    focal Leydig cell hyperplasia (lesions less than the diameter of three
    adjacent tubules) was observed in male rats exposed to 1000 and
    5000 ppm (6.25 and 31.3 g/m3). The incidence of diffuse retinal
    atrophy was increased in both sexes at all exposure levels. Serum
    triglycerides and cholesterol continued to be decreased in both sexes
    by 46-75% and 31-48%, respectively.

         As there were changes in clinical chemistry parameters and an
    increased incidence of hepatocellular and Leydig cell adenomas at the
    lowest dose tested (300 ppm [1.88 g/m3]), a NOAEL was not
    established in this study.

    8.5  Genotoxicity and related end-points

         HCFC-123 was not mutagenic in  Salmonella typhimurium strain
    TA98, TA100, TA1525, TA1537, or TA1538 with or without metabolic
    activation, even at concentrations of 750 mg per vessel or 150 000 ppm
    (938 g/m3), which were clearly toxic (Callander, 1989). HCFC-123 was
    found to be clastogenic in two separate studies in human lymphocytes
     in vitro, both with and without metabolic activation, at relatively
    high concentrations that also reduced the mitotic rate (Table 3). It
    was also noted to be clastogenic in the absence, but not in the
    presence, of a metabolic activation system in human lymphocytes
    exposed to the chemical at 500 µg/ml; further details were not
    available (ICI, 1992). No transformation to anchorage-independent
    cells was observed when HCFC-123 was tested in baby hamster kidney
    fibroblasts (BHK21 cells) with and without metabolic activation
    (Longstaff et al., 1984).


        Table 1: Summary of effect levels in subchronic inhalation toxicity studies.
                                                                                                                          

    Species             Study design            Effects                         Effect levels          Reference
                                                                                                                          

    Rats, albino,       Exposed to 0, 500,      Body weight marginally          LOAEL = 500 ppm        Industrial Bio-Test
    35 males and        1000, or 5000 ppm       decreased in females at         (3.13 g/m3)            Laboratories, 1977;
    25 females          (0, 3.13, 6.25, or      1000 ppm and in both sexes                             Rusch et al., 1994
    per group           31.3 g/m3) HCFC-123     at 5000 ppm. Kidney weight
                        for 90 days, with a     increased in all male test
                        30-day recovery         groups and in females at
                        period.                 5000 ppm (% change not
                                                reported). Relative liver
                                                weight increased in females
                                                at all exposure levels and
                                                in males at 5000 ppm 
                                                (% change not reported).
                                                Microscopic liver lesions
                                                included mild focal necrosis
                                                in males from all test groups
                                                and minimal bile duct
                                                proliferation in males at
                                                5000 ppm. At end of recovery
                                                period, there were no
                                                exposure-related body or organ
                                                weight changes or
                                                histopathological findings.

    Rats,               Exposed to 0, 1000,     Reversible motor                LOAEL = 1000 ppm       Doleba-Crowe, 1978;
    Sprague-Dawley,     or 10 000 ppm (0,       incoordination and              (6.25 g/m3)            Rusch et al., 1994
    27 per sex          6.25, or 62.5 g/m3)     unresponsiveness to noise       
    per group           HCFC-123 for 90 days.   at 10 000 ppm. Reduced body     
                        Histopathological       weight (8-17%) and increased    
                        examination performed   relative liver weight           
                        on 6 animals per        (% change not reported) in      
                        group.                  both test groups.

    Table 1 (cont'd)
                                                                                                                          

    Species             Study design            Effects                         Effect levels          Reference
                                                                                                                          

                                                No exposure-related gross or    
                                                histopathological findings.     
                                                Elevated levels of AST in       
                                                males at both exposure levels,  
                                                ALT in males at 1000 ppm, and   
                                                blood urea nitrogen (BUN) in    
                                                males at both exposure levels   
                                                and in females at 1000 ppm;     
                                                glucose decreased in females    
                                                in both test groups and in      
                                                males at 10 000 ppm (% change   
                                                not reported).                  

    Rats,               Exposed to 0, 300,      Reduced responsiveness to       LOAEL = 300 ppm        Malley, 1990; 
    Sprague-Dawley,     1000, or 5000 ppm       auditory stimuli at 1000 and    (1.88 g/m3)            Rusch et al., 
    10 per sex          (0, 1.88, 6.25, or      5000 ppm. Relative liver                               1994
    per group           31.3 g/m3) HCFC-123     weight increased by 12-17%      
                        for 90 days.            and 19-22%, respectively, at    
                                                1000 and 5000 ppm. No           
                                                exposure-related gross or       
                                                histopathological findings.     
                                                Dose-dependent elevations of    
                                                AST, ALT, lactate               
                                                dehydrogenase (LDH) in males    
                                                at 1000 and 5000 ppm and BUN    
                                                in females in all test groups   
                                                and in males at 1000 and 

    Table 1 (cont'd)
                                                                                                                          

    Species             Study design            Effects                         Effect levels          Reference
                                                                                                                          

                                                5000 ppm. Triglycerides and     
                                                glucose markedly decreased      
                                                and hepatic ß-oxidation         
                                                activity increased 2- to        
                                                4-fold in all test groups.      
                                                Dose-dependent decrease in      
                                                cholesterol in females at       
                                                1000 and 5000 ppm.

    Rats,               Exposed to 0, 300,      Reversible reduction in         NOAEL = 300 ppm        Coombs, 1994
    Sprague-Dawley,     1000, or 5000 ppm       arousal at 1000 and 5000        (1.88 g/m3)
    10 per sex          (0, 1.88, 6.25, or      ppm. No exposure-related
    per group           31.3 g/m3) HCFC-123     gross or histopathological
                        for 90 days, with a     findings in cerebrum,
                        28-day recovery         medulla/pons, cerebellar
                        period. Histological    cortex, spinal cord, ganglia,
                        examinations limited    dorsal and ventral root
                        to nervous tissues.     fibres, or peripheral nerves.

    Dogs, beagles,      Exposed to 0, 1000,     Reversible motor                LOAEL = 1000 ppm       Doleba-Crowe, 1978;
    4 males per group   or 10 000 ppm           incoordination and              (6.25 g/m3)            Rusch et al., 1994
                        (0, 6.25, or 62.5       unresponsiveness at
                        g/m3) HCFC-123 for      10 000 ppm. At 10 000 ppm,
                        90 days.                discoloured livers with
                                                hepatocyte hypertrophy and
                                                necrosis with inflammatory
                                                cell infiltration. Elevated
                                                levels of ALP in both test
                                                groups and of BUN at 10 000
                                                ppm (% change not reported).
                                                                                                                          

    Table 2: Incidence of selected non-neoplastic and neoplastic lesions in the liver, pancreas, and testes
    in the 2-year rat inhalation study.a,b
                                                                                                                 
                                                            Incidence of lesions
                                                                                                        
                                            0 ppm         300 ppm            1000 ppm           5000 ppm
                                                                                                                 

    Male
                                                                                                                 
    Liver

          Hepatocellular adenoma            3/67          2/66               2/66               8/66c

          Basophilic foci of alteration     8/67          10/66              20/66d             30/66d

          Clear cell foci of alteration     8/67          9/66               30/66d             19/66d

          Mixed foci of alteration          3/67          6/66               6/66               12/66d

          Eosinophilic foci of alteration   8/67          16/66              18/66d             13/66

          Cholangiofibroma                  0/67          0/66               0/66               0/66

          Cholangiofibrosis                 0/67          0/66               0/66               0/66

    Pancreas

          Acinar cell adenoma               1/67          4/66               12/64e             14/66e

          Focal acinar cell hyperplasia     5/67          6/66               13/64d             19/66d

    Testes

          Leydig cell adenoma               4/67          12/66f             9/66f              14/66f

          Leydig cell hyperplasia           8/67          15/66              23/66d             30/66d

    Table 2 (cont'd)
                                                                                                                 
                                                            Incidence of lesions
                                                                                                         
                                            0 ppm         300 ppm            1000 ppm           5000 ppm
                                                                                                                 
    Female
                                                                                                                 
    Liver

          Hepatocellular adenoma            0/65          5/67e              2/67               7/69e

          Basophilic foci of alteration     17/65         26/67              32/67d             46/69d

          Clear cell foci of alteration     14/65         7/67               16/67              15/69

          Mixed foci of alteration          2/65          3/67               13/67d             22/69d

          Eosinophilic foci of alteration   8/65          11/67              22/67              30/69d

          Cholangiofibroma                  0/65          0/67               0/67               6/69e

          Cholangiofibrosis                 0/65          0/67               0/67               9/69d

    Pancreas

          Acinar cell adenoma               0/65          2/66               0/67               2/69

          Focal acinar cell hyperplasia     0/65          4/66               6/67d              8/69d
                                                                                                                 

    a From Malley (1992); Malley et al. (1995).
    b Only lesions whose incidence attained statistical significance in at least one male or female dose
      group are included in the table. Other non-statistically significant lesions are discussed in the
      text. The figures give the number of lesions per number of tissues available for histological
      examination. A few animals and tissues were lost due to autolysis.

    c P < 0.05 (Cochran-Armitage test for trend).
    d P < 0.05 (Fisher's exact test compared with controls).
    e P < 0.05 (Cochran-Armitage test for trend and 2/2 tests for mortality-adjusted statistical analysis).
    f P < 0.05 (Cochran-Armitage test for trend and 1/2 tests for mortality-adjusted statistical analysis).

    


          In vivo, a test for chromosome aberrations in the lymphocytes
    of rats exposed by inhalation to up to 5000 ppm (31.3 g/m3) HCFC-123
    for 6 h per day, 5 days a week, for 2 weeks was negative (Marshal,
    1992), although the failure to induce signs of cytotoxicity cast doubt
    on the validity of this finding. No increase was found in the
    incidence of micronuclei or in the ratio of polychromatic to
    normochromatic erythrocytes in a micronucleus test in mice exposed
    nose-only to up to 18 000 ppm (113 g/m3) HCFC-123 for 6 h (Muller &
    Hofmann, 1988). In the livers of rats exposed to 12 500 or 20 000 ppm
    (78.1 or 125 g/m3) HCFC-123 for 6 h, neither net nuclear grain count
    nor percentage cells in repair showed any evidence of unscheduled DNA
    synthesis (Kennelly, 1993).

         Although HCFC-123 was clastogenic  in vitro at high
    concentrations, all other  in vitro and  in vivo tests for genetic
    toxicity were negative. Overall, the available studies suggest that
    HCFC-123 is unlikely to be genotoxic  in vivo.

    8.6  Reproductive and developmental toxicity

         In studies conducted according to OECD guidelines, HCFC-123 was
    neither embryotoxic nor teratogenic in pregnant rats exposed for 6 h
    per day on days 6-15 of gestation by inhalation to 0, 5000, or 10 000
    ppm (0, 31.3, or 62.5 g/m3) HCFC-123, although maternal toxicity in
    the form of reduced weight gain and CNS depression were observed at
    both exposure levels (Culik & Kelly, 1976; Brewer & Smith, 1977). In a
    range-finding study in which fetal examinations were limited to
    external structural abnormalities, HCFC-123 was not embryotoxic or
    teratogenic in pregnant rabbits exposed for 6 h per day on days 6-18
    of gestation by inhalation to 0, 500, 1500, or 5000 ppm (0, 3.13,
    9.38, or 31.3 g/m3) HCFC-123, although dose-related maternal
    toxicity characterized by reduced weight gain and food consumption was
    evident at all exposure levels (Malinverno et al., 1996).

         In a two-generation reproductive toxicity study in Sprague-Dawley
    rats conducted in accordance with OECD guidelines, male and female
    animals were exposed for 6 h per day, 7 days a week, by inhalation to
    0, 30, 100, 300, or 1000 ppm (0, 0.188, 0.625, 1.88, or 6.25 g/m3)
    HCFC-123 (Hughes, 1994; Malinverno et al., 1996). The F0 (parental
    generation) animals were exposed from 6 weeks of age for 23-39 weeks,
    including a 2-week mating period, the gestation period, and, except
    for maternal animals on postpartum days 0-4, until the offspring were
    weaned. The F1 generation was exposed from 4 weeks of age through to
    weaning of their litters (F2 generation), for a total of
    approximately 28 weeks.


        Table 3: Chromosome aberrations in human lymphocytes in vitro.
                                                                                                                      

    Physical form of    Exposure            Concentrationb      Mean mitotic      Number of            Reference
    HCFC-123            protocola                               index             cells with
                                                                                  aberrations
                                                                                  (excluding gaps)
                                                                                                                      

    Liquid              3-h exposure        0 µg/ml             25.2              1                    Dance, 1991
                        (without S9)        73 µg/ml            19.6              2
                                            146 µg/ml           21.7              3
                                            292 µg/ml           21.1              3
                                            CBC (2 µg/ml)       14.0              91

                        3-h exposure        0 µg/ml             23.8              1
                        (with S9)           146 µg/ml           21.8              2
                                            292 µg/ml           14.7              6
                                            584 µg/ml           6.6               5
                                            CP (6 µg/ml)        8.4               106

                        24-h exposure       0 µg/ml             30.7              2
                        (without S9)        36 µg/ml            27.4              3
                                            73 µg/ml            21.5              10c
                                            292 µg/ml           9.7               31d
                                            CBC (2 µg/ml)       22.9              70

                                                                                                                      

    Vapour              3-h exposure        0 ppm               24.9              1                    Edwards, 1991
                        (without S9)        75 000 ppm          23.9              3
                                            150 000 ppm         17.9              0e
                                            300 000 ppm         10.3              5e
                                            CBC (2 µg/ml)       18.5              60

    Table 3 (cont'd)
                                                                                                                      

    Physical form of    Exposure            Concentrationb      Mean mitotic      Number of            Reference
    HCFC-123            protocola                               index             cells with
                                                                                  aberrations
                                                                                  (excluding gaps)
                                                                                                                      

                        3-h exposure        0 ppm               22.2              4
                        (with S9)           75 000 ppm          24.1              3
                                            150 000 ppm         21.0              4
                                            300 000 ppm         9.5               23e,f
                                            CP (6 µg/ml)        15.2              107

                        24-h exposure       0 ppm               16.6              1
                        (without S9)        25 000 ppm          19.1              9d
                                            50 000 ppm          13.2              18f
                                            100 000 ppm         5.9               24f
                                            CBC (2 µg/ml)       13.5              118
                                                                                                                      

    a S9 = metabolic activation system.
    b Positive controls: CBC = chlorambucil; CP = cyclophosphamide.
    c P < 0.05.
    d P < 0.01.
    e Increase in number of polyploid cells.
    f P < 0.001.
    


         The only adverse reproductive effect was a 17% decrease in
    implantation count among F1 females at the highest exposure level.
    In terms of development, pup growth was impaired during the
    pre-weaning period when exposure was confined to the lactating parent
    female. In the F1 generation, mean pup weight was decreased by
    approximately 10% at exposures at and above 100 ppm (0.625 g/m3),
    whereas mean pup weight in F1 offspring (F2 generation) was
    decreased by approximately 20% at all exposure levels. In adult rats,
    retarded weight gain was observed at 100 ppm (0.625 g/m3) and above
    in F0 animals and at 300 ppm (1.88 g/m3) and above in the F1
    generation. There was a dose-dependent, 8-39% increase in liver weight
    in all exposed F0 groups and an 8-10% increase at 100 ppm (0.625
    g/m3) and above in F1 animals. In F1 animals exposed to HCFC-123
    for approximately 28 weeks, exposure-related histopathological changes
    were confined to a dose-related increase in the incidence of
    centrilobular hepatocyte enlargement and in the incidence and degree
    of hepatocyte vacuolation at 300 ppm (1.88 g/m3) and above. No
    microscopic changes were detected in the livers of F2 weanling rats
    from the 1000 ppm (6.25 g/m3) exposure group. In both generations,
    there was a decrease in serum triglycerides in both sexes, whereas
    serum cholesterol was increased in males and decreased in females.
    Levels of ALT, AST, or other liver enzymes were not determined. Male
    rats exposed at or above 300 ppm (1.88 g/m3) had increased plasma
    levels of luteinizing hormone (LH) after 10 weeks of exposure, which
    had reverted to normal at week 38. In this study, the NOAEL, based on
    effects on fertility, was 300 ppm (1.88 g/m3). The LOAEL, based on
    developmental effects (retarded neonatal growth during lactation) and
    on increased liver weight and changes in liver-related clinical
    chemistry parameters, was 30 ppm (0.188 g/m3). 

         After 22 weeks of exposure, a sample of F1 male rats was drawn
    from the two-generation reproductive toxicity study for
    endocrinological investigations (Sandow et al., 1995b). In 10 males
    from each exposure group, serum levels of LH and testosterone were
    determined before and after an injection of LH releasing hormone. The
    testes of another eight males per group were incubated  in vitro with
    human chorionic gonadotropin (which stimulates steroid hormone
    biosynthesis). The incubation medium and testis tissue were analysed
    for content of testosterone, progesterone, estradiol-17-ß, 17
    alpha-OH-progesterone, and delta-4-androstenedione. Basal serum LH and
    testosterone levels were similar to those of controls. However, after
    stimulation with LH releasing hormone, the LH in rats exposed to 300
    ppm (1.88 g/m3) was 32% lower than in controls; at 1000 ppm (6.25
    g/m3), LH was 39% and testosterone 46% lower than in the control
    group. In the  ex vivo test, HCFC-123 inhalation did not affect the
    secretory capacity for steroid hormones or alter the content of these
    hormones in the testes at the end of the incubation period, except for
    a slight reduction of delta-4-androstenedione at 1000 ppm (6.25
    g/m3).

         In an endocrinological study in rats of both sexes, exposure to
    5200 ppm (32.5 g/m3) HCFC-123 for 6 h per day (similar to the
    highest dose level in the 2-year bioassay) for 14 consecutive days was
    associated with sedation, decreased body, kidney, ovary, and pituitary
    weights in females, and increased relative liver weight in males
    (Hofmann, 1995; Sandow et al., 1995a). In males, the prolactin
    response after monoiodotyrosine stimulation, the testosterone response
    after stimulation with buserelin (a synthetic gonadotropin releasing
    hormone), and the testicular testosterone content were all reduced by
    approximately 50%. In females, the gonadotropin response to buserelin
    stimulation was enhanced and the pituitary content of follicle
    stimulating hormone and prolactin was reduced, in both cases by
    approximately 50%.

         These endocrinological investigations indicate that HCFC-123 has
    little, if any, effect on steroid production in rat testes, but
    impairs the prolactin, LH, and testosterone response to pituitary
    stimulants. The NOAEL based on this effect was 100 ppm (0.625 g/m3).

         A lactation study was conducted in groups of pregnant and
    lactating Sprague-Dawley (Crl:CD BR) rats exposed to 0 or 1000 ppm (0
    or 6.25 g/m3) HCFC-123 for 6 h per day on days 5-19 of gestation and
    on days 5-21 postpartum (Buschman, 1996). Within 2 days of birth,
    litters were crossed over between dams to create four groups
    comprising exposed or control dams rearing litters from different
    exposed or control mothers. Absolute and relative liver weights were
    increased and serum triglycerides, cholesterol, and glucose decreased
    in dams exposed to HCFC-123. The milk of dams exposed to HCFC-123 was
    of normal quantity and quality (with regard to content of protein,
    lactose, and fat) but contained trifluoroacetic acid at an average
    concentration of 50 µg/ml. Trifluoroacetic acid was also found in the
    urine of pups reared by dams exposed to HCFC-123. There were no
    differences in absolute or relative liver weight or any abnormal
    clinical signs or gross findings in any of the groups of pups, but
    pups reared by dams exposed to HCFC-123 had a 10% lower growth rate
    and decreased serum triglycerides compared with pups reared by
    non-exposed dams. Before crossover, there was no difference between
    groups with respect to mean pup and litter weight. As such, these
    findings indicate that the retarded neonatal growth observed in the
    two-generation reproductive toxicity study was due to factors in the
    milk of exposed mothers, probably trifluoroacetic acid, rather than to
    exposure  in utero.

         When groups of four lactating rhesus monkeys and their neonates
    were exposed to either 0 or 1000 ppm (0 or 6.25 g/m3) HCFC-123 for 6
    h per day for 21-22 consecutive days, there were no effects on
    maternal body weight, serum triglycerides, cholesterol, and glucose,
    or milk composition (Slauter, 1997). Liver biopsy specimens taken from
    the mothers at the end of the study revealed exposure-related lesions,

    including mild to moderate centrilobular hepatocyte vacuolation, trace
    to moderate centrilobular hepatocyte necrosis, and trace to mild
    subacute inflammation. As a rule, HCFC-123 was not detected in the
    blood of mothers or neonates, whereas trifluoroacetic acid was present
    at concentrations of 9-70 µg/ml in exposed mothers and of 17-190 µg/ml
    in neonates, with individual blood levels being 2-6 times higher in
    the neonates than in their corresponding mothers. Milk from exposed
    mothers contained HCFC-123 and trifluoroacetic acid at concentrations
    of 1-5 µg/ml and 17-30 µg/ml, respectively. Although no statistical
    analysis was attempted because of the small number of observations,
    the average growth rate was 10% lower in exposed neonates than in
    unexposed controls. 
    

    9.  EFFECTS ON HUMANS

         The available data on the human health effects of HCFC-123 were
    limited to a single case report of dizziness, headache, and nausea in
    workers exposed to unknown levels of the chemical following the
    rupture of an industrial chiller1 and three case reports of hepatic
    effects involving 26 workers following repeated exposure to HCFC-123
    vapours.

         Nine cases of liver effects were reported in gantry drivers at a
    smelting depot in Belgium (Hoet et al., 1997). They occurred 1-4
    months after the refrigerant utilized in the crane cabin
    air-conditioning system had been replaced by a blend containing 57%
    HCFC-123, 40% HCFC-124 (1-chloro-1,2,2,2-tetrafluoroethane), and 3%
    propane.2 One driver admitted to hospital was found to have
    increased levels of AST, ALT, ALP, gamma-glutamyl transferase, and
    total and conjugated bilirubin and decreased prothrombin activity,
    with AST and ALT levels being 15-23 times above the upper limit of the
    normal range. Autoimmune, viral, and drug- or alcohol-induced
    hepatitis were ruled out. A liver biopsy showed focal liver cell
    necrosis, plugging of bile ducts, and the presence of
    trifluoroacetylated proteins. The symptoms regressed during the period
    of non-exposure but recurred when the driver returned to work 2 months
    later. Eight other drivers showed signs of varying degrees of liver
    abnormalities. Serum antibodies to human liver enzymes (CYP2E1 and/or
    protein disulfide isomerase isoform P58) were detected in five of six
    cases examined. A workplace inspection revealed that the plastic pipes
    of the air-conditioning system were perforated and that refrigerant
    was leaking into the crane cabin. No further cases occurred after the
    system was repaired. Although the workers were exposed to both
    HCFC-123 and HCFC-124, the latter is unlikely to have contributed to
    the observed effects, as the NOAEL for HCFC-124 was 50 000 ppm (280
    g/m3) in a 90-day inhalation toxicity study in rats (Malley et al.,
    1996), whereas the LOAEL for HCFC-123 in a similar study in the same
    strain and laboratory was 300 ppm (1.88 g/m3) (Table 1).

         Eight cases of liver effects were reported in workers exposed to
    the vapours of a solvent degreaser containing HCFC-123.3 Two months
    after a US factory converted to using HCFC-123 in its degreaser, two
    employees who worked closely with the degreaser were found to have
    liver disease. They had elevated blood levels of liver enzymes,
    particularly ALT (32-56 times above the upper limit of the normal
                    

    1 Carrier Canada Ltd, personal communication, 1993 [cited in 
      NICNAS, 1996].

    2 N. Verlinden, personal communication, 1997 [cited in 
      NICNAS, 1999].

    3 AlliedSignal Inc., personal communication, 1998 [cited in 
      NICNAS, 1999].

    range) and AST (14-33 times above the upper limit of the normal
    range), had elevated total and conjugated bilirubin, and tested
    negative for viral hepatitis. Subsequent testing of all 27 factory
    employees revealed four additional cases of elevated liver enzymes.
    When retested 1 month later but before the use of HCFC-123 was
    discontinued, five of the affected employees had improved markedly,
    whereas one had deteriorated, and there was one new case with slightly
    elevated ALT and AST levels. All in all, liver enzymes were elevated
    in 3 of 4 employees who worked with the degreaser and in 4 of 23
    workers who did not. Air monitoring was conducted when HCFC-123 use
    began and again shortly after the first cases were diagnosed. Personal
    air monitoring during normal degreaser operations showed 5.5-h
    time-weighted average levels of HCFC-123 that ranged from 5.3 to 
    12.0 ppm (33.1 to 75.0 mg/m3) throughout the facility, whereas 
    short-term breathing-zone levels ranging from 160 to 460 ppm (1000 to 
    2880 mg/m3) were measured in workers charging and unloading the
    degreaser. There was also one case of elevated liver enzymes with
    negative tests for viral hepatitis in a technician employed in the
    manufacturer's research laboratory where the degreaser was tested and
    evaluated. Static air levels in the laboratory were reported to be
    generally below 50 ppm (313 mg/m3) HCFC-123. 

         In a factory in Japan where miniature heat exchangers were filled
    with HCFC-123 in a poorly ventilated room, 9 out of 14 workers were
    found to have elevated levels of liver enzymes 4-5 weeks after
    production had commenced (Takebayashi et al., 1998a,b).1 Four of
    them were clinically ill, and two had jaundice. In these workers, AST
    and ALT were up to 20-30 times above the upper limit of the normal
    range. After an exhaust system was installed that maintains the
    concentration of airborne HCFC-123 at about 1 ppm (6.25 mg/m3),
    trifluoroacetic acid was not detected in the workers' urine; at
    follow-up 1 year later, there were no further cases of clinical
    illness or elevated liver enzymes.1 Exposure levels were not
    measured, but a simulation of the original working conditions
    indicated static air levels ranging from 5 to 1125 ppm (31.3 to 
    7030 mg/m3) (6-h time-weighted average), depending on the distance
    from the filling area.

                 

    1 Also T. Takebayashi, personal communication, 1999 [cited in
      NICNAS, 1999].



        Table 4: Summary of effects of HCFC-123 in aquatic organisms.
                                                                                                                         

    Test                        Species               Effects and effect         Comments               Reference
    levels
                                                                                                                         

    Acute toxicity (96 h),      Fathead minnow        Lethargy                   Rapid degassing        Pierson,
    flow-through conditions     (Pimephales           LC50 > 76 mg/litre         of HCFC-123            1990a
                                promelas)             (measured)                 from test
                                                                                 solutions

    Acute toxicity (96 h),      Rainbow trout         Lethargy, darkened                                Jenkins, 1992b
    static conditions           (Oncorhynchus         pigmentation at
                                mykiss)               15 mg/litre and
                                                      above
                                                      LC50 = 56 mg/litre
                                                      (measured)

    Immobilization (48 h),      Daphnia magna         Lethargy                                          Jenkins, 1992c
    static conditions                                 EC50 = 17 mg/litre
                                                      (measured)

    Immobilization (48 h),      Daphnia magna         Lethargy                   Measured               Pierson, 1990b
    static conditions                                 EC50 = 45.8 mg/litre       concentrations
                                                      (nominal)                  <75% of nominal

    Algal growth inhibition     Selenastrum           EC50 = 68                  Based on biomass       Jenkins, 1992d
    (96 h), static conditions   capricornutum         mg/litre (measured)        integral
                                                                                                                         
    
    


    10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         The available ecotoxicological data for HCFC-123 are summarized
    in Table 4. The data indicate that the chemical is, at most, slightly
    toxic to aquatic organisms under conditions of acute exposure. Chronic
    effects would not be expected because of limited aquatic persistence.

         Trifluoroacetic acid, which is formed by atmospheric breakdown of
    HCFC-123, has been found to be of low toxicity in stream mesocosms,
    algae, higher plants, fish, and mammals (Boutonnet et al., 1999). The
    lowest threshold for any effect was 0.12 mg sodium
    trifluoroacetate/litre, above which the chemical had reversible
    effects on the growth of the alga  Selenastrum capricornutum. In the
    most sensitive terrestrial species tested (sunflower), sodium
    trifluoroacetate at 1 mg/kg dry soil had clear effects on vegetative
    growth, whereas long-term root exposure of wheat and soya to sodium
    trifluoroacetate at 1 mg/litre had no effect.
    

    11. EFFECTS EVALUATION

    11.1 Evaluation of health effects

    11.1.1 Hazard identification and dose-response assessment

         There was inadequate information on the human health effects of
    short-term exposure to HCFC-123. In laboratory animals, HCFC-123
    exhibits low acute toxicity, with an approximate oral lethal dose of 
    9 g/kg body weight, a 4-h LC50 by inhalation in the range of
    28 400-52 600 ppm (178-329 g/m3), and a dermal LD50 in excess of
    2000 mg/kg body weight. It is not a skin irritant or sensitizer, but
    liquid HCFC-123 produces mild to moderate eye irritation. The critical
    effects associated with acute exposure are non-fatal liver damage, CNS
    depression, and cardiac sensitization to adrenaline. When inhaled in
    lethal concentrations, death was caused by severe CNS depression. For
    a single, 4-h exposure by inhalation, the LOAEL was 1000 ppm 
    (6.25 g/m3) for liver damage, based on liver cell necrosis and 
    increased levels of circulating liver enzymes in guinea-pigs, and 5000 
    ppm (31.3 g/m3) for CNS depression, based on failures in 
    unconditioned reflexes in rats. The NOAEL for cardiac sensitization to
    adrenaline in dogs was 10 000 ppm (62.5 g/m3). Although the dog is 
    a very sensitive species, cardiac sensitization to adrenaline-induced
    arrhythmia is likely to be a relevant critical effect resulting from
    short-term exposure in humans, such as the sudden discharge of fire
    extinguishants in occupied rooms (NAS, 1996). Under these
    circumstances, CNS depression may also be a critical effect. A large
    number of short-chain halogenated hydrocarbons with different
    metabolic patterns have similar CNS and cardiac effects, which likely
    result from a direct anaesthetic action on neurons and myocardial
    cells (IPCS, 1990, 1991, 1992).

         The critical effects associated with repeated exposure to
    HCFC-123 vapours are liver damage in humans as well as experimental
    animals, in addition to neonatal growth retardation, an increased
    incidence of benign tumours, and CNS depression, which have been
    recorded only in animals.

         Based on a limited number of case reports, biochemical
    abnormalities associated with liver injury have been observed in
    humans at exposure levels in the order of 5-1125 ppm (31.3-7030
    mg/m3). The available data are insufficient to define the
    dose-response relationship in humans. Liver damage was also seen in
    rats, guinea-pigs, dogs, and monkeys. The lesions generally involved
    increased liver weight accompanied by hepatocyte enlargement and
    vacuolation at the lowest exposure levels, with necrosis, fatty
    change, and mild subacute inflammation at higher concentrations. They
    were associated with or preceded by increased levels of circulating
    liver enzymes and decreased serum triglycerides, glucose, and
    cholesterol. The LOAEL for liver effects in animals recorded in a
    well-conducted two-generation reproductive toxicity study in rats
    equalled 30 ppm (188 mg/m3).

         The cytotoxicity of HCFC-123 is probably due to the reactive
    metabolite trifluoroacetyl chloride, which can bind covalently to
    proteins and interfere with their function and/or alter their
    antigenicity. The 200 : 20 : 1 ratio of trifluoroacetylation of liver,
    kidney, and heart tissue proteins reported by Huwyler et al. (1992)
    and Huwyler & Gut (1992) correlates well with the observed effect
    levels for these organs in subchronic toxicity studies (Table 1) and
    probably reflects tissue differences in metabolic capacity.

         There is no evidence that HCFC-123 is teratogenic in laboratory
    animals or induces reproductive or fetal toxicity at levels of
    exposure lower than those that cause other systemic effects in adults.
    Growth was retarded in neonatal rats and monkeys reared by dams
    exposed by inhalation to HCFC-123, with a LOAEL of 30 ppm
    (188 mg/m3). The main metabolite of HCFC-123, trifluoroacetic acid,
    was found in the milk of the dams. As such, breastfed babies may
    represent a subpopulation that is uniquely sensitive to HCFC-123.

         Reversible CNS depression was seen consistently in repeated-dose
    inhalation studies, but did not change in severity or duration with
    the number of exposures and was not associated with morphological
    changes in nervous tissues. As such, the mechanism of action is
    probably the same for both acute and chronic CNS depression. The
    lowest NOAEL for CNS effects from repeated administration was recorded
    in a neurotoxicity study in rats and equalled 300 ppm (1880 mg/m3),
    based on a reduction in arousal.

         Although there was evidence of clastogenic activity in human
    lymphocytes  in vitro at high, cytotoxic concentrations, all other
     in vitro and  in vivo tests for genetic toxicity were negative.
    Therefore, the evidence suggests that HCFC-123 is unlikely to be
    genotoxic  in vivo.

         In a 2-year inhalation study in rats, there was no
    exposure-related effect on the incidence of malignant tumours, but
    there was an increased incidence of hepatocellular adenomas,
    cholangiofibromas, pancreatic acinar cell adenomas, and Leydig
    adenomas. There was also an increase in the pre-cancerous lesions of
    hepatic foci of alteration, cholangiofibrosis, focal pancreatic acinar
    cell hyperplasia, and Leydig cell hyperplasia (Table 2). As stated
    above, HCFC-123 is unlikely to be genotoxic  in vivo. The minor,
    non-mutagenic metabolite 2-chloro-1,1,1-trifluoroethane caused an
    increased incidence of uterine carcinomas and Leydig cell adenomas in
    rats when given by oral gavage at 300 mg/kg body weight for 52 weeks
    (IPCS, 1992). However, only trace quantities would be formed from the
    metabolism of HCFC-123. Therefore, it is necessary to examine the
    mechanisms of tumour formation to establish if the modes of induction
    can be ruled out as relevant for humans:

    *     Hepatocellular adenomas. Several repeated-exposure studies have
         shown that HCFC-123 and its main metabolite, trifluoroacetic
         acid, like several other structurally diverse chemicals, induce
         peroxisome proliferation in rat hepatocytes (Warheit, 1993; Rusch
         et al., 1994; Malley et al., 1995; Keller et al., 1998).
         Peroxisome proliferators are generally not genotoxic but induce
         hepatocellular proliferation in rats and mice through a mechanism
         that appears to involve the expression of growth factors by
         hepatic macrophages, thus leading to liver tumour formation
         (Chevalier & Roberts, 1998). The hepatocellular adenomas seen in
         rats exposed to HCFC-123 may be related to the induction of
         peroxisome proliferation, which is a mechanism of questionable
         relevance for humans (Ashby et al., 1994). However, since the
         chemical is also hepatotoxic, which may have a role in the tumour
         formation, it is not possible to discount the hepatocellular
         adenomas as being of no concern to humans. It is, however,
         reasonable to adopt a threshold approach, based on adverse
         effects on the liver in subchronic exposure studies.

    *     Cholangiofibromas. Cholangiofibromas in the rat are atypical
         glandular structures lined by intestinal-like epithelium
         surrounded by dense connective tissue. Limited evidence from
         animal studies of various non-genotoxic chemicals, including
         chloroform and furan, suggests that this tumour type is
         associated with significant hepatocyte necrosis and regenerative
         cell proliferation that are relevant only at high dose/exposure
         levels (Elmore & Sirica, 1993; Jamison et al., 1996). In the
         2-year rat study, cholangiofibromas and cholangiofibrosis
         occurred only in females exposed to HCFC-123 at 5000 ppm (31.3
         g/m3). The incidence of basophilic and eosinophilic foci of
         hepatocellular proliferation was also higher in females than in
         males (Table 2). Although the threshold level for the induction
         of cholangiofibromas in female rats was high, there is no
         mechanistic evidence that this tumour type can be dismissed with
         regard to its relevance to humans.

    *     Pancreatic acinar cell adenomas. Some hepatocarcinogenic
         peroxisome proliferators have been reported to induce tumours in
         other organs, including pancreatic acinar cell adenomas and
         Leydig cell adenomas, although these extrahepatic tumours appear
         not to be associated with peroxisome proliferation in the target
         organ (IARC, 1995). Although pancreatic acinar cell adenomas were
         found only in males at 1000 and 5000 ppm (6.25 and 31.3 g/m3),
         the incidence was dose-related. Moreover, pancreatic acinar cell
         hyperplasia occurred in both sexes, likewise in a dose-dependent
         manner (Table 2). As such, until more is known about the
         mechanism for acinar cell tumour induction in animals and humans,
         the possibility that the pancreatic adenomas found in rats
         exposed to HCFC-123 may have some relevance to humans cannot be
         discounted.

    *     Leydig cell adenomas. The available studies indicate that
         exposure to HCFC-123 may be associated with endocrine
         disturbances in male rats, particularly in relation to prolactin
         release and serum LH concentrations. In rats, but not in humans,
         a decrease in serum prolactin causes a decrease in the number of
         LH receptors on Leydig cells and thus a decrease in testosterone
         production, which results in increased LH levels that in turn may
         induce Leydig cell hyperplasia and adenomas (Clegg et al., 1997).
         As such, it is conceivable that intermittent exposure to HCFC-123
         could lead to fluctuations in prolactin and testosterone that in
         rats could induce transient increases in LH and, with time,
         Leydig cell growth and tumours. Although prolactin fluctuations
         would not be of concern in men, the effects of HCFC-123 on the
         sex hormone system are complex. Thus, in the absence of data from
         studies in primates, the increased incidence of Leydig cell
         adenomas in the 2-year rat study cannot be dismissed with respect
         to its relevance for humans.

         In summary, it is likely that the benign tumours in the 2-year
    rat bioassay involve one or more non-genotoxic mechanisms, including
    peroxisome proliferation, hepatocellular damage, necrosis and
    regenerative proliferation, and disturbance of the
    hypothalamic-pituitary-testicular axis. Although humans may be less
    sensitive to tumours arising from some of these actions, overall it is
    not possible to discount the tumours in an evaluation of the potential
    risk for humans. Therefore, the increased incidence of benign tumours
    in the rat raises some concern with respect to the potential
    carcinogenicity in humans. The tumours probably arise from
    non-genotoxic mechanisms. In the 2-year bioassay, the tumour incidence
    was increased at 300 ppm (1.88 g/m3), the lowest level tested, and a
    NOAEL was not established. In subchronic toxicity studies, the LOAEL
    based on any adverse effect on the liver was 30 ppm (0.188 g/m3)
    (Hughes, 1994; Malinverno et al., 1996).

    11.1.2 Criteria for setting tolerable intakes or guidance values
           for HCFC-123

         Derivation of a guidance value for HCFC-123 was outside the scope
    of the source documents (NICNAS, 1996, 1999). General advice about the
    derivation of tolerable intakes and guidance values for health-based
    exposure limits is set out in Environmental Health Criteria 170 (IPCS,
    1994).

         Exposure of the general public to HCFC-123 is likely to be
    minimal. The main risk to human health is through repeated
    occupational exposure via inhalation.

         The critical effects of repeated low-level exposure to HCFC-123
    are liver damage, which has been observed in all species investigated,
    including monkeys and humans, and retarded neonatal growth during
    lactation, which has been observed in rats and monkeys. In the absence
    of sufficient data to establish a dose-response relationship in
    humans, a guidance value for exposure to HCFC-123 must be based on the
    observed effect levels for liver lesions and retarded neonatal growth
    during lactation in pivotal animal studies. For both of these critical
    effects, a LOAEL of 30 ppm (188 mg/m3) was established in a
    well-conducted two-generation reproductive toxicity study in rats,
    whereas a NOAEL was not achieved (Hughes, 1994; Malinverno et al.,
    1996).

         The uncertainty factor applied to extrapolate from the LOAEL to a
    NOAEL must allow for the fact that whereas the recorded liver effects
    at the LOAEL were mild, hepatotoxicity may have a role in the
    induction of benign liver tumours in rats. Moreover, the growth
    retardation in neonates during lactation was in the order of 10-20%.
    It is likely that the liver effects are related to the formation of
    protein adducts with trifluoroacetyl chloride and that growth
    retardation in neonates is related to exposure to trifluoroacetic acid
    in maternal milk. Therefore, the uncertainty factor used to
    extrapolate the NOAEL from rats to humans must allow for the lack of
     in vivo data on the metabolic rate and other toxicokinetic
    properties of HCFC-123 in humans. Finally, an additional uncertainty
    factor must be applied to allow for human variability in
    toxicokinetics, as the metabolism of HCFC-123 to trifluoroacetyl
    chloride and trifluoroacetic acid is catalysed by CYP2E1 
    (Urban et al., 1994), whose activity is known to be influenced by 
    genetic polymorphism, body weight, and dietary factors (Le Marchand 
    et al., 1999).

    11.1.3 Sample risk characterization

         Adverse effects of HCFC-123 in animals and humans have been
    observed only at concentrations that were several orders of magnitude
    higher than those in the only known medium of exposure (air) in the
    general environment. The likelihood of public exposure as a
    consequence of catastrophic accidents or fire extinguishant discharges
    is very small, and the scale and duration of such exposures are
    expected to be low.

         With respect to repeated occupational exposures, 3- to 8-h
    time-weighted average personal exposure levels in an HCFC-123
    manufacturing plant were reported to be below 10 ppm (62.5 mg/m3).
    Reported 2- to 12-h time-weighted average breathing-zone levels in
    machinery rooms containing air-conditioning equipment generally ranged
    from below 1 to 5 ppm (below 6.25 to 31.3 mg/m3), whereas the use of
    a liquid HCFC-123 degreaser was associated with concentrations in the
    range of 5.3-12 ppm (33.1-75.0 mg/m3) HCFC-123. The available case
    reports indicate that humans may develop biochemical signs of liver

    disease, such as elevated AST and ALT, after 1-4 months of repeated
    exposure to HCFC-123 at levels above 5 ppm (31.3 mg/m3). Because the
    effects of low levels of HCFC-123 are due to toxic metabolites formed
    through CYP2E1, genetic, lifestyle, and dietary factors are expected
    to cause considerable variability in human susceptibility to the
    chemical.

    11.2 Evaluation of environmental effects

         Because of its high volatility, HCFC-123 released to the
    environment will partition almost entirely to the atmosphere. It is
    removed predominantly in the troposphere by reaction with hydroxyl
    radicals to form trifluoroacetic acid, and only a small fraction is
    transported to the stratosphere, where it may undergo photolysis and
    release chlorine radicals that catalyse the destruction of ozone.
    Because of its short atmospheric lifetime, estimated at 1.4 years, its
    ozone-depleting potential is low (0.02 relative to CFC-11). The global
    warming potential of HCFC-123 relative to carbon dioxide is 300, 93,
    and 29 over a time horizon of 20, 100, and 500 years, respectively
    (WMO, 1995).

         The aquatic EC50/LC50 values were below 100 mg/litre but
    above 10 mg/litre. As such, the chemical meets the European Community
    criteria for classification as harmful to the environment (Berends et
    al., 1999) and the globally harmonized criteria for classification as
    hazardous to the aquatic environment (Class: Acute III) (OECD, 1998).
    However, while HCFC-123 may be released to surface waters or soil, it
    is unlikely to persist in these media because of its high volatility.
    As such, it is considered that HCFC-123 does not constitute a
    long-term or delayed danger to the aquatic environment.

         Trifluoroacetic acid formed by degradation of HCFC-123 will
    precipitate in rain and may accumulate in closed aquatic systems such
    as salt lakes and seasonal wetlands. The maximum total contemporary
    deposition rate of trifluoroacetic acid from fluorocarbons has been
    estimated at 2800 tonnes a year, with 27% derived from HCFC-123 and
    the remainder from HCFC-124, HFC-134a, HFC-227ea, and the anaesthetic
    gases halothane and isoflurane (Boutonnet et al., 1999). In 2020, the
    maximum deposition from fluorocarbons is predicted to reach 160 000
    tonnes a year, yielding a maximum average concentration of
    trifluoroacetic acid in rainwater of 0.1 µg/litre, which is several
    orders of magnitude lower than the no-effect level in both surface and
    soil water. By that year, HCFC-123 emissions will have declined, as
    the chemical will have been phased out in accordance with the Montreal
    Protocol. As such, it can be concluded that environmental levels of
    trifluoroacetic acid resulting from the breakdown of HCFC-123 do not
    pose a threat to the environment.
    

    12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         A previous evaluation of HCFC-123 has been carried out by the
    International Programme on Chemical Safety (IPCS, 1992).

         Information on international hazard classification and labelling
    is included in the International Chemical Safety Card reproduced in
    this document (Appendix 4).
    

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    APPENDIX 1 -- SOURCE DOCUMENTS

    NICNAS (1996):  Priority Existing Chemical No. 4 --
     2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123), full public report,
     National Industrial Chemicals Notification and Assessment Scheme

         Copies of the NICNAS (1996) report on HCFC-123 (prepared by S.
    Batt, L. Onyon, L. Slosu, and D. Willcocks) may be obtained from:

         NICNAS
         Existing Chemicals
         GPO Box 58
         Sydney NSW 2001
         Australia

         NICNAS reports are prepared to meet the requirements of the
     Industrial Chemicals Notification and Assessment Act, 1989, as
    amended. In the preparation of the assessment report, both internal
    and external peer reviews are undertaken. Under the NICNAS
    legislation, applicants for the assessment of a chemical (i.e.,
    importers and manufacturers of a chemical) may apply for variations to
    the draft report. The following companies and industry associations
    participated in the review of the assessment at this stage:
    Association of Fluorocarbon Consumers and Manufacturers, Elf Atochem
    (Australia) Pty Ltd, Lovelock Luke Pty Ltd, and North American Fire
    Guardian Technology (Australia) Pty Ltd. The report was also open for
    public comment.

    NICNAS (1999):  2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123):
     Secondary Notification No. 4S, full public report. National
     Industrial Chemicals Notification and Assessment Scheme

         Copies of the NICNAS (1999) report on HCFC-123 (prepared by S.
    Batt, S. Kristensen, and C. Lee-Steere) may be obtained from:

         NICNAS
         Existing Chemicals
         GPO Box 58
         Sydney NSW 2001
         Australia

         NICNAS reports are prepared to meet the requirements of the
     Industrial Chemicals Notification and Assessment Act, 1989, as
    amended. In the preparation of the assessment report, both internal
    and external peer reviews are undertaken. Under the NICNAS
    legislation, applicants for the reassessment of a chemical (i.e.,
    importers and manufacturers of a chemical) may apply for variations to
    the draft report. The following companies participated in the review
    of the assessment at this stage: Du Pont (Australia) Pty Ltd, Elf
    Atochem (Australia) Pty Ltd, GSA Industries (Australia) Pty Ltd, MSA
    (Australia) Pty Ltd, North American Fire Guardian Technology
    (Australia) Pty Ltd, and Solvents Australia Pty Ltd. The report was
    also open for public comment.
    

    APPENDIX 2 -- CICAD PEER REVIEW

         The draft CICAD on HCFC-123 was sent for review to institutions
    and organizations identified by IPCS after contact with IPCS National
    Contact Points and Participating Institutions, as well as to
    identified experts. Comments were received from:

         Alexandria University, Faculty of Agriculture, Department of
         Pesticide Chemistry, Egypt

         AlliedSignal, Department of Toxicology and Risk Assessment,
         Health, Safety, Environment and Remediation, USA

         Department of Health, Protection of Health Division, 
         United Kingdom

         DuPont Fluoroproducts, Haskell Laboratory for Toxicology and
         Industrial Medicine, USA

         Federal Institute for Health Protection of Consumers and
         Veterinary Medicine, Germany

         Glaxo Wellcome Research and Development, Medicines Safety
         Evaluation Division, United Kingdom

         Health and Safety Executive, United Kingdom

         Institut de Recherche en Santé et en Sécurité du Travail du
         Québec, Canada

         Institute of Terrestrial Ecology, United Kingdom

         National Chemicals Inspectorate (KEMI), Sweden

         National Institute for Occupational Safety and Health, USA

         National Institute of Environmental Health Sciences, National
         Institutes of Health, USA

         National Institute of Public Health, Centre of Industrial Hygiene
         and Occupational Diseases, Czech Republic

         Université Catholique de Louvain, Faculté de Médecine, Belgique

         US Environmental Protection Agency, Drinking Water Program,
         Region VIII, USA

         World Health Organization, International Programme on Chemical
         Safety, Switzerland
    

    APPENDIX 3 -- CICAD FINAL REVIEW BOARD

    Sydney, Australia, 21-24 November 1999


    Members

    Dr R. Benson, Drinking Water Program, US Environmental Protection
    Agency, Region VIII, Denver, CO, USA

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

    Dr R.M. Bruce, National Center for Environmental Assessment, US
    Environmental Protection Agency, Cincinnati, OH, USA

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

    Dr R.S. Chhabra, National Institute of Environmental Health Sciences,
    National Institutes of Health, Research Triangle Park, NC, USA

    Dr S. Chou, Agency for Toxic Substances and Disease Registry, Atlanta,
    GA, USA

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

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

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

    Dr J. Kielhorn, Fraunhofer Institute for Toxicology and Aerosol
    Research, Hannover, Germany

    Dr S. Kristensen, National Occupational Health and Safety Commission
    (Worksafe), Sydney, NSW, Australia

    Mr C. Lee-Steere, Environment Australia, Canberra, ACT, Australia

    Ms M. Meek, Environmental Health Directorate, Health Canada, Ottawa,
    Ontario, Canada

    Ms F. Rice, National Institute for Occupational Safety and Health,
    Cincinnati, OH, USA

    Dr J. Sekizawa, National Institute of Health Sciences, Tokyo, Japan

    Dr D. Willcocks, National Industrial Chemicals Notification and
    Assessment Scheme (NICNAS), Sydney, NSW, Australia  (Chairperson)

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

    Observers

    Mr P. Howe, Institute of Terrestrial Ecology, Huntingdon,
    Cambridgeshire, United Kingdom

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

    Secretariat

    Dr A. Aitio, International Programme on Chemical Safety, World Health
    Organization, Geneva, Switzerland

    Ms M. Godden, Health and Safety Executive, Bootle, Merseyside, United
    Kingdom

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


        APPENDIX 4 -- INTERNATIONAL CHEMICAL SAFETY CARD
                                                                                                            
    2,2-DICHLORO-1,1,1-TRIFLUOROETHANE                                         ICSC: 1343
                                                                               November 1998
                                                                                                            
    CAS#           306-83-2                        HCFC 123
    RTECS#         KI1108000                C2HCI2F3/CHCI2CF3

                                            Molecular mass: 152.9
                                                                                                            
    TYPES OF HAZARD        ACUTE HAZARDS/             PREVENTION               FIRST AID / FIRE
    / EXPOSURE             SYMPTOMS                                            FIGHTING
                                                                                                            
    FIRE                   Not combustible.           NO open flames.          In case of fire in the
                                                                               surroundings: all
                                                                               extinguishing
                                                                               agents allowed.
                                                                                                            
    EXPLOSION                                                                  In case of fire: keep
                                                                               drums, etc., cool by
                                                                               spraying with water.
                                                                                                            

    EXPOSURE

                                                                                                            
    Inhalation             Confusion. Dizziness.      Local exhaust            Fresh air, rest.
                           Drowsiness.                or breathing             Artificial respiration
                           Unconsciousness.           protection.              if indicated. Refer for
                                                                               medical attention.
                                                                                                            
    Skin                                              Protective gloves.       Rinse skin with plenty
                                                                               of water or shower.
                                                                                                            
    Eyes                   Redness. Pain.             Safety spectacles.       First rinse with plenty
                                                                               of water for several
                                                                               minutes (remove contact
                                                                               lenses if easily possible),
                                                                               then take to a doctor.

                                                                                                            
    Ingestion              (See Inhalation).                                   Rest.

                                                                                                            

    SPILLAGE DISPOSAL                                 PACKAGING & LABELLING

                                                                                                            

    Collect leaking liquid in sealable containers.    EU Classification
    Absorb remaining liquid in sand or inert          UN Classification
    absorbent and remove to safe place. Do NOT
    let this chemical enter the environment.
    Chemical protection suit including
    self-contained breathing apparatus.


    EMERGENCY RESPONSE                                STORAGE

                                                      Keep in a well-ventilated room.







                                                                                                            

                                      IMPORTANT DATA
                                                                                                            

    PHYSICAL STATE; APPEARANCE:                       ROUTES OF EXPOSURE:
    COLOURLESS LIQUID, WITH CHARACTERISTIC ODOUR.     The substance can be absorbed
                                                      into the body by inhalation.

    PHYSICAL DANGERS:                                 INHALATION RISK:
    The vapour is heavier than air and may            No indication can be given
    accumulate in low ceiling spaces causing          about the rate in which a
    deficiency of oxygen.                             harmful concentration in the
                                                      air is reached on evaporation
                                                      of this substance at 20°C.

    CHEMICAL DANGERS:                                 EFFECTS OF SHORT-TERM EXPOSURE:
    The substance decomposes on heating               The substance irritates the eyes.
    producing phosgene, hydrogen fluoride and         The substance may cause effects on
    hydrogen chloride.                                the central nervous system and
                                                      cardiovascular system, resulting in
                                                      narcosis and cardiac disorders.

    OCCUPATIONAL EXPOSURE LIMITS:                     EFFECTS OF LONG-TERM OR REPEATED EXPOSURE:
    TLV not established.                              The substance may have effects on the liver.
                                                                                                            

                                   PHYSICAL PROPERTIES

    Boiling Point:    28°C
    Melting Point:    -107°C
    Relative density (water = 1): 1.5
    Solubility in water, g/100 ml at 25°C: 0.21
    Vapour pressure, Pa at 25°C:  14
    Relative vapour density (air = 1): 6.4
                                                                                                            

                                    ENVIRONMENTAL DATA

    This substance may be hazardous to the environment; special attention should be given to the
    ozone layer. It is strongly advised not to let the chemical enter into the environment because
    it persists in the environment. Avoid release to the environment in circumstances different
    to normal use.
                                                                                                            

                                           NOTES

    High concentrations in the air cause a deficiency of oxygen with the risk of
    unconsciousness or death. Check oxygen content before entering area.

                                                                                                            
                                 ADDITIONAL INFORMATION
















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

    RÉSUMÉ D'ORIENTATION

         Ce CICAD repose principalement sur un certain nombre
    d'évaluations relatives aux effets du
    2,2-dichloro-1,1,1-trifluoréthane (HCFC-123), évaluations qui relèvent
    soit de la protection de l'environnement, soit de la médecine du
    travail. Ces travaux ont été effectués dans le cadre de l'Australian
    National Industrial Chemicals Notification and Assessment Scheme
    (NICNAS) et publiés en mars 1996 (NICNAS, 1996) et en juillet 1999
    (NICNAS, 1999). Les données intéressantes publiées depuis la parution
    des rapports du NICNAS ou obtenues par une recherche approfondie
    portant sur plusieurs bases de données jusqu'à août 1999 ont également
    fait l'objet d'une étude critique et incluses dans le présent CICAD.
    Ce document constitue une mise à jour de l'étude du HCFC-123 qui
    figure dans la monographie consacrée à ce type de composé (Critère
    d'Hygiène de l'Environnement No 139) (IPCS, 1992). Cette mise à jour à
    été suscitée par la publication de données nouvelles et importantes
    sur le composé. On trouvera à l'appendice 1 des indications sur la
    nature des examens par des pairs ainsi que sur les sources
    documentaires utilisées. L'appendice 2 donne des renseignements sur
    l'examen de ce CICAD par des pairs. La publication de ce CICAD a été
    approuvée lors d'une réunion du Comité d'évaluation finale qui s'est
    tenue à Sydney (Australie) du 21 au 24 novembre 1999. La liste des
    participants à cette réunion figure à l'appendice 3. La fiche
    d'information internationale sur la sécurité chimique (ICSC 1343)
    relative au 2,2-dichloro-1,1,1-trifluoréthane, établie par le
    Programme international sur la sécurité chimique, est également
    reproduite dans l'appendice 4 (IPCS, 1998).

         Le HCFC-123 (No CAS 306-83-2) est un composé de synthèse qui se
    présente sous la forme d'un liquide volatil incombustible. Il est
    utilisé comme réfrigérant dans les installations de climatisation
    commerciales et industrielles; il entre dans la composition de certain
    produits gazeux anti-feu et sert également d'agent d'expansion pour
    mousses. On l'emploie aussi pour le nettoyage des métaux et du
    matériel électronique. Son agressivité vis-à-vis de la couche d'ozone
    ne représente que le 2 % de celle du CFC-11 (trichlorofluorométhane).
    Par rapport au dioxyde de carbone, on estime que son potentiel de
    réchauffement du climat est de 300 sur une vingtaine d'années. C'est
    pourquoi on l'utilise provisoirement pour remplacer les chloro- et
    bromofluorocarbures auxquels il a été décidé de renoncer aux termes du
    Protocole de Montréal sur les substances qui détruisent la couche
    d'ozone. Selon l'Amendement de Copenhague au Protocole de Montréal, le
    HCFC-123 et les autres hydrocarbures fluorés devront être éliminés
    d'ici 2020.

         Les émissions de HCFC-123 se font principalement dans l'air
    ambiant. Bien que légèrement toxique pour les poissons, les daphnies
    et les algues, ce composé ne devrait pas constituer de réel danger
    pour le milieu aquatique car il ne persiste pas dans l'eau, même à des

    concentrations inférieures à sa limite de solubilité. On estime que sa
    demi-vie dans l'atmosphère est inférieure à 2 ans. Comme pour d'autres
    fluorocarbures plus courants, son principal produit de décomposition
    dans l'atmosphère est l'acide trifluoracétique, qui se répartit dans
    les diverses phases aqueuses de l'environnement. L'acide
    trifluoracétique est difficilement dégradable et il est susceptible de
    s'accumuler dans certains systèmes aquatiques fermés, mais sa
    concentration actuelle ou prévisible compte tenu des émissions de
    HCFC-123 est inférieure au seuil de toxicité.

         On pense que l'exposition de la population générale au HCFC-123
    est minime. Il existe cependant une possibilité d'exposition
    professionnelle lors de la production du composé ou de la préparation
    et de l'utilisation de produits qui en contiennent.

         On sait peu de chose concernant les effets du HCFC-123 sur
    l'organisme humain. On a fait état de cas d'étourdissements, de
    céphalées et de nausées à la suite d'une seule et unique exposition à
    une concentration inconnue de ce composé dans l'air ambiant. Par
    ailleurs, des cas d'atteinte hépatique manifeste ou infraclinique ont
    été également observés après exposition professionnelle pendant 1 à 4
    mois à des vapeurs de HCFC-123 dont la concentration était comprise
    entre 5 et 1125 ppm (31,3-7030 mg/m3).

         Le HCFC-123 présente une faible toxicité aiguë pour les animaux
    de laboratoire. En le faisant inhaler pendant quelques minutes à
    plusieurs heures par divers animaux d'expérience on a constaté à la
    dose de 1000 ppm (6,25 g/m3) des lésions au niveau du foie chez les
    cobayes, une dépression du système nerveux central (SNC) chez toutes
    les espèces à la dose de 5000 ppm (31,3 g/m3) et une arythmie
    cardiaque induite par l'adrénaline à la dose de 20 000 ppm (125
    g/m3) chez des chiens. Chez le rat et le hamster, l'inhalation du
    composé à des doses supérieures à 30 000 ppm (188 g/m3) pendant 4
    heures provoque une grave dépression du SNC conduisant à la mort. Le
    HCFC-123 n'est pas irritant pour la peau et il ne produit pas de
    sensibilisation, mais il peut irriter la muqueuse oculaire lorsqu'il
    est à l'état liquide. Lors d'études toxicologiques de 2 à 39 semaines
    consistant à faire inhaler de manière répétée le produit par des
    animaux de laboratoire (rats, cobayes, chiens et singes), on a
    constaté que les principaux organes cibles étaient le foie, le système
    endocrine hypothalamo-hypophyso-gonadique et le SNC. La concentration
    minimale produisant un effet nocif observable (LOAEL) avec comme
    critère les effets hépatiques a été trouvée égale à 30 ppm (188
    mg/m3). En prenant comme critère les effets sur le système
    endocrine, la concentration sans effet nocif observable (NOAEL) était
    égale à 100 ppm (625 mg/m3) et dans le cas des effets sur le SNC,
    elle était égale à 300 ppm (1880 mg/m3). Rien n'indique que le
    HCFC-123 ait des effets tératogènes chez les animaux de laboratoire,
    ni qu'il présente une toxicité génésique ou foetale à des doses

    inférieures à celles qui ont d'autres effets toxiques généraux. Des
    ratons et des singes nouveau-nés dont les mères allaitantes avaient
    été exposées à du HCFC-123 à une concentration égale à la LOAEL (30
    ppm ou 188 mg/m3), ont présenté un retard de croissance. Le
    métabolite principal (acide trifluoracétique) a été retrouvé dans le
    lait des mères allaitantes.

         Des signes d'activité clastogène ont été relevés dans des
    lymphocytes humains mis en présence de HCFC-123  in vitro à des doses
    suffisamment élevées pour être cytotoxiques, mais tous les autres
    tests de génotoxicité effectués  in vitro ou  in vivo se sont
    révélés négatifs. On voit donc que ce composé est vraisemblablement
    dénué de génotoxicité  in vivo.

         Lors d'une étude de 2 ans au cours de laquelle on a fait inhaler
    le produit à des rats, on a constaté une augmentation de l'incidence
    des lésions précancéreuses et des tumeurs bénignes du foie, du
    pancréas et des testicules, mais aucun accroissement de l'incidence
    des tumeurs malignes qui soit attribuable à ce traitement. Il est
    probable que la formation de ces tumeurs implique un ou plusieurs
    mécanismes non génotoxiques, notamment une prolifération des
    peroxysomes, des lésions au niveau des hépatocytes, une nécrose et une
    prolifération dégénérative ainsi qu'une perturbation de l'axe
    hypothalamo-hypophyso-gonadique. Il est possible que l'organisme
    humain soit moins sensible à la formation de tumeurs par l'un ou
    l'autre de ces mécanismes, mais on ne peut cependant ne pas tenir
    compte de ces tumeurs dans une évaluation du risque pour l'Homme.

         L'effet le plus significatif dans le cas d'une seule et unique
    exposition au HCFC-123, comme cela peut se produire lors de son
    utilisation pour éteindre un feu, consiste dans son action dépressive
    sur le système nerveux central à laquelle s'ajoute la possibilité d'un
    accroissement des arythmies cardiaques induites par l'adrénaline. En
    cas d'exposition répétée, l'effet le plus significatif est la
    possibilité de lésions hépatiques, effet qui a été observé chez des
    ouvriers exposés à des concentrations atmosphériques supérieures à 5
    ppm (31,3 mg/m3) pendant 1 à 4 mois.
    

    RESUMEN DE ORIENTACI²N

         Este CICAD se basa principalmente en las evaluaciones de la salud
    ocupacional y los efectos en el medio ambiente del
    2,2-dicloro-1,1,1-trifluoroetano (HCFC-123) realizadas en el marco del
    Plan Nacional Australiano de Notificación y Evaluación de Sustancias
    Químicas Industriales (NICNAS) y publicadas en marzo de 1996 (NICNAS,
    1996) y julio de 1999 (NICNAS, 1999). También se ha evaluado e
    incorporado a este CICAD la información aparecida desde la terminación
    de los informes del NICNAS y la obtenida en una búsqueda amplia
    efectuada en varias bases de datos en línea hasta agosto de 1999. Este
    CICAD es una actualización del examen del HCFC-123 de la monografía
    Criterios de Salud Ambiental 139 (IPCS, 1992), necesaria tras la
    aparición de nuevos datos significativos. La información relativa al
    carácter del examen colegiado y a la disponibilidad de los documentos
    originales figura en el apéndice 1. La información sobre el examen
    colegiado de este CICAD se presenta en el apéndice 2. Su publicación
    se aprobó en una reunión de la Junta de Evaluación Final celebrada en
    Sydney, Australia, los días 21-24 de noviembre de 1999. En el apéndice
    3 figura la lista de participantes en la Junta de Evaluación Final. La
    Ficha internacional de seguridad química (ICSC 1343) para el
    2,2-dicloro-1,1,1-trifluoroetano, preparada por el Programa
    Internacional de Seguridad de las Sustancias Químicas (IPCS, 1998),
    también se reproduce en el apéndice 4.

         El HCFC-123 (CAS No 306-83-2) es un líquido sintético, no
    combustible, volátil, que se utiliza como refrigerante en
    instalaciones de aire acondicionado comerciales e industriales, en
    extintores de incendios gaseosos, como agente espumante y en la
    limpieza de metales y de componentes electrónicos. Su capacidad de
    agotamiento del ozono es solamente el 2% de la que tiene el CFC-11
    (triclorofluorometano). Su potencial de calentamiento de la Tierra es
    de 300 en una perspectiva cronológica de 20 años con respecto al
    anhídrido carbónico. El HCFC-123 como tal se utiliza en la actualidad
    de manera transitoria para sustituir los clorofluorocarburos y los
    bromofluorocarburos, que son objeto de supresión progresiva en
    aplicación del Protocolo de Montreal relativo a las sustancias que
    agotan la capa de ozono. La Enmienda de Copenhague al Protocolo de
    Montreal de 1992 exige la eliminación progresiva del HCFC-123 y de
    otros hidroclorofluorocarburos para el año 2020.

         El HCFC-123 se libera en el medio ambiente fundamentalmente en el
    aire atmosférico. Si bien es ligeramente tóxico para los peces,
     Daphnia y las algas, no es probable que represente un peligro
    importante para el medio acuático, dada su escasa persistencia en el
    agua, incluso en concentraciones inferiores al límite de solubilidad.
    En la atmósfera, el HCFC-123 tiene una vida estimada de menos de dos
    años. El principal producto de degradación atmosférica del HCFC-123 (y
    de otros fluorocarburos más ampliamente utilizados) es el ácido
    trifluoroacético, que se distribuye en las fases acuosas del medio
    ambiente. Aunque este ácido es resistente a la degradación y puede

    acumularse en determinados sistemas acuáticos cerrados, las
    concentraciones actuales y previstas a partir de las emisiones de
    HCFC-123 son inferiores a los umbrales tóxicos.

         Se prevé una exposición mínima del público general al HCFC-123.
    Sin embargo, es posible la exposición ocupacional durante la
    fabricación del HCFC-123 y la fabricación y el uso de productos que lo
    contienen.

         Se dispone de una información limitada sobre los efectos del
    HCFC-123 en el ser humano. Se han notificado casos de vértigo, dolor
    de cabeza y náuseas tras una exposición aislada a concentraciones
    desconocidas de HCFC-123 en el aire, así como casos de enfermedad
    hepática manifiesta o subclínica asociada con exposiciones
    ocupacionales repetidas a vapores de HCFC-123 en concentraciones de
    5-1125 ppm (31,3-7030 mg/m3) durante 1-4 meses.

         La toxicidad aguda del HCFC-123 en animales de laboratorio es
    baja. La inhalación durante un período comprendido entre unos minutos
    y unas horas provoca lesiones hepáticas en los cobayas con 1000 ppm
    (6,25 g/m3), depresión del sistema nervioso central en todas las
    especies examinadas con 5000 ppm (31,3 g/m3) y arritmia cardíaca
    inducida por la adrenalina en perros con 20 000 ppm (125 g/m3). En
    la rata y el hámster, la inhalación de más de 30 000 ppm (188 g/m3)
    durante cuatro horas provoca una fuerte depresión del sistema nervioso
    central y la muerte. El HCFC-123 no es irritante o sensibilizador
    cutáneo, pero en forma líquida puede causar irritación ocular. En
    estudios de toxicidad por inhalación con exposiciones repetidas
    durante un período de 2 a 39 semanas en ratas, cobayas, perros y
    monos, los órganos más afectados fueron el hígado, el sistema
    endocrino del hipotálamo, la hipófisis y las gónadas y el sistema
    nervioso central. La concentración más baja con efectos adversos
    observados (LOAEL) basada en los efectos hepáticos fue de 30 ppm
    (188 mg/m3). La concentración sin efectos adversos observados
    (NOAEL) fue de 100 ppm (625 mg/m3) basada en los efectos endocrinos
    y de 300 ppm (1880 mg/m3) basada en los efectos en el sistema
    nervioso central. No hay pruebas de que el HCFC-123 sea teratogénico o
    induzca toxicidad reproductiva o fetal con niveles de exposición
    inferiores a los que provocan otros efectos sistémicos. Se observó un
    crecimiento retardado en ratas y monos recién nacidos de madres
    expuestas al HCFC-123, con una LOAEL de 30 ppm (188 mg/m3). En la
    leche de las madres se detectó ácido trifluoroacético, principal
    metabolito del HCFC-123.

         Aunque se obtuvieron pruebas de actividad clastogénica en los
    linfocitos humanos expuestos a concentraciones altas citotóxicas de
    HCFC-123  in vitro, todas las demás pruebas de toxicidad genética
     in vitro e  in vivo dieron resultados negativos. Por consiguiente,
    las pruebas parecen indicar que no es probable que este producto
    químico tenga actividad genotóxica  in vivo.

         En un estudio de inhalación de dos años en ratas se observó una
    mayor incidencia de lesiones precancerosas y tumores benignos en el
    hígado, el páncreas y los testículos, pero no se detectó un aumento de
    la incidencia de tumores malignos relacionado con la exposición.
    Probablemente se debe a que en estos tumores intervienen uno o más
    mecanismos no genotóxicos por ejemplo, la proliferación de
    peroxisomas, los daños hepatocelulares, la necrosis y la proliferación
    regenerativa y el trastorno del eje hipotálamo-hipófisis-testículos.
    Aunque el ser humano puede ser menos sensible a los tumores derivados
    de algunos de estos mecanismos, en conjunto en una evaluación del
    riesgo potencial para las personas no es posible descatar los tumores.

         Los efectos críticos más importantes de una exposición breve
    aislada al HCFC-123, por ejemplo debido a la descarga de un extintor
    de incendios, son la depresión del sistema nervioso central y la mayor
    probabilidad de arritmia cardíaca inducida por la adrenalina. Los
    principales efectos derivados de una exposición repetida son las
    lesiones hepáticas, notificadas en trabajadores expuestos a
    concentraciones en el aire superiores a 5 ppm (31,1 mg/m3) durante
    un período de 1 a 4 meses.
    


    See Also:
       Toxicological Abbreviations