partially halogenated chlorofluorocarbons ( ethane

Environmental Health Criteria 139

Partially halogenated chlorofluorocarbons ( ethane derivatives)

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INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

ENVIRONMENTAL HEALTH CRITERIA 139

PARTIALLY HALOGENATED CHLOROFLUOROCARBONS(ETHANE DERIVATIVES)

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

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

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

World Health Orgnization Geneva, 1992

The International Programme on Chemical Safety (IPCS) is a joint venture of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization. The main objective of the IPCS is to carry out and disseminate evaluations of the effects of chemicals on human health and the quality of the environment. Supporting activities include the development of epidemiological, experimental laboratory, and risk-assessment methods that could produce internationally comparable results, and the development of manpower in the field of toxicology. Other activities carried out by the IPCS include the development of know-how for coping with chemical accidents, coordination of laboratory testing and epidemiological studies, and

Chlorofluorocarbons, partially halogenated (ethane derivatives) (EHC 139, 1992)

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promotion of research on the mechanisms of the biological action of chemicals.

WHO Library Cataloguing in Publication Data

Partially halogenated chlorofluorocarbons (ethane derivatives).

(Environmental health criteria ; 139)

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

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

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR PARTIALLY HALOGENATED CHLOROFLUOROCARBONS (ETHANE DERIVATIVES)

1. SUMMARY

1.1. Identity, physical and chemical properties, and analytical methods

1.2. Sources of human and environmental exposure1.3. Environmental transport, distribution and transformation1.4. Environmental levels and human exposure1.5. Kinetics and metabolism in laboratory animals and humans1.6. Effects on laboratory mammals and in vitro test systems1.7. Effects on humans


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1.8. Effects on other organisms in the laboratory and field1.9. Evaluation and conclusions

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

2.1. Identity2.1.1. Technical products

2.2. Physical and chemical properties2.3. Conversion factors2.4. Analytical methods

3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1. Natural occurrence3.2. Anthropogenic sources

3.2.1. Production levels3.2.2. Manufacturing processes3.2.3. Loss during disposal, transport, storage and

accidents 3.3. Use patterns

3.3.1. Major uses

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

4.1. Biodegradation and bioaccumulation4.2. Environmental transformation and interaction with other

environmental factors

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

5.1. Environmental levels5.1.1. Air5.1.2. Water, food and other edible products

5.2. Human exposure

6. KINETICS AND METABOLISM

6.1. Animal studies6.1.1. Absorption6.1.2. Distribution6.1.3. Metabolic transformation

6.1.3.1 General considerations 6.1.4. Covalent binding to macromolecules6.1.5. Elimination

6.2. Human studies

7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

7.1. Single exposure7.1.1. Acute oral toxicity7.1.2. Acute inhalation toxicity7.1.3. Acute dermal toxicity

7.2. Short-term inhalation exposure7.3. Skin and eye irritation; sensitization

7.3.1. Skin and eye irritation7.3.2. Skin sensitization

7.4. Long-term exposure7.5. Reproduction, embryotoxicity, and teratogenicity

7.5.1. Reproduction7.5.2. Embryotoxicity and teratogenicity

7.6. Mutagenicity7.7. Carcinogenicity


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7.8. Special studies - cardiovascular and respiratory effects

8. EFFECTS ON HUMANS

8.1. General population exposure8.2. Occupational exposure

9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

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

10.1. Direct health effects10.1.1. HCFC 141b10.1.2. HCFC 142b10.1.3. HCFC 132b10.1.4. HCFC 133a10.1.5. HCFC 12310.1.6. HCFC 124

10.2. Health effects expected from a depletion of stratospheric ozone

10.3. Effects on the environment

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

11.1. Conclusions11.2. Recommendations for protection of human health and the

environment

REFERENCES

RESUME

RESUMEN

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

Members

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

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

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

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

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

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

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

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


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

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

Observers

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

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

Secretariat

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

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

NOTE TO READERS OF THE CRITERIA MONOGRAPHS

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

* * *

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

ENVIRONMENTAL HEALTH CRITERIA FOR PARTIALLY HALOGENATED CHLOROFLUOROCARBONS (ETHANE DERIVATIVES)

A Task Group on Environmental Health Criteria for Partially Halogenated Chlorofluorocarbons (Ethane Derivatives) met at the British Industrial and Biological Research Association (BIBRA), Carshalton, Surrey, United Kingdom, from 30 September to 5 October 1991. Dr S.D. Gangolli opened the meeting on behalf of the host institute and greeted the participants on behalf of the Department of Health. Professor F. Valic welcomed the participants on behalf of the heads of the three cooperating organizations of the IPCS (UNEP/ILO/WHO). The Task Group reviewed and revised the draft monograph, made an evaluation of the direct and indirect risks for human health from exposure to the partially halogenated chlorofluorocarbons reviewed, and made recommendations for health protection and further research.

The draft was prepared by Professor D. Beritic-Stahuljak and Professor F. Valic, using the texts made available by Dr R. Millischer, ATOCHEM, Paris, France (HCFC 141b), Dr S. Magda, Kali-Chemie, Hanover, Germany (HCFC 142b), Mr D.J. Tinston, Central Toxicology Laboratory, ICI, Alderley Park, United Kingdom (HCFC 133a), Dr H.J. Trochimowicz, E.I. Du Pont de Nemours, Newark, Delaware, USA (HCFC 132b), and Dr G.M. Rusch, Engineered Materials Sector, Allied-Signal Inc., Morristown, New Jersey, USA (HCFC 123 and HCFC 124).


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

INTRODUCTION

The global concern over the depletion of the stratospheric ozone layer by active chlorine from fully halogenated chlorofluorocarbons resulted in the development of the Vienna Convention for the Protection of the Ozone Layer, adopted in March 1985, and its Montreal Protocol on Substances that Deplete the Ozone Layer, signed in 1987. The agreement required a freeze in the production and use of the fully halogenated chlorofluorocarbons 11, 12, 113, 114 and 115 at l986 levels by mid-1989, a 20% reduction from 1 July 1993 and a further 30% reduction from 1 July 1998. Sixty-seven countries and the European Economic Community have signed the Protocol. A total phase-out of 15 fully halogenated chlorofluorocarbons by the year 2000 was agreed by the Parties to the Protocol in June 1990.

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

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

1. SUMMARY

1.1 Identity, physical and chemical properties, and analytical methods

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

Under normal temperatures and pressures these compounds are flammable (HCFC 142b) or non-flammable gases (HCFC 133a, HCFC 124) or non-flammable volatile liquids (HCFC 141b, HCFC 132b, HCFC 123). They are colourless and the majority are practically odourless or have a


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faint ethereal odour (HCFC 141b and HCFC 123). They are slightly or moderately soluble in water and miscible with many organic solvents.

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

1.2 Sources of human and environmental exposure

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

1.3 Environmental transport, distribution and transformation

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

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

1.4 Environmental levels and human exposure

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

1.5 Kinetics and metabolism in laboratory animals and humans

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

1.5.1 HCFC 141b

Results from toxicity studies suggest that absorption of HCFC 141b takes place across the respiratory epithelium. No information is available on the distribution of HCFC 141b in mammals. In recent

in vitro single-exposure studies in rats, 2,2-dichloro-2-fluoro- ethyl glucuronide and 2,2-dichloro-2-fluoroacetic acid were identified in the urine.

A pilot study for absorption and metabolism of HCFC 141b in rats exposed to its vapour suggested that metabolic transformation occurs


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only to a very small extent.

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

1.5.2 HCFC 142b

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

1.5.3 HCFC 132b

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

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

1.5.4 HCFC 133a

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

1.5.5 HCFC 123

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

1.5.6 HCFC 124

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

1.6 Effects on laboratory mammals and in vitro test systems

1.6.1 HCFC 141b

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

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

No mortality in rats or rabbits was observed after dermal


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exposure to 2 g/kg.

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

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

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

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

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

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

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

1.6.2 HCFC 142b

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

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

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

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

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


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incidence were reported.

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

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

1.6.3 HCFC 132b

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

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

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

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

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

Based on the limited data available, there is no evidence for in vitro mutagenicity of HCFC 132b. The carcinogenicity of the

compound has not been studied.

1.6.4 HCFC 133a


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

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

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

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

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

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

1.6.5 HCFC 123

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

The acute inhalation toxicity of HCFC 123 is also low. Effects seen are similar to those of chlorofluorocarbons, i.e. loss of coordination and narcosis. The 4-h LC50 is 178 g/m3 in hamsters, 463 g/m3 in mice and ranges from 200 to 329 g/m3 in rats. Cardiac sensitization after a challenge with injected adrenaline occurred in dogs at concentrations of 119 g/m3 or more. Liquid HCFC 123 produces


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"mild" irritation of the skin and eye in rabbits. It does not cause skin sensitization in guinea-pigs.

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

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

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

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

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

1.6.6 HCFC 124

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

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

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

In three limited teratogenicity studies on rats, in which HCFC 124 was tested at 30 g/m3 or in the range 3-279 g/m3, there was no


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evidence of embryotoxicity or teratogenic effects. Maternal toxicity was demonstrated at 84 g/m3. No information is available on the effects of HCFC 124 on reproductive potential. Full teratogenicity studies are in progress.

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

1.7 Effects on humans

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

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

1.8 Effects on other organisms in the laboratory and field

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

1.9 Evaluation and conclusions

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

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

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

Since the toxicity of HCFC 142b is low and the ozone-depleting and global-warming potentials are lower than those of the fully halogenated chlorofluorocarbons, it can be considered as a transient substitute for the chlorofluorocarbons included in the Montreal Protocol.

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

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


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

2.1 Identity

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

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

2.1.1 Technical products

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

2.2 Physical and chemical properties

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

Table 1. Identity of hydrochlorofluorocarbonsa

HCFC 141b HCFC 142b

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

Chemical formula CCl2F-CH3 CClF2CH3

Common names dichlorofluoroethane chlorodifluo

Common synonyms 1,1-dichloro-1-fluoroethane; 1-chloro-1,1


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1-fluoro-1,1-dichloroethane; 1,1-difluoro ethane, 1,1-dichloro-1-fluoro; difluoromono HCFC 141b; Propellant 141b; HCFC 142b; R-141b

CAS Registry number 1717-00-6 75-68-3

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

Table 1 (contd).

HCFC 133a HCFC 123

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

Chemical formula CH2Cl-CF3 CHCl2-CF3

Common names chlorotrifluoroethane dichlorotrif

Common synonymsb 1-chloro-2,2,2-trifluoroethane; 1,1-dichloro 1,1,1-trifluoro-2-chloroethane; 2,2-dichloro 2,2,2-trifluorochloroethane; ethane, dich 1,1,1-trifluoroethyl chloride; carbon 123; CFC 133a; HCFC 133a; R-133a 123; Refrige

CAS Registry number 75-88-7 306-83-2

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

a Chlorofluorocarbons are numbered as follows: the first digit = number of C 1); second digit = number of H atoms plus 1; third digit = number of F atom

b The trade names Arcton, Freon, Genetron and Isotron are used with the corre

Table 2. Physical and chemical properties of the hydrochlorofluorocarbonsa

HCFC 141b HCFC 142b HCFC 132b HCFC

Physical state liquid gas liquid gas

Colour colourless colourless colourless colo

Relative molecular mass 116.95 100.47 134.92 118.

Boiling point (°C) 32.0 -9.2 46.8 6.93

Freezing point (°C) -103.5 -131.0 -101.2 -105

Liquid density (g/ml) 1.24c 1.123c 1.42c 1.389

Vapour pressure


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(25 °C, psia) 11.5 49.2 6.1 29.7

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

Flammability non-flammablee flammable non-flammable non-

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

Flammability limits in air (% vol) - 6.0-14.8 - -

Table 2 (contd).

HCFC 141b HCFC 142b HCFC 132b HCFC

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

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

a From: Graselli & Ritchey (1975), Hawley (1981), Horrath (1982), Sax (1984),b At 25 °C c At 20 °C d At 11.3 °C e No flash point between 21 °C and 33 °C; no explosive properties, but can be

Solvay et Cie, 1989). Millischer (1990) lists HCFC 141b as non-flammable. f Log Kow cited in SRC (personal communication by H. Trochimowicz (1991), C-5

2.3 Conversion factors

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

2.4 Analytical methods

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

Table 3. Analytical methods for the determination of hydrochlorofluorocarbon

Hydrochlorofluorocarbons Medium Analytical method

HCFC 141b air absorption on silica gel, thermal desorpt gas chromatography with flame ionization

corn oil gas chromatography with electron capture

HCFC 142b air gas chromatography with flame ionization


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water head space analysis using gas chromatogra electron capture detection

HCFC 132b air gas chromatography with thermal conductiv detection

HCFC 133a air gas chromatography with flame ionization air gas chromatography with flame ionization air gas chromatography with thermal conductiv air gas chromatography with flame ionization

tissue head space analysis using gas chromatogra flame ionization detection

tissue head space analysis using gas chromatogra flame ionization detection

HCFC 123 air single beam photometry air gas chromatography with flame ionization air gas chromatography with thermal conductiv

HCFC 124 air gas chromatography with thermal conductiv air gas chromatography with dual flame ioniza

3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1 Natural occurrence

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

3.2 Anthropogenic sources

3.2.1 Production levels

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

3.2.2 Manufacturing processes

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

3.2.3 Loss during disposal, transport, storage and accidents

Since two of the hydrochlorofluorocarbons reviewed which are


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

No information is available on accidental release.

3.3 Use patterns

3.3.1 Major uses

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

HCFC 123 is used in large industrial chillers.

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

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

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

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

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

4.1 Biodegradation and bioaccumulation

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

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

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

4.2 Environmental transformation and interaction with other environmental factors

The scaled atmospheric lifetimes, ozone-depleting potentials and global-warming potentials of the hydrochlorofluorocarbons reviewed are


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shown in Table 4, where they are compared to those of methylchloroform (1,1,1-trichloroethane). The physical and chemical properties suggest that these hydrochlorofluorocarbons would be rapidly mixed within the lower region of the troposphere. Mixing would be expected to be complete in the hemisphere of the emission (northern or southern) within months and in the entire troposphere possibly within about three years. Reaction with naturally occurring hydroxy radicals (OH€) in the troposphere is expected to be the primary degradation route (Makide & Rowland, 1981; Prinn & Golombek, 1990).

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

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

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

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

Table 4. Tropospheric lifetime, ozone-depleting potential and global-warming of hydrochlorofluorocarbonsa,b

Hydrochlorofluorocarbon Scaled atmospheric Ozone-depleting potenti lifetime (years)c 1-dimensional model 2-dimensio

HCFC 141b 7.8 0.066-0.092 0.065-0.14

HCFC 142b 19.1 0.05-0.06 0.05-0.08

HCFC 132b 4.2 0.025 -

HCFC 133a 4.8 - -

HCFC 123 1.6 0.013-0.019 0.013-0.02

HCFC 124 6.6 0.016-0.021 0.013-0.03

Cl3C CH3 6.3 0.092-0.14 0.11-0.20

a From: Fisher et al. (1990a,b) and Freemantle (1991). See also Prinn & Golomb The ozone-depleting and global-warming potential values for CFC-11 are defi

in the table refer to this standard and the ranges are scaled assuming a me lifetime of 6.3 years (UNEP/WMO, 1989).


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c Other atmospheric lifetimes are: CFC 11 - 75 years, CFC 12 - 110 years and

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

5.1 Environmental levels

5.1.1 Air

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

5.1.2 Water, food and other edible products

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

5.2 Human exposure

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

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

6. KINETICS AND METABOLISM

6.1 Animal studies

6.1.1 Absorption

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

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

6.1.2 Distribution

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

6.1.3 Metabolic transformation

6.1.3.1 General considerations

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


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

6.1.3.2 HCFC 141b

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

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


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any metabolism occurred it was at a low level (Zwart, 1989).

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

6.1.3.3 HCFC 142b

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

6.1.3.4 HCFC 132b

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

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

6.1.3.5 HCFC 133a

Evidence for dechlorination of HCFC 133a was provided by an in vitro study using a microsomal preparation derived from

Aroclor-1254a-induced rat liver homogenates (Salmon et al., 1981).

6.1.3.6 HCFC 123

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

6.1.4 Covalent binding to macromolecules

6.1.4.1 HCFC 141b 19F-NMR analysis of microsomal and cytosolic proteins isolated

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

6.1.4.2 HCFC 132b


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

6.1.4.3 HCFC 123

Harris et al. (1991) exposed adult male Fischer-344 rats to HCFC 123 (43 or 68 g/m3) or to halothane (105 g/m3) in air for 2 h.

19F-NMR analysis of cytosolic protein and immunoblotting of microsomal and cytosolic hepatic protein using antibodies against trifluoroacetylprotein at 15 h after the exposure demonstrated covalent binding of fluorinated metabolites.

a Aroclor-1254 is a polychlorinated biphenyl mixture.

6.1.5 Elimination

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

6.2 Human studies

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

7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

7.1 Single exposure

7.1.1 Acute oral toxicity

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

7.1.1.1 HCFC 141b

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

7.1.1.2 HCFC 142b

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

7.1.1.3 HCFC 132b

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

A 2-g/kg dose of HCFC 132b in corn oil was applied by stomach tubes to five male and five female Wistar rats, and the animals were observed for 14 days. The clinical signs were indicative of an effect


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on the autonomic nervous system (ptosis), on the central nervous system (diminished alertness and startle response, and positional passivity), on motor coordination (abnormal body posture and gait, and loss of righting reflex), on motor activity and on muscle tone (paralysis). Macroscopic examination showed swollen livers in some males, and a decrease in absolute and relative liver weights. However, no treatment-related effects were found during microscopic examinations (Janssen & Pot, 1989b).

7.1.1.4 HCFC 123

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

7.1.2 Acute inhalation toxicity

7.1.2.1 HCFC 141b

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

7.1.2.2 HCFC 142b

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

7.1.2.3 HCFC 132b

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

7.1.2.4 HCFC 133a

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

7.1.2.5 HCFC 123

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

7.1.2.6 HCFC 124

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

7.1.3 Acute dermal toxicity

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


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Table 5. Effects of a single inhalation exposure to HCFC 141b in mice and ra

Species Exposure Exposure Effects (strain) concentration duration (g/m3) (h)

Rat 142-366 4 LC50 = 295 g/m3 (Sprague-Dawley) No deaths were observed at 142 or at higher concentrations (323 and during exposure, and were precede Reduced motor activity, abnormal behaviour and exaggerated respira at all concentrations during expo macroscopic findings were seen. F was observed in the renal cortica rats at 217 g/m3 and 2 out of 10 histopathological effects were se

Rat (strain unspecified 6 The lowest concentration producin unspecified) range

Mouse 17-388 6 Deaths preceded by signs of narco (Crl: CD-1) occurred within 30 min of exposur occurred at the next highest (199 of CNS depression (lethargy, abno eyes) were seen at 165 and 199 g/ concentrations of 145 g/m3 or les

Mouse (strain unspecified 2 LC16 = 115 g/m3; LC50 = 151 g/m3; L unspecified) range CNS depression and anaesthesia we preceded by laboured breathing.

Mouse (Schofield unspecified 0.5 LC50 = 115 g/m3; concentration pro strain) range 50% of animals = 62 g/m3. No othe

Table 6. Effects of single inhalation exposure to HCFC 142b in mice and rats

Species Strain Exposure Exposure Effects concentration duration (g/m3) (h)

Mouse "white" up to 2050 2 death; LC50 = 1514 g/m3

Mouse AP unspecified 0.5 death; LC50 = 1228 g/m3 range

Rat "white" 615-3280 0.5 death at 2050 g/m3 and unconsc 1230 g/m3; postural, righting reflexes were lost at 820 g/m3

Rat Sherman 525 4 death (approx 50%) at 525 g/m3

Table 7. Effects of single inhalation exposure to HCFC 132b in mice and rats

Species Strain Exposure Exposure Effects


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concentration duration (g/m3) (h)

Mouse unspecified range not given 0.5 LC50 = 269 g/m3; AC50 (a

Rat Wistar derived 55 and 110 4 lethalities at 110 g/m3 drowsy at 55 g/m3

Rat Wistar derived 33-72 6 anaesthesia at 82 g/m3; CPB-WU at all dose levels, mal and testis weight, and weights

Rat Wistar derived 55 0.4 decreased respiratory r CPB-WU after exposure

Table 8. Effects of single inhalation exposure to HCFC 133a

Species Exposure Exposure Effectsa (strain) concentration duration (g/m3) (min)

Mice, male unspecified 10 anaesthesia and death; convulsi (white) range LC50 were 394 and 1230 g/m3, res

Mice (strain unspecified 30 anaesthesia, convulsions and de unspecified) range 212 and 738 g/m3, respectively

Mice (strain 123-1230 10 rapid onset of anaesthesia, rap unspecified) exposure but no convulsions; AC 1033 g/m3, respectively

Rats, female 2500 - lack of muscular coordination i (strain unspecified) and death within 8 min

Dogs unspecified - anaesthesia at 492 g/m3, respir range occurred at 1131 and 1427 g/m3, 2902 g/m3

a AC50 = calculated concentration expected to produce anaesthesia in 50% of th

Table 9. Acute inhalation toxicity of HCFC 123

Species Exposure Exposure Effects (strain) concentration duration (g/m3)

Mouse (strain not given 30 min LC50 = 463 g/m3 unspecified)

Rat (Charles 129-344 4 h LC50 = 200 g/m3; loss of mobilit River CD) at all concentrations; full rec 30 min post exposure

Rat (Charles 49-767 6 h LC50 = 329 g/m3; anaesthesia at River CD) concentrations; discoloration o


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died, discoloration of liver in

Rat (strain 6, 16, 31, 62 15 min unconditioned reflexes, locomot unspecified) affected at 31 and 62 g/m3; ful post exposure

Hamster 63-194 4 h LC50 = 178 g/m3; incoordination, (Chinese) concentrations; full recovery o 0% mortality at 163 g/m3, 100 m

Table 10. Acute inhalation toxicity of HCFC 124

Species Strain Exposure Exposure Effects concentration duration (g/m3) (min)

Mouse unspecified 594 10 no effect 837 10 narcosis 2230 10 no mortality 2460 10 death

Rat Sprague-Dawley 268 240 no effect Charles River COBS 558 300 reduced activity Sprague-Dawley 893 240 prostration, leth Sprague-Dawley 1283 240 prostration, leth Sprague-Dawley 1674 240 death Charles River COBS 2009 300 narcosis, no mort

Dog 2230-3910 10 narcosis

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

7.1.3.1 HCFC 141b

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

7.1.3.2 HCFC 132b

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

7.1.3.3 HCFC 123

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


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observed (Trochimowicz, 1989).

7.2 Short-term inhalation exposure

7.2.1 HCFC 141b

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

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

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

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

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

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

7.2.2 HCFC 142b

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


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number of erythrocytes, and an increase in the number of leucocytes. Swelling of the alveolar septa and peribronchitis were the histopathological changes observed in the lungs.

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

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

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

7.2.3 HCFC 132b

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

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

7.2.4 HCFC 133a

Shulman & Sadove (1965) exposed mice to anaesthetic concentrations (the actual concentration was not specified) of HCFC 133a for 30 min per day on 12 consecutive days, and the animals were


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killed for pathological evaluation after the last exposure by overdosage of HCFC 133a. None of the mice showed any treatment-related

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

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

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

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

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

In two dominant lethal studies (for experimental details see section 7.5.1.4), male mice were exposed to between 0.5 and 49 g/m3, 6 h/day, for 5 days (Hodge et al., 1980; Kilmartin et al., l980). The


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mice were subdued at exposure concentrations of 2 g/m3 or more. Deaths occurred as follows: in the first study 0/60 mice died at 0 g/m3, l7/60 at l2 g/m3, and 28/80 at 49 g/m3; in the second study 0/80 died at 0 g/m3, 2/59 at 0.5 g/m3, 0/60 at 2.5 g/m3, 5/60 at 5 g/m3, and 20/60 at 12 g/m3.

7.2.5 HCFC 123

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

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

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

In a 4-week inhalation toxicity study (Kelly, 1989; Trochimowicz, 1989), rats (10 of each sex at each exposure level) were exposed to 0, 6, 31, 62 or 125 g/m3 (6 h/day, 5 days/week) for 4 weeks. Statistically significant body weight depression occurred in all female groups and in the two highest male groups, but was dose-related only in the male rats. At concentrations of 31 mg/m3 or more, rats exhibited dose-related anaesthesia. At 62 and 125 g/m3, rats became lethargic during exposure but were normal when they were examined again 16 to 18 h after exposure. A dose-related increase in liver/body weight ratio was observed in all female groups (a 27% increase at the highest level) and in the two highest-exposure male groups (an 18% increase at the highest level). Decreased cytochrome P-450 activity in the liver was also found in all female exposure groups and in the male groups exposed at the two highest levels. Histopathological examination showed no adverse effects attributable to HCFC 123 in liver or in any other organ at any exposure level. Microscopic


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examination revealed that testicular degeneration and hypospermia occurred in two out of four male exposure groups, but this was believed to be due to reduced body weight (because of an increase in relative testicular weight without a corresponding increase in absolute testicular weight) or may have resulted from spontaneous lesions. The fact that the incidence of testicular degeneration was highest in the 31- and 125-g/m3 exposure groups (5 out of 10 and 6 out of 10 animals, respectively), and lower in the 0-, 6-, and 62-g/m3 exposure groups (2 out of 10, 1 out of 10 and 2 out of 10 animals, respectively) is consistent with the sporadic nature of this lesion in this strain of rat. However, it is not possible to evaluate the significance of this testicular effect from the information available.

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

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

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

7.2.6 HCFC 124


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

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

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

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

Malley (1991) exposed Crl:CDRBR rats (20 rats of each sex at each exposure level) to HCFC 124 at concentrations of 0, 28, 84 and 279 g/m3 (6 h/day, 5 days/week) for 90 days. As part of this study, a functional observation battery (FOB) was conducted on 10 rats of each sex at each exposure level at various intervals during the course of exposure. There were no compound-related effects relative to body weight, food consumption, mortality, haematology, organ weights or histopathology at any exposure concentration. However, male rats, at a level of 84 and 279 g/m3, had lower serum triglyceride concentrations and a decreased arousal (4 of 10 and 6 of 10 rats, respectively). Persistent decrease of forelimb grip strength was found


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in high-dose females. However, there was no associated decrease in hindlimb grip strength or change in gait or footplay. Females at the highest concentration showed an increase in alkaline phosphatase. Both sexes at 279 g/m3 were less responsive to auditory stimuli, as demonstrated by a decreased reaction to a sharp knock on the chamber wall. Plasma fluoride, urinary fluoride and fractional clearance of free fluoride were also increased at all exposure levels in both sexes. The author concluded that the no-observed-effect level (NOEL) was 28 g/m3 for male rats and 84 g/m3 for female rats.

7.3 Skin and eye irritation; sensitization

7.3.1 Skin and eye irritation

7.3.1.1 HCFC 141b

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

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

7.3.1.2 HCFC 142b

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

7.3.1.3 HCFC 132b

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

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

7.3.1.4 HCFC 123

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

Brittelli (1976c) reported HCFC 123 to be a "mild" ocular irritant causing reversible corneal opacity in rabbits. In another study by Daly (1979)a, HCFC 123, when instilled undiluted (0.1 ml) into the conjunctival sac of the rabbit eye without subsequent


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washing, produced "mild" to "moderate" conjunctival irritation. With washing, "mild" transient corneal opacity and "mild" to "moderate" conjunctival irritation were observed. With or without washing, complete recovery occurred within 3-7 days.

7.3.2 Skin sensitization

7.3.2.1 HCFC 141b

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

7.3.2.2 HCFC 132b

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

7.3.2.3 HCFC 123

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

7.4 Long-term exposure

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

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

7.4.1 HCFC 142b

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

7.4.2 HCFC 123

Findings associated with the first year of the PAFT-supported study were provided by Malley (1990c). Following 12 months of inhalation exposure to 0, 2, 6 or 31 g/m3, 10 rats (Crl:CDRBR) of each sex at each concentration were sacrificed, selected organs were weighed, and tissues were examined for gross and microscopic lesions. Body weight and body weight gain were significantly lower in high-dose males and in mid- and high-dose females. Food consumption was higher


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

7.5 Reproduction, embryotoxicity, and teratogenicity

7.5.1 Reproduction

7.5.1.1 HCFC 141b

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

7.5.1.2 HCFC 142b

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

7.5.1.3 HCFC 132b

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

7.5.1.4 HCFC 133a

No studies are available in which the effects of HCFC 133a on reproduction were investigated. Some information is available, however, on the effects on male fertility from a series of dominant lethal and "combined dominant lethal fertility" studies in mice (Hodge et al., 1979, 1980; Kilmartin, 1980). In these studies groups of male mice were exposed to between 0 and 98 g/m3, 6 h/day, for 5 consecutive days. At the end of the treatment, dominant lethal and fertility effects were assessed in 15 males (30 controls) from each treatment group, which were each housed with two virgin females for four consecutive nights. This 4-nightly mating procedure was continued for 8-9 consecutive weeks. In the two later studies, satellite group


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males (at least two from each group per week) were killed, their epididymal sperm assessed for abnormalities and their testes examined histopathologically. A reduction in male fertility (seen as exposure-related decreases in the proportion of pregnant females: e.g., 0-60% of pregnant females in treatment groups compared to 90-100% in controls) was seen between weeks 2-8 following exposure. The severity of the effects were related to time, the maximum reductions in pregnancies being seen at around 3-6 weeks after exposure. No effect on fertility was seen at 0.5 g/m3. Reduced fertility was observed at concentrations of 2.5 g/m3 or more, and histopathological evidence of degeneration of spermatogenic cells was seen at concentrations of 5 g/m3 or more. There was a slight and transient increase in the percentage of abnormal sperm at 2.5 g/m3 or more.

7.5.1.5 HCFC 123

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

7.5.2 Embryotoxicity and teratogenicity

7.5.2.1 HCFC 141b

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

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

7.5.2.2 HCFC 142b

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

Damske et al. (1978) exposed groups of 20 pregnant female Sprague-Dawley CD rats to concentrations of 0, 13 and 39 g/m3 for 6 h/day on days 6-15 of gestation. There were no treatment-related effects in the dams or evidence of exposure-induced terata, variations in sex ratio, embryotoxicity or inhibition of fetal growth and development. There was an increase in the incidence of delayed


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ossification of the supraoccipital bone in both exposure groups; this effect was not observed in the control group.

7.5.2.3 HCFC 132b

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

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

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

7.5.2.4 HCFC 133a

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

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

exposure levels. An increased incidence of hydronephrosis was reported in all treated groups. Thus, the no-observed-effect level for


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embryolethality was 2 g/m3 but, in view of the reduced fetal size and weight at this exposure level, the no-observed-effect level for embryotoxicity was not established from this study.

7.5.2.5 HCFC 123

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

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

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

7.5.2.6 HCFC 124

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

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

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

Schroeder (1991), in a range-finding study, exposed New Zealand


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

7.6 Mutagenicity

7.6.1 HCFC 141b

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

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

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

Chromosomal aberrations were induced in two in vitro studies with CHO (Chinese hamster ovary) cells, but this activity was not apparent either in one assay with cultured human lymphocytes or in two

in vivo studies for micronucleus induction in mouse bone marrow cells.

7.6.2 HCFC 142b


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

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

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

7.6.3 HCFC 132b

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

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

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

7.6.4 HCFC 133a


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

Chromosomal aberrations were not induced in a single rat bone marrow test using high concentrations. There were small, statistically


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significant increases in the incidences of early deaths in two of three male mouse dominant lethal assays. These increases occurred in mating weeks 6-8 in one study and in mating week 7 in the other, in which the lowest effective dose was 12.3 g/m3. No increases in early deaths were observed in the third study, in which the highest concentration tested was 12.3 g/m3.

7.6.5 HCFC 123

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

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

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

Table 11. Genetic toxicity of HCFC 141b

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

Escherichia coli, DNA repair - - 10 mg/ml, 18 hc

Salmonella typhimurium, reverse + + 1455 g/m3, mutation with TA98, TA100, TA1535, 48 hc TA1537, TA1538

S. typhimurium, reverse mutation with - - 1455 g/m3, TA98, TA100, TA1535, TA1537, TA1538 48 hc

E. coli, reverse mutation with WP2 uvrA - - 1455 g/m3, 48 hc

Gene mutation in vitro, V79 cells, hprt - - 1430 g/m3, locus 3 hc

Chromosomal aberrations in vitro, CHO ± - 1 mg/ml cells

Chromosomal aberrations in vitro, CHO + + 485 g/m3, cells 3 hc

Chromosomal aberrations in vitro, CHO + + 485 g/m3, cells 4 hc

Table 11 (contd).


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Chromosomal aberrations in vitro, human - - 1700 g/m3, lymphocytes 3 h (+ema)c 243 g/m3, 24 h (-ema)

Micronucleus test in vivo, mouse bone - NA 165 g/m3, marrow 6 h

Micronucleus test in vivo, mouse bone - NA 95 g/m3, marrow 6 h

a NA = not applicable; ± = inconclusive b LED = lowest effective dose; HED = highest effective dose; +ema = with exog

metabolic activation c in vitro assay in an enclosed system



Salmonella typhimurium, reverse - - 1640 g/m3, mutation with TA98, TA100, TA1535, 6 hd TA1537

S. typhimurium, reverse mutation with + + 2050 g/m3, TA98, TA100, TA1535, TA1537, TA1538 48 hd

S. typhimurium, reverse mutation with + + not specif TA98, TA100, TA1535, TA1537, TA1538

S. typhimurium, reverse mutation with - + 2050 g/m3, TA98, TA100, TA1535, TA1538 48 hd

S. typhimurium, reverse mutation with - + 2050 g/m3, TA98, TA100, TA1535, TA1538 48 hd

Cell transformation, in vitro BHK 21 ND + not specifi cell growth in soft agar assay


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Table 12 (contd).


Chromosomal aberrations, in vivo rat - NA 82 g/m3, bone marrow 6 h/day, 5 week for 1

Dominant lethal assay, male CD-1 rat - NA 82 g/m3, 6 h/day, 5 week for 1

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


Test system Results Dose LED/HEDa Without With exogenous exogenous metabolic metabolic activation activation

Salmonella typhimurium, reverse - - 4 mg/plate mutation with TA98, TA100, TA1535, TA1537, TA1538

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

S. typhimurium, reverse mutation with - - 578 g/m3b TA98, TA100, TA1535, TA1537, TA1538

Chromosomal aberrations, in vitro CHO - - 14.2 mg/ml cells 3 h (+ema) 3.0 mg/ml, 21 h (-ema

a +ema = with exogenous metabolic activation; -ema = without exogenous metabo HED = highest effective dose

b in vitro assay in an enclosed system

Table 14. Genetic toxicity of HCFC 133a

Test system Resultsa Dose


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LED/HEDb Without With exogenous exogenous metabolic metabolic activation activation

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

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

S. typhimurium, reverse mutation with - - 49 g/m3, TA98, TA100 8 hd

Cell transformation, in vitro BHK 21 - - gas, 3 h cell growth in soft agar assay

Chromosomal aberrations, in vivo, - NA 98 g/m3, 6 male AP rat bone marrow and 6 h/da 5 days/wee

Dominant lethal assay, male CD-1 + NA 49 g/m3, 6 mouse day, 5 day

Dominant lethal assay, male CD-1 + NA 12 g/m3, 6 mouse day, 5 day

Table 14 (contd).


Dominant lethal assay, male CD-1 - NA 12 g/m3, 6 h mouse day, 5 days/

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

Table 15. Genetic toxicity of HCFC 123



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Salmonella typhimurium, reverse - - 937 g/m3, mutation with TA98, TA100, TA1535, TA1537, TA1538

S. typhimurium, reverse mutation with - - not specif TA98, TA100, TA1535, TA1537, TA1538

S. typhimurium, reverse mutation with - - 625 g/m3, TA98, TA100, TA1535, TA1538

S. typhimurium, reverse mutation with - - not specif TA98, TA100, TA1535, TA1537, TA1538

Sacharomyces cerevisiae: D4, forward - - not specif mutation

Chromosomal aberrations, in vitro, + - 75 µg/ml, human lymphocytes 24 h

Chromosomal aberrations, in vitro, + + 1875 g/m3, human lymphocytes 3 h (+ema)c 156 g/m3, 24 h (-ema)

Cell transformation, in vitro, BHK 21 ND - not specifi cell growth in soft agar assay

Table 15 (contd).


Micronucleus test, in vitro, mouse - NA 112 g/m3, bone marrow

a ND = not determined; NA = not applicable b LED = lowest effective dose; HED = highest effective dose; +ema = with exog

activation c in vitro assay in an enclosed system

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

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

7.6.6 HCFC 124

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


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

7.7 Carcinogenicity

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

7.7.1 HCFC 142b

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

7.7.2 HCFC 133a

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

Table 16. Genetic toxicity of HCFC 124

Test system Results Dose LED/HEDa Without With exogenous exogenous metabolic metabolic activation activation

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

S. typhimurium, reverse mutation with - - 2790 g/m3, TA98, TA100, TA1535, TA1537, TA1538 48 hb

S. typhimurium, reverse mutation with - - 2790 g/m3, TA98, TA100 48 hb


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Escherichia coli, reverse mutation with - - 2790 g/m3, WP2 uvrA 48 hb

Chromosomal aberrations, in vitro, - - 3348 g/m3, CHO cells 48 h (-ema 3348 g/m3, 4 h (+ema)

a LED = lowest effective dose; HED = highest effective dose; +ema = with exog metabolic activation

b In vitro assay in an enclosed system

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

7.7.3 HCFC 123

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

7.8 Special studies - cardiovascular and respiratory effects

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

7.8.1 HCFC 141b

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

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

No effect on respiratory rate was observed when three groups of three male Wistar rats were exposed to approximately 45 g/m3 for 25


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min. However, there was a small change in respiratory amplitude suggesting a decrease in tidal volume (Janssen, 1989a).

7.8.2 HCFC 142b

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

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

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

7.8.3 HCFC 132b

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

7.8.4 HCFC 123

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

7.8.5 HCFC 124

Van Poznak & Artusio (1960) found that HCFC 124 caused anaesthesia in dogs at concentrations ranging from 2230 to 3910 g/m3; blood pressure was lowered in a dose-dependent fashion. Although ventilation was adequate even at the highest exposure level, the femoral arterial systolic pressure fell to as low as 40 mmHg (5.33 kPa). Little or no anaesthetic effect was observed at exposure levels that did not depress blood pressure. Atropine had little effect on hypotension. Phenylephrine partially reversed the hypotension and


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caused several premature ventricular contractions but no ventricular fibrillation. Similar effects were produced by intravenously administered adrenaline. Mullin (1976) reported that the NOEL of HCFC 124 for cardiac sensitization after a challenge injection of adrenaline in the dog was 56 g/m3, while the next exposure level tested (140 g/m3) induced sensitization, as did higher concentrations.

8. EFFECTS ON HUMANS

8.1 General population exposure

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

8.2 Occupational exposure

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

9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

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

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

Daphnia magna, also using a sealed vessel, was 31.2 mg/litre (Brinard & Hervouet, 1989).

The 96-h EC50 of HCFC 142b for guppies ( Poecilia reticulata), tested in a static system in accordance with OECD

Guidelines, was reported to be 220 mg/litre (Groenevald & Kuijpers, 1990a). Groenevald & Kuijpers (1990b) found a 48-h EC50 for Daphnia

magna of 160 mg/litre. No immobilization of Daphnia magna at 190 mg/litre in 48 h was found (Hutton & Lieder, 1989a).

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

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

10.1 Direct health effects

10.1.1 HCFC 141b


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

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

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

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

Mutagenicity testing of HCFC 141b yielded conflicting results. In vitro studies with CHO cells indicated clastogenic potential, but

this was not reflected in a single human lymphocyte test or two in vivo mouse studies.

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

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

10.1.2 HCFC 142b

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

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

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

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

HCFC 142b has mutagenic potential in bacterial systems. Data from in vitro mammalian cell systems are lacking. No mutagenic activity


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was seen in two in vivo rat studies.

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

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

10.1.3 HCFC 132b

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

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

maternally toxic at the lowest dose tested (3 g/m3). NOEL values have not been established for systemic toxicity or for embryotoxicity. The available mutagenicity studies, which are limited to a few

in vitro experiments, did not suggest that HCFC 132b is genotoxic. Long-term and carcinogenicity studies have not been performed.

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

10.1.4 HCFC 133a

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

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


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epithelium have been observed in male mice at exposure concentrations of 2.5 g/m3 and 5 g/m3, respectively.

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

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

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

10.1.5 HCFC 123

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

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

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

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

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

There is evidence of clastogenic effects in human lymphocytes in vitro, although this was not supported by an in vivo mouse

micronucleus study. HCFC 123 is not mutagenic in microorganisms. The carcinogenicity of HCFC 123 is being investigated in rats and thus cannot be evaluated at present.


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

10.1.6 HCFC 124

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

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

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

10.2 Health effects expected from a depletion of stratospheric ozone

The possible indirect health effects (e.g., an increase in the incidence of skin cancer and immunotoxic and ocular effects) of fully halogenated chlorofluorocarbons, resulting from an increase in UV-B radiation due to a depletion of the ozone layer, have been discussed in the Environmental Health Criteria 113: Fully Halogenated Chlorofluorocarbons (WHO, 1990).

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

10.3 Effects on the environment

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

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

11.1 Conclusions


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

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

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

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

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

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

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

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

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

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

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


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warming.

11.2 Recommendations for protection of human health and the environment

1. Since the toxicity of HCFC 142b is low, and the ozone-depleting and global-warming potentials are considerably lower than those of the fully halogenated chlorofluorocarbons, HCFC 142b can be considered as a transient substitute for the chlorofluorocarbons included in the Montreal Protocol. However, in line with the conclusions of the 1990 London Meeting of the Montreal Protocol Parties, efforts should be maintained to develop substitutes that would pose no risk to the environment and to develop alternative technologies. Care should be exercised in the use of HCFC 142b because of its flammability.

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

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

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

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Millischer R (1990) Joint assessment of commodity chemicals No. 15: 1-Fluoro-1,1-dichloroethane. Brussels, European Chemical Industry Ecology and Toxicology Centre (ECETOC), 21 pp.

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Moore BL & Trochimowicz HJ (1976) Subacute (two-week) inhalation toxicity. Wilmington, Delaware, Du Pont de Nemours and Co., Haskell Laboratory (Report No. 145-76).

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Mullin LS (1969) Cardiac sensitization (HFA 142b). Newark, Delaware, Du Pont de Nemours and Co., Haskell Laboratory (Report No. 354-69).

Mullin LS (1970) Cardiac sensitization - fright exposures (HFA 142b). Newark, Delaware, Du Pont de Nemours and Co., Haskell Laboratory (Report No. 81-70).

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Rickard LB (1990a) Mouse bone marrow micronucleus assay of HCFC-124. Newark, Delaware, Du Pont de Nemours and Co., Haskell Laboratory (Report No. 52-90).

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Schroeder R (1989a) An inhalation range-finding study to evaluate the toxicity of CFC 123 in the pregnant rabbit. Final report. Newark, Delaware, Du Pont de Nemours and Co., Haskell Laboratory (Project No. 88-3303).

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Yano BL, Ciezlak FS, & Landry TD (1989) 1,1-Dichloro-1-fluoroethane: 4-week inhalation toxicity study with Fischer 344 rats. Midland, Michigan, Dow Chemical Company, Toxicology Research Laboratory, Health and Environmental Sciences (Study DR-0006-8553-002A).

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RESUME

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


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

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

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

2. Sources d'exposition humaine et environnementale

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

3. Transport, distribution et transformation dans l'environnement

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

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

4. Concentrations dans l'environnement et exposition humaine

Comme le HCFC 141b, 132b, 133a, 123 et 124 ne sont pas encore


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

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

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

5.1 HCFC 141b

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

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

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

5.2 HCFC 142b

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

5.3 HCFC 132b

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

5.4 HCFC 133a

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

5.5 HCFC 123

On ne dispose d'aucune donnée toxicocinétique sur l'HCFC 123. Toutefois on peut penser qu'il y a absorption d'après les effets généraux et les taux élevés de fluorures urinaires observés lors


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d'études toxicologiques chez le rat. On a montré que l'HCFC 123 était métabolisé par l'organisme du rat. On ne sait pas quelle peut être l'ampleur de cette métabolisation mais, à côté des fluorures, l'acide trifluoracétique (TFA) apparaît comme un des principaux métabolites urinaires. On a mis en évidence dans le cas du HCFC 123 une liaison covalente aux protéines du foie.

5.6 HCFC 124

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

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

6.1 HCFC 141b

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

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

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

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

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

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

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


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traitement in vitro de cellules ovariennes d'hamsters chinois, mais ce phénomène n'a pas été observé lors d'une étude in vitro sur des

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

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

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

6.2 HCFC 142b

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

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

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

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

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

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

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


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première.

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

6.3 HCFC 132b

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

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

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

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

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

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

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

6.4 HCFC 133a


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

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

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

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

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

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

6.5 HCFC 123

Le HCFC 123 présente une faible toxicité aiguë par voie orale et cutanée. La dose orale la plus faible qui soit mortelle pour le rat


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est de 9 g/kg. Administré à raison de 2 g/kg à des rats ou à des lapins, ce composé n'a entraîné aucune mortalité.

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

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

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

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

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

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

6.6 HCFC 124

Chez l'animal, le HCFC 124 n'a qu'une faible toxicité aiguë par la voie respiratoire. Une mortalité a été observée chez des rats à la


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dose de 1674 g/m3 (exposition de 240 minutes) et chez des souris à la dose de 2460 g/m3 (exposition de 10 minutes). Les effets observés sont caractéristiques des chlorofluorocarbures, c'est-à-dire perte de coordination et narcose. A des doses supérieures ou égales à 140 g/m3, on a observé chez des chiens une sensibilisation cardiaque après une injection d'épreuve d'adrénaline. On ne dispose d'aucune donnée sur l'irritation oculaire ni sur l'irritation ou la sensibilisation cutanée que ce composé pourrait provoquer.

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

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

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

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

7. Effets sur l'homme

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

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

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

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

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


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9. Evaluation et conclusions

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

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

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

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

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

RESUMEN

1. Identidad, propiedades físicas y químicas y métodos analíticos

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

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

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


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2. Fuentes de exposición humana y ambiental

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

3. Transporte, distribución y transformación en el medio ambiente

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

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

4. Niveles ambientales y exposición humana

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

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

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

5.1 HCFC 141b

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

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


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5.2 HCFC 142b

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

5.3 HCFC 132b

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

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

5.4 HCFC 133a

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

5.5 HCFC 123

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

5.6 HCFC 124

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

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

6.1 HCFC 141b

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

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

Tras la exposición cutánea a 2 g/kg no se observó mortalidad en


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ratas ni en conejos.

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

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

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

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

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

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

6.2 HCFC 142b

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

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

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

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

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


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inducían arritmia cardíaca.

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

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

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

6.3 HCFC 132b

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

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

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

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

Las consecuencias principales de la exposición de ratas macho a la inhalación de HCFC 132b durante un breve período fueron, además de la depresión del SNC, atrofia del timo y efectos en la espermatogénesis. Se observó alteración de la espermatogénesis tras un tratamiento con dosis de 3 g/m3 o superiores durante 13 semanas. Otros efectos que se detectaron fueron una proliferación del conducto


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biliar y un aumento de la relación ponderal hígado/cuerpo en machos, incluso con la aplicación de los niveles más bajos de exposición (3 g/m3). Las ratas hembras resultaron menos sensibles que los machos a los efectos hepáticos.

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

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

6.4 HCFC 133a

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

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

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

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

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

En los estudios disponibles no hay pruebas de su capacidad mutagénica en bacterias. En un estudio no se observó aumento en la proporción de células renales de hámster que producían colonias transformadas. Se detectaron efectos letales dominantes en dos de tres estudios tras la exposición de ratones machos a concentraciones de 12 g/m3 o superiores durante 5 días la proporción de células de la médula ósea con aberraciones cromosómicas se mantuvo inalterada en


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ratas expuestas a 98 g/m3 (6 h al día durante 5 días como máximo). En el único estudio de carcinogenicidad se observó un aumento de la incidencia de adenocarcinomas del útero y de tumores benignos de las células intersticiales de los testículos en ratas que recibieron 300 mg/kg de aceite de maíz administrados por sonda durante 52 semanas (seguidas de un período de observación de 73 semanas).

6.5 HCFC 123

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

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

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

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

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

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

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


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los resultados completos.

6.6 HCFC 124

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

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

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

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

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

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

7. Efectos en el ser humano

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

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

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

No se dispone de información acerca de los efectos de los hidroclorofluorocarburos estudiados sobre los organismos presentes en el medio ambiente, excepto algunos datos limitados de los HCFC 141b y 142b. La CL50 a las 96 h del HCFC 141b para Brachydanio rerio es de 126 mg/litro y la CE50 a las 48 h para la inmovilización de

Daphnia magna de 31 mg/litro, habiéndose realizado ambas observaciones en recipientes cerrados. En el caso del HCFC 142b, la CE50 a las 96 h para Lebistes reticulatus es de 220 mg/litro, mientras que la CE50 a las 48 h para la inmovilización de Daphnia

magna varía de 160 a > 190 mg/litro. La CL50 a las 96 h del HCFC


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142b para la trucha arco irís es de 36 mg/litro.

9. Evaluación y conclusiones

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

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

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

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

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

See Also: Toxicological Abbreviations


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partially halogenated chlorofluorocarbons ( ethane

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