INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 139
PARTIALLY HALOGENATED CHLOROFLUOROCARBONS
(ETHANE DERIVATIVES)
This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organisation, or the World Health Organization.
Published under the joint sponsorship of
the United Nations Environment Programme,
the International Labour Organisation,
and the World Health Organization
Draft prepared by Professor D. Beritc-Stahuljak and Professor
F. Valic (University of Azgreb, Croatia) using texts made
available by Dr R. Millischer (ATOCHEM, Paris, France),
Dr. S. Magda (Kali-Chemie, Hanover, Germany), Mr D.J. Tinston
(ICI Central Toxicology Laboratory, United Kingdom), Dr. H.J.
Trochimowicz (E.I. Du Pont de Nemours, Newark, Delaware, USA)
and Dr G.M. Rusch (Engineered Materials Sector, Allied-Signal Inc.,
Morristown, New Jersey, USA).
World Health Orgnization
Geneva, 1992
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WHO Library Cataloguing in Publication Data
Partially halogenated chlorofluorocarbons (ethane derivatives).
(Environmental health criteria ; 139)
1.Freons - adverse effects 2.Freons - toxicity
I.Series
ISBN 92 4 157139 X (NLM Classification: QV 633)
ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR PARTIALLY HALOGENATED
CHLOROFLUOROCARBONS (ETHANE DERIVATIVES)
1. SUMMARY
1.1. Identity, physical and chemical properties, and analytical
methods
1.2. Sources of human and environmental exposure
1.3. Environmental transport, distribution and transformation
1.4. Environmental levels and human exposure
1.5. Kinetics and metabolism in laboratory animals and humans
1.6. Effects on laboratory mammals and in vitro test systems
1.7. Effects on humans
1.8. Effects on other organisms in the laboratory and field
1.9. Evaluation and conclusions
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
METHODS
2.1. Identity
2.1.1. Technical products
2.2. Physical and chemical properties
2.3. Conversion factors
2.4. Analytical methods
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural occurrence
3.2. Anthropogenic sources
3.2.1. Production levels
3.2.2. Manufacturing processes
3.2.3. Loss during disposal, transport, storage and
accidents
3.3. Use patterns
3.3.1. Major uses
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1. Biodegradation and bioaccumulation
4.2. Environmental transformation and interaction with other
environmental factors
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental levels
5.1.1. Air
5.1.2. Water, food and other edible products
5.2. Human exposure
6. KINETICS AND METABOLISM
6.1. Animal studies
6.1.1. Absorption
6.1.2. Distribution
6.1.3. Metabolic transformation
6.1.3.1 General considerations
6.1.4. Covalent binding to macromolecules
6.1.5. Elimination
6.2. Human studies
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
7.1. Single exposure
7.1.1. Acute oral toxicity
7.1.2. Acute inhalation toxicity
7.1.3. Acute dermal toxicity
7.2. Short-term inhalation exposure
7.3. Skin and eye irritation; sensitization
7.3.1. Skin and eye irritation
7.3.2. Skin sensitization
7.4. Long-term exposure
7.5. Reproduction, embryotoxicity, and teratogenicity
7.5.1. Reproduction
7.5.2. Embryotoxicity and teratogenicity
7.6. Mutagenicity
7.7. Carcinogenicity
7.8. Special studies - cardiovascular and respiratory effects
8. EFFECTS ON HUMANS
8.1. General population exposure
8.2. Occupational exposure
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1. Direct health effects
10.1.1. HCFC 141b
10.1.2. HCFC 142b
10.1.3. HCFC 132b
10.1.4. HCFC 133a
10.1.5. HCFC 123
10.1.6. HCFC 124
10.2. Health effects expected from a depletion of stratospheric
ozone
10.3. Effects on the environment
11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH
AND THE ENVIRONMENT
11.1. Conclusions
11.2. Recommendations for protection of human health and the
environment
REFERENCES
RESUME
RESUMEN
WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR PARTIALLY
HALOGENATED CHLOROFLUOROCARBONS (ETHANE DERIVATIVES)
Members
Dr U. Andrae, Genetic Toxicology Group, Research Centre for
Environment and Health, Neuherberg, Germany
Professor D. Beritic-Stahuljak, Medical School, University of Zagreb,
Zagreb, Croatia
Dr J. Delic, Toxicology Unit, Health and Safety Executive, Bootle,
United Kingdom
Dr B. Gilbert, Technology Development Company (CODETEC) Cidade
Universitaria, Campinas, Brazil ( Joint Rapporteur)
Ms G. Hodson-Walker, Cell Biology Department, Life Science Research
Ltd., Eye, United Kingdom
Dr W. Jameson, National Institute of Environmental Health Sciences,
Research Triangle Park, North Carolina, USA
Dr J. Kojima, Division of Environmental Chemistry, National Institute
of Hygienic Sciences, Tokyo, Japan
Dr J. Sokal, Institute of Occupational Medicine, Sosnowiec, Poland
Dr S. Swierenga, Health and Welfare Canada, Ottawa, Canada ( Joint
Rapporteur)
Dr V. Vu, Oncology Branch, Office of Toxic Substances, US
Environmental Protection Agency, Washington, DC, USA ( Chairman)
Observers
Dr R. Millischer, Department of Toxicology, ATOCHEM, Paris, France
Dr H. Trochimowicz, E.I. Du Pont de Nemours & Co., Haskell Laboratory
for Toxicology and Industrial Medicine, Newark, Delaware, USA
Secretariat
Dr D. McGregor, Unit of Carcinogen Identification and Evaluation,
International Agency for Research on Cancer, Lyon, France
Professor F. Valic, IPCS Consultant, World Health Organization,
Geneva, Switzerland, also Vice-Rector, University of Zagreb,
Zagreb, Croatia ( Responsible Officer and Secretary)
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
Every effort has been made to present information in the criteria
monographs as accurately as possible without unduly delaying their
publication. In the interest of all users of the Environmental Health
Criteria monographs, readers are kindly requested to communicate any
errors that may have occurred to the Director of the International
Programme on Chemical Safety, World Health Organization, Geneva,
Switzerland, in order that they may be included in corrigenda.
* * *
A detailed data profile and a legal file can be obtained from the
International Register of Potentially Toxic Chemicals, Palais des
Nations, 1211 Geneva 10, Switzerland (Telephone No. 7988400 or
7985850).
ENVIRONMENTAL HEALTH CRITERIA FOR PARTIALLY HALOGENATED
CHLOROFLUOROCARBONS (ETHANE DERIVATIVES)
A Task Group on Environmental Health Criteria for Partially
Halogenated Chlorofluorocarbons (Ethane Derivatives) met at the
British Industrial and Biological Research Association (BIBRA),
Carshalton, Surrey, United Kingdom, from 30 September to 5 October
1991. Dr S.D. Gangolli opened the meeting on behalf of the host
institute and greeted the participants on behalf of the Department of
Health. Professor F. Valic welcomed the participants on behalf of the
heads of the three cooperating organizations of the IPCS
(UNEP/ILO/WHO). The Task Group reviewed and revised the draft
monograph, made an evaluation of the direct and indirect risks for
human health from exposure to the partially halogenated
chlorofluorocarbons reviewed, and made recommendations for health
protection and further research.
The draft was prepared by Professor D. Beritic-Stahuljak and Professor
F. Valic, using the texts made available by Dr R. Millischer, ATOCHEM,
Paris, France (HCFC 141b), Dr S. Magda, Kali-Chemie, Hanover, Germany
(HCFC 142b), Mr D.J. Tinston, Central Toxicology Laboratory, ICI,
Alderley Park, United Kingdom (HCFC 133a), Dr H.J. Trochimowicz, E.I.
Du Pont de Nemours, Newark, Delaware, USA (HCFC 132b), and Dr G.M.
Rusch, Engineered Materials Sector, Allied-Signal Inc., Morristown,
New Jersey, USA (HCFC 123 and HCFC 124).
Professor F. Valic was responsible for the overall scientific content
and for the organization of the meeting, and Dr P.G. Jenkins, IPCS,
for the technical editing of the monograph.
INTRODUCTION
The global concern over the depletion of the stratospheric ozone layer
by active chlorine from fully halogenated chlorofluorocarbons resulted
in the development of the Vienna Convention for the Protection of the
Ozone Layer, adopted in March 1985, and its Montreal Protocol on
Substances that Deplete the Ozone Layer, signed in 1987. The agreement
required a freeze in the production and use of the fully halogenated
chlorofluorocarbons 11, 12, 113, 114 and 115 at l986 levels by
mid-1989, a 20% reduction from 1 July 1993 and a further 30% reduction
from 1 July 1998. Sixty-seven countries and the European Economic
Community have signed the Protocol. A total phase-out of 15 fully
halogenated chlorofluorocarbons by the year 2000 was agreed by the
Parties to the Protocol in June 1990.
This phase-out has created an urgent need for acceptable substitute
chemicals. These should have similar properties to the
chlorofluorocarbons included in the Protocol, but their
ozone-depleting potentials and possibly global-warming potentials
should be lower, and their atmospheric residence times shorter. In
addition, the substitute chemicals should not pose an unreasonable
risk to human health or the environment.
The hydrogenated partially halogenated chlorofluorocarbons constitute
a class of chemicals being considered as substitutes. The
ozone-depleting potentials and the global-warming potentials of the
partially halogenated chlorofluorocarbons are considerably lower than
those of the fully halogenated chlorofluorocarbons, and their
atmospheric residence times are shorter. Therefore, the partially
halogenated chlorofluorocarbons for which the toxicity evaluations
suggest no unreasonable health risks could be considered as possible
substitutes for the unacceptable fully halogenated
chlorofluorocarbons, particularly in the case of those for which the
production should be technologically feasible. The evaluation of two
partially halogenated methane derivatives of chlorofluorocarbons
(hydrochlorofluorocarbons 21 and 22) has been completed and published
as monograph No. 126 in the WHO Environmental Health Criteria series
(WHO, 1991). The present monograph evaluates six partially halogenated
ethane derivatives of chlorofluorocarbons (hydrochlorofluorocarbons
141b, 142b, 132b, 133a, 123 and 124).
1. SUMMARY
1.1 Identity, physical and chemical properties, and analytical
methods
This monograph concerns six hydrochlorofluorocarbons (HCFCs)
derived from the partial substitution of the hydrogen atoms in ethane
with both fluorine and chlorine atoms. The compounds considered in
this report are 1,1-dichloro-1-fluoroethane (HCFC 141b), 1-chloro-1,1-
difluoroethane (HCFC 142b), 1,2-dichloro-1,1-difluoroethane (HCFC
132b), 1-chloro-2,2,2-trifluoroethane (HCFC 133a), 1,1-dichloro-2,2,2-
trifluoroethane (HCFC 123) and 1-chloro-1,2,2,2-tetrafluoroethane
(HCFC 124).
Under normal temperatures and pressures these compounds are
flammable (HCFC 142b) or non-flammable gases (HCFC 133a, HCFC 124) or
non-flammable volatile liquids (HCFC 141b, HCFC 132b, HCFC 123). They
are colourless and the majority are practically odourless or have a
faint ethereal odour (HCFC 141b and HCFC 123). They are slightly or
moderately soluble in water and miscible with many organic solvents.
Analytical methods available for the determination of these
hydrochlorofluorocarbons include gas chromatography with flame
ionization and electron capture detection. Relatively high
concentrations in air can be monitored by single-beam photometry.
1.2 Sources of human and environmental exposure
The hydrochlorofluorocarbons reviewed in this monograph are not
known to occur as natural products. Due to the fact that these
compounds are not produced commercially on a large scale for end use,
there is little human exposure or release to the environment. Some of
these compounds may be used in the future as substitutes for fully
halogenated chlorofluorocarbons (e.g., CFC 11, CFC 12, and CFC 113).
HCFCs 133a and 142b are intermediates in the manufacture of other
fluorinated products. HCFC 133a is an in vivo metabolite of the
anaesthetic halothane.
1.3 Environmental transport, distribution and transformation
Data on biodegradation in the environment is limited to studies
of HCFCs 141b and 142b, which have been shown to be not readily
biodegradable by microorganisms. Little information on log
octanol/water partition coefficients is available, but that for HCFC
141b is 2.3 and so bioaccumulation of this hydrochlorofluorocarbon is
unlikely. In the troposphere these compounds are mainly decomposed by
reactions with hydroxy radicals. Their atmospheric lifetimes (relative
to an atmospheric lifetime of methyl chloroform of 6.3 years) lie
between 1.6 years (HCFC 123) and 19.1 years (HCFC 142b). (The
atmospheric lifetime of CFC 11 is 75, CFC 12 is 110, and
CFC 113 is 90 years). With the exception of HCFC 133a, for which there
are no values, the ozone-depleting and global-warming potentials of
these compounds are less than or equal to one-tenth of that of CFC 11,
the fully halogenated chlorofluorocarbon with the highest
ozone-depleting and global-warming potential (HCFC 142b, for which the
global-warming potential is approximately one-third that of CFC 11, is
an exception).
1.4 Environmental levels and human exposure
As HCFCs 141b, 132b, 133a, 123 and 124 are not yet in large-scale
commercial production and HCFC 142b is only used as an intermediate,
these substances are not released significantly into the environment.
There are therefore no data on environmental levels or human exposure.
1.5 Kinetics and metabolism in laboratory animals and humans
No data are available on the toxicokinetics in humans of any of
the HCFCs reviewed.
1.5.1 HCFC 141b
Results from toxicity studies suggest that absorption of HCFC
141b takes place across the respiratory epithelium. No information is
available on the distribution of HCFC 141b in mammals. In recent
in vitro single-exposure studies in rats, 2,2-dichloro-2-fluoro-
ethyl glucuronide and 2,2-dichloro-2-fluoroacetic acid were identified
in the urine.
A pilot study for absorption and metabolism of HCFC 141b in rats
exposed to its vapour suggested that metabolic transformation occurs
only to a very small extent.
An in vitro study indicated that HCFC 141b is dechlorinated to
a limited extent by hepatic microsomes.
1.5.2 HCFC 142b
There is no information on toxicokinetics for HCFC 142b. From
animal toxicity studies it can be inferred that absorption takes
place. An in vitro study suggested that dechlorination may occur.
1.5.3 HCFC 132b
In a metabolism study using intraperitoneal administration of
HCFC 132b to rats, 2-chloro-2,2-difluoroethylglucuronide,
chlorodifluoroacetaldehyde (hydrated and conjugated) and
chlorodifluoroacetic acid were identified in the urine. Formation and
excretion of chlorodifluoroacetic acid were increased after repeated
injection of the animals with HCFC 132b. In vitro experiments using
rat liver microsomes suggested the involvement of cytochrome P-450
IIEI in the initial hydroxylation step. No evidence for covalent
binding of fluorinated metabolites to liver proteins has been
observed.
1.5.4 HCFC 133a
No information is available on the toxicokinetics of HCFC 133a.
That absorption occurs following exposure of animals can be inferred
from the toxic effects seen in various studies. Dechlorination of HCFC
133a has been observed in vitro.
1.5.5 HCFC 123
There are no toxicokinetic data on HCFC 123. Absorption, however,
can be inferred from systemic effects and the elevated urinary
fluoride levels seen in toxicity studies in rats. HCFC 123 has been
shown to undergo metabolic transformation in rats. The extent of
metabolism is not known, but trifluoroacetic acid (TFA) has been
identified as a major urinary metabolite, in addition to fluoride.
Covalent binding to liver protein has been demonstrated for HCFC 123.
1.5.6 HCFC 124
There are no data on the kinetics and metabolism of HCFC 124. It
may be inferred from inhalation toxicity studies that absorption of
HCFC 124 occurs in the respiratory tract.
1.6 Effects on laboratory mammals and in vitro test systems
1.6.1 HCFC 141b
The acute oral toxicity of HCFC 141b is low. No signs of toxicity
were observed after rats were dosed with 5 g/kg.
In acute inhalation studies in rats and mice, central nervous
system (CNS) depression, anaesthesia and death were observed at high
exposure levels. No treatment-related macroscopic or histopathological
effects were observed. The 4-h LC50 reported for rats in one study
was 295 g/m3, and the 2-h LC50 in mice was reported to be 151
g/m3 in another study. In rats, the lowest concentration inducing
lethality was reported to be 242 g/m3 for 6 h.
No mortality in rats or rabbits was observed after dermal
exposure to 2 g/kg.
No marked toxicity was observed in short-term inhalation studies
at exposures ranging from 10 to 97 g/m3 and lasting up to 90 days.
Effects seen included reduced body weight gain, "slight
biochemical changes" and CNS depression. A no-observed-effect level
was not achieved in the 90-day study.
HCFC 141b did not produce signs of dermal irritation in rabbits,
or eye irritation in one of the two studies performed. In the second
study, a "mild" irritant response in the eye was observed. No skin
sensitization was observed in guinea-pigs.
A 2-generation reproduction study with HCFC 141b is currently in
progress. In developmental studies, increased incidences of
subcutaneous oedema and haemorrhaging in the fetuses and of embryonal
deaths were observed, but only at the maternally toxic concentration
of 97 g/m3 in a rat study. There were no teratogenic effects. No
treatment-related effects on embryo or fetal development were observed
in a rabbit study.
HCFC 141b was not mutagenic in a bacterial DNA repair assay and
produced conflicting results in other bacterial mutation tests. It had
no effect on V79 cells in the hprt locus assay. Chromosome
aberrations were observed after in vitro treatment of Chinese
hamster ovary (CHO) cells, but this was not reflected in an in vitro
human lymphocyte study. Two in vivo micronucleus assays in mice were
also negative.
A combined chronic inhalation toxicity/carcinogenicity study on
rats is in progress.
HCFC 141b exhibits cardiac sensitization potential to exogenous
adrenaline in dogs. The lowest concentrations of HCFC 141b inducing
responses were 24 and 48 g/m3 in dogs and monkeys, respectively.
1.6.2 HCFC 142b
Orally administered HCFC 142b produced only slight signs of
toxicity in rats at single doses of up to 5 g/kg.
Single inhalation exposure of rats to 525 g/m3 for 4 h killed
approximately 50% of the animals. Other studies with shorter duration
exposures yielded LC50 values in excess of 1000 g/m3.
Repeated inhalation exposure studies did not produce any adverse
responses in rats at a concentration of 41 g/m3 (6 h/day, 5 days per
week for 90 days). At much higher dose levels, death in rats was
associated with severe pulmonary irritation.
There are no reports of studies with HCFC 142b on skin and eye
irritation or skin sensitization. In cardiac sensitization experiments
(using exogenous adrenaline), mice, dogs and monkeys were tested. Dogs
were most sensitive; the NOEL was 102.5 g/m3 for a 5-min exposure,
while 205 g/m3 (also a 5-min exposure) induced cardiac arrhythmia.
There has been a single long-term study reported, in which rats
(130 males and 110 females per group) were exposed to HCFC 142b at 4,
41 and 82 g/m3 for 6 h/day, 5 days/week, for up to 104 weeks. No
treatment-related effects were observed in any of the parameters
studied, which included haematology, blood and urine chemistry and
histopathology. No significant treatment-related changes in tumour
incidence were reported.
No conventional studies have investigated the effect of HCFC 142b
on reproduction, but no effect on male fertility was observed in a
dominant lethal study. Two rat teratogenicity tests have been
performed. In one teratogenicity study, Sprague-Dawley rats were
exposed to 4 and 41 g/m3 (6 h/day from day 3 to day 15 of
pregnancy), while in the other study, Sprague-Dawley rats were exposed
to 13 and 39 g/m3 (6 h/day from day 6 to day 15 of pregnancy). No
teratogenic effects were noted. Reduced ossification was observed in
small numbers of fetuses at both dose levels in the latter study, but
not in the former.
HCFC 142b induces mutations in bacteria, but there is a lack of
data from genotoxicity assays with cultured mammalian cells. In vivo
assays did not show any increases in chromosomal aberrations in bone
marrow or dominant lethal effects in male rats.
1.6.3 HCFC 132b
The acute oral toxicity of HCFC 132b in the rat is low. The
lowest dose at which mortality was observed was 25 g/kg. After oral
dosing with 2 g/kg, depression of the autonomic and the central
nervous system was observed, together with effects on motor
coordination, motor activity and muscle tone. In males, swollen livers
and reduced liver weights were noted.
The acute inhalation toxicity of HCFC 132b is characterized by
anaesthesia at high exposure levels. The lowest dose at which
mortality was observed in rats during a 4-h exposure was 110 g/m3.
In mice, the LC50 for a 30-min exposure was 269 g/m3; anaesthesia
occurred at 71 g/m3. In one study, decreases in the weight of
testis, and increases in the weight of liver and lungs of male rats
were observed following exposure to 33 g/m3 for 6 h.
Dermal application of HCFC 132b (2 g/kg) in rats resulted in
clinical signs of CNS effects and swollen livers in some of the
animals. The undiluted compound produced "mild" skin irritation in
guinea-pigs and "mild to moderate" eye irritation in rabbits. No
evidence for skin sensitization in guinea-pigs was obtained. Cardiac
sensitization of dogs to adrenaline by inhaled HCFC 132b occurred at
exposure levels of 27 g/m3 or more.
The predominant consequences of short-term inhalation exposures
of male rats to HCFC 132b, besides CNS depression, were thymic atrophy
and effects on spermatogenesis. Disruption of spermatogenesis was
observed after treatment with 3 g/m3 or more for 13 weeks. Other
effects included bile duct proliferation and increased liver/body
weight ratio in males, even at the lowest exposure level applied (3
g/m3). Female rats appeared to be less sensitive than males to the
liver effects.
HCFC 132b induced embryotoxicity in rats after inhalation
exposure to 3-28 g/m3 during days 6-15 of gestation, this resulting
in increased numbers of resorptions (at 11 and 28 g/m3) and in
decreased fetal weight at all exposure levels. Maternal toxicity was
observed at all dose levels tested.
Based on the limited data available, there is no evidence for
in vitro mutagenicity of HCFC 132b. The carcinogenicity of the
compound has not been studied.
1.6.4 HCFC 133a
No data are available on the acute oral toxicity of HCFC 133a. It
is of low acute toxicity by the inhalation route (the 30-min LC50 in
mice is 738 g/m3), and the principal toxic effects seen are those
associated with anaesthesia. No information is available on cardiac
sensitization, skin or eye irritation or skin sensitization.
Repeated exposures (90 days) of rats to 49 g/m3 produced
chronic inflammation of the nasal passages, pulmonary emphysema and
oedema, bronchitis and pneumonia. Atrophy of the thymus, testis, ovary
and spleen was also observed. No effects were seen in rats or dogs
repeatedly exposed to HCFC 133a for 7 (rats) or 90 (dogs) days at a
concentration of about 25 g/m3, although deaths were observed in
mice exposed for 5 days to 0.5 g/m3 or more (excepting 2.5 g/m3).
Although no conventional studies on the effects of HCFC 133a on
reproduction are available, effects on male fertility and testicular
histopathology were observed in three dominant lethal studies in mice.
Exposures at concentrations of 2.5 g/m3 or more for 5 days resulted
in a reduced number of pregnant females and an increase in the
proportion of abnormal sperm, while exposure at a concentration of 5
g/m3 resulted in histopathological damage to the seminiferous
epithelium.
Studies on rats (treated on days 6-16 of gestation), at exposure
concentrations producing signs of only slight maternal toxicity, have
demonstrated that HCFC 133a is embryotoxic at concentrations of 2
g/m3 or more and embryolethal at 10 g/m3 or more. Progesterone
pretreatment of the pregnant females did not influence the
embryotoxic/lethal effects. Indications of teratogenic effects
(external anomalies of limb and tail) were seen in one study. HCFC
133a produced spontaneous abortions and total embryolethality in
rabbits exposed to 25 g/m3 on days 7-19 of gestation, a
concentration that produced only slight maternal toxicity.
From the studies available, there is no evidence of mutagenic
potential in bacteria. No increase was seen in the proportion of
hamster kidney cells producing transformed colonies in one study.
Dominant lethal effects were observed in two out of three studies
after exposure of male mice to 12 g/m3 or more for 5 days. The
proportion of bone marrow cells with chromosomal aberrations was
unaffected in rats exposed to 98 g/m3 (6 h/day for up to 5 days). In
the single carcinogenicity study, an increase in the incidence of
adenocarcinomas of the uterus and of benign interstitial cell tumours
of the testis was observed in rats that received 300 mg/kg in corn oil
by gavage for 52 weeks (this being followed by an observation period
of 73 weeks).
1.6.5 HCFC 123
HCFC 123 has low acute oral and dermal toxicity. The reported
lowest oral dose of HCFC 123 producing lethality in rats is 9 g/kg. No
mortality was found at a dose level of 2 g/kg in either rats or
rabbits.
The acute inhalation toxicity of HCFC 123 is also low. Effects
seen are similar to those of chlorofluorocarbons, i.e. loss of
coordination and narcosis. The 4-h LC50 is 178 g/m3 in hamsters,
463 g/m3 in mice and ranges from 200 to 329 g/m3 in rats. Cardiac
sensitization after a challenge with injected adrenaline occurred in
dogs at concentrations of 119 g/m3 or more. Liquid HCFC 123 produces
"mild" irritation of the skin and eye in rabbits. It does not cause
skin sensitization in guinea-pigs.
Several short-term toxicity studies have been conducted on HCFC
123 using the inhalation route. Signs of CNS depression are
consistently observed in rats at concentrations of 31 g/m3 or more.
HCFC 123 also caused some liver effects in rats at exposure
concentrations of 31 g/m3 or more. Long-term exposure (4 weeks or
longer) to HCFC 123 also affects lipid and carbohydrate metabolism as
reflected by consistent reduction of serum triglyceride cholesterol
and glucose levels in rats. Interim results from an ongoing chronic
inhalation toxicity/oncogenicity study in rats indicate that HCFC 123
induces effects following long-term exposure to 2, 6 or 31 g/m3. The
no-observed-effect level (NOEL) was not recorded in this study, based
on the effects on lipid metabolism and increased hepatic peroxisomal
activity.
A 2-generation reproduction study in rats exposed by the
inhalation route is currently being conducted on HCFC 123. No evidence
of embryotoxicity was seen in two limited studies in rats at
concentration producing slight maternal toxicity. There is evidence of
embryotoxicity only at high maternally toxic concentrations (more than
62.5 g/m3) in rabbits. Maternal toxicity (lower body weight, CNS
depression) was seen in rats at exposure levels of 31 g/m3 or more,
and in rabbits at 3 g/m3 or more. No evidence of teratogenicity was
seen in either rats or rabbits.
HCFC 123 shows no evidence of mutagenic activity in bacterial and
yeast assays. However, there is evidence of clastogenic activity in
human lymphocytes in vitro, but this finding was not supported by
data from an in vivo mouse micronucleus assay.
A combined chronic inhalation toxicity/carcinogenicity study on
rats is in progress. A preliminary communication indicated that HCFC
123 produces increased incidences of benign tumours of the testis and
exocrine pancreas in male rats. However, an evaluation of the
potential carcinogenicity of HCFC 123 cannot be made until complete
results become available.
1.6.6 HCFC 124
The acute inhalation toxicity of HCFC 124 in animals is low.
Death occurred in rats at 1674 g/m3 (240-min exposure) and in mice
at 2460 g/m3 (10-min exposure). The effects seen are typical of
those of chlorofluorocarbons, i.e. loss of coordination and narcosis.
Cardiac sensitization after a challenge injection of adrenaline
occurred in dogs at concentrations of 140 g/m3 or more. No
information on skin or eye irritation or skin sensitization is
available for this compound.
Short-term inhalation toxicity has been investigated in five
experiments on rats with exposure durations ranging from 14 to 90
days. Histopathological changes in the organs were not observed even
at the highest exposure levels studied (560 g/m3 in a 14-day
experiment, 279 g/m3 in a 90-day study). The NOEL of 28 g/m3 was
reported on the basis of functional observations and blood chemistry
determinations in the 90-day study.
A chronic inhalation toxicity study on HCFC 124 is in progress.
In three limited teratogenicity studies on rats, in which HCFC 124 was
tested at 30 g/m3 or in the range 3-279 g/m3, there was no
evidence of embryotoxicity or teratogenic effects. Maternal toxicity
was demonstrated at 84 g/m3. No information is available on the
effects of HCFC 124 on reproductive potential. Full teratogenicity
studies are in progress.
Available data from several bacterial studies and a single
mammalian cell study, show no evidence of mutagenic potential of HCFC
124. An inhalation carcinogenicity study is in progress.
1.7 Effects on humans
No data are available on the effects of HCFC 141b, HCFC 132b,
HCFC 133a, HCFC 123 or HCFC 124 on humans.
The data from a single study on humans occupationally exposed to
HCFC 142b do not allow the effects of HCFC 142b upon humans to be
evaluated independently of many other exposures.
1.8 Effects on other organisms in the laboratory and field
No information is available on the effects on environmental
organisms of the hydrochlorofluorocarbons reviewed, except for limited
data on HCFC 141b and HCFC 142b. The 96-h LC50 of HCFC 141b for
zebra fish is 126 mg/litre and the 48-h EC50 for the immobilization
of Daphnia magna is 31 mg/litre, both observations having been made
in closed vessels. In the case of HCFC 142b, the 96-h EC50 for
guppies is 220 mg/litre while the 48-h EC50 for the immobilization
of D. magna varies from 160 to > 190 mg/litre. The 96-h LC50 of
HCFC 142b for rainbow trout is 36 mg/litre.
1.9 Evaluation and conclusions
Environmental levels for the six HCFCs reviewed are unknown, but
are considered to be low based on current use patterns.
HCFC 142b has a low toxic potential and is not considered to pose
a significant risk to human health under non-accidental exposure
conditions. The toxicological information on HCFC 141b, HCFC 123 and
HCFC 124 are incomplete and more data are required before an
evaluation of the human health hazard can be made. Both HCFC 133a and
HCFC 132b pose a hazard to human health.
All the six hydrochlorofluorocarbons reviewed either have, or are
expected to have, lower ozone-depleting potentials and have
considerably lower atmospheric residence times than the fully
halogenated chlorofluorocarbons. They should, therefore, pose a lower
indirect health risk. The global-warming potentials are, or are
expected to be, lower than those of the fully halogenated
chlorofluorocarbons and should not contribute significantly to global
warming.
Since the toxicity of HCFC 142b is low and the ozone-depleting
and global-warming potentials are lower than those of the fully
halogenated chlorofluorocarbons, it can be considered as a transient
substitute for the chlorofluorocarbons included in the Montreal
Protocol.
No recommendations can be made for HCFC 141b, HCFC 123 or HCFC
124 until more toxicity data become available. Although HCFC 133a and
HCFC 132b pose low environmental and indirect health risks, they are
not recommended as substitutes for the chlorofluorocarbons included in
the Montreal Protocol because of their toxic potential.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
METHODS
2.1 Identity
The hydrochlorofluorocarbons (HCFCs) considered in this monograph
are compounds derived by the partial substitution of the hydrogen
atoms in ethane with both fluorine and chlorine atoms. The chemical
formulae, chemical structures, common names, common synonyms, CAS
registry numbers and conversion factors of the compounds reviewed
(HCFC 141b, HCFC 142b, HCFC 132b, HCFC 133a, HCFC 123 and HCFC 124)
are presented in Table 1.
The individual chemical substances have many different trade
names and are characterized by code numbers which are explained in
Table 1.
2.1.1 Technical products
The HCFCs are being developed in part as substitutes for fully
halogenated chlorofluorocarbons: HCFCs 123 and 141b for CFC-11 and in
admixture for CFC-113; HCFCs 124 and 142b for CFC-12 (Hoffmann, 1990).
HCFCs 133a and 142b are chemical intermediates, and one of the
compounds reviewed, HCFC 132b, is still essentially experimental (see
section 3.3.1). When marketed they are usually available at 99.8% (or
more) purity. Impurities in HCFC 142b have been reported at levels of
0.06% HCFC 141b, very much smaller levels of HCFC-22, CFC-11,
HFC-152a, CFC-113 and traces of other compounds (Hutton & Lieder,
1989a).
2.2 Physical and chemical properties
Some physical and chemical properties of the
hydrochlorofluorocarbons reviewed in this monograph are summarized in
Table 2. Under normal temperatures and pressures, they are flammable
(HCFC 142b) or non-flammable gases (HCFC 133a, HCFC 124) or
non-flammable volatile liquids (HCFC 141b, HCFC 132b and HCFC 123).
They are colourless, and the majority of them are practically
odourless or have a faint ethereal odour (HCFC 141b and HCFC 123).
They are slightly or moderately soluble in water and miscible with
many organic solvents. On heating to decomposition, HCFCs 124, 132a
and 142b produce toxic fumes of fluorine- or chlorine-containing
compounds (Sax, 1984) and this is probably true also of the other
hydrochlorofluorocarbons reviewed. HCFC 142b can react vigorously with
oxidizing materials (Sax, 1984).
Table 1. Identity of hydrochlorofluorocarbonsa
HCFC 141b HCFC 142b HCFC 132b
Chemical structure Cl H F H Cl Cl
' ' ' ' ' '
F - C - C - H Cl - C - C - H F - C - C - H
' ' ' ' ' '
Cl H F H F H
Chemical formula CCl2F-CH3 CClF2CH3 CClF2-CH2Cl
Common names dichlorofluoroethane chlorodifluoroethane dichlorodifluoroethane
Common synonyms 1,1-dichloro-1-fluoroethane; 1-chloro-1,1-difluoroethane; 1,2-dichloro-1,1-difluoroethane;
1-fluoro-1,1-dichloroethane; 1,1-difluoro-1-chloroethane; HCFC 132b
ethane, 1,1-dichloro-1-fluoro; difluoromonochloroethane;
HCFC 141b; Propellant 141b; HCFC 142b;
R-141b
CAS Registry number 1717-00-6 75-68-3 1649-08-7
Conversion factors (20 °C)
ppm -> mg/m3 4.85 4.1 5.5
mg/m3 -> ppm 0.206 0.243 0.181
Table 1 (contd).
HCFC 133a HCFC 123 HCFC 124
Chemical structure H F H F F F
' ' ' ' ' '
H - C - C - F Cl - C - C - F Cl - C - C - F
' ' ' ' ' '
Cl F Cl F H F
Chemical formula CH2Cl-CF3 CHCl2-CF3 CHClF-CF3
Common names chlorotrifluoroethane dichlorotrifluoroethane chlorotetrafluoroethane
Common synonymsb 1-chloro-2,2,2-trifluoroethane; 1,1-dichloro-2,2,2-trifluoroethane; 1-chloro-1,2,2,2-tetrafluoroethane;
1,1,1-trifluoro-2-chloroethane; 2,2-dichloro-1,1,1-trifluoroethane; 1,1,1,2-tetrafluoro-2-chloroethane;
2,2,2-trifluorochloroethane; ethane, dichlorotrifluoro-; Fluoro- Fluorocarbon 124; HCFC 124
1,1,1-trifluoroethyl chloride; carbon 123; HCFC 123; Propellant
CFC 133a; HCFC 133a; R-133a 123; Refrigerant 123; R-123
CAS Registry number 75-88-7 306-83-2 2837-89-0
Conversion factors (20 °C)
ppm -> mg/m3 4.92 6.25 5.58
mg/m3 -> ppm 0.203 0.160 0.179
a Chlorofluorocarbons are numbered as follows: the first digit = number of C atoms minus 1 (for ethane derivatives it is therefore
1); second digit = number of H atoms plus 1; third digit = number of F atoms
b The trade names Arcton, Freon, Genetron and Isotron are used with the corresponding numbers by different manufacturers
Table 2. Physical and chemical properties of the hydrochlorofluorocarbonsa
HCFC 141b HCFC 142b HCFC 132b HCFC 133a HCFC 123 HCFC 124
Physical state liquid gas liquid gas liquid gas
Colour colourless colourless colourless colourless colourless colourless
Relative molecular mass 116.95 100.47 134.92 118.49 152.91 136.48
Boiling point (°C) 32.0 -9.2 46.8 6.93 27.97 -11.0
Freezing point (°C) -103.5 -131.0 -101.2 -105.5 -107.0 -199.0
Liquid density (g/ml) 1.24c 1.123c 1.42c 1.389c 1.46b 1.4d
Vapour pressure
(25 °C, psia) 11.5 49.2 6.1 29.7 14 61
Density of saturated
vapour at boiling
point (g/litre) 4.82 4.72 5.15 5.17 6.38 6.88
Flammability non-flammablee flammable non-flammable non-flammable non-flammable non-flammable
Auto-ignition
temperature (°C) - 632 - - - -
Flammability limits in
air (% vol) - 6.0-14.8 - - - -
Table 2 (contd).
HCFC 141b HCFC 142b HCFC 132b HCFC 133a HCFC 123 HCFC 124
Solubility in water
(g/litre) 4-13b 1.9b 4.9c 8.9b 2.1b 17.1c
Octanol/water partition
coefficient (log Pow) 2.3 1.60f - - - -
a From: Graselli & Ritchey (1975), Hawley (1981), Horrath (1982), Sax (1984), Weast (1985), Solvay et Cie (1989)
b At 25 °C
c At 20 °C
d At 11.3 °C
e No flash point between 21 °C and 33 °C; no explosive properties, but can become flammable as a vapour (personal communication by
Solvay et Cie, 1989). Millischer (1990) lists HCFC 141b as non-flammable.
f Log Kow cited in SRC (personal communication by H. Trochimowicz (1991), C-57 file Haskell Laboratories).
2.3 Conversion factors
Conversion factors for the hydrochlorofluorocarbons reviewed in
this monograph are given in Table 1.
2.4 Analytical methods
Of the analytical procedures described for the determination of
the hydrochlorofluorocarbons reviewed, by far the most frequently
applied methods use gas chromatography with various detection
techniques. For measuring the relatively high chamber concentrations
in toxicology experiments, single beam photometry has been used.
Examples are listed in Table 3.
Table 3. Analytical methods for the determination of hydrochlorofluorocarbons
Hydrochlorofluorocarbons Medium Analytical method Detection limit Reference
HCFC 141b air absorption on silica gel, thermal desorption and - Coombs et al. (1988)
gas chromatography with flame ionization detection
corn oil gas chromatography with electron capture detection - Liggett et al. (1989)
HCFC 142b air gas chromatography with flame ionization detection - Seckar et al. (1986)
water head space analysis using gas chromatography with - Hutton & Lieder (1989)
electron capture detection
HCFC 132b air gas chromatography with thermal conductivity - Hall (1976)
detection
HCFC 133a air gas chromatography with flame ionization detection 0.2 ppm Plummer et al. (1987)
air gas chromatography with flame ionization detection - Kilmartin et al. (1980)
air gas chromatography with thermal conductivity detection - Leuschner et al. (1977)
air gas chromatography with flame ionization detection Hodge et al. (1980)
tissue head space analysis using gas chromatography with - Chapman et al. (1967)
flame ionization detection
tissue head space analysis using gas chromatography with 2.5 pmol/ml blood Maiorino et al. (1979)
flame ionization detection 10 pmol/g liver
HCFC 123 air single beam photometry - Müller & Hofmann (1988)
air gas chromatography with flame ionization detection - Deleba-Crowe (1978)
air gas chromatography with thermal conductivity detection - Trochimowicz & Mullin (1973)
HCFC 124 air gas chromatography with thermal conductivity detection - Hall (1976)
air gas chromatography with dual flame ionization detection - Brewer (1977)
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural occurrence
The hydrochlorofluorocarbons reviewed in this monograph are not
known to occur in nature.
3.2 Anthropogenic sources
3.2.1 Production levels
The manufacturing process for HCFC 124 is still in the
developmental stage, since it is not produced for commercial use but
only in research quantities. HCFC 133a is produced in small quantities
as a chemical intermediate in the manufacture of the anaesthetic
halothane (1-bromo-1-chloro-2,2,2-trifluoroethane) (McNeill, 1979),
and HCFC 142b is produced at the rate of several thousand tonnes per
year as an intermediate in the production of vinylidene fluoride for
the manufacture of fluoropolymers (Seckar et al., 1986). Commercial
quantities of HCFCs 123 and 141b were produced in 1991 (Anon., 1991;
personal communication by R. Millischer, 1991). HCFC 132b does not
appear to be envisaged as a commercial product but it occurs, as do
HCFCs 133a and 141b, as a by-product in the manufacture of other
halogenated ethanes. Others of the hydrochlorofluorocarbons reviewed
probably also occur in this way.
3.2.2 Manufacturing processes
HCFC 133a is produced from trichloroethene and anhydrous hydrogen
fluoride in the presence of an antimony trifluoride catalyst (McNeill,
1979). Similarly, HCFC 142b is produced by hydrofluorination of
methylchloroform or vinylidene chloride in the liquid phase (Seckar et
al., 1986).
3.2.3 Loss during disposal, transport, storage and accidents
Since two of the hydrochlorofluorocarbons reviewed which are
produced in commercial quantities (HCFC 142b and HCFC 133a) are used
as intermediates for subsequent conversions into other fluoro
compounds, the current release into the environment is expected to be
low. There are no published data on losses of any of the
hydrochlorofluorocarbons reviewed.
No information is available on accidental release.
3.3 Use patterns
3.3.1 Major uses
HCFC 133a has a limited use as a chemical intermediate in the
manufacture of the anaesthetic halothane, 1-bromo-1-chloro-2,2,2-
trifluoroethane (McNeill, 1979).
HCFC 123 is used in large industrial chillers.
HCFCs 123 and 141b were developed as substitutes for CFC-11, i.e.
as foam-blowing agents in the plastics industry, aerosol propellants
and, to a lesser degree, refrigerants, but their use requires
equipment changes and they have a slightly poorer performance than the
fully halogenated compounds (Hoffmann, 1990; Prinn & Golombek, 1990;
Ahmadzai & Hedlund, 1990).
A mixture of HCFCs 123 and 141b can substitute for CFC-113, a
washing fluid in the electronic industry (Montague & Perrine, 1990).
HCFCs 124 and 142b have been reported, in admixture with other
compounds, as substitutes for fully halogenated chlorofluorocarbons,
particularly as foam blowing agents and refrigerants. However, the
mixtures developed which contained HCFC 142b were flammable (Hoffmann,
1990; Shankland, 1990). HCFC 142b in admixture with CFC-22 has a small
application as an aerosol propellant.
HCFC 132b appears to be an experimental chemical with no
commercial application at the present time.
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1 Biodegradation and bioaccumulation
Information on biodegradation in the environment is limited to
studies on HCFCs 141b and 142b. Oyama (1990) tested the
biodegradability of HFA 141b by microorganisms (closed bottle method)
at test substance concentrations of 2.0 and 9.0 mg/litre and reported
a biodegradation of 2-10% after 28 days. The biodegradability values
of HCFC 142b at concentrations of 52 and 105 mg/litre were 5.6 and
4.4%, respectively, after 28 days (Matla & Blom, 1991). In both cases
the authors concluded that these compounds are not readily
biodegradable.
The log octanol/water partition coefficient of HCFC 141b is 2.3
and therefore bioaccumulation of this hydrochlorofluorocarbon is
unlikely.
A study on the biodegradation of HCFC 142b is in progress
(personal communication by Ch. de Rooij, Solvay et Cie, 1990).
4.2 Environmental transformation and interaction with other
environmental factors
The scaled atmospheric lifetimes, ozone-depleting potentials and
global-warming potentials of the hydrochlorofluorocarbons reviewed are
shown in Table 4, where they are compared to those of methylchloroform
(1,1,1-trichloroethane). The physical and chemical properties suggest
that these hydrochlorofluorocarbons would be rapidly mixed within the
lower region of the troposphere. Mixing would be expected to be
complete in the hemisphere of the emission (northern or southern)
within months and in the entire troposphere possibly within about
three years. Reaction with naturally occurring hydroxy radicals (OH€)
in the troposphere is expected to be the primary degradation route
(Makide & Rowland, 1981; Prinn & Golombek, 1990).
The hydrochlorofluorocarbons reviewed do not have high
ozone-depleting potentials. This is defined as the calculated
depletion due to the emission of a unit mass of the
hydrochlorofluorocarbon divided by the ozone depletion calculated to
be due to the emission of a unit mass of CFC 11 (the ozone-depleting
potential of CFC 11 is 1.0); calculations are based on steady-state
conditions.
However, if the ozone-depleting potentials listed are compared
with those of methylchloroform (1,1,1-trichloroethane), it can be seen
that those of HCFCs 141b and 142b are of a similar order. The parties
to the Montreal Protocol decided in June 1990 to phase out
methylchloroform manufacture by the year 2005 (Ahmadzai & Hedlund,
1990).
When the global-warming potentials are similarly compared, three
of the compounds reviewed, HCFCs 141b, 142b, and 124, have higher
values than that of methylchloroform and HCFC 123 is only slightly
lower. This effect however, is considered less critical (Montague &
Perrine, 1990).
The possible impact of HCFCs 141b, 142b, 123 and 124 on
tropospheric ozone formation has been estimated to be extremely low
(UNEP/WMO, 1989).
Table 4. Tropospheric lifetime, ozone-depleting potential and global-warming potential
of hydrochlorofluorocarbonsa,b
Hydrochlorofluorocarbon Scaled atmospheric Ozone-depleting potential Global-warming
lifetime potential
(years)c 1-dimensional model 2-dimensional model (1-dimensional model)
HCFC 141b 7.8 0.066-0.092 0.065-0.14 0.087-0.097
HCFC 142b 19.1 0.05-0.06 0.05-0.08 0.34-0.39
HCFC 132b 4.2 0.025 - -
HCFC 133a 4.8 - - -
HCFC 123 1.6 0.013-0.019 0.013-0.027 0.017-0.020
HCFC 124 6.6 0.016-0.021 0.013-0.030 0.092-0.10
Cl3C CH3 6.3 0.092-0.14 0.11-0.20 0.022-0.026
a From: Fisher et al. (1990a,b) and Freemantle (1991). See also Prinn & Golombek (1990).
b The ozone-depleting and global-warming potential values for CFC-11 are defined as 1.0. The values reported
in the table refer to this standard and the ranges are scaled assuming a methylchloroform atmospheric
lifetime of 6.3 years (UNEP/WMO, 1989).
c Other atmospheric lifetimes are: CFC 11 - 75 years, CFC 12 - 110 years and CFC 113 - 90 years.
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1 Environmental levels
5.1.1 Air
HCFCs 141b, 132b, 133a, 123 and 124 are not yet in large-scale
commercial production. HCFC 142b is used as an intermediate and is not
released significantly to the atmosphere. There are, therefore, no
data on environmental levels but these compounds are unlikely to be
present at detectable levels.
5.1.2 Water, food and other edible products
For the reasons cited above (section 5.1.1), no data are
available on the concentrations in environmental water, food or other
edible products of the partially halogenated chlorofluorocarbons
reviewed in this monograph.
5.2 Human exposure
There are no data on human exposure to any of the
hydrochlorofluorocarbons reviewed.
As HCFC 133a is a major metabolite of the anaesthetic halothane,
the use of this anaesthetic may constitute an exposure to this
hydrochlorofluorocarbon.
6. KINETICS AND METABOLISM
6.1 Animal studies
6.1.1 Absorption
No data are available concerning direct measurements of the
absorption of the hydrochlorofluorocarbons reviewed, but it may be
inferred from toxicity studies that absorption occurs (see chapter 7).
The increased urinary fluoride levels observed in inhalation
toxicity studies of HCFC 141b (Doleba-Crowe, 1977), HCFC 132b, HCFC
123 (Doleba-Crowe, 1978; Trochimowicz, 1989; Malley, 1990a) and HCFC
124 (Brewer, 1977; Malley, 1991) also indicate that absorption takes
place (see section 7.1).
6.1.2 Distribution
No data are available on the distribution in animals of the
hydrochlorofluorocarbons reviewed.
6.1.3 Metabolic transformation
6.1.3.1 General considerations
The compounds reviewed in this monograph fit into three
generalized structural classes: 1,1,1-trihaloethanes (HCFC 141b and
142b), 1,1,1-trihalo-2-monohaloethanes (HCFC 132b and 133a) and
1,1,1-trihalo-2,2-dihaloethanes (HCFC 123 and 124). Metabolic studies
have been conducted on a representative from each class and have
demonstrated similar metabolic pathways for each one as shown in
Fig. 1.
Based on the available literature (Harris & Anders, 1991a,b;
Harris et al., 1991), it is expected that all six chemicals reviewed
would be metabolized by a cytochrome P-450-dependent monooxygenase
liver enzyme to give reactive metabolic products including
1,1,1-trihaloacetic acid and 1,1,1-trihaloethanol. The
1,1,1-trihalo-2,2-dihaloethanes are the only ones that go through the
electrophilic acid chloride in their metabolic pathway. This may
explain why HCFC 123 is the only one, of the three compounds for which
there are data, that shows covalent binding to macromolecules. Salmon
et al. (1981) reported on microsomal dechlorination of chloroethanes
and structure-activity relationships and observed that the
reactivities of the various structural types are markedly different:
RCHCl2 >> RCH2Cl > RCCl3 (in the case of polyhalogenated
ethanes where a less reactive group is linked to the one under
consideration, the contribution of the less reactive group is
ignored). The authors concluded that the dechlorination process shows
the structural specificity commonly seen in enzyme-catalysed
reactions.
6.1.3.2 HCFC 141b
Harris & Anders (1991a) studied the in vivo metabolism of HCFC
141b. A single fluorinated urinary metabolite, identified as
2,2-dichloro-2-fluoro-ethyl glucuronide, was found in rats exposed to
HCFC 141b (56 g/m3) in air for 2 h. The metabolism was reported to
be similar to that of its chlorinated analogue 1,1,1-trichloroethane,
which is metabolized to 2,2,2-trichloroethanol and excreted as its
glucuronate conjugate (Hake et al., 1960) and as trichloroacetic acid
(Koizumi et al., 1982). It was claimed (although no data were given)
that 2,2-dichlorofluoroacetic acid was also detected in the urine of
rats exposed to a concentration of 194 g/m3 for 4 h, but not to 56
g/m3 for 2 h (Harris & Anders, 1991a).
In a pilot study for absorption and metabolism of HCFC 141b,
seven groups of five male rats were exposed to the vapour by
inhalation in a closed loop exposure system (concentrations ranging
from 0.4 to 12 g/m3). No metabolism was detected but the sensitivity
of the method is such that it will not detect metabolism below 0.15%.
The results suggested that absorption did not take place, but that if
any metabolism occurred it was at a low level (Zwart, 1989).
Evidence of dechlorination was observed when rat hepatic
microsomes were incubated with about 1% HCFC 141b in vitro (Van
Dyke, 1977).
6.1.3.3 HCFC 142b
No in vivo studies on the metabolism of HCFC 142b have been
reported. One in vitro study provided evidence for dechlorination
when rat hepatic microsomes were incubated with 0.6% HCFC 142b (Van
Dyke, 1977).
6.1.3.4 HCFC 132b
Harris & Anders (1991) identified a number of metabolites in the
urine of male Fischer-344 rats given one or four doses of 10 mmol/kg
dissolved in corn oil by intraperitoneal injection. Approximately 1.8%
of the single administered dose was recovered in the urine. The
metabolites excreted in urine during the first 6 h were
2-chloro-2,2-difluoroethyl glucuronide, chlorodifluoroacetic acid and
chlorodifluoroacetaldehyde hydrate (free and conjugated). Repeated
injection of rats with HCFC 132b significantly increased both the rate
of chlorodifluoroacetic acid excretion and the relative fraction of
the HCFC 132b dose excreted as chlorodifluoroacetic acid. The
incubation of HCFC 132b with rat hepatic microsomes yielded
chlorodifluoroacetaldehyde hydrate as the only fluorinated product.
The in vitro metabolism of HCFC 132b was increased in microsomes
from pyridine-treated rats and inhibited by p-nitrophenol. This
inhibition by p-nitrophenol led the authors to suggest an
involvement of cytochrome P-450 IIE1 in the initial hydroxylation of
HCFC 132b.
6.1.3.5 HCFC 133a
Evidence for dechlorination of HCFC 133a was provided by an
in vitro study using a microsomal preparation derived from
Aroclor-1254a-induced rat liver homogenates (Salmon et al., 1981).
6.1.3.6 HCFC 123
Harris et al. (1991) exposed adult male Fischer-344 rats to HCFC
123 (43 g/m3 or 68 g/m3) or to halothane (2-bromo-2-2
chloro-1,1,1-trifluoroethane) (1.05 g/m3) in air for 2 h. The
pattern of proteins immunoreactive with haptens-specific
anti-trifluoroacetylprotein antibodies was found to be identical in
livers of the rats exposed to HCFC 123 and halothane. Trifluoroacetic
acid was detected in urine of rats exposed to HCFC 123 or halothane by
nuclear magnetic resonance (NMR) and by gas chromatography with mass
spectrometry (GCMS), as had been reported previously (Maiorino et al.,
1980; Trochimowicz, 1989).
6.1.4 Covalent binding to macromolecules
6.1.4.1 HCFC 141b
19F-NMR analysis of microsomal and cytosolic proteins isolated
from the livers of rats killed 15 h after a 2-h exposure to HCFC 141b
(56 g/m3) did not yield any evidence for covalent binding of
fluorinated metabolites (Harris & Anders, 1991a).
6.1.4.2 HCFC 132b
19F-NMR analysis of microsomal and cytosol proteins isolated
from the livers of rats killed 15 h after a single intraperitoneal
dose of HCFC 132b (10 mmol/kg) did not yield evidence for covalent
binding of fluorinated metabolites (Harris & Anders, 1991a).
6.1.4.3 HCFC 123
Harris et al. (1991) exposed adult male Fischer-344 rats to HCFC
123 (43 or 68 g/m3) or to halothane (105 g/m3) in air for 2 h.
19F-NMR analysis of cytosolic protein and immunoblotting of
microsomal and cytosolic hepatic protein using antibodies against
trifluoroacetylprotein at 15 h after the exposure demonstrated
covalent binding of fluorinated metabolites.
a Aroclor-1254 is a polychlorinated biphenyl mixture.
6.1.5 Elimination
No data are available from animal studies on the elimination of
the hydrochlorofluorocarbons reviewed. However, based on the
information on chlorofluorocarbons, it is likely that the main route
of excretion for hydrochlorofluorocarbons is through the respiratory
tract. Increased urinary inorganic fluoride has been observed in some
inhalation toxicity studies with HCFCs 141b, 132b, 123, and 124
(Doleba-Crowe, 1977, 1978; Brewer, 1977; Trochimowicz, 1989; Malley,
1990a, 1991).
6.2 Human studies
No data are available on the absorption, distribution, metabolic
transformation or elimination of the hydrochlorofluorocarbons
reviewed.
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
7.1 Single exposure
7.1.1 Acute oral toxicity
Available data indicate low toxicity following single oral
exposure associated with four hydrochlorofluorocarbons, i.e. HCFC
141b, 142b, 132b and 123.
7.1.1.1 HCFC 141b
No mortality was observed in rats given a single oral dose of
HCFC 141b (5 g/kg body weight) dissolved in corn oil (Sarver, 1988).
7.1.1.2 HCFC 142b
Other than piloerection, oral dosing with HCFC 142b (up to 5 g/kg
body weight) dissolved in corn oil resulted in no signs of toxicity
(Liggett et al., 1989).
7.1.1.3 HCFC 132b
According to Henry (1975), the lowest dose at which mortality was
observed in rats treated with HCFC 132b was 25 g/kg.
A 2-g/kg dose of HCFC 132b in corn oil was applied by stomach
tubes to five male and five female Wistar rats, and the animals were
observed for 14 days. The clinical signs were indicative of an effect
on the autonomic nervous system (ptosis), on the central nervous
system (diminished alertness and startle response, and positional
passivity), on motor coordination (abnormal body posture and gait, and
loss of righting reflex), on motor activity and on muscle tone
(paralysis). Macroscopic examination showed swollen livers in some
males, and a decrease in absolute and relative liver weights. However,
no treatment-related effects were found during microscopic
examinations (Janssen & Pot, 1989b).
7.1.1.4 HCFC 123
The lowest dose of HCFC 123 producing lethality in rats was
reported to be 9 g/kg when it was administered as a corn oil solution
by intragastric intubation (Henry, 1975a).
7.1.2 Acute inhalation toxicity
7.1.2.1 HCFC 141b
The effects of a single inhalation exposure of rodents to HCFC
141b are shown in Table 5. The main effects at high exposure
concentrations include central nervous system depression, anaesthesia
and death.
7.1.2.2 HCFC 142b
Table 6 summarizes the effects of single inhalation exposure to
HCFC 142b in mice and rats. At high exposure levels, HCFC 142b induces
anaesthesia and death.
7.1.2.3 HCFC 132b
Table 7 summarizes the effects of single inhalation exposures of
mice and rats to HCFC 132b.
7.1.2.4 HCFC 133a
Inhalation of high concentrations of HCFC 133a is characterized
by signs of anaesthesia followed by death, but recovery from nonlethal
exposure is rapid. The effects of inhalation exposure to HCFC 133a are
summarized in Table 8.
7.1.2.5 HCFC 123
The results of studies on the acute inhalation toxicity of HCFC
123 are summarized in Table 9. Anaesthesia and death at higher
exposures were reported for rats and hamsters. No gross morphological
changes were observed in animals that died during exposure. Survivors
recovered within several minutes without showing any observable
clinical signs.
7.1.2.6 HCFC 124
Table 10 summarizes the effects of single inhalation exposure to
high concentrations of HCFC 124. As with other
hydrochlorofluorocarbons, the main effects observed were anaesthesia
and death.
7.1.3 Acute dermal toxicity
There is information only on the hydrochlorofluorocarbons that
are liquid at ambient temperatures, i.e. HCFC 141b, HCFC 132b and HCFC
123.
Table 5. Effects of a single inhalation exposure to HCFC 141b in mice and rats
Species Exposure Exposure Effects Reference
(strain) concentration duration
(g/m3) (h)
Rat 142-366 4 LC50 = 295 g/m3 Hardy et al. (1989a)
(Sprague-Dawley) No deaths were observed at 142 or 217 g/m3. All deaths
at higher concentrations (323 and 366 g/m3) occurred
during exposure, and were preceded by disturbed breathing.
Reduced motor activity, abnormal body carriage, restless
behaviour and exaggerated respiratory movements were seen
at all concentrations during exposure. No treatment-related
macroscopic findings were seen. Focal basophilic staining
was observed in the renal cortical tubules of 4 out of 10
rats at 217 g/m3 and 2 out of 10 rats at 142 g/m3. No
histopathological effects were seen in decedents.
Rat (strain unspecified 6 The lowest concentration producing lethality was 242 g/m3. Doleba-Crowe (1977)
unspecified) range
Mouse 17-388 6 Deaths preceded by signs of narcosis in 6 out of 10) animals Vlachos (1989)
(Crl: CD-1) occurred within 30 min of exposure to 388 g/m3. No deaths
occurred at the next highest (199 g/m3) concentration. Signs
of CNS depression (lethargy, abnormal gait, partially closed
eyes) were seen at 165 and 199 g/m3. No effects were seen at
concentrations of 145 g/m3 or less.
Mouse (strain unspecified 2 LC16 = 115 g/m3; LC50 = 151 g/m3; LC84 = 200 g/m3. Signs of Nikitenko & Tolgskaja
unspecified) range CNS depression and anaesthesia were observed. Death was (1965)
preceded by laboured breathing.
Mouse (Schofield unspecified 0.5 LC50 = 115 g/m3; concentration producing anaesthesia in Davies et al. (1976)
strain) range 50% of animals = 62 g/m3. No other information was given.
Table 6. Effects of single inhalation exposure to HCFC 142b in mice and rats
Species Strain Exposure Exposure Effects Reference
concentration duration
(g/m3) (h)
Mouse "white" up to 2050 2 death; LC50 = 1514 g/m3 Nikitenko & Tolgskaja (1965)
Mouse AP unspecified 0.5 death; LC50 = 1228 g/m3 Davies et al. (1976)
range
Rat "white" 615-3280 0.5 death at 2050 g/m3 and unconsciousness at Lester & Greenberg (1950)
1230 g/m3; postural, righting and corneal
reflexes were lost at 820 g/m3
Rat Sherman 525 4 death (approx 50%) at 525 g/m3 Carpenter et al. (1949)
Table 7. Effects of single inhalation exposure to HCFC 132b in mice and rats
Species Strain Exposure Exposure Effects Reference
concentration duration
(g/m3) (h)
Mouse unspecified range not given 0.5 LC50 = 269 g/m3; AC50 (anaesthesia) = 71 g/m3 Raventós & Lemon (1965)
Rat Wistar derived 55 and 110 4 lethalities at 110 g/m3; rats unsteady, weak and Torkelson (1971)
drowsy at 55 g/m3
Rat Wistar derived 33-72 6 anaesthesia at 82 g/m3; kidney swelling at autopsy; Janssen (1988)
CPB-WU at all dose levels, males showed decreased growth
and testis weight, and increased liver and lung
weights
Rat Wistar derived 55 0.4 decreased respiratory rate with rapid recovery Janssen (1989b)
CPB-WU after exposure
Table 8. Effects of single inhalation exposure to HCFC 133a
Species Exposure Exposure Effectsa Reference
(strain) concentration duration
(g/m3) (min)
Mice, male unspecified 10 anaesthesia and death; convulsions on recovery; AC50 and Robbins (1946)
(white) range LC50 were 394 and 1230 g/m3, respectively
Mice (strain unspecified 30 anaesthesia, convulsions and death; AC50 and LC50 were Raventós & Lemon (1965)
unspecified) range 212 and 738 g/m3, respectively
Mice (strain 123-1230 10 rapid onset of anaesthesia, rapid recovery after cessation of Shulman & Sadove (1965)
unspecified) exposure but no convulsions; AC50 and LC50 were 397 and
1033 g/m3, respectively
Rats, female 2500 - lack of muscular coordination in 3 min, anaesthesia in 4 min Diggle & Gage (1956)
(strain unspecified) and death within 8 min
Dogs unspecified - anaesthesia at 492 g/m3, respiratory depression and arrest Shulman & Sadove (1965)
range occurred at 1131 and 1427 g/m3, and circulatory arrest at
2902 g/m3
a AC50 = calculated concentration expected to produce anaesthesia in 50% of the test group
Table 9. Acute inhalation toxicity of HCFC 123
Species Exposure Exposure Effects Reference
(strain) concentration duration
(g/m3)
Mouse (strain not given 30 min LC50 = 463 g/m3 Raventós & Lemon (1965)
unspecified)
Rat (Charles 129-344 4 h LC50 = 200 g/m3; loss of mobility, lethargy, prostration Hall & Moore (1975)
River CD) at all concentrations; full recovery of survivors within
30 min post exposure
Rat (Charles 49-767 6 h LC50 = 329 g/m3; anaesthesia at 145 g/m3 and higher Coate (1976a)
River CD) concentrations; discoloration of lungs in most animals that
died, discoloration of liver in some of them
Rat (strain 6, 16, 31, 62 15 min unconditioned reflexes, locomotor activity, coordination Trochimowicz (1989)
unspecified) affected at 31 and 62 g/m3; full recovery within 30 min
post exposure
Hamster 63-194 4 h LC50 = 178 g/m3; incoordination, prostration at all Darr (1981)
(Chinese) concentrations; full recovery of survivors after exposure;
0% mortality at 163 g/m3, 100 mortality at 194 g/m3
Table 10. Acute inhalation toxicity of HCFC 124
Species Strain Exposure Exposure Effects Reference
concentration duration
(g/m3) (min)
Mouse unspecified 594 10 no effect Wada (1977)a
837 10 narcosis Wada (1977)a
2230 10 no mortality Wada (1977)a
2460 10 death Wada (1977)a
Rat Sprague-Dawley 268 240 no effect Kelly (1990)
Charles River COBS 558 300 reduced activity Coate (1976b)
Sprague-Dawley 893 240 prostration, lethargy, incoordination Kelly (1990)
Sprague-Dawley 1283 240 prostration, lethargy, incoordination Kelly (1990)
Sprague-Dawley 1674 240 death Kelly (1990)
Charles River COBS 2009 300 narcosis, no mortality Coate (1976b)
Dog 2230-3910 10 narcosis Van Poznak & Artusio (1960)
a Attachment to correspondence from H. Wada, Daikon Kogyo Company Ltd. to M.B. Berenbaum, Allied Chemical Corporation,
entitled Anaesthetic activity and fatality (F-123, 123a, 124 and 11)
7.1.3.1 HCFC 141b
No deaths occurred at dermal doses of 2 g/kg body weight either
among rats (Janssen & Pot, 1988; Gardner, 1988) or rabbits (Brock,
1988a).
7.1.3.2 HCFC 132b
When Janssen & Pot (1989a) applied a single dose of HCFC l32b (2
g/kg) under an occluding dressing to the shaved skin of five male and
five female Wistar rats, there were no deaths. The clinical signs
observed were decreased respiratory rate, decreased startle response,
altered locomotor activity, restlessness and vocalization. Three male
and four female rats had swollen or slightly swollen livers on
autopsy.
7.1.3.3 HCFC 123
Several limit tests for dermal toxicity of HCFC 123 were
conducted. No mortality was observed at the limit dose of 2 g/kg body
weight in rats (Brock, 1988d; Trochimowicz, 1989) or rabbits (Brock,
1988e,f; Trochimowicz, 1989). The only clinical signs of toxicity were
red nasal or ocular discharges in one of five male and one of five
female rats, and slight to moderate body weight losses (up to 12% of
initial body weight). No gross pathological abnormality was observed
(Trochimowicz, 1989). In rabbits, only slight to moderate erythema was
observed (Trochimowicz, 1989).
7.2 Short-term inhalation exposure
7.2.1 HCFC 141b
Nikitenko & Tolgskaja (1965) reported a reduction in body weight
gain, a slight decrease in haemoglobin level and moderate
leucocytosis, some "minor changes" in blood parameters related to
liver and kidney function, and histopathological effects in the
respiratory tract of rats and guinea-pigs (number and strains
unspecified) that had been exposed to 40-50 g/m3 (2 h/day, 6
days/week) for 4 weeks. The purity of the substance and the specific
isomer were not indicated.
No adverse clinical signs and only "slight biochemical changes"
(no details given) were reported in rats (number and strain
unspecified) exposed to 48.5 g/m3 (6 h/day, 5 days/week) for 2 weeks
(Pennwalt Corporation, 1987).
In a 2-week inhalation toxicity study, Doleba-Crowe (1977)
exposed groups of 10 male rats to 0 or 48 g/m3 for 6 h/day, 5
days/week. The animals were observed for 14 days after exposure. No
adverse clinical signs were observed, and there were no differences in
body weights between treated and control animals. After the tenth
exposure, elevated red blood cell counts, plasma bilirubin level and
increased urinary fluoride concentrations were found, but all these
parameters returned to normal after 14 days. The treated animals
showed a more severe focal interstitial pneumonitis than controls 14
days after exposure, but no other treatment-related change was
observed.
Coombs et al. (1988) exposed five groups of 10 male and 10 female
Sprague-Dawley rats to 0, 24, 42, 68 and 97 g/m3 (6 h/day for 9
days, i.e. 5 days of exposure followed by 1 day without exposure and
then 4 days with exposure). Signs of central nervous system (CNS)
depression were seen during exposure to concentrations of 42 g/m3 or
more. At 97 g/m3, these signs were accompanied by a decrease in body
weight gain in males and a slightly reduced food intake in both sexes.
Glucose and aspartate serum transaminase (AST) levels were increased
at 97 g/m3, protein, cholesterol and sodium from 68 g/m3,
phosphate from 42 g/m3 and calcium from 24 g/m3. No
treatment-related histopathological changes were observed at any dose
level.
In a 13-week inhalation study (some animals were killed after 4
weeks), four groups each of 15 male and 15 female Fischer-344 rats
were exposed to 0, 10, 39 or 97 g/m3 (6 h/day, 5 days/week) as
described in two reports (Yano et al., 1989; Landry et al., 1989).
Alertness was reduced at 97 g/m3, and body weight gain and food
consumption were slightly reduced in all exposed groups. After both 4
and 13 weeks of exposure, plasma cholesterol, triglycerides and
glucose were slightly elevated in the rats exposed to 97 g/m3. No
changes in haematological or histopathological parameters were found.
7.2.2 HCFC 142b
Rats and guinea-pigs (numbers and strains not specified) were
exposed to a concentration of 448 g/m3 (isomer not specified), 2
h/day, 6 days/week, for 4 weeks (Nikitenko & Tolgskaja, 1965). A
decrease in the rate of body weight gain was observed at the end of
the study, as well as a reduction in haemoglobin concentration and the
number of erythrocytes, and an increase in the number of leucocytes.
Swelling of the alveolar septa and peribronchitis were the
histopathological changes observed in the lungs.
In a study in which 10 adult white rats were exposed to 410
g/m3 for 16 h/day, all animals died within 9 exposures. All of them
showed severe signs of pulmonary irritation at autopsy (consolidation
and hepatization of the lungs). The other organs appeared normal. No
signs of ill health were apparent in five rats exposed to a
concentration of 41 g/m3 (16 h/day for 2 months). Gross examination
of the organs on autopsy revealed no pathological changes, but
microscopic examination of the lungs showed round cell infiltration in
the lung of two animals. The appearance of sections of the livers was
normal (Lester & Greenberg, 1950).
No clinical, haematological, blood chemical, urine analytical or
histopathological evidence of effects attributable to repeated
exposure to HCFC 142b was found in 10 male Charles River CD rats
exposed to a concentration of 82 g/m3 (6 h/day, 5 days/week) for 2
weeks (Moore & Trochimowicz, 1976).
Kelly (1976) did not find any adverse clinical, haematological,
blood chemical, urine analytical or histopathological effects
attributable to HCFC 142b at exposure levels of either 4.1 g/m3 or
41 g/m3 (6 h/day, 5 days/week for 90 days) in groups of male and
female Charles River CD rats (27 of each sex at each treatment level)
or groups of male dogs (4 at each treatment level).
7.2.3 HCFC 132b
When 20 male Crl:CDRBR rats were exposed to 55 g/m3 (6 h/day,
5 days/week) for 2 weeks, reduction in body weight gain, irregular
respiration and CNS depression (lethargy, poor coordination,
occasional tremors and prostration) were seen. The CNS effects
disappeared within 30 min after each exposure. Pathological
examinations of rats sacrificed immediately after the tenth exposure
showed thymic atrophy and spermatogenesis arrest, but these changes
were not present in rats sacrificed 14 days after exposure ceased
(Hall, 1976).
Groups of 20 male and 20 female Crl:CDRBR rats were exposed to
0, 3, 11 and 27 g/m3 (6 h/day, 5 days/week) for 13 weeks (Kelly,
1988). Male rats exposed at all the concentrations of HCFC 132b showed
bile duct proliferation and disruption of spermatogenesis with cell
debris in the epididymides at the two higher concentrations. Other
effects included increases in liver/body weight ratio in males at all
concentrations and in females at the two higher concentrations.
Elevation of serum alkaline phosphatase activity was found in both
sexes exposed to 11 or 27 g/m3. During the study, all groups exposed
to HCFC 132b showed reduced food consumption and body weight gain. In
the two highest exposure groups there were depressions in the absolute
but not relative brain and testes weights. Other organ weight changes
were also seen (slight increases in heart, lung and kidney weights).
The biological significance of these weight changes is not clear since
there were no accompanying histological findings. During exposure to
27 g/m3, rats showed CNS depression as indicated by decreased
activity and low responsiveness to sound.
7.2.4 HCFC 133a
Shulman & Sadove (1965) exposed mice to anaesthetic
concentrations (the actual concentration was not specified) of HCFC
133a for 30 min per day on 12 consecutive days, and the animals were
killed for pathological evaluation after the last exposure by
overdosage of HCFC 133a. None of the mice showed any treatment-related
clinical effects, and no pathological changes were found in the organs
(heart, lung, liver, kidney, adrenal gland, spleen and pancreas)
examined microscopically.
Diggle & Gage (1956) investigated the effects of repeated
exposure (up to 8 days) of groups of 2-3 female rats. Concentrations
of HCFC 133a between 50 and 125 g/m3 caused incoordination and
lethargy, while at 250 or 500 g/m3 rats become comatose. They
recovered between each exposure and no dose-related pathological
changes were found on histological examination. No effect was seen at
25 g/m3 during seven exposures lasting 6 h/day.
In a study by Leuschner et al. (1977), 20 male and 20 female
Sprague-Dawley rats were exposed to 49 g/m3 (6 h/day, every day) for
90 days. Corresponding groups of 20 male and 20 female rats were used
as controls. Observations for overt clinical signs of toxicity and
investigations on body weight, food consumption, haematology, blood
and urine biochemistry, urine sediments, ophthalmology, auditory
reflex, organ weights, and histopathology were performed. There were
no treatment-related deaths. The rats were sedated during each
exposure but appeared normal before and after. Seventeen out of 40
rats developed bloody and inflamed noses; this was associated with
histological evidence of inflammatory changes of the mucosa. Body
weight gain was reduced, so that the terminal average body weights
were approximately 28 and 17% lower than those of male and female
controls, respectively. Food consumption in the treated groups was
also lower than in the controls. Haemoglobin concentration,
haematocrit, red blood cell counts and platelet counts were all
slightly reduced. Reduction in leucocyte counts of approximately 30%
and increase in reticulocyte counts of approximately 40% were seen.
There were reductions in plasma glucose levels of approximately 15%
and in protein levels of approximately 10%. Bromosulfophthalein
retention time was increased by approximately 35% and 62% in males and
females, respectively. There was no change in plasma enzyme
glutamic-pyruvic transaminase (GPT), alkaline phosphatase (AP) or
glutamicoxalacetic transaminase (GOT) activity. The thymus to body
weight ratio was reduced by approximately 50% and the testis and ovary
to body weight ratios by approximately 60 and 35%, respectively.
Histologically, these organs showed atrophy. Thyroid to body weight
ratio was increased by approximately 45% in males only. Atrophy of the
spleen was also observed. The exposure induced emphysema and oedema of
the lungs as well as bronchitis and pneumonia. The testicular atrophy
was consistent with the findings in three dominant lethal studies in
mice (Hodge et al., 1979, 1980; Kilmartin et al., 1980) and a
carcinogenicity study in rats (Longstaff et al., 1984) (see section
7.6 and 7.7).
Six beagle dogs were exposed by Leuschner (1977) to 24 g/m3
(6 h/day, daily) for 3 months and six control dogs were used. No
effects were seen on external appearance, faeces, food and water
consumption, body weight gain, haematology, blood and urine
biochemistry, urine sediments, electrocardiography, blood pressure,
ophthalmology, hearing or dentition. There was no effect on organ
weight at autopsy. No treatment-related histopathological changes were
seen on microscopic examination of a standard range of 24 tissues.
In two dominant lethal studies (for experimental details see
section 7.5.1.4), male mice were exposed to between 0.5 and 49 g/m3,
6 h/day, for 5 days (Hodge et al., 1980; Kilmartin et al., l980). The
mice were subdued at exposure concentrations of 2 g/m3 or more.
Deaths occurred as follows: in the first study 0/60 mice died at 0
g/m3, l7/60 at l2 g/m3, and 28/80 at 49 g/m3; in the second
study 0/80 died at 0 g/m3, 2/59 at 0.5 g/m3, 0/60 at 2.5 g/m3,
5/60 at 5 g/m3, and 20/60 at 12 g/m3.
7.2.5 HCFC 123
In a study by Doleba-Crowe (1978), Sprague-Dawley rats and beagle
dogs were exposed to concentrations of 0, 6 and 62 g/m3 (6 h/day, 5
days/week) for 90 days. At the high exposure level, both species
exhibited lack of motor coordination soon after the start of exposure.
This was followed by reduced motor activity and reduction in
responsiveness to noise. After removal from exposure, coordination and
activity returned to normal within 20 min. Other than final body
weight reductions and increased urinary fluoride level at both
exposure levels, no significant exposure-related effects were observed
in rats. At the high exposure level, dogs exhibited histopathological
changes in the liver and clinical chemistry changes including
increased levels of serum GOT and GPT, which might indicate slight
liver damage. No exposure-related effect was noted at the lower
exposure level.
In a 90-day inhalation study, albino rats obtained from Charles
River Breeding Laboratory were exposed to nominal levels of 0, 3, 6,
and 31 g/m3, 6 h/day, 5 days/week (Rusch, 1985). No
treatment-related deaths occurred in the study and mean body weight
reductions observed in the males at the highest exposure level and in
females at the two highest exposure levels were significant only at
the end of the study. Slight depression was observed in heart weight
in both male and female rats exposed to 31 g/m3. While depressions
of the kidney weights and kidney/brain weight ratio (but not kidney to
body weight ratio) were observed in male rats in all the three
exposure groups, these effects were outside the normal range only at
the highest exposure level. A similar depression in kidney weight and
kidney/body weight ratio (but not in kidney/brain ratio) occurred in
females at the highest exposure level. Increased liver/body weight
ratios (but not liver weight or liver/brain weight ratios) were
observed in all three exposure groups of females, but in males only at
the highest exposure level. No significant difference was found in
organ weights or ratios in animals sacrificed at the end of a 30-day
recovery period. The absence of histopathological findings and of
effects at the end of the recovery period indicates that the
toxicological significance of the organ weight changes in this study
is unclear.
In a 4-week inhalation toxicity study (Kelly, 1989; Trochimowicz,
1989), rats (10 of each sex at each exposure level) were exposed to 0,
6, 31, 62 or 125 g/m3 (6 h/day, 5 days/week) for 4 weeks.
Statistically significant body weight depression occurred in all
female groups and in the two highest male groups, but was dose-related
only in the male rats. At concentrations of 31 mg/m3 or more, rats
exhibited dose-related anaesthesia. At 62 and 125 g/m3, rats became
lethargic during exposure but were normal when they were examined
again 16 to 18 h after exposure. A dose-related increase in liver/body
weight ratio was observed in all female groups (a 27% increase at the
highest level) and in the two highest-exposure male groups (an 18%
increase at the highest level). Decreased cytochrome P-450 activity in
the liver was also found in all female exposure groups and in the male
groups exposed at the two highest levels. Histopathological
examination showed no adverse effects attributable to HCFC 123 in
liver or in any other organ at any exposure level. Microscopic
examination revealed that testicular degeneration and hypospermia
occurred in two out of four male exposure groups, but this was
believed to be due to reduced body weight (because of an increase in
relative testicular weight without a corresponding increase in
absolute testicular weight) or may have resulted from spontaneous
lesions. The fact that the incidence of testicular degeneration was
highest in the 31- and 125-g/m3 exposure groups (5 out of 10 and 6
out of 10 animals, respectively), and lower in the 0-, 6-, and
62-g/m3 exposure groups (2 out of 10, 1 out of 10 and 2 out of 10
animals, respectively) is consistent with the sporadic nature of this
lesion in this strain of rat. However, it is not possible to evaluate
the significance of this testicular effect from the information
available.
Another 28-day inhalation toxicity study in rats was conducted to
characterize further the potential effects of HCFC 123 on the liver
(Lewis, 1990). In addition, urine samples were examined to identify
metabolites of HCFC 123. Groups of six male Charles River CD rats were
exposed to 0, 6, 31 or 125 g/m3 (6 h/day, 5 days/week) for 4 weeks.
Body weights were statistically significantly reduced in all treated
groups compared to controls, the greatest reduction occurring in the
high-dose group. A concentration-related decrease in serum cholesterol
levels was found in all test groups. This reduction was statistically
significant compared to controls at the medium and high
concentrations. Serum triglyceride levels were significantly reduced
to a similar extent in all treated groups. A statistically significant
increase in absolute and relative liver weights compared to controls
was seen in the high-dose rats. Hepatocyte hypertrophy and mild fatty
vacuolation was found at all concentrations tested but the severity
was greatly reduced at the low exposure level. Electron microscopic
examination revealed a treatment-related induction of peroxisome
proliferation at the medium and high exposure concentrations. A
statistically significant concentration-related increase in relative
testes weight was observed in all treated groups (11-30% above
control), but no compound-related morphological or microscopic changes
were observed. Urine analysis indicated the presence of
trifluoroacetic acid as a major metabolite.
In a study by Malley (1990a), groups of 10 male and 10 female
Crl:CDRBR rats were exposed to concentrations of 0, 2, 6 or 31
g/m3 (6 h/day, 5 days/week) for 90 days. No effect on food
consumption or body weight was observed. At the highest exposure level
the animals exhibited anaesthesia and a decreased response to auditory
stimuli. Serum triglyceride and glucose levels were significantly
decreased at all exposure levels, while serum cholesterol was
significantly lower in females exposed to the two highest
concentrations. The mean lymphocyte and white blood cell counts in
female rats were decreased at the highest exposure level. Male rats
had significantly higher alanine aminotransferase and alkaline
phosphatase activity at the two highest exposure levels. In female
rats alanine aminotransferase activity was elevated at the highest
exposure level. Urine fluoride concentrations were increased in
females at all exposure levels, but in males only at the highest
exposure level. Absolute liver weights were significantly higher in
male rats at the highest exposure level and in female rats at the two
highest exposure levels, while relative liver weights in both male and
female rats were higher at the two highest exposure levels. Hepatic
peroxisomal beta-oxidation activity in both male and female rats was
1.9 to 3.8 times higher than in controls, indicating an induction of
hepatic peroxisome proliferation. No treatment-related gross or
microscopic liver changes were observed.
7.2.6 HCFC 124
When ten male rats were exposed to approximately 560 g/m3 (6
h/day, 5 days/week) for 14 days, no adverse haematology, clinical
chemistry, urine analysis or histopathological changes were observed.
Rats showed irregular respiration, lethargy and poor coordination
(Hall, 1976).
Trochimowicz et al. (1977) reported no adverse effect following
the clinical and histopathological evaluation of rats exposed to
concentrations of 560 g/m3 (6 h/day, 5 days/week) for 2 weeks.
Brewer (1977) exposed groups of 60 Sprague-Dawley rats (35 males and
25 females) to concentrations of 0, 3, 5 or 28 g/m3 (6 h/day, 5
days/week) for 3 months. Ten male and ten female rats were examined
and sacrificed after 45 days and a similar number after 92 days. Ten
male and five female rats of each group were maintained without
further exposure for an additional 30-day period after exposure.
Clinical signs were observed, body and organ weights determined, and
haematological, biochemical and histopathological examinations carried
out on all animals. No statistically significant differences in body
weight gain were noted. Haematology, clinical chemistry, and urine
analysis in treated rats were normal and comparable to findings in
control animals. Urinary fluoride excretion was increased after 45
days of exposure in both males and females (4.0 and 3.5 times,
respectively) at an exposure level of 28 g/m3; at the two lower
levels, determinations were not made. After 95 days of exposure, the
urinary fluoride level was elevated only in males at all three
exposure levels (by 1.5, 1.7 and 1.8 times, respectively), and this
effect persisted throughout the 30-day period after exposure. Gross
and histopathological examinations did not reveal any
treatment-related changes in any group of animals. Statistically
significant difference in organ weights between treated and control
rats were found. Liver weights were increased significantly in males
at 5 and 28 g/m3, while the lung and adrenal gland weights were
significantly decreased in males at all three exposure levels. In the
absence of any histopathological change, the biological significance
of these organ weight changes is unclear.
Malley (1990b) exposed groups of ten male and ten female rats to
HCFC 124 concentrations of 0, 3, 11, 56 or 279 g/m3 (6 h/day, 5
days/week) for 4 weeks. Treatment-related effects on body weight, food
consumption, mortality, clinical laboratory parameters, organ weights,
and tissue morphology changes were not found at any exposure level.
During exposure, rats exposed to 279 g/m3 were lethargic and
uncoordinated. However, no evidence of lethargy and incoordination was
observed shortly after exposure. The author considered the exposure
concentration of 56 g/m3 the no-observed-adverse-effect level
(NOAEL) based on the clinical observation of lethargic and
uncoordinated movement during exposure to 279 g/m3, which was not
observed at 56 g/m3.
Malley (1991) exposed Crl:CDRBR rats (20 rats of each sex at
each exposure level) to HCFC 124 at concentrations of 0, 28, 84 and
279 g/m3 (6 h/day, 5 days/week) for 90 days. As part of this study,
a functional observation battery (FOB) was conducted on 10 rats of
each sex at each exposure level at various intervals during the course
of exposure. There were no compound-related effects relative to body
weight, food consumption, mortality, haematology, organ weights or
histopathology at any exposure concentration. However, male rats, at
a level of 84 and 279 g/m3, had lower serum triglyceride
concentrations and a decreased arousal (4 of 10 and 6 of 10 rats,
respectively). Persistent decrease of forelimb grip strength was found
in high-dose females. However, there was no associated decrease in
hindlimb grip strength or change in gait or footplay. Females at the
highest concentration showed an increase in alkaline phosphatase. Both
sexes at 279 g/m3 were less responsive to auditory stimuli, as
demonstrated by a decreased reaction to a sharp knock on the chamber
wall. Plasma fluoride, urinary fluoride and fractional clearance of
free fluoride were also increased at all exposure levels in both
sexes. The author concluded that the no-observed-effect level (NOEL)
was 28 g/m3 for male rats and 84 g/m3 for female rats.
7.3 Skin and eye irritation; sensitization
7.3.1 Skin and eye irritation
7.3.1.1 HCFC 141b
Treatment of the intact skin of New Zealand albino rabbits with
0.5 ml of undiluted HCFC 141b under occlusive patch (during 4 and 24
h in the two respective studies) did not produce signs of dermal
irritation during a 3-day observation period (Liggett, 1988a; Brock,
1988b).
Two studies were conducted with HCFC 141b on groups of six New
Zealand albino rabbits where the undiluted compound (0.1 ml) was
instilled into the eyes. No signs of irritation occurred within 3 days
in one study (Liggett, 1988b), but the compound was found to be a
"mild" irritant in the other study (Brock, 1988c). The majority of
rabbits in the latter study showed conjunctival redness (5/6), mild
chaemosis (3/8) and blood-tinged discharge (4/6).
7.3.1.2 HCFC 142b
Brittelli (1976a) observed no effects on the cornea or iris but
slight conjunctival swelling with some discharge in an eye irritation
test with HCFC 142b.
7.3.1.3 HCFC 132b
One drop (approximately 0.05 ml) each of 100% HCFC 132b and a 10%
solution in propylene glycol was applied and slightly rubbed into the
shaved intact shoulder skin of 10 male albino guinea-pigs, but the
area was not occluded. The pure compound produced only mild irritation
in one animal only. No irritation was induced by the 10% solution
(Goodman, 1976).
Undiluted HCFC 132b (0.1 ml) was placed into the right
conjunctival sac of two albino rabbits, and after 20 seconds one
treated eye was washed with water for 1 min. Observations of the
cornea, iris and conjunctiva were made after 1 and 4 h, and 1, 2, 3
and 7 days later. Slight corneal opacity and "mild" to "moderate"
conjunctival irritation were seen in both rabbits up to 3 days after
dosing, but had disappeared by 7 days after dosing (Brittelli, 1976b).
7.3.1.4 HCFC 123
Minimal dermal irritation with HCFC 123 was observed in rabbits
(Brock, 1988e,f). HCFC 123 (purity 99.0%) produced no skin irritation
when 0.5 ml/6 cm2 was applied to the clipped intact skin of four
male and two female New Zealand rabbits for 4 h (Trochimowicz, 1989).
Brittelli (1976c) reported HCFC 123 to be a "mild" ocular
irritant causing reversible corneal opacity in rabbits. In another
study by Daly (1979)a, HCFC 123, when instilled undiluted (0.1 ml)
into the conjunctival sac of the rabbit eye without subsequent
washing, produced "mild" to "moderate" conjunctival irritation. With
washing, "mild" transient corneal opacity and "mild" to "moderate"
conjunctival irritation were observed. With or without washing,
complete recovery occurred within 3-7 days.
7.3.2 Skin sensitization
7.3.2.1 HCFC 141b
No delayed contact hypersensitivity was found in any of the 20
Hartley Dunkin guinea-pigs in a Magnusson-Kligman maximisation test
with HCFC 141b (Kynoch & Parcell, 1989).
7.3.2.2 HCFC 132b
A series of four sacral intradermal injections of HCFC 132b was
given (once per week at 7-day intervals) over a 3-week period to
groups of nine male albino guinea-pigs (0.1 ml of a 1% solution in
dimethyl phthalate). Fourteen days after the last application, the
animals were challenged with either 1 drop (0.05 ml) of undiluted
liquid or a 19% solution of test material in propylene glycol on the
shaved skin. No evidence of sensitization was observed (Goodman,
1976).
7.3.2.3 HCFC 123
When applied topically to the back of male guinea-pigs as 10% or
50% solutions in propylene glycol, HCFC 123 produced no sensitization
at challenge (Goodman, 1975; Daly, 1979).
7.4 Long-term exposure
Combined chronic inhalation toxicity/carcinogenicity studies on
HCFC 141b, HCFC 123 and HCFC 124 are in progress within the Programme
for Alternative Fluorocarbon Toxicity Testing (Rusch, 1989) sponsored
by an international industry consortium. An interim report after the
first year of the study is available on HCFC 123 (Malley, 1990b).
a Personal communication entitled "Toxicity testing summary for
alternative fluorocarbons" by J.J. Daly to CFTA Interindustry
Safety Committee, Wilmington, Delaware, USA, E.I. Du Pont de
Nemours and Co.