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Chlorodifluoromethane
CASRN 75-45-6
Contents
0657
Chlorodifluoromethane; CASRN 75-45-6
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Chlorodifluoromethane
File On-Line 11/01/1993
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) on-line 11/01/1993
Carcinogenicity Assessment (II.) no data
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Chlorodifluoromethane
CASRN -- 75-45-6
Primary Synonym -- HCFC-22
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Chlorodifluoromethane
CASRN -- 75-45-6
Primary Synonym -- HCFC-22
Last Revised -- 11/01/1993
The inhalation Reference Concentration (RfC) is analogous to the oral RfD and
is likewise based on the assumption that thresholds exist for certain toxic
effects such as cellular necrosis. The inhalation RfC considers toxic effects
for both the respiratory system (portal-of-entry) and for effects peripheral
to the respiratory system (extrarespiratory effects). It is expressed in
units of mg/cu.m. In general, the RfC is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily inhalation exposure of the
human population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Inhalation RfCs
were derived according to the Interim Methods for Development of Inhalation
Reference Doses (EPA/600/8-88/066F August 1989) and subsequently, according to
Methods for Derivation of Inhalation Reference Concentrations and Application
of Inhalation Dosimetry (EPA/600/8-90/066F October 1994). RfCs can also be
derived for the noncarcinogenic health effects of substances that are
carcinogens. Therefore, it is essential to refer to other sources of
information concerning the carcinogenicity of this substance. If the U.S. EPA
has evaluated this substance for potential human carcinogenicity, a summary of
that evaluation will be contained in Section II of this file.
___I.B.1. INHALATION RfC SUMMARY
Critical Effect Exposures* UF MF RfC
-------------------- --------------------------- ----- --- ----------
Increased kidney, NOAEL: 35,370 mg/cu.m 100 1 5E+1
adrenal and pituitary (10,000 ppm) mg/cu.m
weights NOAEL(ADJ): 5260 mg/cu.m
NOAEL(HEC): 5260 mg/cu.m
Chronic Rat Inhalation
Study LOAEL: 176,800 mg/cu.m
(50,000 ppm)
Tinston et al., 1981a LOAEL(ADJ): 26,300 mg/cu.m
LOAEL(HEC): 26,300 mg/cu.m
Reduced maternal NOAEL: 3537 mg/cu.m
weight gain NOAEL(ADJ): 909 mg/cu.m
NOAEL(HEC): 909 mg/cu.m
Rat Developmental
Study LOAEL: 176,800 mg/cu.m
(50,000 ppm)
Palmer et al., 1978a LOAEL(ADJ): 44,200 mg/cu.m
LOAEL(HEC): 44,200 mg/cu.m
Conversion Factors and Assumptions -- Tinston et al., 1981a: MW = 86.47.
Assuming 25 C and 760 mm Hg, NOAEL(mg/cu.m) = 10,000 ppm x 86.47/24.45 =
35,400 mg/cu.m. NOAEL(ADJ) = NOAEL(mg/cu.m) x 5 hours/24 hours x 5 days/7
days = 5260 mg/cu.m. The NOAEL(HEC) was calculated for a gas:extrarespiratory
effect assuming periodicity was attained. Since the b:a lambda values are
unknown for the experimental animals species (a) and humans (h), a default
value of 1.0 is used for this ratio. NOAEL(HEC) = 5260 x [b:a lambda(a)/b:a
lambda(h)] = 5260 mg/cu.m.
Palmer et al., 1978a: MW = 86.47. Assuming 25 C and 760 mm Hg,
LOAEL(mg/cu.m) = 50,000 ppm x 86.47/24.45 = 176,800. LOAEL(ADJ) =
LOAEL(mg/cu.m) x 6 hours/24 hours x 7 days/7 days = 44,200 mg/cu.m. The
LOAEL(HEC) was calculated for a gas:extrarespiratory effect assuming
periodicity was attained. Since the b:a lambda values are unknown for the
experimental animals species (a) and humans (h), a default value of 1.0 is
used for this ratio. LOAEL(HEC) = 44,200 x [b:a lambda(a)/b:a lambda(h)] =
44,200 mg/cu.m.
___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC)
Tinston, D.J., I.S. Chart, M.J. Godley, C.W. Gore, M.H. Litchfield, and M.
Robinson. 1981a. Chlorodifluoromethane (CFC 22): Long term inhalation study
in the rat. Report No. CTL/P/548. Imperial Chemical Industries Limited,
Central Toxicology Laboratory, Alderley Park, Cheshire, UK.
Palmer, A.K., D.D. Cozens, R. Clark, and G.C. Clark. 1978a. Effect of Arcton
22 on pregnant rats: Relationship to anophthalmia and microphthalmia. Report
No. ICI 174/78208. Huntingdon Research Centre, Huntingdon, UK.
Tinston et al. (1981a) exposed groups of 80 Alderley Park Wistar-derived
rats/sex to 0 (two control groups), 1000, 10,000, or 50,000 ppm (0, 3540,
35,370, and 176,800 mg/cu.m, respectively) HCFC-22 for 5 hours/day, 5
days/week (duration-adjusted concentrations = 0, 526, 5260, 26,300 mg/cu.m,
respectively) for up to 118 weeks (females) or 131 weeks (males). Ten
animals/group were sacrificed at 52 weeks for hematological, clinical
chemistry, and histopathological evaluation. Remaining animals were
sacrificed when there was 80% mortality in all groups. The animals were
exposed in 2-cu.m stainless steel chambers with an air flow of 280 L/minute.
The test atmosphere was generated by dilution of HCFC-22 with air and was
measured periodically by gas chromatography. Concentrations were found to be
within 15% of target. Hematological and clinical chemistry parameters were
measured, and urinalysis was conducted prior to sacrifice. Histopathological
examination of approximately 30 tissues (including the lungs and nasal cavity)
was conducted on all animals that died during the study or were sacrificed.
No exposure-related effects on survival, clinical signs, body weight,
hematology, clinical chemistry, or urinalysis parameters were observed. The
female rats in the 50,000-ppm group exhibited a statistically significant
increase in liver (absolute and relative), kidney (absolute), adrenal
(absolute), and pituitary (absolute, at interim sacrifice--pituitaries were
not weighed at terminal sacrifice) weights. No nonneoplastic
histopathological changes attributable to exposure to HCFC-22 were observed.
The liver weight effect was not considered adverse because it did not exceed a
10% weight change and there was no histopathology observed. Based on effects
on kidney, adrenal, and pituitary weight, a NOAEL of 10,000 ppm [NOAEL(HEC) =
5260 mg/cu.m] and a LOAEL of 50,000 ppm [LOAEL(HEC) = 26,300 mg/cu.m] can be
estimated.
Palmer et al. (1978a) conducted a large developmental study in an attempt
to elucidate the role of CFC-22 exposure in the eye lesion seen in the
previous studies (see Culik et al., 1977, and Culik and Crowe, 1978, in the
Additional Studies/Comments section). In this study, an experimental design
was used in which 34 control pregnant rats were used, and 22/group were
exposed to 100, 1000, or 50,000 ppm of CFC-22 (354, 3,540, or 176,800 mg/cu.m,
respectively) for 6 hours/day on gestation days 6-15. This protocol was
repeated 19 times so that more than 6000 control fetuses and 4000 fetuses from
each exposed group were thoroughly examined for the eye defect. Maternal body
weight gain was consistently lower in the dams exposed to 50,000 ppm. The
average maternal weight on day 20 was lower than controls in 15/19 replicate
experiments, and the overall average maternal weight in the treated groups was
96.6% of the controls. The average weight gain from day 6-17 of gestation was
decreased by 3, 3, and 15% in the groups exposed to 100, 1000, and 50,000 ppm,
respectively. Although this effect was statistically significant in all
exposed groups, it is considered to be adverse only in the group exposed to
50,000 ppm. No other adverse effects were noted in the dams, and there was no
evidence of exposure-related effects on pregnancy outcome or the incidence of
gross terata. In the animals exposed to 50,000 ppm, fetal weight was lower
than in controls, and the difference was statistically significant in three of
the individual repetitions as well as for all repetitions using a
nonparametric rank sum analysis. The eye abnormalities (small or missing eye)
were noted again in all exposure groups, but statistical significance for
these effects was achieved only in the 50,000-ppm group. The combined
incidences of microphthalmia and anophthalmia were 3/607, 5/393, 3/390, and
10/383 in the control, 100, 1000, and 50,000-ppm groups, respectively.
Additional data on the control incidence of the eye effects during 10 years
after the Palmer et al. (1978a) study was conducted are presented in European
Chemical Industry Ecology and Toxicology Center (ECETOC) (1989). The data
were analyzed in blocks of 19 studies, and the control incidence in the first
six blocks was similar to the controls in the Palmer study, while in later
studies, the control incidence increased (0.4-2.4% in the last four blocks)
and, in one experiment, was similar to the incidence found in the high-dose
group in the Palmer study (2.6%). The incidence of the eye abnormality in the
high-concentration group in the Palmer et al. (1978a) study is significantly
increased compared with the overall controls in the studies conducted in the
10-year period after the study (ECETOC, 1989), adding strength to the
interpretation that this is an adverse, treatment-related effect. This study
identifies a LOAEL for maternal weight, fetal weight, and fetal abnormalities
at 50,000 ppm. The LOAEL(HEC) is 176,800 mg/cu.m for the fetal effects (no
duration adjustment is applied) and 44,200 mg/cu.m for the maternal toxicity
(exposure is adjusted for duration).
___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC)
UF -- The uncertainty factor of 100 reflects a factor of 10 to protect
unusually sensitive individuals, 3 for interspecies extrapolation, and 3 for
data base deficiencies including lack of a two-generation reproductive study.
MF -- None
___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC)
A long-term study was conducted in Alderley Park Swiss-derived mice
(Tinston et al., 1981b). In this study, 80 mice/sex/group were exposed to 0,
1000, 10,000, or 50,000 ppm (0, 3540, 35,370, and 176,800 mg/cu.m,
respectively) HCFC-22 for 5 hours/day, 5 days/week (duration-adjusted
concentrations = 0, 526, 5260, and 26,300 mg/cu.m, respectively) for up to 83
weeks (males) or 94 weeks (females). Ten animals/group were sacrificed at 38
weeks for hematological, clinical chemistry, and histopathological evaluation.
The same clinical, gross, and microscopic evaluations were conducted on the
mice as those described for the rats in the chronic rat study (Tinston et al.,
1981a). No exposure-related effects on body weight gain; hematological,
clinical chemistry, or urinalysis parameters; or gross or microscopic
pathology were noted. Data on organ weights were not reported. Hyperactivity
in the 50,000-ppm males was the only consistent effect noted that could be
attributed to HCFC-22 exposure. However, no definition of hyperactivity or
scoring criteria was provided. Nonneoplastic lesions seen in the respiratory
tract at comparable incidences in both the exposed and control groups were
indicative of Sendai virus infection. This study identifies a LOAEL for the
clinical observation of hyperactivity of 50,000 ppm [LOAEL(HEC) = 26,300
mg/cu.m] and a NOAEL of 10,000 ppm [NOAEL(HEC) = 5260 mg/cu.m].
Two subchronic inhalation toxicity studies support the relatively low
toxicity of HCFC-22 seen in the chronic studies. Leuschner et al. (1983)
exposed 20 Sprague-Dawley rats/sex/group and 3 beagle dogs/sex/group to 0,
5000 (17,680 mg/cu.m, dogs), or 10,000 ppm (35,370 mg/cu.m, rats) HCFC-22 for
6 hours/day, 7 days/week, for 13 weeks by whole-body exposure [duration-
adjusted concentrations = 0, 4420 (dogs), or 8840 (rats) mg/cu.m]. Clinical
signs, body weight, hematology, clinical chemistry, urinalysis, organ weights,
and histopathology were assessed in both rats and dogs, and electrocardiogram
and circulatory function (blood pressure with and without norepinephrine
stress) were also evaluated in the dogs. Microscopic examination of 27 organs
(not specified) was carried out on both rats and dogs at study termination.
No exposure-related effects on any of the parameters evaluated were noted in
either species. This study identifies a free-standing NOAEL of 5000 ppm
[NOAEL(HEC) = 4420 mg/cu.m] in dogs and 10,000 ppm in rats [NOAEL(HEC) = 8840
mg/cu.m].
Lee and Suzuki (1981) exposed groups of 16 male Sprague-Dawley rats to 0
or 50,000 ppm HCFC-22 for 5 hours/day, 7 days/week for 8 weeks (duration-
adjusted concentrations = 0 or 36,800 mg/cu.m, respectively). Six rats/group
were sacrificed at 8 weeks, and the rest were used in a fertility study
(discussed below). The only exposure-related effects noted were a slight
decrease in prostate weight (without accompanying histopathological changes),
an increase in plasma cholesterol, and decreases in plasma glucose and
triglycerides. The toxicological significance of these changes is not clear
because functional studies on adrenal or hepatic function were not undertaken,
and there were no histopathological changes in these organs. Nevertheless, a
LOEL of 50,000 ppm [LOEL(HEC) = 36,800 mg/cu.m] can be estimated from this
study.
One study is available that investigated the potential reproductive
toxicity of HCFC-22 in male animals. As discussed previously, Lee and Suzuki
(1981) exposed male Sprague-Dawley rats to 0 or 50,000 ppm HCFC-22 (duration-
adjusted concentrations = 0 or 36,800 mg/cu.m, respectively) 5 hours/day, 7
days/week for 8 weeks. Six rats/group were sacrificed at this time and the
rest were used in the fertility study. In the animals sacrificed immediately
after the last exposure, prostatic fructose and acid phosphatase activity were
measured, as well as plasma follicle stimulating hormone and luteinizing
hormone. The surviving animals were then serially mated with virgin unexposed
females for 7-day periods for a total 10 weeks. The mated females were killed
9 days after removal from the males and the number of corpora lutea, total
implants, live implants, resorption sites, and dead implants were counted.
Except for the decrease in prostate weight mentioned above, no exposure-
related effects were noted in any of these parameters.
Two developmental studies in rats were reported by Culik et al. (1977).
In the first study, 21 or 22 female albino rats were exposed to 0, 1000, or
10,000 ppm CFC-22 for 6 hours/day. Half of the rats were exposed on days 4-13
of gestation and half on days 6-15 of gestation. No maternal toxicity (i.e.,
changes in body weight gain, clinical signs, or gross pathology) was observed
in this study. Indices of pregnancy outcome and fetotoxicity were also
unaffected by exposure to HCFC-22. However, rare eye abnormalities (small or
missing eyes) were noted in one fetus from the lower concentration and in two
fetuses from the higher concentration groups. Because this abnormality has a
low spontaneous incidence, a second study was performed with a larger number
of animals. Groups of 33-35 pregnant rats were exposed to 0, 500, 1000, or
20,000 ppm CFC-22 for 6 hours/day on days 6-15 of gestation. As in the first
study, there were no effects on maternal or fetal toxicity and no
malformations except the eye defect. One litter from each exposed group
showed microphthalmia (small eye) or anophthalmia (absent eye), and in the
1000-ppm litter, two pups were affected. Although not statistically
significant, these findings are suggestive of a developmental effect because
of the relative rarity of this lesion. The incidence was reported to be
statistically significant compared to historical control data, which were
cited as one fetus with microphthalmia in 411 litters. This finding was not
considered to be adverse.
A follow-up to the Culik et al. (1977) studies was reported by Culik and
Crowe (1978), in which the same rat strain (35-41/group) was exposed on days
6-15 of gestation to 0, 100, 300, or 10,000 ppm CFC-22. There were no effects
on maternal weight, clinical signs, gross pathology, or in indices of
pregnancy outcome. No effects on fetal weight or crown-rump length were
observed. The only malformation observed was unilateral microphthalmia in
three fetuses, one in the group exposed to 100 ppm and two (from different
litters) exposed to 10,000 ppm.
No adverse maternal or developmental effects were noted in rabbits exposed
to concentrations of HCFC-22 up to 50,000 ppm (176,800 mg/cu.m) (Palmer et al.
1978b).
Pharmacokinetic data indicate that HCFC-22 is rapidly absorbed and
eliminated following inhalation exposure (Litchfield and Longstaff, 1984;
Sakata et al., 1981). Peter et al. (1986) demonstrated in studies in rats
that HCFC-22 undergoes very little metabolism in the body and is eliminated
largely unchanged.
___I.B.5. CONFIDENCE IN THE INHALATION RfC
Study -- High
Data Base -- Medium
RfC -- Medium
The principal studies were well-conducted, used a sufficient number of
animals, and identified a NOAEL and a LOAEL. The chronic studies are
supported by subchronic studies, and the developmental toxicity following
inhalation exposure has been adequately studied. The data base is given a
medium-to-high level of confidence because the chronic inhalation study in
mice lacks reporting of some endpoints and because the data base lacks a two-
generation reproductive study. Medium to high confidence in the RfC follows.
___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC
Source Document -- This assessment is not presented in any existing U.S. EPA
document.
Other EPA Documentation -- None
Agency Work Group Review -- 09/23/1992
Verification Date -- 09/23/1992
___I.B.7. EPA CONTACTS (INHALATION RfC)
Please contact the IRIS Hotline for all questions concerning this
assessment or IRIS, in general, at (301) 345-2870 (phone), (301) 345-2876 (FAX)
or Hotline.IRIS@epamail.epa.gov (internet address).
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Chlorodifluoromethane
CASRN -- 75-45-6
Primary Synonym -- HCFC-22
This substance/agent has not undergone a complete evaluation and determination
under US EPA's IRIS program for evidence of human carcinogenic potential.
_VI. BIBLIOGRAPHY
Substance Name -- Chlorodifluoromethane
CASRN -- 75-45-6
Primary Synonym -- HCFC-22
Last Revised -- 12/01/1993
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfD REFERENCES
Culik, R., D.P. Kelly, and B.A. Burgess. 1977. Embryotoxic and teratogenic
studies in rats with inhaled chlorodifluoromethane (FC-22). Haskell
Laboratory Report No. 970-76.
Culik, R. and C.D. Crowe. 1978. Embryotoxic and teratogenic studies in rats
with inhaled chlorodifluoromethane (FC-22), third study. Haskell Laboratory
Report No. 314-78.
ECETOC (European Chemical Industry Ecology and Toxicology Center). 1989.
Joint Assessment of Commodity Chemicals. No. 9. Chlorodifluoromethane.
European Chemical Industry Ecology and Toxicology Center. Brussels, Belgium.
Lee, I.P. and K. Suzuki. 1981. Studies on the male reproductive toxicity of
Freon 22. Fund. Appl. Toxicol. 1: 266-270.
Leuschner, F., B. W. Neumann, and F. Hubscher. 1983. Report on subacute
toxicological studies with several fluorocarbons in rats and dogs by
inhalation. Arzneim.-Forsch. 33(10): 1475-1476.
Litchfield, M.H. and E. Longstaff. 1984. Summaries of toxicological data.
The toxicological evaluation of chlorofluorocarbons 22 (CFC 22). Fd. Chem.
Toxicol. 22(6): 465-475.
Palmer, A.K., D.D. Cozens, R. Clark, and G.C. Clark. 1978a. Effect of Arcton
22 on pregnant rats: Relationship to anophthalmia and microphthalmia. Report
No. ICI 174/78208. Huntingdon Research Centre, Huntingdon, UK.
Palmer, A.K., D.D. Cozens, R. Clark, and G.C. Clark. 1978b. Effect of Arcton
22 on pregnancy of the New Zealand white rabbit. Report No. ICI 177/78505.
Huntingdon Research Centre, Huntingdon, UK.
Peter, H., J.G. Filser, L. V. Szentpaly, and H.J. Wiegand. 1986. Different
pharmacokinetics of dichlorofluoromethane (CFC 21) and chlorodifluoromethane
(CFC 22). Arch. Toxicol. 58: 282-283.
Sakata, M., H. Kazama, A. Miki, A. Yoshida, M. Haga, and M. Morita. 1981.
Acute toxicity of fluorocarbon-22: Toxic symptoms, lethal concentration, and
its fate in rabbit and mouse. Toxicol. Appl. Pharmacol. 59: 64-70.
Tinston, D.J., I.S. Chart, M.J. Godley, C.W. Gore, M.H. Litchfield, and M.
Robinson. 1981a. Chlorodifluoromethane (CFC 22): Long term inhalation study
in the rat. Report No. CTL/P/548. Imperial Chemical Industries Limited,
Central Toxicology Laboratory, Alderley Park, Cheshire, UK.
Tinston, D.J., I.S. Chart, M.J. Godley, C.W. Gore, B.A. Gaskell, and M.H.
Litchfield. 1981b. Chlorodifluoromethane (CFC 22): Long term inhalation
study in the mouse. Report No. CTL/P/547. Imperial Chemical Industries
Limited, Central Toxicology Laboratory, Alderley Park, Cheshire, UK.
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
None
_VII. REVISION HISTORY
Substance Name -- Chlorodifluoromethane
CASRN -- 75-45-6
Primary Synonym -- HCFC-22
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
10/01/1992 I.B. Inhalation RfC now under review
11/01/1993 I.B. Inhalation RfC on-line
11/01/1993 VI.B. Inhalation RfC references on-line
12/01/1993 VI.B. References corrected
04/01/1997 III.,IV., Drinking Water Health Advisories, EPA Regulatory Actions, and
V. Supplementary Data were removed from IRIS on or before April
1997. IRIS users were directed to the appropriate EPA Program
Offices for this information.
VIII. SYNONYMS
Substance Name -- Chlorodifluoromethane
CASRN -- 75-45-6
Primary Synonym -- HCFC-22
Last Revised -- 10/01/1992
75-45-6
Methane, chlorodifluoro-
Chlorodifluoromethane
fluorocarbon 22
Hydrochlorofluorocarbon 22
Algeon 22
ALGOFRENE TYPE 6
Arcton 4
CCRIS 858
Chlorofluorocarbon 22
Clorodifluometano [Spanish]
Difluorochloromethane
Difluoromonochloromethane
ELECTRO-CF 22
Eskimon 22
F 22
FC 22
FC22
FLUOROCARBON-22
FREON
Freon 22
Frigen
Frigen 22
Genetron 22
HSDB 143
Isceon 22
Isotron 22
Khladon 22
Monochlorodifluormethane
Monochlorodifluoromethane
Propellant 22
R 22
Refrigerant 22
UCON 22
HCFC-22
.
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/subst/0657.htm
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