United States
Environmental Protection
1=1 m m Agency
Provisional Peer-Reviewed Toxicity Values for
(CASRN 75-69-4)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

Benchmark Dose
Integrated Risk Information System
inhalation unit risk
lowest-observed-adverse-effect level
LOAEL adjusted to continuous exposure duration
LOAEL adjusted for dosimetric differences across species to a human
no-ob served-adverse-effect level
NOAEL adjusted to continuous exposure duration
NOAEL adjusted for dosimetric differences across species to a human
no-ob served-effect level
oral slope factor
provisional inhalation unit risk
provisional oral slope factor
provisional inhalation reference concentration
provisional oral reference dose
inhalation reference concentration
oral reference dose
uncertainty factor
animal to human uncertainty factor
composite uncertainty factor
incomplete to complete database uncertainty factor
interhuman uncertainty factor
LOAEL to NOAEL uncertainty factor
subchronic to chronic uncertainty factor

On December 5, 2003, the U.S. Environmental Protection Agency's (U.S. EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	U.S. EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in U.S. EPA's Superfund
3.	Other (peer-reviewed) toxicity values, including
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in U.S. EPA's IRIS. PPRTVs are developed according to a
Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific
literature using the same methods, sources of data, and Agency guidance for value derivation
generally used by the U.S. EPA IRIS Program. All provisional toxicity values receive internal
review by two U.S. EPA scientists and external peer review by three independently selected
scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multiprogram consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all U.S. EPA programs, while PPRTVs are developed
specifically for the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.

It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. EPA programs or
external parties who may choose of their own initiative to use these PPRTVs are advised that
Superfund resources will not generally be used to respond to challenges of PPRTVs used in a
context outside of the Superfund Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the U.S. EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
An RfD of 3 x 10"1 mg/kg-day for trichlorofluoromethane (also known as FC-11 or
Freon 11) is available on IRIS (U.S. EPA, 2008). The assessment, verified 5-31-1985 and
described in the Health Effects Assessment (HEA) for Fully Halogenated Methanes
(U.S. EPA, 1987), is based on a duration-adjusted LOAEL of 349 mg/kg-day for decreased
survival in rats in a National Cancer Institute (NCI, 1978) gavage cancer bioassay. The
composite UF of 1000 included factors of 10 each for use of a LOAEL, interspecies
extrapolation, and protection of sensitive populations. This RfD is also included in the Drinking
Water Health Advisory list (U.S. EPA, 2006), which is based on a Drinking Water Health
Advisory (DWHA) for trichlorofluoromethane (U.S. EPA, 1989), and in the Health Effects
Assessment Summary Tables (HEAST; U.S. EPA, 1997). The HEAST also lists a subchronic
RfD of 0.7 mg/kg-day, described in the HEA (U.S. EPA, 1987), based on a duration-adjusted
LOAEL of 714 mg/kg-day for decreased body weight and increased mortality in the 6-week
range-finding study for the NCI (1978) cancer bioassay and a composite UF of 1000 (10 each for
use of a LOAEL, interspecies extrapolation, and protection of sensitive populations). The HEA
and DWHA are the only relevant documents included in the Chemical Assessments and Related
Activities (CARA) list (U.S. EPA, 1991, 1994a). The Agency for Toxic Substances Disease
Registry (ATSDR, 2008) has not developed a Toxicological Profile for trichlorofluoromethane.
An Environmental Health Criteria Document for fully halogenated chlorofluorocarbons includes
trichlorofluoromethane (WHO, 1990), but it did not derive toxicity values.
There is no RfC for trichlorofluoromethane on IRIS (U.S. EPA, 2008). The HEAST
(U.S. EPA, 1997) lists a subchronic RfC and chronic RfC of 7 mg/m3 and 7 x 10"1 mg/m3,
respectively, for trichlorofluoromethane derived in the HEA (U.S. EPA, 1987) from a subchronic
inhalation study by Jenkins et al. (1970) using methods no longer supported by U.S. EPA. The
critical effect was increased blood urea nitrogen (BUN) in exposed dogs at 1008 ppm
(5746 mg/m3). In a route-to-route extrapolation, the California Environmental Protection
Agency (CalEPA, 1997) used this LOAEL as the basis for calculation of a Public Health Goal of
700 ppb in drinking water. At the time of the initial literature search (May 7, 2008), CalEPA

2	3
(2005) listed a chronic inhalation recommended exposure limit (REL) of 7 x 10 |ig/m for
trichlorofluoromethane to protect against nervous system effects. However, this REL was
eliminated when the table of RELs was updated on May 22, 2008. The American Conference of
Governmental Industrial Hygienists (ACGIH, 2001, 2007) recommends a threshold limit value
(TLV) ceiling of 1000 ppm (5600 mg/m ) for trichlorofluoromethane to prevent acute cardiac
sensitization in workers. The National Institute for Occupational Safety and Health
(NIOSH, 2005) REL is also a ceiling level of 1000 ppm, while the Occupational Safety and
Health Administration (OSHA, 2008) permissible exposure limit (PEL) is 1000 ppm as an
8-hour time-weighted average (TWA).
IRIS (U.S. EPA, 2008) does not contain a cancer assessment for trichlorofluoromethane,
and neither does the HEAST (U.S. EPA, 1997). The HEA (U.S. EPA, 1987) assigned
trichlorofluoromethane to U.S. EPA (1986) weight-of-evidence Group D—"Not classifiable as to
human carcinogenicity"—based on the lack of data regarding the carcinogenic effect of the
chemical in humans and insufficient evidence in animals. Trichlorofluoromethane is also
classified as Group D in the DWHA list (U.S. EPA, 2006) based on the DWHA for
trichlorofluoromethane (U.S. EPA, 1989). ACGIH (2007) has designated
trichlorofluoromethane as A4—"Not classifiable as a human carcinogen."
Trichlorofluoromethane is not included in the National Toxicology Program Report on
Carcinogens (NTP, 2005). Results of the NCI (1978) bioassay were inconclusive for rats (due to
low survival) and negative for mice. The carcinogenicity of trichlorofluoromethane has not been
assessed by the International Agency for Research on Cancer (IARC, 2008).
Literature searches were conducted from 1960s through June 2009 for studies relevant to
the derivation of provisional toxicity values for trichlorofluoromethane. Databases searched
DART/ETIC, GENETOX, HSDB, RTECS, and Current Contents (last 6 months).
Human Studies
Oral Exposure
A 38-year-old man who accidentally ingested a small amount of trichlorofluoromethane
suffered multiple perforations of the stomach; the effects were presumed to result from the
freezing action of the compound (Haj et al., 1980).
Inhalation Exposure
Stewart et al. (1975, 1978) exposed 8 male volunteers to 1000 ppm (5620 mg/m3)
trichlorofluoromethane 8 hours/day, 5 days/week, for a total of 18 exposures (3.5 weeks). The
subjects served as their own controls, with comprehensive pre-exposure testing providing
baseline measurements. The study authors recorded subjective symptoms before exposure and
hourly until 5 hours after exposure was concluded for the day. They collected blood for serum
chemistry (alkaline phosphatase [ALP], aspartate aminotransferase [AST], lactate dehydrogenase
[LDH], bilirubin, glucose, calcium, phosphorous, BUN) and hematology (complete blood count)
before and after exposure; urinalysis (parameters not specified) was assessed at the same times.
Other evaluations included electrocardiogram, pulmonary function (computerized spirometry

measurement), neurological evaluation (modified Romberg test and heel-to-toe test),
electroencephalogram, visual evoked potentials, and cognitive tests (Flanagan coordination tests,
Marquette time estimation test, and random number inspection test). The data showed no effects
on any parameters other than the cognitive tests. Statistically significant decrements were
observed in cognitive performance tests (data presented graphically,/? < 0.02). The study
authors described these effects as "minor and transient" and considered the significance of these
effects to be questionable because similar effects were not observed in experiments wherein
groups of male and female volunteers were acutely exposed to the same concentration
(1000 ppm or 5620 mg/m ) for up to 8 hours. However, as noted by the World Health
Organization (WHO, 1990), several other studies have indicated a potential association between
psychomotor impairment and chlorofluorocarbon exposure (Stopps and McLaughlin, 1967;
Kehoe, 1943; Azar et al., 1972; Geller et al., 1977, all as cited by WHO, 1990), lending credence
to the observed association with cognitive effects. In addition, higher concentrations of
trichlorofluoromethane have resulted in neurological effects and/or brain histopathology in rats
(Lester and Greenberg, 1950; Clayton, 1966; described below under "Other Studies"). Thus, the
exposure concentration used in this study (5620 mg/m3) is considered a LOAEL for mild effects
on cognitive performance.
Animal Studies
Oral Exposure
Subchronic Studies—Both CalEPA (1997) and NRC (1980) discussed a 1-month study
in mice (Kudo et al., 1971, as cited in CalEPA, 1997); this paper was published in Japanese and
was not retrieved for this review. According to CalEPA (1997), mice (both sexes, but strain and
number per sex not reported) were given trichlorofluoromethane at doses of 16.2, 54.5, or
218 mg/kg-day via daily oral administration (method not specified) for 1 month
(Kudo et al., 1971, as cited in CalEPA, 1997). The toxicological evaluations were not described
by CalEPA. The only effects reported in the summary were a slight decrease in food
consumption and one case of liver cell vacuolation in the animals exposed to the highest dose.
The available information is inadequate for the determination of effect levels.
CalEPA (1997) cited two oral studies that were not discussed in any other secondary
references; efforts to obtain the original reports were not successful. In the first study,
DuPont (1972, as cited in CalEPA, 1997) administered gavage doses of 0, 5, or 30 mg/mL
trichlorofluoromethane in corn oil to albino ChR-CD rats (20/sex/group) for 90 days. The
dosing frequency was 7 days/week for the first month and then 5 days/week for the remainder of
the exposure period. CalEPA (1997) reported average daily doses of 41 to 73 mg/kg-day
(low-dose group) and 245 to 450 mg/kg-day (high-dose group). Parameters monitored to assess
toxicity included body weight, food intake, behavioral observations, hematology, and serum and
urine chemistry (including BUN, ALP, creatinine, and AST). Upon sacrifice, half of the animals
in each group were sacrificed for histopathology evaluation of unspecified tissues.
CalEPA (1997) reported that there were no treatment-related differences in any of the parameters
An experiment with dogs was also conducted by DuPont (1972, as cited in
CalEPA, 1997). Trichlorofluoromethane in corn oil was administered at doses of 0, 250, or
500 mg/mL via gelatin capsule to groups of dogs (4/sex/dose; strain not specified).
CalEPA (1997) reported the average daily doses to be 40 to 69 mg/kg-day (low-dose group) and
170 to 346 mg/kg-day (high-dose group); the frequency of administration is not reported.

Toxicity in dogs was assessed using the same parameters assessed in rats. According to
CalEPA (1997), there were no treatment-related effects. No other information on the DuPont
studies is provided by CalEPA (1997); however, the studies were reported to contain "a number
of shortcomings and inconsistencies," which CalEPA (1997) characterized as limiting their
usefulness for risk assessment. The information available for these studies is inadequate for the
determination of effect levels.
NCI (1978) conducted a dose range-finding study of trichlorofluoromethane in rats and
mice (NCI, 1978). Groups of Osborne-Mendel and B6C3F1 mice (5/sex/species/dose) were
given trichlorofluoromethane via gavage at doses of 0, 1000, 1780, 3160, 5620, or
10,000 mg/kg-day, 5 days/week, for 6 weeks. Survival and body-weight gain were the only
parameters monitored in the dose range-finding study. In rats, at least one death occurred in each
male group exposed to >1780 mg/kg-day and each female group exposed to >3160 mg/kg-day.
Body weight was significantly reduced (26% less than controls) in male rats exposed to
1000 mg/kg-day; in females, body weight was reduced (11%) at 1780 mg/kg-day. Among mice,
deaths occurred in males exposed to doses >5620 mg/kg-day and in females exposed to doses
>3160 mg/kg-day. No body-weight changes occurred in mice exposed to doses below those
causing mortality. No other dose-response information is provided in the study. This study
identifies a FEL of 1000 mg/kg-day for marked body-weight reduction in male rats, and a FEL
of 3160 mg/kg-day for mortality in female mice.
Chronic Studies—NCI (1978) administered trichlorofluoromethane in corn oil to
Osborne-Mendel rats (50/sex/dose) and B6C3F1 mice (50/sex/dose). Untreated and vehicle
control groups (20/sex/species) were maintained. The test material was administered via gavage
5 days/week for 78 weeks. Doses were adjusted at Week 12 in rats and at Week 7 in mice; the
authors estimated TWA doses of 488 and 977 mg/kg-day for male rats, 538 and 1077 mg/kg-day
for female rats, and 1962 and 3925 mg/kg-day in mice of both sexes. The author-supplied
time-weighted doses reflect doses administered 5 days/week; they were not adjusted to reflect
continuous (e.g., 7 days/week) exposure. After exposure was terminated, rats were observed for
28 to 33 weeks, and mice were observed for 13 weeks. Daily observations for mortality were
conducted, and body weight, food consumption, clinical signs, and palpable tissue masses were
assessed weekly for the initial 10 weeks and monthly for the remainder of the study. Upon
death, humane sacrifice, or terminal sacrifice, all animals were necropsied; comprehensive
histopathology evaluations (29 tissues) were performed on all animals.
In rats, a statistically significant (p < 0.001) dose-related increase in mortality (relative to
the vehicle control group) occurred in both males and females (NCI, 1978), with deaths
occurring as early as Week 4 of treatment in the high-dose females and Week 15 in other treated
groups. The authors reported that chronic murine pneumonia was evident in 88 to 100% of all
rats and that this infection probably contributed to the early mortality. Signs of illness, including
hunched appearance and labored respiration, occurred at higher frequency than in controls at
both doses during the beginning of the study; frequencies of these effects were similar to controls
for the remainder of the study. Gross necropsy and histopathology examinations revealed
pleuritis and pericarditis in treated, but not control rats. Tumor incidences were not significantly
higher in exposed male or female rats; however, NCI (1978) concluded that inadequate numbers
of rats survived long enough to be at risk from late-developing tumors. The U.S. EPA (IRIS RfD
derivation, verified 5-31-1985) identified the low dose (488 mg/kg-day in male rats) as a
LOAEL for accelerated mortality, pleuritis, and pericarditis.

In mice, NCI (1978) documented a statistically significant (p = 0.009) dose-related
acceleration of mortality in females but not in males. Based on graphical presentation of the
survival data, the earliest deaths in female mice occurred between Weeks 7 and 15 in both
treated groups, while no control female deaths occurred until around Week 37. The pneumonia
observed in rats was not observed in mice. The study authors reported no treatment-related
effect on body weight or the incidence of clinical signs or nonneoplastic or neoplastic pathology.
NCI (1978) concluded that, despite the increased mortality in females, enough male and female
mice survived through study termination for assessment of late-developing tumors. The low
dose (1962 mg/kg-day) represents a LOAEL for early mortality in females.
Inhalation Exposure
Subchronic Studies—Clayton (1966) reported the previously unpublished results of
three experiments with trichlorofluoromethane. In the first, several species of laboratory animals
were exposed to trichlorofluoromethane (purity not specified) at a concentration of 4000 ppm
(22,500 mg/m3). Groups of rats (6/sex), mice (4/sex), and guinea pigs (2 males), along with
1 male rabbit, were exposed for 6 hours each day, for 28 days. Following exposure, the animals
were observed for a 15-day recovery period. It is not clear whether concurrent control groups
were maintained; no data on control animals are reported. Mortality, body weight, hematology
(erythrocyte count, leukocyte count, hemoglobin, and hematocrit, in rats only), and histology
(organs and tissues not specified) were monitored. No effects were observed on any of these
parameters (data not shown). In other experiments reported by this author, several species were
exposed to trichlorofluoromethane 3.5 hours/day for 20 days. In these experiments, two cats,
three guinea pigs (sex of these species not reported), and 5 male rats were exposed to
25,000 ppm (140,500 mg/m ), while two dogs (sex not reported) were exposed to 12,500 ppm
(70,200 mg/m3). No effects were observed on body weight, hematological parameters
(erythrocyte count, total and differential leukocyte count, hemoglobin, and hematocrit), or on
urinalysis (protein and sediment). The study authors reported that there were no pathology
changes to the liver, kidneys, heart, lungs, or spleen; it is not clear whether this refers to gross or
microscopic pathology. The information presented in this report is inadequate for the definition
of effect levels—especially in the absence of control data.
Jenkins et al. (1970) exposed several species of animals to nominal
trichlorofluoromethane concentrations of 0 or 1000 ppm (5620 mg/m ) via whole-body
inhalation continuously for 90 days. They used Sprague-Dawley rats (8 males and 7 females per
group), Princeton-derived guinea pigs (8 males and 7 females per group), Beagle dogs
(2 males/group), and squirrel monkeys (9 males/group). The study authors observed all animals
daily for clinical or behavioral signs of toxicity. Body weight and hematology (hemoglobin
[Hgb], microhematocrit, and total leukocyte count) were assessed before and after the
experiment. At sacrifice at the end of the exposure period, serum levels of urea nitrogen and
alanine aminotransferase (ALT) were measured in all animals. Liver samples were collected
from rats and guinea pigs for measurement of ALP and tyrosine aminotransferase. ALP and
creatinine were also measured in serum from these species. Liver function, as assessed by
bromosulfophthalein retention, was assessed in dogs. In rats and guinea pigs, 24-hour urinary
excretion of fluoride was measured. The study authors performed histological examinations on
the heart, lung, liver, spleen, and kidney (all species); brain and spinal cord (dogs and monkeys);
and adrenal and thyroid (dogs only). They also subjected tissues from all dogs and monkeys to
histopathologic examination, while tissues from half of the rats and guinea pigs were examined.

The average measured concentration of trichlorofluoromethane was 1008 ± 44 ppm
(5660 mg/m3). Jenkins et al. (1970) reported no deaths among the rats, and the data showed that
body weight was not affected by exposure. There were no statistically significant effects on
hematology, serum, or liver chemistry, or 24-hour fluoride excretion in rats. Upon necropsy, the
study authors grossly observed mild liver discoloration in about one-fourth of rats, and they
reported one male rat as having an enlarged right kidney (no further details reported). No
treatment-related effects on survival, body weight, hematology, serum chemistry, or urinary
excretion of fluoride were observed in guinea pigs; however, about one-fourth of the animals
were reported to exhibit liver discoloration (no further details reported). In dogs, the study
authors documented no treatment-related effects on survival, body weight, hematology, liver
function, or gross necropsy. Levels of BUN were significantly increased in exposed dogs (2-fold
higher than controls; p < 0.01 by /-test performed for this review); there were no other serum
chemistry changes in dogs. On Day 78 of the experiment, one monkey died. Necropsy showed
hemorrhagic lesions on the lung surface of the monkey. The study authors considered the death
unrelated to exposure. The authors indicated that, in about 50% of the monkeys, they detected
microfilarial (Dipetalonema sp.) infections in the abdomens; the significance of this infection is
uncertain. The study authors reported that microscopic examination revealed "nonspecific
inflammatory changes" in the lungs of all species, mild vacuolar changes in the liver of guinea
pigs, and focal degeneration of the renal tubular epithelial cells in rats; no further details (or
incidences) are provided. The study authors concluded that none of the histopathology effects
could be related to exposure. A LOAEL of 5660 mg/m is identified for dogs based on increased
BUN; this same concentration is a freestanding NOAEL for the other species.
Jenkins et al. (1970) also assessed the effects of discontinuous exposure to nominal
concentrations of 0 or 10,000 ppm (0 or 56,200 mg/m3) 8 hours/day, 5 days/week, for 6 weeks.
The species, group sizes and sexes, and toxicity evaluations were the same as for the continuous
exposure experiment described above. The concentration of trichlorofluoromethane was
measured to be 10,250 ±100 ppm (57,600 mg/m ). As in the continuous exposure experiment,
the BUN levels were statistically significantly increased in exposed dogs (2.2-fold higher than
controls; p < 0.01 by /-test performed for this review). The study authors also reported the
following effects: mild discoloration, characterized as a darkening of the tissue, of the liver in
rats and guinea pigs (incidence reported to be about one-fourth of these animals), a single
grossly-observed liver lesion (2 mm x 4 mm in size) in one monkey; focal myocytolysis in one
rat; focal nonspecific myocarditis in two rats; and nonspecific inflammatory changes of the lungs
in guinea pigs, rats, and monkeys (incidences not reported). As with the continuous exposure
experiment, the study authors concluded that none of the histopathology effects could be related
to exposure. A LOAEL of 57,600 mg/m3 is identified for dogs based on increased BUN; this
same concentration is a freestanding NOAEL for the other species.
Leuschner et al. (1983) exposed male and female Sprague-Dawley rats (20/sex/group,
whole body) to 0 or 10,000 ppm (0 or 56,200 mg/m ) trichlorofluoromethane (>99.9% pure) for
6 hours/day, 7 days/week, for 90 days. The parameters monitored to assess toxicity included
hematology (hemoglobin; erythrocyte, total and differential leukocyte, reticulocyte, and platelet
counts; hematocrit; methemoglobin; clotting time; and Heinz bodies); clinical chemistry (AST,
ALT, ALP, glucose, BUN, total protein, bilirubin, lipids, cholesterol, electrolytes, calcium,
chloride, uric acid, creatinine, and protein); urinalysis (color, specific gravity, protein, glucose,
bilirubin, hemoglobin, ketone bodies, pH, and sediment analysis); liver function
(bromosulfophthalein retention) sight, hearing, and dental examinations; and organ weights

(11 organs, not specified) and histological examinations of 27 tissues including the lungs (on
10 rats/sex/group). No significant changes in body-weight gain, hematology, clinical chemistry,
urine composition, sight, hearing, or dentition were observed (data not shown). In addition, no
histological alterations attributable to trichlorofluoromethane exposure were observed. Areas of
focal alveolar over-inflation and an intraalveolar accumulation of macrophages were observed to
the same extent in the exposed and control groups. This study identifies a freestanding NOAEL
of 56,200 mg/m3.
Leuschner et al. (1983) also assessed the effects in purebred Beagle dogs exposed
(3/sex/group, whole body) to 0 or 5,000 ppm (0 or 28,100 mg/m ) trichlorofluoromethane
(>99.9% pure) 6 hours/day, 7 days/week, for 90 days. The same toxicological parameters that
were assessed in rats were also assessed in dogs, with the following additional evaluations: free
cholesterol, triglycerides, phosphatides, and fatty acids in serum; renal function; glycogen in
heart, liver, and muscle; blood pressure; and electrocardiogram. No treatment-related effects
were observed on any of the parameters (data not shown). A freestanding NOAEL of
28,100 mg/m is identified from these data.
Chronic Studies—In a chronic-duration study focused on assessing carcinogenicity,
trichlorofluoromethane (99.95% purity) was administered by inhalation (whole body) to
Sprague-Dawley rats (90/sex/group) and Swiss mice (60/sex/group) at 1000 or 5000 ppm
(5620 or 28,100 mg/m ) 4 hours/day, 5 days/week, for 104 weeks (rats) or 78 weeks (mice)
(Maltoni et al., 1988). Control groups of rats (150/sex) and mice (90/sex) were maintained
concurrently. Animals were observed until spontaneous death. All animals underwent full
necropsy, and histological examinations were performed on an extensive collection of organs
and tissues. In rats, survival and body weight were comparable between control and treated
groups (data not shown). In mice, survival of control animals was lower than that of exposed
animals. The body weight of mice was not affected by treatment (data not shown). The study
authors reported no other information on nonneoplastic findings for either species. The data
showed that trichlorofluoromethane did not induce statistically significant differences in the
incidence of total benign or malignant tumors when compared with groups of unexposed rats or
mice. Concentration-related increases in the incidences of lung adenomas, leukemias, and total
tumors were observed in treated female mice, but the increases were not statistically significant.
In high-dose female mice, the study authors documented a statistically significant difference in
the incidence of mammary tumors in comparison with controls (6/60 vs. 1/90 controls, /?-value
not reported), even after the data were adjusted for reduced control survival. However, the study
authors reported that the incidence observed in the high-dose group (10%) was within the range
observed in control mice in other experiments conducted in their laboratory (2.0—15.2%).
Other Studies
WHO (1990) reviewed the available toxicokinetic data on trichlorofluoromethane; no
newer toxicokinetic studies were identified in the literature search. There are no data on the
toxicokinetics of trichlorofluoromethane after oral exposure in any species. Radiolabelling
studies have been used to estimate the absorption of inhaled trichlorofluoromethane to be about
82%) in humans and 77% in dogs (as reviewed by WHO, 1990 and CalEPA, 1997). Available in
vivo data suggest little or no metabolism of inhaled trichlorofluoromethane in humans or in dogs;
most of the compound is rapidly eliminated unchanged via exhaled air (reviewed by
WHO, 1990). After inhalation exposure to radiolabeled trichlorofluoromethane, only traces of

radioactivity are recovered in the urine or feces (reviewed by WHO, 1990). Wolf et al. (1978),
an in vitro study, suggests that rat liver microsomes could dechlorinate trichlorofluoromethane to
dichlorofluoromethane (Wolf et al., 1978); however, there are currently no in vivo data to
support this finding.
Acute/Short-term Toxicity
In an acute inhalation study, Clayton (1966) exposed three male rats to 12,000 ppm
(67,416 mg/m ) trichlorofluoromethane 4 hours/day for 10 days, followed by an 11-day recovery
period. It is unclear whether a control group was used. The rats exhibited a slight tachypnea and
an increase in tidal volume, as well as slight muscle twitching, during exposure. The authors
reported that there was a rapid recovery from these effects after exposure was terminated.
Histological examination revealed neuronal edema and neuroglia vacuolization in the brain,
edema and emphysema in the lungs, vacuolation of cells in the liver, and increased
hematopoiesis in the spleen. The significance of these findings is uncertain considering the lack
of control data.
Lester and Greenberg (1950) observed neurological changes in rats exposed to high
concentrations of trichlorofluoromethane for 30 minutes. Groups of white rats (strain, sex, and
group size not reported) were exposed to 5, 6, 7, 8, 9, 10, 15, 20, 30, or 50% by volume (v/v)
trichlorofluoromethane (equivalent to concentrations of 281, 337, 393, 449, 506, 562, 843, 1124,
1685, or 2809 g/m3). No changes in postural, righting, or corneal reflex were observed at
3	3
281 g/m , but altered postural reflex was observed in rats exposed to 337 g/m and higher
concentrations. At exposures >449 g/m3, a change in righting reflex was noted. Rats exposed to
>506 g/m became completely unconscious, and those exposed to higher concentrations died
during the exposure period.
Kyrklund et al. (1988) measured the lipid and fatty acid composition in the cerebral
cortex of male Sprague-Dawley rats exposed continuously for 30 days to trichlorofluoromethane
at a concentration of 580 ppm (3260 mg/m ). Body and brain weights were also assessed at
study termination. There were no treatment-related changes in body or brain weight, or in brain
lipid or fatty acid composition.
Trichlorofluoromethane was not mutagenic, with or without metabolic activation, in
Salmonella typhimurium TA98, TA100, TA1535, TA1537, and TA1538 or Escherichia coli
WP2 uvrA (Araki et al., 1994; Longstaff et al., 1984; Greim et al., 1977; Uehleke et al., 1977;
Zeiger et al., 1987), or Chinese hamster ovary cells (Krahn et al., 1982). Negative results were
also obtained for trichlorofluoromethane in a BHK21 mammalian cell mutagenicity test
(Longstaff et al., 1984; WHO, 1990). All of these studies were conducted using test systems
appropriate for volatile chemicals.

Subchronic p-RfD
The database for subchronic oral exposure to trichlorofluoromethane is very limited.
There were three oral studies that were described by secondary sources (Kudo et al., 1971 and
two unpublished studies conducted by DuPont, 1972, both as cited by CalEPA, 1997). The first
(Kudo et al., 1971, as cited by CalEPA, 1997) was a 1-month mouse study published in Japanese
and was not retrieved for this review. Efforts to obtain the unpublished studies (subchronic
gavage studies in rats and dogs, DuPont, 1972, as cited by CalEPA, 1997) were not successful.
Based on the information provided by CalEPA, none of these three studies document clearly
adverse effects. While additional efforts to obtain these studies might yield reliable effect levels,
it is not clear that any of them would support the derivation of a subchronic p-RfD. The only
other oral study of subchronic duration is a dose range-finding study conducted by NCI (1978) in
which mortality and body weight were the only parameters assessed. This study cannot support
the derivation of a subchronic p-RfD.
Chronic p-RfD
A chronic oral RfD of 3 x 10"1 mg/kg-day for trichlorofluoromethane is available on IRIS
(U.S. EPA, 2008).
Table 1 summarizes the data available for use in the derivation of subchronic and chronic
p-RfCs for trichlorofluoromethane. To provide a common basis for comparing the studies, the
effect levels from each study are adjusted to equivalent continuous exposure concentrations. The
adjusted animal NOAELs and LOAELs were then converted to human equivalent concentrations
(NOAELhec and LOAELhec) using the appropriate dosimetric adjustment (U.S. EPA, 1994b)
and as further described below. As an extrarespiratory effect (increased BUN) was observed in
the only animal study that identified a LOAEL (Jenkins et al., 1970), trichlorofluoromethane was
treated as a Category 3 gas, and the ratio of blood:gas partition coefficients was used to make the
dosimetric adjustment for all of the studies. A blood:gas partition coefficient for
trichlorofluoromethane in humans was identified (0.87; Abraham et al., 2005), but values for
other species were not. In the absence of chemical-specific blood:gas partition coefficients for
the relevant species, the default ratio of 1.0 is used. The equation used to calculate the
LOAELhec is as follows:
LOAELhec = (LOAELadj) x [(Hb/g)ANiMAL (Hb/g)HUMAN]
(Hb/g)A ^ (Hb/g)H = animal-to-human blood:air partition coefficient ratio
Table 2 shows the NOAELhec and LOAELhec values calculated for each of the studies.

Table 1. Summary of Inhalation Noncancer Dose-Response Information
8 hr/d, 5 d/wk, for 2-4 wk
Small decrements in
Stewart et al.,
1975, 1978
0, 5660,
(continuous) or
24 hr/d for 90 d
(continuous) or 8 hr/d,
5 d/wk, for 6 wk
0, 5660,
(continuous) or

Jenkins et al.,
0, 56,200
6 hr/d, 7 d/wk for 90 d

Leuschner et
al., 1983
0, 5660,
(continuous) or
24 hr/d for 90 d
(continuous) or 8 hr/d,
5 d/wk, for 6 wk
0, 5660,
(continuous) or
One monkey died in the
continuous experiment;
authors considered the
death unrelated to
Jenkins et al.,
0, 5660,
(continuous) or
0, 57,600
24 hr/d for 90 d
(continuous) or 8 hr/d,
5 d/wk, for 6 wk
Increased BUN
Jenkins et al.,
0, 28,100
6 hr/d, 7 d/wk, for 90 d

Leuschner et
al., 1983

Table 2. Calculation of Human Equivalent Concentrations
Effect Level (mg/m3)
Duration-Adjusted Effect
Level" (mg/m3)
Human Equivalent
Concentration0 (mg/m3)
Stewart et al., 1975, 1978
LOAEL = 5620
LOAELadj =1338
LOAEL = 1338
Jenkins et al., 1970,
continuous exposure
Rat, Guinea pig
NOAEL = 5660
NOAELadj = 5660
NOAELhec = 5660
Jenkins et al., 1970,
discontinuous exposure
Rat, Guinea pig
NOAEL = 57,600
NOAELadj = 13,700
NOAELhec = 13,700
Leuschner et al., 1983
NOAEL = 56,200
NOAELadj = 14,100
NOAELhec = 14,100
Jenkins et al., 1970,
continuous exposure
NOAEL = 5660
NOAELadj = 5660
NOAELhec = 5660
Jenkins et al., 1970,
discontinuous exposure
NOAEL = 57,600
NOAELadj = 13,700
NOAELhec = 13,700
Jenkins et al., 1970,
continuous exposure
LOAEL = 5660
LOAELadj ~ 5660
LOAELhec = 5660
Jenkins et al., 1970,
discontinuous exposure
LOAEL = 57,600
LOAELadj = 13,700
LOAELhec = 13,700
Leuschner et al., 1983
NOAEL = 28,100
NOAELadj = 7030
NOAELhec = 7030
'Adjusted to equivalent continuous exposure concentration based on exposure regimen shown in Table 1 as in the following equation: NOAELadj = NOAEL x
exposure hours/24 hr x exposure days/7 d
bRatio of blood:gas partition coefficients
Calculated as shown in this equation: NOAELHec = NOAEL x dosimetric adjustment
dNo dosimetric adjustment is necessary for the human study

Subchronic p-RfC
As shown in Table 2, the LOAEL (1338 mg/m3) calculated for the human study by
Stewart et al. (1975, 1978) was one-fourth the value of the only other LOAELhec (5660 mg/m3). The
remaining studies identify freestanding NOAELhec values (generally in other species) that exceeded the
two LOAELhec values. Because the study used only a single exposure concentration, benchmark dose
modeling of the data is not possible. For the subchronic p-RfC derivation, the LOAEL of 1338 mg/m3
from the human study (Stewart et al., 1975, 1978) is divided by a UF of 1000 to derive a subchronic
p-RfC as shown below:
Subchronic p-RfC = LOAEL UF
= 1338 mg/m3 - 1000
= 1 mg/m3
The composite UF of 1000 consists of the following:
•	A 10-fold UF is used for protection of sensitive individuals in the absence of information
to determine potentially susceptible populations.
•	A UF of 10 is applied for use of a LOAEL.
•	A database UF of 10 is used for database limitations. The database lacks reproductive,
developmental, and comprehensive neurobehavioral toxicity studies.
Confidence in the key study (Stewart et al., 1975, 1978) is medium-to-low. The study assessed
sensitive toxicological endpoints and was well documented. However, the exposed group consisted of
only eight male volunteers, only a single exposure concentration was used, and the study duration was
less than 1 month. Confidence in the database is low because it includes limited subchronic studies in
several species and a chronic study in two species focusing on carcinogenicity. The database lacks
reproductive, developmental, and comprehensive neurobehavioral toxicity studies. Low confidence in
the subchronic p-RfC follows.
Chronic p-RfC
Due to the brevity of available studies and insufficient justifications for considering long-term
effects, no chronic value is developed.
Weight-of-Evidence Descriptor
Under the U.S. EPA (2005) Guidelines for Carcinogen Risk Assessment, there is "Inadequate
Information to Assess the Carcinogenic Potential of Trichlorofluoromethane." There are no human data
on the potential carcinogenicity of trichlorofluoromethane. The one chronic oral bioassay of this
compound (NCI, 1978) provides no evidence of carcinogenicity in mice, and is inconclusive in rats
because inadequate numbers survived long enough to be at risk from late-developing tumors. The
chronic inhalation study by Maltoni et al. (1988) indicates a statistically significant increase over
controls in the incidence of mammary carcinomas in Swiss mice exposed to 5000 ppm of
trichlorofluoromethane; however, the incidence is within the range observed in control mice from other

experiments conducted in the same laboratory. Trichlorofluoromethane gave negative results in the
available tests of genotoxicity, which include tests of mutagenicity in bacterial and mammalian cells in
Quantitative Estimates of Carcinogenic Risk
Human cancer data are lacking, and the available animal data are inadequate to assess potential
carcinogenicity, precluding the derivation of a p-OSF and a p-IUR for trichlorofluoromethane.
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