United States
Environmental Protection
1=1 m m Agency
EPA/690/R-16/013F
Final
9-26-2016
Provisional Peer-Reviewed Toxicity Values for
1,1,2-Trichloro-1,2,2-trifluoroethane
(CASRN 76-13-1)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Q. Jay Zhao, MPH, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Elizabeth Owens, PhD
National Center for Environmental Assessment, Cincinnati, OH
Anuradha Mudipalli, MSc, PhD
National Center for Environmental Assessment, Research Triangle Park, NC
This document was externally peer reviewed under contract to:
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this PPRTV assessment should be directed to the EPA Office
of Research and Development's National Center for Environmental Assessment, Superfund
Health Risk Technical Support Center (513-569-7300).
li
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS	iv
BACKGROUND	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVs	1
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER)	5
HUMAN STUDIES	12
Oral Exposures	12
Inhalation Exposures	12
ANIMAL STUDIES	16
Oral Exposures	16
Inhalation Exposures	17
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	25
Tests Evaluating Genotoxicity and/or Mutagenicity	25
Acute Toxicity Studies	28
Short-Term Studies	28
Cardiac Sensitization Studies	29
Metabolism/Toxicokinetic Studies	30
DERIVATION 01 PROVISIONAL VALUES	31
DERIVATION OF ORAL REFERENCE DOSES	32
Derivation of a Subchronic Provisional Oral Reference Dose	32
Derivation of a Chronic Provisional Reference Dose	32
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	32
Justification for the Critical Effect	32
Justification for the Principal Study	33
Approach for Deriving the Subchronic p-RfC	33
Derivation of a Chronic Provisional Reference Concentration (p-RfC)	35
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR	37
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	38
Derivation of a Provisional Oral Slope Factor	38
Derivation of a Provisional Inhalation Unit Risk	38
APPENDIX A. SCREENING PROVISIONAL VALUES	39
APPENDIX B. DATA TABLES	40
APPENDIX C. BENCHMARK DOSE MODELING RESULTS	48
APPENDIX D. REFERENCES	49
in
1,1,2-Trichloro-1,2,2-trifluoroethane

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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
MN
micronuclei
ACGIH
American Conference of Governmental
MNPCE
micronucleated polychromatic

Industrial Hygienists

erythrocyte
AIC
Akaike's information criterion
MOA
mode of action
ALD
approximate lethal dosage
MTD
maximum tolerated dose
ALT
alanine aminotransferase
NAG
N-acetyl-P-D-glucosaminidase
AST
aspartate aminotransferase
NCEA
National Center for Environmental
atm
atmosphere

Assessment
ATSDR
Agency for Toxic Substances and
NCI
National Cancer Institute

Disease Registry
NOAEL
no-observed-adverse-effect level
BMD
benchmark dose
NTP
National Toxicology Program
BMDL
benchmark dose lower confidence limit
NZW
New Zealand White (rabbit breed)
BMDS
Benchmark Dose Software
OCT
ornithine carbamoyl transferase
BMR
benchmark response
ORD
Office of Research and Development
BUN
blood urea nitrogen
PBPK
physiologically based pharmacokinetic
BW
body weight
PCNA
proliferating cell nuclear antigen
CA
chromosomal aberration
PND
postnatal day
CAS
Chemical Abstracts Service
POD
point of departure
CASRN
Chemical Abstracts Service Registry
PODadj
duration-adjusted POD

Number
QSAR
quantitative structure-activity
CBI
covalent binding index

relationship
CHO
Chinese hamster ovary (cell line cells)
RBC
red blood cell
CL
confidence limit
RDS
replicative DNA synthesis
CNS
central nervous system
RfC
inhalation reference concentration
CPN
chronic progressive nephropathy
RfD
oral reference dose
CYP450
cytochrome P450
RGDR
regional gas dose ratio
DAF
dosimetric adjustment factor
RNA
ribonucleic acid
DEN
diethylnitrosamine
SAR
structure activity relationship
DMSO
dimethylsulfoxide
SCE
sister chromatid exchange
DNA
deoxyribonucleic acid
SD
standard deviation
EPA
Environmental Protection Agency
SDH
sorbitol dehydrogenase
FDA
Food and Drug Administration
SE
standard error
FEVi
forced expiratory volume of 1 second
SGOT
glutamic oxaloacetic transaminase, also
GD
gestation day

known as AST
GDH
glutamate dehydrogenase
SGPT
glutamic pyruvic transaminase, also
GGT
y-glutamyl transferase

known as ALT
GSH
glutathione
SSD
systemic scleroderma
GST
glutathione-S-transferase
TCA
trichloroacetic acid
Hb/g-A
animal blood-gas partition coefficient
TCE
trichloroethylene
Hb/g-H
human blood-gas partition coefficient
TWA
time-weighted average
HEC
human equivalent concentration
UF
uncertainty factor
HED
human equivalent dose
UFa
interspecies uncertainty factor
i.p.
intraperitoneal
UFh
intraspecies uncertainty factor
IRIS
Integrated Risk Information System
UFS
subchronic-to-chronic uncertainty factor
IVF
in vitro fertilization
UFd
database uncertainty factor
LC50
median lethal concentration
U.S.
United States of America
LD50
median lethal dose
WBC
white blood cell
LOAEL
lowest-observed-adverse-effect level


iv	1,1,2-Trichloro-1,2,2-trifluoroethane

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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
1,1,2-TRICHLORO-1,2,2-TRIFLUOROETHANE (CASRN 76-13-1)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (http://www.epa.gov/iris). the respective PPRTVs are
removed from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVs
Questions regarding the content of this PPRTV assessment should be directed to the EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center (513-569-7300).
1
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INTRODUCTION
l,l,2-Trichloro-l,2,2-trifluoroethane, CASRN 76-13-1, also known as
chlorofluorocarbon 113 (CFC-113) and Freon 113, is currently used as an intermediate for
producing halogenated vinyl resins. Throughout this document, the chemical name is
abbreviated as CFC-113. Former domestic uses include as a dry cleaning solvent, as a
degreasing agent for cleaning semiconductor wafers and printed circuit boards, as a refrigerant in
centrifugal compressor systems for water or brine chilling, as an organic tracer in hydrology, and
as a foaming or blowing agent in the manufacture of flame-retardant polymers (HSDB. 2013).
CFC-113 is regulated under the Clean Air Act (CAA), the Toxic Substances Control Act (TSCA)
Sections 8a and 8d, the Emergency Planning and Community Right-to-Know Act (EPCRA)
Section 313, the Federal Insecticide, Fungicide, and Rodenticide Act-Inerts (FIFRA-Inerts), and
the Resource Conservation and Recovery Act (RCRA) (U.S. EPA 2015).
The molecular formula for CFC-113 is C2CI3F3 (see Figure 1). Table 1 provides
physicochemical properties for CFC-113. CFC-113 is a volatile, colorless liquid. Its high vapor
pressure and high estimated Henry's law constant indicate that it will rapidly volatilize from both
dry and moist surfaces. CFC-113 is virtually inert to reaction with photochemically generated
radicals in the troposphere. However, if CFC-113 elevates to the stratosphere, it will react with
ultraviolet radiation to release chlorine and cause ozone depletion (U.S. EPA, 2012b). It is
expected to contribute to radiative forcing of the climate at magnitudes somewhat less than
carbon dioxide and methane and somewhat more than nitrous oxide (U.S. EPA 2012b). The
moderate water solubility and moderate soil adsorption coefficient of CFC-113 indicate that it
may leach to groundwater or undergo runoff after a rain event if deposited on soil. As a result,
removal of CFC-113 from soil by leaching with water may compete with volatilization,
depending on the local conditions (wet, dry, etc.).
CI
CI	
1
F CI
Figure 1. l,l?2-Trichloro-l,2,2-trifluoroethane (CFC-113) Structure
2
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Table 1. Physicochemical Properties of l,l92-Trichloro-l,2,2-trifluoroethane
(CASRN 76-13-1)
Property (unit)
Value
Physical state
Clear, colorless liquid3
Boiling point (°C)
47.7a-b
Melting point (°C)
-35.03
Density (g/cm3 at 25 °C)
1.564b
Vapor pressure (mm Hg at 25 °C)
362.5a
pH (unitless)
NV
pKa (unitless)
NV
Solubility in water (mg/L at 25 °C)
170a,b
Octanol-water partition constant (log Kow)
3.16^
Henry's law constant (atm-m3/mol at 20°C)
0.53 (estimated)3,13
Relative vapor density (air = 1)
6.5b
Molecular weight (g/mol)
187.38a,b
"U.S. EPA (2012b).
bHSDB (2013).
NV = not available.
A summary of available toxicity values for CFC-113 from EPA and other
agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for l,l?2-Trichloro-l,2,2-trifluoroethane
(CASRN 76-13-1)
Source
(parameter)ab
Value (applicability)
Notes
Reference
Noncancer
IRIS (RfD)
30 mg/kg-d
Based on route-to-route extrapolation from study
showing no adverse effects observed in humans
occupationally exposed at 5,358 mg/m3 for 2.77 yr.
U.S. EPA (1987)
HEAST (sRfD)
3 mg/kg-d
Based on route-to-route extrapolation from study
showing decreased body weight in rats exposed by
inhalation for 24 mo.
U.S. EPA (2011)
HEAST (RfC)
30 mg/m3
Based on decreased body weight in rats exposed by
inhalation for 24 mo.
U.S. EPA (2011)
HEAST (sRfC)
30 mg/m3
Based on decreased body weight in rats exposed by
inhalation for 24 mo.
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2012a)
ATSDR
NV
NA
ATSDR (2016)
IPCS
NV
NA
IPCS (2016);
WHO (2016)
Cal/EPA
NV
NA
Cal/EPA (2014);
Cal/EPA (2016a);
Cal/EPA (2016b)
OSHA (PEL)
1,000 ppm
(7,600 mg/m3)
8-hr TWA
OSHA (2014)
NIOSH (REL)
1,000 ppm
(7,600 mg/m3)
10-hr TWA during a 40-hr work week.
NIOSH (2015)
ACGIH
(TLV-TWA)
1,000 ppm
(7,670 mg/m3)
Set to minimize the potential of narcosis, asphyxia,
cardiac sensitization, and arrhythmia.
ACGIH (2015)
Cancer
IRIS
NV
NA
U.S. EPA (2016)
HEAST
NV
NA
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2012a)
NTP
NV
NA
NTP (2014)
IARC
NV
NA
IARC (2015)
4
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Table 2. Summary of Available Toxicity Values for l,l?2-Trichloro-l,2,2-trifluoroethane
(CASRN 76-13-1)
Source
(parameter)ab
Value (applicability)
Notes
Reference
Cal/EPA
NV
NA
Cal/EPA (20 ID:
Cal/EPA (2016a):
Cal/EPA (2016b)
ACGIH (WOE)
A4; not classifiable as
a human carcinogen
Tumors in test animals were concluded to be not
dose-related.
ACGIH (2015)
"Sources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Research; Cal/EPA = California Environmental Protection Agency; DWSHA = Drinking
Water Standards and Health Advisories; HEAST = Health Effects Assessment Summary Tables;
IARC = International Agency for Research on Cancer; IPCS = International Programme on Chemical Safety;
IRIS = Integrated Risk Information System; NIOSH = National Institute for Occupational Safety and Health;
NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration.
Parameters: PEL = permissible exposure level; REL = recommended exposure limit; sRfC = subchronic reference
concentration; sRfD = subchronic reference dose; TLV = threshold limit value; TWA = time-weighted average;
WOE = weight of evidence.
NA = not applicable; NV = not available.
Non-date-limited literature searches were conducted in February and September 2016 for
studies relevant to the derivation of provisional toxicity values for
l,l,2-trichloro-l,2,2-trifluoroethane (CASRN 76-13-1). Searches were conducted using
U.S. EPA's Health and Environmental Research Online (HERO) database of scientific literature.
HERO searches the following databases: PubMed, ToxLine (including TSCATS1), and Web of
Science. The following databases were searched outside of HERO for health-related values:
ACGIH, ATSDR, Cal/EPA, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA Office of Water
(OW), U.S. EPA TSCATS2/TSCATS8e, NIOSH, NTP, and OSHA.
REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide overviews of the relevant noncancer and cancer databases for
CFC-113, respectively, and include all potentially relevant acute, repeat-dose short-term-,
subchronic-, and chronic-duration studies as well as reproductive and developmental toxicity
studies. Principal studies are identified in bold. The phrase "statistical significance," used
throughout the document, indicates ap-walue of < 0.05 unless otherwise specified.
5
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Table 3A. Summary of Potentially Relevant Noncancer Data for l,l?2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1)
Category3
Number of Male/Female,
Strain Species, Study
Type, Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(comments)
Notes0
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)a
Acute
experimental
2 M/0 F, human, 1.5 hr
0, 1,500, 2,500,
3,500, 4,500 ppm
(in series)
0, 11,500, 19,160,
26,820, 34,490
Deficits in complex psychomotor
tasks (manual dexterity, Short
Employment Test-Clerical, and card
sorting with auxiliary task) and
clinical signs of toxicity (loss of
concentration, drowsiness, feeling of
heaviness, effects on vision) at
>19,160 mg/m3
11,500
NA
19,160
Haskell Laboratories
(1964)
NPR
Short-term
experimental
4 M/0 F, human, 6 hr/d
(3-hr exposures twice
daily), 5 d/wk stepwise
increase in concentrations
for 3 wk
0, 500, 1,000 ppm
ADJ: 0, 958, 1,920
(in series;
1 concentration per
wk)
No significant adverse effects on
clinical signs (including
temperature, pulse, and equilibrium
assessments), hematological,
clinical chemical, and urinalysis
parameters; pulmonary function, or
psychomotor parameters
1,920
NA
NDr
Reinhardt et al. (1971)
PR
Occupational
10 M/6 F, human, low
concentration (precleaning
rooms) or high
concentration (cleaning
rooms) during 7-hr work
shifts 2 wk apart; average
of 7.8 yr of employment
64.4, 442.1 ppm
ADJ: 154, 1,059
No differences with respect to
clinical signs or cardiac function
(EKG parameters) during exposure
in workers on high-exposure days
compared to low-exposure days
1,059
NA
NDr
Eeeland et al. (1992)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data for l,l,2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1)
Category3
Number of Male/Female,
Strain Species, Study
Type, Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(comments)
Notes0
Long-term
occupational
6 M/0 F exposed, 11 M/0 F
unexposed, human, mean
duration of 2.5 yr
0, 523
ADJ: 0, 187d
No significant adverse effects on
liver function (based on clinical
chemistry); observed changes in
serum bile acid levels were of
uncertain biological significance
187
NA
NDr
Neehab et al. (1997)
PR
Long-term
occupational
50 M/0 F exposed and
50 M/0 F unexposed,
human, average of
2.77 yr
0, 699 ppm
ADJ: 0, l,440d
No significant effects with respect
to physical examinations, EKG
parameters, visual or auditory
exams, chest x-ray or timed vital
capacity, hematology, clinical
chemistry, and urinalysis
evaluations
1,440
DUB
NDr
Imtuis and Adkins
(1972)
PS, PR
Animal
1. Oral (mg/kg-d)a
Developmental
0 M/8 F, rabbits (strain not
specified), oral (not further
specified), dosing for 4 d
starting on GD 8
0, 1,000, 5,000
Does: high mortality; other effects
in exposed animals included clinical
signs of toxicity, reductions in food
and water consumption, and
decreased body weights
Pups: high number of dead pups in
high-dose group
ND
NA
NDr
Hazleton Laboratories
(1967)
(Treatment was
stopped after the
fourth dose owing to
indications of severe
toxicity)
NPR
2. Inhalation (mg/m3)a
Subchronic
20 M/20 F, S-D, rat,
whole-body inhalation,
6 hr/d, 7 d/wk, 13 wk
0, 9,928.6 ppm
HEC: 0, 19,023
No significant exposure-related
effects with respect to mortality,
clinical signs, food consumption,
body weights, hematology, clinical
chemistry or urinalysis parameters,
organ weights, or macroscopic and
microscopic examinations
19,023
NA
NDr
LPT (1976)
NPR
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Table 3A. Summary of Potentially Relevant Noncancer Data for l,l?2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1)
Category3
Number of Male/Female,
Strain Species, Study
Type, Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(comments)
Notes0
Subchronic
3 M/3 F, beagle, dog,
whole-body inhalation,
6 hr/d, 7 d/wk, 13 wk
0, 5,011.4 ppm
HEC: 0, 9,601.6
No significant exposure-related
effects with respect to mortality,
clinical signs, food consumption,
body weights, hematology, clinical
chemistry or urinalysis parameters,
heart function, organ weights, or
macroscopic and microscopic
examinations
9,601.6
NA
NDr
LPT (1976)
NPR
Subchronic
15 M/15 F, CD, rat,
whole-body inhalation,
6 hr/d, 5 d/wk, 13 wk
0,7,471, 12,414,
19,186 ppm
HEC: 0, 10,220,
16,989, 26,257
No significant, exposure-related
effects on clinical signs, body
weights or body-weight gain, organ
weight, or histopathology
26,257
NA
NDr
Haskell Laboratories
(1981)
(Tabular data in the
study report were
largely illegible)
NPR
Chronic
toxicity
100 M/100 F, Crl:CDBR
rat, whole-body inhalation,
6 hr/d, 5 d/wk for 2 yr with
interim sacrifice of
10 rats/sex/group at 1 yr
0, 2,000, 10,000,
19,000 ppm
HEC: 0, 2,740,
13,700, 26,000
Significantly decreased body weight
in females in high concentration
group throughout the study
(frequently 10-14% lower than
controls)
13,700
DUB
26,000
Trochimowicz et al.
(1988): Haskell
Laboratories (1985)
(Bacterial infection
starting in Week 59
caused mortality in all
exposure groups
(including controls);
efforts to control the
infection included
quarantine and
temporary cessation of
exposure)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data for l,l?2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1)
Category3
Number of Male/Female,
Strain Species, Study
Type, Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(comments)
Notes0
Reproductive
12 M/24 F, Alderley Park
Wistar-derived, rat,
whole-body inhalation,
6	hr/d;
5 d/wk for 10 wk
premating and 7 d/wk for
2	wk during mating (M);
5 d/wk for 3 wk premating,
7	d/wk for 2 wk during
mating, and 7 d/wk for
3	wk during gestation
(Subgroup A [F]); or
5 d/wk for 3 wk premating
and 7 d/wk for 2 wk during
mating (Subgroup B [F])
0, 5,019,
12,531 ppm
HEC: 0, 7,327,
18,292 (M)
HEC: 0, 8,586,
21,436
(Subgroup A [F])
HEC: 0, 7,968,
19,893
(Subgroup B [F])
Parental and reproductive: No
significant exposure-related effects
21,436
NA
NDr
Central Toxicol Lab
(1981b)
(Significantly
decreased numbers of
corpora lutea were
within the historical
range for this rat
strain. Significant
reductions in
implantations and
fetuses were attributed
to decreased numbers
of corpora lutea)
NPR
Developmental
0 M/24 F, Alderley Park,
rat, whole-body inhalation,
6 hr/d, GDs 6-15
0, 4,985, 12,532,
25,265 ppm
HEC: 0, 9,551,
24,011,48,407
Maternal: Decreased body-weight
gain. No significant
exposure-related effects on gravid
uterine weight, numbers of corpora
lutea, and implantations
Developmental: Dose dependent
increases in fourteenth rib. No
significant exposure-related effects
on, early or late deaths, or fetal body
weights; no gross or soft tissue
abnormalities
NDr
9,551
DUB
NA
9,551
24,011
Central Toxicol Lab
(1982)
NPR
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Table 3A. Summary of Potentially Relevant Noncancer Data for l,l?2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1)
Category3
Number of Male/Female,
Strain Species, Study
Type, Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(comments)
Notes0
Developmental
0 M/12 F, NZW, rabbit,
whole-body inhalation,
2 hr/d, GDs 8-16
0, 2,000,
20,000 ppm
HEC: 0, 1,280,
12,800
Maternal: Slight eye irritation
Developmental: No significant
effects
1,280
12,800
NA
NA
12,800
NDr
Hazleton Laboratories
(1967)
(Study limitations
included small litter
sizes and inadequate
data reporting with no
statistical analyses)
NPR
aDuration categories are defined as follows: Acute = exposure for <24 hours; short-term = repeated exposure for 24 hours to <30 days; long-term (subchronic) = repeated
exposure for >30 days <10% lifespan for humans (>30 days up to approximately 90 days in typically used laboratory animal species); and chronic = repeated exposure
for >10% lifespan for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 20021.
bDosimetry: Values are presented as ADJs (mg/kg-day) for oral noncancer effects and as HECs (mg/m3) for inhalation noncancer effects. In contrast to other repeated
exposure studies, values from animal gestational exposure studies are not adjusted for exposure duration in calculation of the ADD or HEC. The HEC from animal
studies was calculated using the equation for extra respiratory effects from a Category 3 gas (U.S. EPA. 19941: HECer = continuous concentration in mg/m3 (unadjusted
concentration for gestational exposure studies) x ratio of animal:human blood-gas partition coefficients (default value of 1 applied).
°Notes: NPR = not peer reviewed; PR = peer reviewed; PS = principal study.
dCONC (HEC) = CONC (mg/m3) x (VEho ^ VEh) x (5 days ^ 7 days); where VEho = default minute volume for human occupational exposure based on an 8-hour shift
(10 m3/day) and VEh = default human minute volume for a 24-hour day (20 m3/day) (U.S. EPA. 1994).
ADJ = adjusted daily dose: DUB = data unsuitable for BMD modeling; EKG = electrocardiogram; F = female(s); GD = gestation day; HEC = human equivalent
concentration; M = male(s); NA = not applicable; ND = no data; NDr = not determined; NZW = New Zealand white; S-D = Sprague-Dawley.
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Table 3B. Summary of Potentially Relevant Cancer Data for l,l92-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1)
Category
Number of Male/Female, Strain,
Species, Study Type, and Duration
Dosimetry3
Critical Effects
BMDL/
BMCLa
Reference
Notesb
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)a
Carcinogenicity
100 M/100 F, Crl:CDBR rat,
whole-body inhalation, 6 hr/d, 5 d/wk
for 2 yr with interim sacrifice of
10 rats/sex/group at 1 yr
0, 2,000, 10,000,
19,000 ppm
HEC: 0, 2,740,
13,700, 26,000
Neoplastic: pancreatic islet cell
adenomas (F) within historical control
range for this rat strain; nasal passage
tumors (not exposure-related)
NA
Trochimowicz et al.
(1988): Haskell
Laboratories (1985)
PR
"Dosimetry: The units for inhalation exposures are expressed as HECs (mg/m3).
bNotes: PR = peer reviewed.
°HECer = (ppm x MW 24.45) x (hours/day exposed 24) x (days/week exposed 7) x blood-gas partition coefficient (default value of 1 applied).
F = female(s); HEC = human equivalent concentration; M = male(s); MW = molecular weight; NA = not applicable; ND = no data.
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HUMAN STUDIES
Oral Exposures
No human experimental or occupational oral exposure studies have been identified. A
case report indicated that ingestion of an unknown quantity of CFC-113 resulted in no clinical
complications (Racon Inc. 1985).
Inhalation Exposures
The database for inhalation exposure of humans to CFC-113 consists of short-term
experimental and long-term occupational exposures to CFC-113, health hazard evaluations of
workers exposed to CFC-113 alone or as the predominant component of a mixture, case reports
of CFC-113 and/or solvent exposure, and occupational studies of chlorinated solvent exposure
(including CFC-113).
Health hazard evaluations were conducted at sites in which workers were exposed to
CFC-113 (alone or as the predominant component of a mixture). With one exception (workers
evaluated at the Kennedy and Johnson Space Centers), measured levels of CFC-113 were below
occupational standards set by OSHA (7,600 mg/m3). Therefore, signs reported by workers
(including drowsiness, dizziness, headaches, chest pain, nausea, chills, fainting, and nasal, eye,
and/or respiratory irritation) were not attributed to CFC-1 13 exposure (NIOSH. 1983. 1981.
1979). In the individual cases in which CFC-1 13 exposures were below 8-hour time-weighted
average (TWA) occupational standards (mean exposures of 274 and 271 ppm [-2,100 mg/m3],
but short-term exposure exceeded OSHA short-term exposure limit of 1,250 ppm
[-9,600 mg/m3]), no significant cardiac dysrhythmias or changes in cardiac activity were
observed (NIOSH. 1991).
Several case reports of acute inhalation exposure in workers exposed to CFC-113 were
located; effects included death (attributed to cardiac arrhythmia/arrest and/or asphyxiation) to
clinical signs (difficulty breathing, pain, paresthesia, and weakness in legs), neuropathy (based
on decreased motor nerve conduction velocity), and psychological impairments (deficits in
learning and memory) (Voge. 1997; Kaufman et al.. 1994; Mcgee et ai. 1990; NIOSH. 1989;
Rasmussen et ai. 1988; NIOSH. 1986; Clark et al.. 1985; May and Blotzer. 1984; Raffi and
Violante. 1981). "Parkinson-like" symptoms of motor dysfunction were described in a woman
chronically exposed to vapors of CFC-1 13 and nitromethane (Sandvk and Gill man. 1984). A
female worker exposed to CFC-113 and a wide range of other solvents over a 10-year period
developed a scleroderma-like disease (Altomonte et al.. 1996).
Several studies have reported associations between occupational exposure to chlorinated
solvents (e.g., among metal degreasers, jet engine mechanics, etc, exposed predominantly to
CFC-113, trichloroethylene [TCE], and other solvents) and effects on the liver (Rasmussen et al..
1993a). kidney (increased activity of/V-acetyl glucosaminidase [NAG] in the serum or urine)
(Rasmussen et al.. 1993a; Brogren et al.. 1986). and nervous system (symptoms consistent with
"psychoorganic syndrome" [characterized as mild dementia with impairments in cognitive
function, personality changes, and decreased motivation/initiative] and neurobehavioral effects)
(Kilburn. 1999; Rasmussen et al.. 1993b. c; Rasmussen and Sabroe. 1986). Because exposures
were based on total chlorinated solvents, no conclusions can be drawn with respect to these
effects and CFC-113 exposure alone.
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Two experimental studies (Reinhardt et aL 1971; Haskell Laboratories. 1964) and four
occupational studies (Neghab et aL 1997; Egeland et aL 1992; Triebig and Burkhardt 1978;
Imbus and Adkins. 1972) evaluated the effects of CFC-1 13 exposure in humans. Only limited
data are available from Triebig and Burkhardt (1978) because the study report is written in
German; the English abstract indicates that the investigators observed no significant changes in
clinical chemistry endpoints in 3 men and 10 women exposed to CFC-113 at workplace
concentrations of 13-111 ppm (100-900 mg/m3). The remaining studies are discussed below.
Experimental Studies
Haskell Laboratories (1964)
In an unpublished study, volunteers (two males) were exposed to CFC-113 (with no
detectable impurities) as a vapor at 0, 1,500, 2,500, 3,500, and 4,500 ppm (presumably in series,
but not explicitly specified). These concentrations are equivalent1 to 0, 11,500, 19,160, 26,820,
and 34,490 mg/m3. Some additional tests were also reportedly conducted at 4,000 ppm
(30,660 mg/m3). Prior to and following each exposure to CFC-113, control (air-only) exposures
were performed. The total duration of exposure was 2.75 hours (45 minutes for chamber
concentrations to reach desired levels, an additional 30 minutes for equilibrium [between the
chamber atmosphere and the subjects' tissues] to be reached, and the effective exposure duration
[with respect to constant CFC-113 exposure] of 1.5 hours). Clinical signs of toxicity were
monitored regularly (time points were not specified). Twice during each exposure, subjects were
evaluated in a series of performance tests, including the Crawford Small Parts Dexterity Test, the
Short Employment Test-Clerical (SET clerical), and card sorting (with or without an auxiliary
task). Average test scores (from two tests conducted during a single exposure) were compared to
average scores for tests conducted during air-only exposures (prior to and following that
exposure). At study initiation and study termination, hematological, liver function, and
urinalysis tests were performed (not further specified).
Results were presented graphically in the study report, and represented as percent change
from control values (Haskell Laboratories. 1964). Statistical analyses were not performed. No
exposure-related effects on performance were reported at 11,500 mg/m3 (generally <10%
deviation from control values). At 19,160 mg/m3, the subjects exhibited deficits in complex
performance tests based on scores for manual dexterity, SET clerical, and card sorting with
auxiliary task tests (-5-15% lower than control values). In general, test performance scores (all
tests) decreased with increasing exposure concentration, so that at 34,000 mg/m3, scores ranged
from about 60-90% of controls. Clinical signs of toxicity (including loss of concentration,
drowsiness, feeling of heaviness in head, and slight loss of visual capabilities) were noted at the
three highest exposure concentrations (presumably 19,160, 26,820, and 34,490 mg/m3, based on
the initial concentrations tested). The authors reported no effects on clinical chemistry or
urinalysis endpoints after exposure compared to pre-exposure values (data not shown). Although
limited by the small number of subjects, lack of statistical analyses, and incomplete reporting of
study results, the results of this study suggest a no-observed-adverse-effect level (NOAEL) and
lowest-observed-adverse-effect level (LOAEL) of 11,500 and 19,160 mg/m3, respectively, for
acute exposure to CFC-113 in humans based on neurological performance tests.
'CONC (mg/m3) = CONC (ppm) x MW - 24.45
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Reinhardt et al. (1971)
Reinhardt et al. (1971) conducted a published, peer-reviewed inhalation study in which
four male human subjects were exposed on consecutive weeks to CFC-113 (99.8% purity) at 0,
500, and 1,000 ppm, 6 hours/day (3-hour exposures twice daily) for 5 days/week. These
exposure concentrations are equivalent to 0, 3,830, and 7,660 mg/m3. The exposure sessions
were conducted such that subjects were exposed to air only during the first week, 3,830 mg/m3
during the second week, and 7,660 mg/m3 during the third week. Daily duration-adjusted
concentrations were 0, 958, and 1,920 mg/m3 using the following equation:
CONCadj = CONC (mg/m3) x (6 hours ^ 24 hours). Before and after CFC-113 exposure,
subjects had a chest x-ray. Hematology (complete blood count), clinical chemistry (alkaline
phosphatase [ALP], lactate dehydrogenase [LDH], aspartate aminotransferase [AST], total
cholesterol, bilirubin, protein, lipids, albumin, globulin, albumin:globulin ratio, creatinine,
glucose, blood urea nitrogen [BUN], and uric acid) and urinalysis endpoints (not further
specified) were also evaluated. Clinical signs of toxicity and body temperature, pulse, and
equilibrium were monitored daily during exposure. Pulmonary function (measured at the end of
the day during the control week and biweekly during CFC-113 exposure periods) was assessed
by measuring carbon monoxide diffusing capacity and the fractional uptake of carbon monoxide.
Subjects completed psychomotor tests [the same tests described for Haskell Laboratories (1964),
but including a time discrimination test] twice daily during exposure.
None of the subjects reported symptoms of toxicity (such as headache, dizziness, or
drowsiness) at any CFC-1 13 concentration level (Reinhardt et al.. 1971). There were no
significant, exposure-related effects on body temperature, pulse, and equilibrium; hematological,
clinical chemistry and urinalysis endpoints; pulmonary function; or psychomotor tests due to
CFC-113 exposure. Performance on psychomotor tests improved over the course of the study;
this improvement was attributed to learning. The results of this study suggest a NOAEL of
1,920 mg/m3 in humans with short-term repeated exposure to CFC-113. A LOAEL was not
identified.
Occupational Studies
Egelandetal. (1992)
In a published, peer-re viewed study, Egeland et al. (1992) monitored cardiac activity of
16 healthy aerospace workers exposed to CFC-113 (purity not reported) while engaged in
cleaning rocket and ground support equipment in precleaning (low-exposure) and clean
(high-exposure) rooms. Workers normally rotated between the high- and low-exposure rooms
every 2 weeks; therefore, data from a worker in the clean room could be compared with data
from the same worker in the precleaning room. Air samples from the breathing zone were
collected using a charcoal tube personal sampler worn by exposed workers (n = 16) during work
hours (samples collected for periods ranging from 30-60 minutes). The mean 7-hour TWA
exposure was 64.4 ± 59.5 ppm (range = 0-200 ppm) on the low-exposure day and
442.1 ± 300.2 ppm (range = 247-1,476 ppm) on the high-exposure day. The mean values for the
low and high exposures are equivalent to 493 and 3,388 mg/m3, respectively. The subjects
(10 males and 6 females; mean age = 41.7 years; average length of employment = 7.8 years)
were simultaneously monitored using ambulatory electrocardiograms (EKGs) for about
7 hours/day. The EKG data collected included the rate of ventricular premature beats (VPBs),
supraventricular premature beats (SPVBs), A-V block, t-wave inversion, ST segment depression,
fluctuations in heart rate, and length of P-R interval. Data regarding smoking, caffeine intake,
medication usage, and symptoms during monitoring days were collected.
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There were no differences between EKG data during low and high exposures, and no
symptoms (palpitations, dizziness, lightheadedness) of exposure were reported (Egeland et aL
1992). Although one individual exhibited sinus rhythm bradycardia for <15 minutes during a
high-exposure day (short-term exposures up to 600 ppm or 4,600 mg/m3), similar EKG patterns
were observed in a different worker with ST segment depression on both low- and high-exposure
days. This study found no effect of exposure to CFC-113 on cardiac activity. The unusual study
design suggests a NOAEL of 3,388 mg/m3 for acute (7-hour) exposure to CFC-113 relative to
baseline exposure among chronically exposed workers. A LOAEL was not identified. The
7-hour	mean exposure concentration of 3,388 mg/m3 was adjusted to 1,059 mg/m3 using the
following equation: CONCadj = CONC (mg/m3) x (VEho ^ VEh) x (7 hr ^ 8 hr) x
(5 days ^ 7 days); where VEho = default minute volume for human occupational exposure based
on an 8-hour shift (10 m3/day) and VEh = default human minute volume for a 24-hour day
(20 nrVday) (U.S. EPA. 1994).
Neghab et al. (1997)
Neghab et al. (1997) examined potential liver effects in workers of an Australian steel
company exposed to CFC-113 (purity not reported) compared to unexposed office workers at the
same company in a published, peer-reviewed study. The exposed workers included 4-6 males
averaging 29 years of age (range = 21-41 years) with a mean duration of employment of
2.5 years (range = 0.1-4 years). Solvent concentrations in the breathing zone were measured
using a charcoal tube personal sampler worn by exposed employees during work hours. The
8-hour	TWA exposure was 68.2 ± 12.6 ppm (range 45-118 ppm), which is equivalent to
523 mg/m3. Blood samples were collected from fasting subjects before starting work on Monday
and Friday to collect pre-exposure and postexposure samples (respectively). Blood samples
were also taken prior to work on Monday from unexposed participants (11 males averaging
35 years of age [range = 22-44 years]). Blood was collected for clinical chemistry evaluations
(ALP, AST, alanine aminotransferase [ALT], y-glutamyl transferase [GGT], 5'-nucleotidase,
albumin, protein, globulin, individual serum bile acids, and total serum bile acids).
Exposed workers showed significantly increased serum concentrations of individual and
total serum bile acids relative to controls (see Table B-l). The study authors reported that bile
acid levels returned to normal 2 weeks after cessation of exposure (data not available). The
researchers suggested that increased bile acid levels may be indicative of exposure, but that no
pathological sequelae or other manifestations of liver injury were likely to be observed in
combination with this effect. Chronic occupational exposure to low concentrations of
chlorinated aliphatic hydrocarbon solvents such as trichloroethylene also appears to alter
cholesterol metabolism in the absence of noticeable hepatocellular damage, as evidenced by lack
of increase in serum liver transaminases (Nagava et al.. 1993). Similarly, serum concentrations
of total and individual bile acids were significantly elevated in a group of workers exposed to
trichloroethylene (Neghab et al.. 1997). Similar alterations in bile acid status have been
observed in experimental animals exposed to trichloroethylene and its metabolites. Because no
association was observed between elevated plasma bile acids and conventional markers of liver
injury, it was concluded that this perturbation in bile acid homeostasis could be indicative of
early changes in liver function independent of hepatocellular damage (NRC. 2006). Therefore,
significant increases in bile acid levels alone after exposure to CFC-113 were not defined as
adverse.
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There were no significant changes in other clinical chemistry endpoints. Therefore, this
study identifies a NOAEL of 523 mg/m3 for long-term occupation exposure to CFC-113. A
LOAEL was not identified. The mean exposure concentration of 523 mg/m3 was adjusted to
187 mg/m3 using the following equation:
CONCadj = CONC (mg/m3) x (VEho ^ VEh) x (5 days ^ 7 days); where VEho = default minute
volume for human occupational exposure based on an 8-hour shift (10 m3/day) and VEh = default
human minute volume for a 24-hour day (20 nrVday) (U.S. EPA. 1994).
Imbus andAdkins (1972)
In a published cross-sectional study, clinical and laboratory examinations were performed
on a group of 50 male workers occupationally exposed to CFC-113 in three clean rooms at
Kennedy Space Center, Florida, and the results compared to those of 50 unexposed male workers
(Imbus and Adkins. 1972). Air samples (// = 161) were collected over a 3-week period and
analyzed by gas chromatography. Personal sampling methods were not used. The measured
concentrations of CFC-113 in the three clean room areas ranged from 46-4,780 ppm
(median = 435 ppm or 3,330 mg/m3), with a mean concentration of 699 ppm (equivalent to
5,360 mg/m3). The mean concentration was reported as 699 ppm in the text of the study report
and 669 ppm (5,130 mg/m3) in an accompanying figure. Because there were no significant
exposure-related effects observed in this study, a higher value of 699 ppm is selected as the
exposure concentration. Fifty male employees, who had worked in the clean rooms for an
average of 2.77 years (maximum duration 4.5 years), were randomly selected as the exposed
subjects. The average time of exposure to CFC-113 was 6 hours per day. The average age of the
exposed and unexposed employees was 34 years (range = 23-51) and 37 years (range = 25-63),
respectively. Additional details were not provided about the unexposed subjects. The
examination of each subject included a complete history, complete physical examination, EKG
taken while the subjects were at rest, visual profile, audiometry, chest x-ray, and timed vital
capacity. Blood was collected for hematology (complete blood count) and clinical chemistry
(ALP, AST, LDH, BUN, cholesterol, calcium, inorganic phosphorous, total bilirubin, albumin,
total protein, uric acid, and glucose) evaluations. Urine was collected for urinalysis, but the
specific tests were not reported.
There were no significant exposure-related differences in any evaluated physical, clinical,
or laboratory measurements between the exposed and unexposed groups (Imbus and Adkins.
1972). These data identify the mean concentration tested (5,360 mg/m3) as the NOAEL in male
workers. The mean exposure concentration of 5,360 mg/m3 was adjusted to 1,440 mg/m3 using
the following equation:
CONCadj = CONC (mg/m3) x (VEho ^ VEh) x (6 hours ^ 8 hours) x (5 days ^ 7 days); where
VEho = default minute volume for human occupational exposure based on an 8-hour shift
(10 nrVday) and VEh = default human minute volume for a 24-hour day (20 nrVday) (U.S. EPA.
1994).
ANIMAL STUDIES
Oral Exposures
The effect of oral exposure of animals to CFC-113 has been evaluated in a developmental
toxicity study in rabbits (Hazleton Laboratories, 1967). No oral subchronic- or chronic-duration
toxicity studies, reproductive toxicity studies, or carcinogenicity studies have been identified.
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Developmental Studies
Hazleton Laboratories (1967)
In a poorly reported study summary, pregnant rabbits (eight/group; strain not reported)
were orally (route not further specified) administered Freon TF (CFC-113) at 0, 1,000, or
5,000 mg/kg-day beginning on Gestation Day (GD) 8. Owing to indications of severe toxicity,
dosing was stopped after 4 days. Substantial mortality occurred during dosing; two and
three animals treated at 1,000 and 5,000 mg/kg-day died, respectively. The death of a single
control animal (prior to the dosing period) was attributed to mucoid enteritis. Clinical signs of
toxicity including increased docility at 1,000 mg/kg-day and marked reductions in food and
water consumption and body weights at 5,000 mg/kg-day were reported (data not shown).
Necropsies performed on CFC-113-treated animals that died during the dosing period showed
discoloration of the lungs (not further described). For does that survived the dosing period
(including one animal/CFC-113 treatment group that died in the postdosing period), data with
respect to pregnancy status and litter size (including numbers of live and dead pups) were
reported on an individual basis only. In general, pregnancy rates were low (3-6 pregnant/group)
in all treatment groups (including controls; pregnancy status was not determined for animal that
died on or before GD 8). Three to five litters were produced at each dosage level, and does from
each treatment group delivered live young. The total numbers of live and dead pups,
respectively, were 21 and 3 at 0 mg/kg-day, 32 and 0 at 1,000 mg/kg-day, and 12 and 20 at
5,000 mg/kg-day (statistical analyses for these data were not performed). Although the study
authors concluded that it was not possible to determine whether maternal deaths were due to the
test substance or to the dosing technique, no control animals died during the dosing period. No
effect levels were derived for this study due to poor reporting and inadequate study design and
execution.
Inhalation Exposures
The effects of inhalation exposure of animals to CFC-113 were evaluated in three
13-week sub chronic-duration toxicity studies, including two "tolerance" studies in rats and dogs
exposed to a single concentration of CFC-1 13 (LPT. 1976. 1975) and one study in rats using
multiple exposure concentrations (Haskell Laboratories. 1981). one chronic
toxicity/carcinogenicity study in rats (Trochimowicz et ai. 1988). a one-generation reproductive
toxicity study in rats (Central Toxicol Lab. 1981a). and two developmental studies in rats and
rabbits (Central Toxicol Lab, 1982; Hazleton Laboratories, 1967).
Subchronic-Duration Studies
LPT (1976)
In an unpublished study, Sprague-Dawley (S-D) rats (20/sex/group) were exposed
whole-body to CFC-113 (unknown purity) at 0 and 9,928.6 ppm, 6 hours/day, 7 days/week for
90 days. These concentrations are equivalent to 0 and 76,091 mg/m3. The animals were
monitored daily for mortality and clinical signs of toxicity. Food consumption was also
measured daily; water intake was monitored regularly (but not quantified). Body weights were
recorded weekly. At study termination, hematology (total and differential white blood cell
[WBC], red blood cell [RBC], reticulocyte [Ret], platelet counts [PLAT], hemoglobin [Hb],
hematocrit [Hct], methemoglobin [MetHb], Heinz bodies, and clotting time); clinical
biochemistry (glucose, BUN, total protein, total bilirubin, sodium, potassium, calcium, chloride,
uric acid, albumin, globulin, creatinine, total cholesterol and lipids, ALT, AST, ALP, and
bromsulphathalein liver function test); and urinalysis (color, specific gravity, protein, glucose,
bilirubin, hemoglobin, ketone bodies, pH, and sedimentation) were evaluated. A limited number
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of clinical biochemistry endpoints (serum glucose, BUN, and ALT and ALP activities) were also
evaluated at earlier time points (prior to exposure, and after 7 days and 6 weeks of exposure).
Prior to necropsy, the animals were subjected to ophthalmology exams and tests of auditory
acuity; dentition was also inspected. All animals underwent necropsy; organ weights (heart,
lungs, liver, spleen, kidney, adrenal, thymus, pituitary, thyroid, brain, and gonads) were
recorded. Histopathology (27 tissues) was performed (10 rats/sex/group). Statistical analyses
were conducted at a significance level ofp < 0.01.
No mortality or clinical signs of toxicity were reported (LPT, 1976). There were no
significant exposure-related effects on food consumption, body weights, hematology, clinical
chemistry, or urinalysis. Clinical examinations performed just prior to sacrifice did not show any
irregularities. Organ weights of exposed rats were not significantly different from controls.
Macroscopic and microscopic examinations of the tissues did not identify any lesions related to
CFC-113 exposure. Although there are study limitations (only one concentration was tested); the
study data identify a NOAEL of 76,091 mg/m3, the only dose tested. No LOAEL was identified.
The exposure concentration of 76,091 mg/m3 was adjusted for discontinuous exposure and
converted to a human equivalent concentration (HEC) of 19,023 mg/m3 for extrarespiratory
effects2.
LPT (1975)
In a similarly designed study (unpublished), beagle dogs (three/sex/group) were exposed
to CFC-113 (unknown purity) at 0 and 5,011.4 ppm, 6 hours/day, 7 days/week for 90 days.
These concentrations are equivalent to 0 and 38,406 mg/m3. The same endpoints were evaluated
as in the rat study with the following modifications: (1) with the exception of a few endpoints
measured only at 13 weeks (blood methemoglobin and Heinz bodies, and serum total and free
cholesterol and fatty acids, triglycerides, total lipids, and phosphatide), all hematology, clinical
chemistry, and urinalysis evaluations, as well as clinical examinations (ophthalmology, hearing,
and dentition), were conducted prior to exposure and after 6 and 13 weeks exposure;
(2) additional evaluations with respect to hematology (blood sedimentation), clinical chemistry
(serum free cholesterol, total and free fatty acids, triglycerides, and phosphatide, glycogen in the
heart muscle and liver, and phenolsulphonphthalein plasma test of renal function); and heart
function (electrocardiography and tests of circulatory function, including diastolic and systolic
pressure, and hypertension under norepinephrine stress at 13 weeks) were performed; and (3) one
additional organ (prostate or uterus) was weighed.
No clinical signs of toxicity were reported, and no deaths occurred (LPT. 1975). There
were no significant exposure-related effects on food consumption, body weights, hematology,
clinical chemistry, urinalysis, or heart function. Clinical examinations did not show any
irregularities. Organ weights of exposed dogs were not significantly different from controls.
Macroscopic and microscopic examinations of the tissues did not identify any lesions related to
CFC-113 exposure. Although there are study limitations (one concentration tested with few
numbers of animals), these data identify the highest dose tested (38,406 mg/m3) as a NOAEL.
No LOAEL was identified. The exposure concentration of 38,406 mg/m3 was adjusted for
2HEC (mg/m3) = CONC (mg/m3) x (hours exposed ^ 24 hours) x (days exposed ^ 7 days) x ratio of blood-air
partition coefficients (U.S. EPA. 1994). In the absence of data for blood-air partition coefficients in rodents (a
predicted value is available in humans, as discussed in the "Metabolism/Toxicokinetic Studies" section), the default
ratio of 1 was applied.
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discontinuous exposure and converted to a HEC of 9,601.6 mg/m3 for extrarespiratory effects
based on the methodology described for the rat study above.
Haskell Laboratories (1981)
In another unpublished, non-peer-reviewed study, male and female CD rats
(15/sex/group) were exposed whole-body to CFC-113 (100% purity) at nominal concentrations
of 0, 7,500, 12,500, and 17,500-20,000 ppm, 6 hours/day, 5 days/week for 13 weeks. The high
concentration was changed from 17,500 to 20,000 ppm on Study Day 29 (nineteenth day of
exposure). The reported TWA concentrations in the exposure chamber were 0, 7,471, 12,414
and 19,186 ppm, respectively. These exposure concentrations are equivalent to 0, 57,260,
95,138, and 147,040 mg/m3. The rats were observed once daily for clinical signs of toxicity.
Body weights were recorded weekly. No hematology, clinical chemistry, or urinalysis endpoints
were evaluated. An interim sacrifice of five rats/sex/group was conducted on Study Day 45
(after 30 exposures); the remaining rats were sacrificed on Study Day 94 or 95 (after
63 exposures). At interim and terminal sacrifice, organ weights (brain, heart, lungs, liver, spleen,
kidneys, testes, thymus, adrenals, and pituitary glands) were recorded. Histopathological
examinations (-36 tissues) were performed for all animals in the control and high-exposure
groups.
Significant exposure-related effects are reported in Table B-2 (Haskell Laboratories.
1981). Owing to illegibility of the data tables, not all of the data for significant effects can be
reported with certainty. One female rat in the control group was sacrificed in extremis on
Day 72 (cause of death not reported). Sporadic signs of narcosis were noted at 147,040 mg/m3
(but not at lower exposure concentrations). There were no significant effects on body
weight/body-weight gain in either sex. Statistically significant changes in absolute and relative
organ weights (absolute testis weight and relative brain and lung weights in males and absolute
adrenal gland weight and relative lung and liver weights in females) were noted at interim
sacrifice (Day 45); however, these alterations were not considered to be related to CFC-113
exposure because they were sporadic in nature (not supported by an exposure-response
relationship) and did not correlate with macroscopic or microscopic findings.
At terminal sacrifice, absolute and relative lung weights were significantly increased in
male rats at 147,040 mg/m3 only. Owing to the illegibility of the data tables, the magnitude of
change in absolute lung weights cannot be quantified with certainty, but relative lung weights
appeared to be increased by about 23% in 147,040-mg/m3 males relative to controls
(see Table B-2). However, the changes in lung weights were also likely associated with
pneumonia (the incidence of which was high in exposed male rats and controls). In female rats
only, significant increases in absolute and relative adrenal weights (of 20 and 13%), respectively)
were observed at 147,040 mg/m3. Additional statistically significant changes in absolute and
relative organ weights (relative kidney weight in males; absolute and relative liver weight and
absolute spleen weight in females) at terminal sacrifice were not clearly associated with
CFC-113 exposure (i.e., an exposure-response relationship was not observed). Other than
focal/multifocal granulomatous interstitial pneumonia, noted in male rats exposed at
147,040 mg/m3, no remarkable histopathological findings were reported. The incidence of
pneumonia was 9/10 in 147,040-mg/m3 males compared to 5/10 in controls. Based on a Fisher's
exact test performed for this review, the incidence of this effect was not significantly increased in
147,040-mg/m3 males (p > 0.05) relative to controls. However, the severity of this effect tended
to be greater in the males exposed to CFC-113 (severity was not evaluated quantitatively, and no
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further information was provided in the study report). The study authors suggested that
CFC-113 exposure exacerbated an existing pneumonic condition in male rats. Although study
limitations are apparent (most notably the illegibility of the data tables and the limited number of
endpoints evaluated), a NOAEL of 147,040 mg/m3 is identified. Exposure concentrations of
57,260, 95,138, and 147,040 mg/m3 were adjusted for discontinuous exposure and converted to
respective HECs of 10,220, 16,989, and 26,257 mg/m3 for extrarespiratory effects using the
methodology described previously.
Chronic-Duration/Carcinogenicity Study
Haskell Laboratories (1985); Trochimowicz et al. (1988)
Trochimowicz et al. (1988) exposed Crl:CD(SD)BR rats (100/sex/group) whole-body to
CFC-113 (99.9% pure) at 0, 2,000, 10,000, and 19,000 ppm, 6 hours/day, 5 days/week for
24 months in a published, peer-reviewed study. Additional unpublished data from this study are
reported by Haskell Laboratories (1985). The tested exposure concentrations are equivalent to 0,
15,300, 76,600, and 145,600 mg/m3. The animals were examined for mortality and clinical signs
of toxicity twice daily Monday through Friday and once daily on weekends and holidays. Rats
were weighed and examined clinically once a week for the first 11 weeks of the study, every
2 weeks thereafter, and just prior to sacrifice. After 3, 6, 12, 18, and 24 months of exposure,
hematology (total and differential WBC, RBC, reticulocyte, platelet counts, Hb, Hct, mean
corpuscular volume [MCV], mean corpuscular hemoglobin [MCH]), clinical chemistry (ALP,
ALT, AST, GGT, BUN, bilirubin, cholesterol, creatinine, glucose, and total protein), and
urinalysis (volume, color, osmolality, pH, sediment, fluoride, blood, sugar, protein, urobilinogen,
bilirubin, and ketones) evaluations were performed (10 rats/sex/group). An interim sacrifice
(10 rats/sex/group) was conducted 12 months after study initiation. All remaining rats were
sacrificed after 24 months of exposure. All rats were subjected to necropsy. Selected organ
weights (adrenals, brain, heart, kidneys, liver, lungs, pituitary, spleen, testes, and thymus) were
recorded. Complete histopathological examinations (-33 tissues) were performed for animals
terminated in extremis, animals found dead, and animals in the control and high-exposure
groups. In addition, tissues with gross lesions and/or tissue masses and the nasal turbinates
(based on findings of nasal tumors in 76,600-mg/m3 males terminated in extremis) were
examined microscopically in rats exposed at 15,300 and 76,600 mg/m3.
During Week 59 of the study, a male in the 145,600-mg/m3 group died from a respiratory
infection caused by Corynebacterium kutscheri (Trochimowicz et al.. 1988). Although efforts
were made to control the onset and spread of infection (quarantine and cessation of exposure for
76,600- and 145,600-mg/m3 males from Weeks 61-63 [14 exposures], and tetracycline therapy
in all animals in Weeks 61-62 and 71-79), mortality as a consequence of infection was 18-35%
in males and 5-8% in females (all exposure groups, including controls), apart from mortality due
to unrelated causes (see Table B-3). Data for these animals were excluded from subsequent
analyses. Causes of mortality unrelated to bacterial infection were not reported. No clinical
signs of toxicity attributed to exposure were observed. The mean body weights of male and
female rats exposed at 145,600 mg/m3 and females exposed at 76,600 mg/m3 were statistically
significantly decreased relative to controls; however, the body weights of males were within
about 3-9%) of the values for control males throughout the exposure period (based on weekly
body weights provided in the unpublished report). In females, body weights at interim sacrifice
were decreased by 11 and 14% at 76,600 and 145,600 mg/m3, respectively, compared to
controls. Body weights of females exposed at 145,600 mg/m3 were 10—14% lower than controls
throughout the second year of the study (body weights were typically decreased by <5% during
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the same time period in females exposed at 76,600 mg/m3). Body-weight decreases in females
were no longer evident at termination after 2 years of exposure. Other than a transient decrease
in serum glucose in 145,600-mg/m3 males (but not females) at 6 months and increased urinary
fluoride excretion (in 145,600-mg/m3 males at all time points and in 76,600- and
145,600-mg/m3 females at 3 and/or 6 months) (see Table B-4), clinical pathology tests
(hematology, clinical chemistry, and urinalysis evaluations) did not indicate any consistent,
exposure-related effects. The study authors indicated that increased urinary fluoride
concentrations might reflect a metabolism of CFC-113.
Organ weights at interim and terminal sacrifice were provided in the unpublished report
(Haskell Laboratories. 1985). After exposure for 1 year, males showed significantly increased
absolute and relative liver weight (at >15,300 mg/m3) and absolute and relative kidney weight (at
145,600 mg/m3 and >15,300 mg/m3, respectively) (see Table B-5). However, these
dose-dependent effects on organ weights were not observed in males exposed for 2 years
(see Table B-6). Females exposed for 1 year showed significantly increased absolute and
relative liver weight and relative (but not absolute) lung and spleen weights (statistically)
compared to controls at 76,600 and 145,600 mg/m3 (see Table B-5). No consistent and
significant exposure-related effects on organ weights were seen in females after 2 years of
exposure (see Table B-6). There were no findings at gross necropsy and no significant
microscopic non-neoplastic changes that appeared to be related to CFC-113 exposure. Although
significant effects on organ weights were observed at the interim sacrifice, these changes are not
considered biologically significant because they occurred in the absence of accompanying
clinical or histopathological effects indicative of organ damage, and the similar organ-weight
effects were not observed at the end of 2-year exposure. This study identifies a LOAEL of
145,600 mg/m3 in female rats based on significantly decreased body weight throughout much of
the study. The NOAEL is 76,600 mg/m3. Exposure concentrations of 15,300, 76,600, and
145,600 mg/m3 were adjusted for discontinuous exposure and converted to respective HECs of
2,740, 13,700, and 26,000 mg/m3 for extrarespiratory effects using the methodology described
previously.
There was a statistically significant increase in pancreatic islet cell adenomas in
145,600-mg/m3 females (5/86 compared to 0/85 in controls; see Table B-7). The incidence of
adenomas in females (all exposure groups) was within the normal historical background levels
for the laboratory, and no such tumors were seen in females exposed at 15,300 and
76,600 mg/m3. Although this tumor type was also seen in the males, tumors were observed at 0,
15,300, and 145,600 mg/m3 with no apparent exposure-response relationship. The study authors
also indicated that in a concurrent chronic inhalation study conducted by the authors, female
controls showed an incidence of 6 out of 95 pancreatic islet cell adenomas. Tumors of the nasal
passages were also noted in one 15,300-mg/m3 male rat and four 76,600-mg/m3 rats (three males
and one female). These tumors were not attributed to CFC-113 exposure because they were not
of the same cell type, an exposure-related response was not apparent, and there were no other
histopathological changes in nasal turbinates. Therefore, there was no adequate evidence of
carcinogenicity following inhalation exposure in this chronic rat study.
Reproductive Study
Central Toxicol Lab (1981a)
In a single-generation reproductive toxicity study that was not published or
peer-reviewed, Alderley Park Wistar rats (12 males and 24 females/group) were exposed
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whole-body to CFC-113 (measured impurities <0.4%) at 0, 5,019, or 12,531 ppm. These
exposure concentrations are equivalent to 0, 38,465, and 96,035 mg/m3. Males were exposed for
6 hours/day, 5 days/week during premating (10 weeks) and 6 hours/day, 7 days/week during
mating (up to 2 weeks). Females (Subgroups A and B) were exposed 6 hours/day, 5 days/week
for 3 weeks during premating, 6 hours/day, 7 days/week until successful mating (maximum of
2 weeks), and 6 hours/day, 7 days/week on GDs 1-20 (Subgroup A females only). All dams
were examined for mortality and clinical signs of toxicity prior to exposure, twice daily during
exposure, and every 3-4 days thereafter. Body weights and food intake were recorded prior to
study initiation, weekly during premating, and every 3-4 days after pairing (of one male with
two females); these parameters were not evaluated during mating. Males were sacrificed and
subjected to necropsy within 1 week of successful mating or the end of the 2-week mating
period. The precoital interval (time in days until positive signs of mating) was evaluated for
each male rat, and coital and pregnancy success rates were determined for each female rat. Half
of the females (Subgroup A) that showed positive signs of mating were exposed until GD 20 and
permitted to deliver; offspring were monitored until 4 weeks-of-age. For the remaining half of
females (Subgroup B), exposure was stopped after successful mating occurred, and gross
necropsies (including evaluations of the numbers of resorptions and live and dead fetuses) were
performed on GDs 17-20. Endpoints evaluated for offspring of Subgroup A females included
the duration of gestation, numbers and sex of live and dead pups per litter (monitored daily until
4 weeks-of-age), pup weights (recorded at birth and every 3-4 days thereafter), and pup
development (ages at which pinna unfolding, hair growth, eye opening, and weaning occurred).
Among Subgroup A females, only dams that: (1) did not produce litters by Day 24; (2) produced
litters that did not survive until 4 weeks-of-age; or (3) did not survive 4 weeks postpartum were
subjected to necropsy.
One 38,465-mg/m3 female from Subgroup B and one 96,035-mg/m3 female from
Subgroup A died on study (Central Toxicol Lab, 1981a). These deaths occurred on GD 12 and
on Postpartum Day 24, respectively. These animals exhibited clinical manifestations of toxicity
(blood stains on whiskers and/or nose, hunched posture), decreased body weight, and/or findings
at gross necropsy (resorbed fetuses or regressed corpora lutea, macroscopic kidney and bladder
effects). However, no clinical signs of toxicity were reported in the surviving animals. No
consistent, exposure-related effects on body weights or body-weight gains were observed.
Statistically significant reductions in food consumption (9-13% lower than controls) were
occasionally observed in 96,03 5-mg/m3 females (during the first week of premating and on
GDs 12/13 and 19/20 for Subgroup A females). No postmortem findings were reported in males.
There were no significant effects on precoital interval (males) or coital and pregnancy success
rates (females) among CFC-113-exposed rats and controls.
Females in Subgroup A (permitted to deliver) showed no statistically significant effects
on the duration of gestation, mean litter size, sex of pups, percent pup mortality, or lactation
index (defined as the number of pups alive at Day 28 ^ number alive at Day 4) (Central Toxicol
Lab, 1981a). No significant effects on fetal body weights or fetal development were observed.
One control female (Subgroup A) was subjected to necropsy on Postnatal Day (PND) 7, owing to
the death of all of its pups by PND 6; the study authors attributed these deaths to impaired
lactation. No remarkable findings attributed to CFC-113 exposure were identified in five
additional Subgroup A females (two controls, two dams exposed at 38,465 mg/m3, and one dam
exposed at 96,035 mg/m3) subjected to necropsy because they failed to produce litters by
Day 24.
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In females exposed to CFC-113 and subjected to necropsy after successful mating
(Subgroup B), there were no significant exposure-related effects on pre- or postimplantation loss
(Central Toxicol Lab. 1981a). Subgroup B females exposed at 96,035 mg/m3 and examined on
GDs 17-20 showed statistically significant reductions in the mean numbers of implantations,
corpora lutea, and fetuses (12-14% lower than controls; [see Table B-8]). While the numbers of
corpora lutea and implantations were not evaluated in Subgroup A females, there was no
significant effect on litter size (i.e., the number of fetuses) in Subgroup A females, which, by
virtue of being exposed during gestation, were more exposed to CFC-113 than Subgroup B
females. Moreover, the study authors indicated that the numbers of corpora lutea, while
statistically significantly decreased, were within the overall range for this strain of rat (citing a
range of 11.67-14.26 based on studies conducted by the study authors since 1979). Reductions
in the numbers of implantations and fetuses were considered by the authors to be downstream
effects of decreased numbers of corpora lutea.
Several study deficiencies are noted: (1) only two exposure levels were evaluated;
(2) only half of the females on study (Subgroup A) were exposed during gestation; (3) no
females were exposed to CFC-113 during the postpartum period; (4) necropsies were not
performed on Subgroup A females or their offspring (precluding an assessment of the
consistency of effects observed in Subgroup B females and in Subgroup A females); (5) organ
weights were not recorded and sperm parameters were not evaluated; and (6) different lots of the
test material were used throughout the study. Nonetheless, this study identifies a NOAEL of
96,035 mg/m3 for systemic and reproductive/developmental effects. The slight decrease in
number of corpora lutea observed in the 96,03 5-mg/m3 group was considered to be incidental to
treatment because the numbers were within the historical control range for this strain and
because there was no supporting effect on litter size in Subgroup A. TWA HECs for
extrarespiratory effects of 0, 7,327, and 18,292 mg/m3 for males; 0, 8,586, and 21,436 mg/m3 for
Subgroup A females; and 0, 7,968, and 19,893 mg/m3 for Subgroup B females were calculated
for this review3.
Developmental Toxicity Studies
Central Toxicol Lab (1982)
In an unpublished, non-peer-reviewed study, groups of 24 female Alderley Park rats were
exposed to CFC-113 (>99.95% purity) at 0, 4,985, 12,532, or 25,265 ppm (equivalent to 0,
38,200, 96,043, and 193,630 mg/m3), 6 hours/day on GDs 6-15. Dams were observed daily for
mortality and clinical signs of toxicity. Body weights were recorded on GDs 0 and 5 (prior to
exposure), daily after exposure (GDs 6-15), and on GDs 16, 18, and 21 (postexposure period).
Food consumption was measured on GD 1, daily on GDs 6-16, and GDs 19 and 21
(observations were based on pairs of females sharing the same food source). At necropsy on
GD 21, the following endpoints were assessed: gravid uterine weight, numbers of corpora lutea,
implantations, early and late intrauterine deaths, and fetal body weights. Live fetuses were
weighed and examined for gross external abnormalities (including cleft palate). Approximately
two-thirds of the fetuses were examined for skeletal anomalies (morphological development and
3TWA exposures were based on exposures at 0, 38,465, and 95,798 mg/m3 for 6 hours/day: 5 days/week for
10 weeks premating and 7 days/week for 2 weeks during mating (males); 5 days/week for 3 weeks premating,
7 days/week for 2 weeks during mating, and 7 days/week for 3 weeks during gestation (Subgroup A females); and
5 days/week for 3 weeks premating and 7 days/week for 2 weeks during mating (Subgroup B females).
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degree of ossification); the remaining third were stained, sexed, and examined for soft tissue
abnormalities. The litter was considered the basis for statistical tests.
Effects in maternal animals and fetuses exposed to CFC-113 are shown in Table B-9
(Central Toxicol Lab. 1982). No exposure-related mortalities were reported. Slight and transient
hyperactivity was observed in dams exposed at 193,630 mg/m3 during 9 of 13 exposure periods;
this effect subsided within 1 hour after cessation of exposure. Statistically significant reductions
in maternal body-weight gain (19-40% lower than controls) were observed during exposure
(GDs 5-15) at all exposure concentrations. Even though body-weight gains among all groups of
exposed rats were similar to controls during the postexposure period (GDs 15-21), overall
body-weight gains for 193,630-mg/m3 females (GDs 0-21) remained significantly lower than
controls (by about 10% based on data presented graphically in the study report). Only data for
body-weight gain (and not mean maternal body weights) were provided. During the exposure
period, females in the 193,630-mg/m3 group also exhibited a significant reduction in food
consumption (14% lower than controls). Thus, without the data on absolute body weight
changes, the changes in the body weight were considered biologically significant. There were no
significant and exposure-related effects on pre- or postimplantation loss, numbers of early or late
intrauterine deaths, sex of fetuses, or fetal body weights. No gross external abnormalities were
reported, and no soft tissue abnormalities attributed to CFC-113 exposure were observed.
Compared with controls, there was a significantly increased incidence of extra (fourteenth) ribs
in all groups of CFC-113-exposed rats (based on analyses for both fetuses and litters;
[see Table B-9]). The fetal incidence of vestigial ribs was significantly increased relative to
controls at >96,043 mg/m3 (based on data for left vestigial rib, and any or both vestigial ribs); the
litter incidence of an extra rib was significantly increased starting at 38,200 mg/m3 (based on
vestigial rib-any). The study authors indicated that although these changes were statistically
significant, the (fetal) incidence of this effect in all groups was approximately within the
background range (8—36%) for this variant. However, consistent dose-dependent increases
occurred at >96,043 mg/m3 based on both fetal and litter incidence.
There were skeletal variations (increased vestigial ribs) observed from exposure to
CFC-113 at >96,043 mg/m3; however, maternal toxicity occurred at all exposure levels. A
maternal NOAEL could not be established. A maternal LOAEL of 38,204 mg/m3 is identified
based on decreased body-weight gain during exposure (GDs 5-15). The developmental NOAEL
is 38,200 mg/m3 and LOAEL is 96,043 mg/m3 based on skeletal variations. Exposure
concentrations in this study were equivalent to HECs of 0, 9,551, 24,011, and 48,407 mg/m3
based the default value of 1 for the ratio of blood-air partition coefficients.
Hazelton Lab (1967)
In an unpublished, non-peer-reviewed teratogenicity study, New Zealand white (NZW)
rabbits (12/group) were exposed whole-body to CFC-113 (purity not reported) at 0, 2,000, or
20,000 ppm (equivalent to 0, 15,300, and 153,000 mg/m3), 2 hours/day on GDs 8-16. The
animals were observed daily for mortality and clinical signs of toxicity. The rabbits were
weighed weekly during gestation and at study termination. The does (five-six/group) were
sacrificed on GDs 29 or 30, and cesarean sections were performed. The developmental
endpoints evaluated in these animals included the number and placement of uterine implantation
sites; numbers of live, dead, and resorbed fetuses; and fetal weight and length, external anatomy,
and gross visceral features. The remaining does were permitted to deliver. Endpoints evaluated
included the numbers of live and dead pups, pup weight and length, and external anatomy. Does
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that failed to deliver were sacrificed starting on GD 35. All animals (does and fetuses/pups)
were subjected to necropsy, and all fetuses and pups were examined (together) for skeletal
abnormalities (including relative differences in size, location, normal or abnormal structure or
formation, degree of ossification, and presence or absence of bone structure). Statistical analyses
were not performed.
One doe exposed at 153,000 mg/m3 was found dead on GD 20 (Hazelton I.ab. 1967).
Examination of the uterine contents of this animal revealed seven resorption sites (right uterine
horn) and no implantation sites (left uterine horn). Additionally, a 153,000-mg/m3 female
aborted two dead pups (one of which was reportedly partially mutilated) on GD 29. Although
the cause of death was not reported, the study authors did not attribute the death (or abortion) to
CFC-113 exposure. Slight eye irritation (during exposure only) was noted in all rabbits at
153,000 mg/m3 (and no animals exposed at 0 or 15,000 mg/m3). The mean body weights of
CFC-113 exposed rabbits remained within 10% of controls throughout the study (including the
time points encompassing exposure [on GDs 8 and 15]). Fertility was low in all groups,
including controls (four, four, and seven does exposed at 0, 15,300, and 153,000 mg/m3,
respectively, became pregnant). Although the numbers of litters evaluated were small (one to
three litters/group, counting the cesarean and natural born litters separately), there were no
significant exposure-related effects on parameters examined at cesarean section or after natural
delivery. Various findings were noted at gross necropsy of does and fetuses/pups; the most
notable of these effects (owing to incidences that possibly correlate with exposure levels) was
pale kidneys in two offspring exposed at 15,300 mg/m3 and six offspring exposed at
153,000 mg/m3. However, the number of total fetuses/pups examined for these effects at each
exposure level is unclear. Based on data for skeletal abnormalities, it appears that as many as 38,
27, and 43 fetuses were examined at 0, 15,300, and 153,000 mg/m3, respectively, (the mutilated
fetus mentioned previously, and one dead control fetus and one dead 15,300-mg/m3 fetus [both
too small for analyses] were excluded). No significantly increased incidences of visceral or
skeletal abnormalities were observed in exposed fetuses/pups compared to controls. The study
appears to identify a NOAEL of 15,300 mg/m3 and LOAEL of 153,000 mg/m3 for maternal
effects, based on slight eye irritation. The high concentration of 153,000 mg/m3 appears to be a
NOAEL for fetal effects. Limitations of the study include short daily exposure durations, small
group sizes, poor reporting, and no statistical analyses. Exposure concentrations in this study
were equivalent to HECs of 0, 1,280, and 12,800 mg/m3 based on the default value of 1 for the
ratio of blood-air partition coefficients. No adjustment for discontinuous exposure was made
because this was a developmental toxicity study.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Tests Evaluating Genotoxicity and/or Mutagenicity
Only a few genotoxicity tests of CFC-113 have been conducted (see Table 4). Tests of
mutagenicity in bacteria have produced negative results with or without metabolic activation at
concentrations up to 20% as a vapor (Benigni et aL 1991; Hoeehst-Celanese. 1989; Longstaff.
1988; Longstaff et al., 1984; Haskell Laboratories, 1977; Simmon et aL 1977; Haskell
Laboratories. 1976). Dominant lethal mutations were not induced in mice administered a single
intraperitoneal (i.p.) dose of CFC-1 13 at up to 1,000 mg/kg during pregnancy (Epstein et aL.
1972).
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Table 4. Summary of l,l?2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results without
Activation3
Results with
Activation3
Comments
References
Genotoxicity studies in prokaryotic organisms
Mutation
Salmonella typhimurium strains TA1535,
TA1537, TA100, and TA98
0, 2, 6, 10, 19%
vapor


Vapor exposure chamber assay,
48-hr exposure. Positive and
negative controls responded
appropriately. Toxicity evidenced
by thinning of background lawn
was seen in TA98 at
concentrations >2% in a second
trial; no toxicity observed in first
trial.
Benieni et al.
(1991): Lonestaff
et al. (1984):
Haskell
Laboratories
(1977); Simmon
et al. (1977)
Mutation
S. typhimurium strains TA1535, TA1537,
TA1538, TA100, and TA98
0, 4.6-4.8,
12.0-13.4% vapor


Vapor exposure chamber assay,
6-hr exposure.
Haskell
Laboratories
(1976)
Mutation
S. typhimurium strains TA1537, TA1535,
TA100, and TA98
0, 10% vapor
—
—
Vapor exposure chamber assay,
48-hr exposure.
Hoechst-Celanese
(1989)
Mutation
S. typhimurium strains TA1535 and TA100
Not specified; up
to 10% (TA1535)
and 20% vapor
(TA100)
(The study
authors did not
indicate whether
metabolic
activation
system was
used.)
(The study
authors did not
indicate
whether
metabolic
activation
system was
used.)
Vapor exposure chamber assay,
72-hr exposure. The ratios of
test/control reversion frequencies
were 2.0 and 1.3 forTA1535 and
TA100, respectively.
Lonestaff (1988)

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Table 4. Summary of l,l?2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results without
Activation3
Results with
Activation3
Comments
References
Genotoxicity studies—in vivo
Dominant
lethal
mutagenicity
7-9 males, ICR/Ha Swiss mice were
administered a single dose of CFC-113 (in
either water or tricaprylin) via i.p. injection.
Treated males were mated with untreated
virgin females for 8 consecutive wk after
treatment. Females were sacrificed 13 d
after the midweek of their presumptive
mating, and scored for percent pregnancy,
total implants, and early fetal deaths per
pregnancy.
200, 1,000 mg/kg


No treated male mice died.
Pregnancy parameters were within
control limits, showing no
evidence of dominant lethal
mutation.
Epstein et al.
(1972)
a- = negative.
i.p. = intraperitoneal
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Acute Toxicity Studies
The acute inhalation and oral toxicity of CFC-113 is generally low.
•	The 4-hour inhalation median lethal concentration (LC50) values in rats range from
295,000-464,000 mg/m3 (Haskell Laboratories. 1973; PRL. 1973; Haskell
Laboratories. 1971b).
•	The 2-hour inhalation LC50 in rabbits is 456,000 mg/m3 (Hazleton Laboratories.
1967). An LC50 was not reported in guinea pigs, but deaths (of "several" animals)
were reported at 383,000 and 728,000 mg/m3 2-3 days after exposure (Eastman
Kodak. 1971).
•	The oral median lethal dose (LD50) in rats is 43,000 mg/kg (Haskell Laboratories,
1978; Eastman Kodak, 1971).
•	The oral LD50 in guinea pigs is >10,000 mg/kg (Dow Chemical Company, 1949).
Clinical signs of toxicity from CFC-113 exposure (via inhalation) included labored or
irregular respiration, excitability, anesthesia, dyspnea, tremors, convulsions, loss of coordination,
hyperemia, and prostration (Haskell Laboratories, 1992. 1975a. b, 1973; PRL. 1973; Huntingdon
Research Center. 1972; Eastman Kodak. 1971; Haskell Laboratories. 1971b; Hazleton
Laboratories, 1967; Haskell Laboratories, 1961). Pathology findings were rarely identified and,
when reported, were mostly limited to the animals that died. Effects consisted of bronchial
obstruction, thymus congestion, and pulmonary congestion, edema, and/or hemorrhage (PRL,
1973; Hazleton Laboratories, 1967; Haskell Laboratories, 1954).
Short-Term Studies
Carter et al. (1970)
In 14-day studies, rhesus monkeys (4 females/group), dogs (8 females/group), rats
(50 males/exposed group and 25 control males), and mice (40 males/exposed group and
20 control males) were exposed to CFC-113 whole-body at 0 or 2,000 ppm (15,300 mg/m3).
Other than minimal effects on the thyroid glands (enlarged in monkeys) and kidney weight
(increased in rats), which were not clearly associated with exposure, no effects on mortality,
clinical signs of toxicity, body weights, hematology and clinical chemistry (endpoints not
specified), relative organ weights (not specified), or electroencephalographic (EEG) recordings
were reported. Data were not shown, and no further information was provided.
Vainio et al (1980)
Groups of male Wistar rats (five/group) were exposed to CFC-113 whole-body as a vapor
at 0, 200, 1,000, or 2,000 ppm (0, 1,530, 7,660, and 15,300 mg/m3), 6 hours/day, 5 days/week for
1 or 2 weeks. At study termination, the livers and kidneys were retained for histopathological
and/or biochemical analyses. The medial lobe of the liver was stained (hematoxylin and eosin,
van Gieson, and periodic acid Schiff [PAS]), embedded in paraffin, and examined
microscopically. Electron microscopy was performed on samples from two control animals and
one animal/treatment group/time point. Two biopsies of the medial lobe (fixed and embedded in
Epon) were taken from each animal; ultrathin sections of midzonal areas were examined using
electron microscopy. Biochemical analyses included reduced glutathione (GSH) and
microsomal cytochrome P450 (CYP450) content, and the activities of 7-ethoxycoumarin
O-deethylase, NADPH cytochrome c reductase, and UDP glucuronosyltransferase.
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Microscopic examinations (of Epon, but not paraffin sections) of the livers of treated rats
showed evidence of lipid accumulation in hepatocytes, Kupffer cells, and lipocytes. Although
these data were not quantified, the study authors suggested that changes in lipid accumulation
were dose related. Electron microscopy of the liver revealed slight to moderate increases in
smooth endoplasmic reticulum (SER) with vacuolization at 7,660 and 15,300 mg/m3 after 1 or
2 weeks of exposure, accompanied by increased numbers of autophagous vacuoles, decreased
glycogen content, and mitochondrial condensation in rats exposed for 2 weeks. GSH was
decreased slightly at 15,300 mg/m3 (6% after 1 or 2 weeks), and microsomal CYP450 content
was decreased by 10% at 7,660 mg/m3 and 25% at 15,300 mg/m3 after 1 week of exposure (no
significant changes after 2 weeks exposure). The activity of the liver enzymes, NADPH
cytochrome c reductase tended to be decreased (as much as 19 and 36% at 15,300 mg/m3,
p < 0.05), and UDP glucuronosyltransferase was increased (34-120%) at 7,660 and
15,300 mg/m3,/? < 0.05). The activities of these enzymes were unchanged in the kidneys of
treated rats.
Savolainen andPfaffli (1980)
Male Wistar rats (15/group) exposed whole-body to CFC-113 at 0, 200, 1,000, or
2,000 ppm (0, 1,530, 7,660, and 15,300 mg/m3), 6 hours/day, 5 days/week for up to 2 weeks
were evaluated after 1 week of exposure, 2 weeks of exposure, and 1 week postexposure
(5 rats/time point) with respect to CFC-113 levels in the area surrounding the kidneys and the
brain (right cerebral hemisphere). Samples from the left cerebral hemisphere were analyzed
biochemically (activities of azoreductase, glutathione peroxidase, and NADPH-diaphorase and
total ribonucleic acid [RNA] and GSH levels). During exposure, CFC-113 accumulated in the
brain and in perirenal fat in an exposure-related manner. Effects noted after 1 week of exposure
only included increased NADPH-diaphorase activity (all exposure levels, but with no strict
exposure-response) and significantly decreased GSH (at 15,300 mg/m3). After 2 weeks of
exposure, glutathione peroxidase activity was significantly decreased, and total RNA tended to
be decreased (not statistically significant) at 15,300 mg/m3. With the exception of RNA levels,
which were significantly decreased at 15,300 mg/m3, all effects returned to control levels within
1 week after cessation of exposure. The study authors suggested that while some of the observed
effects may have been adaptive, the observation of decreased glutathione peroxidase activity
may be biologically significant, as it protects cells from oxidative damage. The authors also
noted that at least one effect (decreased RNA in the postexposure period) is similar to that
observed for other neurotoxicants (ethanol or styrene), and may partially explain clinical nervous
system effects observed in workers exposed to CFC-113 and other fluorohydrocarbons.
Cardiac Sensitization Studies
In a series of unpublished studies, CFC-113 has been consistently shown to induce
arrhythmias and cardiac sensitization in animals. Male Swiss mice were administered
epinephrine intravenously at 0.006 mg/kg prior to acute (6 minutes) vapor exposures to CFC-113
at concentrations of 5 and 10%> (383,000 and 766,000 mg/m3) ( Aviado and Belei- 1974). During
exposure, a second (challenge) dose of epinephrine was administered. Additional groups of
animals (three/group) were exposed to CFC-113 alone. Based on constant monitoring of EKG
data, one animal exposed to CFC-113 alone (at 766,000 mg/m3) showed evidence of a heart
irregularity (inverted T-wave). In mice challenged with epinephrine, one of three and three of
three mice exposed to CFC-113 at 383,000 and 766,000 mg/m3, respectively, showed evidence
of cardiac arrhythmias (ventricular ectopics and ventricular bigeminy). Therefore, CFC-113
induced arrhythmias and also sensitized the mouse heart to epinephrine.
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Similarly designed experiments conducted in dogs have also provided evidence for the
sensitizing potential of CFC-113. Beagles (usually males) exposed to vapors of CFC-113
(commercial grade) and a challenge dose of epinephrine (0.004 or 0.008 mg/kg) showed
evidence for arrhythmias following exposures as low as 0.5% (38,300 mg/m3) CFC-113 for
5-10 minutes (Haskell Laboratories. 2000. 1989b). Multiple ventricular beats or ventricular
fibrillation with cardiac arrest was observed in >35% of dogs exposed to 38,300 mg/m3 for
10 minutes in the presence of epinephrine; 100% of animals were affected at 2%
(153,000 mg/m3) CFC-113 (exposure groups ranged from 2-29 animals) (Haskell Laboratories.
2000). Exposures as short as 30 seconds could induce cardiac sensitization at higher
concentrations of CFC-113. In an experiment using purified CFC-113, it was shown that the
cardiac sensitization potential of purified CFC-113 is similar to that of its commercial
counterpart (four of six dogs affected after exposure at 0.5% [38,300 mg/m3] for 5 minutes)
(Haskell Laboratories. 1989b). Other experiments comparing the effect of epinephrine with
"fright" responses (noise or shock) showed that CFC-113 sensitized the dog heart to epinephrine
(one of six dogs affected after exposures >2,000 ppm [15,300 mg/m3] for >30 minutes), but not
to other stimuli (Haskell Laboratories. 1989a). Higher exposures to CFC-113 (about 10%
[766,000 mg/m3]) in conjunction with epinephrine have been shown to induce ventricular
marked fibrillation (Haskell Laboratories, 1989c).
Metabolism/Toxicokinetic Studies
Studies in humans have shown that CFC-113 can penetrate the human skin, as evidenced
by its presence in the end-tidal breath of volunteers administered CFC-113 via the dermal route
of exposure (Haskell Laboratories. 1971a). CFC-113 applied to the scalp was absorbed more
readily than sites such as the hand or forearm, possibly owing to the scalp's increased vascularity
(Haskell Laboratories. 1968). Data from inhalation exposures in volunteers indicate that only
small amounts of CFC-113 (<~20%) are retained after exposure; a majority of CFC-113 (>50%)
is rapidly eliminated in expired air unchanged (Woollen et al, 1990; Morgan et al, 1972). In
rats exposed to CFC-113 by both the oral and inhalation routes of exposure, expired air was also
the primary route of elimination, accounting for >94% of the total administered radioactive dose
(Haskell Laboratories. 1982).
With respect to the fraction that is absorbed, an initial increase in CFC-113 levels in the
blood is observed after exposure. Data from a study in dogs showing higher arterial (than
venous) concentrations of CFC-113 during exposure and higher venous (than arterial)
concentrations of CFC-113 in the postexposure period suggest that CFC-113 is distributed to and
slowly released from the tissues (presumably unchanged) (Trochimowicz et al, 1974). Studies
in rodents exposed continuously to CFC-113 (or chlorofluorocarbons in general) have shown
preferential partitioning of CFC-113 to lipid-rich tissues including the adipose tissue and (in
lesser amounts) the brain, liver, and kidney (including perirenal fat) (Furuva. 1980; Savolainen
andPfaffli. 1980; Carter et al. 1970). A blood-air partition coefficient of 0.240 was predicted
for CFC-113 based on algorithms using partition coefficient values for water:air and
octanol:water (Haick et al, 2014).
In general, toxicokinetic studies provide little evidence for significant metabolism of
CFC-113. Based on studies in humans and rats (oral and inhalation), the amount of CFC-113
excreted in the urine (and feces) is negligible (below the limits of detection in humans and <3%
of the administered dose in animals) (Woollen et al. 1990; Haskell Laboratories. 1982).
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However, radioactivity detected in the urine of rats was not unchanged CFC-113, suggesting that
metabolism may occur for a small proportion of CFC-113 (Haskell Laboratories. 1982).
A physiologically based pharmacokinetic (PBPK) model developed to predict
concentrations of CFC-113 in the end-tidal breath and the blood of humans generally showed
good correlations with experimental data (with predicted blood concentrations falling below
experimental values over time). Blood and breath concentrations of CFC-113 (during and after
exposure) were not sensitive to metabolic clearance; therefore, the role of metabolism in human
exposures is uncertain (Auton and Woollen, 1991).
DERIVATION OF PROVISIONAL VALUES
Tables 5 and 6 present summaries of noncancer and cancer reference values, respectively.
IRIS data are indicated in the tables, if available.
Table 5. Summary of Noncancer Reference Values for
l,l?2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1)
Toxicity Type
(units)
Species
Critical
Effect
p-Reference
Value
POD
Method
POD (HEC)
UFc
Principal
Study
Subchronic p-RfD
(mg/kg-d)
NDr
Chronic p-RfD
(mg/kg-d)
Oral RID value of 3 x 101 is available on IRIS (U.S. EPA. 1987)
Subchronic p-RfC
(mg/m3)
Human
No effects
observed
5 x 101
NOAELadj
1,440
30
hnbus and
Adkins (1972)
Chronic p-RfC
(mg/m3)
Human
No effects
observed
5
NOAELadj
1,440
300
linbus and
Adkins (1972)
HEC = human equivalent concentration; NOAELadj = no-observed-adverse-effect level adjusted daily dose;
NDr = not determined; POD = point of departure; p-RfC = provisional reference concentration; p-RfD = provisional
reference dose; UFC = composite uncertainty factor.
Table 6. Summary of Cancer Reference Values for
l,l92-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1)
Toxicity Type (units)
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3)
NDr
NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
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DERIVATION OF ORAL REFERENCE DOSES
Derivation of a Subchronic Provisional Oral Reference Dose
No subchronic oral exposure studies are identified in the literature for derivation of a
subchronic provisional reference dose (p-RfD). Although a developmental toxicity study in
rabbits is available, it is of limited utility owing to poor reporting and inadequate study design
and execution. IRIS has developed a chronic oral RfD of 3 x 101 mg/kg-day based on a
route-to-route converted human equivalent NOAEL from a human occupational inhalation
exposure study that examined physical, clinical, or laboratory measurements in a cohort of
Kennedy Space Center workers (Imbus and Adkins. 1972). In the absence of suitable subchronic
oral studies, and uncertainties associated with the route-to-route extrapolation from occupational
inhalation study to oral exposure, no subchronic p-RfD is derived.
Derivation of a Chronic Provisional Reference Dose
An RfD of 3 x 101 mg/kg-day is available in the IRIS database (U.S. EPA. 1987) based
on a human occupational inhalation study by Imbus and Adkins (1972). Users should check the
current IRIS database to determine whether any changes have been made.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
The cross-sectional study of occupational exposure in humans exposed by inhalation to
CFC-1 13 for an average of 2.77 years (Imbus and Adkins. 1972) is selected as the principal
study for the derivation of the subchronic provisional reference concentration (p-RfC). In this
study, no significant effects related to CFC-113 exposure were observed.
Justification for the Critical Effect
The NOAELad.i of 1,440 mg/m3 from the cross-sectional occupational study by Imbus
and Adkins (1972) is selected for the derivation of a subchronic p-RfC. A wide range of
endpoints were assessed in this study (Imbus and Adkins, 1972), and this NOAEL value
represents the highest NOAEL from the available studies of long-term human occupational
exposure; the only human LOAEL identified was based on slight impairment of psychomotor
performance reported in two male volunteers exposed to CFC-113 concentrations of
19,160 mg/m3 for 1.5 hours (Haskell Laboratories. 1964). Additional support from human and
animal studies for the selection of this point of departure (POD) includes:
1)	Other human occupational exposure studies did not identify significant adverse
effects from CFC-113 exposure. No significant adverse effects on liver function were
observed in humans occupationally exposed to CFC-113 at a TWA exposure level of
523 mg/m3 (duration adjusted to 187 mg/m3) for 2.5 years (Neghab et al.. 1997). and
no effects on cardiac activity were noted in workers exposed to CFC-113 for 7-hour
shifts at TWA exposure levels of 3,388 mg/m3 (duration-adjusted exposure of
1,059 mg/m3) (Egeland et al.. 1992).
2)	A short-term experimental study revealed no effects on clinical pathology or
psychomotor activities in human subjects exposed to CFC-113 at up to 7,660 mg/m3,
6 hours/day for 5 days (duration-adjusted exposure of 1,920 mg/m3) (Reinhardt et al..
1971).
3)	Thirteen-week subchronic toxicity studies in animals identified no significant
treatment-related effects at up to 26,257 mg/m3 (HEC) in rats and 9,602 mg/m3
(HEC) in dogs (Haskell Laboratories. 1981; LPT. 1976. 1975).
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4)	A chronic study in rats observed effects (decreased body weight in females) only at
26,000 mg/m3 (HEC) (Trochimowicz et ai. 1988). There were no effects at
13,700 mg/m3 (HEC) or lower.
5)	A single-generation reproduction study in rats found no reproductive effects
associated with exposure to CFC-113 at concentrations up to 21,436 mg/m3(HEC)
(Central Toxicol Lab, 1981b).
6)	Developmental toxicity studies in rats and rabbits do not identify the fetus as a
sensitive target for CFC-113 exposure. There were some skeletal variations
(increased fourteenth rib) in rats at doses (>24,011 mg/m3 [HEC]) associated with
maternal toxicity. There were no developmental effects in rats exposed at
9,551 mg/m3 (HEC) on GDs 6-15 (Central Toxicol Lab. 1982) or in rabbits exposed
at 12,800 mg/m3 (HEC) on GDs 8-16 (Hazleton Laboratories, 1967).
Justification for the Principal Study
The cross-sectional human study by Imbus and Adkins (1972) included environmental
sampling of workroom air (161 samples collected over a 3-week period) and examined 50
exposed and 50 unexposed workers at a single time with respect to physical exams (including
visual and hearing tests), EKGs, lung capacity and chest x-rays, and hematology, clinical
chemistry, and urinalysis parameters. Thorough analyses were conducted, and the NOAELadj of
1,440 mg/m3 from this study represents the highest NOAEL from studies of long-term human
occupational exposure. Animal studies only identified significant exposure-related effects on
body weights, but at a much higher exposure concentration (26,000 mg/m3 HEC).
Approach for Deriving the Subchronic p-RfC
The NOAEL from the study of occupational exposure in humans exposed via inhalation
to CFC-113 for an average of 2.77 years was selected as the POD for the p-RfC. The subchronic
p-RfC for CFC-113 based on this POD is derived as follows:
Subchronic p-RfC = NOAELadj ^ UFc
= 1,440 mg/m3 ^ 30
= 5 x 101 mg/m3
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Table 7 summarizes the uncertainty factors for the subchronic p-RfC for CFC-113.
Table 7. Uncertainty Factors for the Subchronic p-RfC for
l,l?2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1)
UF
Value
Justification
UFa
1
A UFa of 1 is applied because the POD is based on a study of human exposure; therefore, there is
no need to account for uncertainty associated with extrapolating animal data to humans.
UFh
10
A UFh of 10 is applied to account for human variability and susceptibility, in the absence of
information to assess the toxicokinetic and toxicodynamic variability of CFC-113 in humans.
UFd
3
A UFd of 3 is applied. The database includes three 13-wk subchronic-duration toxicity studies,
including two "tolerance" studies in rats and doss exposed to a sinsle concentration CLPT. 1976.
1975) and one studv in rats using multiple exposure concentrations (Haskell Laboratories. 1981);
one chronic toxicitv/carcinoeenicitv studv in rats CTrochimowicz et al.. 1988); two developmental
studies in rats and rabbits (Central Toxicol Lab. 1982; Hazleton Laboratories. 1967); and a
one-seneration reproductive/developmental studv in rats (Central Toxicol Lab. 1981b) via the
inhalation route of exposure. No two-generation reproduction studies are available. Slight
impairment of psychomotor performance was reported in humans exposed to high concentration of
CFC-113, but there are no neurobehavioral studies in animals.
UFl
1
A UFl of 1 is applied because the POD is a NOAEL.
UFS
1
A UFS of 1 is applied because the POD comes from a subchronic-duration study. The duration of
exposure in male workers averaged 2.77 yr.
UFC
30
Composite UF = UFA x UFH x UFD x UFL x UFS.
NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfC = provisional reference
concentration; UF = uncertainty factor.
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Confidence in the subchronic p-RfC for CFC-113 is medium as explained in Table 8.
Table 8. Confidence Descriptors for the Subchronic p-RfC for
l,l?2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1)
Confidence Categories
Designation
Discussion
Confidence in study
M
Relatively thorough analyses were conducted in the cross-sectional
human studv bv I tubus and Adkins (1972). The studv included
environmental sampling of workroom air (161 samples collected over a
3-wk period) and examined 50 exposed and 50 unexposed male workers
with respect to physical exams (including visual and hearing tests),
EKGs, lung capacity and chest x-rays, and hematology, clinical
chemistry, and urinalysis parameters. However, this study only
identified a NOAEL while the only human LOAEL identified was based
on slight impairment of psychomotor performance reported in only two
male volunteers exposed to CFC-113 for a short period of time (1.5 hr).
Confidence in database
M
Confidence in the database is medium. The database includes three
13-wk subchronic-duration toxicity studies, including two "tolerance"
studies in rats and doss exposed to a sinsle concentration (LPT. 1976.
1975) and one studv in rats usins multiple exposure concentrations
(Haskell Laboratories. 1981); one chronic toxicitv/carcinoeenicitv studv
in rats (Trochimowicz et al.. 1988); two developmental toxicity studies in
rats and rabbits (Central Toxicol Lab. 1982; Hazleton Laboratories.
1967); and a one-eeneration reproductive/developmental studv in rats
(Central Toxicol Lab. 1981b). No two-seneration reproduction studies
are available. Slight impairment of psychomotor performance was
reported in humans exposed to high concentration of CFC-113, but there
are no neurobehavioral studies in animals.
Confidence in
subchronic p-RfCa
M
The overall confidence in the subchronic p-RfC is medium.
"The overall confidence cannot be greater than the lowest entry in the table (medium).
EKG = electrocardiogram; LOAEL = lowest-observed-adverse-effect level; M = medium;
NOAEL = no-observed-adverse-effect level; p-RfC = provisional reference concentration.
Derivation of a Chronic Provisional Reference Concentration (p-RfC)
A chronic p-RfC for CFC-113 is derived from the same POD as used in the derivation of
the subchronic p-RfC. Justifications for selecting the principal study and the POD are described
in the previous section of this document.
The chronic p-RfC for CFC-113, based on a NOAELadj of 1,440 mg/m3 in male workers
exposed to CFC-113 for an average of 2.77 years, is derived as follows:
Chronic p-RfC = NOAELadj ^ UFc
= 1,440 mg/m3 ^ 300
= 5 mg/m3
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Table 9 summarizes the uncertainty factors for the chronic p-RfC for CFC-113.
Table 9. Uncertainty Factors for the Chronic p-RfC for
l,l?2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1)
UF
Value
Justification
UFa
1
A UFa of 1 is applied because the POD is based on a study of human exposure; therefore, there is
no need to account for uncertainty associated with extrapolating animal data to humans.
UFh
10
A UFh of 10 is applied to account for human variability and susceptibility, in the absence of
information to assess the toxicokinetic and toxicodynamic variability of CFC-113 in humans.
UFd
3
A UFd of 3 is applied. The database includes three 13-wk subchronic-duration toxicity studies,
including two "tolerance" studies in rats and doss exposed to a sinsle concentration CLPT. 1976.
1975) and one studv in rats using multiple exposure concentrations (Haskell Laboratories. 1981);
one chronic toxicitv/carcinoeenicitv studv in rats (Trochimowicz et al.. 1988); two developmental
studies in rats and rabbits (Central Toxicol Lab. 1982; Hazleton Laboratories. 1967); and a
one-seneration reproductive/developmental studv in rats (Central Toxicol Lab. 1981b) via the
inhalation route of exposure. No two-generation reproduction studies are available. Slight
impairment of psychomotor performance was reported in humans exposed to high concentration of
CFC-113, but there are no neurobehavioral studies in animals.
UFl
1
A UFl of 1 is applied because the POD is a NOAEL.
UFS
10
A UFS of 10 is applied because the POD comes from a subchronic-duration human study. The
duration of exposure in male workers averaged 2.77 yr.
UFC
300
Composite UF = UFA x UFH x UFD x UFL x UFS.
NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfC = provisional reference
concentration; UF = uncertainty factor.
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Confidence in the chronic p-RfC for CFC-113 is medium as explained in Table 10.
Table 10. Confidence Descriptors for the Chronic p-RfC for
l,l?2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1)
Confidence Categories
Designation
Discussion
Confidence in study
M
Relatively thorough analyses were conducted in the cross-sectional study
bv Itubus and Adkins (1972). The studv included environmental sampling
of workroom air (161 samples collected over a 3-wk period) and
examined 50 exposed and 50 unexposed workers with respect to physical
exams (including visual and hearing tests), EKGs, lung capacity and chest
x-rays, and hematology, clinical chemistry, and urinalysis parameters.
However, this study only identified a NOAEL while the only human
LOAEL identified was based on slight impairment of psychomotor
performance reported in only two male volunteers exposed to CFC-113
for a short period of time (1.5 hr).
Confidence in database
M
Confidence in the database is medium. The database includes three 13-wk
subchronic-duration toxicity studies, including two "tolerance" studies in
rats and doss exposed to a sinsle concentration (LPT. 1976. 1975) and one
studv in rats usins multiple exposure concentrations (Haskell
Laboratories. 1981); one chronic toxicitv/carcinoeenicitv studv in rats
(Trochimowicz et al.. 1988); two developmental toxicity studies in rats
and rabbits (Central Toxicol Lab. 1982; Hazleton Laboratories. 1967); and
a one-eeneration reproductive/developmental studv in rats (Central
Toxicol Lab. 1981b). No two-generation reproduction studies are
available. Slight impairment of psychomotor performance was reported
in humans exposed to high concentration of CFC-113, but there are no
neurobehavioral studies in animals.
Confidence in chronic
p-RfCa
M
The overall confidence in the chronic p-RfC is medium.
"The overall confidence cannot be greater than the lowest entry in the table (medium).
EKG = electrocardiogram; LOAEL = lowest-observed-adverse-effect level; M = medium;
NOAEL = no-observed-adverse-effect level; p-RfC = provisional reference concentration.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Table 11 identifies the cancer weight-of-evidence (WOE) descriptor for CFC-113.
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Table 11. Cancer WOE Descriptor for l,l92-Trichloro-l,2,2-trifluoroethane
(CASRN 76-13-1)
Possible WOE Descriptor
Designation
Route of
Entry
Comments
"Carcinogenic to
Humans "
NS
NA
There are no human data to support this.
"Likely to Be Carcinogenic
to Humans "
NS
NA
Results from available animal studies are not sufficient
to support this, and no human data are available.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
Results from available animal studies are not sufficient
to support this, and no human data are available.
"Inadequate Information
to Assess Carcinogenic
Potential"
Selected
Inhalation and
oral
No adequate evidence of carcinogenicity was seen
following inhalation exposure in a chronic rat study
(Trochimowicz et al. 1988). No carcinogenicity
studies are available that evaluated oral exposure.
"Not Likely to Be
Carcinogenic to Humans "
NS
NA
The available data do not support this.
NA = not applicable; NS = not selected; WOE = weight of evidence.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of a Provisional Oral Slope Factor
No studies on the oral carcinogenicity of CFC-113 have been identified; therefore,
derivation of a provisional oral slope factor (p-OSF) is precluded.
Derivation of a Provisional Inhalation Unit Risk
The chronic inhalation study by Trochimowicz et al. (1988) does not provide sufficient
evidence for carcinogenicity and, thus, precludes the derivation of a provisional inhalation unit
risk (p-IUR). Although the incidence of pancreatic islet cell adenomas in females at the
high-dose group (5/86) was significantly increased compared with the control and low- and
mid-dose groups (0/85, 0/36, and 0/30, respectively), the study authors did not consider the
occurrence to be treatment related because it was within historical control levels for the
laboratory. Additionally, a concurrent chronic inhalation study conducted by the same study
authors showed an incidence of 6/95 pancreatic islet cell adenomas in the control group.
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APPENDIX A. SCREENING PROVISIONAL VALUES
No provisional screening values are derived.
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APPENDIX B. DATA TABLES
Table B-l. Concentrations of Serum Bile Acids in Workers Exposed to
l,l?2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1)3
Bile Acid (jimol/L)
Control (n = 11)
Pre-exposure (n = 4)
Postexposure (n = 6)
/7-Value
GC
0.46 ± 0.23b
0.46 ±0.16 (0)
2.44 ±0.43*** (430)
0.0003
GCDC
1.98 ±0.34
2.76 ±0.31 (39)
3.91 ±0.47* (97)
0.007
Subtotal (GTOT)
3.22 ±0.68
3.91 ±0.55 (21)
7.37 ±0.89*** (129)
0.003
TC
0.33 ±0.06
0.18 ±0.05 (-45)
0.78 ±0.20*** (136)
0.009
TUDC
0.15 ±0.04
0.12 ±0.04 (-20)
0.27 ±0.03** (80)
0.05
TCDC
0.59 ±0.13
0.85 ±0.19 (44)
1.53 ±0.18*** (159)
0.001
Subtotal (TTOT)
1.44 ±0.27
1.52 ±0.31 (6)
3.21 ±0.51*** (123)
0.005
Total (TSBA)
7.10 ± 1.00
7.06 ±0.74 (-1)
13.35 ± 1.48*** (88)
0.002
aNegfaab et at (1997).
bValues represent means ± standard error of the mean (percent change from control).
* Significantly different from control at p< 0.05 (Duncan's multiple comparison test).
**Significantly different from pre-exposure group only atp< 0.05 (Duncan's multiple comparison test).
***Significantly different from both control and pre-exposure group at p< 0.05 (Duncan's multiple comparison
test).
GC = glychocholic acid; GCDC = glycochenodeoxycholic acid; GTOT = subtotal of glycine conjugated bile acids;
TC = taurocholic acid; TUDC = taurousodeoxycholic acid; TCDC = taurochenodeoxycholic acid; TTOT = subtotal
of taurine conjugated bile acids; TSB A = total serum bile acids.
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Table B-2. Organ-Weight Effects in CD Rats Exposed to
l,l,2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1) 6 Hours/Day,
5 Days/Week for 13 Weeks"
Parameter0
Exposure Group, mg/m3 (HEC)b
0
57,260 (10,230)
95,138 (16,988)
147,040 (26,257)
Males
Number of animals
10
10
10
10
Lung weight:
Absolute (g)
Relative (%BW)e
1.919 ± 0.161°
0.403
2.133 ±0.249d (11)
0.435 (8)
2.137 ±0.240d (11)
0.440 (9)
2.304 ± 0.368d* (20)
0.495* (23)
Females
Number of animals
9
10
10
10
Adrenal weight:
Absolute (g)
Relative (%BW)e
0.076 ±0.011
0.024
0.088 ±0.009*d (16)
0.025 (4)
0.077 ± 0.009 (1)
0.023d (-4)
0.091 ±0.007* (20)
0.027* (13)
aHaskell Laboratories (1981).
bAnalytical concentrations have been converted to HECs based on the following equation:
CONC (HEC) = CONC (mg/m3) x (hours exposed ^ 24 hours) x (days exposed ^ 7 days) x blood-air partition
coefficient ratio (U.S. EPA. 1994). The value for the rat blood-air partition coefficient is unknown (a predicted
value for humans is available), so the default ratio of 1 was applied.
°Values are expressed as mean ± standard deviation when possible (percent change compared with control).
dValues are not clearly legible in the study report.
Standard deviation for relative organ weights were not provided in the study report.
* Significantly different (p < 0.05) from control based on statistics performed by the study authors.
BW = body weight; HEC = human equivalent concentration.
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Table B-3. Mortality in Rats Exposed to l,l,2-Trichloro-l,2,2-trifluoroethane
(CASRN 76-13-1) Vapor for 2 Yearsa b


Exposure Group, mg/m3 (HEC)C

Parameter
0
15,300
(2,740)
76,600
(13,700)
145,600
(26,000)
Males
First 18 mo
Corynebacterium kutscheri-related mortality
0
1
16
15

Mortality from other causes
16
23
18
11
18-24 mo
C. kutscheri-related mortality
35
26
2
11

Mortality from other causes
23
22
29
22
Survival to 2 yr
16
18
25
31
Females
First 18 mo
C. kutscheri -related mortality
1
0
2
1

Mortality from other causes
20
11
11
11
18-24 mo
C. kutscheri -related mortality
7
7
3
2

Mortality from other causes
25
24
24
19
Survival to 2 yr
37
48
50
57
aTrocMmowicz et al. (1988).
hn = 90; does not include 10 rats/sex/group terminated at 12 months.
Analytical concentrations have been converted to HECs based on the following equation:
CONC (HEC) = CONC (mg/m3) x (hours exposed ^ 24 hours) x (days exposed ^ 7 days) x blood-air partition
coefficient ratio (U.S. EPA. 1994). The value for the rat blood-air partition coefficient is unknown (a predicted
value for humans is available), so the default ratio of 1 was applied.
HEC = human equivalent concentration.
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Table B-4. Effects in S-D-Derived Rats Exposed to l,l,2-Trichloro-l,2,2-trifluoroethane
(CASRN 76-13-1) 6 Hours/Day, 5 Days/Week for up to 2 Years3

Exposure Group, mg/m3 (HEC)b
Parameter
0
15,300 (2,740)
76,600 (13,700)
145,600 (26,000)
Males
Number of animals
10
10
10
10
Serum glucose (mg %):
6 mo
105 ± 6°
104 ± 9 (-1)
104 ± 8 (-1)
92 ± 4* (-12)
Urinary fluoride (|ig)'d:
3 mo
6 mo
12 mo
24 mo
17	±4
16	±7
18	±6
17	±3
18 ± 4 (6)e
21	±5 (31)
18 ± 4 (0)
22	± 8 (29)
21	±5 (24)
23 ± 7 (44)
22	± 4 (22)
22 ± 4 (29)
28 ± 6* (65)
26 ± 8* (63)
26 ± 6* (44)
24 ±5* (41)
Females
Number of animals
10
10
10
10
Serum glucose (mg %):
6 mo
122 ± 11
116 ±6 (-5)
120 ± 10 (-2)
116 ±8 (-5)
Urinary fluoride (|ig)'d:
3 mo
6 mo
12 mo
24 mo
9 ± 3
11 ± 3
11 ± 3
15 ±5
9 ± 4 (0)
14 ± 3 (27)
12 ± 3 (9)
17 ±6 (13)
15 ± 5* (67)
13 ±5 (18)
13 ±5 (18)
17 ±2 (13)
16	±3* (78)
17	±6* (55)
16 ± 6 (45)
20 ± 3 (33)
aHaskell Laboratories (1985): Trochimowicz et al. (1988).
bAnalytical concentrations have been converted to HECs based on the following equation:
CONC (HEC) = CONC (mg/m3) x (hours exposed ^ 24 hours) x (days exposed ^ 7 days) x blood-air partition
coefficient ratio (U.S. EPA. 1994). The value for the rat blood-air partition coefficient is unknown (a predicted
value for humans is available), so the default ratio of 1 was applied.
°Values are expressed as mean ± standard deviation (percent change compared with control).
dTotal F = (ig/mL F x mL (urine volume).
* Significantly higher than controls, p < 0.05, statistical test performed by the study authors.
HEC = human equivalent concentration; S-D = Sprague-Dawley.
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Table B-5. Organ-Weight Effects in S-D-Derived Rats Exposed to
l,l,2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1) 6 Hours/Day,
5 Days/Week for 1 Year"
Parameter0
Exposure Group, mg/m3 (HEC)b
0
15,300 (2,740)
76,600 (13,700)
145,600 (26,000)
Males
Number of animals
10
10
10
10
BW at necropsy (g)
773.3 ±90.1
743.7 ±50.7 (-4)
745.6 ±86.1 (-4)
748.3 ±83.7 (-3)
Liver weight:
Absolute (g)
Relative (%BW)
18.450 ±4.433
2.361 ±0.397
21.517 ±2.917 (17)
2.900 ±0.391* (23)
22.512 ±3.137* (22)
3.039 ±0.420* (29)
23.618 ±3.518* (28)
3.153 ±0.266* (34)
Kidney weight:
Absolute (g)
Relative (%BW)
3.975 ±0.842
0.511 ±0.068
4.316 ±0.225 (9)
0.583 ±0.048* (14)
4.299 ± 0.506 (8)
0.584 ±0.098* (14)
4.615 ±0.811 (16)
0.617 ±0.086* (21)
Females
Number of animals
10
10
10
10
BW at necropsy (g)
388.2 ±71.6
347.3 ±43.6 (-11)
346.2 ±35.8 (-11)
334.9 ±63.8 (-14)
Liver weight:
Absolute (g)
Relative (%BW)
9.506 ± 1.448
2.472 ±0.216
9.008 ± 1.567 (-5)
2.584 ±0.235 (5)
12.175 ± 1.310* (28)
3.537 ±0.406* (43)
11.730 ± 1.387* (23)
3.593 ±0.675* (45)
Kidney weight:
Absolute (g)
Relative (%BW)
2.312 ±0.253
0.607 ± 0.084
2.272 ±0.359 (-2)
0.652 ± 0.045 (8)
2.382 ±0.313 (3)
0.696 ±0.115 (15)
2.318 ±0.262 (0)
0.713 ±0.144 (17)
Lung weight:
Absolute (g)
Relative (%BW)
1.650 ±0.151
0.434 ±0.060
1.679 ±0.224 (2)
0.485 ± 0.044 (12)
1.750 ±0.133 (6)
0.510 ±0.060* (18)
1.765 ±0.160 (7)
0.539 ±0.081* (24)
Spleen weight:
Absolute (g)
Relative (%BW)
0.493 ±0.112
0.127 ±0.018
0.514 ±0.083 (4)
0.148 ±0.016 (16)
0.529 ± 0.087 (7)
0.155 ±0.034* (22)
0.534 ±0.060 (8)
0.164 ±0.035* (29)
"Haskell Laboratories (1985): TrocMniowi.cz et al. (1988).
bAnalytical concentrations have been converted to HECs based on the following equation:
CONC (HEC) = CONC (mg/m3) x (hours exposed ^ 24 hours) x (days exposed ^ 7 days) x blood-air partition
coefficient ratio (U.S. EPA. 1994). The value for the rat blood-air partition coefficient is unknown (a predicted
value for humans is available), so the default ratio of 1 was applied.
0Values are expressed as mean ± standard deviation (percent change compared with control).
* Significantly different (p < 0.05) from control, statistical tests performed by study authors.
BW = body weight; HEC = human equivalent concentration; S-D = Sprague-Dawley.
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Table B-6. Organ-Weight Effects in S-D-Derived Rats Exposed to
l,l,2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1) 6 Hours/Day,
5 Days/Week for 2 Years"
Parameter0
Exposure Group, mg/m3 (HEC)b
0
15,300 (2,740)
76,600 (13,700)
145,600 (26,000)
Males
Number of animals
16
18
25
31
BW at necropsy (g)
789.0 ± 137.9
810.5 ± 183.1 (2.7)
832.5 ± 138.9 (5.5)
810.5 ±94.1 (2.7)
Liver weight:
Absolute (g)
Relative (%BW)
23.363 ±4.478
2.9737 ±0.4178
27.962 ± 7.848* (20)
3.5376 ± 1.1416* (19)
26.256 ± 5.087 (12)
3.1906 ±0.5960 (7)
24.063 ±4.472 (3.0)
2.9779 ± 0.4798 (0.1)
Kidney weight:
Absolute (g)
Relative (%BW)
5.497 ±0.899
0.7072 ±0.1231
5.924 ± 1.580 (7.8)
0.7508 ± 0.2283 (6.2)
6.200 ±2.061 (13)
0.7539 ±0.2392 (6.6)
5.467 ± 1.516 (-0.5)
0.6789 ±0.1873 (-4.0)
Females
Number of animals
37
48
50
57
BW at necropsy (g)
476.5 ± 95.6
474.6 ± 90.7 (-0.4)
464.9 ±83.6 (-2.4)
450.6 ± 89.0 (-5.4)
Liver weight:
Absolute (g)
Relative (%BW)
16.238 ±4.533
3.4076 ±0.6648
16.342 ±4.147 (6.4)
3.4425 ±0.5856 (1.0)
15.576 ±4.324 (-4.1)
3.3325 ±0.5097 (-2.2)
15.356 ±3.878 (-4.4)
3.4207 ±0.6491 (0.4)
Kidney weight:
Absolute (g)
Relative (%BW)
3.121 ±0.744
0.6701 ±0.1887
3.186 ±0.531 (2.1)
0.6902 ±0.1503 (3.0)
3.153 ± 1.534 (1.0)
0.6969 ±0.3859 (4.0)
2.893 ± 0.521 (-7.3)
0.6518 ±0.1023 (-2.7)
"Haskell Laboratories (1985): Trochimowicz et al. (1988).
bAnalytical concentrations have been converted to HECs based on the following equation:
CONC (HEC) = CONC (mg/m3) x (hours exposed ^ 24 hours) x (days exposed ^ 7 days) x blood-air partition
coefficient ratio (U.S. EPA. 1994). The value for the rat blood-air partition coefficient is unknown (a predicted
value for humans is available), so the default ratio of 1 was applied.
0Values are expressed as mean ± standard deviation (percent change compared with control).
* Significantly different (p < 0.05) from control, statistical tests performed by study authors.
BW = body weight; HEC = human equivalent concentration; S-D = Sprague-Dawley.
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Table B-7. Neoplastic Effects in S-D-Derived Rats after Exposure to
l,l,2-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1) 6 Hours/Day, 5 Days/Week for

2 Years"



Exposure Group, mg/m3 (HEC)b
Parameter
0
15,300 (2,740)
76,600 (13,700)
145,600 (26,000)
Pancreatic islet adenomas:




Males
2/88°
1/64
0/58
2/87
Females
0/85
0/36
0/30
5/86*
"Trochimowicz et at (1988): Haskell Laboratories (1985).
bAnalytical concentrations have been converted to HECs based on the following equation:
CONC (HEC) = CONC (mg/m3) x (hours exposed ^ 24 hours) x (days exposed ^ 7 days) x blood-air partition
coefficient ratio (U.S. EPA. 1994). The value for the rat blood-air partition coefficient is unknown (a predicted
value for humans is available), so the default ratio of 1 was applied.
°Number observed/number examined.
* Significantly higher than controls, p < 0.05, statistical test performed by study authors.
HEC = human equivalent concentration; S-D = Sprague-Dawley.
Table B-8. Effects in Female Alderley Park Wistar Rats (Subgroup B) Exposed to
l,l92-Trichloro-l,2,2-trifluoroethane (CASRN 76-13-1) 6 Hours/Day, 5 Days/Week during
Premating and 6 Hours/Day, 7 Days/Week during Mating"
Parameter
Exposure Concentration, mg/m3 (HEC)b
0
38,465 (7,968)
96,035 (19,893)
Number of pregnant females
11
T
10
Number of implantations
13.55 ±2.34
12.86 ± 1.07 (-5)
11.90 ± 1.45* (-12)
Number of corpora lutea
14.18 ± 1.54
13.71 ± 1.60 (-3)
12.40 ±0.70** (-13)
Number of fetuses
13.55 ±2.34
12.57 ± 1.13 (-7)
11.60 ± 1.58* (-14)
"Central Toxicol Lab (1981b).
bAnalytical concentrations have been converted to HECs based on the following equation:
CONC (HEC) = CONC (ppm) x (molecular weight ^ 24.45) x (hours exposed ^ 24 hours) x (days
exposed ^ 7 days) x blood-air partition coefficient ratio (U.S. EPA. 1994). The value for the rat blood-air partition
coefficient is unknown (a predicted value for humans is available), so the default ratio of 1 was applied.
°One female from this group was excluded from analyses because it died on GD 12.
dValues are expressed as mean ± standard deviation (percent change compared with control).
* Significantly different from the control group mean, p < 0.05, statistical test performed by study authors.
**Significantly different from the control group mean, p < 0.01, statistical test performed by study authors.
GD = gestation day; HEC = human equivalent concentration.
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Table B-9. Effects in Alderley Park Rats Exposed to l,l,2-Trichloro-l,2,2-trifluoroethane
(CASRN 76-13-1), 6 Hours/Day on GDs 6-15a
Parameter
Exposure Concentration, mg/m3 (HEC)b
0
38,200 (9,511)
96,043 (24,011)
193,630 (48,407)
Maternal effects
Number of pregnant females
24
22
23
23
Body-weight gain (g):
GDs 5-15
43.5°
34.3* (-21)
35.2** (-19)
26.3** (-40)
Food consumption (g/day)d:
GDs 6/7-15/16
28.1
28.3 (1)
27.5 (-2)
24.3** (-14)
Fetal effects
Extra rib; fetal incidence:
Fourteenth left, vestigial
Fourteenth right, vestigial
Fourteenth both, vestigial
Fourteenth any, vestigial
2/184 (l%)e
5/184 (3%)
11/184 (6%)
18/184 (10%)
7/169 (4%)
11/169 (7%)
13/169 (8%)
31/169(18%)
14/161** (9%)
7/161 (4%)
19/161* (12%)
40/161** (25%)
17/169** (10%)
8/169 (5%)
38/169** (23%)
63/169** (37%)
Extra rib; litter incidence:
Fourteenth left, vestigial
Fourteenth right, vestigial
Fourteenth both, vestigial
Fourteenth any, vestigial
2/24 (8%)e
3/24 (13%)
5/24 (21%)
6/24 (25%)
5/22 (23%)
8/22 (36%)
8/22 (36%)
15/22** (70%)
10/23** (43%)
6/23 (26%)
8/23 (35%)
15/23** (65%)
8/23* (35%)
8/23 (35%)
15/23** (65%)
19/23** (83%)
"Central Toxicol Lab (1982).
bAnalytical concentrations have been converted to HECs based on the following equation:
CONC (HEC) = CONC (ppm) x (molecular weight ^ 24.45) x (hours exposed ^ 24 hours) x (days
exposed ^ '7 days) x blood-air partition coefficient ratio (U.S. EPA. 1994). The value for the rat blood-air partition
coefficient is unknown (a predicted value for humans is available), so the default ratio of 1 was applied.
Data represent means (percent change compared with control). No measures of variance (standard error or
standard deviation) were provided in the study report.
dThe number of observations were 12, 10, 11, and 11 at 0, 5,000, 12,500, and 25,000 ppm, respectively.
"Number affected/number examined (percent incidence).
* Significantly different from the control group mean (p < 0.05) based on statistics performed by study authors.
**p < 0.01.
GD = gestation day; HEC = human equivalent concentration.
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APPENDIX C. BENCHMARK DOSE MODELING RESULTS
There are no benchmark dose (BMD) modeling outputs.
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Central Toxicol Lab (Central Toxicology Laboratory)- (198la). 1,1,2-trichloro-1,2,2-
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(OTS0520487). MacClesfield, Cheshire, UK: Imperial Chemical Industry.
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trifluoroethane (Arcton 113): Teratogenicity study in rats with attachments.
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