FINAL
09-30-2015
Provisional Peer-Reviewed Toxicity Values for
1,1,1 -Trifluoroethane
(CASRN 420-46-2)
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
Dan D. Petersen, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
National Center for Environmental Assessment, Cincinnati, OH
PRIMARY INTERNAL REVIEWERS
Ambuja Bale, PhD
National Center for Environmental Assessment, Washington, DC
Paul Reinhart, 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 document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).
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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 9
Oral Exposures 9
Inhalation Exposures 9
ANIMAL STUDIES 9
Oral Exposures 9
Inhalation Exposures 10
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 14
Acute Toxicity 14
Genotoxicity 15
Metabolism/Toxicokinetic Studies 16
Mechanistic Studies 16
DERIVATION 01 PROVISIONAL VALUES 19
DERIVATION OF ORAL REFERENCE DOSES 19
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 19
Derivation of Subchronic p-RfC 20
Derivation of Chronic p-RfC 22
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR 24
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 24
APPENDIX A. SCREENING PROVISIONAL VALUES 25
APPENDIX B. DATA TABLES 26
APPENDIX C. BENCHMARK DOSE MODELING RESULTS 28
APPENDIX D. REFERENCES 29
in
1,1,1 -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
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
1,1,1 -TRIFLUOROETHANE (CASRN 420-46-2)
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 contents and appropriate use 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).
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INTRODUCTION
1,1,1-Trifluoroethane, CASRN 420-46-2, also referred to as HFC-143a, is a flammable
hydrofluorocarbon used as a heat transfer agent and refrigerant in blends for air conditioning
used for stationary and transport systems (Solvav, 201 1). Although 1,1,1-trifluoroethane is
flammable, blends containing this chemical are not considered flammable. Under EPA's
Significant New Alternatives Policy (SNAP) program, blends containing 1,1,1-trifluoroethane
have been approved as replacements for Class I and II ozone-depleting substances in various
industrial, commercial, and household refrigeration systems, including refrigerated transport,
retail food refrigeration, commercial ice machines, vending machines, and household
refrigerators and freezers (U.S. EPA, 1995, 1994a, c). Blends containing 1,1,1-trifluoroethane
are also approved as replacements for CFC-12 (dichlorodifluoromethane) in polystyrene
boardstock and billet foams (U.S. EPA, 1994b).
1,1,1-Trifluoroethane exists primarily as a gas (its boiling point is -47.5°C), although it is
generally supplied as a liquefied gas under pressure in compressed gas cylinders. It is flammable
at concentrations >70,000 ppm (240,000 mg/m3) (Brock et al, 1996). Although
1,1,1-trifluoroethane does not react with ozone and has no ozone-depleting properties, it has a
very high global warming potential (GWP) of 3,800 (compared to 1 for carbon dioxide) (Solvav,
2011). 1,1,1 -Trifluoroethane will react with hydroxy radicals in the atmosphere; its measured
atmospheric OH rate constant indicates an atmospheric half-life of approximately 9 years
(ChemlDplus, 2015). 1,1,1 -Trifluoroethane has a moderate water solubility, but its high
estimated Henry's Law constant indicates that, if released to water, it will rapidly volatilize from
the water surface. Although 1,1,1-trifluoroethane may exhibit some leaching from moist soil to
groundwater or undergo runoff after a rain event, the predominant environmental fate pathway is
expected to be volatilization. The molecular formula for 1,1,1-trifluoroethane is C2H3F3. A table
of physicochemical properties for 1,1,1-trifluoroethane is provided in Table 1. The chemical
structure is shown in Figure 1.
Figure 1. Chemical Structure of l,l?l-Trifluoroethane
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Table 1. Physicochemical Properties of 1,14-Trifluoroethane (CASRN 420-46-2)
Property (unit)
Value
Physical state
Colorless, odorless gas, typically supplied as a
liquefied gas under pressure3
Boiling point (°C)
-47.5b
Melting point (°C)
-lllb
Density (g/cm3)
ND
Vapor pressure (mm Hg at 25°C)
9,540b
pH (unitless)
ND
pKa (unitless)
ND
Solubility in water (mg/L at 25°C)
760a
Octanol-water partition constant (log Kow)
1.74 (estimated)0
Henry's Law constant (atm-m3/mol at 20°C)
7.70 x 10_1 (estimated)0
Soil adsorption coefficient Koc (mL/g)
43.9 (estimated)0
Relative vapor density (air = 1)
2.9
Molecular weight (g/mol)
84.04b
"Solvav (2011).
bChemIDplus (2015).
CU.S. EPA (2012a).
ND = no data.
A summary of available toxicity values for 1,1,1-triflouroethane from U.S. EPA and
other agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for
1,1,1-Trifluoroethane (CASRN 420-46-2)
Source/
Parameter3
Value
(applicability)
Notes
Reference
Noncancer
IRIS
NV
NA
U.S. EPA (2015)
HEAST
NV
NA
U.S. EPA (201 la)
DWSHA
NV
NA
U.S. EPA (2012b)
ATSDR
NV
NA
ATSDR (2015)
WHO
NV
NA
WHO (2015)
Cal/EPA
NV
NA
Cal/EPA (2014);
Cal/EPA (2015a):
Cal/EPA (2015b)
OSHA
NV
NA
OSHA (2006b):
OSHA (2006a):
OSHA (2011)
NIOSH
NV
NA
NIOSH (2015)
ACGIH
NV
NA
ACGIH (2015)
AIHA/WEELb
1,000 ppm
(3,400 mg/m3)
8-hr TWA; Based on low acute and subchronic toxicity
in animals, analogy to other structurally related
hydrofluorocarbons (i.e., HFC-152a, HFC-134a) and
good industrial hygiene practices.
AIHA (1996):
AIHA (2011)
Cancer
IRIS
NV
NA
U.S. EPA (2015)
HEAST
NV
NA
U.S. EPA (2011a)
DWSHA
NV
NA
U.S. EPA (2012b)
NTP
NV
NA
NTP (2014)
IARC
NV
NA
IARC (2015)
Cal/EPA
NV
NA
Cal/EPA (2011):
Cal/EPA (2015a):
Cal/EPA (2015b)
ACGIH
NV
NA
ACGIH (2015)
"Sources: ACGIH = American Conference of Governmental Industrial Hygienists; AIHA = American Industrial
Hygiene Association; ATSDR = Agency for Toxic Substances and Disease Registry; 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; IRIS = Integrated Risk
Information System; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology
Program; OSHA = Occupational Safety and Health Administration; WHO = World Health Organization.
Parameters: TWA = time weighted average; WEEL = workplace environmental exposure levels.
NA = not applicable; NV = not available.
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Non-date-limited literature searches were conducted in February 2015 and updated in
September 2015 for studies relevant to the derivation of provisional toxicity values for
1,1,1-trifluoroethane (CASRN 420-46-2). 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,
CalEPA, 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
1,1,1-trifluoroethane, and include all potentially relevant short-term-, subchronic-, and
chronic-duration toxicity studies as well as developmental and reproductive toxicity studies.
Principal studies are identified. The phrase "statistical significance," used throughout the
document, indicates ap-walue of < 0.05, unless otherwise noted.
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Table 3A. Summary of Potentially Relevant Noncancer Data for 1,1,1-Trifluoroethane (CASRN 420-46-2)
Category
Number of Male/Female,
Strain, Species, Study
Type, Study Duration
Dosimetry3
Critical Effects
NO A EL1
BMDL/
BMCLa
LOAELa
Reference (comments)
Notesb
Human
1. Oral (mg/kg-d)a
ND
2. Inhalation (mg/m3)a
ND
Animal
1. Oral (mg/kg-d)a
Subchronic
ND
Chronic/
carcinogenicity
36 M/36 F (treated),
32 M/32 F (untreated
control), 40 M/40 F
(vehicle-only control),
Alpk/Ap Wistar-derived, rat,
gavage, 5 d/wk for 52 wk
(sacrifice at Wk 125)
0, 300
ADD: 0,214
Significantly decreased
mean body weight in
males from Wk 28-88
ND
NA
ND
Lonestaff et al. (1984)
(Uncertainty in dose
received [see text] and
magnitude of
body-weight change
precludes effect level
identification)
PR
Reproductive
ND
Developmental
ND
2. Inhalation (mg/m3)a
Short-term
Initial experiment:
10 M/10 F, Crl:CDBR, rat,
nose-only, inhalation, 6 hr/d,
5 d/wk, 4 wk
Repeat experiment:
10 M/0 F, Crl:CDBR, rat,
whole-body, inhalation,
6 hr/d, 5 d/wk, 4 wk
0, 2,000, 10,000,
40,000 ppm
HEC: 0, 1,228, 6,138,
24,550
No treatment-related
effects
24,550
NA
ND
Brock et al. (1996)
(NOAEL determination
based on the absence of
exposure-related effects
in the repeat
experiment)
PR
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Table 3A. Summary of Potentially Relevant Noncancer Data for 1,14-Trifluoroethane (CASRN 420-46-2)
Category
Number of Male/Female,
Strain, Species, Study
Type, Study Duration
Dosimetry3
Critical Effects
NO A EL1
BMDL/
BMCLa
LOAELa
Reference (comments)
Notesb
Subchronic
20 M/20 F, Crl:CDBR rat,
whole-body inhalation,
6 hr/d, 5 d/wk, 90 d
0,2,000,10,000,
40,000 ppm
HEC: 0,1,228,
6,138, 24,550
No treatment-related
effects
24,550
NA
ND
Brock et al. (1996)
PR,
PS
Developmental
0 M/25 F, Crl:CDBR rat,
whole-body inhalation,
6 hr/d, GDs 6-15
0, 2,000, 10,000,
40,000 ppm
HEC: 1, 1719, 8,593,
34,380
No treatment-related
effects
34,380
NA
ND
Brock et al. (1996)
PR
Developmental
0 M/24 F, New Zealand,
rabbit, whole-body
inhalation, 6 hr/d, GDs 6-18
0, 2,000, 10,000,
40,000 ppm
HEC: 0, 1,719, 8,593,
34,380
No treatment-related
effects
34,380
NA
ND
Brock et al. (1996)
PR
aDosimetry: Values are presented as adjusted daily dose (ADD, in mg/kg-day) for oral noncancer effects and as human equivalent concentration (HEC, in mg/m3) for
inhalation noncancer effects.
bNotes: PS = principal study; PR = peer reviewed.
Treatment/exposure duration (unless otherwise noted): Short-term = repeated exposure for >24 hours <30 days (U.S. EPA. 20021: long-term (subchronic) = repeated
exposure for >30 days <10% lifespan for humans (more than 30 days up to approximately 90 days in typically used laboratory animal species) (U.S. EPA. 2002):
chronic = repeated exposure for >10% lifespan for humans (more than approximately 90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 2002).
F = female; GD = Gestation Day; M = male; NA = not applicable; ND = no data.
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Table 3B. Summary of Potentially Relevant Cancer Data for l,l?l-Trifluoroethane (CASRN 420-46-2)
Number of Male/Female,
Strain, Species, Study
BMDL/
Category
Type, Study Duration
Dosimetry3
Critical Effects
BMCLa
Reference (comments)
Notesb
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)a
Carcinogenicity
36 M/36 F (treated),
0, 300
No treatment-related neoplastic
NA
Lonestaff et al. (1984)
PR
32 M/32 F (untreated
lesions were observed
(This study is not considered an
control), 40 M/40 F
HED: 0, 51.4
adequate basis for evaluating
(vehicle-only control),
carcinogenicity because only one dose
Alpk/Ap Wistar-derived, rat,
level was tested, the dose received by
gavage, 5 d/wk, 52 wk
the animals is uncertain [see text], the
(sacrifice at Wk 125)
study did not report quantitative
information on results.)
2. Inhalation (mg/m3)
ND
aDosimetry: the units for oral exposures are expressed as human equivalent dose (HED, mg/kg-day). HED = ADD (210 mg/kg-day) x default dosimetric adjustment
factor (U.S. EPA. 201 lb).
bNotes: PR = peer reviewed.
NA = not applicable; ND = no data.
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HUMAN STUDIES
Oral Exposures
No studies investigating the toxicity or carcinogenicity of 1,1,1-trifluoroethane in humans
exposed orally were located in the available literature. Because 1,1,1-trifluoroethane exists as a
gas except at very low temperatures (its boiling point is -47.5°C), oral exposure to this
compound is unlikely except in very unusual circumstances.
Inhalation Exposures
There are very limited data on effects of 1,1,1-trifluoroethane inhalation exposure in
humans. In an acute experimental exposure study aimed at investigating the uptake, disposition,
and selected effects of 1,1,1-trifluoroethane in humans (Gunnare et aL 2007). nine male
volunteers were exposed whole-body to 1,1,1-trifluoroethane at 500 ppm (1,720 mg/m3) for
2 hours during light physical exercise. Volunteers were permitted to participate in the study
(conducted according to the Helsinki Declaration) after giving written consent and receiving
approval by the Regional Ethics Committee at Karolinska Institutet (Stockholm, Sweden). All of
the subjects in this study, although deemed healthy by an examining physician, had been
occupationally exposed to hydrofluorocarbons, and previously participated in a study of
1,1,1,2-tetrafluoroethane. Acute effects from 1,1,1 -trifluoroethane exposure were assessed by
electrocardiogram (monitored throughout exposure), questionnaires regarding perceived
discomfort with respect to irritation and CNS symptoms (including discomfort in the eyes, nose,
throat, and airways, breathing problems, headache, fatigue, nausea, and dizziness; questionnaire
administered prior to exposure, twice during exposure, and 220 minutes postexposure), and
blood analyses for inflammatory markers (C-reactive protein, amyloid A protein, fibrinogen,
D-dimer) and uric acid from samples collected prior to exposure and 21 hours postexposure.
Symptoms were rated on an ordinal scale.
There were no exposure-related effects on electrocardiographic readings or on
self-reported symptoms (Gunnare et aL 2007). The mean concentration of fibrinogen in plasma
was significantly increased after exposure (by 11%; p = 0.0006) relative to the mean
pre-exposure value; no other inflammatory marker was affected by exposure, nor was serum uric
acid. The authors did not have any explanation as to why this marker was affected when more
sensitive markers of inflammation were not. Gunnare et al. (2007) noted that they had observed
the same effect in a related study on 1,1,1,2-tetrafluoroethane, which suggested that this finding
warranted further examination. The biological significance of the finding is uncertain. Given its
brief exposure duration and limited scope, this study is not suitable for the derivation of a
reference toxicity value for 1,1,1-trifluoroethane.
In an abstract that appears to report additional results from the study published by
Gunnare et al. (2007) and Gunnare et al. (2005) reported that blood samples, collected 22 hours
after exposure, were tested for anti-CYP2El antibodies (these antibodies have been detected in
humans accidentally exposed to hydrochlorofluorocarbons). No anti-CYP2El antibodies were
detected in the blood of the nine male volunteers.
ANIMAL STUDIES
Oral Exposures
The database for the oral toxicity of 1,1,1-trifluoroethane is limited to a single
chronic-duration/carcinogenicity study in rats using a single dose level. No other oral route
toxicity studies were identified.
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Chronic-Duration/Carcinogenicity Studies
Lonsstaff et al (1984)
Alpk/Ap (Wistar-derived) 6-week-old rats (36/sex) were administered
1,1,1-trifluoroethane (99.5% pure) via gavage at 300 mg/kg-day 5 days/week for 52 weeks and
sacrificed at Week 125; this dose corresponds to an adjusted daily dose (ADD) of 214 mg/kg-day
and HED1 of 51.4 mg/kg-day. Untreated (32/sex) and vehicle-only (40/sex) control groups were
used. The test material was dissolved in corn oil and stored in pressurized, sealed containers at a
temperature of 4°C to minimize volatilization; however, stability of the test solutions was not
evaluated, and the dosing solutions were not verified analytically. All animals were examined
daily for mortality and clinical signs of toxicity. Body weights were recorded weekly for the
first 12 weeks and every 4 weeks thereafter. At study termination, all animals were subjected to
necropsy; the lungs, liver, spleen, kidneys, brain, as well as gross lesions were examined
microscopically. Statistical analysis was not described in the report.
No significant effects on mortality or clinical signs of toxicity were reported (Longstaff
et al.. 1984). The study authors reported a significant decrease in the mean body weight of
treated males (but not females) from study Weeks 28-88; however, the magnitude of the
decrease was not provided, and body-weight data were not given in the study report. No
histopathology data were shown; the study authors indicated only that there were no significant
increases in the incidence of neoplasms relative to controls (with no mention of non-neoplastic
effects). The lack of stability testing and/or analytical verification of the dosing solution is an
important limitation of this study; because 1,1,1-trifluoroethane is extremely volatile, the actual
dose received by the animals is highly uncertain in the absence of this information. Due to the
uncertainty in dose and the lack of quantitative information on results, effect levels cannot be
identified for this study, and it is not suitable for use in deriving a provisional oral reference dose
for 1,1,1-trifluoroethane.
Inhalation Exposures
The inhalation toxicity of 1,1,1-trifluoroethane has been studied in two 4-week studies in
rats, one 90-day study in rats, and in developmental toxicity studies in rats and rabbits, all
published by Brock et al. (1996). No other repeated-exposure toxicity studies were identified.
Subchronic-Duration Studies
Brock et al. (1996) (4-week study)
In an initial study, Crl CDBR rats (10/sex/group, 3-8-weeks-old) were exposed
nose-only to 1,1,1-trifluoroethane (>99.9% pure) at 0, 2,000, 10,000, or 40,000 ppm 6 hours/day,
5 days/week, for 4 weeks. Chamber atmospheres were generated by metering the vapor from a
cylinder through a flow meter into a mixing vessel where dilution air was added. The
chemical/air mixture then flowed into the chamber. Chamber concentrations were controlled by
varying the test material flow rates into the mixing vessel. These concentrations are equivalent
to 0, 6,874, 34,370, and 137,500 mg/m3. Animals were observed daily for mortality and clinical
signs of toxicity. Body weights were recorded twice per week and food consumption was
monitored weekly. Hematology (red blood cell [RBC] count, total and differential white blood
cell [WBC] counts, hematocrit [Hct], hemoglobin [Hb], and mean corpuscular volume [MCV],
hemoglobin [MCH], and hemoglobin concentration [MCHC]), clinical chemistry (activities of
alkaline phosphatase [ALP], alanine aminotransferase [ALT], aspartate aminotransferase [AST],
'HED = ADD (214 mg/kg-day) x default dosimetric adjustment factor (0.24 for rats) (U.S. EPA. 201151.
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y-glutamyl transferase [GGT], lactate dehydrogenase [LDH], creatine kinase [CK], serum
glucose, blood urea nitrogen [BUN], albumin, globulin, creatinine, bilirubin, total protein,
triglycerides, cholesterol, fluoride, sodium, potassium, chloride, and calcium), and urinalysis
(color, volume, pH, specific gravity, sediment, occult blood, glucose, protein, urobilinogen,
bilirubin, and ketones) parameters were evaluated at study termination. Ocular examinations
were conducted 1 day prior to study initiation and at study termination. All animals were
subjected to necropsy; select organ weights (of the brain, spleen, lungs, liver, kidneys, testes,
ovaries, and adrenals) were recorded. Complete histopathological examinations (>45 tissues)
were performed.
No data were shown for any of the endpoints evaluated (Brock et aL 1996). Measured
exposure concentrations were not reported; however, procedural problems (including ill-fitting
conical-restraining devices and exposure to excessively high temperatures), were noted by the
study authors. Early deaths occurred in 1/10 males exposed at 6,874 and 34,370 mg/m3 and
1/10 females exposed at 137,500 mg/m3. These deaths were not considered by the study authors
to be treatment-related. No significant clinical signs of toxicity were observed during or after
cessation of exposure. Periodic reductions in the mean body weights of male (but not female)
rats were reported in all exposure groups. No significant, exposure-related effects on food
consumption, clinical pathology, ocular examinations, or organ weights were observed.
Histopathological findings were confined to males. Male rats from all 1,1,1-trifluoroethane
exposure groups showed degenerative changes of the testes, characterized by the accumulation
of eosinophilic debris within the lumen of the seminiferous tubules; these lesions reportedly
occurred in the absence of germ cell necrosis or tubular structural changes. Although incidence
data from control animals were not provided, the study authors indicated that seven to
eight animals in each exposure group were affected. Epididymal effects (decreased sperm
density and increased exfoliated germ cell debris) were seen in conjunction with testicular
damage. Histopathological changes to the epididymis occurred in 3/10 males exposed at
6,874 mg/m3 (classified as very slight) and 7 to 8 males exposed at 34,370 and 137,500 mg/m3
(minimal to mild). No NOAEL or LOAEL is established for testicular effects because: (1) the
incidence rates in the control rats are unreported; (2) rats were exposed to extreme conditions
associated with experimental procedure problems (e.g., high temperatures in habitat); and,
(3) testicular injury could not be replicated in rats when extraneous factors were controlled (see
below).
In a follow-up experiment to determine if testicular effects were related to test substance
administration or temperature stress from the procedural problems encountered during the initial
experiment, male CrlCDBR rats (10/group) were exposed whole-body to 1,1,1-trifluoroethane
under the same exposure conditions (Brock et aL 1996). In this study, no clinical signs of
toxicity or testicular effects were observed at any exposure concentration. No further
information was provided. Combined, these two studies identify a NOAEL of 137,500 mg/m3.
No LOAEL was determined. Exposure concentrations of 6,874, 34,370, and 137,500 mg/m3
were adjusted for discontinuous exposure and converted to HECs of 1,228, 6,138, and
24,550 mg/m3 (see derivation section for details).
Brock et al. (1996) (90-Day Study)
The 90-day rat study reported in Brock et al. (1996) is considered the principal
study for derivation of the subchronic and chronic p-RfCs. Crl:CDBR rats (20 sex/group,
3-8-weeks-old; actual age not reported) were exposed whole-body to 1,1,1-trifluoroethane at 0,
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2,000, 10,000, or 40,000 ppm (0, 6,874, 34,370, and 137,500 mg/m3)6 hours/day, 5 days/week,
for 90 days. Mortality and clinical signs of toxicity were monitored daily; body weights and
food consumption were recorded weekly. Hematology, clinical chemistry, and urinalysis
parameters, organ weights, and gross and microscopic pathology were evaluated as described
previously for the 4-week studies by the same authors (Brock et aL 1996). In addition to these
endpoints, liver samples collected at study termination (from five rats/group; sex not specified)
were analyzed for hepatic P-oxidation activity (a measure of peroxisome proliferation).
No data were shown for any of the endpoints evaluated (Brock et aL 1996). No
mortality, clinical signs of toxicity, or changes in food intake were observed. Changes in body
weights (direction and magnitude not reported; statistical significance of changes not specified)
were observed "sporadically" throughout the study, but were not considered exposure-related as
the changes were inconsistent and an exposure-response relationship was not evident. No
changes in clinical pathology (hematology, clinical chemistry, or urinalysis parameters) or
P-oxidation were reported. Organ weights were unaffected by exposure; no gross or adverse
histopathological changes were noted. This study identifies aNOAEL of 137,500 mg/m3. No
LOAEL was determined. Exposure concentrations of 6,874, 34,370, and 137,500 mg/m3 were
converted to HECs of 1,228, 6,138, and 24,550 mg/m3 as described previously for the 4-week
study.
Developmental Studies
Brock et al. (1996) (rat study)
Mated female Crl CDBR (about 25/group, 3-8-weeks-old; actual age not reported) were
exposed whole-body to 1,1,1-trifluoroethane (>99.9% pure) at 0, 2,000, 10,000, or 40,000 ppm
6 hours/day on Gestation Days [GDs] 6-15. These concentrations are equivalent to 0, 6,874,
34,370, and 137,500 mg/m3. Dams were monitored daily for mortality and clinical signs of
toxicity; body weights were recorded on GDs 1, 7, 9, 11, 13, 15, 17, and at sacrifice. Food
consumption was measured over each weighing interval. No maternal toxicity endpoint data was
reported. Dams were sacrificed on GD 20. Endpoints evaluated included numbers of
resorptions, implantations, corpora lutea, and live and dead fetuses. The uteri of nonpregnant
rats were stained with ammonium sulfide to detect early resorptions. Fetuses were weighed,
sexed, and then examined for external malformations. Live fetuses were sacrificed (time point
not specified) and evaluated for visceral (including delays in renal development) and skeletal
variations. Fetuses with external malformations were likewise examined for delays in
development (no further information was provided). Preimplantation loss was calculated as a
percentage by subtracting the number of total implantations from the number of corpora lutea
divided by the number of corpora lutea. Similarly, the percentage of postimplantation loss was
determined by subtracting the number of live young from the number of total implantations
divided by the number of implantations. Litter weights and mean fetal weights were calculated
from individual fetal weights. Data from rats with whole litter loss and those that did not become
pregnant were excluded from statistical analyses. Statistical analyses were performed using the
litter as the unit of measure.
No mortality among dams or fetuses was reported (Brock et al.. 1996). Dams showed no
clinical signs of toxicity, and there were no significant effects on body weight/body-weight gain
or food consumption. No exposure-related effects on the numbers of resorptions, corpora lutea,
implantations (pre and postimplantation loss), or live and dead fetuses were observed. Fetal
body weights were unaffected by exposure. Litter data for one of the high-dose dams were
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missing from the tabulated data on malformations and variations. The publication does not
indicate any reason for this other than the statement that data from rats with whole litter loss and
those that were not pregnant were excluded; however, the dam was apparently pregnant as it was
included in the data on corpora lutea, implants, resorptions, live young, and fetal weights. The
incidence of total malformations (combined across skeletal, soft tissue, and external) in the
exposed groups was not significantly different from controls (data for individual types of
malformations were not provided by the study authors).
No external variations were observed in any group. When all variations (visceral and
skeletal) were combined, the mean percentage per litter of fetuses with variations was
statistically significantly increased at the highest concentration, with mean values of 7.9, 12.8,
12.6, and 16.7% for the control, low-, mid-, and high-concentration groups, respectively
(see Table B-l). The mean percentage per litter of fetuses with visceral variations due to delayed
development was statistically significantly increased at all concentrations relative to the control
group, with mean percentages of 1.6, 10.5, 8.7, and 10.0% for the control, low-, mid-, and
high-concentration groups, respectively (see Table B-l) (Brock et aL 1996). The percentages
per litter of fetuses with skeletal variations owing to delayed development were not provided in
the study report. The increased incidence in visceral variations was attributable to patent ductus
arteriosus and small papilla; the increase in skeletal variations was attributed to wavy ribs,
partially ossified/unossified skull, partially ossified sternebra, and partially ossified vertebra (see
Table B-l). The incidences of skeletal variations in exposed animals did not differ significantly
from the incidences in controls, and there were no indications of dose-response relationships in
the incidences of skeletal variations (see Table B-l).
The study authors considered the significant increase in visceral variations at all
concentrations to be a reflection of an unusually low incidence (1.6%) in the control group. The
historical control range for visceral variations in developmental inhalation toxicity studies in rats
for the laboratory ranges from 6.8-16.2%), with a mean of-10.5%. Thus, the incidence of
visceral variations in the control group for this study is not within the historical control range.
Furthermore, the historical control average is similar to the mean observed for the
1,1,1-trifluoroethane-exposed groups for visceral variations in this study. This unusually low
incidence in the control also affects the total variations (which includes visceral variations). It is
also important to note that the numbers of litters with all variations actually decreases with dose.
Based on the rational above and because no other developmental effects were observed, the
increased incidence of visceral variations in this study is not considered by U.S. EPA to be
clearly related to exposure to 1,1,1-trifluoroethane. As no effects that were considered to be
treatment-related occurred, the NOAEL for maternal and developmental toxicity is
137,500 mg/m3, and no LOAEL is identified. Exposure concentrations in this study were
equivalent to HECs of 0, 1,719, 8,593, and 34,380 mg/m3 based on an adjustment for
discontinuous exposure of 6 hours/day, and the default value of 1 for the ratio of blood:air
partition coefficients between rats and humans.
Brock a ul. (1996) (rabbit study)
In a developmental toxicity study, artificially inseminated New Zealand 4-5-month-old
female rabbits (24/group) were exposed to 1,1,1-trifluoroethane (>99.9% pure) at concentrations
of 0, 2,000, 10,000, or 40,000 ppm via whole-body inhalation for 6 hours daily on GDs 6-18.
These concentrations are equivalent to 0, 6,874, 34,370, and 137,500 mg/m3, respectively.
Although chamber concentrations were monitored periodically during the exposures, measured
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1,1,1-trifluoroethane concentrations were not reported. The animals were observed daily for
clinical signs and were weighed on GDs 0, 6-19, 24, and 29. Food consumption was determined
daily. No maternal toxicity endpoint data were reported. On GD 29, the maternal animals were
sacrificed and the internal organs evaluated for gross abnormalities. The ovaries and uteri were
examined for the number of corpora lutea, live young, early and late embryo/fetal deaths, and
fetal abnormalities. Total litter weights were calculated from individual fetal weights. The same
criteria as described above for the developmental toxicity study in rats (Brock et aL 1996) were
used to evaluate fetal deaths. Uteri without macroscopic evidence of nidation were examined for
early implantation loss. Live young were examined externally for malformations. Visceral and
skeletal malformations and variations were characterized.
No clinical signs were noted in maternal animals at any exposure level during or after the
exposures (Brock et aL 1996). No statistically significant effects on maternal body weights,
body-weight gains, or food consumption were noted. There were no treatment-related effects on
corpora lutea or implants. A slight increase in the incidence of combined (external, skeletal, and
soft tissue) malformations, expressed as mean percentage per litter, was observed in the low- and
high-concentration groups, with values of 3.1, 8.2, 3.4, and 7.1% for the control, low-, mid-, and
high-concentration groups, respectively; however, these changes were not statistically significant
(see Table B-2). The authors noted that the increase was primarily related to an increase in
skeletal malformations at the low and high concentrations; the percentage incidences per litter
were as follows: 1.5, 7.5, 3.4, and 6.3% for the control, low-, mid-, and high-concentration
groups, respectively. The incidences of external and soft tissue malformations were similar to
controls. The increase in skeletal malformations was primarily associated with rib anomalies
(e.g., extra site of ossification) and vertebral anomalies. No clear concentration-response
relationship was apparent for either the types or numbers of malformations, and the incidence in
all dose groups was well within the historical laboratory control range for total malformations
(0-12.9%)). The study authors considered the modest increases in skeletal malformations at the
low and high concentrations to be unrelated to 1,1,1-trifluoroethane exposure. The skeletal or
visceral variations are considered not treatment-related effects based on Carney and Kimmel
(2007). As no effects that were considered to be treatment-related occurred, the NOAEL for
maternal and developmental toxicity is 137,500 mg/m3, and no LOAEL is identified. Exposure
concentrations in this study were equivalent to HECs of 0, 1,719, 8,593, and 34,380 mg/m3 based
on an adjustment for discontinuous exposure of 6 hours/day, and the default value of 1 for the
ratio of blood:air partition coefficients between rabbits and humans.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Acute Toxicity
Brock et al. (1996) also evaluated the acute lethality of 1,1,1-trifluoroethane in rats.
Crl CDBR rats (6 males/group, 3-8-weeks-old; actual age not reported) were administered
1,1,1-trifluoroethane (>99.9% pure) at concentrations of 97,000 (333,400 mg/m3) or
540,000 ppm (1,856,000 mg/m3) via nose-only exposure for 4 hours. The animals were weighed
and observed for clinical signs during a 14-day postexposure observation period. No mortalities
or treatment-related clinical signs occurred during the study. Body-weight losses were observed
at both concentrations on the day following exposure. The body-weight losses were considered
to be slight at the low concentration (<10 g/rat) and moderate to severe at the high concentration
(10 - >20 g/rat); however, bodyweight data were not provided in the study report. Normal
body-weight gains were observed by postexposure Day 2 and throughout the remainder of the
14-day observation period. The results of this study are consistent with other acute lethality
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studies on other hydrofluorocarbons (ECETOC. 2006). which show median lethal concentration
(LC50) values >500,000 ppm.
A study of the cardiac sensitization potential of 1,1,1-trifluoroethane was also reported by
Brock et al. (1996). Male Beagle dogs (5-6/group, 16-20-months-old) were administered
1,1,1-trifluoroethane (>99.9% pure) at concentrations of 0, 50,000, 100,000, 150,000, 200,000,
250,000, or 300,000 ppm (171,860, 343,720, 515,580, 687,440, 859,310, and 1,031,200 mg/m3)
via single-pass-through face mask while the dog was restrained in a canvas sling (the dogs had
been previously trained to accept this sling). Electrocardiogram (ECG) leads were placed on
each dog and the ECG was recorded throughout the 17-minute exposure pretest. After 2 minutes
of breathing only room air, a subthreshold intravenous dose of epinephrine (i.e., control dose at
2-12 |ig/kg determined based on a preliminary study to confirm the tolerable dose for each dog)
was administered to each dog in order to establish a background ECG response. Five minutes
after the control dose of epinephrine was administered, vapor administration of
1,1,1-trifluoroethane was initiated for 10 minutes. After 5 minutes of 1,1,1-trifluoroethane
exposure, epinephrine was administered again, and changes in the ECG recording were noted.
Evidence of cardiac sensitization was determined if multiple ectopic beats (>5) or ventricular
fibrillation was observed.
No evidence of cardiac sensitization was observed at 171,860, 343,720, or
5 15,580 mg/m3 (Brock et al. 1996). At 687,440 mg/m3, 1/6 dogs exhibited an equivocal
response consisting of two ectopic beats with normal sinus rhythm occurring between the ectopic
beats. At 859,300 mg/m3, however, none of the dogs exhibited an arrhythmia, including the dog
that previously showed an equivocal response at 687,440 mg/m3. Therefore, the response
observed in the one dog exposed to 687,440 mg/m3 was classified as a negative response. At
1,031,200 mg/m3, 2/5 dogs showed evidence of a cardiac sensitization response, including
multiple ectopic beats or a burst of ventricular fibrillation. Another dog exhibited whole-body
tremors, verging on convulsions, a response that interferes with the ECG readings; thus, no
higher concentrations of 1,1,1-trifluoroethane were tested. The study authors concluded that
1,031,200 mg/m3 represented the threshold for cardiac sensitization in dogs under the conditions
of the study.
Genotoxicity
1,1,1-Trifluoroethane did not induce gene mutations in Salmonella typhimurium strains
TA97, TA98, TA100, TA1535, TA1537, or TA1538, or in Escherichia coli strain WP2uvrA,
either in the presence or absence of metabolic activation (Brock et al.. 1996). Although an
additional study (Longstaff et al.. 1984; Central Toxicol Lab. 1976) also showed that mutations
were not induced in strains TA98 and TA1538, this study showed that 1,1,1-trifluoroethane was
positive for gene mutations in strains TA100 and TA1535, both with and without metabolic
activation. The reason(s) for the discrepancy in results between the studies conducted by Brock
et al. (1996) and Longstaff et al. (1984) is unknown. However, the 50% concentration (above
the explosive concentration) in the Longstaff et al. (1984) studies may have had nonspecific
mutagenic effects (changes in pH, etc) that could account for the discrepancy.
1,1,1-Trifluoroethane was negative for cell transformation (Styles assay) in BHK21 cells in the
presence of metabolic activation (Longstaff et al.. 1984). 1,1,1 -Trifluoroethane did not induce
chromosomal aberration in vitro in cultured human lymphocytes, either with or without
metabolic activation (Brock et al.. 1996). The frequency of micronuclei was not increased in
polychromatic erythrocytes of 7-week-old mice exposed to 1,1,1-trifluoroethane via inhalation
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6 hours/day for 2 days (Brock et aL 1996). Table 4 provides an overview of genotoxicity studies
of 1,1,1 -trifluoroethane.
Metabolism/Toxicokinetic Studies
1,1,1-Trifluoroethane is absorbed rapidly after inhalation exposure. As part of the acute
human exposure study by Gunnare et al. (2007). the toxicokinetics of 1,1,1-trifluoroethane were
evaluated in nine male volunteers exposed for 2 hours to 500 ppm (1,720 mg/m3) during light
physical exercise. Samples of the volunteers' blood, urine, and exhaled air were collected
before, during, and for up to 19 hours after the end of exposure, for analysis of
1,1,1-trifluoroethane by gas chromatography. Concentrations in blood rapidly (within a few
minutes) reached steady-state and remained unchanged during the exposure period. At the end
of exposure, blood levels declined rapidly; 1,1,1-trifluoroethane could not be detected in blood
1 day after exposure. Analysis of exhaled air showed no measureable differences between the
concentration in inhaled and exhaled air, suggesting low respiratory uptake. As with blood
levels, 1,1,1-trifluoroethane levels in exhaled air declined rapidly upon cessation of exposure,
with a decay time profile parallel to that of blood. Small amounts of unchanged
1,1,1-trifluoroethane were measured in the urine. Based on analysis of urine samples, the
half-life of 1,1,1-trifluoroethane in urine was calculated to be 53 minutes. Total urinary
excretion was estimated to represent 0.0007% of the amount inhaled, suggesting very poor
absorption; however, the study authors indicated that absorption could not be estimated from the
experimental data.
The measured blood and exhaled air levels were in good agreement with values simulated
using a perfusion-limited physiologically based toxicokinetic model developed by (Ernstgard et
al.. 2014; Gunnare et al.. 2007). The model predicted that relative respiratory uptake of
1,1,1-trifluoroethane was -2% of the inhaled dose.
Ernstgard et al. (2010) measured the blood:air partitioning coefficient for
1,1,1-trifluoroethane in human blood using a modified head-space vial equilibrium method. The
blood:air partitioning coefficient for 1,1,1-trifluoroethane was 0.15. No experimental data on the
blood:air partitioning of 1,1,1-trifluoroethane in rat blood were available. Loizou et al. (1996)
estimated the rat blood:air partitioning coefficient for 1,1,1-trifluoroethane based on the
relationship between measured rat blood:air partitioning for other trihaloethanes and the amount
retained in the body in rats exposed via inhalation. The estimated value for 1,1,1-trifluoroethane
was 0.91.
Mechanistic Studies
Loizou et al. (1996) exposed rats to concentrations of 0, 10,000, 15,000, 20,000, or
30,000 ppm 1,1,1-trifluoroethane (34,370, 51,555, 68,740 and 103,110 mg/m3, respectively) for
3 hours. Blood was collected 2 hours later for analysis of serum sorbitol dehydrogenase (SDH),
glutamate dehydrogenase (GDH), and LDH. In addition, glutathione and glutathione disulfide
levels in liver and lung were measured. No changes to serum dehydrogenase levels were
observed at any concentration. Total glutathione in the liver was significantly decreased at all
exposure levels; glutathione disulfide levels were not affected in either organ, nor were
glutathione levels in the lung. The authors attributed the decline in liver glutathione to P450
uncoupling (in which the fluorinated compound forms a P450-substrate complex, triggering
electron flow to the cytochrome and oxygen activation), which leads to formation of reactive
oxygen species.
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Table 4. Summary of 1,1,1-Trifluoroethane Genotoxicity Studies
Endpoint
Test System
Doses/Concentrations Tested
Results
Without
Activation3
Results With
Activation3
Comments
References
Genotoxicity studies in prokaryotic organisms
Mutation
S. typhimurium strains
TA97, TA98, TA100,
TA1535 (Test 1);
S. typhimurium strains
TA98, TA100,
TA1535, TA1537,
TA1538 (Test 2)
Test 1: 0, 0.5, 1.5, 2.5, 3.5% (v/v)
(±S9) (gas dissolved in liquid)
Test 2: 0, 20, 40, 60, 80,100%
(Trial 1;-S9); 0, 10, 30, 50, 70,
90% (Trial 2; ±S9) (gas in air
space)
Preincubation assay (closed
vessels at 37°C for 48 hr).
Exposure concentrations were
changed after the first trial of
Test 2 because of difficulty in
generating a vapor with 100%
concentration.
Brock et al.
(1996)
Mutation
S. typhimurium strain
TA98, TA100,
TA1535, TA1538
Test 1:0, 1,33,50%
Test 2: 50% (TA100 and TA1535
only)
+
TA100,
TA1535
TA98,
TA1538
+
TA100,
TA1535
TA98,
TA1538
Modified Ames assay for testing
gases; incubation for 24 hr
(Test 1) or 48 hr (Test 2). Gas In
air space.
Longstaff et al.
(1984): Central
Toxicol Lab
(1976)
Mutation
E. coli strain
WP2uvrA (pkm 101)
(Test 1);
E. coli strain
WP2uvrA (Test 2)
Test 1: 0, 0.5, 1.5, 2.5, 3.5% (v/v)
(±S9) (gas dissolved in liquid)
Test 2: 0, 20, 40, 60, 80,100%
(Trial 1;-S9); 0, 10, 30, 50, 70,
90% (Trial 2; ±S9) (gas in air
space)
Preincubation assay (closed
vessels at 37°C for 48 hr).
Exposure concentrations were
changed after the first trial of
Test 2 because of difficulty in
generating a vapor with 100%
concentration.
Brock et al.
(1996)
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Table 4. Summary of 1,1,1-Trifluoroethane Genotoxicity Studies
Endpoint
Test System
Doses/Concentrations Tested
Results
Without
Activation3
Results With
Activation3
Comments
References
Genotoxicity studies in mammalian cells in vitro
Chromosomal
aberrations
Human lymphocytes
0, 17,190, 51,560, 95,930, 120,
300 mg/m3
No significant increase in the
frequency of aberrations at
95,930 or 120,300 mg/m3.
Scoring was not conducted at
17,190 and 51,560 mg/m3
because of the lack of findings at
higher concentrations.
Brock et al.
(1996)
Cell
transformation
BHK21 cells
NR
NA
-
No significant increase in cell
transformation.
Longstaff et al.
(1984)
Genotoxicity studies in vivo
Mouse bone
marrow MN test
(inhalation)
Mice (5/sex/group;
unspecified strain)
exposed 6 hr/d for
2 consecutive days,
and sacrificed
24-48 hr after second
exposure for analysis
of bone marrow
smears
0, 2,000, 10,000, 40,000 ppm
(0, 6,874, 34,370, 137,500 mg/m3)
No significant increase in
micronucleated polychromatic
erythrocytes.
Brock et al.
(1996)
NA = not available; NR = not reported.
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DERIVATION OF PROVISIONAL VALUES
Tables 5 and 6 present summaries of noncancer and cancer reference values, respectively.
Table 5. Summary of Reference Values for 1,14-Trifluoroethane (CASRN 420-46-2)
Toxicity Type (units)
Species/
Sex
Critical
Effect
p-Reference
Value
POD
Method
POD
UFc
Principal Study
Subchronic p-RfD (mg/kg-d)
NDr
Chronic p-RfD (mg/kg-d)
NDr
Subchronic p-RfC (mg/m3)
Rat, M/F
NR
2 x 102
NOAELhec
24,550
100
Brock et al. (1996)
Chronic p-RfC (mg/m3)
Rat, M/F
NR
2 x 101
NOAELhec
24,550
1,000
Brock et al. (1996)
NDr = not determined; NR = none reported.
Table 6. Summary of Cancer Values for 1,14-Trifluoroethane (CASRN 420-46-2)
Toxicity Type
Species/Sex Tumor Type Cancer Value Principal Study
Provisional oral slope factor (p-OSF)
NDr
Provisional inhalation unit risk (p-IUR)
NDr
NDr = not determined.
DERIVATION OF ORAL REFERENCE DOSES
The database for oral exposure to 1,1,1-trifluoroethane is limited to a single
chronic-duration study of rats exposed by gavage (Longstaff et aL 1984). In this study, a
significant decrease in the mean body weight of treated males (but not females) from study
Weeks 28-88 was reported, but the magnitude of change was not provided and body-weight data
were not given. No other effects were observed. Longstaff et al. (1984) did not perform
analytical verification of the dosing solutions. Because 1,1,1-trifluoroethane is extremely
volatile, the actual doses received by the animals are highly uncertain in the absence of analytical
verification. Due to the uncertainty in doses and the lack of quantitative information on results,
these data are not considered to be suitable for use in deriving a provisional oral RfD for
1,1,1 -trifluoroethane.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
The peer-reviewed experiments published by Brock et al. (1996) include short-term,
subchronic, and developmental toxicity assays in rats, and a developmental toxicity study in
rabbits. None of these studies identified any statistically or biologically significant health effects
attributable to 1,1,1-trifluoroethane exposure at HEC concentrations as high as 24,550 mg/m3 for
90 days or 34,380 mg/m3 during gestation. The Brock et al. (1996) experiments, along with an
acute lethality and a cardiac sensitization experiment described in the same publication, comprise
the entire database of information on inhalation toxicity of 1,1,1-trifluoroethane in experimental
animals. In the acute lethality and cardiac sensitization studies, no mortality was seen among
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groups of six rats exposed for 4 hours to concentrations up to 1,856,000 mg/m3, but evidence for
cardiac sensitization was observed in dogs exposed to 1,031,200 mg/m3 1,1,1-trifluoroethane for
10 minutes.
The low systemic toxicity of 1,1,1-trifluoroethane is supported by toxicokinetic studies
indicating low absorption of this compound after inhalation exposure, and by similar findings in
studies of the related compound, 1,1-difluoroethane. The IRIS chronic RfC for
1,1-difluoroethane is based on aNOAEL of 67,500 mg/m3 (25,000 ppm) from a 2-year
inhalation study (U.S. EPA, 2005).
1,1,1-Trifluoroethane is flammable at concentrations >240,000 mg/m3 (70,000 ppm)
(Brock et al, 1996). Thus, it is unlikely that repeated exposure toxicity testing will be performed
at concentrations much higher than those already tested (137,500 mg/m3 or 40,000 ppm).
Derivation of Subchronic p-RfC
The NOAELhec of 24,550 mg/m3 from the 90-day principal study (Brock et al.. 1996) is
chosen as the POD for the derivation of a subchronic p-RfC, because this experiment used the
longest exposure duration and examined comprehensive toxicity endpoints. Because there were
no significant responses at the highest concentration tested, BMD modeling is not conducted;
thus, the NOAELhec is used as the POD. The NOAELhec was calculated based on
extrarespiratory effects, as the only health effect observed in any of the experiments by Brock
et al. (1996) was cardiac sensitization in dogs.
Exposure concentration adjustment for continuous exposure:
NOAELadj = NOAEL x (MW ^ 24.45) x (hours exposed ^ 24) x (days
exposed ^ 7 days)
= 40,000 ppm x (84.04 ^ 24.45) x (6 hours ^ 24 hours) x (5 days ^ 7 days)
= 24,550 mg/m3
HEC conversion for extrarespiratory effects:
NOAELhec = NOAELadj x DAF;
DAF (dosimetric adjustment factor for the specific site of effects such as
extrarespiratory regions).
The DAF for gases/vapors with toxicity effects at sites remote of the respiratory
tract (extrarespiratory effects) is based on the ratio of the animal blood:gas
partition coefficient (Hb/g-animai) and the human blood:gas partition coefficient
(Hb/g-human) •
DAF = ([Hb/g]A - [Hb/g]H)
[The value of 1.0 is used when the rat partition coefficient exceeds the human
partition coefficient, as recommended by U.S. EPA (1994b). 1
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NOAELhec — NOAELadj x DAF
= 24,550 x 1.0
= 24,550 mg/m3
The provisional subchronic p-RfC of 2 x 102 mg/m3 was calculated as follows:
Provisional Subchronic p-RfC = NOAELhec ^ UFc
24,550 mg/m3- 100
2 x 102 mg/m3
The uncertainty factors are described in Table 7.
Table 7. Uncertainty Factors for the Subchronic p-RfC for 1,14-Trifluoroethane
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty associated with extrapolating from
animals to humans when cross-species dosimetric adjustment (HEC calculation) is
performed.
UFh
10
A UFh of 10 is applied to account for human variability in susceptibility, in the absence of
information to assess toxicokinetic and toxicodynamic variability of 1,1,1 -trifluoroethane
in humans.
UFd
3
A UFd of 3 is applied because there are two 4-wk studies and a subchronic study conducted
in rats and developmental toxicity studies in rats and rabbits via the inhalation route;
however, there are no two-generation reproduction studies.
UFl
1
A UFl of 1 is applied because the POD is a NOAEL.
UFS
1
A UFS of 1 is applied because a subchronic study is utilized as the principal study.
UFC
100
Composite UF = UFA x UFH x UFD x UFL x UFS.
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The confidence descriptors for the subchronic p-RfC are explained in Table 8.
Table 8. Confidence Descriptors for Subchronic p-RfC for 1,1,1-Trifluoroethane
Confidence
Categories
Designation
Discussion
Confidence in
study
M
The principal study included appropriate numbers of animals in exposure and control
groups for meaningful statistical analyses and assessment of a wide range of
toxicological endpoints (clinical signs, body weight, food consumption, hematology,
serum chemistry, urinalysis, selected organ weights, and comprehensive gross and
microscopic pathology). The major factor restricting confidence in the principal
study is the failure to include an exposure concentration high enough to permit
identification of a LOAEL.
Confidence in
database
M
Confidence in the database is medium. The inhalation database for noncancer effects
of 1,1,1-trifluoroethane consists of two 4-wk studies in rats, a subchronic study in
rats, and developmental toxicity studies in rats and rabbits. There are no pertinent
human data, and no reproductive toxicity studies in animals.
Confidence in
subchronic
p-RfC
M
The overall confidence in the subchronic p-RfC for 1,1,1-trifluoroethane is medium.
M = medium.
Derivation of Chronic p-RfC
In the absence of chronic data from which to derive the provisional chronic p-RfC, the
NOAELhec from the subchronic experiment (Brock et aL 1996) is selected as the POD for the
provisional chronic p-RfC.
The provisional chronic p-RfC of 2 x 10 mg/m3 is derived as follows:
Provisional chronic p-RfC = NOAELhec ^ UFc
24,550 mg/m3-1,000
= 2 x 101 mg/m3
The uncertainty factors are described in Table 9.
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Table 9. Uncertainty Factors for the Chronic p-RfC for 1,1,1-Trifluoroethane
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty associated with extrapolating from
animals to humans when cross-species dosimetric adjustment (HEC calculation) is
performed.
UFh
10
UFh of 10 is applied to account for human variability in susceptibility, in the absence of
information to assess toxicokinetic and toxicodynamic variability of 1,1,1-trifluoroethane in
humans.
UFd
3
A UFd of 3 is applied because there are two 4-wk studies and a subchronic study conducted
in rats and developmental toxicity studies in rats and rabbits via the inhalation route;
however, there are no two-generation reproduction studies.
UFl
1
A UFl of 1 is applied because the POD is a NOAEL.
UFS
10
A UFS of 10 is applied because a subchronic study is used as the principal study, and there
is no chronic study in the database.
UFC
1,000
Composite UF = UFA x UFH x UFD x UFL x UFS.
The confidence descriptors for the chronic p-RfC are explained in Table 10.
Table 10. Confidence Descriptors for Chronic p-RfC for l,l?l-Trifluoroethane
Confidence Categories
Designation
Discussion
Confidence in study
M
The study included appropriate numbers of animals in exposure and
control groups for meaningful statistical analyses and assessment of a
wide range of toxicological endpoints (clinical signs, body weight, food
consumption, hematology, serum chemistry, urinalysis, selected organ
weights, and comprehensive gross and microscopic pathology). The
major factor restricting confidence in the principal study is the failure to
include an exposure concentration high enough to permit identification
of a LOAEL.
Confidence in database
L
Confidence in the database is low. The inhalation database for
noncancer effects of 1,1,1-trifluoroethane consists of two 4-wk studies
in rats, a subchronic study in rats, and developmental toxicity studies in
rats and rabbits. There are no pertinent human data, and no chronic and
reproductive toxicity studies in animals. All of the available
experiments were conducted bv Brock et al. (1996). and apart from
cardiac sensitization after acute exposure to a very high concentration,
no health effects were observed.
Confidence in chronic
p-RfC
L
The overall confidence in the subchronic p-RfC for
1,1,1-trifluoroethane is low.
M = medium; L = low.
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CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
Table 11 provides the cancer WOE descriptor for 1,1,1-trifluoroethane.
Table 11. Cancer Weight-of-Evidence Descriptor for 1,1,1-Trifluoroethane
Possible WOE
Descriptor
Designation
Route of
Entry (oral,
inhalation, or
both)
Comments
"Carcinogenic to
Humans "
NS
NA
NA
"Likely to Be
Carcinogenic to
Humans "
NS
NA
NA
"Suggestive
Evidence of
Carcinogenic
Potential"
NS
NA
NA
"Inadequate
Information to
Assess
Carcinogenic
Potential"
Selected
Both
No studies assessing the carcinogenicity of
1,1,1-trifluoroethane in humans exposed by any route or in
animals exposed by inhalation are available in the
literature. Lonsstaff et al. (1984) evaluated the
carcinogenicity of 1,1,1-trifluoroethane administered by
gavage to rats for 52 wk; however, this study is not
considered an adequate basis for evaluating carcinogenicity
because only 1 dose level was tested, the dose received by the
animals is uncertain, the study did not report quantitative
information on results, and the exposure duration and
observation period were less than the animals' lifespan.
"Not Likely to Be
Carcinogenic to
Humans "
NS
NA
NA
NA = not applicable; NS = not selected.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
There are insufficient data to assess the carcinogenic potential of 1,1,1-trifluoroethane via
any route; therefore, derivation of provisional cancer potency values is precluded.
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APPENDIX A. SCREENING PROVISIONAL VALUES
No provisional screening values were derived.
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APPENDIX B. DATA TABLES
Table B-l. Developmental Toxicity of l,l?l-Trifluoroethane in Rats"
Endpoint
Exposure Concentration in mg/m3 (ppm)
0
6,874
(2,000)
34,370
(10,000)
137,500
(40,000)
Malformations and variations
Number of fetuses examined for malformations'3 (litters)
341 (22)
357 (24)
352 (23)
273 (19)
Number of fetuses with malformations'5 (litters)
2(2)
0(0)
1(1)
0(0)
Mean percent of fetuses with malformations'3 per litter
0.6
0
0.4
0
Number of fetuses examined for visceral variations0 (litters)
178 (22)
185 (24)
181 (23)
142 (19)
Number of fetuses with visceral variations0 (litters)
3(3)
19(11)
15(8)
14 (9)
Mean percent of fetuses with visceral variations0 per litter
1.6
10.5*
8.7*
10.0*
Number of fetuses with all variations'1 (litters)
27 (17)
42 (16)
42 (18)
48 (14)
Mean percent of fetuses with all variations'1 per litter
7.9
12.8
12.6
16.7*
Visceral variations
Number of fetuses with patent ductus arteriosus (litters)
0
0
5(1)
1(1)
Number of fetuses with small papilla (litters)
3(3)
19(11)
10 (8)
13(8)
Skeletal variations
Number of fetuses with wavy ribs (litters)
3(2)
2(2)
0
2(1)
Number of fetuses with skull partially ossified (litters)
8(7)
13(9)
11(5)
13(7)
Number of fetuses with sternebra partially ossified (litters)
2(2)
4(2)
2(5)
5(4)
Number of fetuses with vertebra partially ossified (litters)
14(7)
6(4)
14 (9)
19(7)
"Brocketal. (1996).
bCombined incidence of skeletal, soft tissue, and external malformations.
°Visceral variations due to delayed development (does not include skeletal or external variations).
dTotal variations due to delayed development; includes visceral, external, and skeletal variations.
* Significantly different (p < 0.05) by Jonckheere's test variation (performed by the study authors).
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Table B-2. Developmental Toxicity Potential of 1,1,1-Trifluoroethane in Rabbits"
Endpoint
Exposure Concentration in mg/m3 (ppm)
0
6,874
(2,000)
34,370
(10,000)
137,500
(40,000)
Malformationsb and variations
Number of fetuses examined for malformations (litters)
98 (21)
147 (22)
125 (19)
149 (24)
Number of fetuses with malformations (litters)
4(3)
14(7)
5(2)
5(5)
Mean percent of fetuses with malformations/litter
3.1
8.2
3.4
7.1
Mean percent of fetuses with visceral variations/litter
20.1
23.4
14.5
16.1
Mean percent of fetuses with skeletal variations/litter
67.5
62.4
66.6
60.0
Mean percent of fetuses with total variations/litter
71.4
69.1
69.1
69.1
"Brock et al. (1996).
bCombined incidence of skeletal, soft tissue, and external malformations.
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APPENDIX C. BENCHMARK DOSE MODELING RESULTS
There are no benchmark dose (BMD) modeling outputs.
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