TECHNICAL REPORT DATA
(flette re*d Instruction! on the reverie before completing)
1. REPORT NO.
EPA/600/8-88/041
2.
3. "ECIPI
4. TITLE AND SUBTITLE
Health Effects Assessment for Fully halogenated
Methanes
ft. REPORT DATE
. PERFORMING ORGANIZATION CODE
AUTHOR(S)
. PERFORMING ORGANIZATION REPORT NO.
9. ftCRFORMING ORGANIZATION NAME ANO ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME ANO ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in 'these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfD$ or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogen!city, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
t. DISTRIBUTION STATEMENT
Public
It. SECURITY CLASS (Thu Report)
Unclassified
21. NO. OF PAGES
2O. SECURITY CLASS
Unclassified
22. PRICE
EPA Per* 3270-1 (R«v. 4-77) PREVIOUS (DITION is OMOLKTK
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EPA/600/8-88/041
June, 1987
HEALTH EFFECTS ASSESSMENT
FOR FULLY HALOGENATEO METHANES
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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DISCLAIMER
This document has been reviewed 1n accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with selected
fully halogenated methanes. All estimates of acceptable Intakes and
carcinogenic potency presented In this document should be considered as
preliminary reflecting limited resources allocated to this project.
Pertinent toxlcologlc and environmental data were located through on line
literature searches of the Chemical Abstracts, TOXLINE, CANCERLINE and the
CHEMFATE/DATALOG data bases. The basic literature searched supporting this
document 1s current up to March, 1986. Secondary sources of Information
have also been relied upon 1n the preparation of this report and represent
large scale health assessment efforts that entail extensive peer and Agency
review. The following Office of Health and Environmental Assessment (OHEA)
sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for
Halomethanes. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati . OH for the Office of Water Regulations and Standards, Wash-
ington, DC. EPA 440/5-80-051. NTIS PB81-117624.
U.S. EPA. 1982. Errata for Ambient Water Quality Criteria
Document for Halomethanes. Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Water Regulations and
Standards, Washington, DC.
U.S. EPA. 1986b. Integrated Risk Information System (IRIS).
Reference dose (RfD) for oral exposure for dichlorodlfluoromethane.
Online. (Verification date 7/22/85). Office of Health and
Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH.
U.S. EPA. 1986c. Integrated Risk Information System (IRIS).
Reference dose (RfD) for oral exposure for trlchlorotrlfluoro-
methane. Online. (Verification date 7/8/85). Office of Health
and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH.
The Intent In these assessments 1s to suggest acceptable exposure levels
for noncarclnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
111
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Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, Is
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants In ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfO$i) and oral (RfD$0)
exposures.
The RfD (formerly AIC) 1s similar In concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the llfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfO Is route-specific and estimates acceptable exposure for either oral
(RfDg) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained In U.S.
EPA (1983).
For compounds for which there 1s sufficient evidence of carclnogenlclty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer Is a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data If available.
1v
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
The RfD$o estimated for tMchlorofluoromethane (F-ll) 1s 50 mg/day,
which Is based on a 6-week feeding study using rats (NCI, 1978). This study
Is weak 1n that the only endpolnts examined were mortality and body weight
depression. The RfDg estimate for F-ll, 20 mg/day, which has been
verified by the U.S. EPA (1986b) as an ADI 1s based on a 2-year feeding
study using rats (NCI, 1978). At the dose which was used to calculate the
RfDg, accelerated mortality was observed. This basis for RfD determina-
tion was accepted because an earlier RfD calculated from an Inhalation study
(U.S. EPA, 1980a) was less conservative. The RfD$j and RfDj estimates
for F-ll are calculated from a 90-day Inhalation study by Jenkins et al.
(1970). The RfD$i estimate for F-ll Is 135.8 mg/day; when an additional
uncertainty factor Is applied the RfOj estimate 1s 13.6 mg/day.
The RfD$Q estimate for dichlorodlfluoromethane (F-12), 63 mg/day, Is
based on a 90-day feeding study using dogs (Clayton, 1967). The RfOg
(RfD) estimate for F-12 Is 10 mg/day. This estimate, which has been veri-
fied by the U.S. EPA (1986a) as an RfD, 1s based on a 2-year feeding study
using rats (Sherman, 1974). The RfD$i and RfDj estimates for F-12 were
calculated from a 90-day Inhalation study by Prendergast et al. (1967). The
RfD$j estimate 1s 33.8 mg/day; when an additional uncertainty factor Is
applied the RfDj estimate for F-12 Is 3.4 mg/day.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office. Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents In this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati. OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
Page
1.
2.
3.
4.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
3.4. TOXICANT INTERACTIONS
CARCINOGENICITY
4.1. HUMAN DATA
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
1
, , , 3
. . . 3
, , , 3
. . . 5
, , , 5
. . . 5
, , , 5
. . , 10
. . . 10
. . . 11
. . . 11
. . . 11
. . . 12
. . . 12
, , 14
. . . 14
. . . 14
. . . 14
14
. . . 15
. . . 15
. . . 16
. . . 17
6.1. SUBCHRONIC REFERENCE DOSE (RfDs) 17
6.1.1. Oral (RfDso) 17
6.1.2. Inhalation (RfDSI) 18
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TABLE OF CONTENTS
Page
6.2. REFERENCE DOSE (RfD) ............... .... 20
6.2.1. Oral (RfD0) ............... .... 20
6.2.2. Inhalation (RfD) ................ 22
6.3. CARCINOGENIC POTENCY (q-|*) ................ 24
6.3.1. Oral ....................... 24
6.3.2. Inhalation .................... 24
7. REFERENCES ............................ 25
APPENDIX A: Summary Table for F-ll .................. 31
APPENDIX B: Summary Table for F-12 .................. 32
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LIST OF TABLES
No. Title Page
1-1 Select Chemical and Physical Properties and Environmental
Fate of F-12 and F-ll 2
3-1 Subchronlc Toxlclty of Inhaled F-ll and F-12 6
6-1 Composite Scores for the Toxlclty of F-ll and F-12
by Oral Exposure 21
6-2 Composite Scores for the Toxlclty of F-ll and F-12
by Inhalation Exposure 23
1x
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LIST OF ABBREVIATIONS
ACTH Adrenocort1ocotrop1c hormone
ADI Acceptable dally Intake
bw Body weight
CAS Chemical Abstract Service
CS Composite score
PEL Frank effect level
HA Health advisory
Koc Soil sorptlon coefficient standardized
with respect to organic carbon
LOAEL Lowest-observed-adverse-effect-level
MED Minimum effective dose
NOAEL No-observed-adverse-effect-level
NOEL No-observed-effect level
PEL Permissible exposure limit
ppm Parts per million
RfO Reference dose
RfD, Inhalation reference dose
RfDQ Oral reference dose
RfDs Subchronlc reference dose
RfDgj Subchronlc Inhalation reference dose
RfDSQ Subchronlc oral reference dose
RV. Dose-rating value
RVe Effect-rating value
SGPT Serum glutamlc pyruvlc transamlnase
SNARL Suggested no adverse response level
TLV Threshold limit value
THA Time-weighted average
UV Ultraviolet
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected chemical and physical properties and environmental fate of
d1chlorod1fluoromethane (F-12) and trlchlorofluoromethane (F-ll) are
presented In Table 1-1.
In the troposphere, F-12 and F-ll remain stable and eventually diffuse
Into the stratosphere or are carried back to earth during the precipitation
process (Callahan et a!., 1979), where re-entry Into the atmosphere by
volatilization occurs. Once In the stratosphere these compounds are
photolyzed by short wavelength UV light, releasing chlorine atoms that
subsequently catalyze the destruction of ozone (Callahan et al., 1979).
The tropospherlc lifetime of these compounds has been postulated to be
-20-30 years, which Indicates that 40 to >90% of the tropospherlc halo-
methanes will eventually reach the stratosphere (Callahan et al., 1979). In
water, F-12 and F-ll will most likely volatilize to the atmosphere.
Based on the method of Lyman et al. (1982), the volatilization half-life
from water 1 m deep has been calculated to be 5.7 hours for F-12 and 6.1
hours for F-ll. The half-lives of these compounds In soil could not be
located 1n the available literature. Based on their high vapor pressures,
F-12 and F-ll are probably removed by volatilization from soil surfaces. An
estimated K value of 252 for F-12 suggests that slight adsorption to
soil may occur (Swann et al., 1983), which would decrease the rate of
volatilization. Adsorption of F-ll to soil should be less significant than
F-12.
0078h -1- > 12/29/86
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Quantitative data regarding the absorption of F-ll and F-12 following
oral administration could not be located 1n the available literature. That
F-ll and F-12 are absorbed from the gastrointestinal tract can be Inferred
from the observation of systemic toxlclty following oral administration
(Sections 3.1.1. and 3.2.1.).
2.2. INHALATION
In a study by Morgan et al. (1972), volunteers Inhaled a known concen-
tration of 38Cl-labeled F-ll or F-12 1n one breath and held that breath
for 40 seconds. The subjects then exhaled through a charcoal trap and the
amount of radioactivity exhaled was determined. The results showed that 45%
of the concentration of Inhaled F-ll was Immediately exhaled, while 90% of
Inhaled F-12 was Immediately exhaled.
A number of studies revlewed'by U.S. EPA (1984a) Indicated that F-ll and
F-12 are readily absorbed. Because these studies do not quantltate absorp-
tion, details will not be presented. A general finding of these acute
studies Is that F-ll Is absorbed to -more readily than F-12.
A more recent study that quantifies absorption of F-ll 1n humans Is
presented by Angerer et al. (1985). Two women and one man were exposed to
F-ll at an average concentration of 657^36 mi/m3 (-980 g/m3) for 150,
264 and 210 minutes, respectively. F-ll concentrations In the alveolar air
and blood were determined. After 1 hour, the concentration of F-ll In the
blood reached steady-state at an average alveolar air F-ll concentration of
537 ml/m3 (-800 g/m3). Pulmonary retention varied from 13.5-21.9X for
the three volunteers, with the pulmonary ventilation rate of the volunteers
equaling 9.4 l/m1nute. The doses absorbed by the three Individuals were
0078h -3- > 11/04/86
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1.08, 1.35 and 1.88 g, correlating positively with the exposure time. The
average F-ll blood concentration measured during the study was 2.8 mg/i.
Brugnone et al. (1984) studied the absorption of F-ll and F-12 during
occupational exposures. By measuring the differences In concentration
between Inhaled and exhaled air the Investigators determined that 19% of
Inhaled F-ll Is retained while 18% of F-12 1s retained by the lungs.
0078h -4- 08/29/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. NCI (1978) studied the subchronlc effects of F-ll 1n mice
and rats In a preliminary dose range-finding study for a chronic toxlclty
and cancer study. Groups of five male and five female Osborne-Mendel rats
and equal numbers of male and female B6C3F1 mice were treated by gavage with
F-ll 1n corn oil 5 days/week for 6 weeks at doses of 0, 1000, 1780, 3160,
5620 and 10,000 mg/kg/day. Significant depression (26%) of body weight was
observed In male rats receiving 1000 mg/kg/day, with at least one male rat
dying In each dose group >1000 mg/kg/day. Female rats receiving 1780
mg/kg/day experienced a significant body weight depression (11%) with at
least one death In each dose group >1780 mg/kg/day. Mice had no body weight
depressions. Mortality began to occur at 5620 mg/kg/day In male mice and at
>3J60 mg/kg/day 1n female mice. Treated animals were not examined further.
In a 90-day feeding study described by Clayton (1967), male and female
rats and male and female dogs received F-12 1n the diet. Rats fed diets
that provided 160-379 mg/kg bw/day did not show any effects on growth,
behavior, hematologlcal and SGPT values or 1n gross and microscopic appear-
ance of an unspecified selection of organs and tissues. The only effect
noted was a slight elevation of plasma alkaline phosphatase activity 1n
females. Dogs fed 85-95 mg F-12/kg/day did not show any treatment-related
effects.
3.1.2. Inhalation. Table 3-1 summarizes the subchronlc Inhalation
studies of F-ll and F-12.
Stewart et al. (1978) studied health effects In humans following repeat-
ed exposures to F-ll or F-12. Eight male volunteers were exposed to 1000
ppm F-ll (5600 mg/m3) or F-12 (4900 mg/m3), 8 hours/day, 5 days/week for
0078h -5- * 08/29/86
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-------
4 weeks. The parameters examined were blood chemistries and hematologles,
heart function, pulmonary function, neurological studies, electroencephalo-
graphy, visual evoked response, ACTH stimulation and cognitive tests. No
effects were observed In Individuals exposed to F-12. The only effect
observed In F-ll exposed Individuals was a statistically significant, but
minute and transient decrease In cognitive test performance. Because this
decrease was not consistent, was transient, was not dose-related (In regard
to total dose) and did not occur 1n subjects acutely exposed to the same
concentrations for the same length of time, the authors concluded that this
effect was not considered to be an adverse effect of exposure to F-ll.
Jenkins et al. (1970) exposed squirrel monkeys, beagle dogs, guinea pigs
and Sprague-Dawley rats to 58,000 mg/m3 F-ll 8 hours/day, 5 days/week for
6 weeks. Compared with controls, effects noted In treated animals were
elevated serum urea nitrogen In dogs (36 mg/100 ml exposed; 16.8 mg/100
ml controls), mild liver discoloration In ~25X of rats and guinea pigs, a
liver lesion In 1/9 exposed monkeys and nonspecific Inflammatory changes In
lungs of rats, guinea pigs and monkeys. No other significant changes were
observed In hematologlcal or biochemical data or body weight.
Jenkins et al. (1970) also exposed squirrel monkeys, beagles, guinea
pigs and rats to 5600 mg/m3 F-ll continuously for 90 days. The results
observed were nonspecific Inflammatory changes In the lungs of all species,
elevated serum urea nitrogen levels 1n dogs (33 mg/100 ml exposed; 16.8
mg/100 ml controls) and mild Hver discoloration In some rats and guinea
pigs. One monkey, which died on day 78, had hemorrhaglc lesions on the lung
surface that were not directly attributed to exposure. About 50% of the
monkeys used 1n the study were found to be Infected with mlcrofllerla
(Dlpetalonema sp.). Hematologlcal and biochemical data or body weight were
not significantly affected.
0078h -8- * 12/29/86
-------
Leuschner et al. (1983) exposed beagle dogs to 28,000 mg/m3 F-ll or
25,000 mg/m3 F-12, 6 hours/day for 90 days and rats to 56,000 mg/m3 F-ll
or 49,000 mg/m3 F-12, 6 hours/day for 90 days. No signs of toxldty were
observed In dogs or rats. The parameters examined were behavior, external
appearance, food and water consumption, body weight, hematology, blood bio-
chemistry, urlnalysls and 1n dogs only, electrocardlography and circulatory
function. At necropsy, organ weights were determined and hVstologlcal
examinations were completed 1n all dogs and In 10 rats/group/sex.
Prendergast et al. (1967) exposed squirrel monkeys, beagle dogs, rab-
bits, guinea pigs and rats to F-12 at 4136 mg/m3, 8 hours/day, 5 days/week
for 6 weeks or to 3997 mg/m3 F-12 continuously for 90 days. The most
severe effect observed was focal necrosis and fatty Infiltration of the
livers of guinea pigs, which was more severe In the continuously exposed
guinea pigs compared with those that received Intermittent exposures. Other
effects observed In the animals exposed Intermittently were nonspecific
Inflammation of the lungs 1n a number of guinea pigs, rats, rabbits and
monkeys, weight loss 1n dogs and monkeys, heavy pigmentation In liver,
spleen and kidney of one monkey and death of one rat. Continuously exposed
rats, rabbits, monkeys and dogs showed a high Incidence of lung congestion
with Inflammatory changes 1n the lungs, depressed body weight gain In
rabbits and gu.lnea pigs, and the deaths of 2/15 exposed rats and 1/15 guinea
pigs.
Sayers et al. (1930) exposed monkeys, dogs and guinea pigs to F-12 at
1.1x10* mg/m3 for 7-8 hours/day, 5 days/week and 4 hours/day, 1 day/week
for -77 days {Sayers et al., 1930). Dogs experienced tremors and ataxla.
Less severe tremors were also observed 1n monkeys. Tremors In both species
lessened 1n severity after several weeks. Deaths of 10/26 exposed guinea
Q078h -9- * 08/29/86
-------
pigs and 6/26 controls were attributed to pneumonia. An Initial Increase 1n
r«d blood cell count and hemoglobin was observed In several guinea pigs. In
dogs and guinea pigs, the number of lymphocytes decreased slightly and the
number of polymorphonuclear neutrophlls Increased slightly. An Initial
weight loss was also observed In exposed dogs and several guinea pigs.
3.2. CHRONIC
3.2.1. Oral. In the NCI (1978) study, F-ll was administered orally In
corn oil to 50 male and 50 female Osborne-Mendel rats and equivalent numbers
of male and female B6C3F1 mice, 5 days/week, with the exception of the high-
dose groups of male mice, which Initially contained 49 mice. Untreated and
vehicle-treated controls consisted of 20 anlmals/sex/specles. Treatments
that were administered for 78 weeks were adjusted at 12 weeks (rats) and 7
weeks (mice) resulting In TWA doses of 488 and 977 mg/kg/day for low- and
high-dose male rats, 538 and 1077 mg/kg/day for low- and high-dose female
rats and 1962 and 3925 mg/kg/day for low- and high-dose mice of both sexes.
These TWA doses are for treatment on 5 days/week and do not reflect expan-
sion to dally treatment. No decrease In body weight was reported 1n rats.
In male and female rats, dose-related early mortality was observed, which
[although significant when compared with controls using the Tarone test
(p<0.001)] was associated with murlne pneumonia, which was observed 1n
88-100% of all rats. Low Incidences (<20%) of pericarditis and pleurHls
were observed In all treated groups of rats but not In controls. In mice,
no statistically significant compound-related effect on body weight gain or
clinical signs was observed. Based on the Tarone test, a significant
(p=0.009) dose-related acceleration of mortality was observed In female but
not male mice.
0078h -10- » 11/04/86
-------
Sherman (1974) fed groups of four male and four female beagle dogs (1-2
years of age) diets containing F-12 that provided 8 mg/kg bw/day for 2
years. No meaningful differences were observed In food consumption, body
weight, hematology, urlnalysls and biochemistry measurements.
Sherman (1974) also studied the effects of F-12 1n rats that were dosed
by 1ntragastr1c Intubation for up to 2 years. Groups of 21 female and 11
male CD rats were utilized. Hales received 11-27 or 130-273 mg/kg/day F-12
In corn oil. Females received 11-25 or 128-242 mg/kg/day. Dose ranges for
each group were estimated by the author. Two vehicle control groups were
Included, each consisting of 11 males and 21 females. After 3 months the
rats were mated. No F-12 was given to pregnant females between days 18 or
19 of gestation and day 5 of lactation. Groups of 50 male and 50 female
offspring received nothing, corn oil, or F-12 at the low or high dose. The
results showed a somewhat depressed body weight gain and food efficiency In
female rats receiving 131-273 mg F-12/kg/day. No differences In food
consumption or mortality between exposed and control groups were noted. No
compound-related changes 1n hematology, urlnalysls, clinical chemistry and
hlstopathologlcal examinations were.noted at either dose level.
3.2.2. Inhalation. Pertinent data regarding the effects of chronic
Inhalation exposure to F-ll and F-12 could not be located In the available
literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. No pertinent data regarding teratogenlc and other reproduc-
tive effects associated with oral exposure to F-ll were located In the
available literature. In the chronic oral study using rats treated with
11-27 or 131-273 mg/kg/day F-12 for up to 2 years, no abnormalities were
observed 1n fertility, gestation, viability and lactation or upon hlsto-
pathologlcal examination (Sherman, 1974). Rats (male and female) received
0078h -11- * 11/04/86
-------
on the average -15 or 150 mg F-12/kg/day In corn oil by gavage. Dosing was
discontinued from days 18 or 19 of gestation until day 5 of lactation. The
experiment was continued for 3 generations.
Cullk and Sherman (1973) treated pregnant Charles River rats (25-277
group) by gavage with 2 mi corn oil containing an average of 0, 16.6 or
170.9 mg F-12/kg on gestation days 6-15. F-12 administration did not affect
maternal weight gain, the numbers of Implantation sites or viable fetuses,
mean fetal body weight or fetal crown-rump length. No major abnormalities
were observed 1n live fetuses, and the numbers of minor defects In offspring
of treated days were similar to those of controls.
3.3.2. Inhalation. In a study by Paulet et al. (1974), groups of 10
pregnant rabbits and 20 pregnant Vllstar rats were exposed to a mixture of
F-ll and F-12 In air for 2 hours/day on days 4-16 of gestation (rat) or days
5-20 of gestation (rabbits). The mixture was at -200,000 ppm (-1 kg/m3)
with the proportion of F-12:F-11 at 9:1. Half of the animals were sacri-
ficed on day 20 (rats) or day 30 (rabbits) of gestation. The remaining
animals were allowed to deliver. No treatment-related adverse effects on
maternal or fetal body weights, number of Implantations, resorptlons,
fetuses, stillbirths or the number of pups surviving at 1 and 4 weeks were
observed. No abnormalities were observed 1n treated Utters; however, the
method of fetal examination was not stated.
3.4. TOXICANT INTERACTIONS
At relatively high concentrations, eplnephrlne has been shown to alter
the sensitivity of the heart to F-ll. In a study by Belej et al. (1974),
anesthetized rhesus monkeys (1.8-2.7 kg) with tracheas cannulated for
artificial respiration were exposed to F-ll 1n air for 5 minutes and then to
0078h -12- > 11/04/86
-------
room air for 10 minutes. The minimal concentrations of F-11 causing cardlo-
texlclty were 5% (280,000 mg/m3) for cardiac arrhythmia and 2.5% (140,000
mg/m3) for depression of myocardlal contractility associated with
hypotension. When eplnephrlne was Infused (Intravenously) the minimal F-11
concentration causing arrhythmia was reduced to 2.5%. Tachycardia also
appeared when F-11 was given while eplnephrlne was Infused. The minimal
concentration of F-ll requlfed to cause arrhythmia was further reduced to
0.5% (28,000 mg/m3) when eplnephrlne Infusion was accompanied by coronary
artery occlusion.
Neither eplnephrlne Infusion nor coronary artery occlusion reduced the
concentration of F-12 required to cause cardiac arrhythmia In rhesus monkeys
(Belej et al., 1974). In the normal heart, a 10% (495,000 mg/m3) concen-
tration of F-12 1n air was required to cause cardiac arrhythmia.
0078h -13- ' 11/04/86
-------
4. CARCINOGENICITY
4.1. HUNAN DATA
Pertinent data regarding the carcinogenic potential of F-l'l or F-12 In
humans could not be located In the available literature.
4.2. BIOASSAYS
4.2.1. Oral. NCI (1978) conducted a carclnogenldty bloassay for F-ll 1n
which groups of male and female Osborne-Mendel rats and male and female
B6C3F1 mice were orally dosed with F-ll In corn oil. Rats received TWA
doses as follows: males, 488 or 977 mg/kg/day; females, 538 or 1077 mg/kg/
day, 5 days/week for 78 weeks. Mice received THA doses of 1962 or 3925
mg/kg/day (both sexes) on the same dosing schedule as the rats. There were
20 untreated and vehicle-treated controls per sex per species (see Section
3.2.1.). There was no significant positive association between tumor
Incidence In rats surviving >52 weeks and F-ll exposure. These results were
Inconclusive, however, because of high early mortality 1n male and female
rats; an Inadequate number of rats survived long enough to be at risk for
late-developing tumors. The results In mice showed no statistically
significant Increase In tumor Incidence and no unusual tumors were found.
In a 3-generatlon study of F-12 using rats, Sherman (1974) analyzed
tumor Incidences. F-12 did not cause an Increase In tumor Incidence In CO
male and female rats treated by gavage with 11-27 (average -15) or 131-273
(average -150) mg F-12/kg/day In corn oil.
4.2.2. Inhalation. Maltonl et al. (1982) exposed groups of 90 male* and
90 female Sprague-Oawley rats to F-ll and F-12 at concentrations of 0, 0.1
or 0.5% (F-ll:5600, 28.000 mg/m3; F-12:4900, 25,000 mg/m3) 4 hours/day,
5 days/week for 104 weeks. Exposed rats were examined only for brain tumors
(ependymomas, gllomas and menlnglomas), but Incidences did not differ
significantly from controls.
0078h -14- ' 12/29/86
-------
4.3. OTHER RELEVANT DATA
F-11 was negative for base-pair substitutions and frame-shift mutations
1n the presence or absence of a metabolic activating system when tested with
Salmonella typhlmurlum strains TA1535 and TA1538 and Escherlchla coll K-12
(Uekleke et al.. 1976. 1977). Longstaff et al. (1984) found both F-11 and
F-12 to be nonmutagenlc with and without S-9 activation In Salmonella typhl-
murlum strains TA100 and TA1535, and the compounds did not transform BHK21
cells. F-11 and F-12 were also shown to be negative for forward mutations
In the Chinese hamster ovary/hypoxanthlne guanlne phosphorlbosyl transferase
assay with or without metabolic activation (Krahn et al., 1979). Van't Hof
and Schalrer (1982) found F-12 to be negative In a mutagenlclty test using a
Trandescantla hybrid.
4.4. WEIGHT OF EVIDENCE
There was no evidence In the available literature Indicating that F-11
or F-12 are carcinogens. An oral NCI (1978) bloassay of F-11 was Incon-
clusive 1n rats because of high early mortality and negative 1n mice.
Orally administered F-12 did not cause an Increase In tumors In CD rats 1n a
3-generatlon study (Sherman, 1974). Inhalation of F-11 or F-12 did not
cause an Increased Incidence of brain tumors In exposed rats. Mutagenlclty
assays support the carclnogenlclty studies; F-11 and F-12 were negative 1n
mutagenlclty assays In bacteria and mammalian cells (see Section 4.3.).
Because of the lack of sufficient evidence concerning the carcinogenic
potential of F-ll and F-12, these compounds can be placed In EPA Group D,
not classified (U.S. EPA, 1986a). Although IARC has not classified F-11 and
F-12 as to their carclnogenlclty to humans, an IARC classification of
Group 3 (I.e., cannot be classified) seems most appropriate.
0078h -15- 12/29/86
-------
5. REGULATORY STANDARDS AND CRITERIA
b
The U.S. EPA (1982) has recommended water quality criteria for F-ll and
F-12. The criterion for F-ll, 12 mg/l, was based on an RfD of 24 mg/day
or 0.35 mg/kg/day (U.S. EPA, 1982) calculated from an NCI (1978) oral study
that defined a rat LOAEL of 488 mg/kg, 5 days/week, which was associated
with accelerated mortality, and an uncertainty factor of 1000. This RfD has
been verified by U.S. EPA (1986c) and rounded to 20 mg/day (0.3 mg/kg/day).
The criterion for F-12 of 28 mg/l was based on an RfD of 56.0 mg/day (0/6
mg/kg/day) (U.S. EPA, 1982). This RfD was calculated from a 2-year oral
study using dogs (Sherman, 1974). which defined a NOAEL of 80 rng/kg/day; an
uncertainty factor of 100 was applied (U.S. EPA, 1982). The RfD of 56.0
mg/day has recently been replaced by a verified RfD of 10 mg/day (0.2
mg/kg/day) based on an oral chronic rat NOEL of 15 mg/kg/day (Sherman, 1974)
and an uncertainty factor of 100 (U.S. EPA, 1986b).
The NAS (1980) has determined a SNARL for F-ll for a 70 kg adult of 88
mg/l for 1-day exposure and 8.0 mg/l for 7-day exposure. The F-12 SNARL
for 1-day exposure of a 70 kg adult 1s 350 mg/l, while the 7-day SNARL is
150 mg/l (NAS, 1980). A chronic SNARL of 5.6 mg/l for F-12 has also
been calculated (NAS, 1980).
The ACGIH (1985) has adopted a celling TLV of 1000 ppm (-5600 rug/m*)
for F-ll. The ACGIH (1985) TWA-TLV for F-12 1s 1000 ppm (-4950 mg/m3).
OSHA (1985) has set the PEL for both F-ll and F-12 at 1000 ppm {F-ll, -5600
mg/m3; F-12, -4950 mg/m3).
0078h -16- "' 12/29/86
-------
6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
w
6.1.1. Oral (RfDcn). The only subchronlc oral study of F-ll available
»>u
was the range-finding experiment for a chronic cancer study by NCI (1978).
Mice and rats were dosed by gavage with the corn oil vehicle or 1000, 1780,
3160, 5620 or 10,000 mg/kg/day of F-ll, 5 days/week for 6 weeks followed by
2 weeks of observation. Male rats showed a 26X depression In body weight at
1000 mg/kg/day and at least one death/group at the higher dose levels.
Female rats showed no effects at 1000 mg/kg/day; body weight depressions but
no deaths occurred at 1780 mg/kg/day. Mice had no effects at doses <5620
mg/kg/day. Because the only endpolnts studied were body weight and mortal-
ity, the LOAEL of 1000 mg/kg/day for rats from this study alone Is a weak
basis for determining an RfDgQ. However, these data are supported by the
available chronic data (see Section 6.2.1.).
An RfO$0 can be estimated from the LOAEL of 1000 mg/kg/day (NCI, 1978)
by multiplying the LOAEL by 5/7 days to convert to dally exposure, and by
dividing by an uncertainty factor of 1000 (10 for Interspedes extrapola-
tion, 10 for Interspecles variability, 10 for deriving an RfDSQ from a
LOAEL). The calculated RfO$() for F-ll Is 0.714 mg/kg/day, or 50 mg/day
for a 70 kg human.
The 90-day feeding study by Clayton (1967) Is the only oral toxldty
study of appropriate duration from which to determine an RfDSQ for F-12.
In this study, oral administration of 160-379 mg/kg/day of F-12 to male and
female rats produced no effects on behavior, growth, hematology, SGPT
activity and the gross and microscopic appearance of tissues and organs.
The only effect observed was a slight elevation of plasma alkaline phospha-
tase activity. Dogs were orally dosed with F-12 at 84-95 mg/kg/day (-90
0078h -17- 06/17/87
-------
mg/kg/day) for 90 days. This treatment did not produce any clinical signs
of toxldty and no changes were detected In blood and urine tests or In
*
hlstologlcal examinations. Because the data for dogs provide a more clearly
defined NOAEl, these data will be used to calculate an RfOSQ.
An RfOso can be estimated from the dog NOAEL of 90 mg/kg/day (Clayton,
1967) by dividing by an uncertainty factor of 100 (10 for Interspedes
extrapolation and 10 for Intraspedes variability). The calculated RfO._
vw
for F-12 Is 0.9 mg/kg/day, or 63 mg/day for a 70 kg human.
6.1.2. Inhalation (RfD..). A number of subchronlc F-lll Inhalation
studies are summarized In Table 3-1. The study by Leuschner et al. (1983)
1s not useful for risk assessment. The study did not define thresholds of
toxlclty In rats or dogs, although transformed doses from this experiment
were higher than those 1n the multlspecles experiment by Jenkins et al.
(1970) In which adverse effects were noted. Transformed doses were
calculated In the following manner: mg/kg/day = mg/m3 x (hours exposed/24
hours) x (days exposed/7 days) x Inhalation rate (mVday) x I/body weight
(kg). [Inhalation rates were calculated using formulas from U.S. EPA
(1986d): Inhalation rate for dogs = 0.92/2.11 (BW)0'9 and Inhalation rate
for guinea pigs * 0.98/2.11 (BW)0'9.] In the study by Jenkins et al.
(1980), squirrel monkeys, dogs, guinea pigs and rats were exposed to F-ll at
58,000 mg/m3, 8 hours/day, 5 days/week for 6 weeks or to 5600 mg/m3
continuously for 90 days. Dogs continuously exposed to F-ll had nonspecific
Inflammation of the lungs and Increased serum urea nitrogen levels (33
mg/100 mi exposed, 16.8 mg/100 ml control). The dogs were exposed to a
transformed dose of -1940 mg/kg/day that was calculated using the body
weight (9.9 kg) provided by the Investigators. Increased serum urea
nitrogen levels were observed only In dogs at 1940 mg/kg, which can be
0078h -18- i 06/17/87
-------
considered to be a LOAEL. This LOAEL Is a more appropriate basis for an
RfDCT than the LOAEL of 381 mg/kg/day 1n humans associated with minutely
*>1
tt
decreased cognitive test performance (Stewart et al.t 1978) because the dog
study was a longer term experiment and a more comprehensive evaluation of
criteria of toxlclty was performed. An RfD$I of 1.94 mg/kg/day or 135.8
mg/day for a 70 kg human can be calculated from the LOAEL of 1940 mg/kg/day
by dividing the transformed dose by an uncertainty factor of 1000 (10 for
Interspecles extrapolation, 10 for Individual variability, 10 for deriving
an RfDSI from a LOAEL).
The study of F-ll exposure In humans by Stewart et al. (1978) Indicates
that an RfDs» of 135.8 mg/day for a 70 kg human should be protective.
Stewart et al. (1978) exposed male volunteers to F-ll at 5600 mg/m3, 8
hours/day, 5 days/week for 4 weeks (381 mg/kg/day). The only effect was a
minute decrease 1n cognitive test performance. An RfD-r calculated from
this exposure would be 266.7 mg/day which Is slightly higher but In close
agreement with the RfDSI calculated from the dog LOAEL.
Prendergast et al. (1967) exposed squirrel monkeys, beagle dogs,
rabbits, guinea pigs and rats to F-12 at 4136 mg/m3 for 8 hours/day, 5
days/week for 6 weeks or to 3997 mg/m3 continuously for 90 days. Guinea
pigs were found to be more susceptible to F-12 than the other species.
Focal necrosis and fatty Infiltration of the liver were found In both
exposure protocols, with an Increase In the Incidence and severity In
animals exposed continuously (1941.6 mg/kg/day; bw = 0.584 kg) compared with
those exposed Intermittently (482.3 mg/kg/day; bw = 0.632 kg). Using 482.3
mg/kg/day as a LOAEL, an RfOSI of 0.482 mg/kg/day or 33.8 mg/day for a 70
kg human can be calculated by dividing the transformed dose by an uncer-
tainty factor of 1000 (10 for Interspecles extrapolation, 10 for 1ntra-
spedes variability, 10 for deriving an RfDSI from a LOAEL).
0078h ' -19- . 06/17/87
-------
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfDQ). The U.S. EPA (1982, 1986c) RfD for F-ll of 0.344
v
mg/kg/day or 24.4 mg/day 1s based on the lowest dose tested (438 mg/kg/day)
In the NCI (1978) chronic oral study In which a dose-related acceleration of
mortality was observed In male and female rats. The Increase In mortality
became apparent In low-dose rats as early as week 15 and In high-dose
females as early as week 4. According to NCI (1978), murlne pneumonia,
which was observed In 88-100X of rats 1n all groups, appeared to be a factor
In early mortality. The preferential acceleration of mortality among
treated groups may have been a result of F-11 lowering the resistance to
pneumonia.
A previous determination of the RfD, calculated from a subchronlc
Inhalation study (Jenkins et al., 1970), was less conservative.. The new RfD
of 24.4 mg/day has been verified by U.S. EPA (1986c) as the best estimate of
an RfD for F-ll and rounded to 20 mg/day for a 70 kg human.
The U.S. EPA (1986b) RfD for F-12 was based on a 2-year oral study In
rats by Sherman (1974) In which male and female CD rats received -15 or ~150
mg/kg/day of F-12 by gavage. The only effects observed were depressed body
weight gain and food efficiency In high-dose female rats. The low dose (-15
mg/kg/day) was therefore used as a NOEL to calculate the RfD. The RfD of
0.15 mg/kg/day or 10 mg/day for a 70 kg human, was calculated using an
uncertainty factor of 100.
CSs for oral exposure to F-ll and F-12 are listed In Table 6-1. A CS
for F-ll was calculated from the NCI (1978) study 1n which accelerated
mortality was observed In rats at 348.6 mg/kg/day. A human MED of 4172
mg/day was calculated by multiplying 348.6 mg/kg/day by the cube root of the
ratio of the rat body weight (0.35 kg, estimated from graphic data provided
0078h -20- . 06/17/87
-------
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by Investigators) to the reference human body weight and by 70 kg. This MED
corresponds to an RV. of 1. The effect that occurred at this dose,
»
accelerated mortality, corresponds to an RVg of 10 and the CS, the product
of RVfi and RVd, for F-ll equals 10.
6.2.2. Inhalation (RfD,). There were no chronic Inhalation studies
available for either F-ll or F-12. Therefore, RfDj values will be
estimated from RfDSI values by applying an additional uncertainty factor
of 10 to the RfD$I value. By this method, the RfD. for F-ll Is 0.194
mg/kg/day or 13.6 mg/day for a 70 kg human, and the RfD~ for F-12 1s
0.0482 mg/kg/day or 3.4 mg/day for a 70 kg human.
CSs for Inhalation exposure to F-ll and F-12 are listed 1n Table 6-2.
Because the data for both compounds were obtained from subchrorilc studies an
additional uncertainty factor of 10 was used when calculating human MEDs.
Since subchronlc Inhalation studies of F-ll used relatively high
exposure concentrations, all MEDs would correlate to an Rv"d value of 1.
Inflammation of the lungs was observed 1n all animal species tested. Other
lesions also occurred In dogs and guinea pigs. In dogs, elevated serum urea
nitrogen was observed and guinea pigs had mild discoloration of the liver
(Jenkins et al., 1970). In both species, an RV of 4 was chosen, based
primarily on the more severe effect of Inflammation 1n the lungs, and the
CSs, calculated as the product of the RV. and RV , are also 4. All
Inhalation CS values calculated were less than the oral CS so they will not
be discussed further.
The data from which CSs for F-12 were calculated were obtained from
Prendergast et al. (1967). The MED calculated for guinea pigs exposed
Intermittently to F-12 (Prendergast et al., 1967) correlates to an RVrf of
1.3. The remaining MEDs correlate to RV.s of 1. The most severe effects
0078h -22- . 06/17/87
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0078h
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were observed In guinea pigs (focal necrosis and fatty Infiltration of the
>1ver). These effects Increased 1n Incidence and severity from the Inter-
mittent exposures to the continuous exposure. The effects from the Inter-
mittent exposures correspond to an RV of 6, while the effects from the
continuous exposure correspond to an RV of 7. The highest CS value, 7.8,
Is from guinea pigs exposed Intermittently; the effects, although similar to
those seen with continuous exposure, occurred at a lower transformed dose.
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. Chronic oral cancer studies of F-ll and F-12 (NCI, 1978;
Sherman, 1974) did not result In any Increased tumor Incidences. The data
base Is considered Inadequate to assess the carcinogenic potential of these
compounds; therefore, an oral q-j* cannot be calculated.
6.3.2. Inhalation. The data base Is considered Inadequate to assess the
carcinogenic potential of these compounds; therefore, an oral q * cannot
be calculated.
0078h -24- * 12/29/86
-------
7. REFERENCES
w
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1985.
TLVs: Threshold Limit Values for Chemical Substances In the Work Environ-
ment, adopted by ACGIH with Intended changes for 1985-1986. Cincinnati, OH.
p. 15, 32.
Angerer, 3., B. Schroder and R. Helnrlch. 1985. Exposure to fluorotrl-
chloromethane (F-ll). Int. Arch. Occup. Environ. Health. 56: 67-72.
Belej, M.A., D.G. Smith and D.M. Avlado. 1974. Toxlclty of aerosol propel-
lants 1n the respiratory and circulatory systems. IV. Card1otox1c1ty 1n the
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Brugnone, F., L. PerbelUnl and P. Apostoll. 1984. Blood concentration of
solvents 1n Industrial exposure. Coll. Med. Leg. Toxlcol. Hed. 125:
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Callahan, M.A., H.W. Sllmak, N.W. Gabel, et al. 1979. Water-related envi-
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OC. EPA 440/4-79-029B.
Clayton, W.J., Jr. 1967. Fluorocarbon toxldty and biological action.
Fluorine Chem. Rev. 1(2): 197-252.
Cullk, R. and H. Sherman. 1973. Teratogenlc study 1n rats with dlchlorodl-
fluoromethane (Freon 12), Haskell Laboratory Report No. 206-273, Courtesy of
DuPont de Numours, Inc. 10 p.
0078h -25- * 11/04/86
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Hansch, C. and A.3. Leo. 1985. MedChem Project Issue No. 26, Pomona
College, Claremont, CA.
Jenkins, L.J., R.A. Jones, R.A. Coon and J. Slegal. 1970. Repeated and
continuous exposures of laboratory animals to trlchlorofluoromethane.
Toxlcol. Appl. Pharmacol. 16: 133-142.
Krahn, D.F., F.C. Borsky and K.T. McCooey. 1982. CHO/HGPRT mutation assay.
Evaluation of gases and volatile liquids. Ln: Genotoxlc Effects of Airborne
Agents. Environ. Sc1. Res. 25: 91-103.
Leuschner, P., B.M. Neumann and F. Huebscher. 1983. Report on subacute
toxlcologlcal studies with several fluorocarbons In rats and dogs by Inhala-
tion. Arznelm.-Forsch. 33(10): 1475-1476.
Longstaff, E., M. Robinson, C. Bradbrook, J.A. Styles and I.F.H. Purchase.
1984. Genotoxlclty and carclnogenlclty of fluorocarbons. Assessment by
short-term Jhi vitro tests and chronic exposure In rats. Toxlcol. Appl.
Pharmacol. 72: 15-31.
Lyman, W.J., W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods Environmental Behavior of Organic Compounds.
McGraw-Hill Book Co., New York. p. 4-9, 5-5, 15-13, 15-21.
Maltonl, C., A. C1l1bert1 and 0. Carrettl. 1982. Experimental contribu-
tions 1n Identifying brain potential carcinogens 1n the petrochemical
Industry. Ann. NY Acad. Scl. 381: 216-249.
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Morgan, A., A. Black, M. Walsh and D.R. Belcher. 1972. Absorption and
retention of Inhaled fluoMnated hydrocarbon vapors. Int. 3. Appl. Radlat.
Isotop. 23: 285-291.
NAS (National Academy of Sciences). 1980. Drinking Water and Health.
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46 p. [Also published as DHEW(NIH)78-1356]
OSHA (Occupational Safety and Health Administration). 1985. OSHA Occupa-
tional Standards. Permissible Exposure Limits. 29 CFR 1910.1000.
Paulet, G., S. Desbrousser and E. VI'dal. 1974. Absence d'effetteratogene
des fluorocarbones chez le rat et le lapln. [Absence of teratogenlc effects
of fluorocarbons 1n the rat and rabbit]. Arch. Mai. Prof. Med. Trav. Secur.
Soc. 35: 658-662. (Fre.)
Prendergast, J.A., R.A. Jones, L.J. Jenkins and J. Slegal. 1967. Effects
on experimental animals of long-term Inhalation of trlchloroethylene, carbon
tetrachloMde, 1,1,1-trlchloroethane, dlchlorodlfluoromethane and 1,1-dl-
chloroethylene. Toxlcol. Appl. Pharmacol. 10: 270-289.
Sayers, R.R., W.P. Yant, J. Chornyak and J.W. Shoaf. 1930. Toxlclty of
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Sherman, H. 1974. Long-term feeding studies In rats and dogs with
(jlchlorodlfluoromethane (Freon 12 Food Freezant). Haskell Laboratory Report
No. 24-74. Unpublished, courtesy duPont de Nemours Co.
Stewart, R.O., P.E. Newton, E.D. Baretta, A.A. Herrmann, H.V. Forster and
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Health Perspect. 26: 275-285.
Swann, R.L., D.A. Laskowskl, P.J. McCall. K. VanderKuy and H.J. Dlshburger.
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octanol/water partition coefficient, soil sorptlon constant, water to air
ratio and water solubility. Res. Rev. 85: 17-28.
Uehleke, H., H. Grelm, M. Kramer and T. Werner. 1976. Covalent binding of
haloalkanes to liver constituents, but absence of mutagenldty on bacteria
In a metabolizing test system. Mutat. Res. 38: 114.
Uehleke, H., T. Werner, H. Grelm and M. Kramer. 1977. Hetabollc activation
of haloalkanes and tests in vitro for mutagenldty. Xenob1ot1ca. 7(7):
393-400.
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for Halomethanes.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regu-
lations and Standards, Washington, DC. EPA 440/5-80-051. NTIS PB-81-117624.
0078h -28- * 02/06/87
-------
U.S. EPA. 19805. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 49347-49357.
U.S. EPA. 1982. Errata for Ambient Water Quality Criteria Document for
Halomethanes. Prepared by the Office of Health and Environmental Assess-
ment, Environmental Criteria and Assessment Office, Cincinnati, OH for the
Office of Water Regulations and Standards, Washington, DC.
U.S. EPA. 1983. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxlclty Data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986a. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1986b. Integrated Risk Information System (IRIS). Reference
dose (RfD) for oral exposure for dlchlorodlfluoromethane. Online. (Verifi-
cation date 7/22/85). Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1986c. Integrated Risk Information System (IRIS). Reference
dose (RfD) for oral exposure for trlchlorotrlfluoromethane. Online.
(Verification date 7/8/85). Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH.
0078h -29- * 02/06/87
-------
U.S. EPA. 1986d. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
»
Assessment Office, Cincinnati, OH for the Office of Solid Waste,, Washington,
DC.
Van't Hof, J. and L.A. Schalrer. 1982. Trandescantla assay system for
gaseous mutagens. A report of the U.S. Environmental Protection Agency.
Gene-Tox. Program. Hutat. Res. 99(3): 303-315.
Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemicals,
2nd ed. Van Nostrand Relnhold Co., New York. p. 484, 676.
0078h -30- i 02/06/87
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