United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington DC 20460
EPA-600/8-82-002F
September 1983
Final Report
Research and Development
xvEPA
Health Assessment
Document for 1,1,2
Trichloro-1, 2, 2-
Trifluoroethane
(Chlorofluorocarbon
CFC-113)
Final
Report
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EPA-COO/8-82-002F
September 1983
Final Report
Health Assessment Document for
1,1, 2-Trichloro-1, 2, 2-Trifluoroethane
(Chlorofluorocarbon CFC-113)
FINAL REPORT
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Research Triangle Park, NC 27711
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NOTICE
This document has been reviewed in accordance with the U.S. Environmental
Protection Agency's peer and administrative review policies and approved
for presentation and publication. Mention of trade names or commercial
products does not constitute endorsement or recommendation for use.
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PREFACE
The Office of Health and Environmental Assessment has prepared this
health assessment to serve as a "source document" for EPA use. Originally the
health assessment was developed for use by the Office of Air Quality Planning
and Standards to support decision-making regarding possible regulation of
CFC-113 as a hazardous air pollutant. However, at the request of the Agency's
Work Group on Solvents the assessment scope was expanded to address multimedia
aspects.
In the development of the assessment document, the scientific literature
has been inventoried, key studies have been evaluated, and summary/conclusions
have been prepared so that the chemical's toxicity and related characteristics
are qualitatively identified. Observed-effect levels and dose-response
relationships are discussed, where appropriate, so that the nature of the
adverse health responses is placed in perspective with observed environmental
levels.
i i i
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TABLE OF CONTENTS
LIST OF TABLES vii
LIST OF FIGURES vii
1. SUMMARY AND CONCLUSIONS 1-1
2. INTRODUCTION 2-1
2.1 REFERENCES 2-2
3. PHYSICO-CHEMICAL PROPERTIES, PRODUCTION AND ENVIRONMENTAL
FATE 3-1
3.1 CHEMICAL AND PHYSICAL PROPERTIES 3-1
3.2 ANALYTICAL METHODOLOGY 3-1
3.2.1 Sampling 3-2
3.2.2 Analysis 3-2
3.2.3 Calibration 3-3
3.3 PRODUCTION, USE, EMISSIONS, AND AMBIENT MIXING RATIOS . 3-3
3.3.1 Production 3-3
3.3.2 Use 3-4
3.3.3 Ambient Air Mixing Ratios 3-5
3.3.4 Other Media 3-8
3.4 ATMOSPHERIC FATE 3-8
3.5 REFERENCES 3-12
4. METABOLIC FATE AND DISPOSITION 4-1
4.1 ABSORPTION AND ELIMINATION 4-1
4.2 DISTRIBUTION AND METABOLISM 4-2
4.3 REFERENCES 4-5
5. HEALTH EFFECTS 5-1
5.1 ANIMAL STUDIES 5-1
5.1.1 Acute Toxicity 5-1
5.1.2 Cardiovascular and Respiratory Effects 5-2
5.1.2.1 Mouse 5-2
5.1.2.2 Dog 5-2
5.1.2.2.1 In Vitro 5-2
5.1.2.2.2 I_n Vivo 5-5
5.1.2.3 Monkey 5-9
5.1.3 Neurological Effects 5-11
5.1.3.1 Frog 5-11
5.1.3.2 Dog 5-11
5.1.4 Hepatotoxicity 5-11
5.1.5 Teratogenic Effects 5-12
5.1.6 Mutagenic Effects 5-14
5.1.6.1 Mouse 5-14
5.1.7 Carcinogenic Effects 5-15
5.1.7.1 Rat 5-15
5.1.7.2 Mouse 5-15
5.1.8 Synergistic Effects 5-16
5.1.9 Dermal Effects 5-16
5.1.10 Inhalation and Ingestion 5-16
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TABLE OF CONTENTS (cont.)
5.2 HUMAN STUDIES
5.2.1 Occupation Exposure Studies
5.2.2 Experimental Exposure Studies
5.2.2.1 Inhalation
5.2.2.2 Ingestion
5.2.2.3 Dermal
5.2.2.4 Synergistic, Carcinogenic, Mutagenic,
and Teratogenic 5-31
5.3 SUMMARY OF ADVERSE HEALTH EFFECTS AND ASSOCIATED LOWEST
OBSERVABLE EFFECTS LEVELS 5-31
5.4 REFERENCES 5-36
6. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS 6-1
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LIST OF TABLES
Table Page
3-1 Physical Properties of trichlorotrifluoroethane 3-2
3-2 Tropospheric levels of CFC-113 3-6
4-1 Dermal exposure of man to CFC-113 4-2
4-2 Mean tissue concentrations of CFC-113 from rats
exposed to 2,000 ppm 4-3
5-1 Effects of CFC-113 on the electrocardiogram of
anesthetized mice 5-3
5-2 Effect of CFC-113 on the canine heart-lung preparation .... 5-3
5-3 Effect of CFC-113 on cardiac sensitization to epinephrine
in the unanesthetized dog 5-6
5-4 Respiratory and circulatory effects of CFC-113 upon
anesthetized Rhesus monkeys 5-9
5-5 Respiratory and circulatory effect of CFC-113 upon
anesthetized Rhesus monkeys 5-10
5-6 Carcinogenic effects of CFC-113 + PB in mice, alone and in
combination 5-17
5-7 Synergistic effect of piperonyl butoxide in combination with
CFC-113 upon neonatal mice 5-18
5-8 Dermal effects of CFC-113 in mammals 5-18
5-9 Inhalation and ingestion toxicities of CFC-113 in mammals . . 5-19
5-10 Post-inhalation breath concentrations of CFC-113 in man .... 5-29
5-11 Lowest observable adverse effect levels 5-34
5-12 No Observed Adverse Effect Level 5-35
LIST OF FIGURES
Page
5-1 Ventricular function curves in canine heart-lung preparations
before and during inhalation of 2.5 or 5.0% propellant in
air 5-4
5-2 Human exposures to CFC-113; timetable of experiment 5-30
5-3 Effect of CFC-113 upon psychomotor performance in man 5-32
VI I
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AUTHORS AND REVIEWERS
The principal authors of this document are:
Richard Carchman, Department of Pharmacology, The Medical College
of Virginia, Health Sciences Division, Virginia Commonwealth
University, Richmond, Virginia. [Chapter 5, Health Effects]
Mark M. Greenberg, Environmental Criteria and Assessment Office,
U.S. Environmental Protection Agency, Research Triangle Park, North
Carolina. [Chapter 3, Physico-chemical Properties; Chapter 4,
Mammalian Fate and Disposition]
Contributing authors:
Dagmar Cronn, Ph.D., Washington State University, Pullman, Washington.
The following individuals reviewed earlier drafts of this document and
submitted valuable comments:
Joseph Borzelleca, Ph.D.
Department of Pharmacology
The Medical College of Virginia
Health Sciences Division
Virginia Commonwealth University
Richmond, Virginia 23298
Herbert Cornish. Ph.D.
Dept. of Environmental and Industrial Health
University of Michigan
Ypsilanti, Michigan 48197
I. W. F. Davidson, Ph.D.
Dept. of Physiology/Pharmacology
The Bowman Gray School of Medicine
300 S. Hawthorne Road
Winston-Salem, North Carolina 27103
Lawrence Fishbein, Ph.D.
National Center for Toxicological Research
Jefferson, Arkansas 72079
Richard Hill, Ph.D.
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C.
John G. Keller, Ph.D.
P.O. Box 12763
Research Triangle Park, North Carolina 27709
VI I I
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Marvin Legator, Ph.D.
Professor and Director
Dept. of Preventive Medicine and
Community Health
Div. of Environmental Toxicity and
Epidemiology
University of Texas Medical Branch
Galveston, Texas 77550
Benjamin Van Duuren, Ph.D.
Institute of Environmental Medicine
New York University Medical Center
New York, New York 10016
Richard Ward, Ph.D.
E. I. duPont de Nemours and Company
Wilmington, DL
Herbert Wiser, Ph.D.
Deputy Assistant Administrator
U.S. Environmental Protection Agency
Washington, DC
Participating Members of The Carcinogen Assessment Group
Roy E. Albert, M.D. (Chairman)
Elizabeth L. Anderson, Ph.D.
Larry D. Anderson, Ph.D.
Steven Bayard, Ph.D.
Chao W. Chen, Ph.D.
Bernard H. Haberman, D.V.M, M.S.
Charaligayya B. Hiremath, Ph.D.
Chang S. Lao. , Ph.D.
Robert McGaughy, Ph.D.
Dharm W. Singh, D.V.M., Ph.D.
Nancy A. Tanchel, B.A.
Todd W. Thorslund, Sc.D.
Participating Members of The Reproductive Effects Assessment Group
Peter E. Voytek, Ph.D. (Chairman)
John R. Fowle III, Ph.D.
Carol Sakai, Ph.D.
Vicki Dellarco, Ph.D.
K.S. Lavappa, Ph.D.
Sheila Rosenthal, Ph.D.
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Members of the Agency Work Group on Solvents
Elizabeth L. Anderson
Charles H. Ris
Jean Parker
Mark Greenberg
Cynthia Sonich
Steve Lutkenhoff
James A. Stewart
Paul Price
William Lappenbush
Hugh Spitzer
David R. Patrick
Lois Jacob
Arnold Edelman
Josephine Brecher
Mike Ruggiero
Jan Jablonski
Charles Delos
Richard Johnson
Priscilla Holtzclaw
of
of
of
of
of
of
of
of
of
Office
Office
Office
Office
Office
Office
Office
Office
Office
Consumer
Office of
Office
Office
Office
Office
Office
Office
Office
Office
Environmental
Environmental
Environmental
Environmental
Environmental
Environmental
Assessment
Assessment
Assessment
Assessment
Assessment
Assessment
of
of
of
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of
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Health and
Health and
Health and
Health and
Health and
Health and
Toxic Substances
Toxic Substances
Drinking Water
Product Safety Commission
Air Quality Planning and Standards
General Enforcement
Toxic Integration
Water Regulations and Standards
Water Regulations and Standards
Solid Waste
Water Regulations and Standards
Pesticide Programs
Emergency and Remedial Response
SCIENCE ADVISORY BOARD ENVIRONMENTAL HEALTH COMMITTEE
The substance of this document was independently peer-reviewed in public
session by the Environmental Health Committee, Environmental Protection Agency
Science Advisory Board.
Chairman, Environmental Health Committee
Dr. Roger 0. McClellan, Director of Inhalation Toxicity Research Institute,
Lovelace Biomedical and Environmental Research Institute, Albuquerque, New
Mexico 87115
Acting Director, Science Advisory Board
Dr. Terry F. Yosie, Science Advisory Board, U.S. EPA, Washington, DC 20460
Members
Dr. Herman E. Collier, Jr., President, Moravian College, Bethlehem,
Pennsylvania 18018
Dr. Morton Corn, Professor and Director, Division of Environmental Health
Engineering, School of Hygiene and Public Health, The Johns Hopkins Univer-
sity, 615 N. Wolfe Street, Baltimore, Maryland 21205
Dr. John Doull, Professor of Pharmacology and Toxicology, University of
Kansas Medical Center, Kansas City, Kansas 66207
Dr. Edward F. Ferrand, Assistant Commissioner for Science and Technology,
New York City Department of Environmental Protection, 51 Astor Place, New
York, New York 10003
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Dr. Herschel E. Griffin, Associate Director and Professor of Epidemiolgy,
Graduate School of Public Health, San Diego State University, San Diego,
California 92182
Dr. Jack D. Hackney, Chief, Environmental Health Laboratories, Professor of
Medicine, Rancho Los Amigos Hospital Campus of the University of Southern
California, 7601 Imperial Highway, Downey, California 90242
Dr. D. Warner North, Principal, Decision Focus, Inc., 5 Palo Alto Square,
Palo Alto, California 94304
Dr. William J. Schull, Director and Professor of Population Genetics,
Center for Demographic and Population Genetics, School of Public Health,
University of Texas Health Science Center at Houston, Houston, Texas 77030
Dr. Michael J. Symons, Professor, Department of Biostatistics, School of
Public Health, University of North Carolina, Chapel Hill, North Carolina
27711
Dr. Sidney Weinhouse, Professor of Biochemistry, Senior Member, Pels
Research Institute, Temple University School of Medicine, Philadelphia,
Pennsylvania 19140
Consultant
Dr. Bernard Weiss, Division of Toxicology, University of Rochester of
Medicine, Rochester, New York 14642
XI
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ABSTRACT
Chiorof1uorocarbon-113 (CFC-113; l,l,2-trichloro-l,2,2-trifluoroethane)
is a solvent characterized by a high vapor pressure and very low solubility in
water. Human exposure to CFC-113 is predominantly by inhalation. There is no
evidence indicating that human health effects are likely to occur at ambient
-3 3
air mixing ratios (e.g. 18 parts-per-tri11 ion or 0.14 x 10 mg/m ) found or
expected in the general environment or even at higher levels (< 4 parts-per-
3
billion or < 0.032 mg/m ) sometimes observed in urban areas. In fact, avail-
able experimental data do not indicate that any adverse health effects are
directly induced in humans at a TLV® of 1,000 ppm (7,700 mg/m ) due to exposure
to CFC-113.
There is presently inadequate published information to assess the carcino-
genic potential of CFC-113. A two-year chronic inhalation study in rats at
exposure levels of 2,000; 10,000; and 20,000 ppm has been completed. Preliminary
observations are consistent with no effects attributable to CFC-113 except
decreased weight gain in animals exposed to 20,000 ppm only. Similarly,
limited testing has not indicated that CFC-113 is teratogenic or mutagenic.
Preliminary results of a one-generation reproductive toxicity/teratogenicity
study in rats suggest that, at exposure levels up to 25,000 ppm, CFC-113 does
not cause teratogenesis or embryotoxic effects.
x i i
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1. SUMMARY AND CONCLUSIONS
Compared with other halogenated hydrocarbon solvents with similar usage
in industry, less information is available from the literature on chlorofluoro-
carbon-113 (CFC-113; l,l,2-trichloro-l,2,2-trifluoroethane). CFC-113 is
primarily of concern as a pollutant of the atmosphere. It has a high vapor
pressure and is practically insoluble in water. No direct ecosystem effects
of CFC-113 have been reported in the scientific literature; however, the high
volatility and the absence of measurable levels in water suggest that CFC-113
poses little or no risk to aquatic species. Similarly, presently available
health effects information indicates that CFC-113 poses little or no risk at
presently encountered environmental concentrations in terms of the direct
induction of adverse human health effects.
Human exposure to CFC-113 is predominantly by inhalation and most CFC-113
is rapidly cleared from the body by exhalation. Animal exposure studies
indicate that CFC-113 partitions preferentially into lipid-rich tissues and is
poorly metabolized. Loss of CFC-113 from all tissues is rapid during post-
exposure periods, with virtually 100 percent clearance within 24 hours after
cessation of acute exposure.
In regard to potential health effects associated with CFC-113, there is
no evidence indicating that human health effects are likely to occur at ambient
-3 3
air mixing ratios (e.g., 18 ppt; 0.14 x 10 mg/m ) found or expected in the
3
general environment or even at higher levels (<4,160 ppt; <0.032 mg/m ) some-
times observed in urban areas. In fact, available experimental data do not
indicate that any adverse health effects are directly induced in humans at a
TLV® of 1,000 ppm (7,700 mg/m3) due to exposure to CFC-113.
3
At exposure levels greatly exceeding 1,000 ppm (7,700 mg/m ), impairment
of neurological and cognitive functions (humans) and detrimental cardiovascular
effects (animals) have been observed following acute exposure to CFC-113.
However, because of the lack of detailed studies in these health areas, a
conclusive assessment of the human health risks posed by levels of CFC-113 in
the range 1,500 to 2,000 ppm (11,550 to 15,400 mg/m3) cannot be made. Also,
before definitive conclusions concerning the effects of chronic long-term
1-1
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exposure to CFC-113 can be drawn, the results of a recently completed two-year
chronic inhalation studyt in rats must be evaluated. What information is
available concerning health effects associated (or potentially associated)
with acute or chronic exposure to CFC-113 is summarized below.
CARCINOGENICITY AND MUTAGENICITY
There is presently inadequate published information to assess the carcino-
genic potential of CFC-113. A two-year chronic inhalation study in rats at
exposure levels of 2,000; 10,000; and 20,000 ppm (15,400; 77,700; and 154,000
mg/m ) has recently been completed at Haskell Laboratories. Histopathology is
in progress. Final assessment is expected to be completed in late 1983.
Chlorof1uorocarbon 113 was negative in one Ames test, with and without
metabolic activation. It was also reported to be negative in a dominant
lethal assay in mice. Because of limited testing performed and the insensi-
tivity of the dominant lethal assays to detect gene mutations, further testing
is needed before definitive conclusions can be drawn.
TERATOGENICITY AND REPRODUCTIVE EFFECTS
No clinical cases associate human exposure to CFC-113 with congenital
malformations in children. No epidemiological studies are available. Although
no published animal studies are available that adequately assess the tera-
togenic or adverse reproductive potential of CFC-113, unpublished data from
two studies conducted for E. I. duPont de Nemours and Company indicate that
CFC-113 did not produce toxic effects unique to rabbit conceptus at levels
that were maternally toxic. It should be noted that these studies have in-
adequacies and are best considered as pilot evaluations only. Maternal and
fetal death precluded evaluation of a sufficient number of litters to estab-
lish the teratogenic potential of CFC-113. Evaluation of the viable litters
showed no indication of a teratogenic effect.
Preliminary results of a recently-completed one-generation teratogenicity/
reproductive toxicity study in pregnant rats also suggest that at the exposure
levels tested (5,000, 12,500, and 25,000 ppm) there was no evidence of terato-
genic or embryotoxic effects attributable to CFC-113.
tPreliminary observations are consistent with no effects attributable to CFC-113
except decreased weight gain in animals exposed to the highest inhalation level
only. Histopathology will be completed in 1983. Exposure levels were 2,000,
10,000, and 20,000 ppm. (See Section 5.1.4 for reference.)
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A definitive assessment of the potential of CFC-113 to cause adverse
teratogenic or reproductive effects can only be made after data from the
two-year chronic inhalation study in rats and other reproductive studies
currently underway are evaluated, and additional data are generated, if needed,
that are in accordance with current teratologic and reproductive testing.
NEUROLOGICAL EFFECTS
A noticeable impairment of psychophysiological function (as measured by
task performance) has been reported in two humans exposed to 2,500 to 4,500
ppm (19,250 to 34,650 mg/m3) of CFC-113 for 30 minutes to 1 hour. Effects
disappeared within 15 minutes after cessation of exposure. No impairment of
performance at exposure levels of 500 and 1,000 ppm (3,850 and 7,700 mg/m )
was observed during two weeks of exposure, or at 1,500 ppm (11,550 mg/m ) for
2.75 hours.
CARDIOVASCULAR EFFECTS
Serious cardiovascular effects are unreported in humans. Various animal
studies (non-human primates and dogs) have indicated that acute exposure to
high concentrations of CFC-113 (as low as 2,000 ppm or 15,400 mg/m in a
6-hour exposure period) followed by a large injected dose of epinephrine re-
sulted in cardiac arrhythmias. Concentrations as high as 20,000 ppm (154,000
mg/m ), however, did not sensitize a dog's heart to its own circulating level
of epinephrine even when it was elevated by exercise. The compound may spon-
taneously induce myocardial depression by a direct effect on cardiac muscle,
decrease contractile performance, and lead to hypotension by decreasing cardiac
output and directly affecting peripheral vasodilation at much higher levels
(at or above 25,000 ppm or 192,500 mg/m3).
HEPATOTOXICITY
Preliminary data from an industry-sponsored, two-year chronic inhalation
study in rats indicate no hepatotoxic effects attributable to CFC-113 at doses
as high as 20,000 ppm (154,000 mg/m3).
STRATOSPHERIC POLLUTION AND OZONE DEPLETION
Chlorof1uorocarbon 113 and other structurally similar compounds, are
very resistant to destruction in lower portions of the atmosphere, i.e., the
troposphere. Because it is essentially inert in the troposphere, CFC-113 is
transported slowly to the stratosphere.
1-3
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A thin shield of ozone (0.,) is located in the stratosphere, 10 to 50
kilometers above the Earth's surface. Because 0, effectively absorbs ultra-
violet-B radiation (in the wavelength range 290 to 320 nm), any actual de-
crease in stratospheric ozone (0.,) concentration is expected to result in an
increased amount of this biologically-damaging radiation (incident at the
earth's surface). Photochemical reactions involving a variety of substances
produced by human activities, including certain halogenated organic compounds,
appear to have some potential to perturb 0., in the stratosphere; and if a
decrease in total 0^ were to occur, it is hypothesized that an increased
incidence in non-melanoma skin cancer might result. However, there is pre-
sently no evidence demonstrating that such an indirect effect of CFC-113 on
human health has occurred or is likely to occur as the result of its entry into
the atmosphere at current emission rates.
Chlorofluorocarbons have exceedingly long atmospheric lifetimes relative
to most other atmospheric pollutants. CFC-113 is estimated to have a stratos-
pheric lifetime in the range of 86 to 100 years, but it remains to be demon-
strated that this results in any significant depletion of stratospheric 0,.
It is not possible to estimate the extent to which perturbation of 0~ may be
associated with atmospheric loadings of CFC-113. All photochemical processes
that may affect 0.,, including those involving substances other than CFCs, must
be taken into account before realistic estimates of 0., change due to CFC-113
or other halocarbons can be made.
RECOMMENDATIONS FOR FURTHER STUDIES
Although the available human and toxicity data indicate that ambient
exposure to CFC-113 does not currently present a human health hazard, it is
apparent that further investigation is needed in several areas. Areas in
which incomplete information is available, and that should be considered in
formulating research needs, are presented below. This is not, however, a list
of research priorities.
1. Neurobehavioral toxicity. Although the effects of acute high-
level exposure to CFC-113 have been documented, there is a
paucity of data regarding the behavioral and neurological
effects of pure CFC-113 at chronic exposure levels less than
1,000 ppm. The extent, nature, and threshold of neurobe-
havioral effects need to be determined to properly evaluate
1-4
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potential risks from chronic ambient exposure. Epidemiological
studies of exposed workers may represent a mechanism by which
these data can be obtained.
2. Carcinogenicity. While the results of the ongoing, industry-
sponsored bioassay may fill the data gaps, it would be desirable
to have confirmation of these results, in another rodent strain,
by independent bioassay. Similar results in two or more animal
strains should provide the level of evidence necessary to more
effectively gauge the cancer potential of CFO113.
3. Teratogenicity and Reproductive Effects. There are no published
animal studies available that adequately assess the teratogenic
or adverse reproductive potential of CFC-113. Although there
are industry-sponsored animal studies in progress, uncertainty
about these biological endpoints in humans should serve as a
stimulus for future research.
4. Mutagenicity. Because of the limited testing performed, further
testing is needed before definitive conclusions can be drawn.
1-5
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2. INTRODUCTION
The principal intent of this document is to evaluate health effects
associated with exposure to chlorof luorocarbon - 113 (CFO113). Chlorof luoro-
carbon 113 is released into environmental air as a result of evaporative loss
during production, storage, consumer, and manufacturing uses. Since its
atmospheric reactivity is sufficiently low to allow it to reach the stra-
tosphere, CFC-113 is also of potential concern with regard to health effects
of an indirect nature.
The nature of the known health effects primarily involve impairment of
neurological and cognitive functions (humans) and the cardiovascular system
(animals) following acute exposure to levels greatly exceeding 1,000 ppm
(7,700 mg/m ). The health information pertaining to CFC-113 is discussed in
Chapter 5. In addition to evaluating the spectrum of health effects asso-
ciated with CFC-113 release to the environment, this document also discusses
analytical methods, production, sources, emissions, and ambient concentrations
to place CFC-113 in a real-world perspective. These aspects are discussed at
the outset, in Chapter 3.
In recent years, a great deal of attention has been focused upon the role
of chlorof luorocarbons, including CFC-113, and related species in possible
perturbations of stratospheric ozone (0,,). Biologically damaging ultraviolet
radiation incident at the Earth's surface would be increased by actual 0^
depletion; and it is hypothesized that, as a result, an increase in the
incidence of non-melanoma skin cancers might occur.
A comprehensive discussion of the role of chlorofluorocarbons in the
photocatalytic destruction of stratospheric 0, is beyond the scope of this
document. This area of stratospheric chemistry is rapidly changing with regard
to refinements of atmospheric models and reaction kinetics. For a more de-
tailed discussion, the reader is referred to publications of The National
Research Council (NRC) (1979a, b; 1982) and The World Meteorological Organiza-
tion (WMO) (1982). The role of all chlorof1uorcarbons in perturbations of stra-
tospheric 0~ is an area of ongoing interest in the U.S. EPA Office of Toxic
Substances. This health assessment document, however, does summarize the major
findings of these groups in relation to estimates of stratospheric 0~ change
associated with chlorofluorocarbons in general, and whenever possible, with
2-1
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CFC-113 in particular. It should be noted that CFC-113 is simply one member of
a group of compounds that have the potential to alter stratospheric CL levels.
2.1 REFERENCES
National Research Council. National Academy of Sciences. Protection Against
Depletion of Stratospheric Ozone by Chlorofluorocarbons, 1979a.
National Research Council. National Academy of Sciences. Stratospheric Ozone
Depletion by Halocarbons: Chemistry and Transport, 1979b.
National Research Council. National Academy of Sciences. Causes and Effects
of Stratospheric Ozone Reductions: An Update, 1982.
World Meteorological Organization. WMO Global Ozone Research and Monitoring
Project Report No. 11, May 1981. The Stratosphere 1981: Theory and
Measurements, 1982.
2-2
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3. PHYSICO-CHEMICAL PROPERTIES, PRODUCTION AND ENVIRONMENTAL FATE
3.1 CHEMICAL AND PHYSICAL PROPERTIES
Chlorof1uorocarbons, in general, are characterized by high density, low
boiling point, low viscosity, low surface tension, and high thermal and photo-
stability (Downing, 1966). They do not react with most metals below 200°C nor
do they generally react with acids or oxidizing agents. However, specific and
unusual applications should be carefully reviewed and tested. To a large
degree, stability is attributed to the number of C-F bonds—bonds exhibiting
high bond strength (Bower, 1971).
Trichlorotrifluoroethane, CCl^F-CCIF^ (CFC-113), is a nonflammable,
colorless liquid, characterized by a moderately high vapor pressure and a low
boiling point (Table 3-1) and by high thermal and photolytic stability. It is
practically insoluble in water, is heavier than water, and is extremely re-
sistant to hydrolysis (E. I. duPont de Nemours, 1976). At equilibrium, with a
partial pressure of one atmosphere and at 86°F, less than 0.005 grams of
CFC-113 per liter of water per year is hydrolyzed (E. I. duPont de Nemours,
1980). Its solubility in water, per atmosphere of partial pressure at 25°C,
is 0.017 grams per 100 grams of water (E. I. duPont de Nemours, 1980). While
CFC-113, as others in this class, is relatively inert upon contact with common
construction materials such as steel, copper, and aluminum, it has the po-
tential to react violently with more reactive metals in their elemental state,
e.g., sodium, potassium, and barium (E. I. duPont de Nemours, 1976). Zinc,
magnesium, and aluminum alloys containing more than two percent magnesium are
not recommended for use in systems where water may be present (Downing, 1966;
E. I. duPont de Nemours, 1969). As a solvent, CFC-113 is often used in azeo-
tropic mixtures with acetone, methylene chloride, and ethyl and methyl alcohol
(Ward, 1981). Blends of CFC-113 and isopropyl alcohol are also used.
3.2 ANALYTICAL METHODOLOGY
Detecting extremely low levels of CFC-113 in ambient air requires so-
phisticated analytical techniques. The two most commonly used systems, both
of which have a lower limit of detection on the order of a few parts per
trillion (ppt), are gas chromatography-mass spectrometry (GC-MS) and gas
chromatography-electron capture detection (GC-ECD). To measure workplace
concentrations, GC coupled with flame ionization or thermal conductivity
detectors is satisfactory.
3-1
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TABLE 3-1. PHYSICAL PROPERTIES OF TRICHLOROTRIFLUOROETHANE*
Molecular weight 187.4
Boiling point 47.6°C (760 mm)
Vapor pressure 6.5 lb/in2 (25°C)
Density 1.5 gm/cm
Solubility 0.017 gm/100 gm H20 (0°C, 760 mm)
Downing, 1966; E. I. duPont de Nemours, 1969, 1976.
3.2.1 Sampling
Because CFC-113 levels in air are typically in the sub parts-per-billion
(ppb) range, the sampling and analysis techniques have been designed to detect
trace levels. Singh et al. (1979a,b) have employed cryogenic trapping of air
containing trace levels of CFC-113. During sampling, traps are maintained at
liquid oxygen temperature. Traps were made of stainless steel packed with a
4-inch bed of glass wool or glass beads. Aliquots are thermally desorbed and
injected directly into the gas chromatograph. More recently, Singh et al.
(1981b) collected air samples in precleaned, 1-liter electropolished stainless-
steel canisters. Samples were then preconcentrated at liquid oxygen temperature
in freezeout traps containing SE-30 or glass wool.
Makide et al. (1980) used electropolished stainless-steel canisters,
followed by preconcentration on a silicone OV-101 column at - 40°C. Column
temperature was raised at a rate of 5°C per minute up to 70°C for separation
of components.
3.2.2 Analysis
Cronn and Harsch (1979) reported a detection limit of 12 ppt (at a mixing
ratio of 50 ppt) with GC-MS. Precision was 10 percent. A lower detection
limit (2 ppt) had been obtained using GC-ECD (Harsch and Cronn, 1978). In
this system, the CFC-113 mixing ratio was 23 ppt and precision was again 10
percent. Cronn and coworkers have reported difficulties in measuring low
levels of CFC-113 in samples collected at high altitudes (Harsch and Cronn,
1978). Contamination resulted when the mixing ratio of CFC-113 in the
3
laboratory air was in the range of 15 to 20 ppb (0.116 to 0.154 mg/m ).
3-2
-------
Measurements of CFC-113 in rural air samples by GOECD using a freezeout
concentration technique resulted in a detection limit of 0.8 ppt with a pre-
cision of 1.8 percent at a mixing ratio of 21 ppt (Rasmussen et al., 1977).
In a comparison of GC-ECD with GC-MS, Cronn et al. (Cronn and Harsch,
1979; Cronn et al., 1976a) judged GC-ECD to be superior in reproducibility and
in yielding a lower limit of detection. Since the presence of water and
oxygen in the EC detector may cause erroneous results for some compounds,
Russell and Shadoff (1977) recommended that oxygen be eliminated during pre-
concentration procedures, while water could be removed through the use of
drying tubes.
The lowest detection limit reported is that of Makide et al. (1980),
<0.05 ppt with a GC-ECD system.
Fabian et al. (1981), using cryogenic sampling with GC/MS analysis,
reported a detection limit for CFC-113 of about 0.1 ppt for a 1-liter sample.
It was indicated that CFC-113 is stable in stainless steel bottles electro-
polished internally, for more than 6 months.
3.2.3 Calibration
Gas chromatographs have generally been calibrated with static dilutions
of ppm-level standards (Harsch and Cronn, 1978; Rasmussen et al., 1977; Makide
et al., 1980) and by use of permeation tubes (Singh et al. 1981b).
®
Singh et al. (1977a) judged FEP Teflon tubing to be satisfactory in
generating primary standards for CFC-113. All tubing materials were either
aluminum or glass. Errors in this approach were less than 10 percent. Similar
results were recently reported by Singh et al. (1981b). Permeation rates
were determined at 30 ± 0.05 °C. Error was < ± 10 percent. Cell permeation
tubes were conditioned for two weeks or longer. These investigators concluded
that permeation tubes offer the most accurate means of generating primary
standards.
3.3 PRODUCTION, USE, EMISSIONS, AND AMBIENT MIXING RATIOS
3.3.1 Production
Chlorofluorocarbons typically are produced by displacing chlorine from
chlorocarbons by fluorine using hydrogen fluoride (HF). The starting material
for CFC-113 is normally tetrachloroethylene (Ward, 1981). Other chlorocarbons
commonly used include carbon tetrachloride (CC1.), and hexachloroethane (C?Clfi).
A reaction sequence employing CpCl. (tetrachloroethylene) to produce
CFC-113 is depicted as follows:
3-3
-------
C2C14 + 3 HF SbC15, C2C13F3 + 3 HC1
ci2
45-200°C
In this method, chlorine gas (C19) maintains the antimony pentachloride (SbClr)
1— «J
catalyst in the pentavalent state (Ward, 1981). The reaction can proceed
either in the liquid or vapor phase. Anhydrous hydrogen chloride (HC1) is the
principal byproduct.
Only two manufacturers currently produce CFC-113 in the United States:
Allied Chemical Corporation, Baton Rouge, Louisiana (SRI Inter., 1979) and E.
I. duPont de Nemours and Company, Inc., at its Montague, Michigan and Corpus
Christi, Texas plants (Ward, 1981).
Accurate U.S. production data for CFC-113 are not readily available.
Production rates for 1979 are estimated to be about 59,000 metric tons (E. I.
duPont de Nemours, 1982). The RAND Corporation (U.S. EPA, 1980a) estimated that
production of CFC-113 in 1977 amounted to about 37,000 metric tons (upper bound)
of which solvent application accounted for 96 percent of the CFC-113 available
for use. The U.S. EPA (1980a) has estimated that by 1990, 71,000 metric tons
could represent an upper bound estimate of production.
3.3.2 Use
Principal uses of CFC-113 fall into several main categories (NRC, 1979a):
(1) degreasing, cleaning, and drying applications; (2) removal of solder flux;
(3) critical cleaning of electronic, electrical and mechanical assemblies; (4)
application as a cutting fluid, carrier and reaction medium, and dry cleaning
solvent. It is an alternative to tetrachloroethylene, currently the solvent
of choice in the drycleaning industry (Fischer, 1980). It is not used in
aerosol formulations as a propellant or as a propellant component, but is used
as a solvent or active ingredient in certain aerosol formulations.
In cleaning and drying operations, two types of solvent losses occur
(U.S. EPA, 1980b): (1) escape in vapor form and (2) in liquid form when tanks
are emptied for cleaning. Although there are no identified reports that
CFC-113 has been detected in surface or drinking waters, this potential exists
since CFC-113 may be sealed in drums and buried. Because CFC-113 has very
limited solubility in water and is highly volatile, all releases of CFC-113
can be expected to eventually be conveyed to the stratosphere.
3-4
-------
Estimates of the NRC (1979a) suggest that CFC-113 emissions during the
period 1976-1977 were 30,000 metric tons. CFC-113 was reported to account for
over 15 percent of chlorofluorocarbon emissions (U.S. EPA, 1980a). The World
Meteorological Organization (1982), citing figures supplied by E. I. duPont de
Nemours and Company, reported a current global annual emissions rate of 91,000
metric tons.
The NRC (1979a) estimated 1976-1977 emissions in the United States by use
category as follows: (1) degreasing, cleaning, and drying, 5,909 metric tons;
(2) solder flux removal, 6,818 metric tons; (3) critical cleaning and drying,
11,818 metric tons; and (4) miscellaneous, 5,454 metric tons (909 metric tons
associated with dry cleaning applications). Substitution of alternative
solvents was considered a possibility to somewhat reduce emissions of CFC-113
in all use categories except (3), where no alternative solvent is available.
In a RAND Corporation report (U.S. EPA, 1980a), all CFC-113 produced for
nonaerosol end uses was expected to "find its way into the ambient air."
CFC-113 accounts for less than one percent of the market for solvents to
dryclean clothes (U.S. EPA, 1980a). In 1976, about 3 percent of CFC-113 sold
in the United States was used as an inert carrier (U.S. EPA, 1980a). Assuming
prompt emissions, the RAND estimate for emissions is 35,000 metric tons (U.S.
EPA, 19805).
3.3.3 Ambient Air Mixing Ratios
The extent to which emissions of CFC-113 contribute to the loading of the
atmosphere is indicated by measurements of ambient air mixing ratios shown in
Table 3-2.
The most recently reported mixing ratios for the northern and southern
hemispheres are those of the World Meteorological Organization (1982). Based
upon the observations of Singh et al. (1981b) and Rasmussen et al. (1981), the
WMO reported ranges of 12 to 25 ppt (northern hemisphere) and 11 to 22 ppt
(southern hemisphere). The estimated limit of detection was 1 ppt with the
estimated accuracy at 20 percent and the estimated precision at 10 percent.
Singh et al., (1981b) reported an average atmospheric growth rate for CFC-113
of 2 ppt per year, based on measurements made at Point Arena, California, a
"clean" air site, from late 1979 to early 1981.
Measurements made in the latter part of 1977 indicated a global average
mixing ratio of 18 ppt (Singh et al. 1979a, b); no gradient was observed
between the northern and southern hemispheres. In comparison, the two most
3-5
-------
TABLE 3-2. TROPOSPHERIC LEVELS OF CFC-113
CO
I
CTi
Location
Arizona
Phoenix
California
Badger Pass
Los Angeles
Point Reyes
Mill Valley
Oakland
Palm Springs
Point Arena
Riverside
San Jose
Stanford Hills
Yosemite
Colorado
Denver
Delaware
Delaware City
Illinois
Chicago
Date of
measurement
4/23/79
5/5/77
4/9/79
4/28/76
12/1/75
1/11/77
6/28/79
5/5/76
5/23/77
8/30/78
12/8/79
4/25/77
7/1/80
8/21/78
11/23/75
5/12/76
6/15/80
7/8/74
4/20/81
- 5/6/79
- 5/13/77
- 4/21/79
- 5/4/76
- 12/12/75
- 1/12/77
- 7/10/79
- 5/11/76
- 5/30/77
- 9/5/78
- 2/18/81
- 5/4/77
- 7/13/80
- 8/27/78
- 11/30/75
- 5/18/76
- 6/28/80
- 7/10/74
- 5/2/81
Concentration (ppb)
max
1.2513
0.255
4.160
0.398
0.450
0.181
0.309
0.105
0.042
0.027
0.137
0.144
2.21
0.365
0.157
0.031
1.608
<0.01
0.359
mm
0.0122
0.014
0.049
0.029
0.012
0.017
0.016
0.012
0.014
0.018
0.024
0.020
0.026
0.017
0.008
0.011
0.028
<0.01
0.020
average
0.1513
0.027
0.305
0.119
0.031
0.042
0.049
0.037
0.023
0.022
0.025
0.099
0.274
0.076
0.031
0.020
0.221
0.082
± 0.2247
± 0.026
± 0.6671
± 0.077
± 0.041
± 0.026
± 0.059
± 0.013
± 0.006
± 0.002
± 0.166
± 0.262
± 0.068
± 0.030
± 0.003
± 0.235
± 0.065
Reference
Singh et al . ,
Singh et al . ,
Singh et al . ,
Singh et al . ,
Singh et al . ,
Singh et al . ,
Singh et al . ,
Singh et al . ,
Ibid
Ibid
Singh et al . ,
Ibid
Singh et al . ,
Singh et al . ,
Singh et al . ,
Ibid
Singh et al . ,
Li 1 1 ian et al .
Singh et al . ,
1981a
1979b
1982
1977b
1977b;1979b
1979b
1982
1979b
1981b
1982
1979b
1977b;1979b
1982
, 1975
1982
-------
TABLE 3-2. (continued)
OJ
I
Location
Kansas
Jetmore
Maryland
Baltimore
Missouri
St. Louis
Nevada
Reese River
New Jersey
Bayonne
Sandy Hook
Seagirt
New York
New York City
Staten Island
White Face Mtn.
Ohio
Wilmington
Pennsylvania
Pittsburgh
Texas
Houston
Date of
measurement
6/1/78
7/11/74
5/29/80
5/14/77
3/73
7/2/74
6/18/74
6/27/74
3/26/81
9/16/74
7/16/74
4/7/81
5/14/80
- 6/7/78
- 7/12/74
- 6/9/80
- 5/20/77
- 12/73
- 7/5/74
- 6/19/74
- 6/28/74
- 4/5/81
- 9/19/74
- 7/26/74
- 4/17/81
- 5/25/80
Concentration (ppb)
max
0.040
0.038
1.792
0.042
38
0.56
<0.01
0.025
0.359
<0.01
0.075
0.162
1.664
mm
0.012
<0.01
0.022
0.004
<0.01
<0.01
<0.01
<0.01
0.059
<0.01
<0.01
0.042
0.037
average
0.023 ± 0.005
0.03
0.132 ± 0.171
0.019 ± 0.006
4.12
<0.08
<0.01
0.025
0.129 ± 0.078
0.016
0.068 ± 0.027
0.199 ± 0.190
Reference
Singh et al . ,
Lillian et al
Singh, et al .
Singh et al . ,
Lillian et al
Ibid
Ibid
Ibid
Singh, et al .
Lillian et al
Ibid
Singh, et al .
Singh, et al .
1979b
. , 1975
, 1982
1979b
. , 1975
, 1982
. , 1975
, 1982
, 1982
Japan
9 rural sites
8/78 - 9/78
0.027 0.021 0.023 ± 0.0016
Makide et al., 1980
-------
dominant chlorof luorocarbons (methane series), CFC-11 and CFO12, were found
at global average mixing ratios of 126 and 220 ppt, respectively. Singh et
al. (1979a,b) expected the stratosphere to be the major reservoir for CFC-113.
Despite extensive study, significant tropospheric sinks for CFC-11, CFC-12,
and CFC-113 have not been confirmed or quantified (NRC, 1979a, b.)
Rasmussen and Khalil (1982) measured the global concentration distribu-
tion of CFC-113 in air samples collected by aircraft in 1978. They found that
CFC-113 was equally distributed in and above the boundary layer (at altitudes
of 0.12-0.36 km and 4.8-5.9 km, respectively), and equally distributed in
latitude. The average ratio was reported to be 13 ppt.
In flights over the Pacific Northwest in March 1976, Cronn and coworkers
(1976b) detected CFC-113 in the upper troposphere at an average mixing ratio
of 21 ± 4 ppt (0.17 ± 0.03 x 10"3 mg/m3). More recently, Cronn et al. (1977a, b)
have detected CFC-113 in whole-air samples collected during high altitude
tropospheric flights over the Pacific Ocean west of San Francisco (37° N). An
average northern hemisphere tropospheric background mixing ratio of 18 ± 2.3
-3 3
ppt (0.14 ± 0.02 x 10 mg/m ) was measured (April 1977).
Fabian et al. (1981) are the first investigators to have measured CFC-113
levels in the stratosphere; samples were collected during balloon descent,
from 28.8 to 14.4 kilometers. The vertical profile obtained suggests that
CFC-113 is rapidly decomposed; at 15 kilometers, the CFC-113 mixing ratio was
10 ppt and had decreased to 0.6 ppt at 28.8 kilometers.
3.3.4 Other Media
No information is available regarding levels of CFC-113 in water or soil.
3.4 ATMOSPHERIC FATE
The potential for ambient air mixing ratios of CFC-113 to pose a hazard
to human health is influenced by many processes, one of which involves trans-
port of CFC-113 to the stratosphere where it participates in ozone (0^) per-
turbation reactions.
It is generally accepted that the longer the tropospheric residence time
for a chemical species, the greater the likelihood of diffusion into the
stratosphere. Current understanding of stratospheric science suggests that
many substances produced by human activities have the potential to alter strat-
ospheric Q~ levels. A major goal of atmospheric scientists is to determine
the net effect of all these substances on 0., simultaneously.
Chlorofluorocarbons are remarkably stable in the troposphere. However,
they do undergo photodissociation in the stratosphere (NRC 1979a, b; NRC 1982;
3-8
-------
WHO, 1982). In a report prepared for the U. S. Environmental Protection
Agency by the Rand Corporation (U.S. EPA 1980a), CFC-113 was described as highly
unreactive and unlikely to decompose prior to entering the stratosphere.
There are no known tropospheric sinks for CFC-113. Hester et al. (1974)
reported that no detectable loss of CFC-113 occurs when it is irradiated,
under simulated atmospheric conditions, in the presence of olefins and nitro-
gen oxides. The possibility exists that some decomposition of chlorofluoro-
carbons may occur upon contact with hot desert sands (NRC, 1979a).
There are two processes for CFC-113 destruction: direct photolysis and
reaction with excited atomic oxygen, the latter being produced upon photodis-
sociation of 0^. Calculations made by Chou et al. (1978) indicate that photo-
dissociation in the stratosphere accounts for 84 to 89 percent of CFC-113 re-
moval. An atmospheric lifetime, based upon measured absorption coefficients,
in the range of 63 to 122 years was estimated. An atmospheric lifetime of 88
years was estimated by Wuebbles (1983) using the one-dimensional (1-D) trans-
port-kinetics model of The Lawrence Livermore National Laboratory.
The wavelength region associated with the photodissociation of chloro-
fluorocarbons is the range from 185 to 227 nm between the Schumann-Runge
absorption band for 0,, and the Hartley band for 0~. Atkinson et al. (1976)
concluded that chlorofluorocarbons with two or more chlorine atoms had suf-
ficiently high ultraviolet absorption in this range that photodissociation was
the predominant mode of decomposition in the critical region (30 kilometers)
of the stratosphere.
The absorption cross section for CFC-113 over the 185 to 227 nm wave-
length range indicates that CFC-113 has approximately the same potential for
photodissociation as dichlorodifluoromethane (CFC-12), but less than that for
trichlorof1uoromethane (CFC-li) (Chou et al., 1978). Upon complete photodis-
sociation, each molecule of CFC-113 and CFC-11 yields an equal number of Cl
atoms. The absorption maxima of CFC-113 and CFC-12 in the near ultraviolet
are 160 nm and 177 nm, respectively (Sandorfy, 1976); the absorption maximum
of CFC-11 is at a higher wavelength, 185 nm. In this narrow wavelength range,
absorption of UV by 0,, is at a minimum, thus allowing for absorption (con-
sequently, destruction) by chlorofluorocarbons.
As shown in the following reaction sequence, release of atomic chlorine
(Cl) leads to the photocatalytic conversion of 0., and 0 to oxygen:
3-9
-------
hv
uu i r~
Cl- + 0- —
3
CIO + 0 —
=• 01^ i
— * cio +
— * Cl- +
CC1F - CC1F2 + Cl
Atomic chlorine, produced in the first reaction, would react with 0, to yield
chlorine oxide (CIO) that, upon subsequent reaction would form a chain re-
action in theory.
As noted by the World Meteorological Organization (1982), the efficiency
of this cycling is closely coupled with other cycles, principally the nitrogen
oxides and hydroxyl radical cycles. In addition, efficiency is, in part,
determined by perturbations in atmospheric temperature such as the strato-
spheric cooling resulting from increases in carbon dioxide levels in the
troposphere (WMO; NRC, 1982; Wuebbles, 1983).
The National Research Council (1982), drawing upon the data base developed
by the World Meteorological Organization (1982), recognized CFC-113 to have
the potential to perturb stratospheric 0~ levels. The Council has stated that
"The abundance of ozone in the stratosphere is determined by a dynamic balance
among processes that produce and destroy it and transport it to the tropos-
phere." Thus, the actual role of CFC-113 in stratospheric processes can best
be elucidated through an examination of multiple perturbation scenarios invol-
ving all the known key contributory factors (NRC, 1982). The potential of
CFC-113, however, can be examined in a context apart from other perturbation
processes. In this manner, important information concerning the atmospheric
chemistry of CFC-113 can be used to develop more representative multiple
perturbation simulations. The development of such models has been recommended
by the Council to describe the combined effects of all relevant compounds on
stratospheric 0~.
Wuebbles (1983) has recently provided a theoretical framework in order to
assess the potential impact of all chlorocarbons presently thought to be of
concern regarding Ov Ameloriating effects of other anthropogenic substances
O
were not included. Assessments were based upon model calculations using the
one-dimensional coupled transport and chemical kinetics model of the tropos-
phere and stratosphere developed at the Lawrence Livermore National Laboratory.
Although the chemistry presently used in the model represents the best current
3-10
-------
evaluation of existing laboratory data, Wuebbles noted that changes in the
chemistry are likely to continue. Wuebbles concluded that, if chlorocarbons
alone are considered, CFC-113 and other chlorocarbons could contribute signifi-
cantly to predicted changes in total 0., based upon their current emission
O
rates.
Wuebbles et al. (1983) extended his "chlorocarbon-only" analyses by exa-
mining the coupling between several possible anthropogenic sources (C0?, N?0,
and NO ) of stratospheric perturbations of past and future changes in total 0,.
X o
Surface methane (CH.) was held constant. They found, using the Lawrence
Livermore one-dimensional transport-kinetics model, that "C09 and NO emissions
L. X
have comparable ameliorating effects on the total ozone decrease otherwise
expected from chlorofluorocarbon emissions.... When all anthropogenic sources
are included the change in total ozone is less than 1% over the next 120
years." Calculations indicated that when all anthropogenic sources were con-
sidered, the change in total 0., over the 1970-1980 timeframe was +0.13 percent,
consistent with available statistical 0, trend analyses.
The recent model calculations of Owens et al. (1982) suggest that natural
and anthropogenic emissions of methane also may significantly moderate the 0,
destroying potential of chlorofluorocarbons. Using a 1-D model with chemical
reaction rates and incident solar fluxes recommended by WMO (1982), Owens and
coworkers have calculated that a doubling of methane, if viewed in isolation,
can lead to a total column 0» increase of 3.5 percent. When coupled with
chlorofluorocarbons, the calculation shows an overall total column 0, change
of -1.6 percent. Khali 1 and Rasmussen (1982) also recently suggested that an
increase in the atmospheric levels of methane may serve to protect 0, levels
in the stratosphere. After examining measurement data as far back as 1965,
they find the data consistent with a rate of increase in methane ranging from
1.2 to 2 percent per year. State-of-the-art instrumentation and statistical
methodology indicate that detection of global average stratospheric 0, trends
is limited to about a 2 percent change per decade. At the present time, the
direction and extent of 03 perturbation cannot be measured. Wuebbles et al.
(1983) reported that a doubling of the present surface ChL concentration, in
the Lawrence Livermore model, would increase total 0., by 2 percent. Because
of difficulties in predicting future trends in atmospheric CH-, Wuebbles
et al. held surface CH. constant in their calculations.
3-11
-------
Among the confounding factors are the uncertainties and limitations of
the models and the complexity of rapidly changing knowledge in atmospheric
chemistry. The NRC (1982) stated that "These results should be interpreted in
light of the uncertainties and insufficiencies of the models and observa-
tions." An evaluation of the impact of CFC-113 upon stratospheric and thus
on total column 03 must take into account all factors affecting stratospheric
and tropospheric processes if realistic estimates of 0^ perturbations are to be
made.
3.5 REFERENCES
Atkinson, R. , G. M. Breuer, J. N. Pitts, Jr., and H. L. Sandoval. Tropo-
spheric and stratospheric sinks for halocarbons: Photooxidation, 0('D)
atom, and OH radical reactions. JGR J. Geophys. Res. 81(33):5765-5770, 1976.
Bower, F. A. Nomenclature and Chemistry of Fluorocarbon Compounds. Aerospace
Medical Research Laboratory, Wright-Patterson Air Force Base, AD 751-423,
December 1971.
Chou, C. C. , R. J. Mil stein, W. S. Smith, H. Vera Ruiz, M. J. Molina, and F.
S. Rowland. Stratospheric photodissociation of several saturated perhalo
chlorof1uorocarbon compounds in current technological use (Fluorocarbons-
1B, -113, -114, and -115). J. Phys. Chem. 82(l):l-7, 1978.
Cronn, D. R. , and D. E. Harsch. Determination of atmospheric halocarbon
concentrations by gas chromatography - mass spectrometry. Anal. Lett. 12
(B14):1489-1496, 1979.
Cronn, D. R., R. A. Rasmussen, and E. Robinson. Phase I Report. Measurement
of Tropospheric Halocarbons by Gas Chromatography - Mass Spectrometry.
Washington State University, August 1976a.
Cronn, D. R. , R. A. Rasmussen, and E. Robinson. Measurement of Tropospheric
Halocarbons by Gas Chromatography-Mass Spectrometry. Report for Phase I.
Submitted to U.S. Environmental Protection Agency, Washington State
University, Pullman, Washington, August 23, 1976b.
Cronn, D. R. , R. A. Rasmussen, and E. Robinson. Measurement of Tropospheric
Halocarbons by Gas Chromatography-Mass Spectrometry. Report for Phase
II. Submitted to U.S. Environmental Protection Agency, Washington State
University, Pullman, Washington, October, 1977a.
Cronn, D. R. , R. A. Rasmussen, E. Robinson, and D. E. Harsch. Halogenated
compound identification and measurement in the troposphere and lower
stratosphere. JGR J. Geophys. Res. 82:5935-5944, 1977b.
Downing, R. C. Aliphatic Chlorof1uorohydrocarbons. In: Kirk-Othmer1s Ency-
clopedia of Chemical Technology, Volume 9, 2nd Edition, 1966.
3-12
-------
E. I. duPont de Nemours^nd Company to U. S. Environmental Protection Agency.
Addendum for Freon* Products Division Bulletins B~2 and S-16, 1980.
E. I. duPont de Nemours and Company. Personal communication from D. Broughton,
17 March 1982.
E. I. duPont de Nemours and Company. "Freon" fluorocarbons. Properties and
Applications. Wilmington, DE, 1969.
E. I. duPont de Nemours and Company. Thermodynamic Properties of "Freon" 113,
Trichlorofluoroethane, CC12F-CC1F2 with addition of other physical proper-
ties. Wilmington, DE, T-113A, 1976.
Fabian, P., R. Borchers, S. A. Penkett, and N. J. D. Prosser. Halocarbons in
the stratosphere. Nature (London) 294: 733-735, 1981.
Fischer, William, personal communication, International Fabricare Institute,
Rockville, Maryland, 1980.
Harsch, D. E. , and D. R. Cronn. Low-pressure sample-transfer technique for
analysis of stratospheric air samples. J. Cnromatogr. Sci. 16:363-367,
1978.
Hester, N. E. , E. R. Stephens, and 0. C. Taylor. Fluorocarbons in the
Los Angeles Basin. J. Air Pollut. Control Assoc. 24(6):591-595, 1974.
Hudson, R. D. and E. I. Reed, eds. The Stratosphere: Present and Future.
NASA Reference Publication 1049, National Aeronautics and Space Administra-
tion, Washington, DC, 1979.
Khali!, M. A. K. and R. A. Rasmussen. Secular trends of atmospheric methane
(CH4). Chemosphere ll(9):877-883, 1982.
Lillian, D., H. B. Singh, A. Appleby, L. Lobban, R. Arnts, R. Gumpert, R.
Hague, J. Toomey, J. Kazazis, M. Antell, D. Hansen, and B. Scott. Atmos-
pheric fates of halogenated compounds. Environ. Sci. Technol. 9(12):1042-
1048, 1975
Makide, Y. , Y. Kanai, and T. Tominga. Background Atmospheric Concentrations
of Halogenated Hydrocarbons in Japan. Bull. Chem. Soc. Japan 53:2681-2682,
1980.
National Research Council. National Academy of Sciences. Protection Against
Depletion of Stratospheric Ozone by Chlorofluorocarbons, 1979a.
National Research Council. National Academy of Sciences. Stratospheric Ozone
Depletion by Halocarbons: Chemistry and Transport, 1979b.
National Research Council. National Academy of Sciences. Causes and Effects
of Stratospheric Ozone Reduction: An Update, 1982.
Owens, A. J., J. M. Steed, D. L. Filkin, C. Miller, and J. P. Jesson. The
potential effects of increased methane on atmospheric ozone. Geophys.
Res. Lett. 9(9):1105-1108, 1982.
3-13
-------
Rasmussen, R. A., M. A. K. K Khalil, and R. W. Callage. Atmospheric trace gases
in Antarctica. Science (Washington, DC) 211:285, 1981.
Rasmussen, R. A. and M. A. K. Khalil. Longitudinal distributions of trace
gases in and above the boundary layer. Chemosphere, Vol. 11, No. 3, pp.
227-235, 1982.
Rasmussen, R. A., D. E. Harsch, P. H. Sweany, J. P. Krasnec, and D. R. Cronn.
Determination of atmospheric halocarbons by a temperature programmed gas
chromatographic freezeout concentration method. J. Air Poll. Cont.
Assoc. 27(6):579-581, 1977.
Russell, J. W. , and L. A. Shadoff. The sampling and determination of halo-
carbons in ambient air using concentration on porous polymer. J. Chromatogr.
134:375-384, 1977.
Sandorfy, C. Review Paper. UV absorption of fluorocarbons. Atmos. Environ.
10:343-351, 1976.
Singh, H. B. , L. J. Salas, R. Stiles, and H. Shigeishi. Measurements of
Hazardous Organic Chemicals in the Ambient Atmosphere. Final Report
Prepared for U.S. Environmental Protection Agency, SRI International,
Menlo Park, California, August 1982.
Singh, H. B. , L. J. Salas, H. Shigeishi, and E. Scribner. Atmospheric halo-
carbons, hydrocarbons, and sulfur hexafluoride. Global distributions,
sources, and sinks. Science (Washington, DC) 203:899-903, 1979b.
Singh, H. B. , L. J. Salas, H. Shigeishi, A. J. Smith, E. Scribner, and L. A.
Cavanagh. U.S. Environmental Protection Agency. Atmospheric Distribu-
tions, Sources, and Sinks of Selected Halocarbons, Hydrocarbons, SF,~ and
N20. EPA-600/3-79-107, November 1979a.
Singh, H. B. , L. J. Salas, and R. Stiles. Trace chemicals in the "clean"
troposphere. EPA-600/3-81-055. SRI International, Menlo Park, California,
1981b.
Singh, H. B. , L. Salas, D. Lillian, R. R. Arnts, and A. Appleby. Generation
of accurate halocarbon primary standards with permeation tubes. Environ.
Sci. Techno!. 11(5):511-513, 1977a.
Singh, H. B. , L. J. Salas, A. J. Smith, and H. Shigeishi. Measurements of
some potentially hazardous organic chemicals in urban environments.
Atmos. Environ. 15:601-612, 1981a.
Singh, H. B., L. Salas, H. Shigeishi, and A. Crawford. Urban-nonurban relation-
ships of halocarbons, SFfi, N?0 and other atmospheric trace constituents.
Atmos. Environ. 11:819-823, M77b.
SRI International. Directory of Chemical Producers, Menlo Park, California,
1979.
3-14
-------
U.S. Environmental Protection Agency. Economic Implications of Regulating
Chlorofluorocarbon Emissions from Nonaerosol Applications. EPA 560/12-80-
001. Report prepared by RAND Corporation, October 1980a.
U.S. Environmental Protection Agency. Regulating Chlorofluorocarbon Emissions:
Effects on Chemical Production. EPA-560/12-80-001b. Report prepared by
RAND Corp., October 1980b.
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to Jean Parker, U.S. Environmental Protection Agency, 29 September 1980,
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1981.
World Meteorological Organization. WMO Global Ozone Research and Monitoring
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1981.
Wuebbles, D. J., F. M. Luther, and J. E. Penner. Effect of Coupled Anthropogenic
Perturbations on Stratospheric Ozone. J. Geophy. Res. 88 (C2):1444-1456,
1983.
Wuebbles, D. J. Chlorocarbon emissions scenarios: potential impact on
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3-15
-------
4. METABOLIC FATE AND DISPOSITION
4.1 ABSORPTION AND ELIMINATION
Use of CFC-113 as a solvent for degreasing fabricated metal parts and dry
cleaning of fabrics suggests that workers will primarily be exposed through
inhalation and contact with the skin.
Limited information has been published concerning the fate and disposi-
tion of CFC-113 and related compounds. Most of the data were necessarily
obtained through experimentation on rodent species and at inhalation exposure
levels well above ambient tropospheric levels.
Chiorof1uorocarbons were judged to be absorbed by dogs through inhalation
in the following descending order: CFC-11 > CFC-113 > CFC-12 > CFC-114 (Shargel
and Koss, 1972). Levels were determined in arterial and venous blood of
anesthetized male and female dogs following exposure to an aerosol mixture
containing 25 percent (by weight) of each compound. Blood samples were ex-
tracted with hexane prior to quantitation by gas chromatography-electron
capture detection. Peak arterial levels accounted for only a small percentage
of total administered dose.
In general, fluorocarbons and chlorofluorocarbons exhibit biphasic ab-
sorption patterns (Azar et al., 1973; Letkiewicz, 1976; Trochimowicz et al.,
1974). A rapid initial increase in blood levels is followed by a slower
increase to maximum concentrations. Equilibrium is reached when arterial and
venous blood concentrations are equal. During elimination, there is a rapid
initial fall in blood levels followed by a slower decline to undetectable
levels. During elimination, venous concentrations exceed arterial concentra-
tions, indicating that fluorocarbons are being released from tissues.
Dermal absorption of CFC-113 has been evaluated in man (Haskell Labora-
tory, 1968). Three subjects were tested. Concentration of CFC-113 in alveolar
air was used as an indication of CFC-113 absorption. The subjects had their
hands and forearms exposed for thirty minutes, and portions of their scalps
exposed for fifteen minutes. The concentration of CFC-113 in their breath was
then measured at various times after termination of the exposure.
The data are presented in Table 4-1. At 90 minutes post-exposure, the
concentrations of CFC-113 in exhaled air in all three subjects had decreased
3 3
from a high of 12 ppm (92 mg/m ) to less than 0.5 ppm (3.8 mg/m ). In one of
3
the subjects, a trace concentration of 0.1 ppm (0.7 mg/m ), the limit of
4-1
-------
TABLE 4-1. DERMAL EXPOSURE OF MAN TO CFC-113
Area exposed
Portions of scalp
Portions of scalp
Hands and forearms
Hands and forearms
Duration of
exposure
15 min.
15 min.
30 min.
30 min.
*
Time of peak
in expired breath
20.5 min.
18.5 min.
11.5 min.
23 min.
Value of
12.7
7.4
9.6
1.7
peak
ppm
ppm
ppm
ppm
Expressed in minutes after termination of exposure; at 90 minutes post-
exposure, exhaled concentration was 0.5 ppm for all four exposures.
Data from Haskell Laboratory, 1968.
detectability in this test, remained 18 hours post-exposure. These data in-
dicate that the human body absorbs CFC-113 as a result of dermal exposure, and
that the amount of CFC-113 absorbed rapidly declines when the exposure ends.
Administration of CFC-12 and CFC-114 to dogs by various routes of exposure
indicate that chlorofluorocarbons are eliminated solely via the respiratory
tract (Matsumato et al., 1968).
4.2 DISTRIBUTION AND METABOLISM
Chlorofluorocarbon 113 can be expected to partition into lipid-rich
tissues during continuous exposure, until equilibrium or steady-state conditions
are reached. During the rapid rise to maximal blood concentration, arterial
concentrations of chlorofluorocarbons have been observed to be greater than
venous concentrations (Azar et al. , 1973). Blood levels of CFC-113 and other
fluorocarbons were measured in beagle dogs during experiments reported by
Trochimowicz et al. (1974). Animals were exposed for 10 minutes to 0.1 percent
(1,000 ppm; 7,700 mg/m ), 0.5 percent (5,000 ppm; 38,500 mg/m ), and 1.0 per-
3
cent (10,000 ppm; 77,000 mg/m ) CFC-113. The investigators recorded higher
levels in arterial blood during exposure and lower levels post exposure. The
authors suggested that these observations reflect an uptake and release by
3
body tissues. At exposure levels (5,000 ppm; 38,500 mg/m ) which have sensi-
tized the heart to exogenous epinephrine, arterial blood levels of 12.5 |jg/ml
and venous blood levels of 4.9 ug/ml were observed (at 5 minutes of exposure).
CFC-113 was extracted from blood with hexane and analyzed by GC-ECD.
4-2
-------
Carter et al. (1970) detected CFC-113 in brain, liver, heart, and fat of
rats exposed, via inhalation, for 7 to 14 days. Levels are shown in Table
4-2. Similar findings have recently been reported by Savolainen and Pfaffli
(1980). Male Wistar rats exposed to 200, 1,000, and 2,000 ppm (1,540, 7,700,
3
15,400 mg/m ) of CFC-113 vapor for 2 weeks, 5 days per week, 6 hours daily
exhibited a dose-dependent partitioning of the compound into perirenal fat
and to a much lesser extent into brain. An approximate 7 to 9 hour half-time
of diminution from adipose tissue is suggested by post-exposure tissue analysis.
The neurochemical effects of CFC-113 exposure were examined by measuring
levels of RNA, glutathione, and oxidative enzymes in brain tissue. After the
3
second week of exposure to 1,000 ppm (7,700 mg/m ), cerebral RNA levels were
14.1 ± 0.7 nmoles/mg protein. Corresponding controls were 12.8 ± 1.0 nmoles/mg
protein. This was statistically significant at p < 0.05. Glutathione levels,
after one week of exposure of animals to 2,000 ppm, were lower than controls
at p < 0.01 (2.4 ± 0.05 nmoles/mg protein compared to 2.6 ± 0.07 nmoles/mg
protein. Glutathione peroxidase, an enzyme which protects cells from oxida-
tive damage, was decreased (p < 0.01), compared to controls, following the
3
second week of exposure to 2,000 ppm (15,400 mg/m ). Exposed animals had a
level of 17.5 ±1.0 nmoles/mg protein compared to 20.6 ±0.5 for controls.
When rats were withdrawn from exposure to 2,000 ppm for 7 days, cerebral RNA
TABLE 4-2. MEAN TISSUE CONCENTRATIONS OF CFC-113 FROM RATS EXPOSED TO
2,000 PPM (Carter et al., 1970)
Exposure
Tissue
Brain
Liver
Heart
(ug/gm)
(ng/gm)
(ug/gm)
Fat (ug/gm)
Adrenal (ng)
Thyroid (ng)
7 days
22.
15.
16.
722.
8.
1.
73 ±
77 ±
59 ±
48 ±
39 ±
09 ±
1.
0.
2.
71
2.
0.
00
87
56
.29
61
46
14
22.
16.
15.
659.
3.
0.
days
65 ±
40 ±
03 ±
24 ±
47 +
94 ±
1.
1.
2.
21
0.
2.
33
72
51
.17
34
00
Postexposure
24 hours
none
none
none
108.45 ± 33.62
none
none
48 hours
none
none
none
5.60 ± 2.94
none
none
4-3
-------
decreased from a level of 13.1 ± 0.4 nmoles/mg protein (controls) to 12.6 ±
0.2 (p < 0.05). Differences in levels for glutathione and glutathione per-
oxidase during this period were no longer observed.
Vainio et al. (1980) observed j_n vivo effects of CFC-113 on a number of
hepatic drug metabolizing enzymes. Male Wistar rats were exposed to 200,
1,000 or 2,000 ppm (1,540, 7,700, or 15,400 mg/m3) CFC-113, 5 days per week, 6
hours daily for 1 or 2 weeks. Animals were sacrificed immediately after
exposure. NADPH cytochrome c reductase activity decreased 36 percent (p<0.01)
and 19 percent (p<0.05) after 1 and 2 weeks of exposure, respectively, to
2,000 ppm. The apparent recovery of reductase activity during the second week
is unexplained. Microsomal cytochrome P-450 showed a statistically signifi-
3
cant decline after 1 week of exposure to 1,000 ppm (7,700 mg/m ) (p<0.01) and
3
2,000 ppm (15,400 mg/m ) (p<0.01). UDP glucuronosyltransferase showed a
dose-related increase in activity after 2 weeks of exposure of rats to 1,000
3
ppm (7,700 mg/m ) (p<0.01) and after 1 and 2 weeks of exposure to 2,000 ppm
3
(15,400 mg/m ) (p<0.01 and <0.05, respectively). UDP glucuronosyltransferase
is a detoxification enzyme dependent on membrane integrity. Whether the
preceding changes represent an adverse effect for instance, a potential pertur-
bance of microsomal membrane integrity, or merely an accomodative effect, is
unknown. Glutathione content showed a statistically significant decrease
3
(p<0.05) after only 2 weeks of exposure at the 2,000 ppm (15,400 mg/m ) level.
Evidence also was presented indicating that CFC-113 was bound to cyto-
chrome P-450 in the hepatic microsomes from um'nduced and phenobarbital-induced
rats. Phenobarbital treatment increased the affinity of CFC-113 to cytochrome
P-450, as judged from the decrease in the apparent spectral dissociation
constant obtained from a type 1 difference spectrum. The observed binding
does suggest that CFC-113 may be a substrate for the mixed function oxidases.
These enzymatic changes accompanied cellular changes in hepatocytes and
are described in section 5.1.4.
4-4
-------
Azar, A., H. J. Trochinowicz, J. B. Terrill, and L. S. Mullin. Blood levels
of fluorocarbon related to cardiac sensitization. Am. Ind. Hyg. Assoc.
J. 34(3):102-109, 1973.
Carter, V. L., P. M. Chikos, J. D. MacEwen, and K. C. Back. Effects of Inhala-
tion of Freon 113 on Laboratory Animals. U.S. Nat. Tech. Info. Service
Report AD 727524, 1970.
Haskell Laboratory. Human Skin Absorption Studies with Trichlorofluoroethane.
Medical Research Project No. MR-1014 (1968), submitted by E. I. duPont de
Nemours and Company to U.S. Environmental Protection Agency, August 1979.
Letkiewicz, F. J. Environment Hazard Assessment Report: Major One- and
Two-Carbon Saturated Fluorocarbons, EPA-560/8-76-003, U.S. Environmental
Protection Agency, Office of Toxic Substances, August 1976.
Matsumato, T., K. C. Pani, J. J. Kovaris, and F. Hamit. Aerosol tissue adhe-
sive spray. Fate of freons and their acute topical and systemic toxicity.
Arch. Surg. (Chicago) 97:727-735, 1968.
Savolainen H. and P. Pfaffli. Dose-dependent neurochemical effects of 1,1,2-
trichloro-l,2,2-trifluoroethane inhalation exposure in rats. Toxicol.
Lett. 6:43-49, 1980.
Shargel, L. and R. Koss. Determination of fluorinated hydrocarbon propellants
in blood of dogs after aerosol administration. J. Pharm. Sci. 61:1445-
1449, 1972.
Trochimowicz, H. J. , A. Azar, J. B. Terrill, and L. S. Mullin. Blood levels
of fluorocarbon related to cardiac sensitizations: Part II. Am. Ind.
Hyg. Assoc. J. 35:632-639, 1974.
Vainio, H. , J. Nickels, and T. Heinonen. Dose-related hepatotoxicity of
l,l,2-trichloro-l,2,2,-trifluoroethane in short-term intermittent inhala-
tion exposure in rats. Toxicol. 3.8:17-25, 1980.
4-5
-------
5. HEALTH EFFECTS
The impact of CFO113 upon human health must be viewed from two perspec-
tives: (1) potential effects resulting from direct exposure to CFC-113 and
(2) possible indirect effects resulting from CFC-113 perturbations of strat-
ospheric 03.
As discussed in earlier chapters, CFC-113 is transported to the strato-
sphere where it is calculated to photocatalytical ly destroy 0,, (Panofsky,
1978; Molina and Rowland, 1974). If sufficient depletion of stratospheric 0,
were to occur without an offsetting increase in tropospheric levels of 0.,,
more damaging ultraviolet (UV-B) radiation would reach the earth's surface.
It is hypothesized that such increased UV-B radiation could result in an
increase in the incidence of non-malignant skin cancers (NRC, 1982). The NRC
(1982) estimated that there could be a 2 to 5 percent increase in basal cell
(non-malignant) skin cancer incidence per 1 percent decrease in stratospheric
0 • and the increase in squamous cell skin cancer incidence could be about
double that. The NRC (1982) concluded that the association between sunlight
and melanoma is not strong enough to make a prediction of increased incidences
due to increased exposure to UV based on epidemiological data. There are no
empirical data which demonstrate such indirect effects (i.e. increased skin
cancer incidence) to be associated with CFC-113 emissions; nor are such effects
now thought to be likely in view of effects of various other air pollutants
(e.g. CO, NO ) on stratospheric ozone that have been calculated to offset any
A.
03 pertubations due to CFC-113 or other halocarbons (see Section 3.4 above).
The ensuing discussion of CFC-113 health effects, therefore, focuses on the
evaluation of animal and human studies of the direct effects of CFC-113.
5.1 ANIMAL STUDIES
5.1.1 Acute Toxicity
Acute inhalation exposures of various animal species to fluorocarbons at
3
levels exceeding 25,000 ppm (192,500 mg/m ) in inhaled air results in adverse
effects. Exposures to concentrations between 50,000 and 250,000 ppm (385,000
/• o
and 1.925 x 10 mg/m ) have been fatal. A characteristic feature of CFC-113
exposure is tachycardia and hypertension at 25,000 and 50,000 ppm (192,500 and
385,000 mg/m ). High concentrations have induced cardiac arrhythmia in dog,
sensitized the heart to the action of epinephrine in dog and mouse, and caused
depression of myocardial contractility in dog.
5-1
-------
5.1.2 Cardiovascular and Respiratory Effects
5.1.2.1 Mouse--Aviado and Belej (1974) evaluated the ability of CFO113 to
induce cardiac arrhythmias and to sensitize the heart to epinephrine. In this
study, male Swiss mice (25 to 35 grams) were anesthetized with sodium pentobar-
bital (i.v., 0.7 mg/10 g). A lead II electrocardiogram was used to monitor
the cardiovascular response. There were three mice in each of four experimental
groups. Group (1) inhaled 5 percent (50,000 ppm; 385,000 mg/m ) CFC-113;
group (2) inhaled 5 percent (50,000 ppm; 385,000 mg/m ) CFC-113 plus a chal-
lenging dose of epinephrine 2 minutes after the initiation of inhalation;
3
group (3) inhaled 10 percent (100,000 ppm; 770,000 mg/m ) CFC-113; group (4)
3
inhaled 10 percent (100,000 ppm; 770,000 mg/m ) CFC-113 and a similar challenge
schedule as described for (2). This dose of epinephrine (i.v., 60 (jg/kg) was
previously found to produce a transient and moderate cardiac acceleration.
The results of this study are presented in Table 5-1. CFC-113 at 5 per-
3
cent (50,000 ppm; 385,000 mg/m ) produced a response (ventricular ectopic
beats) in the presence of a challenging dose of epinephrine while inhalation
3
of 10 percent (100,000 ppm; 770,000 mg/m ) CFC-113 resulted in cardiac abnor-
malities both with and without epinephrine.
5.1.2.2 Dog
5.1.2.2.1 In vitro. Aviado and Belej (1975) tested the ability of CFC-113 to
depress myocardial contractility in a canine heart-lung preparation. The dogs
were anesthetized with sodium pentobarbital (i.v., 30 mg/kg). The force of
myocardial contractility was measured by a Walton strain-gauge and was plotted
as ventricular function curves. The experimental groups consisted of three
dogs each: group 1 inhaled 2.5 percent (25,000 ppm; 192,500 mg/m ) CFC-113
and group 2 inhaled 5.0 percent (50,000 ppm; 385,000 mg/m3) CFC-113.
The results are presented in Table 5-2 and Figure 5-1. Both 2.5 percent
(25,000 ppm; 192,500 mg/m3) and 5.0 percent (50,000; 385,000 mg/m3) CFC-113
caused no decrease in myocardial contractility as measured by the strain-gauge
while both ventricular function curves show a shift to the right. This shift
indicates a decrease in ventricular output for the same filling pressure, or a
decrease in myocardial contraction, indicating that the ventricular function
curve is the more sensitive of the two measures. Both 2.5 percent (25,000
ppm; 192,500 mg/m3) and 5.0 percent (50,000 ppm; 385,000 mg/m ) CFC-113 caused
myocardial depression in the canine heart-lung preparation.
5-2
-------
TABLE 5-1. EFFECTS OF CFC-113 ON THE ELECTROCARDIOGRAM OF ANESTHETIZED MICE
Concentration
% V/V
5
10
Exposure
No. of
Exposures
3
3
to CFC-113 alone
Type of Arrhythmia
(incidence)
none
inverted T wave (1)
Exposure to
No. of
Exposures
3
3
CFC-113 and Epinephrine
Type of Arrhythmia
(incidence)
ventricular ectopics
ventricular bigeminy
(1)
(3)
Data from Aviado and Belej (1974).
en
I
GO
TABLE 5-2. EFFECT OF CFC-113 ON THE CANINE HEART-LUNG PREPARATION:
ADMINISTRATION OF 2.5 AND 5% PROPELLANTS TO HEART-LUNG PREPARATIONS FIXED
AT 5 cm LEVEL OF VENOUS RESERVOIR (MEAN ± S.E.M.)
Propel 1 ant
fluorocarbon
No.
Trichlorotri-
f luoroethane
CFC-113
Inhaled
concen-
tration
2.5
5.0
Number
of
prepar-
ations
3
3
Heart rate
Myocardial force
(beats/mi n)
Con-
trol
147
± 12.
148
± 13.
Re-
sponse
148
5 ±10.6
150
1 ±12.5
% A
- 2
± I
- 1
± I
Con-
trol
82
± 1.5
90
± 2.7
(g)
Re-
sponse
80
± 0.6
86
± 2.1
Left atrial pressure Cardiac output
(mm Hg)
% A
- 3
± 1
- 4
± 1
Con-
trol
2.9
± 0.2
2.9
± 0.2
Re- % A
sponse
3.0 + 2
± 0.2 ± 3
3.0 + 3
± 0.1 ± 3
(1/min)
Con-
trol
1.31
± 0.17
1.27
± 0.02
Re-
sponse
1.28
± 0.02
1.23
± 0.02
% A
- 3
± 1
- 3
± 0.1
Data from Aviado and Belej (1975).
-------
16
14
12
c
1
5 10
13
O.
O
O 16
5
DC
O
14
12 _
10 ~
1
O CONTROL
O FC113
25% v/v
O CONTROL
D FC113
50% v/v
I
I
I
2468
LEFT ATRIAL PRESSURE, mm Hg
Figure 5-1. Ventricular function curves in canine
heart-lung preparations before and during inhal-
ation of 2.5 or 5.0% propel I ant in air. Each point
represents the mean and standard error of the
mean in groups of 3 preparations.
Source: Aviado and Belej (1975).
5-4
-------
5.1.2.2.2 In vivo. Reinhardt et al. (1973) tested the ability of CFC-113 to
sensitize the heart to exogenous epinephrine. Unanesthetized male beagle dogs
were exposed to CFC-113 concentrations of 0.25 percent (2,500 ppm; 19,250
3 3
mg/m ), 0.50 percent (5,000 ppm; 38,500 mg/m ) and 1.0 percent (10,000 ppm;
77,000 mg/m ). Electrocardiograph recordings monitored the cardiovascular
response. A marked response (see Table 5-3) was defined as the development of
a life-threatening arrhythmia (e.g., multiple consecutive ventricular beats)
not present following the first (control) dose of epinephrine. Epinephrine
was administered 5 minutes before and 5 minutes after the initiation of the 10
minute CFC-113 inhalation period following a 7-minute period of inhalation of
room air. It was previously shown that doses of epinephrine (i.v., 8 pg/kg)
administered 10 minutes apart did not produce additive effects. The results
are presented in Table 5-3. No marked responses were observed in twelve
3
exposures at 0.25 percent (2,500 ppm; 19,250 mg/m ) CFC-113. CFC-113 causes
cardiac sensitization to exogenous epinephrine at a CFC-113 concentration of
0.5 percent (5,000 ppm; 38,500 mg/m3).
In an earlier unpublished report, Reinhardt and coworkers cautioned that
results obtained at exogenous epinephrine concentrations should not be extra-
polated to humans at lower chlorofluorocarbon exposure levels (Mullin et al.,
1971). It was noted that a much higher concentration of chlorofluorocarbon
3
(20,000 ppm; 154,000 mg/m ) did not sensitize a dog's heart to the action of
its own circulating level of epinephrine, even when this level was elevated
through exercise. It was suggested that there is a considerable margin of
safety between effect levels in dogs given exogenous epinephrine and levels
that humans would normally experience. The rate of epinephrine secretion from
the human adrenal gland in time of stress was reported to reach a level of
0.004 mg/kg/min (as cited in Mullin et al., 1971). Exogenous epinephrine, as
employed in the Haskell Laboratory experiments, was reported to yield a dose
of about 0.050 mg/kg/min, or ten times higher than a human would be likely to
secrete in time of stress.
Clark and Tinston (1973) determined the EC™ for the cardiac sensitizing
effects of CFC-113 using unanesthetized beagle dogs (10-13 kg). Lead II elec-
trocardiograms were recorded to monitor the cardiovascular response. The
experimental groups consisted of four to seven dogs each. The dogs inhaled
CFC-113 for 5 minutes, receiving equal doses of epinephrine (i.v., 5 ug/kg) 30
seconds before the end of the inhalation period and 10 minutes post-exposure.
Cardiac arrhythmias were never observed prior to the first or second
injection of epinephrine even when it followed a challenge injection that had
5-5
-------
in
i
cr>
TABLE 5-3. EFFECT OF CFC-113 ON CARDIAC SENSITIZATION
TO EPINEPHRINE IN THE UNANESTHETIZED DOG
Concentration of CFC-113
Nominal
0.25
0.50
1.0
% (U/V)
Analytical
0.25 -
0.40 -
0.90 -
(gas. chrom.)
0.27
0.57
0.95
No. of
Dog Exposures
12
29
4
No. of
Marked Responses
0
10 (1)
3 (1)
°/
7o
Marked Responses
0.0
34.5
75.0
Numbers in parentheses indicate number of cases of ventricular fibrillation and cardiac arrest
included in marked responses.
Data from Reinhardt et al. (1973).
-------
caused an arrhythmia. At 1.0 percent (10,000 ppm; 77,000 mg/m3) CFC-113, 50
percent of the animals can be sensitized to the effects of exogenous epineph-
rine with a 95 percent confidence interval of 0.5 percent to 1.4 percent
around this value.
It should be pointed out that the above-mentioned cardiac sensitization
studies are used to rank substances and because exogenous epinephrine was
administered, cannot be extrapolated to human situations in which epinephrine
is endogenously released in certain situations.
Blood levels of CFC-113 and other fluorocarbons in beagle dogs that are
associated with the cardiac sensitizing effect of CFC-113 have been examined
by Trochimowicz et al. (1974). Exogenous epinephrine was not administered to
the animals. After recovery from surgery during which indwelling catheters
were implanted, four dogs were exposed via face mask for 10 minutes to CFC-113
at levels of 0.1 percent (1,000 ppm; 7,700 mg/m ), 0.5 percent (5,000 ppm;
3 3
38,500 mg/m ), and 1.0 percent (10,000 ppm; 77,000 mg/m ). The investigators
recorded an arterial-venous difference during and after exposure. The authors
suggested that this observation reflects an uptake by body tissues. After
exposure, levels for all fluorocarbons were higher in venous blood. At the
3
sensitizing level (5,000 ppm; 38,500 mg/m ), blood concentrations of 12.5
ug/ml arterial blood and 4.9 ug/ml venous blood were recorded (at 5 minutes of
® 3
exposure). At the TLV (1,000 ppm; 7,700 mg/m ), blood concentrations were
2.6 ug/ml (arterial) and 1.5 ug/ml (venous).
In a followup study, Trochimowicz et al. (1976) tested dogs with experi-
mentally-induced myocardial infarctions to determine if heart damage might
lower the apparent threshold for cardiac sensitization due to chlorofluoro-
carbons. Although CFC-113 was not used (methyl chloroform, trichlorofluoro-
methane, and bromotrifluoromethane were the test substances), the test results
were reported to indicate that the halocarbons had no greater potential for
cardiac sensitization among dogs having recovered from myocardial infarction
than normal, healthy dogs. Concentrations of the test chemicals ranged from
0.25 percent (v/v) for methyl chloroform to 10 percent (v/v) for bromotri-
fluoromethane. The test method involved exposure to test chemicals, followed
by an intravenous dose (8 ug/kg) of epinephrine, a dose which, given to animals
exposed to air only, caused only mild ECG alterations.
Unpublished data of Mullin and coworkers (1971) suggest that, in beagle
dogs trained to run on a treadmill (up to 16 minutes) while being exposed to
CFC-113 (8 dogs to 10,000 ppm; 77,000 mg/m3 and 4 dogs to 20,000 ppm; 154,000
5-7
-------
mg/m ), endogenous epinephrine is not high enough to cause cardiac arrhythmias
at CFC-113 levels below 20,000 ppm (154,000 mg/m3).
In cardiac sensitization studies conducted by E. I. duPont de Nemours and
Company, it was concluded that CFC-113 is capable of sensitizing a dog's heart
to exogenous epinephrine following exposure to concentrations between 2,000 to
3
2,500 ppm (15,400 to 19,250 .mg/m ) for periods of 0.5, 1, or 6 hours. One of
six dogs exposed to 2,500 ppm (19,250 mg/m ) for both 0.5 and 1 hour gave a
marked response. However, it was reported that exposures (12) of dogs to
3
concentrations of 10,000 ppm (77,000 mg/m ) CFC-113 for a duration of 5 minutes
did not cause cardiac arrhythmias in dogs frightened by a loud noise or electric
shock (Haskell Laboratory, 1979).
5.1.2.3 Monkey—Belej et al. (1974) tested the effects of CFC-113 upon heart
rate, myocardial force, aortic blood pressure, left atria! pressure, and
pulmonary arterial pressure in anesthetized rhesus monkeys. The monkeys were
anesthetized with sodium pentobarbital (i.v., 30 mg/kg), and their tracheas
were cannulated for artificial respiration. A lead II EKG recorded cardio-
vascular responses; myocardial contraction was measured with a strain-gauge.
The experimental groups, which consisted of three animals each, inhaled either
2.5 percent (25,000 ppm; 2,500 mg/m3) or 5.0 percent (50,000 ppm; 385,000
T
mg/m ) CFC-113 for 5 minutes alternating with inhalation of room air for 10
minutes.
The results presented in Table 5-4 indicate that 2.5 percent (25,000 ppm;
3
192,500 mg/m ) CFC-113 is capable of inducing both tachycardia and myocardial
depression. The authors report that both concentrations caused cardiac arrhyth-
mias.
Aviado and Smith (1975) tested the effects of CFC-113 upon respiration
and circulation using rhesus monkeys anesthetized with sodium pentobarbital
(i.v., 30 mg/kg). The tracheas were cannulated for artificial respiration.
Lead II EKG and femoral arterial blood pressure were continuously recorded.
The following parameters were determined: pulmonary resistance, pulmonary
compliance, and respiratory minute volume. Each test group consisted of three
monkeys. Each group inhaled either 2.5 percent (25,000 ppm; 192,500 mg/m ) or
5.0 percent (50,000 ppm; 385,000 mg/m3) CFC-113 for 5 minutes, alternating
with room air for 15 minutes.
The results are presented in Table 5-5: 2.5 percent (25,000 ppm; 192,500
mg/m3) and 5.0 percent (50,000 ppm; 385,000 mg/m ) CFC-113 caused a decrease
in pulmonary resistance, an increase in pulmonary compliance, no change in
5-8
-------
TABLE 5-4. RESPIRATORY AND CIRCULATORY EFFECTS OF CFC-113 UPON ANESTHETIZED RHESUS MONKEYS
(BASED ON STUDY OF BELEJ AND COLLEAGUES)
CFC-113
% Inhaled
Concentration
2.5
5.0
CFC-113
% Inhaled
Concentration
2.5
5.0
CFC-113
% Inhaled
Concentration
2.5
5.0
Heart rate (beats/mi n)
Monkey #
3
3
Monkey #
3
3
Monkey #
3
3
Control
150.0
0.0
155.0
± 2.9
Aortic bl
Control
mm Hg
80.0
± 2.9
80.7
± 0.7
Pulmonary
Control
9.0
0.0
9.5
± 0.3
Response
163.0
± 8.8
185. Oa
±13.2
A %
+ 8.9
± 5.9
19.8
±10.8
ood pressure
Response
76.7
± 2.7
61. 3a
± 9.3
arterial
Response
9.2
± 0.4
9.6
± 0.2
A %
- 4.1
± 2.5
-23.8
± 7.0
pressure
A %
+ 3.3
± 4.2
+ 1.1
± 1.1
Myocardial force (g)
Control
47.5
± 7.7
45.3
± 5.1
Left
Control
3.7
± 0.4
3.8
± 0.4
(mm Hg)
Mean
S.E.M.
Mean
S.E.M.
Response
38.4
± 4.2
29.3
± 7.5
atrial pressure
Response
4.1
± 0.8
4.9
± 1.0
A %
-17.1
± 6.8
-35.8
±12.6
A %
10.8
± 1.0
37.2
± 7.2
p <0.05 compared with control
Data from Belej et al. (1974)
-------
TABLE 5-5. RESPIRATORY AND CIRCULATORY EFFECTS OF CFC-113 UPON ANESTHETIZED RHESUS MONKEYS
(BASED ON STUDY BY AVIADO AND SMITH)
Ol
1—>
o
% Pulmonary resistance
Concentration
CFC-113
2.5
5.0
Concentration
CFC-113
2.5
5.0
%
Concentration
CFC-113
2.5
5.0
Monkey #
3
3
Monkey #
3
3
Monkey #
3
3
Control
cm HpO/1/sec
21.78
± 3.49
21.58
± 3.00
Respiratory
Control
ml/min.
1230
47.3
1292
± 99
Aortic blood
Control
mm Hg
101.67
± 1.67
110.67
± 5.78
Response
19.69
± 2.71
18.84
± 2.47
minute
Response
1250
± 28.9
1302
± 72
pressure
Response
93.00
± 3.05
82.33
± 2.33
% A
- 8.87
+ 4.75
-12.07
± 6.64
% A
+ 1.80
± 1.80
+ 1.10
± 3.20
% A
- 8.54a
± 2.36
-25.153
± 4.75
Pulmonary compliance
Control
(jl/cm H,,0
6.87
± 0.43
6.67
± 0.58
Control
bpm
169
± 13.65
173.33
± 12.02
Response
7.27
+ 0.41
7.50
± 0.25
Heart rate
Response
199
± 19.09
221.67
±21.67
% A
+ 5.97
± 2.30
±13.95
± 8.80
% A
+18.07
± 8.14
+27.S53
+ 8.58
p <0.05
Data from Aviado and Smith (1975).
-------
respiratory minute volume, a significant increase in heart rate for the group
that inhaled 5.0 percent (50,000 ppm; 385,000 mg/m ) CFC-113, and a signifi-
cant decrease in aortic blood pressure for both groups.
5.1.3 Neurological Effects
5.1.3.1 Frog—Young and Parker (1975) studied the effect of CFC-113 on the
activity of acetylcholinesterase, an enzyme required in the repolarization of
nerve fibers. A vagal heart preparation of the leopard frog (Rana pipiens)
was used. The heart was stimulated by a pair of platinum electrodes and was
triply cannulated to allow for the introduction of the test compound. The
specifics of the experimental procedure were not given.
Their results indicated that the ED™ for a CFC-113-induced increase in
50 _4
acetylcholinesterase activity was 1.6 x 10 gm/ml, a level close to its
saturation concentration in water.
5.1.3.2 Doc|--Carter et al. (1970) studied the effects of CFC-113 on neural
transmission through autonomic ganglia. Spinal preparations of four female
beagle dogs (8.0-13.7 kg) were tested using heart rate as an indicator of the
cardiac response to pre- and postganglionic stimulation. Control responses
were determined prior to the administration of 2 percent (20,000 ppm; 154,000
mg/m ) CFC-113 with and without atropine (0.05 mg/kg). The experimental
values were determined at the end of the ten-minute exposure period. The
control values were then verified 15 minutes after the termination of the
3
exposure. Approximately two percent (20,000 ppm; 154,000 mg/m ) CFC-113 had
no effect upon postganglionic stimulation, although it did reduce an increase
in the heart rate response to preganglionic stimulation and further decreased
it when atropine was added. The authors believe that the further decrease in
response in the presence of atropine, a muscarinic blocking agent, could be
indicative of CFC-113-induced nicotinic blockade in the stellate ganglion.
Neurochemical effects in rats exposed to 1,000 and 2,000 ppm (7,700 and
15,400 mg/m ) CFC-113 are described on page 4-3 and 4-4.
5.1.4 Hepatotoxicity
Proliferation and vacuolization of the smooth endoplasmic reticulum of
the liver was observed when male Wistar rats were exposed to 1,000 and 2,000
ppm (7,700 and 15,400 mg/m3) CFC-113 for 1 and 2 weeks (Vainio et al., 1980).
The rough endoplasmic reticulum showed no clear alteration. Observations were
made by electron microscopy. Hepatocyte microvilli were normal while some
mitochondria showed condensations. No effects of exposure to 200 ppm (1,540
mg/m ) were noted. Effects of CFC-113 exposure on hepatic enzymes are dis-
cussed in Chapter 4.
5-11
-------
The exposure phase of a 90-day and two-year inhalation study in rats,
conducted for Allied Corporation and E.I. Dupont de Nemours and Company, has
been completed. It was reported that the gross and microscopic pathology
evaluation on the 90-day study and on the one-year interim sacrifice(s) of the
two-year study show no evidence of toxicity at concentrations as high as
20,000 ppm (154,000 mg/m ) (E.I. duPont de Nemours and Company, 1983). Final
assessment of the two-year exposures is underway and will be completed in 1983.
5.1.5 Teratogenic Effects
The following discussion subscribes to the basic viewpoints and defini-
tions of the terms "teratogenic" and "fetotoxic" as summarized by the Office of
Pesticides and Toxic Substances (U.S. EPA, 1980) as follows:
Generally, the term "teratogenic" is defined as the tendency to produce
physical and/or functional defects in offspring i_n utero. The term "fetotoxic"
has traditionally been used to describe a wide variety of embryonic and/or
fetal divergences from the normal which cannot be classified as gross terata
(birth defects) -- or which are of unknown or doubtful significance. Types of
effects which fall under the very broad category of fetotoxic effects are:
death, reductions in fetal weight, enlarged renal pelvis edema, and increased
incidence of supernumerary ribs. It should be emphasized, however, that the
phenomena of terata and fetal toxicity as currently defined are not separable
into precise categories. Rather, the spectrum of adverse embryonic/fetal
effects is continuous, and all deviations from the normal must be considered
as examples of developmental toxicity. Gross morphological terata represent
but one aspect of this spectrum, and while the significance of such structural
changes is more readily evaluated, such effects are not necessarily more
serious than certain effects which are ordinarily classified as fetotoxic—
fetal death being the most obvious example.
In view of the spectrum of effects at issue, the Agency suggests that it
might be useful to consider developmental toxicity in terms of three basic
subcategories. The first subcategory would be embryo or fetal lethality.
This is, of course, an irreversible effect and may occur with or without the
occurrence of gross terata. The second subcategory would be teratogenesis and
would encompass those changes (structural and/or functional) which are induced
prenatally, and which are irreversible. Teratogenesis includes structural
defects apparent in the fetus, functional deficits which may become apparent
only after birth, and any other long-term effects (such as carcinogenicity)
which are attributable to i_n utero exposure. The third category would be
embryo or fetal toxicity as comprised of those effects which are potentially
reversible. This subcategory would therefore include such effects as weight
reductions, reduction in the degree of skeletal ossification, and delays in
organ maturation.
Two major problems with a definitional scheme of this nature must be
pointed out, however. The first is that the reversibility of any phenomenon is
extremely difficult to prove. An organ such as the kidney, for example, may
be delayed in development and then appear to "catch up." Unless a series of
specific kidney function tests are performed on the neonate, however, no
conclusion may be drawn concerning permanent organ function changes. This
same uncertainty as to possible long-lasting aftereffects from developmental
deviations is true for all examples of fetotoxicity. The second problem is
5-12
-------
that the reversible nature of an embryonic/ fetal effect in one species might,
under a given agent, react in another species in a more serious and irrever-
sible manner.
The teratogenic potential of CFO113 was recently evaluated in rats by
Imperial Chemical Industries (Ward, 1983). In the summary, it is stated:
Groups of twenty-four pregnant rats were exposed to 5,000,
12,500, and 25,000 ppm ARCTON* 113 in air for six hours per day on
days 6-15 (inclusive) of gestation. A concurrent control group was
exposed to air only.
A reduction in maternal bodyweight gain, food utilization and
food consumption occurred in the 25,000 ppm group compared with
controls. Signs of hyperactivity were seen in the 25,000 ppm group
during exposure but there were no macroscopic abnormalities at
autopsy in this group or in the 12,500 or 5,000 ppm groups, which
could be attributed to ARCTON* 113.
There was no evidence of embryotoxicity which could be related
to exposure to ARCTON* 113. The only increase in fetal abnormali-
ties was the incidence of extra ribs at all exposure levels, but the
incidences were within the background control range. Therefore,
ARCTON* 113 is not teratogenic in rats at the exposure concentra-
tions used in this investigation.
Two unpublished studies in rabbits are available from E.I. DuPont de
Nemours and Company, Inc. (Hazelton Laboratories, 1967). In both studies, the
number of pregnant animals and fetuses evaluated was inadequate for use in
assessing the teratogenic potential of CFC-113. In both studies, the treat-
ment period was shorter than those suggested for current teratogenicity test-
ing. In both the inhalation and feeding studies, dosages administered pro-
duced signs of maternal toxicity.
The first study, performed in 1967, exposed 12 rabbits per dosage group
via inhalation to 0 (air), 2,000 or 20,000 ppm (15,400 or 154,000 mg/m ) of
CFC-113 for 2 hours daily on days 8 through 16 of presumed gestation (equiva-
lent to days 6 through 14 of gestation when day 0 = day of insemination).
Pregnancy occurred in 4, 4 and 7 rabbits in the respective dosage groups.
3
Signs of maternal toxicity in rabbits exposed to 20,000 ppm (154,000 mg/m ) of
CFC-113 consisted of lowered body weight gain during the first week of expo-
sure, and eye irritation. One doe in the 20,000 ppm (154,000 mg/m ) dosage
group died; another delivered prematurely on day 29.
*ARCTON is the trademark used by Imperial Chemical Industries for their
fluorocarbon products.
5-13
-------
A total of 19/4 (pups/litter), 8/4 (pups/litters), and 24/5 (pups/litters)
was evaluated in the control, low and high dosage groups, respectively. One
pup in the low and two in the high dosage group were dead at examination. No
remarkable variations were observed in external soft tissue or skeletal exam-
inations of the fetuses.
The second study, performed in 1967, evaluated 8 rabbits per dosage
group, and 0 (distilled water), 1 and 5 gm/kg/day CFC-113 were administered
orally by stomach tube on days 8 through 11 of gestation (gestation day 0 was
the second day of mating). One, 3 and 4 rabbits died in the groups adminis-
tered 0, 1 and 5 gm/kg/day CFC-113, respectively. In high dosage group rabbits,
food and water consumption were reduced during the treatment period, and body
weight loss (300 to 500 grams) occurred. Only 3, 6 and 4 rabbits in the
respective dosage groups became pregnant. The three control rabbits delivered
naturally 21 live and 3 dead pups.
In low dosage group rabbits, one of the pregnant rabbits died following
the third dose, another died during natural delivery, and the third rabbit
survived to deliver pups. The remaining three rabbits in the lowest dosage
groups that were pregnant were Caesarean-sectioned. A total of 32 live fetuses
or pups was evaluated.
Death in one rabbit in the high dosage group after the first dose pre-
cluded evaluation for pregnancy in one rabbit. One rabbit died after the
fourth dose and apparently had 9 live embryos i_n utero. One rabbit died on
day 16 (day 14 when day 0 = insemination) of gestation and had nine dead
fetuses i_n utero. Another rabbit aborted four dead fetuses on day 29 (day 27
when day 0 = insemination) of gestation. One rabbit was Caesarean-sectioned
and had 10 fetuses j_n utero, 7 of which were dead.
As a result of non-pregnancy, maternal death or j_n utero embryo/fetal
death, only 21/3 (pups/litters), 32/5 (pups/litters), and 3/1 (pups/litters)
delivered naturally or Caesarean delivered were evaluated for malformations.
Eleven dead fetuses in two litters, either aborted or dead J_n utero, were also
evaluated for malformations. No remarkable anatomical changes were reported
in the fetuses which were examined.
5.1.6 Mutagenic Effects
5.1.6.1 Mouse—Using a dominant lethal assay, Epstein et al. (1972) tested
the mutagenic effects of CFC-113. Swiss mice (8-10 week old males and virgin
females) were used. The following criteria for determining mutagenicity were
used: "(1) one or more weeks with a mean of 0.90 or more early fetal deaths per
5-14
-------
pregnancy regardless of the percent of pregnant females with early deaths; (2)
one or more weeks with 55 percent or more of the pregnant females having early
deaths; (3) one or more weeks with a mean of less than 9 total implants per
pregnancy." There were two experimental groups of males injected i.p. with
CFC-113: group 1, 200 mg/kg (7 mice); group 2, 1000 mg/kg (9 mice). Each
male was subsequently caged with three virgin females which were replaced
weekly for eight weeks. The females were sacrificed and autopsied thirteen
days after the midweek of the caging.
Neither experimental group met the above criteria. The authors concluded
that CFC-113 was not mutagenic under the concentrations tested, or under the
route of administration, strain and test system employed.
CFC-113 was tested in four strains (TA 1535, 1537, 98 and 100) in the S.
typhimurium microsome test (Haskell Laboratory, unpublished, 1977). CFC-113
were reported to be negative because the reversion frequency was less than two
times the spontaneous frequency and because less than 0.02 revertants/ nmole
was observed. Negative responses were obtained both in the presence and
absence of a rat-liver homogenate activation system. The experiment was
carried out in 9-liter glass chambers with CFC-113 in air at concentrations
of 2 percent, 6 percent, 10 percent, and 19 percent by volume. Chloroethylene
served as the positive control. The cytotoxicity of the test sample in the
presence and absence of an activation system as measured in TA 1535 was the
basis for selective concentrations for mutagenesis testing.
The negative results obtained from the dominant lethal test and the
Salmonella/mammalian microsome test are too limited to provide sufficient
evidence to classify CFC-113 as non-mutagenic. Furthermore, the dominant
lethal test is not considered to be a sensitive test because of the high
background of spontaneously-occurring dominant lethals (Russell and Matter,
1980). Additional tests are needed before a conclusive determination of the
mutagenic potential of CFC-113 can be made.
5.1.7 Carcinogenic Effects
5.1.7.1 Rat--A two-year chronic inhalation study in rats at exposure levels
of 2,000; 10,000; and 20,000 ppm (15,400; 77,700; 155,400 mg/m3) has been
completed recently by Haskell Laboratories. Although histopathological evalu-
ations are still in progress, preliminary data indicate no gross pathological
effects attributable to CFC-113 except decreased weight gain at 20,000 ppm
3
(154,000 mg/m ) (E.I. duPont de Nemours and Company, 1983).
5.1.7.2 Mouse—The use of sprays containing a pesticide, a piperonyl syner-
gist and a solvent prompted Epstein and coworkers (1967a) to evaluate the
5-15
-------
potential of CFC-113 to potentiate the action of piperonyl butoxide (PB), a
pesticide synergist. Incidences of hepatomas and lymphomas were used to indi-
cate carcinogenicity. The number of mice and litters in each of the four test
groups presented in Tables 5-6 and 5-7 is indicated in Table 5-7. Each group
received the following subcutaneous injections into the neck: 0.1 ml on days
1 and 4 and 0.2 ml on days 14 and 21 after birth. The groups were differen-
tiated according to the solution injected (each group was injected sub-
cutaneously with test material): (1) solvent controls (redistilled tricaprylin);
(2) 10 percent (100,000 ppm; 7.7 x 10 mg/m ) CFC-113 in tricaprylin; (3) 5
percent PB in tricaprylin; (4) CFC-113 and PB as indicated in (2) and (3).
The data are presented in Table 5-6. They indicate that 10 percent
(100,000 ppm; 7.7 x 10 mg/m ) CFC-113 did not alter the incidence of hepatomas
or the incidence of malignant lymphomas beyond the control values. One case
of a mammary carcinoma was also found among the females of group two. No
mammary carcinomas were found in the control group. It is important to note
that the statistical significance of these data was not evaluated.
Conney et al. (1972) reported that environmental exposure to piperonyl
butoxide is unlikely to inhibit human microsomal enzyme function.
5.1.8 Synergistic Effects
Epstein et al. (1967a, 1967b) tested the potential of CFC-113 to potentiate
the action of piperonyl butoxide (PB) upon neonatal Swiss mice. Percent mortality
prior to weaning was used to indicate the effects of CFC-113 and PB alone or in
combination. This study was part of the study discussed previously.
Table 5-7 suggests a synergistic effect between CFC-113 and PB. The
mortality rate of CFC-113 + PB (46 percent) was greater than either compound
alone (2 percent and 15 percent). The data in Table 5-6 do not permit con-
clusions on the synergistic hepatotoxicity or synergistic lymphotoxicity of
CFC-113 and PB.
5.1.9 Dermal Effects
Table 5-8 summarizes the data found on the dermal effects of CFC-113 in
mammals. Few effects have been observed, other than a drying of the skin due
to lipid removal.
5.1.10 Inhalation and Ingestion
A variety of acute and subchronic inhalation exposures of rodent species
to levels of CFC-113 ranging from 2,000 to 400,000 ppm (15,400 to 3.1xlO-6
mg/m ) has been reported. The spectrum of effects observed ranges from reported
5-16
-------
TABLE 5-6. CARCINOGENIC EFFECTS OF PIPERONYL BUTOXIDE IN COMBINATION WITH CFC-113 IN MICE,
ALONE AND IN COMBINATION
en
i
Hepatomas
Treatment group
Solvent controls
CFC-113
PB
CFC-113 and PB
Sex
M
F
M
F
M
F
M
F
# of mice autopsied,
al ive at week 51
(# at risk)
48
68
21
20
20
36
18
24
# of tumors
as % of # of
(number)
4
0
1
0
0
0
3
0
in each period
mice at risk
(percent)
8
0
5
0
0
0
17
0
Mai ignant
# of tumors
as % of # of
(number)
1
0
0
1
0
0
0
1
lymphomas
in each period
mice at risk
(percent)
2
0
0
5
0
0
0
4
In addition, one mammary carcinoma occurred in one female of the CFC-113 alone group.
Data from Epstein et al. (1967a).
-------
TABLE 5-7. SYNERGISTIC EFFECT OF PIPERONYL BUTOXIDE IN COMBINATION
WITH CFC-113 UPON NEONATAL MICE
Treatment group
Solvent controls
10% CFC-113
5% PB
10% CFC-113 + 5% PB
#
of mice
Weaning
(# of litters) mortality
170
52
91
94
(16)
(4)
(8)
(8)
14
2
15
46
Average
at
M
F
M
F
M
F
M
F
51
50.
45.
53.
48.
52.
47.
59.
57.
wt. (g)
weeks
5
3
6
2
0
0
0
0
% Increase
in weight
over controls
6.
6.
3.
3.
16.
25.
1
4
0
8
8
8
Data from Epstein (1967a).
Concentration
40% in sesame
seed oil
100%
100%
5 g/kg
TABLE 5-8.
Duration
daily,
12 days
5 x/w,
20 w
1 x/d,
5 d
DERMAL EFFECTS OF CFC-113 IN MAMMALS
Effects
No effect on shaved skin
of rabbits
No visible effect on
shaved back of rabbits
Practically non-
irritating to eye
and paw of rabbit
Weight fluctuations,
skin damage, liver
Reference
U.S. EPA, 1976
Desoil le
et al. , 1968
Duprat et al .
1976
Desoille
et al . , 1968
g/kg
changes (microscopic),
no other systemic
effects in rabbits
Largest feasible dose
(rats). Dermal and tissue
damage at site of appli-
cation; no other systemic
effects in rats. No deaths
Clayton, 1966
5-18
-------
no effect/slight narcotic effects (up to about 50,000 ppm; 385,000 mg/m ) to
anesthesia and ensuing death, at an approximate dose level of 100,000 ppm
(770,000 mg/m3).
Due to the amount and diversity of data on CFC-113, this information is
presented in tabular form (Table 5-9).
TABLE 5-9. INHALATION AND INGESTION TOXICITIES OF CFC-113 IN MAMMALS
Animal
(Number) % ppm A/S*
Mice 5.7 57,000 A
5-12 50,000- A
120,000
9.5 95,000 A
>10 >100,000 A
(40<*) 0.2 2,000 S
Guinea
Pigs
(12) 1.0 10,000 A
to to
(9) 1.2 12,000 A
(6) (51% A
humidity,
(3) 58°F) A
Duration Effects
30 min Anesthetic; delayed death
with >6%
15 min Initial excitement and
convulsions during
anesthesia
2 hr LC5Q
30 min LCrn
bO
2 w Hematological values;
clinical chemistries;
EEC; body weight; organ-
to-body weight ratios:
no change
5 min No adverse effects;
recovered quickly
^ hr Same
1 hr Same
2 hr Same
Reference
Raventos and
Lemon, 1965
Burn, 1959
Desoil le
et al. , 1968
Raventos and
Lemon, 1965
Carter et al . ,
1970
Underwriters'
Laboratories ,
1941
1.1 11,000 A
2 hr Slight narcotic effect
AIHAC, 1968
5-19
-------
TABLE 5-9. (continued)
Animal
(Number) %
Guinea
Pigs
(12) 2.5
to
2.9
(9)
(6)
(3)
(12) 4.8
to
5.2
(9)
(6)
(3)
(12) 9.5
to
11.3
(9)
ppm A/S* Duration
25,000 A 5 min
to
29,000
A % hr
(41%
humidity;
67-68°F)
A 1 hr
A 2 hr
48,000 A 5 min
to
52,000
A \ hr
(67%
humidity;
68-70°F)
A 1 hr
A 2 hr
95,000 A 5 min
to A
113,000 A
A \ hr
(51%
humidity;
70-72°F)
Effects Reference
No adverse effects; Underwriters'
recovered quickly Laboratories,
1941
Slight tremors within 10';
rapid breathing;
eyes partially closed;
slight lachrymation;
recovered quickly
Same
Same; recovered within
2 days
No adverse effects; Underwriters'
recovered quickly Laboratories,
1941
Coordination loss;
tremors; unable to stand
within 10' ; irregular
breathing; eyes partially
closed; lachrymation;
recovered within one day
Semi-conscious; convulsive
tremors; irregular breath-
ing; deaths of 2 animals
4 and 5 days post-exposure;
recovery within 8 days
Same; deaths 2 and 3 days
post-exposure
Coordination loss; Underwriters'
tremors; unable to stand; Laboratories,
recovery within 1 day 1941
Unconscious; convulsive
tremors; lachrymation and
nasal discharge; breathing
fast and irregular; death
of 2 animals 3 and 4 days
post-exposure
5-20
-------
TABLE 5-9. (continued)
Animal
(Number) % ppm
Guinea
Pigs
(6)
(3)
Hartley 12 120,000
albinos
(12) 16.4 164,000
to to
16.6 166,000
(9)
(73°F)
(2)
(109) 0.51 5,100
(3) 2.5 25,000
Rats
(5=0 1.14 11,400
A/S* Duration
A 1 hr
A 2 hr
A 2 hr
A 5 min
A h hr
A 1 hr
S 6 hr/day
5 day/wk
4 wk
S 3.5 hr/day
20 days
A 6 hr
Effects
Same; deaths 1 and 4 days
post-exposure
Same; all animals dead
within I day post-exposure
LC50
.JU
Coordination loss within
1' ; unable to stand;
convulsive tremors;
recovered within 1 day
Unconscious; convulsive,
tremors; deaths; 5 animals
within first 20' ; 2 animals
1 and 2 days post-exposure
Unconscious; deaths:
1 animal within first 45';
1 animal 2 days post-
exposure
No change in growth rate,
organ-to-body weight
ratios, appearance upon
necropsy
0/3 deaths; no changes in
weight gain, rbc, wbc,
differential white count,
hemoglobin, urinary pro-
tein and sediment, heart,
lungs, liver, kidney,
spleen; no signs of
toxicity
Rotobar performance: no
Reference
Desoil le
et al . , 1968
Underwriters'
Laboratories,
1941
Steinberg
et al . ,
1969
Clayton,
1966
Steinberg
1.3 13,000 A
change
6 hr 1 h: restlessness
2 h: quiet; rotobar test,
no change
5-21
-------
TABLE 5-9. (continued)
Animal
(Number) % ppm
1.76 17,600
5.5 55,000
8.7 87,000
10.0 100,000
(5<*) 10.0 100,000
Wistar 11 110,000
albinos
15 150,000
20 200,000
22.2 222,000
(IQtf 0.21 2,075
and to to
109) 0.29 2,885
Rats
(5controls),
no adverse symptomology
See Table 10
No deaths, no weight gain,
slight liver damage
0/12 deaths, abnormal
weight gain; 3 rats:
Reference
AIHAC, 1968
U.S. EPA, 1966
Clayton, 1962
AIHAC, 1968
Clayton, 1966
Desoi 1 le
et al. , 1968
Kuebler, 1964
U.S. EPA, 1966
AIHAC, 1968
Clayton, 1966
Carter et al . ,
1970
Clayton, 1962
Clayton, 1966
slightly pale livers,
others normal; kidneys
normal
5-22
-------
TABLE 5-9. (continued)
Animal
(Number) %
(5(X*) 0.51
(5rf) 0.51
(109 0.51
and
lOrf)
(5<*) 2.5
ppm
5,100
5,100
5,100
25,000
A/S*
S
S
S
S
Duration
6 hr/day
5 day/wk
4 wk
6 hr/day
5 day/wk
4 wk
6 hr/day
5 day/wk
4 wk
3.5 hr/day
20 days
Effects
Rotobar test: no change
Voluntary movement
(activity wheels) and
necropsy: no changes
Growth rate, organ-to-
body weights, necropsy:
no changes
0/5 deaths; weight gain,
rbc, wbc, differential
Reference
Steinberg
et al. , 1969
Steinberg
et al. , 1969
Clayton, 1966
Rats
(5)
(4)
Wistar
albinos
60,000
40 400,000
1.2 12,000
Sprague-Dawley
30 g/kg
1 hr/day
5 days
1 hr/day
5 days
2 hr/day
5 day/wk,
365-
730 days
undiluted
dosed
orally,
Ix
white count, hemoglobin,
urinary protein and
sediment, heart, lungs,
liver, kidney, spleen:
no changes; no signs of
toxicity
Deaths: 0/5; liver:
2 rats fair amounts of
fat in Kupffer cells
Deaths: 0/4; mild hepato-
toxicity; moderate degree
of mitotic activity in
liver cells of one rat;
others showed similar
activity but to a lesser
degree
Deaths: 3/6 (3/6 Controls
died also); sleepiness
0/5 deaths; lethargy;
facial edema; abdominal
distension; liquid fecal
discharge: symptoms
disappeared after 24 h;
ruffled coat; autopsies:
no gross pathological
changes; avg wt. change:
+46 g
Burn et al. ,
1959
Desoille
et al., 1968
Michael son and
Huntsman,
1964
5-23
-------
TABLE 5-9. (continued)
Animal
(Number)
(5*)
(5*)
(5*)
% ppm A/S* Duration
35 g/kg I Same
50 g/kg I Same
43 g/kg I Undiluted
dosed
oral ly,
Ix
Effects Reference
Same; avg. wt change:
+41 g
Same; avg wt. change:
+19 g
43 ± 4.8 g/kg = LD50 Michael son and
Huntsman,
1964
(5*)
45 g/kg I Same Lethargy; facial edema;
abdominal distension;
liquid fecal discharge:
symptoms disappeared after
24 h; ruffled coat;
deaths: 3/5, 5-24 hr post-
ingestion; avg wt. change
of survivors +25 g; avg wt.
change of dead animals:
-12g; autopsy of dead
animals: lung
hemorrhaging, possibly
due to contact with CFC-113
livers: mottled surface,
normal color; stomach and
GI tract: abnormally
distended with gas and
fluid
Michael son and
Huntsman,
1964
45 g/kg I
(5tf) 50 g/kg I
(5tf) 55 g/kg I
Rabbits, albino
1.1 11,000 S
17 g/kg I
Undiluted
dosed
oral ly ,
Ix
Same
2 hr/day
5 day/wk
120 wk
ALC
Same effects as 45 g/kg;
deaths: 4/5, days 1-7
post-exposure; avg. wt.
change survivors: 31 g;
avg. dead animals: -49 g
Same; deaths: 5/5, days
3-9 post-exposure;
avg. wt. change: 0 g
Deaths: 0/6; no variation
Approximate lethal dose
Clayton, 1966
Michael son
and Huntsman,
1964
Desoil le
et al . , 1968
AIHAC, 1968
5-24
-------
TABLE 5-9. (continued)
Animal
(Number) %
Dogs
(2? 1.14
and
ppm
11,400
A/S*
A
Duration
6 hr
Effects
2 hr: vomiting, lethargy,
nervousness; 4 hr: stupor
Reference
Steinberg
, et al. , 1969
lethargy; 5-6 hr: tremors;
15 minutes post-exposure:
no signs
Dogs
(1
-------
TABLE 5-9. (continued)
Animal
(Number) % ppm
Dogs
(1? 200 ml.
and into
1^ ) exposed
stomach
(2) 1.25 12,500
Monkeys
(4$ ) 0.2 2,000
A/S* Duration Effects Reference
2 hr Stomach exposed, cardiac Clayton,
and pyloric sphincters 1966
ligated, CFC-113 added;
2 h: gastric juices
measured; volume = 200 ml.;
gross appearance gastric
mucosa: normal
S 3.5 hr/day 0/2 deaths; weight gain, Ibid.
20 days rbc, wbc, differential
white count, hemoglobin,
urinary protein and sedi-
ment, heart, lungs, liver,
kidney, spleen: all normal;
no signs of toxicity
S 2 wk 0/4 deaths; hematological Carter et al.,
values, clinical chemis-
tries, EEG, body weight:
no changes; organ-to-body
weight ratios: all monkeys,
enlarged thyroids; control:
monkeys: all thyroids
normal
1970
*T -
I = Ingested; A = acute; S = Subchronic; C = Chronic
5-26
-------
5.2 HUMAN STUDIES
Much of what is known is derived from instances in which individuals were
accidentally or experimentally exposed to high concentrations of chlorofluoro-
carbons.
5.2.1 Occupational Exposure Studies
Triebig and Burkhardt (1978) observed the effects of occupational inha-
lation exposures to CFC-113. Ten women (25-54 years of age; length of exposure
1-14 years, average 8.7 years) and three men (27-43 years of age; length of
exposure 6-21 years, average 11 years) were used in the study. Case histories,
clinical chemistry (blood Hb, Hbp, erythrocytes, leukocytes, SCOT, SGPT,
fasting blood sugar, urine protein, sugar, bile pigment, and sedimentation
rate), and breath analyses were performed before the one-week exposure period.
After the exposure period, blood chemistry, urinalysis, and breath analyses
were performed again. The concentration of CFC-113 in the workroom was deter-
mined by infrared spectrometry. Room air measurements indicated average daily
levels between 23.3 ±9.2 and 62.4 ± 29.5 ppm (180 ± 71 and 480 ± 227 mg/m3)
during the exposure period. Prior to the commencement of this experiment,
each of the women had worked at least one day in the workroom (concentration
3
CFC-113, 11 to 113 ppm; 85 to 870 mg/m ) and each of the men had worked 15 to
20 minutes/day for 2 to 3 days/week. During the one week observation period,
each woman spent one day in the workroom (3.5 to 5.8 hours) while the men had
irregular and brief periods of exposure. Analysis of blood and urine revealed
no abnormalities. At the end of the daily exposure, breath analyses indicated
a range of 1.0 to 33.8 ppm (7.7 to 260 mg/m ) CFC-113 in the women.
Imbus and Adkins (1972) also conducted studies of the effects of occupa-
tional exposures to CFC-113. Only males were observed. Clinical examination
and blood chemistry (cholesterol, calcium, inorganic phosphorus, total bili-
rubin, albumin, total protein, uric acid, BUN, glucose, lactate dehydrogenase,
alkaline phosphatase, and SCOT) were used as an indication of adverse effects.
There were fifty males in each of the two groups: (1) those unexposed to
CFC-113 (average age 37 years); (2) those exposed to CFC-113 (average age 34
years; average exposure 2.77 years; exposure values determined from one day's
161 samplings: range 46 to 4,780 ppm (354 to 36,806 mg/m3), mean 699 ppm
3 3
(5,382 mg/m ), 50th percentile estimate 521 ppm (4,012 mg/m ), median 425 ppm
(3,272 mg/m ). The results indicated no adverse effects other than one case
of CFC-113-induced dermatitis.
5-27
-------
5.2.2 Experimental Exposure Studies
5.2.2.1 Inhalatiorr-Reinhardt et al. (1971) also conducted experiments on the
effects of exposure to CFO113 using four healthy male volunteers (22-30
years of age). A broad base of responses was measured in terms of clinical
tests (equilibrium, breath analysis, chest x-ray, urinalysis, and blood chem-
istries: alkaline phosphatase, cholesterol, total bilirubin, total protein,
albumin, globulin, A/G ratio, total lipids, SCOT, LDH, creatinine, glucose,
BUN, and uric acid), psychomotor tests and subjective impressions. The sub-
jects were exposed to CFO113 for 3 hours in the morning and 3 hours in the
afternoon, 5 days/week, for 2 weeks in an environmental chamber (6' x 6 1/2' x
10'). The concentration of CFC-113 in the environmental chamber was deter-
mined by gas chromatography. During week 1, the concentration was 500 ppm
3 3
(3,850 mg/m ). During week 2, the concentration was 1,000 ppm (7,700 mg/m ).
Psychomotor tests were administered to each individual prior to and after
exposure at each level. The authors reported no evidence of a detrimental
effect due to exposure to CFC-113, based on test scores. Clinical testing,
conducted before each exposure and three days after final exposure, indicated
no abnormal findings regarding hematology, blood chemistry, or urinalysis.
These findings were supported by no adverse subjective impressions or disturb-
ances of equilibrium. The results of breath analyses performed after each
exposure are shown in Table 5-10. As shown in Table 5-10, the morning samples
3
obtained during the week of exposure to 1,000 ppm (7,700 mg/m ) indicate that
not all of the CFC-113 was eliminated overnight. Only one individual had a
3
measurable breath level (1.5 ppm; 11.6 mg/m ), about 48 hours following the
last exposure to 1,000 ppm (7,700 mg/m ). These data show that essentially no
CFC-113 is retained by tissues 48 hours after repetitive exposures.
Stopps and McLaughlin (1967) tested the psychomotor effects of CFC-113.
Two healthy males were used in the study. Four different psychomotor tests
performed by each subject were used to determine adverse effects. The sub-
jects were exposed to CFC-113 for two and three-quarter hours in an environ-
mental chamber (2 1/2' x 3' x 5'). The timetable of the experiment is shown
in Figure 5-2. The concentrations of CFC-113 in the environmental chamber
were determined by gas chromatography and the concentrations tested were
1,500; 2,500; 3,500; 4,000; and 4,500 ppm (11,500; 19,250; 26,950; 30,800; and
34,650 mg/m3).
5-28
-------
TABLE 5-10. POST-INHALATION BREATH CONCENTRATIONS OF CFC-113 IN MAN
Summary of Breath Sampling Data
(Chlorof1uorocarbon 113 Concentration (ppm) in Alveolar Air)
Exposure
Day of
Subject Week
I M
T
W
T
F
II M
T
W
T
F
III M
T
W
T
F
IV M
T
W
T
F
500
a.m.
< 1
< 1
< 1
< 1
< 1
< 1
< 1
2.0
< 1
< 1
< 1
< 1
1.5
< 1
3.0
< 1
< 1
< 1
1.0
< 1
ppm
p.m.
60
65
59
57
51
61
56
51
49
55
45
27
18
18
31
47
44
35
35
41
1000
a. m.
< 1
< 1
2.0
1.5
1.5
< 1
1.5
1.5
1.0
1.5
< 1
< 1
2.0
3.0
1.0
< 1
1.0
1.5
2.0
2.0
ppm
p. m.
113
88
71
105
93
115
85
102
79
103
88
66
57
54
60
84
67
56
60
71
Post-
exposure
a.m.
< 1
< 1
-
-
—
1.5
< 1
-
-
—
< 1
< 1
-
-
—
< 1
< 1
-
-
Note: (-) Indicates not measured (detection limit about 1 ppm).
Data of Reinhardt et al. (1971).
5-29
-------
SUBJECT SUBJEC
ENTERS LEAVE
CHAMBER CHAMBEI
c_n
i
00
o
1
"0'
PERIOD OF BUILDUP IN "F-113"
CONCENTRATION IN CHAMBER
^- 45m ins. -^>
r 1
' time 45 n
PERIOD OF EQUILIBRATION
BETWEEN SUBJECT'S TISSUES
AND ENVIRONMENT
•<- 30 mins. -^-
1
1 ho
lins. 15 m
FIRST
BATTERY
OF
TESTS
-^- 17 mins. -^-
' 1
ur 1 h
ins. 32
r \
our 2 ho
nins. 10 rr
SECOND
BATTERY
OF
TESTS
r 1
urs 2h
lins. 27
•<- 18mins.>i
F 1
ours 2 h
mins. 45 1
r
Ol
n
Figure 5-2. Human exposures to CFC-113; timetable of experiment.
Source: Stopps and Mclaughlin (1967).
-------
The results are presented in Figure 5-3. Because the results of the
first and second series of psychomotor tests during each exposure showed no
consistent trends, the scores are presented as the average of the individual
scores, expressed as the percentage change from control values. The results
3
indicate no adverse effects at 1,500 ppm (11,550 mg/m ) for 2.75 hours. At
concentrations of 2,500 ppm (19,250 mg/m ), there was a slight but definite
impairment of psychomotor performance. In addition, both subjects reported
the following effects after one half to one hour exposures at the three highest
concentrations tested: loss of concentration on the task at hand, drowsiness,
"heaviness" in the head with no actual headache, and dizziness upon lateral
shaking of the head. These effects were gone fifteen minutes after having
left the chamber. Post-exposure psychomotor testing, breath and blood analyses
for CFC-113 were not performed.
5.2.2.2 Ingestion--0n1y one report on the effects of human ingestion of
CFC-113 has been found. Approximately one liter of cold CFC-113 was accidental-
ly delivered into the stomach of an anesthetized patient, producing immediate
but transient cyanosis. The patient survived and reported only severe rectal
irritation and diarrhea for 3 days thereafter (Clayton, 1966).
5.2.2.3 Dermal—The results of unpublished dermatological experiments with
CFC-113 conducted for E.I. duPont de Nemours and Company suggested that human
scalp and forehead were not adversely affected when CFC-113 was applied over a
30-day period (Betro Research Laboratory, 1967). Twenty volunteers received
applications to entire scalp and most of forehead according to the following
schedule: (1) For first five days, CFC-113 was applied three times daily for
30 seconds, (2) the 6th day exposure consisted of a single 30-second applica-
tion; (3) thereafter, CFC-113 was applied for 1.5 minutes, once daily. Tests
included permeability, eccrine sweat secretion, sebum production, UV response,
response to chemical irritants, and determination of bacterial flora.
5.2.2.4 Synergistic, Carcinogenic, Mutagenic, and Teratogem'c--No information
pertaining to any of these categories of effects of direct exposure to CFC-113
in man have been found.
5.3 SUMMARY OF ADVERSE HEALTH EFFECTS AND ASSOCIATED LOWEST OBSERVABLE
EFFECTS LEVELS
Levels of CFC-113 above "2,000 ppm (15,400 mg/m ) have been reported to
result in cardiac sensitization of dogs only after the administration of
exogenous epinephrine. No evidence of cardiac sensitization of animals in the
absence of exogenous epinephrine at CFC-113 levels at or below 20,000 ppm
(154,000 mg/m ) has been reported.
5-31
-------
MANUAL DEXTERITY A
MANUAL DEXTERITY B
1500 2500 3500
ppm
4500
CARD SORTING
+10%
0
-10%
-20%
-30%
-40%
I- CARD SORTING WITH AUXILIARY TASK
D O G.J.S.
D.D.
I
1500
2500
3500
4500
ppm
Figure 5-3. Effect of CFC-113 upon psychomotor performance in man.
Source: Stopps and McLaughlin (1967).
5-32
-------
Animal studies with mice, rats, dogs and monkeys that had been exposed to
levels exceeding 5,000 ppm (38,500 mg/m ) have shown that arrhythmias, tachy-
cardia, hypotension, and depression of myocardial contractility could be
elicited.
Inhalation studies have shown that exposure to 2,000 to 19,000 ppm (15,400
3
to 146,300 mg/m ) CFO113 (in guinea pigs, rats, dogs, and monkeys) can result
in a slight narcotic effect, liver and kidney congestion, and kidney and
thyroid enlargement. Often these effects are not revealed by the usual hema-
tological or clinical tests, indicating that these tests do not always show
the full extent of changes induced by CFO113.
No direct effect of CFO113 exposures upon humans at ambient concentra-
tions is known or expected. No conclusions can be drawn, at this time, with
regard to the carcinogenic, mutagenic, or teratogenic potential of CFO113.
Because of the practical limitations on the acquisition of data concern-
ing chronic human exposure situations, it is difficult to estimate, with
confidence, a lowest-observed-adverse-effect level (LOAEL) for CFO113. The
LOAEL is defined as the lowest dose in a study or group of studies producing
functional impairment, behavioral abnormality, and/or pathological lesions
which hinder the performance of the whole organism. Table 5-11 summarizes the
results of the few presently available studies which might reasonably be used
to derive an estimated LOAEL for CFO113 at this time. Inhalation studies
with animals and the acute human exposure data of Stopps and McLaughlin suggest
that the LOAEL may be in the range of 2,000 to 2,500 ppm (15,400 to 19,250
3
mg/m ). However, this level should be regarded with caution until recently-
completed bioassays are comprehensively evaluated.
The data of Reinhardt et al. (1971), Triebig and Burkhardt (1978), Imbus
and Adkins (1972), and Stopps and McLaughlin (1967) suggest a no-observed-
adverse-effect level (NOAEL), for short-term CFC-113 exposure situations, in
the range of 1,500 to 2,000 ppm (11,550 to 15,400 mg/m3). The NOAEL is defined
as that dose which produces observed effects which do not in themselves repre-
sent known functional impairment, behavioral abnormality, and/or pathological
lesions which hinder the performance of the whole organism. The data supporting
the NOAEL conclusion are shown in Table 5-12.
It should be noted that the above, tentatively-derived LOAEL and NOAEL
estimates for CFC-113 are orders of magnitude higher than the highest ambient
3
air concentrations (38.0 ppb; 0.29 mg/m ) of CFC-113 encountered thus far in
urban areas of the United States or elsewhere (see Table 3-2 in Chapter 3).
5-33
-------
TABLE 5-11. LOWEST OBSERVABLE ADVERSE EFFECT LEVELS (LOAEL)
CO
-pi
Criteria
Cardiac Sensitization
Liver damage
Thyroid
Psychomotor ability
No. of
Species Mode of Treatment Subjects
beagle dog 8 (jg/kg epinephrine 6
given i.v. prior to
CFC-113 and again
after exposure
8 ug/kg epinephrine 6
i.v. prior to exposure
and again after
exposure
rat 20
rat 12
monkey 4
human inhalation 2
Duration
of Exposure
0.5 hour
6 hours
7 hr/day
5 day/wk
30 days
7 hr/day
5 day/wk
30 days
2 weeks
0.5 to 1
hour
Concentration Response
(ppm)
2,500
2,000
5,000
5,000
2,000
2,500
cardiac sen-
si tizati on to
exogenous epi-
nephrine (1/6)
cardiac sen-
si tizati on to
exogenous epi-
nephrine (1/6)
slight liver
damage
abnormal
weight gain,
3 rats pale
1 ivers
enlarged
thyroid (4/4)
loss of con-
centration,
drowsiness,
Reference
Haskell
Laboratory, 1969
Ibid
Clayton, 1962
Clayton, 1966
Carter et al . ,
1970
Stopps and
McLaughlin,
1967
dizziness
(reversible
upon cessation
of exposure)
-------
TABLE 5-12. NO OBSERVED ADVERSE EFFECT LEVEL
en
i
GO
en
Criteria Species
Cardiac beagle
Sensitization dog
dog
Liver rat
and other
organs
guinea pig
dog
Clinical human
Examination
Psychomotor human
Effects
human
Mode of
Treatment
treadmill
inhalation
chamber
fright
(electric shock
and f luorocarbon
chronic
inhalation
subacute
inhalation
subacute
inhalation
subacute
inhalation
subacute
inhalation
inhalation
inhalation
inhalation
No. of
Subjects
Deaths/Total
0/8
0/4
0/12
or noise)
inhalation
0/20
0/20
0/5
0/3
0/2
0/50
0/2
0/4
Duration
of Exposure
16 minutes
5 minutes
6-hr/day
5 day/wk
90 days.l year
7-hr/day
30 days
3. 5-hr/day
20 days
3. 5-hr/day
x20 days
3. 5-hr/day
x20 days
3-yrs.
2 3/4 hrs.
6 hrs/day
5 days
Cone.
(ppm)
10,000
20,000
12,000
20,000
2000-
3000
25,000
25,000
12,500
700
(46-5,000)
1,500
1,000
Response
no effect on
cardiac
rhythm
no effect on
cardiac rhythm
no effect on
1 iver or
other organs
Pathology
Normal
no change,
1 iver or
other organs
no change,
1 iver or
other organs
liver, other
organs, all
normal
no effects
no effect
manual testing
card sorting
no effect
clinical testin
Reference
Mul lin et al . ,
1971
Haskell Laboratory,
1969
Schneider, 1982
(90-day data)
Clayton, 1966
Clayton, 1966
Clayton, 1966
Clayton, 1966
Imbus & Adkins, 1972
Stopps & McLaughlin,
1967
Reinhardt, 1971
g
psychomotor
performance
subjective
impression
-------
5.4 REFERENCES
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Hyg. Assn. J. 29:521-525, 1968.
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Substances in Workroom Air, 3rd Edition, 1971.
Amer. Conf. Govern. Ind. Hyg. Threshold Limit Values for Chemical Substances
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Aviado, D. M., and M. A. Belej. Toxicity of Aerosol Propellants on the Res-
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Toxicology 3:79-86, 1975.
Aviado, D. M., and D. G. Smith. Toxicity of Aerosol Propellants in the Res-
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Primates. Toxicology 3:241-252, 1975.
Belej, M. A., D. G. Smith, and D. M. Aviado. Toxicity of Aerosol Propellants
in the Respiratory and Circulatory Systems. IV. Cardiotoxicity in the
Monkey. Toxicology 2:381-395, 1974.
Betro Research Laboratories, Inc. Unpublished data of E.I. duPont de Nemours
and Company. HLO-0260-67, MRO-0916-001 (1967). Submitted to U.S. En-
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Burn, J. H. Pharmacological Testing of Anesthetics. Proc. Soc. Med.
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31:518-529, 1959.
Carter, V. L., P. M. Chikos, J. D. MacEwen, and K. C. Back. Effects of Inhal-
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Report AD727524, 1970.
Clark, D. G., and D. J. Tinston. Correlation of the Cardiac Sensitizing
Potential of Halogenated Hydrocarbons with their Physiochemical Proper-
ties. Br. J. Pharmacol. 49:355-357, 1973.
Clayton, J. W., Jr. The Toxicity of Fluorocarbons with Special Reference to
Chemical Constitution. J. Occup. Med. 4(5):262-273, 1962.
Clayton, J. W. The Mammalian Toxicology of Organic Compounds Containing
Fluorine. Handbuch Exp. Pharmakol. 20:459-500, 1966.
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Conney, A. H., R. Chang, W. M. Levin, A. Garbut, A. D. Moore-Faure, A. W. Peck,
and A. Bye. Effects of piperonyl butoxide on drug metabolism in rodents
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Desoille, H., L. Truffert, A. Bourguignon, P. Delavierre, M. Philbert, and C.
Girard-Wallon. Experimental Study on the Toxicity of trichlorotrifluoro-
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Duprat, P., L. Delsuat, and D. Gradiski. Pouvoir Irritant des Principaux
Solvants Chlores Aliphatiques sur la Peau et les Muqueuses Oculaires du
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Epstein, S. S. , J. Andrea, P. Clapp, D. Mackintosh, and N. Mantel. Enhancement
by piperonyl butoxide of acute toxicity due to Freons, Benzo ( a )
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Epstein, S. S., E. Arnold, J. Andrea, W. Bass, and Y. Bishop. Detection of
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Kuebler, H. The physiological properties of aerosol propellants. Aerosol Age
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Underwriters' Laboratories, Inc. The Comparative Life, Fire, and Explosion
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5-39
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6. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS
In March 1978, both the U.S. Environmental Protection Agency and the Food
and Drug Administration banned fully-halogenated chlorofluorocarbons as pro-
pellants in nonessential aerosol uses (Fed. Reg., 1978). It should be noted
that while this ban applied to CFC-113 used as the propel lant or as a com-
ponent of the propellant in nonaerosol products, the ban does not cover use of
CFC-113 as a solvent or active ingredient in aerosol formulations, nor does it
apply to the main uses of CFC-113 in nonaerosol applications.
The concentration of CFC-113 in the workplace to which nearly all workers
3
may be repeatedly exposed without adverse effect is 1,000 ppm (7,700 mg/m ).
This Threshold Limit Value (TLV®) has been established for CFC-113 by the
American Conference of Governmental and Industrial Hygienists (ACGIH, 1981).
This value was recommended as a limit of good hygiene control for vapors of
low toxicity (ACGIH, 1971).
References are cited in Section 5.4, Chapter 5.
6-1
•frU. S. GOVERNMENT PRINTING OFFICE 1983/659-095/0750
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