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Health Assessment
Document for 1,1,2-
Trichioro-1,2,2 -
Trifiuoroethane
(Chiorcfluorocarbon
FC-113)
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EPA-600/8-82-002
Review Draft
Draft
Do not cite or quote
HEALTH ASSESSMENT DOCUMENT FOR
1,1,2-TRICHLORO-1,2,2-TRIFLUOROETHANE
(CHLOROFLUOROCARBON FC-113)
NOTICE
This document is a preliminary draft. It has not been formally released by EPA
and should not at this stage be construed to represent Agency policy. It is being
circulated for comment on its technical accuracy and policy implications.
,,«0j, ii)i,;c!3 GG"wG4
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
Project Coordinator: Mark M. Greenberg
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DISCLAIMER
This report is an internal draft for review purposes only and does not
constitute Agency policy. 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, in consultation with
an Agency work group, has prepared this health assessment to serve as a
"source document" for Agency-wide use. Originally the health assessment was
developed for use by the Office of Air Quality Planning and Standards;
however, at the request of the Agency's Work Group on Solvents the assessment
scope was expanded to address multimedia aspects. This assessment will help
insure consistency in the Agency's consideration of the relevant scientific
health data associated with chlorof1uorocarbon FC-113.
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 are placed in perspective with observed environmental
levels.
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TABLE OF CONTENTS
Page
LIST OF TABLES .
LIST OF FIGURES
1. SUMMARY AND CONCLUSIONS 1-1
2. INTRODUCTION 2-1
2.1 REFERENCES 2-3
3. PHYSICO-CHEMICAL PROPERTIES, PRODUCTION AND ENVIRONMENTAL
FATE 3-1
3.1 CHEMICAL AND PHYSICAL PROPERTIES 3-1
3.2 ANALYTICAL METHODOLOGY 3-2
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 3-6
3.3.4 OTHER MEDIA 3-6
3.4 ATMOSPHERIC FATE 3-6
3.4.1 Persistence Time and Stratospheric Reactions . 3-9
3.5 REFERENCES 3-14
4. MAMMALIAN FATE AND DISPOSITION 4-1
4.1 ABSORPTION AND ELIMINATION 4-1
4.2 DISTRIBUTION AND METABOLISM 4-2
4.3 REFERENCES 4-6
5. HEALTH EFFECTS 5-1
5.1 ANIMAL STUDIES 5-2
5.1.1 Acute Toxicity 5-2
5.1.2 Cardiovascular and Respiratory Effects 5-2
5.1.2.1 Mouse 5-2
5.1.2.2 Dog 5-3
5.1.2.2.1 In Vitro -. 5-3
5.1.2.2.2 In Vivo 5-7
5.1.2.3 Monkey 5-11
5.1.3 Neurological Effects 5-14
5.1.3.1 Frog 5-14
5.1.3.2 Dog 5-14
5.1.4 Hepatoxicity 5-17
5.1.5 Teratogenic Effects 5-17
5.1.6 Mutagenic Effects 5-20
5.1.6.1 Mouse 5-20
5.1.7 Carcinogenic Effects 5-21
5.1.7.1 Mouse 5-21
5.1.8 Synergistic Effects 5-23
5.1.8.1 Mouse 5-23
5.1.9 Dermal Effects 5-25
5.1.10 Inhalation and Ingestion 5-25
5.2 HUMAN STUDIES 5-34
5.2.1 Occupation Exposure Studies 5-34
5.2.2 Experimental Exposure Studies > . . . 5-36
5.2.2.1 Inhalation 5-36
5.2.2.2 Dermal 5-39
5.2.2.3 Ingestion 5-41
V
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5.2.2.4 Synergistic, Carcinogenic, Mutagenic,
and Teratogenic. . 5-41
5.3 SUMMARY OF ADVERSE HEALTH EFFECTS AND ASSOCIATED LOWEST
OBSERVABLE EFFECTS LEVELS 5-42
5.4 REFERENCES 5-45
6. ECOLOGICAL EFFECTS 6-1
6.1 CLIMATE 6-1
6.2 AGRICULTURAL CROPS 6-2
6.3 DOMESTIC AND WILD ANIMALS 6-2
6.4 AQUATIC SPECIES AND ECOSYSTEMS 6-2
7. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS 7-1
8. COLLATED BIBLIOGRAPHY 8-1
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LIST OF TABLES
Table Page
3-1 Physical Properties of trichlorotrifluoroethane . 3-2
3-2 Tropospheric levels of FC-113 3-7
3-3 Efficiency of various halocarbons in destroying
stratospheric ozone relative to the ozone destruction
efficiency of CFCL, (FC-11) 3-11
3-4 Important atmospheric reactions that affect
stratospheric ozone 3-13
4-1 Mean tissue concentrations of FC-113 from rats
exposed to 2,000 ppm 4-3
5-1 Effects of FC-113 on the electrocardiogram of
anesthetized mice 5-4
5-2 Effect of FC-113 on the canine heart-lung preparation .... 5-5
5-3 Effect of FC-113 on cardiac sensitization to epinephrine
in the unanesthetized dog 5-8
5-4 Respiratory and circulatory effects of FC-113 upon
anesthetized Rhesus monkeys 5-12
5-5 Respiratory and circulatory effect of FC-113 upon
anesthetized Rhesus monkeys 5-13
5-6 Carcinogenic effects of FC-113 + PB in mice, alone and in
combination 5-22
5-7 Combined toxicity of FC-113 + PB upon neonatal mice 5-23
5-8 Dermal effects of FC-113 in mammals 5-24
5-9 Inhalation and ingestion toxicities of FC-113 in mammals . . . 5-25
5-10 Post-inhalation mean tissue concentrations of FC-113 in rats . 5-34
5-11 Post-inhalation breath concentrations of FC-113 in man .... 5-37
5-12 Effects of dermal exposure to FC-113 in man 5-41
5-13 Lowest observable adverse direct exposure effect levels . . . 5-44
Vll
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LIST OF FIGURES
Figure Page
5-1 Ventricular function curves in canine heart-lung preparations 5-6
5-2 Effect of 2% FC-113 on preganglionic stimulation of canine
spinal preparations 5-15
5-3 Effect of 2% FC-113 on postganglionic stimulation of canine
spinal preparations 5-16
5-4 Human exposures to FC-113; timetable of experiment 5-38
5-5 Effect of FC-113 upon psychomotor performance in man 5-40
Vlll
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AUTHORS AND REVIEWERS
The authors of this document are:
Dr. Richard Carchman, Department of Pharmacology, The Medical College
of Virginia, Health Sciences Division, Virginia Commonwealth
University, Richmond, Virginia. [Chapter 5, Health Effects]
Mr. 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:
Dr. Jeff Beaubier, Health Effects Research Laboratory, U.S. Environmental
Protection Agency, Research Triangle Park, North Carolina.
Dr. Dagmar Cronn, Washington State University, Pullman, Washington.
IX
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The following individuals reviewed an early draft of this document and
submitted valuable comments:
Or. Joseph Borzelleca
Department of Pharmacology
The Medical College of Virginia
Health Sciences Division
Virginia Commonwealth University
Richmond, Virginia 23298
Dr. Herbert Cornish
Dept. of Environmental and Industrial Health
University of Michigan
Ypsilanti, Michigan 48197
Dr. I. W. F. Davidson
Dept. of Physiology/Pharmacology
The Bowman Gray School of Medicine
300 S. Hawthorne Road
Winston-Sal em, North Carolina 27103
Dr. Lawrence Fishbein
National Center for Toxicological Research
Jefferson, Arkansas 72079
Dr. John G. Keller
P.O. Box 12763
Research Triangle Park, North Carolina 27709
Or. Marvin Legator
Professor and Director
Dept. of Preventive Medicine and
Community Health
Div. of Environmental Toxicity and
Epidemiology
University of Texas Medical Branch
Galveston, Texas 77550
Dr. Benjamin Van Duuren
Institute of Environmental Medicine
New York University Medical Center
New York, New York 10016
Dr. Richard Ward
E. I. duPont de Nemours and Company
Wilmington, DL
Dr. Herbert Wiser
U.S. E.P.A.
Washington, DC
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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.
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
Office of
Office of
Office of
Office of
Office of
Office of
Office of
Office of
Office of
Consumer
Office of
Office of
Office of
Office of
Office of
Office of
Office of
Office of
Office of
and
and
and
and
and
and
Environmental
Environmental
Environmental
Environmental
Environmental
Environmental
Assessment
Assessment
Assessment
Assessment
Assessment
Assessment
Health
Health
Health
Health
Health
Health
Toxic Substances
Toxic Substances
Drinking Water
Product Safety Commission
Air Quality Planning and Standards
General Enforcement
Toxic Integration
Water Regulations
Water Regulations
Solid Waste
Water Regulations and Standards
Pesticide Programs
Emergency and Remedial Response
and
and
Standards
Standards
XI
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1. SUMMARY AND CONCLUSIONS
Compared with other halogenated hydrocarbon solvents with similar usage
in industry, relatively little information is available from the literature on
FC-113 (1,1,2-trichloro, 1,2,2-trifluoroethane), particularly with regard to
its effects on mammalian organ systems. Existing evidence suggests that
FC-113 is poorly metabolized, although recent data suggest that it is a sub-
strate for the cytochrome P-450 mixed function oxidase system. Animal exposure
studies indicate that FC-113 is retained in lipid-rich tissues. At ambient
air mixing ratios (e.g., 18 ppt; 0.14 x 10 mg/m ) found or expected in the
general environment and probably even at the higher levels (<4,160 ppt; <0.032
mg/m ) observed in urban areas, its potential for causing adverse, direct
health effects are, thus far, undocumented. The limited experimental data do
not indicate adverse health effects in humans at a TL\r of 1,000 ppm (7,700
mg/m ) due to exposure to FC-113.
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. Because of the lack of detailed studies
in these health areas, a conclusive assessment of the human health risks posed
by ambient levels of FC-113 cannot be made. Before conclusions concerning the
effects of long-term exposure to FC-113 can be drawn, more studies involving
chronic exposure of animals are needed.
Chlorofluorocarbon 113 is primarily of concern as a pollutant of the atmos-
phere; it has a high vapor pressure and is practically insoluble in water.
Direct effects of FC-113 upon the ecosystem have not been reported in the scien-
tific literature; however, the high volatility and the absence of measurable
levels in water suggest that FC-113 poses a low risk to aquatic species.
The known information concerning the health effects of FC-113 is des-
cribed in sections below.
1-1
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STRATOSPHERIC POLLUTION AND OZONE DEPLETION
In contradistinction to an absence of demonstrated adverse health effects
at FC-113 exposure levels below 1,000 ppm (7,700 mg/m ), the present concern
focuses mainly on the potential contribution of FC-113 to health effects pro-
jected to result from the photocatalytic destruction of stratospheric ozone
(0-). A thin shield of ozone is located in the stratosphere, 10 to 50 kilometers
above the earth's surface. Because it effectively absorbs ultraviolet-B
radiation (in the wavelength range 290 to 320 nm), any decrease in 03 concen-
tration is expected to result in an increased amount of this radiation (incident
at the earth's surface) and human health effects associated with such radiation.
More specifically photochemical reactions involving a variety of halogenated
organic compounds, principally chlorof1uorocarbons, appear to have the potential
to destroy ozone in the stratosphere to the extent that an increased incidence
in certain types of skin cancer would likely result.
It is difficult to estimate with much certainty the rate of 0, depletion
that may be associated with atmospheric loadings of FC-113. The destruction
of 0, in the stratosphere has been theorized to be catalyzed by atomic chlorine,
released during photodestruction of halogen-containing species (such as FC-113)
that are transported to the stratosphere. 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, FC-113 slowly is transported to the stratosphere.
Chlorofluorocarbons have exceedingly long atmospheric lifetimes relative to
most other atmospheric pollutants. FC-113 is estimated to have a stratospheric
lifetime in the range of 86 to 100 years. Taking this and other information
into account, recent modeling estimates of steady-state 0- depletion, consid-
ering only current releases of FC-113, project less than one percent depletion
per about 100 years.
1-2
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CARCINOGENICITY AND MUTAGENICITY
The carcinogenic potential of FC-113 is unknown. Aside from a few studies
that examined this issue, there is inadequate information to assess the carcino-
genic potential of FC-113.
Chiorofluorocarbon 113 has been reported to be nonmutagenic in the Ames
assay system, with or without metabolic activation, and was reported to be
nonmutagenic in a dominant lethal assay in the mice. Further testing is
needed before any conclusions can be drawn with regard to the mutagenic po-
tential of FC-113.
TERATOGENICITY AND REPRODUCTIVE EFFECTS
No clinical cases associate human exposure to FC-113 with congenital
malformations in children. No epidemiological studies are available. In
addition, no published animal studies are available which adequately assess
the teratogenic or adverse reproductive potential of FC-113. Unpublished data
from two studies conducted for E. I. duPont de Nemours and Company indicate
that FC-113 did not produce toxic effects unique to rabbit conceptus at levels
which were maternally toxic. It should be noted that these studies have major
inadequacies and should be considered as pilot evaluations only. Maternal and
fetal death precluded evaluation of a sufficient number of litters to establish
a teratogenic effect.
It is suggested that an assessment of the full potential of FC-113 to
cause adverse teratogenic or reproductive effects can only be made after data
are generated that are in accordance with current teratologic and reproductive
testing (U.S. EPA, 1978, 1979).
NEUROLOGICAL EFFECTS
A noticeable impairment of psychophysiological function (as measured by
task performance) has been reported in humans exposed to 2,500 to 4,500 ppm
1-3
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(19,250 to 34,650 mg/m ) of FC-113 for 30 minutes to 1 hour. Effects dis-
appeared within 15 minutes after cessation of exposure. No impairment of
exposure levels of 500 and 1,000 ppm (3,850 and 7,700 mg/m ) were observed
during two weeks of exposure.
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 FC-113 (as low as 2,000 ppm or 15,400 mg/m in a 6-hour
exposure period) induces cardiac arrhythmias by sensitizing the heart to
epinephrine. The compound may also induce myocardial depression by a direct
effect on cardiac muscle, decrease contractile performance, and lead to hypo-
tension by decreasing cardiac output and directly affecting peripheral vasodi-
lation.
A more definitive assessment of cardiovascular health hazards of FC-113
depends on future research.
HEPATOXICITY
Alterations of the smooth endoplasmic reticulum in livers of rats exposed
to 1,000 and 2,000 ppm (7,700 and 15,400 mg/m3) FC-113 for 1 to 2 weeks as
well as changes in drug-metabolizing hepatic enzymes have been observed. Some
limited evidence suggests that FC-113 may act synergistically with other
compounds; an increased mortality of mice was observed when FC-113 was admin-
istered in combination with a pesticide synergist.
1-4
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2. INTRODUCTION
The principal intent of this document is to evaluate the health hazards
associated with exposure to chlorofluorocarbon - 113 (FC-113). Chlorofluro-
carbon 113 is released to ambient 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 stratosphere, FC-113
also is of concern with regard to health effects of an indirect nature.
In recent years, a great deal of attention has been focused upon the role
of chlorofluorocarbons, including FC-113, and related species in the destruc-
tion of stratospheric ozone (Oo). Depletion of 0., would increase the level of
biologically-damaging ultraviolet radiation incident at the earth's surface.
As a result, an increase in the incidence of certain types skin cancers would
be likely to occur.
A comprehensive discussion of the role of chloroflurocarbons 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 recent publications of The National
Research Council (1979a, b; 1982) and The World Meteorological Organization
(1982). 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
FC-113 in particular.
It should be noted that FC-113 is simply one member of a group of struc-
turally and chemically - related compounds that have the potential to alter
stratospheric 0- levels. Others include: trichlorof1uromethane (FC-11),
2-1
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dichlorodifluoromethane (FC-12), dichlorotetrafluoroethane (FC-114), chloropenta-
fluoroethane (FC-115), chlorodifluoroethane (FC-1426), and 1,1,1-trichloroethane
(methylchloroform).
In addition to evaluating the spectrum of health effects associated with
FC-113 release to the environment, this document also discusses analytical
methods, production, sources and emissions, ambient concentrations, and
effects of an ecological nature to place FC-113 in a real-world perspective.
2-2
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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. WHO Global Ozone Research and Monitoring
Project Report No. 11, May 1981. The Stratosphere 1981: Theory and
Measurements, 1982.
2-3
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3. PHYSICO-CHEMICAL PROPERTIES, PRODUCTION AND ENVIRONMENTAL FATE
3.1 CHEMICAL AND PHYSICAL PROPERTIES
Chlorofluorocarbons, 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 bondsbonds exhibiting
high bond strength (Bower, 1971).
Trichlorotrifluoroethane, CC12F-CC1F2 (FC-113), is a non-flammable,
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
FC-113 per liter of water per year are 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
FC-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, FC-113 is often used in azeo-
tropic mixtures with acetone, methylene chloride, and ethyl and methyl alcohol
(Ward, 1981). Blends of FC-113 and isopropyl alcohol are also used.
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/m2 (25°C)
Density 1.5 gin/cm
Solubility 0.017 gm/100 gm H20 (0°C, 760 mm)
Downing, 1966; E. I. duPont de Nemours, 1969,1976.
3.2 ANALYTICAL METHODOLOGY
Detecting extremely low levels of FC-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.
3.2.1 Sampling
Because FC-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., (1979) have employed cryogenic trapping of air
containing trace levels of FC-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.
3-2
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Makide et al., (1980) used electropolished stainless-steel canisters,
followed by preconcentration on a silicone OV-101 column at - 40°C. Column
termperature 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) was found using GC-ECD (Harsch and Cronn, 1978). In this
system, the FC-113 mixing ratio was 23 ppt and precision was again 10 percent.
Cronn and coworkers have reported difficulties in measuring low levels of
FC-113 in samples collected at high altitudes (Harsch and Cronn, 1978).
Contamination resulted when the mixing ratio of FC-113 in the laboratory air
was in the range of 15 to 20 ppb (0.116 to 0.154 mg/m ). Measurements of
FC-113 in rural air samples by GC-ECD using a freezeout concentration
technique resulted in a detection limit of 0.8 ppt with a precision 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,
oxygen should be eliminated during pre-concentration procedures while water
can be removed through the use of drying tubes (Russell' and Shadoff, 1977).
The lowest detection limit reported is that of Makide et al. , (1980),
<0.05 ppt with a GC-ECD system.
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).
3-3
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Singh et al. (1977a) judged FEP Teflon tubing to be satisfactory in
generating primary standards for FC-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 per-
meation 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
Chiorofluorocarbons typically are produced by displacing chlorine from
chlorocarbons with hydrogen fluoride (HF). The starting material is normally
tetrachloroethy1ene (Ward, 1981). Other chlorocarbons commonly used include
carbon tetrachloride (CC1.), and hexachloroethane (C2Clg).
A reaction sequence employing C-Cl. (tetrachloroethylene) to produce
FC-113 is depicted as follows:
C2C14 + 3 HF SbC15 C2C13F3 + 3 HC1
ci2
45-200°C
In this method, chlorine gas (C12) maintains the antimony pentachloride
(SbClg) 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 FC-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).
3-4
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Accurate U.S. production data for FC-113 are not readily available.
Production rates for 1979 are estimated to be about 59,000 metric tons (E. I.
duPont, 1982). The RAND Corporation (USEPA, 1980a) estimated that production
of FC-113 in 1977 amounted to about 37,000 metric tons (upper bound) of which
solvent application accounted for 96 percent of the FC-113 available for use.
In 1990, about 71,000 metric tons can be projected to be produced (USEPA,
1980a). The NRC (NRC, 1979a) projects that, based on extrapolation of histo-
rical data, usage could increase by a factor of 2 or 3 by 1990.
3.3.2 Use
Principal uses of FC-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 has not been used
previously in aerosol formulations.
In cleaning and drying operations, two types of solvent losses occur
(USEPA, 1980b): (1) escape in vapor form and (2) in liquid form when tanks
are emptied for cleaning. Although there are no identified reports that
FC-113 has been detected in surface or drinking waters, this potential exists
since FC-113 may be sealed in drums and buried. Because FC-113 has very
limited solubility in water and is highly volatile, all releases of FC-113 can
be expected to eventually be conveyed to the stratosphere.
Estimates of the National Research Council (NRC, 1979a) suggest that
FC-113 emissions during the period 1976-1977 were 30,000 metric tons. FC-113
was reported to account for over 15 percent of chlorofluorocarbon emissions
(U.S. EPA, 1980a). The World Meterological Organization (WHO, 1982),
3-5
-------
citing figures supplied by E. I. duPont de Nemours and Company, reported a
current global annual emissions rate of 91,000 metric tons.
The National Research Council (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 FC-113 in all use categories except (3), where no al-
ternative solvent is available.
In a recent RAND Corporation report (U.S. EPA, 1980a), all FC-113 pro-
duced for nonaerosol end uses was estimated to "find its way into the ambient
air." FC-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 FC-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, 1980b).
3.3.3 Ambient Air Mixing Ratios
The extent to which emissions of FC-113 contribute to the loading of the
atmosphere is indicated by recent measurements of ambient air mixing ratios
(Table 3-2).
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
dominant chlorof1uorocarbons (methane series), FC-11 and FC-12, were found at
global average mixing ratios of 126 and 220 ppt, respectively. Singh et al.
(1979) expected the stratosphere to be the major reservoir for FC-113;
3-6
-------
despite extensive study, tropospheric sinks for FC-11, FC-12, and FC-113 are
uncommon, and there is now little expectation that they exist (NRC, 1979a,b.)
The most recently reported mixing ratios for the northern and southern
hemispheres are those of the World Meteorological Organization (WHO, 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 FC-113 of 2 ppt per year, based on measurements made at Point Arena,
California, a "clean" air site, from late 1979 to early 1981.
In flights over the Pacific Northwest in March 1976, Cronn and coworkers
(1976b) detected FC-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 FC-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
ppt (0.14 ± 0.02 x 10 mg/m ) was measured (April 1977).
3.3.4 Other Media
No information is available regarding levels of FC-113 in water or soil.
3.4 ATMOSPHERIC FATE
The potential for ambient air mixing ratios of FC-113 to pose a hazard to
human health is influenced by many processes. Of principal concern is trans-
port to the stratosphere where it participates in ozone (OO destruction
reactions.
3-7
-------
TABLE 3-2. TROPOSPHERIC LEVELS OF FC-113
OJ
I
00
Location
Arizona
Phoenix
Cal ifornia
Badger Pass
Los Angeles
Point Reyes
Mill Valley
Oakland
Palm Springs
Point Arena
Riverside
San Jose
Stanford Hills
Yosemite
Delaware
Delaware City
Kansas
Jetmore
Maryland
Baltimore
Nevada
Reese River
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
8/21/78
11/23/75
5/12/76
7/8/74
6/1/78
7/11/74
5/14/77
- 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
- 8/27/78
- 11/30/75
- 5/18/76
- 7/10/74
- 6/7/78
- 7/12/74
- 5/20/77
Concentration (ppb)
max
1.2513
0.255
4.1601
0.315
0.450
0.181
0.3088
0.105
0.042
0.027
0.137
0.144
0.365
0.157
0.031
<0.01
0.040
0.038
0.042
mm
0.0122
0.014
0.0488
0.029
0.012
0.027
0.0163
0.012
0.014
0.018
0.024
0.020
0.017
0.008
0.011
<0.01
0.012
<0.01
0.004
average
0.1513
0.027
0.3048
0.118
0.031
0.042
0.0494
0.037
0.023
0.022
0.025
0.099
0.076
0.031
0.020
0.023
0.03
0.019
±
±
±
±
+
±
±
±
±
±
±
±
+
±
±
±
0.2247
0.026
0.6671
0.077
0.041
0.026
0.0591
0.013
0.006
0.002
0.166
0.068
0.030
0.003
0.005
0.006
Reference
Singh et al. ,
Singh et al. ,
Singh et al. ,
Ibid
IbTd
TFTd
Singh et. al.
Singh et. al.
Ibid
Ibid
Singh et. al.
Ibid
TFTd
Ibid
TbTd
Lillian et al
Singh et al. ,
Lillian et al
Singh et al. ,
1981a
1979
1981
, 1981
, 1979
, 1981b
. , 1975
1979
. , 1975
1979
-------
TABLE 3-2. (continued)
CO
1
UD
Location
New Jersey
Bayonne
Sandy Hook
Seagirt
New York
New York City
White Face Mtns.
Ohio
Wilmington
Japan
9 rural sites
Date of
measurement
3/73
7/2/74
6/18/74
6/27/74
9/16/74
7/16/74
8/78
- 12/73
- 7/5/74
- 6/19/74
- 6/28/74
- 9/19/74
- 7/26/74
- 9/78
Concentration (ppb)
max
38
0.56
<0.01
0.025
<0.01
0.075
0.027
mm
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
0.021
average
4.12
<0.08
<0.01
0.025
0.016
0.023 ± 0.016
Reference
Lillian et al. ,
1975
Ibid
TbTd
Ibid
Ibid
Ibid
Makide et al., 1980
-------
3.4.1 Persistence and Stratospheric 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. Concern that FC-113 is destroying stratospheric 0., and thus may
contribute to an increase in the incidence of skin cancer has intensified
recently.
Chi orof 1 uorocarbons are remarkably stable in the troposphere. However,
they do undergo photodissociation in the stratosphere (NRC 1979a, b; NRC
1982; WMO, 1982). In a recent report prepared for the U. S. Environmental
Protection Agency by the Rand Corporation (USEPA, 1980a), FC-113 was described
as highly unreactive and may not decompose prior to entering the stratosphere.
There are no known tropospheric sinks for FC-113. Japar et al. (unpub-
Ifshed) and Hester et al. (1974) reported that no detectable loss of FC-113
occurs when it is irradiated, under simulated atmospheric conditions, in the
presence of olefins and nitrogen oxides. The possibility that some decomposi-
tion of chl orof 1 uorocarbons may occur upon contact with hot desert sands was
examined by the National Research Council (1979a) and a small allowance in
their estimate of 0- depletion was made.
As shown in the following reaction sequence, release of atomic chlorine
(Cl) leads to the photocatalytic destruction of 0,:
hv
- > CC1F - CC1F + Cl
Cl- + 03 - » CIO + 02
CIO + 0 - > Cl- + 02
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, resulting in a continual depletion of 0.,.
3-10
-------
As noted by the World Meteorological Organization (WMO, 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 (World Meteorological Organization, 1982; National Research
Council, 1982).
Wuebbles and Chang (1981) recently have evaluated the impact of FC-113
and other chlorofluorocarbons on stratospheric 0.,. through use of the 1-0
Lawrence Livermore National Laboratory Model. This model uses chemistry
recommended by the NASA Panel on Laboratory Measurements (Hudson and Reed,
1979). If FC-113 were to be released at the same rate as FC-11 and FC-12
Wuebbles and Chang (1981) calculated an 0- loss, at steady-state, of 8.5
percent, due to FC-113.
There are two processes for FC-113 destruction: direct photolysis and
reaction with 0('D), excited atomic oxygen, the latter being produced upon
photodissociation of 0,. Calculations made by Chou et al. (1978) indicate
that photodissociation accounts for 84 to 89 percent of FC-113 removal. An
atmospheric lifetime, based upon measured absorption coefficients, in the
range of 63 to 122 years was estimated. An atmospheric lifetime of 86 years
was recently estimated by Wuebbles (1981) using the one-dimensional (1-0)
transport-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 03- 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
3-11
-------
the predominant mode of decomposition in the critical region (30 kilometers)
of the stratosphere.
The absorption cross section for FC-113 over the 185 to 227 nm wavelength
range indicates that FC-113 has approximately the same potential for photo-
dissociation as dichlorodifluoromethane (FC-12), but less than that for tri-
chlorofluoromethane (FC-11) (Chou et al., 1978). Upon complete photodis-
sociation, each molecule of FC-113 and F-ll yield an equal number of Cl atoms.
The absorption maxima of FC-113 and FC-12 in the near ultraviolet are 160 nm
and 177 nm, respectively (Sandorfy, 1976); the absorption maximum of FC-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 (consequently,
destruction) by chlorofluorocarbons.
Preliminary data in a modelling study using the Lawrence Livermore 1-0
model suggest that FC-113 has a calculated efficiency in reducing strato-
spheric 03 comparable to that of FC-11 and FC-12 (Table 3-3) (Wuebbles, 1981).
The World Meteorological Organization (WMO, 1982), assuming continued
release at the 1979 estimated emissions rate for FC-113 and using the model of
Wuebbles (1981) and revised reaction rate kinetics, calculated an estimated
steady-state depletion of the total 0., column of 0.8 percent. The overall 03
depletion estimate for steady-state release of FC-11 and FC-12 (principal
stratospheric contaminants) is in the range of 5 to 9 percent (World Meteoro-
logical Organization, 1982; National Research Council, 1982). If other stra-
tospherically - important halocarbons are considered (particularly FC-113,
carbon tetrachloride, and methyl chloroform) at the current release rates, WMO
estimates that the predicted column 0- depletion would be increased about
4
one-third. In scenarios more representative of real-time conditions, for
example, considering the variations in carbon dioxide, and nitrogen oxides,
the WMO derived other estimates of steady-state 0~ depletion. In each scenario,
3-12
-------
TABLE 3-3. EFFICIENCY OF VARIOUS HALOCARBONS IN DESTROYING STRATOSPHERIC OZONE
RELATIVE TO THE OZONE DESTRUCTION EFFICIENCY OF CFC1, (FC-11) (Adapted
from Wuebbles, 1981) J
Compound
FC-11
FC-12
FC-113
FC-114
FC-115
CH3CC13
FC-22
FC-21
FC-13
FC-112
FC-142b
Relative Efficiency
per Pound Emitted
1.00
0.85
0.80
0.60
0.32
0.14
0.05
0.04
0.45
0.96
0.05
Relative Efficiency
per Molecule Emitted
1.00
0.75
1.09
0.75
0.36
0.13
0.03
0.03
0.34
1.42
0.04
Relative Efficiency
per Chlorine
Atom Emitted
1.00
1.12
1.09
1.13
1.08
0.13
0.10
0.05
1.02
1.07
0.12
a continued increase in upper stratosphere 0, depletion is predicted. As
noted by the WMO (1982). the 5 to 9 percent depletion
estimate due to FC-11 and FC-12, if correct, suggests that less than a 1
percent decrease in global average stratospheric 0- should have occurred to
date. 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.
3-13
-------
In addition to the uncertainties and limitations of the models used to
estimate the impact of FC-113 upon CL, the complexity and rapidly changing
knowledge of the atmospheric chemistry make it difficult to assess such impact
in quantitative terms. Among the atmospheric reactions that can act to en-
hance or restrict 0- depletion due to FC-113, the NRC (1979b) cited those
described in Table 3-4 as important determinants.
An evaluation of the impact of FC-113 upon stratospheric 0- must take
into account these and other atmospheric processes if realistic estimates of
0, depletion are to be made.
TABLE 3-4. IMPORTANT ATMOSPHERIC REACTIONS THAT
AFFECT STRATOSPHERIC OZONE (NRC, 1979b)
Cl -i
CIO
CIO
Cl H
HC1
CIO
CIO
CIO
°3 -
+ 0 -
+ NO
KCH4
+ OH
+ N02
N02 +
+ H02
- CIO + 02
» Cl + 0-
. Cl * N02
. MPT + PH
. pi + U n
+ M C10N02 + M
hv > Cl + N03
» HOC! * 02
HOC! * hv > Cl + OH, CIO + H
3-14
-------
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. J. Geophy. 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. Milstein, W. S. Smith, H. Vera Ruiz, M. J. Molina, and F.
S. Rowland. Stratospheric photodissociation of several saturated perhalo
chlorofluorocarbon compounds in current technological use (Fluoro
carbons-IB, -113, -114, and -115). J. Phys. Chem. 82(1):1-7, 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. Measure ment
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. J. Geophys. Res. 82:5935-5944, 1977b.
Downing, R. C. Aliphatic Chlorofluorohydrocarbons. In: Kirk-Othmer1s Ency-
clopedia of Chemical Technology, Volume 9, 2nd Edition, 1966.
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.
3-15
-------
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.
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. Chromat. 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.
Japar, S. , J. N. Pitts, Jr., and A. H. Winer. The photostability of fluoro-
carbons, unpublished.
Lillian, D. , H. B. Singh, A. Appleby, L. Lobban, R. Arnts, R. Gumpert, R.
Hague, J. Toomey, J. Kazan's, M. Antell, D. Hansen, and B. Scott.
Atmospheric 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.
McCarthy, 1963. Cited in: U.S. Environmental Protection Agency Environmental
Hazard Assessment Report: Major one- and two-carbon saturated fluoro-
carbons, review of data. EPA-560/8-76-003, August 1976.
National Research Council. National Academy of Sciences. Protection Against
Depletion of Stratospheric Ozone by Chloroflurocarbons, 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.
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. Chromat.
134:375-384, 1977.
Sandorfy, C. Review Paper. UV absorption of fluorocarbons. Atmos. Environ.
10:343-351, 1976.
Singh, H. B. , L. J. Salas, H. Shigeishi, and E. Scribner. Atmospheric halo-
carbons, hydrocarbons, and sulfur herafloride. Global distributions,
sources, and sinks. Science 203:899-903, 1979b.
3-16
-------
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, SFfi and
N20. EPA-600/3-79-107, November 1979. b
Singh, H. B. , L. J. Salas, and R. Stiles. Trace chemicals in the "clean"
trosphere. 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, 1977.
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.
SRI International. Directory of Chemical Producers, Menlo Park, California,
1979.
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. Environmental Hazard Assessment Report.
Major one- and two-carbon saturated fluorocarbons, review of data.
EPA-560/8-76-003, August 1976.
U. S. Environmental Protection Agency. Regulating Chlorofluorocarbon Emissions:
Effects on Chemical Production. EPA-560/12-80-001b. Report prepared by
RAND Corp., October 1980b.
U.S. Environmental Protection Agency. Proceedings of the Conference on Methyl
Chloroform and Other Halocarbon Pollutants. EPA-600/9-80-003. January
1980c.
U.S. Environmental Protection Agency. Unpublished data from modelling studies
being conducted by the Lawrence Livermore Laboratory, 1980d.
Ward, Richard B. E. I. duPont de Nemours and Company to Jean Parker, U. S.
Environmental Protection Agency, 29 September 1980, and to Mark Green-
berg, personal communication U.S. Environmental Protection Agency, March 6,
1981.
Wuebbles, D. J. The relative efficiency of a number of halocarbons for des-
troying stratospheric ozone. Lawrence Livermore National Laboratory.
UCID 18924, 1981.
Wuebbles, D. J. , and J. S. Chang. A study of the effectiveness of the C1X
catalytic ozone loss mechanisms. J. Geophy. Res. 86(10):9869-9872, 1981.
3-17
-------
-------
4. MAMMALIAN FATE AND DISPOSITION
4.1 ABSORPTION AND ELIMINATION
Use of FC-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.
Little information has been published concerning the fate and disposition
of FC-113 and related compounds. Most of the data was obtained through ex-
perimentation on rodent species and at inhalation exposure levels well above
ambient tropospheric levels.
Chlorof1uorocarbons were judged to be absorbed by dogs through inhalation
in the following descending order: FC-11 > FC-113 > FC-12 > FC-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-e1ectron
capture detection. Peak arterial levels accounted for only a small percentage
of total administered dose.
In general, fluorocarbons and chlorof1uorocarbons exhibit biphasic ab-
sorption patterns (Azar et al., 1973; Letkiewicz, 1976). A rapid initial
increase in blood levels is followed by a slower increase to maximum concen-
trations. Equilibrium is reached when arterial and venous blood concentra-
tions are equal. During elimination, there is a rapid initial fall in blood
levels followed by a slower decline to undetectable levels. During elimin-
ation, venous concentrations exceed arterial concentrations, indicating that
fluorocarbons are being released from tissues.
4-1
-------
Unpublished data from E. I. duPont de Nemours and Company (1979) indicate
that FC-113 is absorbed upon skin exposure (hands, arms, and scalp). The
scalp was particularly absorbent: after one individual's scalp was exposed
for 15 minutes, the maximum FC-113 concentration in expired breath was 12.7
ppm (98 mg/m ) in 20 minutes; with another individual similarly treated, a
maximum concentration of 7.4 ppm (57 mg/m ) was reached in 18.5 minutes.
Ninety minutes after exposure, FC-113 concentrations were below 0.5 ppm (3.8
mg/m ) in all subjects.
Administration of FC-12 and FC-114 to dogs by various routes of exposure
indicate that chlorof1uorocarbons are eliminated solely via the respiratory
tract (Matsumato et al., 1968).
4.2 DISTRIBUTION AND METABOLISM
Chlorofluorocarbon 113 can be expected to be stored in lipid-rich tissues
during continuous exposure. During the slow rise to maximal blood concentra-
tion, arterial concentrations have been observed to be greater than venous
concentrations (Azar et al., 1973). Blood levels of FC-113 and other fluoro-
carbons were measured in beagle dogs during experiments reported by Trochi-
mowicz et al. (1974). Animals were exposed for 10 minutes to 0.1 percent
(1,000 ppm; 7,700 mg/m3), 0.5 percent (5,000 ppm; 38,500 mg/m3), and 1.0 per-
cent (10,000 ppm; 77,000 mg/m ) FC-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
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 pg/ml
and venous blood levels of 4.9 ug/ml were observed (at 5 minutes of exposure).
Carter et al. (1970) detected FC-113 in brain, liver, heart, and fat of
rats exposed, via inhalation, for 7 to 14 days. Levels are shown in Table
4-1. Similar findings have recently been reported by Savolainen and Pfaffli
4-2
-------
TABLE 4-1. MEAN TISSUE CONCENTRATIONS OF FC-113 FROM
RATS EXPOSED TO 2,000 PPM (Carter et al.t 1970)
Exposure
Tissue
Brain
Liver
Heart
(ug/gm)
(ug/gm)
(ug/gm)
22.
15.
16.
7 days
73 ±
77 ±
59 ±
1.
0.
2.
00
87
56
14 days
22.
16.
15.
65 ±
40 ±
03 ±
1.
1.
2.
33
72
51
Postexposure
24 hours 48 hours
none none
none none
none none
Fat (ug/gm) 722.48 ± 71.29 659.24 ± 21.17 108.45 ± 33.62 5.60 ± 2.94
Adrenal (ug) 8.39 ± 2.61 3.47 ± 0.34 none none
Thyroid (ug) 1.09 ± 0.46 0.94 ± 2.00 none none
(1980). Male Wistar rats exposed to 200, 1,000, and 2,000 ppm (1,540, 7,700,
15,400 mg/m ) FC-113 vapor for 2 weeks, 5 days per week, 6 hours daily
exhibited a dose-dependent accumulation of the compound in peri renal fat and
brain suggesting a long half-time of diminution from adipose tissue or organs
with high lipid concentrations. The neurochemical effects of FC-113 exposure
were examined by measuring levels of RNA, glutathione, and oxidative enzymes
in brain tissue. After the 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 oxidative damage, was decreased (p < 0.01) compared to controls
following the 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,
4-3
-------
cerebral RNA 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
peroxidase during this period were no longer observed.
Vainio et al (1980) observed j_n vivo effects of FC-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) FC-113, 5 days per week, 6
hours daily for 1 or 2 weeks. 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. Microsomal cytochrome P-450 showed a statistic-
ally significant decline after 1 week of exposure to 1,000 ppm (7,700 mg/m )
(p<0.01) and 2,000 ppm (15,400 mg/m ) (p<0.01). UDP glucuronosyl-transferase
showed a dose-related increase in activity after 2 weeks of exposure of rats
to 1,000 ppm (7,700 mg/m ) (p<0.01) and after 1 and 2 weeks of exposure to
2,000 ppm (15,400 mg/m ) (p<0.01 and <0.05, respectively). Glutathione content
showed a statistically significant (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 FC-113 was bound to cytochrome
P-450 in the hepatic microsomes from uninduced and phenobarbital-induced rats.
Phenobarbital treatment increased the affinity of FC-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 FC-113 may be a substrate for the
mixed function oxidases. The authors suggested that FC-113 may have the
potential to perturb microsomal membrane integrity. UOP glucuronosyltrans-
ferase is a detoxification enzyme dependent on membrane integrity.
IH vitro experiments with FC-11 (trichlorofluoromethane) suggest that
some irreverible binding to phospholipids and protein occurs (Uehlehe and
4-4
-------
Werner, 1975). Minor amounts of urinary non-volatile metabolites have been
demonstrated in man after exposure to FC-11 (Mergner et al., 1975).
4-5
-------
4.3 REFERENCES
Azar, A., H. J. Trochinowicz, J. B. Terrell, and L. S. Mull in. Blood levels
of fluorocarbon related to cardiac sensitization. Amer. Ind. Hyg. Assoc.
J. 34(3):102-109, 1973.
E. I. duPont de Nemours and Company. Data submitted to the U.S. Environmental
Protection Agency, Environmental Criteria and Assessment Office, August
20, 1979.
letkiewicz, F. J. Environment Hazard Assessment Report: Major One- and
Two-Carbon Saturated Flourocarbons, 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. 97:727-735, 1968.
Mergner, G. W. , D. A. Blake, and M. Helrich. Biotransformation and elimina-
tion of 14C-trichlorofluoromethane (FC-11) and 14C-dichlorodifluoro-
methane (FC-12) in man. Anesthes. 42:345-351, 1975.
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.
Uehleke, J. , and Th. Werner. A comparative study of the irreversible binding
of labelled halothane, trichlorof1uoromethane, chloroform, and carbon
tetrachloride to hepatic protein and lipids in vitro and in vivo. Arch.
Toxicol. 34:289:308, 1975.
Vainio, H. , J. Nickels, and T. Heinonen. Dose-related hepatotoxicity of
l,l,2-trichloro-l,2,2,-tr.fluoroethane in short-term intermittent inhala-
tion exposure in rats. Toxicol. 18:17-25, 1980.
4-6
-------
5. HEALTH EFFECTS
The impact of FC-113 upon human health must be viewed from two separate
perspectives: (1) potential effects resulting from direct exposure and (2)
possible indirect adverse effects resulting from pertubations of stratospheric
°3'
INDIRECT EFFECTS
As discussed in earlier chapters, FC-113 is transported to the strato-
sphere where it is predicted to photocatalytically destroy 03 (Panofsky, 1978;
Molina and Rowland, 1974). Depletion of stratospheric 03, in turn, allows
more damaging ultraviolet (UV-B) radiation to reach the earth's surface. Such
projected depletion of stratospheric 0, resulting in increased UV-B radiation
has the potential to result in an increase in the incidence of certain types
skin cancers as well in mortality (National Research Council, 1979a,b; 1982).
Skin cancer is of two general types. It is the most common neoplasm in
man and is increasing rapidly (Beaubier, 1980). One type of skin cancer, mel-
anoma, arises in the pigment-producing melanocytes and/or in nevocytes (cells
comprising moles). Unlike nonmelanomas (which arise in skin cells), melanomas
metastasize readily to brain, heart, liver, and kidneys (Beaubier, 1980).
Thus, melanoma is highly fatal. Whereas nonmelanoma occurs about 50 times
more frequently than melanoma, melanoma is responsible for more lethality
(Beaubier, 1980). Experimentally, UV-B radiation (wavelength range 290-320
nm) has been shown to cause mutations and cellular death (Smith, 1976,; Setlow,
1974), and produce nonmelanoma cancers in mice (Forbes and Urbach, 1975). In
contrast, there are no reliable models for light - induced melanoma. Further-
more, exposure to sunlight is only one of several factors associated with the
occurrence of melanomas, making it difficult to estimate the relative contri-
bution of UV-B radiation.
5-1
-------
The National Research Council (1979a) reported that recent epidemiologic
studies of the National Cancer Institute have concluded that the biological
amplification factor (fractional change in skin cancer incidence rates per
fractional change in UV-8 radiation) is two, rather than one as previously
presented. Also, when the fractional change in UV-8 radiation per fractional
change in Og concentration is considered, the overall amplification factor
(fractional change in skin cancer incidence rate per fractional change in 0,
concentration) is four, rather than two as previously presented. Taking this
and other information into account, the NRC (1982) estimated that there will
be a 2 to 5 percent increase in basal cell skin cancer incidence per 1 percent
decrease in stratospheric 0-; the increase in squamous cell skin cancer in-
cidence will be about double that. Because of data limitations implicating
UV-B as the only responsible wavelength region, the NRC (1982) did not make a
prediction about the increase in incidence of malignant melanoma associated
with a decrease in 0,.
DIRECT EFFECTS
5.1 ANIMAL STUDIES
5.1.1 Acute Toxicity
Acute inhalation exposures of various animal species to fluorocarbons at
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
and 1.925 x 10 mg/m ) have been fatal. A characteristic feature of FC-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.
5.1.2 Cardiovascular and Respiratory Effects
5.1.2.1 MouseAviado and Belej (1974) evaluated the ability of FC-113 to
induce cardiac arrhythmias and to sensitize the heart to epinephrine. In this
5-2
-------
study male Swiss mice (25 to 35 grams) were anesthetized with sodium pentobar-
bital (i.v., 0.7 mg/10 g). This dosage is equivalent to 70 mg/kg. 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 ) FC-113; group (2) inhaled 5 percent (50,000 ppm;
385,000 mg/m ) FC-113 plus a challenging dose of epinephrine 2 minutes prior
to the initiation of inhalation; group (3) inhaled 10 percent (100,000 ppm;
770,000 mg/m ) FC-113; group (4) inhaled 10 percent (100,000 ppm; 770,000
mg/m ) FC-113 and a similar challenge schedule as described for (2). This
dose of epinephrine (i.v., 60 ug/kg) was previously found to produce a tran-
sient and moderate cardiac acceleration.
The results of this study are presented in Table 5-1. FC-113 at 5 per-
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
of 10 percent (100,000 ppm; 770,000 mg/m ) FC-113 resulted in cardiac abnorma-
lities both with and without epinephrine.
5.1.2.2 003
5.1.2.2.1 J.n vitro. Aviado and Belej (1975) tested the ability of FC-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 ) FC-113;
group 2 inhaled 5.0 percent (50,000 ppm; 385,000 mg/m ) FC-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) FC-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
5-3
-------
TABLE 5-1. EFFECTS OF FC-113 ON THE ELECTROCARDIOGRAM OF ANESTHETIZED MICE
Concentration
% V/V
5
10
Exposure to FC-113 alone
No. of Type of Arrhythmia
Exposures (incidence)
3 none
3 inverted T wave (1)
Exposure
No. of
Exposures
3
3
to FC-113 and Epinephrine
Type of Arrhythmia
(incidence)
ventricular ectopics (1)
ventricular bigeminy (3)
Data from Aviado et al. (1974).
en
-------
TABLE 5-2. EFFECT OF FC-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.)
Propellant
f luorocarbon
No.
Trichlorotri-
fluoroethane
FC-113
Inhaled
concen-
tration
2.5
5.0
Number
of
prepar-
ations
3
3
Heart rate
Myocardial force
(beats/min)
Con-
trol
147
± 12.5
148
± 13.1
Re-
sponse
148
± 10.6
150
± 12.5
% A
- 2
± 1
- 1
± 1
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 trol
3.0 + 2
± 0.2 ± 3
3.0 + 3
± 0.1 ± 3
(1/minl
Con-
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).
en
i
en
-------
16
14
12
e
I
5 10
&
O
a
ac
u
14
12
10
O CONTROL
O PC 113
I
25% v/v
O CONTROL
0 FC113
50%v/v
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% propellant in air. Each point
represents the mean and standard error of the
mean in groups of 3 preparations. From Aviado
and Belej. 1975.
5-6
-------
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/m ) and 5.0 percent (50,000 ppm; 385,000 mg/m ) FC-113 caused
myocardial depression in the canine heart-lung preparation. 5.1.2.2.2 Li
vivo. Reinhardt et al. (1973) tested the ability of FC-113 to sensitize the
heart to exogenous epinepnrine. Unanesthetized male beagle dogs were exposed
to FC-113 concentrations of 0.25 percent (2,500 ppm; 19,250 mg/m ), 0.50 per-
3 3
cent (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 follow-
ing the first (control) dose of epinephrine. Epinephrine was administered 5
minutes before and 5 minutes after the initiation of the 10 minute FC-113
inhalation period following a 7-minute period of inhalation of room air. It
was previously shown that doses of epinephrine (i.v., 8 ug/kg) administered 10
minutes apart did not produce additive effects. No marked responses were
observed in twelve exposures at 0.25 percent (2,500 ppm; 19,250 mg/m ) FC-113.
The results are presented in Table 5-3. FC-113 causes cardiac sensitiza-
tion to exogenous epinephrine at a concentration of 0.5 percent (5,000 ppm;
38,500 mg/m ). Autopsies performed on both dogs that developed fatal arrhyth-
mias revealed no gross or microscopic abnormalities indictive of a pathological
condition.
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 fluorocarbon exposure levels (Mullin et al., 1971).
It was noted that a much higher concentration of fluorocarbon is needed to
sensitize a dog's heart to the action of its own circulating level of epine-
phrine, even when it is elevated through exercise. It was suggested that
there is a considerable margin of safety between effect levels in dogs given
5-7
-------
TABLE 5-3. EFFECT OF FC-113 ON CARDIAC SENSITIZATION
TO EPINEPHRINE IN THE UNANESTHETIZED DOG
Concentration of FC-113
en
i
CO
Nominal
0.25
0.50
1.0
Data from
Numbers in
% (U/V)
Analytical (gas. chrom. )
0.25 - 0.27
0.40 - 0.57
0.90 - 0.95
Reinhardt et al. (1973).
parentheses indicate number of
No. of No.
Dog Exposures Marked
12
29
4
cases of ventricular fibri
of
Responses
0
10 (1)
3 (1)
llation and
%
Marked Responses
0.0
34.5
75.0
cardiac arrest
included in marked responses.
-------
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 experi-
ments, 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 EC5Q for the cardiac sensitizing
effects of FC-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
FC-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
caused an arrhythmia. At 1.0 percent (10,000 ppm; 77,000 mg/m ) FC-113, 50
percent of the animals can be sensitized to the effects of epinephrine 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 FC-113 and other fluorocarbons in beagle dogs that are
associated with the cardiac sensitizing effect of FC-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 FC-113 at
levels of 0.1 percent (1,000 ppm; 7,700 mg/m3), 0.5 percent (5,000 ppm; 38,500
3 3
mg/m ), and 1.0 percent (10,000 ppm; 77,000 mg/m ). The investigators recorded
5-9
-------
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 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 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 FC-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-
fl uoromethane. Test method involved exposure to test chemicals, followed by
an intravenous dose (8 .ug/kg) of epinephrine. This dose of epinephrine was
reported to cause only mild ECG alterations.
Unpublished data of Mull in and coworkers (1971) suggest that, in beagle
dogs trained to run on a treadmill while being exposed (up to 16 minutes) to
FC-113, (8 dogs to 10,000 ppm; 77,000 mg/m3 and 4 dogs to 20,000 ppm; 154,000
mg/m ), endogenous epinephrine is not high enough to cause cardiac arrhythmias
at FC-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 FC-113 is capable of sensitizing a dog's heart
to exogenous epinephrine following exposure to concentrations between 2,000 to
2,500 ppm (15,400 to 19,250 mg/m3) for periods of 0.5, 1, or 6 hours. One of
six dogs exposed to 2,500 ppm (19,250 mg/m3) for both 0.5 and 1 hour gave a
5-10
-------
marked response. However, it was reported that exposures (12) of dogs to
concentrations of 10,000 ppm (77,000 mg/m ) FC-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 MonkeyBelej et al. (1974) tested the effects of FC-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/m ) or 5.0 percent (50,000 ppm; 385,000
mg/m ) FC-113 for 5 minutes alternating with inhalation of room air for 10
t
minutes.
The results presented in Table 5-4 indicate that 2.5 percent (25,000 ppm;
192,500 mg/m ) FC-113 is capable of inducing both tachycardia and myocardial
depression. The authors report that both concentrations caused cardiac
arrhythmias.
Aviado and Smith (1975) tested the effects of FC-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 com-
pliance, 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/m ) FC-113 for 5 minutes, alternating with
room air for 15 minutes.
5-11
-------
TABLE 5-4. RESPIRATORY AND CIRCULATORY EFFECTS OF FC-113 UPON ANESTHETIZED RHESUS MONKEYS
en
l
FC-113
% Inhaled
Concentration
2.5
5.0
FC-113
% Inhaled
Concentration
2.5
5.0
FC-113
% Inhaled
Concentration
2.5
5.0
Heart rate (beats/min)
Monkey # Control
3 150.0
0.0
3 155.0
± 2.9
Response
163.0
± 8.8
185. Oa
±13.2
A %
+ 8.9
± 5.9
19.8
±10.8
Aortic blood pressure
Control
Monkey # mg/Hg
3 80.0
± 2.9
3 80.7
± 0.7
Pulmonary
Monkey # Control
3 9.0 ,
0.0
3 9.5
±0.3
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
Myocardial force (g)
Control
47.5
± 7.7
45.3
± 5.1
Left
Control
3.7
± 0.4
3.8
± 0.4
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
pressure (mm/Hg)
A %
+ 3.3
± 4.2
+ 1.1
± 1.1
Mean
S.E.M.
Mean
S.E.M.
p <0.05 compared with control
Data from Belej et al. (1974)
-------
TABLE 5-5. RESPIRATORY AND CIRCULATORY EFFECT OF FC-113 UPON ANESTHETIZED RHESUS MONKEYS
tn
l
%
Concentration
FC-113 Monkey #
2.5 3
5.0 3
%
Concentration
FC-113 Monkey ft
2.5 3
5.0 3
Pulmonary resistance
Control
cm H20/l/sec
21.78
± 3.49
21.58
± 3.00
Respiratory
Control
ml/min.
1230
47.3
1292
± 99
Response
19.69
± 2.71
18.84
± 2.47
minute
Response
1250
± 28.9
1302
± 72
% A
- 8.87
+ 4.75
-12.07
± 6.64
% A
+ 1.80
± 1.80
+ 1.10
± 3.20
Pulmonary
Control
ul/cm H20
6.87
± 0.43
6.67
± 0.58
Control
bpm
169
± 13.65
173.33
± 12.02
compliance
Response % A
7.27 + 5.97
±0.41 ± 2.30
7.50 ±13.95
±0.25 ± 8.80
Heart rate
Response % A
199 +18.07
± 19.09 ± 8.14
221.67 +27.85a
±21.67 + 8.58
% Aortic bloodj>ressure
Concentration
FC-113 Monkey #
2.5 3
5.0 3
Control
mm/Hg
101.67
± 1.67
110.67
± 5.78
Response
93.00
± 3.05
82.33
± 2.33
% A
- 8.54a
± 2.36
-25.153
± 4.75
p <0.05
Data from Aviado and Smith (1975).
-------
The results are presented in Table 5-5: 2.5 percent (25,000 ppm; 192,500
mg/m ) and 5.0 percent (50,000 ppm; 385,000 mg/m ) FC-113 caused a decrease in
pulmonary resistance, an increase in pulmonary compliance, no change in respira-
tory minute volume, a significant increase in heart rate for the group that
inhaled 5.0 percent (50,000 ppm; 385,000 mg/m3) FC-113, and a significant
decrease in aortic blood pressure for both groups.
5.1.3 Neurological Effects
5.1.3.1 FrogYoung and Parker (1975) studied the effect of FC-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 ED50 for an FC-113-induced increase in
-4
acetylcholinesterase activity was 1.6 x 10 gm/ml, a level close to its
saturation concentration in water.
5.1.3.2 DOCJ--Carter et al. (1970) studied the effects of FC-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 reponses
were determined prior to the administration of 2 percent (20,000 ppm; 154,000
mg/m ) FC-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 exposure.
The results are presented in Figures 5-2 and 5-3. Approximately two
percent (20,000 ppm; 154,000 mg/m3) FC-113 had no effect upon postganglionic
stimulation though it did reduce an increase in the heart rate response to
preganglionic stimulation and further decreased it when atropine was added.
5-14
-------
160
140
s
I 120
M
°. 100
K
! »
K
| 60
40
20
T
T
I I I I
-O CONTROL
100% OXYGEN
-O2% FC-113IN
OXYGEN
- 2% FC-113IN
OXYGEN PLUS
ATROP1NE
0.05 mg/kg
STANDARD
ERROR
-I
0.1 0.3 1 36 10 20 40
FREQUENCY OF STIMULATION, stim/iec
Figure 5-2. Effect of 2% FC-113 on preganglionic
stimulation of canine spinal preparations.
Source: Carter et al. (1970).
5-15
-------
140
J
IU
ec
UJ
I I
CONTROL
(100% OXYGEN)
O-2%FC-113IN
OXYGEN
40
20
0.1 0.3 136 10
FREQUENCY OF STIMULATION, itim/jec
Figure 5-3. Effect of 2% FC-113 on postganglionic
stimulation of canine spinal preparations.
Source: Carter et al. (1970).
5-16
-------
The authors believe that the further decrease in response in the presence of
atropine, a muscarinic blocking agent, could be indicative of FC-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 ) FC-113 are described on page 4-3 and 4-4.
5.1.4 Hepatoxicity
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) FC-113 for 1 and 2 weeks (Vainio et al.t 1980).
The rough endoplasmic reticulum showed no clear alteration. Hepatocyte
microvilli were normal while some mitochondria showed condensations. No
effects of exposure to 200 ppm (1,540 mg/m ) were noted. Effects of FC-113
exposure on hepatic enzymes are discussed in Chapter 4.
5.1.5 Teratogenic Effects
The following discussion subscribes to the basic viewpoints and defini-
tions of the terms "teratogenic" and "fetotoxic11 as summarized and stated by
Chernoff (1980):
Generally, the term "teratogenic" is defined as the tendency to produce
physical and/or functional defects in offspring j_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 supernumary 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
5-17
-------
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 HI 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 reversiblity 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 after effects from developmental
deviations is true for all examples of fetotoxicity. The second problem is
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.
Two unpublished studies in rabbits are available from E.I. duPont deNemours
and Company, Inc. (Hazelton Laboratories, 1967). In both studies, the number
of pregnant animals and fetuses evaluated were inadequate for use in assess-
ing the teratogenic potential of FC-113. In both studies, the treatment
period was shorter than those suggested for current teratogenicity testing.
In both the inhalation and feeding studies, dosages administered produced
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
FC-113 for 2 hours daily on days 8 through 16 of presumed gestation (equivalent
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. Signs of
maternal toxicity in rabbits exposed to 20,000 ppm (154,000 mg/m ) of FC-113
consisted of lowered body weight gain during the first week of exposure and
eye irritation. One doe in the 20,000 ppm (154,000 mg/m ) dosage group died;
another delivered prematurely on day 29.
A total of 19/4 pups/litter, 8/4 pups/litter, and 24/5 pups/litter were
evaluated in the control, low and high dosage groups, respectively. One pup
5-18
-------
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 examina-
tions of the fetuses.
The second study, performed in 1967, evaluated 8 rabbits per dosage
group, and 0, 1 and 5 gm/kg/day FC-113 was administered on days 8 through 11
of gestation (days 6 through 9 of gestation when day 0 = day of insemination).
It is assumed that the agent was given orally, via stomach tube, since refer-
ence was made to the possible toxic effect of the "dosing technique"; however,
the method of agent administration was not cited in the report.
One, 3 and 4 rabbits died in the groups administered 0, 1 and 5 gm/kg/day
FC-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 were 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 jjn 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 in utero, 7 of which were dead.
5-19
-------
As a result of non-pregnancy, maternal death or i_n utero embryo/fetal
death, only 21/3 pups/litter, 32/5 pups/litter, and 3/1 pups/litter delivered
naturally or Caesarean delivered were evaluated for malformations. Eleven dead
fetuses in two litters, either aborted or dead rn utero, were also evaluated
for malformations. No remarkable anatomical changes were reported in the few
fetuses which were examined.
5.1.6 Mutagenic Effects
5.1.6.1 MouseUsing a dominant lethal assay, Epstein et al. (1972) tested
the mutagenic effects of FC-113. Swiss mice (8-10 week old males and virgins)
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
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
FC-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 FC-113 was not mutagenic under the concentrations tested, route of admin-
istration, strain and test system employed.
Unpublished data of E. I. duPont de Nemours and Company indicate FC-113
was nonmutagenic in four strains (TA 1535, 1537, 98 and 100) of S. typhimurium
(Haskell Laboratory, 1977). FC-113 was classified as non-mutagenic since the
reversion frequency was less than two times the spontaneous frequency and
since less than 0.02 revertants/ nmole were observed. FC-113 was nonmutagenic
in the presence and absence of a rat-liver homogenate activation system. The
5-20
-------
experiment was carried out in 9-liter glass chambers with four concentrations
of FC-113, 2 percent, 6 percent, 10 percent, and 19 percent. 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 S-9 assay are not considered to provide sufficient evidence to
classify FC-113 as non-mutagenic. The dominant lethal test is not considered
to be a sensitive test because of the high background of spontaneously-occur-
ring dominant lethals (Russell and Matler, 1980). The Ames test may not
necessarily be effective in assessing the mutagenicity of certain halogenated
hydrocarbons (Ames, 1979). Additional tests are needed to determine the
mutagenic potential of FC-113.
5.1.7 Carcinogenic Effects
5.1.7.1 MouseThe use of sprays containing a pesticide, a piperonyl syner-
gist and a propel 1 ant prompted Epstein and coworkers (1967a) to evaluate the
Id vivo interactions between FC-113 and piperonyl butoxide, a pesticide syner-
gist. Incidence of hepatomas and lymphomas were used to indicate carcino-
genicity. 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 re-
ceived 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 differ-
entiated according to the solution injected: (each group was injected
subcutaneously with test material) (1) solvent controls (redistilled
5 3
tricaprylin); (2) 10 percent (100,000 ppm; 7.7 x 10 mg/m ) FC-113 in
tricaprylin; (3) 5 percent piperonyl butoxide (PB) in tricaprylin; (4) FC-113
and PB as indicated in (2) and (3).
5-21
-------
TABLE 5-6. CARCINOGENIC EFFECTS OF FC-113 + PB IN MICE, ALONE AND IN COMBINATION
Ul
ro
Hepatomas
Treatment group
Solvent controls
FC-113
PB
FC-113 and PB
Sex
M
F
M
F
M
F
M
F
# of mice autopsied,
alive at week 51
(# at risk)
48
68
21
20
20
36
18
24
# of tumors
as % of it 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
Malignant
ft 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 FC-113 alone group.
Data from Epstein et al. (1967a).
-------
TABLE 5-7. COMBINED TOXICITY OF FC-113 + PB UPON NEONATAL MICE
Treatment group
Solvent controls
10% FC-113
5% PB
10% FC-113 + 5% PB
# of mice Weaning Average wt. (g)
(# of litters) mortality at 51 weeks
170 (16)
52 (4)
91 (8)
94 (8)
14 M
F
2 M
F
15 M
F
46 M
F
50,5
45.3
53.6
48.2
52.0
47.0
59.0
57.0
% Increase
in weight
over controls
6.1
6.4
3.0
3.8
16.8
25.8
Data from Epstein (1967b).
The data are presented in Table 5-6. They indicate that 10 percent
(100,000 ppm; 7.7 x 10 mg/m ) FC-113 did not alter the incidence of hepatomas
beyond the control values though it did increase the incidence of malignant
lymphomas. 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
5.1.8.1 MouseEpstein et al. (1967a, 1967b) tested the synergistic toxicity
and hepatotoxicity of FC-113 and piperonyl butoxide (PB). Neonatal Swiss mice
were used in the study. Percent mortality prior to weaning was used to indi-
cate the effects of FC-113 and PB alone or in combination. This study was
part of the study discussed previously.
5-23
-------
Table 5-7 illustrates the synergistic toxicity of FC-113 and PB. The
mortality rate of FC-113 + PB (46 percent) was greater than either compound
alone (2 percent and 15 percent). Table 5-6 shows that the combined presence
of FC-113 and PB did not produce a synergistic lymphotoxicity while it did
produce a synergistic hepatotoxicity. There was also an anomalous weight gain
in all but the control mice. The gain was greatest in the FC-113 + PB treat-
ment group, indicating that the effects were synergistic. The authors did not
ascertain the nature of this weight gain.
5.1.9 Dermal Effects
Table 5-8 summarizes the data found on the dermal effects of FC-113 in
mammals. Few effects have been observed, other than a drying of the skin due
to lipid removal.
TABLE 5-8. DERMAL EFFECTS OF FC-113 IN MAMMALS
Concentration Duration
Effects
Reference
40% in sesame
seed oil
100%
100%
5 g/kg
g/kg
daily, No effect on shaved skin
12 days of rabbits
5 x/w, No visible effect on
20 w shaved back of rabbits
Practically non-
irritating to eye
and paw of rabbit
1 x/d, Weight fluctuations,
5 d skin damage, liver
changes (microscopic),
no other systemic
effects in rabbits
Approximate Lethal Dose
(rats). Dermal and tissue
damage at site of appli-
cation; no other systemic
effects
EPA, 1976
Desoille
et al., 1968
DuPrat et al.
1976
Oesoille
et al., 1968
Clayton, 1966
5-24
-------
5.1.10 Inhalation and Ingestion
Due to the amount and diversity of data on FC-113, this information is
presented in tabular form (Tables 5-9 and
5-10).
TABLE 5-9. INHALATION AND INGESTION TOXICITIES OF FC-113 IN
MAMMALS
Animal
(Number) % ppm A/S* Duration
Mice 5.7 57,000 A 30'
5-12 50,000- A 15'
120,000
9.5 95,000 A 2 h
>10 >100,000 A 30'
15 150,000 A 15'
(4Qrf) 0.2 2,000 S 2 w
Guinea
(12) 1.0 10,000 A 5'
to to
(9) 1.2 12,000 A h h
(6) (512 A 1 h
humidity,
(3) 58°F) A 2 h
1.1 11,000 A 2 h
Effects
Anesthetic; delayed death
with >6%
Initial excitement and
convulsions during
anesthesia
LC50
LC50
Anesthetic
Hema to logical values;
clinical chemistries;
EEC; body weight; organ-
to-body weight ratios;
no change
No adverse effects;
recovered quickly
Same
Same
Same
Slight narcotic effect
Reference
Raventos and
Lemon, 1965
Burn, 1959
Oesoille
et al . , 1968
Raventos and
Lemon, 1965
EPA, 1966
Carter et al . ,
1970
Underwriters
Laboratories,
1941
AIHAC, 1968
5-25
-------
TABLE 5-9. (continued)
Animal
(Number) %
Guinea
Pigs
TTfy 2.5
to
2.9
(9)
(6)
(3)
(12) 4.8
to
5.2
(9)
ppm A/S*
25,000 A
to
29,000
A
(41*
humidity;
67-68°F)
A
A
48,000 A
to
52,000
A
(67%
humi di ty ;
58-70°F)
Duration Effects Reference
5' No adverse effects; Underwriters
recovered quickly Laboratories
1941
h h Slight tremors within 10';
rapid breathing;
eyes partially closed;
slight lachrymation;
recovered quickly
1 h Same
2 h Same; recovered within
2 days
5' No adverse effects; Underwriters
recovered quickly Laboratories
1941
h h Coordination loss;
tremors; unable to stand
within 10'; irregular
breathing; eyes partially
closed; lachrymation;
recovered within one day
(5)
1 h Semi-conscious; convulsive
tremors; irregular breath-
ing; deaths of 2 animals
4 and 5 days post-exposure;
recovery within 8 days
(3)
(12)
(9)
9.5 95,000
to to
11.3 113,000
(51%
humidity;
70-72°F)
A
A
A
A
A
2 h Same; deaths 2 and 3 days
post-exposure
5' Coordination loss;
tremors; unable to stand;
recovery within 1 day
h h Unconscious; convulsive
tremors; lachrymation and
nasal discharge; breathing
fast and irregular; death
of 2 animals 3 and 4 days
post-exposure
Underwriters
Laboratories
1941
5-26
-------
TABLE 5-9. (continued)
Animal
(Number) %
ppm
A/S* Duration
Effects
Reference
Guinea
Pigs
(6) A
(3) A
12 120,000 A
1 h Same; deaths 1
post-exposure
and 4 days
2 h Same; all animals dead
within 1 day
2 h LC50
JU
post-exposure
Desoille
et al . , 1968
(12)
(9)
(2)
16.4 164,000
to to
16.6 166,000
5'
(73°F)
1 h
Coordination loss within
I1 ; 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
Underwriters
Laboratories,
1941
(109)
0.51 5,100
6 h/d, No change in growth rate, Steinberg
5 d/w, organ-to-body weight . et al.,
4 w ratios, appearance upon 1969
necropsy
(3)
2.5 25,000 S
3.5 h/d, 0/3 deaths; no changes in
20 d weight gain, rbc, wbc,
differential white count,
hemoglobin, urinary pro-
tein and sediment, heart,
lungs, liver, kidney,
spleen; no signs of
toxicity
Clayton,
1966
5-27
-------
TABLE 5-9. (continued)
Animal
(Number) %
Rats
(5*) 1.14
(5*) 1.3
1.76
5.5
8.7
10.0
(5*) 10.0
11
15
20
22.2
(10* 0.21
and to
10?) 0.29
ppm
11,400
13,000
17,600
55,000
87,000
100,000
100,000
110,000
150,000
200,000
222,000
2,075
to
2,885
A/S*
A
A
A
A
A
A
A
A
A
A
A
S
Duration
6 h
6 h
2 h
4 h
6 h
3 h
6 h
2 h
15'
45'
7 n/d,
30 d
Effects
Rotobar performance: no
change
1 h: restlessness
2 h: quiet; rotobar test,
no change
Liver and kidney congestion
ALC
Convulsions; unresponsive-
ness; respiratory impair-
ment; microscopic exam:
pulmonary edema; ALC
Convulsions, rapid breath-
ing, unresponsiveness,
cyanosis, death in 2-3 hrs
ALC
LC50; some delayed
mortality
Anesthetic
ALC
3-15': convulsions, rapid
breathing, unresponsive-
ness, cyanosis, death
0/20 deaths; body weights,
gross and microscopic
pathology: normal ;
no signs of toxicity
Reference
Steinberg
et al . , 196!
AIHAC, 1968
EPA, 1966
Clayton, 1962
AIHAC, 1968
Clayton, 1966
Desoille
et al . , 196£
Kuebler, 1964
EPA, 1966
AIHAC, 1968
Clayton, 1966
5-28
-------
TABLE 5-9. (continued)
Animal
(Number) %
ppm
A/S'
Duration
Effects
Reference
Rats
0.2 2,000 S
2 w 0/5 deaths; hematological
values, clinical chemis-
tries, EEC, body weight,
organ-to-body weight
ratios: no changes except
in kidneys (wt >controls),
no adverse symptomology
Carter et al.,
1970
(20)
(12)
(50*)
(5*)
(109
and
10*)
0.2 2,000 S 2 w
0.5 5,000 S 7 h/d,
5 d/w,
30 d
0.5 5,000 S 7 h/d,
30 d
0.51 5,100 S 6 h/d,
5 d/w,
4 w
0.51 5,100 S 6 h/d,
5 d/w,
4 w
0.51 5,100 S 6 h/d,
5 d/w,
4 w
See Table 10
No deaths, no weight gain,
slight liver damage
0/12 deaths, abnormal
weight gain; 3 rats:
slightly pale livers,
others normal; kidneys
normal
Rotobar test: no change
Voluntary movement
(activity wheels) and
necropsy: no changes
Growth rate, organ-to-
body weights, necropsy:
no changes
Clayton, 1962
Clayton, 1966
Steinberg
et al . , 1969
Steinberg
et al., 1969
2.5 25,000
3.5 h/d, 0/5 deaths; weight gain,
20 d rbc, wbc, differential
white count, hemoglobin,
urinary protein and
sediment, heart, lungs,
liver, kidney, spleen:
no changes; no signs of
toxicity
Clayton, 1966
5-29
-------
TABLE 5-9. (continued)
Animal
(Number) % ppm A/S*
Rats
~75) 6 60,000 S
(4) 40 400,000 S
1.2 12,000 C
(5*) 30 g/kg I
Duration
1 h/d,
5 d
1 h/d,
5 d
2 h/d,
5 d/w,
365-
730 d
undi 1 uted
app 1 i ed
orally,
Ix
Effects
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
Reference
Burn et al. ,
1959
Desoille
et al., 196
Michael son a
Huntsman ,
1964
disappeared after 24 h;
ruffled coat; autopsies:
no gross pathological
changes; avg wt. change:
+46 g
(5*)
(5*)
(5*)
35 g/kg
50 g/kg
43 g/kg
I
I
I
Same
Same
Undiluted
Same; avg. wt change:
+41 g
Same; avg wt. change:
+19 g
43 ± 4.8 g/kg = LD,n
Michael son a
applied
orally,
Ix
Huntsman,
1964
5-30
-------
TABLE 5-9. (continued)
Animal
(Number) %
ppra
A/S>
Duration
Effects
Reference
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 h 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 FC-113;
livers: mottled surface,
normal color; stomach and
GI tract: abnormally
distended with gas and
fluid
Michael son and
Huntsman,
1964
(5*)
45 g/kg
50 g/kg
I
I
Undiluted
applied
orally,
Ix
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
Clayton, 1966
Michael son
and Huntsman,
1964
55 g/kg I
Same
Same; deaths: 5/5, days
3-9 post-exposure;
avg. wt. change: 0 g
Rabbits
1.1 11,000 S
17 g/kg I
Dogs
(29 1.14 11,400 A
and
2*)
2 h/d, Deaths: 0/6; no variation
5 d/w,
120 w
Approximate lethal dose
6 h 2 hr: vomiting, lethargy,
nervousness; 4 hr: stupor,
lethargy; 5-6 hr: tremors;
15 minutes post-exposure:
no signs
Desoille
et al., 1968
AIHAC, 1968
Steinberg
et al . , 1969
5-31
-------
TABLE 5-9. (continued)
Animal
(Number) % ppm A/S* Duration Effects Reference
Dogs
(1<* 1.3 13,000 A 6 h 5 min: depressed placing Steinberg
and reflex; 10 min: nervous- et al . , 19f
19) ness; 15': extreme pupil
dilation, trembling; 30min:
loss of muscle coordination;
1 hr: vomiting, trembling;
5 min. post-exposure: de-
pressed front and rear hopping
reflex; 15 min. post-exposure:
no signs
0.2 2,000 S 2 w Hematological values; Carter et al.
clinical chemistries; EEC; 1970
body weight; organ-to-body
weight ratios: no changes;
0/8 deaths
0.51 5,100 S 6 h/d, Plasma LDH, amylase activ- Steinberg
and 5 d/w, ity, BUN, hematocrit, et al., 1969
2<*) 4 w % neutrophils, % lympho-
cytes checked weekly: no
changes; organ-to-body
weight ratios, food con-
sumption, olfactory, hear-
ing, following with eyes;
blinking, facial skin sen-
sation, tone of face and jaw
muscles, gag reflex, tongue
control, light-pupillary
reflex, optic disc appear-
ance, flexor, extensor
postural thrust, placing,
righting, hopping, knee
jerk: no changes; no
pathological changes
^^.^^^^^^^^^^WMVWVHWVMBVlVMVMMVVMWVV
(2) 1.25 12,500 S 3.5 h/d, 0/2 deaths; weight gain, Clayton, 1966
20 d rbc, wbc, differential
white count, hemoglobin,
urinary protein and sedi-
ment, heart, lungs, liver,
kidney, spleen: all normal;
no signs of toxicity
5-32
-------
TABLE 5-9. (continued)
Animal
(Number) % ppm A/S* Duration Effects
Reference
Dogs
it?
and
)
200 ml.
into
exposed
stomach
2 h Stomach exposed, cardiac
and pyloric sphincters
11 gated, FC-113 added;
2 h: gastric juices
measured; volume = 200 ml
gross appearance gastric
mucosa: normal
Clayton,
1966
(2) 1.25 12,500 S
Monkeys
(49 ) 0.2 2,000 S
3.5 h/d, 0/2 deaths; weight gain, Ibid.
20 d rbc, wbc, differential
white count, hemoglobin,
urinary protein and sedi-
ment, heart, lungs, liver,
kidney, spleen: all normal;
no signs of toxicity
2 w 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
*I = Ingested; A = acute; S = Subchronic; C = Chronic
5-33
-------
TABLE 5-10. POST-INHALATION MEAN TISSUE CONCENTRATIONS
OF FC-113 IN RATS
Tissue
Brain ug/g
Liver ug/g
Heart |jg/g
Fat |jg/g
Adrenal ug
Thyroid ug
Exposure
7 day
22.73
(1.00)
15.77
(0.87)
16.59
(2.56)
722.48
(71. 29)
8.39
(2.61)
1.09
(0.46)
14 day
22.65
(1.33)
16.40
(1.72)
15.03
(2.51)
659.24
(21.17)
3.47
(0.34)
0.94
(2.00)
Postexposure
24 hours
None
None
None
108.45
(33.62)
None
None
48 hours
None
None
None
5.60
(2.94)
None
None
( ) Standard Deviation
Data from Carter et al. (1970), addendum.
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 FC-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
5-34
-------
exposure 6-21 years, average 11 years) were used in the study. Case histories,
clinical chemistry (blood Hb, Hbg, 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 FC-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/m )
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
FC-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. Breath analyses
indicated a range of 3.6 to 9.75 mg FC-113/liter (average 6.33 mg/1) in the
women and a range of 1.20 to 4.85 mg/1 (average 2.48 mg/1) in the men. Two of
the women experienced headaches, dizziness, and nausea at the end of the
exposure period. Another woman had similar complaints after only 3 hours of
exposure.
Imbus and Adkins (1972) also conducted studies of the effects of occupa-
tional exposures to FC-113. Only males were observed. Clinical examination
and blood chemistry (cholesterol, calcium, inorganic phosphorous, total bili-
rubin, albumin, total protein, uric acid, BUN, glucose, lactate dehydrogenase,
alkaline phosphatase, and SGOT) were used as an indication of adverse effects.
There were fifty males in each of the two groups: (1) those unexposed to
FC-113 (average age 37 years); (2) those exposed to FC-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/m ), mean 699 ppm
5-35
-------
(5,382 mg/m ), 50th percentile estimate 521 ppm (4,012 mg/m3), median 425 ppm
(3,272 mg/m3).
The results indicated no adverse effects other than one case of FC-113-
induced dermatitis.
5.2.2 Experimental Exposure Studies
5.2.2.1 Inhalati onRei nhardt et al. (1971) also conducted experiments on the
effects of exposures to FC-113 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 chemistries:
alkaline phosphatase, cholesterol, total bilirubin, total protein, albumin,
globulin, A/G ratio, total lipids, SGOT, LOH, creatinine, glucose, BUN, and
uric acid), psychomotor tests and subjective impressions. The subjects were
exposed to FC-113 for 3 hours in the morning and 3 hours in the afternoon, 5
days/week, for 2 weeks in an environmental chamber (61 x 6 1/2' x 10'). The
concentration of FC-113 in the environmental chamber was determined by gas
chromatography. During week 1, the concentration was 500 ppm (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 FC-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 5-11. As shown in Table 5-11, the morning samples
obtained during the week of exposure to 1,000 ppm (7,700 mg/m ) indicates that
not all of the FC-113 was eliminated overnight. Only one individual had a
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 suggest that exposure
5-36
-------
over longer periods would be needed to determine if FC-113 is retained by
tissues during repetitive exposures.
Stopps and Mclaughlin (1967) tested the psychomotor effects of FC-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 FC-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 5-4. The concentrations of FC-113 in the environmental chamber were
TABLE 5-11. POST-INHALATION BREATH CONCENTRATIONS OF FC-113 IN MAN
Summary of Breath Sampling Data
(Chiorof1uorocarbon 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-
expgsure
a.m.
< 1
< 1
-
-
-
1.5
< 1
-
-
-
< 1
< 1
-
-
-
< 1
< 1
-
-
Note: (-) Indicates not measured.
Reinhardt et al. (1971).
5-37
-------
on
OJ
CX>
SUBJECT SUBJECT
ENTERS LEAVES
CHAMBER CHAMBER
^
..,
PERIOD OF BUILDUP IN "F-113"
CONCENTRATION IN CHAMBER
^- 45 mint. -^
1 ^
' lim» 46 n
PERIOD OF EQUILIBRATION
BETWEEN SUBJECT'S TISSUES
AND ENVIRONMENT
-^- 30 mini. «^
\
i
FIRST
BATTERY
OF
TESTS
^ 17 mini. *»
1 \
' \
SECOND
BATTERY
OF
TESTS
r '
^- It mini>
r i
r
1 hour 1 hour 2 houri 2 hour* 2 hour*
lint. 16 mini. 32 mini. 10 mini. 27 mini. 45 mint.
Figure 5-4. Human exposures to FC-113; timetable of experiment.
and Mclaughlin, 1967.
From Stopps
-------
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
3
mg/m ).
The results are presented in Figure 5-5. 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. In general,
the results indicate no adverse effects were apparent at 1,500 ppm (11,550
mg/m3). At concentrations of 2,500 ppm (19,250 mg/m ), an adverse effect is
apparent. In addition to an impairment of psychomotor performance, 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 FC-113 were not performed.
5.2.2.2 DermalDermal absorption of FC-113 has been evaluated in man (Has-
kell Laboratory, 1968). Three subjects were tested. Concentrations of FC-113
in alveolar air was used as an indication of FC-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 FC-113 in their
breath was then measured at various times after termination of the exposure.
The data are presented in Table 5-12. At 90 minutes post-exposure, the
concentrations of FC-113 in exhaled air in two of the three subjects had
3 3
decreased from a high of 12 ppm (92 mg/m ) to less than 0.5 ppm (3.8 mg/m ).
In one of the subjects, a concentration of 0.1 ppm (0.7 mg/m ) remained 18
hours post-exposure. These data indicate that the human body absorbs FC-113
5-39
-------
MANUAL DEXTERITY A
MANUAL DEXTERITY B
1500 2500 3500
ppm
4500
+10% H-
CARD SORTING
+10%
0
10%
20%
30%
-40%
- CARD SORTING WITH AUXILIARY TASK
J_
1500
2500
3500
4500
ppm
Figure 5-5. Effect of FC-113 upon psychomotor performance in man. From
Stopps and Mclaughlin, 1967.
5-40
-------
as a result of dermal exposure, and that the amount of FC-113 absorbed does not
immediately disappear when the exposure ends.
TABLE 5-12. EFFECTS OF DERMAL EXPOSURE TO FC-113 IN MAN
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*
20.5 min.
18.5 min.
11.5 min.
23 min.
Value of peak
12.7 ppm
7.4 ppm
9.6 ppm
1.7 ppm
^Expressed in minutes after termination of exposure
Data from Haskell Laboratory, 1968
The results of unpublished dermatological experiments with FC-113 con-
ducted for E.I. duPont de Nemours and Company suggested that human scalp and
forehead were not adversely affected when FC-113 was applied over a 30-day
period (Betro Research Laboratory, 1967). Twenty volunteers received applica-
tions to entire scalp and most of forehead according to the following sche-
dule: (1) For first five days, FC-113 was applied three times daily for 30
seconds, (2) the 6th day exposure consisted of a single 30-second application;
(3) thereafter, FC-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.
5.2.2.3 Ingesti'onOnly one report on the effects of human ingestion of
FC-113 has been found. Approximately one liter of cold FC-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).
5.2.2.4 Synergistic, Carcinogenic, Mutagenic. and Teratogem'c--No information
pertaining to any of these categories of effects of direct exposure to FC-113
in man have been found.
5-41
-------
5.3 SUMMARY OF ADVERSE HEALTH EFFECTS AND ASSOCIATED LOWEST OBSERVABLE
EFFECTS LEVELS
Levels of FC-113 above 2,000 ppm (15,400 mg/m ) have been reported to
result in cardiac sensitization of dogs after the administration of exogenuos
epinephrine. No evidence of cardiac sensitization of animals in the absence
of exogenous epinephrine at FC-113 levels below 10,000 ppm (77,000 mg/m ) has
been reported.
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, tachycar-
dia, hypotension, and depression of myocardial contractility could be elicited.
Inhalation studies have shown the between 2,000 to 19,000 ppm (15,400 to
146,300 mg/m ) FC-113, 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 hematological
or clinical tests, indicating that these tests do not always show the full
extent of damage induced by FC-113.
The direct effect of FC-113 exposures upon humans, particularly at ambient
concentrations found or expected, is unknown. No conclusions can be drawn, at
this time, with regard to the carcinogenic, mutagenic, or teratogenic potential
of FC-113 until more extensive testing is initiated.
Because of the limited amount of data concerning human chronic exposure
situations, it is difficult to estimate, with confidence, the lowest observed
adverse effect level (LOAEL). The LOAEL is defined as the lowest dose in a
study or group of studies producing functional impairment, behavioral abnorm-
ality, and/or pathological lesions which hinder the performance of the whole
organism. 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 mg/m ). However, this level should be regarded
with caution until additional chronic testing, using sensitive parameters of
liver, kidney, and CNS damage, is performed.
5-42
-------
The data of Reinhardt et al. (1971), Triebig and Burkhardt (1978), and
Imbus and Adkins (1972) suggest a no-observed adverse-effect level (NOAEL),
for short-term exposure situations, in the range of 500 to 1,000 ppm (3,850 to
7,700 mg/m ). The NOAEL is defined as that dose which produces observed
effects which do not in themselves represent known functional impairment,
behavioral abnormality, and/or pathological lesions which hinder the perform-
ance of the whole organism.
Of concern, however, is the role of FC-113 in the possible depletion of
stratospheric ozone. Photochemical reactions involving FC-113 have the poten-
tial to destroy ozone in the stratosphere and one result would be an increase
in the incidence of certain types of skin cancers.
5-43
-------
TABLE 5-13. LOWEST OBSERVABLE ADVERSE DIRECT EXPOSURE EFFECT LEVELS
No. of Duration
Criteria Species Mode of Treatment Subjects of Exposure Concentration Response Reference
(ppm)
Cardiac Sensitization beagle dog 8 ug/kg epinephrine 1/6
given i.v. prior to
FC-113 and again
after exposure
8 ug/kg epinephrine 1/6
i.v. prior to exposure
and again after
exposure
Liver damage rat
£ rat 12
Thyroid monkey 4
Psychomotor ability human inhalation 2
i
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
2,500 cardiac sen-
sitization to
exogenous epi-
nephrine
2,000 cardiac sen-
si tizati on to
exogenous epi-
nephrine
5,000 slight liver
damage
5,000 abnormal
weight gain,
3 rats pale
livers
2,000 enlarged
thyroid
2,500 loss of con-
centration,
drowsiness,
Haskell
Laboratory,
Oct. 1969
Ibid
Clayton
1962
Clayton
1966
Carter,
et al. ,
1970
Stopps and
McLaughlin
1967
dizziness
(reversible
upon cessation
of exposure)
-------
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Depletion by Halocarbons: Chemistry and Transport, 1979b.
National Research Council. National Academy of Sciences. Causes and Effects
of Stratospheric Ozone Reduction: An Update, 1982.
Panofsky, N. A. Earth's endangered ozone. Environ. 20(3):17-40, 1978.
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Jr. Human Exposures to Fluorocarbon 113. Amer. Ind. Hgy. Assn. J.
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Cardiac Arrhythmia Potential of Some Common Industrial Solvents. J.
Occup. Med. 15(12):953-955, 1973.
5-47
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Setlow, R. 8. The Wavelengths in Sunlight Effective in Producing Skin Cancer:
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5-48
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6. ECOLOGICAL EFFECTS
The effects of FC-113 upon the environment must be viewed in terms of the
role of this compound and other halocarbons in the destruction of strato-
spheric ozone (0.,). The effects of 0, depletion upon the environment have
recently been examined by the National Research Council (1982). (See Section
5.4).
Among the conclusions of the NRC (1982) are:
1. The adaptability of plant species appears to be sufficient, under
current ambient levels of UV-B, to maintain food crop yields. The potential
for further adaptation to predicted increases in ambient UV-B is not known.
2. There is no information from which to predict the magnitude of
adverse effects of enhanced UV-B on aquatic organisms. Natural populations of
aquatic organisms have adapted to current UV-B levels so as to maximize repro-
duction potential.
3. Although different species of both plants and animals have different
sensitivities to increases in UV-B above current levels, the data currently
available are not complete enough to predict population dynamics or the dis-
placement of an individual species under current environmental conditions.
4. Only minor effects of increased UV-B levels are predicted for
animals used for human food.
6.1 CLIMATE
As discussed in detail in the 1979 NRC report (National Research Council,
1979a), the climatic effects of an increase in the atmospheric burden of
chlorofluorocarbons are twofold: (1) they can contribute to the "greenhouse"
effect; (2) perturb climate by altering the amount or distribution of 0-,
which will then affect the radiation balance.
6-1
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6.2 AGRICULTURAL CROPS
Of 82 species tested, about 60 percent exhibited intermediate degrees of
sensitivity to UV-B radiation. Radiation affected plant dry weight of yield
and proportion of plant material represented in roots, shoots, and leaves
(National Research Council, 1979a). The NRC (National Research Council,
1979a) concluded that "even though a reduction of atmospheric ozone of the
magnitude now envisaged could have significant effects on crop yields in
certain plant varieties, the proportion of general agricultural crops in
various parts of the world that might be affected, and the degree to which
yields might be reduced, cannot be meaningfully surmised at this time."
6.3 DOMESTIC AND WILD ANIMALS
The NRC (National Research Council, 1979a; 1982) concluded that the
impact of increased UV-B radiation would have no serious impact. The most
likely impact would be an increased incidence of "cancer eye," a carcinoma of
the conjunctiva in certain cattle varieties.
6.4 AQUATIC SPECIES AND ECOSYSTEMS
The NRC (National Research Council, 1979a) concluded that "any ozone-
layer reduction will lead to an increase in DUV (damaging ultraviolet) at all
depths in the water column...we must accept the possibility that ozone deple-
tion could seriously affect the aquatic biosphere." The impacts of 0- deple-
tion on fishery species raise a concern for supplies of human food derived
from aquaculture. However, there has not been any experimental work to explore
this potential problem (National Research Council, 1979a). The NRC (1982)
recently concluded that the magnitude of adverse effects of enhanced UV-B
radiation on aquatic organisms cannot be predicted.
It should be noted that the high volatility of FC-113, absence of measured
levels in water, and low toxicity indicate that FC-113 presents a low direct
risk to aquatic organisms (U.S. E.P.A. , 1981).
6-2
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7. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS
In March 1978, both the U.S. Environmental Protection Agency and the Food
and Drug Administration banned CFCs as propel 1 ants in nonessential aerosol
uses (Fed. Reg., 1978). It should be noted that while this ban applied to
FC-113, FC-113 previously had been used in nonaerosol applications, applica-
tions not covered by the ban.
The concentration of FC-113 in the workplace to which nearly all workers
may be repeatedly exposed without adverse effect is 1,000 ppm (7,700 mg/m ).
This Threshold Limit Value has been proposed by the American Conference of
Governmental and Industrial Hygienists (ACGIH, 1979). This value was recom-
mended as a limit of good hygiene control for vapors of low toxicity (ACGIH,
1971).
References are cited in Section 5.4, Chapter 5.
7-1
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Illinois 60604
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