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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                             Do not cite or quote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 bonds—bonds 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

-------
     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

-------
     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

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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

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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

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                       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

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     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

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                  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

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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

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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

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                              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  Mouse—Aviado 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

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                           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

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                               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

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   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

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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  Monkey—Belej 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  Frog—Young 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

         -O—2% 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  Mouse—Using 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  Mouse—The 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

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                        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  Mouse—Epstein 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 on—Rei 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  Dermal—Dermal 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

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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'on—Only 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)

-------
5.4  REFERENCES
Amer. Conf. Govern. Ind. Hyg.  Threshold Limit Values for  Chemical  Substances
     in Workroom Air Adopted by ACGIH for 1979.

Amer. Conf. Govern. Ind. Hyg.  Documentation of the Threshold  Limit Values  for
     Substances in Workroom Air, 3rd Edition, 1971.

Amer. Ind. Hyg. Assn.  Comm.  l,l,2-Trichloro-l,2,2-trifluoroethane,  Am.  Ind.
     Hyg. Assn. J. 29:521-525, 1968.

Ames, B. N.  Identifying environmental chemicals causing mutation  and  cancer.
     Science 204:587-593, 1979.

Aviado, D. M., and M.  A. Belej.  Toxicity of Aerosol Propellants on the  Res-
     piratory and Circulatory Systems.  I.  Cardiac Arrhythmia in  the  Mouse.
     Toxicology 2:31-42, 1974.

Aviado, D. M., and D.  G. Smith.  Toxicity of Aerosol Propellents in the  Res-
     piratory and Circulatory Systems.  VIII.  Respiration and Circulation  in
     Primates.  Toxicology 3:241-252, 1975.

Aviado, O.M.  Toxicity of Aerosol Propellents in the Respiratory and Circula-
     tory Systems.  X.  Proposed Classification.  Toxicology 3: 321-332,  1975.

Aviado, D. M., and M.  A. Belej.  Toxicity of Aerosol Propellants in the  Res-
     piratory and Circulatory Systems.  V.  Ventricular Function in the  Dog.
     Toxicology 3:79-86, 1975.

Beaubier, J.  The Skin Problem.  Proceedings of the Quadrennial International
     Ozone Symposium,  Boulder, CO.  August 4-9, 1980.

Belej, M. A., D. G. Smith, and D. M. Aviado.  Toxicity of  Aerosol  Propellents
     in the Respiratory and Circulatory Systems.  IV.  Cardiotoxicity  in  the
     Monkey.  Toxicology 2:381-395, 1974.

Betro Research Laboratories, Inc.  Unpublished data of E.I. duPont de  Nemours
     and Company.  HLO-0260-67, MRO-0916-001 (1967).  Submitted to U.S.  En-
     vironmental Protection Agency, 20 August 1979.

Burn, J. H., H. G. Epstein, and P. J. Goodford.  The Properties of the Anaes-
     thetic Substance 1,1,2-Trifluro- 1,2-Oichloroethane.   Brit. J.  Anaesth.
     31:518-529, 1959.

Burn, J. H.  Pharmacological Testing of Anesthetics.  Proc. Royal  Soc. Med.
     52:95-98, 1959.

Carter, V. L. , P. M.  Chikos, J. D. MacEwen, and K. C. Back.  Effects of  Inhal-
     ation of Freon 113 on Laboratory Animals.  U.S. Nat.  Tech. Info.  Service
     Report AD727524,  1970.

Clark, D. G. , and D.  J.  Tinston.  Correlation of the Cardiac Sensitizing
     Potential of Halogenated Hydrocarbons with their Physiochemical Proper-
     ties.  Brit. J.  Pharm. 49:355-357, 1973.
                                    5-45

-------
Clayton, J.  W.,  Jr.  The Toxicity of Fluorocarbons with Special Reference to
     Chemical Constitution.  J. Occup.  Med. 4(5):262-273, 1962.
Clayton, J.  W.
     Fluorine.
The Mammalian Toxicology of Organic Compounds Containing
Handbuch Exp. Pharmakol. 20:459-500, 1966.
Conney, A. H.,  R. Chang, W. M. Levin, A. Garbut, A. D. Moore-Faure, A. W.  Peck,
     and A. Bye.   Effects of piperonyl butoxide on drug metabolism in  rodents
     and man.  Arch. Environ. Health 24:97-106, 1972.

Desoille, H., L.  Truffert, A. Bourguignon, P. Delavierre, M. Philbert, and C.
     Girard-Wallon.  Experimental Study on the Toxicity of  trichlorotrifluoro-
     ethane (Freon 113).  Archives des Maladies Professionnelles de Medicine
     de Travail et de Securite Sociale 29:381-388, 1968.

Duprat, P., L.  Delsuat, and D. Gradiski.  Pouvoir  Irritant  des  Principaux
     Solvants Chlores Aliphatiques sur la Peau et  les Muqueuses Oculaires  du
     Lapi.  Eur.  J. of Tox. 9(3):171-177.

Epstein, S. S., J. Andrea, P. Clapp, D. Mackintosh, and N.  Mantel. Enhancement
     by piperonyl butoxide of acute toxicity due to Freons,  Benzo  (  a  )
     pyrene, and Griseofulvin in infant mice.  Tox. and Appl Pharm. 11:442-448
     1976b.

Epstein, S. S.,  E. Arnold, J. Andrea, W. Bass, and Y. Bishop.   Detection of
     Chemical Mutagens by the Dominant  Lethal Assay  in the  Mouse.  Tox.  and
     App.  Pharm.  23:288-325, 1972.

Epstein, S. S.,  S. Joshi, J. Andrea, P. Clapp, H.  Falk, and N.  Mantel.   Syner-
     gistic toxicity and carcinogenicity of  'Freons'  and  piperonyl butoxide.
     Nature  214:526-528, 1967a.

Forbes, P.  D. and  F. Urbach.  Experimental Modification of  Photocarcinogenesis.
     I. Food Cosmet. Toxicol.  13:335,  1975.

Haskell Laboratory.  Unpublished data  of E.I. duPont  de Nemours and  Company.
     MR-2363-001,  HL-0325-69  (1969).   Submitted  to U.S. Environmental  Protec-
     tion  Agency,  20 August  1979.

Haskell Laboratory.  Unpublished data  of E.I. duPont  de Nemours and  Company.
     MRO-1015-001,  HL-0242-67  (1967).   Submitted to  U.S.  Environmental Protec-
     tion  Agency,  20 August  1979.

Haskell Laboratory.  Unpublished data  of E.I. duPont de  Nemours and  Company.
     MR-1127-001,  HL-0325-69  (1969).   Submitted  to U.S.  Environmental  Protec-
     tion  Agency 20, August  1979.

Haskell  Laboratory.  Unpublished data  of  E.I. duPont de  Nemours and Company.
     MR-2627-001,  HL-915-77  (1977).   Submitted  to U.S.  Environmental  Protec-
     tion  Agency,  20 August  1979.
                                     5-46

-------
Haskell Laboratory.  Human Skin Absorption Studies with Trichlorofluoroethane.
     Medical Research Project No. MR-1014 (1968), submitted by E.  I. Dupont
     de Nemours & Co.to U.S.  Environmental Protection Agency, August 1979.

Hazleton Laboratories, Inc.  Unpublished data of E.I. duPont de Nemours  and
     Company.   MRO-1962-001,  HLO-0258-67 (1967).  Reproduction Study in  Rab-
     bits.   Submitted to U.S. Environmental Protection Agency, 20  August 1979.

Hazleton Laboratories, Inc.  Unpublished data of E.  I. DuPont de Nemours and
     Company.   MRO-1015, HLO-242 (1967).  Final Report.  Teratology Study in
     Rabbits.   Submitted to U.S. Environmental Protection Agency,  20 August
     1979.

Huempfner,  K.  H.   The Toxicity of Frigen 113 TR-T.   Zentralblatt fuer  Arbeits-
     medizin and Arbeitsschutz 4:118-119, 1974.

Imbus, H. R. and C. Adkins.  Physical Examinations of Workers Exposed  to Tri-
     chlorotrifluoroethane.  Arch. Environ. Health 24:257-261, 1972.

Kuebler, H.   The physiological properties of aerosol propellants.   Aerosol Age
     9:44,  1964.

Michaelson,  J. B., and D. J.  Huntsman.  Oral Toxicity of 1,2,2-trichloro-l,
     1,2-trifluoroethane.  J. Med. Chem. 7:378-379,  1964.

Molina, M.  J.  , and F. S. Rowland.  Stratospheric Sink for Chlorof1uoromethanes:
     Chlorine Atom-Catalyzed Destruction of Ozone.   Nature 249:810-812,  1974.

Mullin, L.  S.  , A. Azar, C. F. Reinhardt, P. E. Smith, and E. F. Fabryka.
     Halogenated hydrocarbon induced cardiac arrhythmias associated with
     release of endogenous epinephrine.  Unpublished report of Haskell Labora-
     tory,  E.I. duPont de Nemours and Company, MR1262, HL 279-71,  (1971).
     Submitted to U.S. Environmental Protection Agency.

National Research Council.  National Academy of Sciences.  Protection  Against
     Depletion of Stratospheric Ozone by Chlorofluorocarbons, 1979a.

National Research Council.  National Academy of Sciences.  Stratospheric Ozone
     Depletion by Halocarbons:  Chemistry and Transport, 1979b.

National Research Council.  National Academy of Sciences.  Causes  and  Effects
     of Stratospheric Ozone Reduction:  An Update, 1982.

Panofsky, N. A.  Earth's endangered ozone.  Environ.  20(3):17-40,  1978.

Raventos, J.,  and P.  G. Lemon.  The impurities in Fluorthane:  Their bio-
     logical properties.  Brit. J. Anesthesia. 37:716-737, 1965.

Reinhardt,  C.  F., M McLaughlin, M. E. Maxfield, L. S. Mullin, and  P. E.  Smith,
     Jr.  Human Exposures to Fluorocarbon 113.  Amer. Ind. Hgy. Assn.  J.
     32:143-152,  1971.

Reinhardt,  C.  F., L.  S. Mullin, and M. E. Macfield.  Epinephrine-Induced
     Cardiac Arrhythmia Potential of Some Common Industrial Solvents.  J.
     Occup.  Med.  15(12):953-955, 1973.
                                    5-47

-------
Setlow, R.  8.   The Wavelengths in Sunlight Effective in Producing Skin Cancer:
     A Theoretical Analysis.   Proc.  National Academy of Sciences 71:3363-3366,
     1974.

Shargel,  L.,  and R. Koss.  Determination of Fluorinated Hydrocarbon Propellents
     in Blood of Dogs after Aerosol  Administration.  J. of Pharm. Sci. 61(9):
     1445-1449, 1972.

Smith, K.  C.   Molecular Changes in the Nucleic Acids Produced by Ultraviolet
     and Visible Radiation:  In:   Sunlight and Man. T. B. Fitzgerald et al.,
     eds.

Smith, K.  C.   Radiation-induced Cross-Linkings of DNA  and Protein in Bacteria.
     j.n:   Aging, Carcinogenesis,  and Radiation Biology,  K. C. Smith, ed.
     Plenum Press, 1976.

Steinberg,  M.  B.,  R. E. Boldt, R. A. Renne, and M. H.  Weeks.  Inhalation
     Toxicity of l,l,2-Trichloro-l,2,l-trifluoroethane (TCTFE),  U.S. Army
     Environmental Hygiene Agency, Study No. 33-18-68/69, 1969.

Stopps, G.  J., and M. Mclaughlin.  Psychophysiological Testing of Human Sub-
     jects Exposed to Solvent Vapors.  Amer. Ind. Hyg. Assn. J.  28: 43-50,
     1967.

Triebig, G., and K. Burkhardt.  Studies on  Persons Occupationally Exposed  to
     l,l,2-Trichloro-l,2,2-Trifluoroethane.  Int. Arch. Occup. Environ. Health
     42:129-135, 1978.

Trochimowicz, H. J., A. Azar, J.  B. Ten-ill, and  L.  S. Mullin.   Blood  Levels
     of Fluorocarbon Related to Cardiac Sensitiration:  Part  II.  Am.  Ind.
     Hyg.  Assn. J.  35:632-639, 1974.

Trochimowicz, H. J., C.  F. Reinhardt,  L. S. Mullin,  A. Azar,  and B. W.  Karrh.
     The effect of myocardial infarction on the cardiac  sensitization  poten-
     tial of certain halocarbons.  J.  Occup. Med.  18(1):26-30, 1976.

Underwriters'  Laboratories, Inc.  The  Comparative Life,  Fire,  and Explosion
     Hazards of Trifluorotrichloroethane ("Freon-113"),  1941.

Vainio, H., J.  Nickels,  and T. Heinonen.   Dose-related hepatoxicity of
      l,l,2-trichloro-l,2,2,-trifluoroethane in short-term  intermittent inhala-
      tion exposure  in  rats.   Toxicol.  18:17-25,  1980.

Young, W., and  J.  A.  Parker.  Effect of Fluorocarbons on Acetylcholinesterase
      Activity  and  Some  Counter Measures.   Combust.  Toxicology 2:286-297,  1975.
                                     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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                           8.  COLLATED BIBLIOGRAPHY

Amer. Conf. Govern. Ind. Hyg. Threshold Limit Values  for  Chemical  Substnaces
     in Workroom Air Adopted by ACGIH for 1979.  Amer.  Conf.  Govern.  Ind.  Hyg.
     Documentation of the Threshold Limit Values for  Substances  in Workroom
     Air, 3rd Edition, 1971.

Amer. Ind. Hyg. Assn. Comm.  l,l,2-Trichloro-l,2,2-trifluoroethane,  Am.  Ind.
     Hyg. Assn. J. 29:521-525, 1968.

Ames, B. N.  Identifying environmental chemicals causing  mutation  and cancer.
     Science 204:587-593, 1979.

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