U.S. DEPARTMENT OF COMMERCE
National Technical Information Service
PB-257 371
Environmental Hazard Assessment Report
Major One- and Two-Carbon Saturated
Fluorocarbons. Review of Data
Environmental Protection Agency
Aug 76
-------
Product Liability Insurance: Assessment of Related
Problems and Issues. Staff Study
PB-252 204/PAT 181 p PC$9.50/MF$3.00
Evaluation of Home Solar Heating System
UCRL-51 711/PAT 154 p PC$6.75/MF$3.00
Developing Noise Exposure Contours for General
Aviation Airports
ADA-023 429/PAT 205 p PC$7.75/MF$3.00
Cooling Tower Environment, 1974. Proceedings of
a Symposium Held at the University of Maryland
Adult Education Center on Mar. 4-6, T974
CONF-74 0302/PAT 648 p PC$13.60/MF$3.00
Biological Services Program. Fiscal Year 1975
PB-251 738/PAT 52 p PC$4.50/MF$3.00
An Atlas of Radiation Hlstopathology
TID-26-676/PAT 234 p PC$7.60/MF$3.00
Federal Funding of Civilian Research and Develop-
ment. Vol. 1. Summary
PB-251 266/PAT 61 p PC$4.50/MF$3.00
Federal Funding of Civilian Research and Develop-
ment. Vol. 2. Case Studies
PB-251 683/PAT 336 p PC$10.00/MF$3.00
Handbook on Aerosols
TID-26-608/PAT 141 p PC$6.00/MF$3.00
for the Assessment of Ocean Outfalls
ADA-023 514/PAT 34 p PC$4.00/MF$3.00
Guidelines for Documentation of Computer Pro-
grams and Automated Data Systems
PB-250 867/PAT 54 p PC$4.50/MF$3.00
NOx Abatement for Stationary Sources in Japan
PB-250 586/PAT 116 p PC$5.50/MF$3.00
U.S. Coal Resources and Reserves
PB-252 752/PAT 16 p PC$3.50/MF$3.00
Structured Programming Series. Vol. XI. Estimating
Software Project Resource Requirements
ADA-016 416/PAT 70 p PC$4.50/MF$3.00
Assessment of a Single Family Residence Solar
Heating System in a Suburban Development Setting
PB-246 141/PAT 244 p PC$8.00/MF$3.00
Technical and Economic Study of an Underground
Mining, Rubblization, and in Situ Retorting System
for Deep Oil Shale Deposits. Phase I Report
PB-249 344/PAT 223 p PC$7.75/MF$3.00
A Preliminary Forecast of Energy Consumption
Through 1985
PB-251 445/PAT 69 p PC$4.50/MF$3.00
HOW TO ORDER
When you indicate the method of pay-
ment, please note if a purchase order is not
accompanied by payment, you will be billed
an addition $5.00 .tliip and bill charge. And
please include the card expiration date when
using American Express.
Normal delivery time takes three to five
weeks. It is vita) that you order by number
or your order will be manually filled, in-
suring a delay. You can opt for airmail
delivery for a $2.00 charge per item. Just
check the Airmail Service box. If you're
really pressed for time, call the NTIS Rush
Order Service. (703) 557-4700. For a
$10.00 charge per item, your order will be
airmailed within 48 hours. Or, you can
pick up your order in the Washington In-
formation Center & Bookstore or at our
Springfield Operations Center within 24
hours for a $6.00 per item charge.
You may also place your order by tele-
phone or TELEX. The order desk number
is (703) 557-4650 and the TELEX number
is 89-9405.
Whenever a foreign sales price is NOT
specified in the listings, all foreign buyers
must add the following charges to each or-
der: $2.50 for each paper copy; $4.50- for
each microfiche; and $10.00 for each Pub-
lished Search.
Thank you for your interest in NTIS. We
appreciate your order.
METHOD OF PAYMENT
Q Charge my NTIS deposit account no._
Purchase order no
NAME.
Check enclosed for $_
Charge to my American Express Card account number
ADDRESS-
1 1 1 1 1 1 1 1 1 1 1 1
Tarrl rupiratinp Hal» 1
Q Airmail Services requested
Clip and mail to:
HTO
National Technical Information Service
U.S. DEPARTMENT OF COMMERCE
Springfield, Va. 22161
(703) $57-1650 TELEX 89-9405
Item Number
Quantity
Paper Copy
(PC)
Microfiche
fMF)
All Prices Subject to Change
11/76
I
Unii Price*
Sub Total
Additional Charge
Enter Grand Tola!
Total Price"
-------
EPA-560/8-76-003
ENVIRONMENTAL HAZARD ASSESSMENT REPORT
MAJOR ONE-AND TWO-CARBON
SATURATED FLUOROGARBONS
REVIEW OF DATA
August 1976
ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF TOXIC SUBSTANCES
WASHINGTON, D.C. 20460
-------
TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
1. REPORT run
EPA-560/8-76-003
J.L.
3. RECIPIENT'S ACCESSION*NO.
4. TITLE ANDSUBTITLE
ENVIRONMENTAL HAZARD ASSESSMENT SERIES
Major One- and Two-Carbon Saturated Fluorocarbons
Review of Data
5. REPORT DATE
August 1976
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
Frank 0. Letkiewicz
8. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
U.S. Environmental Protection Agency
Office of Toxic Substances
401 "M" Street, S.W.
Washington, D.C. 20460
10. PROGRAM ELEMENT NO.
2LA328
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
U.S. Environmental Protection Agency
Washington, D.C. 20460
13. TYPE OF REPORT AND PERIOD COVERED
Final
14. SPONSORING AGENCY CODE
15. SUPPLEMENTARY NOTES
16. ABSTRACT
JThis report is a review of the available information on the commercially
important one- and two-carbon saturated fluorocarbons (i.e., fluoromethanes
and fluoroethanes) pertinent to an assessment of the potential environmental
hazard posed by these compounds. Aspects discussed are production, uses,
environmental effects and biological effects. Major topics are the potential
stratospheric ozone depletion effect from continued emissive uses of certain
fluorocarbons and the cardiovascular effects resulting from inhalation of
these compounds.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS
c. COS AT I Field/Group
fluorocarbons / dichlorotetrafluoroethane
fluoromethanes / chloropentafluoroethane
fluoroethanes / chlorodifluoroethane
trichlorofluoromethane / difluoroethane
dichlorodifluoromethane / bromotrifluoro-
chlorodifluoromethane methane
trichlorotrifluoroethane / halothane
18. DISTRIBUTION STATEMENT
Unlimited
19. SECURITY CLASS (This Report I
unclassified
21. NO. OF PAGES
20. SECURITY CLASS (This page)
unclassified
EPA Form 2220-1 (9-73)
-------
EPA-560/8-76-003
; ENVIRONMENTAL HAZARD ASSESSMENT REPORT
Major One- and Two-Carbon Saturated Fluorocarbons
Prepared by
Office of Toxic Substances
Environmental Protection Agency
Washington, D.C. 20460
August 1976
ju-.
-------
PREFACE
Our society uses thousands of chemical substances with many
of them released into the environment in varying quantities as
production or handling losses, as waste materials, or as a direct
consequence of intended or unintended uses. Concern over possible
effects of these chemicals has prompted the establishment of a
program by the Early Warning Branch of the Office of Toxic Sub-
stances to review release, exposure, and effects data to assist in
setting priorities for further study or possible regulatory action.
Detailed analyses on every commercial chemical are not prac-
tical. Selected materials are initially screened by a simple
literature search and a limited number of these chemicals are
selected for more detailed study. Criteria for this selection
include volume of production, manner of use, market growth poten-
tial, exposure patterns, detection in the environment, known toxic
effects, and functional or chemical relationships to known environ-
mental pollutants. The early warning system, which first brings
chemicals to the attention of the program uses diverse sources,
including opinions of experts, referrals from other units of
government, reports in the scientific and trade literature, predic-
tive modelling, and public inquiries. This study was initiated
because of the association'of f1uorocarbons used as aerosol pro-
pell ants with a number of deaths in recent years of person inhaling
aerosol products to achieve an intoxicated state, and because
exposure to the fluorocarbons from their use as aerosol propellants
was known to be widespread. Additional impetus for this study was
the emergence of the theory that continued use of fluorocarbons may
result in depletion of stratospheric ozone, with potentially severe
effects on life.
These hazard assessments are prepared from reviews of the
subject substances supplemented by additional searches and inquir-
ies to obtain the most complete and recent information available.
- ii -
-------
Only data considered pertinent to an assessment of environmental
hazard are reported 1n this series.
Although the assessment uses as complete an Information base
as possible, additional Information may be available or may become
available. Therefore, these assessments are subject to revisions.
The Office of Toxic Subs taxes would welcome any additional perti-
nent data.
Any recommendations in this document are those of the Office
of Toxic Substances and may not represent an Agency consensus. Nor
do they represent commitment to further action by the Environmental
Protection Agency or any other organization. Mention of tradenames
and manufacturers of specific products in this document are for
purposes of clarity and specificity only and does not constitute an
endorsement of any product.
The Environmental Hazard Assessment Series is being prepared
under the guidance of Dr. Farley Fisher, Chief of the Early Warning
Branch, Office of Toxic Substances. This report was written by
Frank J. Letkiewicz.
This assessment was preceded by a general literature review of
the f1uorocarbons conducted by Dr. Philip Howard and Mr. Patrick
Durkin of the Syracuse University Research Corporation, Syracuse,
New York, and by a more intensive review of the one and two carbon
fluorocarbons conducted by Dr. Philip Howard, Mr. Arnold Hanchett
and Mr. Patrick Durkin, again of Syracuse University Research
Corporation. The reports which were prepared from these reviews
are entitled Preliminary Environmental Hazard Assessment of Chlo-
rinated Naphthalenes, Si 11 cones, Fluorocarbons. Benzenepolycar-
boxylates and Chlorophenols and Environmental Hazard Assessment
of One and Two Carbon Fluorocarbons, both available through the
National Technical Information Service, Springfield, Virginia 22151
under NTIS accession numbers PB-238 074 and PB-246 419, respec-
tively.
- 111-
-------
TABLE OF CONTENTS
PREFACE i i
SUMMARY. 1
I. INTRODUCTION 7
II. STRUCTURE, PROPERTIES, AND REACTIVITY 10
III. PRODUCTION.. 13
A. Production Methods 13
B. Producers 15
C. Quantity Produced and Price 15
IV. USES.. 21
V. ENVIRONMENTAL ASPECTS 26
A. Release to the Environment 26
B. Methods of Analysis and Environmental
Detection 28
C. Environmental Fate of Fluorocarbons 33
VI. STRATOSPHERIC OZONE DEPLETION FROM FLUOROCARBONS.. 36
VII. EFFECTS OF OZONE DEPLETION 59
VIII.BIOLOGICAL PROPERTIES OF FLUOROCARBONS 68
A. Absorption and Elimination 68
1. Inhalation 68
2. Other Routes of Entry :...' 69
B. Transport and Distribution 71
C. Biochemical Interactions 71
D. Metabolism 72
- iv -
-------
TABLE OF CONTENTS (cont.)
IX. HUMAN TOXICITY STUDIES 79
X. EXPERIMENTAL TOXICITY STUDIES 88
A. Inhalation 88
1. Acute Exposure 88
2. Subacute Exposure 89
3. Chronic^ Exposure 89
B. Dermal Exposure 94
C. Oral Exposure 95
D. Carcinogenicity 96
E. Mutagenicity and Teratogenicity 96
F. Behavioral Effects ... 97
G. Phytotoxicity 98
H. Toxicity to Microorganisms 99
XI. CARDIOVASCULAR EFFECTS 100
A. Cardiac Arrhythmia 100
B. Respiratory and Other Cardiac Effects 103
C. Classification of Fluorocarbons Based on Car-
diac and Pulmonary Effects 104
D. Increased Sensitivity in Diseased Animals 106
XII. REGULATIONS AND STANDARDS 108
LITERATURE CITED 112
APPENDIX A - Fluorocarbon Absorption/Elimination
Data A-l
APPENDIX B - Fluorocarbon Experimental Toxicity
Data B-l
APPENDIX C - Fluorocarbon Cardiovascular Effects
Data C-l
- v -
-------
LIST OF TABLES
Table I Molecular Formulae and Physical
Properties of Commercially
Important Fl uorocarbons 11
Table II Fluorocarbon Producers and Plant
Capacities..... 16
Table III Foreign Fluorocarbon Producers 17
Table IV Production of Fluorocarbons 11,
12 and 22 in the U.S. and Market
Values 18
Table V Uses of Fluorocarbons 19
Table VI Use of Fluorocarbon Refrigerants... 23
Table VII Atmospheric Concentrations of
Fl uorocarbons 11 and 12 30
Table VIII Stratospheric Measurements of
Fl uorocarbons 39
Table IX Concentrations of Species and Rate
Constants of Reactions Used to
Determine C1X Profile (From Data
Given in Rowland and Molina,
1974) 47
Table X Stratospheric Ozone Depletion From
F-ll and F-12 50
Table XI Underwriters' Laboratories
Comparative Toxicity Classification
Of Refrigerants 110
Table XII TLVs and Underwriters' Laboratories
Comparative Toxicity Classification
for Various Fluorocarbons Ill
- vi -
-------
LIST OF TABLES (cont.)
Table A-I Absorption/Elimination Data on
Various Fluorocarbons Inhaled from
Table B-I
Table B-II
Table B-III
Table C-I
Table C-II
Ambient Air
Acute Inhalation Toxicity of
Fluorocarbons 11 and 12
Subacute Inhalation Toxicity
of Major Fl uorocarbons
Chronic Inhalation Toxicity of
Fl uorocarbons
Induction of Cardiac Arrhythmias
by Fl uorocarbons
Fluorocarbon Sensitization to
Arrhythmias from Injected
Eoineohrine
A-l
B-l
B-5
B-ll
C-l
C-8
Table C-III
Table D-I
Summary of Bronchopulmonary and
Cardiovascular Effects Other than
Arrhythmi a
Fluorocarbon Numbers and Molecular
Formulae of the Major One and Two
Carbon Saturated Fluorocarbons
C-ll
D-l
- vii -
-------
LIST OF FIGURES
Figure 1 Flow Diagram of Fluorocarbon Manu-
facture from Chlorinated Hydro-
carbons ............................ 14
Figure 2 The Vacuum Ultraviolet Spectrum of
CFC13 .............................. 41
Figure 3 The Vacuum Ultraviolet Spectrum of
C12C12. ............................ 41
Figure 4 C1X Mixing Ratios as of Late 1974
from F-ll, F-12, CC14 and CHgCl as
Calculated by Cicerone et a! .
(1975) ............................. 57
Figure 5 Noon Direct Irradiance at 297.5 nm
Plotted Against Latitude for the
Northern Hemisphere in the Spring.. 62
Figure A-l Venous Blood Concentrations of F-ll
in Dogs Exposed to 1.25% or 0.63%
F-ll in Ambient Air for 30
Minutes. ........................... A-7
Figure A-2 Venous Blood Concentrations of F-12
in Dogs Exposed to 4% or B% F-12 in
Ambient Air for 30 Minutes ......... A-7
Figure A-3 Venous Blood Concentrations of
F-ll 4 in Dogs Exposed to 5% or 10%
F-114 in Ambient Air for 30
Minutes ............................ A-8
-------
! SUMMARY
The one- and two-carbon saturated fluorocarbons are organic com-
pounds of the methane and ethane series, respectively, which have one
or more fluorine atom substituents. In addition, these compounds may
contain chlorine, hydrogen, and/or bromine. The major commercial
compounds in this group are (with fluorocarbon number following):
trichlorofluoromethane (F-ll), dichlorodifluoromethane (F-12), chloro-
difluoromethane (F-22), trichlorotrifluoroethane (F-ll3), dichloro-
tetraf1uoroethane (F-114), chloropentafluoroethane (F-115), chlorodi-
fluoroethane (F-142b), and bromotrif1uoromethane (F-13B1). Minor
amounts of chlorotrifluoromethane (F-13), tetrafluoromethane (F-14),
dichlorofluoromethane (F-21), and trifluoromethane (F-23) are also
produced for specialty applications. 2-Bromo-2-chloro-l,l,1-trifluo-
roethane (halothane) is a widely used anesthetic for surgical procedures.
The fluorocarbons were introduced commercially in the 1930's as
non-flammable, non-corrosive, and non-toxic refrigerants and by virtue
of these attributes became, as they are today, the mainstay of the
refrigeration industry. In the 1950's these compounds were commer-
cialized as propel!ants for aerosol products, and are today the major,
but not the only, class of compounds used for this purpose.
In general the fluorocarbons are volatile substances and display
low solubility in aqueous media. They are very stable, often to the
point of being referred to as "inert". They are resistant to hydrol-
ysis, oxidation and thermal decomposition except under conditions more
severe than those encountered in the environment. Hydrogen-containing
fluorocarbons are more readily hydrolyzed and oxidized than are the
completely halogenated compounds. The fluorocarbons photodissociate
when they are exposed to ultraviolet radiation (wavelength below 220 nm).
The fluorocarbons are produced by fluorination of various chloro-
carbons, primarily carbon tetrachloride (CCl^), chloroform (CHC13) and
hexachloroethane (C0CK). •' There are several U.S. producers of fluoro-
i
carbons and current total plant capacity is approximately 1.2 billion
-------
pounds per year. Domestic production of these compounds is in the
area of 900 million pounds per year, of which fluorocarbons 11, 12,
and 22 comprise about 90%. Total world production of the fluoro-
carbons is estimated to be approximately twice that of the U.S.
The major uses of the fluorocarbon compounds are as aerosol
propel 1 ants, refrigerants, foaming (or blowing) agents for plastic
foams, degreasing solvents, fire-extinguishing agents, and as inter-
mediates for the production of polymers. One fluorocarbon, halothane,
is a widely used general anesthetic for surgical procedures.
The amount of fluorocarbon which is lost to the environment on an
annual basis is difficult to quantify due to uncertainties in the
annual losses from refrigerant and closed-cell blowing agent appli-
cations. However, because of their volatility and the manner in which
these compounds are used, it can be estimated that, except for that
used as intermediates, eventually all of the fluorocarbons produced
are released to the atmosphere. Aerosol propel1 ants are released
directly during use and from the eventual destruction of the cannis-
ter. Refrigerants are lost through leakage, during replacement, and
from discarded units. Fluorocarbons used as open-cell blowing agents
are lost to the environment immediately during use, while closed-cell
blowing agents are lost on destruction of the product. Most of the
current production of the fluorocarbon degreasing solvent, F-113, is
used to replace evaporative losses.
By using extremely sensitive gas-chromatographic methods, fluoro-
carbons 11 and 12 have been detected in the ambient atmosphere at
concentrations of about 100 parts per trillion by volume. These
levels, when multiplied by world-wide atmospheric volume roughly
correspond to total production of these compounds since they were
first commercialized. Increases in atmospheric concentration over
recent years similarly correspond to the increases in usage during
that time. As would be expected, fluorocarbon levels are higher in
areas of high population and industrialization than in rural areas,
over oceans, or at high altitudes. Measurements taken near factories
- 2 -
-------
using fluorocarbons, in public buildings, homes, and special areas
such as beauty parlors show levels somewhat higher than ambient
levels. These levels, however, are still in the parts per billion by
volume range.
The fluorocarbons, because of their stability, are quite persis-
tent in the environment. Although the hydrogen-containing fluorocar-
bons are more susceptible to hydrolysis and oxidation than the
completely halogenated compounds, it has not been demonstrated that
these will be subject to rapid degradation under environmental con-
ditions.
The persistence of the fluorocarbons F-ll and F-12 in the atmos-
phere was recognized with the earliest reports of environmental
detection, but at that time they were considered to pose no hazard to
the environment because of their stability and lack of biological
effects. In 1974, a theory was put forth which stated that continued
release of F-ll and F-12 will cause a depletion of stratospheric
ozone. The significance of this lies in the fact that stratospheric
ozone acts as a filter which shields the earth from ultraviolet radi-
ation. Because of the harmful biological effects of ultraviolet
radiation, it is believed that life as we know it would not exist
without the protective ozone shield. The ozone depletion theory
states that because of their stability, the fluorocarbons, ,particu-
larly F-ll and F-12, diffuse into the stratosphere and undergo photo-
lytic decomposition from the high-energy ultraviolet radiation there,
which results in the release of chlorine atoms. These chlorine atoms
will then react with the ozone (03) to convert it to molecular oxygen
(Op). The key aspect of this reaction is that the chlorine, having
destroyed an ozone molecule, is returned to react destructively with
still more ozone molecules. Because of this catalytic activity, it is
believed that a single chlorine atom will destroy many thousands of
ozone molecules before the chlorine atom reacts with other substances
in the stratosphere which convert it to hydrogen chloride to terminate
the sequence. The hydrogen chloride will diffuse back down to the
troposphere. The initial calculations based on the ozone depletion
- 3 -
-------
theory predicted that continued use of the fluorocarbons would result
in 6.5-13% reduction in stratospheric ozone by the middle of the 21st
century. Since these initial calculations were made, a number of the
key reaction rates and concentrations of important substances in the
stratosphere have been refined. The net effect of these refinements
has essentially been one of cancellation, and the current predictions
of future ozone depletion due to fluorocarbons (7-13%; 8-16%) do not
differ significantly from the initial estimates.
Although it is clear that the presence of ozone in the strato-
sphere is essential for the continuance of life, the consequences of
partial ozone depletion and a concomitant increase in ground-level
ultraviolet radiation are not known in detail. Most of the concern
has focused on a possible increase in skin cancer among humans. There
is also concern that increased ultraviolet radiation will result in
increased skin cancer among domestic animals. Other studies indicate
the possibility of reduction in plant growth, interference with
photosynthesis, and mutations in plants. Climatological changes,
including alterations in temperature distribution and rainfall pat-
terns, are also considered to be possible. Except perhaps for the
increases in skin cancer, the magnitude of biological and climato-
logical consequences of increased ultraviolet radiation due to ozone
depletion are presently hypothetical. Furthermore, accurate predic-
tions of the extent to which such effects might occur as the result of
a partial ozone depletion are not currently possible.
The ozone depletion predictions have prompted an interagency task
force to recommend that fluorocarbon applications resulting in their
release to the atmosphere be banned by 1978 unless information emerges
which indicates gross inaccuracies in the current models. Both the
Federal government and industry are sponsoring research aimed at
determining the validity of the fluorocarbon-initiated ozone depletion
theory, and studies on the impact of partial ozone depletion on man
and his environment are to be pursued. Studies are also being under-
taken to identify possible alternatives for F-ll and F-12 and of the
- 4 -
-------
potential economic and social disruptions which would accompany fluo-
rocarbon restrictions.
In addition to the concern for stratospheric ozone depletion due to
fluorocarbons, there has also been some concern regarding the direct
health effects of these compounds. The fluorocarbon aerosol propel 1 ants
have been responsible for several deaths when they were intentionally
inhaled by individuals attempting to achieve an intoxicated state. The
cause of death was probably cardiac arrhythmia, aggravated by elevated
blood levels of epinephrine due to stress and/or an increase in blood
carbon dioxide. The fluorocarbon anesthetic halothane has been asso-
ciated with liver injury, headache, and mood alterations in patients,
and with liver injury, spontaneous abortion and congenital abnormalities
in chronically exposed operating room personnel. Studies have shown
that inhaled fluorocarbons are rapidly absorbed into the blood and under
conditions of continuous exposure they can enter certain tissues. When
exposure is terminated, the fluorocarbons are rapidly eliminated through
•exhaled air with no indication that they accumulate in any tissue.
Limited data indicate that some metabolism to carbon dioxide (about 1%)
may occur with F-11 and F-12. The metabolism of the fluorocarbon
anesthetic halothane to compounds which bind covalently to cell lipid
and protein has been demonstrated. The formation of bound metabolites
has been associated with the liver toxicity of this and other compounds.
Limited data indicate that inhaled F-ll and F-12 may also result in some
cellular binding. More detailed studies on the formation of bound
metabolites from the commercially important fluorocarbons are needed.
Such studies are also indicated for the hydrogen-containing fluorocar-
bons which have been suggested as replacements for F-ll and F-12 since
these are structurally similar to halothane.
In laboratory animals, the acute lethality of inhaled fluorocarbons
is very low, with F-ll and F-113 being lethal at 5-25% in air and the
other fluorocarbons being fatal only at concentrations of 40% to 80% or
more. Acute inhalation studies on the ability of the fluorocarbons to
produce cardiac arrhythmias, as well as their effects on other cardio-
vascular and respiratory parameters have shown that F-ll and F-113 are
- 5 -
-------
the most toxic of the commercially significant fluorocarbons. F-ll
and F-113 produce cardiac arrhythmias, sensitize the heart to epi-
nephrine-induced arrhythmias, and influence other cardiac parameters.
Some studies have demonstrated that animals with diseased cardiac and
respiratory systems are more sensitive to the acute cardiovascular and
respiratory effects of the fluorocarbons than healthy animals. A
possible increase in sensitivity to the fluorocarbons in humans with
cardiac or respiratory illness may exist, but this is difficult to
determine definitively on the basis of these animal studies.
Except for halothane and one 10-month study with F-22, the "chron-
ic" toxicity testing of the fluorocarbons has thus far been limited to
periods of 90 days or less. While no remarkable toxicological conse-
quences have been reported in these studies, pathological changes in
the liver and inflammatory infiltration of the lung have been observed
in some studies. Chronic inhalation of 10 ppm halothane in rats has
been shown to result in ultrastructural changes at the cellular level
in the liver, kidney and central nervous system. Offspring of exposed
pregnant rats have been found to have similar ultrastructural changes
and also decreases in performance on behavioral tests. Long-term
exposure studies of adult and developing animals to the commercially
important fluorocarbons in the parts per million range utilizing
electron microscopic examination of cell structures as in these halo-
thane studies are needed to assess the chronic toxicity of these
compounds.
6 -
-------
I. INTRODUCTION
During the decades surrounding the turn of the century, scien-
tists and engineers worked tenaciously toward the production of a
practical mechanical refrigeration device. While a machine essen-
tially the same as that which is used today existed in 1928, no com-
pletely satisfactory substance was available for use as the refrig-
erant. Of the compounds proposed at that time, all had serious
disadvantages: ethylene was flammable; sulfur dioxide was corrosive
and toxic; ammonia possessed all three of these drawbacks; and carbon
dioxide required bulky equipment to handle the necessary high pres-
sures. To make the mechanical refrigeration devices commercially
feasible, an acceptable refrigerant had to be found. This material
had to have the necessary physical properties, yet be non-flammable,
non-corrosive, and non-toxic. In 1930, a group of scientists commis-
sioned by the General Motors Corporation announced that a compound
meeting all these criteria had been found. The compound was dichlo-
rodifluoromethane, CC12F2, and its introduction marked the birth of
the fluorocarbon industry.
While the fluorocarbon refrigerant market was quite successful,
it was not long before the industry received a significant boost stem-
ming from the development of aerosol insecticides during World War II.
Because of their chemical inertness and negligible toxicity, along
with their suitably high vapor pressures, certain fluorocarbons were
the materials of choice for use as propellants for these aerosol
products. Commercialization of aerosols began in the early 1950's and
today there are innumerable items available as aerosols using fluoro-
carbon propellants.
Today, the major commercial fluorocarbons are trichlorofluoro-
methane (CC1,F), dichlorodifluoromethane (CC12F2), chlorodifluoro-
methane (CHC1F2), trichlorotrifluoroethane (C2C13F3), dichlorotetra-
fluoroethane (CgClgF^), chloropentafluoroethane (C2C1F5), chlorodi-
fluoroethane (C-H-jClFp), and bromotrif1uoromethane (CBrF^). 2-Bromo-
2-chloro-l,l,l-trifluoroethane (CF3-CHBrCl), also known commonly
- 7 -
-------
as halothane, is a widely used general anesthetic. Minor amounts of
chlorotrifluoromethane (CC1F3), tetrafluoromethane (CF^), dichloro-
fluoromethane (CHClpF), and trifluoromethane (GHF-1) are also produced
for specialty applications. The major uses of the fluorocarbons
remains in the refrigerant and aerosol propel 1 ant areas.
The virtual non-toxiclty and inertness of these compounds, which
made them so attractive in their applications, have come under ques-
tion recently, and their environmental safety, so long assumed, has
been challenged on two fronts. It has been hypothesized that the two
fluorocarbons produced in the greatest amounts, trichlorofluoromethane
and dichlorodifluoromethane, can effect a depletion in the ozone
levels of the stratosphere. Because of the protection which stratos-
pheric ozone affords to life on earth, the Federal Task Force on the
Inadvertent Modification of the Stratosphere (IMOS) has concluded in a
report on the fluorocarbon/ozone problem that the continued release of
these compounds to the environment is a legitimate cause for concern,
and has recommended that, unless new data emerge which remove the
cause for concern, trichlorofluoromethane and dichlorofluoromethane
uses be restricted by 1978 to those not resulting in release to the
environment. In addition to the ozone question, there has also been
some concern for the direct effects of the fluorocarbons on human
health because of deaths in recent years among individuals intention-
ally inhaling fluorocarbon-propelled aerosol products for the purpose
of achieving an intoxicated state. This paper will consider these
topics and others relevant to the evaluation of the environmental
safety of the fluorocarbons.
Throughout this paper a standard shorthand numerical system will
be used to identify the compounds, rather than the often cumbersome
chemical nomenclature. The numerical system consists of a four-digit
number, ABCD, where D is the number of fluorine atoms in the molecule,
C is the number of hydrogen atoms in the molecule plus 1, B is the
number of carbon atoms minus 1, and A equals the number of double
bonds in the molecule. Whenever A or A and B are zero, the digits are
- 8 -
-------
omitted from the number. When bromine is substituted for chlorine, a
B plus the number of bromine atoms follows the number of fluorine
atoms (e.g., CC1F- is 13 whereas CBrF- is 13B1). The fluorocarbon
numbers are preceded by the letter "F" or,"in the refrigeration
industry, "R". This is to avoid confusion with a second system (the
Halon system) often used for the bromine containing fire-extinguishing
agents. In the Halon system ABCD signify the number of carbon,
fluorine, chlorine and bromine atoms, respectively, and the number is
preceded by the letter "H". Fluorocarbon numbers are given for the
major one and two carbon saturated fluorocarbons in Table D-I (Appendix D.)
-9-
-------
II. STRUCTURE. PROPERTIES. AND REACTIVITY
The fluorocarbons under discussion are one- or two-carbon satu-
rated compounds containing fluorine. The compounds may also contain
chlorine, bromine, and/or hydrogen atoms.
Chemical formulae and some physical properties of the commer-
cially important fluorocarbon compounds are shown in Table I. Typical
characteristics of the fluorocarbon compounds are high vapor pressure,
low boiling point, high density, and low water solubility. The degree
of fluorine substitution affects the physical properties. Generally,
as the number of fluorine atoms replacing chlorine atoms in the
molecule increases, the vapor pressure goes up, while the boiling
point, density and the solubility decrease. Bromine atoms tend to
increase the density and lower the vapor pressure.
The major applications of the fluorocarbons, as refrigerants and
aerosol propel!ants, are based on their chemical stability rather than
their reactivity. This stability is due largely to the strength of
the C-F bond and the increase in the C-C1 bond energy associated with
increased fluorine substitution. Although they are often referred to
as "inert", the fluorocarbons, like other halogenated organic com-
pounds, may react violently with highly reactive materials and should
not be exposed to alkali or alkaline earth metals (sodium, potassium,
barium, etc.).
Most of the common construction metals, such as steel, copper,
aluminum, etc., are compatible with the fluorocarbons. The more
reactive metals, such as zinc, magnesium, and aluminum alloys con-
taining more than 2% magnesium, may be used with the fluorocarbons
under anhydrous conditions. They are not recommended for use with
i
fluorocarbons where water or alcohol are present.
The fluorocarbons exhibit low rates of hydrolysis, usually too
low to be determined when water alone is used. The presence of metals
or, in the case of hydrogen-containing fluorocarbons, alkaline con-
ditions will tend to increase the rates of hydrolysis.
- 10 -
-------
Table I
lae and Physical Properties of Commercially Important
Fluorocarbons
Fluorocarbon Number
11
CC13F
137.37
23.82
74.87
-111
-168
12
CC12F2
120.92
-29.79
-21.62
-158
-252
11
CC1F3
104.5
-81.4
-114.6
-181
-294
22
CHC1 F2
86.47
-40.75
-41.36
-160
-256
113
C2C13F3*
187.38
47.57
117.63
-35
-31
114
C2C12F4**
170.93
3.77
38.78
-94
-137
115
CC1F2-CF3
•154.47 '
•-39. 1
-38.4
-106
-159
13B1
CBrF3
148.S2
-57.75
-71. S5
-168
-270
Molecular Formula
Molecular Weight
Boiling Point °C
(1 atm) °F
Freezing Point °C
°F
Vapor Pressure, psia 15 92 510 150 6.4 31 130 230
(at 25°C) .
Solubility of Compound 0.11 0.028 - 0.30 0.017 0.013 0.006 0.03
in water, wt. % (sat'n pres.)
(1 atm, 25°C)
Density, liquid g/cc 1.476 1.311 - 1.194 1.565 1.456 1.291 1.538
(25°C) Ibs/ft3 92.14 81.84 - 74.53 97.69 90.91 80.60 96.01
Density, Sat'd Vapor g/1 5.86 6.33 - 4.72 7.38 7.83 8.37 8.71
(at boiling
point) lbs/ft3 0.367 0.395 - 0.295 0.461 0.489 0.522 0.544
* Predominately CC12F-CC1F2 (Hamilton, 1962)
** Predominately CC1F,-CC1F, (Hamilton, 1962)
-------
The fluorocarbon compounds are highly resistant to attack by
conventional oxidizing agents at temperatures below 200°C (Bower,
1971; Downing, 1966).
Because of the presence of a hydrogen atom in the molecule,
fluorocarbons such as F-22, F-142b and F-152a are probably more
susceptible to hydrolysis and oxidation than the completely halogen-
ated fluorocarbons (Hamilton, 1962). Whether hydrogen-containing
fluorocarbons are subject to hydrolytic or oxidative degradation under
environmental conditions has yet to be adequately demonstrated. One
study by Cox ejt al_. (1976) discussed in Section V.C. does indicate
that F-142b reacts with »OH radical (simulating photochemical oxida-
tion) whereas F-ll and F-12 do not.
The fluorocarbons als6 have a high degree of thermal stability,
with the more highly fluorinated compounds being generally more
stable. Specific rates of thermal decomposition depend on experi-
mental conditions and the presence of contaminants such as air or
water. Thermal stability data have been presented by Callighan (1971)
and DuPont (1969).
Photodissociation of the fluorocarbons occurs when they are
irradiated with ultraviolent light with wavelengths below 200 nm.
Because of the possible effects of this reaction on stratospheric
ozone, it is dealt with in more detail in the context of that problem
in Section VI. The lack of photolysis of fluorocarbons with longer
wavelengths of light under conditions simulating photochemical smog
is discussed in Section V.C.
-------
III. PRODUCTION
A. Production Methods
The most widely used method for commercial synthesis of the
major fluorocarbons consists of the catalytic displacement of
chlorine in chlprocarbons by fluorine from reaction with anhy-
drous hydrogen fluoride (Hamilton, 1962). The commonly used
chlorocarbons are carbon tetrachloride (CC1.), chloroform (CHCl,),
and hexachloroethane (CpClg). A more recent process developed by
DuPont in the U.S. and Montecatini Edison in Italy uses the
direct reaction of methane with a mixture of chlorine and hydro-
gen fluoride.
The several steps in the conventional chlorocarbon process
are shown in Figure 1. The reaction phase uses antimony penta-
chloride as a catalyst and some chlorine gas which maintains the
catalyst in its pentavalent rather than its trivalent state. The
reaction can be conducted in either liquid or vapor phases.
The liquid-phase operation is carried out by feeding liquid
hydrogen fluoride (HF) and chlorocarbon to the reactor and simul-
taneously withdrawing hydrogen chloride (HC1) and the desired
organic product as vapor from the top of the reflux condenser.
Reaction conditions can vary from pressures of 0 to 500 psig,
temperatures of 45° to 200°C, catalyst concentrations from 10 to
90 weight per cent, and take-off temperatures of -30 to +100°C
(Hamilton, 1962). The liquid process is characterized by simple
and flexible operation. The quick removal of final product
avoids overfluorination.
The vapor-phase process consists of a heated tube filled
with a granular catalyst. The feed is a vaporized mixture of HF
and chlorocarbons. The process is frequently used for the
production of the highly fluorinated compounds.
- 13 -
-------
Chlorinated
Hydrocarbon
CHC13, CC1.,, C2C16
, Recycled
Intermediate
Hydrogen
Fluoride
Reactor
Containing
SbCls Catalyst
Distillation
Column
Product + HC1
Distillation
Column
Drying
Distillation
Drying
Low Boiling
Drying
High Boiling
Low Boiling, Temp
Product
No. 12, 22, 114
Recycled
Chloro-
carbons
High Boiling Temp
Product
No. 11, 113
for sale or disposal
Spent acid to
disposal
Figure 1
Flow Diagram of Fluorocarbon Manufacture from Chlorinated Hydrocarbons
-------
In both processes, the proportion of the mixed fluorinated
products is determined by the chlorocarbon used and by the temper-
ature, pressure, and reaction time. By-product hydrogen chloride can
be separated either by distillation or by scrubbing. The distilled
hydrogen chloride has the advantage of being extremely pure and,
therefore, can be used directly in some associated synthesis or
packaged for sale. Unreacted hydrogen fluoride may also be recovered.
Bromotrifluoromethane is made by a similar process, starting with
carbon tetrabromide., However, it can also be made by the bromination
of trifluoromethane or by the replacement of chlorine in chlorotri-
f1uoromethane by reaction with hydrogen bromide.
Fluorocarbon production equipment is generally conventional in
design, using standard distillation columns, scrubbers, and drying
towers. The reactors are jacketed or tubular vessels made of carbon
or stainless steel. Since the reaction is slightly endothermic, heat
is supplied by steam, by flue gas, or by electrical heaters.
B. Producers
The major U.S. producers are listed in Table II along with the
trade names and numbers of their fluorocarbon products and an estimate
of total plant capacities (Directory of Chemical Producers, 1975; U.S.
International Trade Commission, 1973).
Table III presents a list of .foreign manufacturers of fluor-
carbons.
C. Quantity Produced and Price
The reported total demand for all fluorocarbons in the U.S. was
945 million pounds in 1974 and 805 million pounds in 1975 (Chemical
Marketing Reporter, 1975). Total U.S. demand in 1973 was 880 million
pounds (Chemical Marketing Reporter, 1973). The world production of
fluorocarbons is approximately twice the U.S. production (McCarthy, 1974).
U.S. production and market values in recent years for F-ll, F-12,
and F-22 are shown in Table IV; production estimates for other fluorocarbons
are included in Table V. Estimated production of F-114 for 1972 was 20
- 15 -
-------
Table II: Fluorocarbon Producers and Plant Capacities
Company
Allied Chemical
Corporation
E.I. duPont de
Nemours & Co.
Kaiser Aluminum and
Chemical Corporation
Pennwalt Chemical
Corp.
Racon, Inc.
Union Carbide
Corporation
Trade Name
Total Plant
Capacity
Millions of Ibs./yr.
Major Fluorocarbon
Compounds Produced
(ID
Genetronviix
Freon^
Kaiser
Isotron^*'
Racon^
UCON®
310
500
50
115
20
200
11, 12, 22, 113,
114, 152a
11, 12, 13, 14, 22,
J13, 114, 115, 142b,
152a, 13B1
11, 12, 22
11, 12, 22, 142b
11, 12, 22
11, 12
-------
Table III; Foreign Fluorocarbon Producers
Country
Argentina
Australia
Brazil
Canada
China
Czechoslovakia
England
France
East Gennany
West Gennany
Greece
India
Israel '
Italy
Japan
Mexico
Netherlands
R mania
South Africa
Spain
D.S.S.R.
Producer
Dueilo S.A.
Fluoder S.A.
I.R.A.S.A.
Australian Fluorine Chemicals
Pacific Chemical Industries
DuPont do Brasil
Hoechst do Brasil Quimica e
Farmceutica
DuPont of Canada
Allied Chemical (Canada)
(State authority)
Slovak Pro Chanickov A Hutni
Vyobu, Ustlnad Cabem
Imperial Chemical Industries
I.S.C. Chemicals
Produits Chimiques Pechiny-
Ugine-Kuhlman
Fhone-Poulenc Industrie
V.E.B. Chaniewerk Nunchritz
Chenische Fabrik von Heyden AG
Farbwerke Hoechst AG
Kali-Chemi Pharma Gmbh
Chemical Industries of Northern
Greece
Everest Refrigerants
Navin Fluorine Industries
Makhetsim-Daran (subsid. Koor
Chemicals)
Montedison
Mitsui Fluorocnemicals Co.
Daikin Kogyo Co.
Asahi Glass Co.
Shows Denko K.K.
Halocarburos S.A.
Quinobasicos
DuPont (Nederland)
Akzo Charlie B.V.
(State authority)
African Explosives & Chemical
Industries
Ugimica
Kali-Chendc Iberia
(State authority)
Trade Name
Freon
Algeon
Frateon
Isceon
Foran,Friqen
Frebn
' Frigen
Freon
Genetron
Ledon
Arcton
Isceon
Forane
Flugene
Frigedohn
(sold by Hoechst)
Frigen
Kaltron
F-ll, F-12
Everkalt
Mafron
Algofrene
Freon
Daiflon
Asahiflon
Flonshowa
Freon
Genetron
Freon
FCC
Arcton
Foianu
Kaltron
.Frigen
Eakijnon
- 17 -
-------
Table IV
i
«j
oo
Production of Fluorocarbons 11, 12 and 22 in the U.S.
Compound
(Fluorocarbon $
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971p
1972p
l?73p
1974D
Smirro- II C 1
Tri chl arofl uoromethane
') (ID
Production
(10s Ib)
91
125
140
148
170
170
182
204
238
244
258
300
334
341
r«+n«.f>4--~--i
. Price
(dollars/lb)
—
—
—
' —
—
: —
•
.18
.19
.19
.18
.19
.24
•r !-*»__' • • •
and Market Value
Dichl orodl fl uoromethane
(12)
Production
(10s Ib)
173
208
217
228
271
286
310
326
368
375
390
439
488
487
Price
(dollars/lb)
m J—
__
.
„
.25
.26
.25
.24
.24
->1
.01
Chlorodifluo
(22)
'Sales
(10s Ib)
24-
i
29
36
43
50
56
59
55
71
73
80
80
102
112
rome thane
Price
(dollars/lb)
.56
.51
.51
.49
.45
.56
p - Preliminary
-------
Table V
Uses of Fluorocarbons in the Unitad States (1972)
Fir*
Aerosol Foaming Extinguishing
Fluorocarbon Production Propellent Refrigerants .Solvents . Agent b Agent
Number Formula 1972 Z Quantity Z Quantity Z Quantity Z Quantity Z Quantity
(106 Ibs.) (106 Iba.) (106 Ibs.) (106 Ibs.) (106 Its.) (106 Ibs.)
11
12
22
113
114
115
13B1
Total
X of Total
CC13F
CC12F2
CHC1F2
CC1F2CFC12
CC1F2CC1F2
CC1F2CF3
CBrF3
Production*
300* 82 246 3 9 15 45
439a 60 264 30 132 10 44
80*>b 100 80
-50C 100-50
-2QC 95 19 5 1
10-90
-ioc ..'••.
5 95-4
-900 529 221 50 89 -4
59Z 25Z 5Z 10Z
* U.S. International Trade Commission, 1972.
b Sales
c Estimates based upon discussions with DuPont and Allied Chemical; 1973 and 1974 production of F-113 approximately
60 million Ibs./year (Shamel et al_., 1975).
The production figures only marginally consider amounts used in the manufacture of fluorocarbon plastics. Fluoro-
carbon 22, 113, and 114 are used to synthesize the plastics. However, 13 million Ibs. of polytetrafluoroethylene
w.is produced in 1972 (U.S. International Trade Commission) from fluorocarbon 22, but that quantity is not reflected
in the SO million Ibs. sales figure.
e Tnc Chemical Marketing Reporter (1975) reports the following percentage of use: propel!ants-50%; refrigerants-28X;
plastics-10*; solvents-5Z; blowing agents, exports, miscellaneous-?* on a .1975 total production of 805 million Ibs.
The percentages reported In this table are similar in magnitude but quantitatively differ mostly because plastics
have not been included.
-------
million pounds, as shown 1h Table V; Shamel e_t al_. (1975) estimated
that production of F-114 was 25 million pounds in 1972, and 27 million
pounds in 1974. Production data for individual fluorocarbons are not
available for 1975; however, the U.S. International Trade Commission
reports that combined production of F-ll and F-12 was approximately
602 million pounds for the period January through November, 1975.
Hoffman (1976) has estimated the 1975 worldwide production of three
minor fluorocarbons F-13, F-14, and F-21 to be 110,000-440,000 pounds,
30,000-120,000 pounds and 30,000-120,000 pounds, respectively. No
information was available on the annual production of halothane, the
widely used fluorocarbon anesthetic.
From 1968 through 1974, U.S. fluorocarbon production increased at
an annual rate of 11$; 1974 production is believed to have increased
only 4.5% over 1973 levels (Stanford Research Institute, 1975). The
Chemical Marketing Reporter (1975) predicts no net growth for 1974-
1978.
Because of the theory that continued use of the two major fluoro-
carbons, F-ll and F-12, may result in a significant decrease in
stratospheric ozone (see Section VI), other fluorocarbons are being
investigated as possible replacements for these two compounds. The
leading candidate substances are, reportedly, F-22 (already produced
in substantial quantity for refrigeration), F-133a (CF3-CH2C1), F-142b
(CC1F2-CH3), F-152a (CHF2-CH3) and a number of compounds in the F-120
series (fluoroethanes containing one hydrogen atom) (Anonymous, 1976).
- 20 -
-------
IV. USES
The major uses of the fluorocarbon compounds are as aerosol
propel!ants, refrigerants, and foaming agents. Certain of the fluo-
rocarbons have major uses as solvents, as fire extinguishing agents,
or as intermediates in the production of fluorocarbon resins and
plastics. The use pattern of the fluorocarbons is shown in Table V,
where polymer intermediate uses are not included since the available
production figures do not encompass this application.
The largest commercial use of the fluorocarbons is as propel1 ants
in aerosol* products. The aerosol packaging industry began during
World War II, when two USDA researchers found that the efficiency of
insecticides was significantly increased when they were mixed with the
fluorocarbons, and dispensed as fine microscopic droplets. Civilian
commercialization began in the early 1950's, and today the world
production of aerosol products is about 6 billion units per year, with
the U.S. accounting for about half of the total. About half of all
aerosol products are fluorocarbon propelled; more than 75% of the
fluorocarbon-propelled aerosol products are for personal use (deodor-
ants, hair care, etc.), with the remainder being household products,
insecticides, coatings, and other industrial and commercial items
(Shamel ejt al_., 1975). Fluorocarbon 115 is approved for use as an
aerosol propel 1 ant in food products.
Use as refrigerants is the next largest application of the
fluorocarbons and is the use for which the fluorocarbons were ori-
ginally commercialized in the 1930's. The fluorocarbons are used for
both refrigeration (localized low temperature cooling) and air-con-
ditioning (cooling of rather large volumes of environmental air). A
distinction can be made between the large commercial units, which
* The term "aerosol" is used to include any "self-dispensing, pres-
surized, self-propelling products dispensed by the use of a liquefied,
non-liquefied or noncondensed gas" (Sage, 1963).
- 21 -
-------
are charged after the units are in place, and the smaller prefabri-
cated units which are charged and sealed at the factory. The dif-
ference between the prefabricated and large commercial units is
important in terms of the environmental release of the fluorocarbon
refrigerants. Table VI divides the use of the three major refriger-
ants, F-ll, 12, and 22, into the above categories for 1972 from
information supplied by Hanavan (1974). F-13 is used in low temper-
ature specialty refrigeration applications employing reciprocal
compressors and in the low temperature segment of cascade refrigeration
systems. F-14, and possibly F-13B1 are also used in the low-tempera-
ture segment of cascade refrigeration systems. The only known use for
F-21 is as a conventional refrigerant for cabin cooling in the NASA
space shuttle (Hoffman, 1976).
Blowing agents are used in the plastics industry to produce a
finished product in a foamed or expanded form. The f1uorocarbons were
first used in the production of polyurethane foams, where they impart
improved thermal insulation properties because of the fluorocarbon
trapped in the cells of the finished product. Fluorocarbons are also
used to form open-cell foams, in which case they are released to the
air. Blowing-agent uses of the fluorocarbons are divided approxi-
mately equally between closed- and open-cell applications.
The higher-boiling fluorocarbons, especially F-113, find use as
selective solvents for cleaning precision equipment and for extraction
of a variety of natural products. Some fluorocarbon solvents are
azeotropes or blends with non-fluorocarbons, such as F-113 and dichlo-
roethane (azeotrope); F-113, methylene chloride and cyclopentane
(azeotrope); F-113 and SDA-30 alcohol (azeotrope); and F-113 and
isopropyl alcohol (blend).
F-22, F-113 and F-142b are used as intermediates in the production
of fluorocarbon resins. F-22 is pyrolyzed to produce tetrafluoroethylene,
which is polymerized to form polytetrafluoroethylene (PTFE). PTFE is
- 22
-------
Table VI
Use of Kluorocurlion Refrigerants
Fluorocarbon Quantity Used Air Conditioning
as Large
Formula Number Refrigerant Prefabricated Commercial
(106 Ibs.) % Quantity % Quantity
106 Ibs. 106 Ibs.
CC13F
11
72%
Prefabricated
% Quantity
106 Ibs.
Refrigeration
Large
Commercial
% Quantity
106 Ibs.
28% 3
ro
to
CC12F2 12
132 45% 59
(automobiles)
29% 38
7% 9
19% 25
CHC1F2
22
80
221
57%
46
105
41%
33
77
% Prefabricated - 52%
% Large Commercial = 48%
2% _2
30
-------
the major fluorocarbon resin produced, accounting for about 80% of all
fluorocarbon resins in 1970. Production of PTFE in 1974 was 18.4
million pounds, which requires approximately 30 million pounds of F-
22. Hexafluoropropylene is also derived from F-22 and is used as a
copolymer with tetrafluoroethylene to produce fluorinated ethylene-
propylene resins and with vinylidine fluoride to produce a vinylidine
fluoride-hexafluoropropylene copolymer. Vinylidine fluoride is a
pyrolysis product of F-142b. Dechlorination of F-113 with zinc produces
chlorotrifluoroethylene, which is used to produce polychlorotrifluoro-
ethylene, and also as a copolymer with vinylidine fluoride to produce
a chlorotrifluoroethylene-vinylidine fluoride resins.
The fluorocarbon resins are used in a number of mechanical,
electrical, and chemical applications where their properties of
strength, chemical inertness, weatherability, resistance to temper-
ature extremes, nonflammability, low coefficient of friction (non-
stick properties), and excellent dielectric properties are of advan-
tage. The amount of fluorocarbons used as plastic intermediates is
not known, but it has been estimated to be 50-100 million pounds for
1972 over and above the 900 million pound total shown in Table V
(Howard ejt al_., 1974).
Use of fluorocarbons as fire-extinguishing agents is a relatively
small application of these compounds. The only fluorocarbon used to
any extent as a fire extinguishing agent in the U.S. is F-13B1 (CBrF3),
while F-12B1 (CBrClF2) is used widely in Europe and Australia. F-13B1
is an effective agent for surface fires, as with flammable liquids,
and on most combustible solids, excepting some of the active metals,
metal hydrides, and materials containing their own oxidizer (Hammack,
1971). In general, these compounds appear to have good application in
situations where the value density is high, such as in aircraft,
spacecraft, mines, and computers (Jensen, 1972).
- 24 -
-------
Halothane (CF3-CHBrCl) 1s a widely used general anesthetic for
surgical procedures. No information was available on the volume of
halothane used in the U.S. annually. Russell (1976) estimates that
about 25 million anesthetics are administered annually in the U.S.,
and that 50% or more are with halothane. Usage has declined steadily
since the mid-19601s due to medical-legal concerns stemming from
reports of various toxic effects both to patients and operating room
personnel.
Some of the minor applications of the fluorocarbons are uses as
dielectric fluids, heat-transfer fluids, power fluids, cutting fluids,
pressurized leak-testing gases, gases in wind tunnels and bubble cham-
bers, and as a drain opener propellant (DuPont, 1969; Dowing, 1966).
The projected growth markets for the fluorocarbons are as heat
and power transfer fluids (especially if adopted for use in the
Rankine cycle engine); as a dry-cleaning solvent (F-1T3); as an
immersion freezing agent for food (F-12); and increased use as inter-
mediates for fluorocarbon resins and elastomers (Drysdale, 1971;
Noble, 1972).
- 25 -
-------
V. ENVIRONMENTAL ASPECTS
A. Release to the Environment
The total amount of fluorocarbons produced annually in the
U.S. is currently greater than 900 million pounds, predominantly
fluorocarbons 11, 12, and 22 (see Tables IV and V). The major
routes by which the fluorocarbons reach the environment involve
their commercial applications. Further, all losses of the fluo-
rocarbons are to the atmosphere. Fluorocarbon losses have been
estimated to be less than 1% during production operations and
less than 1% during storage and transport (McCarthy, 1973).
While 1% translates to roughly 9 million pounds per year, which
is a considerable amount of material, it is practically insig-
nificant when compared to total environmental losses described
below.
Estimating the annual release of fluorocarbons from their
commercial uses is difficult due largely to uncertainties in the
rate of fluorocarbon losses from the refigerant applications. In
the refrigerant use, especially when prefabricated, sealed
appliances such as home refrigerators, freezers, and air con-
ditioners are considered, there is a significant time delay (10
years or more) between production of the refrigerant and disposal
of the appliance when corrosion, damage, etc. result in release
of the refrigerant to the atmosphere. Large commercial and
industrial refrigeration and air conditioning units are subject
to losses from leakage during their lifetime and require recharg-
ing to replace lost refrigerant. Of the refrigerant loss esti-
mates which have been reported (Howard e_t al_., 1974; Howard and
Hanchett, 1975; Shame! et al_., 1975), that of Shamel e_t aj_.
(1975) considers the problem in most detail. These authors
calculated that, in 1973, a total of 212.3 million pounds of
fluorocarbon was lost to the environment from refrigerant uses.
- 26 -
-------
All of the fluorocarbon which is used as an aerosol propel1 ant is
released to the environment. About 1% or less is lost during charging
and sealing of the containers (Harmon, 1974), and the remainder is
lost during the actual use of the aerosol product or from the destruc-
tion and eventual corrosion of the discarded containers. It is esti-
mated that there is a delay of approximately one year between production
and release to the atmosphere from aerosol products. Therefore,
losses in 1973 are approximately equal to 1972 aerosol propel 1 ant
consumption, or about 500 million pounds. The fluorbcarbons which are
of most importance in environmental contamination by this pathway are
F-ll and F-12.
The rate of loss of f1uorocarbons from solvent uses, primarily
F-113, is also difficult to estimate because of uncertainty in the
amount recovered for reuse. Information presented by DuPont (1975)
indicates that the current growth of F-113 solvent uses (i.e., for new
equipment other than replacement of scrapped units) is negligible.
Hence, the annual loss rate is probably close to the annual produc-
tion, or 50-60 million pounds in 1973.
Loss of fluorocarbons used as blowing agents is estimated to be
about 100% from open-cell foams, and negligible from closed-cell
foams. Since the fluorocarbon blowing agents are approximately
equally divided between open-cell and closed-cell applications,
losses are about 50% of the annual blowing-agent demand.
Except for polymer Intermediate uses, fluorocarbons will also be
lost to the environment from the minor applications, although it is
impossible to estimate such losses on an annual basis.
Using the above information, it is estimated that more than 700
million pounds of fluorocarbon was emitted from U.S. applications in
1973. Assuming that the future U.S. consumption pattern remains con-
stant, future annual, losses will probably continue to be equivalent to
about 80% of production in that year. Worldwide emissions, as with
production, are approximately twice those for the U.S.
- 27 -
-------
While estimates of annual loss rates are useful guides, they
should not overshadow the point that, eventually, al1 of the fluoro-
carbon produced (with the exception of that used as an intermediate)
will be released to the environment as either the direct (as with
aerosol propel 1 ants) result of the applications for which they are
produced or the eventual disposal of the products in which they are
incorporated.
Because of the characteristic high vapor pressures, low boiling
points, and low water solubilities of this class of compounds and
because all losses are initially to the atmosphere, it would be
expected that released fluorocarbons would be present primarily in the
air. This is shown to be the case by actual measurements, which are
described below.
B. Methods of Analysis and Environmental Detection
The method most often used to detect fluorocarbons in the air at
low levels is direct analysis of air-fluorocarbon mixtures using gas
chromatography with an electron capture detector (GC-EC). This
technique, which is specific for halogenated compounds, is extremely
sensitive to F-ll, being typically capable of detecting it at 5-10 ppt
v/v (parts per trillion by volume). This method can also typically
detect F-12 at 100 ppt v/v (Hester e_t al_., 1974). Recently, Hester e_t
al. (1975b) reported improvements in the GC-EC techniques which make
it possible to routinely measure F-ll at 1 ppt v/v and F-12 at 10 ppt
v/v. For fluorocarbons with fewer than two chlorine substituents, or
with more fluorine and hydrogen substituents (such as F-22, F-115),
the sensitivity of GC-EC falls off. For these compounds, gas-chroma-
tography with a flame-ionization detector is as sensitive as GC-EC
(demons and Altschuller, 1966). Unlike electron capture, however,
flame-ionization is not specific for halogenated compounds. Lillian
e_t aJK (1975) have used a gqs chromatography with both an electron
capture detector and flame ionization detector for simultaneous
measurement of a number of halocarbons, including fluorocarbons, in
atmospheric samples.
- 28 -
-------
Gimsrud and Rasmussen (1975) have used a gas chromatograph
linked directly to a mass spectrometer for measuring F-ll and F-12 in
atmospheric samples. This method has approximately the same sensi-
tivity as GC-EC for F-ll and F-12 (5 ppt v/v for each), and offers the
advantage of giving positive identification of the sample components
from the mass spectra.
Hanst e£ al_. (1975) have used long path infrared absorption
spectroscopy to measure the fluorocarbons in atmospheric samples. The
method offers no advantages over the others in sensitivity and air
samples must be concentrated (Hanst e_t a_K use a cryogenic procedure)
to permit detection of the fluorocarbons. The method is useful,
however, for verifying the identity of substances measured by gas
chromatography.
While production and release of the fluorocarbons, especially
F-ll and F-12, have been significant since the early 1950's, detection
of fluorocarbons in the environment did not occur until 1970. Although
some F-12 measurements have been reported, the fluorocarbon most often
measured is F-ll. This is due largely to the availability of the GC-
EC method which, as mentioned above, is extremely sensitive to F-ll.
Published F-ll and F-12 measurements are shown in Table VII. The
levels of F-ll over urban areas are several times those levels found
in rural areas and over oceans. This is not surprising since the
primary mode of F-ll entry into the environment is from aerosols and
refrigeration devices, use of which is, of course, much greater in
areas of high population and industrialization.
The data of Wilkness et al_. (1975) for Washington, D.C. show high
levels of F-ll during stagnant air conditions, with a decrease as
clean air arrives and displaces the polluted air mass. From another
point of view, Lovelock's data (1971; 1972) for a rural area in south-
west Ireland show low levels of F-ll when winds are from the Atlantic
Ocean, but the levels increase when polluted air arrives from the
European continent with easterly winds.
- 29 -
-------
TABLE VII
Atmospheric Concentrations of Fluorocarbons 11 and 12
Site, Date, and Conditions
Urban Sites;
Los Angeles Basin, July 25, 1972
(inversion layer present)
Los Angeles Basin, Sept - Oct, 1972
(various conditions)
San Diego, California (downtown), 1973
LaJolla Pier, (San Diego), Calif., 1973
Washington, D.C., July 9, 1974
.(airpollution conditions)
Washington, D.C., July 11, 1974
(advancing Canadian cold front)
Washington, D.C., July 12, 1974
(following Canadian cold front passage)
Concentration
(parts per trillion by volume)
F-ll F-12
560
650
290* 240
370* 560
380
200
160
700
3200* 1400
5800± 4600
References
Hester ejt al_., 1974
Simmonds et^ §]_., 1974
Su and Goldberg, 1973
Su and Goldberg, 1973
Wilkness et al.., 1975
Wilkness e_t a^L, 1975
Wilkness et al., 1975
-------
TABLE VII (cont.)
Atmospheric Concentrations of Fluorocarbons 11 and 12
Site. Date, and Conditions
Ocean Sites:
Atlantic Ocean, voyage from United Kingdom
to Antartica, and return, 1971-1972
Atlantic Ocean, voyage from Hamburg to
Santo Doming, October, 1973
Pacific Ocean, November - December, 1972
Pacific Ocean, March - April, 1974
Concentration
(parts per trillion by volume)
F-ll F-12
49.6± 7.1
ppt above 40°N;
ppt at 20°N;
^40 ppt between '
0°-60°S)
88.6± 4.05
~70 at 20°N
~65 at 0°
~60 at 60°S
-87 at 20°N
~80 at 0°
115.2± 33.1
References
Lovelock et al., 1973
Lovelock, 1974
Wilkness et al., 1973
Wilkness et al., 1975
-------
The F-ll levels found over the Atlantic and Pacific Oceans indi-
cate the ubiquity of this compound in the atmosphere. Wilkness et al.
(1975) have compared their data over the Pacific for 1972 and 1974
with the Atlantic data of Lovelock for 1971-1972 and have calculated
that the background level of atmospheric F-ll increased 22% between
November 1971 and November 1972, 31% between November-December 1972,
and March-April 1974, with an overall increase of 60% between November
1971 and March-April 1974. These increases are proportional to the
estimated world-wide production and release increase of F-ll during
these periods. The ocean data also indicate higher levels in the
northern hemisphere than in the southern hemisphere, which is to be
expected since the major use areas of F-ll (North America, Europe) lie
in the northern hemisphere.
Lovelock et al. (1973) and Wilkness et al_. (1975) have reported
the presence of F-ll in ocean surface waters. The F-ll was not
measured as the concentration within the water in either case, but was
instead measured as the aerial concentration above the water sample
after equilibrium was achieved. While these measurements do indicate
that some F-ll is present in the well-mixed surface waters of the
ocean, the significant finding was that no F-ll was detectable in
samples taken from below the surface waters (about 200 meters depth)
indicating that the oceans are not a significant sink for F-ll.
Of special interest in considering environmental exposure to the
fluorocarbons are the levels which occur at or near the sites where
fluorocarbons are released. Hester e_t al_. (1974) measured F-ll and
F-12 levels proximal to two factories known to use these compounds.
Near a cosmetics plant where fluorocarbon-propelled aerosol cans are
filled, levels were 3-4 times the typical city readings. Near a
polyurethane plant (blowing agent use), concentrations of F-ll which
were detected (24-42 ppb v/v) were 100 times the average city readings.
Hester e_t al_. (1974) also examined F-ll and F-12 levels in homes
and in public buildings. In homes, F-ll concentrations ranged from
0.3 to 510 ppb v/v. While F-ll and F-12 concentrations in homes were
- 32 -
-------
generally higher than levels outside the home, there was no "typical
level" in the homes nor Were exceptional levels detected in any
particular room. Levels in public buildings where fluorocarbons are
apt to be used (drug store, beauty shop, hospital, etc.) were also
higher than outside air levels, and, except for the high levels found
in the beauty shop (50 ppb v/v F-ll; 370 ppb v/v F-12), the levels
were similar to the home samples.
Bridbord e_t al_. (1974) presented data showing that the F-12 level
in a 29,300-liter room during a 60-second release of hair spray was
62,100 ppb, falling off to 2,500 ppb in 30 minutes and 100 ppb in 60
minutes. Air sampled in a 21,400-liter room one minute after a 30-
second release of an insect spray had an F-12 level of 466,400 ppb,
declining to 26,400 ppb after 60 minutes and 11,500 ppb after 150
minutes.
C. Environmental Fate of Fluorocarbons
A boundary occurs in the earth's atmosphere known as the tropo-
pause, the height of which varies with latitude, season and particular
weather conditions. Near the polar regions the height of the tropo-
pause may be only 8 kilometers, increasing to about 18 kilometers in
tropical regions. Below the tropopause is the portion of the atmos-
phere known as the troposphere which is characterized by a monotonic
decrease in temperature with increasing altitude. Above the tropo-
pause and extending to an altitude of about 50 kilometers is the
portion of the atmosphere known as the stratosphere where temperature
increases with increasing altitude, although the maximum temperature
reached at the top of the stratosphere is still less than 0°C. Within
the troposphere there are no apparent sinks for the fluorocarbons.
While there is no published information on the bioaccumulation or
biodegradability of the fluorocarbons, the volatility and general
resistance of these compounds to metabolism and biotransformation
would limit, if not preclude, interactions in the biosphere as sinks
for the fluorocarbons. [Unpublished data indicate that soil and plant
uptake of F-ll and F-12 is not significant (Taylor, unpublished).]
- 33 -
-------
Although F-ll and F-12 are detectable in the well-mixed surface waters
of the oceans, the levels found eliminate the oceans as a significant
fluorocarbon sink (Lovelock et al_., 1973; Wilkness e_t aj_., 1975).
Using wavelengths above 310 nm, Japar e_t aK (unpublished) found
no evidence of reaction with fluorocarbons 11, 12, 113, 114, and 115
during irradiations of mixtures of the fluorocarbons with olefins and
nitrogen oxides in a long-path infrared cell reaction vessel. Hester
e_t al_. (1974) placed F-ll and F-12 in ambient air samples in a 20-
liter Pyrex carboy and irradiated them for a period of almost two
months with eleven blacklight fluorescent lights; they found no
detectable change. Hester e_t a\_. (1975b), using identical procedures
but including F-ll3 and F-114 in the sample, were again unable to
detect any loss of fluorocarbon. Hester et'aj. (1975b) detected no
loss of fluorocarbon in an air sample containing F-ll, F-12, F-113,
F-114, propene, and nitrogen dioxide irradiated with simulated sun-
light for seven hours. Addition of sulfur dioxide and irradiation for
up to seven days resulted in aerosol formation, but again no detec-
table loss of fluorocarbon. Saltzman et aK (1966) found no photo-
chemical reactivity for F-13B1 irradiated with fluorescent blacklights.
Cox et a]_. (1976) have measured the reactivity of F-ll,'F-12,
F-142b, and other halocarbons with hydroxyl radical, 'OH. (Photooxida-
tion of hydrocarbons is primarily initiated by the reaction with -OH.)
F-ll and F-12 were essentially unreactive with «OH. The calculated
tropospheric lifetimes with respect to oxidation by *OH were much
greater than 1000 years for F-ll and greater than 330 years for F-12.
The calculated lifetime of F-142b, a hydrogen-containing fluorocarbon,
was 8 years. For comparison, the lifetimes of chloro-, dichloro-, and
trichloromethane were 0.37, 0.30, and 0.19 years, respectively.
The persistence of the fluorocarbons, particularly F-ll and F-12,
is further demonstrated by the fact that currently measured concentra-
tions of these compounds in the troposphere roughly account for all of
these materials produced to date, given the uncertainties in the
- 34 -
-------
assumed volume of the atmosphere, In the non-uniform global distribu-
tion of the compounds, and in the worldwide release estimates which
are introduced into the calculations (Howard and Hanchett, 1975;
Lovelock e_t al_., 1973; Wilkness e_t al_., 1973). These claims imply
that the tropospheric lifetimes of F-ll and F-12 are at least 40 years
(the span of production of the fluorocarbons) and are possibly infi-
nite. Sze and Wu (1975) argue that the current tropospheric levels of
F-ll and F-12 are also consistent with lifetimes of only 10-20 years,
since most of the production and release of these materials has
occurred in the past 20 years (approximately 98% for F-ll and 92% for
F-12). Still, no tropospheric sinks have been found for F-ll or F-12
that could support lifetimes shorter than 40 years. Krey et al.
(1976), using measured stratospheric and tropospheric concentrations,
industrial production rates, and a photolysis half-life of 2-4 years
in the stratosphere, calculated the total atmospheric half-life of
F-ll to be 15-30 years.
The environmental fate of the fluorocarbons other than F-ll and
F-12 has not been reported in the literature. Although the hydrogen-
containing fluorocarbons are expected to be more susceptible to
hydrolytic and photooxidative degradation than the perhalogenated
compounds (Hamilton, 1962), it has yet to be shown that these com-
pounds will degrade readily in the troposphere.
While the persistence of the fluorocarbons in the troposphere was
recognized with the earliest reports of detection, it was assumed then
that because of their high degree of stability, the fluorocarbons
presented no threat to the environment. A theory has recently emerged
which suggests that these compounds will diffuse upward into the
stratosphere and will catalytically destroy stratospheric ozone. The
mechanism and significance of this possible adverse environmental
effect of the fluorocarbons follows.
- 35 -
-------
VI. STRATOSPHERIC OZONE DEPLETION FROM FLUOROCARBONS
Ozone, Og, is a natural minor ingredient of the earth's atmos-
phere found predominantly in the stratosphere in a layer between about
15 and 50 kilometers above the earth's surface, maximizing at about 25
kilometers. Although referred to as the "ozone layer" it should be
pointed out that this is by no means a region of pure ozone. Even at
the 25-kilometer altitude of maximum occurence, the density of ozone
does not exceed 10 molecules per cubic centimeter. Compared to
18
approximately 10 molecules of air per cubic centimeter at this
altitude, the peak ozone mixing ratio is less than 10 ppm by volume.
The ozone layer acts as a filter, shielding the earth's surface from
practically all solar radiation of wavelengths shorter than 300 nm,
_K_e_._, ultraviolet light.
The mechanism by which ozone is produced in the atmosphere was
first described by Chapman (1930). The two-step scheme he proposed,
as shown in reactions [1] and [2], involves the photolysis of molec-
ular oxygen by radiation of wavelengths below 242 nm, and the subse-
quent combination of the atomic oxygen formed in [1] with molecular
oxygen, involving a third body, M, which is usually N~ or 0».
09 u.v. radiation 20- [1]
£ - _> .
0» + 02 + M + 03 + M [2]
Ozone is destroyed, according to Chapman, by reactions [3] and
[4].
u.v. radiation 09 + 0» [3]
>
03 + 0- -»• 202 [4]
Reaction [3] occurs primarily with radiation of wavelengths below
300 nm.
- 36 -
-------
Ozone can also be destroyed by a catalytic reaction with
naturally occurring nitric oxide as shown in reactions [5] and [6].
This sequence, identified by Crutzen (1970), is referred to as the
"NO" cycle.
/\
NO + 03 -*• N02 + 02 [5]
N02 + 0- -»• NO + 02 [6]
The NO cycle is considered to be the most important
/v • , -
natural control of ozone levels in the stratosphere. Recently,
there has been concern that supersonic transport planes will inject
significant amounts of nitrogen oxides into the stratosphere and
upset the natural balance of the cycle, perhaps resulting in ozone
depletion.
An ozone reduction sequence similar to the NO cycle occurs
with natural odd-hydrogen species (H, »OH, H02), but is not sig-
nificant compared to the NO cycle.
^
A chain reaction sequence resulting in ozone destruction
involving chlorine atoms, as shown in reactions [7] and [8], was
investigated by Stolarski and Cicerone (1974) and Wofsy and McElroy
(1974).
Cl' + 03 •»• CIO + 02 [7]
CIO +.-0- •* Cl' + 02 [8]
This "C1X" cycle may also interact with the NOX cycle thus:
CIO + NO -" CT + N02 [9]
N02 .+ 0- •»• NO + 02 [6]
Cl- + 03 •*• CIO + 02 [7]
- 37 -
-------
Initially, the C1X cycle was not considered important since no
major source of Cl« entry into the stratosphere was known. Molina and
Rowland (1974), noting the measurements of Lovelock e_t aj_. (1973) and
their own work on photochemistry, proposed that the flourocarbons,
particularly F-ll and F-12, constitute a significant source of chlo-
rine entry into the stratosphere. The basis of this theory is that
these compounds, because of their high degree of stability in the
troposphere, diffuse upward into the stratosphere where (unlike in the
troposphere) sufficient ultraviolet radiation of wavelengths lower
than 220 nm exists, and are thus photolysed, resulting in the release
of free chlorine atoms. The fluorocarbons may supply enough chlorine
to the stratosphere for the C1X cycle to surpass the NO cycle as the
^
primary mechanism of ozone destruction. Further, there is concern
that, as a result, an overall depletion of the amount of ozone in the
stratosphere will ensue.
It is evident from the measurements of F-ll and F-12 in remote
areas that these two compounds are very stable and mobile in the
troposphere and would, therefore, most probably persist long enough to
diffuse upward into the stratosphere. Although actual measurements of
the fluorocarbons in the stratosphere are limited (Table VIII), these
data clearly demonstrate that the fluorocarbons do in fact reach the
stratosphere. An older data point for stratospheric F-ll and F-12
has been reported recently. Murcray (1975) reexamined data taken in
1968 at 60,000 ft. (about 18.3 km) by balloon over New Mexico and
reported that F-ll and F-12 concentrations at that time were 20 ppt
and 50-60 ppt, respectively. According to Murcray, this represents an
annual increase of about 14 percent, similar to the annual increase in
fluorocarbon use. Because extensive data on stratospheric levels are
not available, it has been necessary to rely upon atmospheric diffu-
sion models, or, more specifically, the sets of empirical equations
which describe the transport of trace substances in the atmosphere, to
predict the stratospheric concentration of fluorocarbons. Although
diffusion models involving all three dimensions (vertical, longitudinal,
- 38 -
-------
TABLE VIII
STRATOSPHERIC MEASUREMENTS OF F-ll AND F-12
Concentration (ppt v/v)
Altitude (km) Date
40-50 5/23/73
34 5/7/74
31 5/7/74
28.6 6/2/75
26.2±1 n.s.
24.5 6/2/75
23 9/9/73
22.3±.7 n.s.
.18. 3 5/23/74
17.7+.5 n.s.
16.9 6/2/75
-12. 2 5/23/74
10 6/74
9 6/74
8.5 6/74
a Measurements taken
b Measurements taken
c Measurements taken
F-11
<0.2
3
9
11
<20
18
45
30+3, -6
57
80±10
95
75
70-80
70-95
70
F-12
< 5
35
48
—
75±5
—
86
135±10
110
210±10
—
140
—
—
—
References
Heidt et al_. , 1975a
Heidt et,al_. , 1975a
Heidt et al_. , 1975a
Heidt et al_., 1975a
Schmeltekopf e_t al. ,
1975b
Heidt et. al_. , 1975
Heidt et. al_. , 1975
Schmeltekopf et al.,
1975
Hester ejt al_. , 1975ac
Schmeltekopf et al. ,
1975
Heidt et al. , 1975
Hester e_t al_. , 1975a
Lovelock, 1974d
Lovelock, 1974d
Lovelock, 1974d
over eastern Texas; tropopause at 15-17 km.
over Wyoming; tropopause at -15 km.
over New Mexico/Colorado; tropopause height
not stated.
d) Measurements taken over United Kingdom; tropopause at -8.5 km.
- 39 -
-------
and latitudinal) have been developed, the one-dimensional (vertical)
models have been used for the fluorocarbon considerations. These one-
dimensional models involve the concept of a "global average eddy
diffusion coefficient," the value of which is generally adjusted to
fit observations of average mixing patterns of some trace species in
the atmosphere. The predicted altitude profile of fluorocarbons (and
the photodissociation products) will, of course, depend on the diffu-
sion model which is used.
It was mentioned earlier that the fluorocarbons F-ll and F-12
will undergo photochemical decomposition when exposed to radiation in
the ultraviolet region, but that this process did not occur in the
troposphere since appreciable amounts of the necessary radiation do
not penetrate to the troposphere. In the stratosphere, sufficient
ultraviolet radiation is available for the photolytic reaction and
there is a competition between upward diffusion and photodissociation
of the fluorocarbons.
Doucet ejt al_. (1973) have determined the ultraviolet absorption
spectra for a series of chlorofluoromethanes. The pectra for F-ll
and F-12 are shown in Figures 2 and 3. While these compounds are
subject to dissociation by the entire range of wavelengths up to about
220 nm, Rowland and Molina (1974) point out that the slow diffusion of
these compounds into the stratosphere, together with the strong absorp-
tion of the lower wavelengths in the photodissociation of 02 (reaction
[1]) at higher altitudes probably limits the fluorocarbon-dissociating
wavelengths to a band between 184-220 nm.
The photodissociation rates (or absorption cross-sections) of the
fluorocarbons have been shown recently to be temperature dependent
(Rebbert and Ausloos, 1975). The values used in the following models
are those taken at room temperature; the effect of the temperature
dependence modification is discussed later.
The photochemical process resulting in dissociation, as shown in
reactions [10] and [11], has been interpreted as involving a transition
- 40 -
-------
Figure 2 (Dducet, et al.., 1973)
Th«
vacuum ultraviolet
spectrum of CFCfe.
The < values of the
two lowest frequency
bands are multiplied
by 100.
175 200
Wavelength, nm
Figure 3 (Doucet, et al., 1973)
The
vacuum ultraviolet
spectrum of Cl-fCli.
The- t values of the
lowest frequency
bands are multiplied
by 100.
125 150 175 200
Wavelength, nm
- 41 -
-------
to a repulsive electronic state that results in immediate dissociation
of the carbon-halogen bond. The energy available from the 184-
CFC13 u.v. radiation CFC12 + Cl [10]
CF2C12 u.v. radiation CF2C1 + Cl [11]
k
220 nm wavelengths far exceeds that required for C-C1 cleavage and is
sufficient to dissociate the C-F bonds as well. There is no informa-
tion showing that the C-F bonds are broken competitively with the C-C1
bonds, and most researchers have assumed that the primary photochemi-
cal decomposition of fluorocarbons follows that shown in reactions
[10] and [11], with loss of one chlorine atom. Rebbert and Ausloos
(1975) have reported that absorption of low wavelength (i.e., high
energy) ultraviolet radiation may result in the release of two chlo-
rine atoms from each F-ll or F-12 molecule per photon.
Rowland and Molina (1974) found that the best estimate of the
qulntum yield (j_.e.-, the measure of the efficiency of the photodisso-
ciation reaction taken as the number of molecules of starting material
changed per photon of radiation of a specified wavelength absorbed) at
213.8 nm for reaction [10] is 1.0 0.1, and that the quantum yield
for reaction [11] at 184.9 nm is also 1.0. Quantum yrelds of unity
have been confirmed at 184.9 nm by Mil stein and Rowland (1975) and at
213.9 nm by Pitts e_t al_. (1974). A quantum yield of unity indicates
an efficient photolytic reaction.
If two chlorine atoms are released from F-ll and F-12 directly
from photolysis, as proposed by Rebbert and Ausloos (1975) with low
wavelength ultraviolet, the residual molecules are CFC1 and CFp,
respectively. Although relatively stable, these species may react
with oxygen and are currently being investigated by the above researchers.
If only one chlorine is released upon photolysis, the residual
CFC12« and CF2C1» radicals, from F-ll and F-12 respectively, probably
- 42 -
-------
form phosgene type molecules. Marsh and Heicklen (1965) found that
F-ll photolyzed in the presence of 02 produced substantial amounts
of CFC10 and that the yield was unaffected by varying the CFC1,/02
ratio from 0.1 to 10. The mechanism of CFC10 formation is not
known, but probably involves a transient intermediate, CFC1202
which may decompose directly to CFC10 and CIO or react by some other
pathway to yield CFC10 and Cl* or CIO. Similarly, photolyzed F-12
should yield CFgO plus either Cl* or CIO. (Since Cl* and CIO rapidly
interchange under stratospheric conditions as in reactions [7] and
[8], the exact species formed is of no consequence.)
The photodissociation of F-ll or F-12 would result in the
formation of two C1X molecules (Cl* or CIO), either directly from
photolysis or one from photodissociation and one from the reaction
of the residual radical with 02- The possible fate of the CFC10 and
CF20 molecules may be additional direct solar photodissociation,
chemical reaction with various radical species, hydrolysis, or
downward diffusion and eventual tropospheric rainout. In many of
the models it is assumed that half of the CFC10 produced by photo-
dissociation of F-ll undergoes further reaction releasing the Cl*
atom, while half diffuses to the troposphere, resulting in a ratio
of 2.5 Cl* atoms per molecule of F-ll initially photolyzed.
The chlorine which is released into the stratosphere from
fluorocarbons may enter Into the reaction sequence as shown in [7]
and [8].
Cl« + 03 -»• CIO + 02 [7]
CIO + 0 -»• Cl- + 00
[8]
Net: 03 + 0 + 202
- 43 -
-------
This is, of course, a chain reaction in which ozone (or more
specifically, total odd-oxygen* species 03 + 0") is catalytically
destroyed.
There are other possible Cl*, CIO reactions in the stratosphere
affecting odd-oxygen removal* CIO may react with NO as in reaction
[9]:
CIO + NO •»• Cl- + N02 [9]
This reaction, competitive with [8], will depend on the 0-/NO ratio
at the altitude where it occurs. The fraction of CIO reacting with
0* increases with altitude (where the 0» concentration is greater),
so that reaction [9] is significant only at lower altitudes. The
effect of reaction [9] on odd-oxygen removal depends upon the fate
of the N02 formed. Reacting with 0* as in [6] results in an overall
depletion of two odd-oxygen equivalents. (This is the interaction
of the C1X and NOX cycles.) However, because of the low concentra-
tion of 0* at the 25-35 km altitude where the NO concentrations are
significant, this reaction is not favored, but rather the photolysis
of N02 to NO •*• 0«, with no overall net change in odd-oxygen concen-
tration is likely to occur.
Free Cl» may react with both stable (CH4, H2, HNOg, etc.) and
radical (H0«) hydrogenous materials. Of the possible reactions,
only those with CH^, H2> and H02 are currently thought to be of
importance. These reactions, [12]-[14], all forming HC1, terminate,
at least temporarily, the C1X chain reaction with odd-oxygen species.
Rowland and Molina (1974) have concluded that the only reactions for
CH4 + CT -* HC1 + CH3' [12]
H2 + Cl* * HC1 + H- [13]
H02 + Cl- -»• HC1 + 02 [14]
I
* It is often convenient to consider variations in the sum of 0, and
0», the "odd-oxygen" species, rather than 03 alone.
- 44 -
-------
terminating the C1X cycle are those producing HC1, which is removed
from the stratosphere by downward diffusion and tropospheric rainout.
Recently it was postulated that CIO reacts in the stratosphere with
N02 to form chlorine nitrate, C1N03> which would diminish the ozone
depleting effect of C1X (and also NO ). This possibility was con-
^
sldered after a reported winter measurement showed only half the
amount of HC1 in the stratosphere as predicted by the models and seen
in measurements taken during other seasons. Initial calculations
based on estimates of the rate of formation and destruction of chlo-
rine nitrate indicated that significant amounts could be formed.
However, as more data were obtained, it became apparent that chlorine
nitrate could play at most only a minor role in stratospheric chlorine
chemistry. Because chlorine nitrate has characteristic infrared
absorption peaks, Dr. Philip Hanst of EPA at Research Triangle Park,
N.C. examined stratospheric Infrared spectra taken by Dr. David Mur-
cray and colleagues at the University of Denver to determine if chlo-
rine nitrate were present in the stratosphere. No significant amount
of chlorine nitrate was found. Furthermore, the anomalous HC1 data
that sparked the interest in chlorine nitrate were found to be in
error by a factor of 2.2. Correcting these data by this factor places
them in agreement with other HC1 data. Thus, formation of HC1 remains
the only known important reaction terminating the C1X cycle for ozone
removal (Cicerone, 1976).
Formation of HC1 does not necessarily terminate the C1X cycle
permanently, however, since it can be renewed by the reactions shown
in [15]-[17]:.
HC1 + »OH •*• H20 + Cl- [15]
HC1 + 0« + -OH + Cl- [16]
HC1 u.v. radiation „ „ t c]. [1?]
The extent to which C1X species are involved in the odd-oxygen deple-
tion reactions is determined by the time spent as Cl« and CIO versus
- 45 -
-------
the time spent as HC1. The C1-/C10 and the HC1/C10 ratios are approx
imated by equations (1) and (2), respectively (Rowland and Molina,
1974):
kg[NO] (1)
[HC1] = Ekx[HX] k8[Q.] + kg[NO]
[CIO] k?[03] k]5[-OH]
where Zk (HX) is the summed reaction rates for Cl- reaction with CH.,
Hp, and H02; numeric subscripts for the rate constants (k) refer to
the reaction involved. Criitzen (1974) included reactions [16] and
[17] in his estimate of HC1 concentrations. Table IX shows the solu-
tions to equations (1) and (2) at various altitudes and the data used
for the calculations. As shown in Table IX, HC1 is the dominant
species at all altitudes. However, the rate of Cl* removal by reac-
tion with 03 is far more rapid (estimated to be 10,000 times more
rapid at 30 km) than by the combined HC1 producing reactions.
It was noted earlier that sufficient ultraviolet radiation
exists to cleave C-F bonds as well as C-C1 bonds, so that the fate of
F» atoms must also be considered. Stolarski and Rundel (1975) have
examined the effect of fluorine atoms on ozone in an manner analogous
to the studies of the effects of the chlorine atoms. The reactions of
F« with Hp and CH. resulting in the formation of HF are much more
rapid than the corresponding reactions for Cl» shown in [12] and [13].
Once formed, HF is not readily destroyed by chemical reaction or
photodissociation. Reaction with «OH is endothermic and the most
likely pathway of HF destruction to give F» is reaction with 0( D),
which is about two orders of magnitude more effective than photodis-
sociation of HF. The catalytic efficiency of ozone reduction by
fluorine atoms was determined ti
the 25 to 50 km altitude range.
-4
fluorine atoms was determined to be less than 10 that of chlorine in
- 46 -
-------
Table IX
Concentrations of Species and Rate Constants of Reactions Used to Determine CU Profile
(From ddta given In Rowland and Molina. 1974)
Altitude. V*
Temperature
Concentrations
°3
0
NO
CH4
H2
H02
OH
Rate Constants
"7
k8
"9
k!2
k13
k!4
k!5
Rate of ,
Removal, sec'
M°3>
*8(0)
n9(i«o)
Ik^HX)
(X-12. 13. 14)
"17
C1/C10
HC1/C10
25
227.1
(on-3)
4.0(12)
6.8(6)
7.5(8)
5.4(11)
6.1(11)
2.4(7)
6.0(5)
30
235.2
3.8(12)
3.2(7)
4.9(8)
2.1(11)
2.8(11)
2.6(7)
1.3(6)
35
251.7
1.8(12)
1.3(8)
5.1(8)
7.6(10)
1.2(11)
1.7(7)
3.2(6)
40
268.2
5.8(12)
3.9(8)
7.0(8)
* 3.1(10)
4.9(10)
8.9(6)
6.7(6)
45
274.5
2.0(12)
1.2(9)
5.9(8)
1.3(10)
2.1(10)
6.3(6)
8.0(6)
50
274.0
7.1(12)
2.7(9)
3.4(8)
6.0(9)
9.2(9)
4.6(6)
6.8(6)
55.
273.6
2.7(12)
4.2(9)
1.8(8)
3.0(9)
3.8(9)
3.3(6)
5.2(6)
1.85 x 10"'1 (temp. Independent)
1.9(-14)
2.7(-15)
4.7(-13)
74
3.6(-4)
1.3(-2)
1.2(-2)
2.8(-7)
7.8
Fraction of time spent by Cl as:
HC1
CIO
Cl
.89
.11
2.0(-5)
Ratio of Cl removal by reaction with 0,
HC1 [k;(03)/rk.(HX)]: J
*
5.9(3)
2.5(-14)
3.8(-15)
4.9(-13)
70
8.3(-3)
6.8(-3)
6.4(-7)
1.5
.60
.40
5.7(-5)
to the combined reactions
. 1.0(4)
5.3 X 10"11
1.7 x W"
4.K-14)
• 7.2(-15)
assumed to
5.4(-13)
33
9.5(-3)
8.7(-3)
4.3(-3>
4.7(-4)
1.2
.54
.46
2.U-4)
leading to
7.7(3)
(temp. Indepedent)
(temp. Independent)
6.4(-14)
1.3(-14)
be 2.x 10" " throughout
5.9(-13)
10.7
2.K-2)
1.2(-2)
2.8(-3)
.4.0(-6)
3.K-3)
2.1
.68
.32
9.8(-4)
3.9(3)
7.5(-14)
1.5(-14)
6.1 (-13)
6,3(-2)
1.0(-2)
1.4(-3)
4.9(-6)
2.0(-2)
5.9
.85
.15
2.9(-3)
2.6(3)
7.4(-14)
1.4(-14)
6.K-13)
1.3
5.8(-3)
6.7(-4)
4.1 (-6)
l.K-D
19
.94
5.0(-2)
5.8(-3)
1.9(3)
7.3(-14)
1.4(-14>
6.K-13)
O.SO
3.K-3)
J.4{-4)
3.2{-6)
4»
.97
2.0{-2)
9.0(-3)
1.5(3)
Numbers 1n parentheses are exponents of .10
-------
Rowland and Mo Una (1974) point out that HF is a reactive gas and
its introduction into the stratosphere may have other effects yet
undefined. Stolarski and Rundel (1975) note a personal communication
from D.D. Davis of the University of Maryland who suggests that the
strong hydrogen bonding tendency of HF may lead to large chain mole-
cule formation and eventually to aerosol formation.
Before presenting the current predictions of ozone depletion from
fluorocarbons, two aspects of the process should be discussed: the
time delay of the effect and the feedback mechanism.
The former aspect takes into account the delay between production
and release of the fluorocarbons at ground level and the time when
they photodissociate in the stratosphere. Rowland and Molina (1974)
have carried out a calculation which demonstrates the time delay.
They examined the altitude profiles of F-12 and C1X following a one-
year hypothetical introduction of F-12 into the troposphere, with no
introduction before or after that year. The results indicate that the
F-12 altitude distribution approaches equilibrium after four years,
while C1X distribution continues to increase for about ten years. The
implication is that the maximum effect of a given year's injection of
F-12 occurs approximately a decade later. The time to reach maximum
effect will, of course, depend on the diffusion model used.
The feedback mechanism involves the observation that a partial
depletion of 03 at high altitude can result in an increased odd-oxygen
production at lower altitudes. With ozone depletion at high alti-
tudes, there will be an increase in the amount of ultraviolet radi-
ation penetrating to the lower altitudes. Some of this radiation
(particularly that in the 200-230 nm region) will be absorbed in the
lower altitudes by 02, rather than Og, resulting in reactions [1] and
[2] and an increase in odd-oxygen. It should be pointed out that
while the feedback mechanism may result in a shift of the ozone
profile to a lower altitude of maximum concentration, the increase in
ultraviolet radiation due to ozone depletion will not result in the
reformation of an equivalent amount of ozone, even at a lower altitude.
- 48 -
-------
This is because the increased ultraviolet radiation due to ozone
reduction is, except for the 200-230 nm region mentioned above, of
longer wavelength (less energy) than that which is responsible for the
02 photolysis which begins the ozone formation process as given in
reactions [1] and [2].
Having determined the C1X concentration profile resulting from
upward diffusion and photodissociation of fluorocarbons, the effect of
the C1X species on local ozone levels can be determined. Predictions
of the effects of fluorocarbons on stratospheric ozone are presented
in Table X. The differences reflect the various diffusion models,
rate constants, and concentrations of minor species used in the cal-
culations. In summary, these predictions indicate that continued F-ll
and F-12 production and release to the atmosphere at current rates
will lead to an overall ozone depletion of between about 6.5% and 13%,
with the full effect occuring sometime in the middle of the 21st
century. Crutzen (1974) in one calculation predicts that in addition
to an overall ozone depletion of 7%, there will be a slight increase
in ozone below 30 km. as a result of the feedback mechanism described
above. Of course, where continued expansion of the fluorocarbon
industry is assumed, the effect on ozone is more severe and the effect
maximizes at an earlier date. Cessation of fluorocarbon production
within 5 years would result in an overall depletion of 2% or 3%,
maximizing around 1990-1995. Both Rowland and Molina (1974) and Turco
and Whitten (1974) conclude that fluorocarbons could currently account
for about 1% ozone depletion currently.
The important reactions of chlorine in the stratosphere which
affect ozone are summarized by the following diagram:
•OH [15] 03 [7]
— > Cl- -> CIO
CH4[12], H2[13], H02[14] 0-[8], N0[9]
(The numbers in brackets refer to reactions given earlier in this
section.) Those reactions proceeding to the right in this diagram
- 49 -
-------
TABLE X
STRATOSPHERIC .OZONE DEPLETION FROM F-11 AND F-12
Reference "
Cicerone et al.,
1974
Crutseru 1974 •
Rowland and Molina,
1974
i
Stratospheric 03 Change
Ozone control passes from NOX
control to C1X control ca. 1985
Ozone control passes from NOX
control to C1X control .ca. 2000
Maximum C1X catalyzed 03 destruc-
tion ca. 1990 at a rate compa-
rable to major natural cycles
persisting several decades.
Overall 71, decrease, slight
Increase -below 30 km due to
feedback mechanism. Maximum
decrease 422 at 40 km. Full
effect ca. 2055
Overall 6.52 decrease. Maximum
decrease 172 at 40 km. Full
effect ca. 2015
Overall 132 decrease at steady
state (ca. 2050?)
F-11, F-12 Injection Pattern
Exponentially increasing with a
doubling time of 3.5 years
(current pattern).
•
Exponential increase as above
from 1960-1975; then constant
at 1975 .rate.
Exponential Increase as above
from 1960-1975; then immediate
cessation.
Constant at 1973 rate of manu-
facture.
Constant at 1973 rate of manu-
facture
Atmospheric Diffusion Model
Eddy Diffusion
Altitude (km) Coefficient (cm*sec
15 1.5 x 104
20 2.5 x 103
25 7.6 x 103
30 3.5 x 103
A
35 6.5 x 10*
40 1 0 x 10^
*TU 1 • V A 1 V
c
45 1.6 x 10s
50 ° 2 5 x Ifl5
dU C. • 3 A 1 VI
15-50 104
50-95 104 (exp. 0.13
[z-50]) ^alti-
tude In km.)
15-20 104 •_,
20-30 104 exp(^y4
30-50 105
50-95 10$ exp(^yy)
16-18.8 4 x 103
above 18.8 rapid rise to
2 x Ifl6 at 80 km.
Notes
03 destruction
rates consider
only one chlorine
atom released per
F-11 or F-12
molecule.
- 50 -
-------
Table X. (cont.)
Reference
Stratospheric 03 Change
F-ll, F-12 Injection Pattern
Atmospheric Diffusion Model
Altitude (km)
Eddy Diffusion
Coefficient (cm sec"1)
Notes
Turco and Whitten,
1974
Wofsy et al... 1975
-6X decrease by 2025, ~10X
decrease by 2065.
-34 decrease ea. 2025
-4% decrease ca. 2025
>20X decrease by 2025
-102 decrease by 2025
>1556 decrease by 2025
-22 maximum decrease by 1995,
small residual ozone deficit
beyond 2050
-10« by 2064, >13X at steady
state.
<3S maximum decrease ca. 1990
-14X maximum decrease ca. 2000,
<5J residual deficit ca. 2064.
Constant at 1974 rate of manu-
facture.
As above.
As above.
Beginning at 1974 level, 8.7X
increase/year.for 20 years,
constant thereafter.
As above, 10 year tropospheric
lifetime.
As above. .
Beginning at 1974 level, 8.7*
Increase for.5 years, then total
cessation.
Constant at 1972 rate of manu-
facture.
Beginning at 1972 level, 10X
Increase/year, with total
cessation in 1978.
As above, with total cessation
in 1995.
15
20
30
40
50
60
-2.5 x 104
-7 x 103
-4 x 103
-6.5 x 103
-7 x 10*
-1.5 x 105
Infinite tropo-
spheric lifetime
10 year tropo-
spheric lifetime.
30 year tropo-
spheric lifetime,
Infinite tropo-
spheric lifetime.
10 year tropo-
spheric lifetime
30 year tropo-
spheric lifetime
Infinite tropo-
spheric lifetime
As in Rowland and Molina, 1974 above
adjusted upward by factor of 2 betweer
16 and 20 km.
- 51 -
-------
Table X. (cont.)
Reference
Stratospheric Oj Change
F-ll. F-12 Injection Pattern
Atmospheric Diffusion Model
Eddy Diffusion
Altitude (km) Coefficient (on'sec'1
Notes
ri.. 1975
(cont)
decrease ^y ca. 2014
-2M aaxtsMi decrease ca. IMS.
-------
result in increased ozone depletion; those proceeding to the left
decrease the depletion of ozone by chlorine.
Since the ozone depletion prediction given above and in Table X
were reported, some of the rate constants of important reactions and
concentrations of trace species in the stratosphere have been refined;
the effect of these changes have been summarized recently by Rowland
(1975). New values of the rates of the reactions shown above (except
reaction [14] which has not been refined) agree with those used in the
ozone depletion calculations within a factor of two. The rate of
reaction [7] has been found to be slower than previously thought,
while reaction [12] has been found to be faster. The result of these
rate changes is to decrease the effect of chlorine on stratospheric
ozone depletion. However, reaction [15] has been found to be faster
than originally thought which increases the ozone depletion by chlo-
rine. Further, the concentration of *OH in the stratosphere as
measured recently by Anderson (1975) is somewhat higher than the
estimated concentration of -OH used in the ozone depletion calcula-
tions, which also increases the calculated rate of ozone removal by
chlorine. The rates of other reactions and concentrations of other
species have not changed significantly with new data. The strato-
spheric concentration of H02 and the rate of reaction [14] have not
been refined; however, Rowland and Molina (1974) pointed out that this
removal path of Cl- is less important than that of reaction [12] (Cl-
+ CH^) and may be of negligible importance. Another important reac-
tion yet unrefined is that of -OH with H02 to yield water and 02. If
this reaction is fast, the effect is to decrease the rate of Cl-
return through reaction [15] and thus decrease the effect of Cl- on
ozone. Most calculations have used the "high" value of the recom-
mended range (between 2 x 10"11 (low) and 2 x 10~10 (high) cm3-
molecule -sec" ) and therefore may be underestimating ozone depletion
by a factor of two if the "low" value is more accurate.
The net effect of all these corrections (also including the
effects of chlorine nitrate as mentioned on page 45) has been basically
- 53 -
-------
one of cancellation, and, according to Rowland and Molina (1975), the
current predictions of ozone depletion due to the fluorocarbons falls
within the range of the initial estimates, that is, 7-13% depletion
with continued production of F-ll and F-12 at present rates. Cicerone
(1976) currently places the depletion estimate at 8-16% with continued
release of F-ll and F-12 at the 1974 rate.
Also, as mentioned earlier, the photodissociation of F-ll and
F-:12 has been found to be temperature dependent and will proceed more
slowly at stratospheric temperature than is indicated in the models
where room temperature rates are used. The effect of this modifica-
tion is not completely clear. One possibility is that the slower
release of 01• from the fluorocarbons would result in a diminished or
more delayed effect on ozone concentrations. On the other hand, such
a temperature dependence may result in longer lifetimes of the fluoro-
carbons in the lower stratosphere allowing them to diffuse higher
where, with the higher temperature and increased ultraviolet flux and
energies, they will dissociate in the more ozone-rich areas of the
stratosphere and an increased effect on ozone depletion could occur.
The chlorine-catalyzed ozone destruction models as presented here
do not include data on other sources of chlorine to the stratosphere,
nor do they consider a natural C1X cycle in the stratosphere, and have
been criticized on these accounts. There are only four compounds
currently recognized as contributing to the stratospheric chlorine
load: F-ll, F-12, carbon tetrachloride (CC1.), and methyl chloride
(CH3C1). Carbon tetrachloride has been detected in the troposphere at
concentrations of 71 ± 7 ppt (Lovelock et aJL, 1973), 75 ±8 ppt
(Wilkness et a_1_., 1973) and 111-118 ppt (Lovelock, 1974); methyl
chloride has been measured in the troposphere at concentrations of 400
ppt (Lovelock, 1975) and 550 ± 50 ppt (Rasmussen, 1975). Methyl
chloride is produced naturally in the sea and anthropogenic sources of
this compound are insignificant by comparison. Carbon tetrachloride
was at one time a widely used industrial compound, but its current
uses resulting in release to the atmosphere are probably about 200
- 54 -
-------
million pounds per year (Molina and Rowland, 1974b). Most of the
current CC1« loading of the atmosphere can be accounted for by man's
activity (Singh e_t al_., 1976; Altschuller, 1976). However, because of
uncertainties in past production and release factors for carbon tetra-
chloride, it is not known for certain if the current atmospheric load
of carbon tetrachloride is of purely anthropogenic origin or if some
is produced naturally.
A natural source of chlorine to the stratosphere such as that
from methyl chloride and possibly some carbon tetrachloride (as well
as the possibility of direct volcanic injection of chloride, indus-
trially released HC1 and C1« from sea spray) would not invalidate the
predicted effects of anthropogenically released chlorine compounds
(l.e_., F-ll, F-12, and some carbon tetrachloride) on the stratosphere.
The concern is essentially one of changes by man's activities from the
natural stratospheric ozone control mechanisms and is analogous to the
concern over NO emissions from supersonic transports perturbing the
A ••
natural NO cycle of ozone control. The major controllable sources of
"
stratospheric chlorine are F-ll and F-12 and, to a somewhat lesser
extent, carbon tetrachloride.
Cicerone et. aJL (1975) have estimated the stratospheric load of
C1X as of late 1974. Although ground level sources of HC1 and dp
from such processes as the conversion of sea-salt aerosols to HC1,
volcanic emissions, diffusion through the earth's crust, and indus-
trial activities were considered, these were found to be insignificant
in their impact on the stratosphere in comparison to F-ll, F-12, CC1.,
and CH3C1. F-ll and F-12 contributions were calculated in a manner
similar to that described previously in this section; for CC1. a
steady-state profile with photolysis as the only sink was assumed.
The steady-state assumption is justifiable since the anthropogenic
sources of CCl^ (at least from the U.S.) have been generally constant
for the past two decades, so that the existence of an equilibrium
between the troposphere and the stratosphere for this compound seems
reasonable. Tropospheric CCl^ concentrations used were those given
- 55 -
-------
above. For CH^Cl, a steady-state based on above tropospheric measure-
ments was assumed because the sources of this compound seem to be
entirely natural. The loss of Cl« from CHgCl was considered to be
entirely through reaction with *OH to yield -CH^Cl (and water), with
immediate decomposition of this product by uncertain reaction(s).
The results of these calculations, shown graphically in Figure 4,
indicate that if the assumptions of steady-state conditions and chlo-
rine release mechanisms for CHgCl and CC1. are correct/the current
contributions of these compounds to the stratospheric load of C1X
species are two to three times greater than that calculated for F-ll
and F-12. If the assumption of a current steady-state for CC1. is
incorrect and anthropogenic sources of this compound are resulting in
increasing atmospheric loads, the future stratospheric C1X from CCl^
will, of course, also increase. However, if it is assumed that CHgCl
and CC1. are presently at steady-state (and, therefore, their contri-
butions to C1X will remain constant in the future), and it is also
assumed that F-ll and F-12 will be released at the 1973 rate, then,
according to Cicerone ejt aj_., the fluorocarbon-derived C1X mixing
-9
ratio will be 4 x 10 when steady-states are achieved for these
compounds in 50-100 years. At that time, F-ll and F-12 would be the
major sources of stratospheric C1X.
Cicerone e_t aj_. (1975) compared their estimates of C1X to recent
measurements of HC1 in the lower stratosphere by Lazrus, whose data
points are also shown in Figure 4. These measurements show substan-
tial agreement with calculated C1X (recall that C1X is predominantly
HC1, particularly at lower stratosphere altitudes) where only F-ll,
F-12, and CCl^ are considered as sources. These HC1 measurements are
lower than would be predicted by C1X estimates which include ChLCI as
a source. This would imply that one or perhaps all.four.of the
sources are being overestimated, if the HC1 measurements are accurate.
However, Cicerone e_t al_. point out that the efficiency of HC1 collec-
tion by Lazrus using impregnated filters may be less than 100% and
that improved calibration may increase these HC1 values.
- 56 -
-------
Figure 4. C!X MIXING RATIOS AS OF LATE 1374 FROM
F-11, F-12, CC!4, :-:.->d CH3CI AS CALCULATED
BY CICERONE ETAL. (1975)
00,
4
• \
i i 4,
i so f-
.
i
'
1
j
i
i
Ul
o
30 -
20
.or
ICT
/ /
, CIX
k
10
-9
CIX MIXING RATIO FROM:
F-11 and F-12 (A)
CCi4 (Bi
CH3CI (C)
F-11, F-12, andCCi4(T1)
F-11, F-12, CCi4 ,-nci CH3C! (T2)
HCI MEASUREMENTS CF LAZRUS INDICATED BY 'X'
- 57 -
-------
Direct proof of the accuracy of the foregoing models of C1X
contributions to the stratosphere and resultant ozone depletion can
probably be attained only by direct measurement of certain species in
the 25 to 50 km altitude ozone-rich area of the stratosphere. Obvi-
ously such measurements should include the C1X species. Also, meas-
urement of F-ll, F-12, CCl^, and CHgCl would provide useful informa-
tion on the rate of diffusion and decomposition of these products for
comparison to the predicted rates in the models to show which species
are in fact contributing to C1X at various altitudes. While methods
are available for measuring these latter compounds and only techniques
for performing them at these altitudes need be developed, the measure-
ment of the C1X species presents a more difficult problem since no
method has been proven successful in measuring stratospheric CIO or
C1-. Lazrus e_t aJL (1975) have developed a method for efficiently
collecting stratospheric HC1 and particulate Cl (as well as HBr and
Br) using balloon-borne alkaline-impregnated filters, although meas-
urements have been carried out only below 30 km. These researchers
may have collected some CIO on their filters at 24 to 27.5 km; they
are currently studying the efficiency of CIO collection on their
filters.
As a final point before discussing the effects of ozone deple-
tion, it should be noted that direct measurement of ozone levels will
not be a useful indicator of the validity of these models. Fluctua-
tions in the ozone level are known to occur daily and seasonally and
possibly in average readings over longer periods; a cycle synchronous
with the 11-year sunspot cycle has been postulated. To measure
directly for a true decrease in ozone would require perhaps two decades
or more, at which point the proposed effects from F-ll and F-12
would be irreversible and significant. The estimate of a current
decrease in ozone of about }% due to F-ll and F-12 already released
is smaller than that which could be established by direct measurement.
- 58 -
-------
VII. EFFECTS OF OZONE DEPLETION
It was stated earlier that the stratospheric ozone layer acts as
a filter which shields the earth's surface from solar ultraviolet
radiation, particularly from wavelengths below 320 hm. While approxi-
mately 90% of the solar ultraviolet radiation of 325 nm incident at
the top of the atmosphere reaches sea level, less than 1% of solar
ultraviolet radiation of 295 nm reaches the earth's surface. The
minimum wavelength observed at sea level is about 288 nm. This
filtering out of solar ultraviolet irradiance is due to its absorption
by oxygen and ozone in reactions [1] and [3]. Ozone is responsible
for absorption of ultraviolet radiation of wavelengths longer than 242
nm, while wavelengths shorter than 180 nm are absorbed almost entirely
by oxygen and are not affected by ozone concentration or its altitude
distribution. The intermediate wavelengths (especially 200-230 nm)
are absorbed by both oxygen and ozone, so that a loss of ozone at high
altitudes will permit a deeper penetration of this radiation into the
lower stratosphere where, being absorbed by oxygen, it will effect an
increase in odd-oxygen. (This is the feedback mechanism mentioned
earlier.)
It is, therefore, the ground level intensity of ultraviolet
radiation of wavelengths above 242 nm which is expected to increase as
a result of ozone depletion. Of most concern, however, are those
wavelengths between 280 nm and 320 nm, the UV-B region, with known and
suspected biological effects.
The amount of a given wavelength of ultraviolet radiation (of
wavelengths longer than 242 nm) which reaches the earth's surface is
primarily a function of the intensity of the solar ultraviolet radi-
ation of that wavelength incident at the top of the atmosphere, the
ozone absorption coefficient for that wavelength, and the amount of
ozone present through which the ultraviolet radiation must pass. The
variable in this relationship is the amount of ozone present, and it
is noteworthy that the intensity of the ultraviolet radiation reaching
- 59 -
-------
the earth's surface is an exponential function with respect to the
amount of ozone present. This means that the amount of additional
ultraviolet radiation reaching the earth's surface per unit decrease
in ozone becomes increasingly greater with each additional unit of
ozone depleted. In addition, the intensity of ultraviolet radiation
at ground level is influenced by the solar zenith angle, scattering
and absorption by particles, droplets, and clouds in the atmosphere,
Rayleigh scattering (i_.e_., the scattering of radiation by particles
which are smaller than the wavelength of the radiation), and planetary
reflection (VenkatesWaran, 1974; Cutchis, 197fc). While these factors
may influence the amount of ultraviolet radiation reaching earth at a
specific time or place, they are independent of the stratospheric
ozone concentration. Therefore, the average amount of ultraviolet
radiation reaching the earth's surface at a particular place over time
is dependent principally upon the amount of ozone through which it
passes.
There are two factors to be considered in discussing the ozone
depletion problem which were omitted in the model used to develop the
quantitative estimates of ozone depletion. These are (a) strato-
spheric circulation patterns and (b) latitudinal and longitudinal
variations in ozone distribution.
The assumption of complete mixing of the fluorocarbons in the
troposphere is not inappropriate, since the long tropospheric life-
times will ensure a tendency toward reducing variations in latitude
and longitude. (It could be expected, though, that higher concentra-
tions will occur in the northern hemisphere, where Europe and North
America, primary users o*f the fluorocarbons, lie.) In the strato-
sphere, however, circulation patterns would favor more rapid upward
diffusion at the equator; movement poleward, and downward diffusion
near the poles.
The ozone layer is not uniformly distributed in the stratosphere,
but varies with latitude and longitude, and with the day, month, and
season. The amount of ozone in a column 1s least at the equator,
- 60 -
-------
increasing significantly at higher latitudes (more so in the northern
hemisphere). Ozone occurs generally at higher altitudes in the lower
latitudes than in the polar latitudes. At the higher latitudes ozone
concentration varies strongly with the season, being highest in spring
and lowest in fall.
Photolysis of the fluorocarbons will prevail in regions of
highest ultraviolet radiation flux, which are the equatorial regions
where the ozone shield is thinnest. Subsequent motions would ulti-
mately carry the C1X species poleward. Ozone depletion may occur more
drastically near the equator, with less substantial effects in the
higher latitudes.
Cutchis (1974), calculated the effects on solar flux of radiation
of wavelength 297.5 nm with hypothetical ozone depletions of 10% and
50%. His results, shown in Figure 5, indicate that relative intensity
increases are larger at the higher latitudes. However, the solar flux
is much greater at the lower latitudes and, therefore, ozone depletion
of equal magnitude at all latitudes results in a much greater absolute
increase in ultraviolet flux in the lower latitudes. If, as postu-
lated above, the ozone depletion occurs predominantly at the lower
latitudes, the increase in ultraviolet radiation here will be even
more dramatic.
From Figure 5 it can be seen that a 10% ozone depletion at all
latitudes translates to roughly doubling the solar irradiance in the
tropical zones and increases it by an order of magnitude or more at
the higher latitudes. Because of the lack of studies on the 280-320
nm region of the ultraviolet spectrum, the exact biological and clima-
tological consequences of such increases are not known. Most studies
of ultraviolet radiation have been done with the 254 nm wavelength
easily generated by mercury vapor lamps. As a result of the concern
for increased ultraviolet flux in the 280-320 nm region, some experi-
ments have been initiated; the preliminary results of these experi-
ments, together with earlier photobiological data, indicate the
following, according to Urbach (1974):
- 61 -
-------
Figure 5. Noon direct irradiance at 297.5 nm
Plotted aqainst latitude for the Northern
0 10 10 10 40 10
UUtud* (d«(r*u)
- 62 -
-------
(1) Most of the biological effects of radiation in the 280-320
nm region are decidedly detrimental.
(2) Most organisms have developed the ability to avoid excessive
ultraviolet radiation, either by behavioral patterns, or by
protective coverings, such as fur, leathers, cuticular wax,
etc. The capacity for avoidance of excessive radiation is
limited in most organisms, and many currently exist near a
threshold where an increase in exposure to ultraviolet
radiation would be detrimental.
The issue which has received the most attention as a result of
the ozone depletion potential is the effects of increased ultraviolet
radiation on humans. Among the effects attributable to ultraviolet
radiation are erythema solare, commonly referred to as sunburn; skin
aging, characterized by wrinkling, blood vessel dilation, atrophy,
etc.; and skin cancer.
The hypothesis of increased skin cancer due to increased ultra-
violet radiation is based on extensive experimental results of effects
on laboratory animals and on limited epidemiological studies. Some of
the arguments, reviewed by Urbach (1974), wfrich indicate a relationship
between human skin cancer and ultraviolet radiation are:
(a) Superficial skin cancers occur most often on parts of the
body habitually exposed to sunlight;
(b) there is a lower rate of skin cancer among pigmented races
who sunburn much less readily than white-skinned peoples;
(c) there is a higher rate of skin cancer in Caucasians who work
predominantly outdoors than in those who work indoors;
(d) genetic diseases (albinism, xeroderma pigmentosum) which
result in greater sensitivity to the dermal effects of solar
ultraviolet radiation are associated with marked increases
and early skin-cancer development.
- 63 -
-------
Although some estimates have been made of the increase in the
number of skin cancers per year as a result of ozone depletion, such
estimates are subject to great, and currently unmeasurable, uncertain-
ty. Early estimates indicated a 2Q% increase in human skin cancer for
a 10% reduction in ozone. It has more recently been estimated that a
10% ozone reduction could lead to 25-35% increases in human skin
cancer. The uncertainty in such estimates notwithstanding, the evi-
dence does lead to the qualitative conclusion than an increase in
ground-level ultraviolet radiation will result in some increase in
the incidence of human skin cancer.
Little is known concerning the effects of increased UV-B on
domestic and wild animals, although some observations were made by the
Federal Task Force on Inadvertent Modification of the Stratosphere
(IMOS, 1975). It has been assumed that the outer covering of most
animals (hair, feathers, shells, normal pigments, etc.) provide pro-
tection from the harmful effects of UV-B. It is not known to what
degree these coverings will provide protection from the effects of
increased levels of ultraviolet radiation. Wild animals are generally
nocturnal in habit, and also tend to remain in the shade provided by
forests during daylight activities. Because of this behavior, increased
ultraviolet radiation may have little effect on these animals in a
practical sense. Certain domestic animals, which may not have protec-
tive shade, are probably at greater risk to the harmful effects of
increased UV-B. Skin cancer is known to occur in cattle, goats, sheep,
and horses, and is found predominantly in parts of the body where the
amount of the pigment melanin is least, such as the eyelids, genitals,
and skin near brand marks. The incidence of "cancer eye" which,
according to IMOS, accounts for more than 90% of all slaughterhouse
condemnations has a higher incidence in white-faced Hereford cattle
than in the more darkly colored species. In addition, geographical
locations with greater exposure to natural sunlight are associated
with higher incidence of cancer eye in these white-faced cattle.
Ultraviolet radiation may increase the effects of the bacteria-Induced
- 64 -
-------
disease of cattle known as pink eye, and may also Increase the number
of cattle affected. Adverse effects from Increased UV-B may also
occur in cattle exposed to photosensitizing materials1, which are known
to occur in a variety of grasses and weeds. Microorganisms and drugs
(such as phenothiazine, commonly used to treat parasitic infections)
are photosensitizers.
There are practically no data available on the effects of in-
creased UV-B on insects. The National Academy of Sciences (1975)
notes that the mortality of caged insect larvae increases with sup-
plemental ultraviolet radiation, but, because these larvae keep shel-
tered from the sun in nature, the significance of this finding is
difficult to determine. Some qualitative observations regarding the
interactions of insects with ultraviolet light have also been made.
For example, insect eyes are capable of detecting ultraviolet radi-
ation; in fact, insects are guided in feeding and pollinating by
ultraviolet reflectance patterns on flowers. In some butterflies and
perhaps other insects, mate selection involves visual cues that
include ultraviolet light reflectance patterns. How increased ultra-
violet radiation due to ozone reduction would affect these mechanisms
is not known at this time.
In addition, little is known about the possible effects of ultra-
violet radiation in the UV-B range on plants. A few studies cited by
the National Academy of Sciences (1975) designed to show the effects
of increased ultraviolet radiation corresponding to a 50% reduction in
ozone showed significant growth reduction in peas (two varieties),
cabbage, collard, and corn. Plant growth was inhibited by 20 to 50%
in greenhouse and growth chamber experiments, while field experiments
showed smaller, but statistically significant decreases for some
plants. The chlorophyll content of beans and cabbage exposed to
supplemental UV-B in growth chambers showed a 10 to 30% decline.
UV-B-exposed collards showed reduction in photosynthetic capacity.
Soybeans exposed to supplemental UV-B in field experiments showed
degenerative changes in the structure of some cells. In spiderwort
- 65 -
-------
exposed to supplemental UV-B under field conditions, an increase in
harmful mutations, determined by abnormal or missing stamen hairs was
observed. With regard to plants in general, seedlings are more sensi-
tive to the effects of ultraviolet radiation than are mature plants,
and single-celled algae are many times more sensitive.
Because of its absorption of ultraviolet radiation, the strato-
spheric ozone layer also serves to warm the upper stratosphere.
Depletion of ozone or shifting to lower altitudes may affect the
temperature structure of the stratosphere which may in turn alter the
tropospheric climate. Possible alterations such as temperature dis-
tribution and rainfall patterns may affect crop yields, timber produc-
tion, and certain aquatic and terrestial ecosystems. In studying the
effects of stratospheric aircraft on ozone, the National Academy of
Sciences (1975) stated that "as far as climatic change and agricul-
tural effects are coricerned, no clear-cut statement can be made
concerning expected changes in temperature and rainfall. Neverthe-
less, a global change in temperature of a few tenths of a degree and
an associated change in rainfall are not ruled out. Local changes may
be larger, and the economic, social, and political effects of such
changes could be substantial".
Except perhaps for the increases in skin cancer, there is insuf-
ficient information currently available to quantify the biological and
climatological effects of partial ozone depletion.
Research is currently being conducted to test the theory of
fluorocarbon-catalyzed ozone depletion. Under the coordination of the
Interdepartmental Committee for Atmospheric Sciences (ICAS), studies
are being performed by the National Aeronautics and Space Administra-
tion, the Energy Research and Development Administration, the Envi-
ronmental Protection Agency, the National Science Foundation, and the
Departments of Commerce', Defense, and Transportation. Additional
research is being sponsored by 19 fluorocarbon manufacturers under the
coordination of the Manufacturing Chemists Association. The principle
areas of investigation include stratospheric measurements of F-ll,
- 66 -
-------
F-12, aand other chlorine species, measurement of other important
species in stratosphere (especially the -OH and H0? radicals), and
measurements of chemical reaction rates. Studies are also being made
to determine what substitutes for fluorocarbons are available and the
economic impact of possible regulatory actions.
Although not involving ozone depletion, another.effect of fluoro-
carbons in the atmosphere that might result in climatological changes
was reported recently by Ramanthan (1975). The presence of these
compounds and other chlorocarbons in the troposphere may enhance the
atmospheric "greenhouse effect". The "greenhouse effect" (a term
which Fleagle and Businger (1975) suggest be replaced by "atmospheric
effect" because of fallacies in the analogy) results from the absorp-
tion of infrared radiation emitted by the earth's surface by compounds
in the troposphere resulting in an increase in the temperature of the
atmosphere. In examining the infrared absorption bands of F-ll and F-
12, Ramanthan concludes that tropospheric levels of 2 ppb of these
compounds (expected to be reached by the year 2000 if present use
patterns are maintained) will result in an increase in the mean global
surface temperature of 0.9°C, which is above that considered suf-
ficient to substantially alter some climatic variables, such as rain-
fall and ice cover, in at least certain parts of the globe. The
results of Ramanthan may, according to Machta (1975), be somewhat
overstated since the overlap in infrared absorption spectra of the
i
fluorocarbons with that of water was not included in the model.
- 67 -
-------
VIII. BIOLOGICAL PROPERTIES OF FLUOROCARBONS
A. Absorption and Elimination
1. Inhalation
Because of the physical properties and uses of the fluorocarbons
under review here, inhalation is the most likely route of entry into
terrestrial vertebrates. Several studies have been reported for both
standard laboratory animals and man on the absorption and elimination
of inhaled fluorocarbons during and after exposure. The method of
exposure may be via inhalation of a known concentration in ambient air
(usually expressed as percent by volume) or via direct inhalation from
a bronchodilator-type nebulizer (usually expressed as milligrams of
fluorocarbon inhaled). The absorption/elimination pattern of fluoro-
carbons may be determined by measurement of blood levels or by meas-
urement of fluorocarbon in expired air. It must be recognized that
parameters other than dose and method of exposure affect the amount
and rate of absorption and elimination of an inhaled gas. Blood
levels attained under similar exposure conditions will vary with
different species, different individuals in the species, and a given
individual at different activity levels. Absorption and elimination
are dynamic processes involving equilibria between the ambient air and
blood, between the blood and body tissues, and between the various
body tissues themselves. Fluorocarbon blood levels as a function of
time during and following exposure are instructive of both the absorp-
tion/elimination pattern and the equilibrium state.
Howard e_t ajL (1974), have discussed the fluorocarbon absorp-
tion/elimination literature in considerable detail. The available
data on blood levels of fluorocarbons in animals exposed to them in
ambient air are presented in Table A-I (Appendix A). Figures A-l -
A-3, from Clark and Tinston (1972a) are typical of the absorption and
elimination patterns of fluorocarbons inspired from ambient air.
- 68 -
-------
Absorption of inhaled fluorocarbons follows a biphasic pattern,
where a rapid initial increase in blood levels is followed by a
slower approach to a maximum concentration, at which point an
apparent equilibrium is reached between blood and ambient air. Azar
et aj_. (1973), Allen and Hanburys (1971) and others have measured
arterial and venous blood levels during this period of apparent
equilibrium. Their data show that arterial concentrations exceed
venous concentrations during the equilibrium period, indicating that
fluorocarbon is being removed from the blood by tissue absorption,
and, therefore, true equilibrium is not reached until the venous-
arterial levels are equal and constant. When exposure is termi-
nated, a similar biphasic pattern of elimination is observed, where
a rapid initial fall in blood levels is followed by a slower decline
to undetectable levels (0.005 yg/ml for F-ll; 0.15 yg/ml for F-12,
Azar e_t a_l_., 1973). During the elimination phase after exposure is
terminated, the venous levels exceed arterial levels, indicating the
removal of fluorocarbons from tissue.
Absorption/elimination of fluorocarbons administered in single
or limited dosages as from a bronchodilator-type nebulizer shows a
similar pattern of rapid initial rise in blood levels, followed by
rapid, then much slower elimination.
The relative order of absorption appears to be F-ll > F-ll3 >
F-12 > F-114 (Shargel and Koss, 1972), with limited data indicating
that F-13B1 is absorbed to about the same degree as F-12 (Griffin et_
al.. 1972). Shargel and Koss (1972) have also shown that there is
no indication that the presence of one fluorocarbon influences the
relative degree of absorption of another fluorocarbon.
2. Other Routes of Entry
Although inhalation is the route of entry of most concern for
the fluorocarbons under review here, other routes of entry have
received some study. In a long-term feeding study of F-12 to
rats and dogs, Sherman (1974) found tissue uptake indicating that
some absorption does occur-across the gastrointestinal tract.
-------
Dermal absorption of F-113 has been tested in man (DuPont,
1968). The hands and arms of two individuals were immersed in F-113
for 30 minutes and portions of the scalp were exposed to F-113 for 15
minutes. Fluorocarbon uptake was measured as F-113 in expired air.
Time to maximum concentration is measured from termination of expo-
sure. The maximum concentrations noted in exposure of the hands and
forearms were 9.6 port after 11.5 minutes for one individual and 1.7
ppm after 23 minutes for the other. The scalp, perhaps because of its
greater vascularity, seems somewhat more absorbent with one individual
reaching a maximum fluorocarbon concentration of 12.7 ppm in 20.5
minutes and the other reaching 7.4 ppm after 18.5 minutes. After 90
minutes, F-113 concentrations were below 0.5 ppm in all subjects. In
the subject showing 1.7 ppm in the hand and forearm exposure, however,
a trace amount of about 0.1 ppm was detected 18 hours after exposure.
Regardless of the route of entry, elimination of fluorocarbons
seems to be solely through the respiratory tract. Matsumato et al.
(1968) administered a mixture of F-12 and F-114 (30/70, v/v) to dogs
intravenously, intraperitoneally, intramuscularly, or sprayed directly
onto the liver and kidney. Elimination occurred through expired air,
with no fluorocarbon detected in the urine or feces.
In summary, the available data on fluorocarbon absorption and
elimination indicate that fluorocarbons are absorbed across the
alveolar membrane, gastrointestinal tract and skin. Inhaled fluoro-
carbons are readily taken up by the blood and, with continued exposure
in ambient air, an equilibrium state is reached between the air, blood
and tissues (indicated by equal concentrations in arterial and venous
blood). Fluorocarbons absorbed by any route are eliminated through
the expired air, with the biphasic pattern of rapid initial elimina-
tion followed by a slower decline as described previously.
- 70 -
-------
B. Transport arid Distribution
It is apparent from the preceding information on absorption and
elimination that the f1uorocarbons are transported by the blood and
that some tissue storage occurs during continuous exposure, as evi-
denced by higher levels in arterial than in venous blood during expo-
sure, with a reversal after exposure is terminated and the compounds
are being eliminated.
Data from Allen and Hanburys, Ltd. (1971) show that subsequent to
a five-minute exposure in ambient air to rats, .F-ll and F-12 are
concentrated from the blood to the greatest extent in the adrenals
followed by the fat, then the heart. Brain and liver levels were
apparently not measured. Carter e_t a_K (1970) exposed rats to F-113
for 7 and 14 days and found F-113 primarily in the fat, with signifi-
cant levels in the brain, liver, and heart. Van Stee and Back (1971)
found that concentrations of F-13B1 during and after five-minute
exposures of rats were significantly higher in the brain than in the
heart. While there is temporary storage in those tissues of high lipid
content during continuous exposure, elimination after termination of
exposure is rapid and there is no indication that the fluorocarbons
are accumulated in any tissue. The ambient air concentrations to
which the test animals were exposed in the above studies were in the
range of about 0.2% to 1.0%, which are about six orders of magnitude
higher than the 100-600 ppt found in urban air.
C. Biochemical Interactions
Griffin et aj,. (1972)'found that inhaled F-12 or F-13B1 had no
effects on oxidation or phosphorylation in isolated mitochondria from
the liver, lung, brain, heart, and,kidney of rats, nor in liver and
heart mitochondria exposed to these compounds in vitro.
Paulet et al_. (1975) studied the metabolic effects of inhaled
F-ll and F-12 1n the rat, rabbit, and dog. With a 5% concentration of
F-ll, given either as a single twenty-minute exposure or for two one-
hour periods daily for fifteen days, there was an observed decrease in
- 71 -
-------
oxygen uptake, slight hyperglycemia and hyperlactacidemia, a slowing
of hepatic glycogen secretion, an increase in the respiratory quo-
tient, a decrease in blood urea, and a slight increase in free fatty
acids. These effects, which indicate a slowing down of cellular
oxidation, were not observed with exposure to 2.5% F-ll, nor with F-12
at single exposure to 20% or repeated exposures to 5%.
D. Metabolism
Of the fluorocarbons under review, only F-ll, F-12, and halothane
are topics of published reports on metabolism. Cox e_t al_. (1972a)
have attempted to demonstrate possible reductive dehalogenation of
F-ll in two ways. First, reasoning that the primary products of
dehalogenation would be F-21 (CHClgF) and F-112 (C2C14F2), they incu-
bated F-ll in microsomal preparations from rats and chickens and from
rats, mice, guinea pigs, and hamsters pretreated with phenobarbital to
stimulate metabolism. No F-21 was detected. Secondly, as an index of
free radical formation, they measured the effect of F-ll on lipid
peroxidation. No evidence of free radical formation was found.
Blake and Mergner (1974) have studied the metabolism of inhaled
F-ll and F-12 using carbon-14 labelled compounds in anaesthetized
beagles. The radiolabelled impurities in F-ll (89.6% pure) were 9%
14CC1. and 1.4% 14CHC1,. The radiolabelled impurities in F-12 (96.0%
1/1 1A
pure) were CF,C1 and/or CF». In both of the fluorocarbon prepara-
T A
tions, less than 0.1% of the radioactivity appeared as COp. Expo-
sures of F-ll ranged from concentrations of 0.19% to 0.55% for periods
of six to twenty minutes. Exposures of F-12 ranged from concentra-
tions of 0.82% to 11.8% over the same period. The exhaled air was
14
assayed for C02 as the index of metabolism; non-volatile urinary and
tissue radioactivity were also measured, but this was not identified
with specific compounds. After removing the C02, exhaled air was
combusted in an oxygen/hydrogen flame which, according to the authors,
converted the unmetabolized exhaled [ C]-fluorocarbon to C02 for
assay. The experiment suffered from this procedure since it precluded
- 72 -
-------
the Identification of volatile metabolites in the exhaled air other
14
than CO,. In both the F-ll and F-12 studies, the total recovery of
exhaled CCL and non- volatile urinary and tissue radioactivity was
about 1% of the administered dose. Because of the radioactive impuri-
ties in the F-ll sample (carbon tetrachloride and trichloromethane
which are both known to be metabolized in animals), the F-ll study
gives no firm evidence for fluorocarbon metabolism. However, in the
F-12 study, all of the administered radioactivity was in the form of
fluorocarbons: 96% F-12 and 4% F-13 and/or F-14. According to the
current view of fluorocarbon biological activity, increasing fluori-
nation leads to increasing stability. Consequently, of these three
compounds, F-12 would probably be the most readily metabolized. The
F-12 study thus seems to indicate that, at most, only about 1% of F-
12 - and/or F-13 and F-14 - are metabolized after relatively brief
exposures.
Eddy and Griffith (1971) observed metabolism in rats following
oral administration of F-12 labelled with carbon-14. About 2% of the
total dose was exhaled as C02 and about 0.5% was excreted in the
urine. By thirty hours after administration, the fluorocarbon and its
metabolites were no longer present in the body.
Blake and Mergner (1974) have indicated that the apparent resist-
ance of F-ll and F-12 to biotransformation may be more a function of
their rapid elimination than their general stability. Over long
periods of exposure, the fluorocarbons will not only be in equilibrium
with tissue for long periods, but will also be more likely to access
"deep" tissue compartments not reached when exposure is terminated and
elimination occurs.
Because the surgical use of the volatile anesthetic halothane
(CFg-CHBrCl) has been associated with occasional incidents of liver
toxicity, the metabolism of this compound has been investigated. The
precise mechanism of halothane metabolism has not yet been established,
but several metabolites have been identified. The primary metabolic
products are trifluoroacetic acid (CF--COOH), inorganic bromide and
- 73 -
-------
products are trifluoroacetic acid (CF3-COOH), inorganic bromide and
inorganic chloride. Based on the amount of trifluoroacetic acid and
inorganic bromide recovered from the urine of humans, approximately
20% of an administered dose of halothane is metabolized in humans
(Rehder e_t aJL, 1967; Stier e_t al_., 1964). More recently, N.-trifluo-
roacetylethanolamine and jf-acetyl-S-(2-bromo-2-chloro-l,1-difluoro-
ethyl)-L-cysteine have also been identified as human urinary metabo-
lites (Cohen, 1971; Cohen et al_., 1975). This latter compound, an
apparent glutathione conjugate, indicates that some halothane under-
goes defluorination, which was previously thought not to occur. Under
conditions favoring defluorination (described below), inorganic fluo-
ride is also a halothane metabolite. In addition to these excretable
metabolites, it is also known that some halothane is transformed to
reactive products which bind covalently to cellular phospholipids and
proteins (Van Dyke and Gandolfi, 1974; Van Dyke and Wood, 1975; Werner
and Uehleke, 1974; Uehleke et a].., 1973).
These bound metabolites are of particular interest with respect
to the liver toxicity of halothane following clinical anesthesia
because (a) trifluoroacetic acid is not toxic at the concentration at
which it appears and (b) the liver toxicity of carbon tetrachloride,
chloroform, acetaminophen, and bromobenzene correlates with bound
metabolites (Van Dyke, 1973; Van Dyke and Wood, 1975). Both in vitro
and in vivo studies have shown that one of the major factors influ-
encing the metabolism of halothane and the formation of bound metabo-
lites is oxygen availability. Using hepatic microsome preparations
from rats and C-label led halothane, it has been observed that under
aerobic conditions the primary metabolites are trifluoroacetic acid
and chloride (bromide not measured), with some binding of C to
phospholipid and protein and with only trace amounts of inorganic
fluoride produced. Under anaerobic conditions (^ atmosphere), only a
trace amount of trifluoroacetic acid is produced and there is a
decrease in the inorganic chloride production, while the amount of
bound metabolites and the level of inorganic fluoride are markedly
increased. However, from the molar amounts of fluoride observed
- 74 -
-------
(assuming that only one fluorine is removed per halothane equivalent
bound), it was evident that metabolites other than the defluorinated
one(s) were also involved in the binding (Van Dyke and Gandolfi,
1976).
Widger et aJL (1976) demonstrated in vivo with rats that halo-
thane metabolism is influenced by oxygen availability. In their
study, rats receiving halbthane with an adequate oxygen supply (25-
60%} showed a lipid/protein ratio for bound metabolites of 0.76 ±
0.14 with no significant increase in fluoride levels. Under hypoxic
conditions (7-14%), there were large increases in the amount of
fluoride produced and, relative to the non-hypoxic group, approxi-
mately twice the amount of total bound metabolites, with a threefold
increase in lipid binding, a decrease in protein binding, and a
lipid/protein binding ratio of 3.24 ±1.29.
These studies indicate that halothane can undergo both oxidative
and non-oxidative metabolism. Van Dyke and Gandolfi (1976) suggest
that the initial step in the metabolism of halothane is the abstrac-
tion of a proton to form a carbanion which, oxygen, can bind to cell
constitutents directly and can also undergo defluorination to form
additional bound metabolites. Where oxygen is available, the car-
banion is oxidized to trifluoroacetic acid, bromide, and chloride.
Although it has yet to be isolated experimentally, trifluoroacetal-
dehyde has been proposed as an intermediate in the oxidative pathway
of halothane metabolism to trifluoroacetic acid. Trifluoroacetal-
dehyde could be involved in the binding observed with oxidative
metabolism of halothane and in the formation of the trifluoroethan-
olamine metabolite which has been identified. The metabolism of
halothane suggested by the currently available data is summarized
schematically below:
- 75 -
-------
CF3-CHBrCl
proton abstraction
CF3-C"BrCl
oxygen available
0
CFgCOH
CF3CH
Br.Cl)
Some binding; protein binding
favored with some lipid binding
possible source of N^trifluoro-
acetylethanolami ne
oxygen unavailable
(1) binding of carbanion
(lipid binding favored)
and/or
(2) defluorination to form
CF2=CBrCl (+ F") and
subsequent binding to
cell constitutents (lipid
binding favored); also
some formation of a gluta-
thione conjugate to yield:
N-acetyl-S^-(2-bromo-2-
chloro-1,1-difluoroethyl)•
L-cysteine
Although halothane contains a hydrogen atom that is lost as the
initial step in its metabolism9 there is evidence that perhalogenated
materials, notably carbon tetrachloride and the fluorocarbons F-ll and
F-12, also form metabolites which can bind to cell constituents.
Uehleke and Werner (1975) have demonstrated in vitro using anaerobic
suspensions of liver microsomes from rabbits (pretreated with pheno-
barbital to stimulate metabolism) that F-ll binds irreversibly to both
endoplasmic phospholipids and proteins. Cox e_t aV. (1972b) have
obtained spectral evidence which indicates that F-ll binds to the
phospholipid environment of cytochrome P-450 from rat-liver microsomal
preparations, and also to another site apparently similar to the CO-
binding site. Further, in the in vivo study of Blake and Mergner
- 76 -
-------
(1974) discussed previously, there was some binding of radioactivity
to tissue which could have been due to F-ll and F-12, but, owing to
the impurities in the radiolabelled materials, this cannot be stated
as conclusive.
If the development of liver toxicity from halothane is associated
with the formation of bound metabolites, as appears to be the case
with carbon tetrachloride and other substances mentioned previously,
these metabolism studies could explain the "occasionality" of the
toxic response. The formation of bound halothane metabolites, par-
ticularly to lipids, is clearly favored by an inadequate oxygen supply
to the liver, a circumstance which could exist during certain surgical
procedures due to the physiologic condition of the patient or to some
degree of hypoxia during anesthesia. It is also conceivable that a
buildup of bound metabolites could occur from repeated exposure to
halothane, even when there is no hypoxia, resulting from either the
binding of an intermediate (trifluoroacetaldehyde) in the oxidative
pathway leading to trifluoroacetic acid and/or from binding of metab-
olites from the non-oxidative pathway which may also occur to some
extent even under conditions of adequate oxygen supply.
The evidence available on the formation of bound metabolites from
halothane, and the scant, but significant, data showing that F-ll and
F-12 may also be metabolized to substances which bind to cell constit-
uents point to the need for further attention to fluorocarbon metabo-
lism. The presence of a hydrogen atom, as in halothane, may be an
important factor in the extent to which the fluorocarbons are metabo-
lized. Because the fluorocarbons which have been proposed as replace-
ments for F-ll and F-12 all contain hydrogen atoms (namely, F-133a
(CF3CHC12), F-142b (CClFg-CHg), F-152a (CHF2-CH3), F-22 (CHC1F2), and
the 120 (monohydrogen ethane) series of fluorocarbons), these mate-
rials clearly need to be examined for metabolism to substances which
bind to lipids and protein. The perhalogenated fluorocarbons may also
form metabolites which bind to lipids and proteins and, although the
data on F-ll and F-12 seem to indicate that this does not occur to a
- 77 -
-------
significant extent with acute exposures to these two compounds, the
extent to which bound metabolites might build up from long-term expo-
sure is worthy of further study. The other commercially important
fluorocarbons, such as F-113, F-114, and F-115, for which no metabo-
lism data were found, should also be examined for the formation of
bound metabolites.
- 78 -
-------
IX. HUMAN TOXICITY STUDIES
Much of the information available on the toxicity of the fluoro-
carbons to humans involves the intentional or unintentional misuse of
fluorocarbon-containing products involving inhalation of high concen-
trations of the compounds. Of particular note is the experience of
abusive inhalation of fluorocarbon propellants by young people attemp-
ting to reach an intoxicated state. Bass (1970) has associated 57
deaths occurring between 1960 and 1969 with inhalation of fluorocarbon
propellants. Kilen and Harris (1972) have reported that over 140 such
cases of fatal intoxication from abusive inhalation of aerosol pro-
pellants have been documented. The method of inhalation involves
spraying the aerosol product into a bag, placing the bag over the nose
and mouth, or over the entire head, and inhaling the contents deeply.
While asphyxia is a potential hazard, the cause of death is most pro-
bably cardiac arrhythmia, possibly aggravated by elevated levels of
catecholamines due to stress and/or an increase in blood carbon
dioxide (Bass, 1970). The cardiac effects of fluorocarbons are described
in Section XI.
While similar concern exists over the role of fluorocarbons in
deaths of asthmatics using fluorocarbon propelled bronchiodilator
drugs (Taylor and Harris, 1970b; Archer, 1973), there is no unequi-
vocal evidence that the fluorocarbons are directly responsible for
fatalities under these circumstances (Silverglade, 1971; Aviado,
1975c).
Except for the hazards of the fluorocarbon anesthetic halothane
to operating room personnel (discussed later in this section), there
has been only one report of a specific adverse effect resulting from
occupational exposure to the fluorocarbons. Speizer et. al_. (1975)
found that persons working in the pathology department of a Boston
hospital who used a fluorocarbon aerosol product (usually F-22,
though some F-12 was also used) in preparing frozen tissue sections
had a 3.6 relative risk of heart palpitations compared to non-exposed
employees in the same department and in a different department (radi-
ology). A dose-response relation was noted between maximum number of
- 79 -
-------
frozen sections prepared weekly and episodes of palpitation. Palpita-
tions were reported by 3 of 6 persons (50%) preparing 10 or more
frozen slides per week; 5 of 11 (46%) preparing 5-9 frozen slides per
week; and 5 of 14 (36%) preparing less than 5 frozen slides per week.
The incidence of palpitation among non-exposed persons was 20 of 87
(23%). In an attempt to estimate F-22 exposure under work conditions,
air from the breathing zone was monitored during the slide preparation
procedure. With two 10-second blasts of the aerosol cannister (100%
F-22), the average exposure of F-22 over the two-minute period was 300
ppm.
Imbus and Adkins (1972) found no signs of toxicity in a group of
50 workers exposed to F-113 (being used for degreasing in "clean
rooms" of Kennedy Space Center) for up to 4.5 years (mean 2.77 years)
at concentrations of 46 to 4700 ppm (mean 669 ppm; median 435 ppm).
Blood levels of F-113 were not measured.
In a study of fluorocarbon blood levels in 20 women using fluoro1
carbon-propelled aerosol products (average of 21.6 g of fluorocarbon
propellants per woman per day), Marier ejt aj_. (1973) found no measur-
able blood levels of fluorocarbons. The limits of detection were
0.004 ppm for F-ll, 0.1 ppm for F-12, and 4 ppm for F-114. Marier e_t
al_. (1973) were also unable to detect any abnormalities in various
hematological and respiratory parameters, nor in the overall health of
the subjects. The women were exposed to the fluorocarbons under
normal use circumstances for the aerosol products, but the amounts of
fluorocarbon to which they were exposed were estimated to be greater
than nine times that of normal use.
Exposure to humans under experimental conditions has been thus
far limited to three of the most common fluorocarbons: F-12, F-113,
and F-13B1.
Fluorocarbon-12 has been tested using human subjects by both
Kehoe (1943) and Azar ejb al_. (1972). Kehoe (1943) exposed one subject
to concentrations of 4%, 6%, 7%, and 11% for periods of 80, 80, 35,
and 11 minutes, respectively. A second subject was exposed to 4% for
- 80 -
-------
14 minutes Immediately followed by 2% for 66 minutes. At 4% F-12, the
subjects experienced a tingling sensation, humming in the ears, and
apprehension. Electroencephalographic changes were noted as well as
slurred speech and decreased performance in psychological tests. In
the one subject exposed to higher concentrations, these signs and
symptoms became more.pronounced with increases in concentration. An
exposure of 11% caused a significant degree of cardiac arrhythmia
followed by a decrease in consciousness with amnesia after ten minutes.
At concentrations of 1% F-12 for 150 minutes, Azar et al_. (1972) noted
a 7% decrease in psychomotor test scores and no effects at 0.1% con-
centration over the same period.
Fluorocarbon-113 has been tested on human subjects by Stopps and
Mclaughlin (1967) and Reinhardt ejt al_. (1971). Psychomotor perform-
ance was evaluated with exposures to 0.15%, 0.25%, 0.35%, and 0.45% F-
113 for 165 minutes (Stopps and Mclaughlin, 1967). At the lowest
level, no effect was noted. At 0.25% there was difficulty in concen-
trating and some decrease in test scores. These effects were more
pronounced at 0.35% F-113. At 0.45% F-113, performance at various
tasks was decreased by between 10% and 30%. These decreases coincided
with sensations of "heaviness" in the head, drowsiness, and a slight
loss of orientation after shaking the head from left to right. Rein-
hardt et^ al_. (1971) exposed human subjects to concentrations of 0.1%
and 0.05% F-113 for 180-minute periods in the morning and afternoon on
five days. No decreases in psychomotor ability were noted. No
abnormal findings were noted during post-exposure physical examina-
tion, hematologic and blood chemistry tests (conducted three days
after final exposure) and steady-state measurements of diffusing
capacity of lungs and fractional uptake of carbon monoxide.
Fluorocarbon-13Bl exposures to human test subjects have been
summarized by Reinhardt and Reinke (1972). Concentrations of 1%, 3%,
and 5% F-13B1 for periods of three to three and a half minutes had no
effect on electrocardiagrams or response times in three subjects.
- 81 -
-------
Concentrations of 7% and 10% over the same period, however, did result
1n slight lessening of equilibrium and increase in response time
(Reinhardt and Stopps, 1966).
Similar results were obtained at Hine Laboratories (1968) over
longer durations. Concentrations of 5% F-13B1 for 20-25 minutes
caused a minimal decrease in psychomotor performance while concentra-
tions of 10% caused a more pronounced decrease in ten subjects.
Drowsiness and an increased sense of well-being were also noted.
Graded concentrations of 5-17% F-13B1 over periods of 15-20 minutes
resulted in central nervous system effects ranging from tingling to a
feeling of impending unconsciousness (14% F-13B1) in nine of ten
subjects, with the remaining subject reporting no effects at concen-
trations up to 15.7%. Cardiac effects were noted in three of ten
subjects. Effects in two subjects at 8.2-15.7% F-13B1 were primarily
T-wave alterations (depression and flattening), with increased sinus
arrhythmias occurring in one of these subjects. The third subject
showing cardiac effects exhibited T-wave flattening after an inital
exposure to 16.9% F-13B1, but 36 hours later, after a five-minute
exposure to 14% F-13B1, developed cardiac arrhythmias including T-wave
flattening, extrasystoles forming bigeminy, A-V dissociation, and
multifocal premature beats. Clark (1970) has also noted T-wave
depression and tachycardia along with loss of equilibrium and pares-
thesia in all subjects after less than a one-minute exposure to 12%
and 15% F-13B1. T-wave depression was noted at 10% exposures for one
minute in two subjects, along with slight dizziness and paresthesia.
Three-minute exposures to 9% and 6% resulted in similar central
nervous system effects and tachycardia.
In addition to these studies, Call (1973) exposed eight subjects
to concentrations of 4% and 7% F-13B1 for three minutes in a hypobaric
chamber maintained at 760 mm Hg, 632 mm Hg (equivalent to 5,000 feet),
and 380 mm Hg (18,000 feet). Although no cardiac effects were noted
in any of these exposures, reaction times were increased from about
550 milliseconds to about 600 milliseconds at both concentrations and
at all altitudes.
- 82 -
-------
There have been two reports dealing with the effects of aerosol
product usage on respiratory parameters in humans. Although the flu-
orocarbons are the most commonly used propel1 ants and tend to be a
common denominator for many aerosol products, it must be emphasized
that, in these studies, the effects observed are not necessarily
attributable to the fluorocarbons. Not all products contain fluoro-
carbons propel1 ants and even those which do also contain diverse other
ingredients to which the user is exposed.
Good ,e_t al_. (1975) report an excess of moderate and marked atypi-
cal metaplastic cells in sputum samples among frequent users of aero-
sol products. None of the frequent users in this study complained of
symptoms of respiratory disease, nor did any have other recognized
disease thought to cause metaplasia or atypical cells in the bronchial
mucosa. The authors suggest that some aerosol products either alter
the flora of the bronchial tree or contain carcinogenic compounds.
Although the authors do not suspect the propel1 ants of being carcino-
genic, they do suggest additional testing of them to determine their
effects on the quantity and quality of mucus, ciliary activity, and on
the susceptibility to infection by microorganisms.
Lebowitz (1976) surveyed 3,485 individuals for frequency and type
of aerosol product usage and for respiratory symptoms (such as per-
sistent cough, phlegm, chronic bronchitis, emphysema, etc.). After
correcting for age, smoking habits, etc., Lebowitz found that the data
suggest a tendency for more symptoms to follow increased aerosol
usage, most consistently among non-smokers.
While these studies themselves do not supply much useful informa-
tion for assessing the hazards associated with exposure to the fluoro-
carbons from aerosol product usage, they do indicate that further
investigation into this area would be prudent.
There has been considerable attention given to the toxic effects
of the fluorocarbon anesthetic halothane toward both the patients
receiving it and the operating-room personnel. Within a few years
- 83 -
-------
following its introduction as a clinical anesthetic (1956 in Great
Britain, 1958 in the United States), a substantial number of reports
began to appear indicating an association between halothane and post-
operative liver necrosis in the patients. Many studies have been made
on the incidence of "halothane hepatitis" and the majority of them
agree that halothane is hepatotoxic, but that the incidence is quite
low in clinical practice.
The National Halothane Study (1969) reported that the incidence
of death from massive hepatic necrosis following halothane anesthesia
was 1 in 9804 and, excluding those cases which could be attributed to
causes other than halothane exposure, the incidence was 1 in 35,250.
Noting that mortality is too gross a criterion to assess the toxicity
of a substance, Carney and Van Dyke (1972) reviewed data from five
other halothane studies and found that the incidence of post-halothane
hepatitis (fatal and non-fatal) was 1 in 2725. Mortality rates from
these and three additional studies averaged 1 in 11,214, quite com-
parable to the mortality rate reported by the National Halothane
Study. The data reviewed by Carney and Van Dyke do not enable exclu-
sion of factors other than halothane as the causative agent, but
assuming that other factors were involved at the same incidence
observed in the National Halothane Study, they calculated that the
incidence of halothane hepatitis would amount to 1 in 9090, and that
the incidence of attendant mortality would be 1 in 40,370.
Carney and Van Dyke (1972) also examined the incidence of fatal
and non-fatal liver injury in patients receiving non-halogenated
anesthetics. The data showed that the mean hepatitis rate in these
patients was 1 in 5,099, with fatalities due to liver injury occurring
in 1 of 12,538. The mortality rate was about the same for halothane
and non-halogenated anesthetics, while the rate of non-fatal hepatitis
with non-halogenated anesthetics was about one half that of halothane
(JLe_. 1 in 2525). It is, therefore, possible that half of the cases
of halothane hepatitis which could not be attributed to factors other
than halothane may, in fact, have been due to other indeterminable
- 84 -
-------
factors. However, Carney and Van Dyke (1972) did not comment as to
whether or not the use of non-halogenated anesthetics in the cases
examined was based on prior determination of existing liver impairment
or surgical procedures where there is an increased risk of liver
injury. Were this the case, the usefulness of these data for compari-
son to the halothane data would be questionable.
Also questionable is the adjustment of the liver toxicity inci-
dence, as in the National Halothane Study, to exclude all cases where
the effect could be attributed to factors other than halothane since
this could, in some cases, underestimate the importance of halothane
as a contributing factor in the liver toxicity observed.
Although the incidence of post-halothane hepatitis is low and
many cases have been studied, there is as yet no clear correlation
with other factors which may influence or predispose individuals to
its development. One possible correlation considered by clinical
studies which is supported by the recent studies of halothane metabo-
lism is inadequate oxygen supply to the liver due to some physiologic
reason or the nature of the surgical procedure. Such conditions
would, based on the metabolism studies, favor the formation of reac-
tive metabolites which bind to cell constituents. The formation of
bound metabolites has been associated with liver toxicity from other
compounds, such as carbon tetrachloride, and may well be the cause of
halothane liver toxicity also. Another correlation, which would also
indicate that bound metabolites are involved, is the observation that
the risk of halothane hepatitis in surgical patients is increased with
repeated exposures.
In addition to the liver effects of halothane, headache, mood
changes, and alterations in intellectual function have been reported
to follow halothane anesthesia (Tyrell and Feldman, 1968; Johnstone ejt
al., 1975). These effects may result from the bromide released in the
metabolism of halothane. Bromism, or chronic bromide intoxication, is
a recognized syndrome characterized by headache, lethargy, dizziness,
mental confusion, and other similar signs. Johnstone e_t al_. (1975)
- 85 -
-------
found blood levels of bromide following halothane anesthesia approach-
ing those associated with its psychoactive effects persisting for a
week or so after anesthesia.
The manifestation of toxicological effects among anesthetists and
other operating room personnel has also received much attention.
Ambient concentrations of halothane in operating rooms have been
reported to be 10 ppm (Linde and Bruce, 1969), 4.9-8.7 ppm (Whitcher
e_t al_., 1971), and 14-59 ppm (Gotell and Sundell, 1972). Halothane is
usually used with nitrous oxide, and there is, therefore, exposure to
this gas as well as to halothane in the operating room. In the study
noted above, where 10 ppm halothane was measured, 130 ppm nitrous
oxide was also found. Other anesthetics, such as methoxyflurane, are
also used. Further, there are many non-anesthetic volatile materials
to which operating room personnel may be exposed (Jenkins, 1973).
Linde and Bruce (1969) also note that there may be significant expo-
sure to radiation among anesthetists. Although exposure to a multi-
plicity of materials makes it difficult to correlate observed effects
among operating room personnel with any specific material, halothane
appears to be a common denominator.
The hazards which have been associated with trace anesthetics in
operating rooms are reported to be (a) increased risk of spontaneous
abortion among exposed pregnant women, (b) increased incidence of
congenital abnormalities in children of women who work in operating
rooms, (c) increased susceptibility to cancer for female, but not
male, anesthetists, and (d) increased risk of liver disease equally
applicable to males and females. These findings are from a nationwide
survey of operating room personnel (Anonymous, 1974).
Cohen e_t al_. (1971) reported a 37.8% abortion rate among anesthe^
tists compared with a 10.3% abortion rate for a control group com-
prised of physicians in non-anesthesia specialties, and a 29.7% abor-
tion rate among operating room nurses, compared with 8.8% for a control
group of general duty nurses. With regard to birth defects, a study
by Corbett (1974) showed that 71 of 434 children (16.4%) born to nurse
- 86 -
-------
anesthetists who continued to work during pregnancy had congenital
abnormalities, whereas 15 of 261 children (5.7%) born to nurse anes-
thetists not working during pregnancy had anomalies. Significant
increases were observed in the incidence of hemangiomas, total skin
anomalies, inguinal hernias, and musculoskeletal anomalies among the
children of mothers who continued working. Slight, but not statis-
tically significant, increases were also observed in the incidence of
cardiovascular, gastrointestinal, and central nervous system anom-
alies.
Bruce ejt aV. (1974) reported that in a controlled study of humans
inhaling 15 ppm halothane with 500 ppm nitrous oxide, significant
decrements were observed in the performance of tasks in which atten-
tion was divided between auditory and visual signals, a visual tach-
istoscopic test and memory tests involving digit span and recall of
word pairs, when compared to controls breathing only air. Subjects
receiving 500 ppm nitrous oxide showed decrements only on the digit
span test, and the authors concluded that the other effects were
likely due to halothane.
In animal studies described in subsequent sections, chronic
exposure to trace amounts of halothane (10 ppm) is shown to result in
changes in liver, kidney, and the central nervous system of adult and
developing animals. These studies support the association of hazards
to operating room personnel with halothane exposure.
- 87 -
-------
X. EXPERIMENTAL TOXICITY STUDIES
A. Inhalation
1. Acute Exposure
The commercially Important fluorocarbons have been tested to some
extent for acute inhalation toxicity. Results are presented in Table
B-I (Appendix B). In that many of these tests were conducted to
determine the potential hazard from occupational exposure, or to
determine anesthetic potency, the response of the animals is often
measured in terms of effects such as tremors, convulsion, and loss of
righting reflex as well as lethality. In Table B-I, the approximate
lethal concentration (ALC) is the minimum concentration causing death
in any of the animals over the exposure period, which is usually less
than the concentration causing death in half of the test animals
(LC50). The anesthetic concentration is that at which certain basic
reflexes are lost. The concentration causing tremors usually repre-
sents the minimum concentration causing any marked response. Non-
lethal concentrations represent levels not causing death in the
exposure period and, in cases where it is less than the concentration
causing tremors, it is an approximation of the "no marked effect"
level.
The fluorocarbons showing the greatest acute inhalation toxicity
are F-ll and F-113, where exposures of 5-25% are fatal. By contrast,
the other fluorocarbons shown in Table B-I do not elicit lethal
responses at concentrations from 40% to 80% or more. Since concentra-
tions of fluorocarbons in ambient air are in the parts per billion and
less range, and may reach only a few hundred parts per million (less
than 0.1%) in a small room where a fluorocarbon-propelled aerosol is
used, there is little reason to be concerned with acute inhalation
toxicity of the fluorocarbons in terms of lethality under normal use
conditions. However, acute inhalation of the fluorocarbons has been
shown to affect certain cardiovascular and pulmonary parameters, which
are discussed in Section XI of this report.
-------
2. Subacute Exposure
The distinction between subacute and chronic exposure to a
substance is usually an arbitrary one, involving consideration of such
parameters as duration, frequency, and number of exposures. For the
purposes of this paper, chronic exposures are taken as those lasting
for at least 6 hours per day and continued for at least 30 days, which
is somewhat similar to occupational exposures. Exposures not fitting
these criteria are here classified as subacute.
Subacute inhalation toxicity data are presented in Table B-II.
No significant signs of toxicity were noted in animals exposed to F-ll
with the possible exception of rats exposed to 1.2% F-ll for 4 hours
per day for 10 days, where, among other pathological changes, emphy-
sema and lung edema were observed. However, no changes were noted in
dogs exposed to 1.25% or in cats exposed to 2.5% F-ll for 3.5 hours
per day for 20 days (Clayton, 1966).
Subacute exposure to F-113 showed some possible liver toxicity
rats to at 6% and 4% administered one hour per day for five days.
F-ll4 was fatal to 4 of 4 dogs exposed 8 hours per day to 20% for
3 or 4 days. All animals died during exposure. However, dogs exposed
to 14.16% F-114 for 8 hours per day developed a tolerance to the
exposure after three days, and showed no significant toxicological
effects after 21 days.
Ross and Cardell (1972) have demonstrated that rats inhaling
0.25% halothane in air 7 hours per day for 7 days develop hepatic
lesions. Hughes and Long (1972) observed hepatic necrosis in 7 of 50
guinea pigs anaesthetized 1-5 times with 1% halothane in oxygen.
3. Chronic Exposure
In assessing the environmental hazards posed by the fluorocarbons
from a health effects standpoint, the most valuable type of studies
is that dealing with long-term inhalation exposure to the materials at
levels below which symptoms of acute toxicity occur, preferably at
- 89 -
-------
levels approaching those to which many persons are continually (or
consistently) exposed (probably in the parts per billion range by
volume according to the data of Hester e_t a\_. (1974)). Unfortunately,
studies at these low concentrations have not been carried out to date
and except for one 10-month'study with F-22, "long-term" studies have
been on the order of 90 days or less. Data are presented in Table
B-III.
The earliest investigation into chronic inhalation toxicity of a
fluorocarbon material was reported by Sayers e_t al_. (1930) where dogs,
monkeys, and guinea pigs were exposed to 20% F-12 for 7-8 hours a day
for 5 days, and 4 hours for 1 day each week over a 12-week period.
The animals were observed for lethality, changes in behavior, weight
gain, red and white blood-cell count (including differential), and
autopsy findings. Tremors were observed in the dogs and, to a lesser
extent, in the monkeys during exposure periods. After two weeks of
exposure, the animals appeared to develop a tolerance to F-12 as the
amount and degree of tremors declined. These animals showed a depres-
sion in weight gain compared to controls during the early part of the
study, which was less significant after the tolerance to development
of tremors occurred. This was probably associated with depressed
appetite and/or increased energy expenditure during the period when
tremors were prevalent. Guinea pigs did not develop tremors, although
some irritation was observed. None of the exposed or control monkeys
and dogs died during the study. Ten of twenty-six exposed guinea pigs
and six of twenty-six control guinea pigs died during the study. The
cause of death among all of these animals was congestion and edema of
the lungs and pneumonia. All but three of these deaths (1 control, 2
exposed) occured among eleven animals from each group used to obtain
blood samples throughout the test. The deaths of these animals were
attributed to either handling technique during blood extraction and/or
increased exposure to other factors which influence respiratory ill-
ness in guinea pigs. It was noted that these studies were performed
in the winter when respiratory illness is prevalent among guinea pigs.
- 90 -
-------
Red blood cells and hemoglobin showed a slight increase during the
first two or three weeks of exposure, but were normal and similar to
controls thereafter. White cell counts were the same for exposed and
control animals, although differential white cell examinations showed
a slight increase in polymorphonuclear neutrophils and a slight
decrease in lymphocytes of the exposed animals. Autopsies revealed no
pathological changes ^n the exposed animals (other than that mentioned
above for the guinea pigs). It was also noted in this study that the
frequency of pregnancy and bearing of normal young were similar for
exposed and control guinea pigs.
Prendergast ejt al_. (1967) also studied chronic inhalation toxi-
city of F-12 using rats, guinea pigs, dogs, monkeys, and rabbits
exposed to 0.081% concentration continuously for 90 days and, in
another study, to 0.084% F-12 for 8 hours per day, 5 days a week for
six weeks. In the continuous exposure study, 2 of 15 rats and 1 of 15
guinea pigs died, but no other visible signs were observed. There was
a high incidence of varying degrees of lung congestion in rabbits,
monkeys, rats, and guinea pigs. Non-specific inflammatory changes
were observed in the lungs of all species, but were also noted for
controls. The incidence of this inflammatory change was not mentioned
for experimental or control animals. Slight to extensive fatty infil-
tration of the hepatic cells was observed in all exposed guinea pig
liver sections examined and several sections exhibited focal or sub-
massive liver necrosis. These liver changes in guinea pigs were
considered to have been induced by the exposure. In the repeated
exposure study, lung congestion and non-specific inflammatory changes
were observed. Several guinea pigs were found to have exposure-
related focal necrosis or fatty infiltration of the liver and one
monkey had heavy deposits of pigment in the liver, spleen, and kidney.
Jenkins elb aJL (1970) studied the chronic inhalation toxicity of
F-ll in rats, guinea pigs, monkeys, and dogs at 0.1% concentration for
90 days or with 8-hour exposures of 1.025% for 5 days per week for six
weeks. One monkey in the continuous 90 day exposure study died,
- 91 -
-------
showing hemmorrhagic lesions on the surface of the lung. The authors
state that necropsy failed to reveal any evidence that death was
directly attributable to F-ll exposure. They do not, however, present
any arguments that the death was attributable to other factors. In
monkeys surviving continuous exposure, a large amount of inflammatory
infiltration was noted, occasionally associated with microfilarial
parasite infestation. Blood smears showed such parasites in approxi-
mately half of the experimental and control animals. There were no
remarkable differences in response between the continuous and repeated
exposure groups. Non-specific inflammation of the lungs was evident
in all experimental species, except in dogs given repeated exposure.
Such changes were not described for control animals. Mild discolora-
tion was noted in the livers of one-fourth of the rats and guinea pigs
in both exposure groups. A single 2 x 4 mm liver lesion was noted in
one of the male rats from the continuous exposure groups. Of eight
rats examined after repeated exposures, one evidenced focal myocy-
tolysis and two showed focal non-specific myocarditis. Marked increases
in serum urea nitrogen were noted in dogs exposed continuously (33
mg/100 ml) and repeatedly (36 mg/100 ml), compared to controls (16.8
mg/100 ml). No change in serum urea nitrogen was observed in any
other animals in either exposure group.
Clayton (1966) referenced a study by Karpov (1963) exposing
rabbits, rats, and mice to 1.42% F-22 for 6 hrs/day for 10 months.
Mice showed lower endurance in a swimming test and an increase in the
number of trials needed to establish a conditioned reflex. Rats
showed a decrease in oxygen consumption and an increase in subthresh-
old stimuli needed to induce a response. Rabbits showed decreases in
red blood-cell count, hemoglobin, lymphocytes, reticulocytes, blood
cholinesterase, and serum albumin and increases in neutrophiles,
eosinophiles, and globulin. Pathological examination revealed degen-
erative changes in heart, liver, kidney, and nervous system as well as
changes in lungs leading to emphysema and exudate alveolar septal
thickening. None of the aforementioned changes were observed in rab-
bits, rats, or mice ekposed to 0.198% F-22 for the same duration.
- 92 -
-------
Three of twenty-one rats exposed to F-113 for 7 hours per day for
31 days showed slightly pale livers, but no other remarkable observa-
tions were made for F-113, or for chronic inhalation studies of F-115
and F-13B1 (Clayton, 1966).
Chronic inhalation studies with halothane have shown effects in
the liver, kidney, and nervous system detectable at the ultrastruc-
tural level with electron microscopy. Adult rats exposed to 10 ppm or
500 ppm halothane for 8 hours per day, 5 days per week for 8 and 4
weeks, respectively, developed pathological changes in the hepatocytes
including crenation of the nucleus, glycogen depletion, dense and
c-shaped transformation of the mitochondria, disorientation or condens-
ation of the rough endoplasmic reticulum, and coagulative necrosis of
the hepatocytes (Chang e_t al_., 1974a). Chang e_t al_. (1975a) found
that rats exposed to 10 ppm halothane for 8 hours per day, 5 days per
week for 8 weeks developed chronic degenerative changes in the kidney.
Pathological changes in the kidney were even more extensive and pro-
nounced in rats exposed to 500 ppm, 8 hours per day, 5 days per week
for 4 weeks. Chang ie_t al_. (1974b) report that exposures of halothane
to rats at 10 ppm for 8 hours per day, 5 days per week for 8 weeks
caused ultrastructural changes in the nervous system such as collapse
of the neuronal rough endoplasmic reticulum, dilation of the Golgi
complex, and focal cytoplasmic vacuolation within cortical neurons.
Again, more extensive damage was observed in rats receiving 500 ppm
for 8 hours per day, 5 days per week for 4 weeks. The levels of
halothane used in these studies were chosen as representative of
levels found in operating rooms and support the contention that halo-
thane is a causative and/or contributory factor in certain effects
observed in operating room personnel.
The type of studies which have been performed to date do not form
an adequate data base for assessing the health hazards associated with
continual environmental exposure to the commercially important fluoro-
carbons such as F-ll, F-12, etc. The observed effects with halothane
and the findings such as inflammatory infiltration of the lung and
- 93 -
-------
liver changes noted in some of studies with the other fluorocarbons do
indicate that long-term inhalation of these materials at levels below
those associated with more acute types of responses (tremors, cardiac
effects, etc.) may not be inconsequential. Chronic inhalation studies
with much longer exposure periods to the commercial fluorocarbons than
those performed to date and at low levels, that is, the parts per
million range, are needed. These studies should include electron
microscopic examination of tissues for ultrastructural changes at the
cellular level.
B. Dermal Exposure
Clayton (1966) reported that the approximate lethal dose of F-113
applied to the skin of rabbits was greater than 11 g/kg, with local
irritation of the skin at the application site and alterations in the
dermis and adjacent connective tissues. No systemic changes were
observed. F-113 applied to rabbit skin at a dose of 5 g/kg daily for
five days results in fluctuations in weight and damage to the skin.
Slight liver changes were observed microscopically but no other
systemic changes were observed. Fluorocarbon-113 has been applied to
the shaved back of rabbits five times a week for twenty weeks with no
visible adverse affects (Desoille elt al_., 1968).
Fluorocarbons-11, -12, -113, or -114 at 40% in sesame oil sprayed
daily for 12 days on rabbits (shaved skin) elicited no effect (Scholz,
1962). Quevauviller e_t al_. (1964) and Quevauviller (1965) have
applied F-ll, F-12, F-114, and mixtures of F-ll and F-12, and F-ll and
F-22 to the skin, tongue, soft palate, and auditory canal of rats 1-2
times per day for 5 days per week for 5-6 weeks. Each compound was
sprayed on the surface for five or ten seconds from a distance of 10-
20 cm. Skin irritation with edema and a slight inflammatory reaction
was observed, most markedly with the F-ll/F-22 mixture. Older rats
were more severely affected than younger rats. The auditory canal of
one rat treated with F-114 showed desquamation of the epithelium and
inflammation. No significant changes were observed in the other areas
of application with these materials. The healing rate of burns was
retarded by application of all the above fluorocarbons.
- 94 -
-------
The rapid evaporation of the fluorocarbons from the skin surface
may result in chilling or freezing of the tissue and is, perhaps, the
principal hazard associated with acute dermal exposure. Since edema
is often an early symptom of frostbite, it is possible that part or
all of the skin reactions noted above were due to this evaporative
effect. Evaporative effects are not as significant a factor in dermal
exposure to the less volatile fluorocarbons, notably F-113. As
indicated previously, F-113 is absorbed through the skin, being detec-
table in the exhaled air of dermally exposed individuals.
C. Oral Exposure
Because of their uses and physical properties, oral exposure to
the fluorocarbons is unlikely and little information is available.
F-ll was not fatal to rats receiving 7.38 g/kg via intubation, nor
were there any histological changes in the liver (Slater, 1965).
Clayton (1966) reported approximate lethal dose values in rats of 1
g/kg for F-ll and 2.25 g/kg for F-114 disolved in peanut oil. Both
Clayton (1966) and Michaelson and Huntsman (1964) report the approxi-
mate lethal oral dose 6f F-113 in rats to be 45 g/kg.
No adverse effects were observed in rats receiving oral doses of
2 g/kg/day of F-114 for 23-33 days (Quevauviller, 1965). No evidence
of toxicity was found in rats receiving oral doses of 140-170 mg/kg/day
of F-ll5 for 10 days (5 days per week for 2 weeks) (Clayton, 1966).
Fluorocarbon-12 is the only major fluorocarbon compound for which
chronic oral toxicity data have been reported. Waritz (1971) sum-
marizes the results of a 90-day feeding study with rats at doses of 35
and 350 mg/kg/day and dogs at doses of 10 and 100 mg/kg/day. No
deviations are noted from either control groups except that experi-
mental rats had elevated but not abnormal levels of urinary fluoride
and plasma alkaline phosphatase.
Sherman (1974) conducted a two-year feeding study of F-12 in rats
and dogs. The approximate dose levels for rats were 15 mg/kg/day and
150 mg/kg/day, administered as a corn oil solution via gastric intuba-
tion. There was a slight decrease in body weight gain in the high
- 95 -
-------
dose groups of rats, but there were no clinical signs of toxicity and
liver function, urine, hematological, and histopathological analyses
were within normal limits as established by controls. In the dog
p
studies, the F-12 was administered by immersion of Gainesburgers into
F-12, and the average doses were approximately 8 mg/kg and 80 mg/kg
for the low and high dietary levels, respectively. There were no
signs of toxicity or changes in the analyses of liver function, urine,
hematological or histopathological parameters. There was an apparent
retention of some F-12 (up to 1 ppm) in the fat and bone marrow.
D. Card nogeni city
Epstein et al_. (1967) found that F-ll, F-113 and F-112 (C2F2C14)
at doses of 0.1 ml of 10% (v/v) solution in redistilled tricaprylin
injected subcutaneously in the neck of neonatal mice are not carcino-
genic. However, when injected in conjunction with a 5% (v/v) solution
of piperonyl butoxide, F-113 and F-112 were found to induce hepatomas
in male mice. (F-ll was not tested with piperonyl butoxide.) Piper-
onyl butoxide, which alone was not hepatotoxic or hepatocarcinogenic,
is a potent inhibitor of microsomal enzyme function (detoxification)
in insects and is thus a useful synergist with insecticides. Piper-
onyl butoxide is also a potent inhibitor of microsomal enzyme systems
in mice, but is much less potent in rats and humans (Conney et al.,
1972). While it is impossible to interpret the significance of this
one study in terms of exposure to the fluorocarbons, it is indicative
of a possible synergistic effect between these compounds and micro-
somal enzyme system inhibitors and remains an avenue of future study.
At this time, F-ll is being tested for carcinogenicity by gastric
intubation at Hazel ton Laboratories. Fluorocarbon-12, while not on
test currently, has been approved for testing via the inhalation route
(Kraybill, 1975).
E. Reproductive Effects, Mutagenicity, and Teratogenicity
Bruce (1973) found no reproductive effects in rats exposed to 16
ppm halothane in air, 7 hours per day, 5 days per week for 6 weeks
- 96 -
-------
prior to mating. Wittmann et^ al_. (1974) reported that female rats
exposed to 0.8% halothane in nitrous oxide-oxygen for 12 hours per day
on gestation day 6 and 10 had an abortion rate of 44%, compared to 13%
among controls receiving nitrous oxide-oxygen. Kennedy ejt al_. (1976)
found no adverse effects on fertility or general reproductive perform-
ance in rats exposed to anesthetic concentrations of halothane (approx-
imately 1.4%) prior to mating. Kennedy ejt al_. (1976) also found no
reproductive or teratogenic effects of halothane in rats or rabbits
exposed to anesthetic concentrations of halothane during gestation.
In three similar studies in which pregnant rats were exposed to
10 ppm halothane for 8 hours per day, 5 days per week throughout
pregnancy, no effects were reported in the number of offspring nor
were there any reported grossly observable teratologic effects.
However, pathological changes were observed with electron microscopy
in the offspring of the halothane treated mothers as follows: degen-
erative changes in the liver (Chang e£ al_., 1974c); kidney lesions
confined to the proximal convoluted tubules (Chang e_t al_., 1975b); and
significant pathological changes in the nervous system, such as weak-
ening of the nuclear envelope of many neurons, dilation and vacuola-
tion of the Golgi complex, and occasional cell death in the neonatal
cortex (Chang et al_., 1976). Enduring learning deficits associated
with ultrastructural evidence of nervous system damage in rats exposed
to halothane from conception to day 60 of age are discussed in the
following section, Behavioral Effects.
Using a dominant lethal test, Sherman (1974) found that F-12
displayed no mutagenic activity in rats during a two-year feeding
study at doses of 15 or 150 mg/kg/day. Administration of F-12 to
parent male and female rats had no effect on fertility or the outcome
of pregnancy, as measured by the number of corpora lutea, implantation
sites, resorption sites, and number of live fetuses per litter.
F. Behavioral Effects
Quimby ejt al_. (1974) reported that rats exposed to halothane from
conception through day 60 of age (dam or neonate exposed to approximately
- 97 -
-------
10 ppm halothane in air, 8 hours per day> 5 days per week) and rats
exposed to halothane from conception to 130-150 days of age exhibited
deficits in learning shock-motivated light-dark discrimination and
food-motivated maze patterns, when compared to either controls with no
halothane exposure or a group of rats that were exposed to halothane
from day 60 of age through day 130-150. These learning deficits were
correlated with electron microscopic evidence of neuronal degenera-
tion, and permanent failure of formation of the synaptic web and
postsynaptic membrane density in 30% of the postsynaptic membranes.
Only slight neuronal damage was evident in the rats exposed from day
60 on. The data indicate that early exposure to halothane, either in
utero or as a neonate, causes apparently permanent learning deficits
since, in the first group of rats described above, halothane exposure
was ended at 60 days of age, yet the deficits were apparent 75-90 days
after termination of exposure when the behavioral testing was conducted.
Karpov (1963) reported an increase in the number of subthreshold
impulses needed to produce a reflex in rats and an increase in the
number of trials needed to establish a conditioned reflex in mice with
exposure to 1.42% F-22 6 hours/day for 10 months. These effects were
not observed with an exposure level of 0.198%. Carter e£ cil_. observed
significant performance decrements in trained monkeys exposed to 20-
25% F-13B1 without indications of analgesia or CNS depression.
The anaesthetic and intoxicant properties of the f1uorocarbons
were mentioned earlier (Section X). The effects of fluorocarbons on
psychomotor test scores in humans and the feelings of drowsiness and
loss of orientation by human test subjects were also mentioned earlier
(Section IX.).
G. Phytotoxicity
Unpublished experiments (Taylor, 1974) indicate that F-ll and
F-12 at concentrations of 0.5-1, 10, or 15 ppm for two weeks were not
toxic to plants.
- 98 -
-------
H. Toxicity to Microorganisms
The comparative toxicity of F-12 and F-142b (CClF2-CHj) have been
determined in liquid and vapor states for a variety of microorganisms
(Prior ejt aJL» 1970). Of the eighteen species tested, seven species
grew as well in contact with gaseous F-12 or F-142b as in their .
absence (different groups for each fluorocarbon). In no instances
were substantial growth reductions noted. However, in the liquid
state both F-12 and F-142b substantially reduced cell viability in all
cultures tested. Because agitation is required to induce the toxic
effects, Prior e_t a_K (1970) conclude that there is probably some
interaction between the compounds and the lipids in the microorganisms.
- 99 -
-------
XI. CARDIOVASCULAR EFFECTS
In Section IX, Human Toxicity, it was mentioned that the fluoro-
carbons were responsible for several deaths associated with the inten-
tional inhalation of fluorocarbon propelled materials by individuals
attempting to achieve an intoxicated state. Bass (1970) concluded
from a study involving more than 50 such deaths (as well as more than
50 additional non-fluorocarbon related fatalities involving the
inhalation of volatile materials) that the cause of death was most
probably due to cardiac arrhythmia, possibly aggravated by elevated
levels of blood catecholamines due to stress, and/or moderate in-
creases in the blood level of carbon dioxide.
A. Cardiac Arrhythmia
Subsequent to the report by Bass (1970), the cardiac arrhyth-
mogenic potential of f1uorocarbons has received considerable investi-
gation. Cardiac arrhythmia, as the name implies, is the occurrence of
an abnormal excitatory pattern within the heart. It may result from a
disturbance of the generation of the heart's impulse in the sinoatrial
node, a disturbance of the spread of this impulse through the conduc-
ting system of the heart, or the generation of an impulse at any site
in the heart other than the sinoatrial node. Arrhythmias result in
less efficient cardiac function and may result in complete cardiac
arrest.
The first report of cardiac arrhythmia in test animals following
inhalation of fluorocarbons was that of Taylor and Harris (1970a), who
described the effect in mice exposed to F-ll, F-12, and F-114. This
study was designed to show that the fluorocarbons tested were sensi-
tizing the heart to the arrhythmogenic effect of asphyxia. Asphyxia
results in a lowering of the oxygen tension which increases the heart
rate (tachycardia). However, the heart, being unable to acquire an
oxygen debt, will slow (bradychardia) and eventually fail. The sensi-
tization effect implies that a degree of asphyxia that will not result
- 100 -
-------
in arrhythmia in normal animals will induce arrythnvia in sensitized
animals. A controversy ensued over the Taylor and Harris experiment
concerning whether or not the degrees of asphyxia applied to the
experimental and control groups were equivalent. Other workers,
including Azar et §1. (1971), Egle et al_, (1972) and McClure (1972)
report that the fluorocarbons do not significantly influence the
cardiac response of mice to asphyxia. Flowers and Horan (1972)
exposed dogs to fluorocarbon-propelled aerosol products (F-ll and
F-12; amount not stated) and carefully controlled the level of oxy-
genation to determine what effect asphyxia played in the arrhythmias.
They found that lethal arrhythmias were produced even in the absence
of asphyxia, indicating that asphyxia may have played only a contrib-
utory role in the fluorocarbon-propelled aerosol deaths, but was not
necessary for production of the fatal arrhythmias. The ability of
various fluorocarbons to induce arrhythmias in different species is
summarized in Table C-I (Appendix C).
In addition to suggesting the influence of asphyxia in the
fluorocarbon propelled aerosol inhalation deaths, Bass (1970) also
postulated that the induction of arrhythmias was enhanced by elevated
blood levels of catecholamines. It has long been known that the
inhalation of certain volatile hydrocarbons can sensitize the heart to
epinephrine-induced cardiac arrhythmia. Epinephrine, a catecholamine
often referred to as adrenaline, is a potent adrenal cortical hormone
which has a variety of cardiovascular effects, chief among which are
vasoconstriction (resulting in increased blood pressure) and increases
in both the heart rate and cardiac output. In man, the blood plasma
concentration is approximately 0.06 yg/1 and, under conditions of
stress, the adrenal gland may secrete epinephrine at the rate of 0.004
mg/kg/minute. Excesses are rapidly eliminated from the body. Abnor-
mally high blood levels may elicit adverse effects including cardiac
arrhythmia (ventricular). The sensitizing effect, similar to that
mentioned before for asphyxia, means that during or immediately fol-
lowing exposure to a sensitizing substance, blood levels of epinephrine
- 101 -
-------
which would otherwise have no adverse effects, may result in cardiac
arrhythmia and possibly cardiac arrest.
In Table C-II, the effects of fluorocarbons on sensitizing the
heart to an injection of epinephrine are summarized. An important
parameter here is the amount and rate of epinephrine infusion, chosen
in these studies at levels found to be non-hazardous and productive of
only transient and moderate cardiac acceleration and which simulate
the quantities of epinephrine known to be released endogenously under
conditions of fright. The results show basically that inhaled concen-
trations of fluorocarbons which sensitize the heart to epinephrine-
induced arrhythmias are lower than those required to induce arrhyth-
mias themselves. For example, exposure to 5% of F-ll or F-113 by
inhalation sensitizes mice to epinephrine; exposure to 10% of these
compounds is necessary for induction of arrhythmias in this species
without epinephrine. This effect is also seen in monkeys exposed to
F-ll or F-12. Certain fluorocarbons which do not induce arrhythmias
in mice at exposures of 40% (F-22, F-114, F-115, and F-152a) do sensi-
tize mice to epinephrine induced arrhythmias, although the required
fluorocarbon concentrations are still relatively high (20% or more).
Also noteworthy is the high sensitivity of dogs to the epinephrine
sensitization effect of F-ll and F-113; unfortunately, the amount of
fluorocarbon which causes arrhythmias in this species without epi-
nephrine has not been reported.
In order to better assess the relevance of the studies using -
injected epinephrine to conditions of actual stress, experiments have
been designed to measure the arrhythmic effect of fluorocarbons on
dogs presumably releasing high levels of endogenous epinephrine.
These include the studies by Reinhardt et al_. (1971) where dogs were
"frightened"'by loud amplified noises and the study of Mullin et al
(1972) where dogs were run on a treadmill under conditions previously
reported to increase blood epinephrine levels five-fold. In general,
the results of these studies indicate that somewhat higher concentra-
tions of fluorocarbons are necessary for the production of arrhythmias
than in the exogenous epinephrine experiments.
- 102 -
-------
For example, 1n the noise experiments of Reinhardt e_t al_. (1971),
dogs were exposed to 80% fluorocarbon/20% oxygen for 30 seconds which
results in arrhythmias with F-ll, F-12, and F-114. However, because
each of these compounds is capable of inducing arrhythmias in other
species at lower concentrations without epinephrine sensitization, it
is difficult to assess the significance of this experiment. In the
treadmill experiments concentrations of 0.5%, 0.75%, and 1.0% F-ll
produced no response. One of six dogs exposed to 10% F-12 developed
arrhythmias, but no effects were observed at 5% or 7.5% levels. With
F-114, one of seven dogs developed arrhythmias when exposed to a
concentration of 5%, but no response was observed at the 2.5% level.
The above studies show that there is little doubt that the deaths
of persons intentionally inhaling fluorocarbon-propelled aerosol
products are attributable to the cardiac toxicity of the fluorocarbon
propellants and that the original postulates of Bass (1970) were
accurate.
B. Respiratory and Other Cardiovascular Effects
Although the major focus of research into the toxicological
aspects of the fluorocarbons in recent years has been on the cardiac
arrhythmia potential of these materials, Aviado and his coworkers at
the University of Pennsylvania School of Medicine have also investi-
gated the effects of the fluorocarbons on other cardiovascular and
respiratory parameters. The parameters which have been measured and
reported are heart rate increase (tachycardia), depression in myo-
cardial contractility (the force of contraction of the heart measured
by a strain gauge), decrease in atrial and pulmonary arterial blood
pressures, depression of the respiratory rate, increase in pulmonary
constriction, and decrease in pulmonary compliance. The results of
these studies are summarized in Table C-III. The purpose of these
studies was to a large extent to determine what role the fluorocarbons
may have played in the deaths of asthmatics using fluorocarbon-pro-
pelled bronchodilators. Although bronchoconstriction and respiratory
depression do occur with acute inhalation of these compounds, they
- 103 -
-------
occur at concentrations which are similar to the arrhythmia-causing
concentrations of the more potent inducers of arrhythmia (F-ll and
F-113) and at concentrations of 10% to 20% among those fluorocarbons
that either do not elicit arrhythmias or do so only at high concen-
trations. These data indicate that the primary hazard associated with
F-ll inhalation, whether by misuse of aerosol products or overuse of
F-ll propelled bronchodilators remains the production of cardiac
arrhythmias. However, the data also indicate that, at least for
abusive inhalation, the non-arrhythmogenic fluorocarbons or those with
low arrhythmogenic activity are not without other potentially adverse
toxicological properties.
C. Classification of Fluorocarbons Based on Cardiac and Pulmonary
Effects
Based on animal studies (mice, rats, dogs and monkeys) of the
cardiac arrhythmia effects discussed above, as well as the effects of
fluorocarbons on other cardiac and respiratory parameters, Aviado
(1975b) has proposed a scheme for classifying the fluorocarbons. This
classification also includes four non-fluorocarbon aerosol propellants
(trichloroethane, methylene chloride, isobutane, propane, and vinyl
chloride) and a four-carbon cyclic fluorocarbon (octafluorocyclobu-
tane) which are outside the scope of this report, but are included in
this discussion for the sake of completeness.
There are four categories into which the aerosol propellants
fall; descriptions of these categories and the compounds placed in
each are as follows:
1. Low pressure propellants of high toxicity (F-11. F-21, F-113,
trichloroethane and methylene chloride). The characteristics of this
class are that they exert their toxicity at concentrations of 0.5-5%
in the monkey and dog, and from 1-10% in the rat and mouse. They
induce cardiac arrhythmias, sensitize the heart to epinephrine-induced
arrhythmias, cause tachycardia (increased heart rate), myocardial
depression (force of mycardial contraction measured by strain gauge),
and hypotension (as measured by aortic, left atrial, and pulmonary
- 104 -
-------
arterial blood pressures). The predominant effects of this class are
on cardiovascular parameters rather than on respiratory parameters.
2. Low pressure propel!ants of intermediate toxicity (F-114, F-142b,
isobutane, and octaflubrocyclobutane). Compounds in this class differ
from those above in the following respects. Concentrations of these
compounds that sensitize the dog to epinephrine range from 5-25%,
compared to 0<5% or less for compounds in the high toxicity class.
These compounds do not induce arrhythmias in the mouse, whereas the
high toxicity compounds do so at concentrations of 10-40%. Concen-
trations of 10-20% influence circulation in the anesthetized dog and
monkey, compared to concentrations of 0.5-2.5% of the high toxicity
group which cause these effects. Lastly, these compounds cause bron-
choconstriction in the dog, an effect not observed with the high
toxicity compounds. On all accounts except the last, these compounds
are less toxic than those in the first group.
3. High pressure propel!ants of intermediate toxicity (F-12, F-22,
propane, and vinyl chloride). Although the concentrations of these
compounds that sensitize the dog to epinephrine and the concentrations
that influence circulation in the monkey and dog are similar for these
compounds and those in the above category, they differ in their effects
on the respiratory parameters. The compounds in this class cause
early respiratory depression and bronchoconstriction which predominate
over their cardiovascular effects. In both of the preceding groups,
cardiovascular effects predominate.
4. High pressure propel!ants of low toxicity (F-115 and F-152b).
These compounds differ from those above in that they do not cause
bronchoconstriction or early respiratory depression. The extent of
the effects of these compounds on circulation is also less than those
in the group above.
Aviado (1975a) has further concluded on the basis of these
results that F-ll is the most toxic of the aerosol propellants, and
the most serious toxic effects are the induction of cardiac arrhythmia
and the sensitization of the heart to the arrhythmogenic effects of
epinephrine.
- 105 -
-------
D. Increased Sensitivity In Diseased Animals
There have been a few studies published which consider the pre-
disposition of test animals with cardiac or pulmonary disease to the
toxic effects of fluorocarbons. Taylor and Drew (1975) compared the
effects of F-11 in normal random-bred hamsters to those observed in
the BIO 82.62 strain of Syrian hamster which possess cardiomyopathy as
an inherited trait. These particular hamsters develop cardiac hyper-
trophy and at the age of 240 days they experience frank congestive
heart failure. F-ll concentrations of 2% or 7.5% were hot lethal to
normal hamsters at age 150 or 240 days, nor to cardiomyopathic ham-
sters at age 150 days. In myopathic hamsters of 240-day age, 4 of
5 died within 48 minutes of exposure to 2% F-ll, the survivor dying 2
days later, and 4 of 4 died within 30 minutes when exposed to 7.5% F-
11. Myopathic hamsters of 240 days age exposed to room air or to a
7.5% nitrogen placebo survived an average of 8.1 and 9.5 days post-
exposure, respectively. All of the preceding were 4-hour exposures.
Cardiomyopathic hamsters were also more sensitive to the arrhyth-
mogenic effects of F-ll. Using five-minute exposures to 2.5% or 5%
F-ll, no arrhythmias were observed in 120 or 180 day old normal ham-
sters. With the cardiomyopathic hamsters, arrhythmias were observed
in 4 of 4 120 day old animals exposed to 2.5% F-ll and also in 4 of
4 120 day old animals exposed to 5% F-ll. In the 180 day old myo-
pathic hamsters, arrhythmias were observed in 1 of 4 exposed to 2.5%
F-ll and 5 of 6 exposed to the 5% level. No arrhythmias were observed
in normal or myopathic hamsters exposed to 7.5% nitrogen placebo, nor
in normal 180 day old hamsters exposed to 7.5% F-ll. Exposure of
normal 180 day old hamsters to 10% F-ll did result in arrhythmias in
4 of 4 animals. The authors caution that since no known correlation
exists between the cardiomyopathic hamster and human heart disease,
direct conclusions drawn from these data to increased risk in humans
with heart disease is inappropriate. However, the authors state that
these data do indicate the possibility of increased toxicity of the
fluorocarbons among persons with impaired cardiac function.
- 106 -
-------
Trochimowicz e_t al_. (1976) studied the effect of myocardial
infarction in beagles on cardiac sensitization with F-ll or F-13B1 to
epinephrine-induced arrhythmias. There was no greater potential for
cardiac sensitization in animals having recovered from myocardial
infarction (12-13 weeks post-infarction) than normal animals. Tests
earlier than 12 weeks post-infarction were not performed.
Brody et al_. (1974) have examined the, influence of a broncho-
pulmonary lesion produced by intratracheal injection of 0.2 mg of
papain on the cardiopulmonary toxicity of F-ll, F-12 and F-152a
(difluoroethane) to mice. Animals with lesions did not show an
increase in adverse respiratory effects, but did show an increase in
adverse cardiac effects. Notably, F-152a, which did not induce
arrhythmias and did not sensitize the heart to epinephrine in control
mice at 40% concentration, did induce arrhythmias in mice with bron-
chopulmonary lesions which were not further provoked by epinephrine
adminstration.
Doherty and Aviado (1975) induced cardiac necrosis in rats by
four daily intramuscular injections of isoproterenol, which decreased
the minimal concentration of F-ll that provoked cardiac arrhythmias,
although there was no increased sensitivity to F-12 or F-152a. They
did observe increased sensitivity to the cardiovascular effects of
F-ll, F-12 and F-152a in rats pretreated with hexachlorotetrafluoro-
butane, which induced thrombosis of the pulmonary arteries.
Watanabe and Aviado (1975) produced pulmonary emphysema in rats
and found a decrease in pulmonary compliance (27%) upon exposure to
F-ll compared to a decrease of 13% in control rats. Inhalation of 40%
F-12 caused electrocardiographic abnormalities (ventricular extra-
systoles) in emphysematous rats which were not observed in control
rats. Inhalation of 10% F-ll and 40% F-12 resulted in tachycardia and
abnormal heightening of the QRS potential in emphysematous rats which
did not occur in controls.
- 107 -
-------
XII. REGULATIONS AND STANDARDS
With the exception of FDA regulations permitting the use of F-12
as a direct contact freezing agent for food and F-115 for sprayed or
foamed foods, there are no current regulations controlling the fluoro-
carbon compounds. Hearings were held in December 1974 before the
House Subcommittee on Public Health and Environment regarding the
potential threat of continued fluorocarbon use to stratospheric ozone.
Regulatory alternatives and Federal authority are discussed in a
report on the fluorocarbon/ozone issue prepared by the Interagency
Task Force on Inadvertent Modification of the Stratosphere (IMOS)
(1975). Currently, no one regulatory authority has jurisdiction over
all uses of the fluorocarbons thay may result in their release to the
environment, although various authorities do apply to certain applica-
tions. EPA, under the Federal Insecticide, Fungicide, and Rodenticide
Act, has the authority to control fluorocarbon uses in pesticide
applications and has recently requested pesticide formulators to seek
suitable substitute propellents for existing and proposed new insec-
ticide products dispensed as aerosols. (This was in the form of a
notice, PR Notice 75-6, December, 1975, not a regulation.)
Though not specific for products containing fluorocarbons, all
pressurized containers must meet ICC regulations for compressed gases
to be shipped.
Two standards are commonly employed in classifying exposure
limits to the fluorocarbons: Threshold Limit Values (TLVs) and the
Underwriters' Laboratories Classification. TLVs are assigned by the
American Conference of Governmental Industrial Hygienists. Most of
the current values were assigned in 1968, but periodic updates are
made if warranted by new information. The values, usually expressed
in parts per million, represent the maximum concentration that should
be present in the working environment. In cases where toxicological
information would indicate high acceptable concentration, these values
are based on good manufacturing practice. Concentrations higher than
- 108 -
-------
1000 ppm for any compound being used indicate poor production or
handling technique and this concentration is thus the upper limit of
acceptability. The definitions by the Underwriters' Laboratories in
their classification are given in Table XI (Underwriters' Laborator-
ies, 1971). The Underwriters' Laboratories Classification and TLVs
for the various f1uorocarbons under consideration in this review are
given in Table XII.
- 109 -
-------
TABLE XI.
Underwriters' Laboratories Comparative
Toxicity Classification of Refrigerants
Toxicity
Group
1
2
3
4
5
6 '
Concentration Per
Cent by Volume
ii to 1
h to 1
2 to 2-'s
2 to 2Ji
Duration of Exposure to
..Produce Death or Serious
Injury to Test Animals
5 minutes
4 hour
1 hour
2 hours
Intermediate between Groups 4 and 6
20 No injury after 2 hours
- no -
-------
TABLE XII.
Compound
C«3F
CCH2F2
CC«.F3
CHCJIF2
CC£F2-CC«,F2
CF3Br
CBrF2-CBrF2
.TLVs and Underwriters' Laboratories Classification for
Various Fluoro carbons.
Threshold Limit Underwriters' Laboratories
Code Value1 Classification2
F-ll
F-12
F-13
F-14
F-21
F-22
F-112
F-112a
F-113
' F-114
F-115
F-12B1
F-13B1
F-14B2
1000*
1000
(1000)*
(1000)*
1000
(1000)
500
500
1000'
1000
1000
5
6
6
6
4-5
5
4-5
6
6
5+
6+
5+
2
A.C.G.I.H., 1973; * Clayton, 1970
Underwriters' Laboratories, 197la; + Underwriters' Laboratories,
1971b
- Ill -
-------
LITERATURE CITED
ACGIH (1973) - American Conference of Governmental Industrial Hygien-
ists, Threshold Limit Values for Chemical Substances and Physical
Agents in the Workroom Environment, Cincinnati, Ohio.
Allen and Hanburys, LTD (1971), "An Investigation of Possible Cardio-
Toxic Effects of the Aerosol Propel 1 ants, Arctons 11 and 12,"
Volume 1, Unpublished Report.
Altschuller, A.P. (1976), "Average Tropospheric Concentration of
Carbon Tetrachloride Based on Industrial Production, Usage and
Emissions," Env. Sci. Tech., U)(6): 596-598.
Anonymous (1974), "The Hazards of Trace Anesthetics in Unvented Oper-
ating Rooms: A Preliminary Report, " Anesth. Rev., 1(1): 22-23.
Anonymous (1976), "Aerosols: Sky Won't Be the Limit," Chemical Week,
May 12, pp. 46-48.
Anderson, J.G. (1975), "The in situ Measurement of Atoms and Radicals
Important to the Photochemistry of the Stratosphere," paper pre-
sented at the 8th International Conference on Photochemistry,
Edmonton, Alberta.
Archer, V. E. (1973), Letter to Editor, Brit. Med. J., 3_(5882).
Aviado, D.M. (1975a), "Toxicity of Aerosol Propellants on the Respira-
tory and Circulatory Systems. IX, Summary of the Most Toxic:
Trichlorofluoromethane (FC-11)," Toxicology, 3_: 311-314.
Aviado, D.M. (1975b), "Toxicity of Aerosol Propellants on the Respira-
tory and Circulatory Systems. X. Proposed classification," Toxi-
cology, 3_: 321-332
Aviado, D.M. (1975c), "Toxicity of Aerosols," J. Clih. Pharm. 15 (1):
86-104. ~
Aviado, D.M. and M.A. Belej (1974), "Toxicity of Aerosol Propellants
on the Respiratory and Circulatory Systems. I. Cardiac Arrhythmia
in the Mouse," Toxicology, 2_: 31-42.
Azar, A., C. F. Reinhardt, M. E. Maxfield, P. E. Smith, and L. S. Mullin
(1972), "Experimental Human Exposures to Fluorocarbon 12 (Dichloro-
difluoromethane)," Amer. Indust. Hyg. Assoc. J. 33_(4):207-216.
Azar, A., J. A. Zapp, C. F. Reinhardt, and G. J. Stopps (1971), "Cardiac
Toxicity of Aerosol Propellants/1 JAMA, 215:1501-1502.
- 112 -
-------
Azar, A., H. J. Troch1now1cz, J. B. Ten-Ill, and L. S. Mullin (1973),
"Blood Levels of Fluorocarbon Related to Cardiac Sensitization,"
Amer. Ind. Hyg. Assoc. J., 34(3):102-109.
Bass, M. (1970), "Sudden Sniffing Death," JAMA, 212:2075-2079.
Belej, M.A. and D.M. Aviado (1975), "Cardiopulmonary Toxicity of
Propellants for Aerosols, " J. Clin. Pharm., 1_5(1):105-115.
Belej, M. A., D. G. Smith and D. M. Aviado (1974), "Toxicity of Aerosol
Propellants in the Respiratory and Circulatory Systems. IV. Cardi-
otoxicity in the Monkey," Toxicology, 2.:381 -395.
Blake, D.A., and 6. W. Mergner (1974), "Inhalation Studies on the Bio-
transformation and Elimination of ['^C]-Trichlorofluoromethane and
[ C]-Dichlorodifluoromethane in Beagles," Tox. Appl. Pharm.,
30:396-407.
Bower, F. A. (1971), Nomenclature and Chemistry of Fluorocarbon Com-
pounds . U.S. Natl. Tech. Info. Service Report AD 751423.
Bridbord, K., P. E. Brubaker, B. Gay, and J. G. French (1974), "Exposure
to Halogenated Hydrocarbons in the Indoor Environment," Presented
at the Conference on Public Health Implications of Plastic Manu-
facture, Pinehurst, NC, July 31, 1974.
Brody, R.S., T. Watanabe and D.M. Aviado (1975), "Toxicity of Aerosol
Propellants on the Respiratory and Circulatory Systems. III.
Influence of Bronchopulmonary Lesion on Cardiopulmonary Toxicity
in the Mouse," Toxicology, 2:173-184.
Bruce, D.L. (1973), "Murine Fertility Unaffected by Traces of Halo-
thane," Anesth., 38_:473-477.
Bruce, D.L., M.J. Bach and J. Arbit (1974), "Trace Anesthetic Effects
on Perceptual, Cognitive and Motor Skills," Anesth., 40(5):
453-458.
Burn, J. H., H. G. Epstein and P. J. Goodford (1959), "The Properties of
the Anaesthetic Substance 1,1,2-Trifluoro-l,2-Dichloroethane,"
Brit. J. Anaesth. ^]_:518-529.
Call, D. W. (1973), "Halon 1301 (CBrF3) Toxicity Under Simulated Flight
Conditions," Aerosp. Med., 44_:202-204.
Callighan, J. A. (1971), "Thermal Stability Data on Six Fluorocarbons,"
Heat., Piping, Air Cond., 43_:119.
Carney, F.M.T. and R.A. Van Dyke (1972), "Halothane Hepatitis: A
Critical Review," Anaesth. Analg., 51_:135-160.
- 113 -
-------
Carter, V. L., P. M. Chikos, J. D. MacEwen, and K. C. Back (1970),
Effects of Inhalation of Freon 113 on Laboratory Animals, U.S.
Natl. Tech. Info. Service Report AD 727524.
Carter, V. L., D. N. Farrer and K. C. Back (1970b), "Effect of Bromotri-
f1uoromethane on Operant Behavior in Monkeys," Tox. Appl. Pharm.,
V7:307.
Caujolle, F. (1964), "Toxicite Comparee de Fluides Frigorigenes," Bull
Ints. Int. du Froid, 44_:21-
Chang, L.W., A.W. Dudley, and 0. Katz (1974a), "Ultrastructural Evi-
dence of Hepatic Injuries Induced by Chronic Exposure to Low
Levels of Halothane," Amer. J. Pathol., 74_:103a-104a.
Chang, L.W., A.W. Dudley, Y.K. Lee, and J. Katz (1974b), "Ultrastruc-
tural Changes in the Nervous System After Chronic Exposure to
Halothane," Expt. Neurol., 45:209-219.
Chang, L.W., Y.K. Lee, A.W. Dudley, and J. Katz (1974c) "Ultrastruc-
tural Evidence of the Hepatotoxic Effect of Halothane in Rats
Following in-Utero Exposure," Canad. Anaesth. Soc. J., 22(3):
330-338.
Chang, L.W., A.W. Dudley, Y.K. Lee, and J. Katz (1975a), "Ultrastruc-
tural Changes in the Kidney Following Chronic Exposure to Low
Levels of Halothane," Amer. J. Pathol., 78(2):225-242.
Chang, L.W., A.W. Dudley, Y.K. Lee, and J. Katz (1975b), "Ultrastruc-
tural Studies on Pathological Changes in the Neonatal Kidney
Following in-Utero Exposure to Halothane," Environ. Res., 10(2):
174-189.
Chang, L.W., A.W. Dudley, and J. Katz (1976), "Pathological Changes
in the Nervous System Following in-Utero Exposure to Halothane,"
Environ. Res., Vh40-51.
Chapman, S. (1930), "A Theory of Upper Atmospheric Ozone," Quart. J.
Royal Met. Soc., 3;103.
Chemical Marketing Reporter (1973), "Chemical Profile: Fluorocarbons,"
Jan. 1.
Chemical Marketing Reporter (1975), "Chemical Profile: Fluorocarbons,"
Sept. 1.
Cicerone, R.J. (1976), private communication, June 2.
Cicerone, R.J., R.S. Stolflrski, and S. Walters (1974), "Stratospheric
Ozone Destruction by Man-made Chlorofluoromethanes, " Science,
185:1165-1167.
- 114 -
-------
Cicerone, R.J., D.H. Stedman and R.S. StoTarski (1975), "Estimate
of Late 1974 Stratospheric Concentration of Gaseous Chlorine
Compounds (C1X)," Geophys. Res. Lett., i(6):219-212.
Clark, D. G. {1970), Unpublished report, summarized in Reinhardt
and Reinke (1972).
Clark, D.G. and D.J. Tinston (1972a), "The Influence of Fluorocarbon
Propel!ants on the Arrhythmogenic Activities of Adrenaline and
Isoprenaline," Proc. Europ. Soc. Study Drug Toxicity, 13:
212-217.
Clark, D. G., and D. J. Tinston (1972b), "Cardiac Effects of Isopro-
terenol, Hypoxia, Hypercapnia and Fluorocarbon Propellants and
Their Use in Asthma Inhalers," Annals of Allergy, 30_:536-541.
Clayton, 0. W. (1966), "The Mammalian Toxicology of Organic Compounds
Containing Fluorine," Handbuch Exp. Pharmakol., 20:459-500.
Clayton, J. W. (1970), "Fluorocarbon Toxicology" in Lab. Diagn. Pis.
Caused Toxic Agents. Ed. Proc. Appl. Semin.. F. W. Sunderman
(W. H. Green, Inc., St. Louis, MO) pg. 198.
demons, C. A., and A. P. Altshuller (1966), "Response of Electron
Capture Detector to Halogenated Substances," Anal. Chem., 3,8:
133-136.
Cohen, E.N. (1971), "Metabolism of the Volatile Anaesthetics," Anesth.,
35_:193-202.
Cohen, E.N., J.R. Trudell, H.N. Edmunds, and E. Watson (1975), "Uri-
nary Metabolites of Halothane in Man," Anesth., 43:392-401.
Conney, A. H., R. Chang, W. M. Levin, A. Garbut, A. D. Munro-Faure,
A. W. Peck, and A. Bye (1972), "Effects of Piperonyl Butoxide on
Drug Metabolism in Rodents and Man," Arch. Environ. Hlth., 24:
97-106.
Corbett, T.H. (1974), "Birth Defects Among Children of Nurse Anes-
thetists," Anesth. Rev., 1(1):23-24.
Cox, P. J., L..J. King and D. V. Parke (1972a), "A Study of the Possible
Metabolism of Trichlorofluoromethane," Biochem. J., 130(l):13p-14p.
Cox, P. J., L. J. King and D. V. Parke (1972b), "A Comparison of the
Interactions of Trichlorofluoromethane and Carbon Tetrachloride
with Hepatic Cytochrome P-450," Biochem. J., 130:87p.
Cox, R.A., R.G. Derwent, A.E.J. Eggleton, and J.E. Lovelock (1976),
"Photochemical Oxidation of Halocarbons in the Stratosphere,"
Atmos. Envir., 10(4):305-308.
- 115 -
-------
Crutzen, P. (1970), "The Influence of Nitrogen Oxides on the Atmospheric
Ozone Content," Quart. J. Royal Met. Soc., 96_:320-327.
Crutzen, P. J. (1974), "Estimates of Possible Future Ozone Reductions
from Continued Use of Fluoro-Chloro-Methanes (CF?C1?, CFCU),"
Geophys. Res. Letters 1(5):205-208. * * J
Culik, R., and H. Sherman (1973), "Teratogenic Study in Rats with
Dichlorodifluoromethane (Freon 12)," Haskell Lab. Report No.
206-73 (unpublished), May 16, 1973.
Cutchis, P. (1974), "Stratospheric Ozone Depletion and Solar Ultra-
violet Radiation on Earth," Science, 184:13-19.
Desoille, H., L. Truffert, A. Bourguignon, P. Delavierre, M. Philbert,
and C. Girard-Wallon (1968), "Toxicity of Trichlorofluoroethane,"
Arch. Mai. Prof. Med. Trav. Secur. Soc. 29:381-388.
Desoille, H., L. Truffert, C. Girard-Wallon, J. Ripault, and M. Philbert
(1973), "Experimental Research of an Eventual Chronic Toxicity of
Dichlorotetrafluoroethane," Arch. Mai. Prof., 34_:117-125.
Directory of Chemical Producers (1975), Stanford Research Institute.
Doherty, R.E. and D.M. Aviado (1975), "Toxicity of Aerosol Propellants
on the Respiratory and Circulatory Systems. VI. Influence of
Cardiac and Pulmonary Vascular Lesions in the Rat," Toxicology
3_: 213-224.
Doucet, J., P. Sauvageau, and C. Sandorfy (1973), "Vacuum Ultraviolet
and Photoelectron Spectra of Fluoro-Chloro Derivatives of Methane,",
Jour. Chem. Phys., 58(1):3708-3716.
Downing, R. C. (1966), "Fluorinated Hydrocarbons," in Encyclopedia of
Chemical Technology, A. Standen (Ed.) (John Wiley and Sons, New
York, 2nd Edition,!966), Vol. 9, pg. 739.
DuPont de Nemours and Co. (1968), "Human Skin Absorption Studies with
Trichlorotrifluoroethane, F-113," Med. Res. Proj. Rept. No. 84-68.
DuPont de Nemours and Co. (1969), Freon Fluorocarbons: Properties and
Applications.
DuPont de Nemours, Inc. (1975), Information Presented by duPont to EPA
Office of Air Quality, Planning and Standards, Durham, North
Carolina, March 26, 1975.
Eddy, C. W., and F. D Griffith (1961), "Metabolism of Dichlorodifluoro-
methane-C'4 by Rats," Presented at Amer. Indust. Hyg. Assoc. Conf.,
Toronto, Canada, May, 1971.
- 116 -
-------
Egle, J. L., J. W. Putney and J. F. Borzelleca (1972), "Cardiac Rate
and Rhythm in Mice Affected by Haloalkane Propel!ants," JAMA,
222:786-789.
Epstein, S. S., S. Joshi, J. Andrea, P. Clapp, J. Falkland N. Mantel
(1967), "Synergistic Toxicity and Carcinogen!city of Freons and
Piperonyl Butoxide," Nature, 214:526-528.
Fleagle, R.G. and J.A. Businger (1975), "The Greenhouse Effect," Science,
190:1042-1043.
Good, W.O., C. Ellison, and V.E. Archer (1975), "Sputum Cytology Among
Frequent Users of Pressurized Spray Cans," Cancer Res., 35:316-
321.
Gotell, P. and L. Sundell (1972), "Anesthetists' Exposure to Halo-
thane," The Lancet, 2_ (Aug. 26):424.
Griffin, T. B., J. L. Byard and F. Coulston (1972), "Tqxicological
Responses to Halogenated Hydrocarbons," Proc. Symp. on Appraisal
of Halogenated Fire Extinguishing Agents (NAS, Wash., DC), pg.
136.
Grimsrud, E.P. and R.A. Rasmussen (1975), "The Analysis of Chloro-
fluorocarbons in the Troposphere bv Gas Chromatography-Mass
Spectrometry," Atmos. Envir., £(11):1010-1013.
Halsey, M. J. (1974), Clinical Research Center, Div. of Anaesthesia,
Middlesex, England, Personal Communication.
Hamilton, J. M. (1962), "The Organic Fluorochemicals Industry," Advances
in Fluorine Chemistry, 3_:117-180.
Hammack, J. M. (1971), "Fire Extinguishing Agents" in Encyclopedia of
Chemical Technology, A. Standon (Ed.) (John Wiley and Sons, New
York, 2nd Edit.), Supplement Volume, pg. 364-383.
Hanavan, G. (1974), DuPont de Nemours, Inc., Personal Communication.
Hanst, P.L., L.L. Spiller, D.M. Watts, J.W. Spence, and M.F. Miller
(1975), "Infrared Measurements of Fluorocarbons, Carbon Tetra-
chloride, Carbonyl Sulfide, and Other Atmospheric Trace Gases,"
J. Air Poll. Contr. Assoc., 25_(12): 1220-1226.
Harmon, G. (1974), Aerosol Machinery Co., Westbury, NY, Personal
Communication.
Heidt, L.E., R. Lueb, W. Pollock and D.H. Ehhalt (1975), "Strato-
spheric Profiles of CC1-, and CC19F " Geophys. Res. Lett., 2(10):
445-447. J £ *
- 117 -
-------
Hester, N. E., E. R. Stephens and 0. C. Taylor (1974), "Fluorocarbons
in the Los Angeles Basin," Air Poll. Control Assoc. J., 24(6):
591-595.
Hester, N. E., E. R. Stephens and 0. C. Taylor (1975a), "Fluorocarbon
Air Pollutants :Fluorocarbon Measurements in the Lower Strato-
sphere," Environ. Sci. Tech., 9_(9):875-876.
Hester, N.E., E.R. Stephens, and O.C. Taylor (1975b), "Fluorocarbon
Air Pollutants II," Atmos. Envir., £: 603-606.
Hine Laboratories (1968), "Clinical Toxicologic Studies on 'Freon1 FE
1301," Unpublished report, summarized in Reinhardt and Reinke,
1972.
Hoffman, C.S. (1976), E.I. DuPont de Nemours and Co., Inc., Freon
Products Division, private communication.
Howard, P. H.s P. R. Durkin and A. Hanchett (1974), "Environmental
Hazard Assessment of One and Two-Carbon Fluorocarbons," (Unpub-
lished Report).
Howard, P. and A. Hanchett (1975), "Chlorofluorocarbon Sources of
Environmental Contaminations," Science 189:217-219.
Hughes, H.C. and C.M. Lang (1972), "Hepatic Necrosis Produced by
Repeated Administration of Halothane to Guinea Pigs," Anesth.,
36(5):466-471.
Imbus, H. R., and C. Adkins (1972), "Physical Examination of Workers
Exposed to Trichlorotrifluoroethanes" Arch. Environ. Hlth., 24:
257-261.
IMOS (1975), "Fluorocarbons and the Environment," Report of Federal Task
Force on Inadvertent Modification of the Stratosphere (June).
Japar, S., J. N. Pitts, and A. M. Winer (Unpublished), "The Photosta-
bility of Fluorocarbons," Accepted by Environmental Science and
Technology, 1974.
Jenkins, L.C. (1973), "Chronic Exposure to Anaesthetics: A Toxicity
Problem?" Canad. Anaesth. Soc. J., 20(1):104-120.
Jenkins, L. J., R. A. Jones, R. A. Coon, and J. Siegel (1974), "Repeated
and Continuous Exposure of Laboratory Animals to Trichlorofluoro-
methane," Toxic. Appl. Pharmocol., 1^:133-142.
Jensen, R. (1972), "Summary," Proc. Symposium on An Appraisal of Halo-
genated Fire Extinguishing Agents (NAS8 Wash., DC), pg. 317-319.
Johnstone, R.E., E.M. Kennel10 M.G. Behar, W.Brummund, R.C. Ebersole
and L.M. Shaw (1975)0 "Increased Serum Bromide Concentration after
Halothane Anesthesia in Man," Anesth., 42(5):598-601.
- 118 -
-------
Kehoe, R. A. (1943)-, Unpublished Report, Summarized in Azar, et al.
(1972).
Kennedy, G.L., S.H. Smith, M.L. Keplinger, and J.C. Calandra (1976),
"Reproductive and Teratologic Studies with Halothane," Toxicol.
Appl. Pharm., 3JK 467-474.
Kilen, S. M., and W. S. Harris (1972), "Direct Depression of Myocardial
Contractility by the Aerosol Propel 1 ant Gas, Dichlorodifluoro-
methane," J. Pharm. Exptl. Therap., 183:245-255.
Kraybill, H. F. (1975), (Scientific Coordinator for Environmental
Cancer), Memo to L. Plumlee, Medical Science Advisor, EPA, January
10.
Krey, P.W., R.J. Lagomassino, and J.J. Frey (1976), "Stratospheric
Concentrations of CCKF in 1974," Jour. Geophys. Res., 81_(9):
1557-1560. J
Kuebler, H. (1964), "The Physiological Properties of Aerosol Propel-
lants," Aerosol Age, 9_:44.
Lazrus, A.L, B.W. Gandrud, R.N. Woodward and U.A. Sedlacek (1975),
"Stratospheric Halogen Measurements," Geophys. Res. Lett., £ (10):
439-441.
Lebowitz, M.D. (1976), "Aerosol Usage and Respiratory Symptoms," Arch.
Env. Hlth., 31_(2):83-86.
Lester, D., and L. A. Greenberg (1950), "Acute and Chronic Toxicity of
Some Halogenated Derivatives of Methane and Ethane," Arch. Indust.
Hyg. Occup. Med., 2.:335-344.
Lillian, D., H.B. Singh, A. Appleby, L. Logan, R. Arnst, R. Gumpert,
R. Hague, J. Toomey, J. Kazazis, M. Antell, D. Hansen, and
B. Scott (1975), "Atmospheric Fates of Halogenated Compounds,"
Env. Set. Tech., 9_(12): 1042-1048.
Linde, H.W. and D.L. Bruce (1969), "Occupational Exposure of Anes-
thetists to Halothane, Nitrous Oxide and Radiation," Anesth.,
30:363-368.
Lovelock, J. E. (1971), "Atmospheric Fluorine Compounds as Indicators of
Air Movements," Nature, 230:379.
Lovelock, J. E. (1972), "Atmospheric Turbidity and CCl^F Concentrations
in Rural Southern England and Southern Ireland," Atmos. Environ.,
6_: 917-925.
Lovelock, J. E. (1974), "Atmospheric Halocarbons and Stratospheric
Ozone," Nature, 252:292-294.
- 119 -
-------
Lovelock, J. E., R. J. Maggs and R. J. Wade (1973), "Halogenated
Hydrocarbons In and Over the Atlantic," Nature, 241:194-196.
Lovelock, J.E. (1975), Natural Halocarbons in the Air and in the Sea,"
Nature, 256:193-194.
Machta, L. (1975), National Oceanic and Atmospheric Adminstration, oral
communication.
McCarthy, R. L. (1973), "Ecology and Toxicology of Fluorocarbons,"
Unpublished Report, DuPont de Nemours, Inc.
McCarthy, R. L. (1974), "Fluorocarbons In the Environment", Presented at
the National Geophysical Union Meeting, San Francisco, CA, Dec. 13.
McClure, D. A. (1972), "Failure of Fluorocarbon Propellents to Alter the
Electrocardiogram of Mice and Dogs," Toxic. Appl. Pharm., 22:221-
230.
Marier, 6., H. 6. MacFarland, and P. Dussault (1973), "Blood Fluorocar-
bon Levels Following Exposures to a Variety of Household Aerosols,"
Household Pers. Prod. Ind., 1J)(12):68.
Marsh, D., and J. Heicklen (1965), "Photolysis of Fluorotrichloromethane",
J. Chem. Phys., 69_: 4410-4412.
Matsumato, T., K. C. Pani, J. J. Kovaris, and F. Hamit (1968), "Aerosol
Tissue Adhesive Spray: Fate of Freons and Their Acute Topical and
Systemic Toxicity," Arch. Surg., 97^:727-735.
Michaelson, J. B., and D. J. Huntsman (1964), "Oral Toxicity of 1,2,2-
Trichloro-l,l,2-Trifluoromethane," J. Med. Chem. 7^:378-379.
Mil stein, R. and F.S. Rowland (1975), Journ. Phys. Chem., in press.
Molina, M. J., and F. S. Rowland (1974). "Stratospheric Sink for Chloro-
f1uoromethanes: Chlorine Atom Catalyzed Destruction of Ozone,"
Nature, 249:810-812.
Molina, n.J. and F.S. Rowland (1974b), "Predicted Present Stratospheric
Abundance of Chlorine Species from Photodissociation of Carbon
Tetrachloride," Geophys. Res. Lett., 1_(7):309-312.
Mullin, L. S., A. Azar, C. F. Reinhardt, P. E. Smith, and E. F. Fabryka
(1972). "Halogenated Hydrocarbons - Induced Cardiac Arrhythmias
Associated with Release of Endogenous Epinephrine," Amer. Ind. Hyg.
Assoc. J., 33:389-396.
Murcray, D.G. (1975), "Fluorocarbon Increases in Stratosphere over New
Mexico," presented at the annual meeting of the American Geophysical
Union, San Francisco, December.
- 120 -
-------
National Academy of Sciences (1975), Environmental Impact of Strato-
spheric Flight, National Academy of Sciences, Washington, D.C.
The National Halothane Study (1969), A Study of the Possible Asso-
ciation Between Halothane Anesthesia and Postoperative Hepatic
Necrosis, J.P. Bunker. VI.H. Forrest. F. Hosteller, and L.D.
Vandam, Eds., available from U.S. Govt. Printing Office, 1969
0-334-553.
Noble, H. L. (1972), "Fluorocarbon Industry Review and Forecast,"
Chem. Market. Research Assoc. Meeting, May 5, 1972.
Paulet, 6. (1962), "lexicological and Physiopathologic Study of Mono-
bromof1uoromethane (CF,Br)," Arch. Mai. Prof. Med. Trav. Secur.
Soc., 23:341-348. J
Paulet, 6. (1969), "Action of Chlorofluorinated Hydrocarbons on the
Human Body," Labo-Pharma-Phrbl. Tech., No. 180, pg. 74.
Paulet, 6., and S. Desbrousses (1969), "Dichlorotetrafluoroethane,
Acute and Chronic Toxicity," Arch. Mai. Prof. Med. Trav. Secur.
Soc., 30:477-492.
Paulet, G., G. Roncin, E. Vidal, P. Toulouse, and J. Dassonville
(1975), "Fluorocarbons and General Metabolism in the Rat, Rab-
bit, and Dog," Toxic. Appl. Pharm., 34:197-203.
Pitts, J. e_t al_ (1974), Information presented at the 168th Meeting
of the American Chemical Society in Atlantic City, N.J.
Prendergast, J. A., R. A. Jones, L. J. Jenkins, and J. Siegel (1967),
"Effects on Experimental Animals of Long-Term Inhalation of Tri-
chloroethylene, Carbon Tetrachloride, 1,1,1-Trichloroethane,
Dichlorodifluoromethane, and 1,1-Dichloroethylene," Tox. Appl.
Pharm., 10:270-289.
Prior, B. A., 0. R. Fennema and E. H. Marth (1970), "Effects of Gas
Hydrate Formers on Microorganisms," Appl. Microbiol., 20_:139.
Quevauviller, A. (1965), "Hygiene et Securite des Pulseurs pour Aerosols
Medicamenteux," Prod. Probl. Pharm., 20_:14-29.
Quevauviller, A., M. Chaignear and M. Schrenzel (1963), "Etude Experi-
mental e Chez la Souris de la Tolerance du Poumon arux Hydrocarbures
Chioroflucres," Ann. Pharm. Fr., 21_:727-734.
Quevauviller, A., M. Schrenzel and H. Vu-Ngoc (1964), "Local Tolerance
in Animals to Chlorofluorinated Hydrocarbons," Therapie, 19:247-
263. ~~
- 121 -
-------
Quimby, K.L., L.J. Aschkenase, R.E. Bowman, J. Katz, and L.W. Chang
(1974), "Enduring Learning Deficits and Cerebral Synaptic Mal-
formation from Exposure to 10 Parts of Halothane per Million,"
Science, 185:625-627.
Ramanthan, V. (1975), "Greenhouse Effect Due to Chlorofluorocarbons:
Climatic Impact," Science, J90:50-52.
Rasmussen, R. (1975), Information presented at U.S. Environmental
Sciences Research Laboratory Research Laboratory Research Pro-
gram Review, October 1975, Research Triangle Park, North
Carolina.
Raventos, J., and P. G. Lemon (1965), "The Impurities in Flouthane:
Their Biological Properties," Brit. J. Anesthesia, 37:716-737.
Rector, D. E., B. L. Steadman, R. A. Jones and J. Siegel (1966),
"Effects on Experimental Animals of Long-Term Inhalation Expo-
sure to Mineral Spirits," Toxic. Appl. Pharm., 9:257-268.
Rebbert, R.E. and P.J. Ausloos (1975), Information presented at the
170th Meeting of the American Chemical Society in Chicago, 111.
To be published in Journal of Photochemistry.
Rehder, K., J. Forbes, H. Alter, 0. Hessler, and A. Stier (1967),
"Halothane Biotransformation in Man: A Quantitative Study,"
Anesth., 28:711-715.
Reinhardt, C. F., M. McLaughlin, M. E. Manfield, L. S. Mullin, and P.E.
Smith (1971), "Human Exposures to Fluorocarbon 113," Amer. Indust.
Hyg. Assoc. J., 32_:143-152.
Reinhardt, C.F., L.S. Mullin, and M.E. Maxfield (1973), "Epinephrine-
Induced Cardiac Arrhythmia Potential of Some Common Industrial
Solvents," J. Occ. Med., 15(12):953-955.
Reinhardt, C. F., and R. E. Reinke (1972), "Toxicology of Halogenated
Fire Extinguishing Agent Halon 1301 (Bromotrifluoromethane)" in
Appraisal Halogenated Fire Extinguishing Agents, Proc. Symp., (NAS,
Wash., DC).
Reinhardt, C. F., and G. J. Stopps (1961), "Human Exposure to Bromotri-
fluoromethane," Unpublished Report, Summarized in Reinhardt and
Reinke (1972).
Rosenberg, P.H. (1972), "Halothane Hepatitis Caused by Halothane Metabo-
lites," Fluoride, 5>(3):106-111.
Ross, W.T. and R.R. Cardell (1972), "Effects of Halothane on the
Ultrastructure of Rat Liver Cells," Am. J. Anat., 135:5-22.
- 122 -
-------
Rowland, F.S. (1975),"Chiorofluoromethanes and Stratospehrlc Ozone
A Scientific Status Report," New Scientist, 2/.8-11.
Rowland, F. S., and M. J. Molina (1974), "Chiorofluoromethanes in the
Environment," Unpublished Report.
Rowland, F.S. and M.J. Molina (1975), "The Ozone Question", Science,
190:1038-1040.
Russell, P. (1976), U.S. Food and Drug Administration, Div. Surgical,
Dental and Drug Products, private communication.
Sage, M.S. (1963), "Aerosols" in Encyclopedia of Chemical Technology,
A. Standen (Ed.) (John Wiley and Sons, New York, 2nd Edition)7
Vol. 1, pg.470.
Saltzman, B. E., A. I. Coleman, and C. A. Clemens (1966), "Halogenated
Compounds as Gaseous Meterological Tracers: Stability and Ultra-
sensitive Analysis by Gas Chromotography", Anal. Chem. 38:753-758.
Sayers, R. R., W. P. Yant, J. Chanyak, and J. W. Shoaf (1930), Toxi-
city of Dichlorodifluoromethane, US Bureau of Mines Report R.I.
sols:
Schmeltekopf, A.L., P.O. Goldan, W.R. Harrop, T.L. Thompson, F.C.
Fehsenfeld, H.I. Schiff, P.O. Crutzen, I.S.A. Isaksen and E.E.
Ferguson (1975), "Measurements of Stratospheric CFC1~, CF9C1?
and N20," Geophys. Res. Lett., 1(9):393-396. J * *
Scholz, 0. (1962), "New Toxicologic Investigations of Freons Used as
Propellents for Aerosols and Sprays," Ber. Aerosol-Kongr., 4_:420-
429.
Shamel, R.E., O.K. O'Neill, and R. Williams (1975), Preliminary
Economic Impact Assessment of Possible Regulatory Action to
Control Atmospheric Emissions of Selected Halocarbons, pre-
pared for U.S. Envir. Prot. Agency, Office of Air and Waste
Management, available through Nat. Tech. Info. Service as
Report No. PB-247-115.
Shargel, L., and R. Koss (1972), "Determination of Fluorinated Hydro-
carbon Propellants in Blood of Dogs After Aerosol Administration,"
J Pharm. Sci., 61_: 1445-1449.
Sherman, H. (1974), "Long-Term Feeding Studies in Rats and Dogs with
Dichlorodifluoromethane (Freon 12 Food Freezant)," Unpublished
Report, Haskell Laboratory.
Silverglade, A. (1971), "Evaluation of Reports of Death from Asthma," J,
Asthma Res., 8:95-98.
- 123 -
-------
Simmonds, P. 6., S. L. Kerrin, J. E. Lovelock, and F. H. Shair (1974),
"Distribution of Atmospheric Halocarbons in the Air Over the Los
Angeles Basin," Atmos. Environ., 8/.209-216.
Singh, H.B., D.P. Fowler, and T.O. Peyton (1976), "Atmospheric Car-
bon Tetrachloride: Another Man-Made Pollutant," Science, 192:
1231-1234.
Slater, T. F. (1965), "Relative Toxic Activities of Tetrachloromethane
and Trichlorofluoromethane," Biochem. Pharmacol., 14.:178-181.
Smith, J. K., and M. T. Case (1973), "Subacute and Chronic Toxicity
Studies of Fluorocarbon Propel1 ants in Mice, Rats and Dogs,"
Toxicol. Appl. Pharm., 26:438-443.
Speizer, F.E., D.H. Wegman, and A. Ramierez (1975), "Palpitation Rates
Associated With Fluorocarbon Exposure in a Hospital Setting," New
Eng. J. Med., 292(12):624-626.
Steinberg, M. B., R. E. Boldt, R. A. Renne, and M. H. Weeks (1969),
Inhalation Toxicity of 1,1,2-Trichloro-l,2,2-Trif1uoroethane
(TCTFE), U.S. Army Environmental Hygiene Agency, study no.
33-18-68/69,
Stier, A., H. Alter, 0. Hessler, and K. Render (1964), "Urinary
Excretion of Bromide in Halothane Anesthesia," Anesth. Analge-
sia, 43(6):723-728.
Taylor, G. J., and W. S. Harris (1970b), "Glue Sniffing Causes Heart
Block in Mice," Science, 170:866-868.
Taylor, G. J., and R. T. Drew (1975), "Cardiomyopathy Predisposes
Hamsters to Trichlorofluoromethane," Unpublished, Submitted to
Toxic. Appl. Pharm.
Taylor, 0. C. (1974), Univ. of California, Riverside, Unpublished Data.
Trochimowicz, H.J., C.F. Reinhardt, L.S. Mullin, A. Azar, and B.W. Karrh
(1976), "The Effect of Myocardial Infarction on the Cardiac Sensiti-
zation Potential of Certain Halocarbons," J. Occup. Med., 18(1):
26-30.
Turco, R. P., and R. C. Whitten (1974), "Freons in the Stratosphere and
Some Possible Consequences for Ozone," Unpublished Report.
Tyrell, M.F. and S.A. Feldman (1968), "Headache Following Halothane
Anaesthesia," Brit. J. Anaesth., 40:99-102.
Uekleke, H., K.H. Hellraer, and S. Tabarelli-Poplawski (1973), "Meta-
bolic Activation of Halothane and Its Covalent Binding to Liver
Endoplasmic Proteins in vitro." Naunyn-Schmiedeberg's Arch.
Pharmacol., 279:39-52.
- 124 -
-------
Uekleke, J. and Th. Werner (1975), "A Comparative Study of the Irre-
versible Binding of Labelled Halothane, Trichlorofluoromethane,
Chloroform, and Carbon Tetrachloride to Hepatic Protein and
Lipids in vitro and in vivo." Arch. Toxicol., 34_:289-308.
Underwriters' Laboratories (1971a), "Comparative Hazards of Modern
Refrigerants," Data Card No. UL5 and UL5-A.
Underwriters' Laboratories (1971b), "Toxicity of Extinguishing Agents,"
Data Card UL608.
Urbach, F. (1974), "Biological Effects of Ultraviolet Radiation", Unpub-
lished.
U.S. International Trade Commission, (formerly U.S. Tariff Commission)
U.S. Production and Sales Reports: Synthetic Organic Chemicals
(1961-1974).
Van Dyke, R.A. (1973), "Biotransformation of Volatile Anaesthetics
with Special Emphasis on the Role of Metabolism in the Toxi-
city of Anaesthetics," Canad. Anaesth. Soc. J., 20.(l):21-33.
Van Dyke, R.A. and A.J. Gandolfi (1974), "Studies on the Irrevers-
ible Binding of Radioactivity from [14C] Halothane to Rat
Hepatic Microsomal Lipids and Protein," Drug Metab. Dispos.,
2.(5): 469-476.
Van Dyke, R.A. and C.L. Wood (1975), "In Vitro Studies on Irrevers-
ible Binding of Halothane MetabolTte to Microsomes," Drug.
Metab. Dispos., 1(1):51-57.
Van Dyke, R.A. and A.J. Gandolfi (1976), "Anaerobic Release of
Fluoride From Halothane," Drug Metab. Dispos., 4^1):40-44.
Van Poznak, A., and J. F. Artusio (1960), "Anesthetic Properties of a
Series of Fluorinated Compounds. 1. Fluorinated Hydrocarbons,"
Toxicol. Appl. Pharmocol., 2_:363.
Van Stee, E. W., and K. C. Back (1971), Brain and Heart Accumulation of
Brgmotrif1uoromethane, U.S. Natl. Tech. Info. Service Report AD
721211.
Venkateswaran, S. V. (1974), "Solar Ultraviolet Radiation Reaching the
Earth's Surface," Proc. 3rd Conf. on the Climatic Impact Assessment
Program, 428-436.
Watanabe, T. and D.M. Aviado (1975), "Toxicity of Aerosol Propel 1 ants
in the Respiratory and Circulatory Systems. VII. Influence of
Pulmonary Emphysema and Anesthesia in the Rat," Toxicology, 3_:225-
240.
- 125 -
-------
Waritz, R. S. (1971), Toxicology of Some Commercial Fluorocarbons,
U.S. Nat. Tech. Inform. Serv. Report AD 751429.
Werner, Th., H. Uehleke (1974), "Covalent Binding of Halothane
and Other Haloalkanes to Microsomal Proteins and Lipids jn^
vivo and in vitro," Naunyn-Schmiedeberg's Arch. Pharmacol.,
H5~(SuppTT)~r90.
Whitcher, C.E., E.N. Cohen, and J.R. Trudell (1971), "Chronic Expo-
sure to Anesthetic Gases in the Operating Room," Anesth.,
30:348-353.
Widger, L.A., A.J. Gandolfi, and R.A. Van Dyke (1976), "Hypoxia and
Halothane Metabolism in vivo." Anesth., 44(3):197-201.
Wilkness, P. E., R. A. Lamontagne, R. E. Larson, J. W. Swinnerton, C. R.
Dickson, and T. Thompson (1973), "Atmospheric Trace Gases in the
Southern Hemisphere," Nature, 245:45-47.
Wilkness, P. E., J. W. Swinnerton, R. A. Lamontagne, and D. J. Bressan
(1975), "Trichlorofluoromethane in the Troposphere, Distribution
and Increase, 1971 to 1974," Science, 187:832-834.
Wittmann, R., A. Doenicke, H. Heinrick, and H. Pausch (1974),
"Abortive Effects of Halothane," Anaesthetist, 23; 30-35.
Wofsy, S. L., and M. B. McElroy (1974), "HO , NOv and ClOy: Their Role
in Atmospheric Photochemistry," Canad.*J. Chem., 52_: 1582-1591.
Wofsy, S. C., M. B. McElroy and N. D. Sze (1975), "Freon Consumption:
Implications for Atmospheric Ozone," Science, 187:535-537.
Yant, W. P., H. H. Schrenk and F. A. Patty (1932), "Toxicity of Dichlo-
rotetraf1uoroethane," U.S. Bureau of Mines Report, R.I. 3185.
Young, W., and J. A. Parker (1972), Effect of Freons on Acetylcho-
linesterase Activity and Some Counter Measures, U.S. Nat. Tech.
Info. Service Report AD 773766.
- 126 -
-------
Table A-I
Absorption/Elimination Data on Various F' uorocarbons Inhalei, from Ambient Air
.
Fluorocsrbon
F-ll
F-ll
Spec.-i
Rats
(n=2)
am
Rats
(anesthetized)
Rats
(n-2)
N 0
• M
H II
Dogs
Concentration Duration of
In Inhaled Air Exposure.
(«u/v) (minutes)
0.23; 5
0.61t 5
O.G41 5
0.491 5
0.491 5
0.64X 5
0.64X . 5
0.64J S
1.00% 5
o.m s
0.15J 5
PeaK uria Lev I: (ug/mi) jjme to Peak
Blood Level
Arterial lenous (minnt-ac)
11 Oi) - 11.70 5
22 M) - 31.00 5
11 ;i: - 16.87 5
i
4.81 5
5..J- 5
Blood I.evels Tine to Reduced Level
After Exposure (minutes after ter-
(uq/m^ mination of exoosure
0.17 - 0.52 5
2.00 - 2.70 5
5.55 - 6.40
0.09 - 0.13 2 hrs.
0.02 - 0.03 4 hrs
0.12 - 0.32 1 hr.
0.007 - 0.014 8 hrs.
0.006 - G.006 24 hrs.
0.002 - 0.003 48 hrs.
1.16 5
0.42 10
0.27 15
0.13 30
1.32 5
0.35 10
0.03 15
0.02 30
Reference
Mien and
•lanbury's. Ltd.
1971
H H M
il II U
11 II M
H W «
II • N H
II H U
HUM
H u n
H n i
it n u
1
If
o
(D
c
o
o
o
01
cr
o
o
•o
OI
r+
.j.
O
3
O
-------
Table A-I. (cont.)
Absorption/Elimination Data on Variou! fluorocarbons Inhalel from Ambient Air
I
ro
Fluorocarbon
F-ll
(cont)
F-12
Species
Dogs
H •
• •
U II
Rats
(anesthetized)
(n-2)
" «
Dogs
Concentration Duration of
in Inhaled Air Exposure.
rv.vfu) (minutes)
0.63J 5 *
1.25J . 30
0.1S 10
0.555 10
l.OS 10
0.64J ; 5
5t 35
2. 41 5
KeaK Biooa Levels (ug/mij jjmg tp Peak
Blood Level
Arterial -/enous (minutocl
;:o 30
"! >& 30
9.0-13.0 .!• - 10.0 10
14.0-44.0 7 0 - 28.0 10
36.0-69.0 - 34.0 - 55.0 7
: .1.0 - 3.75 5
-1 ('ng/g) 35
...5.00 5
Blood Levels Time to Reduced Level
After Exposure iminutes after ter-
yuQ/fnl^ - fjiination of exposure
-15 10
-9 30
-20 ,10
-15 30
1.5 - 4.5 (Art) 5
2.9 - 3.0 (Ven)
0.5 - 1.0 (Art)
0.8 - 1.3 (Ven)
5.7 - 9.1 (Art) 5
9.1 - 11.0 (Ven) 5
2.1 - 3.2 (Art) 15
0.3 - 3.5 (Ven) 15
8.5 - 17.0 (Art) 5
9.0 - 22.0 (Ven) 5
2.3 - 4.5 (Art) 15
4.5 - 7.7 (Ven) 15
0.50 - 0.75 5
0.03 - 0.03 1 hr.
-2 (ug/g) 5
-------
Table A-I. (cont.)
Absor;>tion/tlimination Data on Various Fl lorocarbons Inhaled from Ambient Air
CO
Fluorocarbon
F-12
(cont)
%
Species
Dogs
n u
• •
II U
• M
U It
II •
N a
II M
Concentration Duration of
in Inhaled Air Exposure.
{'.u/u) (minutes)
2.52% 5
2.72 5
4.21S 5
4.832 . 5
5. Oil 5
0.82J 15
0.98J 12
0.99X 20
LOW 15
Peak Blood Lev<;.i (ug/ml) r^ to Peak
Blood Level
Arterial V>nous (mimitps)
!5.00 5
;i0.65 5
44.20 5
•!6.25 5'..
;J2.75 5
. ;E.O is
. '1.3 12
12.7 20
8.4 15
Blood .evels Time to Reduced Level
After Exposure (minutes after ter-
(ug/ml rainatioh of exoosure
1.65 5
0.70 10
0.30 15
0.07 30
2.30 5
0.30 10
0.55 15
0.10 30
5.40 5
2.20 10
0.70 15
0.12 30
2.50 5
0.90 10
0.38 15
0.25 30
3.80 5
1.10 10
0.75 15
0.30 30
Reference
Allen and
Hanbury's. Ltd.
1971
ti n n a
nun*
!
II « M H
it n M M
Blake and
Mergner, 1974
u n n n
.1 II n II
-------
Table A-I. (cont.)
Absorption/Elimination Data on Variou: I luorocarbons Inhaled from Ambient Air
Fluorocarbon
F-ll
(cont)
Species
Dogs
• n
N N
„.
tl II
n «
n N
N II
H n
Concentration Duration of
in Inhaled I'r Exposure.
(*u/i/) (minutes)
0.47X 5
0.49S 5
0.9U 5
1.14J 5
0.47X 23
0.53J ; 20
0.55* 19
0.63X 5
1.25J 5
Peak mood tevc'i; lug/ml) TJ^ tp Peak
Blood Level
Arterial /enous fmlnnta^)
17.50 5
2S.40 5
38.00 5
.54.00 5.
24.7 23
22.6 • 20
19.3 19
10 5
20. 5 .
Blood ,evels Time to Reduced Leve
After Exposure (minutes after ter-
(uq/ml mi n^ ion of exoosure
5.40 5
1.45 10
1.30 15
0.61 • 30
4.40 5
1.40 10
0.65 15
0.5 30
6.20 5
2.70 10
0.75 15
0.16 30
7.80 5
2.95 10
2.25 IS
0.74 30
-6 5
-5 10
-2.5 30
Reference
Allen and
Hanbury's, Ltd.
1971
N n u
ti it ti
Blake and
Mergner, 1974
n o «
nun
;iark and
Tlnston, 1972a
1972b
II • tl
-------
Table A-I. (cont.)
Absorption/Elimination Data on Various F'uf-ocarbons Inhaled from Ambient Air
i
en
Fluorocarbon
F-12
.
i
i
F-114
i
i
Species
Dogs
n n
m M
• M
« ft
a n
Dogs
Concentration Duration of
in Inhaled .'• • Exposure
(«>//«} {minutes )
1.18% 20
« 30
8S 30
0.11 10
5. OX 10
10. OX 10
5S 30
i
n n
lOt 30
Pea* Blood Levei: (ug/ml) jjme tp pea|<
Blood Level
Arterial 'enous (minntpc)
14.0 15
30 20
-65 30
0.9 - 1.2 0.4 - 1.0 10
30.0 - 42.0 19.2 - 35.0 1.0
47.0 - 61.0 22.0 - 47.0 10
. -19 -30
-40 -10
Blood Levels Time to Reduced Level
After Exposure (minutes after ter-
(uq/ml) mination of exposure
-3 5
-2 10
<1 30
-8 10
-1 30
-15 10
-6 30
<0.1 - 0.2 (Art) 5
<0.1 - 0.3 (Yen) 5
<0.1 - 0.1 (Art) 15
<0.1 (Ven) 15
1.2 - 2.0 (Art) 5
4.0 - 5.8 (Ven) 5
0.6 - 0.8 (Art) 10
2.2 - 3.1 (Ven) 10
1.2 (Ven) 15
5.5 - 8.6 (Art) 5
9.2 - 11.3 (Ven) 5
0.6 (Art) 15
1.2 - 5.0 (Ven) 15
-5 10
-1 30
-10 10
-6 30
Reference
Blake and
Mergner. 1974
Clark and
Tinston, 1972a
N H II •
Azar et al.,
1973
II II H M
n ti n u
tt
Clark and
Tinston, 1972i
"
-------
Table A-I. (cont.)
Absorption/Elimination Data on Various 'ijorocarbons Inhaled from Ambient Air
Oi
Fluorocarbor.
F-1301
(CF38r)
Species
Rats
Rabbits
Concentration
1n Inhaled Air
Duration or
Exposure.
(minutes)
50
30
•eaie HI coo Lev ft (ug/mO Time to Peak
Blood Level
Arterial
.'•'iDOlis
5.6
-15
50
15
(decline to
<10 at -25
minutes, then
-15 at 30
minutes)
Blood
After
(uq/ml
.eveIsTime to Reduced Leve
xposure (minutes after ter-
minatlon of exposure
0.62
0.35
0.05
0.07
15
1 hr. .
2 hrs.
4 hrs.
Reference
Griffin et
al... 1972"
-------
INHALATION
EXHALATION
• 1.25KFLUOROCARBON 11
o 0.63% FLUOROCAHBON 11
TIM! (mtaj
Fig. Arl.Venous blood concentrations of F-ll
in dogs exposed to 1.25% or 0.63% F-ll
in ambient air for 30 minutes (Clark
and Tinston, 1972a).
INHALATION
tXMALATION
9t FLUOROCARBON 12
o 4% FLUOROCARBON 12
60
60
TMEMnJ
Fig.A-2. Venous blood concentrations of F-12
in dogs exposed to 4% or 8% F-12 in
ambient air for 30 minutes (Clark and
Tinston, 1972a).
A-7
-------
to- •
40. .
• HMFLUOMOCARBON114
O S% FLUOROCARBON 114
1
Flg.A-3 Venous blood concentrations of F-114
in dogs exposed to 5% or 102. F-114 in
ambient air for 30 minutes (Clark and
Tinston, 1972a).
A-8
-------
Table B-I.
Acute Inhalati n Toxicity of Fluorocarbons
1
Compound
F-ll
•
i
!
I
!
i
i
•-
1 F-12
i
I
i
1
i
t
•_/»
. .J* p
*•+
Rats
Rats
Rats
Rats
Rats
Rats
Rats
Mice
Rabbi t
Guinea Pig
Guinea Pig
Rats
Rats
Rets
Rats
Res arse
ALC I.CSQ Ane ». Tremors Non-lethal
61
10*
20*
15*
in1
IUi
<9t
334
101
25*
25*
10*
>80*
en '
3U
30-40S
80*
Duration
4 hrs.
20-30 ml n.
5 mtn.
30 min.
20 min.
U.S.
N.S.
30 min.
30 min.
30 min
2 hrs.
30 min.
1 hr.
N.S.
4-6 hrs.
Reference
Waritz. 1971
Lester and Green-
berg, 1950
Kuebler, 1964
Paulet. 1969
Kuebler, 1964
Lester and Green-
berg, 1950
Haritz, 1971
Paulet. 1969
Paulet, 1969
Paulet, 1969
Clayton, 1966
Paulet, 1969
Kuebler, 1964 j
1
Lester ar.d Gresn- !
berg, 1950 i
Lester and Green-
berg, 1950
| ' "
[
Bf
o
(V
o.
X
03
o
3
o
Q>
V
O
m
.x
•a
rt-
O*
O
X
«J<
o
_t.
£
o
tu
r+
O)
-------
Table B-I. (cont.)
Table ft-I. Acute Inhalati .n Toxiclty of Fluorocarbons
CO
ro
Compound
.
•F-ll/F-12
'
F-22
'
F-113
Animal
Mice
Guinea Pigs
Guinea P1gs
Guinea Pigs
Rabbits
Rats
Mice
Guinea Pigs
Mice
Guinea P1gs
Guinea Pigs
Dogs
Rats
Rats
Rets
Rats
Res cnse
ALC I^CJQ Ane tli. Tremors Non-lethal
76X
>80X .
' 20X
>80X
, >80X
30X
22t
SOX
40X
10X
20X
70X 4
-------
Table B-I. (cont.)
TdbVe tf-1. Acute Inhalatlc . "oxlclty of Fluorocarbons
09
CO
Compound
F-113
F-114
(CC1F2-CC1F2)
' ' •
. .a "
.r .•-*
Animal
Rats
Nice
Mice
Mice
Mice
Guinea Pigs
Dog
Dog
Rats
Rats
Mice
Mice
Guinea Pigs
Dogs
Reap n;e_
ALC L.C5Q • Anes h. Tremors Non-lethal
15% :
>1«
9.5X
15X
5.7: [delayed death with >6X]
iax
1.1X
1.3*
601
SOX
701 [delayed death -71 hrs.]
[lOi: alveolar hemorrhage]
20X
20X
Duration
15 mln.
30 nln.
2 hrs.
15 n1n.
30 o1n.
2 hrs.
6 hrs.
1 hr.
2 hrs.
2 hrs.
30 rain.
24 hrs.
8 hrs.
2-5 mln.
Reference
Kuebler, 1964
Raventos and Lemon.
1965
Oesollle et al.,
1968
Kuebler. 1964
Raventos and Lemon,
1965
Desollle et al.,
1968
Steinberg et al.,
1969 ~
Steinberg et al.,
1969
Warltz, 1971
Kuebler, 1964
Paulet and
Desbrousses, 1969
Quevauviller et al,
1963
Yant et al., 1932
Yant et ai- , 1932
-------
Table B-I. (cont.)
Table B-I. Acute Inhalation Tixlcity of Fluorocarbons
00
Cor.pound
F-Wa
(CF3-CC12F)
F-115
(CF3-CC1F2)
F-13B1
(CF3Br)
.
An inn 7
Rats
Rats
Mice
Rabbit
Rats
Rats
Rat
Mice
Mice
Mice
Guinea Pigs
Guinea Pigs
Rabbits
Response
ALC 1,050 Anestsv Tremors Non-lethal
72*
20* [delayed death]
70* [delayed death, K) hrs.]
75*
801
(2M 02)
SOt (in 02)
80* (in 02)
80* (in °2)
85* (In 02) [delayed death. 2 da./:]
80* 'in 02)
85* (in 02) [delayed death, 2 day.;
80* r 02) .
80* (in 02)
Duration
30 rain.
N.S.
30 min.
30 mln.
4 hrs.
30 min.
2 hrs.
30 min.
2 hrs.
2 hrs.
2 hrs.
2 hrs.
2 hrs.
Reference
Paulet, 1969
Caujolle, 1964
Paulet and
Oebrousses, 1969
Paulet, 1969
Clayton. 1966
Laujolle, 1964
Paulet, 1962
Caujolle, 1964
Paulet, 1962
Paulet, 1962
Paulet, 1962
Paulet, 1962
Paulet, 1962
i
-------
Table B-II.
Tatk>€ B-II. Subacute Inhalation .ox-: i :y of Major Fluorocarbon
Fluorocarbon
Ml
F-12
Animal
Rats
Mice
Guinea Pigs
Rabbits
Rats
Dogs
Cats
Guinea P1gs
Rats
Cats
Guinea pigs
Rats
Dogs
.Concentration
* >/v)
_%
o.«
0.4J
O.tt
0.4X
1.21
1.251
2.5S
2.5t
2.5%
in
10S
10%
10*
Dose Schedule
6 hr/day x 28 days
6 hr/day x 28 days
6 hr/day x 28 days
6 hr/day x 28 days
4 hr/day x 10 days
3.5 hr/day x 20 da>
3.5 hr/day x 20 days
3.5 hr/day x 20 day
3.5 hr/day x 20 day
3.5 hr/day x 20 day
3.5 hr/day x 20 day
3.5 nr/day x 20 day
3.5 hr/day x 20 day
Mortality
or?
0/8.
0/2
0/1
0/4
0/2
0.2
0/3
0/5
0/2
0/3
0/5
.0/2
Comments
o significant signs of toxlclty
n any animals either during
xposure or after 15 days recovery.
: . '
light respiratory increase twitch-
ng, chewing motion; rapid recovery
fter exposure.
athology: Braln-neuronal edema ant
euronolial vacuol; Liver-vacuola-
ion of cells; Lungs - emphysema
nd edema; Spleen-increased
•ematopolesls.
to signs of toxicity.
No signs of toxicity
Reference
Clayton, 1966
Clayton, 1966
'
.
Clayton, 1966
.
•
Clayton. 1966
00
en
-------
Table B-II. (cont.)
.•>'*Tat "• > B-II. Subacute Inhalation Toxiclt/ of Major Fluorocarbon
as
CTV
Fluorocarbon
F-113
Animal
Cats
Dogs
Guinea P1gs
Rabbits
Rats
Rats
Mice
Dogs
Mor • .ys
Dogs
Guinea pigs
Rats
Rats
Concentration
X (v/v)
1.25X
1.25X
2.5X
1.1X
1.2X
0.21
0.21
0.2%
0.2X
0.51X
0.511
0/51S
6X
Dose Schedule
3.5 hr/day x 20 days
3.5 hr/day x 20 days
3.5 hr/day x 20 days
2 hr/day, 5 days/wk
x 120 1080 days
2 hr/day. 365-730 day
5 days/wk.
24 hr/day x 14 days
24 hr/day x 14 days
24 hr/day x 14 days
24 hr/day x 14 days
6 hr/day, 5 days/wk.
x 4 wk.
6 hr/day, 5 days/wk.
x 4 wk.
6 hr/day, 5 days/wk
x 4 wk.
1 hr/day x 5 days
Mortality
0/2
0/2
0.2
0.6
3/6
0/50
0/40
0/8
0.4
0/4
0/10
0/20
0/5
1
Comments
No signs of toxlclty.
.
No variation from controls
Deaths not associated with
exposure. Slight sleepiness
during exposure.
Rat kidneys Increased In weight
dbove controls; enlarged thyroid
gland In all monkeys exposed.
Nelghter effect conclusively
attributed to exposure.
No toxic effects.
Liver: two rats showed fair
amount of fat In Kupffer cell
possibly Indicative of change
In llplds or llpoprotelns; not
definitely attributable to
exposure.
Reference
Clayton. 1966
'
Oesoille et al., >
1968 ~
Desoille et al..
1968
Carter et al.,
1970
1
Steinberg et al.,
1969
;
1
|
Burn et al_. , 1959
i
j
i
'
-------
Table B-II. (cont.)
B-II. Subacute Inhalation Toxici'.y 3f Major Fluorocarbon
03
Fluorocarbon
F-113
(cont)
F-114
-.
Animal
Rats
Cats
Guinea Pigs
Rats
Dogs
Mice
Rat-.
Mice
Rats
Rats
Guinea P1gs
i
Concentration
2 (v/v)
402
102
102
102
102
102
102
202
202
12
14.162
Dose Schedule •
'
1 hr/day x 5 days
i
3.5 hr.day x 20 days
3.5 hr/day x 20 days
3.5 hr/day x 20 days
3.5 hr/day x 20 days
2.5 hr/day. 5 days/wk.
x 10 days
2.5 hr/day, 5 c-.ys/wk
x 10 days
2.5 hr/day, 5 days/wk.
x 10 days
2.5 hr/day. 5 days/wk. ,!
x 10 days
2.5 hr/day. 5 days/wk.
x 50 days '
8 hr/day x 21 days
Mortality
0/4
0/2
0/3
0/5
0/2
0/10
0/10
0/10
0/10
0/30
1/6
Comments
Reference
Mildly toxic effect in liver.
Moderate degree of mitotic
activity in liver cell of one
rat; others showed similar
activity to a lesser degree.
Burn et al.., 1959
No signs of toxlcity
Clayton. 1966
No signs of toxlcity
Exudative and congested lesions
of the alveoli and bronchioles i
without cell structure alteration'.
Slight decrease in equilibrium, j
No toxic effects i
Paulet and
Desbrousses, 1969
No signs of toxicity. Death not
related to exposure. Occasional
slight fatty degeneration of
liver.
i Quevauviller.
I e_t al.., 1963
j Yant et al., 1932
-------
Table B-II. (cont.)
Table B-I.' Subacute Inhalation Toxic t: of Major Fluorocarbon
1
O3
i
Fluorocarbon
F-114
(cont)
Animal
Guinea pigs
Guinea pigs .
Dogs
Dogs
Dogs
Rats
Rabbits
Concentration
X (v/v)
20X
,
20X
14.16*
14.16*
20X
.
IX
12X
!
Dose Schedule
i
8 hr/day x 4 days
8 hr/day x 2 days
8 hr/day x 3 days :
8 hr/day x 21 days
8 hr/day x 3-4 days
2 hr/day, 5 days/wk.
x -184 days
2 hr/day, 5 days/wk.
x -207 days
"
Mortality
0/6
0/10
0/1
0/2
4/4
2/6
0/6
I
Comments j Reference
j
Ruffled fur and occasional f Yant et al., 1932
convulsive jerk. Increase in
excreta.
Salivation and wretching.
Occasional convulsions with
tremors during first three days,
followed by definite development
of tolerance to exposure.
Increase In hemoglobin, red
blood cells, and younger forms
of polyraorphonuclear leucocytes.
All died during exposure. Effects.
same as above but more severe.
Pathology as follows. Brain-
congestion of meningeal vessels;
Heart - nypcardium, congested;
liver -very marked congestion;
kidney - congested, pale
yellowish glandular cortex;
gastrointestinal tract - gastric
and duodenal mucosa markedly
congested and swollen. One dog
had suggestion of duodenal ulcer
Small Increase In number of red Desollle et al.,
blood cells in rats. 1973
No signs of t ox 1 dty Desollle et al..
1973 •
f
-------
.y«
Table B-II. (cont.)
Table B-II. Subacute Inhalation Toxici y of Major Fluorocarbon
Fluorocarbcn
F-13B1
Mixture
F-12(48.9X)
F-ll (251)
F-114 (2SI)
F-113(1.1I)
Mixture
F-12 (401)
F-114 (50?)
Ethyl alco-
hol (10t)
Mixture
F-21 -
(CHCKF)
(40'.)2
F-22 (60S)
Mixture
F-12 (4W)
F-114(5(H)
Ethyl alco-
hol (lOt)
Animal
Mice
Rats
Guinea pigs
Mice
Rats
Puppies
Dogs
Concentration
i ( . v)
502
SOS
sot
970 mg/kg/day
164 rag/ kg/day
1714 mg/kg/day
700 mg/kg/day
Dose Schedule
2 hr/day x IS days
2 hr/day x 15 days
Mortality
1/2.:
0
2 hr/day x 15 days ! , 1/10
5 mi n. exposure in a
chamber, twice daily !
5 day/wk. x 23 roontt- ••
0/30
5 m1n. exposure in i.
chamber, twice daHj ,'
7 days.wk. x 93 day;.
5 mln. exposures in •
chamber, twice dail>
5 days/wk. x 2 wks.
Exposure by face ma; ,
twlc-: daily, 7 daysAk
x 93 days
0/16
0/2
0/4
Comments
Death not related to exposure
Death not related to exposure
.
No signs of toxlcity
Ho signs of toxlcity
Reference
Paulet. 1966
Smith and Case.
1973
Sedate and atoxic during
exposure
No signs of toxlcity
CO
VO
-------
Table B-II. (cont.)
vwTable B-II. Subacute Inhalation Toxfc.t/ of Major Fluorocarbon
I
.^
o
Fluorocarbon
Mixture
F-12 (SOX)
F-114(2S:0
F-U(Z4.5X)
Span 85
(0.5S)
Mixture
(as above)
•
Animal
Dogs
Dogs
Concentration
X (v/v)
560 mg/kg/day
2240 mg/kg/day
-.
Dose Schedule ,
1
Exposure by face masl.
twice dally, 7 days.v
x 90 days.
Exposure by face mask
twice dally, 7 days/t. .
x 1 year
Mortality
0/4
-
0/6
i
Comments | Reference
No signs of toxlclty Smith and Case,
1973
i
i
Occasional slight depression or !
drowsiness Immediately after j
dosing, lasting only minutes.. , ::
i
i
*
i
>
i
i
i
i
i
i
1. -
i •
-------
Table B-III.
Table B-III. Chronic Inhalation Tox' :ity of Major Fluorocarbon
Fluorocarbon
F-ll
-.
F-12
;
Animal
. Rats
Guinea pigs
Dogs
Monkeys
Rats
Guinea pigs
Dogs
Monkeys
Dogs
Monkeys
Guinea pigs
Rats
Guinea pigs
Rabbits
Dogs
Monkeys
Concentration
. % (v/v)
1.025%
1.0251
1.0251
1.025*
0.1%
0.1S
0/1%
0/1%
20%
Zui
20*..
0.0841
0.084J
0.084%
0.084%
0.084%
Oose Schedule
8 hr/day x 30 days
8 hr/day x 30 days
8 hr/day x 30 days
8 hr/day x 30 days
24 hr/day x 90 day:
24 hr/day x 90 day:
24 h./day x 90 day:.
24 hr/day x 90 day:
7-8 hr/day x 52 days
7-8 hr/day x 35-53 c
7-8 hr/day x 35-56 J
8 hr/day, 5 days/w-:
x 30 days
8 hr/day, 5 days/w .
x 30 days
n n u
M.I, M
M n M .1
Mortality
0/15
.0/15
0/2
0/9
C.'IS
0/15
0/2
1/9
0/2
0/2
r--26
1/15
0/15
0/3
1/2
0/3
Comments
Reference
No outward signs of toxiclty.
(See text for discussion.)
! Jenkins et al.,
1S70
Hemorrhagic lesions on surface
of lung not directly attribut-
able to exposure.
Dogs and monkeys apparently j Sayer et al.,
developed tolerance to exposure, { 1930
tremors disappearing after two I
weeks. Guinea pigs deaths not !
related to exposure (see text), j
Several guinea pigs showed focal j Prendergast e_t
necrosis or fatty infiltration
of liver; one monkey had heavy j
pigment deposits in liver, spleen;
and kidney.
aj_., 1967
-------
Table B-III. (cont.)
Tab>e*S-tII. Chronic Inhalation Toxlclty.of Fijcrocarbons (cont.)
00
PO
Fluorocarbon
F-12
(cont)
->
F-22
F-U3
F-115
F-13B1
.
.
.
Animal
Rats
Guinea pigs
: Rabbits
Dogs
Monkeys
Rabbits
Rats
Hicr
Rat.
Mice
Rats
Rats
Rats
Nice
Rabbits
Dogs
Rats
Dogs
i
i
Concentration
0.08U
0.0811 .
O.OSlt
o.oaix
O.OSlt
1.42i
1.42%
1.42%
0.1931
0.198%
0.0252X
0.5*
10S
lOt
10«
lot
2.31
2.3X
Dose S-.le-.lule
24hr/d i •• < 90 days
24hr/d < 90 days
24hr/d.v ( 90 days
. 24hr/d. • < 90 days
24hr/d; ; 90 days
6hr/daj X 10 mont.i
6hr/da> X 10 months
6hr/daj X 10 months
6hr/daj 1 10 months
6hr/da> '. 10 months
Thr/day < 30 days
7hr/day f 30 days
6hr/day. !> days/Mks.
X 90 da ;
6hr/day. 5 days/wks.
X 90 da; .
' 6hr/^ay •> days/wks.
X 90 daj
6hr/day. 5 days/Mks.
X 90 das
6hr/day '10 days
6hr/day "0 days
Mortality
2/1S
I/IS
0/3
0/2
0/3
N.S.
N.S.
N.S.
N.S.
N.S.
0/21
0/12
0/20
0/10
0/4
0/4
0/30
0/3
Comments
Guinea pigs all
showed slight to
excessive fatty
Infiltration of
liver and several
had focal or sub-
massive necrosis
of liver (see text.;
(see text.)
No toxic effects
No toxic effects
Three rats showed
slightly pale livers
No toxic effects
No toxic effects
1
i
I
Prendergast et
al... 1967 ~
Clayton, 1966
Clayton. 1966
Clayton. 1966
Clayton. 1966
Clayton. 1966
Clayton, 1966
-------
o
• I
Table C-I. '
Table C-rl. Induction of Cardiac Arrnythmias by Fluorocarbons
•y*
••'••' Species
Fluorocarboh (number)
F-ll Mice (3)a
.
Mice (3)a
Mice (5)a
Retsa
Ratsa
Rats8 -
Concentration (% by
volume) and Duration
2% x 6 min.
,
5% x 6 min. !
10X x 6 min.
Type of Arrhythmia
(Incidence)
None
None
2nd degree AV block (4)
3rd degree AV block (1)
2.5%
5.02
10X
Bradychardia
Bradychardia
Bradychardia
and
ectopic beats (77. 8%)
Rats'1
Ratsb
Rots"
Rats (5)c
:
5.0«
.
10.0?
20.0%
2.5X x 5 min.
Bradychardia
Bradychardia
ectopic beats
Bradychardia
ectopic beats
Tachychardia,
fibrillation,
-
and
(14.3JS).
and
(100%)
atrial
ventricu-
Reference
Aviado and Belej
(1974)
Aviado and Belej
(1974)
Aviado and Belej
(1974)
Doherty and Aviado
(1975)
Doherty and Aviado
(1975)
Doherty and Aviado
(1975)
Doherty and Aviado
(1975)
Doherty and Aviado
(1975)
Doherty and Aviado
(1975
Watanabe and Aviado
(1975)
• i
£
o.
:x
o
• •
c
o
3
o
rv
O
8
-*
Q.
O
fit
.
"Ej
»
in
:|T|
^
•£t
a
-O)
Q>
lar extrasystoles (1) .
Rats (5)c 5.01 x 5 min. Tachychardia, atrial Watanabe and Aviado
fibrillation, ventricu- (1975)
lar extrasystoles (2)
-------
FT uorocarbon
ro
F-12
Table C-I. (cont.)
Table C-I. Induction of Cardiac Arrhythmias by Fluorocarbons (cont)
Species
(number)
Rats (5)
Concentration (I by Type of Arrhythmia
volume) and Duration (Incidences
c
10* x 5 min.
Rats (4)a- 2.5X x 5 min.
Rats (4)a 5.OX x 5 min.
,\ats (4)*
Monkeys
10% x 5 min.
2.5X x 5 min.
Monkeys (7)a 5.OX x 5 min.
Rats"
Rats"
10X
ZOX
Tachychard^d, atrial
fibrillation, ventricu-
lar extrasystoles (4)
0 arrhythmias, no
change in heart rate
1 arrhythmia, no
change in heart rate
4 arrhythmias, no
change in heart rate
Tachycardia
Tachcarcia; ventricular
premature beats; AV
block (29X)
Reference
Watanabe and Aviado
(1975)
Watanabe and Aviado
(1975)
Watanabe and Aviado
(1975)
Watanabe and Aviado
(1975)
Mice (3)a
Mice (3)a
Ratsa
40X
60X
5*
x 6 min.
x 6 min.
None
None
None
Arrhythmias (10X)
Bradychardia and
arrhythmias (10X)
Siil.
Belej et a1_. (1974)
Aviado and Belej
(1974)
Aviado and Belej
(1974)
Ooherty and Aviado
(1975)
Ooherty and Aviado
(1975)
Doherty and Aviado
(1975)
-------
Table C-I. (cont.)
Table Crl. Induction of Cardiac Arrhytimias by Fluorocarbons (cont)
o
i
co
••/*
' „-> Species
Fluorocarbbn (number)
F-12 Ratsb
Ratsb
Ratsb
Rats (5)c
Rats (5)c
Rats (4)c
Rats (4)a
Rats (4)a
Rats (4)a
Monkeys (3)a
Monkeys (3)a
F-22 Mice (3)a
Concentration (% b./
volume) and Duration
10%
20%
40%
10%
20%
402
10*
20%
40%
5.0% x 5 min.
10% x 5 min.
20% x 6 min.
Type of Arrhythmia
(Incidence)
Bradychardia
•
Bradychardia
Bradychardia and
arrhythmias (16.7%)
Tachycardia, no
arrhythmias
Tachycardia, no
arrhythmias
Tachycardia, no
arrhythmias
0 arrhythmias, no
change in heart rate
0 arrhythmias, no
change in heart rate
1 arrhythmia, no .
change in heart rate
None
Arrhythmias
None
Reference
Doherty and Aviado
(1975)
Doherty and Aviado
(1975)
Doherty and Aviado
(1975)
Watanabe and Aviado
(1975)
Watanabe and Aviado
(1975)
Watanabe and Aviado
(1975)
Watanabe and Aviado
(1975)
Watanabe and Aviado
(1975)
Watanabe and Aviado
(1975)
Belej et a1_. (1974).
Belej e_t al_. (1974)
Aviado and Belej
(1974)
-------
'.I1*
Fluorocarbon
F-22
F-113
F-114
Table C-I. (cont.)
Table C-i. Induction of Cardiac Arrv;hmias by Fluorocarbons {cont)
F-1T
F-142b
(Chlorodifluoro-
ethane)
Species
(number)
Mice (7)a
Concentration (", by Type of Arrhythmia
volume) and Pur*, c on (Incidence)
40% X 6 min.
Monkeys (3)a 1055 x 5 min.
Monkeys (3)a 20% ;> 5 min.
Mice (3)a 5.OX x 6 min.
Mice (3)'
10% x 6 min.
Monkeys (J)a 2.5% x 5 min.
Monkeys (3)a 5.OX x 5 min.
None
None
None
None
Invertet T wave (1)
None
Tachycardia and
arrhythmia
Mice*
Monkeys
Monkeys3
Mice*
Monkeys
Mice3
10%,20% or 40% x 5 min.. None
5% x 5 min.
None
10% or 20% x 5 m i . Tachycardia and
arrhythmia
10%,2^x1 or 40% x 5 min. None
10% or 20% x f> m>n. None
40% or 60% x 6 min None
Reference
Aviado and Belej
(1974)
Belej e_t aj_. (1974)
Belej et.al. (1974)
Aviado and Belej
(1974)
Aviado and Belej
(1974)
Belej e_t aj,. (1974)
Belej et al_. (1974)
Aviado- and Belej
(1974)
Belej.et ai. (1974)
Belej et al (1974)
Aviado and Belej
(1974)
Belej ejtaj.. (1974)
Aviado and Belej
(1974)
-------
<-)
. I
Table C-I. (cont.)
Table C-I. Induction of Cardiac Arr!y;hmias by Fluorocarbons (cont)
.-•'*
Fluorocarbon
F-142b
(Chlorodifluoro-
ethane)
F-152a
(Difluoroethane)
•
F-21
Species
(number)
Monkeys8
*
Mice3
Rats3
Rats3
Rats3
Rats5
Rats (4)a
Rats (5)c
Mice (3)a
Mice (4)£
Mice (10)a
Concentration ('. :>y
volume) and Our. t ion
5% or 10% x 5 m n.
20% or 40% x 5 i i;u
5%
10%
20%
10%, 20% or 40%
40%
40%
50% x 6 min.
10% x 6 min.
20% x 6 min.
Type of Arrhythmia
(Incidence)
None
None
Arrhythmias (10%)
Arrhythmias (10%)
Arrhythmias (16.7%)
None
Arrhythmia (1)
None
None
2nd degree AV block (1)
2nd degree AV block (9)
Reference
Belej et al_- (1974)
Aviado and Belej
(1974)
Doherty and Aviado
(1974)
Doherty and Aviado
(1974)
Doherty and Aviado
(1974)
Doherty and Aviado
(1974)
Watanabe and Aviado
(1975)
Watanabe and Aviado
(1975)
Aviado and Belej
(1974)
Aviado and Belej
(1974)
Aviado and Belej
(1974)
-------
Table C-I. (cont.)
Table C-I. Induction of Cardiac Arrhythmias by Fluorocarbons (cont)
';•'' *
Species
Concentration -'f, by
Fl uorocafb'on (number) volume) and Du»*r:1on
F-21
Monkeys
Monkeys
(3)a 2.5% x 5 min.
(3)a 5.0% x 5 min.
Type of Arrhythmia
(Incidence)
None
Arrhythmias
Reference
Belej
Belej
et.
it
Si-
al_.
(1974)
(1974)
o
I
Anaesthetized
Anaesthetiz d and adrenalectomized
Unanaesthetir^d
-------
Table C-'II.
Table C-I . Fluorocarbon Sensitization to Arrh/thnrlas froa Injected Eplnephrlne
Minimum Concentration
of Fluorocarbon Elicit-
Fluorocarbon Species
F-ll Mice
Dogs
1"* Monkeys
F-12 Nice
Dogs
Monkeys
Concentration (X by
Volume) and Pupation
2X x 5 min.
51 x 5 min.
.09-.13X x 5 min.
.35-.61X x 5 min.
.96-1.21* x 5 m1n.
2.5X x 5 ml.,.
20X or 40X x 5 m1n.
2.5X x 5 min.
5. OX x S min.
51 x 5 min.
Dose of
Eplnephrlhe
6 vg/kg
6 us/kg
8 yg/kg 1n 9 sec.
8 yg/kg in 9 sec.
8 vg/kg In 9 sec.
0.5 yg/kg/min.
6 yg/kg
8 ug/kg in 9 sec.
8 yg/kg in 9 sec.
0.5 yg/kg/min.
Type of
Arrhythmia (Incidence)
•: 0/3
2nd degree AV block (3/3)
0/12
Ventricular fibrillation
(1/12)
Arrhythmias (5/12; 3 with
ventricular fibrillation)
Arrhythmias
lone
tone
\rrhythmias (5/12; 1 with
/entricular fibrillation)
.lone
ing Arrhythmia without
Eplnechrine
10X
Not tested
5. OX
Does not elicit arrhth-
mias in mice at 40X
Not tested
10X
Reference
Aviado & Belej
(1974)
Reinhardt et al.
(1971)
Belej et el.
(1974)
Aviado & Selej
(1974)
Reinhardt et al.
(1971)
Belej et al.
(1974)
-------
Table C-II. (cont.)
Table C-II. Fluorocarbon Sensltlzatlon to Arrhythn as from Injected Eplnephrine (cont.)
Minimum Concentration
•of Fluorocarbon Elicit-
Concentration (1 by
Fluorocarbon Species Volume) and Duration
F-22 Mice 201 x 5 min.
402 x 5 min.
Dogs 2.51 x 5 min.
..02 x 5 mm.
0
c'a f-m Mice 5S x 5 m1n.
102 x 5 ain.
Dogs 0.21-0.25X x 5 min.
0.46-0. 56% x 5 Din.
0.97-1.161 x 5 nln.
F-rt Mice lot x 5 nln.
20X x 5 min.
40% x 5 qrtn.
Dogs 2. SI x 5 min.
5. OX x 5 min.
Dose of
Eplnephrlne
6 yg/kg
6 yg/kg
8 yg/kg in 9 sec.
8 yg/lk in 9 sec.
6 vg/kg
6 ug/kg
8 ug/kg In 9 sec.
8 yg/kg In 9 sec.
8 yg/kg In 9 sec.
6 yg/kj
6 yg/kg
6 yg/kg
8 yg/kg In 9 sec.
8 yg/kg in 9 sec.
Type of
Vrhythmla (Incidence)
3/3
Jr.d degree AV block (3/5)
V12
Arrhythmias (2/12; no
veitrtcular fibrillation)
'e.itricular ectopics (1/3)
Ventricular begem) ng (3/3)
r.2
•; 8
2/12 (1 ventricular fibril-
i. ;1on and cardiac arrest)
•I.'-'
n< degree AV block (1/4)
o- degree AV block (2/3)
/12
'12 (2 ventricular fibril-
Ing Arrhythmia without
Epinephrine
Does not elicit arrhyth-
mias In mice at 401
Not tested
10%
Not tested
Does not elicit arrhth-
mlas in mice at 402
Not tested
Referencg
Avlado S Belej
(1974)
.
Relnhardt et al.
(1971)
Avi ado S Belej
(1974)
Relnhardt et al.
(1973)
Aviado & Belej
(1974)
Relnhardt et al.
(1971)
"Ion and cardiac arrest)
-------
Table C-II. (cont.)
Table C-IT. Fluorocarbon Sensltlzatlon to Arrhythmias from Injected Eplnephrlne (cont.)
r'.'jcrocirbon Species
F-115 Mice
o
I
F-133!
Dogs
Dogs
Minimum Concentration
of Fluorocarbon Elicit-
Concentration (* by
Volume) and Djration
10S X 5 mln.
20% X b mln.
40Z X 5 rain.
151 X 5 inn.
25% X 5 m1r
S% X 5 mln
7.5S X 5 mln.
10% X 5 min.
151 X 5 mln
20% X 5 min
Dose of
Epinephrine
6 ug/kg
N
M
8 ug/kg tn 9 sec.
u
8-10 ug/kg
N
Type of
Arrhythmia (Incidence)
0/3 .
2nd degree AV blacn (2/4)
Ventricular fibrillation
(l/4); Ventricular ec topics
(1/4).
1/13
4/12 (no ventricular
fibrillations
0/62
1/18 (5.6*)
8/69 (11,6*
2/7 (28. 6X)
8/13 (61.5*)
ing Arrhythmia without
Epinephrine
Does not elicit
arrhythmias In nice
at 40*
Not tested
Not tested
Reference
Aviado and Belej
(1974)
Relnhardt et al.
(1971)
Reinhardt and
Reinke (1972)
F-142b Mice
(Chlorodlfluoroethsne)
4CX or
X 5 min.
6 ug/kg
None
Does not elicit
Arrhythmias in
mice at 60S
Aviado and Belej
(1974)
Dogs
2.5S X 5 mln.
5.01 X 5 mln.
10S X 5 mln.
8 ug/kg 1n 9 sec
0/6
5/12
12/12
Not tested
Relnhardt et al
(1971)
-------
Table C-II. (cont.)
Table C-II. Fluorocarbon Sensltlzatlon to A.-ihythro1as from Injected Eplnephrlne (cant.)
Minimum Concentration
of Fluorocarbor. Elicit-
o
1
Fluorocarfaqn
F-152a
(difluoro-
ethane)
F-21
Species
Nice
Dogs
Mice
Concentration (I by
Volume) and Duration
20% or 401 x 5 min.
55! x 5 nln.
15% x 5 nrin.
5S x 5 Tin.
101 x 5 IE' .
Dose of
Eplnephrlne
6 ug/kg
8 ug/kg In 9 sec.
8 wg/kg 1n 9 sec.
6 ug/kg
6 ug/kg
Type of
Arrhythmia (Incidence)
None
0/12
3/12
0/3
2nd degree AV block (6/6)
Ing Arrhythmia without
Epinephrine
Does not elicit arrhyth-
mias in mice at 40X
. Not tested
10%
Reference
Avlado S Belej
(1974)
Reinhardt et al.
(1971)
Aviado S Belej
(1974)
-------
^ Table C-III.
Table C-IILSumrary of Brpnchopulmonary and Cardlpvatcular Effects other than Ar
Fluorocarbon
F-ll
F-12
F-22
F-113
F-114
F-115
F-21
F-142b
F-152a
Tachycardia
Dog Monkey
(1)***
(10)*
(10)*
(20)*
(2.5)**
(20)*
0
(2.5)**
(10)*
(20)*
(5.0)*
(10)*
0
(5.0)*
0
0
Hvocardlal
Doa
(2.5)**
(5.0)*
(20)*
A
(20)*
Deoress1«H
Monkey
(2.5)**
(10)*
(20)*
(5.0)*
(10)*
0
(5.0)*
(10)*
0
Hyootenslon
Dog Honkey
(2.5)**
0
(20)*
(20)*
(10)*
(10)*
(2.5)**
(10)*
f OA V
(20r
(5.0)*
(10)*
0
(5.0)*
(20)*
o
-------
•?" Table C-III. (cont.)
Table C-III-Suimiary of Bronchopulmonary and Cardiovascular Effects other than Arrhythmia9 (continued)
Fluorocarbon
F-ll
F-i2
F-22
F-113
--w
F-115
F-21
F-142b
F-152a
Early Respiratory Depression
Mouse Rat Dog Monkey
(2.5)** (2.5)** (10)*
(5.0)* (10)* (20)*
0 0
0 0
(2.5)** 0
0
(5.0)* 0
(5.0)*
CO)*.
(20)*
0
(20)*
0
(2:5)**
0
0
Broncfroconstrl ctlon
House ttt_ Dog
(1)** 2.5)** 0
(2)* ) (10)*
V'.)* (10)*
in)** (10)*
0 (2.5)**
(10)*
(2)* 0
Monkey
0
(10)*
(20)*
0
(20)*
0
0
0
0
Decreased Compliance
Mouse Rat Dog Monkey
(1)** (2,5)**
(2)* (10)*
(10)*
(10)*
0
(2)*
0 0 -
(10)* (10)*
0
0
(5)* 0
(20)* 0
(2.5)** 0
a
0 0
0 0
•} Data from Avlado (1975b) and Avlado (1975c)
Nwbers In parentheses are approximate minimal Inhaled concentration (X •. / volume) eliciting the effect; 0 Indicates absent or opposite responses;
*, **• +** Indicate Intensity of response
-------
Table D-I.
Fluorocarbon Numbers and Molecular Formulae
of the Major One and Two Carbon Saturated Fluorocarbons
Fluorocarbon Number* Chemical Name Molecular Formula
F-ll Trichlorofluoromethane CC13F
F-12 Dichlorodifluoromethane CC12F2
F-13 Chlorotrifluoromethane CC1F-,
i j
F-14 Tetrafluoromethane CF
F-21 Dichlorofluoromethane
F-22 Chlorodifluoromethane CHC1F2
F-23 Trifluoromethane CHF3
F-113 Trichlorotrifluoroethane CC12F-CC1F2
F-114 Dichlorotetrafluoroethane CC1F2-CC1F2
F-115 Chloropentafluoroethane CC1F2-CF3
F-142b Chlorodifluoroethane CC1F2~CH3
F-152a Difluoroethane CHF2-CH3
F-13B1 Bromotrifluoromethane CBrF3
(Halothane) Bromochlorotrifluoroethane CBrCIH-CF.,
* See Introduction for description of fluorocarbon numbering system.
D-l
------- |