-------
-------
NOTICE
The report has been reviewed by the Office of Toxic Substances,
EPA, and approved for publication. Approval does not signify
that the contents necessarily reflect the views and policies
of the Environmental Protection Agency, nor does mention of
trade names or commercial products constitute endorsement or
recommendation for use.
ii
-------
TABLE OF CONTENTS
INTRODUCTION 1
I. STRUCTURE and PROPERTIES ........ 2
A. Chemical Structure 2
B. Physical Properties 4
C. Principal Contaminants in Commercial Proper tie's . . 8
II.' PRODUCTION . 9
A. Quantity Produced 9
B. Producers, Major Distributors, and Importers .... 9
C. Production Sites . . . . 9
D. Production Methods and Processes . . . 15
E. Market Price 18
III: USES 19
A. Major Uses 19
1. Aerosol Propellants 19
2. Refrigerants ...... 22
3. Blowing Agents ..... . 25
4. Solvents 27
5. Intermediates . . . 27
6. Fire Extinguishing Agents 27
B. Minor Uses 28
C. Discontinued Uses . 28
D. Projected or Proposed Uses . . 28
E. Possible Alternatives to Uses . 29
1. Refrigerants 30
2. Aerosols 31
IV. CURRENT PRACTICES 33
A. Special Handling in .Use 33
B. Methods of Transport and Storage . . . . 34
C. Disposal Methods ......... 34
D. Accident Procedure 35
iii
-------
Table of Contents
(continued)
Page
V. ENVIRONMENTAL CONTAMINATION 37
A. Contamination from Production • • • 37
B. Contamination from Transport and Storage 37
C. Contamination from Use .... * • . • • • 38
1. Propellants . • 38
2. Refrigerants ............... - . . 39
3. Solvents ....'.' 40
4. Blowing Agents i- ...... 40
5. Plastics ..... 41
D. Contamination from Disposal 41
E. Fluorocarbon Contamination Levels in the Atmosphere . 41
VI. CONTROL TECHNOLOGY 50
A. Currently Used '50
B. Under Development 50
VII. MONITORING AND ANALYSIS 51
A. Analytical Methods and Sensitivity . 51
B. Current Monitoring 53
VIII. CHEMISTRY • • • 58
A. Reactions Involved in Use 58
B. Hydrolysis 60
C. Oxidation . 62
D. Thermal Stability 62
E. Photochemistry 65
F. Other Chemical Reactions . . 66
IX. BIOLOGY 67
A. Absorption/Elimination 67
1. Fluorocarbons in Expired Air .......... 68
2. Fluorocarbon Blood Levels after
Nebulizer Administration 73
3. Fluorocarbon Blood Levels after Inhalation
of Fluorocarbon-containing Ambient Air ..... 82
4. Other Routes of Entry 93
iv
-------
Table of Contents
(continued)
B. Transport and Distribution 97
C. Metabolic Effects 107
D. Metabolism Ill
X. ENVIRONMENTAL TRANSPORT AND FATE ............ 117
A. Persistence 117
B. Biological Degradation 117
C. Chemical Stability in the Environment 118
D. Environmental Transport 118
E. Bioaccumulation 118
XI. HUMAN TOXIC1TY 119
A. Accidental Exposures and Misuse 119
B. Occupational Exposure and Normal Use 120
C. Controlled Human Studies 122
D. Epidemiology 125
<
XII. TOXICITY TO BIRDS AND MAMMALS 127
A. Acute Toxicity 127
1. Acute Inhalation Toxicity 127
2. Acute Oral Toxicity ....... 139
e. Acute Dermal Toxicity 141
B. Subacute Toxicity . . 142
1. Subacute Inhalation Toxicity ... L42
2. Subacute Oral Toxicity 148
3. Subacute Dermal Toxicity 148
C. Chronic Toxicity 150
1. Chronic Inhalation Toxicity 150
2. Chronic Oral Toxicity 154
3. Chronic Dermal Toxicity 156
D. Cardiovascular Effects of Fluorocarbons 157
1. Cardiac Sensitization to Exogenous Epinephrine
Induced Arrhythmias .... 157
2. Cardiac Sensitization to Endogenous
Epinephrine Induced Arrhythmias 171
-------
Table of Contents
(continued)
3. Cardiac Sensitization to Asphyxia
Induced Arrhythmia 176
4. Arrhythmias Not Associated with
Asphyxia or Epinephrine . . . 194
5. Cardiac Responses Related to Arrhythmias .... 202
E. Sensitization - Repeated Doses . . . 211
F. Teratogenicity • . . . 211
G. Mutagenicity . . 212
H. Carcinogenicity ....'.. 213
I. Behavioral Effects 216
J. Possible Synergisms p ....... 217
XIII. TOXICITY TO LOWER ANIMALS . 219
»
XIV. TOXICITY TO PLANTS 219
XV. TOXICITY TO MICROORGANISMS 219
XVI. CURRENT REGULATION ................... 223
XVII. CONSENSUS AND SIMILAR STANDARDS ..'... 224
XVIII. FLUOROCARBONS: SUMMARY AND CONCLUSIONS ... 226
References 230
vi
-------
TABLES
Number
Title
I. Major Commercial Fluorocarbons 1
II. Physical Properties of Fluorocarbon Compounds ........ 3
III. Typical Blends of Fluorocarbons with Non-Fluorocarbons ... 4
IV. Fluorocarbon Solubility Relationships ....... 6
V. Swelling of Elastomers by Fluorocarbons and other Compounds . 7
VI. Typical Analysis of Fluorocarbon-12 8
VII. Production of Fluorocarbons in the U.S 10
VIII. Fluorocarbon Producers and Plant Capacities .... 12
IX. Foreign Fluorocarbon Producers .... 13
X. Fluorocarbon Production Sites 14
XI. Market Value of Fluorocarbons 18
XII. Uses of Fluorocarbons 20
XIII. U.S. Aerosol End-Use Pattern 23
XIV. World Aerosol Pattern 24
XV. Use of Fluorocarbon Refrigerants 26
XVI. Properties of the Hydrocarbon and Nonliqueiied
Gas Propellants 32
XVII. Potential Hazards of Fluorocarbons .... 33
XVIII. Fluorocarbons Released to the Environment in 1972
from U.S. Applications 42
XIX. Estimate of Average Concentration of Fluorocarbon 12
in the Atmosphere . . i . 47
XX. Electron-Capture Detector Response to Various
Fluorinated Compounds ..... 54
XXI. Fluorocarbon Concentrations'in the Atmosphere 57
XXII. Bond Energies of Chlorofluorocarbons . 58
XXIII. Hydrolysis Rate in Water ..... 61
XXIV. Thermal Stability of Fluorocarbon Compounds ... 63
XXV. Decomposition Values of Fluorocarbons at 400°F 64
XXVI. Partition Coefficients of Various Fluorocarbons 69
XXVII. Elimination of Fluorocarbons as Measured in Expired Air ... 71
XXVIII. Concentration of F-113 in Alveolar Air (ppm) After
Exposure to 0.05% and 0.1% F-113 72
XXIX. Some Biochodilator Drugs and the Amount of Fluorocarbons
Used as Propellants 73
XXX. Peak Arterial and Venous Blood Levels of Fluorocarbons
in Dogs 74
XXXI. Absorption/Elimination Data in Various Mammalian Species
after Inhalation of F-ll and F-12 from Nebulizers .... 76
XXXII. Concentration of F-ll and F-12 in Venous Blood of Three
humand exposed to ten doses of 25.5 mg F-11/dose 79
XXXIII. Venous Blood Levels of F-ll and F-12 in Mice after three
Inhalations from One dose of & Ventolin inhalater .... 80
XXXIV. Arterial Blood Levels of F-12 and F-114 in Monkeys 85
XXXV. H-1301 in Rat Blood Following a Single 50-Minute
Exposure to a Vapor Concentration of 5% (V/V) . . 86
vii
-------
Tables
(continued)
XXXVI. Blood Levels of H-2404 in Rats After a 30-Minute
Exposure to 3.7% H-2402 .. 87
XXXVII. Absorption/Elimination Data on Various Fluorocarbons
after Inhalation . . 88
XXXVIII. Arterial and Venous Blood Concentrations of F-ll in Dogs
Exposed to 0.2% and 0.5% F-ll 90
XXXIX. Elimination of Fluorocarbons in Dogs Breath 93
XL. Concentration of F-ll in the Blood, Heart, Fat, Adrenals
and Thymus of Rats at various times after Exposure
to F-ll for 5 minutes ....... 98
XLI. • Concentration of F-12 in the Heart, Fat, and Adrenals of
Rats at Various Times after Exposure to F-12 for 5 minutes 99
XLII. Mean Tissue Concentrations of F-113 in Rats Exposed
to 0.2% F-113 for 7 & 14 days '.•••, 100
XLIII. . Tissue Concentrations of H-2404 in Rats after 30 minutes
Exposure to 3.7% H-2404 101
XLIV. Tissue Distribution of Residual F-12 in Control Rats and in
Rats Red 0.2% and 2.0% F-12 over a two-year period .... 103
XLV. Tissue Distribution of Residual F-12 in Control Dogs and
Dogs Fed 0.03% and 0.3% F-12 over a two-year period .... 104
XLVI. Recovery and Inhalation of F-ll and F-12 in Beagles .... 112
XLVII. Tissue Concentrations of Non-volatile Radioactivity in
Beagles 24 hours after Inhalation of F-ll and F-12 .... 112
XLVIII. Delayed Death After DCHFB Administration of Rabbits ..... 115
IL. Acute Inhalation Toxicity of Perhalomethanes in Laboratory
Mammals 129
L. Acute Inhalation Toxicity of Halo-unsaturated Methanes
in Laboratory Animals 130
LI. Acute Inhalation Toxicity of Perhaloethanes in
Laboratory Mammals ....... 131
LII. Acute Inhalation Toxicity of Halo-unsaturated Ethanes
in Laboratory Mammals 132
LIII. Acute Inhalation Toxicity of Bromofluoromethanes in
Laboratory Mammals .......... 133
LIV. Acute Inhalation Toxicity of Bromofluoroethanes in
Laboratory Mammals 134
LV. Acute Oral Toxicity of Various Fluoroalkanes in Rats .... 139
LVI. Acute Oral Toxicity of F-113 in Rats 140
LVII. Subacute Inhalation Toxicity of Various Fluorocarbons .... 143
LVIII. Chronic Inhalation Toxicity of Various Fluorocarbons .... 151
LIX. Percent Reduction of the Surface of Burns in Control Rats
and Burns Sprayed with Various Fluorocarbons . . ... . . 156
LX. Outline of a Procedure for Determining the Ability of
Various Vapors to Sensitize the Heart to ... . 158
LXI. Epinephrine Dosage Used in Determining the Effect of
Fluorocarbons in cardiac Sensitization to
Exogenous Epinephrine 159
viii
-------
Tables
(continued)
LXII. Cardiac Responses to Mammals Exposed to Fluorocarbons
and Challenge Injections of Epinephrine 161
LXIII. Cardiac Responses of Dogs Exposed to F-12 for Varying
Periods with Challenge Injections of Epinephrine 164
LXIV. Percent of one and two Carbon Fluorocarbons Causing
Arrhythmias in Dogs on Epinephrine Challenge.... 165
LXV. Blood Levels, Air Concentrations, and Exposure Periods
of Various Fluorocarbons causing Cardiac Sensitization. . . 166
LXVI. Cardiac Responses of Dogs Exposed to Continuous Loud Noise
& 80% Fluorocarbon/20% Oxygen for Thirty Seconds 172
LXVII. Cardiac Responses of Dogs Exposed to Various Fluorocarbons
While Running . . 174
LXVHI. Comparison of Results of Screening Experiments of
Reinhardt e± a±. , 1971 & Treadmill Experiments of
Mullin et al., 1972 175
LXIX. Responses of Mice to Asphyxia, Propellants, and
Propellants plus Asphyxia 178
LXX. Responses of Mice to Asphyxia 181
LXXI. Responses of Mice Exposed to "total" and "partial"
Asphyxia 183
LXXII. Responses of Mice to Asphyxia 185
LXXIII. Percent change in the Heart Rates of Mice at 25 Seconds
After Exposure to Various Fluorocarbon Propellants
and Nitrogen with and Without Asphyxia. . , 187
LXXIV. Number of Mice Which Experienced and Time to Onset of
2:1 AV Block and Bradycardia 188
LXXV. Cardiac Responses of Dogs to a Mixture of F-ll and F-12
from Antiseptic or Hair Spray 195
LXXVI. Effects of Nitrogen and Fluorocarbon Exposure on... 196
LXXVII. Cardiac Responses of Monkeys to Fluorocarbon Inhalation . . . 197
LXXVIII. Individual Cardiac Responses of Three Monkeys Exposed
Twice to Fluorocarbon Inhalation 198
LXXIX. Arterial Blood Levels of F-12 and F-114 at Time of Onset
of Ventricular Premature Beats in Monkeys 198
LXXX. Cardiac Responses of Dogs to Varying Concentrations of
H-1301 in Oxygen 199
LXXXI. Cardiac Responses in Normal Cats and in Cats before, during
and after H-1301 Exposure at 165 ft. sea water 200
LXXXII. Cardiac Responses of Dogs to H-1211 201
LXXXIII. Responses of Dogs to Exposure of H-1301 (70%) in Cross-
circulation Experiments 204
LXXXIV. Conditions of Exposure of Rat Left Ventricular Papillary
Muscles in Muscle Bath and Effect on Po2 .... 208
LXXXV. Effects of Freon 12 Administered Orally ro the Parent
Female and Male Rats on Fertilization, ati: 212
LXXXVI. Tumors Induced in Swiss Mice by Injection of "Freons"
and Piperonyl Butoxide Shortly after Birth 213
ix
-------
Tables
(continued)
LXXXVII. Toxicity Induced in Swiss Mice by Neonatal and Perinatal
Subcutaneous Injections of F-112 and F-113 Alone and
in Combination with a 'Synergist1, Piperonyl Butoxide . . .
LXXXVIII. Mean dose-response Curves for Halothane (HAL), F-22,
and a Variety of Other Agents on Bioluminescence in
Photobacterium phpsphoreum
LXXXIX. Comparison of the ED_Qs of Bioluminescence inhibition in
I Bacteria and the AD" s in Mice for Halothane, F-22 and F-12
XC. Underwriters' Laboratories Comparative Toxicity
Classification of Refrigerants '.••••
XCI. TLVs and Underwriters' Laboratories Classification for
Various Fluorocarbons
217
220
220
224
225
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
1-4.
15.
16.
17.
FIGURES
Pressure-Temperature Relationships of Freon Compounds .... 5
Production and Production Capacity of Fluorocarbons in the U.S. 11
Geographic Locations of Fluorocarbon Production Plants ... 15
Flow Diagram of Fluorocarbon Manufacture from Chlorohydro-
carbons 17
Cross Section of Typical Aerosol Package 21
Projections of Average Global and U.S. Atmosphere
Concentration of Fluorocarbons 11, 12, and 22 48
Hydrolysis Mechanism of Fluorocarbon 31 .......... 60
Concentrations of Some Halogenated Hydrocarbons in the
Alveolar Air of Man after Varying Periods of Breath-holding 69
Retention Times of Halogenated Hydrocarbons Following
Single Breath Administration in Man ............ 70
Venous Blood Concentrations of Human Inhaling 86 mg F-ll
and 258 mg F-ll from a Nebulizer 77
Venous Blood Concentrations of F-ll in a Human
Inhaling 50 mg F-ll 77
Changes in Venous Blood Concentrations of F-ll in Dogs
Exposed to (A) 1.25% and 0.65% F-ll for 30 minutes
and (b) 0.55% F-ll for 20 minutes 83
Changes in Venous Blood Concentrations of F-12 in Dogs
Exposed to (A) 8% and 4% F-12 for 30 minutes and (B)
1.18% for 20 minutes 83
Changes in Venous Blood Concentrations of F-114 in Dogs
Exposed to 10% and 5% F-114 for 30 minutes ... 84
Increase in Fluorocarbons (FCC) Concentrations in rat
Blood during inhalation of a combination of FCC's etc. . . 85
Freon 12 in Blood of Rabbit during 5% Atmospheric Exposure . 86
Fluorocarbons in Blood of Rabbits during 5% Atmospheric
Exposures . 86
-------
Figures
(continued)
Number Title Page
18. (A) Venous and Arterial Blood Concentrations of F-ll
and (B) Arterial and Venous Differences in Dogs
exposed to 0.1%, 0.5%, and 1.0% for 10 minutes 92
19. (A) Venous and Arterial Blood Concentrations of F-12
and (B) Arterial and Venous Differences in Dogs
exposed to 0.1%, 5.0% and 10% F-12 for 10 Minutes 92
20. Blood Concentration of F-ll in Dog Following an Intra-
venous Infusion of 28 rag F-ll 94
21. Rat Brain and Heart Concentrations of CBrF During
and After. 5-minute Exposures to 71-76% CBrF- in 0_ etc. . . 102
22. Oxygen Consumption in Mitochondria from rats Exposed
to Halocarbons . . . ; . . . 107
23. Oxidative Phosphorylation in Mitochondria from rats
Exposed to Halocarbon • . 108
24. The Effect of Freon-21 on Coupling Parameters of
Rabbit Liver and Mung Bean Mitochondria. 109
25. Possible Metabolic Pathways for Halothane . 114
26. Comparative Toxicity of Various Fluorocarbons 135
27. Growth of Male and Female Rats Orally Administered F-12 . . . 154
28. Number of Arrhythmic Heart Beats in Responses to
Different Doses of Epinephrine Administered during
Exposure to 0.87% F-ll 163
29. The Minimal Blood Pressure Necessary to Trigger Arrhythmias
Varied Inversely with the Concentration of CBrF» ..... 170
30. Heart Rate Response of Mice Exposed to Compounds for
Five Seconds Followed by Asphyxia 181
31a. Heart Rates during total Asphyxia of control mice and animals
Exposed to nitrogen; as well as propellant alone, and
propellant with isoproterenol 184
31b. Ibid., propellant with isoproterenol, etc 184
32. Percent Change in Heart Rate After Exposure to Asphyxia . . . 190
'33. Percent Changes in pulmonary resistance' and heart rate . . . 203
34. Decreased Myocardial Contractility in Dogs After Exposure
to 50% and 75% H-1301 for Five Minutes .......... 206
35. Changes in Isometric Contraction in Rats During
Exposure to H-1211 206
36. Effect of Exposures to Various Gases in vitro Mycardial
Contractility ..... 209
37. Dose-response Curves for the effects of dichloro-
difluoromethane gas (F-12) on isometric developed
force in 15 isolated rat papillary muscles etc . 210
xi
-------
COMMERCIAL FLUOROCARBON AEROSOL PROPELLANTS, SOLVENTS, FIRE EXTINGUISHING
AGENTS AND REFRIGERANTS
INTRODUCTION
This report reviews the potential environmental hazard from the com-
mercial use of large quantities of saturated, one and two carbon fluoro-
carbon compounds which are used for the most part as aerosol propellants,
»
solvents, fire extinguishing agents or refrigerants. The major compounds
of interest in this report are listed in Table I. Assessments of environ-
mental hazard for a broader spectrum of fluorocarbons are presented
elsewhere (Howard and Durkin, 1973; Lutz ejt al., 1967).
Table I
Major Commercial Fluorocarbons
Chemical Formula Fluorocarbon //
Trichlorofluoromethane CC13F 11
Dichlorodifluoromethane CC12F2 12
Chlorodifluoromethane CHC1F2 22
Trichlorotrifluoroethane CC12F-CC1F2 113
Dichlorotetrafluoroethane CC1F2-CC1F2 114
Chloropentafluoroethane CC1F2-CF3 115
Bromotrifluoromethane CBrF3 13B1 (H1301)
Information on physical and chemical properties, production methods and
quantities, commercial uses and factors affecting environmental contamina-
tion as well as information related to health and biological effects are
reviewed.
-------
Throughout the report a shorthand numerical system will be used instead
of the cumbersome but more precise chemical nomenclature. The most common
system used by industry and the system utilized in this report consists of
a 4-digit number—for example, fluorocarbon ABCD, where D is the number of
fluorine atoms in the molecule, C is 1 plus the number of hydrogen atoms
in the molecule, B is equal to the number of carbon atoms minus 1, and A
equals the number of double bonds in the molecule. Whenever A or B
equal zero, the digits are omitted from the number. This system works well
with low molecular weight chlorofluorocarbons which are the major commercial
products. When bromine is substituted for chlorine, a B plus the number of
bromine atoms follows the number of fluorine atoms (e.g., CC1F3 is 13
whereas CBrF3 is 13B1). The appropriate numbers for the seven commercially
important fluorocarbons are presented in Table I. With the fire extinguisher
agents, such as bromotrifluoromethane, a different numbering system (Halon
system) is frequently used which results in the number 1301 rather than 13B1:
ABCD signifying the number of carbon, fluorine, chlorine, and bromine atoms,
v. • - .
respectively. This numbering system is used in discussing the toxicologic
literature on fire extinguishing agents. Such numbers are preceeded by an
"H" rather than an "F".
I. Structure and Properties
A. Chemical Structure
The fluorocarbons under review are saturated compounds containing
one or two carbon atoms and fluorine. Chlorine, bromine, and hydrogen atoms
also may be present. Although some refrigerant, solvent and aerosol
propellant formulations are mixtures of fluorocarbons, most of the commercial
products consist of a pure compound. The chemical formula and molecular
weight of these chemicals and the frequently used azeotropic refrigerant
mixtures are listed in Table II.
-------
Table II: Physical Properties of Fluorocarbon Compounds
(DuPont, 1969a; Allied Chemical, no date (a); Union Carbide, 1973-4)
Major Commercial Products
nyroc-tfeg
Cbc»lc*l Fonuli
feUcmUz y«l«ht
»otLIfl« Faint « 1 M>
FnnUB Point
Critical Tn.ycr«turc
Critical Frc«iur«
ItaMltr. Liquid
*t 25-C <77'F)
»t lolllo* Point
S*«ClftC R«4t . Uqutd
(But &?•(.!::•> e
«t 25'e (!."F;
•pKlttc BMC. Vapor
tu »'C (771) to
Be*i
?«poc (1 «u>)
s^n/^*i« " :s"= r7"n
•tetractlv* Index of ' Iquld
Dielectric Ci-nitir.-.
SolufcJlU. ,--! C -wfJumJ
25'C C7T-
S«I«*lli.v « i-'iT^r ID
^..,^.iw,-;.r. cu:r:. :..:
j03 1- J. .'. O" .. 3*3.91
li
CC1,F
117.37
*C 2J.82
*r 74.87
*C -111
*C 19«.0
• Ut 41.5
t'cc l.4;6
Ibc/co tt 92.14
I/I S.W
Iba/ce ft O.36?
.„<„<-« 0,0,
•i/(c>caa It, . ia*c
•/••IWfFl (100*F>
Ben/U> 77.'S8
cmttpotw 0.010*
IB
,.,7,
l:S»lZi ;
•-: I 0.11
ut : o.dii
BO,,^.,^,,
CCIFj'Sy Jel('.iJ
, CHjClj, C»cl»p«iit*.«)
12
«U2Fj
U0.92
-21.42 -
-15*
-252
112.0
UJ.*
40.6
1.111
81. H
6.13
0.395
0.212
0.145
19.47
71.0*
0.20
0.0125
9
1.287
•^•-
O.O:B
O.OC5
22_
CHCUj
s*.*;
-40.75
-41. 30
-16C
-25*
W.O
204. S
49.12
721.9
1.19*
74.S1
4.J2
0.295
0.100
O.li?
55.81
1O0.45
0.18
0.013
8
1.25*
6.11 t 24*C
:.<•«);; ^ 2j.4-c
O.JO
O.ll
ill
eel* F-CC: F;
187.3o
i.7. 57
117. t.J
-IS
-11
214.1
13.;
1.565
7.38
0.461
0.218
».i*i #(ltS.*r,
15.07
63.12
0.68
3.010
(0.1 UB)
17.3
,.».
,„,„
„.,.•:?;:.,.
0.0)1
Hi
CUlij-CtlF;
170.43
3.77
1A.78
-94
-137
143.7
294.)
32.2
473.1
1.456
90.91
7.83
0.489
0.141
0.170
12.51
58.33
0.1*
0.0112
12
1.7M
2.ib i IVC
0.013
O.wirt
us irt-mu i>J. u »o*
OClfj-CFj arfi CBjCBF- CC1T.
154.47 149.92 66.1 M>*.5 W.I
:S:1 :":« :":; -u":. -a.3
:15 :2" :!« -"Si -2»
8O.O t'.O 113^ 2S.9
17S.9 153.* 216.1 "-» "^
».» 19.1 *4-17
«1 5.'5 652 642
1.291 1.538 0.902
90.60 94.01 5*. 11
4,37 i.71 •
0.321 O.S44
0.285 0.208
0.164 0.112
30.11 28-3S
34.70 SI. 08
0.1* O.135 0.217
0.0127 0.0158
S 4
1. *!4 l.'TS
i.ocis s :?.-*;
o.ooe ;.oj
. o.*m<;o*n
s«;
111.61
:?«:"
82.2
179.» '
591.0
1.217
75.94
0.388
0.2,3
0.1W
74*. 18
0.1*
0.01)
8
'••'»
O.OS6
0.68 (M'T) 0.44 (WO 0.»
21.2 (Mf) 2J.! !75-n 1».2 t
0.02 '.7i-F) O.O2
1IVEA.
-------
The fluorocarbons may also be formulated with non-fluorocarbons.
Table III lists some typical blends of fluorocarbons with rion-fluorocarbon
chemicals. In addition, stabilizers such as nitromethane are sometimes
added to alcohol-based aerosols (0.3% by weight).
Table III: Typical Blends of Fluorocarbons with Non-Fluorocarbons
(Union Carbide, 1973-74, P 28)
Blend Application
45% F-ll, 45% F-12, 10% isobutane Propellant
Azeotrope: F-113 and Dichloroethane Solvent
Azeotrope: F-113, CH2C12, cyclopentane Solvent
Azeotrope: F-113 and SDA-30 alcohol Solvent
Blend: F-113 and Isopropanol Solvent
B. Physical Properties
The fluorocarbons usually are characterized by high vapor pressures
(low boiling point), high density, low viscosity, low surface tension, low
refractive indices, and low solubility parameters. The common physical
properties are tabulated in Table II.
-------
The degree of fluorine substitution greatly affects Llie physical.
properties. Generally, as the number of fluorines replacing chlorines
increases, the vapor pressure goes up, but the boiling point, the density
and the solubility parameter decrease. Bromine atoms have a tendency to
increase the density and lower the vapor pressure. The vapor pressure/
temperature plots for various fluorocarbons given in figure 1 illustrate
the fluorine substitution effect. For example, in the chlorofluoroethane
series, vapor pressures increase with fluorination: 112 < 113 < 114 < 115 <
116.
1000p
-1T78 -100
Temperature "C
-80 -60 -40-20 0 20 40 60 80 100 1201«L
0.3
01
-180 -130 -KO -120 -100 -80 -60 -40 -20 0 20 «) 60 80100 UO 180
Temperature
220
260 300
°F
Figure 1
Pressure-Temperature Relationships of Freon Compounds
(DuPont, 1969a)
-------
The solvent power of the fluorocarbons ranges from poor for the
highly fluorinated compounds to fairly good for the less fluorinated com-
pounds (DuPont, 1969a). Being typical nonpolar liquids they exhibit low
water solubility. The highly fluorinated compounds are generally considered
both hydrophobic and oleophobic. Some solubility relationships for fluoro-
carbons are shown in Table IV. The kauri-butanol test consists of the
titration to a cloudy end-point of a kauri-resin dissolved in butanol.
The higher the kauri-butanol value, the higher the solvent power.
Table IV: Fluorocarbon Solubility Relationships
(DuPont, 1969a; Union Carbide, 1973-4)
Solubility of
Water at 32°F
Product . (0°C)j % by Wt.
11
12
21
22
113
114
502
113-C2H1+C12
113-CH2C12C5H10
•
0.0036
0.0026
0.055
0.060
0.0036
0.0026
0.022
0.02 (75°F)
0.02 (75°F)
Oil
Solutions
Miscible
Miscible
Miscible
*
Miscible
*
*
-
-
1
Kauri-butanol
Number !
1
60 ;
18
102
25
32
12
14 (est.)
51
98
*Two Liquid Phases at Low Temperatures.
The low solubility parameter for fluorocarbons allows their use around
elastomers without adverse effects of swelling. Comparison of the linear
swelling of elastomers with the various fluorocarbons is presented in
Table .V.
-------
Table V: Swelling of Elastomers by Fluorocarbons and Other Compounds
(DuPont, 1969a)
Product
"Freon" 11
"Freon" 12
"Freon" 13
"Freon" 21
"Freon" 22
"Freon" 113
"Freon" 114
"Freon" 115
"Freon" 502
"Freon" 13B1
"Freon" 114B2
"Freon" C-318
Methyl chloride
Methylene chloride
Per Cent Increase in Length at Room Temperature
Neoprene
GN
17
0
0
28
2
3
0
0
1
2
7
0
22
37
Buna N
(butadiene/
acrylonitrile)
6
2
1
48
26
1
0
0
7
1
7
. 0
35
52
Buna S
(butadiene/
styrene)
21
3
1
49
4
9
2
0
3
1
15
0
20
26
Butyl
(isoprene/
isobutylene)
41
6
0
24
1
21
2
0
1.6
2
22
0
16
23
Polysulf ide
Type
2
1
0
28
4
1
0
0.2
1.6
0
1
0
11
59
Natural Rubber
23
6
1
34
6
17
2
0
4
1
26
0
26
34
-------
C. Principal Contaminants in Commercial Products
The commercial fluorocarbons rank among the highest purity organic
materials sold in this country (Bower, 1973). The purity of a typical
commercial product will commonly exceed 99.9% (Hamilton, 1962). This lack
of contaminants is a result of several carefully performed purification
steps. In most cases, the starting material and by-products are separated
by fractional distillation followed by basic washing and drying over a
suitable desiccant. A typical analysis of fluorocarbon-12 is presented
in Table VI.
Table VI: Typical Analysis of Fluorocarbon-12
(Bower, 1973)
Fluorocarbon !
12 99.96+ vol. % i
13 0.010
II 0.002
21 0.003
.22 0.017
H20 4.5 ppm
Non-volatile <0.01 vol. %
The predominant isomers of the ethane series (113, 114)
. are the more symmetrical isomers, e.g. CC12F-CC1F;;> and CC1F2-CC1F2.
Fluorocarbon-113 usually contains no more than a few tenths of one percent
of CC13-CF3, while fluorocarbon-114 usually contains no more than 7-10
percent CC12F-CF3 (Hamilton, 1962).
-------
II. PRODUCTION
A. Quantity Produced
The reported total demand for all fluorocarbons in the U.S. in 1973
was 880 x 106 Ibs. (Chemical Marketing Reporter, 1973), or approximately
0.5% of the total production of synthetic organic chemicals in the U.S.
(Drysdale, 1971). The historical trends of production are presented in numerical
and graphic form in Table VII and Figure 2, respectively. The world produc-
tion of fluorocarbons is considered to be approximately twice the U.S.
production (McCarthy, 1974).
B. Producers, Major Distributors, and Importers
The major U.S. producers are listed in Table VIII along with the
trade names and numbers of their fluorocarbon products and their total
plant capacities. Table IX presents a list of foreign manufacturers of
fluorocarbons.
In the U.S., the large manufacturers of the basic fluorocarbon com-
pounds distribute the chemicals to large users such as aerosol packaging
companies and refrigerator manufacturers. For example, Allied Chemical
sells its Genetron refrigerants through wholesalers located around the
country (Allied Chemical, no date, a).
C. Production Sites
The product plant locations are listed in Table X and their
geographic positions are depicted on the map in Figure 3.
-------
Table VII
Production of Fluorocarbons in the U.S.
(U.S. Tariff Commission, 1961-1971; Stanford Research Institute, 1973)
Compound
Fluorocarbon
Chlorodifluoro-
, methane
g)
22
Dichloro-
difluorome thane
Trichlorofluoro-
methane
11
(IO6 Ibs.) (10? g) (10s Ibs.) (109 g)' (iO6 Ibs.)
Dichlorotetra-
fluoroethane
114
(IO3 g) (IO6 Ibs.)
. l-chloro-1,1-
di£luoroethane
142a
(IO9 g) (IO6 Ibs.)
1961
1962
1963
1964
1965
1966
1967
196s
1969
1970
197Lp
I972p
10
13
16
19
22
25
26
24
32
33
36
36
.9*
.2*
.3*
.5*
.7*
.4*
.3*
.9*
.?*'
.1*
.3*
.3*
24*
29*
36*
43*
50*
56*
59*
55*
71*
73*
80*
80*
78
94
98
103
122
129
140
i,r
ICc
170
1'6
i99
.5
.3
.4
.4
.9
.7
.6
.9
.*
.1
.9
.1
173
208
217
228
271
286
310
326
368
375
390
439
41
56
63
67
77
77
82
92
107
110
117
136
.3
.7
.5
.1
.1
.1
.6
. 5
.9
.7
.0
.1
91
125
140
148
170
170
182
204
238
244
258
300
4.1
5.0
5.4
5.9
10.0
•7.7
10.0
7.7
9
11
12
13
22
17*
22*
17*
.091*
0.2*
*Sales
p - Preliminary
-------
CO
3
g
3
i
IUUUU rrrr»T 3^ gr= = -r-- = Trrr;= = =^--
7000 F. . T I .--:. •'.
Rnnfl - . ,,-i. -L- . T -,.,_„,.- --,,, -- -f,,. , ,-
r ' J .
-"...[ - :.:-- ' :-..-.::_
°°" ^ :::.).. : .. f.- ;• : •: •; r ." - .. • .-. :. r _ :: .; -
— j. |_ „ ..t . . , _.._..._. . . ......_..._
2000 E^-^tj-T™- --= = ---"
p ]t| iflSpif 1
i
1 000 U- j i t i f r-
900 r--j-4-—f-Srr^r=- = T^r=r^^
800 = .Ti."': -f -TT-r-T------ -i-r
""" -fiil- :^~ --==:-. r: - .". : - .:. ~
i^i-.r : - -4. jr - - -. --.-.-•• . - .-: ..-•
600 ipt-^--p^t; ------------;-
r.r-7: _ - -:.;.:. :i:i ~ .. - !.:.::;??
500 :r- — 7.r-" :--" "--: -*-.-
\ — -.._..
:':• /f L :u .-- -•'/''. T ! K _J_ T ' ' ' - "•
-'- ---- = --: -:• .-- -.' .-•:: -.. --
- - 7JT _ .. . r
_._:L :)>?-.
I""T7""... .." . -T.
4 '1
" t "~ " ""4 ;
100 f — £,-,*f,^,-,,^^,-*-r.^
90 =i = 2S5i = = |Si = ?Mii=i=si^
80 = = = = r-- = ^ = = = = ?=Tr=: = = ^ = T
60 g-7-^ • M'l) r-rrl-l^pl----^
40 ^rrr4-.| Li''[- r r - - - -- - - - r - j^
30 EP^-^ffTrt-ri^i-r---^
r EppJ: j ri'jt ::]- " : :: . '\. ~ - . ~±
^\ .j- -p. ; -i- p- - - !• & - ••
2Q - - :££ ' . ', '^ f" :3£i:.iE:--::3
A
-Z
in I I I I I I I I M I II I I I I I I I I I I N
- ^ .-..•• .• : •• 7 ; - -^ -. . ; ' [ f •
i±::i .::::::::;:_]>:.-;:.- .to.
.~r~ ^ . ^. Tt
.--•„-,-.*. - , - - - - . •-,.,. :,.
: T ]t 1 1
i
""" T i ; . i .
^ MM
i j '•
:. i-i:ii:::. - 1 •'!.-: '.:! -
||i|ffl
--- - - i] 1-
•j L ^ TOTAL FLt
J Jf
:;|M|jijr|:||tjffl||,^
"ffflfijit f flpfpi {|p|- 1-
?^r;:--'-7 - ;..":.-:_-':.:'.:' t
- — rrrt-TT---":-^--- DICHLORC
- :--- ;-•£ ^'; PRODUCTI
a~_LL.
...-la •
JOROCA
i 1 | 1
: 1 1 :i !'. :
t"lT:-
.=•'.-:'.•
••--.:-
i !
i ' '
i
;
1 !-
f. _ : i-
nrf-
^
kRBON
i4f
te
t
: i i.
• *• K'f '
. . !_-«-. ...
CAPA
TE
.L.i'l !l • i
DIFLUOROMETHAN
ON
'rr?:-- "1.1 • ^ '• ; ! ! , i ; j j i
j: j
I
:ITY
E, 12
;1 j. ••~ji*i.. TRICHLOROFLUOROMETHANE, 11
..•; • .^«?p--: . "JK'. PRODUCTI
... j "..__.. . . ' . i !
-^ -• -- -., i , j |:, , 1
. d E " . i- ',
S ...'...' ~ . " : . ' r
r1 M . i
. 1 111 ! , I
- -j-j-j-- -j ;• •+
ON
I'll
i 1 ' !•
' I
: i i I.
' ! i
1 i .
].1t
1 , 1.
:.t
'•
i
! '. i
i
-.=_^.--:- — -- . .. ... VJj ; CHLUHOD ruuunuiYicinM
•• = •: ':r^£7 :i- ^rT'-l! '• SALES
?-•-. ., = = •-;:...•./- :.-:-:L. -..-•• : ...
-^-fU-T^rsflc "5~^T -'M J 1 ' i '•' ' i'j i.
r-i:rrrE::irr-:r::r::r ~--^--^- DICHLORO
-^^--^^i^l.ii^.^- PRODUCTI
'i'i'r.tf :
TETRA
ON(*>
_ : - . 7 .. t . i g ^ : : : : . .. ;[ [: :f ; -Fr -| i ril J:£ •: 't :
j — _c_^ rr. _ . _ ... (_!_ „ SALtS ( © ) "p . - -
L ' ' ' 1 i_ i_L 1
~* ""' ' ii'll
K' 1 ' ft
.. y_. :"": "i" ' r " H i ~
--/- - Jl'l" ! " i
^ " I rt "T
j: j .:
• | -it
. ;..
" ' 1 1 '
r^.t.^.
rr.L
rrJ-
FLUC
:.~:
. . .
| i
iili
f
)F
..
M
•?•:£.
f
i
Hi
:|r
-------
Table VIII: Fluorocarbon Producers and Plant Capacities
(Chemical Marketing Reporter, 1973; U.S. Tariff Commission, 1972)
Company Trade Name
Allied Chemical Genetron
Corporation
E.I. duPont de Freon
Nemours & Co.
Kaiser Aluminum and Kaiser
Chemical Corporation
Pennwalt Chemical Corp. Istron
Racon, Inc.
Union Carbide , . . UCON ,-
Corporation
Total Plant
Capacity
10b/yr. in 1973
310
500*
50
115
20
200**
Compounds
Produced
11, 12, 22,
113, 114, 152a
11, 12, 22,
113, 114, 115,
13B1, 152a
11, 12, 22
11, 12, 22
11, 12, 22
11, 12
*A 500 x 106 Ibs./yr. facility is being built at Corpus Christi, Texas by
DuPont and is expected to be operating at full capacity by 1977 (Anon., 1974b)
DuPont is also building a 10 x 106 Ibs capacity plant for CBrFs in Deepwater,
N.J.,'which should be operating in 1975 (Anon., 1974c).
,**Anon., 1974a.
12
-------
Table IX: Foreign Fluorocarbon Producers
(Noble, 1972)
Country
Argentina
Australia
Brazil
Canada
England
France
West Germany
Japan
Mexico
Netherlands
Italy
India
South Africa
Spain
Producer
Ducilo Siac
Australian Fluorine Chemicals PTY.
Pacific Chemicals Industries
DuPont Do Brazil
Fougra
Allied Ghemical of Canada, Ltd.
DuPont of Canada
Imperial Chemical Industries
Imperial Smelting
Ugine Kuhlman
Perchinery
Kali Chemie
Hoechst
Von Helyden
Chemishe Fabrik
UVI5 A.I fid Fluorowerke
Daikin
Mitsui Fluoro
Asaki Glass
Quimobasicos
Halocarbures
Zinc Organon
DuPont
Liquid Nitrogen Processing
Unichemie
Montecatini Edison
Everst Refrigerant
Naren Fluorine
African Exposives & Chem. Industries
Kali Chemie
Electro Quimica de Flix
Ugine
13
-------
Table X: Fluorocarbon Production Sites
(Chemical Marketing Reporter, 1973)
Company
Allied Chemical Corporation
E.I. DuPont de Nemours & Co,
Kaiser Aluminum & Chemical Corp.
Pennwalt Chemical Corp.
Racon, Inc.
Union Carbide Corp.
Location
Baton Rouge, La.
Danville, 111.
Elizabeth, N.J.
El Segundo, Calif.
Antioch, Calif.
Carney's Point, N.J.
Corpus Christi, Texas*
East Chicago, Ind.
Louisville, Ky.
Montague, Mich.
Gramercy, La.
Calvert City, Ky.
Thorofare, N.J.
Wichita, Kan.
Institute, W. Va.
^Construction started in the fall of 1973.
-------
Figure 3
Geographic Locations of Fluorocarbon Production Plants
D. Production Methods and Processes
The most widely used method for commercial synthesis of the major
fluorocarbons consists of the catalytic displacement of chlorine from
chlorocarbons (commonly CCli^, CHCls, and C2Clg or C^Cl^ 4- Cl2) with fluorine
by reaction with anhydrous hydrogen fluoride (Hamilton, 1962). 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 hydrogen fluoride.
It is reported that this process will be used by UuPont at the plant being
constructed in Corpus Christi, Texas (Noble, 1972), but few details are avail-
able on the process. However, it has been noted that the process will produce
three times the amount of hydrochloric acid which will be converted back to
chlorine in a Kel-chlor plant (Noble, 1972).
15
-------
The several steps in the conventional chlorocarbon process are
shown in Figure 4. The reaction phase uses antimony pentachloride as a
catalyst with the catalyst actually chemically entering the reaction
sequence. Some chlorine gas is also added in order to maintain the
catalyst in its pentavalent rather than its trivalent state.
SbCl5 •+ 3HF -> SbCl2F3 + 3HC1
SbCl2F3 + 2CClit +SbCl5 + CC13F + CC12F2
The reaction can be conducted in either liquid or vapor phases.
The liquid phase operation is carried out by feeding liquid HF and chloro-
carbon. to the reactor and simultaneously withdrawing 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 wt 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 over f luorination.
The vapor phase process consists of. a heated tube filled with a
granular catalyst. The feed is a vaporized mixture of HF and chloro-
carbons . This process is frequently used for the production of the highly
fluorinated compounds. In both processes, the proportion of the mixed
fluorinated products is determined by the chlorocarbon, and by the temper-
ature, pressure and time considerations.
In all processes by-product hydrogen chloride results. This can
be separated either by distillation or scrubbing. The distilled product
16
-------
Chlorinated
Hydrocarbon
CHC13, CCli,, C2C16
H2S(V
Recycled
Intermediate
Reacter
Containing
SbCl5 Catalyst
Distillation
Column
Product + KC
Distillation
Column
Drying
Distillation
Drying
Low Boiling
Drying
High Boiling
Low Boiling Temp
Product
No. 12, 22, 114
Hydrogen
Fluoride
Recycled
Chloro-
carbons
High Boiling Temp
Product
No. ]2, 113
HCL
for sale or disposal
Spent acid to
disposal
Figure 4
Flow Diagram of Fluorocarbon Manufacture from Chlorohydrocarbons
(Hamilton, 1962; Anon., 1965)
17
-------
HC1 has the advantage of being extremely pure and, therefore, can be used
directly in some associated synthesis, or packaged for sale. It also
allows the recovery of urireacted hydrogen fluoride.
Bromotrifluoromethane is made by a similar process, starting with
the tetrabromide. However, it can also be made by the bromination of
trifluoromethane or by the replacement of chlorine in chlorotrifluoro-
methane by reaction with hydrogen bromide.
The equipment is generally conventional in design, especially the
distillation columns, scrubbers and drying towers. The reactors are
jacketed or tubular vessels made of carbon or stainless steel. Since the
f •.
reaction is slightly endothermic, heat is supplied by steam, flue gas or
by electrical heaters.
E. Market Price
Fluorocarbon-^12, with the largest sales volume, has the current
(1973) price in bulk of, 29c/lb. Over the past ten years this has fluctuated
between a high of .31c/lb. and a low of 24£/lb. (Chemical Marketing Reporter,
1973). Table XI lists the major fluorocarbon products and their market
value
Table XI: Market Value of Fluorocarbons
Value/Pound
Compound (dollars)
CHC1F2 22 0.49* 0.48**
CC12F2 12 0.24* 0.34**
CC13F 11 0.18* 0.30**
*U.S. Tariff Commission, 1972.
**Chemical Marketing Reporter, 1974b.
18
-------
III. USES
A. Major Uses
Fluorocarbohs are commercially important because of their unique
physicochemical properties and relatively low physiological activity. The
major applications include uses as aerosol propellants, refrigerants,
solvents, blowing agents, fire extinguishing agents, and as intermediates
for plastics. Table XII lists the major uses, size of the market, as well
as the amount of each fluorocarbon utilized in each application. Plastic
intermediates are not included in Table XII since the production figures do
not encompass this application. The following paragraphs will briefly dis-
cuss the major fluorocarbon applications.
1. Aerosol Propellants
The largest commercial application of fluorbcarbons is for
propellants in the aerosol* products industry (see Figure 5). The idea of
using aerosol propellants dates back to 1863 (Crossland, 1974), but its
commercialization did not occur until after World War II. The industry
got its start when two USDA researchers found that combining insecticides
with liquid refrigerant gases showed an extraordinary increase in insecti-
* • ' •• ' . '
cide efficiency due to the dispersion as a true aerosol (Hamilton, 1962).
During World War II literally millions of the aerosol "bug bombs" were
produced.
*"Self dispensing, pressured, self-propelling products, dispensed by
the use of a liquefied, nonliquefied, or noncondensed gas" (Sage,
1963).
19
-------
Table XII: Uses of Fluorocarbons
Fire
, Aerosol Foaming Extinguishing
Fluorocarbon Production Propellant Refrigerants Solvents Agent Agent
Number Formula 1972 %c Quantity Zc Quantity %C Quantity 2C Quantity 7.c Quantity
(106 Ibs.) (106 Ibs.) (106 Ibe.) (106 Ibs.) (106 Ibs.). (106 Ibs.)
11
12
22
113
114.
115
13B1
Total
% of Total
CC13F
CC12 F2
CHC1F2
CC1F2CFC12
CC1F2CC1F2
CC1F2CF3
CBrF3
Production
300a 82 246 3 9 15 15
439a 60 264 30 • 132 10 44 '.
80U(b 100 . 80
-50C 100 -50
J
-20C 95 19 5-1
10-90
-10C
5 • 95-4
-900 . 529 222 50 89 -4
59% 25% 5% 'lO%
^I.S. Tariff Commission, 1972.
bSales
CEstimates based upon discussions with DuFont and Allied Chemical.
The production figures only marginally consider amounts used in the manufacture of fluorocarbon plastics. Fluorocarbon 22,
113, and 114 are used to synthesize the plastics. However, 13 million Ibs. of po.lytetraf luoroethylene was produced in 1972
(U.S. Tariff Commission) from fluorocnrbon 22, but that quantity is not reflected In the 80 million Ibs. sales figure.
The Chemical Marketing Reporter (1973) reports the following percentage of use: propellants-50%; rcfrigerants-28%; plastica-
10%; solventB-5%; blowing .ip.ents, exports, mlscellanoous-7% on a 197'! total production of B80 million Ibs. The percentage-!:,
reported in this table are similar IT magnitude but quantitatively differ mostly lifcuusc; u.lnsticu have not been included.
20
-------
OPERATES BY
PRESSING DOWN
VALVE
Frew* g»
lf*»MHH ttfnt.
Bit* IITO?I
Solution of
Freon" propellent *nd
active ingredients
Hgure 5
Cross Section of Typical Aerosol Package
(Sage, 1963)
Permission granted by John Wiley & Sons, Inc.
21
-------
Civilian commercialization began in the early 1950's after
low-pressure valves and nozzles were devised to function below 55 psia and
ICC raised its regulations to apply only to containers of 55 psia or more,
thus freeing the industry from elaborate control and regulation which are
i
required of high pressure vessels. Today the world production is as much
I as 6 billion units with the U.S. accounting for approximately 50% of the
total. In 1973 the U.S. market grew by an estimated 3.5 to 4% while an
increase of 21.4% was reported in the United Kingdom. It is projected
that the major growth in the future market will be overseas and a global
output of 10 billion units is suggested (Chemical Marketing Reporter, 1974).
An aerosol end use pattern in the U.S. is depicted in Table XIII and the
i
i
global production pattern is displayed in Table XIV. As can be seen ifrom
Table XIV, the U.S. percentage of the world production has been steadily
decreasing. .
2. Refrigerants
The fluorocarbons industry was first founded in the 1930*s as
a result of a search for new refrigerant gases to replace the highly toxic
refrigerant gases being used—e.g., sulfur dioxide and ammonia (Downing,
1966; Crossland, 1973). Their special properties, such as nonflammability,
low toxicity, chemical stability, and good thermodynamic properties, made
them ideal for use as refrigerants.
This application can be divided into two major categories:
(1) refrigeration - localized low temperature cooling; and (2) air-conditioning
- cooling of rather large volumes of environmental air. Within each of these
22
-------
Table XIII: U.S. Aerosol End-Use Pattern
(Chemical Marketing Reporter, 1974)
1970
1972
1973
1974
Household Products
Cleaners
Laundry Products
Room Deodorants
Waxes, Polishes
Other
Total
630
185
185
180
100
50
700
725
750
Personal Products
Colognes & Perfumes
Deodorants
Hair Care
Medicinals
Shave Creams
Other
Total
145
480
490
65
150
50
1,380
135
515
460
65
165
63
1,403
140
570
460
70
180
75
1,495
1,535
All Other
Automotive
Coatings
Industrial
Insecticides
Other
Total
50
230
90
120
22
512
Grand Total (non-foods) 2,522
620
2,723
85
255
130
140
40
650
2,870
685
2,970
Millions of units. Source: Chemical Specialties Manufacturers Association
and industry estimates. Food aerosols total in excess of 100 million units
annually.
23
-------
Table XIV: World Aerosol Pattern
(Chemical Marketing Reporter, 1974)
US, Canada W. Europe Others* World
'1974** 3,185 1,850 765 5,800
»
1973** 3,105 1,750 645 5,500
i
1972 2,983 1,620 597 5,200
1971 2,695 1,600 550 4,845
1970 2,756 1,425 507 4,690
1968 2,400 1,030 370 3,800
Millions of units. *Includes Australia, Japan, Central and South America
and Africa, but excludes USSR and Russian Bloc countries. Source: The
Metal Box Company, Risdon Manufacturing Company and Chemical Specialties
Manufacturers Association. **Data for 1973-1974 are Chemical Marketing
Reporter estimates.
24
-------
categories, a distinction can be made between prefabricated units, in
which the fluorocarbons are charged and sealed at the factory, and large
commercial units where the charging is done after the units are in place.
In most cases, the distinction corresponds to the size - smaller units
being prefabricated while the larger commercial units are filled after
placement. The difference between prefabricated and large commercial units
is quite important in terms of environmental release because the prefabri-
cated units last an average of ten years, whereas the iarge commercial
units have to be recharged every five years (approximately 80% reclamation
of the original refrigerant). Table XV divides the three major refrigerants
into the categories mentioned above.
3. Blowing Agents
Blowing agents are used to produce a finished product in a
foamed or expanded form. One technique commonly used in the plastics
industry consists of dissolving the blowing agent in a plastic and then
triggering the gasification by a change in temperature or by a sudden
release of a confining pressure (Hamilton, .1962) .
Fluorocarbons were first used in the production of polyure-
thane foams because they impart a significant increase in the thermal
insulation properties. They are also used to form open cell foams, in
which case the blowing agent is released after its use. Fluorocarbons
are divided approximately equally into closed and open cell applications.
25
-------
Table XV: Use of Fluorocarbon Refrigerants
(Hanavan, 1974)
N>
Fluorocarbon;
Formula Number
CC13F
CC12F2
11
12
Quantity Used
as
Refrigerant
(106 Ibs.)
Refrigeration
Prefabricated
% Quantity
106 Ibs.
132 45% 59
(automobiles)
Large
Commercial
% Quantity
106 Ibs.
72% 6
29% 38
Air Conditioning
Prefabricated
% Quantity
106 Ibs.
7%
Large
Commercial
% Quantity
106 Ibs.
28% 3
19% 25
CHC1F2
22
80
221
57% 46
41%
105
% Prefabricated = 52%
% Large Commercial = 48%
^3
77
2% _2
30
-------
4. Solvents
Fluorocarbons find use as a selective solvent for cleaning
precision equipment and for extractions of a variety of natural products.
With precision equipment, the fluorocarbons, usually 113, provide enough
solvent action to remove grease and dirt, but not enough action to swell
and damage the plastic and elastomeric components (see Section I). With
extraction, the desirable component is separated from the undesirable. A
variety of extractions have been reported, including the isolation of edible
oils of cotton seed, safflower and soy beans, as well as active ingredients
of perfumes, essential oils, spices, coffee and even fish (Hamilton, 1962).
5. Intermediates
Some, plastic monomers are made from the basic fluorocarbon
compounds. For example, fluorocarbon 22 can be pyrolyzed to form tetra-
fluoroethylene and hexafluoropropylene. Dechlorination of fluorocarbon 113
yields chlorotrifluoroethylene. The production figures in Table XII do not
consider quantities used as feedstocks for fluorocarbon resins. The U.S.
Tariff Commission has reported that 13 million Ibs. of polytetrafluoro-
ethylene was produced in 1972 (need 15 million Ibs. of fluorocarbon 22
assuming 100% efficiency). The Chemical Marketing Reporter (1973) suggests
that 10% of 825 million Ibs. produced in 1972 are used for plastics. It
appears that for 1972 a more plausible figure is 50-100 million Ibs. over
and above the 900 million Ibs. reported in Table XII.
6. Fire Extinguishing Agents
The use of fluorocarbons as fire extinguishing agents is a
considerably smaller application than those previously mentioned. The
27
-------
compounds are commonly used in confined areas where it is believed that the
chemical acts to extinguish the fire by chain termination of the free
radical propagating mechanism of the fire (Hamilton, 1962). An added
advantage of these materials is that they present a relatively small threat
to life at concentrations and exposure periods necessary to extinguish fires.
JThe fluorocarbon extinguishing agents (collectively referred to as halons)
find good application in specialized situations, usually where the value
density is high, such as in aircraft, mines, spacecraft, tanks, and computers
(Jensen, 1972). The most widely used compound is fluorocarbon 13B1, CBrF3.
: B. Minor Uses
Minor applications of the fluorocarbons being reviewed include their
use as dielectric fluids, heat-transfer fluids, power fluids, cutting fluids,
pressurized leak-testing gases, gases in wind tunnels and bubble chambers,
and as a drain opener propellent (DuPont, 1969a; Downing, 1966).
C. Discontinued Uses
The fluorocarbon C318, octafluorocyclobutam:, was used as an aerosol
propellant with food products. This has largely been replaced by the use of
fluorocarbon 115, which has been accepted as a food additive by the U.S. Food
and Drug Administration (DuPont, 1969a) [see Section XVI , Current Regulations],
i
D. Projected or Proposed Uses
There are several applications for the fluorocarbons that could
possibly develop into rather large markets for these materials. Both
Callighan (1971) and Noble (1972) have noted that the market for the use of
fluorocarbons as heat and power transfer fluid has great potential. If the
28
-------
fluorocarbons were adopted for use in the Rankine cycle engine, which uses
the same principle as the steam engine, the market would be extremely large,
perhaps as large as the total market that now exists (Noble, 1972).
)
Fluorocarbon-113 is being considered for use in the dry-cleaning
solvent market (Noble, 1972; Drysdale, 1971; Lutz £t al., 1967). However,
it is relatively expensive compared to perchloro- and trichloroethylene and,
therefore, the market has not grown appreciably.
Immersion freezing of food with fluorocarbon-12 has also been cited
as a potential growth market (Bucholz and Pigott, 1972; Drysdale, 1971;
Noble, 1972). Tha boiling point of fluorocarbon-12 (-21.6°F) is ideal for
this application.
Another application of possibly large magnitude is contact freezing
with brackish water as a desalination process (Stepakoff and Modica, 1973).
The hydrolysis rate of the fluorocarbon seems to be the important factor
determining whether this application will be commercially significant.
E. Possible Alternatives to Uses
With every commercial chemical, there are two alternatives to its
use - (1) substitution with another chemical, or (2) elimination of the
use. In order to understand the possibility of either of these two alter-
natives, one needs to understand what physical and/or chemical properties led
to the use of the present compound and what motivated the development of the
application. This section will briefly discuss these parameters for the
two major applications of fluorocarbons.
29
-------
1. Refrigerants
The development of the refrigerant industry closely parallels
the development of the food preservation and air-cooling industries. Many
compounds were evaluated for use as refrigerants but all had serious draw-
backs. "Some, like ethylene, were flammable; others, like S(>2, were corrosive
and toxic; and still others, like ammonia, combined all three hazards"
(Hamilton, 1962). Carbon dioxide was nearly ideal, but necessary high opera-
ting pressures made the equipment prohibitively bulky and expensive. In
the 1920's a series of fatal accidents traceable to refrigerants led to a
development effort to synthesize new chemicals that would overcome the adverse
effects described above. Fluorocarbon-12, the first fluorocarbon introduced,
was non-flammable and of low toxicity and had a convenient boiling point.
-30°C. Thus, the fluorocarbons are used today because they are non-corrosive,
non-flammable, have convenient boiling points, and exhibit a low order of
toxicity, the last being perhaps the most important. The possibility of
these chemicals being replaced by other compounds seems relatively remote.
The possibility of eliminating the need for refrigerants also
seems remote. Refrigeration of food is paramount to its preservation both
on the way to the consumer and in storage by the consumer. Air condition-
ing is less a necessity than a convenience, although it was first developed
by a physician to cool the rooms of feverish patients. It is a necessity
in hospitals and in many industrial operations', such as textiles, paper,
photographic film and precision machinery, where climate-controlled air is a
requirement. However, air conditioning for residential homes, office build-
ings, and automobiles is more of a luxury, although some people in tropical
and semi-tropical climates would still categorize it as a necessity.
30
-------
2. Aerosols
The first application of aerosol packaging with insecticides
resulted in an increase of efficiency of the active ingredient because it
was dispersed as a true aerosol. However, for most products commercially
available today, aerosol packaging is not accompanied by an increase in
efficiency, and therefore, the packaging is more one of convenience than
necessity. Recently, aerosol packaging has come under a great deal of
criticism (see Fritsch e£ _al., 1973 and Crossland, 1974).
Fluorocarbons are used as propellants because of their rela-
tively low degree of acute toxicity, non-flammability, inertness toward the
active ingredients in aerosol products, and appropriate vapor pressures—
i.e., between 15 and 100 psig (Sage, 1963). Table XVI provides a list of
possible alternatives to fluorocarbon propellant use. In most cases, the
compounds are either flammable or do not have an appropriate vapor pressure.
Other compounds such as methyl chloride, methylene chloride,
ethyl chloride, dichloroethylene, and vinyl chloride have been considered as
candidate aerosol propellants (Caujolle, 1964), but are considerably more
toxic than the commonly used fluorocarbons. In fact, vinyl chloride was
shown to cause a rare form of liver cancer and its use in hair sprays and
pesticide products has been eliminated (Crossland, 1974). Thus, if one is
going to use aerosol packaging, the fluorocarbon compounds seem to be the
safest propellant to use. However, exposure to high concentration of
fluorocarbons is not recommended (DuPont, 1969b) and the effects of long-
term exposure to fluorocarbons have not been completely defined (see
Sections XI and XII).
31
-------
Table XVI: Properties of the Hydrocarbon and Nonliquefied Gas Propellents
(Sage, 1963)
U)
NJ
chemical formula
molecular weight
boiling point, °F
freezing point, °F
vapor pressure, psig
70°F
130 °F
liquid density at 68°F,
g/ml
heat of vaporization,
Btu/lb
flammable limit, vol. %
in air
toxicity, UL rating
sys tern
solubility in water at
77°FC
Propane
CH3CH2CH3
44.1
-43.9
-275
110
260
0.5005
183.1
2.3-7.3
5
Isobutane
(CH3)2CHCH3
58.1
13.6
-229
31
96
0.5788
165.6
1.8-8.4
5
n-Butane
CH3(CH2)2CH3
58.1
30.9
-211
16
66
0.5571
157.5
1.6-6.5
5
Carbon
dioxide
C02
44.0
-109a
837
nonf lam
5
0.7
Nitrous
oxide
N20
44.0
-127
720
nonf lam
0.5
Nitrogen Air
N2 N2 + 02
28.0 29
-320
477b
nonf lam nonf lam
*
6 6
0.014 0.017
f±
Sublimes.
At critical point, -233°F.
volume of gas at atmospheric pressure soluble in one volume of water.
-------
IV. CURRENT PRACTICES
A. Special Handling in Use
Because the fluorocarbons are commonly used under pressure, the
possibility of container explosion always exists. For this reason, con-
tainers, especially aerosol containers, should not be exposed to heat.
Both injury and death have been reported from exploding aerosol containers
that were heated (Fritsch et_ al., 1973). ^
Contact with large concentrations of the fluorocarbons should also
be avoided. Over 200 deaths from the abusive use of fluorocarbons (getting
"high") have been reported (Jritsch £t al., 1973). This hazard as well
as some other general hazards and some preventive actions are summarized
in Table XVII.
Table XVII
Potential Hazards of Fluorocarbons
(DuPont 1969a)
Condition
Pocential Hazard
Sal t
Vapors may decompose in flames ur in
contact with hoc surf.'n es.
Vapors are 4 to 5 MmM.a heavier than
air. High concentrations may tend
to accumulate in low places.
Deliberate inhalation to produce
intoxication.
Some fluorocarbon liquids tend to
remove natural oils from the skin.
Lower boiling 1 iquidu may be splashed
on skin.
Liquids may be splashed into eyen.
Contact with highly reactive metals.
Inhalation of t.oxic ducompciRl t ion
products.
Inhal.'U Ion of concent rated vapors
can be fatal.
Can be fatal.
Irritation of dry, oen-sitive skin.
Freezing.
Lower boil Ing 1iqulds may raust1
freezing* HlKher boil ing liquids
may cause temporary irritation nnd
If other chemicals are didsolv.-d,
may cause serious damage.
Violent explosion may occur.
i'.HOCI vt-nr. 1 la l ion. Tux 1 c dccompoai t ion
products KL-rvi' as warning agents.
Avoid misuse.
Kon-ed-air ventilation at the level of
vapor concentration.
Individual breathing devices with air
supply.
Lifelines when entering tanks or
other confined areas.
Do not administer ephinephrine or
other similar drugs.
Cloves and protective clothing.
and protective clothing.
Wear <-ye protection. Get medical
;it t ent ion .' Flush eyes for scvera 1
minutes with running water.
'IVst t-tiL1 proposed aysi ura and take
.-ijjpropr tat e safety precautions.
33
-------
B. Methods of Transport and Storage
The principal factor required for the transport and storage of the
major fluorocarbons is adequate design to meet the elevated pressures.
Interstate Commerce Commission Code gives detailed specifications covering
the major fluorocarbon chemicals and allowable containers for transport
purposes (Du Pont, 1973).
The products are shipped in a wide variety of pressure containers
ranging from 5 gallon drums to 20,000 gallon tank cars. The range of sizes
and types of containers is as follows:
Nonreturnable steel drums - 5 to 55 gallon
Steel and aluminum cylinders - 1 to 2000 pounds
Tank truck trailers - 2000 to 5000 gallons
Tank cars - 6000 to 20,000 gallons j
The containers are fitted with safety valves, rupture discs and
fusible plugs according to ICC specifications, as well as requirements
for labelling and for leak and pressure testing. The loading or filling
limits are also specified for each fluorocarbon in accordance with its
physical properties. Procedures for transferring the products between
storage and transport facilities are well established by fluorocarbon
manufacturers for their own and their customers' operations (Allied Chemical,
1969).
C. Disposal Methods
Disposal of the fluorocarbon products in other than intended purposes
(e.g., disposal from propellant use) results principally from the following:
34
-------
1. Unreclaimed refrigerants in the cooling systems of scrapped
prefabricated type refrigeration and air conditioning units. Disposal of
these old appliances is usually to scrap yards or waste dumps. With this
fate,-the refrigerant eventually escapes to the environment by vaporiza-
tion as a result of corrosion, dismantling or destruction of the units.
2. Products accidentally contaminated in use by customers. When
large refrigerator or air conditioner installations are involved, the
fluorocarbons are sometimes returned to the fluorocarbon manufacturer for
reprocessing, or are purified by the customer by distillation.
Because of the high vapor pressure of all the products at
ambient temperature, eventual disposal from the foregoing, as well as from
accidental leakage, spillage and from all uses where the compounds are not
altered chemically, is to the atmosphere.
i
D. Accident Procedure
Accidental rupture can be almost completely eliminated by pro-
viding appropriate safety valves, rupture discs and fusible plugs. However,
when an accident does occur, the following safety precautions should be
followed to avoid potential hazards from accidental leakage.
1. Because of their high density, fluorocarbon vapors or gases
can accumulate in low confined spaces when accidental releases occur.
Provisions for forced ventilation or for use of individual air hoses are
required to avoid suffocation or cardiac sensitization in otherwise poorly
ventillated areas. Monitoring devices to detect high concentrations should
be provided for checking concentrations before entering unventillated areas.
35
-------
2. To avoid injuries from direct exposure1 to the chemical escaping
from the system, protective clothing, gloves and safety glasses should be
used when repairing leaks. The invisible nature of the escaping gas
necessitates special precautions.
3. Decomposition of the compounds into toxic chemicals (e.g.,
phosgene, HC1, HF) can occur if the leaking chemical contacts heated sur-
0 '
faces, sparks or flames, such as occur during welding. Good ventilation
and monitoring should be provided if exposure to high temperature is likely.
Contact with highly reactive metals should also be avoided as a potentially
explosive condition.
36
-------
V. ENVIRONMENTAL CONTAMINATION
Because of the high volatility and chemical stability of the major
fluorocarbons, these chemicals are likely to be released to and persist
in the atmospheric environment. Korte and Klein (1971) and Iliff (1972)
have briefly discussed the environmental pollution potential from fluoro-
carbons. This section will (1) estimate the quantities lost from pro-
5
duction, transport and storage, use, and disposal; and (2) discuss the
general environmental contamination from fluorocarbons and project future
contamination levels.
A. Contamination from Production
The production processes described in Section II D give very high
yields. Losses are limited to small mechanical leakage, small amounts
leaving with byproduct hydrogen chloride, and miscellaneous venting. The
total material loss is estimated to be, at the most, 1% (McCarthy, 1973)
for the production operations excluding transport and storage. On this
basis, the annual losses of fluorocarbon chemicals to the environment from
manufacturing operations would be considerably less than 10 million Ibs.
at current production rates.
B. Contamination from Transport and Storage
The fluorocarbon products are transported in containers having a
wide range of capacities (see Section IV B). All containers are designed,
tested and labelled according to ICC specifications for pressurized uses.
Similarly, storage tanks both at producers' and customers' plants are
designed and operated to meet established specifications for the pressure .
conditions. Procedures for transferring the products between storage and
transport facilities are well established (Allied Chemical, 1969).
37
-------
Loss of product during transport and storage is relatively minor
as a consequence of the completely closed system that is used. Losses
are further controlled by monitoring discrepancies, if any, between product
billings and receipts. In addition, the high cost of the products provides
an added incentive to control losses. The total industry-wide loss in
transport and storage is judged to be less than 1% of the total quantity
3 •
of the product handled, or a loss of less than 10 million Ibs.
C. Contamination from Use
The major loss of fluorocarbons to the environment is due to their
intentional or unintentional release while they are being used. Estimates
i • . .
of loss from the major uses are derived in the following sections. <
1. Propellants ;
The major loss of fluorocarbon products to the atmosphere
results from aerosol propellant applications. Essentially, all fluoro-
carbons consumed by this application enter the atmosphere. It is judged
that there is a one-year inventory lag and, therefore, at a growth rate of
6%, the current release is 6% less than production. For 1972 (see Table XII),
the loss would be .94 x 529 x 106 Ibs. = 496 x 106 Ibs.
The predominant method of charging of aerosol containers is a
pressure method that is carried out at ambient temperatures. The loss of
propellant, which occurs principally while sealing the container, amounts
to less than 1% (Harmon, 1974). For 1972, this would amount to a loss of
0.1 x 529 x 106 Ibs. = 5.29 x 106 Ibs., a relatively insignificant amount
compared to the loss from the aerosol use.
I
38
-------
2. Refrigerants
Loss of fluorocarbons during use as refrigerants may occur in
the following ways: •
a. charging the refrigerants into the
factory sealed prefabricated-type
units
b. Loss from abandoned, scrapped, or
junked prefabricated-type units
c. Recharging or replacing large commercial
and industrial installations with
refrigerants.
The loss from (a) is estimated to be about the same order as the mechanical
losses at production plants, namely 1%. The demand for prefabricated units
is about 52% of the total refrigerant market (see Table XV) and, therefore,
the loss from (a) is approximately .01 x .52 x 221 x 106 Ibs. = 1.15 x
106 Ibs.
Refrigerants in abandoned prefabricated units (b) eventually
escape as the parts corrode or are destroyed. The average life for these
appliances is at least 10 years, or annually about 10% of the total installed
units are scrapped (ASHRAE, 1972a, b, 1973). The total installed units can
be calculated by assuming that the total demand is equal to the units lost
plus a 6% increase in new units
221 x 106 Ibs. x 0.52 (demand) = 0.06A + .10A (A = total installed units)
. 115 x 106 Ibs. ,,,„ 1fl6 ...
A = .06+ .10 = 72° x 10 lbs' "
Therefore, the amount lost from (b) is 720 x 106 lbs. x .10 = 72 x 106 lbs.
39
-------
The loss from (c) is judged to be annually about 4% of the total
installed units, based on the assumption that the units will be recharged
every 5 years and that 80% of the original refrigerant will be recovered.
Assuming 48% of the total refrigerant market consists of the large commer-
cial units and using similar reasoning to that described above, the total
installed large commercial units can be calculated.
221 x 106 Ibs. x 0.48 (demand) = 0.06A + .04A (A = total installed units)
Therefore, the loss from (c) is .04 x 1060 x 106 Ibs. = 42.4 x 106 Ibs.
3. Solvents
;
It is estimated that the industry-wide efficiency of the i
recovery systems used with fluorocarbon solvents is approximately 80%.
Using an annual growth rate of 6% and a 1972 solvent use quantity of
50 x 106 Ibs., the following loss calculation is possible.
T on [50 x 106 Ibs. 1 „£, c In6 ,,
Loss = .20 ^Q6 + >2Q - J = 38.5 x 106 Ibs.
4. Blowing Agents
As explained in Section III A, the f luorocarbons used as blow-
ing agents are approximately equally divided between open cell and closed
cell applications. Loss from the closed cell foams should be negligible
while 100% of the f luorocarbons used for open cell foams should be immed-
iately lost. Therefore, the loss for 1972 should be >.50 x 89 x 106 Ibs. =•
44.5 x 106 Ibs.
40
-------
5. Plastics
Fluorocarbons used as intermediates for plastic monomers
probably experience some loss during transport and storage and in the
synthesis process. Losses from transport and storage have been considered
previously. The loss during synthesis is considered to be negligible.
D. Contamination from Disposal
The release of fluorocarbons to the environment from disposal is
principally caused by scrapping prefabricated refrigeration and air con-
ditioning equipment. This has been covered in the section on losses from
use.
E. Fluorocarbon Contamination Levels in the Atmosphere
Table XVIII summarizes the fluorocarbon losses for 1972 described
in the previous sections. It appears that a substantial amount of fluoro-
carbons are being released to the environment from use in the U.S. World
losses could quite easily double the quantity released.
The high vapor pressure of the major fluorocarbon compounds at
ambient temperatures (Section I), the high chemical stability and inertness
of the compounds (Section VIII), and the low solubility in aqueous media
suggest that a high fraction of the fluorocarbons that are released will
accumulate and persist in the atmosphere. This suggestion combined with
the fact that sizable quantities of fluorocarbons are being released has
prompted a number of monitoring studies, the results of which have been
reviewed in Section VII B and are summarized in Table XXI of that section.
41
-------
Table XVIII: Fluorocarbons Released to the Environment in 1972 from U.S. Applications
Losses From (106 Ibs.)
Fluorocarbon
11 CC13F
12 CC12F2
22 CHC1F2
113 CC1F2CFC12
114 CC1F2CC1F2
Production
3
4
.8
Transport
& Storage
3
4
.8
-.5 j -.5
!
-.2 ;. -.2
Uses
Propellants
231
247
.
18
1 i
r • • • .
Refrigerants
-4
-67
-41
-3
Solvents
38.5
Foaming
Agents
22.5
22
Total
263.5
344.0
42
40
22
Total
496
115
38.5
44.5
711
-------
In this section the extent that the concentrations of fluorocarbon
chemicals may increase in the atmosphere during the next 50 years has been
projected. In doing this, information on production and use (sections II
and III), monitoring data (Section III B), and information on the atmos-
pheric stability of the fluorocarbons (Section X) has been utilized. The
projections are based upon the following assumptions:
1. The 1972 annual U.S. production for the several commercial
fluorocarbons is approximately as follows: (see Table XII)
106 Ibs.
Fluorocarbon 11 300
12 , 440
22 80
113 50
114 20
115 & 13B1 10
Total 900
2. Distribution by uses are approximately as follows (Table XII
combined with Table XV):
Percentage
Fluorocarbon
11
12
22
113
114
115
13B1
Aerosol
82
60
95
10
Refrigeration
Prefab.
Units
15.5
57
Large
Commercial
Units
3
14.5
43
5
90
5
Foaming
Agent
15
10
Solvent
100
Fire
Extinguishing
Agent
95
43
-------
3. Annual growth of each compound has been taken uniformly at
6%. Although the past growth rate has been about 8-10% (8.5% per year
for 1962-1972, Chemical Marketing Reporter, 1973), there are indications
that the rate is slowing in the U.S.
4. The world consumption has been projected at double the U.S.
production. Although the ratio has been less up to the present, it in-
creased from 1.58 in 1968 to 1.75 in 1972 for aerosol use (see Table XIV).
5. Because of the uncertain data on the persistence or residence
time of each of the compounds (see Section X) , the projections have been
estimated only for an infinite residence time in order to give an upper
limit value for the concentration.
6. The rate of release of each compound, depends upon the use as
developed in the preceding sections. These release factors are(J summarized
as follows:
PropellantK = immediate except for approximately one year lag
due to inventory.
Refrigerants = total loss after 10 years for prefabricated units;
42
for large commercial units the loss is -r^r = 40% of
the total production used in that application (see
Section V, C, 2 annual loss calculation for 1972) .
Foaming Agents = 50% is lost immediately (open cell foams); 5.0% is
never lost (closed cell foams) .
38 5
Solvents = — =•=— or 77% of the new production is lost immediately
(see Section V, C, 2 for the annual loss calculation
for 1972).
44
-------
For example, if the total production of fluorocarbon 12 was 100 x 106 Ibs.,
the amount lost immediately would be:
100 x 106 Ibs. x [0.60 + ^|£ + (0.145) (0.40)]= 100 x 106 Ibs. X 0.708
amount half of amount amount
used amount used for lost
for used for large from
aerosols foams commercial large
refrigeration commercial
refrigeration
and ten years later
100 x 106 Ibs. x .155
would be lost from prefabricated refrigeration units (see Table XIX for
the calculation of fluorocarbon 12).
7. The volume of the global troposphere is assumed to be 1.8 x 1020
ft.3 (5.09 x 1021+ ml), based on an average altitude of the troposphere of
30,000 to 35,000 feet, or near the lower limit of the reported range of
25,000-60,000 feet (Van Nostrand's Scientific Encyclopedia). The surface
area of the planet was taken as 200 x 106 square miles. The selected height
of the troposphere was used in order that the projected results will tend
to be conservatively high. The concentration is calculated on a volume/
volume basis at standard temperature and pressure.
For the U.S. concentration, the global volume is divided by 4:
453.6 gms 1 mole 22,400 ml
Concentration in U.S. CCl2F2 = Ibs. released X 1 Ib. x 121 gm 1 mole
5.09 x
4
Ibs. released x 6.61 x 10~20
For the global concentration the quantity released is doubled and the total
global volume is used.
45
-------
Table XIX presents the calculations and projected concentra-
tions for fluorocarbon-12. The results of calculations for fluorocarbons
11, 12 and 22, the major commercial products, are depicted in Figure 6.
It is felt that these projections are reasonable since the calculated values
correspond well with available monitoring data. For example, the calculated
average global concentration for CClsF is 66 ppt. Lovelock £t al. (1973)
has reported an average concentration of 48 ppt over the Atlantic Ocean.
Much higher values were observed (60-80 ppt) in the Northern Hemisphere.
The concentration of 97 ppt reported by Su and Goldberg (1973) for CC13F
in an air sample taken from a desert corresponds well with the calculated
U.S. background level of 133 ppt. The slightly higher calculated value may
be attributed to the deliberate choice of factors (e.g., atmospheric:
volume, infinite stability) to project the upper limits of concentration.
However, the calculated values do conflict with the CCl2F2 concentration of
700 ppt measured by Su and Goldberg (1973) in the desert 100 km northeast
of San Diego. We find it hard to believe that the 700 ppt concentration
is a background level, especially when this is the average concentration
for CC12F2 observed by Hester e± al.(1973) in the Los Angeles basin and
our upper limit calculated value is 133 ppt for the U.S.
Su and Goldberg (1973) have suggested that a longer residence
time can explain the higher levels of fluorocarbon 12 than, fluorocarbon 11.
We have calculated some concentrations using residence times of 10 years
for CC12F2(Lovelock et al., 1973) and 30 years for CC13F (Su and Goldberg,
1973). These residence times have almost no effect on 1972 concentrations
although they have some effect on future projections and, therefore, they do
not explain the discrepancy.
46
-------
Table XIX: Estimation of Average Concentrations
of Fluorocarbori 12 in the Atmosphere
Year
1952
1957
1962
1967
1972
1977
1982
1987
1992
1997
2002
2007
2012
2017
2022
Annual
Production
Rate in U.S.
106 Ibs.
50
100
208
310
439
590
790
1055
1400
1890
2580 '
3400
4550
6100
8200
Total
Consumed
During
5-year
Period
106 Ibs.
200
300
750
1,200
1,750
2,480
3,320
4,450
5,950
7,900
10,700
14,300
19,200
25,500
34,000
Total
Consumed
to Date
in U.S.
106 Ibs.
200
500
1,250
2,450
4,200
6,680
10,000
14,450
20,400
28,300
39,000
53,300
72,500
98,000
132,000
Accumulated Quantity
Released to Atmosphere
in U.S. (106 Ibs.)
Immediate
0.708 xfT)
0
142
212
354
531
885
850
1,735
1.240
2,975
1.755
4,730
2.350
7,080
3.150
10,230
4,212
14,442
5.593
20,035
7.575
27,610
10.124
37,734
13.594
51,328
18.054
69,382
24.072
93,454
After 10 vears
.155 x(7)
10 years before
-
—
31
46
77
116
193
186
379
271
650
384
1,034
515
1,549
690
2,239
922
3,161
1.224
4,385
1.658
6,043
2.216
8,259
2.976
11.235
Total in
Atmosphere
no
degradation
142
354
916
1,812
3,168
5,109
7,730
11,264
15,991
22,274
30,771
42,119
57,371
77,641
104,689
Concentration
in Parts Per Trillion
(10-12) by volume
U.S.
Atmosphere
©
9
23
61
120
209
337
511
745
1057
1472
2034
2784
3792
5132
6920
Global
Atmosphere
©
5
12
30
104
168
254
371
526
733
o
1012
1385
1887
2554
3444
-------
0 FLUOROCARBON 11, C CI3 F
• FLUOROCARBON 12, C CU F,
* FLUOROCARBON 22, CH Cl f.
}
HIGHER VALUE UNITED STATES
AVERAGE CONCENTRATION
LOWER VALUE GLOBAL
AVERAGE CONCENTRATION
5000-
4000--
3000- -
to
(N
o
oc
2000- -
1000- -
1952 1962
1972 1982 1992
YEARS
2002
2012
2022
Figure 6 Projections of Average Global and U.S.
Atmosphere Concentration of Fluorocarbons
11, 12, and 22
48
-------
The calculated values are only averages and, therefore, regional
fluctuations can be expected. By comparing the variations in 1972-3 moni-
toring data, it is expected that highly populated centers may have average
concentrations 10-15 times the global concentrations (e.g., CClaF - global
48 ppt - highest average value measured 650 ppt, Hester e£ a^., 1973). In
addition, for short periods of time, concentrations several thousand times
the background levels may be observed. Thus, in the year 2000, the average
concentration in urban areas of fluorocarbon 11 would be approximately 10 ppb
with high fluctuations to possibly 10 ppm.
-------
VI. CONTROL TECHNOLOGY
A. Currently Used
Control technology associated with production, storage, and trans-
port takes the form of preventive maintenance and monitoring for leaks.
The industry applies these controls for its own economic benefit. By
1 controlling temperature and pressure a minimum of loss is possible. The
monitoring devices can vary from the simplest and oldest technique of
using a soap solution to a more sophisticated approach using flame ioni-
zation or electron capture techniques.
Loss from use is the major source of fluorocarbon contamination.
The major loss is from aerosol propellants and, by its very nature,
recovery is impossible. When large quantities of fluorocarbons are used
in one place such as in large commercial refrigeration applications 'or
solvent uses, considerable amounts of the materials are recovered by
condensation and redistillation. For example, cooling coilings were used
to recover solvent loss from a degreaslng plant (Greve, 1971). Efficiencies
of recovery are kept as high as possible because of the high price of the
materials involved.
B. Under Development
No new control technology is under development.
50
-------
VII. MONITORING AND ANALYSIS
A. Analytical Methods and Sensitivity
Development of analytical techniques for determining fluorocarbons
in trace amounts was first undertaken in order to allow the use of fluoro-
carbons as a tracer of atmospheric dispersion. Schultz (1957) found that
dichlorodifluoromethane was a promising tracer chemical. He used a modified
ionization-type leak detector which was sensitive to a concentration of
approximately 1 ppm; however he was plagued by non-reproducibility (Collins
e£ al., 1965) .
Marcali and Linch (1966) reported a colorimetric method for per-
fluoroisobutylene and hexafluoropropene in air samples capable of detecting
these compounds at 0.1 ppm and 0.02 ppm, respectively. The method is based
on a chemical reaction between the fluorocarbon and pyridine and piperidine
in methanol (collection solvent) due to the unsaturated system (X-C=dCF2, X =
halogen) and, therefore, is only good for unsaturated fluorocarbons.
McFee and Bechtold (1971) studied a combined pyrolyzer-microcoulomb
detector system as a continuous monitoring system. The limits of detection
for trichlorotrifluoroethane and tetrachlorodifluoroethane were 0.3 ppm and
0.9 ppm, respectively. The authors suggested that this instrument would be
useful for testing air cleaning systems and for measuring toxicants with low
threshold limit values.
Shargel and Koss (1972) used a gas chromatographic method with
e
electron-capture detection for determining chlorofluorocarbons in dog blood.
The method used a hexane extraction and the lower limits of quantification
51
-------
were 3.3, 10, 40, and 80 yg/1 of blood for trichlorofluorometliane, dichloro-
difluoromethane, trichlorotrifluoroethane, and dichlorotetrafluoroethane,
respectively.
Collins and Utley (1972) studied the possible use of mass spectrometry
for detection and identification of organic pollutants in the atmosphere. They
used a silicone rubber membrane direct inlet system (similar to GC-MS inter-
faces) which allowed 1000 fold increases in minor components of air. With
!
this system, they could detect trichlorotrifluoroethane at 0.1 ppm.
Two techniques have been used to detect fluorocarbons in air at
ppb to ppt (10~9 - 10~12) concentration ranges; (1) direct analysis of
air-fluorocarbon mixtures with gas chromatography with an electron-capture
detector (GC-EC), and (2) sampling tube concentration with gas chromatography
and flame ionization detection (GC-FI). Collins ejt ail. (1965) used the GC-EC
technique to study the use of sulphur hexafluoride and dichlorodifluoro-
methane as gas air tracers. They found the sensitivity for dichlorodifluoro-
methane to be only in the 50 to 100 ppb range. Saltzman et^ _al. (1966) used
a similar GC-EC system with bromotrifluoromethane and octafluorocyclobutane.
A sensitivity of about 0.3 ppb was achieved without concentrating the sample.
Gelbicova-Ruzickova et al. (1972) developed a method for determining
minute quantities of halothane (2-chloro-2-bromo-l,l,l-trifluoroethane) in
the air of operating theaters. They used a porous polymer packing (Porapak
P and Q) in a sampling tube to preconcentrate the sample. Detection was
carried out with a flame ionization detector (GC-FI). Concentrations down
to 10 ppb could be determined. These authors referenced a report that noted
a low stability of the electron capture detector if the electrodes are con-
taminated by large amounts of water vapor and oxygen. However, Lovelock and
52
-------
coworkers (Lovelock, 1971, 1972; Lovelock
-------
TABLE XX
Electron-Capture Detector Response to Various Fluorinated Compounds
(Clemens and Altshuller, 1966)
Compound
SF6
CFC13
(CF3)2C=CF2
C1F2C-CFC12
CF2CF2CF2CF2
CF3Br
CF2C12
C1F2CCF2C1
CF2=CC12
CHFC12
CF3CF2C1
CF2-CFC1
CF3C1
CHF2C1
r.F
Fluorocarbon #
11
1218
113
C318
13B1
12
114
1112
21
115
1113
13
22
1A
Response Response
(sq.in. ppm) Flame-ionization
(sq.in. ppm)
(all compounds)
r r\r\
370
90
50
30-40
12-40
9
2
i
0.2 0.1-1.0
5 x ID"2
5 x 10-2
3 x 10~2
1 x KT3
3 x 10~3
•^ v in"1*
54
-------
wind was blowing from the west (Atlantic Ocean) both the CC13F concentration
(10 ppb by volume) and the turbidity were less than when the wind came from
the European continent (CClsF concentration 190 ppb). Lovelock (1972)
reported similar, but more detailed results of monitoring data in Ireland.
When the wind was blowing from the west the average concentration was about
50 ppt; when from the east, 100 ppt. In 1973, Lovelock and coworkers (1973)
monitored CC^F above the Atlantic Ocean in both the Northern and Southern
Hemisphere. A global mean concentration of 48 ppt was reported, with a high
in the Northern Hemisphere of 78 ppt and a low in the Southern Hemisphere
of 38 ppt. Concentrations in the sea water ranged from 20-70 ppt.
Su and Goldberg (1973) monitored ambient levels of both CClaF and
CC12F2. In La Jolla and San Diego, California, they found averages of
370 ± 560 ppt and 290 ± 249 ppt for CClsF and averages of 5800 ± 4600 ppt
and 3200 ± 1400 ppt for CC12F2, respectively. In a desert 100 km north-east
of San Diego, they reported 97 ppt and 700 ppt for CC13F and CC12F2, respec-
tively.
Hester ejt al. (1973) monitored CCl^F and CC^Fj in ambient air
samples and in air samples from homes in the greater Los Angeles basin. In
ambient air samples the average readings were 560 ppt for CCl^F and 700 ppt
for CC12F2, but the concentrations varied by more than a factor of ten.
For each sample, the ratio of CC13F/CC12F2 was compared. If the changes in
concentration were due only to dilution, the ratio should be fairly constant.
However, the ratios varied as much as the concentrations. The average ratio
of CCl2F2/CCl3F (1.29) corresponded to a weight ratio of 1/1 gram CC12F2 to
1 gram of CClaF. The effects of altitude clearly showed that the
55
-------
fluorocarbons were trapped by an inversion layer (above inversion CC13F ^ 80 ppt;
CCl2F2= <100 ppt) as were the visable pollutants. Concentrations of fluoro-
carbons near a cosmetic plant were only 3-4 fold over typical ambient levels
suggesting that the loss suffered in filling aerosol cans is small. Monitoring
near a polyurethane plant showed similar low results suggesting small losses
'from closed-cell foaming operations. The levels of both fluorocarbons 11 and
12 in homes, are, on the average higher than the typical ambient air samples.
In some cases, the concentrations were several thousand times higher (CC^F
range 220-1200 ppt; CC^Fa range 300-510,000 ppt).
Simmonds jet al. (1974) also monitored CCl^F in the Los Angeles basin.
They reported an average level of 650 ppt and a lower concentration of 110 ppt
when the wind was blowing in from the Pacific. The highest concentration
for CClsF was observed at 8 a.m., which the authors suggest is due to the
early morning use of aerosol propellants. In a few measurements of CC12F2
the authors found similar variations in concentration with time, again
suggestive of aerosol dispensers as the source (many aerosols used a propellant
mixture of 50:50 CC13F/CC12F2). Above an inversion, the authors found a
concentration of 260 ppt.
The above monitoring data is summarized in Table XXI.
56
-------
Table XXI. Fluorocarbon Concentrations
in the Atmosphere
(ppt, 10~12, by volume)
Reference
Lovelock,
1971 (CC13F)
Lovelock,
1972 (CC13F)
Lovelock et al,
1973 (CC13F)
Su & Goldberg,
1973 (CC13F)
(CC12F2)
Hester et al.
1973 (CC13F)
(CC12F2)
Simmonds
et al., 1974
(CC13F)
Above
the
Ocean
Above
Land
Wind
from
Ocean
10
50
48 (aver)
78 high
38 low
110
Above
Land
Rural
190
100
Above
Land
Urban
aver.
370 ± 560
aver.
290 ±240
Aver. 5800
± 4600
Aver. 3200
± 1400
Aver. 560
Aver. 700
Aver. 650
Above
Land
Desert
97
700
In Homes
220-
12,000
300 -
510,000
Above
an
Inversion
^80
<100
260
57
-------
VIII. CHEMISTRY
A. Reactions Involved in Use
With the exception of their use as chemical intermediates, the
fluorocarbon compounds being reviewed find applications due to their
chemical stability rather than chemical reactivity. This chemical
stability is a result of the strength of the C-F bond and the increase
in the bond energy of the C-C1 bond as the fluorine substitution in-
creases. This is illustrated in Table XXII.
Table XXII: Bond Energies of Chlorofluorocarbons
(Kcal/mole)(Bower, 1973)
Compound C-C C-Cl C-F
CClij - 69 -
CC13F - 74 99
CC12F2 - 81 107
CClFa - 85 114
C?n - . 122
C2C16 63 68
C2C15F 67 69 97
73
C2ClkF2 72 74 99
C2C13F3 77 75 106
79
C2C12F4 83 80 100
108
C2C1F5 88 81 109
115
C2F6 94 - 116
The hydrolytic and thermal stability, which will be discussed in the
following sections, closely parallels these bond energies.
58
-------
Although quite inert, the fluorocarbons do exhibit some chemical
reactivity in various applications. Corrosion of aerosol cans due to the
decomposition of the propellants is commonly studied. For example, tri-
chlorofluoromethane is considered unsuitable for water-based products
packaged in metal containers since some metals may catalyze the hydrolysis
of trichlorofluoromethane with liberation of acid. Sanders (1960) has
demonstrated a free-radical reaction between trichlorofluoromethane and
alcohols resulting in dichlorombnofluoromethane and small amounts of
tetrachlorodifluoroethane. The reaction is inhibited by high concentra-
tions of oxygen and, therefore, it is not likely that it will occur in
nature. Similar corrosion studies of fluorocarbons 11 and 12 in aerosol
cans have been reported (Bohac, 1968; Minford, 1964).
Most common construction metals can be used with the fluoro-
carbons at normal temperatures although at elevated temperatures they may
act as catalysts for the breakdown of compounds. The general order of
thermal reactivity with metals is: Least decomposition - Inconol
< 18-8 stainless steel < nickel < 1340 steel ' aluminum < copper < bronze
< brass < silver - Most decomposition. The order of reactivity may vary
somewhat with individual compounds. Magnesium alloys and aluminum con-
taining more than 2 percent magnesium are not recommended for use with
the fluorocarbons where water may be present (DuPont, 1969a).
Some of the fluorocarbons under review are used to synthesize
ethylene monomers which are used in the synthesis of fluorocarbon resins
and elastomers. The most important process commercially is the pyrolytic
dimerization of chlorodifluoromethane to form tetrafluoroethylene;
500 - 1000°C
2CHC1F2 — ' * CF2 • CF2 + 2HC.L.
59
-------
The perhalogenated ethanes can be dehalogenated by zinc (also
magnesium and aluminum) in the presence of polar solvents:
CC12F - CC1F2 — — — > CC1F = CF2 + ZnCl2
Alcohol
B. Hydrolysis ,
The hydrolysis of the fluorocarbons has received a great deal of
study due to its economic importance in the Hydrate Process for desalina-
tion (Colten e_t al. , 1972; Stepakoff and Modica, 1973; Johnson et al. ,
1972). The hydrolysis reaction is considered to be a first order reaction
with the rate determining step being the slow ionization of the fluoro-
carbon to a carbonium ion and halide ion followed by a faster reaction of
the carbonium ion with water (Johnson e_t £]L . , 1972), as depicted for
fluorocarbon 31 in Figure 7.
CH2C1F -- — > CH2?+ + Cl~ (slow)
CH2F+ + H20 2 > CH2FOH + H+ (fast)
CH2FOH — ^-jf HCHO + HF (faster than 1)
Figure 7: Hydrolysis Mechanism of Fluorocarbon 31
(Johnson e* al. , 1972)
The carbon-chlorine bond is probably the first bond broken in the hydrolysis.
Experiments with l-chloro-3-fluoropropane indicate the rate of hydrolysis
of the carbon-chlorine bond is 100 times faster than the carbon-fluorine
bond (Bower, 1973).
60
-------
The fluorocarbons as a group exhibit a low rate of hydrolysis in
comparison to other halogenated compounds. Table XXIII presents some rates
of hydrolysis in water. When water alone is used, the rate is too low to
t
be determined by the analytical method. Johnson and coworkers (1972) have .
reported a half-life of 1.2 x 106 hr at 1 atm and 25°C for the hydrolysis
of fluorocarbon 114 based on the first order model. The rate of hydrolysis
H
Table XXIII: Hydrolysis Rate in Water17
Grams/(liter of Water)(year)
(DuPont, 1969, no date b)
Compound
CH3C1
CH2C12
"Freon" 113
"Freon" 11
"Freon" 12
"Freon" 21
"Freon" 114
"Freon" 22
"Freon" 502
1 atm Pressure
86°F
Water Alone
*
*
<0,005
<0.005
<0.005
<0.01
<0.005
<0.01
<0.01t
With Steel
*
*
ca. 50**
ca. 10**
0.8
5.2
1.4
0.1
<0.1t
Saturation
Pressure
122°F
With Steel
110 '
55
40
28
10
9
3
*
1% Na2C03
Solution
0.12
0.04
0.01
0.6***
10% NaOH
Solution
100
40
3
955***
//Grams of refrigerant hydrolyzed per liter of solution saturated with gas
*Not Measured
**0bserved rates vary
***grams/liter/day
tEstimated
is greatly affected by temperature and pressure and the presence of other
materials. For example, metals have a tendency to catalyze the hydrolysis
61
-------
reaction. The pH of the water also has an effect on the rate of hydrolr-
ysis of fluorocarbons containing hydrogen (e.g., fluorocarbon 22).
Under alkaline conditions, these compounds tend to hydrolyze more rapidly
than under neutral or acidic conditions. The results depicted in Table
XXIII generally indicate the retarding effect of fluorine substitution on
the hydrolysis rate. ' This has also been demonstrated on a series of
chloromethanes (CH3C1, CH2FC1, CHF2C1) by Boggs and Mosher (1960).
On theoretical grounds (bond strength of C-Br bond), bromotri-
fluoromethane should hydrolyze more rapidly than the chlorofluorocarbons.
However, Saltzman e_t^ al. (1966) found no detectable loss of the compound
in moist air mixtures which were aged for several days, but this may be
attributed to the lack of sensitivity of the technique used.
C. Oxidation
The fluorocarbon compounds are highly resistant to attack by
conventional oxidizing agents at temperatures below 200°C (Bower, 1973;
Downing, 1966). At elevated temperatures, air contamination can increase
the decomposition rates by 300 percent or more (Callighan, 1971).
D. Thermal Stability
In general, the fluorocarbons exhibit a high degree of thermal
stability. As noted earlier, the degree of stability is dependent upon
the degree of fluorine substitution (see discussion on bond energies in
section VIII A). The stability of the compounds is dependent upon the
test conditions used and the materials to which the compound is exposed.
62
-------
Table XXIV: Thermal Stability of Fluorocarbon Compounds
(DuPoht, 1969a)
Compound
11
113
12
114
22
502
13
Formula
CCljF
CC12F-CC1F2
CCljK2
CC1F2-CC1F2
CHC1F2
CHC1F2/CC1F2CF3
CC1F3
Maximum
Temperature for Continuous
Exposure In the Presence of
Oil, Steel and Copper,
°F
225
225
250
250
300
300
>300
Di.'compusl t i on
Rate at 400°F in Stet.1,
Per Cent/Year
2
6
<1
1
*
*
*
Temperature for
First Trace of Decomposition
In Quartz, °F
840
570
1000
*
»
550
*
if
*Not measured
Table XXIV presents some thermal stability data. The recommended
maximum temperatures are based on laboratory tests, but have been in sub-
stantial agreement with field experience. The decomposition rates are
determined from six-day exposures.
Callighan (1971) has reviewed the available thermal stability data
on fluorocarbons 11, 12, 22, 113, 114, and 116 and converted the various
test results into "standard" percent per year values. The results can vary
considerably depending upon the contaminants (e.g., water and air), exposure
time, and whether the experiment was run long enough to reach a steady state.
With this in mind, the following approximate decomposition rates were tabulated.
63
-------
Table XXV: Decomposition Values of Fluorocarbons at 400°F
(Callighan, 1971)
Percent Per Year in Presence of
Fluorocarbon
.114
113
11
22
12
Fe Only Fe + Cu -I- Al + oil (naphthenic)
Lower Upper Lower Upper
Limit Limit Limit Limit
0.055 1.0 9 22
0.2 6 700 710,000
2.0 60 too high to estimate
0.1 9.0 0.35 9
0.3 1.0 3500 7*100,000
stability rank
highest
lowest
114
22
113
12
11
114
12
113
22
11
22
114
113
12
11
22
114
113
12
11
64
-------
In general, these results agree well with the fluorine substitution pattern.
The pyrolysis products usually include hydrofluoric and hydrochloric acid
and, if a source of water or oxygen is available, a small amount of phosgene.
Thermal dehydrohalogenation can occur with appropriate chlorofluoroethanes
to yield substituted ethylenes (Hyskins et_ al.*, 1951).
E. Photochemistry
o
Sandorfy and coworkers (Doucet et^ ail., 1973)' have7examined the vacuum
ultraviolet spectra of a series of methane fluorocarbons (13, 13B1, 22, 31,
21, 12 and 11) and have observed ho absorption above 200 nm for the chloro-
fluorocarbons. They have also completed studies with the ethane series
(fluorocarbon 113, 114 and 115) and these also exhibit no absorption above
200 nm (Doucet e_£ al., 1974). Since the wavelength of sunlight at altitudes
below approximately 50 kilometers falls above 280 nm, there is no mechanism
for direct photoalteration of these chemicals in the lower atmosphere.
Experimental results under atmospheric conditions uphold this postulated lack
of photochemical reactivity. Japar et al. (1974) found no evidence of reaction
with fluorocarbons 11, 12, 22, 113, 114, 115 during irradiations (X>310 nm)
of mixtures of the fluorocarbons with olefins and nitrogen oxides in a long
path infrared cell reaction vessel. Hester e_t^ al. (1973) placed fluorocarbons
11 and 12 in ambient air samples and photolyzed them in a 20 liter pyrex car-
boy with 11 blacklight fluorescent lights for a period of almost 2 months.
No change was detected. Also, Saltzman et__al. (1966) found no photochemical
reactivity for bromotrifluoromethane (13B1) from irradiation with fluorescent
black lights.
65
-------
Photolysis of the fluorocarbons at altitudes above 50 kilometers,
where the high energy sunlight is not filtered out by the ozone layer, may
be a major decomposition route for the removal of the fluorocarbons from the
atmosphere. Doucet «*£ aJ^. (1973) suggests that the photochemical reactivity
*•
at these high energies should increase in the series CF3C1 -> CF2HC1 ->• CFH2C1
-*• CHsCl and the same is expected when the number of chlorine atoms is increased
or a chlorine is replaced with a bromine.
F. Other Chemical Reactions
The carbon-fluorine bond is extremely resistant to almost all chemical
reagents. Reduction with hydrogen does not occur until above 830°C and often
the C-C bond is also cleaved
C6F12 + H2 >8306C> CF2H2
Strong reducing agents such as lithium aluminum hydride will reduce other
halogens but not the C-F bond
CF2 - CFC1 _,..„ CF2-CFH
CF2 — CFC1 CFj-CFH
*
In contrast, trlfluoromethyliodide will undergo a free radical type reduction
simply in the presence of a hydrogen donor (Bower, 1973).
CF3I + C6H11+ - * CF3H + C6H13I
The fully halogenated chlorof luorocarbons are inert to halogenation,
but unsaturated compounds and the compounds containing a hydrogen will add
or substitute a halogen relatively easily (Bower, 1973) .
CF2 - CF2 + Br2 - >• CF2Br-CF2Br
CF3H + Br2 - »• CF3Br + HBr
The fluorocarbons also will react violently with alkali and alkaline
earth metals such as sodium, potassium, and barium.
66
-------
IX. BIOLOGY
A. Absorption/Elimination
Under normal conditions, the fluorocarbon propellants, solvents, and
fire extinguishing agents have three routes of entry into terrestrial verte-
brates: inhalation, ingestion, and dermal absorption. However, because of
the physical properties and uses of these compounds, inhalation is by far
the most common route of entry and elimination.
Many of these fluorocarbons have been extensively tested on both
standard laboratory mammals and man to determine their absorption and
elimination patterns during and after exposure. Generally, two types of
exposure have been used: inhalation of air containing a known concentration
of fluorocarbons (usually expressed as per cent by volume) and
direct inhalation of propellants from bronchodilator-type nebulizers
(usually expressed as mg. of fluorocarbon inhaled). For the most part, two
techniques have been used for determining fluorocarbon retention: measurement
of fluorocarbon blood levels and measurement of fluorocarbons in expired air.
Of these techniques, blood levels have been the more used because, in dealing
with fluorocarbon exposure, it is often desirable to know or be able to
predict the blood levels which will be reached under a given set of conditions
e.g. concentration, duration, activity, species, etc. However, the amount
and rate of any gas absorbed and/or eliminated during respiration will depend
on a variety of factors such as the physical and chemical properties of the
gas, concentration of the gas in inspired air, the breathing patterns of the
animal, the size and surface characteristics of the absorbing surface, and
the characteristics of the absorbing elements (e.g. blood cells and plasma).
67
-------
Consequently, blood levels of a gas under similar conditions of exposure may
vary with the species, individuals in the species, and a given individual at
differen^t activity levels. Further, absorption and elimination are dynamic
processes involving equilibria states between the ambient air and blood,
between the blood and body tissues, and between the various body tissues
themselves. Thus, fluorocarbon absorption data are often given as peak
blood levels for a given concentration x time exposure. For those
concerned with long term exposures, these values are most instructive when
equilibria is reached. Elimination data is similarly given as half-life,
time to total or partial elimination, or percent elimination at a given time
measured either as blood levels or percent eliminated in expired air.
Although the various types of information available on fluorocarbon
absorption are not contradictory, they are nonetheless difficult to
i
compare, either because of the units in which they are expressed or the!
experimental conditions under which they are obtained. Therefore, three
types of information will be considered separately: 1) information derived
on fluorocarbon retention from concentrations in expired air; 2) fluorocarbon
blood levels after inhalation from nebulizer apparatus; and 3) fluorocarbon
blood levels after inhalation of fluorocarbon-containing ambient air.
1. Fluorocarbons in Expired Air
The relative amounts of fluorocarbons F-ll, F-12, F-113, and F-114
absorbed by manhavebeen measured in breath holding experiments (Morgan
et_ al., 1972). Such experiments involve having the subject inhale a known
•JQ
concentration of a Cl-labelled fluorocarbon, then measuring the activity
in alveolar air after varying periods of breath holding. The results are
given in Figure 8.
68
-------
-2«o
r- «WO
5 80
t 70
S 60
7
6 so
u
;,' 4O
—
§ 3O
u.
0
* 20
UJ
U
IT
U
o.
cr 10
< *
u
< 7
-J 6
O
u 5
= 3
7.
O
5 2
cr
t-
z
u
Z
O I
U 'C
r \
\ \
" \ \
\ \
\ \
\ *\
\ ^»
\ \
V N. '
\ \^- •
: \ > :
. • •
*
1 F LUO-^OC All bott 12 ' 1
1 ~ "f L U O W O C A H 1>O II "i i'3 1 + j
F LUOROC AM [iON II j o I
1, 1,1,- TRICHLOROETHANT I • "1
1, 1,2 - TRICHLOROETHANE | 4 j
i i . i i i
) IO ?O 3O 4O 5O 6
BREATH HOLDIHC TIME (SECONDS)
Figure 8: Concentrations of Some Halogenated Hydrocarbons
in the Alveolar Air of Man after Varying Periods
of Breath-holding (Morgan et al., 1972)
Reprinted with permission from A. Morgan,
Copyright 1972, Pergamon Press.
Qualitatively, these results agree well with other information on the amount
of fluorocarbons absorbed by the blood indicating the following order:
F-11>F-113>F-114~F-12. As pointed out by the various Investigators refer-
enced in Table XXVI, this order agrees well with the blood/gas partition
coefficients for these compounds in blood, blood serum, and olive oil.
Table XXVI: Partition Coefficients of Various Fluorocarbons
Compound
F-ll
F-12
F-113
F-114
Whole blood
(rat)1
1.4
0.2
Whole blood
(man) 2
0.87
0.15
0.15
Blood serum
(man) 3
0.9
0.2
0.8
0.2
Olive Oil3
27
3
32
5
1 Allen and Hanburys Ltd., 1971
2 Chiou and Niazi, 1973
3 Morgan et al., 1972
-------
The values for olive oil compare reasonably well enough to those of blood
so that they might be indicative of blood/gas partition coefficients for
fluorocarbons. Halothane (l-bromo-l-chloro-2,2,2-trifluoroethane), a potent
anesthetic, has a partition coefficient in human blood of 2.3 (Larson, 1962).
The blood gas partition coefficients for 1,1,1-trichloroethane and
1,1,2-trichloroethane (see Figure 8) are 7 and 56 respectively, indicating
that correlation of blood/gas partition coefficient to absorption may hold
for all volatile halocarbons. When exposure is terminated and equilibria
forces are reversed, the more readily absorbed compounds are retained
longer. This is demonstrated in Figure 9 for F-ll and F-12.
T)
-------
The inverse relationship between ease of elimination and absorption is further
illustrated by data on percent retention after 30 minutes and the number of
respiratory cycles to total elimination as given in Table XXVII.
Table XXVII. Elimination of Fluorocarbons
as Measured in Expired Air
Fluorocarbon % Retained after Number of Respiratqry
30 Minutes1 Cycles to 100%
Mean (S.D.) Elimination2
F-ll ' 23.0 ± 2.2 127
F-12 10.3 ± 2.2 41
F-113 19.8 ±0.9 -
F-114 12.3 ± 4.1 39
1 Morgan et al., 1972
2 Paulet and Chevrier, 1969
Additional data by Faulet and coworkers (1969) indicate that the differences
between F-12 and F-114 are insignificant. Thus, the retention of fluorocarbons
after inhalation follows the same order as the amount absorbed during
exposure: F-11>F-113>F-114=F-12.
The above exposures, while useful in determining relative rates of
absorption and elimination, are obtained over relatively short periods
of time and offer little information on long term exposure. Reinhardt and
coworkers (1971b) have conducted retention experiments on F-113 in man over
occupationally relevant periods. They measured the retention of F-113 as
indicated by fluorocarbon concentration in expired air from human volunteers
exposed to 0.05% and 0.1% F-113. Exposure periods were three hours in the
71
-------
morning and three hours in the afternoon. Breath samples were taken before
the morning exposure (A.M. data) and after the afternoon exposure (P.M. data).
The results are given in Table XXVIII.
Table XXVIII. Concentration of F-113 in Alveolar Air (ppm) After
Exposure to 0.05%'and 0.1% F-113
(Reinhardt et al., 1971b).
Subject
I
II
III
IV
Day of
Week
M
T
W
T
F
M
T
W
T
F
M
T
W
T
F
M
T
W
T
F
500
a.m.
< 1
< 1
< 1
< 1
< 1
< 1
< 1
2.0
< 1
< 1
< 1
< 1
1.5
< 1
3.0
< 1
< 1
< 1
1.0
< 1
Exposure
ppm
p.m.
60
65
59
57
51
61
56
51
49
55
45
27
18
18
31
47
44
35
35
41
1000
a.m.
< 1
< 1
2.0
1.5
1.5
< 1
1.5
1.5
1.0
1.5
< 1
< 1
2.0
3.0
1.0
< 1
1.0
1.5
2.0
2.0
Post
Exposure
ppm
p.m. a.m.
113
88
71
105
93
115
85
102
79
103
88
66
57
54
60
84
67
56
60
71
< 1
< 1
—
—
— . ,
1.5
< 1 i
—
—
—
< 1
< 1
—
—
—
< 1
< 1
—
—
•W
Note: (—) Indicates not measured.
Although there is no indication of fluorocarbon accumulation, detectable levels
were retained over night in four cases at 0.05% and in fourteen cases at
0.1% exposure levels. In one instance, a detectable level was found on the
Monday morning after a two day weekend following the final exposure to 0.1%
72
-------
F-113 (Reinhardt et al., 1971). This information would seem at least an
indirect indication of tissue storage requiring a "wash out" period of over
60 hours.
2. Fluorocarbon Blood Levels After Nebulizer Administration
Studies of the amount of fluorocarbons in the blood have concentrated
on two types of exposures, those resulting from inhalation of air with known
concentrations of the gases and those from direct inhalation of propellants
from bronchodilator-type nebulizers. The analytical techniques used in these
experiments - headspace, direct injection, and solvent extraction - are
discussed elsewhere (Terrill, 1972a and b; Chiou and Niazi, 1973).
Bronchodilator drugs, such as isoproterenol are frequently provided
in nebulizers and propelled by various fluorocarbons. With each depression
of the value or puff, a fixed amount of drug and fluorocarbon mixture is
released. Some of these drugs and the amounts of various fluorocarbons
released with each puff are given in Table XXIX.
Table XXIX. Some Bronchodilator Drugs and the amount of
Fluorocarbons used as Propellants (Patterson
et al., 1971).
Fluorocarbon content (rog.) per puff
Fluorocarbon
11
12
113
114
'Medlhaler Iso'
(iHoprcuallne)
8.57
17.14
0.35-
8.57
'Medlhaler Isoforte1
(isoprenaline)
8.62
16.55
0.35
8.27
'Alupent '
(orctprenaline)
15^30
35.92
2.45
15.30
of:
1 tsorais r. '
( Isop renal j ne)
28.0
40.0
'Ventolln1 "Thll65a*
(salbutamol)
25.0 28.7
65.0 41.0
* Contains 1-(3,5-dihydroxypheny1)-l-hydroxy-2-l-(4-hydroxyphenyl)-Isopropy 1aminoethane.
73
-------
These are given only as examples and may not reflect the precise amounts
currently used. Typically, in experiments used to determine blood levels
from such administrations, various mixtures of propellants are used. At
present, there is no definite indication that the presence of one propellant
influences the relative degree of absorption of another propellant. This
is demonstrated in the work of Shargrel and Koss (1972) who have exposed
dogs to an equal weight mixture of F-ll, F-12, F-113, and F-114. The dogs
were given five and ten doses containing 16.8 mg of each fluorocarbon per
dose. The peak arterial and venous blood levels are given in Table XXX.
Table XXX. Peak arterial and Venous Blood Levels of
Fluorocarbons in dogs (Shargrel and Koss, 1972)
Peak Arterial
Level as
Percent of
Administered
Dose
10 5
Actu- Actu-
ations ations
Fluorocarbon
Peak Level, ug ./ml.
10 Actuations 5 Actuations
F-ll
Arterial
Venous
F-12
Arterial
Venous
F-113
Arterial
Venous
F-114
Arterial
Venous
22.3 ±
6.22 ±
6.17 ±
1.54 ±
11.56 ±
2.96 ±
3.80 ±
0.87 ±
1.0
2.6
0.38
0.84
1.78
1.40
0.52
0.41
13.2 ±
2.45 ±
3.16 ±
0.56 ±
6.43 ±
0.79 ±
2.32 ±
0.26 ±
1.4
0.29
0.06
0.04
0.61
0.06
0.12
0
15.9 8.89
.
.4.41 4.51
8.26 9.19
2.71 3.31
74
-------
These results are in agreement with the order of fluorocarbon absorption given
previously: F-11>F-113>F-12SF-114. Considering only the above data, it is
tempting to speculate that the order generally follows the blood/gas partition
coefficients, with the smaller molecules being more readily absorbed in cases
where partition coefficients are approximately equal. Data presented in Part 3
of this section seems to support this assumption (see page 85 ). Special note
should be taken of the sharp drop in arterial/venous ratios seen in all of these
fluorocarbons indicating tissue absorption. These data along with other
detailed kinetic studies of the arterial/venous drop are discussed in the
latter part of this section (see page 90 ff.).
Further absorption and elimination data are available in F-ll and
F-12 for nebulizer administration and are summarized in Table XXXI followed
by a discussion of the more significant results.
Dollery and coworkers (1970) measured the venous concentration of
F-ll in two human volunteers inhaling discharges from a nebulizer adminis-
tering F-ll, F-12, and F-llA at 8.6 mg, 17.2 mg, and 8.6 rag per dose,
respectively. Volunteer A Inhaled ten doaes for a total F-ll exposure of
86 rag and volunteer B inhaled thirty doses for a total F-ll exposure of
258 mg» resulting in peak venous blood concentrations of 0.3 ug/ml and
1.10 ug/ml, respectively. Concentration-time plots for these two exposures
are given in Figure 10.
75
-------
Table XXXI: Absorption/Elimination Data in Various Mammalian Species
After Inhalation of F-ll and F-12 from Nebulizers
Amount Eli-
minated U)
Exposure Absorption °r Ven°'J' _.
Fluoro- r Blood Time to
carbon mg/puff Dosage Inualfd Peak Blood Levels (ug/ml) Half Life Levels Elimination
CCSF3 Human 8.6 x 10 86 mg 0.3
(F~lil 8.6 x 30 285 mg 1.10
8.6 x 3 JS.5 ng 1.7
Human 'U.L.J 8.6 x 6 51.5 rr.g 0.63
Hunans 25 x 2 50 mg 0.68 (30 sec)* 0.5
0.27 (75 sec)* 1.0
0.29 (90 sec)* 1.5
2.60 (30 sec)* 0.3
0.52 (69 sec)* 0.9
Humans 25.5 .< 10 -;40 ng 0.93 0.32 9
(0.51-1.20) (O.iS-0.47)
Dogs 75 x 25 1880 ng -.60-75 0.6 ± 0.10
initial
4.03 r 0.25
terminal
Dogs (S) 24 x 22-30 528-720 mg 22.8-75 3
Dogs (S) 24 x 25 600 mg 29.6-88.1
Dogs 16.8 x 5 84 ng. 13.2 ± 1.4 2.45 ± 0.29
16.8 x 10 168 mg. 23.3 ± 1.0 6.22 ± 2.6
Mice*(G) 24 mg/puff ? 6-97 (2.86- . i.15 15
11.48) 13.10-5.85)
* - '3 33 (8 0- '56
Mlce 24 mg/putf ' '20.0) ' u. o-2.o)
'.45 -,e 2.17 ' O.-i 9
CCU; F; husans - - (1.40-2.70)
(F-12)
Dogs (V 61 x 22-30 1342- 12.5-118.0
1S30 mg.
Dogs 16.8x5 64 mg 3.16 r 0.06 0.56^0.04
16.8 x 5 168 mg 6.17 i 0.38 1.54 - 0.84
Mice* 61 mg/puff . ? J2-2 (16.2-
56 . 4)
Cotsnents Reference
see Fig. 10 Dollery e£ al, 1970
Patterson et al, 1971
see Fig. 11
with F-12, see
Table XXXII Allen & Hanburvs Ltd.,
1971
with F-12 McClure, 1972
with F-12 Allen & Hanburvs .Ltd. ,
1971
with F-12
see Table JKX
with F-12, Shargel & Koss,
F-113, and 1972
F-114
see Table Allen & Hanburvs, Ltd.,
XXXIII 1971
with F-12
with F-12
with F-ll Allen 4 Hanburvs, Ltd.,
see Table 1971
XXXII
vith F-ll Allen & Hanburvs, 1971
see Table Shargel & Kosi, 1972
XXX
with F-ll,
F-113, and
F-114
See Table Allen & Hanburvs, Ltd..
XXXIII «'l
with F-ll
(.:>• = under atrusr.
(U.L.)-ubstructetl lung*
from spray as in Taylor and Harris, ".370:.
* = ' »me to peak
.' = 3 i nhalat ions
-------
JU
5:
0)
5
HTRATIOH FLUam
(ftg. per ml. )
O f
- 0
n ni
•X
A *^>^ Volunteer D
. 1 ^-— .
o Volunteer A
0 10 20 30 10 SO 60 70
Minutes
Figure 10. Venous Blood Concentrations of human inhaling
86 mg F-ll (Volunteer A) and 258 mg F-ll
(Volunteer B) from a nebulizer (Dollery
et al., 1970).
Permission granted by Little Brown, publishers.
However, in a different individual a dose of only 50 mg F-ll resulted in a
peak venous blood concentration of 0.52 pg/tal as indicated in Figure 11.
01 2345676 9 10
Figure 11. Venous Blood Concentrations of F-ll in a
Human Inhaling 50 mg F-ll (Patterson et al. ,
Permission granted by Little Brown, publishers.
77
-------
While the general patterns of the preceding figures are quite similar, showing
the same rapid initial rise in blood levels with dosing followed by an
initially rapid then slower decline in blood levels when exposure is terminated,
there is some evidence that the amount of fluorocarbons absorbed may vary
considerably among different individuals* Dollery and coworkers (1970) noted
that a healthy individual inhaling 25.8 mg F-ll reached a maximum arterial
blood level of 1.7 yg/ml F-ll, while a patient with obstructed lungs inhaling
51.4 mg F-ll reached a maximum arterial blood level of only 0.63 yg/ml F-ll.
In this instance, the difference is probably attributable to diminished lung
capacity in the patient inhaling the higher dose. Patterson and coworkers
(1971) noted a ten-fold difference in peak venous blood concentrations and
a five-fold difference in F-ll blood half lives among five patients ;
inhaling 50 mg F-ll (see Table XXXI). This variation could not be explained by
differences in lung capacity. However, an inverse correlation is noted
between the venous peaks and the half-lives, indicating that wide variations
noted reflect different inhalation techniques - e.g. the individual breathing
most deeply reached the highest blood level (2.60 pg/ml) most quickly
(30 seconds) and eliminated the fluorocarbon most rapidly (t*i = 18 seconds),
with the converse being seen in the patients breathing most shallowly: peaks
of 0.27 and 0.29 yg/ml, time to peaks of 75 and 90 seconds,'half lives of
90 and 60 seconds, respectively.
Experiments conducted at Allen and Hansbury Ltd. (1971), noted
similar differences in maximum venous concentrations in three humans deeply
inhaling or not inhaling ten doses of F-ll (25.5 mg/dose) and F-12 (64.5 mg/
dose), one dose every six seconds sprayed into the mouth. The results are
given in Table XXXII.
78
-------
Table XXXII.
Concentration of F-ll and F-12 in venous blood
of three humans exposed to ten doses of 25.5 rag
F-11/dose and 64.5 mg F-12/dose, one dose every
six seconds (Allen and Hansbury Ltd., 1971).
Time after
exposure
(minutes)
0
1
2
5
10
0
1
2
5
10
yg/mg. Blood
Volunteer A U Volunteer B
Arcton 11
0.81
1.10
Arcton 12 Arcton 11
II
Deep Inhalation
1.60
2.40
No specimen
0.79
0.25
1.62
0.63
0.27
0.20
0.13
1.50
0.35
No Inhalat
2.07
0.80
0.25
0.15
0.08
1.18
1.20
0.96
0.80
0.47
ion
0.34
0.33
0.26
0.22
0.15
Arcton 12
2.45
2.70
2.00
1.25
0.60
0.47
0.40
0.28
0.20
0.13
Volunteer C
Arcton 11
0.31
0.51
0.49
0.39
0.25
0.93
1.24
1.07
0.93
0.64
Arcton 12
0.75
1.40
1.36
0.95
0.50
1.55
,1.58
1.07
0.95
0.68
The wide differences noted in blood concentrations, especially in volunteers
B and C, demonstrate the importance of inhalation technique on the absorption
of these fluorocarbons into the blood. The ratio of administered
79
-------
F-12 to F-ll in the above exposures is 2,58 to 1, while the ratios of
maximum levels found in the blood after deep inhalation are 2.18, 2.25, and
2.75 for volunteer A, B, and C, respectively. Thus, F-ll seems to be more
readily absorbed than F-12 in volunteers A and B but not in volunteer C.
This might be seen as an indication that there is individual variation not
i
only in the amounts of fluorocarbons absorbed but also in relative degrees
of absorption. While F-ll is usually considered more readily absorbed than
F-12, volunteer C in Table XXXII presents an apparent exception. Further
exceptions are apparent with studies on anesthetized mice (Allen and Hanbury
Ltd., 1971). In this study, mice were allowed three inhalations from one
dose of a Ventolin inhaler. A gauze filter was inserted into the mouth of
the nebulizer to screen out the active ingredients. The amount of fluoro-
carbons in such a dose are 25 mg F-ll and 65 mg F-12 with a weight ratio of
F-12 to F-ll of 2.6 (Patterson e_t al., 1971). The venous blood levels found
in these mice are given in Table XXXIII.
Table XXXIII. Venous blood levels of F-ll and F-12 in mice
after three inhalations from one dose of a
Ventolin inhaler (Allen and Hanbury Ltd., 1971)
Mouse
Number
1
2
3
4
5
6
yg./mg. Blood
Arcton 11
9.06
5.78
8.26
2.86
5.39
11.48
Arcton 12
16.2
47.3
56.4
18.9
26.6
27.8
Ratio
F-12 /F-ll*
1.8
8.2
6.8
6.6
4.9
2.4
* F-12/F-11 in administered dose equals 2.6.
80
-------
The ratios above 2.6 might seem to indicate that mice #2-5 absorbed F-12
more readily than F-ll. An alternate explanation implied by the original
investigators is that the relatively non-volatile F-ll was preferentially
absorbed into the gauze and thus the actual dose of F-ll received by the
mice was lowered. This is supported by the higher blood levels of F-ll
(8.0, 12.0, and 20.2 yg/ml) in mice exposed without gauze.
In a similar series of experiments on hypoxic dogs, using the same
ratio of F-12 to F-ll (2.6), F-12/F-11 ratios in venous blood varied from
0.55 to 1.57, indicating preferential absorption of F-ll in all cases
but not uniformly so. Thus, this series of studies seems to indicate that
while F-ll is more readily absorbed by mammals than F-12, the degree of
preferential absorption may vary among individuals. Whether this difference
is actual or merely an artifact of the relatively high volatility of F-12
N
over F-ll has not been conclusively demonstrated.
From the data presented on mice, dogs, and humans exposed to fluoro-
carbons from bronchodilator-type nebulizers, it would be desirable to
determine and quantify interspecific differences. Jack (1971), in discussing
the data presented by Allen and Hansbury's Ltd. (1971), concluded that dogs
absorb fluorocarbons to a much greater extent than man. For the most part,
this conclusion is supported by the data presented in Table XXXI for both F-ll
and F-12. However, the wide variety of blood levels after identical exposures
(e.g., Patterson et al., 1971) should not be minimized. In one human receiving
50 mg F-ll, venous blood levels peaked at 2.60 ug F-ll/ml (Patterson et al.,
1971). In dogs inhaling 84 mg F-ll, venous blood levels peaked at 2.45 ±
0.29 yg F-ll/ml (Shargrel and Koss, 1972). Also, dogs have a much smaller
81
-------
respiratory volume than man. Consequently, an equal dose of fluorocarbons
x'
is less diluted in the alveolar air resulting in artificially higher blood levels
in dogs than in man. Thus, differences irf levels of absorption between man
and dog might best be demonstrated in exposures to concentrations of fluoro-
carbons in ambient air rather than direct administration from nebulizers.
i
The data on mice are of little use in determining comparative absorption
because the actual doses cannot be fixed. These exposures relate more to
experiments on fluorocarbon sensitization to asphyxia induced arrhythmias
'(see Section XII, Part D-3). Lastly, it is of interest to note that all
of the blood levels obtained are well below'the level of halothane stage-3
anesthesia, 173 yg/ml (Dollery et al., 1970).
3. Fluorocarbon Blood Levels after Inhalation of Fluorocarbon-
containing Ambient Air
Exposures to fluorocarbons at fixed concentrations in inspired air
generally reflect the same basic pattern as those seen for nebulizer
exposures (see Figures 10 and 11). Changes in venous blood concentrations in
dogs during and after exposure to F-ll have been measured at ambient concen-
trations of 1.25% and 0.65% for 30 minutes (Clark and Tinston, 1972a) and
at 0.55% for 20 minutes (Blake and Mergner, 1974). The results of these
investigations are given in Figure 12.
82
-------
B22968-U
INHALATION
EXHALATION
INHALATION
EXHALATION
• 1.25% FLUOROCARBON 11
O 0.63% FLUOROCARBON 11
10 20
30 40
TIME (min.)
(a)
50
0 10 20 30 4D SO 60
Figure 12. Changes in Venous blood concentrations of F-ll
in dogs exposed to (A) 1.25% and 0.63% F-ll for
30 minutes (Clark and Tinston, 1972a) and (B)
0.55% F-ll for 20 minutes (Blake and Mergner, 1974)
Similar studies have been conducted on F-12 and F-114 and are summarized in
Figures 13 and 14.
INHALATION
EXHALATION
INHALATION
EXHALATION
80--
• 8% FLUOROCARBON 12
o 4% FLUOROCARBON 12
10 20 30 40
TIME (min.)
(b)
50 60
Figure 13. Changes in Venous Blood Concentrations of F-12 in dogs
Exposed to (A) 8% and 4% F-12 for 30 minutes (Clark and
Tinston, 1972a) and (B) 1.18% for 20 minutes (Blake and
Mergner, 1974)
83
-------
,i
• 1WFLUOHOCAHBON114
o 5% FLUOROCARRON 114
40--
Figure 1A. Changes in Venous Blood Concentrations of F-114
in dogs exposed to 10% and 5% F-114 for 30 minutes
(Clark and Tinston, 1972a).
As in the studies usin,? expired air or blood levels from nebulized adminis-
tration as indices of absorption, the above data indicate that F-ll is much
more readily absorbed and retained than either F-12 or F-114. However, in
the data from Clark and Tinston (1972a), F-12 seems appreciably better absorbed
than F-114, which seems to reach an equilibria concentration of 10% in inspired
air to 40 yg/ml in blood after ten minutes.
In rats, the absorption of F-12 also seems much greater than that of
F-114 as shown in a study by Ramus and coworkers (1973) in which rats were
exposed to a mixture of F-ll, F-12, and F-114 (weight ratio of 1:2:1 respec-
tively). As indicated in FigurelS, F-12 was absorbed about four times more
readily.
84
-------
300
£ 200
c
u
8
u
u
too.
Figure 15. Increase of fluoro-
carbons (FCC) concentrations in
rat blood during inhalation
of a combination of FCC's 11 (0), 12 (A)
and 114 (0) (weight ratio 1:2:1, mean ±
s.d., 6 rats) .(Rauws, et^ a±. , 1973);
reprinted with permission from A.G. Rauws,
Copyright 1973, Pharmaceutical Society of
Great Britain.
20 40
Time (rnln)
A similar pattern is also seen in the work of Taylor and coworkers (1971) who
have exposed monkeys to a mixture of 30% F-12 and 9% F-114 (ratio 3.3:1::F-12:
F-114) for varying periods. The arterial blood levels monitored are given
in Table XXXIV.
Table XXXIV. Arterial blood levels of F-12 and F-114 in monkeys
exposed to 30% F-12 and 9% F-114 (3.3:1, v/v;
2.35:1, w/v) [Taylor e£ al. , 1971].
Duration
35 sec.
42 sec.
45 sec.
Arterial Blood Cone, (mg/100 ml.)
V-12 F-114 Ratio
5.5 1.8 3.06
6.3 2.3 2.74
6.5 2.2 2.96
In each instance, the ratio of F-12 to F-114 in arterial blood is higher
than the w/v ratio of exposure indicating that F-12 is slightly better
absorbed than F-114. Thus, as mentioned previously, it seems reasonable
i '
to assume that ease of absorption for the fluorocarbon gases follow the
blood/gas partition coefficients, with the smaller molecules being more readily
absorbed in cases where partition coefficients are approximately equal.
There is also some indication in these exposures of interspecific
differences in absorption. Griffin and coworkers (1972) have exposed
rabbits to 5% F-12 for thirty-five minutes. The resulting venous blood
levels are summarized in Figure 16.
85
-------
10
20
30 f 5
TIME, MINUTES CNOOF
FXPOSUBE
Figure 16. Freon 12 in blood of rabbit
during 5% atmospheric exposure. Blood
samples were withdrawn from the animals
before, during and after exposure to
Freon 12 and the halocarbon concentra-
tions determined by gas-liquid chromato-
graphy. (Griffin.et al., 1972)
10
The peak blood levels (about 15 yg/ml) are about 5 ug/ml below those noted
in dogs exposed to 4% F-12 for 30 minutes (see Figure 13, Clark and Tinston,
1972a), indicating, that dogs aay absorb F-12 more readily than rabbits,
Information on the absorption of F-116 and H-1301 are also available
on rabbits during 30 minute exposures to 5.0% fluorocarbon.
Figure 17. Fluorocarbons in blood of
rabbits during 5% atmospheric expo-
sures. Blood samples were withdrawn
from the animals before, during and
after exposures to either H-1301
(open circles) or F-116 (solid
circles). Concentrations of the
halocarbons in blood were determined
by gas-liquid chromatography
(Griffin et al., 1972).
TIME, MINUTES eN(J0,
t XPOSuRE
An exposure to 5% H-1301 for 50 minutes resulted in a much lower blood
concentration in rats as shown in Table XXXV.
Table XXXV.
H-1301 in Rat Blood Following a Single 50-Minute
Exposure to a Vapor Concentration of 5% (V/V)
(Griffin et al., 1972).
Post-Inhalation
Time (Hrs)
0
0.25
1.0
2.0
4.0
Venous Blood Level
M8/g
5.6
0.62
0.35
0.05
0.07
This would seem to indicate that rats absorb H-1301 less readily than do
rabbits.
86
-------
Exposure of rats to 3.7% H-2402 for 30 minutes resulted in a much
higher blood concentration and correspondingly longer retention times as
shown in Table XXXVI, than the comparable exposure to H-1301 shown in Table XXXV.
Table XXXVI. Blood Levels of H-2402 in Rats After a 30-Minute
Exposure to 3.7% H-2402 (Griffin £t al., 1972).
Post-Inhalation Venous Blood Levels
Time (Hrs) pg/g
0 87
1.5 7°
3 0.23
24 0.22
Data on these and other exposures are summarized in Table XXXVII.
All of these exposures show a similar pattern, an initial rapid rise
in fluorocarbon blood levels at the onset of exposure followed by a slower
rise approaching equilibrium.
In the above cited studies, air-blood equilibrium seems to have been
reached with 10% F-114 after ten minutes (Figure 14) and 4% or 5% F-12 after
a somewhat longer period (Figure 13 A and Figure 16). However, complete
equilibrium would be demonstrated only by knowing both the arterial and
venous concentration (see discussion on tissue uptake at end of section).
The biphasic rates of absorption are paralleled by elimination rates after
termination of exposure. Initially, a sharp drop in fluorocarbon blood
levels is seen followed by a much slower fall. The dual rates of
elimination have been quantified by McClure (1972), as indicated in Table XXXVII
for F-ll. These dual rate patterns of absorption and elimination would
seem to indiate that these fluorocarbons are deposited from the blood into
body tissues during exposure.
C7
-------
Table XXXVII: Absorption/Elimination Data on Various Fluorocarbons after inhalation
Exposure Absorption Elimination
Fluorocarbon
(Code) Animal
CCIF3 (F-ll) Rats
• *
Rats
Dogs A
B
B
C
A
C
*
Dog D
D
Dogs
Dogs
Dogs
Dogs
! Concen-
Duration of
Exposure
(minutes)
5
5
5
5
5
5
5
5
5
20
30
30
5
5
10
10
10
t ration in
Air (I V/V)
or Dosage
Inhaled (mgl
0.231
0.61%
0.64%
0.11%
0.15%
0.47%
0.49%
0.91%
1.14Z
0.2%
0.5%
0.55%
0.65X
Peak Blood Levels (jjg/ml)
Arterial
6.40
32.25
1.25%
0.65%
1.25%
0.1/5 ilO.S (S.6-
Venous
11.25 (11.00-
11.70)
26.6 (22.3-
Jl.O)
14.06 (11.25-
16.87)
4.80
5.80
17.50
25.40
38.00
54.00
3.50
23.50
19.00
20.00
46.00
10.00
20.00
6.6(5.0-
| 12.0) | 9.8)
0.5% ;28.b U3.0-| 19.7 (13.8-
1 43.5)
l.QZ J53.. 2
24.0)
37.^
(34. 0-76. CM (31.0--3.0)
1
Half Life
3 nin.
Blood Levels
After Exposure
(Hg/nl)
0.34 (0.17-0.52)
2.35 (2.00-2.70)
5.97 (55.55-6.40
Blood
Level
Reduction
5 min.
5 min.
5 min.
Comments
See Table
XXXVIII, b.
See Fig. 12B
See Fig. 12 A
See Fig. 18
Reference
Allen & Hanburys, Ltd..
1971
Mien & hanburys, Ltd..
1971
Allen & Hanburys, Ltd.,
1971
Blake «& Mergner, 1974
Clark '& Tlnston, 1972a
1972b
Azar el_ al., 1973
oo
CO
-------
Table XXXVII (continued)
oo
VO
Exposure Absorption Elimination
Fluorocarbon
(Code) Animal
CC12F2 (F-i2) Bass*
Rabbit
Monkey
Dogs A
B
C
C
B
A
C.-.CvF,. (F-114)
Uogs
*
Monkeys
C2F6 (F-116) Rabbit
CCl¥;,Al (H-1211)
Dog
CF3Br (n-1301)
Rat
Rabbit
CrF,,Br; (H-2402)
Rats
1 Concen-
Duratlon of
Exposure
(minutes )
5
35 min.
0.59
0.70
0.75
5
5
5
5
5
5
20
30
30
10
10
10
30
30
0.5S
0.70
0.7?
30
1
2
5
50
30
30
t ration in
Air (2 V/V)
j or Dosage
1 oh a led (eg)
0.64Z
5Z
301
30Z
302
2.40S
2.522
2.72J
4.21Z
4.83Z
5.01Z
1.182
4.0Z
8.0Z
0.1Z
5.0Z
10.0%
5!.
10.02
o;
s«
*:;
5Z
8.0i
5.0*
2.0Z
5. OX
5.0t
3.r.
Peak Blood Levels (ug/ml)
Arterial
5.5
6.3
6.5
l.t
35.3
46.3
1.8
2 . 3
-•2
i
Venous
3.47 C2.80-
3.75)
"-15
25.00
25.00
20.65
44.20
46.25
32.75
1.14.5
"•33.0
1-65.0
0.9
22.8
39.8
-19.0
-40.0
<0.5
21
23
24
5.6
15.0
87
Half Life
~
I
Blood Levels
After Exposure
(iJ& /ml)
0.62 (0.50-0.75)
Blood
Level
Reduction
C
Comments Reference
Allen & Hanbuzye Ltd. ,
1973.
See Fig. 16 Griffin et al. , 1972
See Table Taylor et al., 1971
XXXIV
with 9Z
F-114
Allen & Hanburys Ltd. ,
1971
See Fig. 13B Blake & Mergner, 1974
See Fig. 13A Clark & Tlnston, 1972a
See Fig. 13A
See Fig. 19 Arar et al. , 1973
See Fig. 14 Clark & Tiostoo. 1972a
See Table Taylor et al. , 1971
XXXIV with
F-12
See Fig. 17 Griffin e^ a_l. , 1972
See Table Griffin ct al. , 1972
XXXV
See Fig. 17
XXXVI
anesthetized
-------
Additional indications of body tissue storage comes from simultaneous
measurements of fluorocarbon concentration in venous and arterial blood.
Such differences have been noted previously in studies by Shargel and Koss
(1972) see Table XXX. Similar differences have been noted by Allen and
Hansburys Ltd. (1971) and Azar and coworkers (1973). The venous and arterial
blood levels during and after exposure of dogs to 0.2% and 0.5% F-ll is
summarized in Table XXXVIII.
Table XXXVIII. Arterial and Venous Blood Concentrations of F-ll
in Dogs Exposed to 0.2% and 0.5% F-ll
(Allen and Hanburys1 Ltd., 1971).
Concentration of
F-ll
0.2$
0.2$
0.2$
0.2$
0.2$
0.2$
0.2$
O.^o
. 0.5$
0.5"/o
0.5$
j
0.5#
0.5$
0.5$
Time
(minutes)
0
.2.5
5
10
15
20
25
«1
0
2.5
5
10
15
20
25
Time sample taken
Start of inhalation
After 2.5 minutes
After 5tO minutes
5 minutes after cess-
ation of inhalation
10 minutes after cess-
ation of inhalation
15 minutes after cess-
ation of inhalation
20 minutes after cess-
ation of inhalation
Start of inhalation
After 2.5 minutes
After 5.0 minutes
5 minutes after cess-
ation of inhalation
10 minutes after cess-
ation of inhalation
15 minutes after cess-
ation of inhalation
20 minutes after cess-
ation of inhalation
yg. F-ll /ml. Blood
Arterial
0,12
3.65
6.40
0.80
0.55
0,31
0.23
0,08
25.15
32.25
4.25
1.52
1.45
0.60
Venous
0.1?
3.25
3.50
0.79
0.69
0.35
0.36
0.06
20.50
23.50
5.52
3.09
1.78
0.97
90
-------
As can be seen in both of the exposures summarized in Table XXXVIII, F-ll is
cleared from the blood by tissue absorption during exposure (arterial con-
centration [Ca]>venous concentration [Cv]) and cleared from tissues by the
blood after exposure (Ca blood and blood -»• tissue uptake after five minutes of exposure to 0.2%
t
and 0.5% concentrations given in Table XXXVIII. The first step is calculated
from the following equation:
C
air ->- blood uptake = — - — X V
C - concentration of fluorocarbon in alveolar air (yg/ml)
3
V = mean minute alveolar ventilation (15 breaths /minute
a x 120 ml/breath)
V = 0.68 V
a a
X - blood/gas partition coefficient (see Table XXXVI)
The second step ie calculated as:
blood ->• tissue uptake = cardiac output (C - C )
3i V
The cardiac output of the dog is assumed to be 1 liter/minute. Thus,
the rates of air — >• blood uptake of F-ll at air concentrations of 0.2% and
0.5% is 5.6 mg/minute and 28.2 mg/minute, respectively; the rates of blood — *•
tissue uptake are 2 mg/minute and 5.4 mg/minute, respectively.
Azar and coworkers (1973) have monitored both arterial and venous
concentrations during and after 10 minute exposures to 0.1%, 0.5%, and 1.0%
F-ll and 0.1%, 5.0%, and 10.0% F-12 in dogs. The results are given in
Figures 18A and 18B for F-ll and Figures 19A and 19B for F-12.
91
-------
• « 1.0% ARTERIAL
< * 0.5% ARTERIAL
* * 0.1% ARTERIAL
o o 1.0% VENOUS
»- _ -, 0.6% VENOUS
„ . 0.1% VENOUS
t
«- - -• 0.5*
»• - -» o i\
0136; 10 I2H IB
EXPERIMENTAL MINUTE
-*-+••*-} t I t * | I I < ' j I t I I ) —
10 1C 20 25
EXPERIMENTAL MINUTE
I—
— r-,i --- 1
Figure 18, (A) Venous and Arterial Blood Concentrations of F-ll
and (B) Arterial and Venous Differences in Dogs exposed
to 0.1%, 0.5%, and 1.0% for 10 minutes (Azar e£-al., 1973)
-« 10.0% ARTERIAL
-• 6.0% ARTERIAL
_v 0.1% ARTERIAL
-o 10.0% VENOUS
-4 5.0% VENOUS
_, 0.1% VENOUS
» « 10.0%
• -* 5.0%
« -T 0.1%
/
01357 10 12% .15 20
EXPERIMENTAL MINUTE
5 10 15 20 25
EXPf HIMEMTAL MINUTE
h- '-« H
—^
Figure 19. (A) Venous and Arterial Blood Concentrations of F-12
and (B) Arterial and Venous Differences in Dogs Exposed
to 0.1%, 5.0%, and 10% F-12 for 10 Minutes
(Azar et al., 1973).
92
-------
The data on the 5.0% exposure to F-12 illustrates the difference between
air «-»• blood equilibrium and blood «-»• tissue equilibrium. While the blood
levels of F-12 remained constant after 3 minutes indicating an apparent
equilibrium between the air and blood, F-12 was still being absorbed by
body tissues as indicated by the positive arterial-venous difference.
Thus, actual equilibrium - air «-> blood •«-»• tissue - had not yet been,
attained. When such an equilibrium is attained, the blood levels should
remain constant and the arterial-venous difference should equal zero.
4. Other Routes of Entry
Although inhalation is the primary route of entry of the one and
two carbon fluorocarbons, other routes of entry have been studied, albeit
much less extensively. Greenburg and Lester (1950) found no evidence for
the absorption of F-112 or F-112a across the gastrointestinal tract in rats.
In long term feeding studies of F-12 to rats and dogs, however, Sherman
(1974) found tissue uptake indicating that some absorption does take place.
Regardless of the route of entry, fluorocarbon elimination seems restricted
almost exclusively to the respiratory tract. Matsumoto and coworkers (1968)
have administered a mixture of F-12 and F-114 (30/70, v/v) intravenously,
intraperitoneally, and directly sprayed onto an internal organ in dogs. No
elimination was noted in the urine or feces. Elimination in the breath is
described in Table XXXIX.
Table XXXIX. Elimination of Fluorocarbons in Dogs Breath
(Matsumoto ej: al. , 1968) '."
Intravenous Intraperitoneal . Direct Spray
Dosage 0.5 cc 2.0 cc
Internal Before Onset
of Elimination 3 sec. 5 min. 5 sec.
Duration of Elimination 12 hours 48 hours 12 hours
93
-------
The four-fold increase in dosage and the corresponding increase in duration
of elimination going from intravenous to intraperitoneal administration
would seem to indicate that the half-life of fluorocarbons in the body is
relatively independent of route of administration. The increased interval
before onset of elimination or intraperitoneal injection probably reflects
only the increased tiaie required for the fluorocarbons to enter the circu-
latory system.
Chiou and Niazi (1973) have conducted similar experiments in the
elimination of F-ll in dogs after intraveneous infusion using blood levels
rather than fluorocarbon concentrations in expired air as an index in removal.
The result of one such experiment is given in Figure 20.
3
I
n
O
o
O
o
500
10
Figure 20. Blood Concentration of F-ll
in Dog following an Intravenous Infusion
of 28 mg F-ll (Chiou and Niazi, 1973)
TIME (Hri.)
94
-------
The biphasic rates of elimination of F-ll from the blood stream on intra-
venous infusion are similar to those by inhalation [e.g. Figures 10-14].
Dermal absorption in man has also been tested using F-113 (DuPont,
1968). The hands and arms of two individuals were immersed in F-113 for
30 minutes and the portions of the scalp for 15 minutes. Fluorocarbon uptake
was measured as F-113 in expired air. Time to maximum concentration is
measured from termination of exposure. The maximum concentrations rioted in
exposure of the hands and forearms were 9.6 ppm after 11.5 minutes for one
individual and 1.7 ppm after 23 minutes for the other. The scalp, perhaps
because of its increased 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. As with
the other exposures previously discussed, elimination was rapid. After
90 minutes, F-113 concentration was below 0.5 ppm in all subjects. In the
subject reading 1.7 ppm in the hand and forearm exposure, however, a trace
amount of about 0.1 ppm was detected 18 hours after exposure.
In summary, the available data on fluorocarbon uptake and elimin-
ation indicate that fluorocarbons can be absorbed across the alveolar
membranes, gastrointestinal tracts, the skin, or internal organs. On
inhalation, fluorocarbons are absorbed rapidly by the blood. As the blood
concentration increases, the rate of absorption by the blood decreases.
Once in the blood, fluorocarbons are absorbed by various tissues. Current
information seems to indicate that blood —*• tissue absorption is the rate
limiting step. If exposure is sufficiently long, blood levels will stabilize
indicating an apparent equilibrium between the air and the blood. However, after
this initial blood level stabilization, fluorocarbons are still absorbed by
95
-------
body tissue and fluorocarbons continue to enter the body. Actual equilibria -
air «->• blood «->• tissues - would be indicated by a zero level arterial-venous
blood level difference. After exposure, fluorocarbons are eliminated rapidly
from the body through the expired air. The relative order of absorption
seems to be F-11>F-113>F-12>F-114. Although data on other fluorocarbons
I
are less complete, H-1301 and H-1211 seem to be absorbed to about the same degree
o
as F-12. Halon-2402 is absorbed to a greater extent than F-12 and may
approximate F-113 but does not exceed F-ll. Fluorocarbon-116 is absorbed
very poorly. Differences in the amounts of fluorocarbons absorbed by various
s'pecies seem evident but are too variable for even a tentative generalized
order. Nebulizer administration - while not the preferred technique for
i •' '.
demonstrating interspecific differences - seems to indicate that dogs absorb
fluorocarbons more readily than man. However, individual differences are
most significant, the amounts of fluorocarbon being absorbed or eliminated
vary widely and this variety seems chiefly due to variations in breathing
patterns.
96
-------
B. Transport and Distribution
As described in the previous section, kinetic studies on absorption
and elimination indicate that fluorocarbons are transported by the blood to
the various organs of the body and that some storage - at least temporarily -
occurs. This is particularly evident in Table XXXyiU (Allen Hansburys Ltd., 1971)
where there is a noticeable decrease in fluorocarbons going from arterial to
venous concentrations during exposure but the reverse after exposure is
terminated.
Allen and Hansburys Ltd.(1971) have studied the distribution in
rats of F-ll and F-12 at varying periods after administration. The results
are summarized in Tables XL and XLI.
Based on the kinetic data for F-ll and F-12 blood levels presented in
Figures 12 & 13, the tissue concentrations immediately after a five minute
exposure to Tables XL and XLI probably do not represent equilibrium concentrations.
These studies, however, do indicate that both F-ll and F-12 are taken up
by heart, fat, and adrenal tissue. Fluorocarbon-11, for which detailed
blood levels are available, is concentrated from the blood to the greatest
extent in the adrenals followed by the fat, then the heart. A similar,
though less pronounced pattern, is evident for F-12. In agreement with
studies presented in the previous section, F-ll is absorbed and concentrated
in all of these tissues to a much greater excent than F-12. The differences
in actual concentrations noted among the various specimens studied may
represent differences in breathing patterns or actual differences in
individual ability to absorb these fluorocarbons.
97
-------
Table XL. Concentration of F-ll in the blood, heart, fat,
adrenals, and thymus of rats at various times after
exposure to F-ll for 5 minutes
(modified from Allen and Hanburys Ltd., 1971)
Animal
No.
1
2
5
6
7*
*
8
3
4
7
8
*
9
10
11
12
1
2
3
4
1
2
3
4
1
2
Concentration
Arcton 11 (Z)
0.23
0.23
0.61
0.61
0.64
0.64
0.23
0.24
0.61
0.61
0.64
0.64
0.64
0.64
0.49
0.49
0.49
0.49
0.64
0.64
0..64
0.64
1.00
1.00
Time after
exposure
Immediate
Immediate
Immediate
Immediate
Immediate
Immediate
5 minutes
5 minutes
5 minutes
5 minutes
5 minutes
5 minutes
1 hour
1 hour
2 hours
2 hours
4 hours
4 hours
8 hours
8 hours
24 hours
24 hours
48 hours
48 hours
Ug. F-ll
Per ml.
Blood
11.00
11.70
22.30
31.00
16.87
11.25
0.52
0.17
2.70
2.00
5.55
6.40
0.32
0.12
0.13
0.09
0.03
0.02
0.007
0.014
0.006
0.006
0.002
0.003
Per g.
Heart
12.00
11.60
26.70
41.40
21.04
21.20
0.87
2.47
2.14
.4.00
6.87
6.86
0.15
0.28
0.05
0.11
0.03
0.01
0.006
0.008
0.011
0.012
0.002
0.005
Per g.
Fat
83.40
61.10
113.00
164.50
39.60
30.85
28.60
34.80
77.00
105.70
16.58
17.46
2.90
3.22
0.64
2.59
0.66
0.15
1.105
1.850
0.011
0.024
0.011
0.008
Per g.
Adrenals
•
-
-
222.0
246.3
-•
-
-
195.4
-
33.75
45.50
2.49
15.88
2.53
1.64
0.347
0.440
0.375
0.305
0.0.77
0.125
Per g.
Thymus
-
-
-
-
• ' - '
-
-
-
-
- -
-
-
0
.
-
0.013
0.027
0.025
0.021
0.005
0.007
* Rats anaesthetized with sodium pentobarbitone prior to exposure to
F-ll/Air mixture
98
-------
Table XLI. Concentration of F-12 in the heart, fat, and
adrenals of rats at various times after exposure
to F-12 for 5 minutes
(modified from Allen and Hansfcury Ltd., 1971)
Animal
No.
9
10
5
6
1
2
*
2*
11
12
7
8
3
4
3*
4*
5
6
Concentration
Arcton 12 (%)
0.18
0.18
D. 68
0.68
0.70
0.70
0.64
0.64
0.18
0.18
0.68
0.68
0.70
0.70
0.64
0.64
0.64
0.64
Time after
exposure
Immediate
Immediate
Immediate
Immediate
Immediate
Immediate
Immediate
Immediate
5 minutes
5 minutes
5 minutes
5 minutes
5 minutes
5 minutes
5 minutes
5 minutes
1 hour
1 hour
yg- F-12
per g.
Heart
4.17
4.51
11.10
11.10
7.58
4.91
1.91
2.08
0.77
0.64
1.93
1.66
3.94
3.50
0.92
0.82
0.13
0.11
per g.
Fat
6.05
5.08
11.50
8.98
9.93
4.57
5.96
4.04
1.73
1.62
2.10
1.74
3.03
0.91
3.91
3.00
0.07
0.06
per g.
Adrenals
78.60
89.10
101.00
70.50
33.10
76.60
45.80
45.10
32.10
9.50
54.50
48.00
18.25
15.60
16.55
22.84
1.00
1.04
* Rats anaesthetized with sodium pentobarbitone prior to exposure to
F-12/air mixture.
99
-------
Carter (1970) summarizes similar distribution data on F«-113 exposure in
rats given in Table XLII.
Table XLII. Mean tissue concentrations of F-^
in rats exposed to 0.2% F-113
for 7 and 14 days (Carter, 1970)
TISSUE
Brain ug/gm
Liver ug/gm
Heart ug/gm
Fat ug/gm
Adrenal ug
Thyroid ug
EXPOSURE
7 Day
22.73
(1.00)
15.77
(0.87)
16.59
(2.56
722.48
(71.29)
8.39
(2.61)
1.09
(0.46)
14 Day
22.65
(1.33)
16.40
(1.72)
15.03
(2.51)
659.24
(21.17)
3.47
(0.34)
0.94
(2.00)
POSTEXPOSURE
24 Hours
None
None
None
108.45
(33.62)
None
None
48 Hours
None
None
None
5.60
(2.94)
None
None
( ) Standard Deviation
The major difference in these findings from those presented for F-ll and
F-12 is that for F-113 almost all of the concentration occurs in the fat
while adrenal levels are relatively low and even decrease as exposure
continues. It must be emphasized that the exposures to F-ll and F-12 were
only for five minutes. The possibility of rapid uptake by the adrenals
during initial exposure followed by active elimination of fluorocarbons
100
-------
from the adrenals during exposure may be worth, exploring. That the various
other organ levels did not alter significantly from the seven to the fourteen-
day exposures is consistant with the idea that such concentrations will
stabilize as equilibria between ambient air concentration, blood level, and
tissue levels are reached. However, there is- some indication that levels
of F-ll and F-12 in various tissues may alter during prolonged exposure as
less accessible tissues are reached (Blake and Mergner, 1974).
<3 .
Similar tissue distribution studies have also been done on rats
with short term exposure to H-2402 (Griffen £t al., 1972). The results
are given in Table XLIII.
Table XL1II. Tissue concentrations of H-2404 in rats
after 30 minutes exposure to 3.7% H-2402
(Griffin et_ al. , 1972)
Tissue
Liver
Lung
Brain
Kidney
Heart
Muscle
Fat
Blood
0
258a
44
0.
82
24
73
365
87
Post- Inhalation
1-1/2
5
18
70 2.1
27
2.1
19
469
7
Interval (Hrs)
3
2
2
0.78.
23
2
2.8
410
0.23
24
0.28
0.18
0.36
0.33
1.1
1.0
11
0.22
All values shown are in yg -2402/g tissue.
101
-------
Increase of H-24Q2 levels in the fat and brain tissue from immediately after
inhalation to one and a half hours after inhalation indicates that the
30 minute exposure period was not long enough for equilibrium to be reached.
Like F-ll, F-12 and F-113, large amounts of H-2402 are stored in fat tissue.
The most striking value, however, is the large amount found in the liver
immediately after inhalation and its rapid elimination after one and a half
hours. Similar levels of liver uptake have not been noted for other fluoro-
carbons under discussion. The anesthetic, halothane (CHBrCl-CF-), however,
is transported to the liver where it is apparently metabolized to trifluoro-
acetic acid (Rosenburg, 1972; Cascorbi and Blake, 1971; Cohen, 1969). A
similar pattern for H-2402 has not been proposed and would not seem indicated
although it cannot be ruled out - on the basis of what is known of its toxic
effects.
Van Stee and Back (1971a) have monitored the levels of H-1301 in
blood, brain, and heart tissue during five-minute exposures to 71-76% H-1301.
The results are given in Figure 21.
Figure 21. Rat brain and heart
concentrations of CBrF3 during
and after 5-minute exposures to
71-76% CBrF3 in 02 (n=10, mean
± SD). The A-»-A line represent,-!
blood concentrations of CBrF3
observed during an experiment
in which the conditions were
similar to those of the brain-
heart experiments (n=l)
(Van Stee and Back, 1971a).
6^'N I MtAN • STANDARD DEVIATION
102
-------
As Figure21 indicates, H-1301 concentration in the brain increased twice as
rapidly and reached levels 50% above those of the heart and blood. Further,
A,
o :
levels of H^1301 two minutes following exposure were significantly higher
in the brain than the heart. This pattern probably reflects the lipid
solubility of H-1301 which is more concentrated in the central nervous system
than the heart because of the high lipid concentration of the former as
compared to the latter (Van Stee and Back, 1971a).
Sherman (1974) has studied tissue distribution of F-12 in rats and
dogs over one and two years of oral administration. A summary of the results
is given in Tables XLIV and XLV.
Table XLIV. Tissue distribution of residual F-12
in control rats and in rats fed 0.2% (w/v)
and 2.0% (w/v) F-12 over a two year period
(Sherman, 1974)
MALE
Year
mg administered
0 Low High
FEMALE
Adrenals
Blood
Bone Marrow
Brain
Fat .
Heart
Kidney
Liver
Muscle
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
< 0.06
1.22
< 0.01
< 0.04
0.05
< 0.01
< 0.01
< 0.06
< 0.01
< 0.02
< 0.02
< 0.02
< 0.02
< 0,01
< 0.01
< 0.01
< 0.03
< 0.01
< 0.04
0.35
< 0.01
< 0.04
< 0.03
0.49
< 0.01
< 0.06
< 0.01
< 0.01
< 0.02
< 0.02
< 0.02
< 0.01
< 0.01
< 0.01
< 0.03
< 0.01
< 0.04
2.11
< 0.01
< 0.05
< 0.03
0.74
< 0.01
< 0.10
0.13
0.17
< 0.02
< 0.02
< 0.02
< 0.01
< 0.01
< 0.01
< 0.03
< 0.01
< 0.06
1.34
< 0.04
< 0.05
< 0.03
0.56
< 0.01
< 0.12
2.28
0.86
< 0.02
< 0.02
< 0.02
< 0.01
0.05
0.02
< 0.03
< 0.01
mg administered
0 Low High
< 0.07
0.68
< 0.01
< 0.04
0.11
< 0.01
< 0.01
< 0.06
< 0.01
< 0.02
< 0.02
< 0.01
< 0.03
< 0.01
< 0.01
< 0.01
< 0.03
< 0.01
< 0.06
0.67
< 0.01
< 0.04
< 0.06
1.70
< 0.01
< 0.10
< 0.01
< 0.01
< 0.02
< 0.01
< 0.03
< 0.01
< 0.01
< 0.01
< 0.03
< 0.01
< 0.04
1.38
< 0.01
< 0.05
< 0.04
0.71
< 0.01
< 0.10
0.11
0.04
< 0.02
< 0.02
< 0.03
< 0.01
< 0.01
< 0.01
< 0.03
< 0.01
< 0.04
1.64
< 0.01
< 0.05
0.07
1.70
< 0.01
< 0.12
1.15
0.71
< 0.02
< 0.01
< 0.03
< 0.01
< 0.01
< 0.01
< 0.03
< 0.01
* pptn » Hg/nil blood or Mg/g wet tissue.
103
-------
Table XLV. Tissue distribution of residual F-12
in control dogs and dogs fed 0,03%
and 0.3% F-12 over a two year period
(Sherman, 1974)
MALE
FEMALE
Adrenals
Blood
Bone Marrow
Brain
Fat
Heart
Kidney
Liver
Muscle
Year
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
ppm administered
0 300 3,000
< 0.01
1.04
< 0.01
< 0.04
< 0.08
0.47
< 0.01
< 0.09
< 0.01
' 0.02
< 0.02
< 0.01
< 0.01
< 0.01
< 0.01
< 0.01
< 0.03
< 0.01
1.23
< 0.04
0.45
< 0.09
0.23
< 0.01
< 0.01
< 0.01
< 0.01
< 0.01
0.88
< 0.01
< 0.04
< 0.07
0.65
< 0.01
< 0.09
0.25
0.12
< 0.02
< 0.01
0.01
< 0.01
< 0.01
< 0.01
< 0.03
< 0.01
ppm
0
< 0.01
1.73
< 0.01
< 0.02
< 0.05
0.50
< 0.01
< 0.09
< 0.01
0.15
< 0.02
< 0.01
< 0.01
< 0.01
< 0.01
< 0.01
< 0.03
< 0.01
administered
300 3,000
-
< 0.02
1.16
< 0.09
0.34
< 0.01
< 0.01
< 0.01
< 0.01
< 0.0.1
1.50
< 0.01
< 0.02
1.55
< 0.01
< 0.09
0.52
1.19
< 0.02
< 0.01
< 0.01
< 0.01
< 0.01
< 0.01
< 0.03
< 0.01
ppm = |ag/ml blood or Hg/g wet tissue.
In rats, there seems to be some indication of tissue storage by the adrenals,
bone marrow, and fat. However, the relatively high concentrations of a
compound with the same peak retention time found in control animals may
indicate either interference from an unrelated material or contamination of
the controls with F-12. A similar pattern is seen in the results of dog
feeding studies. Because the postulated interferring agent was not identified,
the quantitative significance of these findings is difficult to assess
(Sherman, 1974).
104
-------
From the information'presented on absorption, elimination, transport,
and distribution, the following general scheme of fluorocarbon uptake seems
evident. Fluorocarbons are absorbed and transported by the blood. Absorption
takes place primarily across the alveolar membranes * The amount and rate of
absorption depends upon a variety of factors including the physical and
chemical characteristics of the particular fluorocarbon, the concentrations
of the fluorocarbon in the ambient air, breathing patterns, and possibly
individual differences in ability to absorb these compounds. If exposure
is sufficiently long, an equilibria is reached among ambient air, blood,
and tissue concentrations. The fluorocarbons, being more lipid than water
soluble, seem to concentrate in areas of high lipid content. All of the
studies monitoring fat tissue indicate some degree of concentration in fat.
The high adrenal levels of F-ll and F-12 (Allen and Hansbury Ltd., 1971)
and brain levels for H-1301 (Van Stee and Back, 1971a) do not represent
equilibrium values. Carter (1970), however, in seven and fourteen-day
exposures did note higher concentrations of F-113 in the brain than in the
heart comparable to those for H-1301. Similarly, Sherman (1974) in long
term feeding studies did note some degree of adrenal concentration for F-12
but its relevance to extremely high values noted by Allen and Hansbury, Ltd.
for F-ll and F-12 (1971) is limited. Thus, until more information becomes
available on equilibria concentration of a wider variety of fluorocarbons,
the most that can be suggested concerning tissue distribution is that,
depending upon the lipid solubility of the fluorocarbon, tissues with a higher
lipid content than blood will probably concentrate fluorocarbons from the
105
-------
blood. The relative amounts of fluorocarbons absorbed by body tissue will
probably correspond to the relative order of absorption by blood from the
air as outlined in the section on absorption/elimination.
106
-------
C. Metabolic Effects
The fluorlnated propellants, solvents, and fire extinguishing agents
are notable for their relatively lovnliver toxicity when compared to other
halocarbons such as carbon tetrachloride and halothane (see Section XII,
Toxicity to Birds and Mammals). Both halothane and carbon tetrachloride
inhibit oxidative-phosphorylation in rat liver mitochondria (Snograss|and
Pinas, 1965). The fluorocarbons under consideration in this review do not,
for the most part, seem to behave in this manner.
As indicated in Figures 22 & 23, Griffin and coworkers (1972) have
shown that a variety of fluorocarbons do not markedly effect oxygen
consumption or oxidative phosphorylation in isolated mitochondria from rats
exposed to fluorocarbons prior to mitochondria! isolation. \
-^F-l RANGE Of CONTROLS
LIVER
L.UNG
EXPOSURE CONDITIONS l0'
COMPOUND %INAlR TIME.MIN
HA
IIA
fK
fK
fK
4-
2-
n-
LON 2402 6.2 10
L.ON 1 301 6.8 30
EON 116 7.3 30
EON C 318 5.0 30
EON 12 7.6 30
BRAIN
[
g§§
.;>;. ;
P
m
&£
tasa
5-
10-
j J
n-
ffiffi
2402
P^
j]
SfiS
^p
1301 116 C-318
HEART
ssw
Sm
'•i-fS
•':
10-
1 V
12
20-
^
10-<
[
[
SS5
JgS
— — -- — —
-;.
m
?40? 1301 116 C-318 12
KIDNEY
2402 1301 116 C318 12 " 24021301 116 C-318 12 " 2402 1301 116 C3I8 12
FIGURE 22. Oxygen consumption in mitochondria from rnf.s exposed to halo-
carbons. Mitochondria were isolated from tissues after the
rats were exposed under the indicated conditions. Mitochon-
dria from controls were assayed simultaneously with the ex-
perimental groups and the range of activities includes data
from all five groups of controls. The rate of oxygen con-
sumption is expressed as myAO consumed/ing protein /min X
10'
'• (Griffin et al., 197?.)
107
-------
tjjgjj RANGE OF CONTROLS
EXPOSURE CONDITIONS I0
COMPOUND %IN AIR TIME.MIN
HALON2402 6.2 10 5-
HALON 1301 6.8 30
FREON 116 7.3 30
FREON C-318 5.0 30
FREON 12 7.6 30
LIVER
LUNG
VS
20
10
BRAIN
2402 1301 116 C-318 12
HEART
«s«
2402 1301 116 C-318 12
KIDNEY
tie c-318
10
?
2402
301 116
12
20
10-
2402 1301 116 C3I8 12
FIGURE23. Oxidative phosphorylation in mitochondria from rals exposed
to halocarbon. Mitochondria were isolntnd froui tissues after
the Vats were exposed under the indicated conditions. Mito-
chondria from controls were assayed simultaneously with the
experimental groups and the range of activities included data
from all five groups of controls. Thp rate of phosphoryla-
tion is expressed as mu Moles P^ esterified/mg protein/min
X ID"1. (Griffin et al., 1972)
Further jjn vitro studies were conducted with liver and heart mitochondria
in which measurements were taken during actual exposure of the mitochondria
to either 20% F-12 or H-1301. No effects were noted on either oxidation or
phosphorylation (Griffin £t. al., 1972).
However, Van Auken and Wilson (1973) have demonstrated that F-21
at concentrations of 0.1% (w/v) decreases respiratory control and ADP/0
ratio in mitochondria isolated from rabbit liver and mung bean.
108
-------
A Mung Bean
B Rabbit
I ;_„
R.C.-13
0.9
Figure 24. The effect of Freon-21 on coupling parameters of rabbit
liver and mung bean mitochondria. A) Mung bean. The
reaction mixture of 3.2 ml contained: 0.3 M mannitol,
4 raM MgCl2, 2 mM K-POi,, pH 7.4, 50 mM tris-ticine, pH 7.4.
Additions include: M Mitochondria (0.15 mg protein), 8 mM
Na-succinate pH 7.4, R.C. respiratory control. Numbers
on traces are ymoles. 0£per rain. B) Rabbit liver. The
reaction mixture of 1.5 ml contained: 0.2 M mammitol,
10 mM tris-tricine, pH 7.2, 4 mM MgCla, 2 mM K-POit, pH 7.2,
8 mM succinate and approximately 0.7 mg protein. ADP was
added as 85 nmoles per aliquot. (Van Auken and Wilson, 1973);
reprinted with permission from Springer-Verlag, Copyright 1973.
The above data would seem to suggest at least some loss of respiratory
control. However, the respiration rates are not altered by F-21 indicating
•i
that it is not a typical uncoupling agent (Van Auken and Wilson, 1973).
A number of investigators have been concerned with the possible
binding of fluorocarbon molecules to portions of biologically important macro-
molecules. Nunn (1972) has postulated a general theory of anesthesia
involving a Van der Waal's attraction between the anesthetic and hydrophobic
areas of macromolecu.les including proteins. Halsey (1974) speculates, on
109
-------
the basis of N.M.R. data, that fluorocarbons such as F-12, F-22, F-14, and
F-116 may behave similarly to conventional anesthetics, interacting with
various hydrophobic sites in macromolecules. Young and Parker (1972),
however, propose that F-12 at least is bound to the hydrophilic areas of
various phospholipids in that potassium chloride stops arrhythmia induced
by epinephrine in hearth sensitized by F-12, apparently displacing the
F-12 molecule held by the phospholipld (see Section XII, D-l, Epinephrine
i
Induced Cardiac Arrhythmia). Cox and coworkers (1972a and b) indicate the
F-ll binds to the phospholipids in the liver cytochrome P-450. Epstein
and coworkers (1967b) indicate that unspecified fluorocarbons induce liver
microsomal enzyme synthesis. Thus, while the lipid soluble fluorocarbohs
may complex with a variety of macromolecules and possibly effect lipid
membrane systems, no clear correlation can yet be drawn between this
possibility and their biological activity.
110
-------
D. Metabolism
Just as the fluorinated propellants, solvents, and fire extinguishing
agents seem to differ significantly from other low molecular weight halocarbons
in metabolic effects, so do they differ in metabolism. The toxic effects of
both carbon tetrachloride and halothane have been linked to their enzymatic
dehalogenatlon involving free radical formation (Slater and Sawyer, 1971;
Rosenburg, 1972).. Although such biotransformation cannot be ruled out over
periods of prolonged exposure at low concentration and low rates of trans-
formation, there is little hard evidence as yet to indicate that Significant
metabolism does occur.
Of the fluorocarbons under review, only the fluoromethanes F-ll and
F-12 are topics of published reports on metabolism. Cox and coworkers (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 and F-112, they incubated 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 (Cox
et al., 1972a).
Blake and Mergner (1974) have studied the possible metabolism in
beagles of both F-ll and F-12 using carbon-14 labelled compounds. The
radiolabelled impurities in F-ll C89.6% pure) were 9% 14CC1, and 1.4% 14CHC13.
The radiolabelled impurities in F-12 (96.0% pure) were 14CF3C1 and/or ^CF^.
Ill
-------
Exposures to F-^ll ranged from concentrations of 0.19% to Q.55% for periods
of from six minutes to twenty minutes. Exposures to F-12 ranged from
concentrations of 0.82% to 11.8% over the same periods. The results are
summarized in Tables XLVI and XLVII.
Table XLVI. Recovery and Inhalation of F-ll and F-12 in Beagles
(adapted from Blake and Mergner, 1974).
Recovery of Radioactivity
(Percent of Inhaled Dose)
Exhaled Exhaled as Urine Total
Unchanged C02
F-ll
F-12
101.6 ±
103.0 ±
14.3 0.30 ± .13 0.0095 ± .007 101.8 ± 13.8
6.2 0.14 ± .04 0.04 ± .02 103.2 ± 6.3
Table XLVI I.
Tissue Concentrations of Non-volatile Radioactivity
in Beagles 24 hours after Inhalation of
F-ll and F-12.
AUrtn.il.
BloM
Brain, C'.rl.ix
Bralr.. Miilhr.u.i
[•„,. M-s-.,,t,,n.:
Hoart, Alrlum
He«rl,.V"nlr».-|(!
lnt«blhic, .'Jmall
Kutnoy
LlVI!)
l.iin.i
Musfh'. Skulo.il
Ovrtty
MiiUi I'omiih'
IS«. 92
u.n. N.I>.
236 VI
>r, I7ii
120 74
271 101
MM 7V
l',l 1
23". HJ
ibi tim
11 i !•'•
:nz M
27V
170
K.I
I HI
'/A II
III
112
-------
14
For both F-ll and F-12, the total recovery of CO™ and non-volatile urinary
and tissue reactivity equals about 1% of the administered dose. Because the
radioactive impurities in the F-ll sample, carbon tetrachloride (.9%) and
trichloromethane (1.4%) are both known to be metabolized in animals, the
F-ll studies 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 fluorination leads to
increasing stability (Clayton, 1970). Consequently, if any or all of these
compounds were to be metabolized, F-12 would probably be the most readily
metabolized. F-12 study thus seems to give a rather sound indication that
about 1% of F-12 - and/or F-13 and F-14 - are metabolized after relatively
.. . • !
brief exposures.
Eddy and Griffith (1971) have obtained results on the metabolism of
carbon-14 labelled F-12 in rats on oral administration showing a somewhat
greater degree of metabolism. About 2% of the total dose is exhaled as CCL
and about 0.5% excreted in the urine. By thirty hours after administration,
the fluorocarbon and its metabolites are no longer present in the body.
Further studies on the metabolism of fluorocarbon propellants,
solvents, or fire extinguishing agents have not been encountered. The
current view of metabolism of the fluorinated anesthetic halothane, however,
is given in Figure 25.
113
-------
F-C -CH2OH •—• f— C — CHO • F- C- C -NH— CH2 - CHj-OH
TRIFLUOROACETY LETHANOLAMINE
Figure 25. Possible Metabolic Pathways for Halothane
(from Rosenburg, 1972)
A number of other fluorocarbons seem to follow a similar pattern. Fluoroxene
(trifluoroethyl vinyl ether) may be metabolized to trifluoroethanol in mice
or trifluoroacetic acid in man (Cascorbi and Singh-Amaranath, 1972).
Hexafluorodichlorobutene may also be metabolized to trifluoroacetic acid
and other unidentified acids (Truhant et ai., 1972). In the metabolism of
halothane, it should be noted that all biotransformations take place in the
non-fluoro-substituted carbon. In the commercially important fluoroethanes,
this type of metabolism would not be expected in that both carbons usually
are fluorosubstituted making both more refractory to biotransformation.
However, the study ot F-12 metabolism by Blake and Mergner (1974) would seem
tp indicate that fluorosubstitution of both carbons would not in itself preclude
metabolism. As these investigators indicate, the apparent resistance of
these compounds to metabolic degradation may be more a function of their
rapid elimination rather than chemical or biological stability. Over longer
periods of exposure, the fluorocarbons will not only be in equilibria with
114
-------
tissue for longer periods but also will be more likely to reach, less
accessable "deep" tissue compartments. Metabolic tests requiring longer
exposure periods will be necessary to assess the significance of such
multicompartment distribution (Blake and Mergner, 1974). However, it would
not be surprising if further studies show that a variety of fluorocarbons
undergo biotransformation. In fact, at low level exposures that would be
found in the general environment or home, such metabolism might be facilitated
by the lack of substrate or product inhibition (Halsey, 1974).
The significance of fluorocarbon metabolism is difficult to assess
with certainty because so little is actually known. Often, of course, a
compound may be metabolized to a compound of greater toxicity, such as
»
halothane to trifluoroacetic acid. Truhaut and coworkers (1972) have noted
a pattern in 2,3-dichloro-l,l,l,4,4,4-hexafluorobutene-2 [DCHFB] of delayed
death similar to that noted in l-chloro-l,2,2-trifluoroethylene (Walther
et_al., 1970).
Table XLVI1I. Delayed Death After DCHFB Administration
to Rabbits [Truhaut ^ al,., 1972]
Concentration 500 ppm 200 100 200 200
Exposure time 1 hour 1 hour 1 hour 30 rain. 15 min.
Delayed 85 min. 12 hours 4 days 3 days 0
Death to 3 1/2
hours
Such a delay may indicate that a metabolite rather than the parent compound
may be the toxic agent (Truhaut et al., 1972). Patterns of delayed death have
115
-------
also been noted for various fluorocarbons under review and will be considered
in the appropriate sections.. However, without clearer experimental evidence
on the possible metabolism of these fluorocarbons, delayed death cannot be
viewed as indicative of toxic metabolites.
116
-------
X. ENVIRONMENTAL TRANSPORT AND FATE
A. Persistence
The chemical stability of the commercial fluorocarbons would lead
one to believe that the compounds are very persistent in the environment.
The ability to monitor at least fluorocarbon 11 in relatively isolated parts
of the Atlantic Ocean (Lovelock &t_ al., 1973) tends to support this conten-
tion. However, the degree of persistence is relatively unknown. Lovelock
jet ,aJL. (1973) have suggested a residence time of 10 years. This assumes
no significant surface or tropospheric degradation and complete destruction
in the stratosphere (Lovelock, 1974). The transfer time to the stratosphere
sets the lower limit of 10 years. Su and Goldberg (1973) have suggested a
residence time of 30 years for fluorocarbon 12. The basis of this assign-
ment is unknown. !
B. Biological Degradation
Information on the biodegradability of the commercial fluorocarbons
is not available. However, their volatility would certainly limit, if not
preclude, biodegradation. Goldman (1972) has reviewed the enzytnology of
carbon-halogen bonds and suggested that although fluorines substituted in
the 2-position of short-chain fatty acids (e.g., fluoroacetate) are replaced
by hydroxyl groups, the high strength of the carbon-fluorine bond would
indicate a high biological stability in other compounds. And, in fact,
with any other compound containing the carbon-fluorine bond, with the
exception of fluoroacetate (e.g., trifluoroacetate, difluoroacetate,
2-fluoroproprionate, and 3-fluoroproprionate), fluoride release could not
be detected.
117
-------
C. Chemical Stability in the Environment
Three studies have examined the stability of fluorocarbons under
atmospheric conditions. Japar et_ al. (1974), Hester £t aJL. (1973), and
Saltzman e£ al. (1966) have all photolyzed fluorocarbons under varying
conditions and found no decomposition. Both Hester e£ al. (1973) and Japar
e£ .al.. (1974) used simulated smog conditions. Hester et_ al. (1973)
photolyzed fluorocarbons 11 and 12 in an ambient air sample for two months
and found no reaction. Saltzman et_ al. (1966) exposed a gaseous mixture of
CBrF3 and C^Q to ultraviolet light, water vapor, ozone, SC>2, and diluted
automobile exhaust and reported no degradation.
D. Environmental Transport
Because of the high vapor pressures of the fluorocarbon compounds,
the major environmental transportation route is through the atmosphere.
For example, Lovelock (1972) has determined that trichlorofluoromethane
concentrations of rural southern England and Ireland can be attributed to
sources on the European continent.
E. Bioaccumulation
Because of the high volatility of the compounds under consideration,
the possibility of bioaccumulation seems rather remote. Information on
this possibility is not available.
118
-------
XI. HUMAN TOXICITY
A. Accidental Exposures and Misuse
Fluorocarbon propellants - primarily F-ll and F-12 - have been associated
with the broader problem of abusive inhalation of aerosols. In an attempt
to achieve an intoxicated state, the aerosol is sprayed into a bag, the
bag placed over the mouth and nose, and the contents inhaled deeply. In
other cases, the bag containing concentrated aerosols is placed over the
head (Crooke, 1972). This procedure presents two potential hazards, the
aerosol itself and asphyxiation. Many of the early reports of aerosol
abuse, while recognizing the intoxicating effects of the fluorocarbons,
assumed on the basis of the then current understanding of fluorocarbon
toxicity that suffocation was the probable cause of death in fatal exposures
(Coleman, 1968; Hoffmann, 1968). However, as this practice became, more
wide spread, cases in which asphyxiation could not be the cause of death
became apparent. Bass (1970) describes one hundred and ten such deaths
occurring between 1962 and 1969, fifty-seven of which were associated with
fluorocarbon propellants. These deaths sometimes involved rigorous activity
during or immediately after inhalation, followed by the rapid onset of death
thus ruling out suffocation as the cause of these deaths. Bass (1970) con-
cluded that these deaths were probably caused by cardiac arrhythmia,
possibly aggravated by elevated levels of catecholamines due to stress and/or
moderate hypercapnia. This deduction was subsequently supported by a
variety of investigators who found that many fluorocarbons can sensitise
the hearts of various mammals to epinephrine induced arrhythmias and that
this effect may be magnified by an increase in blood carbon dioxide (e.g.,
Reinhardt £t al., 1971).
119
-------
A similar concern over the role of fluorocarbons in causing human
deaths has been expressed in cases of possible over use by asthmatics of
bronchiodilator drugs in aerosol nebulizers propelled by various fluoro-
carbons (Taylor and Harris, 1970a). Such nebulizers deliver a fixed amount
of fluorocarbon gases and bronchiodilator drugs per actuation. Two of the more
commonly cited formulations Medihaler-lso^and Isuprel Mistometer^ release
12.5 ml propellant (F-12 and F-114) and 5.8 ml propellant (F-ll, F-12, and
F-114) per actuation, respectively. In an acute asthmatic attack, Taylor
and Harris (1970a) postulate that these propellants may be inhaled in
sufficient quantities to cause cardiac arrhythmias. As with instances of
abusive inhalation, stress and oxygen deficiency may be contributing
factors. Although supported by some epidemiologic evidence -(see Part D
of this section), there is little hard data to indicate that this does occur
in man. However, this possibility has stimulated intense investigation and
considerable controversy in studies of laboratory animals (see Part D,
Section XII, Cardiac Effects of Fluorocarbons).
Clayton (1966) reports that approximately one liter of cold F-11.3
was accidently released into the stomach of an anesthetized patient. The
immediate effect of this exposure was transient cyanosis. For the next
three days, the patient experienced severe rectal irritation and diarrhea.
B. Occupational Exposure and Normal Use
The fluorocarbon gases have not presented a documented hazard in
terms of industrial hygiene and occupational safety. In 1952, Mendelhoff
associated chronic exposure to F-12 with malaise, chills, fever, nausea,
120
-------
abdominal pain and eventual death in a repair mechanic for refrigeration
equipment. However, in that exposure to methyl chloride and sulfur dioxide
as well as a moderate degree of alcoholism for several years were also
noted, this isolated case cannot be construed as a substantial indication
of F-12 toxicity. A similar case reported by Marti (1948) also included
exposure to sulfur dioxide and F-12 thermal decomposition products and thus
cannot be considered as indicative of F-12 human toxicity. In a recent study,
women using an average of 21.6 g of fluorocarbon propellents per woman per day
for four weeks did not evidence any adverse effects of measurable fluorocarbon
blood levels. The investigators estimate that the average exposure of the test
subjects was over nine times the amount normally used (Marier et al, 1973).
A group of fifty workers who were exposed to F-113 for a period of
up to four and a half years (mean 2.77 years) were evaluated for possible
V
adverse effects from concentrations of 46 to 4,700 ppm (mean 669 ppm;
median 4.35 ppm). No signs of toxicity were noted (Imbus and Adkins, 1972).
Only one investigator has implicated the fluorocarbons with a
serious health problem. Good (1974) contends that fluorocarbons used as
aerosol propellents may be a major cause of lung cancer in the United States.
This hypothesis is based largely on clinical data without follow-up animal
experiments. Sputum cytological techniques are used in which changes are
classified in five stages—Class I being normal and Class V showing marked
atypia. In a group of 200 heavy aerosol users, precancerous changes of
lung cells were noted in each individual which were reversed when aerosol
use was discontinued. In a second study (Good e_t_ al_., 1974) comparing 50
heavy users to 250 non-users or light users, 12 of the heavy users showed
moderate to marked atypical cell changes which were seen in only two of the
non-user/light user group. Good (1973) found that use of even such innocuous
121
-------
agents as breath fresheners in aerosols will result in Class 1,11 changes in
4-5 months. The resulting clinical syndrome, polymyalgia rhumatica, is
described as a low-grade fever, emotional upsets, without coughing. The
etiological progression is presumed to be ciliary paralysis resulting in
chronic gram negative infection of the lung. These organisms may produce a
mild toxin which causes the clinical symptoms and atypical changes in the
lung. A number of investigators are currently conducting research in this
;,
'area (Archer, 1974).
C. Controlled Human Studies
, Exposure to humans under experimental conditions has been thus far
restricted to three of the most common fluorocarbons: F-12, F-113, and
F-1301. Of these, F-1301 has received by far the most attention because of
its use as a fire extinguishing agent. !
Fluorocarbon-12 has been tested using human subjects by both
Kehoe (1943) and Azar and coworkers (1971). Kehoe (1943) exposed one sub-
ject 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 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
and coworkers (1972) noted only a 7% decrease in psychomotor test scores
and no effects at 0.1% concentration over the same period.
122
-------
Fluorocarbon-113 has been tested on human subjects by Stopps and
Mclaughlin (1967) and Reinhardt and coworkers (1971). Psychomotor per-
formance 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 concentrating 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. Reinhardt and coworkers (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 psycho-
motor ability were noted. No abnormal findings were noted during post-
exposure physical examination, 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-1301 exposures to human test subjects have been
summarized by Reinhardt and Reinke (1972). Concentrations of 1%, 3%, and
5% F-1301 for periods of three to three and a half minutes had no effect on
electrocardiograms or response times in three subjects. Concentrations of
7% and 10% over the same period, however, did result in 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% for 20-25 minutes caused a minimal decrease
in psychomotor performance while concentrations of 10% caused a more pronounced
123
-------
decrease in ten subjects. Drowsiness and an increased sense of well-being
were also noted. Graded concentrations of 5-17% H-1301 over periods of
15-20 minutes resulted in central nervous system effects ranging from
tingling to a feeling of impending unconsciousness (14% H-1301) in nine
out of ten subjects, with the remaining subject reporting no effects at
concentrations up to 15.7%. Cardiac effects were noted in only three of
the ten subjects. Effects in two subjects at 8.2-15.7% H-1301 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 initial exposure to
16.9% H-1301 but 36 hours later, after a five-minute exposure to 14% "H-1301,
developed cardiac arrhythmias including T-wave flattening, extrasystoles
forming bigeming, A-V dissociation, and multifocal premature beats. Clark
(1970) has also noted T-wave depression and tachycardia along with loss
of equilibrium and paresthesla in all subjects after less than a one-minute
exposure to 12% and 15% H-1301. 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 but no arrhythmias. In
addition to these studies, Call (1973) exposed eight subjects to concen-
trations of 4% and 7% B-1301 for three minutes In a hypobaric chamber main-
tained at 760mm Hg, 632mm Hg (equivalent to 5,000 feet), and 380 mmHg
(18,000 feet). Although no cardiac effects were noted in any exposures,
reaction times were increased from about 550 milliseconds to about 60Q
milliseconds at both concentrations and at all altitudes.
124
-------
Halon-1211, another fire extinguishing agent, has been
administered to humans at concentrations of 4-5%. After 30-40 seconds,
the subjects became dizzy and light-headed. These symptoms increased
after 'one minute and were accompanied by paresthesia of the fingers and
toes. One subject, exposed for two minutes, showed central nervous system
stimulation and a transient cardiac irregularity. Recovery was rapid and
without noticeable after-effects (Clark, 1972).
D. Epidemiology
In the narrowest sense, epidemiological investigations have not
been conducted and would not seem to apply to these fluorocarbons. As
indicated in a previous section, these compounds have not presented an
appreciable hazard in manufacture and although they are commonly u^ed in
most households, no wide-spread adverse effects have been unequivocably
attributed to these compounds under normal use. The patterns of abusive
inhalation have been studied by Bass (1970) and reviewed by Crooke (1972).
The abuse first appeared on the west coast in the early 1960's, moved
eastward and apparently gained some popularity by 1967, and has persisted
at least into 1972. Fluorocarbons, while the most popular, are only one
of many classes of compounds used in this practice; others include toluene,
benzene, trichloroethylene, acetone, and isopropyl alcohol. Kilien and
Harris (1972) have reported that over 140 cases of death from abusive
inhalation of aerosol propellants have been documented. These deaths have
occurred in individuals from 11 to 23 years of age, with the majority coming
from middle-income families (Bass, 1970). Such studies are of little use
125
-------
in assessing the environmental hazard of fluorocarbons since they indicate
only the potential for fatal abuse under environmentally unrealistic
conditions.
Taylor and Harris (1970b) have associated increasing deaths in
England due to asthma with increasing use of fluorocarbon propelled
ibronchodilators. The potential role of fluorocarbon propellants in such
deaths has also been underscored by Archer (1973). In England, asthmatics
have been found dead with empty aerosol nebulizers in their hands and in
other cases patients have been known to use two nebulizers prior to death
(Taylor and Harris, 1970b). However, such evidence is, at best, highly
circumstantial. While not denying the potential danger from overuse of
these nebulizers, a variety of factors must be considered in asthma deaths
before a correlation can be accepted as a cause-effect relationship
(Silverglade, 1971b).
126
-------
XII. TOXICITY TO BIRDS AND MAMMALS
A. Acute Toxicity
1. Acute Inhalation Toxicity
A variety of fluoromethanes and ethanes, including those of
commercial importance, have been tested for acute inhalation toxicity in
standard laboratory mammals. For the most part, these tests have attempted
to evaluate either the human health hazard from occupational exposure
(e.g., Desoille et^ al., 1973; Steinberg et _al., 1969; Yant e£ al., 1932) or'
their anesthetic potency (e.g., Carpenter, 1954; Miller et_ al^., 1967;
Van Poznak and Artusio, 1960). Thus, much of the information is given in
terms of lethality, loss of responsiveness, or other adverse effects such
as convulsions or tremors. Summaries of the available data are given in
Tables IL-LIV. In these tables, some attempt is made to give dose-response
relationships by using five response categories. Approximate lethal con-
centration (ALC) is the minimum concentration causing death in any of the
animals over a given exposure period and is usually only somewhat less than
the concentration causing death in half of the exposed animals (LCso). The
anesthetic concentrations usually represent the concentration at which
certain basic reflexes are lost; e.g., the righting reflex. The concentra-
tion causing tremors is used rather than the concentrations causing convul-
sions because the former usually represents the minimum concentration causing
any marked response. It will be noted that the concentration causing tremors
is usually below that causing anesthesia; thus most of the fluorocarbons are.
not satisfactory anesthetics. The non-rlethal concentration is admittedly
somewhat ambiguous. In most cases, it merely represents a concentration not
127
-------
causing death. However, in instances where it is lower than the tremor
concentration, the non-lethal concentration is a reasonable approximation of
the "no marked effect" level. In a few cases, important observations not
fitting the above categories are included in brackets. Information not
supplied in the original study is indicated by "N.S.".
Many review articles, especially those of Clayton (1962, 1966,
1967a and b, 1970) have emphasized the relationship between fluorination
and toxicity: as the degree of fluorination increases in a given series,
the toxicity decreases. This relationship and the relationships between
the various groups presented in Tables IL-LIV are given in Figure 26 using
LCso's or ALC's. To make the comparison as valid as possible, preference
is given to data on rats and exposure periods of four hours. Values ;Of
i
less than one-half hour or greater than six hours are not used. In cases
where there is more than one compound in a single category, the most
halogenated is plotted first.
128
-------
Table IL. Acute Inhalation Toxicity of Perhalomethanes in Laboratory Mammals.
Responses
Fluorocarbon Code
CC13F F-ll
CC12F2 F_12
F-ll/F-12 (1:1, v/v)
cc.;r3 F-IJ
C?u F-U
Animal
Rats
Mice
Rabbit and Guinea Pig
Guinea Pig
Rats, Guinea Pigs
and Rabbits
Rats
Mice
Rats
Higher Vertebrates (N.S.)
Rats
Dogs , Monkeys and
Guinea Pigs
Guinea Pig
Mice
Rats
Guinea Pig
Guinea Pig
S.S.
ALC l>C5o Anesth. Tremors Non-lethal Duration
6?, 4 hr.
10% 20-30 min.
20Z 5 min.
15% 30 min.
10% 20 rain..
<9Z ' ' N.S.
3.3* N.S.
102 30 min.
252 30 min.
10% 2 hr.
>80Z 30 min.
.801 4-6 hrs.
76Z 30 min.
50Z 1 hour
40X N.S.
30-40% N.S.
20Z Prolonged
20% 2 hr.
22Z 30 min.
30% 30 min.
50% 30 min.
2\>T. 2 hr.
20S 2 hr.
Reference
Waritz, 1971
Lester and Greeaburg,
Kuebler, 1964
Paulet, 1969
Keubler, 1964
Lester and Greenburg,
Waritz, 1971
Paulet, 1964
Paulet, 1964
Clayton, 1966
Paulet, 1969
Lester and Greenburg,
Paulet. 1969
Keubler, 1964
Caujolle, 1964
Lester and Greenburg,
Sayers e£ al. , 1930
Clayton, 1966
Paulet, 1969
Paulet, 1969
Paulet, 1969
Clayton, 1966
Zapp, no date
1950
1950
1950
1950
-------
Table L. Acute Inhalation Toxicity of Halo-unsaturated Methanes in Laboratory Animals
Fluorocarbon
Code Animal
Anesth.
Tremors
Non-lethal
Duration
Reference
CHC12F
CHClFj
CHF,
F-21 Guinea Pig
Higher Vertebrates
F-22 Guinea Pigs
Dogs
Mice
F-23 Rat
Dogs
52
10Z
10%
70Z
40Z
<2 hr.
1 hr.
brief
1-22 several
minutes
10% 2 hr.
202 2 hr.
40Z <90 min.
2 hr.
202 2 hr.
802 <90 mln.
Caujolle, 1964
Clayton, 1966
Caujolle, 1964
Caujolle, 1964
Waritz, 1971
Caujolle, 1964
Van Poznak and Artusio,
Clayton, 1966
Zapp, oo date
Van Poznak and Artusio,
1960
1960
u>
o
-------
Table LI. Acute Inhalation Toxicity of Perhaloethanes in Laboratory Mammals
u>
Fluorocarbon
CC12F-CC12F
CC13-CC1F2
CF2C1-CFC12
CC1F2-CC1F:.
CF-,-CFC:2
CF3-CC!.F;
CFj-CF,
F-22/F-115
Code Animal
112 Rat
Rat
112a Rat
113 Rat
Mice
Mice
Mice and Rats
Mice
Rats
Guinea Pig
Dog
F-114 Rats
Mice
Dogs
Guinea Pig
Miv.i
J!4.i ••H.:i-
!"..l
*n:it: i t.
K.-ils
n:> K.its
lit Rats
F-502 Rats •
ALC 1X50 Anesth. Tremors Xon-letnal
1.5S
32 [severe pulmonary hemorrhage]
0.5" (delayer death, 18-36 hrs.j
1.5%
2-3%
5.5%
8.69::
10%
20%
11% [some delayed death <2 hr.)
>10Z
9.5!:
15%
5.7% [delaved death with >6Z]
2.5-2.9-
i . ir.
4.8-5.2%
12%
1.1:
1.3%
60%
502
20.'.
20-'
i iOi:alveolar hercc/rrhaee)
70^ rde!.ivec desvh, 43 ::r~ . "t
ii:.
75^.
20:. [iii Uyed death)
80.%(20i 0;)
80% (20% 0;)
[20% * pulmonary congestion]
Duration
4 hr.
40-60 min.
18 hr.
4 hr.
I!j-2l5 hr.
4 hr.
4 hr.
4 hr.
45 din.
2 hr.
30 min.
2 hr.
15 min.
30 min.
30 nin.
6 hrs.
1 hr.
2 hr.
6 hr.
1 hr.
2 hr.
2 hr.
1f\ ml r\
j\J ml.n .
2-5 inin.
? hr.
J 4 h r .
30 min.
30 min.
30 rain.
V c
4 hr.
N.S.
N.S.
Reference
Clayton e_t al. , 1964
Greenburg and Lester, 1950
Clayton et al. , 1964
Greenburg and Lester, 1950
Waritz, 1971
Clayton, 1966
DuPont, S-24, no date
Kuebler, 1964
Desoille et_ al. , 1968
Raventos and Lemon, 1965
Desoille et al. , 1968
Kuebler, 1964
Raventos and Lemon, 1965
DuPont, S-24, no date
Steinberg et al. , 1969
DuPont, S-24, no date
Desoille et_ al. , 1968
Steinberg et al^. , 1969
Steinberg et al. , 1969
Warltz; 1971
Kuebler, 1964
Paulet and Dcsbrousses t 1969
Yant et al., 1932
Yant et_ £l . , 1932
Quevauviller et_ aj^. , 1953
Paulet and Desbrcusses, 1969
Paulet, 1969
Paulet, 1969
Caujolle, 1964
Clayton, 1966
Caujolle, 1964
Caujolle, 1964
-------
Table LIT. Acute Inhalation Toxicity of Halo-unsaturated Ethanes In Laboratory Mammals
ro
Fluorocarbon
CF2C1-CH2C1
CC1F2-CH3
CHF2-CH3
CF3-CHC12
CC1F2-CHC1F
CF3-CH2C1
CF3-CH3
CClF2-CHFi
CF;-CHClr
CHFj-CF-,
Code Animal
F-H2 Mice
Mice
Rabbits
F-142H Mice
F-152a Rats
F-l23a Mice
F-123 Dog
Mice -
F-133
F-143 Mice
F-124 Guinea Pig
F-124a Dog
K-125 Rats
Uog
ALC LCso Anesth. Tremors Non-lethal
^•3" 1.31 [delaved death in 24-48 hrs.]
4.9Z 1.29Z[no delayed death noted
in IS days] 3Z [lung
lesions]
12. 8X
20Z
50-55%
<45%
6.4Z
7.4Z
7.7Z
2.4Z
2.7Z
7Z norie
4» none
7%
25% 8Z
152 «.3Z
50Z
202
• iOS '
10%
(30;.= Long lasting excitement stage]
Duration
10 siin.
30 min.
N.S.
4 hr.
S.S.
10-25 min.
N.S.
4 hr.
30 min.
10 min.
30 min.
10 Bin.
15 min.
30 min.
1 hr.
10 min.
30 min.
10 min.
2 hr.
2 min.
4 hr.
rapid onset
Reference
Robbins, 1«46
Raventos and Lemon ( 1965
Raventos and Lemon, 1965
Carpenter elt al_.y- 1949 . .. .. .
Lester and Greenburg, 1950
Lester and Greenburg, 1950
Carpenter et al. , 1949
Raventos and Lemon, 1965
Robbins, 1946
Baventos and Lemon, 1965
Robbins, 1946
Burn, 1959
Robbins, 1946
Raventos and Lemon, 1965
Robbins, 1946
Clayton, 1966
Van Poznak and Artusio, 1960
Clayton, 1966
Van Foznak and Artusio, 1960
-------
Table LIII. Acute Inhalation Toxicity of Bromofluoromethanes In Laboratory Mammals
u>
Fluorocarbon
CCl2FBr
CF2Br2
CClF2Br
CF3Br
Code Animal
H-1121 Mice
H-1202 Rat
H-1211 Rat
Mice and Rats
Rat
Guinea Pig
Dog
Monkey
H-1301 Rat
Mice and Rats
Mice and Guinea Pigs
Dogs
Mice, Rats, Rabbits
and Guinea Pigs
ALC LCso Anesth. Tremors Non-lethal
•>2Z
-2r:
5.52
30;
30-32*
23Z
6%
25X
23Z
62
52
7.8%
83.2Z[in 02 ]
80Z [in 02]
85% [in 02][ delayed death, .2 davs]
20%
80.'; [in 0: )
Duration
30 mln.
3Q nin.
15 min.
15 mln.
15 min.
30 nin.
12 min.
30 aln.
15-30 min.
21 nin.
3 min.
10 min.
15 nin.
30 min.
2 hr.
1-3 =in.
N.S.
Reference
Raventos and Lemon,
Raventos and Lemon,
Clayton, 1966
Beck et al., 1973
Clark, 1972
Clark, 1972
Beck et al., 1973
Caujolle, 1964
Clark, 1972
Beck et al., 1973 .
Beck et al., 1973 '
Beck et al., 1973
DuPont, S-35A, 1971
Caujolle, 1964
Paulet, 1962
Van Stee and Back,
Paulet, 1962
1965
1965
1969
-------
Table LIV. Acute Inhalation Toxicity of Bromofluoroethanes in Laboratory Mammals
OJ
Bluorocarbon
CH2Br-CF2Br
CH2Br-CHF2
CHBr2-CF3
CH2Br-CF,
CBrF2-CBrF2
CHBrF-CF3
Code Animal
H -220? Rats
H-2201 Rats
H-2302 Mice
Mice
H-2301 Mice
H-2402 Rats
H-2401 Dogs
ALC i-Cjo Anesth. Treaors Non-lechal Duration
0.5*
b
4.61 1
1.2Z 0.
2.0* 0,
9.76Z 2.
11. n 2.
17. 3Z
.25%
.31
.53
. 42
.51*
,8Z
25Z
18 hr.
18 hr.
10 min.
30 nin.
10 nin.
30 min.
10 min.
4 hr.
13.1 4 hr.
rapid
Reiereace
Lester and Greenburg, 1950
Lester and Creenburg, 1950
Bobbins ,
Robbins,
Raven tos
Robbins,
Rainaldi,
Kainaldi,
1946
1946
and Lemon, 1965
1946
1972
1972
Van Poznak and Artusio, 1&60
-------
100
90
2 3
NUMBER OF FLUORINE ATOMS
DATA FROM
TABLE IL: PERHALOMETHANES
TABLE L: HALO-UNSATURATED METHANES
TABLE LI: PERHALOETHANES
TABLE III: HALO-UNSATURATED ETHANES
TABLE Llll: BROMOFLUOROMETHANES
TABLE LIV: BROMOFLUOROETHANES
CCI3F
CH Cl F 2
C Cl 2 F Br
CCI2F2
CH Cl 2 F
CCI2 H - CCI., F
132. 142b. 1ft2a
CF2CIBi
CF Cl 2 - C CM 2
CF3 - CH Cl 2
CF3Bt
CH Br 2 - CF 3
CCI F2 CCI If
CBt F2 - CBi l-j
Figure 26: Comparative Toxicity of Various Fluorocarbons
135
-------
Similar relationships showing increasing potency with decreasing fluorina-
tion can be made in other responses given in Tables IL-LIV.
Although most of the published information on acute inhalation
toxicity is in relative agreement, certain studies warrant further elabora-
tion either because of unresolved details or information that could not
be adequately tabulated.
In evaluating the toxic effects of F-112 (CC12F-CC12F) and
F-112a (CCl3-CClF2), Greenburg and Lester (1950) noted that both compounds
were fatal to .rats at. 3%, although F-112a caused death in 1-2 1/2 hours
while F-112 was fatal in 40-60 minutes. However, the primary difference
*
noted was varying degrees of pulmonary hemorrhage caused by F-112 which
were not seen in F-112a exposed rats. Clayton and coworkers (1964), using
the same compounds, exposed rats for four hours and noted an ALC of approxi-
mately 1.5%. While unspecified effects were observed on the nervous .and
respiratory system, no pathology is reported.
Fluorocarbon-113 (CC12F-CC1F2) has been rather extensively
studied for acute inhalation toxicity. Although lethal concentrations
range between 5.5-20%, a two-hour exposure to 1.76% was associated with
moderate liver and kidney congestion in rats, while causing no loss of
coordination. A similar exposure to 3.91% F-113 did cause loss of coordina-
tion and pathological examination showed pale kidney and liver with some
fatty deposition. A ten-minute exposure to 5.09% caused similar loss of
coordination and pathological examination revealed mild liver congestion
and pale kidneys with focal necrosis (OuPont, S-34, no date).
136
-------
• Similar pathological data has not been reported and the rapid
reversibility of adverse effects on exposure termination has been emphasized
(Steinberg e± al., 1969). This is also noted by Desoille and coworker
(1968) who, however, also noted periods of torpor persisting several hours
after exposure to higher concentrations (=10%). These investigators further
observed delayed death up to two hours following exposure and, in
two animals, delayed death during the following week. This information is,
of course, equivocal. The data presented do not offer conclusive proof
that the fluorocarbon exposure actually caused the pathological observations
or the delayed death. However, delayed death may suggest that a metabolite
rather than the parent compound may be the toxic agent (Truhaut et_ _al_., 1972).
Metabolites would also be consistent with liver damage. Both Yant and
coworkers (1932) and Paulet and Desbrousses (1969) noted similar delayed
death with F-11A in dog at 20% and mice at 50% concentration. With Yant
and coworkers (1932), one dog died 69 hours after exposure and another
died 7.3 days after 16 hours of exposure to 20% F-114. Pathological find-
ings included moderate to marked congestion of lungs with areas of hemorrhage,
very marked congestion of the liver, and congested kidneys with pale
yellowish granular cortex.
The central nervous system effects of acute fluorocarbon
exposure have been most extensively studied for H-1301 (CBrFs). In terms
of lethality, this compound is among the least toxic of the fluorocarbons
with ALC's ranging from 80-85% in oxygen (see Table LIII). Paulet (1962)
noted fatality in mice and guinea pigs at concentrations of 80% H-1301
(in 20% Q£). Both guinea pigs and rats responded to ten-minute exposures
with general instability, difficulty in walking, and lethargy. Mice showed
137
-------
greatly reduced activity, more severe instability, tremors, and labored
breathing. Rabbits responded the most severely with protruding eye balls,
extreme dialation of the pupils, tremors, and brief convulsions. Rhoden
and Gabriel (1972), however, noted a much more severe response in Westar
rats at concentrations of 79% H-1301 (21% 02), consisting of convulsions
followed by respiratory arrest within 40 minutes of exposure. Van Stee and
Back (1969) noted species differences between monkeys and dogs. Dogs,
exposed to 50-80% H-1301 for 3-12 minutes, had epileptiform convulsions
of 10-30 seconds duration including rigidity, apnea, and cyanosis of the
tongue. At lower concentrations, dogs appeared agitated and exhibited
transient tremors. Monkeys, however, evidenced cortical depression,
shivering, and a tranquilization of their normally aggressive behavior.
In a subsequent study, Carter and coworkers (1960b) demonstrated that
20-25% H-1301 significantly impaired the performance of trained monkeys
and higher concentrations completely disrupted operant behavior without
signs of CNS depression or analgesia.
138
-------
2. Acute Oral Toxicity
Because of their uses and physical characteristics, very little
information is available on the acute oral toxicity of the fluorocarbons.
Such information is briefly summarized in Table LV.
Table LV. Acute oral toxicity of various fluoroalkanes in rats
(Clayton, 1966)
Fluorocarbon
CC12 F2
CHC12-CC1F2
CC12F-CC12F
CC1F2-CC13
CC1F2-CC12F
CC1F2-CC1F2
= Maximum feasible dose of fluorocarbon dissolved in peanut oil.
With the exception of a slight increase in liver weight at 25,000 mg/kg
CClF2-CCl3, no histological findings are noted by Clayton (1966) for these
exposures.
Michaelson and Huntsman (1964) determined the acute oral toxi-
city of F-113 in Sprague-Dawley male rats and arrived at the same figures as
those presented by Clayton (1966)—i.e. ALD = 45 g/kg, LDso = 43 g/kg.
The details of Michaelson and Huntsman's study are given below.. (See
Table LVI).
Code
F-12
F-122
F-112
F-112a
F-113
F-114
ALD, mg/kg
- 1 , 000
7,500
25,000
25,000
45,000 (LD50 =
+
>2,250
43,000)
139
-------
Table LVI. Acute Oral Toxicity of F-113 in Rats
(Michaelson and Huntsman, 1964)
Animal
group
1
2
3
4
5
6
Dose,
mg. /kg.
30
35
40
45
50
55
Mortality
total
animals
0/5
0/5
0/5
3/5
4/5
5/5
Approx.
time
of death
5 to 24 hr.
1 to 7 days
3 to 9 days
'
Av. wt.
change at
death, g.
• • •
• • •
• • •
-12
-49
0
Av. wt.
change of
survivors ,
g-
+46
+41
+19
+25
+31
* • *
The more rapid onset of death from lower lethal concentrations is noted but
no explanation is offered by the original investigators. Survival seems
to be related to weight maintenance but the mechanism involved is not
clear. All animals were reported to have liquid fecal discharge but
increased frequency of discharge is not noted. Significant pathological
findings in fatally exposed animals include hemorrhage in the lungs and
mottled surface but not discolored livers. Surviving animals showed only
slight lung hemorrhage at higher exposures. Introduction of 200 ml
(302g) F-113 into the stomachs of two dogs for two hours resulted in no
gross histological change.
Fluorocarbon-11 (CClaF) was intubated into albino female rats
at doses of 7.38 g/kg (Slater, 1965). Tests at three and twenty-four
hours after exposure showed normal serum beta-glucuronidase and, after one
hour, levels of liver NADP and NADPH2 were also normal. Histological
examination of the liver at three and twenty-four hours failed to show
any necrosis. No fatalities were noted.
140
-------
3. Acute Dermal Toxicity
\
Fluorocarbon-112 and F-112a have been applied on the skin of
rabbits at doses of 7.5 g/kg and 11 g/kg, respectively (the highest feasible
doses). Although no fatalities resulted, F-112 did cause skin erythema but
no systemic or histological effects. Fluorocarbon-112a caused severe skin
irritation in ethanol, weight loss, and histological changes in skin
musculature. Guinea pigs responded similarly to F-112 with mild irritation
but no sensitization.
Fluorocarbon-113 (CC12F-CC1F2) produced only local irritation
when applied at 11 g/kg to the skin of rabbits.
Fluorocarbon-114 produced no irritation when sprayed directly
on the backs of guinea pigs (Clayton, 1966).
141
-------
B. Subacute Toxicity
1. Subacute Inhalation Toxicity
Defining subacute and chronic toxicity studies of the various
fluorocarbons is somewhat arbitrary in that both duration of exposure (hrs/day)
and the number of days on which the exposures are repeated must be considered.
Most reviews do not differentiate between subacute and chronic studies (e.g.
Clayton, 1966; Waritz, 1973) and, in view of the paucity of demonstrable
toxic effects, this approach is justifiable. However, such classification includes
such exposures as 2 hrs/day x 20 days and 8 hrs/day x 3 days along with
exposures of 6 hrs/day x 300 days and 24 hrs/day x 92 days. In that most
present information indicates that these fluorocarbons are rapidly eliminated
from the body after terminating exposure, relatively brief exposures even
when repeated over a number of days probably represent a different type of
potential hazard than longer exposures repeated over comparable periods.
Thus, in this review, chronic exposures will be defined as those lasting
for at least 6 hrs/day [approximating occupational periods] and continued
for at least 30 days. Exposures not falling in this category are classified
as subacute. Using this admittedly arbitrary definition, data on subacute
inhalation toxicity is summarized in Table LVII.
142
-------
Table LVII. Subacute Inhalation Toxicity of Various Fluorocarbons.
Acute
Fluorocarfooo Code ALC Animal
G«3F F-ll 6Z x 4 hr. Rats
Mice
G. Pigs
Rabbits
Rats
Dog
Cats
G. Pigs
Rats
Mice
Dogs
Dogs
I (V/V)
Cone.
0.41
1.2Z
1.2SZ
2.5Z
25. OZ
24. 5Z
24. SZ
Hr/Day
6 hr.
4 hr.
3.5 hr
3.5 hr
0.83
(bid)
0.83
(bid)
0.83
(bid)
Days Mortality
28 0/12
0/8
0/2
0/1
10 0/4
20 0/2
20 0/2
0/3
0/5
1000 0/30
90 0/4
365 0/6
Comments
No significant signs of toxlcity
In any animals either after
exposure or after 15 days
recovery.
Slight twitching, chewing
•otlon, respiratory Increase
during exposure.
Pathology: Brain-neuronal edema
and neurollal vacuol; Ll«er-
vacuolatloo of cells; Lungs-
eiphyseoa and edema; Spleen-
Increased hematopolesls.
Mo signs of toxlclty
No signs of toxlclty
Ho signs of toxlclty
Total dose of 970 mg/kg/day
No signs of toxlclty
Total dose of 560 mg/kg/day
Transient drowsiness after
exposure.
Reference
Clayton
Clayton
Clayton
Clayton
Smith &
1973
Smith &
1973
Smith &
, 1966
, 1966
, 1966
, 1966
Case,
Case,
Case,
Total dose 2240 mg/kg/day
-------
Table LVII (continued)
Acute
Pluorocarbon Code ALC
CC*2F2 F-12 >80Z
Hats,
G. Pigs,
Rabbits
CCtF3 Frl3
CBrF3 F-1301 85Z x 2 hr
Mice &
K^ Guinea
*- Pigs
CHC*2F F-21 10Z x 1 hr
G. Pig
CHCtF2 F-22 403; x 2 hr
Mice
Ca2F-CC£2F F-112 1.5Z x
4 hr. , Rat
CCt3-CClF2 F-112a 1.52 x
4 hr. , Rat
Aaiaal
Cats
G. Pigs
Rats
fogs
House
Rat
Dog
Dog
Dog
Rats
Mice
Rats
G.Pigs
Puppies
Puppies
Rats
Rats
Rat
t (V/V)
Cone.
10Z
48.91
40. OZ
42.0Z
50. OZ
50. OZ
1Z
501
50Z
50Z
401
60Z
0.3Z
o.u
0.1Z
Hr/Day
3.5
0.83 (bid)
0.83 (bid)
0.83 (bid)
0.83 (bid)
0.83 (bid)
6
2
2
2
5 nin.
(bid)
5 min.
(bid)
4
18
18
Days
20
1000
93
93
90
365
20
15
15
15
14
14
10
16
16
Mortality
0/2
0/3
0/5
0/2
0/30
0/16
0/4
0/4
0/6
0/6
1/20
0
1/10
0/2
0/2
0/4
0/6
0/6
Comments
No signs of toxicity
No signs of toxicity
No signs of toxicity
No signs of toxicity
No signs of toxicity
Occasional depression and drowsi-
ness during exposure.
No signs of toxicity
Mortality not related to exposure
" " "
Sedation and ataxia during
exposure
Sedation and ataxia during
exposure
Prostrate and incoordinate during
first exposure. Rapid and shallow
respiration. Hyper-responsive
during each exposure. Immediate
recovery after exposure.
No evident effect
No evident effect
Reference
Clayton, 1966
Smith & Case,
1973
Clayton, 1966
Paulet, 1966
Smith & Case,
1973
Smith & Case,
1973
Clayton, 1966
Greenburg &
Lester, 1950
Greenburg &
Lester, 1950
-------
Table LVII (continued)
tn
Acute
Fluorocarbon Code ALC Animal
CCi2F-CCtF2 F-H3 5.5Z x Mice
4 hr.. Rats Cats
Dogs
G. Pigs
Rabbits
Rats
Rat
Mice
Dogs
Monkeys
Dogs
G. Pigs .
Rats
Rats
Z (V/V) Hr/Day
Cone.
1.1Z 0.83 (bid)
1.25Z 3.5
2.5Z 3.5
1.1Z 2*
j.
1.2Z 2
0.2Z 24
0.511 6
61 1
Days
690
20
20
120-1080
365-730
14
20*
5
Mortality
0/30
0/2
0/2
0/2
0/6
3/6
0/50
0/40
0/8
0/4
0/4
0/5
Cements
No signs of toxicity.
No signs of toxiclty
No variation from controls
Deaths not associated with
exposure. Slight sleepiness
during exposure.
Enlarged thyroid glands In all
nonkeys exposed. Rat kidneys
Increased In weight above controls.
Neither effect conclusively
attributed to exposure.
No toxic effects.
Liver: Two rats showed fair
amount of fat In Kupffer cells
Reference
Smith & Case, '73
Clayton, 1966
Desollle et al. ,
1968
Desollle et al. ,
1968
Carter et al. ,
1970
Steinberg et al.
1969
Burn et al. ,
1959
41
possibly Indicative of change
In llplds or llpoprotelns by
compound. Not definitely attri-
butable to exposure.
0/4 Mildly toxic effect In liver.
Moderate degree of mltotlc activity
In liver cell of one rat. Three
others showed similar activity at
a lesser degree.
-------
Table LVII (continued)
Acute
Fluorocarbon Code ALC
Z (V/V) Hr/Eay
Animal Cone -
Days Mortality
Reference
CCt¥2-CCi?2 F-114 60% x Cats 10 3.5
2 hr. , Rats G. Pigs
Rats
Dogs
Mice 10 2.5*
Hats
Mice 20
Rats
Rats LZ 2.5*
20 0/2
0/3
0/5
0/2
10 0/10
0/10
0/10
0/10
50 0/30
No signs of toxicity
No signs of toxicity
Exudative & congested lesions
of the alveoli and bronchioles
without cell structure alteration.
No toxic effects
Clayton, 1966
Faulet i
Desbrousses,
1969
Quevauviller,
e£ al. , 1953.
C. Pigs
14.161
20%
Dogs
21 1/6 So signs of toxicity. Death not Yant et al. ,
related to exposure. Occasional 1932
slight fatty degeneration of liver.
4 0/6 Ruffled fur and occasional
2 0/10 convulsive jerk. Increase In
excreta.
'!» 0/1' Salivation and -'retching.
21 0/J Occasional convulsions with
incoordicatior. and tremors during
first three days. After this, a
definite tolerance developed to
exposure. Increases in hemoglobin,
red blood cells, and younger forms
of pclymoryhonuclear leucocytes..
-------
Table LVII (continued)
Acute
Fluorocarbon Code ALC Animal
I (V/V)
Cone.
Hr/Day
Days
Mortality
Reference
F-114 cont.
20
F-142b 12.8°'. x
4 hr. . Rats
10Z
3-4 4/4 Sane as above, but more severe
Plus pathology as follows: Brain-
congestion of meningeal vessels;
heart-myocardium congested; liver-
very marked congestion with fri-
ability in some instances; Kidneys-
congested, pale yellowish glandular
cortex; Gastrointestinal tract-
gastric and duodenal mucosa markedly
congested and swollen. One dog had
suggestion of duodenal ulcer.
Rats
Rabbits
Mice
Rats
Dogs
Dogs
Dogs
U
12
25Z
502
50Z
25Z
252
2*
2*
0.83 (bid)
0.83 (bid)
0.83 (bid)
0.83 (bid)
0.83 (bid)
= 184
=207
690
93
93
90
365
2/6
0/6
0/30
0/16
0/4
0/4
0/6
16
Small increase in number of red
blood cells in rats.
No signs of toxicity
No toxic effects
No toxic effects
No toxic effects
So toxic effects
Occasional depression during
exposure.
7-9 10/10 Extensive consolidation and
hepatiz^cion of lung.
Desoille et al.
1973.
Smith & Case,
1973
Lester,Si
Greenburg, 1950
*Five days/week
-------
2. Subacute Oral Toxicity
As in cases of acute exposure, the subacute and chronic oral
toxicity of the fluorocarbons has not stimulated as extensive investigations
as the more common route of inhalation.
Fluorocarbons F-112 (CC12F-CC12F) and F-112a (CC1F2-CC13) have
been studied by both Greenburg and Lester (1950) and Clayton (1966). Rats
fed 2 gm/kg/day of either compound for 23 to 33 days exhibited no signs of
toxicity and no pathological changes in any organs (Greenburg and Lester, 1950).
At concentrations of 5g/day for ten days, both compounds caused tremors, inactivity,
initial weight loss, diahrhea, and slight increase in liver weight. In
addition, F-112 caused slight reversible histological change in the liver
(Clayton, 1966).
Similar to the above compounds, fluorocarbon 114 is tolerated by
rats at doses of 2g/kg/day for 23-33 days (Quevauviller, 1964).
Fluorocarbon 115 has also been tested at concentrations of
140-172 mg/kg/day for ten days (five days a week for two weeks). No evidence
of toxicity was found either immediately or ten days after exposure (Clayton,
1966).
3. Subacute Dermal Toxicity
Fluorocarbon-113 (CC12F-CC1F?) applied to rabbit's skin at
5g/kg/day for five days caused gross and histological damage to the skin as
well as slight changes in the liver (Clayton, 1966). Fluorocarbon-11, F-12,
F-113, and F-114 at 40% in sesame oil have been sprayed onto shaved rabbit
skin for twelve exposures with no effect. Severe local irritation is
148
-------
produced by F-113 at 5g/kg/day on shaved rabbit skin after five days. In
this instance, however, the sprayed surface was covered for two hours after
each application (Waritz, 1973).
149
-------
C. CHRONIC TOXICITY :
1. Chronic Inhalation Toxicity
Similar to information presented on subacute exposure in Table LVI1,
Table LVIII summarizes the work of various investigators on chronic exposures.
Jenkins and coworkers (1970), as indicated in Table LVIII,
studied the chronic toxicity of F-ll in rats, guinea pigs, rabbits, and
monkeys with exposures of 1.025% x 5 days/week x 6 weeks and 0.1% x 24 hrs/day
x 90 days. Only one animal died, a monkey used in the continuous exposure,
showing hemorrhagic lesions on the surface of the lung that was not directly
attributed to inhalation. In monkeys surviving continuous exposure, a large
amount of inflamatory infiltration was noted, occasionally associated with
microfilarial parasite infestation. Blood smears of half of all monkeys,
both experimental and control, showed such parasites. Nonspecific inflamation
of the lungs was evident in all experimental species except dogs used in
repeated exposure. Such changes were not described for control animals.
Mild discoloration was noted in the livers of one-fourth of the rats and
guinea pigs in both exposures. A 2 x A mm liver lesion was noted in one of
the male rats from the continuous exposure. Of eight rats examined after
repeated exposures, one evidenced focal myocytolysj.s and two showed focal
nonspecific myocarditis. The investigators iid not relate these, changes
to F-ll exposure. Marked increases in serum urea nitrogen were noted in
dogs exposed continuously (33 mg/100 ml) and repeatedly (36 ing/100 ml)
[control = 16.8 mg/100 ml]. This was not noted in any other animals tested.
150
-------
Table LVIII. Chronic Inhalation Toxicity of Various Fluorocarbons
Pluorocarbon
CCC3P
CC12F2
a\ct r2
C8rF3
cctyt-a:i,t
1
CCt;>P-CClF::
C«F?-CF3
CHj-CHFj
dl-i-CCH F?
Acute
Code AJ.C
F-ll 6Z x 4 hr.
Rats
F-12 -80X, Rats,
(;. Pign,
Rabbits
P-22 70!;, Rats
H-1301 85* x 3 hr.
Mir.c 4,
Ouine.a Pigs
F-112 1.5* x
4 lir. , Rats
F-113 5.5* x
4 hr. ,
Rats
F-115 -801 x
4 hr.,
Ruts
K-152a b.4X x
4 h r . ,
Kats
V-142a 12. 8Z x
4 hrs..
Racn
Z (V/V)
Animal Cone. Hr/D«y
Rats 1.025Z 8
C. Pigs
Dogs
Monkeys
Rats 0.1X 24
C. Pigs
Dogs
Monkeys
Dogs 20Z 7-8
Monkeys 20X 7-8
G. Pigs 20X 7-8
Rars 0.08402 8*
C. rit;n
Rabbits
Dogs
Monkeys
Rats 0.0810X 24
C. Pigs
Rabbits
Dogs
Monkeys
Rabbits 1.42 6
Ratu
Mice
Rats 0.1981 6
Mice
Rats 2.3X 6
Rats 0.1X 6
Mice
G. PigH
Ral.b i t
Rats 0.0252Z 7
Rats 0.5X 7
Rats 10X 6*
Mice
Rabbits
Dogs
Rats 10X 16
Rota 1Z 16
Mortal-
Days ley
30 0/15
0/15
0/2
0/9
°0 0/15
0/15
0/2
1/9
52 0/2
35-52 0/2
35-56 10/26
30 .'/I!)
1/15
0/3
0/2
0/3
90 1/15
0/15
0/5
0/2
0/'J
300 N.S.
N.S.
S.S.
300 N.S.
N.S.
N.S.
90 0/30
O/'J
31 0/H.
0/10
0/2
0/1
30 0/21
30 0/12
90 0/20
0/10
0/4
0/4
60 0/8
60 (>/'•
Comments
No outward signs of toxicity.
See text for detailed discussion.
Hemorrhaglc lesions on surface of
lung not directly attributable to
compound.
Dogs and monkeys apparently
developed tolerance to exposure.
tremors disappearing after first
two weeks. Deaths in Guinea pigs
not related to exposure. . See
text for more detailed discussion.
dilncu l'igs--'ieveral showed focal
necrosis or fatty Infiltration of
liver. Monkey-heavy pigment
deposits in liver, spleen, and
kidney.
Guinea pfgti-all showed slight to
extensive fatty infiltration of
liver and several had focal or
aubmasslve necrosis of liver
(see text) .
j
see text
Mo toxli- effects
No signs of Loxirtty
Kemale rats (8)': significant
ill-crease In leukocyte count.
Male Rats: liver and kidney
weights {{renter than control.
Transient liver reactions In rats.
No signs of toxicity
Three rats showed slightly
pale livers.
No signs of toxicity
No signs of Loxlcity. Mild
chronic Irritation of lungs In
five rats.
No signs ol toxictty. Mild
chronic irritation of lungs In
two rats.
Reference
Jenkins, et al. .
1970
Sayers et al. ,
1930
Prtnderna^t
ej. al. , 1967
Clayton, 1966
Clayton, 1966
Clayton, 1966
Clayton, 1966
Clayton, 1966
Clayton, 1966
Clayton et al . ,
1966
Lester s
Creenbun;, 1"50
Lester &
Creenhur:1, , ;•- '
* • 5 dayt/week
151
-------
Sayers and coworkers (1930) exposed dogs, monkeys, and guinea pigs
to CC«,2F2 at 20% for 7-8 hrs/day for periods of 35-52 days in most cases.
Ten of the twenty-six guinea pigs died during the test. These deaths, however,
were associated with handling procedures and not to fluorocarbon exposure.
During the first couple of weeks, dogs and to a lesser extent guinea pigs
developed tremors and ataxia during exposure. The subsidence of these effects
seemed to indicate a tolerance to F-12 exposure. Guinea pigs did not have
these signs. Also, during the first two or three weeks, a slight to moderate
weight loss was noted along with an increase In red blood cell count and
hemoglobin. Differential leucocyte count showed a slight decrease in
lymphocytes and an increase in polymorphonuclear neutrophils. No variations
from controls in frequency of pregnancy and bearing healthy young was noted
in exposed guinea pigs.
Prendergast and coworkers (1967) did note liver damage in guinea
pigs on both repeated and continuous exposures to F-12 at concentrations
below the TLV (1000 ppm). This effect does seem related to exposure in that
the severity of the affect increased in continuous as opposed to repeated
exposures. In referring to a study indicating that guinea pigs are parti-
cularly susceptible to liver damage and fatality when exposed to mineral
spirits (Rector et al., 1966), Prendergast and coworkers (1967) do not
definitely attribute the liver necrosis to F-12. However, it should be noted
that Rector and coworkers (1966), although recognizing that liver damage and
death may not be indicators of occult toxicity, do conclude that the guinea
pig is the best rather than an unsuitably susceptible test animal in setting
guidelines on long-terra low level exposure.
152
-------
Clayton (1966) referenced a study by Karpov (1963) exposing
rabbits, rats, and mice to 1.42% F-22 for 6 hrs/day x 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 subthreshold stimuli needed to induce a
response. Rabbits showed decreases in red blood cell count, hemoblobin,
lymphocytes, reticulocytes, blood cholinesterase, and serum albumin and
increases in neutrophiles, eosinophiles, and globulin. Pathological examina-
tion revealed degenerative changes in heart, liver, kidney, and nervous
system as well as changes in lungs leading to emphysema and exudate
alveolar septal thickening.
153
-------
2. Chronic Oral Toxicity
Fluorocarbon-12 is the only compound studied in which chronic
oral toxicity studies have been obtained: Studies of F-ll and F-114 have
also been recently completed (Waritz, 1973).
Waritz (1973) summarizes the results of a 90-day feeing 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 rats had elevated but not abnormal levels of urinary fluoride and
plasma alkaline phosphatase.
Sherman (1974) has conducted a two year feeding study in rats
using doses of 15 and 150 mg/kg/day. At the higher concentration, a rate
of body weight gain was decreased in both male and female rats (see Fig. 27).
•..„•••• °
FEMALES
. • CONTROL
•-• CONTROL
o LOW LEVEL FREON®I2
• • HIGH LEVEL FREON®I2
16 24 32 40 46 56
TIME IN WEEKS
64
BO
86
96
104
Figure 27. Growth of Male and Female Rats
Orally Administered F-12
(Sherman, 1974);
reprinted with permission from DuPont deNemours Co.
154
-------
A slight decrease was noted in the food use efficiency (g. wgt. gained/g. food
consumed) of female rats at the higher dosage level and this seems to be
reflected in growth curves. Levels of elevated urinary fluoride were not
noted. Other parameters tested - including liver function, hematology,
and histopathology - were normal.
155
-------
3. Chronic Dermal Toxicity
Fluorocarbon-H3 (CC&2F-CCilF2) has been applied to the shaved back
of rabbits five times a week for twenty weeks with no visible adverse affects
(Desoille et^ al., 1968) .
Quevauviller and coworkers (1964) and Quevauviller (1965) have
applied F-ll (CC43F), F-12 (CW2^), F-112, 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/day x 5 days/week x 5-6 weeks. Each compound was sprayed on the
surface for five or ten seconds from a distance of 10-20 cm. Slight irritation
was noted in the skin and no significant effects in Lhe other areas. However,
the healing rate of burns was noticeably retarded by all of the compounds as
indicated in Table LIX.
Table LIX. Per Cent Reduction of the Surface of Burns in Control
Rats and Burns Sprayed with Various Fluorocarbons
(Quevauviller, 1965)
Days
4
6
8
12
14
18
Control
31
48
65
80
87
100
F-ll
0
2.8
14
30
48
87
F-12
0
14
21
50
71
100 ?
F-ll
+ F-12
6.8
17
24
65
69
89
F-ll
+ F-22
5
36
55
79
92
100 ?
F-114
+ 6
+14
3
57
68
82*
156
-------
D. Cardiovascular Effects of Fluorocarbons
1. Cardiac Sensitization to Exogenous Epinephrine Induced Arrhythmias
Epinephrine, a catecholamine, is a potent adrenal cortical hormone.
In man, the mean blood plasma concentration is approximately 0.06 yg/H and
excesses are eliminated rapidly from the body, primarily through 0-methylation.
In stress, the human adrenal gland may secrete 0.004 mg/kg/min. The compound
has a variety of cardiovascular effects, chief of which are vasoconstriction -
resulting in increased blood pressure - and increases in both heart rate and
cardiac output. A variety of hydrocarbons, with and without halogen substi-
tution, have long been known to sensitize the heart to epinephrine induced
arrhythmias including ventricular fibrillation (Garb and Chenoweth, 1948;
Hays, 1972; Reinhardt «rt ,al., 1973). At various concentrations, f luorocarbons
used for aerosol propellants, solvents and fire extinguishing agents have
been shown to produce this effect. Because this arrhythmogenic action may be
related to a variety of human health hazards—e.g. bronchodilator nebulizer
over-use by asthmatics, "aerosol sniffing syndrome", exposures to high
concentrations of fire extinguishing agents [see Sect ion XI > Human Toxicity].-
a great deal of research has been stimulated in ihis area focused primarily on
determining the minimum concentration of fluorocarbons and epinephrine required
to produce arrhythmias in various mammals.
Reinhardt and coworkers (1971) have detailed what has been the most
common procedure for testing the ability of various fluorocarbons to sensi-
tize the heart to injected doses of epinephrine. The basic procedure is
outlined in Table LX.
157
-------
Table LX: Outline of a procedure for determining the ability of various
vapors to sensitize the heart to exogenous epinephrine-induced
arrhythmias (Reinhardt et al., 1971)
Minutes Conditions
0 Allow animal to breathe normal air.
2 Inject I.V. with dose of epinephrine
in normal saline over nine seconds
(control injection).
7 Expose to known concentration of gas.
12 Re-inject with epinephrine (challenge
injection).
17 Discontinue exposure to gas.
In most experiments, the animals are not anesthetized and all gases -
including normal air - are administered through a face mask. The standard
exposure period is five minutes and EGG recordings, generally lead II,
are continuous. By far the most critical parameter, however, is the dosage
of epinephrine administered, since in sufficient quantity this compound
alone may induce arrhythmias. Reinhardt and coworkers (1972), in formula-
ting their protocol, found that most previous investigators used between
0.004-0.04 mg/kg, the usual amount being 0.01 mg/kg. Because this type of
experiment is designed to simulate conditions of stre'.ss, the rate at which
the compound is administered is probably more important than the total dose.
The relevant data on epinephrine administration for the series of experi-
ments to determine the effects of fluorocarbon cardiac sensitization is
given in Table LXI.
158
-------
Table LXI. Epinephrine dosage used in determining the effect of fluorocarbons in
cardiac sensitization to exogenous epinephrine#
Epinephrine Dose
0.008 mg/kg
0.01 mg/kgH
0.007 rag/kg*?'
0.005 mg/kg
0.010 mg/kg
0.015 mg/kg
Duration of Administration Rate of Epinephrine Injected
9 seconds
25-40 seconds
2 minutes
2 minutes
2 minutes
2 minutes
0.053 mg/kg/min.
0.015-0.024 mg/kg/min.
0.0035 mg/kg/min.
0.0025 rag/kg/min.
0.005 mg/kg/min.
0.0075 mg/kg/min.
Author
Reinhardt et_ al. , 1971
Reinhardt e_t _al. , 1973
Mullin, 1970
Reinhardt and Reinkz, 1972
Burgison et al. , 1955 '
Wills (1972)
Wills (1972)
Wills (1972)
Wills (1972)
0.005 mg/kg
0.10 mg/kg*
0.002-0.003 mg/kg
O.OOJ-0.004 mg/kg+
O.iJIG rag./kgX(I.M.)
0.005 rag/kg1
10 seconds
not spec.
not spec.
not spec.
10 seconds
0.030 mg/kg/min.
0.030 mg/kg/min.
Clark & Tins ton, 1972
Van Stee and Back, 1969
Van Stee and Back, 1969
Van Stee and Back, 1969
Call, 1972
Beck ejt al.', 1973
//-Dogs, unless otherwise specified .
fl-Dogs and cats
j^-!)ogs and guinea pigs
t-Dogs and rabbits
x-rats
+-monkey
*-concentration used in all experiments but those designed to study dose-response of epine^hrine.
5 ug/kg/min. released by dogs during conditions of max. emotional stress - Satake, 1955.
-------
The rationale for these doses is two-fold. First, within the
experimental framework, they should represent doses which will not elicit
serious cardiac arrhythmias: this is determined by the control injection.
Secondly, in terms of applicability to hazard assessment, they should
approximate or exceed the endogenous output under conditions of stress.
The results obtained by the various investigators for a wide range of
0
one and two carbon fluorocarbons are summarized in Table LXII.
Although the results of the various investigators are in relative
agreement as to the concentrations of the fluorocarbons In inhaled
air necessary to cause arrhythmias, the other parameters which influence
these results must be fully appreciated. The most important of these are
the amount of epinephrine used and duration of exposure to the fluorocarbons.
The effect of epinephrine dosage on cardiac response to a 0.87%
F-ll over varying durations of exposure has been demonstrated by Wills (1972)
(see Figure 28).'
As would be expected, increasing the amount of injected epinephrine
increases the arrhythmic response. This is consistent with the earlier work
of Van Stee and Back (1969) who used epinephrine concentrations of
2-10 yg/kg. The control level sensitization five minutes after exposure
to F-ll is terminated reflects the rapid elimination of the compound from
the body. Similar observations of rapid loss to sensitization have been
made by Clark and Tinston (1972 a and b) . However, Wills (.1.972) notes
that maximum sensitization occurs after ten minutes exposure to F-ll and
falls off sharply thereafter. This decrease in response from the ten
minute exposure injection to the fourteen minute exposure injection cannot
be explained on the basis of other time-response studies.
160
-------
Table LXII. Cardiac responses of mammals exposed to fluorocarbons
and challenge injections of epinephrine
Compound
METHANES
CC1..F
CC1-F,
"
C1ICIK.,
ETHANES
C2C13F)
CC1F.-CC1F-
CF.j-CClF2
C2!6
CC1F.-CII
*
CHF -CH
F-22/F-115
Reference
v/v
Cone.
No. Animal %
F-U DORS .09-. 13
.32
.35-. 61
.63
.96-1.21
1.25
Guinea Pig .87
F-12 DORS 2.0
2.5
4.0
5.0
8.0
H-22 2.5
5.0
F-113 Dogs .25'-. 27
.40-. 57
.90-. 95
F-114 Dogs 2.5
2.5
5.0
5.0
10.0
F-llb Dugs 15
25
F-116 Dog 2.2
Guinea Fig 2.2
8.7
11. n
K-|.'.21. l)oK 2.5
5.0
10.0
F-152a Dog 5.0
15.0
F-502 Dog 5.0
10.0
20.0
key: 1. Beck et al
Duration
Mln.
5
3
5
5
5
5
15
5
5
5
',
5
5
•-•
5
5
5
5
5
5
5
5
5
5
15
15
15
'''
5
5
5
5
5
5
5
5
., 1973
2. Burgison et al. ,
3. Call, 1972
4. Clark and
5. Reinhardt
Tinston
et al. ,
No. Anlmuiu
Tested
12
4
12
4
12
4
6
4
12
4
12
4.
12
12
12
20
*
12
4
12
4
4
11
12
4
10
'1
'
I)
12
12
12
12
1:
12
12
1955
, 1972
1971
No
Si-nnl t-lzi-t! Z Sensitized
0
0
1
0
5
b
0
0
0
5
2
0
2
0
. 10
1
0
1)
7
0
*
i
4
2
',
2
(:
't
12
0
J
n
5
1 .*
6.
7.
8.
9.
0.0
0.0
8.1
0.0.
41.7
50.0
100.0
0.0
0.0
0.0
41.7
50.0
0
16. 1
0.0
•J4.5.
75.0
0
0
58.3
0
50.0
7.7
JJ.1
511. U
50.0
66.6
inn.n
0.0
41 . 7
100. 0
0.0
25.0
0.0
Ml.'
100.0
Reinhardt et
Reinhardt and
Van Stee and
Wills, 1972
Reference
5
4
5
4
5
4
9
4
5
4
5
4
',
•'
li
6
U
5
U
5
4
4
b
5
V
9
y
^
j
'i
j
.j
5
.3
;.
3
al., 1973
Reinke, 1972
Back, 1969
161
-------
Compound
ETHYLENES
CF.-CP,
!C H,F
C2C1F3
C2HC1F2
W
Bromo-su
substituted
CBrF..
CBrClF.
W'4
V/V
Cone.
No. Animal Z
Doc 25-50
Cat 25-50
Dog 25-50
CHI 25-50
Dog 25-50
Dog 25-50
Dog 25-50
H-1301 Dog 2.2
5.0
7.5
10.0
15.0
20.0
80.0
10.0-80.0
Guinea Pig 2.2
.8.7
Monkeys 20.0-80.0
Kuts 24.0
H-1211 Dog 0.5
1.0
2.0
4.0
Rabbit 2.0
4.0
H-2402 D°» !-8
i..uinea rig 1 .«
Table LXZI
(Continued)
Duration
Min.
5-15
5-15
5-15
5-15
5-15
5-15
5-15
15
5
5
5
5
5
35, 40
15
15
10+
5
5
5
5
5
5
15
Ir>
No. Animals No.
Tested
4
7.
8
'
4
"
2
4
62
18
69
7
1 3
2
10
6
see
KCU
4
7
4
2
/
''
4
Ml
Sensitized
0
0
0
II
4
4
2
3
0
1
8
2
H
2
' + . .
4
2
text for details
text for dft.-ills
1)
1
2
?•
0
1
L
'I
2 Sensitized
0.0
0.0
0.0
0.0
Idli.i)
100.0
100.0
75.0
0.0
5.0
ll.b
28. ft
61.5
100.0
40.0
33.3
O.CI
14.3
50.0 ,
100.0
0.0
33.3
25.0
')! 1 . 0
Reference
2
2
2
-
2
2
2
V
7
7
7
7
7
8
8
9
y
8
3
1
1
1
I
1
1
'9
'<
162
-------
IS
8
<
0 12/ng/kg
4
10
TIME (min.)
15
-H
20
EXPOSURE TO 0.87% F - 11
Figure 28: Number of Arrhythmic Heart beats in responses .to different
doses of epinephrine administered during exposure to
0.87% (V/V) F-ll (data from Wells, 1972).
163
-------
Reinhardt and coworkeis (1971) exposed dogs to varying concentrations of
F-12 for periods ranging from .5 minute to 10 minutes (see Table LXIII).
Table LXIII: Cardiac responses of dogs exposed to F-12 for varying
periods with challenge injections of epinephrine
(Reinhardt et al., 1971)
Duration of
Exposure
Concentration,
% V/V
No. of dog
exposures
No. of marked
responses
Percent marked
responses
0,
7.0*
6
1
16.7
.5 Min
7.0
7
0
0.0
5 Min
13.5
7
2(1)*
28.6
2.5
12
0
0.0
5.0
12
5(1)#
41.7
0.5 Hr
(2.48-2.58)t
6
0
0.0
1 Hr
(2.48-2.
6
0
0.0
50)t
* Oxygen concentration reduced to approximately 8.0%.
t Analytic concentration.
# Numbers in parentheses indicate number of cases of ventricular fibrillation
and cardiac arrest included in marked responses.
These results seem to indicate that a minimum concentration of F-12 in air
is necessary to sensitize the heart to epinephrine and that increasing the
period of exposure to lower concentrations will not result in arrhythmias.
Similarly, Beck and coworkers (1973), using H-1211, indicate that as the dura-
tion of exposure is increased, the concentration necessary to cause arrhythmias
decreases only to a point after which further exposure has no marked effect.
Neither of these studies, however, are designed so that they would show a
decreased response to epinephrine challenge with continued exposure as noted
by Wills (1972). Even though this decreased effect may be of significance
in determining the mechanism(s) involved in arrhythmias, most durations used
in Table LXII are for five minutes, and as such, the comparative arrhythmagenic
potentials of these compounds may be tentatively proposed. For the most part,
164
-------
the comparison is similar to that noted in standard inhalation studies: as
fluorination increases within a homologous series, toxicity tends to decrease.
Thus, for the fluoromethanes, the arrhythmagenic potency seems to be
F-ll > F-12 = F-22. A similar pattern is seen in the perhalo-ethanes
(F-113 > F-114 > F-115) and the bromochlorofluoromethanes (H-1211 > H-1301).
However, as illustrated in Table LXIV, an attempt to compare the potencies among
homologous series yields no definite pattern in terms of substitution.
Table LXIV. Percent of one and two carbon fluorocarbons causing arrhythmias
in dogs on epinephrine challenge after exposure of five minutes, (from Table LXII)
Halo-substitution
F Cl Br
F-ll
F-113
H-1211
F-12
F-22
F-114
F-142b
H-1301
F-152a
F-115
1
3
2
2
2
4
2
3
2
5
3
3
1
2
1
2
1
0
0
0
0
0
1
0
0
0
0
1
0
0
% (V/V)
Minimum
Cone. Noted to
Cause Arrhythmias
0.35
0.40
1.0
5.0
5.0
5.0
. 5.0
7.5
15.0
15.0
% V/V
Maximum Cone.
Causing No
Arrhythmias
0.32
0.27
0.5
4.0
2.5
2.5
2.5
5.0
5.0
165
-------
Although such comparisons are of interest in determining relative potencies, the
scope of Table LXIV is probably too narrow to be of any actual use other than
demonstrating the lack of absolute correlation between halosubstitution and
cardiac activity. For less readily absorbed compounds, exposure duration of
longer than five minutes must be considered. In so doing, compounds such
as F-116, H-1301 and H-1211 have sensitization potentials between F-12 and
F-113. Indeed, current information of blood levels causing sensitization,
as given in Table LXV, indicates that differences among the fluorocarbons may
primarily reflect differences in absorption characteristics rather than any
toxic mechanisms on the molecular level.
Table LXV: Blood levels, air concentrations, and exposure periods of various
fluorocarbons causing cardiac sensitization.
Compound '
F-ll
F-12
F-114
H-1211
F-12/ F-114
7.
Exposure
Cone.
0.1
0.5
0.63
1.0
1.5
0.1
4.0
5.0
8.0
10.0
5.0
10.0
8
5
2
30/9
Duration
(Mln.)
10
10
5
10
j
10
5
10
5
10
5
. 5 .
1.0
2.0
5.0
0.58
0.70
0.7V
Number of
Dogs
Sensitized
0/12
1/12
0/4
5/12
+•
•' / '+
N.n.
0/4
5 /.I 2
ll~>
M.U.
-t-
' 0/4
2/4
2/4
1/4
2/4
m*
1/1*
i/i*
Blood Concentrations
(pg/ml)
Arterial Venous
10.9 6.6
28.6 19. '1
10
53.2 37.2
20-25
20
1.0 0.9
;:2
3J.3 2:.h
)•>.'.)
46. J Vl. n
liU-'.ii
l.j
]4
21
2'i
24
',.:,/!. 8
6.3/2.3
6.V2.7
Reference
Azar et al., 1973
Azar et al . , 1973
Clark and Tinston,
Azar et al., 1973
Jack, 1971
Clark and Tinston,
i\7.:ir et. aJ . , !') 7 3
CUrk and Tinston,
AV..ir e^ jU. , ". 97 )
Clnrk .'iiitl Tln:;Lor.,
Az.ir et a! ., 197)
J.ick, 197!
Olark and Tlnscon,
Clnrk and Tinston,
licc-.k et al. , 1973
Ucck £t al_., .1973
Beck et al., 1973
Taylor et al. , 1971
Taylor e£ a±. , 1.971
1972a
1972a'
I'i'r.u
19?::.-.
1972a
1972a
Taylor et al. , 1971
*Monlteys
N.D. » not determined.
166
-------
Although blood level data is currently available only on these four
fluorocarbons, the remarkable similarities in lowest venous blood concen-
trations associated with cardiac sensitizatiqn in these various studies might
lead one to suspect that these compounds act in a similar and perhaps non-
specific manner in causing arrhythmias. This type of speculation is at
least circumstantially supported by the basic similarities in cardiac effects
caused by these and other halo-substituted hydrocarbons.
Having briefly reviewed the basic dose-response results available
on cardiac .sensitization to injected epinephrine, certain details of some
of these experiments should not be overlooked. As noted by Reinhardt and
coworkers (1971), the results obtained with F-502 may indicate potentiation
(see Table LXI1). Fluorocarbon 502 - an azotropic mixture of F-22 and F-115
approximately 61:39 (V/V) respectively - causes multiple ventricular beats
in five out of twelve dogs at a concentration of 10%—or 6.1% F-22, 3.9% F-115.
Alone, however, F-22 at 5% causes multiple ventricular beats in only two out
of twelve animals and F-115, at about four times its concentration in F-502,
causes this response in only one of thirteen dogs. Although this data is
quite limited, the possibility of potentiation is apparent.
Similarly, Reinhardt and coworkers (197.1) observed a slight increase
in response to 7.0% F-12 with hypoxia (see Table LXJLI). Wills (1973) also
notes that sensitization to injected epinephrine after exposure to 0.87%
F-ll is increased by low oxygen tension and decreased by high oxygen tension.
Although these observations are in themselves inconclusive, their possible
relevance to cardiac sensitization to asphyxia induced arrhythmias cannot
be ruled out (see Section XII, Part D-3).
167
-------
The work 'of Call (1972) differs radically from the other investi-
gations reported in this section and may be of only peripheral use in com-
paring results. Call's experiment tested the effects of a hypobaric atmosphere
on the response of rats to F-1301. Epinephrine was administered at 10 pg/kg
I.M. rather than I.V. The use of I.M. would be expected to produce much
lower blood levels of epinephrine than l.V. injection. Hall and Morris (1958),
for instance, have demonstrated that the lethal dose of epinephrine I.M. is
about twenty times greater than the lethal dose I.V. in dogs exposed to
fluothane. With these differences in mind, Call's (1972) observation of
only one epinephrine injected rat out of twenty-seven developing premature
atrialcontractions after exposure to 24% H-1301 at 632 mm Hg. may reflect
the low dose of epinephrine rather than any species difference in the
response of rats to bromofluorocarbons.
Differences in species response to injected epinephrine have been
noted by Beck and coworkers (1973) between dogs and rabbits, with dogs
appearing to be twice as sensitive to H-1211 as rabbits.
Perhaps a more important species specific difference, at least in
terms of assessing hazard to man, has been noted by Van Stee and Back (1969)
between dogs and primates. Two anesthetized dogs.exposed to 80% H-1301 and
20% 0- for forty minutes and injected with 10 pg/kg ep:lnephrin« developed
ventricular fibrillation followed by cardiac arrest. In other dogs, exposed
to 20-80% H-1301 not showing arrhythmias, arrhythmias could be induced with
2-3 Mg/kg epinephrine I.V. In these cases, a somewhat less than usual
increase in blood pressure for the dosage of epinephrine was noted prior to
onset of the cardiac response. In monkeys and baboons, however, an
168
-------
exposure to 80% H-1301 and 20% 0- with 10 yg/kg epinephrine produced only
brief transient periods of ventricular fibrillation and no cardiac arrests.
Only one-half the normal increase in blood pressure was caused by a dose of
3-4 yg/kg in monkeys inhaling 80% H-1301/20% 0^. Further, a monkey did not
show an increase in blood pressure with direct stimulation of the femoral
nerve when exposed to 80% H-1301 which did cause a 20 mm Hg rise when
breathing normal air. Subsequently, Van Stee and Back (1971b) demonstrated
that the arrhythmic response to 30-80% H-1301 could be reversed by lowering
blood pressure through venous bleeding and that an arrhythmic response to
10-20% H-1301 could be elicited by injecting epinephrine to raise the blood
pressure. In the same study (Van Stee and Back, 1971b), blood pH was found
to influence the blood level threshold at which arrhythmias occurred.
Acidosis (blood pH of 7.10-7.30) increased the blood pressure threshold
at which arrhythmias occurred on exposures of 10-20% H-1301 but had no
effect in exposures of 30% or more as shown in Figure 29. A similar
effect is noted by Flowers and Horan (1972) for unspecified fluorocarbon
propellants at "high" concentrations. Eleven of the thirteen animals which
survived exposure had blood pH levels below 7.35 and developed only sinus
bradycardia. Conversely, eleven of the thirteen animals which died had pll
levels between 7.35 and 7.47. All of this latter group exhibited asystole
and ventricular fibrillation.
However, the arrhythmic response to injected epinephrine has not
yet been completely defined and the role of fluorocarhons on the molecular
level is little understood. The work of Wills (1972) illustrates the many
different factors which need to be defined. In studies with F-ll and F-116,
.169
-------
D
10
f-
Cl
LU
CC
D
tu
cc
Q.
Q
O
O
CO
O
_l
O
CO
CO
200 --
180 --
160 --
140
120
100
80
60
10 20
30
40 50
CBrFg {%)
60
70
80
Figure 29: Tin.', minimal biood pressure necessary to trigger arrhythmias
varied inversely with the concentration of CBrF« (Van Stee
and Back, 1971) .
Alkalosis elevated and acidosis lowered the blood pressure
threshold during exposure to 10 and 20 percent CBrF3 but was
without significant effect at concentrations of CBrFs of
30 percent or greater. The vertical bars represent ± 1 stan-
dard deviation. Since no statistically significant differences
existed above 20 percent CBrFa the standard deviations are not
shown.
170
-------
endogenous levels of norepinephrine was not -influenced in the hearts of
guinea pigs. Injections of another catecholamine, dopamine, did not
increase sensitization. In terns of ion balance, blood plasma potassium leveU.
was not markedly affected by a fifteen-minute exposure to 0.4% F-ll.
further, a 6 ml/kg I.V. injection of 3.3% MgSO, did not affect sensitization
to injected epinephrine, which would further indicate that fluorocarbons
do not alter the myocardial membrane permeability to potassium. While
potassium may not be involved, the mycardial membrane permeability to calcium
may be a factor. Preliminary experiments indicate that an infusion of
CaCl? into cats (5 mg/kg/min.) produces cardiac sensitization to epinephrine
similar to that of F-ll. On the interneural level, both alpha- and beta-
adrenergicreceptors may be involved in that arrhythmias are prevented by
either phenoxybenzamine or propanol, both of which block these receptors
(Wills, 1972).
Young and Parker (1972) have used a vagal heart preparation from
frogs (Rana pipiens) to measure the effects of i: luorocarbons on cardiac
arrhythmias. Similar to in vivo studies, F-12 was h'ound to sensitize the
heart to both direct sympathetic stimulation and exogenous epinephrine.
F-12 (unspecified concentration) alone resulted in bradycardia and decreased
_T
contractility. With 10 g/ml epinephrine, partial then complete AV block
I |
was induced. Rhythmicity was restored by KC1 but not Mg . Contractility was
restored by the addition of glucose.
2. Cardiac Sensitization to Endogenous Epinephrine Induced Arrhythmias
In order to assess the relevance of experiments using injected
epinephrine to conditions of stress, experiments have been designed to
171
-------
measure the effects of fluorocarbons on dogs presumably releasing high
levels of endogenous epinephrine. Reinhardt and coworkers (1971) conducted
"fright" experiments in which the release of endogenous epinephrine was
induced by exposure to continuous loud noise while administering 80%
fluorocarbon and 20% oxygen.' The results of these experiments are given
in Table LXVI.
Table LXVI: Cardiac Responses of dogs exposed to continuous loud noise and
80% fluorocarbon/20% oxygen for thirty seconds (Reinhardt et al.,
1971).
No. of No. of No. of Percent No. of Percent
Dog Mild Marked Responses Convul- Convul-
Compound
Fluorocarbon 11
Fluorocarbon 114
Fluorocarbon 12
Fluorocarbon 142b
Compound & noise
Compound alone
Noise alone
Exposures
12
12
12
12
12
6
Responses
9
1
2
4
3
1
Responses Mild Marked sions
2*
1*
0
5
1
0
71).0
8.3
16.7
33.3
25.0
16 . 7
16.7
8.3
0.0
41.7
8.3
0.0
0
5
. 9
9
5
0
sions
0.0
41.7
75.0
75.0
41.7
0.0
* Bigeminal rhythm with areas suggestive of multiple ventricular beats.
A comparison of these results with those using exogenous epinephrine
(see Table LXII under Reinhardt ejt al. , 1971) is difficult to interpret. In
the exogenous experiments, the following order of potency, at concentrations
varying from 0.1-5%, seems evident: F-ll > F-114 > F-1425 = F-12. In these
endogenous experiments, however, F-142b seems by far more potent eliciting
cardiac sensitization even without the presumed induction of endogenous
epinephrine by "fright". While F-12 produced no marked arrhythmias, it
and F-114 did frequently induce marked tachycardia (300-500 beats/minute).
In addition, the convulsions indicated in the above table are not identical.
172
-------
Fluorocarbon-142b and F-12 produced convulsions characterized as "severe,
generalized clonic, tonic seizures", while those elicited by F-114, however,
were much less severe consisting of "spasticity of the extremities"
(Reinhardt e_t al., 1971). Thus, on the basis of tachycardia, arrhythmias,
and type of convulsion, all of these fluorocarbons may be distinguished from
each other by the type of responses observed. However, to read too much into
these results would be an error. The apparent shift in potency of F-142b may
be insignificant in that the concentrations used are greatly increased (from
5% or less in exogenous experiments to 80%). The different responses noted may
merely reflect differences in actual absorption of the various fluorocarbons
because of different breathing patterns in the dogs or actual difference in
absorptive characteristics of the compounds. Lastly, because of the method used to
induce "fright"—i.e., "a loud noise provided by an amplified sound-effects
*
tape recording having sounds of sirens, gongs, jet takeoffs, etc.'! (Reinhardt
et_ jil_., 1971)—and the uncertain and possibly variable responses of dogs to
fear, any conclusions drawn from the results must be tentative.
Procedurally, Mullin and coworkers (1972) overcome the difficulties
associated with study of endogenous epinephrine by having the dogs run on a
treadmill for twenty-one minutes at 300 feet per minute, referencing a study
indicating that the circulating level of epinephrine increases by five-fold
in dogs running at 300 feet per minute for fifteen minutes. The experimental
protocol called lor the first two minutes to serve as a control, the following
sixteen minutes as an exposure period, and the last three minutes as a
recovery period, with electrocardiograms being recorded continuously. The
types of exposure and responses are given in Table LXVTI.
173
-------
Table LXVII: Cardiac responses of dogs exposed to various fluorocarbons
while running (Mullin e_t al., 1972)
Test Compound Concent r.-il inn
(% V/V)
Number of Percent
?iuml>er of Marked Marked
Dog UxposureK Responses Responses
Common Is
Air
Fluorocarbon 12
Fluorocarbon 114
Fluorocarbon 11
-
3 .
( 4.45 •
7.
10.
10.
(10.04 >
2.
( 2.53 '
5.
(.4.63 :•
10.
( 8.44 i
0.
( 0.48 i
0.
( 0.75 .'.
1.
( 0.96 '.
0
0.
r,b
ob
u
0.
5
0.
0
0.
0
1.
5
0.
75
0.
0
0.
49)"
96)
20)
21)
03)
03)
12)
11)
8
6
6 (3/4)*
6
6
7 (2/3)
7 (2/3)
8 (1/3)
B (1/3)
7 (3/4)
0
0
1
0
0
1
1
0
0
0
0
0
16.
0
0
14.
14,
0
0
0
7 Reaction questionable bigeminal rhythm
or multiple ventricular beats (MVB's).
Ten percent levels not tolerated -
exposures lasted from 1*5 to 16 minutes.
> Klvr pori'-nt exposures repeated on four
ol tlie tiuj':,; and ihr same dog had a
'iv ,-.uJ fT.p'MiSc tirst response was
MVH's-sucond was liige.minal rhythm
suggestive-, of UVR's.
.3 Response was bigeminy suggest tve 'of MVS's-
rp ;H. lion was nr ]'-, minutes after start
ill exposure, out. Tilt ration not liulli
up t'o ]OZ-only ').6^; neith'tr 1J7 nor
107. levels I ojer ai.ed- exposures to
i-nmpoiuvl lastcil I1} to l(< mliMJIi-H .
i-Jo IfVt'ls ot thlr. rrmpouiid were wt-J]
l.olorati'd.
Compound DCHOHUIC t Imi-H l.-i'itr-l 1 In
ib minulL*>;.
Numbers in parentheses represent analytical c.oni-fnt rations ' staiidaril dovi at i.m.
Nomtn.il concentrations (tl« concentrations given the dogs were proba'ly h:';.!ur ri.'a:-. !."> ard jO.OX).
*
Fraction of prematurely terminated exposures as given by the original investigators In tne test.
These results are somewhat difficult to interpret. All of the marked
responses are those of a single and presumably "sensitive" dog and occurred
between llg and 3 minutes of exposure when the amount of endogenous epine-
phrine induced by S1-; - 5 minutes of running is undetermined. Further,
many of the exposures had to be terminated prematurely because the dogs
became partially anesthetized. Thus, the value of the percentage
figures given in Table LXV11 is questionable. Nevertheless,
Mullin and coworkers (1972), comparing their results with the screening
174
-------
experiments of Reinhardt and coworkers (1971), conclude that higher con-
centrations of these propellants are necessary to induce arrhythmias from
endogenous epinephrine than from an injected dose of 0.008 mg/kg in dogs
(see Table LXVIII).
Table LXVIII: Comparison of Results of Screening Experiments of Reinhardt et
_al., 1971 and Treadmill Experiments of Mullin e_£ ail», 1972
(Mullin et al., 1972)
Percent Marked Responses
Test Compound
Concentration
(% V/V)
Endogenous
Epinephrine
Injected
Epinephrine
Fluorocarbon 12
Fluorocarbon 114
Fluorocarbon 11
2.5
5.0
Norn. 7.5
Norn. 10.0
10.0
2.5
5.0
10.0
0.1
0.5
0.75
1.00
Not tested
0
0
16.7
0
0
14.3
14.3
Not tested
0
0
0
0.0
41.7
Not tested
Not tested
Not tested
8.3
58.5
Not tested
0.0
8.3
Not tested
41.7
175
-------
3. Cardiac- Sensitization to Asphyxia* Induced Arrhythmia
Perhaps the greatest controversy concerning the toxicjty of the
fluorocarbon gases has been stimulated by the work of Taylor and Harris
(1970a), which may indicate tnat these compounds on innalation are toxic to
the hearts of mice. This toxicity is evidenced in fluorocarbon exposed
mice by the rapid onset of sinus bradycardia and atrioventricular block
induced by a degree of partial asphyxia which causes tachycardia in mice
not previously exposed to the fluorocarbons. These investigators have
reproduced their original findings in over 2QO mice using
F-ll, F-12, and F-114 from a variety of sources (Harris, 1972b) and firmly
assert the validity of both their technique and results (Harris, 1973).
However, four other groups of investigators (Azar ej^ _al. , 1971; Egle et al. ,
1972; Jack, 1971; McClure, 1972) using similar experimental techniques are
unable to reproduce the results of Taylor and Harris in mice. Instead,
they find that the effect caused by fluorocarbons does not vary significantly
from those effects caused by nitrogen or asphyxia controls, i.e., bradycardia
and AV block due to asphyxia and not related to fluorocarbon exposure. In
review, Silverglade (1972) describes the conclusions of Taylor arid Harris as
having "no sound scientific basis" and characterizes their experimental
approach as "poorly designed." Yet, Harris (1973) contends that the four
other groups of investigators for the most part apply inappropriate degrees
of asphyxia and their results, when valid, tend to confirm the original
results of Taylor and Harris (1970a). Because the possible direct toxicity
of these aerosol propellants is related to the interpretation of human
deaths associated with aerosol abuse or unintentional overdose by asthmatics,
176
-------
the nature of the discrepancies between the results of Taylor and Harris
and the findings of the subsequent investigators deserves careful attention.
Asphyxia can influence cardiac function in a variety of ways. A
lowering of oxygen tension will increase the heart rate (tachycardia) but
the heart, unable to acquire an oxygen debt, will eventually slow (bradycardia),
become arrhythmic, and fail. Similarly, a small increase in carbon dioxide
tension will stimulate vasoconstriction causing an increase in blood pressure
and reflex bradycardia As carbon dioxide tension further increases,
atrioventricular conduction is impeded, the heart slows and eventually
stops. The crux of the Taylor and Harris (1970a and b) experiments is in
producing a degree of asphyxia in the asphyxia-control mice that causes
tachycardia and applying the same degree of asphyxia to mice previously
exposed to fluorocarbons. Their basic approach is outlined below (Taylor
and Harris, 1970a):
i) Anesthetize ICR adult mice with 0.5 ml of 0.3% pentobarbitol
sodium (43-60 mg/kg).
ii) Insert snout of mouse into mouthpiece of commercial nebulizer
<§) ®
(Medihaler-Isc^or Isuprel Mistometer) for exposure to propellants
or insert head into loosely fitted 5 ml. plastic bag containing
60% F-12 and 40% F-114.
iii) When using nebulizer, allow only single discharge (none in
placebo group).
iv) Allow only three inspirations.
v) Asphyxiate "with a form-fitting plastic bag wrapped tightly around
nostril and mouth, rostral to the ears."
177
-------
vi) Continue asphyxia until 2:1 AV block [two atrial beats/ventricular
coniraction] or life-threatening sinoatrial (SA) bradycardia
[subsequently defined as slowing of 200 or more beats per
minute(Harris, 1972a)].
vii) Allow surviving animals to recover.
viii) Reapply asphyxia at 5, 10, 20, 40, 60, and 120 minutes after
exposure.
Some of the results are given below in Table LX1X.
Table LXIX: Responses (Mean *-• SE) of Mice to Asphyxia, Propellants,
and Propellants plus Asphyxia (Taylor and Harris, 1970a)
Uliinnc1:; in IU;;irt Unl>' _ No. <>l 'lice IU'_yt.' lup i njj^ . - <>i).;.'i (if
Nu. 2r> Sfronil:: Aflur M.irl»-.l 'llri.r-; Hi .I'ly.'u rhylhmf .1
<>l As|>hyxl>i lli'l;un Hr.-nlv. :it'l i:i />tu-r A.'iplivxlii
Mi'" (Ur.-llh/nilllJ 'f.:\ AV lilnik Wl Limn! W 111'irl- II'-;'.IH1 f'ifc-)
.:r,.,,,, ]
'r.ph\ '-:iii .'mil .'ropi-1 liint
!'ni|)fl liinl 8
i'r.tpe 1 l.inL .-iini i soprutt;rfn ' U.5 (.
-VI )6.7 1. 2
-•114 ' '.'..5 i, II
-m IH.O ', \
-t'lO i,.', .) '.
-1-4! 1 1. 5 (,
!H ' 4.<»
3b • !.«
47 .'i.7.
2« • n.'J
l':hnni,.'s in llf.irl Itnl i
?') S,'>-('llcl-, A I tlT
nip.'!!. ..... nli.il.-it I.'
I Hi>. i Is, 'in in)
' ^ l-ijjtL> i ilit'iit .isiihyxi ,-i
rr-jpt-l Inut 4 -!) ' 9.'i
! i upc I lani ,ind istj;irot ( fi_"i"l 4 f 9 ' 1(J . ,'
•li.-turu * . i -]'> • 5.0
* 6 OX (licit lurodi f luoromuthatif , 4D'i J fch lorotr' i ;i II iiurtu't h.inc ml >.i ur*.1 .
A^jjhyx la wl thouf proprl Inn I w.is ;ipp1 h.-'t for I " r m i mil cs .
178
-------
Further, of the 12 mice in Group 1 which survived the initial exposure to
asphyxia, all died during subsequent asphyxia 10 to 160 minutes (average
50 minutes) without further exposure to propellants and without an increase
in the time from asphyxia to arrhythmia. Similarly, mice from Group 3
developed 2:1 AV block in 24 ± 2.1 seconds when asphyxia was applied
15 minutes after fluorocarbon exposure.
Taylor and Harris (1970a) interpret their experimental results as
cardiac sensitization to asphyxia-induced arrhytlimias by the fluorocarbons.
In a subsequent paper (Harris, 1972a), the duration of this effect is
specified as 15-30 minutes. In that atropine, which supresses vagal
inhibition of the heart, does not block the effect, Taylor and Harris (1970a)
state that the bradyarrythmia may "more likely reflect a direct action on
the SA node and AV conduction." i
It is regrettable that in their study Taylor and Harris (1970a) omitted
®
certain details from their presentation. Both Medihaler-Iso and Isuprel
®
Mistometer are apparently used as sources of propellant. However, as Taylor
®
and coworkers (1971) indicated in a later paper, Medihaler-Iso discharges
®
12.5 ml of gas while Isuprel Mistometer discharges only 5.8 ml gas/activation.
®
Further, Medihaler-Iso contains F-ll, F-12, and F-11A, while Isuprel
®
Mistometer contains F-12 and F-114. Thus both the amount and types of
propellants to which the mice were exposed varied. The significance of this
variation cannot be evaluated from the data which Taylor and Harris present.
Interpretation is further restricted by the lack of detailed time-response
data. For instance, from the data presented in Table LXIX, atropine in
combination with asphyxia and propellant seems to have a much greater
179
-------
depressant effect on heart rate at 25 seconds (-134 •'- 44.5 heats/minute),
than does propellant and asphyxia alone (-66 ± 14.5 beats/minute), but the
atropine group requires a longer time to the onset of bradycardia (47 ± 5.7
seconds) than does the group exposed only to asphyxia and propellant
(38 ± 4.9 seconds). Lastly, and probably most important, the investigators
fail to describe in sufficient detail the technique that they used to apply
asphyxia. Their description of a "form fitting plastic ba;.; wrapped tightly
around nostril and mouth" could quite reasonably be construed as total
asphyxia. Subsequent publications (Harris, 1971, L972a and b, 1973) have
described partial asphyxia only in the effect, that it causes - i.e., tachycardia
in untreated mice - and not in the techniques used to induce it.
Using the Taylor and Harris (1970a) study as a model, Azar and coworkers
(1971), Egle and coworkers (1972), and McClure (1972) hnvo published'relatively
detailed reports on attempts to reproduce this effect under experimental
conditions presumably approximating those of Taylor and Harris (1970a).
Azar and coworkers (1971) uniformly anesthetized the mice (60 mg/kg
pentobarbital sodium, i.p.) and used four exposure groups: asphyxia alone,
®
100% F-12, 100% H™, and a single discharge from l.supre.l Mistometer (5.8 ml
mixture of F-12 and F-114, plus isoproterencl hydroch.lort.de). Exposure lasted
for five seconds and asphyxia was applied with ''a close fitting vinyl mask."
Besides these variations, the procedure seems to follow closely that of.
Taylor and Harris (1970a). The results are given below in Table I,XX and
Figure 30.
180
-------
Table LXX: Responses (Mean ± SE) of Mice to Asphyxia
(modified from Azar et al., 1971}.
Condition _ _
Asphyxia alone
Nitrogen and asphyxia
Isuprel Mistometer
and asphyxia
Dichlorodifluoromethane
and asphyxia
No. of Mice
Developing
Onset of
Changes in Heart Marked Sinus Bradyarrhy-
No. Rate 25 sec After Bradycardia thtnia After
of Asphyxia Begun Heart Without Asphyxia Begun
Mice (Beats/min) Block Heart Block (sec)
12
-143 ± 48.2
12
-168 ± 43.6
12
-155 ± 41.6
10
12.
-143 ± 33.9
64 ± 23.4
18 ± 4.8
30 ± 7.9
23 ± 5.9
'••00 —i
— : 1 1 I' -•'- I- ~ T^ ' ~
111 (ill 'A! I.'U l:>0 1KO ^11*'
TIM (StQ'Nl)S AI'Ti.K ASl'liVXl A i U'!. >
Figure 30: Heart rate response of mice exposed to compounds for five
seconds followed by asphyxia (redrawn from Azar et al., 1971).
181
-------
Similar to Taylor and Harris (1970a), atropine - 50 mg/kg i.p. - does not block
bradycardia in nitrogen exposed mice indicating a direct effect on the heart
rather than reflex inhibition. However, because there is no appreciable
(|)
difference in nitrogen groups compared with the F-12 or Isuprel Mistometer
group, Azar and coworkers (1971) conclude that bradycardia and heart block
is caused by hypoxia rather than the fluorbcarbons.
Egle and coworkers (1972a, see also I972b) report similar results with
a greater variety of propellantu and some significant modj f Lc;tt ions in
experimental design. Along with an asphyxia control, the mien arc exposed to
the following compounds for five seconds:
Propellant - one discharge of nebulizer, 70-77 mg [approx. 5.5-
6.0 ml] 28% F-ll, 72% F-12.
Propellant and isoproterenol (100 pg and 70 yg/discharge).
Propellant and albuterol
Nitrogen, 100%
[no variation in propel.lant is specified]
Asphyxia is applied in two ways. For most exposures, the snout of the mouse
was covered with a "form fitting plastic bag." This w.i 11 be; referred to as
"total asphyxia." However, a lesser degree of asphyxia is also induced when
"the plastic bag covering the animal's snout was fastened somewhat less
securely and 'permitted passage of a limited amount of air." This is referred
to as "partial asphyxia." For two other sets of mice, asphyxia is applied
thirty seconds after exposure to the propellant and nitrogen. The results
are given in Table LXXI and Figures 31a and b.
182
-------
Table LXXI: Responses (Mean ± SE) of mice exposed to "total" and
"partial" asphyxia (modified from Egle £t aK, 1972a).
Condition
% Control Heart Rate Event
No. of at 24 seconds after AV
Mice Asphyxiation
Time to Onset
of Event in
Block Bradycardia Minutes
Total Asphyxia with immediate'exposure
8
71 ± 7
89 ± 10
101 ± 3
0.66 ± 0.09
0.67 ± 0.06
0.73 ± 0.06
Propellant (alone)
Propellent and
isoproterenol
(100 pg)
Propellant and
isoproterenol
(70 pg)
Propellant and
albuterol
Asphyxia alone
3tal Asphyxia with :
Propellant (alone)
Nitrogen
artial asphyxia wit!
Propellant (alone)
Nitrogen
Asphyxia (control)
* In this table, 2:1 AV block is considered at least five instances of 2:1 AV Block
per 0.1 minutes and bradycardia as a 50% decline from controls.
6
11
10 second delay
4
4
103 i 10
. 94 ± 7
88 ± 12
70 ± 7
0
2
1
0
6
9
3
4
0.93 ± 0.08
. 0.77 ± 0.08
0.77 ± 0.06
0.78 ± 0.08
i
i immediate exposure
10
5
13
110 ± 6
113 ± 15
104 ± 5
4
1
11
6
4
2
1.80 ± .0.14
2.50 ± 0.29
2.51 ± 0.20
183
-------
A.
500
u
r n ,».
• *-^U., jj
• •
D 05 10 15 ?0 ,
TIME (n.inules)
6.
E
N
500
400
300
2
r- 200
tt
ki
100
-• Contrnl. As|ihyxi;i i
" Nitrotien
•* Isoproterniuil, 100
" Albuterol
0L
0
05 IO
TIME (minutes)
Figures 31a and b: Heart rates during total asphyxia
of control (asphyxia alone) mice and animals
exposed to nitrogen; as well as (a) propellant alone,
and propellant with isoproterenol (70 ug):
(b) propellant with isoproterenol (100 ug) and
propellant with albuterol [from Egle gt a_l. , 1972b]..
184
-------
As with the previously discussed study (Azar et al., 1971), the authors
conclude that their results do not support those of Taylor and Harris (1970a)
•
and that the cardiac responses noted are caused by hypoxia (Egle je_t ed. , 1972).
McClure (1972) similarly exposed anesthetized mice (pentobarbital sodium,
65 mg/kg i.p.) to asphyxia, after three inhalations of propellant (approxi-
mately 12 ml; 25% F-ll, 50% F-12, 25% F-114), and asphyxia after three
inhalations of the propellant with 0.075 mg isoproterenol. Asphyxia was applied
by''placing a small finger cot over the snout of the mouse." There are no other
apparent differences of significance in the experimental approach from those
outlined previously. The results, as presented by McClure (1972),are given
in Table LXXII.
Table LXXII: Responses (Mean ± SD) of Mice
to Asphyxia (McClure, 1972)
Time3
Control
15 Sec
30 Sec
1 Min
2 Min
4 Min
No propellant
(negative control)
n - 12
Heart rate
(beats /rain)
X ± SD % A
439 ±62
415 ± 74 -5
411 ± 35 -7
435 ± 84 -1
350 ± 52C -20
317 ± 74d -28
Propellant
n '= 10
Heart rate
(beats/min)
X ± SD % A
474 ±85
454 ± 86 -4
470 ± 88 -1
453 + 70 -4
425 ± 84 -10
394 ± 42b -17
Propellant +
isoproterenol
n •" 6
Heart rate
(beats/min)
X ± SD % A
484 ±42
477 ± 60 -2
500 ±40 4-3
510 ± 55 +5
514 ± 84 +6
482 ± 62 -1
P-R interval
QRS amplitude*
Arrhythmias
2:1 AV block
Deaths
3/12 (increase)
10/12 (decrease)
9/12
4/12
6/12
4/10 (increase)
8/10 (decrease)
7/10
9/10
4/10
3/6 (increase)
6/6 (decrease)
3/6
3/6
3/6
a Time during asphyxia.
b Significantly different from control p <0.02.
c Significantly different from control p<0.01.
d Significantly different from control, p<0.001.
e Change from control.
185
-------
As with the previous two studies (Azar £t jd., 1971 and Egle et al. , 1.972),
McClure (1972) concludes that fluorocarbons do not significantly influence
the cardiac response of mice to asphyxia. Jack (1971), in summarizing the
work of Allen and Hansbury, Ltd. (1971), reports that in similar experiments
the same conclusion is reached.
i .
The information as presented in this series of studies is not only
difficult to resolve but also awkward to compare: besides the eight different
types of propellants or propcllant with active agent: combinations - with only
two types being used by more than one investigator - many of the results are
not expressed in the same way. Thus, to facilitate a comparison between
these studies, data concerning the effect of propellant exposure and asphyxia
on heart rate is presented in Table LXXIII as percent of original heart rate
25 seconds after asphyxia or after exposure to the propellant in cases where
no asphyxia is applied. It should be emphasized that because of the various
ways that the data is presented in the original papers, this comparison is,
in some cases, only approximate (see notes to Table LXXIII). Similar data on the
number of mice experiencing 2:1 AV block or bradycardia and the time to onset
of these events after application of asphyxia is presented in Table LXX1V.
186
-------
Table LXXIII: Percent change in the heart rates of mice at
25 seconds after exposure to various fluorocarbon
propellants and nitrogen with and without asphyxia.
Prop la = 60% F-12; 40% F-114 inhaled from nebulizer, 1 activation
Prop Ib » 60% F-12; 40% F-rlU inhaled from 5 ml plastic bag, 3 activations
Prop 2 - 50% F-12; 25% F-114, 25% F-ll, inhaltcd from nebulizer, 1 activation
Prop 3 - 72% F-12; 28% F-ll, inhaled from nebulizer, 1 activation
Conditions Taylor and Harris,
197031
Propellants and Asphyxia
Prop, la or 2 -14 ± 2
Prop. Ib -17 i 4
Prop. 3
F-12 (100%)
Prop, la or 2 and
Isoproterenol -21 i 8
Prop. 3 and ,..
100 yg
Isoproterenol 70 lag
Prop, la or 2 and
Atropine -28 ± 9
Prop. 3 and
Albuterol
Asphyxia (alone) + 6 ± 1
Asphyxia with
placebo +913
N2 (100%) and
Asphyxia
No Asphyxia
Prop, la or 2 -112
Prop. Ib -3 i 1
Prop, la or 2 and
Isoproterenol +2 .t 4
Azar et al. ,
19717 ~
-34 ± 8
-34 t 9
-30 t 10
-39 t 10
Egle et al. ,
19 721"
-29 ' 7,
+10 .*. 6.*
-12 .' 1.2
-11 ', 10
+ 1 i 3
+ 3 t 10
-6 t 7,
+4 ± 5+
-30 ' 7
+13 i 15*
McClure, 19721*
-1 ± 18
-1 •.'. 10
-6 i 6
-3 ± 7
-1 t 8
1 Calculated from mean control heart rate of 482 for all 46 animals.
2 Calculated by readings from Fig.30 (this paper) of initial heart races.
3 Reading at 24 seconds after asphyxia.
4 Data from linear graph of Table LXXII (this :>aper). s^ approximated, and
^ Table 1 of McClure's paper.
30 second delay between end of exposure and asphyxia.
Termed "partial asphyxia" by Egle c± a\_. , 197 ii
187
-------
Table LXXIV:
Number of Mice Which Experienced and Time to Onset
of 2:1 AV Block and Bradycardia.
00
CO
Asphyxia with _J
Propellant la or 2
Propellant Ib
Propellant 3
F-12 (100%)
Propellant la or 2
and Isoproterenol
Propellant 3 100 yg
and Isopro-
terenol 70 pg
Propellant la or
2 and At repine
Prop ell ant 3 and
Albuterol
N2 (100%)
Asphyxia alone
I Taylor & Karris, 1970a !
Time to
Onset
(seconds)
No. of
2:1 AV
Blocks
,
38 ± 4.9 6/8
28 ± 6.9
36 ± 2.4
47 ± 5.7
> 240
5/6
2/4
4/4
No. of
Brady-
cardia
2/8
1/6
2/4
0/4
Azar et al. , 1971
Time to
Onset
(seconds)
23 ± 5.9
30 ± 7.9
No. of
2:1 AV
Blocks
9/12
10/12
t
'
18 ±4.8
64 ± 23
9/12
5/12
No. of
Brady-
cardia
3/12
2/12
3/12
7/12
Egle et al. , 1972
Time to
Onset
(seconds)
39 = 5.4
46 - 3.6*
108 - 8.44
40 ± 3.6
44 r 3.6
56 - 4.8
47 r 4.8*
15C rl7.4+
46 = 4.8
150 r 12+
No. of
2:1 AV
Blocks
1/8
1/4
4/10
3/6
3/6
0/6
0/4
1/5
2/11
11/13
No. of
Brady-
cardia
7/8
3/4
6/10
3/6
3/6
6/6
4/4
-4/5
9/11
2/13
McClure, 1972
Time to
Onset
(seconds)
No. of
2:1 AV
Blocks
9/10
3/6
No. of
Brady-
cardia
7/10
3/6
4/12 |
9/12
* 30 secot:d delay; + "partial asphyxia1'; Fropellant Key: same as Table LXXx..!.
-------
A number of factors might account for the wide variety of experimental results
both within and among the various studies. Although there is little evidence
in these studies to indicate that the different propellants used have
markedly different effects, such a possibility cannot be ruled out. Further,
potential effects of albuterol (Egle et al., 1972) and to a lesser extent
atropine (Taylor and Harris, 1970a) may deserve more careful investigation.
Based on the conclusions drawn by Azar and coworkers (1971), Jack (1971),
Egle and coworkers (1972) and McClure (1972), Taylor and Harris (1970a) may
have been mislead by their failure to use a nitrogen control and what they
observed as cardiac toxicity might merely be the effect of cinoxia on the
somewhat more hypoxic propellant exposed mice. This explanation is supported
by the time-response data presented by both Azar and coworkers (1971) and
Egle and coworkers (1972) [see Fig. 30 and 31a, respectively] indicating that
exposure to either propellants or nitrogen results in a somewhat greater
degree of asphyxia-induced bradycardia than does asphyxia alone. However,
Taylor and Harris (1970a) indicate that rapid (24 ±2.1 seconds) 2:1 AV block
developes in mice allowed to recover for fifteen minutes after propellant
exposure before asphyxiation and that this response does not develop without
propellant exposure.
•
Harris (1973) proposes that the other investigators do not duplicate
the results of Taylor and Harris (1970a) because they apply an incorrect
degree of asphyxia. Based on the available time-response data on exposure
to asphyxia alone, presented in Figure 32, this explanation seems plausible.
189
-------
110
100
90
80
0)
a
u 70
Ui ••
QJ
7i 6° -
•H
4J
3 50
o
a 40 _
Hi
u
i.
o
fc 30 _
10 _
A A iayior a Harris, j?/ua: see laoie W.IA
+• + Aznr et al., 1971: adapted from Figure 'i'..'
»—. 8 McClure, 1972: see Table LXXtl
• • Egle e_t_ al., 1972H: ndnptfil from Figure 31,
Total asphyxia
^f^^~~'~^ Parti.-il .ispliyxfa
\\^^x7°-— — -- ^___^
\ XVVN • —
\ ', v „ " " ^_:
\ \ v v
\ \
\
\ \ ' '
\ \
+"T"\ ;x.
\ ' ~~^~^--~4.'
-~-// ^'\ - ~~ ~~— — ~—
^1— ••^ ^-. ""
\
\^
; I i i
'Hi 60 90 120 r>i> l«o 2!0 ':',
Time in seconds
Figure 32: Percent Change in Heart Rate. After Exposure
to Asphyxia Based on Data from the Above Sources
190
-------
Given this data, some of the criticisms by Harris (.1973) do seem warranted.
Azar and coworkers (1971) and Egle and coworkers (1972) - using total
asphyxia - do seem to use a degree of asphyxia that might mask any possible
demonstration of fluorocarbon cardiac toxicity. Harris (1973), however, is
probably in error when he classifies the "partial asphyxia" (Egle £t al., I972a)
as closer to his earlier work (Taylor and Harris, l970a) than that of McClure
(1972). Although Egle and coworkers (1972) do not give detailed time-response
data for partial asphyxia, the tachycardia at twenty-four seconds is probably
quite transitory as indicated by the relatively rapid onset (151 seconds) of
50% bradycardia. Nevertheless, all of these investigators do use a degree
of asphyxia that, when measured in terms of heart rate response, varies
noticeably from that of Taylor and Harris (1970a).
The conclusion to be drawn from this rather detailed comparison of these
various studies is inescapable in terms of technique but inconclusive as to
the results. The technique used to apply asphyxia is in all probability,
the critical step. These techniques are described as "a plastic bag wrapped
tightly around the nostril and mouth" (Taylor and Harris, 1970a), "a close
fitting vinyl mask" (Azar et^ al., 1971), "a small finger cot over the snout"
(McClure, 1972), "covering the snout with a form-fitting plastic bag" or the
same "fastened somewhat less securely" (Egle et_ ad. , 1972&). Such techniques
and descriptions seem somewhat vague. This controversy has occupied a great
deal of space in a variety of review articles and letters to the editor
columns. It addresses an important aspect of fluorocarbon toxicity of concern
to manufacturers, physicians, patients, and the public at large. Thus it
seems peculiar that no published tests of this effect have been run in
191
-------
controlled atmospheres in which the amounts of oxygen, carbon dioxide, and
nitrogen necessary to induce prolonged tachycardia could be monitored and
the effects of various concentrations of different propellants measured.
Given the results that are available, no firm conclusion can be drawn.
Harris (1973) seems to have effectively countered the results of Azar and
coworkers (1971) and Egle and coworkers (1972) on the basis of
inappropriate degrees of asphyxia. However, the attempt by Harris (1973) to
use part of the data of Egle and coworkers(1972a) to support his results is
rather feeble. Egle and coworkers (1972a) did notice a difference with
"partial asphyxia" in the onset time of bradycardia (50% decrease) and 2:1 AV
block between asphyxia alone exposures (150 ±12 seconds) and asphyxia after
propellant exposures (108 ± 8.4 seconds). However, given the limited time-
response data (see Figure 32),it seems likely that the asphyxia alone group
was also showing marked bradycardia at 108 seconds. Thus, while this
difference may be significant statistically by P<.02 (Harris, 1973), its
physiological significance may prove tenuous.
By far the most damaging evidence to the conclusions of Taylor and
Harris (1970a) is the work of McClure (1972). McClure (1972) seems to maintain
a degree of asphyxia only moderately greater than that of Taylor and Harris
(1970a) with bradycardia never exceeding minus seventeen per cent during the
first four minutes in the asphyxia alone group (see Figure 32). Thus, if the
same degree of asphyxia is applied after exposure to a propellant, McClure
(1972) should still be able to note a profound decrease in heart rate as
might be expected by the conclusions of Taylor and Harris (1970a). No such
192
-------
observation is reported (see Table LXXII). That McClure (ly?2) did note an
AV block in 4/12 of the mice exposed to asphyxia alone but a 9/10 incidence
of AV block in the propellant plus asphyxia group may again be significant -
?<.025 (Harris, 1973). However, considering that there is no marked difference
in the number of mice showing arrhythmias or fatal exposures, and no indication
of the time to onset of AV block, the actual significance of the 9/10 figure
cannot be fully appreciated.
Assuming that the results of both Taylor and Harris (1970a) and McClure
(1972) are valid indications of the cardiac tox Icily <;l fluoroearbon propel lant;
the following characterization might be proposed: under conditions of mild
asphyxia that would normally cause tachycardia, the propeHants may cause
rapid and pronounced bradycardia and AV block in mice but as the severity of
asphyxia is increased, the toxic response is either inhibited or masked.
This characterization, however, is merely speculative. Further experimental
work, in which the various relevant parameters are closely monitored, would
be necessary to define this effect.
193
-------
4. Arrhythmias Not Associated with Asphyxia or Epinephrine
A variety of fluorocarbons have been found to affect cardiac
function under conditions of adequate oxygenation or in the absence of
elevated epiriephrine levels.
Studies dealing with adequate oxygenation parallel closely those of
asphyxia-induced arrhythmias as described above. Arrhythmias, in the
absence of hypoxemia or hypercarbia, has been demonstrated both in dogs
(Flowersand Koran, 1972b) and monkeys (Taylor at ajL., 1971).
Flowers and Horan (1972b) exposed dogs to a mixture (unspecified)
of F-ll and F-12 by spraying this mixture on the inside of a plastic: bag
and fastening the bag "loosely over the head of the dog, allowing the active
agent to be present in high concentration". In a group of six dogs, the,
bag was continuously oxygenated; in the remaining dogs, the only oxygen
supply was by incidental mixing with room air. At the first indication of
cardiac disturbance, the bag was removed. Although this technique does not
allow an accurate estimation of the fluorocarbon dose, measurements were.
made of blood P and P . In the dogs receiving direct oxygenation, no
°2 c°2
significant changes were seen in these values. In dogs not receiving
supplementary oxygen, P remained at control levels but there was a fall
c°2
in P from a control level of about 75 mm Hg to post-exposure level of
°2
about 40 mm Hg. Although this fall is significant, it is not so marked as
those "usually associated with profound or dangerous hypoxia" (Flowers and
Horan, 1972).
In spite of sufficient oxygenation as demonstrated by blood gas
measurements, the same types of arrhythmias were noted in both groups of dogs,
194
-------
These arrhythmias included sinus bradycardia, AV dissociation or AV block,
sinus arrest, and asystole. The details of the various responses are given
in Table LXXV.
Table LXXV: Cardiac Responses of Dogs to a Mixture of F-ll and F-12
from Antiseptic or Hair Spray (Flower and Horan, 1972b).
Arrhythmias, Onset Time, and Mode of Death.
Experiment
and Substance
1
2
3
4
5
6
7
8
9
10*
11
12
13
14
15
Antiseptic Spray
Antiseptic spray
Antiseptic spray
Antiseptic spray
Antiseptic spray
Antiseptic spray
Antiseptic spray
Hair spray
Hair spray
Antiseptic spray
Antiseptic spray
Antiseptic spray
Antiseptic spray
Antiseptic spray
Antiseptic spray
8 min
10 min
1 min
1 min
T ii. .11 ... .-_
5 min
SB + 1° t
4 min
CD _L. 1 O A T
SB + 1 A\
4 min
nT1
1 min
20 min
3 min
45 sec
SB + 1° i
4 min 55
10 min
r-r*
Oi)
8 min
>-SB H
nn
45 min
Rhythm and Onset
.. > C A 4- T7T?.. - .. .
^ WT? .1. A VD
^ Vll/ r AVK
, trpn_
' VI US
____. \rrj i pp A
i\7n l Til' 1 ITfA
rn ,.« ° A 1 TF i • ..
. TTf
'S TP
> AJK
' oA 1 Vli
^ \m , i i ° A .i. ^n? ..
\V1J ' OA 1 Vlj
sec
1° A T7TT k. T17
Avo ••-•>J1S
fc A TT>
' AJ K
Time Death
u ITT _ , t yi?
. TTT .» V
->~ v i •*• i\
+- V
^ 1\
ii. > VI?
.1 K
n.._t V
'•""» JSw
> K
: : . * A
' A
> A
1 .. ,. v c II .L. O° A tfR
, > oli t ^ AVJJ
,. ,. -b ir i. \n? .1,1., . .k
> Jo r Vli >
X ) \
\ in i \n? .\ *i
*SB signifies sinus bradycardia; SA, sinus arrest; JE, junctional escape;
JS, junctional slowing; VE, ventricular escape; AJR or AVR, accelerated junctional
or ventricular rhythm; RCA, retrograde conduction to the atria; VPB, ventricular
premature beats; VT, ventricular tachycardia; K, killed; Ace, accidental deaths;
VF, venticular fibrillation; A, asystole.
//Supplemental oxygen supplied in dogs #10-15.
195
-------
In several species of monkeys, a fluorocarbon mixture - 30 ± 2.0%
F-12 and 9 i 0.5% F-114 in either compressed air or 100% oxygen - is
reported to induce ventricular arrhythmias in the absence of hypoxemia or
hypercarbia (Taylor £t al., 1971). In this study, fourteen conscious or
anesthetized monkeys are exposed to compressed air (3), asphyxia (4), or
100% nitrogen (7) for three minutes, allowed to breathe room air for fifteen
or thirty minutes, then exposed to the fluorocarbon-oxygen mixture (all 14)
until the appearance of the first ventricular uxl.rasysto.le. After a thirty
minutes recovery period, three of the animals are re-exposed to tlte fluoro-
curbon mixture and the remaining eleven are given a iwo-minuti- l.V. infusion
of 0.07 mg/kg propanolol hydrochloride [to block beta adrenergic receptors]
and, after fifteen minutes, are re-exposed to the fluorocarbon mixture for
two minutes or until arrhythmias or convulsions appear. Arterial Po-,
Pco2, pH, blood pressure, and fluorocarbon concentration are monitored in
various animals.
As indicated in Table LXXVI, the fluorocarbon mixture does not signi-
ficantly alter arterial Po_, Pco?, or pH, whereas the 1.00% nitrogen does
cause marked hypoxemia as compared to control.
Table DCIVI: Effects of (Mean ± SE) of Nitrogen and Fluorocarbon Exposure on
Pn Pco , and pH of Arterial Blood in Seven Monkeys (modified
from Taylor e± ^1., 1971) .
Conditions Po~ Pco,, pH
Control 106 6.2 26 2.7. 7.41 0.01
Nitrogen 30 3.2* 26 2.3 7.39 0.03
Fluorocarbon 121 5.5 23 1.5 7.39 0.03
*Significantly different from control and fluoro<-arhon values (P <0.00i).
196
-------
Exposure to compressed air, asphyxia, or 100% nitrogen for three minutes
failed to produce any arrhythmias, except in one nitrogen exposed animal
with an arterial blood Po« of 16 mm Hg which experienced ventricular pre-
mature beats at 105 sec.
Exposure to the fluorocarbon mixture, however, produced cardiac
irregularities in all monkeys, the details of which are given in Table LXXVII,
Table LXXVII: Cardiac Responses of Monkeys to Fluorocarbon Inhalation
(data from Taylor e* al., 1971)
Rate (per minute)
Number/Animals Measured in Time to Onset ;
Experiencing 3 sec. intervals (seconds) Duration
Event Event Mean ± SE Range Mean ± SE Range (Seconds)
Extrasystoles
Initial 14/14 40 ± 7 8-90 39 ± 4.2+ 20-72 30-180*
Maximum 11/14 90 ± 11 25-120 10-30// :
Bigeminy 3/14
Ventricular
Tachycarida 4/14
*Recovery time breathing room air and excluding those monkeys experiencing
bigeminy of ventricular tachycardia.
+Time to onset after exposure to propellant mixture.
//Time to onset after appearance of initial extrasystoles.
A similar pattern of increase in the rate of extrasystoles despite the dis-
continuance of fluorocarbon gas after the initial appearance of premature
ventricular beats is seen in Table LXXVIII for three' monkeys exposed twice, to
the propellant mixture.
197
-------
.Table LXXVIII: Individual Cardiac Responses of Three Monkeys Exposed Twice
to Fluorocarbon Inhalation (data from Taylor £t al^., 1971).
First Exposure Second Exposure
//2 //3 //I //2 //3
_
Time to Ventricular : '• ~
Extrasystoles (sec.) 30 42 35 25 36 20
Initial Frequency
(per minute) 18 40 60 20 30 60
Maximum Frequency
(per minute) 120 80 110 40 110 120
The arterial blood levels of the fluorocarbons ;il. UK- onset of ventricular
premature beats are given in Table LXXIX.
Table LXXIX. Arterial Blood Levels of F-12 and F-114 at Time of Onset
of Ventricular Premature Beats in Monkeys
Arterial Blood Concentrations (rug/100 ml)
Time of Onset F-12 F-114 Total
(seconds)
35 5.5 1.8 7.3
42 6.3 2.3 8.6
45 6.5 2.2 8.7
Fluorocarbon inhalation caused a decrease in blood pressure just
prior to ventricular arrhythmias. The type, time to onset, and frequencies
of the arrhythmic responsesare apparently not influenced by anesthesia, but
extrasystoles is blocked by propanolol.
These results may be interpreted in two genera.! ways (Taylor et al.,
1971). First, the fluorocarbon gases at the concentration observed may be
exerting a direct stimulating effect on the beta adrenergic receptors or
198
-------
some direct toxic effect on the myocardium. Secondly, they may have sensi-
tized the ventricular myocardium to endogenous catecholamines and/or stimu-
lated the release of such catchecolamines. This latter interpretation is
consistent with the blocking of arrhythmias by propanolol.
The cardiovascular effects of the brominated fiuorocarbons, especially
H-1301 and H-1211, have been extensively studied because of their use as fire
extinguishing agents. Although some of these studies have been concerned
with sensitization to epinephrine-induced arrhythmias as discussed in a
previous section, much of the work has been conducted without injected
epinephrine or attempts to induce endogenous epinephrine. Van Stee and
Back (1969) have described the effects of H-1301 at concentrations of 20-80%
in dogs as tabulated below.
Table LXXX: Cardiac Responses of Dogs to Varying Concentrations of H-1301
in Oxygen (from Van Stee and Back, 1969).
Time to Onset After
Concentration Response Start of Exposure
20-30% Tachycardia (10-15%) in some few seconds
animals
Arrhythmias first minute of exposure
T-wave depression (lasted until 2-4
unifocal and multifocal minutes post-exposure..)
ventricular arrhythmias
bi- and trigeminy
40%< Tachycardia as above in all few seconds
animals
50%< Blood pressure full of 20-60 mm llg.
Irregular changes in heart rate
proportional to cardiac output.
Decrease in pulse pressure to 25-30 min.
0-30 mm Hg. from a normal of
45-50 mm Hg.
Lowering of peripheral vascular resistance.
80% More rapid decrease in pulse pressure
All of the above-noted effects were reversible in ab;>ut tv
-------
Monkeys exhibited the same type of arrhythmias as described in dogs.
Halon-1301 has also been evaluated under both hypo- and
hyperbaric conditions. Rats were exposed under hypobaric conditions
(632 mm Hg and 380 mm Hg) to 8, 16 and 24% H-1301 for five minutes (Call,
1972). The arrhythmias noted consisted of premature atrial contractions
occurring after one minute of exposure. These occurred in only two out of
twenty-seven rats, one at 24% H-1301 and 632 mm Hg and the other at 16%
H-1301 and 380 mm Hg. However, as indicated by Call (1972), these results
cannot be readily compared to the above work of Van Stee and liack (1969)
because of probable species specific differences in response. Paulet (1962)
has noted such variations in response to H-1301 in mice, rats, rabbits, and
guinea pigs.
Cardiac response of cats to H-1301 under hyperbaric conditions
have been studied by Greenbaum and.associates (1972). Exposure of 5% H-1301
for 2 min. and 5 min. were given to cats pressurized at 73 psig (165 ft.
sea level). Under these conditions, the partial pressures in inspired air
were 228 mm llg for H-1301, 866 mm Hg for 0 , and 3466 mm Hg for N . This
is equivalent t.o 30% H-1301 at standard atmospheric pressure.
Table LXXXI: Cardiac Responses in Normal Cats and in Cats before, during
and after H-1301 exposure at 165 ft. sea water (Greenbaum et al.,
1972). ~
Group Rate PR interval QRS duration
(mean (mean with range) (mean with range)
with range) (sec) (sec) "_
Normal 145(105-194) 0.08 (0.065-0.09) 0.037 (0.035-0.040)
Control 212(178-272) 0.08(0.06-0.1.2) 0.050(0.04-0.06)
2 min on Fe 1301 212(160-272) 0.08 (0.07-0.12) 0.056 (0.04-0.07)
5 min on Fe 1301 212(160-270) 0.08 (0.06-0.12) 0.060 (0.04-0.08)
1 min on air 212(155-288) 0.09 (0.07-0.12) 0.059 (0.04-0.08)
200
-------
Three of the twelve animals showed abberent ventricular conduction associated
with frequent nodal beats. This response is reflected in the slight increase
in QRS duration in the average figure given for the 12 cats. In seven cats,
responses ranged from infrequent premature atrial contraction to frequent
nodal beats. Two cats did not show any abnormal cardiac activity. The blood
pressures in 10 of 12 cats fell from a control mean of 160/115 to an exposure
mean of 148/96. The range was a 10-50 mm Hg drop in blood pressure, which
is quite similar to the hypotension noted by Van Stee and Back (1969) at
comparable concentrations in dogs at standard pressure.
Halon-1211 shows a response sequence similar to H-1301 but a lower
concentrations. Table LXXXII (Beck e£ al., 1973) .summarizes the cardiac
responses of dogs to H-1211 and should be compared to the data on -1301 in
Table LXXX. :
Table LXXXII: Cardiac Responses of Dogs to H-1211 (Heel: et al., 1973)
Concentration Duration Response
1% 5 min. no effect
2% 5 min. tachycardia (20%), slight T-wave
depression
5% 30 min. tachycardia in all dogs; severe convul-
sion in 1 of 6 dogs followed by several
ventricular ec.topic beats, ventricular
fibrillation and death
7% 15-30 min. bursts of marked tachycardia (up to
350%) associated with convulsions
As with R-1301 exposed dogs, the tachycardia ceased in 1-2 minutes after
exposure was discontinued. Further similarities of H-1211 to H-1301 can be
201
-------
noted in the cardiovascular response. At concentrations of 17, U-1211, a
slight decrease in systolic blood pressure was noted. At 5% H-1211, a 10%
decrease in blood pressure, slight T-wave depression, and occasional pulsus
alternans were noted. At 20-30% H-1211, pulsus alternans became more frequent
at ten minutes of exposure and were characterized by alternate strong and weak
ventricular contractions. As with the other effects, these were reversible on
return to normal air (Beck jet al.., 1973). Van Stee and Back (1972b) also
report a fall in systolic blood pressure in dogs after exposure to 15% H-1211
for five minutes.
5. Cardiac Responses Related to Arrhythmias
In an attempt to better understand the arrhythmogenin activity oi
the fluorocarbons, various experiments have been conducted in. attempts to
define the cardiopulmonary, hypotensive and negative intropic effects of
these compounds.
Aviado (1971) has measured the effects of F-ll, F-12, and F-114 in
dogs on pulmonary resistance and compliance, bronchial smooth muscle,
pulmonary blood vessels and the heart in an attempt to determine if the
cardiopulmonary effects of these propellants could be related to sensory
receptor initiation in the respiratory tract. Exposure of only the upper
respiratory tract (nose,, pharynx, and larynx) to 200 ml of 50% F-ll resulted
in apnea, bradycardia (-55%), and an initial deerearfe followed by an increase
in aortic blood pressure with no significant changes in pulmonary resistance
or compliance. Less severe bradycardia (not specified) was induced by F--114
but F-12 did not affect either cardiovascular responses, lixposure to the
lower respiratory tract of F-1L, F-12, F-114 al closes of .S, 10, 13, and 20
202
-------
puffs (amount released/activation not specified) from an aerosol unit
resulted in changes of pulmonary resistance and heart rate as indicated
in Figure 33.
Co *20
UJ
h-
o:
+10
LJ
I
UJ
O 0
I
o
-10-
20 NUMBER OF
ACTUATIONS
(3)
120 NUMBER OF
1 ACTUATIONS
Figure 33: Percent changes in (A) pulmonary resistance and (B) heart:
rate following exposure of various propellents to the lower
respiratory tract in dogs (Aviado, 1971).
203
-------
As in exposure to the upper respiratory tract, F-12 did not alter heart rate
and F-ll resulted in a slightly greater response, than did F-1.U but in this
case causing tachycardia rather than bradycardia. The decrease noted in
pulmonary resistance for F-ll was accompanied by a simultaneous increase in
pulmonary compliance (maximum of 27% at 15 puffs) and a fall in aortic blood
pressure (maximum of -8% at 15 puffs). Thoracic sympathectomy prevented
tachycardia caused by F-ll and F-11A. In that blocking of the beta adrenergic
receptors with sotalol does not inhibit tachycardia, tachycardia is attributed
to the sympathetic afferent fibers.
Van Stee and Back (1972a) have studied tin- mechanism by which H-1301
lowers blood pressure (Van Stee and Back, 1969; Greenbaum £t _al., 1972).
Using pairs of male beagle dogs in cross-perfusion experiments with exposure
of 70% H-1301, they measured perfusion pressure at constant perfusion flow as
a function of vascular resistance. The results are summarized in Table. LXXXI1I
(Van Stee and Back, 1972a).
Table LXXXIII: Responses of Dogs to Exposure of H-1301 (70%) in Cross-circulation
Experiments (Van Stee and Back, 1972a).
'.n.i>lu^ic iict inn un Ulii-i l n-,spoiine, Indirect (m-urnj'.-n i - ) i e.;j>on- t-,
ular .imooth muscle donor do^ exposed , M-ctpiuiit .tin-, exposed
• ' i 'T v;i!.ori lat lun
A i i t vat Ion of chol I nerjjl c
MM-«|itnrn NII dlr.M.i Affect rri'trearincnl. nf Hi,'1 vascular bed or
rtK.lpirnr witli atn-plitf «l|r| not
alter 111, response i •» fxposun* nf
recipient to CBrK
Ai: Li vat ion of M-adri-n- No dl i L-CI effect
t-r^Ic rec'-ptorn Fret ri-atmnnt of HI. wi<;cul.ir l.ud w tn
propranolol tllil iu.t .ilirr hi. ri~-
tu oxpixurp of ii'i-inh nt i.. cu,
,L*:-ivtj vasotll Jat i"n Nn din-'^t lifloi-i I'n-t • ea? n »?nt .1! Hi. .M...uliii
inliibitlun ol thu actl- plH'noxyb«-nz^mi ne ;; re.illy «l
vat Ion ot n-adrenc-rKlf HL re.spcnst: m c<|-i'sur*- >1
rt-cepiors to CBrF
Inhibition of sytnpatht- NA* Preircnlir.t!rit df
}
tic postgangUonlc liex«net!ionlum abollshoij Hi.
activity ' lo exposure to n-c ipl^nt to CHrF
Increased local con- No .-ffci-t on IIL NA
centratlou of tUsut- durinft .-xposuro
metabolites or other nf den^:
vasodilator aubHtances
rt-ctplpnt hind limh.
204
-------
To measure the possible effects of ganglionic blockade, nictitating
membrane tension was measured during electrical stimulation of the right
vagosympathetic trunk in anesthetized dogs before, during and after exposure
to 80% H-1301. A 40% decrease was noted in membrane tension during exposure,
with a recovery period of 30 minutes post exposure. Further, vagal inhibition
of the heart was significantly decreased.
These results seem to indicate that while direct alpha-adrenergic
blockage may not be involved in decreased vascular resistance, ganglionic
blockage may be an important factor (Van Stee and Back, 1972a).
In a similar cross-circulation experiment (Van Stee and Back, 1972b),
H-1211 at 15% has also been shown to decrease peripheral vascular resistance
in dogs. As with H-1301, this decrease was not associated with the; peripheral
adrenergic receptors. Lastly, neither H-1301 nor H-1211 have a direct effect
on the peripheral vascular smooth muscle (Van Stee and Back, 1972 a and b).
Exposing anesthetized dogs to 70% H-1301, Van Stee and Back (1971a)
noted a rise in left ventricular end diastolic pressure as an indication of
reduced myocardial contractility. This has been subsequently shown to be a
common characteristic of a variety of fluorocarbons.
Pursuing their initial observation, Van St.ee and Back (1972b)
demonstrated the negative inotropic effect of H-1301 in beagle dogs by measuring
the maximum rate of ventricular pressure change divided by total pressure
developed [peak dP/dt f P] in exposure tc 50% and 75% H-1301 for five
minutes. As indicated in Figure 35, a definite dr-t-e-related reduction in
myocardial contractility can be noted.
205
-------
60 --
I
O
". 50 - -
a.
•l-
a.
•o
LD
a.
2 40
S
0 25 50
BTFM NOMINAL CONCENTRATION
Figure 34: Decreased Myocardial Contractility in Dogs after Exposure to
50% and 75% H-1301 for Five Minutes (Van Stee and Back, 1972b)
Similar to arrhythmagenic potencies, H-1211 has been shown to reduce
myocardial contractility at significantly lower concentrations. Beck and
associates (1973), using a force displacement transducer, measured isometric
contractions at the apex of the heart in open-chest spinal rats in exposures
of 5%, 10% and 20%. The results are given in Figure 35-
hO-
§
O 30 -(-
i^
O
8
§20-|-
10 IS
CONCENTRATION f - 1211 (%)
Figure 35: Changes in Isometric Contraction in Rats During Exposure to H-1211
(Beck et al., 1973)
206
-------
Tlit: validity ol continuing the regression line on tin.- above graph is most
questionable in that Beck and associate^ (1973) specifically mention that
concentrations below 5% of E-1211 rarely produced any forced reduction.
Azar (1972) has made a similar criticism of the data presented in Figure 34.
Fluorocarbon -12 has also been shown to reduce myocardial contractility
over concentrations of 2-25% in close-chested cats (Taylor and Harris, 1972b).
At 25% F-12 in inspired air, F-12 blood levels in cats reached (mean ± SE)
9 ± 0.4 mg/100 ml. Thin concent rat. ion increased cinl <\ i us i.o I .i r prt'.sf.iirc* by
1.6 ± 0.4 mm Hg and lowered arterial pressure I row 135/93 to 10.1/65 mm lig.
At a left ventricular pressure of 60 mm Hg, the instantaneous rate of
ventricular pressure developed dropped from 3369 to.T972 mm Hg/sec. The
instantaneous velocity of contractile element shortening (dP/dt T 32P)
was decreased from 3.5 to 1.9 muscle lengths/sec.
Fluorocarbon -12 has also been shown to reduce the rate and the intensity
of force development in rat mycardial tissue In vitro. The effect is dose-
related and occurs in the presence or absence of a«i. quate oxygenation. This
has been demonstrated by Kilen and Harris (1972) using muscle bath prepara-
tions of rat left ventricular papillary muscles anil exposing the baths to a
variety of gas mixtures. The composition of these g.is mixtures and their
effect on Po. is given in Table LXXXIV. No significant effect is noted on
either pH (mean, 7.53; range 7.46 - 7.67) or Pco0 (Mean, 10; range 9 - 12).
207
-------
Table LXXX1V: Conditions of Exposure of Rat Left Ventricular Papillary
Muscles in Muscle Bath and the Effect ou Po? (Kilen & Harris, 1972)
% ml/rain. min. Hg+
Flow
Condition Code
Control °2~C02
Hypoxia N2~C°2
Nitrogen N2-02-C02
Freon CCl^F^-O-.-CO-
Hypoxia &
Freon*
°2
99%
-
99%
99%
-
co2
1%
1%
1%
1%
1%
N2
-
99%
100%
-
99%
F-12 Rate Po2
54
68
54
68
54
100% 42
68
100%
.8
.8 .
.8
•8
.8
.8
.8
613 ±
36 ±
464 ±
493 ±
32 ±
7
3
18
22
3
•f after 15 minutes
* Hypoxia for 30 min. with F-12 added in last 15 minutes reduced Po,
to 26 ± 1 min Hg. i
Time-response data for these exposures is given in Figure 36 and indicate
that F-12 with adequate oxygenation decreases myocardial contractility more
rapidly than does hypoxia although the amount of decrease is similar for
both conditions at fifteen minutes.
208
-------
•i N2 i IP •/ > CO?
T rncvjm '• \j y r i^u A
-{«• FREON INTROOUCED
> HYPOXIA* FHEON
Figure 36: Effect of Exposures to Various Gases in vitro Mycardial
Contractility (Kilen and Harris, 1972)
The effect of Freon plus hypoxia is engaging especially in view of the time-
response data given in Figure 36. F-12 and hypoxia alone have similar effects
at fifteen minutes although mechanisms, in view o*: the differences in oxygen
tension and rapidity of depression, are probably different. The effects of
F-12 and hypoxia together seem very much the same whether F-12 is administered
directly with hypoxia from a well oxygenated state or after fifteen minutes
of hypoxia alone. Although no time-response data is available for F-12 or
hypoxia alone for thirty minutes, it might be concluded that the mechanisms
209
-------
of myocardial depression by F-12 and hypoxia are not only different but
also quite independent of each other. The linear dose-response relation-
ship of F-12 concentration to in_ vitro myocardial contractility is
illustrated in Figure 37 for groups of 4-10 muscles.
u
oc
2
o
100- -
90- -
80-
70-
60-
'50-
40-
30--
20-
10-
0
n» 10
n 5
n G
-I 1 1 t I I |
4 6 8 10
LOG FLOW (ml/mm.)
(a)
20
40
-
i
z
8
u.
O
Z
OL
h*
Z
IU
1
_t
UJ
UJ
O
UJ
£
u.
0
ul
H
cc
100
90
80
70
60
SO
41)
30
20
10
0
.
.
.
-
n = 3 n .=• 3
n-2 n »4
—I"
20
I ^ I
40 . fiO
LOG FLOW (ml/min.)
(b)
Figure 37: Dose-response curves for the effects of dichlorodifluoromethane
gas (F-12) on isometric developed force in 15 isolated rat
papillary muscles (A) and on maximal rate of isometric force
development, dP/dt, in six of these muscles (B). Each point is
the mean ± SE of four to ten muscles in A and two to five muscles
in B. The n value next to each point is the number of muscles
studied at that flow. The bath concentration of F-12 at 2.7
ml/min is 1.06 ± 11 mg/100 ml and at 42.8 ml/min is 11.35 ± 0.52
mg/100 ml (Kilen and Harris, 1972).
210
-------
E. Sensitization - Repeated Doses
Hypersusceptibility on repeated dosing has not been clearly
demonstrated in any of the fluorocarbon propellants, solvents, or fire
extinguishing agents. In fact, Yant and coworkers (1932) note that dogs
seem to develop a definite tolerance to repeated exposures to 14.16% F-114.
The animals were exposed for eight hours per day for 21 days. After three
days, dogs no longer convulsed, tremors were less severe, and they showed a
less pronounced loss of equilibrium and increased alertness during exposure.
After 18 to 20 days, the dogs showed no adverse'- effects to the exposure
after the initial 30 seconds.
Fluorocarbon-112 did not produce sensitization when applied to the
skin of guinea pigs (Clayton £t ajL., 1964).
Repeated exposures to F-1211-did not result in increased sensitiza-
tion to epinephrine induced arrhythmias (Beck e£ aJL., .1973).
F. Teratogenicity
There is no information indicating that the fluorocarbons under
review are teratogenic. In long-term feeding studies of F-12 to rats
(see Section XII, C, Chronic Toxicity), no abnormalities were noted in
fertility, gestation, viability and lactation indices (Sherman, 1974).
Further, pregnant.rats have been intubated with F-12 at levels of 16.6
and 170.9 mg/kg/day from day six to day fifteen of their gestation. No
effects were noted in embrional development or abnormalities in live
fetuses (Culik, 1973).
211
-------
G. Mutagenicity
As with teratogenicity , the fluorocarbons have not been implicated
in mutagenicity . Sherman (1974) has determined the mutation rates in rats
during a two-year feeding study. The results are summarized in Table LXXXV.
Sherman (1974) indicates that mutation rate increases of less than +25%
are not significant.
fib
Table LXXXV. Effects of Freori^ 12 Administered Orally to the Parent
Female and Male Rats on Fertilization, Implantation and
early Development of the Fetuses - Dominant Lethal Effects
i!-'j'*66 - MH-] •'•'•)
No. of Females Bred
No. of Female:1. Pregnant (Fertility 1nd<-v.l
Nc. of Live Fetuses
No. of Pond Fetuses
No. of Livo Fet.^es/Litti-r
>.:.<.!) No. o." Con-crn l.i:ton
No. of Corpora lutea/Prernnit't Female
No. of Implantation Sites
No. of Iir.plant.-.tlon Sites/Prep. Female
No. a;' Early Kesorptior. ;ttfl£:(>:clduomata}
No. of Ute Re'sorptlon Sitc.-
-•-. • ; Nnnber of Resorptlonr.
Prelmpliiitatlor. I/us (y)
Mutation Kale (''})
^i:'.e'. Ion ll-te Ccmpare-i VI i.c "•.nl.r'vl 1 "• i
•«!utntlot Rat* fonparfd With '.'intrnl Jl (.'i>
I (Control
iy
17 (SfJ.1";)
200
0
11.8
"*<*'
16.,?
.-•5U
lli.Q
V
19
'A
8.051
_ilJ>L._
II (Control)
30
20 (100)
150
0
6.0
• 'T7
1J.9
?51
12.6
102
19
131
9.H
- -^£
Lov. Lovi-1
Frcotf'1 12
PO
13 (Q0>
1(0
0
R.'J
.?• -'
lii. 9
i-,8 '
H. 5
rt?
11
91.'
ii.l*
— ?f—
-"'.<)
HlSll Irwl
Frcori"" 12
19
17 <*<,.',}
178
0
.".Un>larl Vr.lu?:: ( K-i i ;.\f '• I jr
Cli'irli;:, UJ V.T TD) Hat: (]}
•»
(c] PreijnL'lanta tion loss: ''Number ^f Corpora Liit.^a - N ij-ihor of Tmulantation ::^t.esl ^ ,,-,-,
riiml»-r of Coi-p'jr>j hitcu
*'. !'\i'.aMor. r'ite: Kur^l-?r ^f J^^LAX^^v?;!Qj^tioj;i lii^c-'- > i^ri j-i_omata > j- j(Jr
N'.i-nher of Irr.pJ.in^aMoi. rilor,
Nt 1CO-, Nwn^r of Live Fetuses/Litter of Control Group
i ••••.
/
212
-------
11. Carcinogenicity
Fluorocarbon-112 and F-113 at doses of 0.1 ml 10% (V/V) solution
injected subcutaneously in the neck of neonatal mice are not carcinogenic.
However, when injected in conjunction with a 5%j(V/V) solution of piperonyl
butoxide, hepatomas are induced in male mice as indicated in Table LXXXVI.
This is particularly marked with F-113.
Table LXXXVI. Tumors Induced in Swiss Mice by Injection .of "Freons"
and Piperonyl Butoxide Shortly After Birth
. . • [from Epstein tM: aj_. , 1.967]
No. of dice, Hubsoqucntly milojisled, In KT >n;i : Mull^nunt lyui|>h:>[aas
alive ai the beginning of etch period N.i. iiuiioi.. i> •• •< !i joil No: tumnrr, in i:*''. peri-id
Treatment^Group S«x (No. at rink) No. n.l * of Nn. of t. as I of No. of nl-e at rUk
Solvent controls P. 72 68 59 55 48 4 0 0 0 ^ I 0 0 0 2
r 69 69 69 68 66 0 0 II ') u 000 0 0
"Fraon" 11 . M i5 25 22 21 21 2« 0 d u 1(1 1 4000
F 20 20 20 20 20 0 0000 0 0 :0 0 0
"Pteon" 112 M 27 27 27 20 17 0 0 0 0 . II 0 0.000
r 22 il 21 20 19 0 0000 6 0000
"Fraon" 113 M 29 39 29 J6 21 1 0 0 ,j 5 0 0000
F 21 21 20 20 20 0 0 •! fi 0 • ! " 0 0 0 5
Piperonyl butoxide M 40 18 35 2.S 10 000 ,' •> ' 0 0 0 0 0
f 36 36 J6 16 36 0 0 •) il 0 0 0 0 0 D
"Preon" 112 and piper- M 30 26 26 14 I] 5 0 0 : • u 00 0 0 0
onyl hutoxlda K 29 29 28 25 24 0 0 II .> 0 3 0408
"Freon" 11.1 and piper M 25 24 24 19 18 3 0 i' .1 ] .' 0 0000
onyl butuxldn K 24 24 24 24 i4 0 0 u i. 0 10004
* One of these iiltto had .1 (mlmonarv ^d'Muima.
213
-------
The apparent synergestic hepatocarcinogenicity of these fluorocarbons with
piperonyl butoxide cannot be explained at present. Long before the tumor*
appeared, the fluorocarbons should have been eliminated from the rats'
bodies. The investigators speculate that piperonyl butoxide nay interfere
with the metabolism of these fluorocarbons (Epstein et al., 1967a).
The significance of this effect ia difficult to interpret because
of the lack of follow-up studies in other species (Tomatis et al.. 1953)
and other fluorocarbons. The results of Epstein and coworkers (1967a),
however, have not been disputed in the literature (e.g.. Friedman et al.,
1972; Jaf fe et aj.. ,1969; Kami ens ki and Murphy, 1971; Redfern et aj.., 1971;
Vogel and Zaldivar, 1971). The increased susceptibility of males to liver
tumors is common for chemical carcinogens (Roe and Grant, 1970), The use of
newborn mice as experimental animals in screening for carcinogenicity is ,
widely accepted as having valid predictive value (Epstein ££ al., 1970; Delia
Porta and Terracini, 1969; Tomatls et al., 1973) although this acceptance is
not universal (Grasso and Crampton, 1972).
On the basis of the study by Epstein and coworkt-rs (J%"/a), "Freons"
have been listed as chemicals inducing tumors in die liver of mice (Tomutis
.$f .al.,- 1973). This is misleading. Only F-112 ami f-IU have bten tested.
A significant increase in hepatomas are induced only with piperonyl butoxide.
Piperonyl butoxide is a potent inhibitor of microsomal enzyme function
'•-.•«• . . - • " .. • . " - • ' '
(detoxification) in insects and is thus a useful nynergist with insecticides
greatly reducing the amount of insecticides that are necessary for insect
control (Casida, 1970; Cooney et al., 1972)... The compound is thermally and
photochemically stable under conditions of normal us<> (Friedman and Kpstein, .
214
-------
1970; Fishbein and Gaibel, 1971). However, the potential hazard posed by
piperonyl butoxide and fluorocarbons has been demonstrated in only the most
preliminary manner. Fluorocarbons-112 and F-113 are not commonly used in
preparations containing piperonyl butoxide (McCaul, 1971). While piperonyl
butoxide has been shown to greatly inhibit microsomal enzyme systems in
mice, it is much less potent in rats and man (Conney e_t^ jal., 1972). Thus,
the most that can be concluded on the basis of current information is that
fluorocarbon propellants may require testing in conjunction with microsomal
inhibitors for potential carcinogenic activity (McCaul, 1971). If micro-
somal enzyme inhibitors are shown to induce liver tumors with the fluoro-
carbons, this information might lead to a better understanding of fluorocarbon
metabolism.
The precancerous lung cell changes noted by Good (1974) are dis-
cussed in Section XI, B, Human Toxicity, Occupational Exposure and Normal
Use.
215
-------
I. Behavioral Effects
Apart from the effects of intoxication and anesthesia as discussed
in previous sections, no behavioral effects have been attributed to these
fluorocarbons in non-human mammals and birds. The work of Carter and
coworkers (1970b) may be considered an exception. Exposure to 20-25%
H-1301 significantly decreased the performance o£ trained monkeys. This
operant behavior was completely disrupted at higher concentrations without
signs of CNS depression or analgesia.
216
-------
J. Possible Synergisms
The synergistic carcinogenic!ty of F-112 and F-113 have been noted
in Part G, Carcinogenicity. Epstein and coworkers (1967a and b) have also
noted synergistic toxicity of these compounds in mice. Ay indicated .in Table
LXXXVII, mortality occurred primarily in the first week and was signifi-
cantly higher in mice receiving both piperonyl butoxide with F-112 or F-113
than in those groups receiving F-112 or F-113 alone.
Table LXXXVII. Toxicity Indui-ed In Svlaa Mice by Neonatal and Perinatal Subrutan.-ou:. ln|c. Uons uf T-l\l mid F-113
Alone and In Ootiib i nat ion wltli a 1Synernlstt, Plpurunyl Dutuxidi- (Pl'.l [Cpsuilii <•( .1]., 19!
Trlcapryllti \.'itly) (tu'lvtMH o'ntni!)
Trlcuprylln (onlv) (control) - - -III) (ID) I4( m :.( •/'
'frcon1 II.' (HIS) Jlone 0.1 n.l I!..' u.J oil u.b ml 56 ( 5) ;( •,:'; .< •> i
'Freon* 112 lltlt) wttli I'll 0.1 n.; u,.i d.j ml ((.(, ml 137 (12) Vl( l-bl '.!! I./.
•fritcm1 UJ (105) alone
'Kreon' 113 (10!) with Pn
ii I 4)
0.1 II. I 0.2 0.2 ul (l.u ml 94 ( H) 451 ','fi
0.1 ml of 5?! synvrglRt In trlcaplylln Injecc^iJ un tiayf 1 & 7 anil U.2 oil on day* 14 (, 21; group;.
drug alone In corresponding volumun of trlcupiylln ut the aaflw InLurvala.
AVf. Uciijlit ',«) of .
raU.o at ap"i:if;^d daya
o j.: ft. ^ U. :i
. / '/•.:. a.- : 1. '•
./ -.i \ii.l Ib.c
.6 i.) «.4 14.,'
.» ..i -i.a 15.0
The increases in average weight gains in fluorocarbon with piperonyl
butoxide exposed animals is not readily explained and is termed "anomalous"
by Epstein and coworkers (1967b). Preferential male survival was not noted
and thus is not a factor in this weight gain. However, it seems probable
that in a given group of animals administered toxic compounds, the more
217
-------
vigorous animals would survive and this group of survivors might be
expected to show increased weight gain over a control group. Thus, the
increased weight gain of the fluorocarbon/piperonyl butoxide exposed
group might be an artifact of experimental design.
The possible potentiating effect of F-22 and F-115 in causing
cardiac arrhythmias by sensitization to exogenous epinephrine has been
discussed (see Section xil Part D-l).
As with the parallel study on the synergistic carcinogenicity of
F-112 and F-113, the above information on synergistic toxicity is quite
limited. However, the interactions of environment pollutants is an area
of legitimate concern (Cooney and Burns, 1972). The possibility of such
reactions involving fluorocarbons cannot be ruled out on the basis of their
presumed low level of biological activity and more experimental work in this
field is warranted, particularly in that fluorocarbons are often used or
administered with compounds of known biological activity (McCaul, 1971).
218
-------
XIII. TOXICITY TO LOWER ANIMALS
No information on the toxicity of fluorocarbons to non-mammalian verte-
brates or any of the Metazoan Phyla has been encountered.
XIV. TOXICITY TO PLANTS
Of the fluorocarbon propellants, solvents, and fire extinguishing agents,
only F-ll and F-12 have been studied for phytotoxicity. Taylor (1974) has
exposed plants to F-ll and F-12 at concentrations of 0.5-1, 10, and 15 ppm
for two weeks. No signs of toxicity, impaired growth,or absorption were noted.
Halothane has been shown to cause metaphase arrest in the root tips Of
Vicia faba, the European broad bean. The EDcn ranges from 0.5-0.9%. Total
——— ——— 5U
arrest is achieved with 2.0% over 8 hours (Nunn et al., J971).
XV. TOXICITY TO MICROORGANISMS
Similar to its effect in Vicia faba (Nunn et al., 1971), halothane has
been shown to cause reversible microtubular disruption at 2% concentration
over a 7 minute period in Actinosphaerium nucleofi Lum, a heliozoan protozoa
(Allison et al., 1970) and decrease the bioluminescence of Photobacterium
phosphoreum at concentrations as low as 0.3% (White and Dundas, 1970).
The latter effect has also been noted for F-22 although the potency of this
fluorocarbon (ED5Q, 37.6%) is much less than that of !:yl.othane (ED5Q, 0.76%).
Dose-response data for these compounds and a number of others screened for
their effect on bioluminescence are given in Table LXXXVIII.
219
-------
Table LXXXVIII. Mean dose-response curves for halottiane (H/VL) , F-22,
and a variety of other agents on bioluminescence in
Photobacterium phosphoreum (White and Dundas, 1970).
reprinted with permission from D.C. White,
Copyright 1970, MacMillan Journals Ltd.
The investigators suggest that this may be a simple, inexpensive, sensitive
screening test for determining the potency of compounds with anesthetic
activity and synergistic effects (White and Dundas, 1970). Ln this respect,
it is interesting to note that F-22 ED5Q of 37.6% is quite close to its
ALC in mice, 40% x 2 hours (see Table L) . This may wi'1.1 be < -on inc: i done a] .
Halsey and Smith (1970) conducted similar tests in the same bacteria. The
results obtained for ED.^s in bacteria compare well witli those of. ADrnS
(dose causing general anesthesia) in mice as summarised in Table LXXX1X.
Table LXXXIX. Comparison of the ED__s of bioluminescence inhibition
in bacteria and the AD,_s in Mice for Halothane, F-22
and F-12 (from Halsey and Smith, 1970).
Compound ^sn ^SO
(atmospheres) (atmospheres)
Halothane 0.0081 ± 0.0001 0.0086
F-22 0.209 ± 0.004 0.16 i 0.05
F-12 0.50 ± 0.01 0.40 ± 0.06
220
-------
The comparative potencies of F-22 and F-12 compare well with those of the
toxic effects described in mammals (see Section XII , Mammalian Toxicity).
Halsey and Smith (1970) further note that site of action in these compounds
is probably hydrophobic in that potencies correlate better with oil/gas
partition coefficients than with hydrate dissociation pressures.
Stephens and coworkers (1970) have proposed a somewhat different system
for assessing the biological effects of various gases. They have exposed
Neurospora crassa - the common bread mold- to a variety of compounds including
F-12 and observed for changes in conidia formation, perithecLa production,
and mutagenicity. Exposures to gas mixture (in oxygen) w.-trt1 30 ml/minute
for 10 minutes - to evacuate air - to innoculations ot five-day old micro-
conidia of opposite mating types. The cultures were then incubated in,a
specified gas atmosphere for 21 days. Phenotypically, F-12 at concentrations
of 50%, 75%, and 100% resulted in light white conidia 48 hours after exposure.
Normal conidia are heavy pink and 100% oxygen control;, caused light pink conidia.
Perithecial formation was not inhibited during any of t'lu: exposures to F-12.
However, exposure to 75% F-12 resulted in a mutation rate of 0.33% and
50% F-12 in a rate of 1.42%. The normal mutation rato.-; for this species is
0.066% to 0.28% and the control rate was 0.13% with no imitations noted in
the 100% oxygen control. Because mutation rates had to 'ie determined on the
basis of crosses producing ripe ascospores, only the 50% F-12 exposure shows
significant mutagenic activity. The same species exposed to F-23 for 18 hr.
at 4°C produced 4.7% yellow, cauliflower, colonial mut.-mts. No mutants were
noted in air or oxygen controls. As Stephens and coworkers (1970) indicate,
221
-------
this type of testing is rather new and its significance to other areas of
fluorocarbon toxicity cannot yet be defined.
The comparative toxicity of F-12 and F-142b have been determined in
liquid and vapor states for a variety of microorganisms (Prior et_ jd. , 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 fluoro-
carbon). In no instances were substantial growth reductions noted.. However,
in the liquid state both F-12 and F-l42b substantially reduced cell viability
in all cultures tested. Because agitation is required to induce the toxic
effects, Prior and coworkers (197) conclude that there, is probably some
interaction between the compounds and the lipids in the microorganisms and
cite a study which attributes the toxic effect of F-ll on Pseudomonas striata
to its strong lipophilic characteristics (Lie, 1966). This is in agreement with
mammalian studies which indicate binding with the lipid portions of membrane
systems as a mechanism of biological activity.
Reed and Dychdala (1964) have exposed three bacteria and two fungi to a
mixture of F-12 and F-114 (40/60) The bacteria were incubated for 48 hours
and growth determined by visual examination. Two aerobic species - Pseudomonas
aeruginosa and Staphylocuccus aureus - were not affected. However, Streplococcus
agalactiae (anaerobic) , Aspergillus niger , and Pae.cilomyces var Loti failed to
grow. The investigators did not attribute this to fluorocarbon toxicity.
Rather, they reasoned that the anerobe was denied sufficient CO^ and the
aerobic fungi denied sufficient oxygen by the addition of the propellunt
(displacement) or the formation of a stratified layer of fluorocarbons between
the culture media and the air in the container.
222
-------
XVI. CURRENT REGULATION
Regulations at all levels of government are currently under review and
evaluation (Hanavanv 1974). With the exception ol FUA regulations on the
use of F-12, F-1J.5, and C-318 (octa-fluorocyclobutane) , regulations of any
type (federal, state, county, foreign, etc.) have not been encountered.
Fluorocarbon-12 has been approved as a food additive provided that it
is 99.97% pure and that it is used only as a direct-contact freezing agent
for foods. The container must be labelled "dichlorodifluoromethane,"
designated as food grade and contain instructions for use (Federal Register,
1967). Fluorocarbon-115 may also be used as a food additive provided that
it is 99.97% pure and contains less than 10 ppm unsaturated fluorocarbons
and 200 ppm saturated fluorocarbons. It may be used w:i th carbon dioxide,
nitrous oxide, propane and/or C-318 as a propellant and aerating agent for
most sprayed or foamed foods. The label must contain the name chloropenta-
fluoroethane, specify the percentage of a mixture, be designated food grade,
and contain proper instructions for use (Federal Register, 1965). Similar
approval has been given to C-318 except that the purity must be 99.99% and
contain less than 0.1 ppm fluoroolefins calculated as perfluoroisobutylene
(Federal Register, 1965).
The DuPont de Nemours and Company's Corpus Christ! plant in Ingleside,
Texas, has requested and been granted exemption of the following fluorocarbons
from Regulation V under the Texas Clean Air Act (Borden. 1973): F-ll, F-L2,
F-13, F-14, F-21, F-22, F-23, F-113, F-114, F-135. and F-116.
223
-------
Because they are shipped in pressurized containers, f luorocarbons must
be shipped in containers meeting ICC requirements for compressed gases
(DuPont, 1973).
XVII. CONSENSUS AND SIMILAR STANDARDS
Two standards are commonly employed in classifying exposure limits to the
f luorocarbons: these are Threshold Limit Values (TLVs) and the Underwriters'
Laboratories Classification. TLV's 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 informa-
tion. 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 con-
centration, these values are based on good manufacturing practice. Concentrations
higher than 1000 ppm foi; any compound being used indicate poor production
or handling technique and thus this concentration is the upper limit of
acceptability. The definitions by the Underwriters' Laboratories in their
classification are given in Table XC.
Table XC. Underwriters' Laboratories Comparative Toxicity
Classification of Refrigerants (Underwriter's
Laboratories, 1971a)
Toxicity
Group
1
2
3
4
5
6
Concentration Per
Cent by Volume
% to 1
h to 1
2 to 2h
2 to 2h
Duration of Exposure to
Produce Death or Serious
Injury to Test Animals
5 minutes
•<• hour
1 hour
2 hours
Intermediate between Groups 4 and 6
20 No injury after 2 hours
224
-------
The Underwriters' Laboratories Classification and TLVs for the various fluoro-
carbons under consideration in this review .are given in Table XCI.
Table XCI. TLVs and Underwriters' Laboratories Classification for
Various Fluorocarbons.
Compound
Code
Threshold Limit
Value1
ca3F
ca2F2
f1 ' f* 0 TT
\*t\^fv p 'j
CF,
fMl ^ n r TJ*
CHC.F2
or^OrtT*1 r^^Ortir
^>\jJvy J:^\>vvX/y i
CC£ 3-CC«.F2
CCJiF2-CC;t2F
CC.iiF2-CC5,F2
CC«.F2-CF3
CCX,F2Br
CF3Br
CBrF2-CBrF2
F-ll
F-12
F-13
F-14
F-21
F-22
F-112
F-112a
F-113
F-ll 4
F-115
H-1211
11-1301
H-2402
1000*
1000
(1000)*
(1000)*
1000
(1000)
500
500
1000
1000
1000
Underwriters' Laboratories
Classification2
5
6
6
6
4-5
5
4-5.
6
6
,-+
A.C.G.I.H., 1973; * Clayton, 1970
Underwriters' Laboratories, 1971a; + Underwriters' Laboratories,
1971b
225
-------
XVIII. Fluorocarbons: Summary and Conclusions
The fluoromethanes and fluoroethanes are widely used as aerosol propellants,
solvents, fire exiinguishing agents, and refrigerant gases. Current world
production is probably approaching two billion pounds per year with an annual
growth potential of approximately 6-8 percent. About half of the production
{and use is currently centered in the United States. The commercial success
and continued growth rate of these fluorocarbons are predicated largely on the
suitability of their physiochemical properties to the above uses and their
relatively low level of demonstrated toxicity. As a result of their commercial
success and use patterns, these fluorocarbons are and will continue to be
ubiquitous atmospheric contaminants with average concentrations (v/v) in the
low (2-15) ppb range and peak concentrations in low (20-30) ppja range are
projected for the next half century. Adverse biological effects from exposure to
such levels cannot be demonstrated from the available toxicity data. However,
fluorocarbons are not biologically inert and the effects of long-term low-level
continuous exposures have not been extensively characterized.
This study concluded that in 1972 approximately 711 x 10 Ibs of the 900 x
10 Ibs produced in the United States was released to the environment. Global
release is perhaps twice that figure. Of the fluorocarbons under study, F-12,.
•F-ll, and F-22 constitute more than 75% of the total market and present the
major sources of fluorocarbon environmental contamination. Fluorocarbon-11
and F-12 have already been monitored at background levels in the 100-500 ppt
range. This monitoring data supports the fact that the fluorocarbons are
extremely persistant, based upon what is known about the physical, chemical
and biological stability of the C-F bond and some experimental evidence.
226
-------
Fluorocarbon use patterns suggest increasing concentrations going from the
background environment, to urban areas, to human dwellings. This pattern is
also supported by monitoring data indicating fluorocarbon concentrations in
homes may vary in the 200ppt-500,000 ppt range, the wide fluctuations
reflecting the sporatic use of aerosols and leaks from refrigerant applications.
The potential hazards posed by the large scale atmospheric release of
fluorocarbons can be anthropocentrically divided into two general classes:
direct hazard to man through exposure to comparatively high concentrations
found in the home or peak concentrations in urban areas: or indirect hazard
to man due to adverse effects from long-term low-level exposure to man or other
ecologically important species. It must be emphasized that the maximum peak
concentrations of total fluorocarbons will probably not exceed 20 ppm and
the maximum background concentrations will probably not exceed 15 ppb. There
f
is absolutely no direct evidence that such levels are in any way detrimental
to any living systems. However, the effect of long-term, low-level, continuous
exposure to f luorocarbons is virtually unexplored. The.- effect of f luorocarbons
on non-mammalian species has also received very little study. Lastly, the
pharmacology and toxicology of these compounds has only recently generated
intense investigation and these investigations are leading to an extensive
reevaluation of fluorocarbon biological activity. Thus, the type, rather than
the amount of toxicity data available prevents the characterization of
fluorocarbons as environmentally innocuous.
Given the lack of direct evidence that f luorocarbons way be. harmful ai
environmentally probable concentrations and the inappropriateness of most
227
-------
current toxicity data in evaluating environmental hazard, r.ertain facets of
o
fluorocarbon toxicology suggest the need for further definition. When fluoro-
carbons were first introduced as aerosol propellants, they were considered
biologically inert. Subsequent investigations, however, revealed a broad
spectrum of cardiovascular effects. That fluorocarbons may have other
unrecognized biological effects cannot be ruled out. Up until quite recently,
the stability of the C-F bond was thought to preclude metabolism. However,
there is now a reasonable indication that F-12 is slightly metabolized after
a relatively short exposure. If F-12 is metabolized, then F-11 may also be
metabolized. The rates of metabolism and the significance of this metabolism
at environmental concentrations are unknown. Lastly, only two continuous
chronic exposures have been conducted with fluorocarbons (see p. 151). One
study clearly indicated liver damage in guinea pigs at a concentration
(810 ppm) usually considered innocuous. While not suggesting that such
damage is typical of fluorocarbon exposure at environmentally probable concen-
trations, the inadequacies of predicting long-term effects on the basis of
short-term exposures is apparent.
An additional factor which requires further investigation is that
fluorocarbons may migrate to the upper atmosphere and reduce the ozone layer
(chlorine atom released from the fluorocarbon would react with ozone), thus
allowing high energy ultraviolet irradiation to reach the earth's surface.
Reductions in the ozone layer have been correlated with increases in skin
cancer. Since this possible effect has only recently been reported (see
Anon., 1974d and 1974e; Cicerone _et_ _al. , 1974), a detailed description of the
effect is not included in the text of this report. Reference should be made
228
-------
to the cited papers. This possible affect is under investigation and may prove
to be the greatest: environmental hazard from commercial use of fluorocarbons.
However, presently, no monitoring of fluorocarbons in the upper atmosphere has
been reported and the relative importance of fluorocarbons in terms of
catalyzing ozone decomposition is unknown.
Thus, considering the projected levels of fluorocarbon contamination
along with what is known of their biological effects, fluorocarbons do not
seem to present anything approaching an imminent environmental threat.
The levels projected in this study are not likely to be exceeded, and,
depending upon the economics and availability of raw materials (e.g. Cal*' -
fluorspar), the actual levels may be much lower. Fluorocarbon toxicology
is currently being investigated by a number of research groups and - j^iven the
use of fluorocarbons in pharmaceutical preparations, ihe potential for abusive
inhalation, and the vague possibility of occupational hazard - such research
will probably continue for many years. However, the data of Cicerone et al.
(1974) sugge.st that the possibility of fluorocarbons catalyzing ozone
destruction should be resolved relatively soon before the rate of ozone
destruction by natural sinks is exceeded.
229
-------
ACGIH (1973), TLVs;Threshold Limit Values for Chemical Substances and Physical
Agents in the Workroom Environment with Intended Changes for 1973
(American Conf. of Governmental Industrial Hygienists, Cincinnati, Ohio).
Allen and Hanburys Ltd., (1971), "An Investigation of Possible Cardio-toxic
Effects of the Aerosol Propellents, Arctons 11 and 12, Volume 1",
unpublished report courtesy of D. Jack, Managing Director, Allen and
Hanburys, Ltd.
Allied Chemical (1969), "Unloading and Handling Genetron from Tank Cars and
Tank Trucks", Product Information Bulletin, RTB-12.
Allied Chemical (no date), "Genetron - Super-Dry Refrigerants".
Allison, A.C., Hulands, G.H., Nunn, G.H., Kitching, J.A., and MacDonald, A.C.
(1970), "The Effect of Inhalation Anesthetics in the Microtubular System.
in Actinosphaerium nucleofilum", J. Cell. Sci., 1_, 483.
Anon. (1958), "Atmosphere" in Van Nostrand's Scientific Encyclopedia
(D. Van Nostrand Co., Ltd., Toronto, Canada, 3rd Edit., 1958), p. 137.
Anon. (1965), "Fluorine-chemicals Complex Getting a Big Boost", Chem. Engr.
12, 92.
Anon. (1974a), "Industry and Business", Chem. Eng. News, Feb. 11, 1974, p. 8.
Anon. (1974b), "Fluorocarbon Shortage Easing But Future Hinges on DuPont",
Chemical Marketing Reporter, April 29, 1974, p.3.
Anon. (1974c), "DuPont Schedules Unit for 'Halon' Extinguishant", Chem.
Marketing Rept., Mar. 4, 1974.
Anon. (1974d), "Scare Over Chemical Threat to Ozone Layer Building Up",
Chem. Engr. News, Sept. 23, 1974, p. 6.
Anon. (1974e), "Chlorofluorocarbons Threaten Ozone Layer", Chem. Engr.
News, Sept. 23, 1974, p. 27.
Archer, V.E. (1974), U.S. Dept. H.E.W., Center for Disease Control, NIOSH,
personal communication.
ASHRAE (1972a), "Refrigerants", in Handbook of Fundamentals, Chapt. 14, Amer.
Soc. Heating, Refrigerating, and Engineers, New York.
ASHRAE (1972b), "Factory Dehydrating, Charging, and Testing", 1972 Guide and
Data Book, Chapt. 22, p. 248, Amer. Soc. Heating, Refrigerating, Air
Conditioning Engineers, New York
ASHRAE (1973), "Engineered Refrigeration Systems (Industrial and Commercial)"
in ASHRAE Handbook Chapt. 24, p. 241, Amer. Soc. Heating, Refrigerating,
and Air Conditioning Engineers, New York.
230
-------
Aviado, D.M. (1971), "Cardiopulmonary Effects of Fluorocarbon Compounds",
U.S. Nat. Tech. Inform. Serv., AD Rep. No. 751426, 10 pp.
Azar, A. (1972), "Comments on paper presented by Van Sfce am1 Rack 'The Negative
Inotropic Effect of Bromotrifluoromethane Exposure i.n tfu; Dog'", Proc.
3rd. Ann. Conf. Environ. Toxicol., U.S. Nat. Tech. Inform. Serv.,
AD Rep. No. 773776, p. 197.
Azar, A., Trochimowicz, H.J., Terrill, J.B. and Mullin, L.S. (1973), "Blood
Level of Fluorocarbons Related to Cardiac Sensitization", Amer. Ind.
Hyg. Assoc. J., 14, 102.
Azar, A., Reinhardt, C.F., Maxfield, M.E., Smith, P.E., and Mullen, L.S.
(1972), "Experimental Human Exposures to Fluorocarbon 12", Amer. Ind.
Hyg. Assoc. J., 13, 207.
Azar, A., Zapp, J.A., Reinhardt, C.F., and Stopps, G.J. (1971), "Cardiac
Toxicity of Aerosol Propellants", JAMA, 215, 1501.
Back, K.C. and Van Stee, E.W. (1972), "Cardiovascular arid Nervous System
Effects of Bromotrifuloromethane: A Short Review", in Appraisal of
Halogenated Fire Extinguishing Agents, Proc. Symp., (Nat. Acad. Sci.,
Washington, D.C.), p. 91.
Bass, M. (1970), "Sudden Sniffing Death", JAMA, 212, 2075. . "• A
• ' w
Beck, P.S., Clark, D.G., and Tinston, D.J. (1973), "Pharmacologic Actions of
Bromochlorodifluoromethane (BCF)", Toxicol. Appl. Pharmacol., 24, 20.
Blake, D.A. and Mergner, G.W. (1974), "Inhalation Stuuius on.the-Blotrans-
formation and Elimination of 14C-trichlorofluorometKane (FC-11) and
^C-dichlorodifluoromethane (FC-12) in Beagles", preprint to be
published in Toxicol. Appl. Pharmacol., courtesy of D.A. Blake.
Bohac, S. (1968), "Conductometric Testing and Corrosion Study of Nonanhydrous
Ethanol Systems for Hair Spray", J. Soc. Cosmet. Chem., 19, 149.
Bower, F.A. (1971), "Nomenclature and Chemistry of Fluorocarbon Compounds",
U.S. Nat. Tech. Inform. Serv., AD Rept. 751423, 9 pp.
Bucholz, S.B., and Pigott, G.M. (1972), "Immersion Frviv.ing of Fish in
Dichlorodifluoromethane", J. Food Sci., 37., 416.
Burgison, R.M., O'Malley, E., Heise, C.C., Forest, J.W., and Krantic, J.C.
(1955),• "Fluorinated Ethylenes and Cardiac Arrhythmias Induced by
Epinephrine", J. Pharmacol. Exp. Ther., 114, 470.
Burn, J.H., Epstein, H.G., and Goodford, P.J. (1959), ''The Properties >">f ; ;K>
Anaesthetic Substance 1:1:2-trifluoro-l:2-dichloroethaiie", Brit. J.
Anaesthesia, 31, 518.
231
-------
Call, D. W. (1972), "Human and Rat Exposures to Halon 1301 Under Hypobaric
Conditions", in Appraisal Halogenated Fire Extinguishing Agents, Proc.
Symp. (Nat. Acad. Sci., Washington, D.C.), p. 127.
Call, D.W. (1973), "Halon 1301 (CBrF3) Toxicity Under Simulated Flight
Conditions", Aerosp. Med., 44, 202.
Callighan, J.A. (1971), "Thermal Stability Data on Six Fluorocarbons",
Heat., Piping Air Cond., 43, 119.
Carpenter, F.G. (1954), "Anesthetic Action of Inert and Unreactive Gases
on Intact Animals and Isolated Tissues", Amer. J. Physiol., 178, 505.
i
Carter, V.L. (1970), "Data Given in Discussion of Carter et_jil., 1970a" NTIS,
AD Rept. 727524, p. 315.
Cartel, V.L., Chikos, P.M., MacEwen, J.D., and Back, K.C. (1970a), "Effects
of Inhalation of Freon 113 on Laboratory Animals", U.S. Nat. Tech. Inform.
Serv., AD Rept. 727523, 18 pp.
Carter, V.L., Farrer, D.N., and Back, K.C. (1970b), "Effect 01 liromotrifluoro-
methane on Operant Behavior in Monkeys", Toxicol. Appl. 1'liarmacol.,
l7_» 307.
Cascorbi, H.F. and Singh-Amaranath, A.V. (1972), "Fluoxene Toxicity in Mice",
Anesthesiology, 37, 480.
Casida, J.E. (1970), "Mixed-Function Oxidase Involvement in the Biucliemistry
of Insecticide Synergists", J. Agr. Food Chem., 18, 753.
Caujolle, F. (1964), "Toxicite" Compared de Fluides Frigorigenes", Bull. Ints.
Int. du Froid, 44, 21.
Chemical Marketing Reporter (1974a), "Aerosols Outlook", May 13, 1974, p. 27.
Chemical Marketing Reporter (197.4b), "Fluorocarbon Supply Tifht, Upward Price
Pressure Grows", Aug. 19, 1974, p. 11.
Chemical Marketing Reporter (1973), "Chemical Profile-Fluorocarbons", January 1,
1973.
Chiou, W.L. and Niazi, S. (1973), "A Simple and Ultra-sensitive Head-space
Gas Chromatographic Method for the Assay of Fluorocarbon Propellants in
Blood", Res. Commun. Chem. Pathol. Pharmacol., 6_, 481.
Cicerone, R.J., e± _al. (1974), Stodarski, R.S., and Walters, S., "Stratospheric
Ozone Destruction by Man-Made Chlorofluoromethanes", Science, 185, 1165.
Clark, D.G. (1970), unpublished report summarized in Reinhardt and Reinke, 1972.
Clarkj, D.G. (1972), "Toxicity of Halon 1211", in Appraisal Halogentatod Fire
Extinguishing Agents, Proc. Symp., (Nat. Acad. Sci., Washington, D.C.),
p. 60.
Clark, D.G. and Tinston, D.J. (1972a),"The Influence of Fluorocarbon Pro-
pellants on the Arrhythmogenic Activities of Adrenaline and Isoprenaline",
Proc. Eur. Soc. Study Drug Toxicity, 13, 212.
232
-------
Clark, D.G. and Tlnston, D.J. (1972b),"Cardiac Effects of Isoproterenol,
Hypoxia, Hypercapnia and Fluorocarbon Propellants and Their Use in
Asthma Inhalers", Ann. Allergy, 30, 536.
Clayton, J.W. (19b(>), "The Mammalian Toxicology of Organic Compounds Containing
Fluorine", Ilandbuch Exp. Pharmakol., 20, 459.
Clayton, Jr., J.W. (1970), "Fluorocarbon Toxicology" in Lab. Diagn. Pis.
Caused Toxic Agents, Ed. Proc. Appl. Seroin., F.W. Sunderman, (Warren H.
Green, Inc., St. Louis, Mo.) p. 199.
Clayton, Jr., J.W., Sherman, H., Morrison, S.D., Barnes, J.R. and Hood, D.B.
(1964), "Toxicity Studies on 1,2-Difluorotetrachloroethane (Freon-112)
and 1,1-Difluorotetrachloroethane (Freon-112A), Toxiol. Appl. Pharmacol.,
6>, 342.
Clayton, J.W., Hood, D.B., Nick, M.S., and Waritz, R.S. (1966), "Inhalation
Studies on Chloropentafluoroethane", Amer. Ind. Hyg. Assoc. J., 27^, 234.
demons, C.A. and Altshuller, A.P. (1966), "Responses of Electron-Capture
Detector to Halogenated Substances", Anal. Chem., 38, 133.
Collins, G.F., Bartlett, F.E., Turk, A., Edmonds, S.M. and Mark, H.L. (1965),
"A Preliminary Evaluation of Gas Air Tracers", J. Air Pollut. Contr.
Assoc., 15, 109.
i
Collins, G.G. and Utley, D. (1972), "Simple Membrane Inlet for Direct Sampling
of Organic Pollutants in the Atmosphere by Mass Spectrometry", Chem. Ind.,
2, 84.
Colten, S.L., Lin, F.S., Tsao, T.C., Stern, S.A. and Bardulm, A.J. (1972),
"Hydrolysis Losses in the Hydrate Process for Desalination: Rate Measure-
ment and Economic Analysis", Dept. Interior, Office of Saline Water,
Research and Development Rept. No. 753.
Conney, A.H. and Burns, J.J. (1972), "Metabolic Interactions Among Environmental
Chemicals and Drugs", Science, 178, 576.
Conney, A.H., Chang, R., Levin, W.M., Garbut, A., Munro-Faure, A.D., Peck, A.W.
and Bye, A. (1972), "Effects of Piperonyl Butoxide on Drug Metabolism in
Rodents and Man", Arch. Environ. Health, 24, 97.
Cox, P.J., King, L.J. and Parke, D.V. (1972a), "A Study of the Possible
Metabolism of Trichlorofluoromethane", Biochem. .T., 130, 13P.
Cox, P.J., King, L.J., and Parke, D.V. (1972b), "A Comparison of the Inter-
actions of Trichlorofluoromethane and CCl^ with Hepatic Cytochrome P-450",
Biochem. J., 130, 87P.
Crooke, S.T. (1972), "Solvent Inhalation", Texas Med., 68, 67.
233
-------
Crossland, J. (1974), "Aerosols", Environment, 16/6), 16.
Culik, R. (1973), "Teratogenic Study in Rats with Diclilorodifluoromethane
(Freon 12)", Haskell Lab. Kept. No. 206-73, 10 pp, courtesy of DuPont
de Nemours, Inc.
Delia Porta, G. and Terracini, B. (1969), "Chemical Carcinogenesis in Infant
Animals", Prog. Exp. Tumor Res., 11, 334.
Desoille, H., Truffert, L., Bourguignon, A., Delavierre, P., Philbert, M.
'and Girard-Wallon, C. (1968), "Toxicity of Trichlorotrifluoroethane",
Arch. Mai. Prof. Med. Trav. Secur. Soc., 29, 381.
Desoille, H., Truffert, L., Girard-Wallon, C., Ripault, J. and Philbert, M.
(1973), "Experimental Research of an Eventual Chronic Toxicity of
Dichlorotetrafluoroethane", Arch. Mai. Prof., 34, 124.
Dollery, C.T., Draffan, G.H., Davii--.s, D.S., Williams, K.M. and Conailv, M.1J.
(1970), "Blood Concentrations in Man of Fiuorinated Hydrocarbons After
Inhalation of Pressurised Aerosol", Lancet, 2.) H64.
Downing, R.C. (1966), "Fiuorinated Hydrocarbons", in Encyclopedia of Chemical
Technology, A. Standen (ed.) (John Wiley and Sons, New York, 2nd Edit:.,
1966) Vol. 9, 739.
Downing, R.C. and Madinabeitia, D. (1960), "Toxicity of Fiuorinated Hydro-
carbon Aerosol Propellants", Aerosol Age, _5_, 25.
Doucet, J., Sauvageau, P. and Sandorfy, C. (1973), "Vacuum Ultraviolet and
Photoele.ctron Spectra of Fluoro-Chloro Derivatives of Methane", J. Chcai.
Phys., _58, 3708. . : <&
Doucet, J., Sauvageau, P. and Sandorfy, C. (1974), "The Photoelectron and Far-
Ultraviolet Absorption Spectra of Chloro-Fluoro Derivatives of Ethane",
in press.
Drysdale, J.J. (1971), "Present and Future Applications of Fluorocarbons",
U.S. Nat. Tech. Inform. Serv., AD Rept. 751424.
Du Pont de Nemours and Co. (1968), "Human Skin Absorption Studies with
Trichlorotrifluoroethane, F-113", Med.. Res. Proj. Rept. No. 84-68.
Du Pont de Nemours and Co. (1969a), "'Freon' Fluorocarbons: Properties and
Applications".
Du Pont de Nemours and Co. (1969b), "Freon Compounds and Safety", Tech. Bull.
5-16.
Du Pont de Nemours and Co. (1973), "Interstate Commerce Commission Regulations
and Containers for 'Freon' Fluorocarbons", iiuli. u-75.
234
-------
Du Pont de Nemours and Co. (1971), "Toxicology of Du Pont. FE 1301 Fire
Extinguishant", Tech. Bull. S-35A.
Du Pont de Nemours and Co. (no date, a), "Physical Properties of Freon
Fluorocarbon Compounds".
Du Pont de Nemours and Co. (no date, b), "Comparative Stability of 'Freon1
Compounds", Tech. Bull. D-6.
Du Pont de Nemours and Co. (no date, c), "Toxicity Studies with 1,1,2-
trichloro-l,2,2-trifluoroethane", Tech. Bull. S-24.
Eddy, C.W. and Griffith, F.D. (1971), "Metabolism of Dichlorodifluoromethane
Cll+ by Rats", presented at 1971 American Industrial Hygiene Assoc. Conf.,
Toronto Canada, May, 1971, summarized in Waritz, 1973.
Egle, J.L. and Putney, J.W. (1972), "Cardiac Function in Mice Following
Exposure to Haloalkane Propellants Alone and in Combination with
Bronchodilators", in 3rd. Ann. Conf. Environ. Toxicol., II.S. Nat.
Tech. Inf. Serv., AD Rept. 773766, p, 239.
Egle, J.L., Putney, J.W. and Borzelleca, J.F. (1972), "Cardiac Rate and
Rhythm in Mice Affected by Haloalkane Propellants", JAMA, 222, 786.
Epstein, S.S., Joshi, S., Andrea, J., Clapp, P., Falk, J. and Mantel, N.
(1967a), "Synergistic Toxicity and Carcinogenicity of Freons and Piperonyl
Butoxide", Nature, 214, 526.
Epstein, S.S., Andrea, J., Clapp, P. and Mackintosh, D. (1967b), "Enhancement
by Piperonyl Butoxide of Acute Toxicity Due to Freons, Benzo[«]pyrene,
and Griseofulvin in Infant Mice", Toxicol. Appl, Pharmacol., 11, 442.
Epstein, S.S., Fujii, K., Andrea, J. and Mantel, N. (1970), "Carcinogenicity
Testing of Selected Food Additives by Parenteral Administration to
Infant Swiss Mice", Toxicol. Appl. Pharmacol., 16_, 321.
F.D.A. (1964), "Octafluorocyclobutane", Fed. Reg., 2£, 14985.
F.D.A. (1965), "Chloropentafluoroethane", Fed. Reg., 30, 7570.
F.D.A. (1967), "Dichlorodifluoromethane", Fed. Reg., _32, 6739.
Fishein, L. and Gaibel, Z.L.F. (1970), "Photolysis of Pesticidal Synergists.
I. Piperonyl Butoxide", Bull. Environ. Contam. Toxicol., 5_, 546.
Flowers, N.C. and Horan, L.G.A. (1972a), "Nonanoxic Aerosol Arrhythmias",
JAMA, 219, 33.
235
-------
Flowers, N.C. and Horan, L.H. (1972b), "Effects oL: Respiratory Aciclosis on
the Cardiac Response to Aerosol Inhalation", Clin. Res., 20, 619.
Friedman, M.A. and Epstein, S.S. (1970), "Stability of Piperonyl Butoxide",
Toxicol. Appl.' Pharmacol., I7_, 810.
Friedman, M.A., Greene, E.J., Csillag, R., and Epstein, S.S. (1972), "Para-
doxical Effects of Piperonyl Butoxide on the Kinetics of Mouse Liver
Microsomal Enzyme Activity", Toxicol. Appl. Pharmacol., 21, 419.
Fritsch, A., Hogan, B., Guhl, S. (1973), How Aerosol Spray Can Affect your
Health, Center for Science in the Public Interest, Washington, D.C.
Garb, S., and Chenoweth, M.B. (1948), "Studies on Hydrocarbon-epinephrine
Induced Ventricular Fibrillation", J. Pharmacol. Exp. Ther., 94, 12.
Gelbicova-Ruzickova, J., Novak, J. and Janak, J. (.1972), "Application ol: the
Method of Chromatographic Equilibrium to Air Pollution .Studies: The
Determination of Minute Amounts of Halothane in the Atmosphere of.an
Operating Theatre", J. Chromatogr., 64, 15.
Good, W.O. (1973), Montrose, Colorado, personal communication summarized in
Fritsch et al., 1973.
Good, W.O. (1974), personal communication.
Good, W.O., Ellison, C. and Archer, V.E. (1974), "Sputum Cytology Among Fre-
quent Users of Pressurized Spray Cans", preprint, courtesy of V.E. Archer.
Greenbaum, L.J., Dickson, L.G., Jackson, D.L. and Evans, D.E. (1972),
"Toxicologic and Physiologic Effects of Bromotrifluoromethane in
Hyperbaric Atmospheres", Toxicol. Appl. Pharmacol., 21, 1.
Greenberg, L.A. and Lester, D. (1950), "Toxicity of the Tctrachlorodifluoro-
ethanes", Arch. Ind. Hyg. Occup. Med., 2^ 345.
Greve, M.H. (1971), "Solvent Losses in Vapor Dtigreasing", Werkstatt Betr. ,
104, 559.
Griffin, T.B., Byard, J.L. and Coulston, F. (1972), "Toxicological Responses
to Halogenated Hydrocarbons", in Appraisal llalogenated Fire Extinguish-
ing Agents, Proc. Symp. (Nat. Acad. Sci., Washington, U.C.), p. 136.
Hall, K.D. and Norris, F.H. (1958), "Fluothane Sejasi tization of Dog Heart to
Action of Epinephrine", Anesthesiol., 19, 631.
Halsey, M.J. (1974), Clinical Research Center, Div. of Anaesthesia, Middlesex,
England, personal communication.
Halsey, M.J. and Smith, E.B. (.1970), "Effects of An.,<.;sl-hptics on l.vmnynis
Bacteria", Nature, 227, 1363.
236
-------
Hamilton, J.M. (1962), "The Organic Fluorochemical Industry", Advances in
Fluorine Chemistry, J3> 117«
Hanavan, T.W. (1974), Du Pont de Nemours, Inc., personal communication.
Harmon, G. (1974), Aerosol Machinery Co., Westbury, N.Y., personal comnuni-
cation.
Harris, W.S. (1971)j "Cardiac Toxicity of Aerosol Propellants", U.S. Nat.
Tech. Inform. Sery., AD Kept. 751425.
Harris, W.S. (1972a), "Toxic Effects of Aerosol Propellants on the Heart",
Arch. Intern. Med., 131. 162.
Harris, W.S. (1972b), "Cardiac Effects of Halogenated Hydrocarbons", in
Appraisal Halogenated Fire Extinguishing Agents, Proc. Symp. (Nat.
Acad. Sci., Washington, D.C.), p. 114.
Harris, W.S. (1973), "Aerosol Propellants Are Toxic to the Heart", JAMA, 223,
1508.
Harris, W.S. and Kilen, S.M. (1971), "Aerosol Propellants Depress Myocardial
Contractility", Clin. Res., P9, 319.
Harris, W.S., Kilen, S.M., Taylor, G.J. and Levitsky, S. (1972), "Evidence From
Animals and Man that Freon Depresses Myocardial Contractility",* Circ. Suppl.,
^4(4), 104.
Hays, H.W. (1972), "Etiology of Cardiac Arrhythmias", Proc. 3rd Ann. Conf.
Environ. Toxicol., U.S. Nat. Tech. Inform. Serv., AD Rept. 773766,
p. 173.
Hester, N.E., Stephens, E.R. and Taylor, O.C. (1973), "Fluorocarbons in the
Los Angeles Basin", Air Pollution Control Association Meeting, Chicago,
June 24-28.
Hine Laboratories (1968), "Clinical Toxicologic Studies on 'Freon' FE 1301",
Report No. 1, unpublished, summarized in Reinhardt and Reinke, 1972.
Howard, P.H. and Durkin, P.R. (1973), "Preliminary Environmental Hazard
Assessment of Chlorinated Naphthalenes, Silicones, Fluorocarbons,
Benzenepolycarboxylates, and Chlorophenols", Syracuse University
Research Corporation.
Huskins, C.W., Tarrant, P., Bruesch, J.F. and Padbury, J.J. (1951), "Thermal
Dehydrohalogenation of Some Chlorofluoroethanes", Ind. Eng. Chem., 43,
1253.
Iliff, N. (1972), "Organic Chemicals in the Environment", New Scientist,
53, 263.
Imbus, H.R. and Adkins, C. (1972), "Physical Examination of Workers Exposed
to Trichlorotrifluoroethane", Arch. Environ. Health, 24, 257.
237
-------
Jack, D. (1971), "Sniffing Syndrome", Brit. Med. .!., 2, 708.
Jaffe, H., Fujii, K., Epstein, S.S. (1969), "Modification of Microsomal Enzyme
Activity by Methylenedioxyphenyl Insecticidal Synergists and Related
Compounds", Toxicol. Appl. Pharmacol., 14, 624.
Japar, S., Pitts, J.N. and Winer, A.M. (1974), "The Photostability of Fluoro-
carbons", Environ. Sci. Technol., in press.
Jenkins, L.J., Jones, R.A., Coon, R.A. and Siegel, J. (1970), "Repeated and
Continuous Exposures of Laboratory Animals to Trichlorofluoromethane",
Toxicol. Appl. Pharmacol., 16, 133.
Jensen, R. (1972), "Summary", in Appraisal of Halogenated Fire Extinguishing
Agents, Proc. Symp., (Nat. Acad. Sci., Washington, D.C.), p. 317.
Johnson, W.E., Ffaser, J.H., Gibson, W., Modica, A.P., Grossman, G., Stepakoff,
G.L. (1972), "Spray Freezing, Decanting, and Hydrolysis as Related to
Secondary Refrigerant Freezing", Office of Saline Water, Research and
Development Prog. Rept. No. 786, avail. U.S. Nat. Tech. Inform. Serv.,
PB Rept. 215 036.
Kamienski, F.X. and Murphy, S.D. (1971), "Biphasic Effects of Methylenedioxy-
phenyl Synergists on the Action of Hexobarbital and Organophosphate
Insecticides in Mice", Toxicol. Appl. Pharmacol., 18, 883.
Karpov, B.C. (1963), Tr. Leningr. Sanit.-Gigien. Med. Inst., 75, 231, sum-
marized in Clayton, 1966. .,, -
-------
Lovelock, J.E. (1971), "Atmospheric Fluorine Compounds as Indicators of Air
Movements", Nature, 230, 379.
Lovelock, J.E. (1972), "Atmospheric Turbidity and Trichlorofluorbmethane.
Concentrations in Rural Southern England and Southern Ireland", Attnos.
Environ., £, 915.
Lovelock, J.E. (1974), Dept. Applied Physical Sciences, Univ. Of Reading,
Berkshire, England, personal communication.
Lovelock, J.E., Maggs, R.J. and Adlard, E.R. (1971), "Gas-Phase Coulometry
by Thermal Electron Attachment", Anal. Chem., 43, 1962.
Lovelock, J.E., Maggs, R.J. and Wade, R.J. (1973), "Halogenated Hydrocarbons
In and Over the Atlantic", Nature, 241, 194.
Lutz, G.A., Gross, S.B., Boatman, J.B., Moore, P.J., Darby, R.L., Veazie,
W.H. and Butrico, F.A. (1967), "Design of an Overview System for Evaluating
the Public-Health Hazards of Chemicals in the Environment: Vol. 1 Test
Case Studies", Battelle Memorial Inst., National Technical Information
Service (PB194398).
McCarthy, R.L. (1973), "Ecology and Toxicology of Fluorocarbons", unpublished
report, Du Pont de Nemours, Inc. ;
McCarthy, R.L. (1974), Du Pont de Nemours, Inc., personal communication.
McCaul, J. (1971), "Mix with Care", Environment, 13(1), 39.
McClure, D.A. (1972), "Failure of Fluorocarbon Propellants to Alter the Electro-
cardiogram of Mice and Dogs", Toxicol. Appl. Pharmacol., 22, 221.
MacEwen, J.D. (1972), "Toxicology of Pyrolysis Products of Halogenated Agents",
in Appraisal Halogenated Fire Extinguishing Agents, Proc. Symp., (Nat.
Acad. Sci., Washington, D.C.), P. 52.
McFee, D.R. and Bechtold, R.R. (1971), "Pyrolyzer-microcoulomb Detector System
for Measurement of Toxicants", Amer. Ind. Hyg. Assoc. J., 32, 766.
Maclntere, H.J. and Hutchinson, F.W. (1954), Refrigeration Engineering,
2nd. Edit., John Wiley and Sons, New York.
Marcali, K. and Linch, A.L. (1966), "Perfluoroisobutylene and Hexafluoropropene
Determination in Air", Am. Indust. Hyg. Assoc. J., 27, 360.
Marier, G., Macfarland, G.H., Dussault, P. (1973), "I'lood Fluorocarbon Levels
Following Exposure to a Variety of Household Aerosols", Household Pers.
Prod. Ind., j.0(12), 68.
239
-------
Marti, T. (1948), "Freon Poisoning", Ann. Med. Legale, Criminol., Police Sci.,
Med. Sociale, Toxicol., 28, 147.
Matsumato, T., Pani, K;C., Kovaric, J.J. and Hamit, U.F. (3968), "Aerosol
Tissue Adhesive Spray: Fate of Freons and Their Acute Topical and
Systemic Toxicology", Arch. Surg., 9^7, 727.
Mendelhoff, J. (1952), "Death After Repeated Exposures to Refrigerant Gases -
Report of a Case", Arch. Ind. Hyg. Occupational Med., 6_, 518.
Michaelson, J.B. and Huntsman, D.J. (1964), "Oral Toxicity of 1,2,2-Trichloro-
1,1,2-trifluoroethane", J. Med. Chem. , _7, 378.
Miller, K.V., Paton, W.D.M. and Smith, E.B. (1967), "The Anaesthetic Pressures
of Certain Fluorine-Containing Gases", Brit. J. Anaesthisiol. , 3>9, 910.
Minford, J.D. (1964), "Compatibility Studies of Aluminum with Propellant and
Solvents for Use in Aerosols", J. Soc. Cosmet. Chem. , .15, 311.
Morgan, A., Black, A., Walsh, M. , Belcher, D.R. (1972), "Absorption and
Retention of Inhaled Fluorinated Hydrocarbon Vapors", Int. J. Appl.
Radiat. Isotop., 23, 285.
Mullin, L.S., Azar, A., Reinhardt, C.F., Smith, P.E. and Fabryka, E.F. (1972),
"Halogenated Hydrocarbonds-Induced Cardiac Arrhythmias Associated with
Release of Endogenous Epineprhine" , Amer. Ind. Hyg. Assoc. J., 33, 389.
Noble, H.L. (1972), "Fluorocarbon Industry Review and Forecast", Chem. Market.
Research Assoc. Meeting, May 5, 1972.
Nunn, J.F. (1972), "Anaesthesia and the Living Cell: Specific] t.y of: Ac.ci.oi-",
Acta Anaesth. Scand., 16, 169.
Paterson, J.W., Sudlow, M.F. and Walker, S.R. (1971), "Blood-levels of Fluorinated
Hydrocarbons in Asthmatic Patients After Inhalation of Pressurised Aerosols",
Lancet, _2, 565. .
Paulet, G. (1962), "Toxicological and Physiopathologic Study of Monobromotri-
fluorome thane (CFsBr)",. Arch. Mai. Prof. Med. Trav. Secur. Soc., 23, 341.
Paulet, G. (1969), "Action of Chlorofluorinated Hydrocarbons on the Human Body",
Labo-Pharma-Phrbl. Tech., No. 180, p. 74.
Paulet, G. and Chevrier, R. (1969), "Elimination of Inhaled Fluorane 11 in
Expired Air by Humans and Animals", Arch. Mai. Prof. Med. Trav. Secur.
Soc., 30, 251.
Paulet, G. and Desbrousses, S. (1969), "Dichlorotetraf luuroethane. Acute
and Chronic Toxicity", Arch. Mai. Prof. Med. Trav. Secur. Soc., 30 1 477.
24"
-------
Paulet, G., Desbrousses, S. and Sorais, J. (1967), "Average Chronic Toxicity
of Two Chlorofluorohydrocarbons, RH and Ri2"» Arch. Mai. Prof. Med.
Trav. Secur. Soc., 28, 4.
Paulet, G., Chevrier, R., Paulet, J., Duchene, M. and Chappet, J. (1969),
"Retention of Freons by the Lungs and Respiratory Tract. Studies in
Humans and Animals", Arch. Mai. Prof. Med. Trav. Secur. Soc., 30, 101.
Pennington, K. and Fuerst, R. (1971), "Biochemical and Morphological Effects
of Various Gases on Rabbit R.B.C.'s", Arch. Environ. Health, 22, 476.
Prendergast, J.A., Jones, R.A., Jenkins, L.J. and Siegel, J. (1967), "Effects
on Experimental Animals of Long-term Inhalation of Trichloroethylene,
Carbon Tetrachloride, 1,1,1-Trichloroethane, Dichlorodifluororaethane, and
1,1-dichloroethylene", Toxicol. Appl. Pharmacol. 10, 270.
Prior, B.A., Fennetna, O.R. and Marth, E.H. (1970), "Effects of Gas Hydrate
Formers on Microorganism", Appl. Microbiol., 20, 139.
Quevauviller, A. (1960), "Skin Tolerance of Chlorofluoromethanes Used as Pro-
pellants in Cosmetology", Parfums, Cosmet., Savons, ^}, 228.
Quevauviller, A.(1965), "Hygiene et Securite des Pulseurs pour Aerosols
Medicamenteux", Prod. Probl. Pharm., 20, 14.
Quevauviller, A., Garcet, S., and Garet-Pottier, J. (1959), "Un Probieme d'Hygiene
Cutanee: L'Uitisation des Chlorofluoromethanes Cotnme Pulseurs en
Cosmetologie", Ann. Pharm. Fr., 17, 430.
Quevauviller, A., Chaignear, M. and Schrenzel, M. (1963), "Etude Experimeutale
Chez la Souris de la Tolerance du Poumon aux Hydiocarbures Chlorofluores",
Ann. Pharm. Fr., 2JL, 727.
Quevauviller, A., Schrenzel, M. and Vu-Ngoc, H. (1964), "Local Tolerance Ln
Animals to Chlorofluorinated Hydrocarbons", Therapie, 19, 247.
Quevauviller, A., Billon, J., Longuet, J. and Pierre, K. (1969), "Nouvelles
recherches chez la souris sur la tolerance du poumon aux hydrocarbures
fluores", Ann. Pharm. Fr., 27, 25.
Rainaldi, N. (1972), "Appraisal of Halogenated Fire Extinguishing Agents", in
Appraisal Halogenated Fire Extinguishing Agents, Proc. Symp., (Nat. Acad.
Sci., Washington, B.C.), p. 79.
Rauws, A.G., Oiling, M. and Wibowo, A.E. (1973), "Determination of Eluoro-
chlorocarbons in Air and Body Fluids", J. Pharm. Pharmacol., 25, 718.
241
-------
Raventos, J. and Lemon, P.G. (1965), "The Impurities in Fluothane: Their
Biological Properties", Brit. J. Anesthesia, 37, 716.
Rector, D.E., Steadman, B.L., Jones, R.A. and Siegel, J. (1966), "Effects on
Experimental Animals of Long-term Inhalation Exposure to Mineral Spirits",
Toxicol. Appl. Pharmacol., 9^, 257.
Reed, A.B. and Dychdala, G.R. (1964), "Microbiological Acitvity of Aeros 1
Propellants", Chem. Specialties Mfrs. Assoc., Proc. Ann. Meeting, 51, 30.
Reinhardt, C.F. and Reinke, R.E. (1972), "Toxicology of Halogenated Fire
Extinguishing Agent Halon 1301 (Bromotrifluoromethane)", Appraisal
Halogenated Fire Extinguishing Agents, Proc. Synip., (Nat. Acad. Sci.,
Washington, D.C.), p. 67.
Reinhardt, C.F. and Stopps, G.J. (1961), "Human Exposure to Bromotrifluoro-
methane", Haskell Laboratory Report No. 230-66, unpublished, summarized
in Reinhardt and Reinke, 1972.
Reinhardt, C.F., Azar, A., Maxfield, M.E., Smith, P.E., and Mullin, L.S.
(1971a), "Cardiac Arrhythmias and Aerosol 'Sniffing'", Arch. Environ.
Health, ^2, 265.
Reinhardt, C.F., McLaughlin, M., Maxfield, M.K., Mullin, L.S., and Smith, P.E.
(1971b), "Human Exposures to Fluorocarbon 113", Amer. Ind. Hyg. Assoc.
J., _32, 143.
Reinhardt, C.F., Mullin, L.S. and Maxfield, M.E. (1973), "Epinephrine-induced
Cardiac Arrhythmia Potential of Some Common Industrial Solvents", Occupa-
tional Med., 15, 953.
Rhoden, R.A. and Gabriel, K.L. (1972), "Effects of Bromor.rifluoromethane
Inhalation on Myocardial Glycolysis", Toxicol. Appl. Pharmacol., 21, 166.
Robbins, B.H. (1946), "Preliminary Study of Anesthetic Activity of Various
Fluorinated Hydrocarbons", J. Pharmacol. Exp. Ther., 86, 197.
Roe, F.J.C. and Grant, G.A. (1970), "Inhibition by Germ-free Status of Develop-
ment of Liver and Lung Tumors in Mice Exposed Neonatally to 7,12-
Dimethlybenz(a)anthracene: Implication in Relation to Tests for Carcino-
genicity", Int. J. Cancer, 6_, 133.
Rosenberg, P.H. (1972), "Halothane Hepatitis Caused by Halothane Metabolites",
Fluoride, _5, 106.
Sage, M.S. (1963), "Aerosols", in Encyclopedia of Chemical Toxicology, A.
Standen (ed.) (John Wiley and Sons, New York, 2nd Edit.) Vol. 1, p. 470.
242
-------
Saltzman, B.E., Coleman, A.I. and demons, C.A. (1966), "Halogenated Compounds
as Gaseous Meterological Tracers: Stability and Ultrasensitive Analysis
by Gas Chromatography", Anal. Chem. 38, 753.
Sanders, P.A. (1960), "Corrosion of Aerosol Cans", Soap Chem. Specialties,
36, 95.
Sarangi, B.K., Morris, L.E. and Householder, J.R. (1962), "Observations on
an Azeotrope of 'Fluomar* and 'Freon-113'", Anesthesia Analg. (Cleveland),
U, 702.
Sayers, R.R., Yant, W.P., Chornyak, J. and Shoaf, J.W...(1930), "Toxicity of
Dichlorodifluoromethane", U.S. Bureau of Mines Report, R.I. 3013, May,
1930, 15 pp.
Schultz, H.A. (1957), "Measurement of Concentrations of Gaseous Halide Tracers
in Air by Positive-ion-emission Techniques", Annal. Chem., 29, 1840.
Shargel, L. and Koss, R. (1972), "Determination of Fluorinated Hydrocarbon
Propellants in Blood of Dogs After Aerosol Administration", J. Phar.
Sci., 6.1, 1445.
Sherman, H. (1974), "Long-term Feeding Studies in Rats and Dogs with Dichloro-
difluoromethane (Freon 12 Food Freezant)", Haskell Laboratory Report No.
24-74, unpublished, courtesy of Du Pont de Nemours Co.
Silverglade, A. (1971a), "Cardiac Toxicity of Aerosol Propellants", JAMA, 215,
1502.
Silverglade, A. (1971b), "Evaluation of Reports of Death from Asthma", J.
Asthma Res., £,95.
Silverglade, A. (1972), "Editorial: Cardiac Toxicity of Aerosol Propellants",
JAMA, 222, 827.
Silverglade, A. (1973), "Fluorocarbon Propellants in AerosoJs", Lancet, j^,
1325.
Simmonds, P.G., Kerrin, S.L., Lovelock, J.E. and Shair, F.H. (1974), "Distri-
bution of Atmospheric Halocarbons in the Air Over the Los Angeles Basin",
Atmospheric Environ., JJ, 209.
Slater, T.F.. (1965), "Relative Toxic Activities of Tetrachloromethane and Tri-
chlorofluoromethane", Biochem. Pharmacol., 14, 178.
Slater, T.F. and Sawyer, B.C. (1971), "The Stimulatory Effects of Carbon Tetra-
chloride and Other Halogenoalkanes on Peroxidative Reactions in Rat Liver
Fractions in Vitro", Biochem J., 123, 805.
243
-------
Smith, J.K. and Case, M.T. (1973), "Subacute and Chronic Toxicity Studies
of Fluorocarbon Propellants in Mice, Rats and Dogs", Toxicol. Appl.
Pharmacol., JZ6_, 438.
Stanford Research Institute (1972), "Fluorinated Hydrocarbons - Salient
Statistics", Chem. Econ. Handbook, 658.2030A-C, July, 1972.
Stanford Research Institute (1973), "Fluorinated Hydrocarbons - Salient
Statistics", Chem. Econ. Handbook. 658.3030B, Aug.,1973.
Steinberg, M.B., Boldt, R.E., Renne, R.A. and Weeks, M.H. (1969), "Inhalation
Toxicity of l,l,2-Trichloro-l,2,2-trifluoroethane (TCTFE)", U.S. Nat.
Tech. Inform. Serv., AD Rept. No. 854705.
Stepakoff, G.L. and Modica, A.P. (1973), "Hydrolysis of Halocarbon Refrigerants
in Freeze Desalination Processes. II Theoretical Prediction of Hydrolysis
Rates and Comparison with Experimental Data", Desalination, 12, 239.
Stephens, S., De Sha, C., Fuerst, R. (1970), "Phenotypic and Genetic Effects
in Neurospora crassa Produced by Selected Gases and Gases Mixed with Oxygen",
Develop. Ind. Microbiol., 12, 346.
Stokinger, H.E. (1972), "General Discussion of Session II", in Appraisal
Halogenated Fire Extinguishing Agents, Proc. Symp., (Nat. Acad. Sci.,
Washington, D.C.), p. 148.
Stopps, G.J. (1971), "Sniffing Syndrome", Brit. Med. J., 7, 708.
Stopps, G.J. and McLaughlin, M. (1967), "Psychophysiological Testing of Human
Subjects Exposed to Solvent Vapors", Amer. Indust. Hyg. Assoc. J., 28, 43.
Struck, H.C. and Plattner, E.B. (1940), "A Study of the Pharmacological Properties
of Certain Saturated Fluorocarbons", J. Pharmacol. Exp. Ther., 68, 217.
Su, C.W. and Goldberg, E.D. (1973), "Chlorofluorocarbons in the Atmosphere",
Nature, 245, 27.
Taylor, G.J. and Harris, U.S. (1970a), "Cardiac Toxicity of Aerosol Propellants",
JAMA, 214. 81.
Taylor, G.J. and Harris, W.S. (1970b), "Glue Sniffing Causes Heart Block in
Mice", Science, 170. 866.
Taylor, G.J. and Harris, W.S. (1971), "Depression of Myocardial Contractility
on the Intact Mammal by Aerosol Propellant Inhalation", Clin. Res., 19,
342.
Taylor, G.J., Harris, W.S. and Bognonoff, M.D. (1971), "Ventricular Arrhythmias
Induced in Monkeys by the Inhalation of Aerosol Propellants", J. Clin.
Invest., 50_, 1546.
244
-------
Terrill, J.B. (1972a), "Determination of Common Fluorocarbon Propellants in
Blood", Amer. Ind. Hyg. Assoc. J., 33, 433.
Terrill, J.B. (1972b), "Determination of Fluorocarbon Propellants in Blood and
Animal Tissue", Amer. Ind. Hyg. Assoc. J., 33, 736.
Tomatis, L., Partensky, C. and Montesano, R. (1973), "The Predictive Value of
Mouse Liver Tumor Induction in Carcinogenicity Testing - A Literature
Survey", Int. J. Cancer, 12, 1.
Trenwith, A.B. and Watson, R.H. (1957), "The Thermal Decomposition of the
Chlorofluoromethanes", J. Chem. Soc., (1957), 2368.
Truhaut, R., Boudene, C., Jouany, J.M. and Bouant, A. (1972), "Experimental
Study of the Toxicity of a Fluoroalkene Derivative, Hexafluorodichloro-
butene (HFCB)", Fluoride, _5, 4.
Ullrich, V. and Diehl, H. (1971), "Uncoupling of Monooxygenation and Electron
Transport by Fluorocarbons in Liver Microsomes", Chem.-Biol. Interactions,
3, 310.
Underwriters' Laboratories (1971a), "Comparative Hazards of Common Refrigerants",
Data Cards No. UL5 and UL5-A.
Underwriters' Laboratories (1971b), "Toxicity of Extinguishing Agents", Data
Card No. UL608.
Union Carbide (1973-1974), "Chemicals and Plastics - Physical Properties",
unpublished booklet.
U.S. Tariff Commission, (1961-1972), "Synthetic Organic Chemicals: U.S.
Production and Sales".
Van Auken, O.W. and Wilson, R.H. (1973), "Halogenated Hydrocarbon Induced
Reduction in coupling Parameters of Rabbit Liver and Mung Bean Mitochondria",
Naturwissenschaften, 60, 259.
Van Poznak, A. and Artusio, J.F. (1960), "Anesthetic Properties of a Series of
Fluorinated Compounds. 1. Fluorinated Hydrocarbons", Toxicol. Appl.
Pharmacol., 2^, 363.
Van Stee, E.W. and Back, K.C. (1969), "Short-term Inhalation Exposure to Bromo-
trifluoromethane", Toxicol. Appl. Pharm., 15, 164.
Van Stee, E.W. and Back, K.C. (1971a), "Brain and Heart Accumulation of Bromo-
trifluoromethane", U.S. Nat. Tech. Inform. Serv., AD Rept. 721211.
Van Stee, E.W. and Back, K.C. (1971b), "Spontaneous Cardiac Arrhythmias
Induced by Bromotrifluoromethane", U.S. Nat. Tech. Inform. Serv.,AD
Rept. No. 723645.
245
-------
Van Stee, E.W. and Back, K.C. (1971c), "Hypotension During Bromotrifluoro-
methane Exposure", U.S. Nat. Tech. Inform. Serv., AD Rept. 781549.
Van Stee, E.W. and Back, K.C. (1972a), "The Mechanism of the Peripheral Vas-
cular Resistance Change During Exposure of Dogs to Bromotrifluoromethane",
Toxicol. Appl. Pharmacol., 23, 428.
Van Stee, E.W. and Back, K.C. (1972b), "The Negative Inotropic Effect of Bromo-
trifluoromethane Exposure in the Dog", Proc. 3rd. Ann. Conf. Environ.
Toxicol., U.S. Nat. Tech. Inform. Serv., AD Rept. 773766.
Van Stee, E.W., Back, K.C. and Prynn, R.B. (1970), "Alterations of the
Electroencephalogram During Bromotrifluoromethane Exposure", Toxicol.
Appl. Pharmacol., 16, 779.
Vogel, N.H. and Zaldvar, R. (1971), "Cocarcinogenesis: The Interaction of
Chemical and Physical Agents", Radiation Research, 47, 644.
Waritz, R.S. (1971), "Toxicology of Some Commercial Fluorocarbons", U.S. Nat.
Tech. Inform. Serv., AD Rept. No. 751429.
White, D.C. and Dundas, C.R. (1970), "Effect of Anaesthetics on Emission of
Light by Luminous Bacteria", Nature, 266, 456.
Wills, J.H. (1972), "Sensitization of the Heart to Catecholamene-induced
Arrhythmia", Proc. 3rd. Ann. Conf. Environ. Toxicol., U.S. Nat. Tech.
Inform. Serv.. AD Rept. No. 773766, p. 249.
Yant, W.P., Schrenk, H.H., and Patty, F.A. (1932), "Toxicity of Dichlorotetra-
fluoroethane", U.S. Bureau of Mines Report, R.I. 3185.
Young, W. and Parker, J.A. (1972), "Effect of Freons on Acetylcholinesterase
Activity and Some Counter Measures", Proc. 3rd. Ann. Conf. Environ.
Toxicol., U.S. Nat. Tech. Inform. Serv.. AD Rept. No. 773766, p. 259.
• _ * . '
Zapp, J.A. (no date), "Overview of Fluorocarbon Toxicity: a Talk", unpublished
report, courtesy of Du Pont de Nemours and Co.
246
-------
TECHNICAL REPORT DATA
(Please read Inunctions on the reverse before completing)
REPORT NO.
EPA-560/2-75-003
3. RECIPIENT'S ACCESSIOWNO.
4. TITLE AND SUBTITLE
Environmental Hazard Assessment of One and Two Carbon
Fluorocarbons
5. REPORT DATE
Sopl
,. PERFO'R
tomhor 1Q7A
MINQ ORGANIZATION CODE
. AUTHOR(S)
P.H. Howard, P.R. Durkln, A. Hanchett
8. PERFORMING ORGANIZATION REPORT NO.
SURC TR-74-572.1
10. PROGRAM ELEMENT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
t,
Life Sciences Division
Syracuse University Research Corporation
Merrill Lane, University Heights
Syracuse, New York 13210
11. CbNTRACf/'dRANt NO.
EPA 68-01-2202
12. SPONSORING AGENCY NAME AND ADDRESS
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C. 20460
13. TYPE OF REPORT AND PERIOD COVERED
Final Torhn-t oa1 Ronnrt-
14. SPONSORING AGENCY CODE
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report reviews the potential environmental hazard from the commercial
use of large -quantities of saturated, one and two carbon fluorocarbon compounds
which are used for the most part as aerosol propellants, refrigerants, solvents,
foaming agents, and fire extinguishing agents. The following seven compounds
were of major interests trichlorofluoromethane, dichlorodifluoromethane,
chlorodifluoromethane, trichlorotrifluoroethane, dichlorotetrafluoroethane,
chloropenfeflfluoroethane, and bromotrifluoromethane. Information on physical
and chemical properties, production methods and quantities, commercial uses and
factors affecting environmental contamination as well as information related to
health and biological effects are reviewed.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDbNTIFIERS/OPEN ENDED TERMS
c. COSATI Held/Group
Fluorocarbons, chlorofluorocarbons,
fluorine organic compounds, dichloro-
difluoromethane, chlorotrifluoromethane,
Freons, toxicology, chemical properties,
pollution, production, utilization.
Pollution
Environmental exposure
Environmental effects
Aerosol propellants
Refrigerants
18. DISTRIBUTION STATEMENT
Document is available to public through
the National Technical Information Service,
Springfield. Virgin-la 221 51
19. SECURITY CLASS (This Report)
Unclassified
21. NO. OF PAGES
246
20. SECURITY CLASS (This page)
Unclassified
22. PRICE
EPA form 2220-1 (1-73)
------- |