PB-238 074
PRELIMINARY ENVIRONMENTAL HAZARD ASSESSMENT OF
CHLORINATED NAPHTHALENES, SILICONES, FLUOROCARBONS,
BENZENEPOLYCARBOXYLATES, AND CHLOROPHENOLS
SYRACUSE UNIVERSITY RESEARCH CORPORATION
PREPARED FOR
ENVIRONMENTAL PROTECTION AGENCY
NOVEMBER 1973
DISTRIBUTED BY:
National Technical Information Service
U. S. DEPARTMENT OF COMMERCE
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ABSTRACT
i
A literature search of pertinent information and data on chlorinated
naphthalenes, silicones, fluorocarbons, benzenepolycarboxylates, and
chlorophenols was conducted to determine any hazard to man or the
environment from commercial use of these chemicals. Information was
gathered on physical and chemical properties, production and usage,
environmental contamination,.monitoring and analysis, environment
transport and fate, environmental effects, and toxicity.
This report was submitted in partial fulfillment of Contract
No. 68-01-2202 by the Syracuse University Research Corporation under
the sponsorship of the U.S. Environmental Protection Agency.
-------
TABLE QF CONTENTS
Page
ABSTRACT i
CHLORINATED NAPHTHALENES
I. Physical Properties 1
II. Production 3
III. Uses 3
IV. Current Practice 5
V. Environmental Contamination 6
VI. Monitoring and Analysis 7
VII. Chemical Reactivity 10
VIII. Biology 11
A. Absorption 11
B. Excretion' 11
C. Transport 11
D. Distribution 12
E. Metabolic Effects 12
F. Metabolism 12
IX. Environmental Transport and Fate 13
A. Persistence and/or Degradation 13
B. Environmental Transport 16
C. Bioaccumulation 16
X. Toxicity 17
A. Human Toxicity 17
B. Toxicity to Birds and Non-Human Mammals 20
1. Acute and Subacute Toxicity 21
2. Chronic Toxicity: Rats and Rabbits 25
a. Mono- and Mono/Di- Combinations 25
b. Dichloronaphthalene 26
c. Tri- and Tri/Tetra- Combinations 26
d. Tetra/Penta- Combinations 27
e. Penta and Penta/Hexa- Combinations 27
f. Hexachloronaphthalene 29
g. Heptachloronaphthalene 29
h. Octachloronaphthalene 29
3. Sensitization 29
4. Teratogenicity 30
5. Carcinogenicity 30
6. Mutagenicity 30
7. Behavior Effects 30
C. Toxicity to Lower Animals 30
D. Toxicity to Plants 30
E. Toxicity to Microorganisms 30
XI. Summary and Conclusions 32
Literature Cited 35
ii
-------
Table of Contents (continued)
SILICONES (SILOXANES)
I. Physical Properties
A. Silicone Fluids
B. Silicone Rubbers
C. Silicone Resins
II. Production
III. Uses
A. Silicone Fluids
1. Waxes and Polishes
2. Cosmetics
3. Urethane Foams
4. Silicone Greases
5. Silicone Emulsions
6. Other
7. New Applications
B. Silicone Rubbers (Elastomers)
C. Silicone Resins
IV. Current Practice
V. Environmental Contamination
VI. Monitoring and Analysis
VII. Chemical Reactivity
VIII. Biology
A. Absorption
B. Excretion
C. Transport and Distribution
IX. Environmental Transport and Fate
A. Persistence and/or Degradation
B. Environmental Transport
C. Bioaccumulation
X. Silicone Toxicity
A. Human Toxicity
1. Occupational Exposure
2. Liquid Injection of Sillcones
3. Toleration by the Human Eye
4. Degeneration of Silicone Heart Valves
5. Adverse Responses to Other Medical Silicones
6. Human Ingestion
B. Toxicity to Birds and Non-Human Mammals
1. Acute and Subacute Toxicity
2. Chronic Toxicity
3. Sensitization
4. Teratogenicity
5. Carcinogenicity
6. Mutagenicity
7. Behavior Effects-Reproductive Activity
39
40
43
43
45
49
49
49
50
50
50
50
51
52
52
54
56
57
58
60
62
62
62
63
66
66
67
68
69
69
69
69
70
70
71
72
72
72
77
78
78
79
79
80
iil
-------
Table of Contents (continued)
C. Toxicity to Lower Animals 82
D. Plant Toxicity 84
E. Microorganism Toxicity 84
XI. Silicones: Summary and Conclusions 85
Literature Cited 90
FLUOROCARBONS
I. Physical Properties 95
II. Production 98
III. Uses 101
IV. Current Practices 104
V. Environmental Contamination 104
VI. Monitoring and Analysis 105
VII. Chemical Reactivity 108
VIII. Biology 111
A. Absorption 111
B. Excretion/Elimination 113
C. Transport 115
D. Distribution 116
E. Metabolism 116
F. Metabolic Effects 118
IX. Environmental Transport and Fate 121
A. Persistence and/or Degradation 121
B. Environmental Transport 122
C. Bioaccumulation ' 122
X. Toxicity 123
A. Human Toxicity 123
1. Acute Inhalation 123
2. Chronic Inhalation 126
3. Ingestion 127
4. Polymer-Fume Fever 127
B. Toxicity to Non-Human Mammals 128
1. Acute and Subacute Toxicity 128
2. Chronic Toxicity 137
3. Sensitization 139
4. Teratogenicity 139
5. Carcinogenicity 140
6. Mutagenicity 140
7. Behavioral Effects 140
C. Toxicity to Lower Animals 142
D. Toxicity to Plants 142
E. Toxicity to Microorganisms 142
XI. Fluorocarbons: Summary and Conclusions 144
Literature Cited 147
iv
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Table of Contents (continued)
BENZENEPOLYCARBOXYLATES 153
I. Physical Properties 155
II. Production 157
III. Uses 160
A. Phthalic Acid (PA) and Phthalic Anhydride (PAN) 160
B. Isophthalic Acid 164
C. Terephthalic Acid (TA) and Dimethyl
Terephthalate (DMT) 165
D. Trimetllitic Acid (TMA) and Trimellitic
Anhydride (THAN) 166
E. Trimesic Acid (TMSA) 166
F. Pyrometllitic Acid (PMA) and Pyromellitic
Dianhydride (PMDA) 166
IV. Current Practice 167
A. Phthalic Anhydride 167
B. Isophthalic Acid 167
C. Terephthalic Acid and Dimethyl Terephthalate 167
D. Trimellitic Anhydride 168
E. Pyromellitic Dianhydride 168
V. Environmental Contamination 169
VI. Monitoring and Analysis 171
VII. Chemical Reactivity 173
VIII. Biology 176
A. Absorption 176
B. Excretion 176
C. Transport 177
D. Distribution 177
E. Metabolism 178
F. Metabolic Effects 179
IX. Environmental Transport and Fate 180
A. Persistence and/or Degradation 180
B. Environmental Transport 182
C. Bioaccumulation 182
X. Toxicity 183
A. Human Toxicity 183
B. Toxicity to Birds and Non-Human Mammals 185
1. Acute and Subacute Toxicity 185
a. Phthalic Anhydride 185
b. Phthalic, Isophthalic, and
Terephthalic Acids 186
c. Trimellitic Acid and Anhydride 190
2. Chronic Toxicity 191
. 3. Sensitization 192
4. Teratogenicity 192
5. Carcinogenicity 192
6. Mutagenicity 193
7. Behavioral Effects 193
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Table of Contents
-------
Table of Contents (continued)
C. Toxicity to Lower Animals
D. Toxicity to Plants
E. Toxicity to Microorganisms
XI. Chlorophenols: Summary and. Conclusions
Literature Cited
LIST OF FIGURES
Figure Pagt
I. Chlorinated Naphthalenes
1 Vapor Pressure of Chlorinated Naphthalene 1
2 Metabolism of Chlorinated Naphthalene and Benzene 14
3 Proposed Mechanisms for Naphthalene Dihydrodiol Formation
in Mammalian and Microbial Systems 15
II. Silicones
1 Viscosity-Temperature Curves for Various Silicones 41
III. Fluorocarbons
1 Concentration of Some Halogenated Hydrocarbons in
Alveolar Air After Various Times of Breath Holding 111
2 Possible Metabolic Pathways of Halothane 117
3 Effect of Halothane on Bioluminescence of P_. phosphoreum 143
IV. Benzenepolycarboxylates
1 Equilibrium Between Benzenecarboxylic Acids and
Anhydrides , 174
2 Equilibrium Between Benzenecarboxylic Acid and Its Anion
Conjugate 175
3 Metabolism of Phthalic Acid 180
V. Chlorophenols
1 Synthetic Routes to Chlorophenols and Chlorophenol
By-Products 211
2 Pentachlorophenol Transport in the Mouse 224
3 Suggested Metabolic Fate of PCP in Rats 226
4 Oxidation of Hydroxy- and Chlorophenols 232
5 Relationship Between the Logarithm of the Solubility
of Chlorophenols and the LDso in Lemna minor 248
6 Relationship Between the Logarithm of the 1C 50 and the
Solubilities of Some Chlorophenols 250
vii
-------
Table of Contents (continued)
LIST OF TABLES
Table Page
I. Chlorinated Naphthalenes
I. Comparative Properties of Halowax Chloronaphthalenes 2
II. Uses of Chlorinated Naphthalenes 4
II. Silicones
I. Physical Properties of Some Technical Methylsilicone
and Methylphenylsilicone Oils 40
II. Vapor Pressure of Silicone Fluids 42
III. Production of Silicone Resins and Elastomers 46
IV. Estimated Silicone Usage in U.S. Market - 1973 48
V. Silicone Rubber Usage by Market: 1964 54
VI. Consumption of Silicone Resins (1962) 55
VII. Distribution of ^C-Labeled Silicone in Rat- Tissues
25 Days after Intraperitoneal Injection of 15 yCi
per Rat 64
VIII. Distribution of lf*C-Labeled Silicone in Rat Tissues
45 Days after Intracisternal Injection of 6 yCi per Rat 64
IX. Mortality and Response Resulting from the Administration
of Silicone Fluids in Single Oral Dose — Guinea Pigs 73
X. Comparative Relative Activities of 32 Organosiloxane
Compounds Based on Effects on the Ovariectomized
Immature Female Rat Uterus 81
XI. Daphnia Mortality (%) in SAG 10 and SAG 530 Solutions 83
III. Fluorocarbons
I. Physical Properties of Commercially Important
Fluorocarbons 96
II. Typical Physical Properties of Polytetrafluoroethylene 97
III. Fluorocarbon Producers and Capacities 99
IV. Production and Capacities of Fluorocarbons 100
V. Uses of Fluorocarbons 102
VI. Electron-Capture Detector Response to Various
Fluorinated Compounds 109
VII. Elimination of Fluorocarbons in Dogs' Breath 114
VIII. Inhalation Toxicity of Fluoromethanes 129
IX. Dose/Effect Relationship for CC12F2 and CC13F 130
X. Cardiac Sensitization to Epinephrine 130
XI. Acute Inhalation Toxicity of Several Fluoroethanes 133
XII. Comparison of Bromine and Chlorine in the Acute
Inhalation Toxicity of Fluoroethanes 134
viii
-------
Table of Contents (continued) (Tables)
III. Fluorocarbons (cont.)
Table
XIII.
XIV.
XV.
XVI.
XVII.
XVIII.
I.
II.
III.
IV.
V.
VI.
VII.
VIII.
IX.
X.
XI.
XII.
XIII.
XIV.
XV.
I.
II.
III.
Inhalation Toxicity of Several Fluoroalkenes 135
Inhalation Toxicity of Several Halogenated Alkenes 135
LCso for DCHFB
Delayed Death after DCHFB Administration to Rabbits 137
Chronic Exposure to Some Fluorocarbons Showing no
Pathology 138
Tumors Induced in Swiss Mice by Injection of "Freons"
and Piperonyl Butoxide Shortly After Birth 141
IV. Benzenepolycarboxylates
Physical Properties of Commercially Important
Benzenepolycarboxylates 156
Production of Benzenepolycarboxylates 158
Capacities for Production of Benzenepolycarboxylates 159
Phthalic Anhydride Consumption - 1968 160
Intermediates and Dyes Produced from Phthalic Anhydride 162-3
Consumption of Isophthalic Acid 164
Contaminants in Phthalic Anhydride Process Off-Gas 169
Excretion of Terephthalic Acid after the Oral
Administration of a Single Dose of 85 mg/kg to Rats 177
Distribution of Terephthalic Acid after a Single Oral
Dose of 85 mg/kg 178
Inhibition of cis-Aconitase by Various Benzenepoly-
carboxylic Acids at 10 mM 179
Biodegradibility of Several Phthalates and Other
Organic Compounds Using a River Die-Away Test 181
Toxicity of Benzenedicarboxylic Acids to Mice 24 Hours
after Intraperitoneal Injection 186
Lethal Doses for Terephthalic Acid by Intraperitoneal
Injection of Mice 187
Acute Toxicity of Terephthalic Compounds in Mice and
other Mammals , 189
Acute Oral Toxicity (LDso) of TMA and TMAN to Mice
and Rats 190
V. Chlorophenols
Physical Properties of Commercially Important
Chlorophenols 205
Chlorophenol Producers and Their Plant Locations
and Capacities 207
Production of Chlorophenols and Related Products 208
ix
-------
Table of Contents (continued) (Tables)
V. Chlorophenols (cont.)
Table Page
IV. Analytical Techniques Used for the Determination
of Chlorophenols in Trace Amounts 221
V. Distribution of Pentachlorophenol in Three Cases of
Fatal Intoxication 225
VI. Metabolic Effects of Pentachlorophenol and Their
Possible Physiological Significance 228
VII. Inhibition of Oxidative Phosphorylation by Various
Chlorophenols 228
VIII. 50% Inhibition of Catalase Activity by Various
Chlorophenols 229
IX. Microbial Decomposition of Chlorophenols in Soil
Suspensions 231
X. Decomposition of Phenol -and Chlorophenol by a Soil
Microflora 233
XI. Maximum Degradation Obtained for Each Compound
at 100 mg/liter 233
XII. LCso's of Various Chlorophenols and Sodium Chloro-
phenates after a Single Oral Administration 241
XIII. Acute LDso's of Chlorophenols Determined by Intra-
peritoneal Injection to Male Albino Rats 242
XIV. Comparison of LDso's for Intraperitoneal Injection in
Rats to 24 Hour TLm of Fishes 246
XV. Median Tolerance Limits of Some Fresh Water Fishes
to Sodium Pentachlorophenate 247
XVI. LDso's of Various Chlorophenols on Lemna minor 248
XVII. Concentrations of Various Chlorophenols Required for
50% Inhibition of Radial Growth (ICso) for J. viride 250
XVIII. Antimicrobial Efficiencies of Pentachlorophenol
(Dowicide EC-7) 251
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CHLORINATED NAPHTHALENES
(HALOWAXES)
I. Physical Properties
In general, the physical properties of the Halowaxes are dependent
upon the degree of chlorination. The mono- and dichloronaphthalenes are
liquids at room temperature whereas the higher chlorinated compositions
are solids. As the chlorine content increases the specific gravity,
boiling point, melting point, fire and flash point all increase while
the vapor pressure and water solubility decrease. The following table
provides a comparison of the properties of Halowaxes. The vapor pressures
of the various isomers are shown in Figure 1.
1000
500
Reciprocal Absolute Temperature x 10'
10 12 14 16 18 20 22 24. 26 28 30 32 34 36 38 40
I—I I I I l~l I I
^3 Vapor Pressures ;
Chlorinated Naphthalenes -
0
a.
I
5!
A. Octachlor
B. Heptachlor
C. Hexachlor Isomers
0. Pentachlor Isomers
E. Tetrachlor Isomers
F. Trichlor Isomers
G. 1-4 Dichlor
H. Monochlor
ro to fo -* —» -» -^ «~i ui
888 3 S Si 8 a s
Temperature Degrees C.
Figure 1. Vapor Pressure of Chlorinated Naphthalene (Koppers, a);
reprinted by permission.
-------
Table I. Comparative Properties of Halowax Chloronaphthalenes (Koppers, a); reprinted by permission
PRODUCT NUMBER
1 Composition
2 Physic*! Font
3 Chlorine Content. % (Approximate)
4 Sptcilic Gravity
5 Initial Boiling Points
(a 25*0
v> 60'C
Co 30 MM
e 100MM
(1.760 MM
6 Distillation Rcnge
7 Sollanlng Point (Melting PolntX *C (Approx.)
» Filth Point, *C. C.O.C.
I Fire Point, *C. 0.0.0.
10 Spieilic Hut, Gm. Cil./GnV'C
11 Utint H»t ol Vaporization. Cal./Gm.
12 Color
13 Acidity. Mnimurn (Mg. ol KOH/Om.)
14 Vnconty. Styboll Univ. Sec. (Approx.)
900 Oi.i. .in Swim IS l<.
In to* 10 Om • Hewn TOT«.
Ont /Sq. Ifi./Hr. •) tWC
16 Penetration. 20043m.. 5 Sees. % 25*0 (Approx.)
17 Dielectric Constant
T8 Power Factor
tj 60 Cycles/Sec.
& 1000 Cycles/Sec.
@. 60 Cycles/Sec.
6 1000 Cycles/Sec.
IV Resistivity, Megohm Centimelers
1031
Mono-Chlor
Liquid
22
1.20
-
144'C
180*0
250'C
5% Mix. 255'C
95% Mln. 265*0
96% Mm. 275*0
—25
135
165
-
-
While to Pale Straw
0.05
35 £25*0
1.0%
-
-
'-
-
-
-
1000
Mono- + Di-Chlor
Liquid
25
1.22
-
1*OC
ieo*c
2SO*C
-
BO%Mln.2B210* 1«10"
1099B
Tri- •*• Tetra-Chlor
Flakes
52
1.65
-
212'C
248'C
322*C
_
-
-
115
210
None to Boiling
-
-
Light Yellow
0.05
31 @. 130'C
-
-
-
2S'C 115'C
— 4.0
SJ 4.0
-
0.002 .01
Overt m 0> UIO>
1013
Teira- — Penu-Ch'o
Flakes
56
1.67
-
222'C
256-C
328'C
-
-
-
120
230
Nona to Boiling
-
-
Light Yellow
0.05
33 @ 130*C
-
0.005
-
25'C 130'C
4.8 3.8
4.8 3.8
0.002 0.45
0.0003 0.04
Over 1x10* mo1
1014
Penta* — Hexi-Chlor
Flikes
62
1.78
-
242'C
278'C
344'C
~
-
-
137
250
None to Boiling
0.19. @ 15«
0.48fe.100*
-
Light Yellow
O.OS
35@1SO*C
-
a 001
-
25'C 150*0
4.4 3.7
4.4 3.7
0.0009 0.99
0.0002 0.44
Over 1x10* 1x10*
1051
Octa-Cmtx
Powde«
70
20C
-
310'C
-
-
-
-
-
IBS
None to 430
None to Boiling
-
-
Light Yeflow
0.1
-
.-
-
-
-
-
-
-
-
-
2141
Blend
Cakes
54
163
-
-
-
-
-
-
—
135
-
-
-
Gray White
O.OS
163 e '*0*C
-
0.06 @ 140*C
24
2S*C
U
3J
00006
0.0002
Over 1x10*
2148
Blend
Flakes
61
176
-
-
-
-
-
-
-
103
250
None to Boiling
-
-
Light Yellow
0.1
-
-
0,001
11
-
-
-
-
-
-
-------
II. Production
In the United States the sole producer of chlorinated naphthalenes
is the Koppers Company, Inc. The chemicals are sold under the trade
name of Halowaxes. Other international manufacturers of chlorinated
naphthalenes are Bayer in Germany (Nibren waxes) and the Imperial Chemical
Industries Ltd. in the United Kingdom (Seekay waxes); Crow (1970) has
stated that presently in the United Kingdom only small firms produce the
chemicals and only chlorinated naphthalenes with four chlorines or less.
Koppers produces their Halowaxes at a plant in Bridgeville,
Pennsylvania, a few miles outside of Pittsburgh. In 1972 the market
Q
for chlorinated naphthalenes was less than 2.27 x 10 g (5 million Ibs.)
Q
(Koppers, c). ,Ihis is down from the 1956 total output of about 3.24 x 10 g
(7 million Ibs.) (Bardie, 1964). Hardie (1964) has suggested that this
decline in use is due to their serious disadvantages such as their toxic
nature in handling.
III. Uses
Table II lists the various Halowax compositions, number of chlorines,
percentage of the market and principal commercial use. The tri- and tetra-
chloronaphthalenes (Halowax 1001 & 1099) make up more than half of the
United States market. They are used as an impregnate in automobile
capacitors. Automobile capacitors are often changed during car engine
tune ups. The second largest part of the market is the mono- and
dichloronaphthalenes (Halowax 1000 & 1031) which are mostly used as an
oil additive to clean sludge and petroleum deposits in engines, although
-------
Table II. Uses of Chlorinated Naphthalenes (Koppers, c)
Halowax
1000
1031
% of Chlorinated
Isomers
60% 1 Cl, 40% 2C1
95% 1 Cl, 5% 2C1
% Market*
(1972)
15-18%
Uses
Engine oil additive
to dissolve sludge
and deposits
1000
1031
60% 1 Cl, 40% 2 Cl
95% 1 Cl, 5%. 2 Cl
~10%
Used in fabric
dyeing industry
1001,
1099'
JlO% 2 Cl, 40% 3 Cl
(40% 4 Cl, 10% 5 Cl
65-66%
Impregnate for auto-
mobile capacitors.
1013
1014
10% 3 Cl, 50% 4 Cl, 40% 5 Cl
20% 4 Cl, 40% 5 Cl, 40% 6 Cl
"8%
Mostly for electro-
plating stopoff
compounds, also
impregnate for carbon
electrodes used for
chlorine production.
1051
10% 7 Cl, 90% 8 Cl
.5%
Unknown
Q
*Based on a market of less than 2.27 x 10 g (5 million Ibs.)
-------
they find some use in the fabrics dyeing industry. The highly chlorinated
naphthalenes are used mostly as electroplating stopoff compounds, but
only in relatively small quantities.
A comparison of the market volume and types of use of chlorinated
naphthalenes to that of PCB's provides some insight into the relative
hazard of chlorinated naphthalenes due to release into the environment.
In 1970, the largest sales year, 73 million Ibs. of PCB's were sold; in
contrast the chlorinated naphthalene market was less than 5 million Ibs.
in 1972. Nisbet and Sarofim (1972) have reviewed the various uses of
PCB's to determine estimates of the quantities discharged into the
environment. Use of PCB's in capacitors (mostly for fluorescent lights)
amounted to 26 million Ibs. as compared to less than 3.25 million Ibs.
for chlorinated naphthalenes capacitor use. The cited authors estimated
that a large proportion of the PCB's capacitors ultimately were deposited
in a dump or landfill. PCB's annual use for hydraulic fluids and lubri-
cants amounts to approximately 7 million Ibs. and was suggested as a major
source of water contamination. Chlorinated naphthalene use as an oil addi-
tive amounts to less than 0.8 million Ibs. Other uses of PCB's such as
plasticizers and heat exchangers, which have been cited as major sources
of air and water contamination, are not uses of chlorinated naphthalenes.
IV. Current Practice
The higli thermal stability and resistance to chemical attack of
chlorinated naphthalenes reduces any instability problems which might
otherwise be encountered during packing and transport. The liquid
-------
chlorinated naphthalenes (Halowax 1031 & 1000) are usually shipped and
stored in 55 gallon steel drums and occasionally they are transported in
tank cars. The higher chlorinated solids are usually shipped in small
quantities (<50 Ibs.) in fiber pack containers.
The manufacturer recommends that equipment using the Halowaxes be
enclosed and fumes and vapors be exhausted; individuals having a history
of skin disease, liver disorders, or alcoholism should not be employed;
work clothing should be completely supplied including close-weave coveralls,
socks, caps, underwear, gloves, and aprons and the clothing should be
changed twice a week; and face and hands should be washed before eating
and a shower taken upon quitting work (Koppers, b).
V. Environmental Contamination
Although a number of researchers have recognized the similarity
between the physical and chemical properties and uses of PCB's and
chlorinated naphthalenes (Armour and Burke, 1971; Goerlitz and Law, 1972)
and have developed analytical procedures for low-level detection in the
environment (see section on Monitoring & Analysis), no report of chlorinated
naphthalene contamination of the environment has been cited. In most cases
the analytical procedures were developed to assure that chlorinated naph-
thalenes were not interfering with analysis for PCB's or organochlorine
pesticides such as DDT. Some of the analytical techniques developed,
especially gas chromatographic-mass spectrometry, would allow for the
detection and quantification of chlorinated naphthalenes in environmental
samples. However, no study specifically directed at detection of
-------
chlorinated naphthalenes in the environment has been reported, although
the development of -the analytical techniques suggests that some researchers
may have attempted such analysis.
In the early 1950's chlorinated naphthalenes were found as a contami-
nant in pelletized feed and they were the principal cause of a man-made
disease called bovine hyperkeratosis (Olson, 1969). This contamination
was due to the use of a lubricant containing chlorinated naphthalenes in
machines for pelletizing feed. The contamination and disease is rarely
encountered today.
Chlorinated naphthalenes have also been detected as a contaminant
in foreign commercial PCB formulations (Phenochlor and Clophen), although
they were not detected in domestic formulations (Aroclor) (Vos et aL., 1970)
VI. Monitoring and Analysis
Bovine hyperkatosis resulting from contamination of commercial
protein concentrates led to the development of monitoring techniques for
chlorinated naphthalenes. Reber e_£ a^. (1956) extracted the protein con-
centrate with methanol and fractionated the ether-soluble fraction on an
alumina column. Quantification was obtained by a combination of colori-
metric, ultraviolet absorption, and infrared absorption procedures.
However, the sensitivity of this method would not be sufficient for trace
analysis of environmental samples as is shown by the fact that the authors
worked with a sample that contained 150 mg of chlorinated naphthalene, a
huge amount compared to the ng and yg quantities usually obtained from
environmental samples.
-------
Vos et al. (1970) have reported .the use of gas chromatographic-mass
spectrometric and microcoulometric analysis for detection of impurities
in commercial samples of PCB's. Hexa- and heptachloronaphthalenes
were detected in some of the commercial products in the ppm range using
that method.
Armour and Burke (1971) first recognized that chlorinated naphthalenes
may interfere with the gas ehromatographie determination of several organo-
chlorine pesticides. They had previously developed a method for separating
PCB's from pesticides (Armour and Burke, 1970) and, thus, were interested
in determining the behavior of chlorinated naphthalenes in the FDA multi-
pesticide residue methods (Food & Drug Administration, 1969).and the
silicic acid column chromatography method developed for PCB's .(Burke and
Armour, 1970). Results showed that chlorinated naphthalenes would inter-
fere using the FDA cleanup (Florisil column chromatograph) whereas the
silicic acid-cleanup method would completely separate the chlorinated
naphthalenes from the organochlorine pesticides. With the silicic acid
column the chlorinated naphthalenes would be recovered in the same eluant
as PCB's. Holmes and Wallen (1972) found similar results with a column
of silica gel eluted with hexane. They were able to remove the possible
interference of chlorinated naphthalenes from PCB's by the selective
oxidation of tlie chlorinated naphthalenes with chromic acid.
Goerlitz and Law (1972) studied which chlorinated naphthalene isomers
might possibly interfere with gas ehromatographie analysis of pesticides
(assuming no column ehromatographie cleanup). They pointed out that the
-------
electron capture chromatographic pattern of compounds and isomers for
commercial Halowax preparations is not as distinct as for PCB's, thus
making it much more difficult to recognize interferences. Their results
i
show that insecticides lindane, heptachlor, aldrin, p,p'-DDE, p,p'-DDD
and p,p'-DDT elute closely to major Cl,, Cl,, Cl,., and Clg chlorinated
naphthalenes. The authors suggest three methods of assuring that chlori-
nated naphthalenes do not interfere with the pesticide analysis:
(1) processing every sample through a scheme such as described by Armour
and Burke (1971); (2) compare the response of a component on electron
capture and microcoulometrie or conductivity detectors; and (3) use gas
chromatographic-mass spectrometry. Rote and Morris (1973) have discussed
how PCB's, chlorinated naphthalenes, and polychlorinated terphenyls can
be distinguished with GC-MS.
Stalling and Huckins (1973) have used reverse phase thin layer
chromatograph (RPTLC) with components of Aroclors, Halowaxes, and several
chlorinated pesticides. The spots were recovered and characterized by
gas chromatography or gas chromatographic-mass spectrometry. The spot
.patterns of individual Aroclors and Halowaxes were reproducible and charac-
teristic but, in the case of Halowaxes, the spots were not completely
resolved into individual components as determined by gas chromatography.
The method appears to be quite useful when the contaminant is an individual
commercial formula and GC-MS is not available. With mixtures of commercial
products or mixtures of Aroclors and Halowaxes, its utility would be
somewhat reduced.
-------
VII. Chemical Reactivity
Chlorinated naphthalenes, like PCB's, exhibit a high degree of
chemical and thermal stability indicated by their resistance to most acids
and alkalies and resistance to dehydrochlorination (Kpppers, a). For
example, 1-chloronaphthalene, at moderate temperatures, is unaffected
by water and alkali and only decomposes to 1-naphthol after prolonged
heating with caustic soda at temperatures above 300°C (Hardie, 1964).
The higher chlorinated naphthalenes are stable to most oxidizing agents
and at 120-125°C in a dry atmosphere are unaffected by copper or mild
steel. In the presence of moisture at 120-125°C, they tarnish copper,
due to the liberation of small amounts of hydrogen chloride (Hardie, 1964)
Chlorinated naphthalenes are not as stable as PCB's to oxidation by
chromic acid. Holmes and Wallen (1972) have used this difference in
resistance to oxidation to eliminate chlorinated naphthalenes from inter-
fering with gas chromatographic detection of PCB's. The product from
chromic acid oxidation is a chlorine substituted phthalic acid (Hardie,
1964). This does not necessarily mean that chlorinated naphthalenes
would be oxidized in the environment, since well-known persistent
environmental pollutants, such as p,p'-DDE, are oxidized with chromic
acid treatment (Holmes and Wallen, 1972).
10
-------
VIII. Biology
The biology of toxic compounds are usually discussed in terms of
their toxic behavior. Consequently, the following topics have
received only cursory attention in the literature.
A. Absorption
Three natural routes are available for the intake of chlorinated
naphthalenes: ingestion, inhalation, and cutaneous absorption. Of these,
inhalation seems to be a primary route in occupational exposure with fumes
sublimating and reaching relatively high'concentrations at temperatures
far below that of boiling (Crow, 1970). While cutaneous absorption is
common, it usually results in far less severe pathological effects
(Bennet, 1938). Collins (1943) noted no indications of such entry in
the handling of cold chloronaphthalene solids,. In domestic animals,
ingestion is by far the most common route and results in the most severe
pathology (Olson, 1969; Huber and Link, 1962).
B. Excretion
In the surveyed literature, male rats were the only subjects used to
study the excretion of chlorinated naphthalenes (Cornish and Block, 1958)-
The lower chloronaphthalenes do not appear to be excreted unchanged.
About 20% of hepta- and penta-chloronaphthalens were found to be excreted
in the urine and feces.
C. Transport
No studies focusing on chloronaphthalene transport were encountered.
It seems reasonable to assume from the abundant toxicological data and
metabolic study (Cornish and Block, 1958) that, regardless of the route
11
-------
of entry, an appreciable amount of chlorinated naphthalenes are transported
to the liver where they are metabolized, excreted and/or stored. Orally,
chlorinated naphthalenes may be transported unaltered along the digestive
tract and be excreted in the feces (Cornish and Block, 1958).
D. Distribution
Again, clinical or experimental data are not available. The liver
is a probable site of chlorinated naphthalene accumulation.
E. Metabolic Effects
The primary metabolic effect of the chlorinated naphthalenes is to
interfere with the metabolism of carotene and its transformation to
Vitamin A as reflected in decreased plasma Vitamin A (Olson, 1969). Also,
1,4-diehloronaphthalene has been found to increase the activity of
0-demethylase in the liver of rats (Wagstaff, 1971). The Vitamin A
effect is highly variable. Goats, sheep, swine, mice, chickens and rats
are much less susceptible than cattle (Olson, 1969). The species specific
variations in the carotene-Vitamin A metabolism necessitates caution in
interpreting these findings (Hansel and McEntee, 1955).
F. Metabolism
Only one study has been encountered that attempts to describe the
metabolism of various chlorinated naphthalenes. Testing for the pre-
sumed metabolites in rat urine, Cornish and Block (1958) concluded that
the mono- to tetra- were able to be metabolized to some extent. The more
highly chlorinated naphthalenes, however, were not so metabolized. The
possibility of alternative pathways and tissue accumulation was proposed
but not investigated.
12
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IX. Environmental Transport and Fate
A. Persistence and/or Degradation
Environmental decomposition of chlorinated naphthalenes has
received little study. Only the monochlorinated naphthalenes have
been studied under biological conditions similar to those found in
the environment. Walker and Witts-hire (1955) have examined the
decomposition of both 1-chloro- and 1-bromonaphthalene by soil
bacteria. They found that five strains of bacteria, obtained from
soil, would grow in a mineral salts medium with 1-chloronaphthalene
as the sole carbon source. The following metabolism route was
suggested:
Cl
Cl
Cl
Similar results were found for the 2-chloronaphthalene by Canonica
and coworkers (1957).
Okey and Bogan (1965) examined the rate of metabolism of 1-chloro
and 2-chloronaphthalene by bacteria that were first grown on unsub-
stituted naphthalene (see Figure 2). The initial concentration of
chlorinated substrates was 1 rag/A and the substrate was the only
source of carbon.
13
-------
SLUDGES GROWN ON THE UNSUBSTITUTED HOMOLOGS .
SUBSTRATE QUANTITY 3 O ma COP— V.S S. BENZENE SLUDGE l60Omg/l
BENZENE O NAPHTHALENE • NAPHTHALENE SLUDGE ISOOmg/l
ZDUU
Izooo
0
UJ
M
=•1500
3
•31
UJ
0
£1000
O
UJ
z
500
0
«
J
f
^
(
/
^— ^— <
v**
-A (
)
1
1
0 200 400 COO 000 1000 1300 I4OO
REACTION TIME— min
Figure 2. Metabolism of chlorinated naphthalene and benzene
[Okey and Bogan, 1965]; reprinted by permission of
publishers of Journal Water Pollution Control Federation.
The following relative rates of metabolism were observed:
naphthalene^>2-chloronaphthalene>l-chloronaphthalene.
The microbial.degradation of the highly chlorinated naphthalenes
has not been studied. However, their metabolism in mammalian systems
(rabbit) has been examined by Cornish and Block (1958). They admin-
istered 1 gm quantities of naphthalene and chlorinated naphthalenes
(1-chloro, di-, tetra-, penta-, hepta-, and octachloronaphthalenes)
i
to male albino rabbits and collected 24-hour urine samples daily
for a 4-day period. Each urine sample was analyzed for creatinine,
glucosiduronic acids, phenolic compounds, sulfur partitions, and
mercapturic acid and in the case of penta- and heptachloronaphthalenes
for the unchanged parent molecule. These researchers concluded that
14
-------
1-chloro and dichloronaphthalene are readily metabolized by the
rabbit; tetrachloronaphthalene is metabolized somewhat slower; and
penta-, hepta-, and octachloronaphthalene do not undergo the usual
metabolic reactions to the measured end products. For penta- and
heptachlorOnaphthalenes only 20% of the 1 gm dose was excreted in
an unchanged form during the 4-day period. Correlation of these
in vivo results to environmental microbial metabolism is question-
able. Gibson (1972) has suggested that the initial reactions in
these two systems (mammalian and microbial) are quite different as
is depicted in the following figure.
Pseudomonas
microsomes
\
2e"
2H+
IH epoxide
hydrase
OH
H OH
Figure 3. Proposed mechanisms of naphthalene dihydrodiol formation
in mammalian and microbial systems
[Gibson, 1972]
15
-------
However, the highly chlorinated PCB's have been found to be stable
to metabolism by either microbial (Sarofim and Nisbet, 1972) or
mammalian systems (Hutzinger et jil., 1972). An intuitive correla-
tion based on the similarity in structure between PCB's and chlori-
nated naphthalenes would suggest that the highly chlorinated
naphthalenes might be quite stable in the environment.
Studies of the photochemical or chemical degradation of
chlorinated naphthalenes have not been undertaken.
B. Environmental Transport
Since chlorinated naphthalenes have not been detected in the
environment, no information is available on their transport within
the biosphere. The similarity between the physical properties (low
water solubility, low volatility) of chlorinated naphthalenes and
PCB's, would suggest that the transport of chlorinated naphthalenes
within the environment might be quite similar to PCB's.
C. Bioaccumulation
Studies of the behavior of chlorinated naphthalenes exposed
to ecological food chains are not available. Again, the physical
properties (water insoluble, soluble in organic solvents) may suggest
a similar behavior for chlorinated naphthalenes to that found for
PCB's.
16
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X. Toxicity
A. Human Toxicity
Because chlorinated naphthalenes have never enjoyed widespread
household use, occupational rather than accidental or environmental
exposure predominates the relevant literature on human toxic effects.
Two clinically distinct but often concurrent and possibly physiologi-
cally related syndromes have been described: liver necrosis and
chloracne. Any attempt to label these syndromes as acute or chronic
•
is potentially misleading. While an exposure of 3-4 months is
often noted in the clinical literature (e.g. Schwartz and Peck, 1943;
Collier, 1943; Greenburg, e£ ad., 1939), histotoxic effects may appear
after a much shorter period (Weil and Goldburg, 1962). Also, human
susceptibility is by no means homogeneous. Standard clinical
parameters such as age, sex, weight, general physical conditions,
and previous medical history show no clear correlation to chloro-
naphthalene pathogenesis (Greenburg, «£ ad., 1939). The situation
is further complicated in that precise dosage values are often not
available. But, if a label would be necessary, chronic is perhaps
the best compromise with the disease appearing after an appreciable:
period of exposure and reversal being relatively gradual after
exposure is discontinued. • A more productive approach would probably
be in terms of degree of damage as adopted by Collier (1943); i.e.,
slight, moderate, and severe.
17
-------
Chloronaphthalene-induced liver necrosis has always been of low
incidence, with the last fatal case in the surveyed literature being
reported by Straus (1944). The symptomatic course of the disease is
not unlike that of other forms of liver damage resulting in hepatitis
with consequent jaundice, and may be accompanied by nausea, vomiting,
loss of appetite, fatigue, fever, and/or acute abdominal pain
(Kleinfeld, e± al., 1972; Collier, 1943). Autopsies of fatally
exposed workers have revealed severe yellow atrophy of the liver.
Most researchers seem to agree that the liver is the only internal
organ directly damaged by chlorinated naphthalenes (Collier, 1943;
Straus, 1944; Kleinfeld, et^ al., 1972). Detailed descriptions of
the pathology are available in the literature—especially Greenburg
(1939). Understandably, very little detailed descriptions of liver
damage are available for non-fatal exposures (Straus, 1944).
Kleinfeld, et al. (1972) could find no evidence of liver damage in a
recent outbreak of chloracne.
Agreement also exists with reference to route of entry. Opinion
favors inhalation as the prime, if not the only, form of hepato-
pathogenic exposure (Kleinfeld, e£ al., 1972; Crow, 1970). The
earlier investigations cited above by and large recognized the
importance of inhalation but did not specifically rule out contact
exposure. Experiments with other mammals support the hepatotoxic
18
-------
effect of inhalation over absorption and also indicate a possible
danger from ingestion. The one accidental case of ingestion reported
by Crow (1970), however, does not allow any sound conclusions to be
drawn.
The primary hepatotoxic agents for man seem to be the penta- and
«
hexachloronaphthalene (Amer. Ind. Hyg. Assoc., 1966). Current
q
hygenic standards are 5 mg/m for trichloronaphthalene and
2
0.5 mg/m for pentachloronaphthalene. These standards seem well
below the minimum toxic doses for man and animals.
In contrast to the low incidence of liver damage, chloracne
resulting from exposure to chlorinated naphthalene is a common and
persistent problem in manufacturing and use. Chlorinated naphthalene
dermatitis was reported as early as 1918 (Jones, 1941) and remains a
problem in spite of advances in industrial hygiene (Kleinfeld, 1972).
Chloracne is a general term and describes the skin irritation that
can be produced not only by chlorinated naphthalenes but also by
other chlorinated compounds including diphenyls, benzenes, and phenols,
Chloracne accompanied by itching, however, may be specific to the
chlorinated naphthalenes. The skin lesion is morphologically similar
in all cases and has been referred to as the chloracne cyst - sores
1 mm to 1 cm in diameter with an ill-defined central opening. These
cysts are formed from necrotic material which is retained in the
hair follicle or sebaceous gland and covered by a horny layer of skin
causing a dark crusty appearance (Crow, 1970). Hair follicles swell
19
-------
into acne-type sores and the sebaceous glands degenerate. In the
more severe cases, which are usually associated with advanced liver
damage, these lesions may cover extensive areas of the body with
pigmentation so dark as to make a Caucasian appear negroid (Greenburg,
et al.f 1939).
Although chloracne can be caused by ingestion or inhalation,
the most common route in man is cutaneous absorption (Crow, 1970).
The lower chlorinated naphthalenes seem to be innocuous with respect
to man. Mixtures of- mono-/dichloronaphthalene and tri-/tetrachloro-
naphthalene at 500 mg/g solvent applied to the ear caused no
response over a 30-day period. A mixture of penta-/hexachloronaphtha-
lene under the same conditions did cause acne but hepta- and octa-
chloronaphthalene did not (Shelly and Kligman, 1957). Even at
concentrations as small as 30 mg/g, typical chloracne develops
in 6 weeks with the application of penta-/hexachloronaphthalene
(Hambrick, 1957).
8. Toxicity to Birds and Non-Human Mammals
Chlorinated naphthalene toxicity in birds and non-human mammals
has been studied in attempts to better understand not only occupa-
tional hazards to man but also highly chlorinated naphthalene
poisoning to cattle. The former investigations have been conducted
primarily with controlled exposures of rats to known concentrations
of the toxic substance in order to supplement available human clinical
data. The latter investigations on cattle toxicity have concentrated
20
-------
primarily on a complete description of the syndrome and on attempts
to induce a toxic response in other farm animals under closely
monitored conditions. Cattle poisoning as described below usually
involves a relatively high dose with rapid physical deterioration.
Thus, it may be characterized as acute. Studies relating to occupa-
tional exposure, however, usually involve attempts to elicit a gradual
response to a minimum dosage and may thus be characterized as chronic.
1. Acute and Subacute Toxicity
Highly chlorinated naphthalene poisoning, also referred to
as bovine hyperkeratosis or X-disease, was of major economic
concern in the United States during the 1940s and 1950s. Basically,
the disease was caused by accidental ingestion of chlorinated
naphthalenes from lubricants in machines used for making pelleting
feed or from wood preservatives (Crow, 1970). The relation of
chlorination to toxicity in accidental cattle poisoning seems to
agree well with that of human toxicity in that the penta-/
hexachloronaphthalenes are usually the toxic agents. However,
octachloronaphthalene has been reported as having greater oral
toxicity than hexachloronaphthalene in cattle (Amer. Indust. Hyg.
Assoc., 1966). As with human exposure, detailed dosage data are
often lacking due not only to uncertain concentrations but also
to ad libitum exposure.
21
-------
The pathological course of bovine hyperkeratosis has been
described in considerable detail and needs only a cursory
examination in this report (See Olson, 1969). As indicated
previously (Sect. VIII, E), a primary effect of chloronaphthalene
poisoning is to interfere with the biotransformation of carotene
to vitamin A. Chronologically, this is one of the first effects
of exposure and many of the subsequent symptoms - especially of the
skin and horns - may be due to vitamin A deficiency in the blood
plasma. Vitamin-A depression is quickly followed by inflamation
of the oral mucosa, weeping, excessive salivation, and irregular
food consumption. As the disease progresses, gross physical
effects may include a general thickening of the skin caused by
over-development of the skin's horny layer with loss of hair
(hyperkeratosis). The horns may show signs of degeneration or
irregular growth. With continued exposure, the disease progresses
i
through anemea, dehydration, loss of weight, fever, and death.
Liver damage may be severe [The resemblance of this syndrome to
severe chloronaphthalene intoxication in man is noted but no
unequivocal comparisons can be made]. A combination of penta-/
hexachloronaphthalene at a total dosage of 5.55 mg/kg body weight
given orally over a five day period will cause a sharp drop in
plasma vitamin A by the end of the third day and depressed plasma
vitamin A for over thirty days. A single dose of hexachloro-
naphthalene at 11 mg/kg body weight has caused mortality within
two weeks (Olson, 1969).
22
-------
Other domestic animals prove much less susceptible to chloro-
naphthalene poisoning than do cattle. Swine show no toxic effects
to hexachloronaphthalene at ten times the above lethal dosage
for cattle. Marked vitamin A depression is noted in swine only
with, dosages of 154 mg/kg body weight and death does not occur
until 198 mg/kg body weight doses are given. Pentachloronaphthalene
applied to the skin at 60 mg/liter, (3 liters per day), six times
a week for six weeks [180 mg/day for a total dose of 6.3 g] causes
only mild hyperkeratosis. (Link £_t al., 1958) Similar doses
administered orally (176-200 mg/kg body weight over a 8-9 day
period) causes only slight systemic effects and ataxia (Huber &
Link, 1962). Although hyperkeratosis did not result from oral
administration, lethal oral doses did result in moderate to
severe liver damage ranging from yellow discoloration to swelling
and hemorrhage. In non-fatal oral doses, depression of plasma
vitamin A was reversible upon oral administration of vitamin A
(Link et^ a^. , 1958). Similar resistence has been noted in sheep
but these studies were not reviewed in this preliminary phase
(see Olson, 1969).
Excellent concentration/effect studies have been conducted
using chickens and may possibly indicate an increased resistance
to chloronaphthalene exposure over that shown by cattle. Exact
comparisons are difficult, however, because feeding was ad libitum;
given the erratic effect of chloronaphthalene on the appetite
exact dosages cannot even be meaningfully approximated. A
23
-------
mixture of penta-/hexachloronaphthalene at concentrations of
5, 10, 20, 50, and 100 ppm (mg/kg feed) for 40 days, gives an
LCcQ of 20 ppm with an average decrease in weight of 51%. Even
at 5 ppm, weight gain was reduced by 33% with a 6.5% mortality
and the prognosis for prolonged feeding as terminal by marketing
age. At 100 ppm, all of the broad breasted bronze chickens
died within 33 days. It is interesting to note that females
were appreciably less sensitive over all dosage ranges; however,
insufficient data is given to rationally assess whatever signi-
ficance, if any, this may have. Gross histologic examination
revealed enlarged and darkened livers as the only histopathologic
manifestation, reenforcing the specificity of action found in
human exposures. Similar to human topical application, octa-
chloronaphthalenes even at 125 ppm in feed caused no significant
effect. [The investigators speculated without elaboration that
this might reflect the high melting point and low solubility of
octachloronaphthalene. ] (Pudelkiewicz et^ al^., 1958).
More relevant from the standpoint of comparative toxicology,
a different variety chicken, the New Hampshire chicken, was
studied in a subsequent experiment and found to be appreciably
more resistant to penta-/hexachloronaphthalene poisoning. The
lethal dose for the broad breasted bronze chickens, 100 ppm,
only prevented egg production in the New Hampshire. . With cases
of 4, 20, 100, 500 and 2500 ppm in feed over 35 days, 100%
fatality was only achieved with the highest level (after a
24
-------
two week exposure period). A four fold increase in vitamin A
markedly decreased the effect. Again, enlarged fibrous livers
were the most common pathological finding. (Pudelkiewicz et al.,
1959). Whether the increased resistance of New Hampshires over
broad breasted bronzes represents a true subspecies variation or
only reflects any of a host of other possible causes (e.g. ,
times of year, ambient temperature, size or health of original
specimens, etc.), it does serve to illustrate the many possible
pitfalls of comparing toxicity studies on widely dissimilar animals.
2. Chronic Toxicity; Rats and Rabbits
The clinical history of occupational poisoning due to
chloronaphthalenes has stimulated much of the work done on
"chronic" exposure to non-human mammals. Copeous and detailed
dosage/response data are available and a selective but repre-
sentative sample is included in the following discussion.
Because the toxic properties of the chlorinated naphthalenes
vary considerably with the degree of chlorine subsitution,
chronic toxicity will be discussed in terms of ascending levels
of chlorination.
a) Mono- and Mono/Pi- Combinations:
These compounds are commonly considered non-toxic.
Topical application of mono/dichlorinated naphthalenes in
the human ear at 500 mg/g solvent for 30 days is non-reactive
(Shelly and Kligman, 1957). However, when applied to the
much more sensitive rabbit ear for 5-7 days, a-chloronaphthalene
25
-------
produces mild reddening at 90 mg/g and severe reddening -
but without decrease of sebaceous glands - at 570 mg/g
(Hambrick, 1957). [Inhalation and ingestion experiments
were not encountered in the literature surveyed.]
b) Dichloronaphthalenes;
When applied topically to the rabbit ear at about half
the above stated concentrations for a-chloronaphthalene
(45 mg/g and 290 mg/g), dichloronaphthalene produced the
same effects over the same period. (Hambrick, 1957). When
ingested in ad libitum feeding by the rat at 5 g/kg of feed
for 15 days, liver weight was increased, growth impaired,
and coat texture roughened. (Wagstaff, 1971). [No
inhalation experiments were encountered.]
c) Tri- and Tri/Tetra- Combinations!
Topical application of trichloronaphthalenes to mice
and rats (at an unspecified concentration) for 2 hr/day x
40-60 days produced no effect (Shakhovskaya, 1953). This
is in agreement with a mixture of tri/tetrachloronaphthalenes
applied to the human ear at 500. mg/g solvent for 30 days
which also had no effect (Shelly and Kligman, 1957).
Feeding experiments of trichloronaphthalene with mice
at 2.5 mg/mouse/day x 20 days produced no effect (Shakhnovsfkaya,
1953). However, at 300 mg/rat/day x 9-136 days (total dose
of 2.7 g-41 g) a slight but progressive increase in fatty
accumulation was evident (Bennett «it al., 1938). Tri/tetra-
26
-------
chloronaphthalene at 15 mg/kg body weight/day x 60 days has
no effect in rabbits - total dose of .9 g/kg body weight
(Greenburg at al., 1939).
Inhalation experiments yield similar results with rats.
At 0.05-0.2 mg/1 for 2 hrs/day x 20 days and 1.31 mg/m for
16 hrs/day x 134 days no toxic signs develope (Shakhnovskaya,
1953, Bennett et al., 1938). But at 10.97 mg/m3 for 16 hrs/day
x 102 days slight liver discoloration is shown and 5% of
the rats show increased fatty degeneration (Bennett, 1938).
d) Tetra/Penta- Combinations:
With the introduction of the five chlorine atom compound,
the first cases of severe poisoning develop. Rats fed
50 mg/rat/day x 63 days - total doses of 3.12 g/rat - are
fatally intoxicated, showing jaundice and fatty degeneration
of the liver (Bennett, et al., 1938). Rabbits seem even
more sensitive with fatal intoxication at 15 mg/kg body
weight/day x 12-26 day - total dose of 18-390 mg/kg body
weight (Greenburg et al., 1939). (No inhalation or topical
experiments encountered.)
e) Penta and Penta/Hexa - Combinations;
i) Pentachloronaphthalene alone has received relatively
little attention. Applied to swine's skin at 60 mg/liter
x 31 x 6 day/wk x 4 weeks - 180 mg/day, total exposure
43.2 gm - slight hyperkeratosis is produced (Link et al.,
1958). When fed to rabbits at 15 mg/kg body weight/day
27
-------
x 12-26 days - total dose of 180-390 mg/kg body weight -
the administration is fatal.
ii) Combinations of penta/hexachloronaphthalenes are
among the most often sighted in human toxicity and have
been studied in some detail in the non-human mammals.
Orally penta/hexachloronaphthalene has been found
highly toxic to rabbits and rats. In rats, oral doses
of 300 mg/rat/day were fatal in 33 days or less - maximum
dose of .99 g/rat. The livers were markedly yellow and
showed extreme signs of fatty degeneration. A dosage of
100 mg/rat/day had the same effect over a 55 day period -
.55 g/rat total dose. Slower and less severe liver
damage was noted with a dose of 62.5 mg/rat/day, but
further details are not given (Bennett eib al., 1938).
In rabbits, the lethal dose is 15 mg/kg body weight/day
for 12-26 days - total doses of 180-390 mg/kg body
weight - with similar toxic effects (Greenburg, 1939).
Inhalation studies with rats show a similar dosage/
3
effect relationship. Exposures to 1.16 mg/m x 16 hr. x
3
134 day and 1.44 mg/m x 16 hrs/day x 52 days yields
jaundice, enlarged yellow liver and 69% fatality
(Bennett, jet^ al., 1938).
Applied to the skin of the rabbit ear, 30 rag/day x
5 days caused only mild dermatitis with follicular
attenuation (Hambrick, 1957)*
28
-------
f) Hexachloronaphthalene;
Like pentachloronaphthalenes, hexachloronaphthalenes have
received little attention. In ad libitum feeding to rats,
20 mg/kg and 63 mg/kg in diet causes weight loss over a 84
day period and 200 mg/kg diet causes fatality in unspecified
numbers (Weil and Goldberg, 1962).
Skin exposure to the rabbit ear at 30 mg/g solvent for
five days caused decrease in sebaceous gland tissue (Hambrick,
1957).
g) Heptachloronaphthalene;
No chronic studies in heptachloronaphthalene were
encountered
h) Octachloronaphthalene;
The toxicity of Octachloronaphthalene is somewhat proble-
matical. Most current investigators consider it innocuous
(Crow, 1970; Olson, 1969). No significant toxic effects have
been observed after testing in man or chicken (Shelly &
Kligman, 1957; Pudelkiewicz e_t al., 1958). However, ad libitium
feeding of rats at dietary concentrations of .5 g, 2 g, and
5g/.kg for 22 days has shown a decrease in liver but not plasma
vitamin A (Deadrick e± al., 1955). Further, a single dose of
1 g/rabbit caused fatality in 7 days (Cornish & Block, 1958).
3. Sensjtization;
In the strictest sense of the word - i.e., an increased
response to a toxic substance based on an antigen/antibody-type
29
-------
activity - .sensitization does not seem to apply to the chloro-
naphthalenes. Further, there is no apparent evidence that any
organism becomes increasingly reactive to chloronaphthalenes
with exposure. This should not be confused with increased
*
susceptibility to chloronaphthalenes because of previous liver
4. Taratogenicity; No studies encountered.
5. Carcinogenicity; No studies encountered.
6. Mutagenicity: No studies encountered.
7. Behavior effects; No studies encountered.
C. Toxicity to Lower Animals
Because the problems encountered in the manufacture and use of
chlorinated naphthalenes center on the "higher" animals, no toxicology
data is available. However, it has been determined that o-chioro-
naphthalene does not effect the schooling behavior of the fish
Kuhbia sandvicensis at 20 ppm. (Hiatt e£ al., 1953).
D. Toxicity to Plants
No studies encountered.
E. Toxicity to Microorganisms
Very few studies have appeared in the literature in relation to
microbiotic toxicity. Those few that have are in the foreign
literature and relate primarily to the use of chloronaphthalenes
as wood preservatives. Hexa- and octachloronaphthalenes were found
to be non-toxic to spores of millet smut at unspecified concentrations
and exposures (Mel' nikov £t_ jl. , 1958). Low but unspecified
30
-------
concentrations of unspecified chlorinated naphthalenes may stimulate
cellulases in Trichnymphia agilis, a flagellated symbiont of the damp
wood termite. This results in increased cell volume, but the
toxicity - if any - is not discussed (Schulze-Dewitz, 1964).
31
-------
XI. Chlorinated Naphthalenes: Summary and Conclusions
The chlorinated naphthalene industry has little apparent growth
potential and may actually be on the wane. Over the past sixteen years,
total production has decreased by 14%. The applications for chlorinated
naphthalenes also seem to have become more restricted. The compounds are
no longer used as wood preservatives, at least not in the United States "
and probably not in other countries. No proposals for new uses have been
encountered. The reason for this decline is most probably attributable
in part to the appreciable mammalian toxicity of the penta- and hexa-
chlorocompounds. Production cost and the availability of alternative
substances may also be factors. However, the five million pound pro-
duction in 1972 is by no means negligible and environmental contamination
is possible. A realistic determination of potential ecological hazard
based on what is known can be made by an integrative evaluation of pro-
duction, use, toxicity, environmental exposure, and persistence for the
various groups of chlorinated naphthalenes.
Mixtures of mono- and dichlorinated naphthalenes (Halowaxes 1000 and
1031) represent about one quarter of the production. Their uses as engine
oil additives and in the fabric industry may indicate more direct routes
of environmental contamination to soil or water than found in the higher
chlorinated naphthalenes. However, these compounds have thus far shown
an extremely low order of toxicity and are likely to be readily decomposed
in the environment.
Combinations of tri/tetra with some di- and pentachloronaphthalene
(Halowax 1001 and Halowax 1099) form the bulk of the market
32
-------
(approximately 65%) and are used exclusively as impregnates for auto-
mobile capacitors. Although most of these capacitors must eventually
be replaced and probably end up in land fills, the extent to which
chlorinated naphthalenes will leach out of the closed system has not
been determined. These compounds might present a serious hazard if
leached into the environment in large enough amounts. Some tetra/penta
combinations have been implicated in liver degeneration and hyper-
keratosis at doses of' 15-50 mg/kg body weight. Further, these compounds
are likely to be relatively stable in the environment.
The tri- through hexachloronaphthalene based products (Halowaxes 1013
and 1014) are also likely to possess a high degree of toxicity and
persistence. Although they represent only about 8% of the market, their
uses as electroplating stopoff compounds and impregnates for carbon
electrodes used in chlorine production would seem to indicate a marked
increase in potential environmental exposure over that shown by
capacitor impregnates.
The last commercial mixture, hepta-/octachloronaphthalene (Halowax
1051), is produced in rather small amounts and for purposes which were
not ascertained. The toxicity data on these compounds are inconclusive.
They are, however, likely to prove quite stable. Because of the lack
of definitive information, a reliable assessment of potential environmental
hazard cannot be made.
33
-------
In summary, even the most toxic of the chlorinated naphthalenes may
present little environmental hazard because of their limited production
and restricted use. However, this type of conclusion could not be
justified based on present information alone. Much that should be known
about the chloronaphthalenes - their environmental fate, the actual degree
and rate of contamination, and their toxicity to intermediate life forms -
is all but unexplored. Thus, none of the chlorinated naphthalenes can
be dismissed in a consideration of potential environmental hazards. The
mono- and dichloronaphthalenes used in the oil and fabric industries
may indeed have a low order of toxicity and be readily biodegraded but
they represent a sizable portion of the market and are liable to direct
environmental exposure. The chloronaphthalenes used in automobile
capacitors (primarily tri- and tetra- compounds) warrent careful eval-
•
uation because of their high production, probable persistence, and
demonstrated toxicity. Further, the possibility of leaching,although
seemingly remote, cannot be disregarded. Similarly, the tri- through
hexachloronaphthalenes used in electroplating and chlorine production,
although produced in limited amounts, must be considered because of their
stability, toxicity, and significant potential for environmental release.
Finally, the hepta-/octachloronaphthalenes require further investigation
in spite of their small production because little is known about the
applications, potential release, and toxicity of these highly stable
compounds.
34
-------
LITERATURE CITED
American Industrial Hygiene Association, (1966) "Chloronaphthalenes"
Hygiene Guide Series, Jan-Feb
Armour, J.A. and Burke, J.A. (1970.), "Method for Separating Pplychlorinated
Biphenyls from DDT and Its Analogs" J. Ass. Off. Anal. Chem.,
53,761
Armour, J.A. and Burke, J.A. (1971), "Behavior of Chlorinated Naphthalenes
in Analytical Methods of Organochlorine Pesticides and Polychlorinated
Biphenyls", J. Ass. Off. Anal. Chem., 54,175
Bennett, G.A., Drinker, C.K., and Warren, M.F. (1938), "Morphological
Changes in the Liver of Rats Resulting from Exposure to Certain
Chlorinated Hydrocarbons", J. Ind. Hyg. Toxicol., 20,97
Canonica, L., Fiecchi, A. and Treccani, V. (1957), "Products of Microbial
Oxidation of Some Substituted Naphthalenes", Rend. 1st. Lombardo Sci.,
Pt. I, 2i,H9
Collier, E. (1943), "Poisoning by Chlorinated Naphthalenes", Lancet, 1^,72
Cornish, H.H. and Block, W.D. (1958), "Metabolism of Chlorinated Naph-
thalenes", J. Biol. Chem., 231.583
Crow, K.D. (1970), "Chloracne" Trans. St. Johns Hosp. Dermatol. Soc.,
5i, 79
Deadrick, R.E., Bieri, J.G., and Cardenas, R.R. (1955), "Effects of
Octachloronaphthalene on Vitamin A Metabolism in the Rat", J.
Nutrition, ^7,287
Food and Drug Administration (1969), "Pesticide Analytical Manual", Vol. 1,
Washington, D.C.
Gibson, D.T. (1972), "Degradation of Aromatic Hydrocarbons - Initial
Reactions" in Degradation of Synthetic Organic Molecules in the Bio-
sphere, National Academy of Sciences, Washington, D.C. p 116
Goerlitz, D.F., and Law, L.M. (1972), "Chlorinated Naphthalenes in
Pesticide Analysis", Bull. Environ. Contain. Toxicol., _7,243
Greenburg, L., Mayers, M.R. and Smith, A.R. (1939), "The Systemic Effects
Resulting from Exposure to Certain Chlorinated Hydrocarbons",
J. Ind. Hyg. Toxicol., 2JL.29
35
-------
Hambrick, G.W, (1957), "The Effect of Substituted Naphthalenes on the
Pilosebaceous Apparatus of Rabbit and Man", J. Invest. Dermatol.,
2.8,89
Hansel, W. and McEntee, K. (1955), "Bovine Hyperkeratosis (X-Disease): A
Review", J. Dairy Sci., 38,875
Hardie, D.W.F. (1964), "Chlorocarbons and Chlorohydrocarbons: Chlorinated
Naphthalenes", in Kirk-Othmer Encycl. Chem. Technol., 2nd Edit.,
J5.297
Hiatt, R.W., Naughton, J.J. and Matthews, D.C. (1953), "Effects of
Chemicals on a Schooling Fish, Kuhlia Sandvicensis", Biol. Bull.,
104.28
Holmes, B.C., and Wallen, M. (1972), "Simple Differentiation of Poly-
chlorobiphenyls from Chlorinated Naphthalenes", J. Chromatogr., 71,
562 '
Huber, W.G. and Link, R.P. (1962), "Toxic Effects of Hexachloronaphthalene
on Swine", Toxicol. Appl. Pharmacol., ^,257
Hutzinger, 0., Nash, D.M., Safe, S., DeFreitos, A.S.W., Norstrom, R.J.,
Wildish, D.J., and Zitko, V. (1972), "Polychlorinated Biphenyls:
Metabolic Behavior of Pure Isomers in Pigeons, Rats and Brook Trout",
Science, 178,312
Jones, T.A. (1941), "The Etiology of Acne with Special Reference to Acne
of Occupational Exposure", J. Ind. Hyg. Toxicol., 23,290
Kleinfeld, M., Messite, J., and Swencicki, R. (1972), "Clinical Effects
of Chlorinated Naphthalene Exposure", J. Occup. Med., 14,377
Koppers Company, Inc., (a), "Halowax, Chlorinated Naphthalene Oils and
Waxlike Solids"
Koppers Company, Inc., (b), "Precautions for Handling Chloro-Naphthalene
Compounds"
Koppers Company, Inc., (c), personal communication, 1973
Link, R.P., Smith, J.C., and Newton, D.I. (1958), "Toxic Effect of
Chlorinated Naphthalenes in Pigs", J. Am. Vet. Med. Assoc., 133,83
Mel'nikov, N.N., Skalozubova, A.V. and Deshevaya, A.S. (1958), Org.
Insektofungitsidy ± Gerbitsidy, (1958).304
36
-------
Nisbet, I.C.T. and Sarofim, A.F. (1972), "Rates and Routes of Transport
of PCB's in the Environment", Environ. Health Perspectives, Expr.
Iss. No. 1, 21
Okey, R.W. and Bogan, R.H. (1965), "Apparent Involvement of Electronic
Mechanisms in Limiting Microbial Metabolism of Pesticides", J. Water
Poll. Contr. Fedr. 37,692
Olson, C. (1969), "Bovine Hyperkeratosis (X Disease, Highly Chlorinated
Naphthalene Poisoning) Historical Review", in Advances in Veterinary
Sciences and Comparative Medicine, Vol. 13 (ed. C.A. Brandly and
C.E. Cornelius) Acad. Press, N.Y.
Pudelkiewicz, W.J., Boucher, R.V., Callenbach, E.W. and Miller, R.C. (1958)
"Some Physiological Responses of Broad Breasted Bronze Poults to
Chlorinated Naphthalene", Poultry Sci., 37,185
Pudelkiewicz, W.J., Boucher, R.V., Callenbach, E.W., and Miller, R.C.,
"Some Physiological Responses of New Hampshire Chickens to a Mixture
of Penta- and Hexachloronaphthalenes", Poultry Sci., 38,424
Reber, E.F., Brader, Jr., J. and Link, R.P. (1956), "Isolation and Identi-
fication of a Hyperkeratogenic Material Present in a Commercial
Protein Concentrate", Cornell Vet., 46.320
Rote, J.W. and Morris, W.J. (1973), "Use of Isotopic Abundance Ratios in
Identification of Polychlorinated Biphenyls by Mass Spectrometry",
J. Ass. Off. Anal. Chem., 56,188
Schultze-Dewitz, G. (1964), "The Termite Flagellate Trichonymphia agilis
and Its Reaction to Low Concentrations of Wood Preservatives", Z.
Allgem. Mikrobiol., 4_,149
Schwartz, L. and Peck, S.M. (1943), "Occupational Acne", N.Y. State J.
Med., 43,1711
Shakhnovskaya, F.B. (1953), Toxicology of Chlorinated Naphthalenes",
Farmakol. i Toksikol., 16,43
Shelly, W.B". and .Kligman, A.M. (1957), "The Experimental Production of
Acne by Penta- and Hexachloronaphthalenes", Arch. Derm. 75,689
Stalling, D.L. and Huckins, J.N. (1973), "Reverse Phase Thin Layer
Chromatography of Some Aroclors, Halowaxes, and Pesticides", J.
Ass. Off. Anal. Chem., 56,367
Strauss, N. (1944), "Hepato-toxic Effects Following Occupational
Exposure to Halowax (Chlorinated Hydrocarbons)", Rev. Gastroenterol.
11,381 •
37
-------
Vos, J.G., Koeman, J.H., Van der Maas, H.L., Ten IJower, de Brauw, M.C.,
and DeVos, R.H. (1970), "Identification and Toxicological Evaluation
of Chlorinated Dibenzofuran and Chlorinated Naphthalene in Two
Commercial Polychlorinated Biphenyls", Food Cosmet. Toxicol.,
8,625 ,
Wagstaff, D.J. (1971), "Detoxification of Lead Acetate and Other Trace
Substance", in Trace Substances in Environmental Health-V, Proceedings
of U. of Missouri Conference (D. D. Hemphill, ed.) p 363
Walker, N. and Wiltshire, G.H. (1955), "Decomposition of 1-Chloro- and
IrBromonaphthalene by Soil Bacteria", J. Gen. Microbiol., 12,478
Weil, C.S. and Goldberg, M.'E. (1962), "Toxicological and Pharmacological
Criteria of Repeated Doses of a Hepatotoxic Agent", Act. Pharmacol.
Toxicol., _19,129
38
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X
SILICONES
(SILOXANES)
I. Physical Properties
Silicones, or more chemically proper — siloxanes, are compounds which
contain a repeating silicon-oxygen backbone with organic groups attached
to the silicon atoms. This inorganic Si - 0 - backbone provides some
extremely unusual physical characteristics to these semiorganic compounds.
R R
~ I I "
- Si - 0 - Si - 0
-I I -
R R
In general, these physical properties can be characterized as high thermal
and oxidative stability and inertness, low surface tension, low polarity
(hydrophobicity), low viscosity for given molecular weight, high compressi-
bility, high permeability to small molecules, and low surface energy (good
release characteristics). In addition, the properties of silicones change
;
less on going to either high or low temperatures than do those of most
other materials. (Nolls, 1968; Meals, 1969; Lichtenwalner and Sprung, 1970;
Hyde, 1965).
The following discussion will be divided into three sections: silicons
fluids, silicone rubbers, and silicone resins. Commercially, these are
quite separate categories. The physical properties of all the commercial
products are quite dependent upon the R-group substitution. This will be
further discussed under each section.
39
-------
A. Silicone Fluids
The bulk of the technical silicone oils consists of dimethyIsilicone
oils with methylphenyIsilicone oils being next most important. These
compounds remain in the liquid phase over, an unusually large range of
molecular weights [MW = 162 (hexamethyldisiloxane) to MW s 500,000]
and provide a wide range of viscosities (0.65 to about 1,000,000 cSt.)
(see Table I).
Table I
Physical Properties of Some Technical
Methylsilicone and MethylphenyIsilicone Oils (Noll, 1968);
reprinted by permission.
Copyright 1968, Acadenic Press.
(cSl)
Pour point Flash point Flame point
a?
" Boiling point is I05"C/I torr.
6 Boiling point is I35"C/I torr.
'« Boiling point is I75"C/1 torr.
J Boiling point is 220°C/1 torr.
«2D°
Methylsilicone Oils
60
140
440
680
1,440
10,000
50,000
100,000
300,000
<
<
<
<
<
<
<
<
<
-60
-50
-50
-50
-50
-50
-50
-50
-40
>300
>315
>315
>315
>320
>320
>320
>350
>350
>350
>380
>380
>380
>390
>390
>390
>400
>400
0.96
0.97
0.97
0.97
0.97
0,97
0.97
0.97
0.97
.4041
.4045
.4053
.4053
.4053
.4058
.4058
.4058
.4058
Mcthylphcnylsiliconc Oils
200
1000
300
1000
~
~
~
*N«
-65
-55
-40
-30
Low Phcnyl
>300
>315
High Phcnyl
>300
>305
Content
>360
>360
Content
>360
>360
1.03
.465
1.04 1.475
1.06
.505
1.09 1.515
Branched Mcthylphcnylsiliconc Oils
5
10
25
75
*N/
f^J
~
~
-102"
-70*
-78r
-62'
130
145
170
210
160
175
200
260
0.92 1.436
0.98 1
.493
0.99 1.457
1.01 1
.469
40
-------
The low variation of the viscosity of methylsilir.one oils with
temperature is one of their most striking properties (see Figure 1)
As the methyl groups are replaced by other aliphatic or aromatic
groups, the temperature dependence of the viscosity increases.
10.000.000
1,000,000
100,000
10.000
1.000
I
I
• 100
a
I
10
100.000 cSt Me2SiO
10,000 cSt Me2SiO
1000 cSt Me2SiO
100 cSt Me2SiO _
Versilube F-50
•SAE-10W Petroleum oil
MIL.-L-7808 Diester
5 cSt Me2SiO
I I 1 I I I I
-100 o 100 200 300
Temperature, *F
400 500 600 700
Figure 1
Viscosity-Temperature Curves for
Various Silicones (Meals, 1969);
reprinted by permission.
Copyright 1969, J. Wiley and Sons
Me thyIsilicone and phenylmethylsilicone are soluble in a large
number of different solvents. Good solvents include hydrocarbons,
chlorinated hydrocarbons, ethers, esters, and alcohols containing
four carbons or more. The solubility depends to some extent on
viscosity, molecular weight, and constitution (Nolls, 1968).
41
-------
Only the lowest members of the linear siloxane oils are distill-
able, although some branched low molecular weight polymers are used
i
as diffusion pump oils because of their steep vapor pressure-tempera-
ture curves. Table II presents some vapor pressure measurements for
the less volatile fluids.
Table II
Vapor Pressure of Silicone Fluids
(Nolls, 1968)
cSt (20°C) Vapor Pressure (mmHg)
140 (dimethyl) <10~ ( 140°C); 1 x 10~ (170°C); 8 x 10* (200°C)
200 - 1000 (methylphenyl) 10" (20°C); 10" (100°C); 10" (150°C)
30,000 (methyl) 5 x 10" (100°C); 3 x 10" (220°C)
The surface tension of liquid silicones is surprisingly low. For
the linear siloxanes it rises from 15.7 dynes/cm for hex.amethyldisiloxane
to about 20 dynes/cm and then remains constant as the viscosity increases.
The surface tension increases as the content of phenyl groups increases.
The dielectric properties are characterized as good in terms of
dielectric constant, loss factor, specific resistance and dielectric
strength and vary only slightly with temperature.
The lubricating properties of silicone oils are generally poor.
The load-bearing properties of the methyl siloxane films are low
because of the weak intermolecular forces. Improved lubricating
properties are obtained by incorporation of phenyl groups (especially
42
-------
substituted phenyl groups, e.g. chldrophenyl) and long chain alkyl
groups.
B. Silicone Rubbers
The type of substitution of the silicone atom is not the only
determinant in silicone rubber properties; other parameters include
the processing technique and the method and type of vulcanization.
However, in general, the silicone rubbers can be characterized as
having high heat resistance (to dry air), low-temperature flexibility,
resistance to ozone and weather, superior mechanical properties at
high or low temperatures, high permeability to gases and liquids,
excellent release properties (even from adhesive materials such as
tar, rubber mixtures, resin, and asphalt), and good electrical proper-
ties, especially at elevated temperatures.
^C. Silicone Resins
The properties of silicone resins make these polymers important
to both the paint and electrical industries. In the paint industry
the mechanical properties of hardness, elasticity and thermoplasticity
(heat resistance) are most important. The film hardness of the pure
silicone resins is generally too low and fhe thermoplasticity too
high for the paint industry. Therefore, cocondensations of silicones
and polyesters are preferred. Silicone resins also exhibit high
weather resistance.
43
-------
The electrical industry uses silicone resins because of their
heat resistance and good electrical properties in terms of loss
factor, dielectric constant, and specific resistance.
44
-------
II. Production
In the United States there are four major producers of silicones:
Dow Corning Corporation, General Electric Company, Stauffer Chemical
i
Company and Union Carbide Corporation. Dow Corning, the largest producer
(approximately % of total production), manufactures silicone fluids, resins,
and elastomers at Midland, Michigan and has a dimethyl silicones plant
at Carrollton, Kentucky. Silicone products are also produced at Elizabethtown,
Kentucky (silicone sealants), Hemlock, Michigan (medical grade silicones)
and Trumbull, Connecticut (rubber compounds). The Silicone Products
Department of GE makes silicone fluids, resins and elastomers at Waterford,
New York and silicone resin based products at Coshocton, Ohio. The
Silicones Division of Union Carbide produces silicone fluids, resins and
elastomers at Sistersville, West Virginia. The Silicone Division of
Stauffer, the smallest producer (approximately 5% of the market), produces
silicone fluids and elastomers at Adrian, Michigan and elastomers at Matawan,
New Jersey. (Lewis, 1967).
Details on plant capacities are not available and total production
figures lack precision due to the fact that many manufacturers fail to
differentiate between finished products, which contain water or solvent,
and 100% silicone material. An estimate for 1965 placed the total produc-
tion of silicones (fluids and silicone content of resins and elastomers)
10
at about 1.13 x 10 gms (25 million Ibs) (Anon., 1965). Table III
provides production levels for silicone resins and elastomers which
were published..by the U.S. Tariff Commission (1951-1971). It is unclear
45
-------
Table III
Production of Sillcone Resins and Elastomers
(U.S. Tariff Commission 1951-1971)
1951
1952
1953
1954
1955
1956
1957
1958
1959
.1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
Resins
9
(10 g/yr)
0.59
0.77
1.18
0.86 '
1.36
1.59
1.54
1.41
2.27
2.31
3.54
3.86
4.49
4.99
6
(10 Ib/yr)
1.3
1.7
2.6
1.9
3.0
3.5
3.4
3.1
5.0
5.1
7.8
8.5
9.9
11.0
Elastomers
4.08
9.0
(10 g/yr)
1.00
7.62
16.8
2.36
2.22
2.59
3.04
3.72
3.76
4.94
6.03
4.31
4.17
6.12
5.58
7.53
(10 Ib/yr)
2.2
5.2
4.9
5.7
6.7
8.2
8.3
10.9
13.3
9-5
9.2
13.5
12.3
16.6
46
-------
how these reported figures relate to 100% silicone material (e.g. silicone-
alkyd resins contain as little as 15JJ!' silicones). Union Carbide (Bailey,
1973) has suggested that the total market (including water in silicone
9
emulsions and solvents in resin solutions) is approximately 91 - 136 x 10 g
(200 - 300 million Ibs,). The Dow Corning Corporation (1973) has estimated
9
the U.S. market for 1973 to be approximately 41.3 x 10 g (.91 million Ibs.)
consisting of the product categories depicted in Table IV.
47
-------
Table IV
Estimated Silicone Usage in U.S. Market - 1973
(Dow Corning Corporation, 1973)
9 6
10 g 10 Ibs % of total
Methyl Siloxanes (fluids (~50% of total),
compounds, rubber,
sealants)
Dimethyl siloxanes 13.61 30 33
Methyl and small quantities of
phenyl, vinyl, chlorophenyl, etc. 13.61 30 33
Silicone Glycols (used with polyurethanes) 8.16 18 20
Chemicals 1.36 3 3
Miscellaneous (resins, resin intermediates
fluorosili cones) 4.54 10 . j.1
Total 41.28 91 100
^Represents silicone content except for silicone glycols. Approximately
30% of the silicone glycol figure represents siloxane compound.
48
-------
III. Uses
Silicone fluids, rubbers and resins are used in an incredible number
of diverse applications in industrial processing and products, consumer
products, and biomedical uses (Thimineur, 1972; Ames, 1958).
The fluids have the most commercial uses with dimethyl and phenylmethyl
fluids being the most important. It has been estimated that 45% of the
total silicone production goes into silicone fluids, 30% into rubbers,
and 10% into resins, with the remainder probably made up of silicone
coupling agents (Lewis, 1967)
A. Silicone Fluids
Although the major technical interest in silicons fluids is due
to their thermal stability, electrical properties and viscosity/temper-
ature characteristics, the commercial utilizations have been based on
their water-repellency, low surface tension, and release properties.
This is undoubtedly due to the high cost of silicones which disallows
their use in bulk quantities (the former properties) except in unusual
circumstances. The commercial utilization of the surface properties
of silicones is discussed in the following paragraphs.
1. Waxes and Polishes
Most furniture, car and gloss waxes and polishes contain
silicone fluids. They reduce the.work required to spread the
polish and they improve the gloss. The silicone content in most
polishes varies from 2 - 5%, while pastes contain somewhat higher
silicone content.
49
-------
2. Cosmetics
The physiological inertness, lubricative properties and water
\
repellent properties of silicone fluids have allowed their use in
cosmetic preparations. These uses have included hand creams and
lotions, hair sprays, preshave lotions, after-shave lotions, shaving
creams, suntan preparations, lipsticks, toothpastes, and deodorants.
3. Urethane Foams
A major use for silicone fluids is in a silicone-polyether
copolymer fluid (silicone glycols) for use in one shot polyurethane
foam, where they act to give control of pore size and to guide
toward closed- or open-cell types of foam. Other uses' for the
copolymer fluids include additives in cosmetics and paints and
use as release agents (Thimineur, 1972). Dow Corning Corporation
(1973) has estimated the 1973 U.S. market of silicone glycols at
8.16 x 10 g (18 million Ibs.).
4. Silicone Greases
By combining grinding fillers and other materials with silicone
fluids, silicone greases are made. These are generally employed
where high temperatures would destroy petroleum or vegetable oil.
5. Silicone Emulsions
Silicone fluids formulated into emulsions are used in a large
number of industries as abherents (release agents) and as antifoam
agents. The emulsions are sprayed on molds in very small quantities
50
-------
to allow the release of shaped material in such industries as the
metal processing industry (die casting and shell-molding), food
industry, rubber processing industry, paper coating and pressure-
sensitive tapes industry (Bey, 1972), and the glass industry
(Kovach, 1963).
Silicone emulsions used as antifoaming agents can be used in
remarkably small amounts (0.0001 to 0.02% of material to be de-
foamed) . They find use in a wide variety of processing applica-
tions including petroleum refining, coatings, textile finishing,
latex processing, food processing, and many more (Thimineur,
1972). r-u
Silicone emulsions are also used in sizable quantities to
impart stain and water repellency to textile products, especially
wash and wear items. In addition, the textile industry uses the
emulsions as fiber and thread lubricants, softeners with durable
press resins and latex coatings, and as a low concentration addi-
tive in textile coatings to eliminate tack and blocking (Blumenstein,
1968).
6. Other
Besides being used in cosmetic preparations, silicones are
also used in such household and consumer products as aerosol
starch, domestic oven treatment, textile and leather treatments,
treatment for ignition systems, rubber lubricants, artificial
snow, and ironing aids.
51
-------
Although the dimethyl and methylphenyl silicones do not provide
good lubricity properties, addition of long chain alkyl groups
or halogenated phenyl groups to the siloxane polymer chain imparts
very good lubricating properties and, therefore, small amounts of
these compounds find use as lubricants.
Other miscellaneous applications include defoaming agents in
pesticide formulations; damping of dashpots, aircraft instruments,
gyros, and meters; use in torsional vibration damping devices;
use as dielectric fluids in transformers and capacitors; and use
as baths in the treatment of burns,.lubricants for artificial eyes,
use for gastric disorders, and use for storage of antibiotics.
7. New Applications
Considerable study of dimethyl silicone fluids as brake fluids
in automobiles has been undertaken. In addition, the possibility
of using fluids as an antitranspirant for plants to reduce the
lost of water in dry areas is being considered. In general, it
5
\
is anticipated that silicone fluids will be replacing other
chemicals in uses that provide human exposure or release to the
environment when the-physical properties of the silicones are
appropriate. The major reason anticipated for this shift is
the relatively low toxicity of the dimethyIpoiysiloxanes.
B. Silicone Rubbers (Elastomers)
Siloxane rubbers can be divided into two categories: (1) heat
vulcanized and (2) room temperature vulcanized (RTV). In 1967 the
52
-------
heat vulcanized rubber comprised by far the largest part of the market
(Lewis, 1967). Both these types of rubbers find application because
of their outstanding resistance to both high and low temperatures.
Their electrical uses include applications in insulation of wire and
cable, coating of glass cloth, or other fabric for insulation, spark-
plug boots, insulation for ignition harness in automobiles, and
potting, encapsulating, and embedding electrical and elctronic devices,
circuits or systems. Other uses include 0-rings, gaskets, and aero-
dynamic seals (e.g., seals for aircraft doors) and molds for casting
epoxy coatings of transistors (RTV). In the construction industry
the RTV rubbers are used to seal spaces between masonry, and between
masonry and windows, as well as to surface roofs and to seal glass
into window-wall construction. In the biomedical field rubber parts
are used for surgical tubing, for heart valves, for prosthetic parts
and contact lenses and RTV rubber is used to encase "pacemakers" for
heart patients. Silicone rubbers have a decided advantage for medical
uses over other materials because they seldom contain materials such
as plasticizers which may be leached out. RTV rubber is also used in
adhesive and sealant consumer products (e.g., caulking around bathtubs
and repairing dishes or plastic parts). Dow Corning also makes small
quantities of fluorosilicone rubber to be employed where resistance
to fuels, oils, and solvents is important. The silicone rubber market
estimates for 1964 are presented in Table V.
53
-------
Table V
Si11cone Rubber Usage by Market: 1964
(Lewis, 1967)
Marke t Percentage
Aircraft and missile 39%
Electronics 18
Electrical 14
Appliances 12
Automotive 6
Government (direct) 6
Miscellaneous 5
100%
C. Si11cone Resins
Silicone resins are particularly valuable to the electrical
industry because of their high temperature resistance. The earliest
use of silicone resins was for coatings in motors, generators, and
transformers. They are' also used to coat or impregnate glass cloth,
mica paper, asbestos paper, and similar materials for electrical
insulation.
Silicone resins also find applications in paints, water repellents,
and release coatings. In paints they are usually blended with other
resins (e.g., alkyd resins) to impart improved weather durability,
heat resistance, and gloss retention (Hedlund, 1959). However, the
increased cost has limited consumer use. In 1962 approximately one
million pounds of silicone resins were reportedly used to treat masonry
54
-------
walls and highways to make them water repellent (Lewis, 1967). Another
use for silicone resins is to treat paper to be used for covering
adhesive surfaces such as "contact paper", adhesive tapes, and
photographic film, and for packaging sticky foodstuffs. Table VI
shows a market breakdown for silicone resins in 1962.
Table VI
Consumption of Silicone Resins (1962)
(Lewis, 1967)
Use Percentage of the Market
Electrical Insulation
Coating and bonding 31.3%
Impregnating 12.5
Laminating 12.5
Paint 18.7
Water Repellents 12.5
Release Coatings 9.4
Molding 3.1
100.0
55
-------
IV. Current Practice
Since silicones are quite stable at ambient temperatures and relatively
physiologically inert, they present little problem during transport and
handling. Most shipments are sent in 55 gal. drums, although some tank
car shipments are used for intercompany transport or for large consumers.
In most cases no special DOT label is required and when it is, it is
usually due to the solvent used.
Correspondence with some of the manufacturers suggests that waste
I
materials are either incinerated or landfilled. Water effluents are
clarified and settled before release.
56
-------
V. Environmental Contamination
No published information is available on environmental contamination
from the use, production or disposal of silicones. Several of the known
uses of silicohe would suggest that they are released into the environ-
ment; for example, defoamers in water systems and pesticides, and car
polishes. The proposed use of dimethyIpolysiloxanes as plant anti-
transpirants would also indicate a high potential for environmental
exposure.
Contamination from silicone production is being studied now by
A.D. Little, Inc. under an EPA contract. The final report is scheduled
for the middle of November, 1973. Union Carbide (Bailey, 1973) has stated
that occasionally a small oil slick is observed in the water effluents
from its Sistersville plant, but that the problem has been largely
eliminated by water clarifiers and settlers. They suggest that the only
significant source of silicones in the environment is from landfilling
solid silicone residues and sludges.
57
-------
VI. Monitoring and Analysis
Although analytical methods for monitoring environmental samples of
silicones have not been reported in the surveyed literature, a number of
methods have been developed for detecting silicones in the ppm range in
food and beverage samples. This is undoubtedly due to the recommended
limit of 10 ppm in foodstuffs.
Homer, et al. (1960) reported both a specific and non-specific method
for detecting trace ampunts of silicones in foods and biological material.
The nonspecific method consisted of a colorimetric silica analysis of
silicones in foods digested with fuming sulfuric and nitric acids.
Jankowiak and LeVier (1971) later modified this procedure in order to
eliminate phosphorus interferences. This method is best applicable to
samples which contain negligible amounts of residual silica. The high
level of silicon occurrences in nature precludes the use of such nonspecific
methods for detecting silicones. The specific method used was a selective
extraction of silicone with infrared quantification (7.95 y band). The
method was utilized in the 2 to 20 ppm range in pineapple juice. Sinclair
and Hallam (1971) have used a similar technique to determine dimethyIpoly-
siloxane in the 0.2 to 2.00 ppm range in beer and yeast. A low tempera-
ture specific extraction of siloxanes from fatty foods with quantification
by atomic absorption (nonspecific but more sensitive than IR) or UV spectro-
metry has been reported by Neal, et. al. (1969).
The Dow Corning Corporation (1973) has reported that it uses an
extraction procedure to determine low levels of silicones in soil and
58
-------
water. The preferred solvent is methyl isobutyl ketbne (MEBK) which can
be used directly for the atoinic absorption quantification of silicon.
Preliminary investigations show this method to be sensitive at the ppb
range for water samples. No actual monitoring data is available yet.
59
-------
VII. Chemical Reactivity
* i
The commercial polysiloxanes are chemically quite stable and inert at
ambient temperatures and neutral conditions. The SiO bond is about 50%
ionic, with silicon the positive-member (Meals, 1969), and this causes
siloxanes to be quite susceptible to heterolytic cleavage, ie., to attack
i .-
by acids or basis. However, at neutral pH hardly any hydrolysis takes
place. Fox e_t _al., (1950) have suggested that "appreciable" hydrolysis
may take place when a large interface exists between water and silicone.
The relative rate of such a process is unknown. The siloxanes are also
stable at normal temperatures to air, oxygen, metals, wood, paper, plastics,
and also to solutions of metal salts, liquid ammonia, and 3% hydrogen
peroxide. They will react, especially at elevated temperatures, with
strong mineral acids, particularly hydrofluoric acid, alkalis, and strong
oxidizing agents such as concentrated nitric acid or elementary chlorine
(Nolls, 1968).
Exposure of silicone polymers to light has a tendency to cause cross
linking of the polymer. For example, Delmar ejt al., (1969) found that
exposure of a methylsiloxane resin to a xenon arc lamp (>28l my) resulted
in an increase of Si-CF^Si linkages.
Several authors have reported studies on the thermal and oxidative
•
stability of silicones. Scala and Hickam (1958) found that phenyl substi-
tuted silicones offer greater resistance to degradation than the methy1-
60
-------
and vinyl-substituted silicones and noted that DC 200 (dimethylpolysiloxane)
gelled to a solid, state in 3 hours at 250°C. Thomas and Kendrlck (1970)
in a thermalgravimetric investigation in vacuum concluded that the activa-
tion energy of depolymerization is mainly a function of the inductive effect
of the substituent group (withdrawing groups increase the activation energy).
No correlation between these chemical reactions and biological processes
has been drawn. However, in actual fact, their chemical inertness is
similar to their apparent biological inactivity.
61
-------
VIII. Biology
A. Absorption
As a rule, long chain polymers are less likely to be absorbed
through the skin than the component monomers (Bischoff, 1972).
Although there is insufficient experimental evidence for absolute
conclusions, silicones seem to cross membranous surfaces only with
difficulty and do not seem to be readily absorbed through skin
surfaces (Hine et al., 1969). This may in part account for the
inability of hexamethyldisiloxane to irritate rabbit skin even
. though the same compound does produce irritation when applied
subcutaneously (Rowe et_ al., 1948). Similarly, Bennett (1973)
indicates that polydimethylsiloxane fluids of six polymer units
or less are absorbed orally but higher molecular weight compounds
are not. Other routes of entry will be discussed in the appropriate
areas under toxicity studies.
8. Excretion
Silicones injected spinally are not excreted in the feces or
the urine (Hine et al., 1969). Excretion data was not given in
other experiments screened. However, the laxative effect noted with
oral administration would lead one to suspect that the silicones
are eliminated in the feces (Rowe et al., 1948). Also, in that
C labeled dimethylpolysiloxane was found to be present but not
accumulated In Bluegill Sunfish after a 30 day exposure period to
62
-------
1 and 10 mg/1 (Hobbs, 1973), an excretory mechanism can be postulated.
This is consistent with the excretion of lower molecular weight
dimethylpolysiloxanes noted by Bennett (1973).
C. Transport and Distribution
The distribution of silicones in the body and the transport
mechanisms involved in distribution are highly dependent upon the
route of administration. Intraperitoneal injection results in high
silicone concentrations in the liver, gastrointestinal tract, and
fatty tissue (Hine e£ al., 1969). After intraperitoneal injection,
the extent of fatty tissue distribution is likely to be dependent
on the partition coefficients of the silicone polymeric species
present (Bennett, 1973).. In contrast to the intraperitoneal route,
intracisternal injection results in high concentrations in the
brain and vertebral column [see Tables VII and VIIl]•
63
-------
Table VII
Distribution of 1(*OLabeled Silicone in Rat Tissues
25 Days after Intraperitoneal Injection of 15 yCi per Rat
(Hine £t al., 1969)
Rat number
Tissue
Fat
Heart
Kidney
Liver
Lung
Muscle
Skin
Brain
Spleen
Testes
Whole blood
Gastrointestinal
1
^M
0.00
"••
0.08
1.50
0.08
0.03
2.80
0.00
—
2
59.00
0.00
0.74
16.1
0.05
0.82
0.10
—
0.17
1.70
0.00
16.80
111 «A
3 ac
43.00
0.00
0.51
13.5
0.08
0.79
0.097
0.05
0.30
0.12
0.00
37.70
rerage percent
:tivity/organ
51.00
0.00
0.63
14.80
0.07
0.10 * ,
0.09
0.04
1.56
0.98
0.00
27.25
Percent activity based on total counts received.
Table VIII
Distribution of1IfC-Labeled Silicone in Rat Tissues
45 Days after Intracisternal Injection of 6 yCi per Rat
(Hine et al., 1969)
Rat number
Tissue
Average percent
activity/organ
Fat
Brain
Vertebral column
Spinal cord
Spleen
Lungs
Liver
Gastrointestinal
tract
Whole blood
5.0
38.9
33.9
8.5
0.09
0.36
1.78
0.0
0.0
6.1
43.4
32.0
12.6
0.58
0.04
2.96
0.0
0.0
10.0
40.0
27.9
6.5
0.0
0.06
0.0
0.0
0.0
10.3
42.0
32.0
12.0
0.16
0.20
0.0
0.0
0.0
7.9
41.1
31.4
9.9
0.21
0.16
1.19
0.0
0.0
Average of 4 animals.
64
-------
This type of route dependent distribution does not necessarily
reflect passive transport mechanisms. When dimethylpolysiloxanes
(350 and 1000 cSt.) are injected intra-articularly - i.e. into the
knee joint of the male rabbit - the silicone fluid is gradually
removed. However, the rate of loss does not vary with the degree
of joint immobilization, thus suggesting an active distribution
mechanism (Donahue, et^ ail., 1971). Artificially induced blood
transport has been examined by I.V. injections but to what extent
this mechanism is used naturally is not clear (Reed and Kittle, 1959).
The commonly noticed distribution of silicones in the kidney and liver
might be explained in terms of filtration of silicones from the blood
but further experimentation is necessary (Nosanchuck, 1968; Cutting,
1952). Because of the general impermiability of membrane systems to
siloxanes, phagocytosis by wandering cells may also be a prime method
of transport (Hine et al., 1969; Bennett, 1973).
65
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IX. Environmental Transport and Fate
A. Persistence and/or Degradation
Under environmental conditions silicones are chemically quite stable
(reaistent to hydrolysis and oxidation) (see section on Chemical Reacti-
vity) . The same appears to be true for biological stability. Olson
et al», (1962) reported that coating of cotton with silicone fluids
made the textile more resistant to biodeterioration. Similar results
were obtained by. Hueck (1960) with silicone coated plastics and by
Glazer (1954) with varnish compositions containing polydimethylsiloxanes.
On the other hand, Zharikova et al., (1971) found that soil bacteria
caused deterioration of organosilicon resin coatings and Inove (1973)
found that molds were grown on silicone resins. Greathouse et al., (1951)
and Caldron and Staffeldt (1965) reported that resins and rubbers made
from the fluids were resistant to biodeterioration by a variety of
soil microorganisms; although the latter observed that soil fungi
were able to colonize on the rubber. Similarly, Ross (1963) found
that silicone rubber-potted firing modules were very susceptible to
fungus growth. In contrast, Muraoka (1966) noted that silicone rubber
was resistant to deep sea microorganisms. The confusion in the results
•
may be due to a lack of distinction between providing a surface for
microbial growth and providing a nutrient source for the microbes.
Dow Corning has evaluated the effect of polydimethylsiloxane fluids
of varying viscosities on the growth of bacterial species. The fluids
66
-------
were non-toxic, but the organisms could not grow without an exogenous
nutrient. Examination of the fluids (20 cSt and 100 cSt) showed no
alteration in the molecular distribution of the fluid components
following the growth of organism (E. coli and S. aureus) (Bennett, 1973).
Both Union Carbide and Dow Corning have run biodegradability tests
on silicone fluids. Union Carbide (Waggy, 1971) determined the stability
of a silicone fluid (50 cSt) (330 ppm) and a silicone glycol fluid
(660 ppm - 1000 ppm) (used for foaming polyurethane) with a Warburg
respirometer system and dilution bottle BOD procedure (silicone glyconol
only). These compounds were found to be completely nonbiodegradable.
Dow Corning (1973) ran a 70 day aerobic biodegradability test on
Ik
C labelled dimethyIpolysiloxane exposed to sewage microorganisms.
No biodegradability was noted under the experimental conditions.
B. Environmental Transport
Little information is known about the transport of silicones through
the environment mainly because of the lack of monitoring data. Dow
Corning (1973) has conducted some preliminary studies on leaching
properties in soil. With damp soil they have concluded that silicones
_5 _6.
are fairly mobile. The vapor pressure of silicone fluids (10 -10 mmHg)
-k _6 _5 _7
is similar to PCB's (10 -10 mmHg) and DDT's (10 -10 mmHg), and,
therefore, atmospheric transport may be an important environmental
route.
67
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C. Bioaccumulation
Although bioaccumulation studies of silicones in low trophic levels
of the food chain have not been reported, some study with fish has been
undertaken by Dow Corning (Hobbs, 1973). Bluegill sunfish were exposed
1»*
to C labelled polydimethyIsiloxane for 30 days at 1 and 10 ppm. No
evidence of accumulation was observed and the tissue storage in these
fish was minimal.
68
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X. Sllicone Toxicity
A. Human Toxicity
1. Occupational Exposure:
Although certain chemical intermediates and silane monomers
used in the preparation of silicone polymers do have considerable
toxic potential, silicone polymers themselves are not reported to
represent an occupational hazard (Hobbs, 1973; Bailey, 1973;
Taylor, 1950). Absolutely no concrete data or observations were
found in the literature surveyed to contradict or in any way
dispute these reports.
2. Liquid Injection of.Silicones:
Liquid silicones have been injected into the human body for
various medical procedures, most involving some form of cosmetic
therapy of which mammap-lasty has stimulated the most controversy.
Mammaplasty, the enlargement of the female breast by the injection
of a fluid, has been accomplished most often using dimethyl-
polysiloxanes (viscosity of 350 cSt.) or a combination of this
silicone with various organic fluids (Bischoff, 1972). In the
late 1960's, various and often severe adverse reactions from
this procedure were noted, ranging from mastitis to loss of the
treated glands (Chaplin, 1969; Symmers, 1968). Although similar
but less severe complications had been noted before this time,
the primary cause was often attributed to the various additives
rather than the silicone itself, with manufacturer*s investigations
69
-------
showing no severe response to the purified silicone (Berger, 1966).
This conclusion would seem within reason; In a case sighted in
which both breasts were lost, an acute allergic response was
noted (Chaplin, 1969), whereas the purified silicone has not
been shown to produce an allergic response at least in rats
(Nosanchuk, 1968). Even now that silicone mammaplasty has been
prohibited in the United States, the culpability cannot be
placed clearly (Bischoff, 1972).
3. Toleration by the Human Eye:
DC 360 Medical Fluid (2000 cSt.) has been injected into the
eye as therapy for retinal detachments. This condition involves
separation of the retina from the choroid membrane. Although
this type of therapy has evolved no clear cases of adverse effect,
a growing concern over possible long term damage has stimulated
detailed investigations on non-human mammal systems and some
controversy (Lee ert al., 1969; Mukai
-------
by molecular oxygen. This mechanism has been proposed to account
for the up to 15% increase in weight found in some defective
valves (Carmen and Mutha, 1972). While this may serve as a
satisfactory explanation for some cases of valve failure, it does
»
not seem to account for all the clinical data. In a study by
Roberts and Morrow (1968), 11 of 12 patients died after a post-
operation period of two years or more. Of these, only five
showed swollen valves. Six had silicone ball atrophy. Although
no detailed data on valve weights are given, it seems unlikely
that all of these cases could be accounted for in terms of lipid
absorption. Recently, it has been reported that improved curing
methods may overcome this problem (Anonymous, 1973).
The main significance of these findings is to indicate that sili-
cone polymers may not be as unreactive in biological systems
as once assumed (Bischoff, 1972).
5. Adverse Responses to Other Medical Silicones:
Similar reactions of other types of prosthetic devices were
not reviewed for this preliminary survey. However, to underscore
the human applications of silicones, some of the further uses and
reactions cited by Bischoff (1972) are briefly summarized.
Adverse responses have been noted in structural support devices
of silicone applied to the human ear. Silicone lubricants in
joints have shown no toxic reactions but do not appear to be of
any benefit. Further, silicone antifearning agents are reported
to ca\ise emboli in the capillaries of the heart, brain, and kidney,
after intravenous injection. \
71
-------
6. Hunan.Ingestion:
Silicones are not uncommon in the food industry both as
additives and packaging materials and may reach the consumer in
dietary doses of up to 10 ppm in most foods and up to 16 ppm
in gelatin desserts (F.D.A., 1972). To date, however, no
adverse effects of dietary consumption in the general population
has been encountered in the literature. However, Bischoff (1972)
references an article noting that hospital patients ingesting
routine dietary silicones showed a decrease in the effectiveness
of anticoagulation drugs. Other cases of drug interference or
synergism have not been encountered and the relevence of this
isolated occurrence .is difficult to assess.
B. Toxicity to Birds and Non-human Mammals
1. Acute and Subacute Toxicity:
Adopting an entirely arbitrary distinction implied in the
literature, acute and subacute toxicity will be used to specify
toxic manifestations elicited in less than four months (see
MacDonald et al., I960; Child e£ al., 1951). Given this division,
acute and subacute toxicity studies encompass a wide scope of
diverse experiments. Thus, for the sake of clarity rather than
classification, the literature will be discussed by the following
i
routes of administration:
i) Ingestion '
i.i) Injection, I.M., I.V., Sub Cu., Intra-articular
iii). Intravitreal Injection
iv) Inhalation.and Dermal Absorption
72
-------
i) The "acute" feeding experiments generally indicate a low
degree of silicone toxicity. D.C. 200 fluids have been
examined for both single and multiple dose toxicity. By
single administration to rats, only absurdly massive doses
gave any toxic response [see Table IX].
Table IX
Mortality and Response Resulting from the Administration
of Silicone Fluids in Single Oral Dose
—Guinea Pigs
(Rowe et al., 1948)
Silicone
DC 200 Fluid (Hexa-
methyldisilpxane)
DC 200 Fluid (Dode-
came thy 1-
pentasiloxane)
DC 200 Fluid
DC 550 Fluid
•
DC 702 Fluid
DC 200 Fluid
DC 200 Fluid
Mineral Oil U.S. P.
Viscosity
in Cstks.
at 25°C
0.65
2.0
50
75
35
350
12,500
Dose
ml. /kg.
3.0
10.0
30.0
50.0
10.0
30.0
50.0
10.0
30.0
50.0
3.0
10.0
30.0
3.0
10.0
30.0
5.0
10.0
30.0
50.0
10.0
30.0
Mortal-
ity
Ratio
0/7
0/7
0/7
1/10
0/3
0/6
3/3
0/2
0/6
0/3
0/3
0/3
0/6
0/3
0/3
0/6
0/2
0/5
0/6
0/3
Observations on the Laxative Effects
at Various Periods of Time after
Administration
2% hrs.
-
-
-
-
4-H-
+++
+
+
_
-
-
-
Could not be
6/2
0/3
-H-
+++
8 hrs.
-
-
+
++
+4+
4-H-
+
.++
++
++
_.
+
+
-
24 hrs.
-
-
—
-
44+
44+
+
+4+
+4+
4++
+
+
+
++
48 hrs.
-
—
—
+
-f-H-
+++
++
_
_
4+
fed satisfactorily
++
+++
+++
+++
+
+
73
-------
The fatalities caused by dodecamethylpentasiloxane and the
central nervous system depression caused by hexamethyldisiloxane
possibly may be attributed at least in part both to physical
aggravation of the alimentary canal by large volumes of a
foreign substance and to trauma caused by dosage administration.
Repeated dosage administration to rats at 1 g - 20 g/kg
body weight x 28 days revealed no toxic effects in growth,
hematology, bone marrow, organ weights, or histopathology
(Rowe et al., 1948). A similar experiment using DC 200
(350 cSt.) on rats and rabbits at lOg/kg feed plus 0.8%
cholesterol x 84-119 days in ad libitum feeding did produce
renal tubular damage in rabbits but not in rats (Cutting,
1952). Negative results for rats were also found with G.E.
Dri-Film No. 9977 - a dimethylsiloxane - at concentrations
up to 20g/kg in feed ad libitum over a 13 week period (Kern
ejt al., 1949). A series of five dimethylpolysiloxanes
(viscosities of 50 - 60,000 cSt.) also were reported to
exhibit no toxic characteristics when fed to rats at con-
centrations of lOg/kg feed ad libitum for 90 days (Mac Donald
£t al., 1960). A similar pattern is seen in studies on
DC Antifoam A. Both Rowe and coworkers (1948) and Cutting
(1952) found this compound to be non-toxic to rats in oral
doses of up to 10 g/kg fed for 90-120 days. Rabbits,
however, showed cellular infiltrations in the liver and
74
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kidney at concentration of 250 mg/kg DC Antifoam A and 0.8%
cholesterol in feed (Cutting, 1952). The histologic damage
in rabbits attributed to siloxanes by Cutting (1952) is
disputed by subsequent investigators. Using an unaltered
basal chow as well as a cholesterol (0.8%) control diet
over an eight months feeding period to rabbits of both
10 g/kg DC 360 (350 cSt.) and 10 g/kg DC Antifoam A with
and without the 0.8% cholesterol supplement, Carson and
coworkers (1966) concluded that cholesterol, rather than
the siloxanes, was the prime cause of tissue damage.
In a very brief summary, Hobbs (1973) indicated that
Mallard Ducklings and Bobwhite Quail showed an LC_n of over
5 g dimethylpolysiloxane/kg feed in 8 days ad libitum feeding.
Hobbs (1973) also indicates that current research is underway
to assess the toxicity of dimethylpolysiloxane on young
chickens.
ii) Injections: I.V., I.M., Subcutaneous, Intraperitoneal,
Intra-articular:
The only reason that these various types of injections
are considered in the same section is that they are non-
controversial and present little difficulty in interpretation.
DC Antifoam A administrered to dogs I.V. into the right
jugular vein had a LD5Q of 0.9 - 1.0 ml/kg body weight.
Death was characteristic of massive obstruction of the
pulmonary artery or branches. In fatal cases, the right
ventricle evidenced extreme distension not noted in surviving
75
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animals. Arterial administration via the carotid artery
gave a much smaller LD5Q of 0.02 ml7kg body weight. Here,
fatal cases showed necrosis due to impeded blood flow to the
brain, and some survivors showed neurologic damage with
limited brain damage as above (Reed and Kittle, 1959).
Intramuscular (I.M.) administration of 1.0 cc of a
dimethylsiloxane (Dri-Film #9977) resulted in slight macrophage
infiltration and limited muscle fiber necrosis in rabbits,
whereas identical subcutaneous dosages showed no response
(Kern et^ a^L., 1949). These results agree well with those
showing that only hexamethyldisiloxane causes appreciable
irritation subcutaneously in rabbits. Intraperitoneal and
intradermal applications of the polysiloxanes indicate
negligible toxic effects (Rowe ejt al., 1948). Dimethyl-
polysiloxane fluid injected into the synqvium of the rabbit
knee produced mild inflammatory response (Donahue et al., 1971).
iii) Intravetreous Injection:
The use of DC 360 Medical Fluid (2000 cSt.) is of
particular interest because current investigators differ
widely on their opinion of its histopathic potential. Lee,
Mukai, and coworkers contend that large numbers of silicone
particles appear in the retina 2-3 hours after injection
r
and cause degenerative lesions. They base these findings
on electron microscopic and histochemical surveys (Mukai et al.,
76
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1972; Lee e£ al., 1969). Labelle and Okum (1972) label the
above microscopic findings as artifacts and report negative
toxicity in their experimental work. Resolution of these
conflicting results should prove critical to an understanding
of both silicone transport in a membrane system and possible
biochemical mechanisms for silicone toxicity.
iv) Toxicity from Inhalation and Dermal Absorption:
Silicones have shown little appreciable toxicity via
these routes. The higher siloxanes have extremely low volatility
and do not cause toxic effects on inhalation. Similarly,
because they are not easily absorbed through the skin,.the
cutaneous toxicity seems negligable (Hecht, 1968).
However, hexamethyldisiloxane is relatively volatile and
in a saturated atmosphere (40,000 ppm) will lead to mortality
in guinea pigs after exposure periods of 15 to 20 minutes.
At lower concentrations or on shorter periods of exposure,
the toxic effects are greatly reduced or disappear (Rowe et al. ,
1948). Thus, this type of toxic response seems to have little
environmental importance.
2. Chronic Toxicity
Chronic toxicity studies have been conducted in long term
feeding of rats and dogs with DC Antifoam A. In both cases, no
toxic signs are manifest. Rats, over a two year feeding period
of 3g*/kg feed (DC Antifoam A) show no pathological signs that can
77
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be clearly associated with silicone adminstration (Rowe e_t al.,
1950). Similarly, dogs show no toxic effects with oral adminis-
tration of up to 3g/kg feed over a six month period (Child et^ al.,
1951). In that the normal usage range of DC Antifoam A is from
10-25 mg/kg, little toxic potential seems indicated.
3. Sensitization
In the only study available, no antigen/antibody-type sensi-
tization could be stimulated in the guinea pig by administration
of dimethylpolysiloxane. Needless to say, this is hardly sufficient
evidence for ruling out the possibility of such a response from
other organisms (Nosanchuk, 1968). However, it seems probable
that if there was an appreciable potential for human sensitization,
it would have already appeared as a problem in industrial hygiene.
Thus far, no such responses are reported (Hobbs, 1973).
4. Teratogenicity
Only one case of silicone induced teratogenicity is available
in the literature surveyed. An equilibrated copolymer
of phenylmethylcyclosiloxanes and dimethylcyclosiloxanes (PMxMMy)
administered at 220mg/kg/day to pregnant rats from the 16th day of
pregnancy caused urogenital malformation in the female - but not
male - pups, accompanied by an inability to control urine flow
(LeFevre et^ al., 1972). In an earlier study, a much more widely
used variety of silicone, DC 200 (viscosity not specified) was
found not to produce teratogenic effects in rats with oral doses
78
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of up to 3.8g/kg/day when administered from the sixth to the
fifteenth day of pregnancy (Barry, 1973).
5. Carcinogenicity
Hueper (1964) using a polydimethysiloxane sheet (200mg,
11 x 8 x 2 mm) implanted subcutaneously in 35 rats induced 10
cancerous tumor formations. These all involved smooth walled
cavity tumors which contained the silicone sheet loosely inside.
Similar results were obtained by Maeda (1971). Although these
results indicate caution in the use of silicone prosthetic
implants in man, the possible environmental correlations seem
limited.
6. Mutagenicity
No detailed study on silicone mutagenicity was encountered.
Hobbs (1973) reports of a study indicating that a dimethylpoly-
siloxane fluid is not mutagenic in albino mice. Drosophila has
recently been the subject of a pilot study of the mutagenic activity
of some organosilicones (Bennett, 1973), but the results have
not been screened for this report.
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7. Behavioral Effects - Reproductive Activity
A recent series of papers has indicated that certain cyclic
siloxanes show a pronounced effect on the sexual physiology of
various non-human mammals. The equilibrated copolymer
phenylmethylcyclosiloxanes and dimethylcyclosiloxanes (PMxMMy)
had been in common use in the cosmetic industry (Olson, 1972).
In rabbits, however, this polymeric mixture was found to produce marked
testicular atrophy and spermatogenic depression both in dermal
and oral administration. Similar effects were noted in oral
but not dermal applications to monkeys (Palazzolo et al., 1972).
LeFevre and coworkers (1972) noted the previously discussed
teratogenic effects of this mixture as well as indicating a
general interruption of the estrous cycle in female rats.
PMxMMy constituents and related cyclosiloxanes were shown to
inhibit reproductive ability in male mice, rats, and rabbits
(Bennett et al.. 1972). This antiandrogenic activity is paralleled
by the estrogenic activity of these, same compounds in the females
of the species (Hayden and Barlow, 1972). The relative activities
s
of the compounds studied are summarized in Table X [from Hayden
& Barlow, 1972].
80
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Table X
Comparative Relative Activities of 32 Organosiloxane Compounds
Based on Effects on the Ovariectomized Immature Female Rat Uterus
Following Oral Administration
[Hayden and Barlow, 1972];
reprinted by permission.
Copyright 1972, Academic press
Relative
Compound activity"
A. Substituted sifoxanes
Disiloxancs
Phcnyl substituted
PhMcjSiOSiMej 0
PhMc2SiOSiMc2H 0
PhMe2SiOSiMe2Ph +2
Ph Vinyl MeSiOSiMcj +1
PhjMcSiOSiMc, 0
(PhCH(CH3)CHj)MejSiOSiMc, +1
Trisiloxanes
Phcnyl substituted
Linear
Me,SiOSiPhOHOSiMe, 0
McjSiOSiPhllOSiMc, +]
McjSiOSiPhjOSiMej +1
Cyclic
[(PhMcSiO)(Me2SiO)2] +2
[(PhMcSiO)2(Me2SiO)J +3
2,4-/ra/«-[(PhMcSiO)2( MejSiO)] +3
2,4-m-[(PhMcSiO)j(Mc2SiO)] 0
c&-[(PhMcSiO)3] +1
«ww-[(PhMcSiO)3] +1
Telrasiloxanes
Cyclic
[(PhMeSiO)(Me2SiO)3] +4
t(o-tolyiMcSiO)(Me2SiO)j] +3
I(HMcSiO)(Me2SiO)3] 0 - +1
[(VinyIMeSiO)(Me2SiO),] 0 - +1
[(«-PrMeSiO)(Me2SiO)3J 0 - +1
[(PhMcSiO).,) +1
[(Me2SiO)4J +J
[(PhMeSiO)2(Mc2SiO)2] (racemic mixture) +4
2,4-m-[(PhMcSJO)2(Me2SiO)j] +1
2,6-/raHj-[(PIiMeSiO)2(Me2SiO)2] +3
2,6-m-[(PhMcSiO)j(Me2SiO)2] ' +4
KPh[ISiO)(Mc2SiO),] +3
t(Ph2SiO)(Mc2SiOh] +1
f(PhOHSiO)(Me2SiO),) +1
B. Miscellaneous
OHMc2SiPhSiMe2OH 0
PhMc[SiCH2CH2SiMcPhO] +3
[(Mc2SiNH)(Mc2SiO),] +1
(Me,SiO),SiPh 0
• Code: 0" No effect; +1 --•• statistically nonsignificant increase <20%;
+2 *= statistically significant increase at 0.05 level of significance; 13 = stati-
stically significant increase at 0.01 level of significance; 14 = increase equal to
or greater than estrogen treated controls.
81
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While presenting a useful tool for. research into hormonal
behavior (LeVier and Jankowiak, 1972), the environmental
\.
significance of these findings is uncertain. The hormonally
active compounds are no longer available commercially. Other poly-
siloxane fluids that are more widely used do not demonstrate
any similar activity (Hobbs et^ al., 1972).
C. Toxicity to Lower Animals
Toxicity studies encountered on non-mammals have concentrated
primarily on various antifoams in an aquatic environment.
Fish seem quite tolerant to relatively high concentrations of
silicone. SAG-10, a dimethylsilicbne oil and silica emulsion, and
SAG-530, a dimethylsilicone-oxyalkylene, both of Union Carbide, have
no toxic effects on the fathead minnow in concentrations up to
2,000 mg/1 over a four day exposure period (Spacie, 1972). Similarly,
1% DC Antifoam C(0.3% DC200), another dimethylsilicone, has no toxic
effects on rainbow trout or bluebill sunfish over the same period
of exposure as above (Barry, 1973).
Daphnia, however, show a much more pronounced toxic response
[See,Table XI from Spacie, 1972],
82
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Table XI
[Spacie, 1972]
Daphnia Mortality (%) in SAG 10 Solutions
Concentration -
Hours
24
48
96
0
0
0
0
Daphnia
1
0
20
30
10
20
20
40
Mortality
100
10
10
40
(%) in
Concentration -
Hours
24
48
96
0
0
0
10
1
0
0
0
10
0
0
10
100
0
0
10
mg/1
500
40
40
50
SAG 530
mg/1
500
10
10
20
1,000
30
50
100
Solutions
1,000
10
30
80
2,000
60
100
100
2,000
40
60
100
The 96 hour LC5Q of 500 mg/1 SAG-10 and 500-1,000 mg/1 SAG-530 might
seem to indicate that these compounds are relatively non-toxic.
However, LC-^s are,not absolute indicators of toxicity. Note that
after 96 hours a 30% Daphnia mortality is achieved at 1 mg/1 SAG-10,
approximately 1 ppm. Needless to say, a 30% mortality of this
important food source in aquatic systems would create considerable
environmental stress. Thus, while this experiment was meant only as a
preliminary evaluation and not as a definitive study, Spacie1s conclusion
that further studies are not required because of the high LC s is
questionable. Detailed investigations on Daphnia and other
environmentally critical invertebrates in aquabiotic systems seem
mandatory. . Dow Corning has a preliminary study on Daphnia underway
(Hobbs, 1973).
83
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No further toxicity studies were found. Unspecified silicones
at 0.1 - 2.0% diet are reportedly fed to silkworms to increase
body and cocoon weights, but no adverse effects are given (Hashimoto
et al., 1972).
D. Plant Toxicity
Parkinson (1970) has applied dimethylpolysiloxanes (1,000 and
12,500 cSt.) to leaf surfaces of short grass, certain farm crops
and trees as antitranspirants. While these applications have proven
effective in conserving water, no toxic effects have been noted. '
A mbre detailed investigation of the antitranspirant effect of these
silicones is in progress. No toxic effects have been noted thus
far on 32 plant species (Bennett, 1973).
E. Microorganism Toxicity
Various fluid polydimethylsiloxanes have been found to elicit
no toxic response from the following bacteria: IS. coli, P_. aeru-
ginosa, A. aerogenes, j». aureus, JB. megaterium, and IJ. subtilis
(Bennett, 1973). Similarly, unspecified polydimethylsiloxanes and
polyphenylmethylsiloxartes have shown no fungicidal properties
(Sharp and Eggins, 1970). Along with the negative microbiocldal
properties of liquid silicones, silicone rubber surfaces seem to
offer a satisfactory growth surface for certain fungi (Calderon and
Staffeldt, 1965; Ross, 1963).
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XI. Silicones: Summary and Conclusions
Because of their unusual physical and chemical properties, siloxanes
enjoy a widening range of utility and a progressive development of
established uses. In that production figures often include various
non-siloxane additives, a precise determination of production growth is
not possible. Yet, based on the available data, siloxane production
has probably doubled and may have tripled since 1965. A projected annual
growth rate of 10% is probably not excessive. Of the three basic types
of siloxanes, the fluids (primarily dimethyl - and phenylmethylsiloxanes),
which comprise over half of the total market, are likely to achieve the
greatest environmental exposure. Their uses in waxes, polishes, cosmetics,
antifearning agents, food additives, textile finishings, and water repellant
surfaces indicate probable environmental exposure. Although they are
relatively hydrophobic, they can form aqueous emulsions with little
difficulty and the possibilities of water transport and eventual dis-
tribution in aqueous systems seems reasonable. Also, the vapor pressures
of the fluid siloxanes are low but not negligible and may allow for
significant atmospheric transport. Unlike the fluids, siloxane rubbers
would seem less available for environmental exposure because they are
used in comparatively nondisposable products (e.g., insulators, plastic
parts) and are less easily transported because of their bulk and/or
surface binding properties. Similarly, siloxane resins are tightly
bound in polymeric formulations. Also, because of their very limited use
and high cost they are not likely to be, released into the environment
85
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in large amounts. Thus, considering the physiochemical properties,
production values, and current uses, the fluid siloxanes seem to represent
the greatest source of environmental contamination. The proposed use
of dimethylpolysiloxane fluids as plant antitranspirants will result in
significant terrestrial exposure. To what extent these fluids will
leach into aquatic systems is yet to be determined.
Once released into the environment, siloxanes would seem to be
extremely stable under normal physical and chemical conditions. Rates
of environmental hydrolysis,photolysis, oxidation, etc. are probably
low and may be negligible. Thus, with continued production and concomitant
release, siloxanes may accumulate in the environment unless biologically
deteriorated. Such activity does not seem likely. Phylogenetically
advanced life forms are not noted for their adaptability and the meta-
bolic degradation of siloxanes would seem to require some radical enzymatic
innovation. Acid cleavage in some mammalian stomachs, (e.g., dog, pH
1.0-4.5; rabbit, pH 1-1.6; sheep, pH 1.02-1.32) while a possible route
of deterioration has not been reported and even if proven would probably
be of too little volume to be of gross environmental importance. Micro-
organisms may have the potential to degrade siloxanes, but such degradation
has not yet been conclusively demonstrated. In fact, mpst tests so far
indicate that siloxanes should be quite persistant.
Given that significant amounts of at least liquid siloxanes may be
released, and may possibly persist and accumulate in the environment, a
reasonable determination of the potential hazard that they pose must be
based on quantitative knowledge of not only the degree of contamination,
86
-------
but also the levels that might be detrimental or lethal to representative
groups of life forms. Neither of these factors have been satisfactorily
described.
Monitoring data on environmental levels of siloxanes were not found
in the literature. Such information should soon become available and
must be critically screened in any assessment of potential siloxane hazard.
Further, since the level of siloxanes may steadily increase with time, such
monitoring reports should be made periodically.
Even once the environmental concentrations are known, establishing
their significance will be difficult in view of the current understanding
of siloxane toxicity. Clearly, much of the acute lethality data has only
tangential relevance. Massive doses of any foreign substance are liable
to produce adverse responses that may be entirely unrelated to low level
exposure pathology. Studies on chronic mammalian toxicity do seem to
indicate that commercial siloxanes are not likely to pose any threat to
mammalian health. Similarly, bacterial and fungi do not seem to exhibit
a toxic response to siloxanes.
This lack of toxicity is probably best explained in terms of bio-
logical non-availability. In mammalian feeding, long chain siloxanes
do not seem to be transported across the gastrointestinal tract and thus
the internal organs are not exposed. Rabbits, and other mammals with a
low gastric pH, may be an exception. Whether or not highly acidic
gastric secretions can cause polymeric cleavage and subsequent absorption
should be determined. Negative toxicity in unicellular organisms may
also be explained on the basis of low membrane permeability of long
87
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chain siloxanes. It seems reasonable to assume that siloxanes seldom
cross the cell membrane. Even if phagocytized coincident with food
particles, the siloxanes would still be bound by a vacuolar membrane
and possibly eliminated unchanged without protoplasmic contact.
Even accepting the low order of mammalian and microbiol toxicity, a
rather large gap in the present state of siloxane toxicology is evident
and comprised of the lack of toxicity data on the non-mammalian
vertebrates and the invertebrates.
Dow Corning is presently conducting research on the possible toxic
effects of some dimethylpolysiloxanes to birds. In that these siloxanes
may be found in the terrestrial environment, these studies are vital and
deserve careful attention. Data thus far available on fish consist of
four-day exposure experiments. These can offer no more definitive environ-
mental information then do acute toxicity studies in mammals. Other
important vertebrates such as the amphibians and reptiles have not been
studied.
The invertebrates, especially the insects and lower aquatic phyla,
are critical links in the food chain. While many possess the type of
membrane systems that would seem to protect them from siloxane exposure,
this assumption should at least be tested. Information available on the
invertebrates is limited almost entirely to Daphnia. Here, the high
incidence of mortality at 1 ppm is hardly conclusive but nonetheless
somewhat disconcerting in that a primary sight of siloxane environmental
contamination nay be the aquatic environment. Daphnia, like many of the
aquatic invertebrates, are filter feeders. This involves particle
88
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clearance by passing relatively large volumes of water over collecting
surfaces. That siloxane molecules may adhere to food particles and/or
be ingested along with such particles cannot be ruled out. Once ingested,
the possibility that these molecules might accumulate in fatty tissue,
excretory organs, or other areas should be considered. Another possibility,
especially in the smaller invertebrates, that the feeding apparatus might
be fouled should also be examined. Similar speculations on possible
modes of siloxane pathology in terrestrial invertebrates could also be
devised. The point is that experimental evidence on critically important
invertebrate groups is not available.
In summary, if there is any danger from the environmental contamination
of siloxanes it will most probably come from the liquid siloxanes and be
located in aquatic systems. The damage might be tissue response to
accumulation of long chain siloxanes and/or cellular absorption of lower
molecular weight siloxanes after chain cleavage. However, siloxanes are
eminently useful compounds and current information indicates that they
may have a low order of biological activity. Nevertheless, the possible
dangers outlined above deserve evaluation.
89
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Muraoka, J.S. (1966), "Effect of Deep Sea Microorganisms on Rubber and
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Noll, W. (1968), Chemistry and Technology of Silicones, Academic Press,
New York
'. . '"..*.-.
Nosanchuk, J.S. (1968), "Injected Dime thyIpolysiloxane Fluid: A Study of
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93
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•
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94
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FLUOROCARBONS
I. Physical Properties
The fluorohydrocarbon compounds, in comparison to hydrocarbons, have
a number of interesting physical properties. The fluorocarbons have a
higher liquid density; for compounds with four or less carbons, the boil-
ing points of the fluorinated compounds are slightly higher; with more
than four carbons, the boiling points are generally lower than the corres-
ponding hydrocarbons. The fluorocarbon viscosities are similar to the
hydrocarbons but change more with temperature. The fluorocarbon surface
tension is low and dielectric properties are good.
The chlorofluorocarbons have similar properties to the fluorohydro-
carbons. They usually have high density, low boiling point, low viscosity
and low surface tension. In addition, many of these compounds have vapor
pressures falling somewhere between 15 and 100 psig, as computed at 70°F,
which allows their use in the aerosol industry. The physical properties
of the bromo- and iodofluorocarbons are similar to those of the chloro-
fluorocarbons, except for higher densities. Some physical properties of
most of the commercially important fluorocarbons are shown in Table I.
Table II presents the physical properties of polytetrafluoroethylene.
95
-------
TABLE I
Physical Properties of Commercially Important Fluorocarbons
(Sage, 1963; Downing, 1966;)
Compound C13CF CljCFj CICHFj ^3^3 C12C2F4 CICjFj CIC^F, ^H^ V* BrCF3 C4F« "(CF2"CF2)"x
(cyclic)
Fluorocarbon Number* 11 12 22 113 114 115 I42b 152a 1114 C318
boiling point, CO
1 reexing point (*C)
vapor pressure Cpsia)
(70'F)
solubility in water
{vt «
liquid density g/al
crit. temperature (°C)
crlt. pressure (atm)
surface tension
(dynes/cii at 77*F)
23.8
-311
13.4
0.11
1.476/25*C
198.0
43.2
19
-29.8
-158
70.2
0.028
1.311/25*C
112.0
40.6
9
-40.8
-160
122.5
0.30
1.194/25*C
96.0
.49.1
9
45.7
14
0.017
1.579/20'C
3.1
-60
12.9
0.013
1.468/70*F
145.6
32.5
-38.7
-106
0.006
1.291/25*C
80.0
30.8
.
15.1'F*
-204 *F
29.1
0.054
1.119/70'F
-24.7
-117
61.7
0.17
0.966/19*C
-76.3
-142.5
1.519/-76'C
33.3
572 pslg
-57.8
-168
0.03
1.538/25*C
67.0
39.1
• t
-5.9
-41
25.4
0.014
0.620#5'<
115.3
27.5
327
* Units digit- f of F a tow; tens digits - * of H atoas +1; hundreds digit •> f of C atoms -1; thousands digit - f of double bonds.
-------
TABLE II
Typical Physical Properties of Polytetrafluoroethylene
(Sherratt, 1966)J
reprinted by permission.
Copyright 1966, J. Wiley and Sons
Properly
tensile strength at. '2'.\"C, psia
elongation at 23°C, %
flexiiral strength at 2:$°C
stiffness at 2:i°G, ])si:i
impact strength, ixoil, (ft)(lb)/in.
-57°C
23°C
77°C
hardness, duroinctor, D
i:ompn>?sive stress at 1% deformation
at 23°C5, psia
deformation under loud at .WO, %
1200 psia, 24 hr
200i> psia, 21 hr
deflection temperature under a load of
GG psi, °C
coefficient of linear thermal expansion
per "C, 25-GO°C
thermal conductivity,* 0.1S in.,
cal/(sec)(cin»)(0C)(f:m)
specific heat, cal/(g)(°C)
water absorption, %
flammability
si)«-ific gravity
resistance to weathering
Vahift
2.100 -1000
200 -400
did lint break
GO.OOO
2.0
3.5
G.O
55-70
noo
4-S
25
121
9.9 X 10-'
5.8 X 10-<
Q.25
0.0
nonburning
2.1-2.3
excellent*
ArtMhod
DIWR-58T
DKiS-wST
})7Wl-r,<)T
D7l7-.r.ST
U256-5G
D25G-50
J525G-5G
J)]70G-r,!)T
. DG95--)I
DG21-50
DG21 -.',!)
DG48-5G
DG9G-44
D69G-44
D570-.VJT
D035-5GT
D792-50
• Tests have been performed by ASTM methods unless othenvise indicatod. Data shown arc
average values and .should not be used for specifications.
* Thermal conductivity measured by Cenco-Fitch apparatus.
«No detectable change after ten years of outdoor exposure in Florida.
Reproduced from
best available copy.
97
-------
II. Production
Fluorocarbon compounds are produced in the United States by six major
chemical manufacturers. Table III lists the U.S. companies, the products
they produce, their plant capacity, and geographical location. In some
other countries, fluorocarbon products and manufacturers are: In England,
Arcton (ICI), Isceon (Imperial Smelting); in West Germany, Heydogen
(Chemische Fabrik von Heyden), Frigen (Farbwerke Hoechst), Kaltron
(Kali-Chemie); in France, Flugene (Pechiney), Forane (Ugine); in Italy,
Algofrene (Montecatini), Edifren, (Sicedison); in the Netherlands, Fresane
(Uniechemie); in East Germany, Frigedohn; in Russia, Eskimon; in Argentina,
Algeon (Fluoder), Frateon (I.R.A.); in Japan, Daiflo (Daikin Kdzyo),
Asahiflon (Asaki Glass). The capacity for these foreign manufacturers
was estimated at 900 million Ibs. in 1972 (Noble, 1972).
The fluorocarbon industry has been growing at a fast pace. During
the period 1962-1972 the annual growth rate was 8.5% and a growth rate
of 6.5%/year through 1977 is projected (Chemical Marketing Reporter, 1973).
Table IV reviews the growth in the industry by major compounds that have
reported production (or sales) levels.
98
-------
TABLE III
Fluorocarbon Producers and Capacities
(Lutz, £t _al. 1967, Chemical Marketing Reporter, 1973)
Company
Trade Names Plant Capacity
106 Ib./yr. in 1973
Plant Locations
Allied Chemical
Corporation
E. I. du Pont
de Nemours and
Company
Kaiser Aluminum
and Chemical
Corporation
Minnesota Mining
and Manufacturing
Company '
National Rolling
Mills Company
Pennwalt Chemical
Corporation
Racon
Thiokol Chemical
Corporation
Union Carbide
Corporation
Genetron
Genesolve
Halon TFE .
Plaskon CTFE
Freon
Teflon TFE
Vitron
Kaiser
Kel-F-81
and 82
Fluorel
310
Istron
Kynar
Thiokol TFE
UCON
500
50
5 (1967)
25 (1967)
115
20
2
150
Baton Rouge, La.
Elizabeth, N.J.
Danville, 111.
El Segundo, Calif.
Antioch, Calif.
Carney's Point, N.J.
East Chicago, Ind.
Louisville, Ky.
Montague, Mich.
Cramercy, La.
Decatur, Ala.
Malvern, Pa.
Calvert City, Ky.
Thorofare, N.J.
Wichita, Kan.
Moss Point, Miss.
Institute, W.Va.
99
-------
TABLE IV
Production and Capacities of Fluorocarbons
(Chemical Marketing Reporter, 1973; U.S. Tariff Commission,
1961-1971; Stanford Research Institute, 1973)
O
o
Compound
Fluorocarbon
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971p
1972
1973
Fluorocarbon
. Capacity
I
U09g)
235.9
254.0
276.7
299.4
326.6
326.6
326.6
326.6
435.5
444.5
458.1
519.4
(10* lb!
520
560
610
660
720
720
720
720
960
980
1010
1145
ihlorodifluoro-
me thane
22
[109g) (106 Ibs,;
10.9
13.2
16.3
19.5
22.7
25.4
26.8
24.9
32.2
33.1
36.3
24*
29*
36*
43*
50*
56*
59*
55*
71*
73*
80*
Dichloro- Trichlorofluo
difluoromethane methane
) (109g)
78.5
94.3
98.4
103.4
122.9
129.7
140.6
147.9
166.9
170.1
176.9
12 11
(106 Ibs.) (109g) (10s 11
173
208
217
228
271
286
310
326
368
375
390
41.3
56.7
63.5
67.1
77.1
77.1
82.6
92.5
107.9
110.7
117.0
91
125
140
148
170
170
182
204
238
244
258
Dichlorotetra-
fluoroethane
[109g)
4.1
5.0
5.4
5.9
10.0
7.7
10. 0
7.7
114
<106 Ibs.)
9
11
12
13
22
17*
22*
17*
Resins
and Elastomers
(109g) (106 Ibs
5.4 12
7.7 17
7.3 16
*Sales
-------
III. Uses
The uses of fluorocarbons are dependent somewhat upon their physical-
chemical properties and physiological activity. Table V lists the major
uses and size of the market as well as the fluorocarbons compounds utilized.
The major fluorocarbon use is for aerosol* propellants. Although
this use is the backbone of the industry, its percentage of the market has
decreased in the last few years (1964 - 60%, 1973 - 50%) (Noble, 1972).
The major industrial products used in this category are dichlorodifluoro-
methane (12), trichlorofluoromethane (11), dichlorotetrafluoroethane (114),
and small amounts of octafluorocyclobutane (C318). Fluorocarbons find use
in this application because they meet the following criteria: (1) appro-
priate vapor .pressure; (2) relatively nontoxic; (3) chemically inert so
they do not react with the active ingredients; and (4) nonflammable and
nonexplosive (Sage, 1963).
The second largest use for fluorocarbons is as a refrigerant for air
conditioning and refrigeration systems. The principal compounds used are
dichlorodifluoromethane (12) and chlorodifluoromethane (22). This was
the very first application of fluorocarbons and they quickly replaced
older refrigeratns because of their inertness and low toxicity. A signi-
ficant growth in this area occurred in the early 1960's with an increase
in the use of auto, home, and commercial air conditioning.
*"Self-dispensing, pressured, self-propelling products, dispensed by the
use of a liquefied, nonliquefied, or noncondensed gas." (Sage, 1963)
101
-------
TABLE V
Uses of Fluorocarbons
(Chemical Marketing Reporter, 1973)
Use Percentage of Fluorocarbons*
the Market
Aerosol propellants 50% 12, 11, 114
Refrigerants 28% 12, 22
Plastics 10% Iil4, 1216, 1132, 1113
Solvents 5% 113, 11, 214
Blowing agents, 7%
exports, and
miscellaneous
*Units digits = // of F atoms; tens digits = // of H atoms +1;
hundreds digits = // of C atoms -1; thousands digit = # of double bonds,
102
-------
Fluorocarbon polymers, or fluoroplastics, provide a sizable category
of fluorocarbon use. Polytetrafluoroethylene (PTFE) (1114) is one of
the major fluoroplastics. Its major applications are in the following
categories: wire and cable insulation; gaskets, seals, valves, diaphragms,
chemical hose, etc.; laboratory ware; threaded pipe joint sealant;
packings, bearings, and piston rings; and non-stick surface coatings.
Other fluorocarbon plastic products include copolymers of tetrafluoro-
ethylene (1114) and hexafluoropropylene (1216), copolymers of vinylidene
fluoride (1132) and hexafluoropropylene (1216) and polymers from chloro-
trifluoroethylene (1113) and from vinylidene fluoride (1132).
Fluorocarbon use in the solvent and degreasing field has grown in
recent years as measured by market percentage (1963 = 2.3%, 1973 = 5.0%)
(Downing, 1963; Chemical Marketing Reporter, 1973). The solvent most
widely used is trichlorotrifluoroethane (113) with small amounts of
trichlorofluoromethane (11) and tetrachlorodifluoroethane (112) being
used. These solvents find special use for dissolving oils and greases
without affecting plastic, elastomeric or metal components. Lutz et^ al.
(1967) have suggested that trichlorotrifluoroethane (113) may challenge
perchloroethylene in the dry-cleaning-solvent field.
Fluorocarbons are also used as blowing agents to impart, for instance,
the thermal insulation properties of urethane foams. Other uses include
applications as general anesthetics (Halothanej CHBrClCFJ; dielectric
fluids; fire-extinguishing agents (CBrFg, CBrF2CBrF2); and as pressurized
leak-testing gases in wind tunnels and in bubble chambers. New applications
103
-------
which may provide a sizable market are uses as a solvent in Rankine
cycle engines, in immersion freezing of foods (Bucholz and Pigott,
1972), and as a drycleaning solvent (Noble, 1972). .
IV. Current Practice
Fluorocarbons, which are gases at ambient temperatures, are Shipped
in tank cars, tank trucks and steel cylinders ranging from approximately
10 Ibs. to several tons. Fluorocarbon solvents (e.g., 11, 112 and 113)
are transported in tank cars, tank trucks, or in steel drums. Drum sizes
range from 5 to 55 gallons.
The fluorocarbons for the most part are nonflammable and, thus, do
not present a fire hazard. The pure compounds are stable, nonirritating,
and have a low order of toxicity. However, combustion products (halogens,
halogen acids, and carbonyl halides) from contact with a flame or hot
metal surfaces are corrosive, irritating and toxic when inhaled.
The high cost of fluorocarbons ($.25/lb. and up) suggests that very
little is disposed of on purpose. Correspondence with major manufacturers
indicates that large quantities of material contaminated or no longer
needed are often reclaimed by the manufacturer at their processing
facilities.
V. Environmental Contamination
Because of the high volatility and chemical stability of fluorocarbons,
these chemicals are likely to be released to and persist in the environment.
Their immediate fate from their use as aerosol propellants is atmospheric
104
-------
release. Partial losses are also expected from their use as solvents
and refrigerants. Korte and Klein (1971) and Iliff (1972) have briefly
discussed environmental pollution potential from fluorocarbons.
Very low concentrations of trichlorofluoromethane and dichloro-
difluoromethane have been detected in both water and air environmental
samples. Lovelock (1971) detected trichlorofluoromethane at concentrations
-12
of 10 to 190 x 10 by volume in the air over southwest Ireland. Highest
concentrations were found when easterly winds from continental Europe
were observed, thus indicating the source of the fluorocarbons as being
from the industrially developed European continent. Su and Goldberg (1973)
were able to detect both trichlorofluoromethane and dichlorodifluoromethane.
Samples were taken in LaJolla, San Diego, and in the desert region 100 km
northeast of San Diego, California. In the desert, which is perhaps more
representative of a background level, a concentration of 0.097 and
^_ t\
0.70 x 10 ml per ml air was detected for trichlorofluoromethane and
dichlorodifluoromethane, respectively. The authors attributed the higher
concentration of dichlorodifluoromethane to slightly higher production
levels and greater environmental stability.
VI. Monitoring and Analysis
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
I
dichlorodifluoromethane was a promising tracer chemical. He used a
-*
modified ionization-type leak detector which was sensitive to a concentration
105
-------
of approximately 1 ppm; however he was plagued by non-reproducibility
(Collins et al., 1965).
Marcali and Linch (1966) reported a colorimetric method for perfluoro-
isobutylene and hexafluoropropene in air samples capable of detections 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 = CF_, 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 electron-
capture detection for determining chlorofluorocarbons in dog blood. The
method used a hexane extraction and the lower limits of quantification were
3.3, 10, 40, and 80 yg/1 of blood for trichlorofluoromethane, 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 silicons rubber membrane direct inlet system (similar to GC-MS
Interfaces) which allowed 1000 fold increases in minor components of air.
With this system, they could detect trichlorotrifluoroethane at 0.1 ppm.
106
-------
Two techniques have been used to detect fluorocarbons in air at the ppt
(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 et^ 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 dichloro-
difluoromethane to be only in the 50 to 100 ppb range. Saltzman £££!.. (1966)
used a similar GC-EC system with bromotrifluoromethane and octafluoro-
cyclobutane. A sensitivity of about 0.3 ppb was achieved without concen-
trating 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 theatres. 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 noted a low stability of the
electron capture detector fend, thus, the use of flame ionization) if the
electrodes are contaminated by large amounts of water vapor and oxygen.
However, Lovelock and coworkers (Lovelock, 1971, 1972; Lovelock et al.,
1973) and Su and Goldberg (1973) have found gas chromatography with an
electron capture detector to be quite satisfactory for determining
trichlorofluoromethane and dichlorodifluoromethane at approximately 1 ppt
and 45 ppt by volume, respectively. Lovelock used experimental conditions
107
-------
where the ionization in the detector is complete, making the system
coulometric. He (Lovelock, 1971) notes that other halocarbons such as
difluorodichloromethane and perf luo,rocyclobutane were not detected because
of their low sensitivity in the electron-capture detector.
demons and Altshuller (1966) reviewed the electron-capture detector
sensitivity of a number of halogenated substances. Table VI lists those
results and compares them to flame-ionization detection. The figures show
that for many compounds (ones with less than 2 chlorines) flame-ionization
detection is just as sensitive as electron-capture. However, because 'the
electron-capture detector is specific for halogenated substances, it is
often used even when the flame-ionization detector would be more sensitive.
VII. Chemical Reactivity
Fluorocarbons have unusually high thermal and chemical stability. The
fluorinated hydrocarbons are the most stable. They will react with molten
alkali metals but are not affected by acids or oxidizing agents. The
stability is dependent upon the number of carbons and the hydrogen/fluorine
ratio; the lower the number of carbons and H/F ratio, the higher the
thermal stability. For example, carbon tetrafluoride shows no reaction
with copper, nickel, tungsten, or molybdenum at 900°C, whereas compounds
of higher molecular weight decompose at temperatures about 400°C. Com-
pounds with only one fluorine atom are quite reactive (Downing, 1966).
Substitution with other halogen atoms decreases the chemical stability.
The chlorofluorocarbons are the most stable halofluorocarbons. They do riot
react with most metals below 200°C or with acids or with oxidizing agents
108
-------
TABLE VI
Electron-Capture Detector Response to Various Fluorinated Compounds
(Clemons and Altshuller, 1966)
Compound
Fluorocarbon //
Response
(sq.in. ppm)
Response
Flame-ionization
(sq.in. ppm)
(all compounds)
"6
CFC13
(CF3)2C=CF2
C1F2C-CFC12
CF-CF-CF-CF.
1 *• *• *• 1 *•
CF33r
CF2C12
C1F2CCF2C1
CF2=CC12
CHFC12
CF3CF2C1
CF2=CFC1
CF3C1
CHF2C1
CF.
11
1218
113
C318
13B1
12
114
1112
21
115
1113
13
22
14
370
90
50
30-40
12-40
9
2
0.2 0.1-1.0
5 x 10~2
5 x 10-2
3 x 10"2
1 x 10-*3
3 x 10"3
3 x 10"1*
109
-------
and react only very slowly with alkali in the presence of water. However,
they are decomposed by molten alkali metals (e.g., dichlorodifluoromethane
reacts vigorously with aluminum). Reaction rates of hydrolysis in neutral
aqueous solutions -at room temperature are quite slow (Stepakoff and
Modica, 1973). Sanders (1960) has reported a free-radical type of reaction
between trichlorofluoromethane and alcohols (biological significance
unknown). The chlorofluorocarbons are not quite as thermally stable as
the fluorocarbons but still show high stability relative to most organic
compounds. Again, the thermal stability is proportional to the fluorine
content in the molecule (Trenwith and Watson, 1957; Calleghan, 1971). With
bromo- and iodofluorocarbons, the stability of the compound decreases as
the ratio of bromine or iodine to fluorine increases (Downing, 1966).
The monomers of the fluorocarbon plastics [e.g., tetrafluoroethylene
(TFE)] are much less stable than the saturated fluorocarbons. For example,
•
TFE is similar in flammability to carbon monoxide. Also, TFE can explode
in the absence of air to give carbon and carbon tetrafluoride. TFE shows
the usual addition reactions of an olefin and will readily polymerize
in the presence of free-radical initiators. Perfluorocyclobutane is formed
slowly at room temperature and rapidly at 500°C (Sherratt, 1966).
Once the fluorocarbon monomers are polymerized into plastics, they
exhibit a high degree of chemical stability. They are resistant to mineral
acids, bases, and common organic solvents. The compounds are resistant
to oxidation and ultraviolet radiation leading to good weathering properties.
They are only attacked by alkali metals, fluorine, and strong fluorinating
agents at elevated temperature and pressure. This stability is dependent
upon the degree of fluorination in the monomer.
110
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VIII. Biology
A. Absorption
The most common route of administration for the fluorocarbon gases
involves absorption of compounds by plasma and/or red blood cells
across the alveolae membrane. However, the ease of absorption from
aveolar air is reported to be directly related to lipid solubility.
Most common fluorocarbons, having a relatively low lipid solubility
are not readily absorbed. Figure 1 illustrates this principle, showing
the decrease in various fluorocarbon gases in static alveolar air
plotted against duration of breath holding.
s
i
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B
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z
u
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a
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e
0
u
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Z
0
<
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z
u
u
z
o
u
100
9O
EO
70
6O
50
4O
30
20
IO
9
e
7
6
S
4
3
2
*
rfw- .'_. . . -.J '
' V ^**" ^~~' ' ^^ "1
.\ \ ^""^.^ *""
' \ ^ ^^^^O"-*^
\ \ • ^^*^^S
- \ \
\ \
- \ \
\ \
\' \
\ \
\ ^^
\ ^V^ *
\ Xt>' .=
j
j
•
FLUOrtQCAR&ON 12 | •
1 FLUOfeOCARBCN 114 -1 •
iFLOOROCAfibOtJ 113 1 +
- i FLUOriOCARbOl; II | o
1, 1, 1,- TR.'CMLOROETHANE I • j
1, 1,2 - TRICHLOROETHANE j *
•
i i i i i
O IO 20 3O 4O SO 6(
BREATH HOLDING TIME (SECONDS)
Figure 1. Concentration of Some Halogenated Hydrocarbons
in Alveolar Air After Various Times of Breath Holding
[Morgan at al., 1972]5
reprinted with permission from A. Morgan,
Copyright 1972, Pergamon Press.
Ill
-------
Note that Fluorocarbon 12 [dichlorodifluoromethane] and Fluoro-
carbon 114 [1,2-dichlorotetrafluoroethane], both of which have low
lipid solubilities, are only slightly absorbed. In contrast, the
lipid soluble chlorocarbons are readily absorbed (Morgan et al., 1972).
While this relationship may hold for the lower molecular weight
fluorocarbons, hexafluorodichlorobutene has been reported 50% absorbed
at a concentration of .1% over a one hour period (Truhant &t^ a±., 1972).
Once into the blood stream, fluorocarbon absorption by the erythrocytes
may be facilitated by the ionization of the polar gases and their
subsequent binding to the positive and negative portions of the
hemoglobin molecule (Pennington and Fuerst, 1971).
In that fluorocarbons are primarily used as gases or aerosol
propellants, other routes of entry by absorption have not been
extensively studied. Greenberg and Lester (1950) found no evidence
for the absorption of l,l,2,2-tetrachloro-l,2-difluoroethane or
l,l,l,2-tetrafluoro-2,2-difluoroethane through the gastrointestinal
tract in rats. However, halothane ingestion by humans had lead to
severe clinical pathology and death where gastrointestinal absorption
would seem indicated (Dykes, 1970).
No studies monitoring the degree of dermal absorption have
been encountered.
112
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B. Excretion/Elimination
With the exception of unchanged and presumably unabsorbed fluoro-
carbons excreted in the feces after oral administration (Greenberg
and Lester, 1950), fluorocarbons are removed from the body via
exhalation and/or urinary excretion.
Removal of absorbed fluorocarbons by the respiratory tract has
been well documented for aerosol propellants. In humans, over half
of the absorbed doses of trichlorofluoromethane, dichlorodifluoro-
methane, trichlorotrifluoroethane, and 1,2-dichlorotetrafluoroethane
are exhaled after 30 minutes representing a 77-90% elimination of
the total administered dose (Morgan et al., 1972). Further
elimination most probably continues for some time after the 30 minute
period, in that rats have been shown to exhale 97% of administered
trichlorofluoromethane unchanged over a 6 hour period (Cox et^ alv, "'
1972a).
Fluorocarbon elimination by the respiratory tract is not merely
coincident to inhalation administration, but also apparent after
direct internal administration. A mixture of dichlorodifluoromethane
and 1,2-dichlorotetrafluoroethane (30/70) injected intravenously
and intraperitoneally or sprayed directly on an internal organ in
dogs is not excreted by urine or feces but is eliminated by the
breath. Table VII indicates that this elimination is of rapid onset
and prolonged duration.
113
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TABLE VII
Elimination of Fluorocarbons in Dogs' Breath
[Matsumoto et al., 1968]
Intravenous Intraperitineal Direct Spray
Dosage 0.5 cc 2.0 cc
Interval before onset of elimination 3 sec. 5 min. 5 sec.
Duration of elimination 12 hours 48 hours 12 hours
Regretably, Matsumoto and associates (1968) did not report quantitative
measurements of exhaled fluorocarbons. However, it is interesting to
note that the four fold dosage increase in intraperitineal as opposed to
intravenous injection leads to a corresponding four fold increase in the
duration of fluorocarbon exhalation. This may indicate that the amount of
a given fluorocarbon expelled by the respiratory system is independent
of the administration route. The significant lag before respiratory
elimination of the intraperitineal administration may reflect relatively
poor membrane absorption characteristics of the fluorocarbons.
In contrast to the respiratory elimination of the aerosol propellants,
the popular anesthetic halothane (2-bromo-2-chloro-l,l,l-trifluoroethane)
seems to undergo appreciable urinary excretion involving metabolic trans-
formation (Geddes, 1972). After a single inhalation administration in
man, halothane metabolites have been monitored in the urine for up to 14
days (Rosenberg, 1972). However, there is some evidence that considerable
variation may be found in the propprtions and rates of excretion by
different individuals. Over a six day period, one individual excreted
85.7% of the original dose as urinary metabolites, while another excreted
114
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only 53.3% (Cascorbe and Blake, 1971). Many complex metabolic and renal
parameters would have to be monitored before the significance of this
variation could be assessed.
I
While most halothaiie studies have concentrated on urinary excretion,
the role of respiratory elimination cannot be discounted. Clinical studies
indicate that absorbed halothane may be eliminated by artificial ventilation
with therapeutic results (Dykes, 1970). Similarly, the role of urinary
excretion must also be considered in non-anesthetic fluorocarbons.
Truhant and coworkers (1972) have shown that, while some hexafluorodicholo-
butene is eliminated in the breath after inhalation by rabbits, urinary
excretion of the fluorocarbon metabolites is of major importance. Thus,
no broad generalizations can be made on fluorocarbon excretion beyond the
obvious fact that both the respiratory and urinary systems are involved.
To what relative extents these systems are involved depends on the specific
fluorocarbons. There is insufficient clinical and experimental data to
clearly relate the physical or chemical characteristics of the fluoro-
carbons to the excretory pathways.
C. Transport
As should be. obvious from the previous discussion on excretion, the
main method of fluorocarbon transport within the organism is by the circula-
tory system. The compounds may be transported by the blood from the
internal organs to the air way (Matsumoto £t al.,1968) or from the air way
to the urinary tract (Cascorbi and Blake, 1971; Geddes, 1972). However,
fluorocarbons seem to be quickly eliminated from the blood stream (Beck
£t _al., 1973). While the role of simple respiratory elimination is not
115
-------
to be minimized, there is considerable evidence - at least for
halothane - that fluorocarbons may be transported by the circulatory
system to the liver where they are removed from the blood (Rosenberg,
1972; Cascorbi and Blake, 1971; Cohen, 1969).
D. Distribution
Fluorocarbons being transported by the blood may be distributed
for short periods throughout the organism. The primary site of
fluorocarbon accumulation, however, seems to be the liver (Cascorbi and
Blake, 1971). In the liver they accumulate as nonvolatile metabolites
(Cohen, 1969). Trifluoroacetic acid is the metabolite most often
cited—especially with reference to halothane—and may remain in the
organism for up to two weeks (Waldron and Ratra, 1972). The metabolite
itself may be stored in the fatty tissue and be gradually released
and bound to the -NH_ and -SH groups of peptides or proteins in the
liver (Rosenberg, 1972).
E. Metabolism
Halothane, because of its importance as an anesthetic agent, has
been the most intensively studied fluorocarbon in terms of metabolism.
Trifluoroacetic acid (TFA) is recognized as the most probable end
product of halothane metabolism in mammals and accounts for a large
i-
percentage of the urinary excretion (Blake et al., 1972). This con-
clusion is supported not only by urinalysis but also by the similar
metabolic effects of halothane and TFA (Stier at al., 1972). Unlike
the chlorocarbons which can be dehalogenated in vivo by enzyme systems,
liberating chlorine ions and free radicals, the C-F bond is extremely
116
-------
stable and resistant to biological breakdown (Clayton, 1970). Thus
14
with C-labelled halothane, dechlorination and debromination do take
place both in vitro and in vivo but no defluorination occurs. Labeled
TFA is recovered as the end product (Geddes, 1972). Trifluoroethanol
may be an intermediate in the formation of TFA in that up to 80% of
14
C-labelled trifluoroethanolmay be recovered from the urine as TFA
(Cascorbi and Blake, 1971). Although TFA seems to be the major meta-
bolite, trifluoroacetylethanolamine and trifluoroacetaldehyde have
been proposed either as end products or intermediates (Rosenburg, 1972)
The current view of halothane metabolism is illustrated in Figure 2.
T
HALOTHANE
Br
F-C — C — H-
* <'\
\
\
NADPH
TFE
f— C -CH2OH
F
F- C — C - NH— CHj- CH2-OH
TRIFLUOROACETYLETHANOLAMINE
Figure 2: Possible Metabolic Pathways of Halothane
[from Rosenberg, 1972]
This general pathway or something similar to it may be common for a
number of other fluorocarbons. Fluoroxene (trifluoroethyl vinyl ether)
may possibly be metabolized to trifluoroethanol in mice or TFA in man
(Cascorbi and Singh-Amaranath, 1972). Hexafluorodichlorobutene may
also be metabolized to TFA and other unidentified acids. This trans-
117
-------
formation may take place directly in the lung (Truhaut £t jil., 1972).
However, not all fluorocarbons can be assumed to follow this
pattern. The one carbon compounds, of course, could not, and seem
to operate by an entirely different mechanism. Trichlorofluoromethane
does not undergo reductive dehalogenation in rat, mous.e, chicken,
hamster, or guinea pig mfcrosomes and exhibits no evidence of free
radical formation. It does not appear to undergo true biotransformation,
but rather binds with hepatic cytochrome P-450 (Cox et jil. , 1972b).
The study of fluorocarbon metabolism is thus rather incomplete.
The metabolic pathways assigned to halothane and related fluorocarbons
are only tentative. The metabolism, if any, of the one carbon and
many of the two carbon aerosol propellants is virtually unexplored.
F. Metabolic Effects
The metabolic effects of most fluorocarbons might be properly
catagorized as cellular toxicity. However, in that most of the clinical
and experimental results are documented only with lethality data or.
gross histopathology, the cellular and subcellular activity of these
compounds can be examined apart from standard toxicity.
Halothane has been found to inhibit the replication of rat hepatoma
cells, cells which usually multiply at a very rapid rate. Because the
hepatoma cells were not in synchrony, a specific effect on a particular
stage of the cell cycle could not be ascertained (Jackson, 1972).
However, the effectiveness of halothane in reversibly dispersing a
broad spectrum of microtubular systems has been extensively documented
118
-------
and is well reviewed by Nunn (1972). The inhibition of hepatoma growth
observed by Jackson could well be accounted for by postulating a
disruption of the mitotic spindle apparatus. Thus, while Jackson
doubts the possibility of a common mechanism for growth inhibition and
the inhibition of mycardial contractility, the universality of
microtubular systems might allow for related mechanisms at least in
terms of cardiac innervation (Nunn et^ al., 1970). Until more is
known about the nature of microtubular systems, however, such
relationships must be considered highly speculative.
Beritic (1971) proposed that halothane may complex with mitochondrial
elements. Such a complex may be involved in the in vitro uncoupling of
oxidative phosphbrylation in liver mitochondria (Snodgrass and Peras,
1965). A similar complex has been proposed for various fluorocarbons
with cytochrone P-450 in liver microsomes uncoupling electron transport
from monooxygenation (Ullrich and Diehl, 1971). Specifically, trichloro-
fluoromethane has been shown to bind hepatic cytochrome P-450 (Cox et al.,
1972a). In agreement with the lipophilic characteristics proposed by
Ullrich and Diehl (1971), the hepatic binding involves phospholipids
and also another area that appears similar to the carbon monoxide binding
site (Cox ejt al., 1972b). This is in further agreement with Ullrich
and Diehl's (1971) characterization of fluorocarbons as "dead-end
inhibitors". A similar type of enzymatic blockage has been proposed for
fluoroacetate by the formation of fluoroacetyl-CoA. This would block
119
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the enzyme aconitase, cause an accumulation of citric acid, and a
corresponding decrease in energy supply by way of the Kreb's Cycle
(Peters, 1963). The effects of fluorocarbons on rabbit red blood
cells in vitro may involve a somewhat related complexing by the ioni-
zation of the fluorocarbon and its binding to the positive and nega-
tive areas of the hemoglobin molecule (Fennington and Fuerst, 1971).
To a greater or lesser extent, all of these observations are in accord
with Nunn's hypothesis' for fluorocarbon molecular activity: the bio-
logical activity of fluorocarbons is caused by Van Der Waal binding
of the fluorocarbons to hydrophobic areas of large molecules (Nunn,
1972).
120
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IX. Environmental Transport and Fate
A. Persistence and/or Degradation
The environmental stability of fluorocarbons has received little
study. Information on biodegradability is not available. Goldman
(1972) has reviewed the enzymology 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. And, in fact, with any other compound
containing the carbon-fluorine bond with the exception of fluoroacetate
(e.g., trifluoroacetate, defluoroacetate, 2-fluoroproprionate, and
3-fluoroproprionate) fluoride release could not be detected.
Because of the volatility of many of the fluorocarbon compounds,
atmospheric stability (chemical and photochemical inactivity) is
likely to be quite important to the residence time of the chemical
in the environment. Su and Goldberg (1973) have suggested that there
is perhaps a similarity between stability in aerosol packages and
thermal oxidative studies and in the atmosphere. Such a correlation
seems to work for trichlorofluoromethane and dichlorodifluoromethane,
with the more highly fluorinated compound being most stable as deter-
mined by monitoring data (see section on Chemical Reactivity).
Saltzman £t al., (1966) have examined the atmospheric stability
of bromotrifluoromethane and octafluorocyclobutane experimentally.
121
-------
They determined the loss of the compound stored in bags exposed to
ultraviolet irradiation, water, water vapor, and atmospheric pollutants
with and without ultraviolet radiation. They concluded that their
most significant loss was diffusion through the plastic bag.
Lovelock ert al., (1973) and Su and Goldberg (1973) have calculated
residence times for trichlorofluoromethane (10 years) and dichlorodi-
fluoromethane (30 years) based on comparisons of world production levels
and ambient air concentrations. These calculated values are quite
dependent upon the sampling data used.
B. Environmental Transport
Atmospheric transport of fluorocarbons, especially the more vola-
tile compounds such as trichlorofluoromethane, appears to be a very
important route of environmental distribution. Lovelock (1972) has
determined that trichlorofluoromethane contamination of south-west
Ireland is due to sources on the European continent. He (Lovelock,
1973) has also shown a correlation of the ambient concentrations of
trichlorofluoromethane in the environment and a numerical model of the
global atmospheric distribution of an ideal inert gas.
C. Bioaccumulation
No experimental information on the bioaccumulation of fluorocarbons
is available in the surveyed literature
122
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X. Toxicity
A. Human Toxicity
1. Acute Inhalation
The human clinical response to relatively high doses of
fluorocarbon gases may be expressed in three ways: central
nervous system depression, cardiac arrhythmias, and hepatic
Depression of the central nervous system by fluorocarbons
is reflected, in their primary medicinal use, .i-.e., anesthetic.
However, the actual degree of central nervous system depression
varies considerably with the specific type of fluorocarbon and
the concentration at which it is inhaled. The reactions may
vary from slight loss of motor ability, to anasthesia, to convul-
sions (Azar et jal., 1972). As a rule, fluorocarbons which contain
more than four fluorine atoms are not useful anesthetics because
at clinically effective doses they produce convulsions. If the
fluorine number is increased to saturation, the compound becomes
relatively inert. Thus, other halogens are often included in
fluorocarbon anesthetics to decrease the adverse effects to an
acceptable level without reducing the anesthetic potential
(Clayton, 1970). Halothane is an excellent example of this
123
-------
type of fluorocarbon, containing only three fluorine atoms along
with both chloro- and bromo- substitution:
Cl
F - C - C - H Halothane
F Br
The cardiac effect of fluorocarbons on humans is less evident
in cases of controlled medical administration then in instances
of abusive inhalation of aerosol p rope Hants by individual
attempting to become intoxicated. As of 1972, one hundred and
forty deaths had been attributed to such aerosol "sniffing"
(Kilen and Harris, 1972). Most of these aerosol propellants are
chlorinated fluorocarbons which have been shown to augment cardiac
muscle response to epinephrine and induce irregular contractions
leading to cardiac arrest (Clayton, 1970). In absence of definitive
•
post-mortem findings, Reinhardt and associates (1971) proposed
that the fluorocarbon propellants in the aerosol spray sensitized
the heart to endogenous epinephrine — which was released into the
subjects blood stream by either physical activity or emotional
stimulation — leading to ventricular fibrillation and death.
While not ruling out the scheme of indirect fluorocarbon toxicity
via epinephrine, Taylor and coworkers (1971) proposed that the
124
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deaths might be accounted for on the basis of direct cardiac
toxicity of the fluorocarbons. Noting that commonly used
*
commercial products administered by fluorocarbon propeilants may
release from 38 ml to 231 ml of gas/sec and that bronchodilation
nebulizers — designed for direct inhalation.— may release 12.5
ml of gas/dose, they concluded that such products may present a
serious threat (Taylor £t al., 1971). The exact nature and extent
of this danger has stimulated lengthy detailed experimentation on
non-human mammals.
Compared to the chlorinated hydrocarbons, the fluorocarbons
possess almost negligible hepatatoxicity (Clayton, 1970). However,
the fluorocarbons do not seem to be entirely benign. Beritic and
Dimov (1971) report that 1.02 out of 10,000 anesthetic administra-
tions of halothane resulted in severe post-operative liver damage
in 1967. Ether resulted in only 0.49: 10,000 cases of such damage.
As yet, neither the extent of halothane involvement in these effects
nor the possible mechanism for such involvement is clearly under-
stood. Both direct hepatatoxicity and an immune response have
been proposed (Beritic and Dimov, 1971) . However, an jji vitro
immune response could not be demonstrated in the lymphocytes of
one group of 29 patients after halothane administration. Yet an
immune response cannot be ruled out in an in vivo system (Waldron
and Ratra, 1972). Also, in that the incidence of liver damage is
125
-------
on the order of 1 in 10,000, a randomly selected group of 29 would
not be expected to demonstrate the allergic mechanism even if such a
a mechanism is involved in hepatotoxicity. No mechanism for direct
liver damage has been postulated in the literature, but the various
biological parameters previously outlined seem to deserve further
investigation (Clayton, 1970).
2. Chronic Inhalation
Studies on long term low level inhalation of fluorocarbons
are primarily concerned with occupational exposure to operating
room personnel or workers in related situations. Recurrent hepa-
titis which lead to cirrhosis of the liver has been reported in an
anesthetist (Beritic and Dimov, 1971). A low incidence of similar
cases are summarized by Waldron and Ratra (1972). Of interest
is a rare case of halothane liver damage which did show halothane
induced lymphocyte stimulation. While this might indicate a form
of allergic response, the sensitivity may be lost over relatively
short periods of time. Similar studies using trichlorotrifluoroethane
(113) indicated no toxic effects at a mean concentration of 699 ppm
over an average of 2.77 years of occupational exposure (Imbus and
Adkins, 1972). Female anesthetists have an increased rate of
spontaneous abortions and the offspring show a higher incidence
of congenital abnormalities, but the role of anesthetics has not
been clearly assessed (Geddes, 1972). Halothane, at any rate does
126
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not seem teratogenic in vivo, causing no marked chromosomal damage
in cultured human leucocytes (Nunn £t _al., 1971). Thus, although
the chronic inhalation data for humans is hardly extensive, fluoro-
carbons seem to have a low order of toxicity but the development
of individual hypersensitivity seems possible (Clayton, 1970)
3. Ingestion
Dykes (1970) has noted three cases of halothane ingestion,
each in relation to a suicide or attempted suicide. In two cases,
*»
250 ml were imbibed by a 48 year-old female and a 28 year-old male.
Both survived, with the female first receiving medical attention
4*5 hours after ingestion (the time before treatment commenced for
the male was not specified). In the third case, a 19 year-old
drank 35 ml of halothane and was found dead after 12 hours. This
death is probably attributed to lack of prompt medical care.
Cases of ingestion, however, are rare and are not likely to pose
any wide-spread threat to human life.
4. Polymer-Fume Fever
Pyrolysis products of tetrafluoroethylene polymers (PTFE) have
been recognized as having adverse effects on man since 1951. The
disease is occupational and usually associated with smoking
cigarettes that have been contaminated with PTFE dust. The
response is characterized by tightness of chest, malaise, shortness
1
of breath, headache, coughing, chills, elevated temperature and
127
-------
sore throat (Lewis and Kerby, 1965). The minimum one time dose
is on the order of 0.40 mg PTFE (Clayton, 1970). The disease seems
specific to man and cannot be reproduced in laboratory animals
I
(Bischoff, 1972). The specific pyrolysis products responsible for
polymer-fume fever have, not been identified. Given the degradation
products of PTFE over the 300-700°C range and the average temperature
of 884°C for the burning zone of a cigarette, any of the following
fluorocarbon products might be involved: octafluoroisobutylene,
tetrafluoroethylene, hexafluoroethane, hexafluoropropylene, octa-
fluorocyclobutane, or perfluoroisobutylene (Williams and Smith, 1972).
The ill effects last for only a few days after removal of the causative
agent (Lewis and Kerby, 1965).
B. Toxicity to Non-Human Mammals
1. Acute and Subacute Toxicity
The toxicity of the fluorocarbons may be discussed in terms of the
various chemical groupings. The first of these, the fluoromethanes,
illustrates well the basic characteristics of fluorocarbon toxicity.
Table VIII indicates the toxicity levels for three groups of fluoromethanes.
128
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TABLE VIII
Inhalation Toxicity of Fluoromethanes
[Clayton, 1970]
EXPOSURE
Concentration Time
Group
A
B
''
C
Structure
CHC13
CHC12F
CHC1F2
CHF3
CC1U
CC13F
CC12F2
CC1F3
CFi,
CH3C1
CH2C12
CHC12F
CC12F2
(%)
2.0
10.0
20.0
20.0
2.0
10.0
20.0
20.0
20.0
2.0
5.0
10.0
20.0
(hr)
2
1
2
2
2
2
2
2
2
2
2
1
2
Fatality
Yes
Yes
No
No
Yes
No
No
No
No
Yes
Yes
Yes
No
*
Class
3
4-5
5a
6***
3
5a
6
6***
6***
4
4-5
4-5
6
**
TLV
50
1000
(1000)
(1000)
10
1000
1000
(1000)
(1000)
100
500
1000
1000
*Clas.«?ified according to Underwriters' classification. The higher
the value the lower the toxicity.
**TLV, threshold limit value assigned by the American Conference of
Governmental Industrial Hygienists, 1968 values. Figures in
parentheses indicate provisional values.
***Based on data from Haskell Laboratory.
As a rule, the toxicity decreases as the number of fluorine atoms increases.
Chemically, the decrease in toxicity may be seen as an increase in the
stability of the molecule due to fluorine substitution (Clayton, 1970).
The above data, in that it indicates only lethal doses, might be con-
sidered only a rough criteria by which to compare toxicity. However,
the detailed studies of Lester and Greenberg (1950) over a wide range of
responses bear out the above generalization. The effect of trichloro-
fluoromethane and dichlorodifluoromethane on rats for 1/2 hour exposure
periods at various concentrations are indicated in Table IX.
129
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TABLE IX
Dose/Effect Relationship for CCl^Fo and CC1»F
[Lester and Greenberg, 1950]
% CC12F2 in air % CClgF in air
No effect 20-40 5
Mild Intoxication 50 6-7
Moderate Intoxication 60 8
Unconsciousness 70-80 9
Mortality - 10
The relationship seems to hold not only for the effect on the central
nervous system, but also for the sensitization of the heart to epinephrine.
Table X shows the response of beagle dogs exposed to various concentra-
tions of CHC1F-, CC12F2, CC1.-F over a five-minute interval.
TABLE X
Cardiac Sensitization to Epinephrine
[Reinhardt et al., 1971]
Compound Cone. (%) % Sensitization
CCLjF 1.21 41.3
CC12F2 5.0 41.7
CHC1F2 5.0 16.7
From this study it might also be tempting to assume not only that toxicity
decreases with the number of fluorine atoms but also that it increases
with the number of chlorine atoms [a standard assumption in simple
chlorocarbon toxicity]. However, biological systems do not readily lend
themselves to firm rules. Note from Table X'(Clayton, 1970) that CHC12F
is significantly more toxic than CC1JP. For this specific case, the
130
-------
significantly higher dipole moment for CHC12F (1.293) over CC13F (0.45)
might result in an increased ability of CHC12F to bind to the positive
and negative areas of macromolecules similar to the effect noted by
Pennington and Fuerst (1971).
The bromine substituted fluorocarbons seem to behave much the same
as the chloroderivatives with respect to the influence of fluorination
on toxicity, but the data obtained thus far is severely limited. Only
two compounds have been compared in this survey: bromotrifluoromethane
(CBrF ) and bromochlorodifluoromethane (CBrCIF-). At concentrations
of 5.0% - 30.0%, CBrCIF- has been shown to have marked central nervous
system and cardiac effects on rats, mice, guinea pigs, dogs, and a monkey'.
The neurologic effects included initial stimulation, tremors, convulsions,
and eventual CNS depression leading to death. The cardiac effects
entail a decrease in the force of contraction and a sensitization to
epinephrine induced arrhythmias (Beck et al., 1973). At comparable
concentrations, 10.5% - 42%, CBrF. leads to some decrease in performance
of pre-conditioned tasks in monkeys but no central nervous system
damage (Carter jit al., 1970). This is similar to the minor effects
noted in man at concentrations of 7% (Call, 1973). At a concentration
of 30% [which caused the most severe damage using CBrClF2], CBrF- did
cause mild to moderate hypotension w ith some indication of arrhythmias
and a slight decrease in neural response in cats (Greenbaum £££!.•» 1972).
At concentrations of 80%, there was a reversible decrease in neural
inhibition of the heart and evidence of significant general neural
suppression (V^n Stee and Back, 1972>. Thus, while both CBrClF_ and
131
-------
CBrF are capable of demonstrating neural and cardiac toxicity» CBrF-
seems appreciably less potent. To what extent this is caused by an
increase of a fluorine atom as opposed to the absence of the chlorine
cannot be determined without more data.
The overall effect of bromination as compared to chlorination on
the methane series also cannot be clearly determined. Detailed data is
available on only one set of comparable compounds, CC12F2 anc* CBrCIF-.
At concentrations of 30% over 30 minutes to rats, CBrCIF- has a much
more deliterious effect on cardiac and neural tissue (Beck et al., 1973)
than the relatively mild muscular twitching caused by CC12F2 (Lester
and Greenberg, 1950). Yet this data does not seem sufficient to warrant
any generalization.
The toxicity of the fluoroethanes is similar to that of the methanes
in that an increased number of fluorine atoms tends to decrease the
toxicity. Table XI illustrates this progression for a series of two to
six fluorine atom molecules (Clayton, 1970).
132
-------
TABLE XI
Acute Inhalation Toxicity of Several Fluoroethanes
[modified from Clayton, 1970]
#F
2
2
3
3
4
4
5
5
6
Structure
CC12F-CC12F
CC1F2-CC13
ALC(%)*
Exposure (hr)
Animal
CC12F-CC1F2
CC1F2-CHF2
CC1F2-CC1F2
CC1F2-CF3
1.5
1.5
3.5**
10.0
>20.0
>20.0
>10.0
>80.0***
>80.0***
4
4
4
4
2
8
4
4
4
Rat
Rat
Rat
Rat
Guinea Pig
Guinea Pig
Rat
Rat
Rat
*ALC, approximate lethal concentration, a reliable estimate of LC
50
**LC
50
***Fluorocarbon, 80%; oxygen, 20%.
A steady decrease is seen along the series with the unexplained exception
of CHF2~CF~. However, equally important, a consistent hydrogen/chlorine
effect seems evident. For the two compounds in the three, four, and
five series, the only difference is a hydrogen in place of a chlorine
atom. In each case, the hydrogen compound is appreciably more toxic.
This may relate to the previously noted greater toxicity of CHC12F over
CC13F. The data presented for the two fluorine atom series shows no
variation in a fluorine/chlorine substitution. Similar studies on the
same two fluorocarbons by Greenberg and Lester (1950) proved similarly
inconclusive. CC12F-CC12F at 0.5% caused death as early as 4 hours and
as late as 36 hours. CC13-CC1F2 at .2.0-3.0% caused death in 1-2 1/2
*
hours. Thus both evidence about the same degree of toxicity. However,
133
-------
in another series of compounds, CH -CHF_ and CH -CC1F-, the chlorine
again causes an apparent decrease in toxicity (Lester and Greenberg,
1950). CH2-CC1F2 caused death in rats at 50%-80% over a 30 minute
period. CH2-CHF2 caused death in rats at 50%-55% over a 10 to 25 minute
period. Consequently, it seems clear that hydrogen substitution of
chlorine may significantly increase the toxicity of chlorofluorocarbons.
The general decrease in toxicity with increased fluorination seems
valid not only for acute inhalation but also for cardiac sensitization.
In the beagle dog over a five minute period of exposure, 5.0% CIF^C-
CF-C1 caused 58.3% sensitization. Under the same circumstances, 25%
C1F2C-CF. caused only 33.3% sensitization (Reinhardt et aL., 1971).
The effect of bromination as opposed to chlorination is indicated
in Table XII.
TABLE XII
-Comparison of Bromine and Chlorine in the Acute
Inhalation Toxicity of Flubroethanes
[Clayton, 1970]
*
Lethal Concentration
Compound (% by volume)
CH2C1-CF3 25.0
CH2C1-CHF2 7.5
CH2Br-CF3 11.7
CH2Br-CHF2 4.6
*Mice were exposed for 10 minutes.
The substitution of bromine for chlorine decreases the toxicity of
fluoroethanes. This effect may be additive in that the lethal concentra-
tion for CH.Br-CBrF2 is 1% as opposed to 4.6% for CH2Br-CHF2 (Lester and
Greenberg, 1950).
134
-------
The effect of fluorination on fluoroethylenes is by no means
clear. Clayton (1970) summarizes data presented in Tables XIII and XIV
indicating that increased fluorination may increase toxicity.
TABLE XIII
Inhalation Toxicity of Several Fluoroalkenes
[Clayton, 1970]
Structure
CH2 = CHF
ft^y — f*U
L»r 2 ~" ^**2
CF2 = CF2
CF3-CF = CF2
(CF3)2 = C = CF2
No. of F Atoms
1
2
4
6
8
Acute Toxicity for
ALC (ppm)
> 800,000**
128,000
> 800,000***
0.5, 0.76****
Rats
LC50
40,000
3,000
*Exposures are for 4 hour duration except where noted. ALC,
approximate lethal concentration. LCso, lethal concentration
for 50% of rats exposed.
**CH2 = CHF, 80%; 02, 20%; 12.5 hour exposure.
***CH2 = CF2, 80%; 02, 20%; 19 hour exposure.
****Exposure at 0.5 ppm, 6 hour; at 0.76 ppm, 4 hour.
TABLE XIV
Inhalation Toxicity of Several Halogenated Alkenes
[Clayton, 1970]
Structure
CC12 = CH2
CHC1 = CC12
CC12 = CC12
CC12 = CF2
CC1F = CF2
No.
F
0
0
0
2
3
of Atoms
Cl
2
3
4
2
1
Acute Toxicity for
ALC (ppm)
32,000
8,000
4,000
1,000
Rats*
LC50
1,000
*Exposures of 4-hour duration. ALC, approximate lethal
concentration. LCso, lethal concentration for 50% of rats
exposed..
135
-------
Clayton (1970) proposes that, the toxicity of these compounds may be
affected primarily by the double bonds rather than the degree of
fluorine substitution. While this may hold true for structurally dis-
similar compounds, there is some indication that closely related com-
pounds do show a decrease in toxicity with increased fluorination.
Lester and Greenberg (1950) found that at concentrations of 80% and
exposure periods of 30 minutes CH2=CF_ had a noticeably less toxic
effect on rats than did CH =CHF. This agrees with the data presented
by Clayton (1970) indicating that 80% CH2=CF2 required 6.5 more hours
of exposure than did 80% CH2=CHF to elicit an acute toxic response in
rats. The relative paucity of experimental data prevents productive
comparison of the fluoroethanes with the fluoroethylenes.
Certain fluorinated butylenes have been studied in some detail and
found to be highly toxic. Beritic and Dimov (1971) have cited 2,3-
dichloro-l,l,l,4,4,4-hexafluorobutene-2[DCHFB] as a 180-300 ppm contam-
inant in halothane. This highly toxic compound has been suspected of
causing the hepatotoxic response to halothane (Clayton, 1970). Toxicity
data on DCHFB is summarized in Table XV.
TABLE XV
LC5Q for DCHFB
[Truhaut et al., 1972]
LCso (1 hr.) LC50(3 hr.) LCso (4 hr.)
16 - 100 ppm
26 ppm
182 ppm
Rats
Mice
Dogs
Monkeys
Rhesus
100 ppm
61-75 ppm
50 ppm
200 ppm
90 ppm
54 ppm
136
-------
Although DCHBF has been shown to cause liver damage (Clayton, 1970),
Truhaut and coworkers (1972) showed that the liver function was
usually normal in fatally intoxicated rabbits (Table XVI). This seems
to agree with the low incidence of "halothane hepatitis", 1:10,000.
The prime characteristic is a delay in lethality similar to that noted
for l-chloro-l,2,2-trifluoroethylene (Walther £t al., 1970).
TABLE XVI
Delayed Death After DCHFB Administration to Rabbits
[Truhaut et al., 1972]
Concentration
Exposure time
Delayed
Death
500 ppm
1 hour
85 min.
to 3 1/2
hours
200
1 hour
12 hours
100
1 hour
4 days
200
30 minutes
3 days
200
15 minutes
0
Such a delay indicates that a metabolite such as trifluoroacetic acid
rather than the parent compound may be the toxic agent (Truhaut et al.,
1972).
As can be seen from Table XIII, perfluoroisobutylene (PFIB) is the
most toxic of the fluoroalkenes cited. However, with the exception of
Clayton's brief summary (Clayton, 1970), no studies on this compound
were encountered in the literature.
2. Chronic Toxicity
Fluorocarbon toxicity has been studied primarily as an acute response.
Chronic data is scarce but a very low level of chronic toxicity seems
indicated. This is to be expected given the body's apparent ability
137
-------
to excrete fluorocarbons. Table XVII summarizes experimental work
showing essentially no pathology with chronic levels of exposure.
TABLE XVII
Chronic Exposure to Some Fluorocarbons Showing No Pathology
Compound
CC13-CC1F2*
CC12F-CC12F*
CC12F-CC12F**
CH -CHF2***
Animal
Rat
Rat
Mice, Guinea
Pig, Rabbit
Rat
Rat
Concentration
0.1%
0.1%
0.1%
1.0%
10.0%
Exposure
18 hr/day x 17 days
18 hr/day x 16 days
6 hr/day x 30 days
16 hr/day x 60 days
16 hr/day x 60 days
*Greenberg and Lester, 1950.
**Clayton et al., 1964.
***Lester and Greenberg, 1950.
The only positive chronic toxicity was obtained with the exposure of
rats to 0.1% CC12F-CC12F for 6 hr/day x 30 days. A slight decrease in
leucocytes in the peripheral blood was noted along with lung irritation
and unspecified histologic changes in the liver (Clayton e£ al., 1964).
While the above studies do deal with chronic exposures in comparison
to other fluorocarbon studies, it must be noted that the concentrations
are extremely high and the exposure period correspondingly short with
reference to environmentally meaningful studies.
138
-------
3. ,Sensitization
There is clear evidence that some humans may become sensitized to
to halothane exposure (Beritic and Dimov, 1971) and similar
sensitization might be expected in other mammals. Nevertheless,
halothane itself has not been shown to act as a partial anti-
gen in rats and is probably not responsible for the sensitization
Since unidentified trifluoropeptides do accumulate in the liver
and circulate in the blood, Rosenberg (1972) proposes that
fluoroacetaldehyde may combine with mitochondrial proteins
thus causing an auto-immune response.
In the only other sensitization study encountered, 1,1,2,2-
tetrachloro-l,2-difluoroethane did not produce skin sensitization
in guinea pigs (Clayton et al., 1964).
4. Teratogenicity
As noted in the discussion of human toxicity, halothane
has been shown to be a reversible mitotic spindle poison
(Nunn et al., 1971). Such compounds must always be considered
potential teratogens due to possible non-disjunction if not
actual chromosomal damage. However, in the absence of
experimental data, the teratogenic effect - if any - of halo-
thane or any other fluorocarbon is speculative at best.
139
-------
5. Carcinogenlcity
Fluorocarbons alone have not been implicated as carcinogenic
agents. However, fluorocarbons - particularly tetrachloro-
difluoroethane(112) - in conjunction with piperonyl butoxide
has been shown to be hepatocarcinogenic in mice (Epstein et al.,
1967). As indicated in Table XVIII, neither compound alone
shows appreciable carcinogenic!ty.
Similar follow up studies have not been encountered, thus
the significance of this study is difficult to evaluate.
However, the possibility of synergistic behavior of the
fluorocarbons with other environmental compounds should be
an area of future investigations.
6. Mutagenicity
No studies on fluorocarbon mutagenicity have been encountered.
7. Behavioral Effects
Intoxication and anesthesia might be considered behavioral
effects but these are amply discussed under toxicity studies.
140
-------
TABLE XVIII
Tumors Induced in Swiss Mice by Injection of "Freons"
and Piperonyl Butoxide Shortly After Birth
[from Epstein e± al., 1967]
Treatment Group
No. of mice, subsequently aucopsied,
alive at the beginning of each period
Sex (No. at risk)
Weeks
11-20 21-30 31-40 41-50 51+
Kepatcoas
No. tumors in each period
No. as Z of No. of mice at risk
Weeks
21-30 31-40 41-50 51+
Malignant lymphomas
No. tumors in each period
No. as % of No. of mice at risk
Weeks
21-30 31-40 41-50 51+
Solvent controls
"Freon" 11
"Freon" 112
"Freon" 113
Piperonyl butoxide
"Freon" 112 and piper-
onyl butoxide
"Freon" 113 and piper
onyl butoxide
* One of these also had a pulmonary adenoma.
M
F
M
F
M
F
M
F
M
F
M
F
M
F
72
69
25
20
27
22
29
21
40
36
30
29
25
24
68
69
25
20
27
22
29
21
38
36
26
29
24
24
59
69
22
20
27
21
29
20
35
36
26
28
24
24
55
68
21
20
20
20
26
20
25
36
14
25
19
24
48
68
21
20
17
19
21
20
20
36
13
24
18
24
4
0
2*
0
0
0
1
0
0
0
5
0
3
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
7
0
0
0
ff
0
10
0
0
0
5
0
0
0
31
0
17
0
1
0
1
0
0
0
0
1
0
0
0
3
0
1
0'
0.
4
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
o .
0
0
0
A
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2
0
0
0
0
0
0
5
0
0
0
8
0
It
-------
C. Toxicity to Lower Animals
No studies of fluorocarbon toxicity to the lower animals have
been encountered.
D. Toxicity to Plants
Halothane has been shown to cause metaphase arrest in the root
tips of Vicia faba, the European broad bean. The ED,_0 ranges from
0.5-0.9%. Total arrest is achieved with 2.0% over 8 hours
(Nunn et^ _al., 1971). Although fluoroacetate can be accumulated by
some plants (Peters, 1963), there is no evidence that it is the
result of fluorocarbon metabolism.
E. Toxicity to Microorganisms
Similar to its effect in Vicia faba (Nunn et al., 1971), halo-
thane has been shown to cause reversible microtubular disruption at
2% concentration over a 7 minute period in Actinosphaerium nucleofilum,
a heliozoan protozoa (Allison et al., 1970).
Halothane and chlorodifluoromethane have both been shown to
decrease the bio-luminescence of Photobacterium phosphoreum (White
and Dundas, 1970). The effect of halothane is shown in detail in
Figure 3.
142
-------
Figure 3: Effect of Halothane on Bioluminescence
of P^. phosphoreum
[from White and Dundas, 1970]
This effect occurs at concentrations comparable to those
causing anesthesia in mice (Halsey and Smith, 1970). Dichloro-
difluoromethane and 1,1-difluoro-l-chloroethane were both found
to be toxic to a wide variety of microorganisms in liquid but not
in vapor stages (Prior _et_.al. , 19-70).
While these few studies do not allow for broad generalizations,
they do indicate that at least some microorganisms respond to
certain fluorocarbons at comparable concentrations causing
physiological responses in higher life forms.
143
-------
XI. Fluorocarbons: Summary and Conclusions
Fluorocarbons are an obvious and growing source of environmental
contamination. An annual production of nearly one billion pounds may be
reached in the next decade. Of this production, over half will be
directly released into the environment as aerosol propellants, solvents,
or refrigerant leakage. The specific types and relative order of
fluorocarbon discharge will probably be dichlorodifluoromethane > tri-
chlorofluoromethane > chlorodifluoromethane » dichlorotetrafluoroethane >
trichlorotrifluoroethane. The two more common of these (dichlorodifluoro-
and trichlorofluoromethane) have already been monitored in the environment
at background concentrations below 1 ppb. The fluorocarbon plastics,
while not used in high turnover products, will eventually enter the
environment either intact or as pyrolysis products in millions of pounds
per year amounts. Proposed new uses for the fluorocarbons (e.g. food
freezing and dry cleaning) may provide high exposure potentials similar
to present uses.'
Under normal environmental conditions, all of the fluorocarbons will
probably show a marked degree of persistence. The C-F bond is highly
stable and biological reductive defluorination does not seem likely.
Although precise estimates of persistance are not yet possible, residence
times on the order of 10-30 years do not seem improbable. Monitoring
information thus far available on dichlorodifluoromethane and trichloro-
fluoromethane indicates that the actual and theoretical orders of fluoro-
carbon persistence may be in agreement. Taking into account both
144
-------
production and persistence, a total environmental load of five billion
pounds may well be a conservative estimate.
Usage and monitoring data both indicate that the fluorocarbons will
be primarily distributed in areas of high population or production. By
far the greatest amount of fluorocarbon release will be consumer based
from aerosol sprays. Dwellings are likely to contain significantly greater
amounts (hundreds of ppb) than the ambient air. Obviously; the air is the
most probable mode of transport with the fluorocarbon concentration
constantly moving toward equilibrium. Thus, as fluorocarbon use proceeds,
background levels in populated and nonpopulated areas are likely to
increase steadily, while levels inside of dwellings will fluctuate
widely depending on the amount of fluorocarbons used.
Although the likelihood of fluorocarbon release into the environment
in increasingly large amounts is well documented, the hazards posed by
such contamination are ill-defined. Cases of aerosol abuse, polymer-
fume fever, and halothane hepatitis are primarily medical problems and
have little, if any, environmental relevance. Mammalian systems do not
seem to exhibit any toxic response in chronic exposures to the commercially
important fluorocarbons at concentrations as high as 100,000 ppm. Micro--
bial organisms 'exhibit a similar degree of fluorocarbon resistance.
However, not enough is known of the biological behavior of these compounds
to rule out long-term occult pathogenesis. There are reasonable indications
that fluoromethanes may bind tightly to biologically important macro-
molecules. Tnis has been shown to result in metabolic interference and
145
-------
may also be used to postulate possible mechanisms for biological
accumulation and magnification. Further, plants and non-mammalian
animals have not been extensively studied for fluorocarbon toxicity.
If macromolecular binding is a reasonable possibility, population
decreases and reduced viability of these organisms might be a good
indicator of fluorocarbon hazard.
Fluorocarbons, like anyf foreign substances that are released in the
environment in large amounts,' are potential environmental poisons.
Although these compounds do not seem to represent an immediate danger,
a steady increase in environmental concentrations may be expected.
Where the danger threshold is cannot be determined without further study.
Present "chronic" toxicity data are given in terms of hundreds of days.
Such information has limited environmental application. Study periods
based on the half life of important organisms would be more helpful.
One point, however, seems relatively certain. If toxic concentrations
are reached before the danger threshold is set^ ecological havoc is
likely to ensue. Fluorocarbons are both plentiful and persistant.
These factors alone would seem to warrant a more precise definition of
their environmental toxicity.
146
-------
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152
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BENZENEPOLYCASBOXYLATES
(Acids, Anhydrides, and Salts)
Because of their commercial importance, this report will focus on
t
the following chemical commodities:
C02H
02H
C02H
C02H
phthalit acid
(PA)
phthalic anhydride
(PAN)
isophthalic acid
(IA)
H02C
C°2H
terephthalic acid
(TA)
dimethyl terephthalate
(DMT)
C02H
H02C
o
trimellitic acid
(TMA)
trimellitic anhydride
(THAN)
C02H
O
C02H
trimesic acid
(TMSA)
H02C
pyromellitic acid
(PMA)
pyromellitic dianhydride
CPHDA)
153
-------
Dimethyl terephthalate was included with terephthalic acid because they
are virtually inseparable so far as their major applications are concerned.
154
-------
I. Physical Properties
The benzenepolycarboxylate compounds are generally crystalline white
or colorless solids Jat ambient temperatures. Terephthalic acid is the
most insoluble in water and has the highest melting point of all the
benzenecarboxylic acids. The high melting point makes it a difficult
material to purify. Therefore, the lower melting dimethyl ester is
often used as a source of terephthalate.
•
' The physical properties of the anhydrides are dependent upon the
equilibrium constant of the reaction: Anhydride + H_0 + Acid. Of
course, anhydrides are only formed in compounds that contain acid
functions ortho to each other (PA, TMA,PMA). Phthalic anhydride at room
temperature is relatively stable, while trimellitic anhydride will react
with water vapor to form the acid.
Physical constants for some of the benzenepolycarboxylates are
listed in Table I.
155
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TABLE I
Physical Properties of Commercially Important Benzenepolycarboxylates
(Towle et. al., 1968)
Compound
Property —
Boiling point *C
Melting point (dry air) °C
Specific gravity or density
Sublimation point °C
lonization Constant
First
Second
Vapor pressure (mmHg)
Solubility g/lOOg solvent
H20
glacial ACOH
methanol or ethanol
Hydrocarbon solvent
halogenatcd solvent
PA
191
1.1 x 10";*
5.5 x 10~°
0.54
(14°C)
12.0
(100°C)
11. 7 (e)
(18'C)
PAN
284.5
131
1.527
6
(132°C)
0.62
(25°C)
IA
345
1.507
3.3 x 10"*
3.2 x 10
0.013
(25°C)
0.078
(25°C) .
2. l(m)
(25°C)
insol.
(benzene)
TA
1.510
g/ml
402
3.1 x 10"*
1.5 x 10
0.5
(120°C)
0.0019
(.25°C)
0.035
(25°C)
O.l(m)
(25°C)
DMT
288
140
10
(141°C)
1.0(m)
(25°C)
2.0
(benzene)
1.5
CC14(25°C)
TMA
216-218
3.0 x 10"?
1.4 x 10
2.1
(25°C)
25. 3 (e)
(25°C)
0.006
(xylenes)
0.004
(CC14)
TMAN
390
168
2
(200' C)
reacts
reacts
0.4
(xylenes)
0.002
(CC14)
TMSA
375-380
(sub lines)
7.4 x 10~*
1.3 x 10
0.24
(25°C)
8.0(m)
(25'C)
<0.01
(o-^xylene)
<0.01
(CC14)
PMA
257-265
(decomp . )
*
1.20 x 10~*
1.29 x 10 J
1 .
(20"C)
10(e)
(10°C)
—/
PMDA
397-400
287
1.68
t
Ol
-------
II. Production
Of the benzenepolycarboxylates, the disubstituted acids and anhydrides
are the most important commercially. Terephthalic acid, the dimethyl
ester of terephthalic aicd, and phthalic anhydride are produced in the
largest quantities. Table II presents the available production figures
for the various benzenecarboxylates. Lack of information on the
trimellitic acid production required the substitution of ester production
figures. The quantity of trimellitic acid produced will be somewhat
smaller than the ester production due to the increase in molecular weight
of the ester product (assuming relatively high reaction yields).
The capacities and plant locations of major producers of benzenepoly-
carboxylates are listed in Table III. A variety of manufacturers and
production sites are involved in the manufacture of these chemicals.
157
-------
wn
CO
TABLE II
Production of Benzenepolycarboxylates
(U.S. Tariff Commission, 1961-1971; Towle et al., 1968, Blackford, 1970)
PAN IA DMT TA Trimellitic Polyimide
Acid Esters Polymers
(TMAN and PMDA based)
1961
1962
1963
1964 .
1965
1966
1967
1968
1969
1970
19 7 lp
109g
172
194
208
253
276
306
330
337
345
333
360
106 Ibs
380
427
459
558
608
675
727
744
760
»
734
794
109g
20
• 25
27
29
32
34
39
43
43
106 Ibs
45
55
60
65
70
75
85
95
95
109g
32*
29*
150
161
247
362
425
594
697
656
789
106 Ibs 109g
70*
65*
331
356
545
797 233
936 315
1,309 420
1,537 474
1,447 603
1,739 718
106 Ibs
514
694
927
1,045
1,329
1,582
109g 106 Ibs lQ9g 106 Ibs
0.40
0.52
0.90*
1.15
2.84
2.15
3.42
4.40
5.14
0.88
1.14 0.11 0.25
1.98*
2.54
6.25
4.73
7.55
9.70
11.34
*Sales
-------
TABLE III
Capacities for Production of Benzenepolycarboxylates
Phthalic Anhydride
(Erskine, 1970; Chemical Marketing Reporter, 1972)
Producer
Allied Chemical Co.
BASF Wyandotte
Chevron Chemical Co.
Enjoy Chemical Co.
W.R. Grace & Co.
Koppers Company, Inc.
Monsanto Company
Puerto Rico Chemical Co.
(Hooker Chem. Corp.)
Reinhold Chemicals, Inc.
Sherwin Williams Chemicals
Stepan Chemical Co.
Union Carbide Corp.
United States Steel Corp.
Plant Capacity
(million Ibs.)
135
Plant Location
El Segundo, Calif.
Frankford, Pa.
40 (not operating)Ironton, Ohio
130
50
90 (in start-up
procedure)
75 (on stand-by) Fords, N.J
220
South Kearney, N.J.
Richmond, Calif.
Baton Rouge, La.
210
100
130 (uncertain
of status)
20 (uncertain
of status)
48
100
125
Bridgeville, Pa.
Chicago, 111.
Bridgeport, N.J.
Texas City, Tex.
Arecibo, Puerto Rico
Elizabeth, N.J.
Morris, 111.
Chicago, 111.
Millsdale, 111.
Institute, W. Va.
Neville Island, Pa.
Isophthalic Acid
(Towle et al., 1968; Blackford, 1970)
Chevron Chemical Co.
Amoco Chemicals Corp.
Atlantic Richfield Co.
35 (closed, 1967) Richmond, Calif.
88 Joliet, 111.
35 Channelview, Tex.
Dimethyl Terephthalate and Terephthalic Acid
(Frey, 1970; Chemical Marketing Reporter, 1973)
900
220
(DMT and TA)
Amoco Chemicals Corp.
E.I. DuPont de Nemours & Co., Inc.
Eastman Kodak Co. (Tennessee Eastman Co.)350 (DMT only)
Hercules,'Inc.
300)
250> (DMT only)
Hoechst Fibers
Mobil Chemical Co.
Amoco Chemicals Corp.
150 (DMT only)
850 (DMT and TA)
150 (DMT only)
150 (TA only)
Trimellitic Anhydride
(Towle. et al., 1968T"
50
Decatur, Ala.
Joliet, 111.
Gibbstown, N.J.
Old Hickory, Tenn.
Wilmington, N.C.
Kingsport, Tenn.
Burlington, N.J.
Wilmington, N.C.
Spartanburg, S.C.
Beaumont, Tex.
Joliet, 111.
159
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III. Uses
Benzenepolycarboxylic acids are important organic intermediates in
the plastics industry. They are used to synthesize plasticizers, alkyd
resins, and condensation polymers of various types, polyesters and poly-
*
amides being the most common. These polymers are used in the production
of fibers, film, surface coatings, and molding polymers. The following
discussion is divided into sections for the commercially important isomers,
A. Phthalic Acid (PA) and Phthalic Anhydride (PAN)
Air oxidation of naphthalene or a-xylene produces phthalic
anhydride, which is the form utilized in the preparation of secondary
products. The major outlet for phthalic anhydride is in the pro-
duction of diesters of monohydric aliphatic alcohols for plasticizers,
as can be seen in Table IV.
TABLE IV
Phthalic Anhydride Consumption-1968
(Erskine, 1970)
Use Quantity (1Q6 Ibs)
Plasticizers 364
Alkyd resins 193
Unsaturated polyester resins 95
Exports 21
Miscellaneous 90
763
160
-------
The largest volume product is the di(2-ethylhexyl)ester (DEHP). DEHP
and other diisooctyl and diisodecyl esters ("iso" means highly
branched in the plasticizer industry) are used in applications where
low temperature properties and low volatility are important. The
more volatile low molecular weight esters are used for polar polymers
like polyvinylacetate and cellulosics. The low price and flexibility
of the phthalate plasticizers suggests that they will continue to be
the most commonly used plasticizer growing at a rate of 8-10% per
year (Erskine, 1970).
Up until 1960, the use of phthalic anhydride in alkyd resins
was the major application. However, since that time, consumption
of phthalic anhydride for plasticizers has far exceeded consumption
for alkyd resins due to a relatively slow growth in alkyd resin
demand. Alkyd resins are produced by reacting polybasic acids or
anhydrides with polyhydric alcohols (e.g. glycerin and pentaerythritol).
These products are usually modified by inclusion of drying oils,
nondrying oils, semidrying oils, natural resins, or acids from
natural resins. These resins impart to the finished coating such
properties as outstanding weather and exposure resistance, flexibility,
and excellent adhesion to the surface to be protected.
The third largest use of PAN is in the preparation of unsaturated
polyesters. These are prepared by combining PAN, a glycol, and an
unsaturated acid or anhydride (usually fumaric acid or maleic
anhydride). This application represents the most dynamic and fast-
* -.
growing end use of PAN. A large portion of these polyesters are
161
-------
used for structural building parts such as in corrugated sheet
and in boat hulls.
Another major use of PAN is in the preparation of various classes
of dyes and various chemical intermediates. Table V lists some of
these dyes and intermediates.
TABLE V
Intermediates and Dyes Produced from
Phthalic Anhydride
(Towle et al., 1968, Erskine, 1970)
Product.
Anthraquinone dyes
Synthesized from
PAN and benzene or
other aromatic hydro-
carbons (Friedel-Crafts
reaction)
Production*
Quantities
(10 Ibs.)
51.97
Phthalocyanine
Xanthene
2-chloroanthraquinone PAN and chlorobenzene
Quinizarin (1,4- PAN and p-chlorophenol
dihydroxy-anthraquinone)
1.61
Rhodine dyes
Fluorescein
Anthraquinone
Phthalimide
PAN and aminophenols
PAN and resorcinol
PAN and benzene
PAN and ammonia
Use
Dye
1.76
1.11
0.53
Dye
Dye
Dye
intermediate
Dye
intermediate
One of the
xanthene dyes
One of the
xanthene dyes
Dye
intermediate
Phthalocyanine
dye intermediate
(general inter-
mediate for other
chemicals)
162
-------
Product
o-Phthalonitrile
Phenolphthalein
Methyl anthranilate
Tetrachloro- and
tetrabromophthalic
anhydride
Sulfathalidine
Lead salt of
phthalic acid
TABLE V
(continued)
Synthesized from
PAN, ammonia, and
then phosgene
PAN and phenol
Derivative of
phthalimide
PAN, bromine or
chlorine in
presence of
sulfuric acid
Production*
Quantities
(106 Ibs.)
.25
(sales)
Use
Phthalocyanine
dye intermediate
(general inter-
mediate for other
chemicals)
pH indicator and
medicinal
(laxative)
Perfume
Impart fire
resistance to
resins and foams
Medicinal chemical
Stabilizer
for PVC
Diallyl phthalate
Benzoic acid
(only in Europe)
Terephthalic acid
(only in Japan)
Sodium salt of
phthalic acid
PAN and allyl
alcohol
PAN decarboxylation
Phthalic acid salt
thermal rearrange-
ment
PAN and sodium
hydroxide
> 5.0
(Erskine, 1970)
small
amount
Cross-linking
agent in un-
saturated
polyesters
Intermediate
Intermediate
Tanning
industry
*U.S. Tarrlff Commission, Synthetic Organic Chemicals, U.S. Production and
Sales, 1970.
163
-------
B. Isophthalic Acid .
The largest application of isophthalic acid is in the production of
unsaturated polyester resins, as can be seen in Table VI.
TABLE VI
Consumption of Isophthalic Acid
(Blackford, 1970) (K)6 Ibs.)
Isophthalic Alkyd Exports Miscellaneous Total
Polyester Resins
Resins
1965
1966
1967
1968
1969
30
30
35
35
40
20
20
20
25
25
10
15
20
25
15
10
10
10
10
15
70
75
85
95
95
These isophthalic polyesters cost more than the general-purpose polyesters
(mostly PAN based) but have been able to capture some of the market because
they have better chemical resistance, more strength, and better high
temperature properties. The largest use of the isophthalic polyesters
is in glass-fiber-reinforced plastics which are utilized in bodies of cars
(e.g., Corvette sports car body), trucks, trailers, and boats, and in
corrosion resistant equipment and pipe. The molded plastic applications
include serving trays, surfboards, bowling balls, skateboards, archery
equipment, fishing rods, safety helmets, highway lane markers (dots), gel
coats, and heat and detergent-resistant buttons (Blackford, 1970).
Isophthalic acid has also entered another market of phthalic anhydride-
saturated polyester (alkyd) resins. Their initial use was in consumer paints
164
-------
and enamels, but the field of industrial coatings is exhibiting a faster
growth rate. Isophthalic acid has replaced PAN in many specialty coatings
markets because it imparts increased film strength, higher gloss, faster
drying, and higher melting properties to the resins.
Miscellaneous applications include use in the preparation of dioctyl
isophthate plasticizers (~2 x 10 Ibs./yr.) and use as modifiers and cross-
linking agents in polyester fibers and films, polyamide fibers, and high-
temperature-resistant polymers (e.g., polybenzimidazoles). Small amounts
of the isophthaloyl chloride find use in dyes, resins, films, and protective
coatings (Blackford, 1970).
C. Terephthalic Acid (TA) and Dimethyl Terephthalate (DMT)
Nearly all (-80-90%, Frey, 1970) the TA and DMT manufactured is used to
produce polyethylene terephthalate, the polymer used for making fibers and
films. The quantity of TA-DMT used for fibers (1,494 x 10 Ibs.) far exceeds
the quantity used for film (121 x 10 Ibs.) in 1969 (Frey, 1970). Polyester
fibers are mostly used in textile products, although a considerable amount
of filament yarn is used as tire cord. The film is used for magnetic tapes,
electrical insulation, packaging, and photographic applications.
Small amounts (-10 x 10 Ibs.) are used in the preparation of adhesives,
herbicides, printing inks, and specialty coatings and paints (Frey, 1970).
Terephthalic acid has also been used as an animal feed supplement to increase
the levels of antibiotics in the blood serum and liver (Towle elt ail., 1968).
165
-------
D. Trimellitic Acid (TMA) and Trimellitic Anhydride (THAN)
Trimellitic anhydride, the commercially used form, finds applications
in plasticizers, alkyd resins, unsaturated polyesters, printing inks, resin
intermediates, adhesives, molding resins, and dyes. The largest outlet for
THAN is in the preparation of specialty plasticizers such as the triisooctyl
and triisooctyl esters of trimellitic acid. These plasticizers find use with
vinyl resins where permanency is required, as in polyvinyl chloride wire
insulation, upholstery, refrigerator gasketing, and thin fabric coatings.
Other major applications include use in the production of poly (amide-imide)
polymers for use in wire enamels and electric-insulating varnishes, poly
(ester-imide) formulations for wire enamels, and water-based alkyd finishes
in the coatings industry.
E. Trimesic Acid (TMSA)
Trimesic acid is still in the development stage in terms of commercial
use. It is used in small quantities as a crosslinking agent and the acid
esters are used as plasticizers (Towle, et^ ^1., 1968).
F. Pyromellitic Acid (PMA) and Pyromellitic Dianhydride (PMDA)
The dianhydride of pyromellitic acid is the commonest commercial form.
PMDA when combined with aromatic diamines gives excellent high-temperature-
resistant polyimide polymers, which find use in molded parts, film, fibers,
and insulating varnishes. The dianhydride is also used as a crosslinking
agent for epoxy and other resins (Towle, eit ail., 1968).
166
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IV. Current Practices
A. Phthalic Anhydride
Phthalic anhydride is sold and transported in both the solid and
molten form. In the solid form it is usually sold in flakes packaged
in 80 Ib. multiwall paper bags. Small amounts of phthalic anhydride
)
are sold in one-trip containers holding up to about 2,000 Ibs. A red
label is not required. Fairly sizable quantities of phthalic anhydride
are shipped in the molten form to large users by tank cars or trucks.
The molten PAN will burn if ignited and its vapor may form an explosive
mixture with air. The Manufacturing Chemists Association (1956)
recommends that container bags be incinerated and that the PAN wastes
be disposed of by dumping in a special area isolated from all operations
and where no contamination of a drinking water supply will be involved.
i
B. Isophthalic Acid
Isophthalic acid is most commonly shipped as a free-flowing powder
in 50 Ib. multiwall paper bags. For large users, one trip palletized
fiberboard containers of 2,000-lb. capacity or hopper-cars may be
used. A red label is not required.
C. Terephthalic Acid and Dimethyl Terephthalate
Neither TA or DMT require a red label. The technical-grade TA
is generally supplied in 50-Ib. multiwall paper bags or 55 gallon
fiber drums while the polymer-grade acid is shipped in 55 gallon
167
-------
fiberboard containers (225-325 Ib. net), palletized fiberboard cartons
(1200-1400 Ib. net), returnable containers (approximately 4,000 Ib. net)
and hopper cars. DMT is usually formed into almond-shaped briquettes,
3
weighing about 5 g each, and shipped in returnable 98- or 100-ft.
metal containers handling 4600-5200 Ib. or in smaller shipments in
bags or 55 gallon fiberboard drums.
D. Trimellitic Anhydride
Trimellitic anhydride is shipped as a solid either in flake or
powder form. The flakes and powders are shipped in 50 Ib. multiwall
paper bags and fiber drums, respectively, and neither requires a
red label.
E. Pyromellitic Dianhydride
PMDA is usually shipped as a white powder in polyethylene bags
in fiber drums. The compound is sensitive to moisture and will
hydrolyze to the acid when exposed to atmospheric moisture for
appreciable lengths of time.
168
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V. Environmental Contamination
Although phthalate esters are often cited as widespread environmental
contaminants (Mayer £t al., 1972; Shea, 1972; Kites and Biemann, 1972;
Fishbein and Albro, 1972) from their use as plasticizers, little is known
about the extent of environmental contamination from benzenepolycarboxylic
acids, anhydrides and salts. No background level monitoring data is
available. However, these compounds are used in large quantities
(phthalic anhydride -800 x 106 Ibs.; TA-DMT ~3,300 x 106 Ibs.) and have
often been cited as pollutants on a local basis.
Phthalic anhydride is most often noted as an air pollutant because of
its low eye irritation threshold (4 ppm by volume). The manufacturing
plants are notorious for odor control problems (Turk et_ _al., 1972; Spitz,
1968). The major source is the process off-gas consisting of large volumes
of air contaminated with small quantities of organic vapor (see Table VII)
(Fawcett, 1970).
TABLE VII
Contaminants in Phthalic Anhydride Process Off-Gas
(Fawcett, 1970)
Contaminant Concentration Ranges
(ppm by vol)
Phthalic Anhydride 40-200
Maleic Anhydride 100-600
Naphthoquinone 10-30
Benzoic Acid 5-40
Aldehydes as CH20 10-100
Carbon Monoxide 1000-10,000
Carbon Dioxide 6000-50,000
169
-------
Scrubbing is capable of removing in excess of 99% of all the organic acids,
but requires neutralization prior to sewering or discharge to a watershed.
The most common form of control is catalytic oxidation equipment. This
type of control or direct flame incineration are estimated to produce at
least 90% combustion of organic contaminants. Without such controls, a
100 million Ibs. phthalic anhydride plant would discharge from less than
300 to over 1200 Ibs./hr. of organics. Other minor air emissions points
from phthalic anhydride plants include spills and losses from tank car
or truck loadings, process venting during re.fining, and emissions from
flaking and bagging (Fawcett, 1970). Water pollution problems from
phthalic anhydride plants are likely to be small since most processes
are dry. When wet scrubbing is used to control air pollution, the water
may sometimes be disposed of in a water shed, but in most cases is sent to
a sewage treatment plant. Phthalic acid wastes have been noted in waste
waters from paint and varnish industries (Mirkind and Sporykhina, 1968) and
alkyd resin plants (Minkoyich, 1960).
Evaluation of environmental contamination from production, use or
disposal of the other benzenepolycarboxylates has not been reported.
170
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VI. Monitoring and Analysis
Few analysis methods, which might be used to monitor environmental
samples containing extremely low concentration of the chemicals, have
been reported .for benzenepolycarboxylates. Most of the methods reported were
used to detect the benzenepolycarboxylate in air or waste water effluents
from industrial concerns. For example, Yurko and Volkova (1964) used a
colorimetric method (react sodium salt of the acid with sulfuric acid
and resorcinol) to determine phthalic anhydride in waste water (limits
of detection not reported). Slavgorodskii (1965) reported an ethanol
absorption with spectrophotometric quantification method for determining
phthalic anhydride in atmospheric samples (no limits of detection).
Kogar (1958) also determined phthalic anhydride in air, but used a filter
paper collection system with polarographic quantification (again no limits
of detection reported). A photometric technique for ug amounts of phthalic
acid, and the anhydride, ester, imide, and substituted monoamide derivatives
in both air and water samples was used by Ciuhandu et al. (1969). Air
samples were collected in alcohol. Quantification was determined by heating
the sample to 210°C with 83% ZnCl2> cooling the sample, adding Na^O-
and then 25% NH,, filtering, and measuring the absorbance at 488 nm.
The relative error was less than 3% for 10 yg of phthalic anhydride.
Levchenko et al. (1968) used gas-chromatographic analysis to detect
benzenepolycarboxylic acids from a terephthalic acid plant (toluene
oxidation process). The acids were first esterified with, diazomethane to
i
the methyl esters. Fishbein and Albro (1972) have also used methylation
171
-------
and gas-chromatography for Structure assignment of the acid moiety of
the ester found in bovine heart muscle mitochondria.
Two relatively sensitive and specific analysis techniques have been
reported for phthalic and terephthalic acids. Kumamaru (1968) reported
an atomic absorption technique for determining phthalic acid by solvent
extraction with neocuproine-copper(I) chelate. Reproducibility of the
method was established at a concentration of 4.00 x 10 M in phthalic
acid (approximately 6 ppm). The method is rapid and accurate and free
from isomeric interferences (isophthalic, terephthalic and benzoic acids)
Giang ££ jjl. (1967) used a fluorometric method with the amino derivative
of terephthalic acid for determining residues in chicken tissues. The
method was reported to be sensitive to 0.1 ppm.
172
-------
VII. Chemical Reactivity (Towle £t al_., 1968)
The chemical reactivity of benzenepolycarboxylates is characteristic
of the two major organic functionalities - the benzene moiety and the
carboxylate moiety. The benzene moiety will undergo typical aromatic
t
substitution and addition reactions such as halogenation, nitration,
sulfonation and hydrogenation. The rate and ease of reaction is dependent
upon the number and isomer distribution of the carboxylate moiety.
The major commercial uses of the benzenepolycarboxylates are dependent
4
upon the reactivity of the carboxylates. Esterification is the most
important. Reaction of the acid or anhydride with monofunctional alcohols
either at elevated temperatures or at low-moderate temperatures with
strong acid catalyst yields esters which are used for plasticizers.
Reactions with polyfunctional alcohols yield polyester polymers which
provide plastics, fiber and film by-products. Even dimethyl terephthalate
undergoes transesterification with simple alcohols, diols, triols, and
other polyglycols in the presence of a basic catalyst.
Acid compounds which contain ortho-substituted dicarboxylates
(PA, TMA, and PMA) will form anhydrides at elevated temperatures or under
173
-------
anhydrous conditions. When the anhydride form is possible, it is the
normal commercial product. An equilibrium exists between the acid and
the anhydride as depicted in Figure 1. ,
FIGURE 1
Equilibrium Between Benzenecarboxylic
Acids and Anhydrides
Therefore, any anhydride that is released into the environment (water
abundant in most cases) is likely to have some of it converted into the
acid form.
Acid halides may be formed by the reaction of the acid with thionyl
halide or phosphorus pentahalide. The benzenecarboxylates will react
with ammonia to form salts, amides, and imides. Metal salts can also
be formed from the acid and they are somethimes used to purify the acid
for use in polyesters. The equilibrium between the acid and its anion
conjugates is pH dependent in aqueous solution (Figure 2) and, therefore,
the solubility in an aqueous solution is pH dependent. The benzene-
carboxylate compounds also undergo Friedel-Crafts condensations with
174
-------
R
C02H
FIGURE 2
Equilibrium between Benzenecarboxylic
Acid and Its Anion Conjugate
other aromatic systems to yield ketones and quinones (e-g« > phthalic
anhydride ^ anthraquinone).
Thermal and oxidative stability of the benzenepolycarboxylate
compounds is not very high. They will burn and some will explode
when combined with air at elevated temperatures. Incineration is
used as a pollution control technique.
175
-------
VIII. Biology
The biology of most benzenepolycarboxylic acids has not been exten-
sively studied. Terephthalic acid, however, is an exception, perhaps
because of its use as an additive in poultry feed in order to retard
the excretion of antibiotics (Boyd et al., 1960).
A. Absorption
When injected intraperitoneally into rabbits, terephthalic
acid is rapidly absorbed by the plasma reaching a maximum plasma
level within one hour. lii oral administration, the maximum plasma
level is not reached for 8-10 hours with an administration of
200 nig/kg resulting in a plasma concentration of 11.7 ug/ml. Thus,
in oral administration, the limiting factor on plasma concentration
is gastrointestinal permeability (Hoshi et al., 1966). Terephthalic
acid is readily absorbed by the gastrointestinal tract with 70%
or more of an oral dose probably being absorbed unchanged by the
stomach and small intestine within 4-24 hours and 22% absorbed by
the cecum and large intestine (Hoshi and Kuretani, 1967). In that
there is some evidence that both terephthalic and phthalic acids
can cause internal damage on inhalation (Sanina, 1965; Stepanov et al.,
1962), similar absorption across alveolar membranes might be supposed
but no such absorption has been documented.
B. Excretion
After ingestion, terephthalic acid is rapidly excreted from the
body. Biological half lives for terephthalic acid in rabbits and
176
-------
rats have been found to be 1.8 hours and 1.2-3.3 hours, respectively
(Hoshi £t ail., 1966; Hoshi and Kuretani, 1967). Using radioactive
terephthalic acid (carboxy- C), it was found that almost all of the
compound is excreted in the urine after a 24-hour period with small
amounts appearing in the feces (see Table VIII).
TABLE VIII
Excretion of Terephthalic Acid after the Oral
Administration of a Single Dose of 85 mg./kg. to Rats
[Hoshi and Kuretani, 1967]
Time
(hr.)
0^
0%
O'v/
0^
0 'u
0 a-
2
4
6
8
24
48
10.
33.
61.
82.
93.
93.
Urine
8 ±
6 ±
5 ±
1 ±
5 ±
8 ±
8.
7.
7.
7.
7.
7.
5
1
8
5
6
6
Excreted TPA (%)a^
Feces
-b) 10.
— b) 33.
-b) 61.
0 82.
3.3 ± 2.1 96.
3.3 ± 2.1 97.
Total
8 ±
6 ±
5 ±
1 ±
8 ±
1 ±
8.
7.
7.
7.
6.
6.
5
1
8
5
4
4
a) Mean value * S.D. (5 rats). b) No evacuation.
C. Transport
Terephthalic acid is readily transported throughout the body
(see Distribution) by the blood and eliminated in the urine via the
kidneys as indicated in the preceding section.
/
D. Distribution
As can be seen in Table IX, terephthalic acid is distributed
throughout the body a very short time after ingestion.
177
-------
Time (hr)
TABLE IX
Distribution of Terephthalic Acid
After a Single Oral Dose of 85 rag/kg
[Hoshi and Kuratani, 1967]
TPA contents (ug/g or
46
8
24
48
Plasma
Kidney
Liver
Brain
Skin
Lung
Pancreas
Spleen
Adipose tissue
(white)
Heart
Muscle (thigh)
Bone (femur), »
Blood cell ;
Uterus
Ovary
Salivary gland
Thyroid gland
Pituitary gland
Adrenal gland
10.
58.
31.
0.
6.
4.
3.
1.
0.
2.
0.
0.
0.
5.
4.
3.
3.
3.
2.
38±
1.74
52±10.71
25±
98±
04±
19±
11±
30±
87±
53±
72±
41±
43±
67±
4 l
16±
0 ±
1 ±
1 ±
2.88
0.05
1.33
0.34
0.37
0.16
0.22
0.41
0.11
0.14
0.07
1.31
0.8
0.68
0.3
0.4
0.2
6.
25.
12.
1.
2.
1.
1.
0.
P.
0.
0.
0.
0.
2.
1.
1.
2.
2.
0.
75±2.05
71+4.60
9612.18
2210.07
9110.45
7210.40
0610.09
4710.09
45+0.05
8410.19
3110.05
1210.04
3210.13
1510.68
5 10.1
5810.33
0 10.3
2 10.6
9 10.2
2.96+0
15.7413
8.1411
1.1710
2.1410
1. 3410
0.63+0
0.34+0
0.3610
0.61+0
0.24+0
0.1010
0.1810
1.7010
1.1 10
1.0010
1.4 +0
1.1 +0
0.5 +0
.32
.03
.40
.11
.42
.04
.16
.11
.09
.19
.10
.04
.06
.54
.4
.08
.3
.3
.1
2.38+0.
8.54+1.
5.1310.
1.3210.
1.9010.
0.63+0.
0.3810.
0.22+0.
0.1610.
0.2910.
0.09+0.
0
0
0.7010.
0.7 +0.
0.8110.
1.0 +0.
0.9 10.
0.2 +0.
37
67
56
08
29
13
05
04
02
05
01
17
2
22
4
1
1
0
0.41+0.04
0.13*0.04
0.0710.01
0.0610.04
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
a) Mean value 1 SE of each 5 rats b) Corresponding to 1 ml of whole blood
The relative amounts in the various tissues do not vary signifi-
cantly with elimination and it is not accumulated in any tissues.
E. Metabolism
Although certain benzenepolycarboxylates may be metabolized by
some microorganisms (see Metabolic Effects), there is no evidence
of such metabolism in the higher animals. It has been demonstrated
that terephthalic acid is not metabolized in the rat (Hoahi and
Kuretani, 1967).
178
-------
F. Metabolic Effects
The metabolic effects of benzenepolycarboxylic acids cannot be
clearly related to their toxicity. As indicated in Table X, several
of these compounds have been tested and found to competitively
inhibit cis-Aconitase.
TABLE X
Inhibition of cis-Aconitase by
Various Benzenepolycarboxylic Acids at 10 mM
[Gawron & Birckbichler, 1971]
Acid % Inhibition
Terephthalic 0
Isophthalic 3
Phthalic 5
Trimesic 20
Trimellitic 33
Pyromellitic 51
Hemimellitic acid has a similar inhibitory effect on citrate trans-
port in rat liver mitochondria with an ED-QO at 25 mM (Robinson et al.,
1971).
Terephthalic acid depresses the rate of dye excretion by the
kidney at 300 mg/kg in rats (Yanai eit al., 1967) and has a similar
effect on the rate of antibiotic excretion in chickens (Giang et al.,
1967).
179
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IX. Environmental Transport and Fate
A. Persistence and/or Degradation
With the exception of benzenedicarboxylic acids, very little
information is known about the environmental stability of the
benzenepolycarboxylates. No reports of environmental monitoring
for these compounds have been uncovered. No information on the
chemical or photochemical stability under environmental conditions
has been reported for .any of the compounds. However, the biode-
gradibility of the disubstituted compounds has been studied by a
number of researchers. Ribbons and Evans (1960) and Perry and
Scheld (1968) were able to isolate microbes thart were capable of
using phthalic acid for a carbon and energy source. Ribbons and
Evans (1960) isolated their microbes from an industrial phthalic
acid waste treatment plant as well as from garden soil, manure, and
coniferous litter. These authors were able to isolate 4,5-
dihydroxyphthalate from the metabolism of phthalic acid and sug-
gested the following metabolic pathway.
C02H HO
C02H HO
FIGURE 3.
Metabolism of Phthalic Acid
[Ribbons and Evans, 1960]
180
-------
Saeger and Tucker (1973) studied the biodegradibility of
phthalic acid with a river die away test (Mississippi River water).
The results are tabulated in Table XI. It is difficult to assess
the results since the phthalic acid degradation half-life is in
between the time for a very degradable compound (LAS) and the time
for a widespread environmental contaminant (DEEP).
TABLE XI
Biodegradibility of Several Phthalates
and Other Organic Compounds
Using a River Die-Away Test
[Saegar and Tucker, 1973]
Compound Tested
1-Phenyl Dodecane-p-Sulfonate
sodium salt (LAS)
Phthalic Acid
Butylphthalylbutyl Glycolate
Butylbenzyl Phthalate
Di-(2-ethylhexyl) Phthalate
(DEHP)
Di-(heptyl-undecyl) Phthalate
Diundecyl Phthalate
Initial Concentration
(ppm)
3.2
12.5
1.0
1.0
1.0
1.0
1.0
Time for 50%
Degradation
(weeks)
0.8
1.5
0.2
0.2
2.5
3.0
2.5
181
-------
Alexander and Lustigman (1966) studied the rate of microbial
degradation of mono- and disubstituted benzenes. Although the method
used had some shortcomings, a marked favorable effect of carboxyl
groups on microbial decomposition was noted. Only benzoic acid and
the isomeric phthalic acids were examined and, therefore, the
environmental stability of the higher benzenepolycarboxylates is
difficult to estimate. It is interesting to note that all the
disubstituted benzenecarboxylie acids were slightly more stable
than benzoic acid. If that trend is real, the higher substituted
benzenecarboxylates should be more persistent.
B. Environmental Transport
No information on environmental transport of benzenepolycarboxy-
lates was available in the surveyed literature.
C. Bioaccumulation
Met calf ejt al. (1973) have studied the uptake of di-2-ethylhexyl
phthalate (DEHP) in aquatic organisms utilizing a model ecosystem
and both phthalic acid and anhydride have been isolated as metabolites.
However, the levels detected were, for the most part, due to uptake
of DEHP and degradation in the organism to the acid or anhydride.
182
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X. Toxiclty
A. Human Toxiclty
Of the benzenepolycarboxylic compounds examined, only phthalic
acid and its anhydride have aroused much interest as human toxicants,
with the concern focusing almost exclusively on potential occupational
hazards. Both compounds are generally considered to have low but
significant levels of human toxicity by any of three routes: eye
contact, skin contact or inhalation. A fourth possible route,
ingestion, has not been reported for humans (Amer. Indust. Hyg.
Assoc., 1967).
Eye Contact: Phthalic anhydride has been reported to effect
the adaptability of the human eye at 920 mg/£ but not at 550 rng/H
(Slavgorodskii, 1967). At higher concentrations, PAN may cause
inflamation of conjunctiva similar to its effect on other mucous
membranes being largely due to the hydrolysis of PAN to PA (Amer.
Ind. Hyg. Assoc., 1967).
Skin Contact: Similar to ocular damage, skin irritation seems
to be caused primarily by PA rather than PAN. Dry skin does not
respond immediately to PAN, but if the skin is not thoroughly
cleansed, inflammation will result. In the more severe exposures,
sores may develope with subsequent shedding and flaking (Manufact.
Chem. Assoc., 1956). However, with prompt treatment, even massive
exposure does not result in a severe response (Manufact. Chem.
Asaoc., 1966). Although BAN is reported to cause sensitization
183
-------
in some individuals over long periods of exposure (Amer. Indust.
Hyg. Assoc., 1967), detailed descriptions of this syndrome have not
been encountered. In an outbreak of acute dematitis associated with
PAN production, naphthaquinone was eventually identified as the
probable toxic agent (Kito et al., 1953), but to what extent presumed
PAN dermatitis may be due to product contaminants has not been
determined.
Inhalation: Exposure by inhalation may proceed in much the way
as skin or eye contact. The mucous membranes and the upper respiratory
tract are the primary sites of attack allowing ready hydrolysis of
PAN to PA (Manufact. 'Chem. Asspc., 1956). In some cases, prolonged
occupational exposure leads to severe inflammation of the upper
respiratory tract that may result in bronchitis as well as severe
nasal and dermal irritation (Anon., 1957). PAN has also been
associated with an increase in vascular penetrability causing a net
loss of proteins (Vychub, 1965) similar to the effect noted in rabbits
(Tsyrkunov, 1966). Along with a decrease in proteins, PAN also
causes an exposure dependent decrease in Vitamin C levels in the blood
(Vychub and Vychub, 1965). While such changes do not seem severe
enough to cause manifest pathologic conditions, Markman and Savinkina
(1964) have reported progressive damage to the respiratory apparatus
with occupational exposure to PAN. Upon X-ray, exposures of two years
showed a more pronounced outlining of the pulmonary vascular system.
Workers with a three year exposure showed an increase in fibrous
184
-------
tissue and distention of the pulmonary vessels. Those exposed for
six years evidenced marked fibrosis of the lungs. In a similar
study, Khasis (1964) concluded that occupational exposure to PAN
may result in subclinical respiratory insufficiency.
B. Toxicity to Birds and Non-human Mammals
1. Acute and Subacute Toxicity
a- Phthalic Anhydride
Although oral toxicity has not been a problem in occupa-
tional exposure, the acute oral toxicity has been determined
in some laboratory animals. At concentrations of 0.68g/kg
body weight no toxic response is observed in rats (Pludro
et al., 1969). The LD__ for mice has been measured as
2.21g/kg. body weight. Yet unlike the damage caused
through the more common routes, ingestion does not effect
the skin, eyes, or upper respiratory tract (Zhilova and
Kasparov, 1968). However, ocular, derma], and respiratory
exposure do elicit responses comparable to those of man.
Direct application to the eyes of rabbits causes conjunctivitis
(Zhilova et al., 1966). Dermal application of 200 g/Jl
ethknol at 0.5 - 1 ml/day to rabbit skin causes acute
inflammation and changes in blood vessel permeability
(Tsyrkunov, 1966). However, direct application to the
isolated frog heart will cause beat failure at 1 g/fc
185
-------
(Stepanov, 1964). Acute inhalation toxicity data is not
available but 350-400 g/£ has been shown to increase the
amino nitrogen level in rat urine (Zhilova and Kasparov, 1966).
b- Phthalic, Isophthalic and Terephthalic Acids
In studying the comparative toxicity of these compounds
through the intraperitoneal injection of mice, Caujolle and
Meynier (1958) determined the following order of toxicity:
PA > TA > IA [see Table XII].
TABLE XII
Toxicity of Benzenedicarboxylic Acids to Mice 24 Hours
After Intraperitoneal Injection [Caujolle and Meynier, 1958]
LD50 LD100
Phthalic Acid 1.67 g/kg 2.41 g/kg
Terephthalic. Acid 3.70 g/kg 4.50 g/kg
Isophthalic Acid 4.20 g/kg . 5.60 g/kg
Of these, however, only terephthalic acid and its disodium
and dimethyl derivatives have received appreciable toxologic
evaluation. Other studies indicate considerably lower lethal
doses for terphthalic acid than those given by Caujolle and
Meynier (1958) [see Table XIII].
186
-------
TABLE XIII
Lethal Doses for Terephthalic Acid
by Intraperitoneal Injection of Mice
Mice LD5Q LD100 Duration Source
* 25 g 1.43 g/kg 3 days Hoshi et al. , 1968
20 g 9 1.9 g/kg 3.2 g/kg 1 -day Grigas et al., 1971
Caujolle and
Meynier, 1958
JL jt
20 g 3.7 g/kg 4.5 g/kg 1 clay Caujolle and
* = female # = male
Obviously, any number of parameters could account for such
discrepancies. The comparison, however, does indicate the
difficulty in precisely determining lethal d'oses even within
a single genus. Also, the difference between lethal and
physiologically significant doses deserves emphasis in dealing
with a compound that may not readily cause dea.th but which may
cause significant alterations in body function. Hoshi and
coworkers (1968), while noting an LD_Q of 1.43 .g/kg intra-
peritoneally, found that 300 mg/kg will cause re-nal function
depression. Intraperitoneal injection of rats gaive a similar
LD- __ to that determined by Grigas and associates (1971) for
mice. Rats intraperitoneally injected with 3.5 g/Ug showed
depressed neural and liver functions, a. decrease in plasma
Vitamin C, and an increase in the globulin fractions1- of
serum "(Slyusar and Cherkasov, 1964). As would be expected,
intravenous injection seems to cause ai lethal response at
t N
lower concentrations. Dogs are fatally intoxicated with
187
-------
767 mg/kg given intravenously at the rate of 2. mg/kg/min,
with death immediately preceded by respiratory arrest
(Grigas et^ _al. , 1971). Thus, this form of acute poisoning
may be physiologically unrelated to death by other routes.
Orally, terephthalic acid is considerably less toxic
than injected doses. In ad libitum feeding of .5% tere-
phthalic acid in feed over a seven day period, the LDrQ is
calculated to be over 5 g/kg body weight (Hoshi et^ _al. , 1968).
In single induced dose feeding experiments, 10 g/kg body
weight gave an LD in 6-12 days after exposure, with death
characterized by cellular infiltration of the mucous
membrane of the gastrointestinal tract, and fluid accumulation
and congestion of the internal organs. Lower doses, while not
fatal, produced marked physiological changes. At 5 g/kg body
weight, both respiratory depression and pronounced vascular
disorders were noted over a 24 hour period. Even at 0.5 g/kg,
a brief period of stimulated activity and subsequent depression
was elicited (Savina, 1965).
Lethal data are not available for the inhalation of
terephthalic acid, but skin irritation and respiratory
stimulation results in rats after exposure to .002-.005 mg/fc
for 2 hr/day after 5 days. More prolonged exposure leads to
skin erosion and unspecified vascular, respiratory, and
neural changes (Sanina, 1965).
188
-------
Both dimethylterephthalate and disodium terephthalate
cause the same type of toxic response as terephthalic acid
(Hoshi et: al., 1968; Slyusar and Cherkasov, 1964). Bearing
in mind the limited reliability of comparative toxicity data,
the degree of potency of the various terephthalates - based
on the data from Table XIV - may be arranged as follows:
terephthalic acid > dimethylterephthalate > disodium
terephthalate.
TABLE XIV
Acute Toxicity of Terephthalic Compounds
in Mice and other Mammals
Route
Oral
Subcutaneous
Intraperi-
toneal
LD5Q (mg/kg)
Terephthalic Disodium
Acid Terephthalate
> 5000* 6300 (5000)*
****
3500 (LD1(JO)
8600 (6800)
1430
Intravenous + 767
**
4600 (3600)
> 1300 (>1000)
Dimethyl-
terephthalate
+ ***
T > 3200
4- ****
+ 4500
3200
***
( ) calculated as free acid + dog + rat
* Hoshi et al., 1968
** Grigas _et al., 1971
*** Fishbein and Albro, 1972
**** Slyusar and Cherkasov, 19^64
189
-------
c. Trimellitic Acid and Anhydride
The only higher benzenecarboxylic acid encountered in
the literature was trimellitic acid and the corresponding
anhydride. On oral administration to both rats and mice,
TMA and THAN elicit the same basic symptoms: swelling of the
internal organs and skin, and respiratory depression
(Batyrova and Uzhdavini, 1970).
TABLE XV
Acute Oral Toxicity (LD50) of TMA and THAN
to Mice and Rats [Batyrova and Uzhdavini, 1970]
TMA THAN
Mice 1.25 g/kg 2.50 g/kg
Rats 1.90 g/kg 6.25 g/kg
As with phthalic acid, inhalation of trimellitic acid seems
to primarily attack the mucous membranes causing signs of
respiratory distress.
190
-------
2. Chronic Toxicity
Long term low level exposure studies have been encountered
only for phthalic anhydride.
In induced oral administration to rabbits at 20 mg/kg body
weight/day over a 120 day period, the number of leukocytes and
blood aldolase activity increased (Zhilova and Kasparov, 1966).
Over the same period, rats fed lOOmg/rat/day showed considerable
weight loss but no lethality. Besides irritation of the mucous
membranes of the trachea, bronchi, and stomach, degeneration was
noted in the liver, kidney, and myocardium (Reznik and Petrishina,
1963).
On inhalation, phthalic anhydride elicits a dosage dependant
response in rats. A 45 day continuous exposure to 20 mg/1
reduces the dehydroascorbic acid content in the testicles. At
concentrations of 100 mg - 200 mg/1 over a two week period,
however, there is a reduction in dehydroascorbic, ascorbic, and
neucleic acids in the testicles as well as a decrease in fecundity
(Protsenko, 1970). Motor activity is influenced by continuous
exposure to 540 mg/1 for 70 days (Slavgorodskii, 1967). Only
at the extremely high concentrations of 30-90 g/1 is an approxi-
mate LD_Q obtained for rats when exposed for two unspecified
periods per day for 135 days. The pathologic signs are similar
to those of oral administration except that the weight loss is
slight and the eyes are severely irritated (Reznik and Petrishina,
1963). Rabbits may be considerably more sensitive than rats,
191
-------
showing abnormal hemoglobin and irritation to the eyes and
respiratory tract at concentrations of 1 mg/1 and exposures of
1-2 hrs/day over a 60-105 day period (Stepanov et jiT., 1962).
3. Sensitization
The ability of phthalic anhydride to cause sensitization to
both humans and other mammals is widely accepted in the litera-
ture (Manufact. Chem. Assoc., 1956). However, detailed studies
of this response have not been encountered. Dueva and Aldyreva
«
(1969) attribute strong allergenic properties to the phthalic
acid radical but the mechanism is not discussed.
4. Teratogenicity
As a metabolite of thalidomide, phthalic acid has beer
studied for teratogenic effects. Although PA was shown not to
have a teratogenic effect in mice (Koehler e£ ad., 1971), it does
stimulate over a two-fold increase in chick embryo teratism
(Verrat et^ al., 1969). Although this does not indicate a high
degree of teratogenicity, the studies thus far conducted cannot
be considered definitive.
5. Carcinogenicity
The benzenepolycarboxylic acids have not been implicated in
carcinogenic agents in the studies thus far screened. Indeed,
terephthalic acid may inhibit spontaneous mammary tumorigenesis
and delay or prevent hepatic carcinogenesis by p-dimethylamino-
benzene (Nagasawa and Fujinoto, 1973; Yanai et_ al., 1967).
192
-------
6. Mutagenicity T no studies encountered.
7. Behavioral Effects - no studies encountered.
C. Toxicity to Lower Animals - no studies encountered.
D. Toxicity to Plants
The phytotoxicity of the benzenepolycarboxylates does not seem
to have been extensively studied. In the only study thus far
encountered, phthalic acid and unspecified derivatives of phthalic
acid were not shown to have any effect on rice plants (Tomizawa
and Koike, 1954).
E. Toxicity to Microorganisms
Phthalic acid is reported to have no toxic effects on 28 strains
of Salmonella at concentrations of 25 mg/1 and 200 mg/1 (Vecchio
^t al_., 1949). At concentrations of 1000 mg/1, however, it causes
a twelve fold decrease in the growth of the flagellate protozoa
Ochromonas danica (Frank je£ ai., 1963). Also, several benzenepoly-
carboxylic acids were found to agglutinate cultures of Escherichia
coli in the following order of potency; terephthalic acid > phthalic
acid > trimesic acid > hemimellitic acid (Maccacaro and Dettori, 1960)
193
-------
XI. Benzenepolycarboxylatest Summary and Conclusions
Of all the benzenepolycarboxylates, the terephthalates - DMT and TA -
are by far the most widely used and represent a total annual production
of over three billion pounds. Phthalic anhydride is the next in importance
with an annual production approaching one billion pounds. Isophthalic
acid is much less extensively used and is probably produced not much
in excess of 100 million pounds yearly. Production figures for the more
highly substituted benzenecarboxylic acids are not available. Although
a meaningful quantitative estimate cannot be made by group, it seems
likely that their total annual production is in excess of 15 million
pounds, but does not exceed 50 million pounds. The trimellitic and
pyromellitic compounds probably constitute the bulk of the higher benzene-
poly carboxy late production.
Although these compounds are as a group produced in very large quantities,
they are used mostly in the synthesis of other commercial compounds and
thus large scale direct environmental contamination does not seem
indicated. Almost all of the terephthalates and pyromellitics are bound
as polymers. Similarly, most of the phthalates, isophthalates, and
trimellitics are used in the formation of diesters for plasticizers, or
polyesters for structural components. Consequently, the prime source
of environmental contamination is likely to occur in manufacture and/or
transport, where some degree of unintentional release must be expected.
In view of the quantitites produced, even a small percentage of such
loss could result in appreciable contamination. Further, the amount of
194
-------
benzenepolycarboxylate release from physical, chemical, or biological
deterioration of the various end products may be significant. Many of
these products are disposable and eventually subject to incineration or
landfill.
Although certain benzenepolycarboxylate esters have received
considerable attention as environmental pollutants, little is known
about the actual degree or extent of acid or anhydride contamination,
except for isolated reports of local pollution from manufacturing
facilities. Along with this lack of monitoring information, the fate
of benzenecarboxylates in the environment has not been conclusively
demonstrated. Although more stable than benzoic acid, the disubstituted
acids would seem to exhibit no exceptional degree of oxidative or
thermal stability and are at least moderately biodegradable. If
extrapolation from data on mono- and dicarboxylic acids is valid, the
higher acids may prove quite stable but no supporting experimental
evidence has been found. Information on bio-accumulation and environ-
mental transport is also unavailable. Their physical properties do not
necessarily preclude either atmospheric or aquatic transport but the
relative importance of either mode will depend on the specific compound,
the industrial process involvedi and/or the method of commercial trans-
port used. Bio-accumulation cannot be ruled out but does not seem
indicated in the dicarboxylic compounds.
At realistic environmental concentrations, these compounds seem to
have a low order of mammalian toxicity. For the disubstituted compounds,
acute lethal toxicities are in the g/kg range in inverse order of
195
-------
production: PA > TA > DMT. Chronic pathology is only an order of
magnitude lower (i.e., > 0.1 g/kg). However, the benzenedicarboxylates
can elicit appreciable physiological changes in the 100 ppm range and
minimal changes in the 10 ppm range. Even at low concentrations (1-4 ppm),
phthalic acid will cause neurosensory excitation. Toxicity information
on the higher substituted compounds is limited. The trimellitic compounds
seem to have acute toxicities on the same order of magnitude (g/kg) as the
dicarboxylic acids. Further evaluations of the toxic effects of these
compounds have not been encountered. Based on enzyme inhibition studies,
higher carboxylation might be expected to lead to increased toxicity
but this supposition must remain questionable pending more conclusive
experimental investigations. The non-mammalian toxicity of these
compounds has received little attention. Possible pathogenesis to plants,
invertebrates, and/or lower vertebrates cannot be discounted on the
basis of the limited available information.
In interrelating data on the various factors involved, the benzene-
polycarboxylates seem to present somewhat dichotomous potentials for
environmental hazard. They are produced in immense quantity but are
used primarily as chemical intermediates, thus limiting direct exposure
•
to the environment. They have a very low order of mammalian toxicity
but a correspondingly low threshold of irritability. However, because
so little is actually known about the degree of contamination or possible
environmental effects, a meaningful estimation of their potential
environmental hazard is not possible at this time. Their uses and
196
-------
known biological effects would not seem to present any great threat.
Yet, their extensive production and possible biological activity would
seem to warrent a more careful resolution of the various problems outlined
above.
197
-------
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200
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203
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CHLOROPHENOLS
I. Physical Properties
All the chlorophenols, with the exception of o-chlorophenol, are solids
at room temperature and all have a pungent, medicinal odor. They are gen-
erally insoluble in water, ethanol, ether and acetone, although the highly
chlorinated phenols are soluble in ethanol, ether and acetone. The volatility
of the compounds generally decreases and the melting and boiling point
generally increase as the number of chlorine atoms substituted on the
benzene ring increases. Table I presents some of the physical properties
of the commercially important chlorophenols.
204
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TABLE I
Physical Properties of Commercially Important Chlorophenols
(Doedens, 1964; Bevenue and Beckman, 1967)
~^~»^_^ Compound
Property --^
Jfeltin'g point (°C)
Boiling point (*C)
Dleaociation
constant (K)
at 25CC
Solubility (g/lOOg)
Water (25«C)
Ethanol (25*C)
Ether (25'C)
Benzene (25*0
Chloroform (25°C)
Carbon
DJ.sulfide (25°C)
Acetone
Temperature at
which the . vapor
pressure equals
lonHg
L-chloro-
plienol
8.7
175-176
3.2xlO~9
<0.1
>200
>200
12.1
2-chloro-
plienol
32.8
215-217
1.4xlO~9
0.26
sol.
sol.
sol.
sol.
sol.
44.2
3-chloro-
phenol
40-41
219
6.6xlO-10
2.71
sol,
sol.
sol.
sol.
sol.
49.8
2,4-dichloro-
phenol
43-44
210-211
Z.lxlO"8
alight
.sol.
sol.
sol.
. .53,0
2,6-dichloro-
phenol
67
219-220
l.oxlO"7
miacible
59.5
2,4.,6-tri-
chloro-
phenol
68
246
3.8xlO"8
insol.
525
(methanol)
500
76.5
2,4,5-trl-
chloro-
phenol
68
245-246
3.7xW"8
72.0
2,3,4,6-tetra-
cliloro-
phenol
69-70
164/23om
4.2xlO"6
0.10
319
(methanol)
570
100.0 '
pentachloro-
phenoi.
190
309-310
1.2xlO~5
14-19 ppm
143
158
53
.00011mm
Hg (20' C)
4-cnlorb-
cresol
48-49
223
4-chloro-
3,5-dimetnyl
pnenol
115-116
246
insol;
86
6
-------
II. Production
Chlorophenols are produced by several companies in the U.S., but
i
Monsanto and Dow are the most prominent. Table III lists the manufacturers
and the products they produce. Plant capacities and locations for penta-
chlorophenol are also presented. As can be seen from Table II, Monsanto
and Dow are the only companies that produce the lower chlorinated com-
pounds. This relatively recent concentration of chlorophenol production
has reduced the amount of information on production levels as is noted in
Table III. The monochlorophenols have for many years been produced by only
Monsanto and Dow and, thus, little information on production quantities
is available. The para-substituted compound is used as a starting material
for a number of by-products, but the. only chemical which has reported
production levels is 1,4-dihydroxylanthraquinone (quinizarin). However,
large quantities of £-chlorophenol are used to synthesize 2,4-dichloro-
phenol. The percentage of the total jpj-chlorophenol production used in the
other various products is unknown.
Production levels for 2,4-dichlorophenol are also unreported. How-
ever, productions figures for 2,4-dichlorophenoxyacetic acid (2,4-D) and
its derivatives are available, and since 2,4-D is the major outlet for the
2,4-dichlorophenol produced, approximate estimates of production can be
derived. A similar relationship can be used for 2,4,5-trichlorophenol
and 2,4,5-trichlorophenoxyaeetic acid (2,4,5-T), although production
levels for trichlorophenol were published up until 1968. Both 2,4-D and
2,4,5-T were produced in high quantities during the Vietnam War, but
currently production levels are decreasing.
206
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TABLE II
Chlorophenol Producers and Their
Plant Locations and Capacities
(Chemical Marketing Reporter, 1972;
U.S. Tariff Commission, 1960-1971)
Producer
Dover Chem.
Dow Chemical Co,
Capacity
(Compound)*
(106 Ibs.)
15 (PCP)
Hooker Chemical Corp.
Monsanto Co. 26 (PCP)
Northeastern Pharma- -
ceutical and Chemical
Co.
Reichhold Chem., Inc. 12 (PCP),
Sonford Chem. Co. 18 (PCP)
(not operating)
Location
Dover, Ohio
Midland, Mich.
Transvaal
Vulcan
7 (PCP)
Niagara Falls,
N.Y.
Sauget, 111.
Verona, Mo.
Tacoma, Wash.
Port Neches,
Tex.
Jackson, Ark.
Wichita, Kan.
Compounds*
Produced by
the Company
PCP
o^CP, £-CP,
2,4-DCP,
2,4,5-TCP,
2,4,6-TCP,
2,3,4,6-TCP,
PCP, and
others.
2,4,5-TCP
o-CP, ja-CP,
2,4-DCP, PCP
2,4,5-TCP
PCP
PCP
2,4,5-TCP
PCP
*Compounds: £-chlorophenol (o-CP); p-chlorophenol (£-CP);
2,4-dichlorophenol (2,4-DCP); 2,6-dichlorophenol (2,6-DCP);
- 2,4,6-trichlorophenol (2,4,6-TCP); 2,4,5-trichlorophenol
. (2,4,5-TCP); 2,3,4,6-tetrachlorophenol (2,3,4,6-TCP);
pentachlorophenol (PCP); 4-ch.lorocresol (4-CC); and
4-chloro-3,5-dimethylphenol (4-C-3,5-DMP).
207
-------
TABLE III
Production of Chlorophenols and Related Products
1 x 10 Ibs. (1 x 109g)
(U.S. Tariff Commission 1960-1971; Doedens, 1964)
p-ehlorophenol
(quinizarin
production)
2,4-dichlorophenol
(2,4-D + deriv.)
2,4,5-Trichlorophenol 2,3,4,5-Tetra- Pentachloro-
2,4,5-T and phenol and chlorophenol phenol
derivatives salts
o
00
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971p
1.12 (0.518)
1.31 (0.594)
1.43 (0.648)
1.41 (0.640)
1.96 (6.889)
2.35 (1.066)
2.07 (0.939)
2.32 (1.052)
2.20 (0.998)
1.61 (0.730)
1.71 (0.776)
70 (31.75)
80 (36.29)
80 (36.29)
91 (41.26)
108 (48.99)
127 (57.61)
141 (63.95)
161 (73.03)
173 (78.47)
114 (51.71)
81 (36.74)
53 (24.04)
14 (6.351
15 (6.80)
19 (6.621
19 (8.62)
24 CIO. 88)
25 (11.34)
33 (14.99)
42 (19.05)
60 (27.22)
18 ( 8.16)
14 (6.35)
WB
10 (4,531 9 (4.081
11 (4.99) -
12 (5.44)
12 C5.44)
14 C6.35)
13 (5.90)
18 (8.16)
25(11.34)
28 (12.70)
— _
—
__ _
39 (17.69.)
55 (24.95)
39 (17.69)
34 0-5.421
37 (16. .78)
11 (4.99)
43(19.50)
44(19.96)
49(22-23)
46(20.87)
47(21.32)
51(23.13)
-------
Of the chlorophenols, pentachlorophenol is produced in the largest
quantity. It has maintained a steady growth over tne past several years
and is projected to continue at an annual growth rate of 4% (Chemical
Marketing Reporter, 1972).
209
-------
III. Uses (Doedens, 1964)
The chlorophenols have outstanding germicidal and insecticidal proper-
ties and enjoy numerous applications as flea repellents, fungicides, wood
preservatives, mold inhibitors, antiseptics and disinfectants, etc. In
general, the effectiveness in these applications increases with the degree
of chlorine substitution. In addition, many chlorophenols are used as
starting materials for the synthesis of compounds which find applications
as dyes and pigments and pesticides. Figure 1 presents a flow diagram of
the relationship between chlorophenol starting materials, intermediate
compounds, and final products. The following will discuss each of the
important commercial chlorophenol compounds.
A. o^Chlorophenol
In the United States, ^-chlorophenol is produced as a by-product
from the manufacture of ^-chlorophenol by direct chlorination. Most
of the production is used as a feedstock for chlorination to 2,4-
and 2,6-dichlorophenol, 2,4,6-trichlorophenol, and pentachlorophenol,
although some small quantities are sold.
B. ^-Chlorophenol
The majority of jv-chlorophenol produced is utilized as a start-
ing material for the manufacture of other products. Large quantities
of ^-chlorophenol are used in the production of 2,4-dichlorophenol
because of the high conversion to the 2,4-isomer. Other by-product
210
-------
SALTS I GERMICIDES AND ANTISEPTICS)
<^
°-0-
CI.—
CN,
SELCCTME SOLVENT
CI -/ 0 \- OH
N«OH
OH-
0...
t.4-0 AND DERIVATIVES IMCniCIOCS)
CI CI
MiTicioes
SALTS (GASOLINE ANTIGUUHING AGENTS AND OERMICIDtS)
OH eACTERICIDE. INSECTICIDE WOOD AND LEATXH mESCNvATIVt
GERMICIDE, WOOD ME SERVANT .RACTERlCIDE.
CHLOHANH. (SEED ntOTECTANT)
0
MCH
-------
compounds include quinizarins, chromones, indophenols, ether germicides,
and sulfonic acid ester miticides. The salts find applications as
antigumming agents for gasoline, wash liquids for fuel gas purification,
and germicides. In addition, p_-chlorophenol finds some use as a
selective solvent in refining mineral oils and as a denaturant for
ethanol.
C. 2,4-Dichlorophenol
The largest application of 2,4-dichlorpphenol is as a raw material
for the production of 2,4-dichlorophenoxyacetic acid (2,4-D) and
derivatives. Alkali metal salts of the phenol have found utility as
germicides, antiseptics, etc. 2,4-Dichlorophenol is also used in the
synthesis of 2,2'-dihydroxy-3,5,3',5'-tetrachlorodiphenylmethane
(mothproofing compound, antiseptic, and seed disinfectant), 2,4-
dichlorophenyl benzenesulfonate (miticide), and other miscellaneous
products.
D. 2,6-Dichlorophenol
The compound is usually produced as a by-product of further chlor-
ination of ^-chlorophenol. It is primarily used as feed stock for
the manufacture of trichlprophenols, tetrachlorophenols, and penta-
chlorophenols.
212
-------
E. 2,4,6-Trichlorophenol
2,4,6-Trichlorophenol has a variety of potential uses, but
the quantities utilized is unknown. The compound has been cited as
an effective germicide' and has possible utility as a wood preserva-
tive, glue preservative, insecticide ingredient, bactericide, and
antimildew treatment for textiles. It is used as a raw material
in the production of the seed protectant, chloranil (2,3,5,6-
tetrachloro-l,4-benzoquinone). Reaction of 2,4,6-trichlorophenol
with formaldehyde or SCI- yields compounds that are used as soap
germicides.
F. 2,4,5-Trichlorophenol
The largest single use of 2,4,5-dichlorophenol is in the manu-
facture of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and related
products [e.g., tt -(2,4,5-trichlorophenoxyl)-propionic acid (2,4,5-TP)],
The compound is also used in the synthesis of Ronnel (2,4,5-trichlo-
ro-O^O-dimethylphosphorochlorodithioate and soap germicides (reaction
with formaldehyde to form the bis-(methylene) derivative or with
SCI. to form the thiobis derivative). The parent phenol compound
is used as a fungicide by the adhesive industry for preserving
polyvinylacetate emulsions; by the textile industry for preserving
emulsions used in rayon spinning, rayon yarns, and silk yarns; and by
*
the automotive industry for preserving rubber gaskets (Dow Chem. Co.,
1969e). The sodium salt is used by the adhesive industry to preserve
adhesives derived from casein as well as pdlyvinylacetate emulsion type
213
-------
adhesives and is added to leather dressings and finishes to prevent
decomposition of nitrogenous components such as casein, gelatin, and
egg albumen. The sodium salt is also added to metal cutting fluids
and foundry core washes to prevent breakdown and spoilage and it is
added to recirculating cooling water of cooling towers to control
bacteria and fungi (Dow Chem. Co., 1969f).
G. 2,3,4,6-Tetrachlorophenol
The chief application of 2,3,4,6-tetrachlorophenol and its salts
include uses as bactericides for latex preservation, insecticides,
wood preservatives, and leather preservatives.
H. Pentachlorophenol
The major use of pentachlorophenol is as a wood preservative for
poles, crossarms, and pilings (75% of total, Chemical Marketing Reporter,
1972) . The sodium salt makes up 15% of the market (Chemical Marketing
Reporter, 1972) and finds a number of antimicrobial uses in the leather,
paper and fiberboard, photographic, paint, construction materials,
and textile industries and has been used as a molluscicide. It is
commonly used in 1 to 10% aqueous solutions. FCP has also been used
in slime control in pulp and paper mills and as a fungicide and/or a
bactericide in the processing of cellulosic products, starches,
adhesives, proteins, leather, oils, paints, and rubber (Bevenue and
Beckman, 1967).
214
-------
I. 4-Chloro-o-cresol
The chief use of this compound is as a raw material for the manu-
facture of 2-methyl-4-chlorophenoxyacetic acid (MCPA) and its deriva-
tives. MCPA is a plant-growth regulator, analogous to 2,4-D, which
is widely used in Europe, but not widely applied in the United States
probably because of different agricultural methods and climatic
conditions.
J. Others
A variety of other chlorophenol antimicrobial agents are on the
market. These include 4-chloro-3,5-dimethylphenol, 2-chloro-4-
phenylphenol (Dowicide 4), 4-chloro-2-cyclopentylphenol (Dowicide 9),
and a mixture of 4-chloro-2-phenylphenol and 6-chloro-2-phenylphenol
(Dowicide 31 and 32).
215
-------
IV. Current Practice
Chlorophenols are corrosive to the skin and eyes and some are readily
absorbed through the skin in toxic amounts. Their vapors and dusts are
very irritating and toxic. These adverse effects require .that protective
clothing and goggles be worn and a well ventilated area used during
handling.
These compounds are transported by truck or rail. The pentachloro-
phenol (PCP) is packaged in 50 Ib. multiwall paper bags, 300 lb. fiber
drums, and 2500 lb. wire-bound boxes. Sometimes PCP is shipped in bulk
trucks.
Information on disposal methods was not available.
216
-------
V. Environmental Contamination
With the exception of pentachlorophenol, documentation of chloro-
phenol contamination of the environment is not very detailed. The lower
chlorinated phenols have often been cited as being responsible for adverse
taste and odor problems in water (Burttschell et al., 1959), but compre-
hensive monitoring data is not available.
One source of chlorophenol contamination which is often overlooked is
the chlorine disinfection of phenol and cresol containing waste water
effluents. Both Aly (1968) and Barnhart and Campbell (1972) have demon-
strated that chlorination of phenols and cresols in aqueous solution can
occur under conditions similar to those used for disinfection. With
phenol, the reaction proceeded stepwise to provide the following compounds:
o- and j>-chlorophenol, 2,6- and 2,4-dichlorophenol and 2,4,6-trichloro-
phenol. Since chlorination of waste water effluents is a widespread
practice for both industrial and municipal concerns, this source of
chlorophenols may be quite significant.
Another source of environmental contamination is from the manufacture
of chlorophenol by-products such as the herbicides 2,4-D, 2,4,5-T, and
2,4,5-TP and the many secondary products that use ^-chlorophenol as a raw
material. The extent of contamination from this source is dependent upon
the number of formulation or manufacturing plants and the degree of waste
treatment. Information on these parameters was not available in the
reviewed literature, but several authors have determined the feasibility
of treating wastes from the herbicide formulation plants (Hills, 1959;
« *•
Sidwell, 1971) and the removal of 2,4-D derivatives from natural waters
(Aly and Faust, 1965).
217
-------
A third potential source of chlorophenol contamination of the environ-
ment is from the use of chlorophenol containing herbicides. The chloro-
phenol moiety of the herbicide has been shown to be a major metabolite in
the environmental degradation of the herbicide (see Section IX A). Large
quantities of herbicides (e.g., 2,4-D and 2,4,5-T) are used in the United
States and, thus, provide a large potential source of chlorophenols in
the environment.
As previously noted, the extent of contamination from the above sources
is not well understood because of the limited monitoring information.
However, Kawahara (1971) has reported the detection of 2,4-dichlorophenol
in the Ohio River and a dam in West Virginia and a concentration of 6.6 ppb
in a local Cincinnati water intake system was noted.
Contamination of the environment from pentachlorophenol appears to
be widespread. Its use in sawmill products, wood chips (fungicide) and
for slime control in pulp and paper mills make it highly suspectible to
discharge into effluent receiving waters (Rudling, 1970). Rudling (1970)
examined samples of water and fish in a lake that received effluents from a
pulp mill and detected 3 pg PCP/A in the water and 0.2 to 3.0 mg PCP/kg
of fish tissue. Stark (1969) studied a lake where large fish kills were
reported and found high concentrations of PCP. Cranmer and Freal (1970)
have analyzed for PCP in human urine. They detected concentrations in the
general population ranging from 2 to 5 ppb and even higher concentrations
for individuals occupationally exposed to PCP. Similarly, an average of
5 ppb PCP in human adipous tissue from the general population was detected
by Shafik (1973).
218
-------
Buhler e£ al. (1973) examined the hourly fluctuations of PCP concentra-
tion In the enfluent from the Corvallis sewage treatment plant as well
as the concentrations of PCP in the Willamette River. The average
24 hour concentration of PCP entering the treatment plant was 4.3 ppb, of
which approximately 60% was removed during treatment. The highest concen-
tration was during the middle of the day, reflecting a probable industrial
discharge. The concentrations in the Willamette River (0.10 to 0.70 ppb)
were at least tenfold higher than a calculated value derived from assuming
the only source of PCP is municipal sewage. The authors suggest that indus-
trial sources may explain the discrepancy. These authors also determined
that water from a water treatment plant which used Willamette River water
still contained 0..06 ppb PCP.
Recently contaminants found in chlorophenols have been cited as extremely
toxic potential environmental pollutants (Rappe and Nilsson, 1972;
Plimmer je_t _al., 1973; Crossland and Shea, 1973; Elvidge, 1971; Jansen and
Renberg, 1972). These contaminants, (chlorinated dibenzo-£-dioxins and
dibenzofurans) are found in chlorophenols (trichlorophenol and PCP) which
are synthesized from chlorobenzenes.
219
-------
VI. Monitoring and Analysis
*
A variety of analytical techniques have been used to detect chloro-
phenols. These have included colorimetric methods, ultraviolet and infra-
red absorption, and paper, thin layer and gas chroraatography. For trace
analysis the colorimetric method with the 4-aminoantipyrine derivative and
gas chromatography with electron capture have been the most widely used
techniques. Some of those meth.ods have been summarized in Table IV.
The colorimetric procedure is subject to criticism because of the many
variables that may affect the analytical results. These include pH of
*
the reactant solution, the time of color development, temperature, and
instability of the color complex, as well as the fact that the chemical
reaction applies to many phenols which give approximately the same adsorption
maximum (Bevenue and Beckman, 1967).
Gas chromatography seems to be the most sensitive, rapid and specific
method.
220
-------
TABU IV
Analytical Technlquee Uud (or tK« MterBlnatlon
of Chlorophenole in Tract Aaouota
Author(a)
Flint and Air (1962)
'AJy (1968)
Bencte (1963)
Zigler nd Phillip.
(19*7)
KUfOn and Ch«ng (1967)
Stark (1969)
Buhl.r at «1. (1973)
Quantitation
Technique
ColorlBetric
4-a»inoantipyrine
derivative pll 8.0
TLC
4-aalnoantipyrlne
and o_-nltro-
phenylaxo
derivative
Colorijnetric
4-aBlnophenazone
dye
TLC (2 directional)
AaKQj development
CC-EC aathyl eater
CG'tC methyl eater
CC-EC methyl eater
laolatlon
Method
Acidify and extract
with. petroleum ether
Dye formation and
then ether
extraction
Collection In baaic
aolutlon vlth a
alntared glaaa
bubbler
Senalctvlty
Coapounda Type of or Llaitu of
Studied Seeple Detection Reearks
2,4-dlchlorophenol water 7 to 70 ug/t Dot. not dl»tlogui.h
auch coapuuadv 4*
o-clllorop!tenol and
T.i-dlchlorophmol
(£-aubetltutl £-chlorophenol weter
J.3-. »,«-. *.»-,
2,6-, and 3,4-
dichlorophenol
1 to 10
221
-------
VII. Chemical Reactivity
The chlorophenols are fairly weak acids, although they are stronger
acids than phenol because of the chlorine atoms. They are converted to
their sodium salts with sodium carbonate (unlike phenols) and this property
affords a method of separating phenol from chlorophenols.
Generally, the chlorophenols react very similarly to phenol itself.
They will form ethers, esters, and salts with metals, amines, etc. due
to the phenol hydroxyl function. The aromatic function of chlorophenols
will undergo substitution reactions such as nitration, alkylation, acetyla-
tion, halogenation, except when the aromatic ring is too highly substituted
with chlorine.
The chlorine atoms can be hydrolized to polyhydroxyl benzenes with
base at elevated temperatures and pressures. This is some times encountered
during the synthesis of chlorophenols from chlorobenzenes.
Many of the chlorophenols can be oxidatively decomposed with strong
oxidizing agents. Under some oxidative conditions the chlorophenols are
transformed to the hydroquinone and benzoquinone. For example, oxidation
of pentachlorophenol with nitric acid yields tetra-chloro-p_-quinone
(chloroanil) and tetrachloro-p_-quinone.
Aqueous photolysis of chlorophenols for the most part leads to hydroxyl
substitution for the chlorines and polymer formation. This is discussed
in detail in Section IX A.
222
-------
VIII. Biology
Very little biological information apart from toxicity data is avail-
able in the literature for any of the chlorophenol compounds except penta-
chlorophenol. In that extrapolation of biological processes (i.e., absorption,
excretion, etc.) from toxicity studies can be misleading, reliance will be
placed on studies specifically designed to monitor the various biological
parameters.
A. Absorption
Both pentachlorophenol and sodium pentachlorophenate can be readily
absorbed through the skin, with the sodium salt being appreciably more
active (Dow Chemical, 1969c, 1969d). A ten minute exposure of hands
to 0.4% pentachlorophenol has been shown to result in urine concentra-
tions of 236 ppb (Benvenue, 1967a). In infants, residues of the sodium
salt can be absorbed directly from linen in toxic amounts and can be
reabsorbed from contaminated diaper urine (Armstrong et al., 1969).
Cutaneous absorption has been demonstrated in laboratory animals
including rabbits and rats (Deichmann ^t al., 1942). Absorption across
14
the intestinal tract has been demonstrated in mice using C-pentachloro-
phenol (Jakobson and Yllner, 1971). The widespread oral toxicity of
pentachlorophenol indicates that such absorption is common after ingestion.
Pentachlorophenol may also be directly absorbed by the aveolar surfaces
in man in toxic amounts (Casarett _et jil., 1969).
223
-------
B. Excretion
Urinary elimination seems to be the primary mode of pentachloro-
phenol elimination in man, mice and rats. The amount and rate of
pentachlorophenol excreted increases as the body content increases
(Benvenue et al., 1967b). Although initial elimination may be rapid,
complete elimination—i.e., to control levels—has been shown to
take about one month (Benvenue et al», 1967a). In the mouse, 72-83%
is excreted in urine over a four-day period. Most of the remaining
compound is excreted in the feces with only trace amounts found in
the expired air (Jakobson and Yllner, 1971). Similar results have
been found in the rat. After a ten-rday period, 65.2% is recovered
in the urine and 3.1% in the feces. Trace amounts of respiratory
excretion (0.4%) have been attributed to impurities of the initial
pentachlorophenol (Larsen et^ al., 1972). Excretion studies on the
lower chlorophenols have not been encountered.
C. Transport
From metabolic studies on the mouse, a probable scheme of penta-
chlorophenol transport has been postulated by Jakobson and Yllner
(1971).
FIGURE 2
Pentachlorophenol Transport in the Mouse
[Jakobson and Yllner, 1971]
224
-------
If modified to include entry into the blood from the skin and lungs,
this diagram would seem to account for all transport in the mammalian
system.
D. Distribution
Pentachlorpphenol distribution data in humans comes almost
entirely from autopsy reports of fatal intoxications.
TABLE V
Distribution^pf Pentachlorophenol in Three Cases of Fatal Intoxication
. . . ., PCP (mg/100 g)
Case 1*
Case 2**
Case 3**
* Armstrong £t al., 1969
** Gordon, 1956
Tissue
~;-' '• - J-:;, sv-jiii
Kidney
Adrenal
Heart & Blood Vessel
Fat
Connective Tissue
Blood
Urine
Lung
Kidney
Liver
Brain
Liver
Stomach
Kidney
Spleen
2.8
2.7
2.1
3.4
2.7
5.0
7.0
14.5
9.5
6.5
2.0
Trace
225
-------
Needless to say, this data does not permit any conclusions. In
non-fatal cases, however, there is evidence that pentachlorophenol
may be bound to plasma protein but not to the blood cells (Casarett
£t al., 1969).
In the mouse, the liver and intestines contain the highest
amounts of residual pentachlorophenol with other organs accounting
for only 0.2% of the original dose (Jakobson and Yllner, 1971).
This is somewhat at variance with distribution studies in the rat
showing that most of the accumulation is in the liver, kidney, and
blood (Larson jrt al., 1972). Distribution studies on lower chloro-
phenols and non-mammals have not been encountered.
E. Metabolism
Although Deichmann and coworkers (1942) indicated a possible
metabolism of pentachlorophenol in mammalian systems, Jakobson and
Yllner (1971) have proposed a metabolic route for the compound in
mice.
PCP - conjugal*
PCP
FIGURE 3
Suggested Metabolic Fate of PCP in Rats
[Jakobson and Yllner, 1971]
226
-------
Although bacterial strains have been shown to degrade chlorophenols
[see Environmental Fate and Transport section], further evidence
for degradation in mammalian systems has not been found.
The potent molluscicide 2,2*,3,3',5,5',6,6'-octachlorobiphenyl-
quinone has been produced in vitro by oxidation of pentachlorophenol
by a peroxidase found in snails. Whether this reaction proceeds in
vivo and can account for the high toxicity of pentachlorophenol to
snails was not indicated (Nabih and Mefcri, 1971).
F. Metabolic Effects
At concentrations as low as .1 ppm, pentachlorophenol radically
affects the various enzyme systems in the fresh water eel in vivo.
These effects stem mainly from the powerful uncoupling of oxidative
phosphorylation. This causes an increase substrate demand by the re-
spiratory cytochrome chain with subsequent increase in critic acid cycle
activity (BostrOm and Johansson, 1972). This increase in activity
is supported by a depletion of the fat deposits (Holmberg et al.,
1972). Weinbach (1957) has attempted to correlate the various in
vitro metabolic effects of pentachlorophenol to its toxic activity
as indicated in Table VI.
227
-------
TABLE VI
Metabolic Effects of Pentachlorophenol and
Their Possible Physiological Significance
[Weinbach, 1957]
Possible
Concentration In Vitro Physiological
of PCP Effect Significance
10 6-10 ''M Uncoupling of oxidative Interference with cellular
phyosphorylation aerobic exergonic
processes
HT^-IO"3*! Inhibition of mitochon- ?
drial ATPase
Inhibition of myosin Interference with phos-
ATPase phate transfer (and
muscle function?)
10 ^M. and higher Inhibition of glycolytic Rapid death of the cell
phosphorylation and of the organism
Inactivation of
respiratory enzymes
Gross damage to mitochon-
drial structure
The lower chlorophenols have been found to show similar biological
activity. A series of mono- through tetrachlorophenols have been
shown to uncouple oxidative phosphorylation with their potency
roughly decreasing with decreased chlorination (Mitsuda e£ _al., 1963).
TABLE VII
Inhibition of Oxidative Phosphorylation
by Various Chlorophenols
[Mitsuda et al., 1963]
Chlorophenol I50 (10-6M) pKa
Penta-(2,3,4,5,6,) 1 4.8
Tetra-(2,3,4,6,) 2 5.3
Tri (2,4,5,) 3 7.0
irl" (2,4,6.) 18 6.1
M (2,4,) 42 7.8
U1 (2,6.) 400 6.8
(2) 520 8.5
Mono- (3) 150 8.9
(4) 180 9.2
2,4-Dinitrophenol 17 4.0
Phenol 5000 10.0
228
-------
Similarly, some lower chlorophenols have been shown to inhibit
catalase activity (Goldacre and Galaton, 1953). Here, however, no
clear correlation can be drawn between the degree of chlorination
and potency as indicated in Table VIII.
TABLE VIII
50% Inhibition of Catalase Activity by
Various Chlorophenols
[Goldacre and Galston, 1953]
Phenol I50 (M)
o-.chloro 4 x 10~
_A
m-chloro 2 x 10
p-chloro 7 x 10~
2,4-dichloro 2 x 10~6
2,5-dichloro 2 x 10~5
2,4,6-trichloro 1 x 10~2
The toxicologic significance of these metabolic effects must await
a more complete definition of the toxic properties of the various
lower chlorophenols.
229
-------
IX. Environmental Transport and Fate
A. Persistence and/or Degradation
The stability of chlorophenols in the environment has received
a great deal of study because the compounds are well recognized
contaminants. They have also received detailed study when it became
recognized that they were major metabolites of pesticide by-products
which utilize chlorophenols as a raw material (Loos et al., 1967a;
Loos e_t al., I967b; Alexander and Aleem, 1961). Both the photo-
decomposition and the biodegradation will be discussed.
In terms of biological degradations, three general conclusions
have been reached: (1) the chlorophenols are much more environmentally
stable than the parent phenol (Ingols e£ £l., 1966); (2) as the
number of chlorine atoms increases the rate of decomposition seems
to decrease (Cambers et al., 1963); and (3) compounds containing a
meta-substituted chlorine are more persistent than compounds lacking
a meta-substituted chlorine (Alexander and Aleem, 1961).
The experimental conditions in these types of studies vary con-
siderably and quite often some of the results conflict with the above
general conclusions. Alexander and Aleem1s (1961) study of the
decomposition of chlorophenols by soil microbes is the most compre-
hensive in terms of the number of compounds studied. They monitored
spectrophotometrically the disappearance of substrate in aqueous
solutions (50 mg/£) with a soil microbial inoculum. The results are
presented in Table IX. The 3-substituted phenols were always
230
-------
resistant to microbial decomposition and the authors suggest that
this explains the greater persistence in field soil of 2,4,5-T
when compared to 2,4-D.
TABLE IX
Microbial Decomposition of
Chlorophenols in Soil Suspensions
[Alexander and Aleem, 1961]
Compound
Phenol
2-Chlorophenol
3-Chlorophenol
4-Chlorophenol
2,4-Dichlorophenol
2,5-Dichlorophenol
2,4,5-Trichlorophenol
2,4,6-Trichlorophenol
2,3,4,6-Tetrachlorophenol
Pentachlorophenol
Wavelength
nm
269
274
274
279
283
279
288
288
300
320
Days for Complete
Disappearance
Dunkirk Mardin
Soil Soil
2
14
72+
9
9
72+
72+
5
72+
72+
1
47
47+
3
5
-
47+
13
-
—
Chambers et al. (1963) examined the oxygen uptake of phenol-adapted
cultures which were exposed to chlorophenol substrates. Figure 4
demonstrates the retarding effect of chlorine substitution.
231
-------
900 I
4 SO
400
350
(A
c
u
300
o
K
U
U Z50
Si
a.
3
5 200
u
i
ISO
100
SUBSTRATE CONCENTRATION • 100 ppn.
EXCEPT 2,4 DICHLOROPHCNOL >60»pm
Phtnol
OH
m-CMorophwiol
OM_
eiAe"
-~"~~ A eni faf
2.6 Dichlo«>phtnolClnCI 2.4 Oiehlorophtnelt/i
i i v i I i a
30
60 90 120 ISO 180
DURATION OF WARBURG RUN, MIN
210
240
FIGURE 4
Oxidation of Hydroxy- and Chlorophenols
[Chambers £t al., 1963];
reprinted by permission of publishers of
Journal Water Pollution Control Federation.
Alexander and Lustigman (1966) studied monochlorbphenols under
conditions similar to Alexander and Aleem (1961). Again, they found
that chlorophenols degrade slower than phenol and the j>-chlorophenol
appears to degrade fastest (see Table X).
232
-------
TABLE X
Decomposition of Phenol and
Chlorophenol by a Soil Microflora
[Alexander and Lustigraan, 1966]
Compound Wavelength Days for Complete
Disappearance
Phenol - 1
o-Chlorophenol - 274 764
m-Chlorophenol 274 764
p-Chlorophenol 279 16
In contrast, Walker (1954) using a soil percolator system found
that ^-chlorophenol and not jv-chlorophenol was the only compound
degraded. However, Beveridge and Tall (1969)', in agreement with
Alexander and Lustigman (1966), showed that only £-chlorophenol
could be degraded by a phenol oxidizing bacterium (NCIB 8250).
Ingols et al. (1966) studied the biodegradation of chlorophenols
with acclimated sludge. Their results are summarized in Table XI
and agree fairly well with the generalizations cited previously.
TABLE XI
Maximum Degradation Obtained
for Each Compound at 100 mg/£
[Ingols et_ al., 1966]
Compound Ring Time Halide Ion
Degradation (Days) Development
% % Time
(days)
o-chlorophenol 100 3 100 4
m-chlorophenol .. 100 2 100 3
£- chlorophenol 100 3 100 3
2,4-Dichlorophenol 100 5 100 5
2,5-Dichlorophenol 52 4 16 4
2,4,6-Trichlorophenol 100 3 75 3
Na 2,3,4,5,6-Pentachlorophenol 0 4 04
233
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Pentachlorophenol has received more detailed study than the
other chlorophenols because of sizable quantities used directly as
herbicides or fungicides. Ide e_t al. (1972) studied PCP decomposi-
tion in rice fields. They found that under rice field conditions
reductive dechlorination occurred and resulted in the following
stable metabolites: 2,3,4,5-, 2,3,5,6-, and 2,3,4,6-tetrachlorophenol,
2,4,5- and 2,3,5-trichlorophenol, 3,4- and 3,5-dichlorophenol, and
3-chlorophenol. .Interestingly enough, these all contain a meta-
chloro substitutent, a structure reported to be extremely persistent
by Alexander and -Aleem (1961) .
Kirsch and coworkers (Kirsch and Etzel, 1973; and Chu and Kirsch,
1972) have isolated bacteria that are capable of degrading and using
PCP as an energy and carbon source. However, the PGP-oxidizing
organisms are slower 'growing than other organisms and when other
nutrient supplies are available the PCP oxidation rate is lower,
thus suggesting that, under normal environmental conditions, PCP
may still be quite persistent.
The photodecomposition of 2,4-dichlorophenol and pentachloro-
phenol with sunlight has been reported. Crosby and Tutass (1966)
in a study of 2,4-D detected 2,4-dichlorophenol as a major photolysis
product. The phenol was further photooxidized to. 4-chlorocatechol
and then to 1,2,4-benzenetriol which is air oxidized to polyquinoid
humic acids. The importance of this pathway to the environmental
decomposition of dichlorophenol is unknown, although practical tests
indicate that sunlight does have an effect on 2,4-D in the field.
234
-------
Munakata and Kuwahara (1969) showed that the toxicity of penta-
chlorophenol in rice field water could be prolonged by covering the
surface of the field with sheets to shut out the sunshine. They
also demonstrated that 50% of a 1 Kg solution of PCP in 50 liters
of water decomposed in ten days when irradiated with sunlight. The
following intermediate products were isolated as well as large
amounts of resineous materials.
OH
Cl Cl
OH HO.
Cl
Cl HO
Cl Cl Cl
.Cl Cl
Cl
Cl
B. Environmental Transport
Mass balances and flow diagrams of chlorophenol transport through
the environment are not available because of the general lack of
monitoring data. Their moderate volatility (PCP 0.00011 mm Hg) would
suggest that atmospheric transport may be a significant route. How-
ever, for the most part, they are considered water and soil contaminants,
235
-------
C. Bioaccumulation
Pentachlorophenol appears to accumulate in the fatty tissues
of various species. Significant concentrations are found in human
I i
adipose tissue (Shafik, 1973). Levels of 105 to 110 ppm have been
detected in guppies exposed to water containing 3 ppm PCP. Also,
levels of from 0.2 to 3 mg/kg flesh tissue were found in fish
samples in a lake containing 3 ug/fc. Highest concentrations were
found in the high fat content species.
Bioaccumulation data on other chlorophenols is not available.
236
-------
X. Toxicity
A. Human Toxicity
Information on pentachlorophenol and its sodium salt comprise
by far the greater part of the available human toxicity data. Be-
cause of the lack of human toxicity information on the lower chloro-
phenols, it is difficult to determine to what extent the preponderance
of the pentachlorophenols is due to an inherently greater human
toxicity of the pentachloro-compoilnds and/or to differences in the
frequency and intensity of human exposure to the various chlorinated
phenols. As the subsequent sections on non-human life forms will
indicate, all of the studied chlorophenols show some degree of toxicity.
However, with the exception of an isolated report of increased neuro-
muscular- excitability and decreased thermoregulatory ability associated
with occupational exposure to p-chlorophenol (Gurova, 1964), 2,4,5-
trichlorophenol and pentachlorophenol are the only compounds listed
in the literature as having caused human toxic responses.
Technical grade 2,4,5-trichlorophenol can cause irritation to
the eyes, skin, nose, and throat. Depending on the degree of exposure,
ocular damage may include the conjunctiva, iris, and/or cornea with
the damage varying from slight irritation to chemical burns (Dow
Chemical Company, 1969a). Skin contact may result in mild to moderate
chemical burns or chloracne (Kimbrough, 1972). However, technical
grade 2,4,5-trichlorophenol may contain a number of impurities including
tri- and tetrachlorodibenzofuran and tetrachlodibenzodioxine. These
237
-------
impurities may well be the causative agents of chloracne (Kimmig and
Schulz, 1957). In follow-up studies on cases of 2,4,5-trichlorophenol
induced chloracne, there may be evidence of psychopathology expressed
in decreased mental and physical activity (Kleu and GBeltz, 1971).
Similar studies have been reported by Kimbrough (1972) implicating
liver damage as part of the long-term exposure effects. Compared to
the trichlorophenol, sodium 2,4,5-trichlorophenate has toxic properties
similar in kind but somewhat more intense in degree (Dow Chemical
Company, 1969b).
Cases of pentachlorophenolic poisoning most often involve dermal
exposure although inhalation can also be pathogenic (Cassaret et al.,
1969). Sodium pentachlorophenate which is much more readily absorbed
through the skin than the phenol (Dow Chemical, 1969c, 1969d) is
usually indicated as the toxic agent. Although the toxic properties
of both the phenol and the sodium salt had been defined in the early
1940's using laboratory animals (Deichmann et al., 1942), cases of
human toxicity were not reported until the following decade. Five
fatal cases are reported involving the use of spray applicators with
concentrations of 1.0%-14.0% sodium pentachlorophenate. The clinical
signs include profuse sweating, thirst, elevated temperature, rapid
pulse and respiration, abdominal pain, and death within about 24 hours
after the first symptoms develop (Gordon, 1956). Similar poisonings
have resulted from manual submersion of wood into solutions of sodium
•
pentachlorophenate. Nine such deaths have been reported after exposure
to 1.5%-2.0% solutions over a 3-30 day period. The disease was characterized
238
-------
by elevated body temperature (101 -108 F), labored breathing, extreme
sweating, and a general increase in the basal metabolic rate (BMR)
due to uncoupling of oxidative phosphorylation (Menon, 1958). Bergner
and associates (1965), in studying similar cases, indicate that death
may be caused by elevated temperature, fluid loss, or cardiac arrest
with histological damage to both the kidney and liver. More recently,
nine infants were poisoned by sodium pentachlorophenate residues on
laundry which led to two fatalities. In this case, the laundry soap
contained 22.9% sodium pentachlorophenate which remained in amounts
of 1.15-195.0 mg/100 g in the diapers, blankets, and other nursery
linen. This compound was absorbed by the infants reaching serum
levels of 118 mg/kg causing severe illness after five days exposure.
In that urinary excretion is a prime mode of chlorophenol elimination,
the immature renal functions of neonates and PCP reabsorption from
diaper urine may have facilitated toxic accumulation (Armstrong, et
al., 1969). As of 1969, thirty fatal cases of pentachlorophenol
poisoning had been reported (Robson et_ ai^., 1969).
Non-fatal exposures commonly involve irritation of the eyes, skin
and upper respiratory tract similar to that outlined for 2,4,5-
trichlorophenol. In addition, less severe systemic disorders of the
kind described in fatal cases are also noted (Bergner et al., 1965).
Symptoms'may be elicited by seemingly small exposures. In one case,
immersion of hands for 10 minutes in a 0.4% solution of pentachloro-
phenol caused severe pain and inflammation (Benvenue et al., 1967a).
239
-------
Similarly, bathing in water containing 12.5 ppm pentachlorophenol
over a 13-day period caused facial inflammation, increased tempera-
ture and pulse rate, and intermittent delerium (Chapman and Robson,
1965).
B. Toxicity to Birds and Non-human Mammals
*
1. Acute Toxicity
Mammalian systems have been used to test the toxicity of a
number of chlorophenols in an .attempt to extrapolate the human
toxic potential of these compounds. Emphasis has been placed
both in comparing the animal response with the human response
and on establishing the relative toxicities of the chlorophenols.
Median lethal doses (LD,-0) have been used as a criterium
with which to compare the toxicities of various compounds. Such
data is presented in Table XII for the acute oral toxicity of
various chlorophenols to laboratory animals.
240
-------
TABLE XII
LD5Q's of Various Chlorophenols and Sodium
Chlorophenates After a Single Oral Administration
Phenol
Compound
p-ehloro-
o-chloro-
ii
2,4-dichloro-
n
ii
2,4,5-trichloro-
n
it
Na 2,4,5-trichloro-
ii
P en tachlor o-
n
it
M
Na Pentachloro-
ii
ii
ti
ii
Animal
rat
blue fox
mice
rat (male)
rat (female)
mice
rat (male)
rat (female)
rat
rat (male)
. rat (female)
rabbit
rat
rat (male)
rat (female)
rabbit
it
rat
it
guinea pig
W5Q
(mg/kg body weight)
500
440
670
3600
4500
1630
2830
2460
2960
1870
1620
70-130*
27.3-77
205
135
250-300*
275
210.6
210
80-160
Reference
Gurova, 1964
Bubnov e_t al.
it
Kobayaski et
M
ii
Dow Chemical,
ti
, 1969
a^., 1972
1969a
McCollister et al. , 1961
Dow Chemical,
ii
Deichmann et
ii
Dow Chemical,
M
Deichmann et
Dow Chemical,
Deichmann et:
Dow Chemical,
n
1969b
al., 1942
1969 d
al., 1942
1969c
al., 1942
1969c
^Minimum Lethal- Concentration
241
-------
Similar information on the acute LD5's from intraperitoneal
injections is available from the work of Farquharson and associates
(1958), and is summarized in Table XIII.
TABLE XIII
Acute LD^Q'S of Chlorophenols Determined by
Intraperitoneal Injection to Male Albino Rats
[Farquharson et al., 1958]
Number of
Chlorine Atoms Phenol LDCn
1 o-chloro-
p-chloro-
m-chloro-
2 2,6-dichloro-
2,4-dichloro-
3 3,4,5-trichloro-
2,4,5-trichloro-
2,3,6-trichloro-
2,4,6-trichloro-
4 2,3,4,6-tetrachloro-
(mg/kg)
230
281
355
390
430
372
355
308
276
130
2,3,4,5,6-pentachloro- 56
242
-------
This data indicates a sharp decrease in toxicity going from the
mono- to di-chlorinated phenols and then a progressive increase
in toxicity with greater chlorination.
Pathological data on the lower chlorophenols is sketchy. At
lethal concentrations, ^-chlorophenol causes fatty degeneration
of the liver, renal granular dystrophy, and necrosis of the stomach
and intestinal mucosa (Bubnov, et^ jl., 1969). In intraperitoneal
injections, the monochlorophenols, 2,6-dichlorophenol, and 2,4,6-
triphenol elicited similar responses including initial excita-
tion, tremors in 40-120 seconds, followed by convulsions, loss
of righting reflex and death. The higher chlorophenols led to
rapid prostration without tremors (Farquharson ££ _al., 1958).
With oral administration of pentachlorophenol, increases were
noted in temperature, blood pressure and initial urinary output.
Muscular weakness developed and autopsy indicated extensive
vascular damage and heart failure (Deichmann et^ai., 1942).
Studies on dermal exposure have not been encountered for the
lower chlorophenols. Both 2,4,5-trichlorophenol and its sodium
salt have been shown to cause a slight reddening of rabbit skin
after brief exposures and mild to moderate chemical burns with
longer exposures (Dow Chemical, 1969a and b; McCollister et al.,
1961). As in human toxicity, cutaneous absorption of sodium
pentachlorophenate can be fatal. Lethal doses for rabbits have
been reported as low as 250 mg/kg in 10% aqueous solution
243
-------
(Deichmann e£ al., 1942). Median lethal doses range between
100-300 mg/kg applied as a 20% solution (Dow Chemical, 1969c).
Pentachlorophenol is reported to be less readily absorbed by
the skin. At doses of 50-100 mg/kg, Dow Chemical (1969d) reports
100% survival in rabbits. Deichmann and associates (1942),
however, report lethal concentrations as low as 40 mg/kg. It
must be kept in mind that this discrepancy may well be due to
impurities in the earlier sample. Both pentachlorophenol and
sodium pentachlorophenate have been shown to cause chloracne in
rabbits (Dow Chemical, 1969c, 1969d).
2. Chronic Toxicity
Long-term feeding studies have been conducted on di-, tri-,
and pentachlorophenols. With dietary feeding of 2,4-dichloro-
phenol at a concentration of 0.1% over a six-month feeding period,
no adverse effects were noted in rats (Kobayaski et al., 1972).
In rats fed up to O.lg/kg/day 2,4,5-trichlorophenol, no adverse
effects were noted over a three-month period. At dosages of
Ig/kg/day, weight loss and degenerative changes of the kidney and
liver were observed (McCollister e± al., 1961). Rats fed 5mg/day
over a six-month period failed to grow and doses of 3.9mg/day
caused retarded growth (Deichmann et al., 1942).
244
-------
3. Sensitization
Although sensitization can be developed in humans exposed to
sodium pentachlorophenol, no similar sensitization has been
reported in lower mammals (Dow Chemical, 1969c). McCollister and
associates (1961) report no sensitization to 2,4,5-trichlorophenol.
4. Teratogenicity
No studies encountered.
5. Carcinogenicity
No studies encountered.
6. Mutagenicity
No studies encountered.
7. Behavioral Effects
No studies encountered.
C. Toxicity to Lower Animals
Toxicity data on the lower animals is based primarily on the bony
fishes. Although most of the information available is on pentachloro-
phenol, the TLm's of some of the lower chlorophenols have been
determined. In fish, these chlorophenols seem to exhibit a reverse
order of toxicity from that shown in mammalian systems, as indicated
in the following table.
245
-------
TABLE XIV
Comparison of LDgo's for Intraperitoneal
Injection in Rats
[Farquharson e_t al., 1958]
to 24 Hour TLm oF Fishes
[Ingols eltal., 1966]
Phenol Compound TLm (mg/i) LD5Q(mg/kg)
o-chloro- 58 230
m-chloro- . 18 355
p-chloro- 14 281
2,4,6-trichloro- 3.2 276
" 1.0-0.1*
*96-hour TLm for fathead minnow (Manufact. Chem. Assoc., 1972).
For the fish, the toxicity seems to increase with oil solubility and
indicates that the primary mechanism of toxicity involves the dis-
solving of fatty tissue by the toxicant (Ingols et al., 1966). This
scheme seems consistent with the almost 100% increase in fatty acid
catabolism noted in salmon after a 14-day exposure to 0.1 mg/£
potassium pentachlorophenate (Hanes et al., 1968). The 24 hour TLm
for sodium pentachlorophenate to the fathead minnow is 0.32-0.35 mg/£
(Crandell and Goodnight, 1959). Other species of fish seem even more
sensitive to this compound as indicated in Table XV.
246
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TABLE XV
Median Tolerance Limits of Some Fresh Water
Fishes to Sodium Pentachlorophenate
[Matida &t_ _al., 1970]
Ultimate
(Observed TLm (Na-PCP, p.p.m.) TLm Body Temp.
6 hr. 12 hr. 24 hr. 48 hr. 96 hr. 240 hr. estimated wt., g °C
Rainbow
trout 0.07 0.056 0.049 0.048 0.0475 0.73 17.2±0.4
Common
carp 0.295 0.195 0.135 0.13 0.13 0.13 0.125 1.36 25.9±0.5
Southern
top-monthed
minnow 0.17 0.16 0.16 0.16 ca 0.16 0.8 25.2±0.5
Sweet fish 0.086 0.068 0.068 ca 0.068 1.9 17.9±0.6
Similar to the effects noted in mammals, pentachlorophenol at 0.1 mg/kg
caused an increase in the metabolic rate and liver enlargement in the
eel (Holmberg e_t al., 1972) . An important point in environmental
considerations is that the toxicity of pentachlorophenol increases
as the pH nears the pK. Thus, organisms in an alkaline aquatic envir-
onment could better tolerate pentachlorophenol than could an organism
in acidic medium (Crandall and Goodnight, 1959).
D. Toxicity to Plants
The chlorophenols have a wide range of phytotoxicity. Perhaps the
most significant studies are those concerning the lower plants.
Blackman and coworkers (1955a) have determined the LD^'s for a number
of chlorophenols on the green-water plant Lemna minor using the con-
centration which caused chlorosis in half the fronds as the index of
toxicity. The results are given in Table XVI.
247
-------
TABLE XVI
LD *s of Various Chlorophenols on Lemna minor
[Blackman £t al., 1955a]
Phenol
p-chloro-
2,4-dichloro-
2,4,6-trichloro-
2,4,5-trichloro-
2,3,4,6-tetrachloro-
2,3,4,5,6-pentachloro-
moles/A
2.2 x 10
3.6 x 10
3.0 x 10
8.4 x 10
2.6 x 10
7.1 x 10
-3
-5
-6
-6
-7
mg/A
282.7 mg/A
58.7 mg/A
5.92 mg/A
1.65 mg/A
.61 mg/A
.19 mg/A
Further, a linear relationship exists between the logarithms of the
LD and the solubility of the chlorophenols as indicated in Figure 5
(Blackman e£ al., 1955b).
o
i/V
e>o
o
-2
-3
-4
-5
111 C minor
23456-
O2 45-
'02346-
-4
-2
Log Solubility
FIGURE 5
Relationship Between the Logarithm of
the Solubility of Chlorophenols and the LD,.-. in Lemna minor
[Blackman et al., 1955b]j
reprinted by permission.
Copyright 1955, Academic Press
248
-------
This seems to indicate that the physiological effect is increased
as the pH of the medium approaches the pK of the chlorophenol
(Crandell and Goodnight, 1959). This conclusion has been verified
by Fujita and Nakajima (1969) for a wide range of biological
activities. Similar generalizations might be found valid for higher
plants if proper screening tests were conducted. Toxic responses
have been elicited in pea stems with 2,3,6-trichlorophenol, whereas
2,6-dichlorophenol has greater growth stimulating properties
(Harper and Wain, 1969). Pentachlorophenol, 2,4-dichlorophenol,
and p-chlorophenol have been shown to cause abnormal mitoses in
Vicia faba, the European Broad Bean (Amer and Ali, 1969). However,
only pentachlorophenol has been implicated in whole plant toxicity.
Fentachlorophenol causes considerable malformation in crested
wheatgrass seedlings at concentrations of 2-4 Ib/acre (Klomp and
Hull, 1968). Although pentachlorophenol has been used extensively
as a desiccant (Bovey, 1969) and weed-killer (Hilton &t al., 1970),
similar malformations have not been noted.
E. Toxicity to Microorganisms
Similar to their work on Lemna minor, Blackman and coworkers
(1955a) have determined the toxicity of various chlorophenols to
the mold Trichoderma viride, using the concentration required
to halve, the growth rate as the, standard.
249
-------
TABLE XVII
Concentrations of Various Chlorophenols Required for
50% Inhibition of Radial Growth (IC5Q) for £. viride
[Blackman et al., 1955a]
Phenol Moles/I
p-Chloro 3.7 x 10
2,4-dichloro 5.3 x 10
2,4,6-trichloro 3.5 x 10
2,3,4,6-tetrachloro- 3.4 x 10
2,3,4,5,6-pentachloro- 1.2 x 10
r4
r5
r5
-6
-6
rng/A
47.5 mg/£
8.64 mg/S,
6.97 mg/Jl
.80 mg/Jt
.32 mg/fc
Again, a linear relationship was demonstrated between the logarithms
of the ICcnS and solubilities of the chlorophenols.
M
60
O
-3
-4
Ib) T. vmd«
02:4-
-4 -2 0
Log Solubility
FIGURE 6
Relationship between the Logarithm of the
ICcQ and the Solubilities of Some Chlorophenols
[Blackman et al., 1955b]^ reprinted by
permission. Copyright 1955, Academic Press.
250
-------
This interpretation of toxicity in terms of physical structure gives
much more satisfactory results than the phenol coefficient method
used by Wolf and Westveer (1952) which indicated a low order of
toxicity for pentachlorophenol. In fact, pentachlorphenol has been
found highly toxic to a wide variety of microorganisms as indicated
in Table XVIII.
TABLE XVIII
Antimicrobial Efficiencies of Pentachlorophenol
(Dowicide EC-7) [Dow Chemical, no date]
Test Organism
Trichoderma viride. ATCC//8678
Trichoderma sp., Madison P-42
Ceratocystis pilifera, ATCC//15457
Polyporus tulipiferae, ATCC#11245
Rhizopus stolonifer, ATCC#6227a
Lenzites trabea, Madison 617
Ceratocystis ip_s_, ATCC//12860
Chaetomium globosum, ATCC//6205
Aspergillus niger. ATCC//6275 j
Bacillus cereus var. mycoides, ATCC#11778
Bacillus subtilis, ATCC//8473
Escherichia coli, ATCC//11229
Pseudomonas aeruginosa, ATCC//15442
Enterobacter aerogenes, ATCC//13048
Streptomyces griseus. ATCC//10137
Flavobacterium arborescens, ATCC//4358
% DOWICIDE EC-7
for Inhibition
0.0025-0.005
0.001-0.0025
0.0005-0.001
Less than 0.0001
0.0001-0.00025
0.0001-0.00025
0.001-0.0025
0.0001-0.00025
0.001-0.0025
0.0005-0.001
0.005-0.01
0.025-0.05
0.1-0.25
0.05-0.1
0.0005-0.001
0.00025-0.0005
251
-------
Other studies have found that the lower chlorophenols also can
inhibit microbial activity. The oxygen uptake of a mixed microbial
population is significantly inhibited by 2,4,6-trichlorophenol
concentrations of 50 mg and 100 mg/& of synthetic sewage but not
a 1 and 10 rag/fc (Manufact. Chem. Assoc., 1972). The growth of the
fungus Aspergillus niger is inhibited by 50% at concentrations of
77.9 mg/«, (4.5 x 10"4M) p-chlorophenol and 1800 mg/£, (14 x 10~4M)
a-chlorophenol (Shirk and Corey, 1952; Shirk et^ al., 1951).
252
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XI. Chlorophenols: Summary and Conclusions
The chlorophenols and their salts comprise an important class of
biocides and chemical preservatives. Although production information
is somewhat fragmentary, the chlorophenol market seems for the most part in
a state of flux. Pentachlorophenol is easily the most important compound in
this class with an annual production of over 50 million pounds and a predicted
growth rate of 4% per year. Although the 2,4 dichlorophenol market may
be dwindling, it is still a significant intermediate in the formation of
2,4-D and may currently be produced in quantities of over 50 million
pounds annually. The 2,4,5-trichlorophenol market may also be decreasing
but production figures are still probably in the tens of millions of
pounds annually. The production of p-chlorophenol cannot be accurately
estimated.
For the most part, all of these compounds are used as biocides or as
raw material in the formation of other biocides or chemical preservatives.
The probability of environmental contamination from these uses is, of
course, high. As molluscacides (PCP), insecticides, or antimicrobials,
they are often released directly into the environment. Used as preserva-
tives for wood, leather, or latex, the probability of leaching seems
evident. Release from water treatment plants, industrial cooling systems,
or biodegradation of herbicides (2,4-D and 2,4,5-T) may also be important
sources of contamination. Monitoring data would tend to support the above
conclusions. 2,4-dichlorophenol has been found in the environment in the
low ppb range. Pentachlorophenol is already wide-spread at concentrations
253
-------
In the high ppb and low ppm range in some parts of the country as evidenced
by direct monitoring data and human urinalysis. Although the common uses
of the chlorophenols would seem to indicate environmental transport
primarily by soil and water, the intermediate volatilities of the
chlorophenols would allow for some degree of atmospheric transport. Such
transport may account for the presence of chlorophenols in areas not
receiving direct exposure.
Once in the environment, in sufficient amounts, there can be little
doubt these compounds will have deleterious effects on a wide range of
life forms. All of the chlorophenols have been found capable of uncoupling
oxidative phosphorylation and inhibiting some enzyme systems. Penta-
chlorophenol is clearly the most powerful biocide. It is toxic to mammals
over short periods at 10 ppm. The long term tolerance for some fish has
been estimated at .05-.16 ppm. Similarly, lower plants and microorganisms
respond adversely in the .1 ppm range. Most significantly, pentachloro-
phenol has been shown to bio-accumulate in fish. Similar accumulations
in mammals are probable. The lower chlorophenols seem to decrease in
biological activity with decreased chlorination. Although their mammalian
toxicity may be low (>1000 ppm), species of fish, plants, and micro-
organisms are injuriously effected by trichlorophenols in the 1 ppm range
and monochlorophenols in the 10 ppm range.
Although the production, uses, and biocidal properties of the
chlorophenols indicate a potential for environmental hazard, a final
determination is somewhat dependent on the degree of chlorophenol persistence.
254
-------
Generally, decomposition tends to decrease with increased chlorination
and meta-substitution. Physical degradation, especially photodecomposition,
may be major route, but a reliable quantitative estimation cannot be made.
In the same way, a number of microorganisms have demonstrated the ability
to metabolize chlorophenols under ideal conditions but the rate at which
this occurs in the environment is not certain. Some studies indicate
persistence time may be measured in weeks. However, the possibility that
the chlorophenols are removed from the samples by biological uptake and
transport rather than biological degradation cannot be ruled out.
The potential for environmental hazard from the chlorophenols seems
clear. Pentachlorophenol, without doubt, poses the greatest danger. It
has the greatest production and most obvious exposure to the environment.
It is certainly the most toxic and probably the most persistent. Although
less is known about the lower chlorinated phenols, they cannot be
discounted. Almost all of the chlorophenols are commercially successful
because they are toxic in some way. That this toxicity might extend
beyond the bounds for which it is intended seems a reasonable possibility.
255
-------
LITERATURE CITED
Alexander, M. and Aleem, M.J.H., (1961), "Effect of Chemical Structure on
Microbial Decomposition of Aromatic Herbicides", J. Agr. Food Chem.,
9_t 44
Alexander, M. and Lustigman, B.K., (1966), "Effect of Chemical Structure
on Microbial Degradation of Substituted Benzenes", J. Agr. Food Chem.,
14, 410
Aly, O.M., (1968), "Separation of Phenols in Waters by Thin-Layer Chroma-
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