EPA 560/2-78-003
INVESTIGATION OF SELECTED POTENTIAL
ENVIRONMENTAL CONTAMINANTS:
ACRYLONITRILE
By:
Lynne M. Miller
Jon E. Villaume
May 1978
Final Report
EPA Contract No. 68-01-3893
FIRL No.80G-C4807-01
Technical Advisor
Dr. Patricia M. Hilgard
Project Officer
Frank J. Letkiewicz
Prepared For:
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C. 20460
Science Information Services Organization
THE FRANKLIN INSTITUTE RESEARCH LABORATORIES
TMC BENJAMIN FRANKLIN FAMKWAV . P H I L A O « !,(• XI A. PENNSYLVANIA 13103
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EPA 560/2-78-003
INVESTIGATION OF SELECTED POTENTIAL
ENVIRONMENTAL CONTAMINANTS:
ACRYLONITRILE
By:
Lynne M. Miller
Jon E. Villaume
May 1978
Final Report
EPA Contract No. 68-01-3893
F1RL No. 800X14807-01
Prepared For:
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C. 20460
Document is available to the
public through the
National Technical Information
Service, Springfield, Virginia 22151
Science Information Services Organization
THE FRANKLIN INSTITUTE RESEARCH LABORATORIES
TMf BENJAMIN PMANKLIN »A«KWAV • I»H I LA 0«1,PHI A. JSMMSYUVAN IA 19103
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NOTICE
This report has been reviewed by the Office of Toxic Substances,
U.S. Environmental Protection Agency, and approved for publication.
Approval does not signify that the contents necessarily reflect the
views and policies of the Environmental Protection Agency, nor does
mention of trade names or commercial products constitute endorsement
or recommendation for use.
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TABLE OF CONTENTS
PREFACE
LIST OF TABLES ix
LIST OF FIGURES xi
EXECUTIVE SUMMARY xii
I. PHYSICAL AND CHEMICAL DATA 1
A. Chemical Structure 1
B. Properties of the Pure Material 1
C. Properties of the Commercial Material 3
D. Chemical Reactions Involved in Use 3
1 . Polymerization 6
2. Reactions of the Nitrile Group 7
3. Reactions of the Double Bond 7
4. Cyanoethylation Reactions 8
II. ENVIRONMENTAL EXPOSURE FACTORS 9
A. Production 9
1. Production Processes 9
2. Quantity Produced 16
3. Domestic Producers and Production Sites 16
4. Imports and Foreign Producers 19
5 . Market Price 19
6. Market Trends 23
B . Use 25
1. Major Uses 25
a. Fibers 27
b. SAN and ABS Resins 27
c. Adiponitrile 29
d. Nitrile Rubber 32
e. Exports 32
f. Miscellaneous Uses 35
ii
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Page
2. Projected Uses 36
3. Alternatives to Use 37
C. Entry into the Environment 37
1. From Production 37
2. From Waste Handling 41
3. From Storage 42
4. From Transportation 42
5. From End Use 43
D. Disposal and Control Methods 52
1. Waste Disposal 52
2. Control Technology 53
E. Fate and Persistence in the Environment 54
1. Degradation in the Environment 54
a. Biological Degradation 54
b. Chemical Degradation 59
1) Atmospheric Reactions 60
2) Reaction with Water 61
2. Transport Within and Between Media 61
3. Persistence and Bioaccumulation 62
F. Hazards from Combustion 64
1. Thermal Degradation 64
2. Mortality from Pyrolysis Products 65
6. Analytical Detection Methods 67
1. In Air 67
2. In Aqueous Solution 71
3. In By-Products 72
4. In Fumigated Food 72
5. In Biological Material 73
III. BIOLOGICAL EFFECTS 74
A. Humans 74
1. Acute Toxicity 74
a. Inhalation Exposure 74
b. Dermal Exposure 75
c. Fumigant Exposure 76
iii
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Page
2. Occupational Exposure 79
a. Signs and Symptoms 81
b. Hematological Alterations 84
c. Effects on Tissues and Organs 85
d. Possible Carcinogenic Effects 90
3. Controlled Studies 92
Nonhuman Mammals 93
1. Absorption and Tissue Distribution 93
2. Biotransformation 94
a. Biotransformation to Cyanide and Thiocyanate 96
b. Reaction with Sulfhydryl Groups 100
c. Coupling with D-Glucuronic Acid 102
d. Minor Metabolites 102
e. Route and Dose Dependence of Metabolite 103
Formation
3. Toxicity 105
a. Acute Toxicity 105
1) Inhalation Exposure 105
a) Lethal Doses 105
b) Signs 110
2) Dermal Exposure 112
a) Lethal Dose Values 112
b) Signs 113
c) Effects on the Skin 114
d) Effects on the Eye 115
3) Oral Administration 115
a) Lethal Dose Values 115
b) Signs 118
c) Tissue and Organ Changes 119
4) Parenteral Administration 120
a) Lethal Dose Values 120
b) Signs 120
c) Effect on the Adrenals 122
d) Effect on Sulfhydryls 124
e) Effect on the Circulatory System 129
iv
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Page
b. Subacute Toxicity 130
1) Inhalation Exposure 130
a) Signs 130
b) Hematological Effects 133
c) Pathology 134
2) Oral Administration 136
a) No Effect Level 136
b) Effect on Weight Gain 136
c) Effect on Clinical Parameters 137
d) Effect on Organ Weights 138
e) Pathology 138
f) Effect on the Adrenals 139
g) Effect on Glutathione 139
ti) Effect on Reproduction 141
3) Percutaneous Administration 141
a) Effect on the Nervous System 1^1
b) Effect on Organs 141
c. Chronic Toxicity 142
1) Inhalation Exposure 142
2) Oral Administration 143
a) Effect on Rats 145
b) Effect on Dogs 152
4. Mechanism of Toxicity 155
a. Action of Cyanide 155
1) Cyanide - Metalloprotein Formation 156
2) Effect on Cytochrome Oxidase 157
3) Effect on Cyanide Antidotes 158
b. Direct Action of Acrylonitrile 159
C. Nonmammalian Vertebrates 160
1. Acute Toxicity 161
a. Freshwater Fish 161
b. Marine Fish 163
2. Subacute Toxicity 164
3. Effect on Taste of Fish 164
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Page
D. Invertebrates 165
1. Aquatic Organism Toxicity l65
2. Nonaquatic Organism Toxicity l6
E. Plants 16&
F. Microorganisms 16S
1 r a
1. Microorganisms Used in Mutagenicity Tests
2. Molds on Food 169
169
3. Aquatic Microorganisms
G. Jn Vitro Studies 17°
170
170
1. Effect on Isolated Nerves 17°
2. Effect on Tissue Respiration
3. Effect on Tissue Sulfhydryl Content l71
IV. SPECIAL EFFECTS 172
A. Mutagenicity 172
1. Broad Bean l72
2. Fruit Fly 172
3. Bacterial Systems 173
a. Ames Standard Plate Method 173
b. Modified Ames Method 174
c. Mutagenicity in Esaherichia aoli 176
4. Yeast I77
5. Mammalian In Vitvo Assays i77
6. DNA Repair Assay 178
B. Cytogenicity 178
C. Teratogenicity I78
D. Carcinogenicity 183
V. REGULATIONS AND STANDARDS 188
A. Federal Regulations 188
1. Occupational Safety and Health Administration 188
2. Department of Transportation 189
3. Environmental Protection Agency 190
a. Federal Insecticide, Fungicide and 190
Rodenticide Act
vi
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Page
b. Clean Air Act 191
c. Federal Water Pollution Control Act 191
d. Federal Water Pollution Control Act as Amended 192
by the Clean Water Act of 1977
e. Solid Waste Act as Amended by the Resource 192
Conservation and Recovery Act
4. Food and Drug Administration 193
B. State Regulations 194
1. Workplace Standards 194
2. Use as a Pesticide 194.
3. Water Quality 194
4. Air Emissions 194
5. Food Contact 198
C. Foreign Countries 198
1. United Kingdom 198
2. Canada 198
3. West Germany 199
4. Belgium 199
5. USSR and Bulgaria 199
D. Other Standards 199
E. Current Handling Practices 199
1. Handling, Storage and Transport 199
2. Personnel Exposure 200
3. Accident Procedures 201
VI. EXPOSURE AND EFFECTS POTENTIAL 202
TECHNICAL SUMMARY 208
BIBLIOGRAPHY 213
CONCLUSIONS AND RECOMMENDATIONS 231
APPENDIX A 233
vii
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PREFACE
This report is a survey and summary of the literature on acrylo-
nitrile available through April, 1978. Major aspects of its chemistry,
environmental exposure, biological effects and regulations are reviewed
and assessed. A list of sources employed in locating the information
in this review is presented in Appendix A.
This document was prepared by the Franklin Institute Research Lab-
oratory for the Environmental Protection Agency under contract 68-01-3893.
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LIST OF TABLES
Table Page
1. Nomenclature and Other Identifiers of Acrylonitrile 2
2. Physical Properties of Acrylonitrile 4
3. Sales Specifications for Acrylonitrile from 2 Producers 5
4. U.S. Production and Sales of Acrylonitrile 17
5. Producers of Acrylonitrile Monomer in the United States 18
6. Imports of Acrylonitrile into the United States 20
7. Western European and Far Eastern Producers of Acrylonitrile 21
8. Market Price of Acrylonitrile in the United States 22
9. Economics for the Manufacture, of Acrylonitrile using the 24
Montedison-UOP Process
10. Producers of Acrylic and Modacrylic Fibers 28
11. Producers of ABS and SAN Resins 30
12. Producers of Polybutadiene-AN Elastomers (NBR) 33
13. Export Data for U.S. Acrylonitrile 34
14. Emission Factors for Acrylonitrile Manufacture 38
15. Sources of Atmospheric Contamination of Acrylonitrile ^0
During Acrylonitrile Manufacture and Bulk Storage
16. Hazards of Acrylonitrile Transportation ^
17. Spill Data for Acrylonitrile 46
18. Acrylonitrile Residues in Walnuts 31
19. Effect of Acrylonitrile on Anaerobic Activity 59
20. Concentration of Acrylonitrile at Sampling Sites after 63
Tank Car Spill of 20,000 Gallons on 12/23/73 near Mapelton,
111.
21. Methods for Determining Acrylonitrile in the Air 69
22. Processes in which Workers are Exposed to AN at Representa- 80
tive Production Sites
23. Association Between Abnormal Findings and Several Variables 83
Associated with Acrylonitrile Exposure
24. Some Indicators of Peripheral Blood in Donors and Workers 84
Involved in Acrylonitrile Production
25. Blood Values of Workers Engaged in the Production of 86
Acrylonitrile in Russia
ix
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Table Page
26. Changes in Some Blood Values in Workers Chronically 89
Exposed to Acrylonitrile
27. Recovery of Radioactivity from Rats Given Acrylonitrile 95
by A) Oral Doses or B) Inhalation Exposure
28. Urinary Metabolites Following the Oral Administration 101
of C-l (Cyano) Labeled Acrylonitrile
29. Metabolites in Rats of 1I+C-AN Separated by High Pressure 104
Liquid Chromatography
30. Inhalation Exposure to Acrylonitrile 106
31. Inhalation Exposure of Acrylonitrile for 4 Hours in 107
Various Mammal Species
32. Inhalation Exposure of Rats to Acrylonitrile 109
33. Acute Dermal LDso for Acrylonitrile 112
34. Acute Oral LD50 for Acrylonitrile 116
35. Acute Parenteral LDso Values for Acrylonitrile 121
36. Catalase, Sulfhydryl and Lactic Acid Levels in Rats 125
Intoxicated with Acrylonitrile
37. Effect of Acrylonitrile (Administered i.p.) on the 126
Hepatic Nonprotein Sulfhydryl Content of Various
Species
38. Effect of Acrylonitrile on Tissue Sulfhydryl 128
39. Mortality in Animals Exposed to Acrylonitrile over 131
90 Days
40. Hematological Values (Venous Blood) in Rabbits Before 135
and After Exposure to 20 ppm Acrylonitrile
41. Effect of Acrylonitrile Administration (21 days) on 140
Hepatic Glutathione in Rats by 2 Routes of Administration
42. Changes in Wistar Rats After Exposure to Acrylonitrile 144
(0, 50, 250 mg/m3) for 3 hr/day, 6 days/week for 6 Months
43. Effect of Long-Term Oral Feeding of Acrylonitrile in Rats 146
44. Acrylonitrile in the Drinking Water of Rats 149
45. Gross Pathologic Findings in Male and Female Rats Main- 151
tained on Water Containing AN for 12 Months
46. Mortality (%) in Several Species After Administration of 160
a Lethal Dose of Acrylonitrile and an Antidote
47. Median Tolerance Limit Values (TI^) for Various Fish 162
Expo&ed to Acrylonitrile
48. Lethal Dose Values of Insects Exposed to Acrylonitrile 167
x
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Table Page
49. Mutagenicity of Acrylonitrile Vapor with 5. typhimurium 175
Strain TA 1535
50. Testing of Acrylonitrile in the Mouse Lymphoma L^UQ^ 179
Assay
51. Incidence of Fetal Alterations Observed During the Ex- 181
ternal or Soft Tissue or Skeletal Examination Among
Litters of Rats Receiving Acrylonitrile by Gavage
52. Carcinogenicity Bioassays on Rats by Mai ton! et al. 186
(1977); Results after 131 Weeks
53 . Regulations for Acrylonitrile Food Contact and Workplace 195
Standards in Selected States
54 . Pesticide Restrictions for Acrylonitrile in Selected 195
States
55. Water Standards for Acrylonitrile in Selected States 196
56 . Air Standards for Acrylonitrile in Selected States 197
57 . Respiratory Protection for Acrylonitrile 202
LIST OF FIGURES
Figure Page
1. U.S. Acrylonitrile Capacity by Process 10
2. Production Process for Acrylonitrile 13
3. Acrylonitrile Demand 26
4. Biological Oxidation of Acrylonitrile in 56
Aqueous Systems
xi
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EXECUTIVE SUMMARY
Acrylonitrile (vinyl cyanide, propenenitrile) is a chemical inter-
mediate used to produce a wide variety of fibers, plastics and elastomers.
A small amount is used as a fumigant. About 1.5 billion pounds of acrylo-
nitrile are produced annually by the reaction of propylene, oxygen and ammonia.
Low levels of acrylonitrile enter the environment during production,
storage, end-product manufacture, and end-product use, although extensive
monitoring data are not available. It is highly reactive chemically and
is subject to biological degradation.
Recent evidence shows acrylonitrile to be carcinogenic in animals and
possibly carcinogenic in humans. Kats exposed.to acrylonitrile for 12
months developed a higher incidence of stomach, central nervous system and
ear canal tumors. Acrylonitrile resulted in birth defects when fed to
pregnant rats and caused mutations in some types of bacteria. At a textile
plant in Camden, S. C., E. I. DuPont de Nemours Company has reported in-
creased cancer among workers exposed to acrylonitrile.
Because of this evidence the Occupational Safety and Health Admin-
istration has limited workplace exposure to 2 ppm (time-weighted average)
in an Emergency Temporary Standard.
For humans, acrylonitrile is toxic if inhaled, ingested, or applied
directly on the skin. Short-term exposure causes headache, mucous membrane
irritation, dizziness, vomiting and incoordination. Several fatalities
have resulted from fumigant use. Direct skin contact produces blisters
xii
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resembling second-degree burns. Long-term occupational exposure may af-
fect the central nervous system, liver and blood.
In laboratory mammals, signs of acrylonitrile intoxication include
altered breathing, incoordination, weakness, convulsions and coma. Signs
vary widely in different species and at different doses. Effects may in-
clude central and peripheral nervous system damage; hemorrhaging of the
lungs, adrenals, or livers; and depressed sulfhydryl content of the
kidneys, liver or lungs.
Long-term administration of acrylonitrile may affect growth, food
and water intake, adrenal function, and the central nervous system, depend-
ing on the dose.
In mammals, acrylonitrile is broken down to cyanide (which is further
metabolized to thiocyanate), and also reacts with sulfhydryl groups. The
toxic action may be due to cyanide formation, but is more likely due to
the direct effects of acrylonitrile.
Acrylonitrile is toxic to several species of fish, insects and micro-
organisms.
xiii
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I. PHYSICAL AND CHEMICAL DATA
A. Chemical Structure
Acrylonitrile (AN) is a flammable colorless liquid of the following
planar structure:
H H
\ x-
C = C
H' \
\\
N
All bond angles equal about 120°. Bond distances have been estimated as
follows: C - H * 1.09 A; C - C - 1.46 A; C = C - 1.38 A; C s N - 1.16 A
(Wilcox and Goldstein, 1954). Table 1 presents synonyms and other iden-
tifiers .
B. Properties of the Pure Material
Some of the important physical properties of acrylonitrile are listed
in Table 2. Acrylonitrile is miscible with most organic solvents including
acetone, benzene, carbon tetrachloride, ether, ethyl acetate, ethyl alcohol,
ethylene cyanohydrin, liquid carbon dioxide, methyl alcohol, petroleum
ether, toluene and xylene (American Cyanamid, 1959). The solubility of
acrylonitrile in water is listed in Table 2. Pure'acrylonitrile is subject
to self-polymerization with rapid pressure development.
Acrylonitrile has a flash point of 0°C so ignition occurs readily
and the vapors are explosive. It forms explosive mixtures with air at
about 3.35 to 17% by volume (explosive range; Patty, 1963).
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Table 1
Nomenclature and Other Identifiers of Acrylonitrlle
Item
Chemical Abstracts Service (CAS)
9th Collective Index name:
CAS Registry No.:
EPA Toxic Substances List No.:
NIOSH Registry No.:
EPA Toxic Substances List No.:
Synonymsa:
Standard Industrial Code
Wiswesser Line Notation:
Molecular Formula:
Chemical Formula:
Data
2-Propenenitrile
107-13-11
R037-2101
AT 52500
R037-2101
ACRN
AN
Cy ano e thy lene
2-Propenenitrile
Vinyl cyanide
VCN
2822; 2824
NC1U1
C3H3N
CH2
fumigant formulations with acrylonitrile included the names
Aery Ion, Carbacryl, ENT 54, Fundgrain and Ventox; these are
no longer manufactured.
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The threshold odor level for acrylonitrile determined by 16 panelists
(total of 104 observations) averages 18.6 ppm ranging f-rom 0.0031 to 50.4
ppm (Baker, 1963).
C. Properties of the Commercial Material
Technical-grade acrylonitrile is a highly pure product (greater than
99% pure, excluding any added stabilizers). The specifications for acrylo-
nitrile available from DuPont and Monsanto appear in Table 3.
Except for water, impurities are present only in ppm. Possible con-
taminants include acetone, acetonitrile, acetaldehyde, iron, peroxides
and hydrocyanic acid (Table 3). Water, present at a maximum of about 0.5%,
improves the stability of the product. Highly pure acrylonitrile may poly-
merize spontaneously. Yellowing upon long exposure to light indicates
photoalteration to saturated derivatives. Commercial acrylonitrile is
stabilized against self-polymerization and color formation with water and
methylhydroquinone. However, hazardous polymerization may still occur in
the absence of oxygen, upon exposure to visible light or in the presence
of alkali (Department of Transportation, 1974).
D. Chemical Reactions Involved in Use
Acrylonitrile is a versatile chemical intermediate. Its reactions may
involve the cyano group (CN), the double bond (C = C) or both. Only a few
representative commercial reactions are listed below, the most important
being polymerization. End uses of acrylonitrile and the preparation of
these products are presented in Section II-B. A thorough discussion of
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Table 2
Physical Properties of Acrylonitrile
(American Cyanamid. 1959, 1974)
Item
Appearance
Boiling Point
Density
Flash Point (Tag Open Cup)
(Closed Cup)
Freezing Point
Ignition Temperature
Molecular Weight
Octanol/H20 Partition Coefficient
Odor
Refractive Index
% Solubility in Waterb
Vapor Pressure (mm Hg)
Partial Vapor Pressure,
Water azeotrope
Conversion Factor for Vapor
(25°C; 760 mm Hg)
Data
colorless liquid
77.3°C at 760 mm pressure
0.8060 (20°C)
0.8004 (25°C)
0°C
-4.4°C
-83.55 ± 0.05°C
481°C
53.06
0.12a
faintly pungent
n£5 = 1.3888
7.2% (0°C)
7.35% (20°C)
7.9% (40°C)
50 (8.7°C)
100 (23.6°C)
250 (45.5°C)
500 (64.7°C)
760 (77.3°C)
Log P =• 7.518 -
1644.7
T°K
(i.e., 80 mm at 20°)
1 mg/1 » 460.5 p
1 mg/1 X 1Q3» mg
1 ppm = .00217B mg/1
1 mg/l» 1 ppm, in water
^origan et al., 1976; antilog of -0.92
AN is miscible with most organic solvents
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Table 3
Sales Specifications for Acrylonitrile from 2 Producers
SPECIFICATIONS
Acetone, ppm max.
Acetonitrile, ppm max.
Aldehydes, as Acetaldehyde, ppm max.
Iron, ppm max.
ECU, ppm max.
Refractive Index at 25 °C
Peroxides, ppm max. as H202
Water, %
Nonvolatile Matter, ppm max.
Appearance
Inhibitor, MEHQ ppm
Acidity, as Acetic Acid, ppm max.
pH, 5% Aqueous Solution
DuPont
n.r.
500
50
0.1
10
1.3880-1.3892
0,3
0.25-0.45
100
Clear and free
35-50
35
5.5-7.5
Monsanto
300
500
50
0.2
5
1.3880-1.3892
1.0
0.25-0.45
100
Clear and free
35-50
20
n.r.
n.r. * not reported
* MEHQ = methylhydroquinone
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the industrial chemistry of acrylonitrile is found in American Cyanamid
(1959).
1. Polymerization
Polymerization, forming high molecular-weight products, is the most
important commercial reaction of acrylonitrile. Acrylonitrile does not
polymerize in the absence of initiators but does polymerize when irradiated
o
with light (wavelength < 2900 A) or when present with active radicals.
Oxygen is a powerful inhibitor of the polymerization of acrylonitrile
(Bamford and Eastmond, 1964)
Acrylonitrile can be polymerized using bulk, solution, suspension or
emulsion techniques to produce polyacrylonitrile:
H
2R- + 2nH2C=C —> R C-C
C=N
H H
Acrylonitrile
R
H C /
III
N N
til .
1
(
1
: i
t
i
E
i i
i
i
n
n
Polyacrylonitrile
As shown above, cyano groups participate in hydrogen bonding with adjacent
hydrogen atoms. Polyacrylonitrile can be copolymerized with a small amount
of methyl methacrylate or vinyl pyridine to introduce reactive dyeing sites;
pure polyacrylonitrile cannot be dyed using conventional techniques (Seymour,
1975).
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It can Be copolymerized with other monomers. Examples of acrylonitrile
copolymers include nitrile rubber, acrylonitrile-butadiene-styrene (ABS)
and styrene-acrylonitrile (SAN) resins. Terpolymers of acrylonitrile or
methacrylonitrile are the so-called barrier resins (Seymour, 1977) . These
products are discussed in Section II-B-l-f. The production and properties
of acrylonitrile polymers are reviewed in Bamford and Eastmond (1964).
2. Reactions of the Nitrile Group (American Cyanamid, 1969;
Fugate, 1963)
Acrylonitrile hydrated at 100°C with 84.5% sulfuric acid produces
acrylamide sulfate, which yields acrylamide upon neutralization as shown
below:
CH2=CHCN + H2°
-f CaO — > CH2»CHCONH2 + CaSO^ + H20
When acrylonitrile is heated with less concentrated sulfuric acid or
if acrylamide is heated with water, acrylic acid (CH2 = CHCOOH) is formed.
Acrylonitrile allowed to react with alcohols in the presence of con-
centrated sulfuric acid produces esters of acrylic acid, with acrylamide
sulfate formed- as an intermediate. If acrylonitrile is mixed with olefins
or alcohols in concentrated sulfuric acid, N-substituted acrylamides are
formed.
3. Reactions of the Double Bond (American Cyanamid, 1959)
Acrylonitrile has an activated double bond which acts as a dienophile
in the Diels-Alder Reaction. When treated with aliphatic or alicyclic
compounds containing conjugated carbon- to-carbon double bonds cyclic pro-
ducts are produced. An example is the reaction with butadiene:
-------
CH2
/ \
CH2=CHCN -I- CH2 - CHCH - CH2 — > HC CHCN
11 '
HC CH2 -
\ /
CH2
A-3-tetrahydrobenzonitrile
Acrylonitrile in the presence of catalysts can be hydrogenated to
propionitrile which can be further hydrogenated to n-propylamine:
CH2 a CHCN — 2> CH3CH2CN — ^ CH3CH2CH2NH2
Reductive coupling of acrylonitrile (shown below with magnesium and
methanol) produces adiponitrile:
2CH2»CHCN + ZCHaOH 4- Mg — > CH2CH2CN + (CH30)2 Mg
I
CH2CH2CN
4. Cyanoethylation Reactions
Cyanoethylation reactions involve the reaction of acrylonitrile with
active hydrogen compounds (AH molecules). Examples of AH molecules are:
water, alcohols, ammonia, amines, mer cap tans, aldehydes, inorganic acids
and their salts, aldehydes and ke tones. The generalized reaction can be
written:
CH2~CHCN + AH — > ACH2CH2CN
(American Cyanamid, 1959) •
The Cyanoethylation of 3 nucleosides (pseudouridine , inosine, 4-
thiouridine) by acrylonitrile has been studied as a model for the cyano-
ethylation of intact tRNA (Ofengand, 1967).
8
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II. ENVIRONMENTAL EXPOSURE FACTORS
More than 1.5 billion pounds of acrylonitrile were produced by four
domestic manufacturers during 1976 (U.S. International Trade Commission,
1976). Aspects of acrylonitrile production, use, and entry into the
environment will be discussed in the following sections.
A. Production
1. Production Processes
In 1893 the French chemist Moreau first prepared acrylonitrile by
the dehydration of either acrylamide or ethylene cyanohydrin with phos-
phorus pentoxide. However, acrylonitrile was not used commercially until
the late 1920's when German chemists used it to make oil-resistant rubber.
Manufacture of acrylonitrile began in 1940 in the United States (Fugate,
1963).
Several processes for the production of acrylonitrile monomer have
been commercialized (Figure 1). Before 1960 the dominant manufacturing
process was the catalytic reaction of acetylene and hydrogen cyanide in
the presence of a cuprous chloride catalyst, according to the equation:
CuCl
C2H2 + HOT > CH2 =» CHCN
acetylene hydrogen AN
cyanide
Until the mid 1960's other less widely used processes included:
(i) the catalytic dehydration of ethylene cyanohydrin
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2000
1500
to
o
z
3
O
Q.
O
1000
500
ACETYLENE-HCN
PROPYLENE- AMMONIA
ETHYLENE OXIDE-HCN
PROPYLENE-NITRIC
OXIDE
1 I I
I960 1962 1964 1966 1968 1970 1972 1974 1976 1978
YEAR
Figure 1. U.S. Acrylonitrile Capacity by Process
(based on Idol, 1974)
10
-------
(CH2)20 + HCN > CH2(OH)CH2CN
ethylene hydrogen ethylene
oxide cyanide cyanohydrin
CH2(OH)CH2CN > CH2 = CHCN + H20
cyanohydrin AN
ii) the catalytic reaction of propylene with nitric oxide
4CH2-CHCH3 + 6NO > 4CH2»CHCN + 6H20 + N2
propylene nitric AN
oxide
In 1960 the catalytic vapor phase oxidation of propylene and ammonia
(ammoxidation of propylene) was introduced. This method is currently used
by all major manufacturers in the United States and throughout the world
(Idol, 1974). This process can be described as follows:
2CH2=CHCH3 + 2NH3 + 302 > 2CH2=CHCN + 6H20
propylene ammonia oxygen AN water
The ammoxidation process is an exothermic reaction, with a heat re-
lease of 17.6 kJ/g AN formed.* Adding by-product reactions and catalyst
regeneration, the total heat released is about 21.93kJ/s AN produced
(Schwartz et al., 1975; Hughes and Horn, 1977). Several propylene ammoxi-
dation processes have been introduced, differing in the catalyst, recovery
and reactor (fixed-bed or fluidized bed). The most important is the Sohio
process, patented by the Standard Oil Company of Ohio, which currently
employs "Catalyst 41".
This catalyst, introduced by Sohio in 1972, is a uranium-free fluid-
bed catalyst based on bismuth phosphomolybdate. Acrylonitrile yields are
theoretically increased 35% over those with the older uranium based cata-
* 1 kJ= 4.18 kcal
11
-------
lyst (catalyst 21) used from 1967 to 1973 (Townsend, 1974). The original
Sohio catalyst (Catalyst A) was used from 1960 to 1967 and was of bismuth
phosphomolybdate composition.
In 1976, Sohio of the United States was licensed by the Nitto Chemi-
cal Industry Co. (Japan) to use Nitto's catalyst ("NS773A") for the
production of acrylonitrlle (Anon., 1976a; Anon., 1977a). This catalyst is
currently used by Nitto in Japan.
In the Sohio process the feedstock consists of anhydrous fertilizer
grade ammonia, propylene and air which yield more than 0.85 pounds of
acrylonitrile per pound of propylene feed (Anon., 1975). The theoretical
yield is 1.26 pounds of acrylonitrile per pound of propylene feed (Town-
send, 1974). About 0.1 pound each of acetonitrile and hydrogen cyanide
are produced as by-products per pound of acrylonitrile produced.
As of 1976 only Vistron and duPont marketed the byproduct acetonitrile.
About 75% of the by-product hydrogen cyanide is marketed (Vistron, 1978,
pers comm.). Remaining acetonitrile and hydrogen cyanide are either incin-
erated or disposed of by deep well injection (Schwartz et al., 1975). See
Section II-C-2 for more information on waste disposal.
In the flow scheme shown in Figure 2, the feeds are mixed and in-
troduced into a fluid bed catalytic reactor which operates at 5 to 30 psig
12
-------
WASTE HEAT
BOILER
COOLING COILS
e
u
o
e
3
/i
o
<
r
^.
3
c
>
u
IAJ
g
y
Q
N^
J
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*
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o
u
oe
J
f\
A
=!
s
a
oc
>«
rzi
@
)
1
l|
fS
8
t/l
0
(2)
*
yy
/^~N
§
I
»
®
i
uj
oe
STEAM
DEEP WELL
POND
DENOTES MAIN PRODUCT ROW
DENOTES ALL OTHER STREAM FLOW
g
o
<
TO DEEP WaL
CRUDE
ACRYLONITRILE
H STORAGE H
ACRYLONITRILE
H STORAGE h
§\
-*- ABSORBER VENT GAS
-*- RARE
FUGITIVE EMISSIONS
INCINERATOR STACK GAS
DEEP wai POND EMISSIONS
STORAGE TANK EMISSIONS
PRODUCT TRANSPORT
LOADING
FACILITY
PRODUCT TRANSPORT LOADING
FACILITY VENT
TANK TRUCK
RAILROAD CAR
Figure 2. Production Process for Acrylonitrile (Hughes and Horn, 1977 which
was redrawn from Schwetz et al., 1975) "
-------
Figure 2 (continued)
Stream number Description
1 Propylene feed
2 Ammonia feed
3 Process air
4 Reactor feed
5 Reactor product
6 Cooled reactor product
7 Quenched reactor product
8 Sulfuric acid
9 Stripping steam
10 Wastewater column volatiles
11 Wastewater column bottoms
12 Absorber vent gas
13 Acrylonitr"ile plant wastewater
14 Absorber bottoms
15 Water recycle
16 Crude acetonitrite
17 Crude acrylonitrile
18 Recovery column purge vent
19 Acetonitrite column bottoms
20 Acetonitrile
21 Hydrogen cyanide
22 Light ends column purge vent
23 Light ends column bottoms
24 Product acrylonitrile
25 Heavy ends
26 Product column purge vent
27 Flare
28 Fugitive emissions
29 Incinerator stack gas
30 Deep well pond emissions
31 Storage tank emissions
32 Product transport loading facility vent
14
-------
and 750° to 950°F (Anon,, 1975). The following discussion is entirely from
Hughes and Horn (1977) to whom the reader is referred for more detail.
Cooled reactor effluent (Stream 6) is sent to a quencher. Here, additional
product cooling takes place and excess ammonia is removed. Bottoms from
the quencher are sent to the wastewater column (Stream 9). The quenched
reactor products (Stream 7) are sent to the absorber for recovery of
acrylonitrile, hydrogen cyanide and acetonitrile. Absorber vent gas may
be routed to the atmosphere (Stream 12).
Bottoms from the absorber are sent to the recovery column where crude
acrylonitrile is separated from crude acetonitrile. Crude acetonitrile
is sent to the acetonitrile column. Acetonitrile column bottoms are sent
to a deep well pond (Stream 19) while acetonitrile is purified or is in-
cinerated (Stream 20). Crude acrylonitrile is purified after storage
(Stream 17) first in the light-ends column and then in the product column.
Hydrogen cyanide from the light ends column (Stream 21) and product column
i
bottoms, and heavy ends from the product (Stream 25) may be incinerated or
purified. In Figure 2 are shown additional process streams which are dis-
posed of by flare (combustion device), incineration and/or deep well injec-
tion. These and other streams will be discussed further in Section II-C
as possible sources of acrylonitrile to the environment.
Montedison-UOP has recently introduced a modified process for the
ammoxidation of propylene using a different catalyst than Sohio (Pujado,
et aJ., 1977). This process, as does Sohio's, uses a fluidized bed reactor
and a feed stock consisting of propylene and ammonia. The Montedison
process claims a more energy-efficient product separation and recovery
system. It does not appear, however, that any process will be able to
economically compete with Sohiofs in the foreseeable future in the U.S.
(Lowenbach et al., 1978).
15
-------
2. Quantity Produced
During 1976 more than 1517 million pounds of acrylonitrile monomer
were produced in the United States (U.S. International Trade Commission,
1976). This represents a 53% increase in production since 1966. Within
this decade, however, year to year production has been erratic (Table 4).
3. Domestic Producers and Production Sites
There are four manufacturers of acrylonitrile monomer in the United
States: American Cyanamid Co., E. I. DuPont de Nemours and Co. Inc.,
Monsanto Co. and Vistron Corp. Their total production capacity is 1650-
1710 million pounds. Individual plant capacities and sites are listed in
Table 5. During 1976 DuPont had the largest production capacity, 610
million pounds (SRI, 1977). However, in 1977 Monsanto?s capacity was in-
creased, so that Monsanto became the largest domestic producer (Anon., 1977b)
Although plant capacities are known, it is difficult to obtain in-
formation on actual plant production. During 1976 Monsanto apparently
operated at capacity for most of the year (Monsanto Company,
1976). SOHIO (Vistron) produced 341 million pounds of acrylonitrile dur-
ing 1976 (Standard Oil Co., 1976), which is about 15% below capacity.
American Cyanamid was expected to produce 245 million pounds of acrylo-
nitrile during 1977 (American Cyanamid, 1977).
Historically, acrylonitrile was produced by Union Carbide (Institute,
W.Va.) from 1954 to 1966 and by B. F. Goodrich (Calvert City, Ky.) from
1954 to 1972. The Union Carbide facility is now involved in the production
of an intermediate polymer which uses acrylonitrile as a starting material.
The Goodrich facility is no longer involved with acrylonitrile manufacture
(Union Carbide, 1977; B. F. Goodrich, 1977).
16
-------
Table 4
U.S. Production and Sales of Acrylonitrile
1976
1975
1974
1973
1972
1971
1970
1969
1968
1967
1966
Production
(1,000 pounds)
1,517,830
1,214,550
1,411,749
1,354,160
1,114,749
978,897
1,039,257
1,156,585
1,020,957
670,764
716,074
Sales
(1,000 pounds)
600,987
523,694
511,701
480 , 715
459,985
429,153
547,124
561,632
N.R.
270,454
318,169
Value of
Sales
(1,000 $)
147,144
122,459
95,111
50,878
49,259
44,364
59,812
65,950
N.R.
31,875
40,285
Average
Cost per
pound ($)
0.24
0.23
0.19
0.11
0.11
0.10
0.11
0.12
N.R.
0.12
0.13
N.R. = not reported
source: U.S. International Trade Commission 1973-1976
U.S. Tariff Commission 1966-1972
17
-------
Table 5
Producers of Acrylonitrile Monomer in the United States
(Vistron, 1978; SRI, 1977; Anon., 1977b.; Monsanto, 1976)
Capacity
(Millions of Lbs.)
American Cyanamid Co. 200-240
Industrial Chemicals and
Plastics Div.
New Orleans, LA
E.I. DuPont de Nemours & 350
Co., Inc.
Polymer Intermediates Dept.
Beaumont, TX
E.I. DuPont de Nemours & 260
Co., Inc.
Industrial Chemicals Dept.
Memphis, IN
Monsanto Co.
Monsanto Polymers and
Petrochemicals Co. ,,-,,«
Alvin, TX 44°-460
Texas City, TX 420a
Vistron Corporation 290
Standard Oil Co. (Ohio) 110
Lima, OH
aAnnual Report Monsanto Co., 1976.
18
-------
4. Imports and Foreign Producers
Imports of aerylonitrlie into the U.S. during 1976 amounted to more
than 13 million pounds and came almost exclusively from The Republic of
China (51.7%) and Japan (48.2%) (Table 6; U.S. Bureau of the Census 1976a).
During 1975 acrylonitrile was imported mainly from Japan (32.3%) and the
United Kingdom (67.5%); since 1970 West Germany and the Netherlands have
also exported acrylonitrile to the U.S.
The current W. European and Far Eastern acrylonitrile producers are
listed in Table 7. The specific foreign producers exporting acrylonitrile
into the United States are not known, only the total amount per country.
As shown in Table 6, total imports steadily increased from 1970 to 1974
but dropped in 1975; 1976 levels were below the peak 1974 levels. His-
torically, high import levels were attained during 1965, 1968 and 1969
(1204, 35 and 55 thousand pounds, respectively; U.S. Bureau of the Census
(1965-1976a).
5. Market Price
The current market price of acrylonitrile is listed in Table 8. The
major producers sell acrylonitrile mainly bulk (i.e., full truck or car
loads); the price ranges from 27 to 27-JC/lb f.o.b. Small quantities
may be purchased from distributors, the price depending on the quantity
ordered.
The price of acrylonitrile was higher during the 1940fs and early
1950's. The list price of acrylonitrile declined from 53c per pound in
1952 to about 14*sc/lb in 1961. Prices remained at about 14J$c/lb
durins 1961 to 1974, except for a 2%
-------
Table 6
Imports of Acrylonitrile
into the United Statesa
1976
China
Japan
Other
1975
Japan
U.K.
Other
1974
U.K.
Nethlds.
W. Germ.
Japan
1973
U.K.
Other
1972
U.K.
Nethlds.
1971
Nethlds.
1970
Germany
Total (Ibs)
13,362,306
7,152,019
15,386,990
18,405
2,492
6,614
265
% of Total,
by Country
51.7
48.2
0.1
32.3
67.5
0.2
73.9
17.8
5.4
2.9
97.6
2.4
60.2
39.8
100
100
source: U.S. Bureau of the Census, U.S. Imports for Con-
sumption and General Imports 1970-1976.
20
-------
Table 7
Western European and Far Eastern Producers of
Acrylonitrile (Olson, 1977)
Country
Austria
France
Germany
Italy
Japan
Korea
Netherlands
Republic of China
Spain
U.K.
Producer
Erdol-Chemie
Nor so lor
PUK
Erdol Chemie
Hoechst
ANIC
Montedison
Rumianca
Asahi
Mitsubishi
Mitsui Toatsu
Nitto Chemical
Showa Denko
Sumitomo
long Suh Petrochemical
DSM
China Petrochemical
Paular
Border
Monsanto
1977 Capacity
(million Ibs.
94
220
110
573
198
176
159
176
517
176
132
310
153
280
110
298
154
198
176
265
21
-------
Table 8
Market Prices of Acrylonitrile in the United States
(12/1/77; industrial sources)
Producer;
American Cyanamid
DuPont
Monsanto
Vistron
Distributor:3
Aldrich Chemical Co., Inc.
159 Forrest St. , Metuchen, NJ
940 W. St. Paul Ave., Milwaukee, WI
East Falls Corp.
Lee Blvd., Frazer, PA
Webb Chemical Corp.
Jarman St.
Muskegon Hts., MI
Quotation
27 c/lb.; f.o.b. ; bulk
27 l/2c/lb.; f.o.b.; bulk
27 C/lb.; f.o.b.; bulk
27 c/lb.; f.o.b.; bulk
$2.00/100 g; $4.45/kilo;
$8.90/3 kilo
53 c/lb. for 1-10 drums
(55 gal/drum)
52 c/lb for 4-9 drums
49 c/lb for 10-19 drums
47 c/lb for 20 drums - truckload
(shipped collect)
40 C/lb. for 1-10 drums
(55 gal/drum)
37 c/lb. for 11-59 drums
35 c/lb. for >60 55 drums
(shipped collect)
not a comprehensive list of distributors; most manufacturers will not
divulge this information.
purchased from DuPont.
22
-------
Stobaugh and Townsend pointed out four factors underlying the decline in
the price of acrylonitrile (and other petrochemicals) (Townsend, 1974):
a) increasing scale economies of larger production facilities; b) effi-
ciency of accumulating production experience (e.g., new catalysts improv-
ing yield); c) more producers [1 producer of AN in 1951 to a high of 6 in
1960-1965]; d) more standardized product. The most important factor, how-
ever, is the significant reduction in the production cost since the intro-
duction of the Sohio process for acrylonitrile manufacture.
The price of acrylonitrile has risen since 1974, partly due to infla-
tion, the increased price of raw materials and higher capital costs. Raw
materials now represent about 75% of the production cost. Capital costs
are three times what they were in the 1960's for the same sized plants,
particularly due to environmental control equipment (Olson, 1977). Latest
price increases of Ic per Ib since January, 1977 reflect increased acrylo-
nitrile demand. Prices are forecasted to continue to reflect the rising
cost of propylene and ammonia (Anon., 1977c) .
Table 9 shows a breakdown of factors contributing to the 1977 transfer
price of acrylonitrile produced by ammoxidation using a Montedison-UOP
catalyst; up-to-date information for SOHIO's catalyst 41 was not available.
6. Market Trends
The average annual growth of acrylonitrile has been about 11% during
1965 to 1975 (Anon,, 1977b). In 1975 the market fell due to decreased
fiber demand but has now recovered (Pujado et al., 1977). An annual growth rate
of 8 to 10% is estimated for 1977 to 1981, especially attributable to
plastics demand (Anon., 1977b). Further growth is expected during the early
1980rs from increased demands for polyacrylamide, to be used in tertiary
oil recovery (Pujado et al., 1977). Growth of individual markets for acrylonitrile
23
-------
Table 9
Economics for the Manufacture of Acrylonitrile
Using the Montedison-UOP Processa
(Pujado et al., 1977)
b
Capital Cost $ MM
Battery limits capital cost (BLCC) 35.3
Offsites (@ 20% of BLCC) 7.1
Estimated erected cost (EEC) 42.4
Estimated working capital (EWC) 8.2
Estimated total investment 50.6
Cost Acrylonitrile
Operating expenses c/lb.
Raw materials 14.7
Propylene, 92% purity @ 9c/lb.
Ammonia, fertilizer grade @ 6.5c/lb.
Catalyst and chemicals 1.4
Utilities 0.4
Labor U.3
Labor, supervision and fringe benefits
Maintenance, @ 3% of EEC 0.6
Expenses 3.3
Property taxes, insurance, interest on
capital (@ 8%), interest on EWC (@ 9%),
depreciation, general plant overhead
Credits (1.2)
HCN @ 22c/lb
Return on investment @ 30% of EEC 5.8
Acrylonitrile transfer price 25.3
"based on 100,000 metric tons/year; propylene ammoxidation process
millions of dollars
24
-------
are discussed in Section II-B-1.
The future of acrylonitrile is tied to the availability of propylene
and ammonia. Acrylonitrile currently uses about 15% of the total supply
of propylene (Ponder, 1976). Although propylene was in tight supply dur-
ing 1976 (Anon., 1976b) a sufficient quantity is expected in the future
(Anon., 1977e; Anon., 1977b). No shortages of ammonia are indicated, al-
though large amounts of ammonia will probably be imported to the U.S. by
1980 (Olson, 1977).
B. Use
1. Major Uses
The major uses of acrylonitrile include acrylic and modacrylic fibers
(50%), acrylonitrile-butadiene-styrene (ABS) and styrene-acrylonitrile
(SAN) resins (20%), adiponitrile (10%), nitrile rubber (5%), exports (10%),
as well as miscellaneous applications (5%) including use as a pesticide
(Anon., 1977b). Acrylonitrile demand (Ib/year) for each of these uses
appears in Figure 3 and totaled almost 1.5 billion pounds during 1976
(Anon., 1977c).
The manufacturers of acrylonitrile use much of their production cap-
tively as suggested by the difference between 1976 domestic production
(>1.5 billion Ibs.) and sales 0.6 billion pounds; Table 4). Among the
major users of acrylonitrile are its manufacturers. During 1977 American
Cyanamid will use about 75% of its production captively (American Cyanamid,
1977). On the other hand, Vistron will use less than 10% of its production
captively (Vistron, 1978). Worldwide, captive consumption of acrylonitrile
was about 58% of production during 1976 (Olson, 1977). Information on the
consumption of acrylonitrile in each of the major use-categories follows.
25
-------
2.0
1.5
1.0
Z
o
0.5
Ktt Other domestic uses
EZZ3 Nitrite elastomers
^: ••"••' ABS and SAN resins
•taoa Aery lie fibers
1976
1980
Figure 3. Acrylonitrile Demand
(based on Anon., 1977c)
26
-------
a. Fibers
By definition, acrylic fibers contain at least 85% AN while modacrylic
fibers contain 35 to 85% acrylonitrile. Acrylonitrile is polymerized with
standard redox catalysts. The polymer is separated as a powder (m.w. 75-
150 x 103) then dry spun or wet spun. Co-monomers for acrylic fibers in-
clude vinyl acetate, acrylic esters and acrylamide. Modacrylic co-monomers
may include vinyl chloride or vinylidene dichloride (Holker, 1975).
Acrylic and modacrylic fibers are used, for example, in apparel (65%;
e.g. knits, broadwoven fabrics, pile fabrics) in home furnishings (32%;
e.g. carpets, blankets, drapery) and industrial and other uses (30%;
e.g. sandbags, hair pieces). Acrylics are the synthetic fibers that most
closely resemble wool and compete with wool in the carpet, knitwear and
woven good market (Stobaugh et al., 1971).
During 1976 about 552 million pounds of acrylonitrile and poly-
acrylonitrile copolymers were produced for acrylic and modacrylic fiber use.
This represents an increase of 4% over 1975 levels (U.S. Int. Trade Coram.,
1975 and 1976). There are 5 manufacturers of acrylic and modacrylic fibers:
American Cyanamid, Dow Badische, Dupont, Eastman Kodak and Monsanto.
Production sites, capacities, and trade names are listed in Table 10.
b. SAN and ABS Resins
Acrylonitrile satisfies only 25-30% of the raw materials needed to
produce styrene-acrylonitrile (SAN) and acrylonitrile-butadiene-styrene
(ABS) resins (Stobaugh et aL,1971). However, these resins demand 20% of
acrylonitrile production.
SAN resins (which contain 20-35% AN) are produced by allowing acrylo-
nitrile to react with styrene in one of several polymerization processes:
emulsion, solution, continuous mass or suspension. ABS resins are produced
27
-------
Table 10
Producers of Acrylic and Modacrylic Fibers
(SRI, 1975)
Capacity
(millions of Ibs.) Tradenames
American Cyanamid Co.
Fibers Division
Pensacola, Fla.
Dow Badische Co.
Williamsburg, Va.
E. I. DuPont de Nemours & Co. Inc.
Textile Fibers Dept.
Camden, S.C.
Waynesboro, Va.
Eastman Kodak Co.
Tennessee Eastman Co., div.
Kingsport, Tenn.
Monsanto Co.
Monsanto Textiles Co.
Decatur, Ala.
Union Carbide Corp.
Films-Packaging Div.
Charleston, W. Va.
120
70
170
140
45
240
Creslan (acrylic)
Zefran II (acrylic)
30
Orion (acrylic)
(acrylic)
Verel (modacrylic)
Acrilan (acrylic
and modacrylic)
Dynel (modacrylic)
28
-------
by the emulsion grafting of styrene and acrylonitrile (70:30) onto rubber
latex or by mass suspension grafting of styrene and acrylonitrile on dis-
solved polybutadiene followed by cross-linking of the rubber particle
(Monsanto, 1977b; Bamford & Eastmond, 1964).
SAN resins are used in compounding (32%), housewares (18%), molded
packaging (10%), export (12%), automotive (6%), small appliances (4%) and
miscellaneous uses (18%) (Anon., 1978a).
Major markets for ABS resins include pipe (29%), automotive (18%),
large appliances (14%), small appliances (5%), recreational vehicles (8%),
business machines and telephones (5.2%), furniture, luggage and packaging
(6.1%), exports (3.2%) and miscellaneous uses (11.5%) (Anon., 1977f)
During 1976 more than 1 billion pounds of ABS (dry weight basis)
were produced in the U.S., up 33% from 1975 (U.S. Int. Trade Comm., 1975
and 1976). SAN production was about 121 million pounds (dry weight basis)
during 1975, up 9% from 1974 (no 1976 data available; U.S. Int. Trade
Comm., 1974, 1975, 1976). There are 9 manufacturers of ABS and/or SAN
resins, as listed in Table 11.
c. Adiponitrile
About 10% of acrylonitrile demand is used in the manufacture of adipo-
nitrile, an intermediate in the preparation of nylon 6,6. The process used
by Monsanto (Decatur, Ala.) is the simultaneous dimerization and hydrogena-
tion of acrylonitrile to form adiponitrile in an electrolytic cell. Other
producers manufacture adiponitrile from butadiene (DuPont) or cyclohexane
(Celanese, El Paso Natural Gas).
29
-------
Table 11
Producers of ABS and SAN Resins3.(SRI, 1977;
Anon, 1977g; Anon, 1977h; Anon', 19771; Anon,
1977j; Anon, 1978b)
Abtec Chemical Co.
Louisville, Ky.
3org-Warner Corp.
Plastics
Ottawa, 111.
Washington, W. Va.
Dart Indust. Inc.
Rexene Polymers Co.
Joliet, 111.
Dow Chemical U.S.A.
Gales Ferry, Conn.
Midland, Mich.
Pevely, Mo.
Torrance, Calif.
Foster Grant Co., Inc.
Leominister, Mass.
Grace Co.
Owensboro, Ky.
Monsanto Co.
Monsanto Polymers &
Petrochemical Co.
Addyston, Ohio
Muscatine, Iowa
Springfield, Mass.
Rexene Styretics
Joliet, 111.
Capacity
(millions of Ibs.)
65
215
300
60
65
70
65
30
n/a
320
125
55
Product
ABS planning ex-
pansion
will add 120-150 million
Ibs in 1979
ABS
ABS
ABS
ABS
will add 150 million
Ibs in Torrance and
at Hanging Rock, Ohio
Pilot program
ABS
ABS (Lustran)
likely to add 50
million Ibs/yr late
1978
ABS (Lustran)
ABS
30
-------
Table 11 (continued)
Producers of ABS and SAN Resinsa (SRI, 1977?
Anon, 1977g; Anon, 1977h; Anon, 19771; Anon,
1977j; Anon, 1978b)
Union Carbide Corp.
Chemicals and Plastics Div.
Bound Brook, N. J.
Uniroyal, Inc.
Baton Rouge, La.
Scotts Bluff, La.
Capacity.
(millions of Ibs.)
[30]
200
Producer
SAN; no longer pro-
ducing SAN after
6/77
ABS (Kralastic ,
AeryIon); expansion
to 250 million Ibs/
yr likely
some capacity figures include ABS and SAN; SAN capacity is considered
proprietary
joint venture of Cosden Oil and Chemical Co. and B. F. Goodrich Chemical Co.
31
-------
d. Nitrile Rubber
Nitrile rubber (NBR) is formed by copolymerizing acrylonitrile and
butadiene, with the proportions varying from 55:45 butadiene:acrylonitrile
to 82:18 butadiene:acrylonitrile (Barnhart, 1968). The higher the propor-
tion of acrylonitrile the higher the oil and gas resistance of the rubber.
Acrylonitrile, butadiene, water, emulsifier, modifier and polymerization
initiator system are added to a pressurized polymerizer. After polymeri-
zation the latex (which is usually steam stripped to remove unreacted
butadiene and acrylonitrile) is allowed to coagulate, and washed to remove
salts and emulsifiers (B. F. Goodrich, 1977). Since nitrile rubber does
not swell or distort when exposed to oil and gas, it is widely used in
products likely to contact petroleum products. End uses of NBR include
hoses (31%), seals/gaskets/0-rings (17%), molded goods (11%), adhesives/
sealants (9%), coated fabrics (8%). plastics-blends (6%), rubber covered
rolls (5%), footwear (5%), and miscellaneous (8%) (Idol, 1974).
Production of NBR during 1976 was in excess of 165 million pounds,
about 20% lower than production in 1973 and 1974 (U.S. Int. Trade Comm.
1973-1976); this decline is partly attributed to the rubber strike of 1976.
The major manufacturers, their capacities and trade names for their nitrile
rubber appear in Table 12.
e. Exports
More than 232 million pounds of acrylonitrile were exported from the
U.S. during 1976, primarily to Latin America (47%), Canada (20%) and
Western Europe (29%) (U.S. Bureau of Census, 1976b). Although imports
have increased steadily since 1972 (Table 13), exports during 1976 did not
reach the high levels of 1969 and 1970 (275 x 10s Ib/yr; Anon, 1977c).
32
-------
Table 12
Producers of Polybutadiene - AN Elastomers (NBR)-
(SRI, 1975)
Copolymer Rubber and Chem. Corp.
Baton Rouge, La.
Firestone Tire and Rubber Co.
Synthetic Rubber and Latex Div.
Akron, Ohio
B. F. Goodrich Co.
Akron, Ohio
Louisville, Ky.
Goodyear Tire and Rubber Co.
Akron, Ohio
Houston, Tex.
W. R. Grace and Co.
Indust. Chems. Group
South Acton, Mass.
Standard Brands, Inc.
Cheswold, Del.
Uniroyal, Inc.
Baton Rouge, La.
Painesville, Ohio
Capacity
(millions of Ibs.)
11
11
Tradename
31
62
11
24
(a)
31
31
Ny Syn
FR-N
Hycar
Hycar
Chemigum
Chemigum
Paracril
Paracril
not currently producing NBR
33
-------
Table 13
u>
Export Data
Exported AN
Total Quantity (Ib.)
Total Value ($)
Where Exported (%)b
Western Hemisphere
Canada
Latin America
Other
Western Europe
Communist Areas in Europe
Asia
Japan
Other Asia
Australia
Africa
for U.S. Acrylonitrile (U.S. Bureau of Census,
1976
232,929,957
51,050,530
19.7
46.9
28.9
-
0.5
3.1
0.9
-
1975
197,882,730
43,966,987
18.3
32.7
1.1
30.5
-
5.0
11.8
0.6
-
1974
154,224,384
37,214,924
31.8
40.5
25.4
1.3
0.1
0.7
0.2
1972-1976)
1973 1972a
105,331,222 51,845,988
12,455,899 5,458,233
37.8 14.5
38.5 66.2
23.4 19.1
-
0.1 <0.1
0.2
0.2 <0.1
a
no data listed prior to 1972 in this source
calculated as a percent of total quantity exported
-------
f • Miscellaneous Uses
Acrylonitrile is used to produce acrylamide and barrier resins and
as a fumigant. It is the major starting material for the manufacture
of acrylamide. A widely used method of production involves direct hydration
of acrylonitrile to produce high yields of acrylamide (Anon., 1973).
Acrylamides have application in water treatment (clarification and
treatment of effluents, food etc.),paper chemistry (dry strength agents,
retention aids, drainage aids), oil-well stimulation (fracturing, flood-
ing), mineral processing (flocculation of ores, tailings, coal etc.)
and soil stabilization, as well as other miscellaneous applications
(Bikales, 1973).
There are currently three producers of acrylamide: American Cyanamid
(Linden, N.J. and New Orleans, La.), Dow Chemical Co. (Midland, Mich.) and
Nalco Chemical (Chicago, 111.).
Another use of acrylonitrile is for nitrile barrier resin containers.
Nitrile beverage bottles might have consumed 10% of the 1980 market for
acrylonitrile (Anon., 1977c) had the Food and Drug Administration not banned
its use Sept. 23, 1977 (Kennedy, 1977).
Nitrile barrier resins also have application in non-beverage pack-
aging, including containers for glue, nail polish (Max Factor), correction
fluid (Liquid Paper Corp.), air freshener (Airwick Industries) and for a
contact lens disinfectant (Flexol). A new application is in the produc-
tion of blister packages currently used for toothbrushes and combs (Anon.,
1977k).
35
-------
A small amount of acrylonitrile is used as a fumigant against insects and
nematodes. It has been used particularly as a grain fumigant. In Florida,
acrylonitrile has been used as a structural pesticide against dry wood
termites, power post beetles and wood borers (Davis et aJU, 1973). Carbon
tetrachloride is usually mixed with equal parts of acrylonitrile to re-
duce the flammability of the fumigant. Fumigant mixtures with methylene
chloride trichloroacetonitrile, methyl bromide and also urea and ammonium
sulfate have been described (Standish, 1974; Bond and Buckland, 1976).
A small use of acrylonitrile is in the cyanoethylation of natural
fibers to improve heat and rot resistance. Another is for the manufacture
of a thermoplastic with a high dielectric constant (Cyanocel manufactured
by American Cyanamid) (Norris, 1967). Another use of acrylonitrile is as
an anti-stall additive (Dow Ambifal 200).
Acrylonitrile is also used as an intermediate in the production of
specialty chemicals, such as:
dimethylaminopropylamina
diethylaminopropylamine
monomethylaminopropylamine
polyglycoldiamine H 221
polyglycolamine
dimethylaminopropionitrile
(A.T. Kearney, Inc., 1978).
2. Projected Uses
The use categories discussed in the last section are projected to
continue. Figure 3 compares acrylonitrile demand for fibers, resins,
36
-------
elastomers, exports and others during 1976 to the projected demand in
. 1980. New forms of acrylic fibers may contribute to the modest growth (5%)
of acrylic fibers projected for the next few years (Anon., 1977c). ABS
and SAN resins are expected to be leaders in the long-term growth of
acrylonitrile (Anon., 1977b). Relatively slow growth is anticipated for
nitrile elastomers, but use in acrylamide may increase substantially (Anon-,
1977c).
3. Alternatives to Use
Major use categories of acrylonitrile include fibers, elastomers and
resins for which substitute products exist. For example, other synthetic
(ex. acetate, polyester, nylon) or natural (cotton, wool) fibers could be
used. Instead of acrylonitrile elastomers, natural rubbers or synthetic
elastomers (polyisobutene and butyl rubber, neoprene, butadiene, isoprene)
might be utilized. ABS/SAN resins may be replaced by styrene-butadiene
(SBR), polystyrene, or styrene-divinyl benzene. However, some companies
have claimed there is no direct substitute for AN-based plastics as AN
imparts very specific qualities to these products, particularly chemical
resistance.
C. Entry into the Environment
Acrylonitrile monomer can enter the environment during its production,
waste handling, storage, transfer, transport and end-use. Little data are
currently available on levels of acrylonitrile in the environment. Informa-
tion to supplement this section, however, will be available in the near
future. The Midwest Research Institute (MRI) is presently taking air,
water and soil samples at and near AN producer and user facilities for the
Environmental Protection Agency (Office of Toxic Substances). In addition,
studies are underway at the EPA Pollutant Strategies Branch to assess at-
mospheric hydrocarbons; data on AN may be gathered.
37
-------
Table 14
Emission Factors for Acrylonitrile Manufacture
(uncontrolled emissions; Hughes and Horn, 1977a)
Material emitted
c
Carbon Monoxide
Hydrocarbons (as CHi,.)
Nitrogen Oxides
Sulfur Oxides
Methane
Ethane
Ethylene
Q
Propane and Propylene
Butene
Benzene
Toluene C-
Acrylonitrile0
Acetonitrile0
Hydrogen Cyanide0
Fumaronitrile
Pyridine0
Prop ionaldehy de
Furan
Ammonia
Allyl Alcohol
Amountb (g/kg of AN produced)
79.30
71.06
0.55
0.18
0.67
1.93
2.57
55.02
0.40
0.15
0.07
0.89
0.63
0.66
0.04
5.2
0.01
0.47
0.00
0.02
aa "representative acrylonitrile plant"; SOHIO process of 140,000 metric
ton/year capacity located in a community with a population density of
402 persons/km2-
data for several emission points were obtained for each material;
some data in reference are given to more significant figures than
reported here.
Vistron (1978) has measured somewhat different values at their production
sites, as follows (in g/kg): CO - 121 to 146; propane and propylene -
57-71; no benzene or toluene; AN - 0.58-2.1; acetonitrile - 0.1-0.25;
HCN - 0.1-0.25; pyridine - 0.5.
38
-------
represents only a small part (0.4%) of total uncontrolled emissions from
AN production (Table 14; data from Hughes and Horn, 1977). These emis-
sions have been the subject of three studies (Patterson et al., 1976;
Schwartz et al., 1975; Hughes and Horn, 1977) to which the reader is re-
ferred for more detail.
As discussed in Section I-A-1, acrylonitrile is manufactured by
the ammoxidation of propylene. The simplified flow diagram in Figure 2
identifies product flow from reactor, to quencher, to absorber to recovery
columns with resultant wastewater stream, by-product flare and inciner-
ation. Acrylonitrile emissions can result during several phases of this
production process. Estimates for a "representative" acrylonitrile plant
(Hughes and Horn, 1977) and for an actual production facility (Vistron,
1978) are given in Table 15. Preliminary information received by the
EPA from acrylonitrile manufacturers indicate that the Hughes and Horn
figures for absorber vent, fugitive emissions and storage may be under-
estimated. This preliminary information indicates that the amount of AN
emitted to the atmosphere during acrylonitrile production is about 1/5 or
1/6 the amount of AN emitted during polymer operations; estimates for
polymer operations are at least 4100 tons AN/year (Mascone, 1978).
39
-------
Table 15
Sources of Atmospheric Contamination of Acrylonitrilea
during Acrylonitrile Manufacture and Bulk Storage
Emission Point
Quantity AN emitted
(g/kg AN produced)
Absorber Vent
Incinerator Stack
Flare Stack
Deep Well Pond
Fugitive Emissions
Product Transport
Loading Facility
Storage Tanks
Total Average
Hughes & Horn, 1977a Vistron, 1978b
0.039 (± 41%) d 0.02-0.74
<0.0015
0.039
c
0.00042 (± 20%?
0.0065 (± 20%)d
0.802 (± 20%)
0.5
0.45
0.888
applies to plants not controlling emissions; if emissions are controlled,
absorber vent is source of <0.002 g/kg AN
measured by Engineering Department at Vistron
CAN is about 0.02% of the wastewater column stream coming from the
wastewater column bottoms
figure may be higher according to EPA; see text
40
-------
2. From Waste Handling
During acrylonicrile production the following wastes are produced:
gaseous wastes, liquid wastes (wastewater column bottoms, acetonitrile
column bottoms, heavy ends, crude acetonitrile, hydrogen cyanide) and
solid wastes (catalyst fines and organic polymers). Three types of on-
site disposal methods are used: 1) flare, 2) thermal incinceration and
3) deep well pond and deep well injection (Hughes and Horn, 1977).
The wastewater column stream coming from the wastewater column bottoms
(stream 11) may contain 500 mg/1 or less of acrylonitrile (but higher levels
of CN~, sulfate, NH3 and acetonitrile) (Lowenbach et al., 1978). This
wastewater is mixed with wastewater from the acetonitrile column (AN not
identified as a component) and then sent to the deep well pond where solids
are separated out. The liquid runoff is disposed of by deep well injection
(Hughes and Horn, 1977, Fitzgibbons et al. 1973) (Figure 2). These wells are
isolated from the groundwater. The possibility of contamination of ground-
water from deep wells is remote (Lowenbach et al., 1978)a According to
Vistron (1978) 590 gallons of wastewater are deep well injected per 1,000
pounds of AN produced; this water contains about 175 ppm AN. They also
reported 130 gallons of wastewater/I,000 pounds AN produced are sent to
a biopond; of this, AN is present at 120 ppm.
The EPA no longer considers deep well injection a "viable" dis-
posal method (Fed. Reg. Jan. 6, 1977). To control the drilling
of new wells, industrial dischargers must re-apply for a permit
under the National Pollution Discharge Elimination System (NPDES).
Also, permit holders are required to submit summaries of current
practices and practicable alternatives (LowenJbach, et al., 1978).
41
-------
3. From Storage
As depicted in Figure 2, crude and purified acrylonitrile are stored
prior to transportation in fixed roof storage tanks. Estimates for
storage losses range from 0.45 (Vistron, 1978) to 0.802 (Hughes and Horn,
1977) g AN/kg AN produced. Losses during loading operations have been
placed at 0.0065 and 0.5 g/kg by Hughes and Horn and by Vistron, re-
spectively.
4. From Transportation
Acrylonitrile is shipped primarily by tank cars (40.4%), tank trucks
(56.5%) and barge (1.7%) (OHM/TADS, n.d.). The following unlined con-
tainers are used: pails (5 gallon; 18 gauge black steel), drums (55 gallon;
18 gauge black steel), tank trucks (4,000-7,000 gal; carbon steel or
aluminum) or tank cars (8,000-40,000 gallon; carbon steel or aluminum).
The truckload minimum for drum shipments is 67 drums (24,000 Ibs.) while
the carload minimum is 84 drums (30,000 Ibs.) (American Cyanamid, 1974,
Vistron, 1978).
Spills of acrylonitrile can potentially enter any environmental
medium. For example, the Intergovernmental Maritime Consultative Organi-
zation estimated 41 tons of acrylonitrile were discharged into the sea
from transport and handling in 1970 (Nat'l. Acad. Sci., 1975). Spills
occurring on land enter soil and groundwater.
In 1974 the Arthur D. Little Co., Inc. analyzed safety aspects of
tank car, tank truck and barge transport for acrylonitrile shipped from
Chocolate Bayou, Texas (AN produced) to Decatur, Alabama (AN used in fibers)
42
-------
By barge, this route covers 1,400 miles, by rail, 770 miles and by truck,
780 miles. The total shipment considered was 80,000 tons/year. Based
on (1) past accident rates, (2) the number of trips made by each mode,
and (3) other factors, the following estimates were made of the annual
number of accidents causing release of cargo: barge, 0.0117; truck, 0.063;
and rail, 0.17. These figures represent the case where the entire com-
modity is transported by one mode. Taking this same model further, A. D.
Little, Inc., in 1974 also estimated the spill pool radius, hazard radius,
population exposure, probability of ignition and amount of property damage.
These estimates appear in Table 16 and are based on flammability and water
toxicity hazards. Transportation by rail is most hazardous and by barge,
least hazardous for these parameters. By rail, spills are likely to occur
more frequently, damage more property, and expose more individuals.
It should be noted that this model is based on the shipment of 80,000
tons/yr between two specified destinations. In actual practice, more than
300,000 tons of acrylonitrile were sold in the U.S. during 1976 (Table 4)
and most was presumably shipped to the major use sites (Section II-B)
located throughout the U.S. Captive consumption also involves some trans-
port. Precise information on current transportation patterns for acrylo-
nitrile, which would be necessary to assess total risk, is not available.
Some data do exist, however, on actual acrylonitrile spills reported to
the Oil and Hazardous Ma terials Spill Information Retrieval System of the
Environmental Protection Agency (OHM-SIRS). OHM-SIRS cautions that only
a small fraction (10-20% ) of all spills are ever reported. From August
1970 to July 1975 12 acrylonitrile spills were reported, 10 of these
43
-------
Table 16
Hazards of Acrylonitrile Transportation
(A.D. Little, Inc., 1974)
ACRYLONITRILE - Flammability + Water Toxicity Hazard
(l)
BARGE
TRUCK
RAIL
Spill Pool
Radius (Feet)
Hazard Radius
(Feet)
Hazard Area
(Acres)
Relative Exposure (%)
Urban /Rural
Expected Number
of Annual Spills
Probability of Ignition
Following Spill
Expected Annual Number of
People ExoosedC5)
Urban/ Rural
Exoected Annual
Prouertv Damage
Urban /Rural
Recurrence Interval
(Years)
200
400
11.53<2>
1.3500
8/92
.0117
.30
129/55
85.5
56
126
23/77
.063
.25
.008/.004 .010/.002
160/20
15.8
104
224
3.3
(3)
27/73
.17
.40
.16/.016
2423/252
5.8
'•Calculations are based upon the assumption that each mode of transportation
handles 100 percent of the quantity shipped.
2Area affected by spills into water which ignite. Assumes entire spill
quantity contributes to burning pool.
3Area affected by spills on land which ignite. If no ignition occurs, the
exposed land area is equivalent to the pool spill area (*R2 Spiij_) .
^For spills into water which do not ignite the water toxicity hazard dis-
tance (feet) measured downstream from spill location for a 500 feet wide,
10 feet deep river flowing at 2.3 feet per second. Assumes vertical
dispersion rate at 1.0 feet per minute until uniform mixing is achieved
44
-------
Table 16 (continued)
Hazards of Acrylonitrile Transportation
(A.D. Little, Inc., 1974)
throughout the entire depth of the river. Thereafter, plug flow is
assumed with no synergistic or antagonistic reaction between the pollutant
and the receiving body of water. For this situation the entire spill
quantity contributes to water.
^Expected number of people exposed annually and property damage is based
upon ignition of the flammable pool for both land and water based spills.
"Average number of years between accidents.
45
-------
Table 17
o\
Spill Data for Acrylonltrlle (E.P.A. Oil and Hazardous
Materials Spill Information Retrieval System)
Date
7/28/71
10/27/71
1/20/72
5/14/72
10/8/72
10/30/73
Location
Beaumont ,
Tex.
Washington,
W. Va.
North of
Richmond, Va.
W. Lafayette,
River Mile
214
Rush, Ky.
Quantity /Source
630 gallons /barge
/storage tank
/truck
/RR cars
35 gallons/barge
went aground
80,000 gal/ tank
car derailment
Damage
unknown
unknown
small fish
kill
P2Ss burned
unknown
large fish
kill
Waters
Affected
DuPont Docks
Ohio River
tributary to N.
N. Anna River
—
Tennessee
River
Little Sandy
& tributaries
Company
Responsible Remarks
Union Carbide Co.
Marbon Chemical Co.
Glosen Motor Lines
Penn Central also spil
phosphorui
n£tnl*£idi1 f
pcnLaoU-LJ.
vinyl chli
Inland Oil Trans-
portation Co.
C & 0 RR evacuatioi
area
11/1/73 Rantoul,
111.
12/23/73 Mapleton,
111.
1/17/74 Austin,
Ohio
and rupture
8,000 Ibs/leak-
ing valve in
tank car
35 tons/tank
car derailment
and tank rupture
unknown/derail-
ment
soaked into
soil
Illinois Central
RR
Toledo, Peoria,
& W. RR
B & 0 RK
leak absorbed
by ballast
-------
Table 17 (continued)
2/23/74 Vandalia,
Ohio
11/19/74 Mansey, S.C.
/74 Dayton,
Ohio
Spill Data for Acrylonltrile (E.P.A. Oil and Hazardous
Materials Spill Information Retrieval System)
Date
Location
Quantity /Source
Damage
Uaters
Affected
Company
Responsible
Remarks
48,000 Ibs/plant
pump malfunction
10 gallons/tank
car
21,000 gallons/
derailment
Poplar Creek
inland bayou
General Motors
Seaboard Coast-
line RR
Texas Solvents
Chem. Co.
-------
occurring during transport (Table 17). Of these 10 spills, 7 occurred
from tank cars, 2 from barges and 1 from a tank truck.
5. From End-Use
Environmental contamination from acrylonitrile is also possible through
end product manufacture and use, resulting in low-level exposure to the
general population. Preliminary information received by the EPA from AN
users indicate that at least 4,100 tons AN are emitted yearly during
polymerization operations per year (Mascone, 1978).
Another source of environmental contamination is from residual mono-
mer in end products; examples are listed below:
Product-Name
Kralastic & Paracril
polymers
Polywet polymer
UCAR-380 latex
UCAR-4358 latex
NIAX Polymer Polyols
Acrylic and Modacrylic
fibers
Acrylamide monomer
Polyacrylanri.de
Crude XT monomer
Acrylic fiber
Hycar rubber
alimit of detection 1 ppm
ppm residual AN
50
<20
250
750
100-300
^ Oa
50-100
1
40-50
< 1
0-100
Source
Uniroyal, Inc., 1977
Uniroyal, Inc., 1977
Union Carbide Corp., 1977
Union Carbide Corp., 1977
Union Carbide Corp., 1977
Dow Badische Co. 1977
American Cyanamid Co., 1977
Kearney, 1978
American Cyanamid Co., 1977
American Cyanamid Co., 1977
B. F. Goodrich, 1977
According to OSHA, levels of AN in fibers are so low that handling of the
fibers is not a likely source of acrylonitrile exposure (Bingham, 1978).
48
-------
In order for acrylonitrile to be released, the product must be heated
(which would spoil the product); but even this would not result in a "sig-
nificant exposure situation". Possibly, acrylonitrile might be leached
from fabrics during laundering (EPA, 1977), although there have been no
studies in this area.
A. T. Kearney Inc. (1978) assessed the residual acrylonitrile content
of consumer products. Based primarily on data from manufacturers, A. T.
Kearney concluded that acrylonitrile contained in acrylic or modacrylic
fabric and in nonfood-contact ABS/SAN products will not migrate under normal
use. Sufficient information on acrylonitrile in nitrile rubber latexes
was not available.
A possible source of acrylonitrile contamination is from acrylamide
products. For example, acrylonitrile might leach into aquatic systems
from acrylamide during use in water treatment (EPA, 1977). Acrylamide
is used as a soil consolidating agent; the presence of acrylonitrile as
a volatile component of this agent was confirmed by Matsumura and Arito
(1975). Acrylamide was obtained from two Japanese manufacturers and the
volatile components were analyzed by gas chromatography both before and after
polymerization. Before acrylami.de polymerization, acrylonitrile was con-
tained up to 0.3 mg/ml as an impurity. After gelation of an acrylamide
solution by polymerization with sand (the way acrylamide is used as a soil
consolidating agent), acrylonitrile evaporated in air up to 4440 mg/m3 at
equilibrium. The purity of Japanese acrylamide was not given.
Acrylonitrile monomer is expected to migrate from barrier nitrile
resins used as beverage containers. This use in beverage containers has
49
-------
been banned by the Food and Drug Administration (Kennedy, 1977), who main-
tains that acrylonitrile is an indirect food additive and has not been shown
to be safe. The F.D.A. concluded "use of acrylonitrile monomer to fabricate
acrylonitrile copolymer beverage containers may reasonably be expected, and
in fact does result in acrylonitrile beverage containers becoming a compon-
ent of ..... foods." Early tests by Monsanto, a manufacturer of the nitrile
resin, found a maximum of 39 ppm residual monomer (average of 15 ppm) in
older bottles but a maximum of 5 ppm (average of 3. 3 ppm) in the newer type
bottle (Anon., 1977 1).
Residual acrylonitrile can also result from its use as a fumigant.
Berck (1960) investigated acrylonitrile residues on shelled walnuts fumi-
gated with Aery Ion (34% AN, 66% CCli*, v/v) .a Walnuts were fumigated either
at atmospheric pressure (3 or 6 ml Aery Ion added; Table 18 A) or at reduced
pressure (vacuum-fumigation; 1.882 g Acrylon added; Table 18B) . When walnuts
were exposed to aery Ion for 18 or 48 hours at atmospheric pressure, reten-
tion of acrylonitrile over 38 days generally was lower when a smaller shorter
Acrylon dose was introduced and when the samples were aerated after exposure
(Table 18A) . For all exposure conditions, acrylonitrile (detected polaro-
graphically) ranged from 17.5-7.5 ppm 2 days and from 8.5-0.0 ppm 38 days
after exposure.
Under vacuum- fumigation conditions, comparable data were obtained over
also known as Acritet (Stauffer Chemical Co.)
50
-------
Table 18
Acrylonitrile Residues in Walnuts
(Berck, 1960)
A. Amount of Acrylonitrile on Atmospheric-Fumigated Walnuts3
Acrvlon Exposure
added (ml) (hr)
3
3
6
6
3
3
6
6
48
48
48
48
18
18
18
18
Fan
(hr)
4
0
4
0
4
0
4
0
PPM Acrylonitrile,
days after packaging"3
2
7.5
10.0
10.0
17.5
5.0
6.0
11.0
13.5
18
0.0
0.8
2.5
6.8
0.0
0.0
2.4
4.1
38
2.5
2.0
3.7
8.5
0.0
0.5
1.0
5.0
Acrylon introduced by syringe into 55 pound bags (polyethylene) of shelled
walnuts. Walnuts were exposed for 18 or 48 hours, then spread out on a
board; sometimes, this was followed by aeration in front of a fan. Samples
were analyzed polarographically for AN on the days shown.
original data presented for days 2, 9, 18, 24, 30, and 38.
B. Amount of Acrylonitrile on Vacuum-Fumigated Walnuts3
Acrylon
added (g)
Exposure
(hr)
Aeration
(hr)
PPM Acrylonitrile,
days after packaging"
1 14
30
1.882 3 at 110 mm Hg 0
1.882 3 at 110 mm Hg 16
16.6
12.5
6.8
2.5
1.3
0.0
Air pressure was reduced before Acrylon was added; ten Ibs (4.55 kg) of
nuts were placed in a 24.1 liter vacuum-fumigating chamber; aeration fol-
lowed exposure. Samples were analyzed polarographically.
Original data presented for 0.75, 1, 4, 8, 14, 21, and 30 days.
51
-------
30' days (Table 18B). It is difficult to compare results of the two
exposure methods, as the initial doses and duration of exposure were differ-
ent.
D. Disposal and Control Methods
1. Waste Disposal
The major treatment technology practiced at acrylonitrile manufactur-
ing plants is direct discharge to deep wells. Subsurface disposal is used
at all production sites except at duPont's plant in Memphis, Tennessee.
Here, some of the wastes are pretreated by alkaline hydrolysis; then the
biodegradable effluent is disposed of in publicly owned treatment works.
In addition, a portion of the Memphis facility wasteload is incinerated
(Lowenbach et al., 1978).
Deep well injection is no longer considered a viable disposal method
and the development of alternate disposal systems appears inevitable.
Lowenbach et al. (1978) extensively reviewed the available literature on
alternate methods of treating wastewaters from acrylonitrile manufacture,
including the following: biological treatment; chemical pretreatment
(chemical oxidation and chemical precipitation); physical pretreatment
(separation and ammonium sulfate recovery); and combination and alternative
techniques (e.g., wet-oxidation with biophysical treatment). The reader
is referred to Lowenbach et al. (1978), as a discussion of treatment
alternatives is out of the scope of this report.
52
-------
The Greater Peoria (111.) Sanitary District tested the potential ef-
fects of acrylonitrile on their wastewater treatment plants (Hughes, 1974).
They evaluated whether to accept groundwater contaminated with acrylonitrile,
as a result of a 20,000 gallon tank car spill (discussed in more detail in
Section II-E). The Director of Waste Treatment Facilities reported inhibi-
tion of indicator microorganisms in the activated sludge system at concen-
trations of 120 mg AN/1. Complete inactivation occurred consistently at
concentrations of 800 mg/1 or more. However, acrylonitrile could be ef-
fectively treated when introduced into the treatment plant's aeration
system at low concentrations. At concentrations of 40 mg AN/1 or less,
less than 1 mg/1 was detected in the settled mixed liquor supernatant after
3 hours of aeration. At concentrations greater than 40 mg/1, concentra-
tions as high as 20 mg/1 remained after 3 hours of aeration.
Assimilation and digestion are discussed in more detail in Section
II-E-1.
2. Control Technology
Emissions resulting from acrylonitrile manufacture occur mainly from
the absorber vent, as previously discussed. All plants use a mist elimin-
ator at the top of the absorber, but this only prevents liquid carryover
to the atmosphere (Schwartz et al., 1975). Monsantofs acrylonitrile plants in
Alvin, Texas and Texas City, Texas were using an effective emission
control device (Hughes and Horn, 1977; Mascone, 1978). This device is a
thermal oxidizer (incinerator) for by-product HCN and acetonitrile disposal and
for vent gas control. The oxidizer removes more than 95% of carbon monoxide
and total hydrocarbons. During 1976 DuPont's plant in Beaumont, Texas will
have been controlled with a catalytic oxidizer. These changes resulted to
meet emission levels for CO and hydrocarbons set by the Texas Air Control
-------
Board (Hughes and Horn, 1977). Current research in industry for air
pollution control involves primarily the development of a more selective
catalyst to reduce by-products and increase ammonia utilization (Schwartz
et al., 1975).
According to Hughes and Horn (1977) the largest single source of
acrylonitrile emissions is from fixed roof storage tanks. One way to control
these emissions is to install tanks with lower loss rates than fixed roof
tanks, such as floating roof tanks, internal floating covers and vapor re-
covery systems. Another way to control emissions is to use retrofitable
controls on existing fixed roof storage tanks such as internal floating
roofs and vapor recovery systems (EPA, 1977).
E. Fate and Persistence in the Environment
In this section the degradation of acrylonitrile is reviewed and used
to assess environmental persistence.
1. Degradation in the Environment
a. Biological Degradation
The environmental fate of acrylonitrile has not been extensively studied
54
-------
(Nat'l. Acad. Sci., 1975). Limited data suggest that loss of small amounts of
acrylonitrile from water systems can be expected to occur by biological de-
gradation. Aerobic bacteria are capable of breaking down acrylonitrile, es-
pecially if already acclimated to this substance (Mills and Stack, 1955;
Ludzack et al., 1958; Cherry et al., 1956). Breakdown products in aerobic
aquatic systems may include ammonia and acrylic acid (Mills and Stack,
1955). Degradation of small amounts of acrylonitrile is also possible by
acclimated anaerobic bacteria (Lank, 1969). Giacin et al. (1973) suggested
terrestrial breakdown by soil fungi. Mills and Stack (1955) suggested a
mechanism for the biological oxidation of acrylonitrile. Acrylonitrile
was seeded with microorganisms from the Kanawha River (W.Va.), which had been ac-
climated to acrylonitrile for 27 days. The rate of biological oxidation
was quite rapid (Figure 4), nearing completion in five days. The follow-
ing nitrogen balance was obtained:
*
Nitrogen Balance, as mg of N
Initial Final Changes
Nitrate and Nitrile 1.4 1.8
Ammonia 130 396 +266
Organic N 118 162 + 44
Total 310 mg N changed
(388 mg N added initially)
From these data the authors suggested that the biological oxidation of
acrylonitrile proceeds by an enzyme-catalyzed hydrolysis of the nitrile
group to .acrylic acid and ammonia. Similarly, experiments at Dow Chemical
Company indicate almost complete oxidation to ammonia 20 days after acrylo-
nitrile was added to activated sludge seed (Nat'l. Acad. Sci., 1975).
55
-------
-6
(A) Mills and Stack, 1955
4567
DAYS OF INCUBATION
10
~ 30
a.
0.
2 20
Q
111
O
X
O
-I
u
X
O
10
(B) Cherry et al., 1956
FORMULA CH2=CHCN
- REOOSE REDOSE
REDOSE
20 30 40
ELAPSED TIME (DAYS)
REOOSE
50
60
8 80
en O
U 111
k
8*
20
-20
10
20°C
5°C
I
I
(C) Ludzack et al., 1958
I ' I I I
20 30 60
70 80
DAYS
90 100 110
Figure 4. Biological Oxidation of Acrylonitrile in Aqueous Systems
(See text for experimental conditions)
56
-------
The assimilation of acrylonitrile in natural water was studied by
Cherry et al. (1956). Acrylonitrile (10 ppm) was added to filtered aer-
ated water from the Hackensack River (N. J.). Nitrogen and phosphorus
were added to supply inorganic nutrients to river microorganisms. Chemi-
cal oxygen demand (C.O.D.) was determined at various intervals. About 20
days were required for acrylonitrile (at 10 ppm) to disappear from the
water (Figure 4). Redosing with acrylonitrile lessened C.O.D. reduction
times. Similar results were ofataind at 25 and 50 ppm acrylonitrile.
Ludzack et al, (1958) found acrylonitrile to be more resistant to
biological degradation than aceto-, adipo-, benzo-, and lacto-nitriles.
Ohio River water or aged sewage seed was treated with 0.1-20 mg/1 acrylo-
nitrile; the resulting biological oxygen demand (B.O.D.) was determined
after 2, 5, and 12 days. The Ohio River water contained organisms more
capable of assimilation than aged sewage seed: on day 15, the average
B.O.D. for sewage and river seed was 5 and 15%, respectively, of theo-
retical oxidation. For both seeds, there was no oxidation after just 5
days.
In another experiment, Ludzack et al. (1958) treated Ohio River water
(at 20°C, summer temperature) with 10 mg/1 of acrylonitrile. As shown
in Figure 4, there was a lag period of about a week, followed by several
days of rapid assimilation, after which a plateau was reached. By day 22
another period of activity occurred. Upon subsequent treatment at 20°C
(the system was now acclimated) the lag period and plateau were not de-
tected (Figure 4). When readministration was at 5°C (winter temperature)
there was a marked reduction in assimilation.
Kato and Yamamura (1976) identified aerobic microorganisms of the genus
Nooardia as capable of degrading cyanides and nitrile.
57
-------
The preceding studies show that breakdown of acrylonitrile can occur
aerobically. Ludzack et al. (1959), Lank (1969) and Hovious et al. (1973)
studied acrylonitrile under anaerobic conditions.
Lank (1969) found that acrylonitrile at a concentration of 10 mg/1
could be treated by anaerobic digestion. Two digesters were used. One
digester fed only raw sludge served as the control; a second was given
acrylonitrile continuously (1, 2, 4 or 10 mg/1) and sludge. Analyses to
evaluate digester performance included volatile solid reduction, chemical
oxygen demand reduction, volatile acid concentration and gas production.
Control and experimental digester performance did not differ.
Although Lank (1969) found small amounts of acrylonitrile can be
treated anaerobically, Hovious et aJ. (1973) determined that higher levels
of acrylonitrile are inhibitory to some anaerobes. They tested the influ-
ence of acrylonitrile on the anaerobic activity of methanogenic bacteria
which metabolize acetate. A Warburg respirometer was used to compare
bacterial gas production in control (no acrylonitrile) and experimental
(50-1,000 mg AN/1) flasks containing unacclimated anaerobic biomass. An
activity ratio was calculated for each experimental concentration tested,
which compares the slopes of the gas produced. An activity ratio of 1.0
indicates no effect, while a ratio less than 1.0 indicates inhibition of
bacterial fermentation. Two separate series of experiments were carried
out: a) food-limited substrate (no acetate added) and b) non-limited
substrate (500 mg/1 acetate added per Warburg flask).
Inhibition was observed at all concentrations tested (50 to 1,000
mg AN/1) but was most severe at the highest concentration (Table 19 ).
58
-------
Table 19
Effect of Acrylonitrile on Anaerobic Activity
(Hovious et al., 1973)
AM
. Activity Ratio'
Concentration '
(mg/1) Non-limited Substrate Substrate Limited
0
50
100
200
300
500
1,000
1
0.6
0.5
-
i
0.4
-
0.3
b
-
0.6
0.42
—
0.38
-
adata from Fig. 10 of Hovious et al., 1973 line indicates no testing
Although inhibition was observed, there was still some residual activity.
Activity ratios were not as low as when known toxicants (chloroform, mer-
curic chloride, hydrochloric acid) were tested; at 1000 mg/1 doses of
these known toxicants, activity ratios ranged from 0.17-0.19.
For terrestrial systems, acrylonitrile can be utilized by soil fungi
as a source of nitrogen and carbon (Giacin et al., 1973). Fungi capable of
acrylonitrile biodegradation include Peneillium, Aspevgillus and Cladospov-
'• ium species. Although other microorganisms slowly degraded acrylonitrile,
best results were obtained with soil fungi.
The preceding discussion considered only papers dealing with the bio-
logical degradation of AN. This is not meant to imply that biological treat-
ment of wastewater from AN manufacturing facilities is desirable or even
possible. These streams contain a complex mixture of organic compounds, not
just acrylonitrile (reviewed in Lowenbach et al., 1978).
b. Chemical Degradation •
Information on industrial and laboratory reactions for acrylonitrile
has been presented in Section I-D. Unfortunately, no controlled studies
59
-------
are available for reactions under environmental conditions. Based on
physical properties, however, it is possible to predict the behavior of
acrylonitrile. Acrylonitrile is a volatile compound; its high vapor pres-
sure (Table 2) would suggest appreciable evaporation. Acrylonitrile is
only moderately soluble in water at about 7%. Possible atmospheric and
aquatic reactions are discussed below.
1) Atmospheric Reactions
Olefins, as a class, generally enhance atmospheric oxidation re-
actions (Seinfeld, 1975). Acrylonitrile, an olefin, might be expected
to participate in these reactions. However, no specific references are
available on the fate of acrylonitrile in the atmosphere, although acrylo-
nitrile is present in the atmosphere near production sites (see
Section II-C-1). The following brief discussion considers the oxidation
of olefins by atomic oxygen, hydroxyl radicals and ozone.
Atomic Oxygen Oxidation (Seinfeld, 1975)
Oxygen atoms, which form in the atmosphere as a result of the photolysis
of nitrogen dioxide, usually add to olefins. Oxygen atoms react with ole-
fins more rapidly than with other hydrocarbons (i.e., aromatics, acetylene).
This addition reaction forms on excited epoxide, which then decomposes to
an alkyl and an acyl radical.
Hydroxyl Radical Oxidation
Hydroxyl radicals (OH«) form in the atmosphere as a result of the
photolysis of nitrous acid and as degradation products of free radicals.
Hydroxyl radicals add at the double bonds (Seinfeld, 1975).
Morris and Niki (1971) measured the reactivity of hydroxyl radicals
with several olefins (but not with acrylonitrile). Their data show that
60
-------
for a given olefin, the rate constant for the hydroxyl-olefin reaction is
about 10 times greater than for the atomic oxygen-olefin reaction.
Ozone Cxidation (Seinfeld, 1975)
Atmospheric ozone forms in significant quantities when N02 levels
are about 25 times NO levels. Ozone, while not as strong an oxidizing
agent as 0 or OH, reacts with olefins at "appreciable rates" when ozone
concentrations reach 0.25 ppm or more (Seinfeld, 1975). Ozone adds across
the olefin double bond forming an aldehyde and a diradical (or Zwitterion)
The diradical might decompose or participate in reactions with 02, N02
and NO.
2) Reaction with Water
Acrylonitrile does not react with water and is labeled 0 (no hazard)
in the N.A.S. Hazard Rating System for reactivity with water (Department
of Transportation, 1974). Hydrogen cyanide is not an expected breakdown
product, as acrylonitrile does not dissociate appreciably in water (McKee
and Wolf, 1963).
2. Transport Within and Between Media
As emphasized in the previous section, acrylonitrile is quite vola-
tile. One would expect, for example, considerable evaporation from land
and water (as in a spill situation) into the atmosphere.
A spill of 36,000 gallons of acrylonitrile onto farmland (Gilford,
Inc., 2/22/77) caused contamination of the groundwater and a nearby creek
after acrylonitrile percolated through frozen soil (Manganaro, pers. comm.,
1977). A spill of 20,000 gallons of acrylonitrile (near Mapleton, 111.,
12/23/73) caused contamination of the groundwater and a creek located
about 750 feet from the spill. Acrylonitrile percolated through clay
61
-------
soil and was detected in nearby monitoring wells almost a year later and
in the creek after about 100 days (Table 20, data provided by the Illinois
EPA).
3. Persistence and Bioaccumulation
Because acrylonitrile is reactive and subject to bacterial degrada-
tion, loss is expected from environmental media. However, since acrylo-
nitrile is toxic to most organisms at low concentrations (see Section
III) these high initial levels may not be tolerated. No food chain con-
centration potential has been noted (Dept. of Transportation, 1974).
No experimental studies on the persistence of acrylonitrile are avail-
able. Data from the Gilford Spill (see previous section) indicate at least
some short-term persistence. For several months after the spill, the con-
centration of acrylonitrile in the groundwater increased after it rained
(Manganaro, 1977). Presumably, rainwater caused acrylonitrile to perco-
late through the soil. Importantly, acrylonitrile must have persisted in
the soil (no quantitative measurements of the soil concentrations were
made); microbial breakdown may have been retarded bv the freezing tempera-
tures .
Data provided by the Illinois Environmental Protection (Table 20)
showed that acrylonitrile persisted for about a year or more in monitoring
wells located near a tank car spill of 20,000 gallons of AN. No attempt
was made by the railroad to contain or clean up the spill until 108 days
after the spill occurred. Monitoring data from wells showed high levels
of acrylonitrile until that time (3520-46 mg/1 in 5 wells located within
100 feet of the spill). On day 108, about 270 cubic yards of contaminated
62
-------
Table 20
ON
10
Concentration of AN (mg/1) at Sampling Sites After Tank Car
Spill of 20,000 Gallons on 12/23/73 near Mapleton, 111.3
Monitoring Well
Distance from Spill (ft):
Date Days
(1974)
1/4
1/9
1/14
1/16
1/17
1/21
2/27
3/18
3/28
4/8
4/18
5/1
5/15
6/20
8/15
9/4
9/17
12/9
Since Spill
13
18
23
25
26
30
58
77
87
98
108
121
135
171
227
247
260
351
1
88
8
330
1,200
2,100
2,700
2,100
14
6
6
46
0
0
3
469
90
40
0
0
2
73
1,150
240
370
430
470
2,000
370
180
120
97
282
1,100
1,100
1,220
1,028
40
4
0
3
73
4,200
3,900
4,200
6,000
6,000
8,800
6,500
5,400
4,400
3,520
3,070
3,260
3,560
2,420
771
1,200
-
1,020
4
73
35,000
35,000
23,000
18,000
15,000
12,000
1,600
540
980
418
174
146
< 1
1.4
0
40
40
-
5 6
94 324
-
-
400 0
400 2
10,500 7
4 , 200 3
2,100 2
1,980 2
2,020 0
1,240 0
1,340 -
901
150
157 -
25 -
0
0
Little Marsh Creek
11 A
600 900
-
-
-
0
0
0
0 0
0
0 0
0 0
0
0
0
0
-
-
-
B C
750 3,000
-
-
-
-
-
32 8
3 5
3 5
2.6 5.6
0 0
0 0
0 0
0 0
0 0
-
-
-
*data provided by Illinois Environmental Protection Agency and contained in a series of letters. Nine additional
wells, located 472-2140 feet (x = 1000 ft) from spill site, were sampled until about 4/8; AN levels were 0 mg/1.
Tap water at 6 nearby residences (220-2120 ft. from site; x~ 1150 ft) sampled throughout year and contained no AN.
-------
soil were removed. After this, levels of AN actually. increased in some
wells. Levels decreased af.ter about 170 days when contaminated ground-
water was pumped into a railroad car. A sample of this groundwater re-
vealed 144 mg/1 of aerylonitrile. About 10 months after the spill, the
still-contaminated groundwater was pumped into a sewage treatment plant.
It is probable that the large volume of acrylonitrile from the spill
was lethal to bacteria, precluding biological degradation. No quantitative
measurements of soil or water organisms were made.
F. Hazards from Combustion
1. Thermal Degradation
Thermal degradation of acrylonitrile or polyacrylonitrile may result
in the production of hydrogen cyanide, but the nature of volatile products
depends somewhat on the temperature used (reviewed in Madorsky, 1964).
Bott et al. (1969) investigated the evolution of toxic gases during
thermal decomposition of acrylonitrile in air and in nitrogen. Acrylo-
nitrile was decomposed in a regulated furnace (± 5°) and the resulting
gases were analyzed spectrophotometrically. Hydrogen cyanide and ammonia
formed in boch air and nitrogen.
At 500°C the following gases were produced in air:
ppm
HCN 3000
CO 400
NH3 7000
Oxides of N 25
64
-------
The lowest temperature that hydrogen cyanide evolved in air was 250°C.
CO, >IH3 and oxides evolved at 360-480°C. Bott et al. (1969) suggested
that the rate of hydrogen cyanide evolution depends on the rate of break-
age of chemical bonds adjacent to the cyanide group in acrylonitrile.
Thermal decomposition of polyacrylonitrile yields primarily hydrogen
cyanide (Tsuchiya and Sumi, 1977). One gram samples of 100% polyacrylo-
nitrile yarn were decomposed in a quartz tube heated to 400°, 600° or
800°C under a flow of nitrogen or air. Decomposition products were de-
termined by gas chromatography and gas chromatography-mass spectrometry.
Hydrogen cyanide was the major product under all decomposition conditions,
the quantity increasing with temperature (e.g., in air at 400°C and 800°C,
the weight of evolved HCN was 2.0% and 13.2%, respectively, of weight of
original polymer). Acrylonitrile was the second predominant decomposition
product, ranging from 0.15-18.3% in nitrogen and 0.99-6.26% in air and
increasing with temperature. Smaller amounts of 15 other nitriles were
identified.
Hydrogen cyanide is also the predominant product upon thermal degrada-
tion of acrylonitrile-styrene (AS) or acrylonitrile-butadiene-styrene
(ABS) (Chaigneau and LeMoan, 1974). AS, ABS, and polyacrylonitrile
(PAN) were pyrolyzed at 500 to 1200°C. Between 2.13-7.42, 3.00-7.61 and
1.86-16.2 g HCN, respectively, were released per 100 g of starting product,
the amount depending on the temperature.
2. Mortality from Pyrolysis Products
Cornish et al. (1975) determined the mortality of thermal degradation
products of styrene-acrylonitrile (SAN) and acrylonitrile-butadiene-styrene
65
-------
(ABS) in male Sprague-Dawley rats (av. wt. 250 g). Two degradation methods
were used: rapid combustion and slow pyrolysis. In the first method,
groups of 15 rats were placed in a 1500 1 stainless steel chamber. The
polymers were quickly pyrolized and rats were exposed to the pyrolysis
products (vapors and particulate matter) over 4 hours; several concentra-
tions of the polymers were tested to determine approximate 0-100% mortality
levels. For the slow pyrolysis method, groups of 5 rats were exposed to
the pyrolysis products only during the time they were released from the
polymer. Air in the pyrolysis chamber was cooled and diluted and entered
a Fyrex exposure chamber housing the rats. Approximate 0-100% mortality
levels were determined using several polymer concentrations.
These data were obtained for the two methods:
0-100% mortality range3
(g pyrolyzed product)
Method SAN ABS
Rapid Combustion 10-28 25-30
Slow Pyrolysis 1.0-2.5 1.5.-2.3
estimated from graphs in text
100% mortality had not been reached at 28 g
The constituents of the exposure atmosphere were not monitored, so relating
these data to acrylonitrile toxicity is difficult.
The toxicity of the pyrolysis products of acrylonitrile-butadiene-
styrene (ABS) was assessed by Hilado et al. (1976). Four Swiss albino
mice were exposed to pyrolysis effluents (1 g ABS pyrolyzed at a maximum
of 791°C) in a 4.2 liter chamber in each of 2 trials. At least one mouse
66
-------
became incapacitated about 11.35 ± 3.2 minutes after exposure, as evidenced
by staggering, prostration, collapse, or convulsion. Death occurred after
about 19.30 ± 4.25 minutes for all mice.
G. Analytical Detection Methods
Titrimetric, polarographic and especially gas chromatographic proce-
dures are often used to determine acrylonitrile. Detection methods for
several media will be described in the following sections.
1. In Air
A widely used procedure to determine the concentration of acrylonitrile
in workroom air is the NIOSH method S156 (NIOSH, 1976). For example, this
method is used by Monsanto, Sohio, and Borg-Warner, and a modification
of this method is used by Union Carbide (Monsanto, 1977b; Sohio, 1977;
Union Carbide, 1977; Borg-Warner, 1977). The procedure involves draw-
ing a known volume of air (20 1 mqytnnim recommended) through a charcoal
tube consisting of 2 sections to trap organic vapors. One sample of char-
coal from each section is transferred to a separate container where each
is desorfaed for 30 minutes in methanol. An aliquot of each desorbed sample
is analyzed by gas chromatography. The area of the resulting peak is de-
termined and compared with standards based on mg/1.0 ml methanol; correc-
tions must be made for the blank (NIOSH, 1976).
This method was originally validated by NIOSH over 17.5-70.0 mg/m3
(8.1-32.3 ppm) (coefficient of variation 0.073) at 22°C and 760 mm Hg
using a 20 liter sample. However, recent studies at OSHA indicate a sen-
67
-------
sitivity of 0.05 ppm based on an air volume of 10 liters. The collection
efficiency was 100% when sampling at 0.1 1pm in the volume range of 12-25
liters. Additional studies were conducted in the presence of 10 or 100 ppm
butadiene, methyl methacrylate and styrene. These three interferences had
no effect on the collection efficiency of acrylonitrile (Madsen, 1978).
The Midwest Research Institute (M.R.I.) is currently sampling the
air near AN producer and user facilities for the Environmental Protection
Agency. Their method involves using charcoal tubes sampling at 1 1/min.
The sample is desorbed with carbon disulfide and analyzed using a flame
ionization detector.
Another method used for detecting acrylonitrile is the older NIOSH
P&CAM 127. (1974) where the sample is desorbed with carbon disulfide (CS2)
rather than methanol. DuPont introduced a method where a CSg-acetone
mixture is the desorber. Acrylonitrile can also be measured with other
adsorber-desorption systems. These methods are listed in Table 21 with
their respective sensitivity, accuracy and interferences.
Direct measurement of acrylonitrile can be made using an infrared
(I.R.) spectrometer, but according to Borg-Warner (1977) this apparatus
costs more, requires more skill to use and is more sensitive to physical
damage than the charcoal-tube method. Jacobs and Syrjala ( in press, 1978)
recommend portable I.R. analyzers for immediate "on-the-spot" detection
of acrylonitrile. They claim detection of acrylonitrile as low as 0.2
ppm with MIRAN LA Analyzer (20 meter cell; Foxboro/Wilks, Inc.). Inter-
ferences are other compounds that absorb infrared energy with a wavelength
68
-------
VO
Table 21
Methods for Determining Acrylonitrile in the Air
Method
NIOSH,
No. S156
DuPont Polymer
Intermediates
Dept., No. 5000
DuPont Polymer
Intermediates
Dept, No. 5004
NIOSH, No.
75-121, P&CAM
127
Monsanto,
No. Ill 9 (TC)
Procedure
absorbed on charcoal;
desorbed with metha-
nola; G.C.C
absorbed on charcoal;
desorbed with carbon
disulf ide-acetone; G.C.
absorbed from known
volume of air in chilled
water; G.C.
absorbed on charcoal;
desorbed with carbon
disulf ide G.C.
adsorption on porous
polymer; thermal de-
sorption; G.C.
Sensitivity and
Accuracy
0.05 ppiu
86.7% (S.D. = 54%)
when 10 ppm AN
sampled
lower unit 5 ppm AN
per cubic foot of
sample
not specified
for acrylonitrile
range 0.2-200 ppm
Interferences
primarily nitrogen con-
taining compounds which
elutc at the same time as
AN when using a nitrogen
detector
any component
not separated
any component not
separated
water; any component
not separated
acetone, isopropanol
Reference
NIOSH, 1976
Monsanto,
1977
Monsanto,
1977
NIOSH, 1974
Monsanto,
1977
a
Union Carbide substitutes ethylene dichloride for methanol (Union Carbide, 1977)
coefficient of variation
c
G.C. = gas chromatography
i
under laboratory, not field, conditions
-------
of 10.5 ym (Jacobs and Syrjala, in press 1978). Another method used by
Borg-Warner is a continuously recording gas chromatograph which reportedly
detects acrylonitrile below 0.5 ppm (Borg-Warner, 1977). Union Carbide is
experimenting with a badge-type, carbon-filled dosimeter for vapor col-
lection, but tests are inconclusive. Direct-injection gas chromatography
for acrylonitrile is being tested; preliminary results indicate detection
below 1 ppm (Union Carbide, 1977). Vistron (1978) is also investigating the
portable gas chromatograph and the badge-type carbon-filled disometer.
The American Industrial Hygiene Association (1970) suggested three
methods for analyzing acrylonitrile in air: vapor phase chromatography.
the infrared absorption method and the hydrolysis method. In the latter,
air is drawn through two adsorbing glass bead traps that have been wetted
with sulfuric acid. Acrylonitrile reacts with the sulfuric acid. The
product is treated with hydrogen peroxide, which liberates the ammonium
ion. The amount of the latter liberated (measured colorimetrically) is
used to determine the amount of acrylonitrile in the air sample; sensitivity
is in the range of 20-300 ug/ml of absorbing solution. The American
Industrial Hygiene Association suggests infrared analysis and chromatography
are more sensitive methods than hydrolysis.
Tada (1971) suggested using the brom-benzidine-pyridine method which
can detect 1-50 ppm AN in the atmosphere. Air is aspirated through a
bubbler containing cooled water. The solution is added to bromine, then
exposed to light. Next, an arsenite and then benzene-pyridine solution
are added. The absorbance of the resulting solution is read.
Older and less precise procedures for determining acrylonitrile in
air include the lauryl mercaptan method (Haslam and Newlands, 1955) and
the potassium permanganate method (Gisclard et al., 1958).
70
-------
2. In Aqueous Solution
For analyses, acrylonitrile can be separated from water and from im-
purities in water by gas chromatography, then measured and compared to AN
standards in water. The detection limit has been reported as 0.1 ppm
by DuPont (1977b) and 50 ppb by Monsanto (Livingston, 1977).
In a sampling program for the Environmental Protection Agency, the
Midwest Research Institute (M.R.I.) has developed a protocol for sampling
water containing acrylonitrile (MRI, 1977). Water samples are collected
then acidified by the addition of sulfuric acid. Two types of analysis
are used: azeotropic distillation and purge and trap techniques.
A modification of the purge and trap techniques can be used to analyze
soil containing acrylonitrile.
Hall and Stevens (1977) developed a spectrophotometric method to de-
tect acrylonitrile in aqueous systems, based on the absorbance of visible
light (at 411 nm) of a pyridine-acrylonitrile complex. An aqueous sample
containing acrylonitrile is added to solutions of pyridine, lithium hy-
droxide and sodium hypochlorite, after which absorbances are determined.
Acrylonitrile forms a complex whose molar absorptivity is 635.4, based
on the acrylonitrile concentration. Acetone and ammonia did not inter-
fere at the 10 or IOC ppm level. Cyanide interferes and must be separated
out of solution; it is easily detected. The range of sample used by the
authors was 5-30 ppm (S.D. = ± 3.18%) of acrylonitrile.
71
-------
3. In By-Products
Residual acrylonitrile monomer in polymer by-products can be deter-
mined by gas chromatography, either by direct injection or by head-space
analysis. Steichen (1976) compared the two methods for acrylonitrile and
found head-space analysis to be more sensitive (detection limit 0.5 ppm)
than direct injection (detection limit 10 ppm). Head-space analysis in-
volves the equilibration of a solid polymer in a closed system. The
residual monomer is partitioned between the polymer phase and the head-space
(air above the sample); the monomer concentration in the head-space is then
determined (Steichen, 1976).
The Food and Drug Administration is using a head-space method to
determine AN in food simulating solvents (heptane; 3% acetic acid; 8 and
50% ethanol) that have been in contact with AN copolymers. AN (0.04-10 ppm) was meas-
ured by gas chromatography with a nitrogen selective detector (FDA,1977).
Monsanto developed a method for extracting residual acrylonitrile in
acrylic polymer and fiber by heating above its glass transition temperature
under a total water reflux. The extract is distilled, then analyzed by
high pressure liquid chromatography. No interferences have been noted.
To determine AN in SAN-based polymers, Monsanto disperses the polymer in
acetone. The acetone is analyzed by gas chromatography using a nitrogen
detector (unpublished methods presented in A. T. Kearney, Inc., 1978).
4. In Fumigated Food
Residues of acrylonitrile, arising out of its use (often with carbon
tetrachloride) as a fumigant, can be detected by several methods. Heuser
and Scudmore (1968) described a procedure for extracting residual acrylo-
72
-------
tiitrile by static cold solvent extraction and gas-liquid chromatography.
Total recovery of 99.1-100.2% was reported.
Berck (1960) used a polarographic method to determine acrylonitrile
residues on walnuts. This method is based on the fact that acrylonitrile
forms an azeotropic mixture with water and therefore can be concentrated
and codistilled out of aqueous suspensions. Ninety five to 100% of the
total acrylonitrile was recovered.
Acrylonitrile residues have also been determined by the lauryl mer-
captan method and by direct gas chromatography (Berck, 1975).
5. In Biological Material
Acrylonitrile is not usually measured in biological material. Rather,
the presence in the blood or urine of thiocyanate, a metabolite of acrylo-
nitrile, is often used as an index of acrylonitrile exposure (e.g. Malette,
1943; Lawton et al., 1943; Efremov, 1976). The colorimetric methods de-
scribed by Lawton et al. in 1943 are still used (e.g. Gut et al., 1975).
For urine thiocyanate detection, urine is added to an albumin-tungstate
reagent and sulfuric acid. Then a ferric nitrate reagent is added, and
the absorbance is determined. Absorbance is determined again after the
addition of mercuric nitrate. The difference in absorbance is compared
to a reference curve for thiocyanate.
Kanai and Hashimoto (1965) determined the concentration of acrylonitrile
in expired air, blood and urine by absorbance. They found that acrylonitrile in
acid solution reacted with bromine in ultraviolet light and developed a
pink color with benzidine-pyridine reagent; the absorbance of this color
was then measured.
73
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III. BIOLOGICAL EFFECTS
The biological effects of acrylonitrile in humans, animals, micro-
organisms and plants are discussed in the following sections. In animals,
the metabolism and toxicity of acrylonitrile varies with duration of ex-
posure, route of administration, and species (e.g. Gut et al., 1975; Young
et al., 1977). Accordingly, sections on human and animal toxicology are
subdivided first by duration of exposure then by route of administration
and, where appropriate, by specific effect or species.
A. Humans
1. Acute Toxicity
Acute effects of acrylonitrile have been described for inhalation,
dermal contact, and exposure to acrylonitrile-containing fumigants.
a. Inhalation Exposure
The effect of acute vapor inhalation has been described by Sartorelli
(1966). A 22-year-old chemist was exposed to acrylonitrile vapors for at
least two hours when a distillation apparatus leaked. Headache, vertigo,
vomiting, tremors, uncoordinated movement and convulsions were observed.
Vomiting and nausea persisted after 24 hours. Upon examination one day
after exposure, the chemist showed slight enlargement of the liver and
congestion of the oral pharynx, but no disorders of the central nervous
system were noted; four days after exposure, no kidney, liver, cardiac
or respiratory abnormalities were detected.
74
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b. Dermal Exposure
An early case involved a male laboratory worker who spilled "small
quantities" of liquid acrylonitrile on his hands (Dudley and Neal, 1942).
After 24 hours there developed diffuse erythema on both hands and wrists.
By the third day blisters appeared on the fingertips; the hands were
slightly swollen, erythematous, itchy and painful. The fingers remained
dry and scaly on the tenth day.
Schwartz (1945) reported acrylonitrile to be a "powerful skin irri-
tant" that can cause dermatitis. Wilson et al. (1948) observed that
direct skin contact causes irritation and erythema followed by scab forma-
tion and slow healing.
Acrylonitrile has been shown to be a sen'sitizer, promoting allergic
contact dermatis (Balda, 1975). A 27-year-old individual developed der-
matitis following the use of a "Plexidur" finger splint (copolymer of
acrylonitrile and methyl methacrylate). A rash developed on the left
middle finger where the splint had contacted the skin for over six weeks.
Subsequent patch testing on this individual revealed a -H- positive reaction
using both "Plexidur" and 0.1% acrylonitrile. Other acrylic resins and
compounds are also implicated as dermal allergens (reviewed by Rycroft,
1977).
Acrylonitrile can penetrate clothing and leather shoes (American
Cyanamid, 1976), thus contacting skin. For example, a chemical burn from
acrylonitrile resulted after a worker failed to remove his shoes after
"gross contamination of the shoes" (Dow Badische Co., 1977).
75
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c. Fumlgant Exposure
Home fumigation with acrylonitrile has resulted in both fatal and non-
fatal intoxication of the returning occupants. In home fumigation, the
usual practice is to place 3% - pounds of AN-carbon tetrachloride or
AN-methylene chloride mixtures per 1000 cubic feet in shallow open pans.
Fans are used to circulate the vapors in a tented structure for 24-72
hours. The tent is removed and the operator decides when the house is
safe for occupancy (Davis et al., 1973).
Home fumigation has been practiced in Florida. During 1971 in Dade
County (Florida) alone there were 279 fumigations involving acrylonitrile.
From January 1957 to October 1971, the Florida Bureau of Entomology re-
ported a total of 24 acrylonitrile fumigation incidents; about equal num-
bers of carbon tetrachloride and methylene chloride mixtures were used.
Some of these incidents involved more than one person, for a total of 8
fatalities and 41 nonfatal casualities (Davis et al., 1973).
Symptoms of nonfatal intoxications included lacrimation, burning in
the throat, coughing, sneezing, dermatitis, nausea, vomiting, dizziness,
visual disturbance, headache, coma and seizures (Davis et al., 1973).
Davis et al. (1973) described several fatal intoxications:
Case I. A 57-year-old alcoholic female was found dead after the
tent used for fumigation was removed from her home; she apparently had not
vacated the premises.
Case II. A 22-month-old male slept for one night in a room that
had been fumigated 6% hours previously; the child died four days later.
Traces of cyanide were detected in the blood. The brain was swollen and
softened; the pituitary was necrotic.
76
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Case 1I±. A 67-year-old man died within 24 hours of returning
to his house that had been fumigated. The man had a past history of hyper-
tension. Autopsy revealed heart disease, emphysema, liver congestion and
cystic infarcts of the basal ganglia and pons. Trace amounts of cyanide
were detected in the blood.
Case IV. A 41-year-old female returned 20 hours after her
apartment had been fumigated, and died 24 hours later. At autopsy, focal
pulmonary congestion and edema were found. Cyanide was found in several
tissues.
Case V. A 63-year-old female died several days after fumigation,
showing signs of tremors and respiratory failure.
Grunske (1949) described another fatal case. A three-year-old girl
died the night after her parent's home was fumigated with acrylonitrile
to control an insect infestation. A doctor attributed death to hydro-
cyanic acid poisoning, noting these signs: breathing disorder, uncon-
sciousness, paleness, tachycardia. Grunske (1949) also briefly mentioned
3 additional deaths in children directly attributable to acrylonitrile
fumigation. He cautioned that children may be particularly sensitive to
acrylonitrile.
Radimer et al. (1974) described 1 nonfatal and 3 fatal cases of non-
staphyloccal toxic epidermal necrolysis (resembling second-degree burns)
induced by a fumigant mixture (AN-CCl^) used in Florida. Skin disease ap-
peared 11 to 21 days after homes of the patients were fumigated.
Radimer et al. (1974) do not exclude the possibility that carbon
tetrachloride may have been the responsible agent. CCl^ acts as a CNS
depressant in high doses and a liver toxin with delayed death at lower
doses; however, such was not observed here. Moreover, as acrylonitrile
is known to cause blisters when absorbed into workmen's shoes,
77
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they suspected acrylonitrile as the likely agent. The author's suggest
inhalation of vapors as the likely route of exposure, rather than absorp-
tion through the skin.
The four cases are described below:
Case I. Three weeks after her house was fumigated, a 64-year-
old woman developed a pruritic eruption on the abdomen and blisters on
the feet. This condition progressed until more than 90% of the skin was
covered with bright erythema and large bullae. The epidermis was necrotic
and separated from the dermis. Despite supportive therapy, the woman
died 2 days later.
Case II. One and one-half weeks after domicile fumigation the
skin of a 41-year-old woman became erythematous. This condition worsened
into a generalized bullous dermatitis, covering the body by day 21. The
woman died on day 27.
Case III. Seventeen days after fumigation, the skin of a 36-
year-old woman was erythematous and covered with vesicles and flaccid
bullae. Preceding dermal symptoms were the following: sore throat, weak-
ness, dizziness, vomiting, and burning sensation of the eyes. The woman
died on day 26.
Case TV. The 10-year-old son of Case 2 developed pruritic erup-
tions that covered one third of his skin 2 weeks after fumigation. New
eruptions emerged over the next few days, but treatment was successful in
preventing death.
Lorz (1950) reported a fatal case of acrylonitrile (Ventox) poisoning
resulting not from vapor inhalation, but rather, from direct skin applica-
tion. A mother applied Ventox to the head of her 10-year-old girl to
78
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control head lice; the head was wrapped in a towel and the child was sent
to bed. Before falling asleep, the child complained of feeling ill, dizzy
and having a headache; she threw up several times. The girl became un-
conscious and went into convulsions and died the next day.
2. Occupational Exposure
The National Institute for Occupational Safety and Health estimates
that 125,000 persons are potentially exposed to acrylonitrile in the work-
place (Finklea, 1977). During 1977, NIOSH and OSHA (Occupational Safety
and Health Administration) requested manufacturers and end-users of acrylo-
nitrile to submit information on acrylonitrile, including employee expo-
sure. Information received in response to these requests is summarized in
Table 22 for the number of employees exposed and the processes in which
these workers are exposed. The current OSHA standard for occupational ex-
posure to acrylonitrile is an 8-hour time weighted average of 2 ppm. NIOSH
recommended that acrylonitrile be handled in the workplace as if it were a
human carcinogen and recommended industrial hygiene practices to reduce
exposure be implemented (Finklea', 1977) .
Measurements at a U.S.S.R. production site confirmed that acrylonitrile
is not just an air contaminant, but is present on equipment and clothing
as well (Zotova, 1975). Samples of workroom air (N = 452), washings from
equipment (N =» 82), washings from worker's skin (N => 398), and clothing
patch samples (N = 35) were taken over a 5 year period (1965-1971). Ini-
tially the workroom air exceeded the Mean Permissible Concentration (MFC =
0.5 mg/m3) by 5-10 times. However, this was reduced to an average of 0.75
mg/m3 after sanitary measures were instituted.
79
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Table 22
Processes in Which Workers are Exposed to AN
at Representative Production Sites
(as reported to OSHA)
Company
Processor Division
Number Exposed'
SOHIO
American
Cyanamid
DuPont
Texaco
B. F. Goodrich
Borg-Warner
Dow Chemical
Union Carbide
Dow Badische
Uniroyal
Barex resin manufacture
AN manufacture
AN manufacture
Acrylamide manufacture
Truck and Barge loading
Laboratory and Plant Opera tLons
Iminodipropionitrile manuf.
XT polymer production
Paper products production
Acrylic Staple & Tow
Cypcin production
Elastomer Chemicals Dept.
Organic Chemicals Dept.
Fabric & Finishes Dept.
Textile Fibers Dept.
Polymer Intermediates Dept.
Elastic Products & Resins
Plastic Products & Resins
Waynes bo ro, Va.
Speciality Chemicals
Hycar rubber & ABS production
AN manufacture
All processes
AN/Styrene copolymerization
AN/vinylidene chloride copolymeriza-
tion
Chemical Intermediates
AN manufacture 1947-1977
AN manufacture 1954-1966
Silane
Others
Polymerization & wet spinning
ABS resin AN-butadiene rubber
41
38
209 overall
1,200
450
350
2,000
350
30
120
1,800
51
84
(since 1940)
(since 1953)
(since 1955-1958)
(since 1950)
(in 1976)
(since 1955)
(since 1956)
(since 1945)
60-70 (1954-1972)
100 exposed for 20
years
178
50
35
50 in 1977
47
70
277
65
344 (1976-1977)
a
numbers refer to workers exposed during 1976-1977 except as noted
80
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Found to be contaminated with acrylonitrile were: equipment (0.002
mg/cm2), handrails of stairways (0.0056 mg/cm2), doors and door handles
(0.0168 mg/cm2), windows and floors.
By the end of a shift acrylonitrile was found to have accumulated on
worker's skin (> 2 mg accumulated on the palms of apparatus operators,
machinists and laboratory workers) and clothing (.00024-.00074 mg/cm2 in
one day). Acrylonitrile was not easily removed from the skin and clothing
by ordinary washing; a protective paste of household soap, mineral oil,
glycerine and china clay reduced AN content on the palms of hands by 67%.
a. Signs and Symptoms
Workmen exposed to "mild concentrations" of acrylonitrile in synthetic
rubber manufacture developed nausea, vomiting, weakness, nasal irritation,
and an "oppressive feeling" in the upper respiratory tract (Wilson, 1944).
Sometimes symptoms of headache, fatigue and diarrhea were observed. In a
few cases mild jaundice appeared, lasting for several days and was accom-
panied by occasional liver tenderness. One severe case of jaundice lasted
for four weeks although the individual complained of "lassitude and fatigue"
after one year. Cases of jaundice were accompanied by low grade anemia.
In 15 years, Zeller et al. (1969) treated a total of 16 workers who
inhaled acrylonitrile fumes. Symptoms appearing within 5 to 15 minutes
were nausea, vomiting, headache and vertigo. In no case was hospitaliza-
tion necessary.
Workmen exposed to atmospheres containing 16-100 ppm acrylonitrile
for 20 to 40 minutes during cleaning operations in polymerizers frequently
complained of a dull headache, fullness in the chest, irritation of all
mucous membranes (including eyes, nose, and throat), and a feeling of
81
-------
apprehension and nervous irritability . (Wilson at al., 1948). Some work-
men had "intolerable itching" of the skin but no accompanying dermatitis.
Direct skin contact with acrylonitrile caused irritation and erythema.
Zeller et al. (1969) treated 50 cases (in 15 years) of skin damage re-
sulting from occupational contact with acrylonitrile. Symptoms occurred
5 minutes to 24 hours after contact. Initially there is a burning sensation,
followed by a reddening of the area, which often blisters after one day.
A group of Japanese workers employed in acrylonitrile manufacture com-
plained of headache, weakness, fatigue, nausea, vomiting, nosebleed, and
insomnia (Sakurai and Kusumoto, 1972). These symptoms correlated signifi-
cantly with length but not with degree of exposure or age of the worker
(Table 23). In all, 576 workers were examined several times so that a
total of 4439 health records were available for analysis.
The health of Russian workers was assessed in 45 individuals employed
in acrylonitrile manufacture from 4-6 years and compared with 25 control
individuals (Zotova, 1975). Acrylonitrile workers complained of poor
health, headache, decreased work capacity, poor sleep, irritability, chest
pains, poor appetite and skin irritation (irritation during the first
months of employment only). Paleness of the skin was noted in many workers.
Spassovski (1976) reported toxic and allergic dermatitis occurring
among acrylonitrile workers in Bulgaria. According to Spassovski (1976)
cumulative effects of acrylonitrile may not be detected due to the worker's
short length of service (3-5 years). Anton'ev and Rogailin (1970) reported
dermatitis among Russian acrylonitrile workers.
82
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Table 23
Association Between Abnormal Findings and Several
Variables Associated with AN Exposure
(Sakurai and Kusumoto, 1972)
Subjective Complaints
Heaviness in Head
Headache
Weakness
Fatigue
Nausea
Vomiting
Nosebleed
Insomnia
Inspection
Skin eruptions
Pallor
Jaundice
Con j unc t ivitis
Specific Gravity of
Whole Blood
Serum Colloid Reaction
Lugol-Test
Hay em-Test
CCLF
Serum Cholinesterase
Activity
Urine Tests
Urobilinogen
Bilirubin
Protein
Glucose
A«b
a
no
no
*yes/-a
? /-a
no
no-
no
no
no
no
no
no
*yes/-
?/+
?/+
no
no
*yes/-
no
yes/+
? /+
Length
Total
*yes/+a
*yes/+
*yes/+
*yes/+
*yes/+
*yes/+
*yes/+
*yes/+
no
no
no
no
no
yes/+
yes/+
no
*yes/+
*yes/+
no
? /+
no
of Exposure0
Group I
yes/+
yes/+
yes/+
yes/+
yes/-»-
yes/+
yes/+
yes/+
no
no
no
no
no
? /+
yes/+
no
? /+
*yes/+
no
no
no
Degree of
Exposure1*
yes/+
? /+a
ves/+
? /+
yes/+
yes/+
yes/+
yes/+
no
no
no
no
no
no
*yes/+
no
no
*yes/+
no
yes/+
no
N
4,439
4,439
4,439
4,439
4,439
4,439
4,439
4,439
4,439
4,439
4,439
4,439
3,520
1,544
3,794
4,293
3,247
4,313
4,354
4,350
3,511
aScoring: no - no association; yes/+ » positive association:
yes/- = negative association; ?/+ = probable positive
association; ?/- = probable negative association
* significant at 95% level
15 to 49 years old
Employment 0->10 years
Jdata for both groups lumped together by authors
(group I - working environment -
-------
b. Hematological Alterations
Workers engaged in the production of acrylonitrile have exhibited
hematological changes
-------
Analysis of blood samples in Russian workers exposed to acrylonitrile
revealed significantly lower erythrocyte counts in laboratory workers and
female apparatus workers and lower leucocyte counts in female apparatus
workers and machinists <£otova, 1975; Table 25). Hemoglobin was lowered in
all apparatus operators and laboratory workers. Catalase activity was re-
duced for all categories of workers examined. Total glutathione was increased
among male apparatus workers, machinists, and lab workers; all workers
showed an increase in oxidized glutathione. Also, all workers had a reduced
sulfhydryl count. Changes from controls for these parameters can be taken
as a measure ot toxicity and would likely reduce worker1 ability to withstand
further toxicological insult. The full significance of these parameters is not
considered by the authors.
Some workmen at B. F. Goodrich Company during the 1940's were routinely
exposed to "several atmospheric concentrations" of acrylonitrile for 20 to
45 minutes at a time. Blood thiocyanate levels in those individuals ex-
posed to concentrations below 22 ppm for 30 minutes returned to normal after
2% hours. However, elevated levels were still present 12 hours after
exposure to more than 50 ppm for 30 minutes (Wilson & McConnick, 1949).
c. Effects on Tissues and Organs
Sakurai and Kusumoto (1972) reported health impairment and especially
liver function abnormality among acrylonitrile workers in Japan. They ex-
amined health records of 576 workers at 5 plants. A total of 4,439 health
records were evaluated; each person was examined an average of 7.7 times.
(However, no control population was examined.) Degree of exposure was clas-
sified as 2 types: I, working environment approximately less than 5 ppm
and II, working environment less than 20 ppm AN (presumably greater than
5 ppm). Exposure was further broken down by length of employment (0-4,
5-9, > 10 years) and by age of worker (15-19, 20-29, 30-39, 40-49). Para-
meters examined are listed in Table 23.
*see page 79 for exposure level
85
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Table 25
00
Blood Values of
Workers Engaged in the Production of Acrylonitrile
Control
Erythrocytes
(x 106)
Leucocytes
(x IQr)
Hemoglobin
Catalase
Index
Total Gluta tui-
on e (mg%)b
Reduced Gluta-
thlone
Oxidized Gluta-
thione
Sll groups
(raM/100 ml)
V
N=13
44610.449
6.3210.31
12.6510.27
3.7710.14
0.3110.014
37.7011.36
32.5111.17
5.2010.48
1236124.2
M
N-12
4. 4 8J 0.066
7.2810.25
14.6410.27
3.4210.13
0.2810.013
35.5010.39
29.7510.51
5.7510.25
1353122.19
(Zotova, 1975)
Apparatus
F
N=28
3.9310.053
6.3610.22
*10. 9010. 14
* 2.6310.09
* 0.2110 ..008
38.2211.42
24.7510.72
*13.4711.09
*1042.9l22.9
a
Operators
M
N=10
4.5410.098
6.1210.49
13.4010.52
*2. 7910. 17
*0. 2210. 014
*39.3812.29
*25. 821 1.59
*13.56i2.12
*1141156
in Russia
Machinists
N=10
4.2910.094
*5. 9010. 32
*12.55i0.26
3.2110.13
*0. 1910. Oil
*38.9011.18
28.0912.12
*9. 811 1.34
*1140147.3
Laboratory
Workers
N=27
* 3.9210.06
5.9610.18
11.9010.33
* 3.3610.08
* 0.2110.01.
*35.7010.90
*23.8110.84
ni. 8910. 84
*1123.7i23.5
*p<.05
a
particular functions of these job descriptions are undefined in original reference
the significance of changes in glutathione and sulfhydryls are discussed in
in section IlI-B-3-4)-d.)
-------
Correlation of these parameters with age of worker, length of exposure and
.degree of exposure was determined by chi-square tests or by regression
analyses. Subjective complaints have been discussed (Section III-A-2-a).
There was no association between skin eruptions, skin color, jaundice,
conjunctivitis and age or any of the variables associated with acrylonitrile
exposure. Positive nonsignificant associations were found for the Lugol
reaction and Hayem flocculation tests (both serum colloid reaction tests)
and total length of exposure. Significant positive associations existed
between these variables: the Hayem test and degree of exposure; serum
cholinesterase activity and total length of exposure; urine urobilinogen
and length of exposure; urine urobilinogen and degree of exposure.
Sakurai and Kusumoto (1972) conclude that mild liver injury (in some
individuals) is indicated by these results. As significant associations
existed between length of employment and several parameters, the authors
feel that workers suffer slight chronic, cumulative effects from acrylo-
nitrile. However, they knew of no specific worker whose health was con-
sistently lowered from one health examination to the next that could de-
finitely be attributed to acrylonitrile. Since even workers exposed to
low acrylonitrile levels (< 5 ppm) had subjective health complaints, the
authors question the allowable limit of 20 ppm in Japan.
Agayeva (1970) reported central nervous system impairment resulting
from chronic acrylonitrile exposure. A group of 122 Russian workers in-
volved in acrylonitrile production were examined; the length of exposure
is not specified. These workers were divided into 3 groups after data were
collected. Of these 122 workers, 77 (Group I) showed significant decreases
in an "epinephrine-like substance" and increased in acetylcholine,
87
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compared to 30 healthy individuals; cholinesterase activity was unchanged
(Table 26). Of these 77 workers, 34% had lowered arterial blood pressure
and 62% had the following: labile pulse, alteration of the Aschner test
(slowing of pulse following pressure on eyeball), diffuse dennographia,
and increased sweating.
A second group of 27 workers out of the total 122 examined had ele-
vated epinephrine levels (Table 26). Almost half of the workers in this
group showed the following signs: neurasthenic syndrome, instability of
arterial pressure, tachycardia-like pulse rate, and change of orthostatic
reflex.
A third group of 10 workers did not differ from the controls in the
parameters examined. .However, these 10 workers were re-examined a year
later; 7 workers showed decreased blood levels of epinephrine and 5 showed
increased acetylcholine (values not given). From these limited data
Ageyeva (1970) concludes that an "increasing service record" is accom-
panied by lowered epinephrine and increased acetylcholine (Why Group II
individuals did not fit this pattern is not explained.) Individuals, from
Groups I and II were not re-examined. According to the author, impairment
of the central nervous system results from chronic acrylonitrile exposure.
However, the author apparently divided the workers into 3 groups after re-
sults were obtained, severely limiting the usefulness of this study.
Several other Russian studies are available which include a discussion
of the toxic effects of acrylonitrile in workers. However, workers were
exposed to other substances in addition to acrylonitrile. For example,
Ostrovskaya et al. (1976) reported electrocardiogram shifts in workers
88
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Table 26
Changes in Some Blood Values in Workers
Chronically Exposed to Acrylonitrile
(Ageyeva, 1970)
Concentration in the Blood
b c
Epinephrine-like Acetylcholine Cholinesterase
substance Cequiv. units) (equiv. units)
fug %)
Healthy individuals 4.4 ± 0.28 0.046 ± 0.004 0.36 ± 0.02
(N = 30)
AN workersd (122 total):
Grp.
Grp.
Grp.
I
II
III
(N
(N
(N
= 77)
= 27)
= 18)
2.
8.
n.
6 ± 0.08*
5 ± 0.41*
s.
0.
n.
n.
058 ± 0.002*
s.
s
n.
n.
n.
s.
s.
s.
*significantly different from control (p < .001)
n.s. - not significantly different from control (values not given in text)
Determined by method of Gosh, Dev and Banerjee
determined by method of Khestrin
Determined by method of Augustinsson and Heimberger
dgroups apparently divided after results obtained
89
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exposed.in the workroom to acrylonitrile, acetonitrile, hydrocyanic acid
and higher than permissible levels of noise. Mavrina and Il'ina (1974)
reported increases in immunologic reactivity among trade school students
exposed to AN, sodium thiocyanate and methyl aerylate. Orushev and Popovski
(1973) observed clinical and electrocardiogram anomalies among 20 workers
exposed to AN (3.0-20.0 mg/m3 in air) and other substances during fiber
production. Shustov and Mavrina (1975) and Mavrina and Khromov (1974)
reported changes in the liver and the nervous, cardiovascular and gastro-
intestinal systems among workers occupationally exposed to acrylonitrile,
methylacrylate and sodium rhodanite during fiber production. Nervous sys-
tem changes, mainly vegetative alterations, were particularly noted among
the 340 workers examined. Skin changes were also observed: dryness, de-
squamation, hand fissures, and diffuse erythema characterizing dermatitis.
d. Possible Carcinogenic Effects
A preliminary report on an epidemiologic study being conducted by
DuPont indicated excess cancer incidence and cancer mortality among workers
exposed to acrylonitrile (O'Berg, 1977). This study focused on a cohort
of 470 males exposed to acrylonitrile at DuPont's textile plant in Camden,
South Carolina at some time during 1950 to 1955; these workers are still
actively employed by DuPont or have retired. A more complete analysis
is planned which will include persons who were exposed to acrylo-
nitrile but no longer work for DuPont. Smoking histories were not
available.
Eight cancer deaths occurred among the cohort of 470 workers between
1969 and 1975 (this allows for a 20 year latency). Only 4 such deaths would
be expected based on DuPontTs Mortality Rates (1969-1975). About 5 deaths
90
-------
would be expected based on national rates for U.S. white males (1970) or
regional rates in South Carolina (1969-1971). In the exposed group, 4 of
the 8 deaths were from lung cancer, the rest resulted from cancers occurring
at different sites.
The number of cancer cases occurring between 1969-1975 was higher
among actively employed workers: 16 cases compared to 5.8 expected, based
on DuFont Company rates or 6.9 expected, based on national rates. Data
for the cancer cases were from DuPont's Cancer Registry. These 16 cases
included cancer of the lung (N = 6) , large intestine (N =» 3) and 7 other
primary sites.
For the cohort of 470 workers, there were a total of 18 cases of cancer
and/or cancer deaths (data from DuPont's Mortality File and/or Cancer Reg-
istry) between 1969-1975. Cancer occurred at these sites: lung (N » 6),
large intestine (N = 3), prostate (N = 2), lymphosarcoma (N = 1) , Hodgkins
(N - 1), penis (N = 1), thyroid (N - 1), nasopharynx (N =» 1). bladder (N = 1),
pancreas (N = 1).
DuPont stresses the preliminary nature of these data. Further analyses
and additional data gathering are in progress.
The DuPont study has raised serious concern about the safety of acrylo-
nitrile. Other epidemiological studies are currently underway or are being
planned. Preliminary tabulation of mortality among workers at Uniroyal's
Baton Rouge/Scotts Bluff Plant (La.) where ABS resin is manufactured re-
vealed 6 deaths from cancer out of 30 total deaths (Uniroyal, 1977). Five
of the 6 workers who died of cancer had been employed 8-20 years (x => 13.8
years) in resin manufacture. Dow Chemical Company made a preliminary review
91
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of, mortality in workers with acrylonitrile exposure which revealed "no pat-
tern of increased mortality due to malignant neoplasms". One employee of
Dow Badische Co. with "routine exposure to acrylonitrile" developed cancer
of the liver and gallbladder. For over one year, this worker was exposed
to 5-10 ppm TWA (.time weighted average) as a dry plant operator. As a
dry area worker, he was exposed to < 1 ppm for 2 years (Dow Badische Co.,
The following is a list of companies undertaking or planning epidemiology
studies of workers exposed to acrylonitrile:
1. DuPont - further analysis of cancer deaths and cancer cases; see
above
2. American Cyanamid (1977) - examining the feasibility of an epide-
miological study
3. Uniroyal (1977) - expects to begin epidemiological studies, under
the auspices of the University of North Carolina, at their Baton
Rouge/Scotts Bluff plant (La.)- An ABS terpolymer (Kralastic)
is manufactured there
4. Dow Chemical (1977b) - 2 studies currently ongoing but not specific
for acrylonitrile
5. Union Carbide (1977) - epidemiology studies underway for all em-
ployees at their Bound Brook (NJ) and Sistersville (VA) plants;
these studies are not specific for acrylonitrile
6. Monsanto (1977b) - epidemiology study on-going at locations where
acrylonitrile has been produced (Alvin, Texas; Texas City, Texas)
or used (Decatur, Ala.; Addyson, Ohio) for 8-26 years.
7. Vistron (1978) - epidemiology study begun in 1977 covering monomer
and polymer production (Lima, Ohio)
3. Controlled Studies
Liquid acrylonitrile was applied to the forearm skin of 4 human volun-
teers (Rogaczewska and Piotrowski, 1968). Based on losses from the skin
-------
surface, it was determined that the absorption rate of acrylonitrile aver-
aged 0.6 mg/sq cm/hour.
The retention of doses of acrylonitrile in the respiratory tract
averaged 46 ± 1.6% in 3 men exposed to about 20 ug/1 for up to 4 hours
(Rogaczewska and Piotrovski, 1968). Retention did not vary between length
of exposure but did vary between individuals, as these data show:
Retention of Acrylonitrile (%)
Minutes Exposed to 20 ug/1 AN
Individual
1
2
3
0-10
59
46
49
10-30
63
44
23
30-60
41
45
29
60-90
52
47
54
90-120
45
45
48
120-180
41
50
32
>180
55
48
49
x 51 43 38 51 46 43 51
These authors showed that absorption by inhalation is about 100 x more
efficient than through the skin.
B. Nonhuman Mammals
The absorption, tissue distribution, biotransformation and toxicity
of acrylonitrile to nonhuman mammals are discussed in the following sections.
This information is then used to assess the mechanism of toxic action.
1. Absorption and Tissue Distribution
Young et al. (1977) specifically looked at absorption and distribution
by using radio-labeled acrylonitrile. Radioactivity was determined by
liquid scintillation counting but small sample sizes somewhat limited the
usefulness of the experiments.
Young et al. (1977) calculated the percentage of oral acrylonitrile
doses absorbed by male Sprague-Dawley rats (Spartan substrain) given single
oral doses of 0.1 mg ltfC-AN/kg (4 rats) or 10 mg 14C-AN/kg (5 rats). After
93
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72 hours, the percentage of the dose recovered was 82.37% and 104.04% at
0.1 and 10 mg/kg, respectively (Table 27). Although significant dose re-
lated differences existed for recove'ry in the urine and carcass, both doses
had a 5% recovery in the feces. Thus, about 95% of the dose had been ab-
sorbed.
Recovery of inhaled acrylonitrile (5 or 100 ppm for 6 hours) was de-
termined in 8 rats exposed in a "nose only" inhalation chamber. More of
the dose was recovered in the urine at the higher dose (Table 27).
The distribution of radioactivity of selected tissues was determined
in rats given single oral or intravenous doses of 1^C-acrylonitrile (Young
et al., 1977). All tissues examined (e.g. lung, liver, kidney, stomach,
intestines, skeletal muscle, blood, etc.) contained acrylonitrile or its
metabolites. High levels were found in the red blood cells, skin and
stomach, regardless of route or dose. Radioactivity of the stomach walls
was particularly high, even after i.v. administration, and therefore was
not due to unabsorbed acrylonitrile when given orally. Analysis of the stomach
after i.v. administration showed the amount of radioactivity increased from
30.33 ugEq at 5 minutes to 68.64 at 24 hours. (This may, in part, explain
the significant increase in stomach tumors observed in rats given AN in chronic
experiments [section IV-D]). The amount of radioactivity in other parts of the
body was decreasing with time due to excretion, so this increase in the stomach
revealed a selective secretion process.
2. Biotransformation
Acrylonitrile is metabolized in laboratory animals to cyanide, which
is subsequently converted to thiocyanate and then eliminated in urine (e.g.
Dudley and Neal, 1942; Brieger et al., 1952). However, less than one-
quarter of an administered acrylonitrile dose has been accounted for by
94
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Table 27
Recovery
nitrile
A. Oral
Urine
Feces
Expired Airb
Carcass
Skin
Cage Wash
Total
B. Inhalation
Urine
Feces
^C02
Body
Cage Wash
Total
of Radioactivity from Rats Given Acrylo-
by A) Oral Doses or B) Inhalation Exposure
(Young et al., 1977)
% of
0.1 mg/kg
(N = 4)
34.22
5.36
4.91
24.24
12.78
0.86
82.37
% of
5 ppm
(N = 4)
68.50
3.94
6.07
18.53
2.95
99.99
Dose Recovered at 72 hra
10 mg/kg
(N = 5)
66.68
5.22
4.32
16.04
10.57
1.22
104.04
Dose Recovered at 220 hra
100 ppm
(N = 4)
82.17
3.15
2.60
11.24
0.85
100.01
Significance
p < .05
n.s.
n.s.
p < .05
n.s .
n.s
p < .05
Significance
p < .05
n.s .
p < .05
p < .05
n.s .
standard deviation of values reported in original reference
'primarily as lkC02
95
-------
this metabolic route (e.g. Benes and Cerna, 1959; Czajkowska, 1971; Gut
et al., 1975). Acrylonitrile reacts with sulfhydryl groups (either cysteine
or glutathione) by cyanoethylation, preventing further metabolism to cya-
nide and thiocyanate. Wright (1977) describes cyanoethylation as the pre-
ferred route. Other reactions may include coupling with D-glucuronic acid
(Hoffman et al., 1976) and production of carbon dioxide (Young et al.,
1977). Evidence from Gut et al. (1975), Young et al. (1977) and Wright
(1977) shows the route, species and dose-dependent fate of acrylonitrile
metabolism.
a. Biotransformation to Cyanide and Thiocyanate
A major metabolite of acrylonitrile is cyanide (CN"~), which is subse-
quently converted to thiocyanate SCN~. The following mechanism has been
suggested by Dahm (1977):
0
i'
M
CH2 - CHCN + H20 —> CH3-C -1- H+ + CN~
+ \ +
£ SCN~
CH3-C*
bH
Although earlier authors doubted that cyanide is a metabolic product of
acrylonitrile (see discussion in Brieger et al., 1952), evidence now
strongly favors this pathway. Evidence to this effect has been presented
by Dahm (1977). Rats were fed radio-labeled acrylonitrile and five uri-
nary metabolites containing labeling on the cyano group were later sepa-
rated by high pressure liquid chromatography (HPLC). The peak suspected
of being thiocyanate matched the retention times of thiocyanate standards.
Also, thiocyanate was detected in the urine colorimetrically. A third
experiment showed that when rats were fed acrylonitrile labeled on either
96
-------
of the 2 olefinic carbons, there was no thiocyanate peak by HPLC as there
had been when the cyano group was labeled. Hence, the thiocyanate comes
from the cyano carbon, as proposed above. Other authors have proposed
the metabolic breakdown of acrylonitrile to thiocyanate via cyanide,
using such evidence as: a) similarity of symptoms between cyanide and
AN intoxication (Dudley and Neal, 1942); b) cyanide antidotes (e.g. sodium
nitrile, sodium thiosulfate, hydroxycolbamine) offer some protection
against acrylonitrile poisoning in some species (Dudley and Neal, 1942;
Benes and Cerna, 1959; Graham, 1962); c) cyanide and cyanmethemoglobin
have been directly measured in the blood after acrylonitrile administra-
tion (Brieger et al., 1952); d) thiocyanate has been directly measured
in the urine after administration of acrylonitrile (Mallette, 1943;
Lawton et al., 1943; Efremov, 1976).
Two studies are presented as examples of thiocyanate levels after
acute acrylonitrile exposure. Lawton et al. (1943) exposed 3 to 6 female
dogs to 0, 24, 40, or 60 ppm acrylonitrile vapor for four hours and measured
thiocyanate levels up to 168 hours post-exposure. All but one treated dog
showed peak serum thiocyanate levels within four hours of exposure. This
level remained high for 8 to 24 hours and returned to near normal within
3 to 7 days. Urine thiocyanate increased 24 to 48 hours after exposure
and decreased by days 4 to 6. There was no thiocyanate in the blood or
urine of control dogs.
The evidence presented above shows only that cyanide and thiocyanate
are metabolites of acrylonitrile. There has been some controversy over
whether acrylonitrile's toxicity is due solely or partly to the cyanide
97
-------
or 'is unrelated to it (see Section III-B-4) . Addressing this controversy,
some investigators have determined the relative amounts of cyanide or
thiocyanate formed after administration of acrylonitrile. For example,
Benes and Cerna (1959) estimated only 19.4% of the acrylonitrile adminis-
tered perorally to rats was metabolized to thiocyanate. Czajkowski (1971)
determined 8.5% of acrylonitrile given i.v. to rats was metabolized to
thiocyanate. Gut et al. (1975) emphasized that the amount of thiocyanate
excreted in the urine varies between the route of administration and also
between the species.
Gut et al. (1975) studied thiocyanate formation in female Wistar rats,
albino mice and Chinese hamsters given 25.4 or 40 mg AN/kg by several
routes (peroral, i.p., s.c., i.v.). In rats, there was a higher transforma-
tion after 48 hours of acrylonitrile to thiocyanate after oral (15-31%),
than i.p. (2-6%) s.c. (6%) or i.v. (1%) administration. After oral dosing
only, there was a distinct lag period before thiocyanate was detected
suggesting that immediately after oral dosing, acrylonitrile is "not ap-
preciably metabolized". Gut et al. (1975) also think that acrylonitrile
is only slightly absorbed from the stomach. In mice there was also more
thiocyanate excreted after oral (35% of AN dose) than i.p. (8-10%) or
i.v. (11%) administration. In contrast to rats, more total thiocyanate
was excreted. Gut et al. hypothesized a higher metabolic capacity and a
possible lower binding capacity for acrylonitrile in mice. In addition,
rates of transformation did not vary between i.p. and i.v. administration as
they did in rats.
For hamsters, as in rats and mice, more thiocyanate was excreted in
the urine after oral than after i.p. administration of acrylonitrile.
98
-------
For both hamsters and mice there was no lag period before thiocyanate
elimination after oral dosing, in contrast to a 4-hour lag in rats. Gut
et al. (1975) suggest body size may be an influencing factor.
The authors also tested the effect of microsomal enzyme induction
on the aerylonitrile-thiocyanate balance by pretreatment with phenobarbi-
tal. Similarly, the effect of microsomal enzyme inhibition was tested
by pretreatment with SKF 525-A. In rats receiving either pretreatment
followed by oral or intraperitoneal administration of aerylonitrile,
thiocyanate metabolism was unchanged. Pretreatment of rats with cysteine
or dimercaprol (both potential antidotes) also did not affect thiocyanate
urine levels. However, pretreatment of rats or mice with thiosulfate
significantly increased the metabolized portion of acrylonitrile when AN
was given intraperitoneally (but not orally). The effect was most marked
in mice; thiocyanate was increased more than 3 times over non-pretreatment
levels. For rats, thiocyanate was increased almost twice.
Gut et al. (1975) suggest that acrylonitrile-to-thiocyanate metabolism
is "closely related to that portion of the dose of acrylonitrile reaching
the liver during the first pass through the body after absorption". For
acrylonitrile, distribution is probably closely related to strong binding
and to non-enzymatic reactions. Gut et al. (1975) suggest strong binding
in blood, and cyanoethylation reactions exclude acrylonitrile from further
metabolism to thiocyanate. In summary, differences between route of
administration (within a species) were caused by factors affecting the
distribution of acrylonitrile, rather than by route-related metabolic dif-
ferences. Gut et al. (1975) suggest cyanide-mediated toxicity is doubtful
in rats but probable in mice.
99
-------
b. Reaction with Sulfhydryl Groups
In addition to forming cyanide and thiocyanate, acrylonitrile reacts
with sulfhydryl compounds by cyanoethylation. Hashimoto and Kanai (1965)
showed that acrylonitrile forms stable conjugates with L-cysteine and L-
glutathione in vitro. Thus, a portion of the acrylonitrile dose is pre-
vented from being metabolized to cyanide and thiocyanate; this reaction
is considered a detoxification mechanism. Gut et al. (1975) determined
that acrylonitrile reacts with cysteine to form S-(2-cyanoethyl)cysteine,
which is excreted in the urine.
Dahm (1977) unequivocally identified two conjugates of acrylonitrile
with cysteine in rats given radiolabeled acrylonitrile:
9,
a) HOC— CH-CH2-S-CH2-CH2-CN
NH
(conjugation product of AN with cysteine and acetate)
b) HOC-CH-CH2-S-CH2-CH2-CN
(conjugation product of AN with cysteine)
Wright (1977) , working out of the same laboratory as Dahm, administered
orally cyano-labeled acrylonitrile to Spartan rats, a Charles River rat,
and rhesus monkeys and measured metabolites collected for 24 hours in urine.
As shown in Table 28, low levels of acrylonitrile (0.1 mg/kg) resulted in
conversion of about 90% of the administered dose to N-acetylated cysteine
and cysteine conjugate. At a higher dose (30 mg/kg) a greater proportion
was excreted as thiocyanate and unidentified metabolite "C". Wright (1977)
100
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Table 28
Urinary Metabolites Following the Oral- Admin-
istration of C-l (Cyano) Labeled Acrylonitrile
(Wright, 1977)
Percent of Radioactivity in
Urinary Metabolites*
ANIMAL
Spartan Rat
Spartan Rat
Charles River
Rat
Rhesus Monkey
Rhesus Monkey
N
1
1
1
1
1
DOSAGE
(me/kg)
0.1
30.0
30.0
0.1
30.0
cysteine-
conjugates
88.6
37.3
47.5
91.
84.
"C"
(unidentified)
3.5
20.5
13.8
6.
14.
thio-
cyanate
8.0
42.1
38.8
3.
2.
*
0-20 hours in rats and 0-24 hours in monkey.
suggested that conjugation with cysteine is the "preferred metabolic ex-
cretory product", at dosages within the "normal metabolic capacity of the
animal" (i.e., 0.1 mg/kg); only small amounts of acrylonitrile will be
excreted in other forms. Wright further suggested that at higher doses
(here, 30 mg/kg) this "preferred metabolic pathway" is overloaded, so
other metabolic pathways are used.
As apparent in Table 28 there may be differences between the two
strains of rats tested. However, the small sample sizes caution against
a definite conclusion. These studies are continuing.
As evidence of an acrylonitrile-sulfhydryl reaction, depressed sulf-
hydryl levels resulting from acrylonitrile administration have been re-
ported (e.g. Dinu and Klein, 1976; Hashimoto and Kanai, 1972; Vainio and
101
-------
MMkinen, 1977; Szabo at al., 1977). Details of these studies are discussed
in Section III-B-3 of the Mammalian Toxicology section.
c. Coupling with D-Glucuronic Acid
Besides forming cyanide and thiocyanate or combining with sulfhydryl
groups acrylonitrile can combine with D-glucuronic acid (Hoffman et al.,
1976). Groups of 20 male Wistar rats were given 1/8, 1/4 or 1/2 the LD50
of acrylonitrile (82 mg/kg used as ID50) by gavage. Rats given the 2 higher
doses showed a significant increase in glucuronic acid excretion in the
urine within 24 hours; levels of glucuronic acid returned to normal after
24 hours. Hoffman et al. (1976) suggested that acrylonitrile is initially
hydrolyzed, after which the resulting product undergoes a condensation re-
action with UDP-glucuronic acid.
d. Minor Metabolites
Young et al. (1977) identified C02 as a metabolite of acrylonitrile
in rats. CO2 was excreted in the breath and comprised 5 to 6% of the
administered dose of acrylonitrile.
Dahm (1977) was unable to identify a metabolite of acrylonitrile
("metabolite C"), as it was unstable. He was unable to detect cyanide
ion and free acrylonitrile in significant quantities in the urine. How-
ever, Hashimoto and Kanai (1965) and Hoffman et al. (1976) estimated that
15% of the administered dose of acrylonitrile is passed unchanged through
the urine and breath.
Hashimoto and Kanai (1965) suggest acrylonitrile may be metabolized
to acrylamide or acrylic acid. However, Young et al. (1977) do not think
acrylamide is a possible metabolite.
102
-------
e. Route and Dose Dependence of Metabolite Formation
Young et al. (1977) isolated 5 metabolites of acrylonitrile in rats.
Except for carbon dioxide (excreted in the breath) these metabolites were
not identified. Presumably, thiocyanate and cyanoethylation products were
detected, but were not identified as such. Both a dose and route dependent
fate were emphasized for all metabolites.
Male Sprague-Dawley rats (Spartan substrain) were given doses of
l-^C-acrylonitrile by several routes. Samples of plasma, bile and urine
were analyzed for metabolites by high pressure liquid chromatography. Five
metabolites were resolved. Three of these (designated A, C, and E) com-
prised more than 95% of the total radioactivity and were excreted in the
urine. A fourth metabolite, C02 was excreted in the breath. Metabolite
A could not be distinguished from acrylonitrile by this method. Although
urinary metabolites were not positively identified, the authors did deter-
mine that aery1amide was not a metabolite, as suspected by Hashimoto and
Kanai (1965).
The proportion of the 3 metabolites in the urine was time dependent.
The urine from one rat exposed to an atmosphere containing 5 ppm ^C-AN
for 6 hours was analyzed for metabolites after 0-8 hours and 40-48 hours.
In the earlier sample the proportion of metabolites was: A, 18%; C, 70%;
E, 13%. After 40 to 48 hours, however, the levels were quite different:
A, 2%; C, 6%; E 92%.
The proportion of metabolites was also route and dose dependent
(Table 29). Zero to 72 hour urine samples showed highest amounts of
metabolite A (73%) after an oral dose of 0.1 mg/kg, but the maximum amount
of metabolite B (61%) occurred after administration of 10.0 mg/kg. When
103
-------
Table 29
Metabolites in Rats of ll*C-AN Separated by High
Pressure Liquid Chromatography
(Young et al., 1977)
|_
Percentage of Total ll*C
Samplea A C E
Urine. 0-72 hr.
0.1 mg/kg; po 12 73 15
10.0 mg/kg; po 61 8 32
5 ppm, 6 hr.; inhalation0 9 30 61
100 ppm, 6 hr.; inhalation 32 33 35
Bile, 1 hr.
1 mg/kg; iv 2 91 1
Stomach, 24 hr.
1 mg/kg; iv 43 93
RBC, 24 hr.
1 mg/kg; iv 7 10 83
Plasma, 24 hr.
1 mg/kg; iv 28 28 42
sample sizes are not clearly stated for urine sample but are likely 4 or fewer
per dose; for all other samples, data are from 1 rat
total less than 100 when minor metabolites B and D were present
Cequivalent dose 0.7 mg/kg
equivalent dose 10.2 mg/kg
104
-------
acrylonitrile was inhaled for 6 hours, a dose of 5 ppm resulted in 61% of
metabolite E, while a dose of 100 ppm resulted in equal proportions of
the 3 metabolites.
The metabolite pattern in the bile, stomach, red blood cells and
plasma after intravenous administration is also summarized in Table 29.
For the stomach RBC and plasma, E was the major metabolite at 24 hours
(93, 83 and 42%, respectively). In the bile, metabolite C comprised 91%
of the total radioactivity.
3. Toxicity
The effects of acrylonitrile administration to nonhuman mammals are
discussed for acute, subacute and chronic exposures.
a. Acute Toxicity
1) Inhalation Exposure
a) Lethal Doses
Mortality data for acrylonitrile exposure to mice, rats, guinea pigs,
rabbits, cats, dogs and monkeys are summarized in Tables 30, 31 and 32.
Dogs appear most sensitive. One fatality occurred after 2 dogs were ex-
posed to 140 mg/m3 AN for 4 hours (Dudley and Neal, 1942) although all 6
dogs died when exposed to 217 mg/m3 for 7 hours (Brieger et al., 1952).
Fatalities occurred after 4 hours of exposure to 1250, 560 and 1300
mg/m3 AN for guinea pigs, rabbits, and cats, respectively (Dudley and
Neal, 1942).
Four fatalities occurred among 5 Osborne-Mendel rats exposed to
680 mg/m3 for 4 hours (Dudley and Neal, 1942) but no deaths occurred in
6 Sherman rats exposed to 1085 mg/m3 for 4 hours (Smyth and Carpenter,
1948). Only 1 death occurred among 6 mice exposed to 900 mg/m3 for 1 hour;
105
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Table 30
o
o\
Inhalation Exposure to Aery Ion it rile
Concentration
converted units original units
Species/Strain
White Mouse/Stock3
Albino Rat/Sherman
Rat/Sherman
Ra t /Sp rague-Dawley
or stock
Rat/Wistar
Dog
Rhesus Monkey
NR = not reported
"1 f\ J *•* • • A l« >•« A •*-
mg/m3
5,800
1,500
600
1,700
900
900
1,085
1,085
2,170
54.25
108.5
162.8
217.0
108.5
162.8
217.0
162.8
c
• •••* 4T*
cone.
5.8 mg/1
1.5 mg/1
0.6 mg/1
1.7 mg/1
0.9 mg/1
0.9 mg/1
500 ppm
500 ppm
1,000 ppm
saturated
air
25 ppm
50 ppm
75 ppm
100 ppm
50 ppm
75 ppm
100 ppm
75 ppm
*t A *•• -1 r ^ m ^1 • mf\.-vt' <* 1 4 t"
Duration
(hr)
0.5
0.5
0.5
1
1
2
4
4
4
.05e
7
7
7
7
7
7
7
7
«r r_m-f I"V\*1 r% 1 /i *4 r»x
Mortality
5/6
5/6
0/6
6/6
1/6
3/6
2/6 or 3/6
or 4/6c
0/6
6/6
0/6
0/20
0/20
0/20
4/20
0/4
O/ 4
6/6
1/3
g
F*^» ol*rf-\t"t-
-------
Table 31
Inhalation Exposure of Acrylonitrile for 4 Hours
in Various Mammal Species (Dudley and Neal, 1942)
Concentration
(mg/m3)a
210
580
1,250
2,520
210
290
560
1,260
210
600
1,300
63
140
Mortality
During Exposure
0/16
0/8
2/8
1/8
0/3
0/2
1/2
1/2
0/4
0/2
0/2
0/3
0/2
Total
Guinea Pigs°
0/16
0/8
5/8
8/8
Rabbits0
0/3
0/2
2/2
2/2
Catsd
0/4
0/2
2/2
Dogs
0/3
1/2
Effects
slight to no effect
slight, transitory
eyes and nose irritated during
test; delayed deaths (3-6 da)
perhaps from lung edema
5 deaths 1.5 hr after test;
2 deaths after 18 hr
slight; transitory
marked ; transi tory
death in 4-5 hr
death in 3-4 hr
slight; transitory; salivation
marked; salivation; pain; no
effects in 24 hr
convulsions; deaths 1.5 hr after
test
slight salivation
survivor had severe salivation and
was weak at end of exposure and
died within 8 hr
213 0/3 0/3 2 had convulsions in 2.5 hr and coma
at end of test (1 recovered in 48
hr; other had hind leg paralysis
for 3 da); 1 had severe salivation
and recovered in 24 hr
240 0/3 2/3 coma at end of exposure; deaths in
3-4 da; survivor refused food for
10 da
107
-------
Table 31 (cont'd)
Inhalation Exposure of Acrylonitrile for 4 Hours
in Various Mammal Species (Dudley and Neal, 1942)
Rhesus Monkeysf
140 0/4 0/4 slight initial stimulation of respir-
ation
198 0/2 0/2 slight weakness during test; redness
of face, genitals, etc.; normal in
12 hr
aoriginal units mg/1, mg/m3 = mg/1 x 103
average wt 695 g; sex and age not reported
jalbino; average wt 4530 g; sex and age not reported
average wt 3620 g; sex and age not reported
^total 12 females, 1 male; average weight 8.1 kg (1 S.D.=2.6) ; age not reported
total 4 females, 2 males; average weight 4.4 kg (1 S.D.=0.24); age not reported
108
-------
Table
Inhalation Exposure of Ralu to Acrylonitrlle
(Dudley and Neal, 1942l))
Duration of
Exposure
(hr)
0.5
1.0
2.0
4.0
8.0
Concentration
(mg/m3)c
1,440
2,750
3,230
5,300
1,440
2,750
3,230
5,300
660
1,290
2,730
280
680
1,380
200
290
460
590
690
No. Dying out of
During Ex-
posure
0
0
0
0
0
0
0
0
0
0
0
0
4
8
0
0
1
7
15
16
Total
0
0
0
0
0
0
4
13
0
6
16
0
5
16
0
0
1
7
15
Effects
moderate transitory
marked; no effects In 24 hr
marked; no effects in 24 hr
marked; slight residual effects in
24 hr
marked; transitory
marked; normal in 48 hr
death in 4 hr; slight residual
effects a t 24 hr
Ibid
slight; transitory
marked; transitory
death in 4 hr
slight transitory
marked; no effects in -24 hr
death in 4 hr
slight discomfort
moderate; transitory
marked ; transl tory
marked; no effects in 24 hr
fatal
adult Osborne-Mendel strain; average weight 295 g; sex not reported
exposure was in an animal chamber with an input of air saturated with AN; a fan in the chamber mixed the
air; Mg AN/1 air was calculated from the amount of AN introduced and the total volume of air passing
through the chamber.
original units in rog/1.
-------
3 deaths occurred after 2 hours exposure at 900 mg/m3 (McOmie, 1949).
Jaeger et al. (1974) reported a 4 hour LC5Q of 275 ppm (597 mg/m3 for
fasted rats. This concentration was without apparent effect on fed rats.
Knobloch et al. (1971) reported LCso (4 hour) values of 300 mg/m3
for mice, 470 mg/m2 for rats and 990 mg/m3 for guinea pigs.
In most cases death did not occur during the 4-hour exposure period
but rather 1.5 to 18 hours thereafter. However, for longer exposures at
higher concentrations, some deaths did occur during the exposure period
(Tables 31 and 32; Dudley and Neal, 1942).
b) Signs
There are apparent dose and duration-related effects of acrylonitrile
exposure, as well as species differences. In general, signs displayed in
all species except guinea pigs given a lethal dose of acrylonitrile are:
initial stimulation of breathing, followed by shallow rapid breathing,
then slow gasping breathing; convulsions; coma, and death (Dudley and
Neal, 1942). Effects are summarized in Tables 31 and 32.
Additional signs in several species are discussed below:
Mice. Toxic signs of acrylonitrile inhalation were de-
scribed for Stock White mice exposed to 900-5800 mg AN/m3 for 0.5 to 1.5
hours. Initially, activity increased and hyperpnea developed. Cessation
of treatment at this point resulted in recovery without apparent after
effects. If treatment continued, shallow breathing ensued, followed by
gasping, apnea, and death. No gross changes were observed upon autopsy
(McOmie, 1949).
Rats. The effects of acrylonitrile exposure in rats at
several concentrations for up to 8 hours are summarized in Table 32. Con-
centrations of 5300 mg AN/m3 for 0.5 hours were tolerated without residual
110
-------
effects while.690 mg/m3 for 8 hours was fatal to all rats. Animals ex-
posed to concentrations above 650 mg/m3 showed mucus membrane irritation.
The skin, nose, ears, and feet became flushed or reddened in all rats at
all concentrations. This condition persisted for several hours after ex-
posure. At the highest exposures there was a nasal exudate and watering
of the eyes (Dudley and Neal, 1942).
Guinea Pigs. Guinea pigs tolerated up to 580 mg AN/m3
for 4 hours without lasting effects (Dudley and Neal, 1942). At higher
concentrations, the following signs were observed: watering of the eyes,
discharge of nasal exudate, and coughing. Absent was the marked respira-
tory impairment observed in other species. Dudley and Neal (1942) sug-
gested that acrylonitrile irritates the mucus and lung membranes in guinea
pigs. There were some delayed deaths from lung edema.
Rabbits. Rabbits exhibited skin redness upon exposure
to acrylonitrile but this was not as marked as in rats (Dudley and Neal,
1942).
Cats. Cats exposed to acrylonitrile showed skin redness,
especially of the mucosa, salivation and vomiting; rubbing of the head and
stomach was also observed (Dudley and Neal, 1942).
Dogs. Dogs exposed to 100 or 75 ppm (217 or 163 mg/m3)
for 7 hours vomited, and exhibited incoordination, convulsions and respir-
atory paralysis, although symptoms were milder at 163 mg/m3 (Brieger et al.,
1952). A slightly higher concentration (210 mg/m3) for 4 hours produced
convulsions as well as transitory paralysis in the hind quarters of one dog.
Effects in these animals lasted 3-10 days, perhaps as a result of tissue
anoxemia (Dudley and Neal, 1942).
Ill
-------
Rhesus Monkei/3- Two monkeys exposed for four hours to
198 mg/m3 exhibited a slight reddening of the face, genitals and oral mu-
cosa; there was some weakness and sleepiness (Dudley and Neal, 1942).
Monkeys exposed to 163 mg/m3 for 7 hours showed vomiting, respiratory dis-
tress, paralytic dilation of the pupil, cyanosis, then unconsciousness
(Brieger et al., 1952).
2) Dermal Exposure
a) Lethal Dose Values
Lethal doses range from 250 to 840 rag/kg when acrylonitrile is applied
directly to the skin of guinea pigs or rabbits (Table 33). Roudabush et al.
(1965) determined the LDso of acrylonitrile to guinea pigs with abraded
skin to be twice that of guinea pigs with intact skin.
Species /Strain
Guinea Pig/Hartley
derived
Guinea Pig
White Rabbit
Table 33
Acute Dermal LDso
Sex/No.
M/at least
12
NR/NR
M & F/at
least 12
For AN
LD50 (ml/kg)
0.46 intact skin
0.84 abraded skina
0.25b
0.28 abraded skin°
Reference
Roudabush et al. ,
1965
Smyth and Car-
penter, 1948
Roudabush et al. ,
1965
NR = not reported
Abdominal hair was removed in all animals by clipping and subsequently apply-
ing barium sulfide for a few minutes. In abraded skin tests, abrasions were
made every 2-3 cm to penetrate the stratum coraeum. AN applied on 1 sq inch
cellulose pad. LD50 calculated by method of Finney
Range finding; determined by poultices.
°Hair was removed by clipping. Procedure described in Federal Hazardous Sub-
stances Labeling Act (21 CFR 191) except that skin was abraded (as described
in footnote "a"). LDgo calculated by method of Finney.
112
-------
The dermal LD50 for AeryIon (AN and CCl^) was 1.592 ml/kg in rabbits
when applied directly on clipped skin and held in place with rubber sheet-
ing (Tullar, 1947).
Although LDso values were not calculated, Rogaczewska (1975) described
concentrations of acrylonitrile that were fatal to rabbits. Acrylonitrile
was not applied directly to the skin. Rather, intact rabbit skin (about
350 cm2) was exposed to acrylonitrile vapors in an exposure chamber, with
simultaneous isolation of the respiratory tract. Exposures of 620-440
mg/m3 for 2.5 to 4 hours were fatal to the 3 rabbits tested. However,
three rabbits exposed to 10-42 mg/m3 for 2.5 to 4 hours survived. By ex-
posing the respiratory tract while the skin was isolated, then comparing
the concentration necessary to produce the same signs, Rogaczewska (1975)
found that absorption rates through the skin and respiratory tract were
quite different. At about the same length of exposure, fatalities from
skin-only exposure occurred at about 100 times the acrylonitrile concen-
tration found to be lethal when only the respiratory tract was exposed.
b) Signs
Direct application of acrylonitrile to the skin of rabbits produced
edema and erythema at the application site (refer to the following sec-
tion). In some cases, however, there may be distant reactions besides
the local one.
Tullar (1947) placed a cuff of rubber sheeting around the body of
rabbits, making contact with clipped skin. Two to 3 cc's of acrylo-
nitrile (N = 2 rabbits) or 1-6 mi's of AeryIon (N = 15 rabbits) were pipet-
ted into the cuff. Immediate reactions included struggling or pronation,
113
-------
difficulty in breathing, mild lacrimation, salivation and nasal discharge.
Both acrylonitrile-treated rabbits died although the time to death was not
stated.
If rabbit skin (315-350 cm2) is exposed to acrylonitrile (440-620
mg/m^ for up to 4 hours) in the air, rather than by direct application,
slowing of the respiratory rate, convulsions and death occur (Rogaczewska,
1975).
c) Effects on the Skin
McOmie (1949) exposed the skin of three rabbits (sex not reported)
to acrylonitrile at 1.0, 2.0, or 3.0 ml/kg. Rabbits' abdomens were shaved
one day before treatment and acrylonitrile was applied directly; animals
were prevented from inhaling the compound. The following data were ob-
tained :
Area covered
ml/kg (cm2) Effect
1.0 100 slight local vasodilation; no
systemic effects
2.0 200 slight local erythema; no systemic
effects
3.0 200 slight local erythema; respiratory
rate increased
Latency to toxic effects was not reported.
Tullar (1947) observed erythema only after application to abraded
skin. Gauze pads containing 1.0 ml of acrylonitrile or AeryIon were applied
to abraded and unabraded skin in 6 rabbits; rubber sheeting placed over
the pads prevented evaporation. After 24 hours, mild erythema was observed
in one of the 3 abraded areas to which acrylonitrile had been applied and
114
-------
2 of 3 abraded areas to which Acrylon had been applied.
Zeller et al. (1969) determined the effect of acrylonitrile on the
skin of white rabbits. The fur on the back was shaved. Acrylonitrile was
applied to the skin on a cotton pad (2.5 x 2.5 cm) for 15 minutes or 20
hours. The reaction was graded from 0 (no effect) to 6 (necrosis). Over
eight days, the 15 minute test was graded "3" (edema) and the 20 hour test
was graded "6" (slight necrosis).
d) Effects on the Eye
McOmie (1949) instilled one drop of acrylonitrile (- 0.05 ml) into
the eye of a rabbit (sex not stated). There was immediate closure of the
eye and shaking of the head. After 1 hour there was mild conjunctivitis
without corneal clouding or pupillary damage, but after 24 hours no effects
were observed.
One drop of acrylonitrile (-50 mm3 or 0.05 ml) was placed on the eye
of rabbits by Zeller et al. (1969) and after 8 days, edema and slight
necrosis developed.
3) Oral Administration
a) Lethal Dose Values
The acute oral LDso for acrylonitrile ranges from 25-128 mg/kg for
laboratory mammals (Table 34). Mice appear most sensitive; LDso values
for several strains are between 25-48 mg/kg. Tullar (1947) reported male
mice to be slightly more sensitive than females (36 vs. 48 mg/kg). Guinea
pigs may be more tolerant than mice, as "LDso values range from 56-85 mg/kg.
Rats are least sensitive to oral doses, the LDso range being between 72-186
mg/kg.
115
-------
Table 34
Species/Strain
White Mouse/Stock
Mouse
Mouse
Mouse/H strain
Rat /Sherman
Rat/Wistar
Rat/Wistar or Stock
Rat/Wlstar-Stamm
Rat/Wlstar-Stamra
Rat
Rat
Rat/Wistar
Rat/Sprague-Dawley
Rat/Sprague-Dawley
Sex/ No
-M
M/ total M&F
F/r
-/169
_/_
-/groups of
-
-
M/-
v/-
-/80
-/51
—
M/20
F/20
Acute Oral LDsQ Values
Vehicle
—
333 water
water
olive oil
physiological
solution
6-10
-
-
-
-
water
olive oil
physiological
solution
1.0% aq. soln.
1.0% aq. soln.
for AN
LD50
(rag/kg)
20 < LD50 < 72
36a
48a
40a
27b
25c
93d
101e
128f
828
(C.L.: 71.9-93.5)
868
(C.L.: 73.4-90.7)
84 a
72a
78b
186h
(175-198)
186h
(175-198)
Reference
McOroie, 1949
Tullar, 1947
Tullar, 1947
Tullar, 1947
Uenes and Cerna, 1959
Smyth and Carpenter,
1948
Paulet and Vidal, 1975
Zeller et al., 1969
von K. Borchardt eL al.,
1970
von K. Borchardt et uL.,
1970
Tullar, 1947
Tullar, 1947
Benes and Cerna, 1959
Monsanto, 1975
Monsanto, 1975
-------
Table 34 (cont'd)
Acute Oral LD Values
Species/Strain
Rat
Guinea Pig
Guinea Pig
Guinea Pig
Sex/ No.
-/-
/29
M&F/30
M&F/30
Vehicle LD50
62
olive oil 85a
56. 941
56 1
Reference
Knobloch et al . ,
Tullar, 1947
Jedlicka et al. ,
Jedlicka et al . ,
1977
1957
1957
jj
ctased on "accumulated" percentage mortalities; animals dying at a lower dose presumed
H susceptible to higher doses; LDso computed graphically by plotting accumulated mortality
against dose.
technical grade (98% pure)
chemical grade
range finding
method of Miller and Tainter; observed for 1 week
observed for 7 days
gmethod of Litchfield and Wilcoxin
h
method of Weil; 95% C.L.
method of Behrens
•'method of Trevan
-------
Tullar determined LDso values for acrylon which is used as a fumi-
gant. Lethal dose values for mice, rats, and guinea pigs, calculated as
mg/kg of acrylonitrile, were within the ranges reported above: mouse,
40 mg/kg; rat, 78 mg/kg; guinea pig, 75 mg/kg.
Acrylonitrile and potassium cyanide were administered jointly and
the potentiation of acute toxicity was determined (Monsanto, 1975).
Observed LDso values of 3 mixtures of AN:KCN (1:1, 1:3, 3:1) were larger
than the "expected" values based on known LDso values of AN and KCN alone,
thus showing there was joint action. However, Smyth et al. (1969) found
fairly good agreement between predicted and observed LDso values when test-
ing the joint toxic action of acrylonitrile and each of 26 chemicals using
the formula of Finney (1952):
P P
1/predicted LDso =* a/LDso component A + b/LDso component B
[P and P, are the proportions of A and B in the mixture]
3i D
This formula is useful to assess the toxicity of a mixture of AN and another
substance when their joint action is unknown.
b) Signs
Signs of acrylonitrile intoxication vary less between route of admin-
istration than between species and dose.
Mice. Mice (strain H) given lethal oral doses of acrylo-
nitrile showed excitation within 5 to 10 minutes; movement became uncoordi-
nated and then drowsiness occurred. Paresis of the limbs, tachypnea, cyanosis,
and convulsions preceded death, which was due to asphyxiation and which
occurred 20 to 120 minutes after dosing (Benes and Cerna, 1959).
118
-------
Hats. Signs of acute acrylonitrile intoxication after
oral administration in Sprague-Dawley rats included reduced appetite and
activity, increasing weakness, tremors, collapse and death within 6 to
20 hours (Monsanto, 1975).
Benes and Cerna (1959) compared effects in mice and Wistar rats.
Whereas mice show signs similar to that in cyanide poisoning (i.e., cya-
nosis), rats do not exhibit such respiratory distress. Rats fatally dosed
with acrylonitrile show mild ruffling of the fur after 15 to 25 minutes,
defecation, mild drowsiness, redness of the mucus membranes, ears and
feet, vomiting and salivation. Convulsions appear within 3 to 4 hours
followed by death after 3 to 5 hours.
Guinea Pigs. Fifteen guinea pigs (400 g) given 50 to
100 mg AN/kg orally showed lacrymal and nasal secretions and coughing
within thirty minutes (Jedlicka et al., 1958). After sixty minutes there
developed rapid, shallow breathing (without coughing), which gradually
changed to abdominal breathing followed by tonicoclonic seizures and ab-
dominal spasms; most animals showed hind limb incoordination. A short
period of coma preceded death.
c) Tissue and Organ Changes
Guinea pigs (400 g) fatally dosed with 50 to 100 mg/kg showed
lung edema, dilation of the right ventricle, filling of the coronary blood
vessels, hepatic and splenic hyperemia, degeneration of the kidneys, harden-
ing of the lymphatics of the stomach and intestines, and inflamed intes-
tinal mucosa (Jedlicka et al., 1958). Similarly, Sprague-Dawley rats
fatally dosed with acrylonitrile showed hemorrhagic areas of lungs and
119
-------
liver, and acute gastrointestinal inflammation (Monsanto, 1975).
Single oral doses of 10, 15, or 20 mg acrylonitrile resulted in
adrenal hemorrhages in 10-40% of treated female ARS-Sprague-Dawley rats
(Szabo and Selye, 1971).
4) Parenteral Administration
a) Lethal Dose Values
LDsO values for percutaneous administration of AN to mice, rats, guinea
pigs and rabbits range from 15 to 130 mg/kg and average about 60 mg/kg
(Table 35). In general, mice are least tolerant and guinea pigs most tol-
erant to acrylonitrile. Most data are available for mice; there appear
to be slight differences between strains, sex, and route of administration.
Wistar rats are less tolerant of subcutaneous injection than intravenous
injection (Table 35; Knobloch et al., 1971).
b) Signs
Paulet et al. (1966) described symptoms of intoxication for rabbits
given a lethal dose of 120 mg/kg acrylonitrile intravenously, but empha-
sized that signs vary little between species.
Four phases were seen:
i. Immediate Excitatory Phase, lasting 3 to 10 minutes. The animal
is agitated, rubs the nose and cries.
ii. Quiet Phase, appearing after 15 to 60 minutes. The ar»tmal is
immobilized, appears somnolent, after which slight trembling appears in
the hind legs and later in the entire body (especially the head).
iii. Phase of Convulsive Epileptiform Crisis. Short bursts of tonic-
tetanic convulsions (30-90 seconds each) appear during this phase, accom-
120
-------
Table 35
Acute Parenteral LDso Values for AN
Species/Strain,
Sex
Route
Vehicle
(mg/kg)
Reference
White Mouse/NR
Mouse/ ICR, F
Mouse/NMRI or SPF
Mouse/NR, M.
Mouse/NR, F
White Mouse/NR
Mouse/H
Mouse/BN
Rat/Wistar
Rat/Wistar
Rat/Wistar
Albino Rat/NR, M.
Guinea Pig/NR
Guinea Pig/NR
Rabbit /NR
i.p.
i.p.
i.p.
i.p.
i.p.
s .c.
s.c.
s .c.
i.p.
i.p.
s.c.
s.c.
s .c.
i.v.
i.v.
NR
NR
NR
water
water
0.9% saline
NR
NR
NR
polyethylene
glycol
NR
NR
NR
water
NR
- 15a
46.99b
50C
40d
48d
50 at 2 hr
25 at 24 hr
35e
34*
100 f
65S
80f
95. 8h
1301
72dO
72
McOmie, 1949
Yoshikawa, 1968
Zeller et al . , 1969
Tullar, 1947
Tullar, 1947
Graham, 1965
Benes and Cerna, 1959
Knobloch et al., 1971
Knobloch et al., 1971
Paulet and Vidal,
1975
Knobloch et al., 1971
Magos, 1962
Ghiringhelli, 1954
Tullar, 1947
Paulet and Vidal,
1975
NR = not reported
abased on 2 stock mice
^adult female mice; based on method of van der Waerden
cobserved for 7 days
dtotal males and females: 325; based on "accumulated" percentage
mortalities, animals dying at a lower dose presumed susceptible to higher doses;
LD50 computed graphically by plotting accumulated m ortality against dose
etechnical grade AN (98% pure); confidence interval 32.1-38.1; calculated by
method of Litchfield and Wilcoxin
fmethod of Litchfield and Wilcoxin
Method of Miller and Tainter; observed for 1 week
^median lethal dose; determined by method of Dreichmann and LeBlanc
*3-6 mo. old guinea pigs; weight 460 g
311 guinea pigs.
121
-------
panied by loss of sphincter control. Each burst leaves the animal pros-
trate and exhausted, with gradual improvement between bursts.
iv. Paralytic or Terminal Phase. The hind limbs become immobile,
convulsive crises become more frequent and body temperature drops. Paral-
ysis progresses until death.
Paulet et al. (1966) stress that polypnea (increased respiratory
rate) does not occur; this condition is characteristic of cyanide poisoning.
Descriptions by other authors, although less detailed, essentially
agree with those of Paulet et al. (1966). For example, Ghiringhelli (1954)
observed the following effects within 4 to 6 hours in guinea pigs (3-6
months old; 460 g) lethally dosed with 130 mg AN/kg subcutaneously: agi-
tation, ruffling of the hair, tachypnea, tremors, diarrhea,'vomiting,
paresis, respiratory disturbances, cyanosis, and eventual death. In anes-
thetized dogs given intravenous injections of 1 to 100 mg AN/kg Graham
(1965) observed: jactitation, convulsion, vomiting, defecation, irregular
breathing, and sometimes apnea. Injection of 200 mg/kg resulted in con-
tinuing apnea and cardiac failure.
Symptoms of trembling and convulsions after acrylonitrile injection
indicate central nervous system damage to areas of the midbrain (Paulet
et al, 1966).
c) Effect on the Adrenals
Single doses of acrylonitrile (i.p. or p.o.) to female ARS/Sprague-
Dawley rats (100 g) produced rapid bilateral adrenal apoplexy and necrosis
(Szabo and Selye, 1971; Szabo et al., 1976).
122
-------
Peroral doses of 10, 15 or 20 mg AN resulted in adrenal hemorrhages in
1, 2, and 4 rats, respectively, per group of 10 rats while 15 mg AN i.v.
resulted in all 10 rats showing adrenal hemorrhages. Although the in-
cidence was higher after i.v. injection, mortality rates for administra-
tion of 15 mg p.o and i.v. were not different.
Both groups (p.o. & i.v.) showed extensive hemorrhage in the adrenal
cortex and, sometimes, the medulla and necrosis in the inner cortical
zones; lesions were more pronounced on the right side.
Twenty mg of injected (i.v.) AN caused bilateral apoplexy to develop
after 1-2 hours. Within 30 minutes, discontinuities developed in the
endothelial lining of the adrenocortical capillaries. Later, extravasion
of erythrocytes with loss of plasma fluid was observed, which eventually
became massive. Parenchyma! cells in the zona fasciculata appeared com-
pressed and/or contracted.
A decrease in the number of blood platelets also occurred. Outward
signs were cyanosis, excitement, tremor, and convulsions. With i.v. in-
jection, head, neck, and often pulmonary edema were also observed.
To further describe adrenal apoplexy, Handin and Szabo (1977, meet-
ing abstract) administered AN i.v. to 200 g female Charles River rats at
15 mg/100 g in 0.5 ml water; controls received water only. After 30
minutes blood samples revealed a significant increase in plasma fibrinogen.
After 60 minutes there were the following statistically significant changes:
thrombocytopenia, prolonged prothrombin time, partial thromboplastin time
and thrombin time. Deposition of fibrin, which often obstructed blood
vessels, was observed in the cortical sinusoids, adrenal medullary veins
123
-------
and, less frequently vessels of the lung. Handin and Szabo (1977) suggest
these changes in blood coagulability and fibrin deposition might have a
role in acrylonitrile induced adrenal apoplexy.
d) Effect on Sulfhydryls
Wisniewska-Knypl et al. (1970) suggested involvement of sulfhydryl groups
to explain the mechanism of acrylonitrile toxicity upon the adrenal gland.
Rats were injected subcutaneously with 100 or 200 mg/kg 3.5 or 1.5 hours,
respectively, before killing. Respiration of tissue slices and activity
of SH-enzymes were determined by standard methods.
At 200 mg/kg (but not 100 mg/kg) there was a significant decrease of
oxygen uptake (after 30, 60, 90 and 120 minutes) in kidney cortex slices
compared to controls. Doses of 100 or 200 mg/kg significantly reduced
the activity of oxoglutarate dehydrogenase (but not succinate oxidase)
in the liver and kidney and also reduced the level of sulfhydryl groups
in the liver; sulfhydryl concentration in the kidney was reduced only
at the higher dose. The authors attribute aerylonitrile's toxicity to
inactivation of the sulfhydryt dependent enzymes. As discussed in the
Biotransformation Section (III-B-2) acrylonitrile has been shown to
combine with sulfhydryl groups.
Dinu and Klein (1976) observed decreased sulfhydryl concentrations
in rats poisoned with acrylonitrile. Male rats (90-120 g) injected with
twice the LDso (dose not specified) showed increased catalase activity in
the liver, but not the kidney, compared to controls. In both the kidney
and liver, lactic acid concentrations increased and nonprotein sulfhydryl
decreased (Table 36). The authors suggest these biochemical changes may
124
-------
result in an accumulation of peroxide, which results in tissue damage.
Table 36
Catalase, Sulfhydryl and Lactic Acid Levels
in Rats Intoxicated with Acrylonitrile (Dinu
and Klein, 1976)
Control
Catalase : liver
kidney
SHb: liver
kidney
Lactic Acid0: liver
kidney
3.76 ±
2.49 ±
421 ±
250 ±
9.62 ±
7.35 ±
0.18
0.18
16.8
9.63
0.43
0.64
Experimental
4.56 ± 0.09
2.48 ± 0.19
24 ±1
24.6 ± 0.6
14.70 ± 0.94
26.60 ± 1.60
P
< 0.01
> 0.1
< 0.01
< 0.01
< 0.01
< 0.01
a
umoles &2Q2 decomposed/15 seconds/ g tissue
Nonprotein sulfhydryl; umoles SH/100 g wet tissue
Cmg/100 g tissue
Vainio and Makinen (1977) investigated acrylonitrile-induced depression of
hepatic nonprotein sulfhydryl content. Rats, mice, guinea pigs and hamsters were
treated intraperitoneally with 0, 20, 40, 60, or 80 mg/kg acrylonitrile
(in 0.9% NaCl) , then decapitated at varying time intervals. The nonprotein
sulfhydryl groups were determined.
As shown in Table 37, acrylonitrile decreased the nonprotein sulfhydryl
content at all concentrations in a dose related manner compared to controls.
A dose of 80 mg/kg to hamsters, guinea pigs and rats resulted in 86.5%,
82.9% and 83.6% sulfhydryl depletion, respectively, after 1 hour compared to
controls. In mice, 60 mg/kg (80 mg/kg not tested) resulted in 80.8% de-
125
-------
Table 37
Effect of Acrylonitrile (administered i.p.) on the
Hepatic Nbnprotein Sulfhydryl Content of Various
Species (Vainio and Makinen, 1977)
Dose
(mg/kg)
0 (saline)
20
40
60
80
Non-protein
Hamster^
7.4
5.1
3.0
1.4
1.0
Sulfhydryl Content
Guinea Piga»c
7.0
5.6
2.0
1.2
1.2
(umol/g liver w.
Rate'c
6.7
4.0
2.8
1.8
1.1
wt.)a
Mouse *
9.9
7.1
3.8
1.9
NR
NR = not reported
a
the number of animals used per dose ranged between 2-4
adult female Syrian golden hamsters; weight not reported
filled 1 hour after AN administration
adult males; 400-550 g
eadult male Sprague-Dawley rats; 160-300 g
adult male GP-20 mice; 22-30 g; killed 0.5 hour after AN
adminis tration
126
-------
pletion after 0.5 hours. Administration of 30 mg/kg in mice resulted in
depletion within 15 minutes but this level rose after 2 hours.
Szabo et al. (1977) demonstrated lowered nonprotein sulfhydryl levels
(expressed as reduced glutathione) in other tissues besides the liver.
They showed 80 to 90% decreases in liver, lung and kidney glutathione
within 5 minutes of acrylonitrile administration (15 mg/100 g i.v.) in
female Sprague—Dawley rats. However, no specific tissue damage was de-
tected. Cerebral and adrenal glutathione decreased more gradually and
reached lowest levels after 60 and 15 minutes, respectively. Szabo et al.
(1977) suggest acrylonitrile or its reactive (probably epoxy) derivative
interacts with reduced glutathione.
Hashimoto and Kanai (1972) suggested the pyruvate oxidation system
might be sensitive to acrylonitrile, possibly due to its reactivity with
sulfhydryls. Male guinea pigs (400 ± 30 g) were used for in vitro exper-
iments. Acrylonitrile (at a final concentration of 2 x 10~3 M or 2 x 10" 2 M)
was added to diluted blood and homogenized liver and brain tissue in vitro;
sulfhydryl content was determined after 30 minutes. For in vivo experi-
ments male guinea pigs and rabbits (2500 ± 250 g) were given 100 mg/kg,
i.p., and 30 mg/kg, i.v., respectively, of a 5% solution of acrylonitrile
in 0.9% saline solution. Sulfhydryl content was determined in both species.
In addition, pyruvic and lactic acids were determined in guinea pigs.
In vitro, acrylouitrile resulted in a decrease of total sulfhydryl,
especially nonprotein sulfhydryls. In blood, liver, and cerebral tissue,
total sulfhydryl was only 83 to 47% of control values and nonprotein sulf-
hydryl was 75 to 7% of controls. Decreases were most marked in liver and
cerebral tissue (Table 38).
127
-------
Table 38
Effect of Aerylonitrlie on Tissue Sulfhydryl
(Hashimoto a,nd Kanai, 1972)a
Treated as % of Controls
Nonprotein SH
Blood
Liver
Cerebrum: gray
white
Protein SHC
Blood
Liver
Cerebrum: gray
white
Guinea Pigs
83
13*
51*
49
53*
34*
45*
53*
Rabbits
70
18*
65*
53*
81
104
57*
61*
*significantly less than control at p < .05 using raw data for
control vs treated animals
aSH measured 1 hour after 100 mg/kg administered to guinea pigs
and 30 mg/kg to rabbits
number of animals per determination:
guinea pigs: 8 treated, 5 control
rabbits: 3-4 treated, 3-6 control
guinea pigs: 6 treated, 5 control
rabbits: 3-4 treated, 3-6 control
128
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In vivo, guinea pigs and rabbits showed significantly decreased non-
protein sulfhydryl in the liver and brain. Protein sulfhydryl was signifi-
cantly decreased in the brain of rabbits and all tissues in guinea pigs
(Table 38).
Seven determinations of sulfhydryl in blood were made over 270 minutes
after AN administration in rabbits. Protein sulfhydryls in red cells ini-
tially decreased (lowest value occurred after about 20 minutes) but re-
covered within 1 hour. Nonprotein sulfhydryl, however, decreased more
slowly (lowest value reached after 60 minutes) and recovered more slowly.
Tissue pyruvate and lactate were measured in guinea pigs 30 (3 animals)
and 60 (6 animals) minutes after administration of 100 mg/kg acrylonitrile,
and 60 minutes (5 animals) after giving a combination of acrylonitrile
(100 mg/kg) and sodium thiosulfate (450 mg/kg). After 60 minutes, in guinea
pigs receiving either treatment, significant increases were observed for
pyruvate and lactate levels in the liver, blood and brain. Elevations in
brain pyruvate were particularly marked.
Hash-imp to and Kanai (1972) suggest that the excess level of pyruvate
in the brain might have caused cerebral dysfunction. Since sodium thio-
sulfate did not prevent accumulation of pyruvate or lactate, they suggested
the pyruvate oxidation system might be sensitive to acrylonitrile, pos-
sibly due to its reactivity with sulfhydryls.
e) Effect on the Circulatory System
Graczyk (1973) examined the effect of acrylonitrile administration
(13, 27, 55 or 110 mg/kg i.v.) on the respiration and blood pressure of
anesthetized rabbits given adrenaline, noradrenaline or acetylchollne.
129
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Appropriate circulatory responses to these substances, although somewhat
weakened, were maintained during acrylonitrile intoxication. It is unlikely,
therefore, that the circulatory system is a major target system in acrylo-
nitrile poisoning.
b. Subacute Toxicity
1) Inhalation Exposure
a) Signs
The effect of inhaling acrylonitrile vapors for 8 weeks (4 hours/day,
5 days/week has been described for several species by Dudley et al. (1942).
A weighed amount of acrylonitrile was vaporized and introduced into an air
current of known minute volume which was blown into a closed chamber. Gen-
eralized effects included weight loss, eye and nose irritation, or weak-
ness. Signs varied among species, dose, and duration as described below.
In another subacute experiment, Brewer (1976) prepared a report for
Industrial Bio-Test Laboratories, Inc., on a 90 day acrylonitrile vapor
inhalation study in CD-I mice, albino rats (Charles River) and Beagle dogs.
Exposure, in 4.5 m3 capacity chambers, was limited to 6 hours/day, 5 days/
week for 13 weeks (total of 57 exposures) at about 0, 30, 60 or 120 ppm.
Acrylonitrile vapor was mixed with clean dry air introduced into the chamber.
Treated mice, rats, and dogs exhibited: ataxia, grooming, ptosis, emacia-
tion, nausea, rhinitis and diuresis. Most animals experienced clonic con-
vulsions prior to death. Mortality rates, which appear in Table 39, appear
unusually high for control mice and rats.
Specific signs and growth effects in different species are described
below:
130
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Table 39
Species
Mice
Rats
Dogs
Mortality in Animals Exposed to
over 90 Days (57 6-hr exposures)
Exposure
(ppm)
0
- 24
- 54
-108
0
- 24
- 54
-108
0
- 24
- 54
Acrylonitrile
(Brewer, 1976)
Mortality
Males
10/15
8/15
8/15
14/15
2/20
4/20
3/20
12/20
0/6
0/6
1/6
Females
4/15
12/15
6/15
13/15
4/20
1/20
2/20
6/20
0/6
0/6
2/6
Rats. Charles River albino rats and CD-I mice exposed to
30, 60 or 120 ppm (65, 130, or 260 mg/nr )for 13 weeks (6 hr/day, 5 days/wk)
showed no statistical growth rate impairment compared to controls (Brewer,
1976). However, weight data were analyzed only for those animals surviving
the entire test period (Table 40), obviously masking possible weight re-
ductions in animals who died.
Sixteen rats exposed to 220 mg/m3 for 8 weeks (4 hr/day 5 days/wk)
showed only slight lethargy during exposure (Dudley et al., 1942). Three
females give birth and raised normal litters. However, 16 rats (8 adults,
8 young animals; sex and weight not reported) exposed to 330 mg/m3 in the
same manner showed weight loss and poor physical health. All 8 young rats
131
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showed growth impairment (no data are presented) and nasal and eye irri-
tation; 5 had died by the sixth week of exposure (Dudley et al., 1942).
Guinea. Pigs. Sixteen guinea pigs exposed to 220 mg/m3
for 8 weeks (4 hr/day, 5 days/wk) showed slight lethargy during exposure
but otherwise exhibited no toxic effects and even gained weight. Sixteen
guinea pigs exposed similarly to 330 mg/m3 initially showed eye and nose
irritation, and salivation; 3 died during the fifth week (Dudley, et al.,
1942).
Rabbits. Three rabbits exposed to acrylonitrile at
220 mg/m3 for 8 weeks (4 hours/day, 5 days/week) were listless during ex-
posure and failed to gain weight. When 4 rabbits were exposed to 330 mg/m3
in the same way there was moderate irritation of the eyes and nose; one
died during the fifth week (Dudley et al., 1942).
Cats. Four cats exposed for 8 weeks (4 hours/day, 5
days/week) to 220 mg/m3 acrylonitrile suffered from vomiting, listlessness,
and weight loss. One cat developed transitory hind leg weakness after the
third exposure and died during the third week. Four cats exposed to 330
mg/kg (in the same way) were in severe distress; all developed transitory
hind leg weakness and irritation of the nose and eyes (Dudley et al., 1942)
•Dogs. Two dogs (breed, sex, age, and weight not speci-
fied) were to be exposed for 4 hours/day, 5 days/week for a 4 week period
to 120 mg/m3 acrylonitrile. One dog died four hours after the first ex-
posure; death was preceded by convulsions. The second dog became weak
after the 5th, 13th, and 14th exposures but otherwise tolerated all others
(Dudley et al., 1942).
132
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Beagles surviving acrylonitrile exposure (30, 60 or 120 ppm) for 13
weeks showed no growth impairment compared to controls (Brewer, 1976).
Monkeys. Four rhesus monkeys (age, sex and weight not
reported) showed no toxic effects when exposed to 120 mg/m3 of acrylo-
nitrile in a closed chamber for 4 hours/day, 5 days/week for 4 weeks. Two
rhesus monkeys exposed to 330 mg/m3for 4 hours/day, 5 days/week over 8
weeks exhibited sleepiness and weakness, appetite loss, salivation, and
vomiting. One monkey died after 6 weeks of exposure; the second monkey
was in collapse after each exposure during the last 2 weeks (Dudley et al.,
1942).
b) Hematological Effects
With respect to total leukocyte count, differential leukocyte count,
erythrocyte count, hemoglobin concentration, hematocrit or erythrocyte
indices, there were no alterations in dogs or rats (data from 3-10 animals/
dose/sex) exposed to 0, 30, 60 or 120 ppm AN for 13 weeks (Brewer, 1976).
Treated rats had elevated blood thiocyanate levels and elevated non-
protein free sulfhydryl content. These parameters were unaffected in
dogs. Urinalyses were normal for treated rats and dogs.
Weekly red blood counts, white blood counts and hemoglobin levels
were within normal ranges while eosinophile counts were increased in 4 rats
and 4 rabbits exposed to 330 mg/m3 of acrylonitrile for 8 weeks (4 hours/
day, 5 days/week) (Dudley et al., 1942).
Ming*^ et al. (1973) exposed 8 male rabbits to 20 ppm (54 mg/m3)
acrylonitrile for 1 day (8 hours) a week for 8 weeks. Before and after
each exposure, 3 ml of blood from the auricular vein were analyzed for:
133
-------
p02, pC02, pH, cyanide and thiocyanate ions, hemoglobin, and hematocrit
(Table. 40). When values for all 8 exposures are summed, pC>2, pH and thio-
cyanate ions were significantly increased while PC02 was significantly
decreased compared to pre-exposure levels.
c) Pathology
Organ weights of mice, rats and dogs exposed for 13 weeks (5 hours/
day, 5 days/week) to a maximum of 120 ppm were within normal units
(Brewer, 1976). Organ weights of liver, kidney, spleen, pituitary gland,
lungs, gonads, thyroid gland, adrenal gland, heart and brain were deter-
mined.
Examination of tissue in treated dogs revealed treatment-associated
changes in the lung. These alterations consisted of focal aggregates
of alveolar macrophages in alveolar lumina, indicative of the irritative
effect of acrylonitrile.
Dudley examined tissue in animals exposed to 220 or 330 mg AN/1 for 8
weeks (4 hours/day, 5 days/week). A total of 680 sections were made (18 rats,
6 rabbits, 6 cats, 16 guinea pigs, 1 monkey) and these changes were observed:
Spleen slight hemosiderosis in rats (indicates blood destruction)
and negligible hemosiderosis in cats, guinea pigs, rabbits.
Kidney renal irritation
hyaline casts in straight collecting tubules of most
individuals
subacute interstitial nephritis (but not extensive), es-
pecially in guinea pigs and rabbits
Liver damage in cats only
134
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Table 40
Hematological Values (venous blood) in Rabbits
Before and After Exposure to 20 ppm Acrylonitrila*
(Minarai at al., 1973)
Before
p02
pC02
PH
Cyanide ions
70.6 i
35.2 ±
7.397 t
0.165 ±
7.35
1.42
.0180
.060
After
80.56
31.15
7.437
0.1825
± 4.75
± 2.96
± .0193
± .034
P.05
P <
P <
P <
n.s .
(15
.01
.01
.001
(yg/ml)
Thiocyanate ions 1.937 ± .120 2.919 ± .403 p < .001
(ug/ral)
Hemoglobin (g/dl)
Hematocrit (%)
12.59 ± 0.36
42.14 ± 1.61
12.33 ± .50
40.91 ± 1.85
n.s.
n.s .
Q
exposure for 8 hr/day/week for 8 weeks;
each value represents average (± S.D.) of 8 exposures
[calculated by LMM]
135
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aubacute bronchopneumonia: congestion and edema of al-
veolar walla, extravasion of red cells and serum into
alveoli, focal collection lymphocytes and polymorpho-
nuclear leukocytes in most guinea pigs, cabbies, the
monkey and 1/3 of the rata.
2) Oral Administration
a) No Effect Level
Ingeation of various doses of acrylonitrile was without effect in
adult albino rats (Porton strain; sex and weight not reported). Over a
period of 7 weeks, 6 rats were given 15 successive daily doses of 30 rag/kg,
and then 7 doses of SO mg/kg, followed by 13 doses of 75 rag/kg. Gait,
stance (both as a measure of nervous system and muscle toxlcity), and
weekly weights were unaffected (Barnes, 1970).
Incorporation of 85 ppm or less of acrylonitrile into the drinking
water for 90 days had no effect on male or female Sprague-Dawley rata
(Humlston et al., 1975; sponsored by the Manufacturing Chemists Associa-
tion). Details of the parameters measured appear in the subsections that
follow.
b) Effect on Weight Gain
Fifteen male and 15 female Spragua-Dawley Spartan substrain SPF-
derived rats (6-7 weeks old) each received 0, 35, 85, 210 or 500 ppm AN
In the drinking water (equivalent to 0, 4, 10, 25 or 60 mg/kg) (Humiaton
et al., 1975). The dosage of acrylonitrile (3Z ± S.D.) calculated from
actual water consumption waa 0, 4 ± 1, 8 ± 2, 17 ±3 or 38 ±8 mg/kg for
males and 5 ± 1, 10 t 1, 22 ± 2 or 42 t 4 mg/kg for females.
136
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Appearance and demeanor were unchanged. Males at 500 ppm showed
significantly depressed body weight gains throughout the 90 days, while
females at 210 and 500 ppm showed significant weight gain depression only
after day 57. All other rats exhibited normal growth.
Mean weekly food consumption by males receiving 210 or 500 ppm was
significantly decreased for a total of 2 and 7 week*, respectively, out
of 9 weeks for which data were presented (weeks 10, 11, and 12 were dur-
ing the mating period). Female rats receiving 210 or 500 ppm showed de-
creased consumption for 6 and 1 weeks, respectively, out of 13 weeks.
Water consumption was significantly decreased for males and females
receiving 85, 210 or 500 ppm AN. Rats often will refuse to drink adverse
water, which will cause a decrease in food consumption. Weight gain, there-
fore, is not always a good measure of the toxic effects of chemicals ad-r
ministered in the drinking water.
c) Effect on Clinical Parameters
As part of a 90 day study incorporating acrylonitrila in the drink-
ing water of rats, Humiston et al. (1975) evaluated blood, urine and
serum.
Hematological evaluations of 5 rats/sex receiving acrylonitrile
at 0 or 500 ppm for 83 days were performed for packed cell volume, red
blood cell count, hemoglobin concentration, white blood cell count and
differential leucocyte count. Values for males were within normal limits.
Females had a statistically significant decrease in red blood cell count
but were otherwise normal.
Although urine pH, sugar, proteins, occult blood and bilirubin were
normal in rats receiving 500 ppm AN in the drinking water, urine specific
gravity was increased significantly the last week of the study. On day
90 males receiving 210 ppm and females receiving 85 ppm also had a higher
-------
specific gravity, che Increase being attributed to decreased water con-
sumption (Humiston «c al., 1975).
With respect to blood urea nitrogen and alkaline phosphatase levels
in 10 mala rats receiving 500 ppm AN, there were significantly higher
valuea than controls but serum glutamic pyruvic transaminase activity
was normal. Hematological chemistry values for all other rats were normal.
d) Effect on Organ Weights
Significant changes in absolute and relative organ weights were seen
among some rats receiving acrylonitrile in the drinking water for 90 days:
35 ppm no changes
83 ppm females: lower absolute brain weight and higher relative
liver weight (however, this increase was accounted for
by one rat with an unusually large liver).
210 ppm females: lower absolute brain weight and higher relative
liver weight; males: higher relative liver weight.
500 ppm females: higher relative liver weight; males: higher
relative liver and kidney weights.
e) Pathology
Gross examination revealed no pathologic alterations related to
acrylonitrile ingestion (in the drinking water) for 90 days (Humiston
et al., 1975). One male rat (receiving 210 ppm) had a small subcutaneous
tumor in the abdominal area possibly of mammary gland origin. The authors
consider the tumor to be of spontaneous occurrence.
Microscopic tissue examination revealed one male rat (at 500 ppm AN)
with a microfocus of intraeplthelial necrosis and edema in the non-
i
glandular portion of the stomach, considered to be of spontaneous origin
(Humiston et al., 1975).
138
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f) Effect on the Adrenals
Szabo et al. (1976) reported that for rats, acrylonitrile at 0.05 or
0.2% in the drinking water (500 or 2000 ppm) for 21 to 60 days affects
the mineral corticoid and glucocorticoid producing cells of the adrenal
cortex. Female Sprague-Dawley rats (200 g; number not specified) were
sacrificed 7. 21 or 60 days into the treatment. Rats on both levels of
acrylonitrile had reduced water intake (3/4 of control) and urine output
(1/3 of control); body weights were slightly reduced during the first
week and growth was only mildly retarded thereafter.
After 21 or 60 days, the adrenals of treated rats showed an atrophic
zona fasciculata but an increased zona glomerulosa. After 21 days at the
higher acrylonitrile dose, plasma Na1" (but not plasma Kj was significantly
increased by 9 mEq/liter. These rats had a reduced plasma cortico-
sterone concentration (24 ug lower than controls).
g) Effect on Glutathione
Female Charles River (Sprague-Dawley derived) rats were given 20, 100,
or 500 ppm acrylonitrile in the drinking water or by gavage (.002, .01,
or .05% AN, respectively) for 21 days (Szabo et al., 1977). These doses
were shown previously to cause adrenocortical hypofunction (refer to pre-
ceding section). Dose dependent increases in liver glutathione levels
were observed and were more marked when the dose was administered by gavage
(Table 41). Increased glutathione had been described previously for chem-
ical carcinogens. The authors maintained "it remains to be seen whether
these changes correlate" with lesions reported for brain and stomach tissue
in rats fed acrylonitrile or with the higher mortality levels among factory
workers exposed to acrylonitrile.
139
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Table 41
Effect of AN Administration (21 days) on Hepatic
Glutathione in Rats by 2 Routes of Administration
(Szabo et al., 1977)
Glutathione
(yg/g liver)
Control 1431.14 ± 24.08
Acrylonitrile
0.002%
-drinking water 1506.00 ± 85.29
-bolus 1535.84 ± 14.44*
Acrylonitrile
0.01%
-drinking water 1492.01 ± 75.59
-bolus 1621.45 ± 26.14**
Acrylonitrile
0.05%
-drinking water 1666.00 ± 68.16**
-bolus 1782.02 ± 84.29**
Mean ± standard error of mean. Student's t-test.
* =* p < 0.05; ** = p < 0.005, as compared to control
The increased hepatic glutathione reported was in direct contrast
to decreased hepatic glutathione levels in acute experiments (Szabo et al.,
1977; see section on Acute Percutaneous Administration).
140
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h) Effects on Reproduction
Murray et al. (1976) reported adverse maternal and fetal effects after
pregnant rats were fed 25 or 65 mg AN/kg/day during gestation. Schuefler
(1976) found AN to be embryotoxic to pregnant mice. Details of these
studies are reported elsewhere (Section IV-C).
3) Percutaneous Administration
The effects of subacute administration by injection have been de-
scribed for central nervous system and organ changes.
a) Effect on the Nervous System
The effect of acrylonitrile on Y-maze performance in rats was carried
out by Krysiak and Knobloch (1971) as a measure of central nervous system
function. Prior to acrylonitrile administration rats were trained for
performance in the maze. Rats given daily i.p. doses of 20 mg AN/kg over
6 weeks or daily s.c. doses of 40 mg AN/kg over 4 weeks showed a signifi-
cant lengthening of time to perform correctly in the maze and a decrease
in the number of correct reactions compared to pre-treatment observations
or controls. Performance improved after treatment was discontinued.
b) Effects on Organs
Daily i.p. administration of 50 mg AN/kg over 3 weeks in adult Wistar
rats caused statistically significant body weight loss, leukocytosis, and
a significant increase in serum asparagine aminotransferase (Knobloch et
al., 1971). The absolute weights of the heart and liver (but not the
brain, lungs, kidneys or spleen) were increased significantly. The rela-
tive weights (organ weight per 100 g body weight) were significantly in-
creased for the heart, liver, kidneys, and spleen. Examination of tissues
141
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revealed slight damage to neuronal cells of the cortex and brain stem;
the liver and kidneys showed parenchymal degeneration.
Daily s.c. administration of 5 mg/kg acrylonitrile to rats for 10
days resulted in decreased total protein content of the liver for 40
days and of the blood for 70 days (Solovei, 1974). The author suggests
acrylonitrile administration may result in decreased liver protein syn-
thesis .
c. Chronic Toxicity
Long-term- studies have been conducted for two routes of administra-
tion: inhalation exposure in rats and rabbits and oral administration in
rats and dogs. Maltoni et al. (1977) have recently completed a 2 year
carcinogenicity bioassay on rats exposed to AN by gavage and inhalation;
these studies are discussed in section IV-D.
1) Inhalation Exposure
A two year inhalation study, sponsored by the Manufacturing Chemists
Association, was recently completed (Jan. 18, 1978). Male and female rats
were exposed to 0, 20, or 80 ppm of acrylonitrile (6 hours/day, 5 days/week).
Microscopic tissue examination has not been completed. Based on a gross
pathologic examination of rats exposed to 80 ppm, there was an increase in
the incidence of ear canal tumors in males and females, of the gastro-
intestinal tract in males and of the mammary region in females. Female rats
exposed to the lower level (20 ppm) showed an increase of subcutaneous
mammary region tumors. Preliminary microscopic examinations revealed an
increase of brain tumors at both exposure levels (Clark, 1978). No other
details are available at this time.
Knobloch et al. (1972) exposed male and female Wistar rats and albino
rabbits to acrylouitrile vapors at concentrations of 0, 250 or 500 mg/m3
142
-------
over 6 months. Exposure was for 3 hours/day, 6 days/week for 6 months.
Throughout the period, body weight gain was significantly reduced for 4
out of 11 weeks in rats subjected to 500 mg/m^ AN. Rats at the lower con-
centration showed normal weight gain.
The number of eosinophiles was significantly reduced in treated rats
after 4 months of the experiment (Table 42). Total blood protein was un-
changed. However, albumin, a-globulin and y-globulin were significantly
increased (Table 42). Kidney dysfunction in rats was suggested by these
changes: increased diuresis at both concentrations, increased urinary
protein at the higher concentration, and areas of degenerated proximal
convoluted tubules at the higher concentration.
Cardiovascular damage in treated rabbits was indicated by statisti-
cally significant decreased blood pressure compared to controls at the
termination of the experiment. In rabbits exposed to the higher concen-
tration, there was a significant increase in the weight of the heart.
Inflammation of the pulmonary system accompanied by an inflammatory
exudate in the bronchial lumen occurred in rats exposed to 250 mg/m -
2) Oral Administration
Several studies have been conducted on the effects of long-term feeding
of acrylonitrile; three of these are unpublished. In one, Tullar (1947)
administered acrylonitrile to male rats for two years. Growth retardation
was observed, along with possible tumorigenicity. The FDA (Kennedy, 1977),
however, described the study as "inadequate by contemporary standards"
because of the small sample size, the use of male animals only, and the
"failure to use a full range- of toxicological criteria". For completeness,
143
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Table 42
Changes in Wistar Rats After Exposure to Acrylonitrile
(0, 50 or 250 mg/m3) for 3 Hours/Day, 6 Days/Week for
6 Mbnths-a( Knob loch et al., 1972)
Control
50 mg/m3
250 mg/m3
Eosinophiles (n):
mo. 0
mo. 5
Total blood protein (g%)
mo. 2
Albumin (g%)
mo. 2
Globulin (g%)
mo. 2
90
400
6.28
2.98
100
1010*
6.45
3.32*
120
700*
6.13
3.25*
Ct i
do
s
Y
Diuresis (ml/ urine/ 24 hr)
mo. 2
Urinary protein (mg/24 hr)
mo. 2
Body wt. (g increase)
wk 10
wk 20
0.64
0.61
1.36
0.64
6.9
17.16
120
160
0.91*
0.63
1.17
0.42*
10.1*
17.16
125
175*
0.81*
0.5.3
1.16
0.38*
15.0*
21.87*
85
140*
*significant difference between experimental and control groups
some values estimated from charts and graphs in text
b
age 1.5 mo.; initial body weight 110-150 g
144
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Tullar's (1947) data on growth are presented in this section.
Another long-term feeding study on rats is in.progress; results after-
13 months are currently available. Marked toxicity was observed in rats
ingesting 100 or 300 ppm acrylonitrile contained in the diet.
A third study assesses the toxicity of acrylonitrile administered
over 6 months to beagle dogs; marked toxicity occurred at 200 or 300 ppm
AN. A discussion of these studies follows.
a) Effect on Rats
Tullar (1947) orally administered acrylonitrile to male albino rats
for 2 years. Groups of 20 animals were allocated according to the follow-
ing design:
Group A, normal control; food and water ad lib.
Group B, paired control for group C
Group C, unlimited water containing 0.05% v/v AN; unlimited food
Group D, unlimited food fumigated with AN; unlimited water.
(25 cc AN added to a drum containing five/1 kg sacks of
meal. Drum sealed for 24 hours, then exposed to air
for at least 10 days)
Rats were individually housed; weekly records were made of body weights and
food and water consumption. Average weights, at 5 week intervals, appear
in Table 43. Acrylonitrile in the drinking water (Group C) retarded growth
consistently from the controls (Groups A and B) and food-treated rats
(Group D).
After two years, total mortality was higher in treated-water rats
(50%) than paired controls (25%), normal controls (15%) or food-treated
rats (5%). Weight gain in rats given acrylonitrile in the food almost
145
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Table 43
Effect
Weeks of
Treatment
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80.6
85
90
95
100
105
of Long-Term
A
Control
Av. Wt. (g)
63
194
280
312
329
338
343
366
383
388
394
398
405
412
405
411
404
400
409
407
416
413
Oral Feeding of Acrylonitrile in Rats
(Tullar, 1947) a
B
Pair ed-Control
For Group C
N Av. Wt. (g) N
20 63 20
179
'254
292
310
322
331
344
369
376
383
390
19 381
379
376 19
387 17
376
18 374
17 390 16
388 15
397
386
C
0.05% AN in
drinking water
Av. Wt. (g) N
62 20
157 19
238
267
282
287
295
317
331
339
340
345
364
347 18
355 16
354
347
343 15
348 14
334
336 13
336 10
D
AN fumi-
gated food
Av. Wt. (g) N
67 20
197
281
307
324
331
336
352
366
377
381
384
395
400 IS
395
391
394
388
391
373
397
404
adata in original reference are presented weekly
146
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reached the weight gain by controls, but was always slightly less. Tullar
(1947) concluded that food fumigated with acrylonitrile, unlike water-
treated acrylonitrile, does not retard growth or the life span of rats,
indicating a lack of cumulative effects.
A separate study by Tullar (1947) was the basis on which methods and
dosages were determined for the chronic study just discussed. A higher
dose of AN in the drinking water (0.1%) was not tolerated for 13 weeks
(82% weight gain during this period compared to 237% gain in paired con-
trols). However, complete recovery of growth followed withdrawal of
acrylonitrile.
In another long-term study, Ferin et al. (1961) incorporated 0.1%
(1000 ppm) or 0.002% (20 ppm) acrylonitrile in the drinking water of 100
rats (strain or sex not specified) for six months. Effects on rats at
the higher dose included increased leukocyte counts and increased relative
liver, spleen, and kidney weights. At the lower dose, functional changes
in the central nervous system (based on a "memory test") and in the de-
toxification function of the liver were noted. However, data are sparse,
making interpretation difficult.
Svirbely and Floyd (1961) administered acrylonitrile at 0.5, 5.0 and
50 ppm in the drinking water of male and female CFW rats for 2 years.
Average drinking water consumption was slightly decreased at the highest
level for both sexes, possibly related to the odor threshold of AN (10 ppm
in humans). Periodic (not specified by authors) hematological observations
indicated normal values for hematocrit, hemoglobin, white blood cells,
and differential count. Cumulative mortality in treated rats was
within the range of controls as the data on the following page show.
147
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Organ weights were reported as with within normal ranges. However, data pre-
sented in this paper are sparse and make evaluation of the results difficult.
Cumulative Mortality
Males/Femalesa
Dose (ppm) Weeks of Test
3 6 12 24 48 52 96 104
0 0/0 0/0 0/0 0/0 1/1 1/1 8/3 9/6
0.5 0/0 1/0 2/0 3/0 3/0 4/0 8/0 9/1
5.0 0/1 0/1 0/1 0/1 0/2 0/2 4/9 5/11
50.0 0/0 0/0 0/0 0/0 0/0 0/0 2/8 3/9
25 rats per level per sex
A 13-month status report on a 24 month study (sponsored by the Manu-
facturing Chemists Association) incorporating acrylonitrile in the drinking
water was issued by Norris (1977) and, in more detail, by Quast et al.,
(1977). Acrylonitrile was incorporated into the drinking water of Sprague-
Dawley (SPF derived) rats at 0, 35, 100, or 300 ppm acrylonitrile (equiva-
lent to 0, 4, 10 or 30 mg/kg body weight/day, respectively). Rats were
initially 6 to 7 weeks old; males weighed about 310 g and females weighed
about 210 g. Ten rats/sex/dose were sacrificed after 12 months.
Statistically significant reductions in body weights at 35, 100 and
300 ppm were associated with dose-related decreased water consumption, and
decreased food consumption at 300 ppm (females consumed less food at 100
ppm also) (Table 44). The following other data were obtained:
Hematologiaal and Urinary Effects. Hematological evalu-
tions and urinalyses were performed on day 353 for males (8-10/dose) and
on day 354 for females (7-10/dose). There were no significant differences
compared to controls for: packed cell volume, red blood cell count,
148
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Table 44
Acrylonitrile in the Drinking Water of Rats
The number of times food or water or weight was significantly
(p < .05) decreased from control values during 12 months (Quast et al., 1977)
( numerator=no. times parameter decreased; denominator^no. times parameter
measured) .
PPM AN in Food* Water Weight
Water
35
100
300
Male
0/20
2/20
10/20
Female
5/20
7/20
11/20
Male
11/22
22/22
22/22
Female
18/22
21/22
22/22
Male
0/13d
7/13
13/13
Female
9/12
12/12
12/12
fcbased on water consumed by 21-30 rats/sex/dose
Tja
after 100 days there was a statistically significant trend toward
cased on food consumed by 24-30 rats/sex/dose
fcbased on water consumed by 21-30 rat
cased on weight of 10 rats/sex/dose
after 100 days there was a statistic
reduced body weight (repeated measures analysis of variance)
hemoglobin concentration, white blood cell count or differential leukocyte
count. No differences were found in urine for: pH, sugar, protein,
ketones, bilirubin, occult blood, or urobilinogen. Males maintained at
300 ppm and females at 100 or 300 ppm had a significantly increased urine
specific gravity.
Blood urea nitrogen (BUN), alkaline phosphatase (AP) activity and
serum glutamic pyruvic transaminase (SGPT) activity were measured on day
368 in fasted rats. AP was significantly increased in females receiving
300 ppm. All other values were within normal limits.
Gross Pathology. On day 368 fasted rats were sacrificed
for autopsy. Organ weights were recorded and tissues were fixed and ex-
amined by standard methods.
The organ to body weight ratios (g tissue/100 g bw) were significantly
increased for heart, liver, and brain in males and for liver and kidney
in females receiving 300 ppm. Males receiving 100 ppm showed significantly
149
-------
increased body weight ratios for the brain only; females at 100 ppm had
significantly lower heart weights. Body weights of fasted males and females
at 300 or 100 ppm were significantly lower than control weights.
Based on 10 males and 9-10 females sacrificed per dose the percent
occurrence of pathologic findings are summarized in Table 45. Males and
females at the two higher doses developed lesions in the non-glandular
portion of the stomach which were characterized by paleness and thicken-
ing of the mucosa, erosions, ulcers and, sometimes, papilloma formations.
Three females at 300 and 100 ppm and 1 male at 300 ppm had ear canal
tumors. Other, less clearly dose related changes appear in Table 45.
Microscopic findings of tissues with tumorous changes revealed in-
creased frequency of gastric cell papillomas, Zymbal (sebaceous) gland tumors
of the ear canal and microtumors of the nervous system in rats receiving
100 or 300 ppm only. The squamous cell papilloma in the stomach is seen only
infrequently in this strain of rat as a spontaneous occurrence. Zymbal gland
tumors do occur spontaneously in this strain but the high frequency in
treated rats is considered significant.
The nervous system changes (possibly of mesodermal origin) suggest
perivascular location at this time. As the lesion advances it appears to
invade brain tissue. Advanced tumors had a sarcomatous appearance. Due
to the small sample size the low occurrence of other tumors can only sug-
gest treatment related effects.
Microscopic nontumorous changes include minimal hepatic lesions in
rats receiving 100 or 300 ppm (possibly related to the decreased nutri-
150
-------
Table 45
Gross Pathologic Findings In Male and Female
Rats Maintained on Water Containing AN for
12 Months (Quast et al., 1977)
Concentration of
GROSS PATHOLOGIC FINDINGS
Number of rats sacrificed
Gastrointestinal Tract
Stomach - nonglandular portion
Pale Thickened foci
Focal gastric papllloma(s)
Gastric erosion or ulcer
Small Intestine tumor
Large intestine tumor
Decreased amount of Intraabdomlnal fat
Kidneys
Pitting of the cortex
Focal scar formation in the cortex
Mineral deposit within the pelvis
Dilated pelvis
Pale-colored foci In the cortex
Unilateral tumor
Liver
Pale foci suggestive of necrosis
Clear fluid cyst in caudate lobe
Testes and Epididymis
Unilateral testlcular edema
Fat necrosis of epididymal fat pad
Eyes
Focal corneal cloudiness
Focal lenticular opacity
Lungs
Pale-colored foci
Epidermal Inclusion Cyst
Ear Canal Tumor, Unilateral
Spleen - Increased in size suggestive
of extramedullary hematopolesls
Clltoral Gland Abscess
Tongue - 1 mm Sized Pale Foci on the"
Surface Near the Base
Subcutaneous Tumor in the Mammary
Region
Subcutaneous Mammary Gland Hyper-
p las la
0
10/9a
0/0
o/ou
0/-b
o/-
o/-
o/-
3/0
21-
3/-
1/2
o/-
o/-
o/-
-/o
O/-
o/-
1/2
1/0
1/0
o/-
0/0
0/0
-/I
-/o
-/2
-12
35
10/9
0/0
0/0
o/-
o/-
o/-
o/-
1/0
21-
21-
3/0
l/-
o/-
0/2
-/I
21-
o/-
3/1
0/0
0/0
o/-
0/0
0/0
-/o
-/o
-/o
-12
AN In the Water (ppm)
100
10/10
1/2
0/0
11-
2t-
o/-
21-
2/0
1/1
o/-
0/0
11-
11-
1/2
-/o
l/-
l/-
3/0
0/0
0/1
o/-
0/2
0/0
-/o
-/2
-/3
-/I
300
10/10
3/3
7/5
l/-
o/-
o/-
6/-
1/1
11-
11-
1/0
o/-
o/-
o/-
-/l
o/-
11-
2/1
1/1
0/0
11-
1/1
1/1
-/o
-/I
-/3
-/2
number of rats affected: Male/Females
dashes indicate data not reported
151
-------
tional state), chronic renal disease In females receiving 300 ppm, and
hyp'erplasia and hyperkeratosls of Che squamous epithelium of the stomach
receiving 100 or 300 ppm.
Quaat et al. (1977) stress that it still remains to be aeen "whether
the tumorgenic activity of acrylonitrile can be differentiated from other
manifestations of toxicity".
b) Effect on Dogs
Purebred beagle dogs were used in a 6 month oral toxicity study
sponsored by the Manufacturing Chemises Association (Quast et al., 1975).
Eight animals (4/sex) were given acrylonitrile in the drinking water
at 0, 100, 200, or 300 ppm, which corresponds to the following doses
(based on body weight and water consumption):
x mg/kg t 3D
ppm Males Females
100 10 t 1 8 ± 1
200 16 ± 2 17 ± 2
300 17 ± 4 18 ± 5
Mortality and Toxic Symptoms. No controls or dogs at
100 mg/kg died during the study. Five dogs at each of the two highest
doses died spontaneously or were euthanized due to their debilitated state.
Early sign* of toxicity included decreased water and food consumption,
decreased body weight, roughened hair coat, cough, and, later, wretching
and vomiting. Terminal sign* of depression, lethargy, weakness, emaciation
and respiratory distress were noted.
152
-------
Food and Water Consumption; 3ody Weight. Daily water
consumption was averaged (by sex) at weekly intervals and compared to
control. Water intake of dogs at 300 ppm was significantly lower 21 out
of 26 weeks for males and 22 out of 26 weeks for females. At lower doses,
drinking was essentially normal. At 200 ppm water ingested was signifi-
cantly lower for only 1 week for males and 7 weeks for females. At 100
ppm, water consumption was higher 7 weeks for males and lower 1 week for
females.
Daily food intake was averaged for each week, by sex, then an over-
all average was computed for all 26 weeks. Males at 300 and females at
all concentrations showed a significant overall decreased food consump-
tion, whereas males at 200 and 100 showed a significant increase.
Dogs that died or were euthanized showed progressive weight loss.
In surviving animals, few significant weight differences were detected.
Ocular Lesions. Slit lamp ophthalmoscopic examinations
conducted on 4 occasions revealed no eye lesions related to acrylonitrile
exposure.
Hematologia Values. The following tests were made 8
days before, and on days 83, 130 and 179 during the investigation: packed
cell volume (PCV); hemoglobin concentration (Hgb); red blood cell (RBC)
and white blood cell (WBC) counts. No significant differences were appar-
ent before testing. On day 83, males at 300 ppm showed significant de-
creases in PCV, RBC count and Hgb; males at 200 ppm showed a decreased
RBC count. At day 83, females on 300 ppm showed a significant decrease in
RBC count. All values were within normal ranges at days 130 and 179, except
153
-------
that females at 300 ppm on day 30 had a significantly lower RBC count.
Urinalyses. Urine samples were collected 8 .days before,
and at days 84, 135 and 176 during treatment, and at necropsy. Parameters
determined were: specific gravity, pH, sugar, protein, ketones, occult
blood, and bilirubin. All values were within normal limits.
Eematologi-oal Chemistry Values. Blood urea nitrogen
(BUN), serum alkaline phosphatase activity (AP), serum glutamic pyruvic
transaminase activity (SGFT) and serum glutamic oxaloacetic transaminase
activity (SCOT) were measured 8 days before treatment and on days 84,
135 and 176. Males consuming all concentrations of acrylonitrile were
always within normal limits. Females at 300 and 200 ppm showed a signifi-
cant increase in SCOT activity at day 135; females at 200 ppm also showed
decreased SGPT activity.
There was no significant change in liver or kidney nonprotein sulf-
hydryl content at 6 months for dogs at 100 ppm. No differences were
apparent at the higher dosages, but sample sizes were too small to permit
analysis.
No differences were detected on day 155 for total protein, albumin,
a1, a2» 3 or y globulin values between control and treated dogs.
Pathology. Dogs surviving until termination of treatment
(males, day 182; females, day 183) were fasted overnight and then exsan-
guinated. The brain, heart, liver, and kidneys were weighed in all animals;
testes weights were determined in males. Weights for dogs at 100 ppm were
normal. At 200 ppm, males (N = 2) had a significantly lower absolute
brain weight, but had a higher kidney/body weight ratio compared to
154
-------
controls (N = 4). Data were obtained for only 1 male at 300 ppm and 1
female at 200 ppm, so statistical analysis was not possible. Females at
300 ppm (N = 2) showed a significantly lower brain/body weight ratio com-
pared to controls.
Gross and histopathological changes in dogs receiving 100 ppm were
comparable to control dogs. Foreign body pneumonia, a result of aspira-
tion of food particles and lung nematodes, was a consistent finding in
dogs receiving 200 or 300 ppm. The pneumonia was associated with gross
and microscopic changes in the tongue and esophagus; the authors suggest
AN in the drinking water might have irritated mucous membranes of the
tongue and esophagus so swallowing was abnormal, resulting in aspiration
of food.
4. Mechanism of Toxicity
There has been considerable disagreement about the mechanism of
acrylonitrile intoxication. Some authors have proposed that the toxic
action is due solely to the liberation of cyanide (which would inhibit
cellular respiration), citing the similarity of symptoms to cyanide poison-
ing or the presence of cyanide or thiocyanate (Dudley and Neal, 1942;
Dudley et al., 1942; Brieger et al., 1952). Other authors deny cyanide
is involved at all (Paulet et al., 1966). A more prevalent opinion is
that the effect of acrylonitrile is due in part to the liberation of cya-
nide, but mostly to direct effects of acrylonitrile. There may be substan-
tial differences in the mechanism of toxicity between species.
a. Action of Cyanide
Although Dudley and his coworkers (Dudley and Neal 1942; Dudley et al.,
1942), and others (Brieger et al., 1952) demonstrated the presence of
155
-------
cyanide or thiocyanate in animals acutely intoxicated with acrylonitrile,
they did not adequately demonstrate that lethal concentrations of cyanide
had been liberated. Several approaches have been taken to assess the role
of cyanide in acrylonitrile intoxication, including: measurement of
CN-metalloprotein complexes; effect on cytochrome oxidase; effect of
cyanide antidotes.
1) Cyanide-Metalloprotein Formation
Cyanide intoxication is characterized by the formation of cyanide-
metalloprotein complexes. Magos (1962) measured complex formation in rats
intoxicated with acrylonitrile and concluded that the mechanism of toxi-
city is not solely due to cyanide liberation.
Cyanide-metalloprotein formation was estimated by determining methemo-
globin and methemoglobin-CN formation (Magos, 1962). Groups of 10 male
albino rats were injected subcutaneously with cyanide compounds (AN, po-
tassium cyanide, acetone cyanohydrin) (dosage: LDso x 1.5). Some animals
from each group were also given 30 mg sodium nitrite (i.p.) 30 minutes
before treatment to increase methemoglobin levels. Dosage schedules and
mortality are presented below:
Mortality
Compound
acrylonitrile
potassium cyanide
potassium cyanide
Dose
millimole/kg
2.8
2.4 x 10"1
3.7 x 10'1
acetone cyanohydrin 1.6 x 10" 1
without sodium
nitrite
5/5
5/5
-
5/5
with sodium
nitrite
5/5
1/5
4/4
0/5
Blood samples from rats given sodium nitrite to determine methemo-
globin-CN levels were taken at death or 1 hour after injection of the
156
-------
cyanide. The optical density of the blood sample. (hemolyzed and centri-
fuged) was read spectrophotometrically before and after addition of a drop
of 20% potassium ferricyanide. A drop of 10% acetone cyanohydrin was added
to the sample to convert methemoglobin to methemoglobin-CN and the optical
density was read again; the decrease in density was inversely proportional
to the original methemoglobin-CN concentration. Total hemoglobin as
methemoglobin-CN after dilution with buffer and addition of ammonium hy-
droxide. These results were obtained:
1.
2.
3.
Compound
Acrylonitrile
Potassium cyanide
Acetone cyanohydrin
N
5
5
9
Time of Meth-CN:
Sample (x ± S.
at death
at death
1 hour after
55 ±
85.6 ±
72.4 ±
total Meth
, D.)
8
8.7
12.7
or potassium cyanide cyanide in-
jection
The rate of methemoglobin-CN formation in rats given acrylonitrile
(group 1) was significantly lower than rats killed by potassium cyanide
(group 2; t = 3.99, p < .002) or rats surviving acetone cyanohydrin or
potassium cyanide (group 3; t = 2.21, p < .02). These data lend weight
to the view that the toxicity of acrylonitrile in rats is not due solely
to the liberation of cyanide.
2) Effect on Cytochrome Oxidase
In cyanide poisoning inhibition of the enzyme cytochrome oxidase
occurs.
Tarkowski (1968), however, determined that cytochrome oxidase was
unaffected in rats intoxicated with acrylonitrile. Cytochrome oxidase
157
-------
activity was determined in brain, kidney and liver homogenates two hours
after acrylonitrile was administered intraperitoneally in rats (100 mg/kg).
In -j-itvo determinations were made in a Warburg flask. Acrylonitrile did
not cause changes in the spectrum of cytochrome oxidase.
3) Effect of Cyanide Antidotes
Dudley and Neal (1942) tested whether administration of sodium ni-
trite, a protective agent in cyanide poisoning, would also act as a protec-
tive agent for acrylonitrile. Dogs, rabbits, and guinea pigs were injected
with sodium 'nitrite immediately before or after exposure to acrylonitrile
vapors. For rats and rabbits, sodium nitrite injected (i.p. or i.v.)
prior to exposure delayed the onset, and reduced the severity of signs,
while injection after exposure often prevented death and hastened recovery.
Injection (i.p.) of sodium nitrite was of no value in guinea pigs. Ghir-
inghelli (1954) confirmed that anticyanide agents (sodium thiosulfate and
nitrite) were ineffectual for guinea pigs. Dudley and Neal (1942) sug-
gested that dogs and rabbits metabolize acrylonitrile to hydrogen cyanide
but guinea pigs may metabolize it in a different manner or detoxify cyanide
efficiently and rapidly.
Benes and Cerna (1959) administered cyanide antidotes (sodium nitrite
or sodium thiosulfate) to Wistar rats or H strain mice intoxicated with
acrylonitrile. Mice tolerated three times the LDso of acrylonitrile when
given a combination of the antidotes, and 30% of the rats survived the
LDiOQ- Benes and Cerna (1959) suggest that acrylonitrile is toxic to mice
by the development of cyanide, but that in rats, the toxicity is not ex-
clusively due to formation of this anion.
158
-------
Inbred male white mice were given hydroxycobalamin and sodium thio-
sulfate (both cyanide antidotes) with acrylonitrile (Graham, 1965). Toler-
ance for acrylonitrile was markedly decreased, as these increased lethal
dose values show (LDso values were determined at 2 and 24 hours):
£
LD50 (mg/kg)
At 2 hr At 24 hr
AN (s.c.) alone 50 25
Hydroxycobalamin and AN no 85
Hydroxycobalamin , AN,
and Sodium thiosulfate 250 120
Sodium thiosulfated >2500 >2500
a.
60-70 male inbred mice used in each of the 4 groups
100 mg/kg i.p.
c d
400 mg/kg, as a solvent for hydroxycolbamin dose not specified
Graham (1965) attributed the immediate lethal effect of acrylonitrile in
mice to cyanide liberation and the delayed effect to a direct effect of
acrylonitrile upon the central nervous system.
Experiments using cyanide antidotes show apparent species differences
regarding the importance of cyanide liberated from acrylonitrile. McLaughlin
et al. (1976) confirmed variations in species susceptibility by comparing
the effect of 3 antidotes in mice, rats, rabbits and dogs (Table 46).
b. Direct Action of Acrylonitrile
Paulet et al. (1966), as a result of their studies on mice, rats and
rabbits, proposed that there were direct toxic effects of acrylonitrile
and that cyanide is not involved to any degree. The following factors
were cited in support of their conclusions:
159
-------
Table 46
Mortality (%) in Several Species after
Adminis-
tration of a Lethal Dose of Acrylonitrile (LDioo)
and an Antidote
Antidote
cysteine hydrochloride
sodium thiosulfate
sodium nitrite and sodium
thiosulfate
(Mclaughlin
mice
30
100
100
et al . ,
rats
10
20
80
1976)a
rabbits
0
50
17
dogs
0
100
100
meeting abstract; number of animals used not specified
i) the signs caused by CN~ and AN are different (AN produces a
nervous reaction while CN~ causes anoxia);
ii) AN depresses respiration while CN~ stimulates respiration;a
iii) AN initially stimulates oxygen consumption which is not seen
in CN" intoxication;
iv) AN causes hyperglycemia and lowers inorganic P in the blood
while in CN" poisoning there is normoglycemia and elevated inorganic P.
Other authors claim some involvement of cyanide in addition to direct
participation of acrylonitrile or its other metabolites (Gut et al., 1975;
Hashimoto and Kanai, 1965).
C.
Vertebrates
Data are available for several species of bony fish. Acute and sub-
acute bioassays, as well as the effect of acrylonitrile on fish flavor,
are presented below. No information was found on the toxicity of
acrylonitrile to nonaquatic nonmammalian vertebrates .
however, CN- also depressed respiration as a secondary effect
160
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1. Acute Toxicity
The acute toxicity of acrylonitrile has been described for several
species of freshwater and marine fish.
a. Freshwater Fish
Henderson et al. (1961) determined the toxicity of acrylonitrile in
fathead minnows (Pimephales promelas), bluegills (Lempomis maorockirue) and
guppies (Lebistes reticulatus). Acute toxicity was determined by a static
bioassay at 25°C. Ten fish per species were added to each of 5 AN concen-
trations (1.0, 1.8, 3.2, 5.6 or 10 mg/1). Twenty-four, 48 and 96 hour
*
TL values were computed by graphical interpolation and appear in Table 47.
TL values ranged from 25.5 to 44.6 mg/1 at 24 hours and from 11.8 to
m
•
33.5 mg/1 at 96 hours. Longer exposure time, therefore, increased toxicity.
This exposure effect was not as marked or was nonexistent for other or-
ganic nitriles tested: lactonitrile, benzonitrile, acetonitrile, adipo-
nitrile, and oxydipropionitrile. For fathead minnows results of tests in
hard or soft water were not appreciably different (Table 47). Bluegills
were most, and guppies were least sensitive to acrylonitrile.
Goldfish ('Carassius sp.) may be somewhat more resistant than guppies.
The LCso after 96 hours is 40 mg/1 (Paulet and Vidal, 1975).
White crappie (Pomoxis armularis) exposed, in a constant-flow constant-
concentration system, to 18 and 24 ppm acrylonitrile, died after 180 and
500 minutes, respectively (Renn 1955). No deaths occurred when exposed to
6 or 10 ppm AN.
Bluegills (Lepomis macJwoohirus) survived 0.1 to 1.0 ppm AN
for more than 24 hours when tested in static and continuously flowing
*TL = median tolerance limit; the concentration of a substance which
m
will kill 50% of the test organisms within a specified time.
161
-------
Table 47
Median Tolerance Limit Values (TL ) for Various
Fish Exposed to Acrylonitrile
Species
Fathead Minnowsb
(Pimphales pvonelas)
Fathead Minnows^
(P. pvomelaa)
Minnow
(Phozinus phosrinus)
Bluegillc
(Lepomis macrochirus )
Guppyd
(Carassius sp.)
Goldfish
(Carassius sp . )
Carp
(Cyprinus oarpio)
Pin PerchS
(Lagodon rhomboides )
Rainbow Trout
(Salmo aairdneri)
Dilution
Water3
hard
soft
NR
soft
soft
NR
NR
NR
hard
TU, (mg/1)
24 hr 48 hr
32.7 16.7
34.3 21.5
38.2 17.6
25.5 14.3
44.6 33.5
37.4 24.0
24.500 -
70
96 hr Reference
14.3 Henderson et al.,
1961
18.1 Henderson et al.,
1961
Marcoci and lonescu,
1974
11.8 Henderson et al. ,
1961
33.5 Henderson et al.,
1961
40e Paulet and Vidal,
1975
- Marcoci and lonescu,
1974
- Daugherty and
Garrett, 1951
Jackson et al, 1970
water - pH 8.2; alkalinity 320 ppm; acidity o ppm; hardness 380 ppm
soft water - pH 7.4; alkalinity 16 ppm; acidity 2 ppm; hardness 20 ppm
50.8-63.5 mm/long (2-2.5 inches); weight 1.5 g
C38.1-50.8 mm/long (1.5-2 inches); weight 2 g
25.4 mm long (1 inch); weight 0.1 g
ein text, identified as LC50; fish observed for 3 days
authors reported similar values for the bitterling (Rhodeus seriaeus) and
fry (LeiusaspitiB delineatus)
g57-113 mm long
NR • not reported
162
-------
systems. According to Renn (1955) the tolerable levels of acrylonitrile
at 25°C is between 10 and 18 ppm for the 2 species tested.
Bandt (1953) determined the effect of acrylonitrile on 2 species of fresh-
water fish, the roach (Alburnus sp.) (11-16 cm long) and the bleak (Rutilus
sp.) (13.5-15.5 cm long). Acrylonitrile was introduced into a 6 liter aquarium
(pH 7.3-7.5; 12.3-18.2°C) at concentrations of 20 to 100 mg AN/1. In all, 10
roaches and 5 bleaks were tested. Two roaches, one each subjected to 30
or 40 mg AN/1, showed no effect by day 11 or 6, respectively. One tested
at 50 mg/1 died after 68 hours while others tested at 60-100 mg/1 died
after 22-29 hours. For bleaks, AN at 20 mg/1 was without effect by day
20 but at 25 mg/1 one bleak died after 16 days. Forty mg/1 was lethal
after 47 hours while 50 mg/1 was lethal after 20 hours. From these limited
data Bandt (1953) suggests fish can tolerate 20-25 mg/1 of acrylonitrile
discharged in wastewater.
b. Marine Fish
Daugherty and Garrett (1951) determined toxicity levels of acrylo-
nitrile in pin perch, Lagodon vhombo-Ld.es. Groups of eight fish acclima-
tized in 30 liters of seawater were used in static tests. Acrylonitrile
was introduced into the aquarium in a series of 16 dilutions (0.25-60.00
mg/1) and the time to death was recorded. Twenty mg/1 was the maximum
concentration at which no deaths occurred, 30 mg/1 being the minimum
lethal concentration. No deaths occurred in control fish. The TL at
m
24 hours, determined by interpolation, was 24.500 mg/1 (Table 47).
163
-------
.2. Subacute Toxicity
Subacute flow-through bioassays were performed on fathead minnows by
Henderson et al. (1961). In five replicate experiments, fifty fish were
exposed to each of 7 concentrations of acrylonitrile for 30 days. Solu-
tions in the aquaria (soft water, at 25°C) were renewed every 100 minutes;
fish were fed daily. Mean TLm values from the 5 replicates appear below:
Exposure (day) 1 2 3 4 5 10 15 20 25 30
TL (mg/1) 33.5 14.8 11.1 10.1 8.1 6.9 5.2 4.2 3.5 2.6
According to Henderson et al. these results indicate a continuous
cumulative effect. The authors point out that shorter term TL studies,
m
therefore, do not adequately indicate acrylonitrile's toxicity.
Jackson et al. (1970) exposed rainbow trout to AN at concentrations
between 2 and 200 mg/1. When exposure was at 2.2 mg/1 (this is 1/25 of
the 48 hr LCso; table 47) fifty percent of the test organisms were dead
in 100 days. The authors identified a further hazard: 1 day exposure to
"certain concentrations" of acrylonitrile, followed by transfer of the
trout to clean water resulted in the deaths of all the fish after 5-10 days.
The first sign of acrylonitrile toxicity in fathead minnows (after at
least 10 hours at 50 mg/1) was darkening of the skin (Henderson et al.,
1961). At some lower concentrations fish would live for 10-20 days, then
darken and die within 1-3 days.
3. Effect on Taste of Fish
Fifteen adult bluegills were exposed to a sublethal concentration of
5.0 mg/1 acrylonitrile (in soft water) for 1 to 4 weeks. Six samples of
164
-------
these fish were baked and flavor was evaluated by 14 persons and compared
to control fish. There was no objectionable taste to the exposed fish
(Henderson et al., 1961).
D. Invertebrates
Limited data are available for aquatic and nonaquatic invertebrates.
1. Aquatic Organism Toxicity
The 24 hour LCso f°r acrylonitrile in Brown shrimp (Crangon crangon)
is 10-33 mg/1. Eight to 25 animals were exposed to serial dilutions in
10 gallons of seawater (15°C) for this static bioassay (Portmann and
Wilson, 1971).
Bandt (1953) exposed several species of arthropods to 25-100 mg of
acrylonitrile per liter of water. The species examined were gammarus
(a freshwater shrimplike crustacean) and larvae of 3 types of insects.
Dose-related effects were obtained as follows:
AN concentration
(mg/1)
25
50
00
Organism
caddis fly larvae
mayfly larvae
gammarus
caddis fly larvae
mayfly larvae
dragonfly larvae
gammarus
gannnarus
caddis fly larvae
No. Tested
2
1
10
4
3
1
10
1
Response
1 dead at 48 hr
dead at 72 hr
(no effect by day 3)
3 dead at 48 hr
dead at 48-72 hr
(no effect by day 4)
9 dead at 22 hr; 1 dead
at 46 hr
dead at 22-48 hr
(no effect by 72 hr)
165
-------
' 2. Nonaquatic Organism Toxiclty
Bond and Buckland (1976) determined lethal dose values of acrylo-
nitrile-methyl bromide mixtures to three species of insects. About 300
granary weevils (Sitophilus grancurius) 300 flour beetles (Tribe/Hum aon-
fusum) and 90 cadelle larvae (Tenebroides rnauritaniaus) were exposed in
each of 5 or 6 concentrations in each of 7 tests. Exposure was for 8 hours
in a 525 liter fumigation chamber. Lindgren et al. (1954) exposed 8 species
of insects for 2 and 6 hours. LDso and LDgg values for acrylonitrile
appear in Table 48. Acrylonitrile alone was more effective at controlling
insects than methyl bromide alone or mixtures of acrylonitrile and methyl
bromide. However, acrylonitrile is not used alone as a fumigant because
it is flammable; methyl bromide is nonflammable (Bond and Buckland, 1976)
Fruit flies (Dvosophila melanogaster) showed no increase in mutation
rates when exposed to acrylonitrile (refer to Section IV-A-2 for details).
E. Plants
Acrylonitrile was one of about 35 compounds tested for biological
activity in pea seedlings (Pisum sativum) (Burg and Burg, 1967). Specifi-
cally, acrylonitrile was inactive in the pea Straight Growth Test, one
which determines elongation using Michaelis-Menten kinetics. Concentra-
tions of 0.17 mM acrylonitrile were "toxic" (undefined by authors) to seed-
lings; lower levels did not affect elongation.
Acrylonitrile-carbon tetrachloride (50 AN:50 CCl^) fumigant mixtures
were tested for adverse effects on seed germination under laboratory con-
ditions (Glass and Crosier, 1949). Fumigation with AN-CCl^ at concentrations
166
-------
Table 48
Lethal Dose Values of Insects Exposed to Acrylonitrile*
Length of
LD5Q Exposure LDaQ
Species (mg/1) (hr) (mg/1)
Granary Weevil
S-itophilus grancanus
Rice Weevil
S-itophilus oryza.
Mexican Bean Weevil
Zabrotes pectoral-is
Drug-store Beetle
Stegobium paniceum
Flour Beetle
Tzn.boii.ian confusion
Bean Weevil
Acanthoscelides ob-
tectus
0
2
4
1
2
1
2
1
3
1
3
6
1
3
.7
.0
.5
.0
.5
.4
.0
.7
.0
.9
.0
.5
.1
.0
8
6
2
6
2
6
2
6
2
8
6
2
6
8
1
2
8
1
6
2
4
2
7
2
4
11
2
5
.2
.9
.0
.8
.5
.1
.0
.5
.0
.5
.9
.0
.0
.5
Length of
Exposure
(hr)
8
6
2
6
2
6
2
6
2
8
6
2
6
8
Bond and
Lindgren
Lindgren
Lindgren
Lindgren
Lindgren
Lindgren
Lindgren
Lindgren
Bond and
Lindgren
Lindgren
Lindgren
Lindgren
Reference
Buckland
et
et
et
et
et
et
et
et
al. ,
al. ,
al.,
al. ,
al. ,
al. ,
al.,
al.,
Buckland
et
et
et
et
al.,
al. ,
al.,
al.,
, 1976
1954
1954
1954
1954
1954
1954
1954
1954
, 1976
1954
1954
1954
1954
Saw-Toothed Grain
Beetle
Ory zaephilus sianna-
mensis
Lesser Grain Borer
Phyzopevtha dcminioa
Cadelle
mcaan-tan-
eus
0.8
3.5
0.8
1.4
2.8
6
2'
6
2
1.4
6.5
2.5
4.0
6.0
6 Lindgren et al., 1954
2 Lindgren et al., 1954
6 Lindgren et al., 1954
2 Lindgren et al., 1954
Bond and Buckland, 1976
aadults tested for all species with the exception of the Cadelle
(4th instar)
167
-------
ranging from 1 to 25 pounds per 1000 cubic feet for 24 to 48 hours had no
effect on germination in any of the seeds tested, which included beans,
beets, corn, lettuce, peas, onions, tomatoes, wheat, and oats.
Acrylonitrile is 'highly toxic1' to nursery stock and growing plants
and'damaged'fresh fruit (WHO, 1965). No other information is given in this
source.
F. Microorganisms
1. Microorganisms Used in Mutagenicity Tests
Acrylonitrile was mutagenic in bacteria and yeast under some experi-
mental conditions, but not others, as discussed in Section IV-A-3. As
part of mutagenicity testing, some investigators reported toxic levels.
Acrylonitrile was slightly toxic at 100 ul/plate while "essentially com-
plete killing" occurred at 500 ul/plate for 5 strains of Salmonella
typhimuriwn and 1 strain of Saooharomyces cerevisiae (Litton Bionetics,
Inc., 1975). Concentrations of 500 to 10,000 ug/plate were not toxic to
three stains of S. typhirmunum (Haskell Laboratory, 1975). Venitt et al.
(1977) reported increasing toxicity to several E. aoli. strains at concen-
trations above 150 ymol/plate.
Loveless et al. (1954) screened acrylonitrile for effects on growth
and division in yeast, Saaaharomyaes eerewisiae3 and in bacteria, Eschevi-
ah-ia aoli strain B. Culture dry weights and direct cell counts were de-
termined to measure growth and division, respectively, during the loga-
rithmic phase of growth. Average cell weights (total mass/number of
cells) were taken as another measure of effects on division. An increase
in the weight of treated cells compared to controls shows interference
168
-------
with division. Acrylonitrile at 1000 yg/ml reduced the growth of E. ooli,
by about 50% but had no effect on cell size. However, at this concentra-
tion, both growth and division were reduced in S. oevewis'ia.e. In yeast,
treated cells weighed 52% of controls and were 170% the size of controls.
Acrylonitrile supported growth of Nooardia rkodoahrous (LL 100-21)
as a source of nitrogen, but not of carbon (DiGeronimo and Antoine, 1976).
Cells were inoculated into culture tubes containing 10 mg AN/ml in broth.
2. Molds on Food
Acrylonitrile effectively controlled mold growth on papads, an Indian
bread (Narasimhan, et al., 1972). Papads are often infested with mold at about
18% moisture. Packages of 16 insect-infested papads (at 18 and 20%
moisture) were fumigated with 32 or 64 mg AN/1. After one month, no mold
growth was observed at the higher dose at either moisture content; at the
lower dose at 18% moisture no effects occurred but moderate mold growth
developed in the presence of 20% moisture.
3. Aquatic Microorganisms
Acrylonitrile was added to aerated.river water supplemented with
nitrogen and phosphorus (Cherry et al., 1956). When 10 or 25 mg/1 AN
was used, a balanced biota developed, including bacteria, diatoms, algae,
protozoa, and rotifers. However, at 50 mg/1, diversity was decreased and
growth was predominantly fungal. The authors suggest acrylonitrile at
50 mg/1 is undesirable in a stream.
The tolerance of river microorganisms to acrylonitrile was discussed
in Section II-E-1 in relation to biological oxidation.
169
-------
G. • In Vitro Studies
1. Effect on Isolated Nerves
Sciatic-gastrocnemius preparations were isolated from frogs (Sana
n-igro rnaculata.) and tested for conductivity after the addition of acrylo-
nitrile and other materials in physiological saline (Hashimoto and Kanai,
1965). Measurements were made of the time required for anesthesia and
the duration of anesthesia. The anesthetic effect of AN was similar to
that of local anesthetics (novocaine and ethyl alcohol) and general nar-
cotics (ethyl ether and urethane). The authors suggest the anesthetic
effect of AN in vitro was stronger than that estimated to be possible
•in vivo.
2. Effect on Tissue Respiration
Brain cortex slices were prepared from male guinea pigs and measured
for oxygen consumption using untreated and K"*"-stimulated tissues (Hashimoto
and Kanai, 1965). At concentrations of 10~"3M acrylonitrile (a toxic con-
centration in vivo'), there was a 20% inhibition of ^"-stimulated respira-
tion but no effect on unstimulated respiration. The inhibitory effect of AN was
unaffected when sodium thiosulfate (a cyanide antidote) was added with
acrylonitrile. Sodium cyanide inhibited both stimulated and unstimulated
respiration but the inhibitory effect was counteracted by sodium thio-
sulfate. These results suggest the effect of acrylonitrile on the brain
might be due to the acrylonitrile molecule per se rather than its metabolite
•
cyanide.
The oxygen consumption of guinea pig liver slices was measured at
concentrations of 10~3 M AN and 5 x 10~2 M AN (Hashimoto and Kanai, 1965).
170
-------
There was no inhibition of oxygen consumption at the lower concentration,
which is toxic in vivo (as just discussed, brain slice respiration was
inhibited at this concentration). At the higher level, there was an in-
hibitory effect on liver slices, probably due to protein denaturation.
Hashimoto and Kanai (1965) suggest that acrylonitrile has little effect
on organs other than the nervous system. At high concentrations, however,
the compound also affects liver function, possibly by changing the struc-
ture of proteins.
3. Effect on Tissue Sulfhydryl Content
Acrylonitrile resulted in decreased sulfhydryl content of in vitro
preparations of blood, liver, and kidney slices from guinea pigs (Hashimoto
and Kanai (1972), as previously discussed (refer to Table 38).
171
-------
IV. SPECIAL EFFECTS
A. Mutagenicity
1. Broad Bean, 7-£g£a -aba
Acrylonitrile was not mutagenic (radiomimetic) in 7i,a^a faba (Love-
less , 1951). Root tips exposed to acrylonitrile for 1 hour at several un-
specified concentrations were unaffected in regard to either dividing cells
(examined 4-6 hours after treatment) or resting cells (examined 18, 36,
or 48 hours after treatment).
Acrylonitrile was also without mutagenic action in Vicia faba when
tested by the light-acridine orange system (Kihlman, 1961), Root tips were
pretreated with acridine orange (functions to absorb light energy) then
exposed to light for 30 minutes. The roots were simultaneously exposed to
a maximum of 1000 uM acrylonitrile (15 minutes before illumination and dur-
ing illumination). Twenty-six hours after treatment the root tips were
fixed and metaphase cells examined. Acrylonitrile had not produced struc-
tural chromosomal changes.
2. Fruit Fly, Drosophila melanoqastev
Benes and Sram (1969) screened acrylonitrile for mutagenic activity
in Drosophila melanogaster using the Muller-5 genetic test. This test de-
tects recessive lethality in the X-chromosome. Acrylonitrile (0.1%) was
injected into the abdomen. Frequency of mutations were 0.35% (2 recessive
lethals out of 572) for postmeiotic germ stages and 0.55% (4 out of 725)
for premeiotic and meiotic stages. These rates are not considered differ-
ent from spontaneous mutation rates (0.14%) by the authors.
172
-------
3. Bacterial Systems
a. Ames Standard Plate Method
Several laboratories have evaluated the mutagenic activity of acrylo-
nitrile in Salmonella, typhimurium using the Ames standard plate method.
Most or all of the following histidine auxotrophs (his) Salmonella strains
were used: a) TA 1535, sensitive to base-pair substitution mutagens;
b) TA 1537 and TA 1538, sensitive to frameshift mutagens; c) TA 98 and
TA 100 (derived from TA 1538 and TA 1535, respectively, by the introduction
of the R factor plasmid pKMlOl). The latter strains may be more sensitive to
some mutagens. The testing procedure includes mixing the indicator or-
ganism with the test chemical, pouring the mixture onto minimal agar plates
then counting the number of his* revertants after an incubation period.
In a similar manner, tests are also made by mixing the indicator organism
and a metabolic activation system (here, rat liver homogenate) with the
test chemical (SRI, 1976). These tests have been carried out for acrylo-
nitrile at the 3 laboratories described below.
Haskell Laboratory (1975; DuPont). Three 5. typhimwrUan strains
were used (TA 1537, TA 1538, TA 1535) with and without metabolic activation.
Concentrations of acrylonitrile ranged from 500 to 10,000 ug per plate
(0.62-12.4 ul) . Weak but reproducible mutagenic activity was observed in
strain TA 1535 with metabolic activation between 500-1500 ug AN/plate
(1.62-1.86 uD. A 4-5 fold increase in the mutation frequency or the spon-
taneous frequency was observed in 5 replicate trials. Inconclusive results
were obtained with non-activated strain TA 1535. In one out of 5 non-
activated trials, there was positive mutagenic activity at 2500 ug AN/plate
(3.1 ul).
Conversion 806 ug * 1 ul 173
-------
Litton Bionetias (1975). Five strains of S. typhimurium (TA 1535,
TA 1537, TA 1538, TA 98, TA 100) were tested with and without metabolic
activation at 0.1-100 ul AN/plate. No nmtagenic activity was observed.
Stanford Research Institute (1976). Five strains of S. typhi-
rrrurium (TA 1535, TA 1537, TA 1538, TA 98, TA 100) were tested with and with-
out metabolic activation at 0.1-5000 ug AN/plate (.0001-6.2 ul). No
mutagenic activity was found. TA 100 was retested at 1000-4000 ug AN/plate
and again there was no mutagenic effect.
b. Modified Ames Method
Milvy and Wolff (1977) tested three strains of 5. typhimuritun: TA 1535,
sensitive to base-pair substitutions; TA 1978 and TA 1538, sensitive to
frameshift mutagens. Three methods of exposure were used: spotting acrylo-
nitrile and liver homogenate on a "lawn" of Salmonella; shaking acrylo-
nitrile, liver homogenate and bacteria; exposing liver homogenate and bac-
teria to acrylonitrile vapors. Low level mutagenic activity was indicated
in strain TA 1535 at 5 or 10 ul AN utilizing the first method and in TA 1535
strains employing the second. Data are not presented for tests in the ab-
sence of microsomes and/or co-factors but the authors stated no mutagenesis
occurred under those conditions.
Milvy and Wolff (1977) pointed out that the ease with which acrylo-
nitrile vaporizes makes uncertain the actual amount of acrylonitrile in
the test system. They found the third method (vapor exposure) to be more
quantitative. Strain TA 1535 was exposed to acrylonitrile vapor at con-
centrations ranging from 2-200 ul for 0.5 to 4 hours; strain TA 1538
was exposed for 2 hours at 200 ul AN. As shown in Table 49, the number
of revertants was increased for every acrylonitrile exposure condition.
174
-------
Table 49
Mutagenicity of Acrylonitrile Vapor With 5.
tyh-imurium Strain TA 1535
(Milvy and Wolff, 1977)
Time of Acrylo-
Method of exposure nitrile
exposure (h) (yl)
Vapor 0.5 200
0
1.1 300
0
200
0
100
0
25
0
1.5 250
0
2 200
0
100
0
5
0
3 5
0
4 2 (57
ppm)
0
Revertants
(per ml)
195 (6) a
111(6)
1770(3)
' 350
100(2)
45(2)
250
110
105(2)
60
157(4)
33(2)
369(12)
79(12)
220(6)
140(6)
250(4)
67(4)
580(6)
162(6)
383(6)
207(6)
Viable cells
per ml
(10~8)
3.8(2)a
4.7(2)
3.2(2)
13.0(2)
4.5
2.7
4.2
4.4
2.7
2.0
1.6
2.2
3.8(12)
4.7(12)
1.8
1.7
8.6(2)
6.1(2)
3.8(4)
4.1(4)
11.5(2)
12.5(2)
Revertants
per 108
viable cells
51
24
553
26
22
12
60
25
39
30
98
15
97
16.8
12
8.2
29
11
153
40
33
17
\Che first number is the number of colonies per plate, averaged over the
number of plates exposed which is shown in parenthesis. When no parenthetical
number is shown, only a single plate was exposed.
175
-------
c. Mutagenicity in Eseherich-ia coli
Venitt et al. (1977) tested the mutagenicity in S. coli WP2 series
bacteria. Strains in this series have an ochre mutation in the trpE
locus of the tryptophan-synthetase operon. Mutants are scored as re-
vertants to tryptophan independence (trp~ —> trp"1"). These strains were
tested: WP2 (DNA - repair proficient); WP2 wurA (lacks excision repair);
WP2 uvrApc/A (lacks both excision repair and DNA-polymerase); WP2 IszA.
(deficient in an. error-prone pathway).
In one series of experiments mutagenicity was assayed by a plate-
incorporation method. Strains were mixed with graded doses of acrylonitrile;
plates were scored for revertant colonies after three days. Mutagenic
effects in 3 strains (WP2, WP2 uvrA; WP2 irt>rApo/A) was weak but reproduci-
ble and statistically significant (analysis of variance). Strain WP2 lexA.
was not reverted by acrylonitrile; marked toxicity might have been a factor.
Addition of a metabolic activation system had no effect on the mutagenic
action of acrylonitrile so the authors concluded the compound to be a
directly acting mutagen.
In a second series of experiments, the simplified fluctuation test
of Green et al. (1976) was used. This test confirmed the mutagenicity of
acrylonitrile at levels as low as 0.1 x 10~3 M.
Further confirmation of acrylonitrile's mutagenic effect was obtained
from tests of E. aoli, WP2 containing the resistance-transfer factor pkMlOl.
Introduction of this plasmid enhanced the mutagenic effects of acrylonitrile.
Venitt et al. (1977) suggest that acrylonitrile acts by causing non-
excisable mis-repair DNA damage associated with the generation of DNA
strand breaks; this is based on the differential response of the tester
strains. The authors hypothesize that acrylonitrile might react with
thymine residues in DNA.
176
-------
4. Yeast, SaQchccromuces o
Litton Bionetics, Inc. (1975) evaluated the ability of acrylonitrile
to induce mutations in strain D4 yeast. Assays were conducted with and
without metabolic activation preparations (rat liver microsome) at 0.1, 1,
10, or 100 ul AN/plate. The number of revertants per plate were counted.
In nonactivation tests, 10 and 100 ul AN/plate indicated possible mutagenic
activity (54% and 64% more revertants/plate, respectively than solvent
controls). Activation tests with D4 were negative.
5. Mammalian in vitro Assays
Acrylonitrile was evaluated for specific locus forward mutation in-
duction in the L5178Y thymidine kinase mouse lymphoma cell assay (Litton
Bionetics, Inc., 1976). No mutagenic activity was found.
The lymphoma cells are heterozygous for a particular autosomal muta-
tion at the TK locus and are bromodeoxyuridine (BUdR) sensitive. Cells
were tested in the presence and absence of a rat liver microsomal system.
The assay will detect forward mutation to TK-/-cells that are resistant
to BUdR. The procedure of Clive and Spector (1975) was used. Concentra-
tions of 0.01-0.0005% AN were tested (initial tests showed levels of 0.05
and 0.1% AN were toxic to the test system). As shown in Table 50, mutation
frequencies were increased at the higher concentrations compared to con-
trol. Litton Bionetics, Inc. (1976) suggest that these increased mutation
frequencies were the result of high toxicity, rather than the induction
of mutations.
6. DNA Repair Assay
Litton Bionetics (1976) reported that acrylonitrile is negative at
10 ul/plate with or without an activation system when tested in the DNA
repair assay (Slater et al., 1971).
177
-------
According Co OSHA the variation of test results discussed above appears
to be "closely related to the differences in the laboratory methods used and
to the high volatility and toxicity of AN...these studies could not be said
to show that AN is non-mutagenic." (Bingham, 1978). Mike Prival, a micro-
biologist at the FDA,evaluated the mutagenicity studies and suggested the
discrepancy in results might be due to the following: i) samples and
purity of the AN used may have been quite different; ii) minor differences
in assay techniques might have facilitated or prevented the evaporation of
AN. He suggests further testing but cautions that unnecessary human exposure
be prevented until the issue of its carcinogenic potential is resolved
(Prival, 1977).
B. Cytogenicity
No chromatid or chromosomal aberrations were detected in 16 male
Sprague-Dawley rats ( Spartan substrain, SPF-derived) exposed for 90 days
to 0, 35, 210, or 500 ppm of acrylonitrile (Johnston et al., n.d.). Bone marrow
cells were scored for aberrations; 25 to 50 metaphase spreads were scored
per animal. No abnormalities were found.
C. Teratogenicity
Murray et al. (1976; MCA sponsored) reported adverse maternal and
fetal effects after pregnant rats were given oral doses of 25 or 65 mg
AN/kg/day during gestation. Groups of 29-39 pregnant Sprague- Dawley rats
(265 g) were given 10, 25 or 65 mg AN/kg by gavage on days 6-15 of gesta-
178
-------
Table 50
Testing of Acrylonitrile in the Mouse Lymphoma
LS178Y Assay (Litton Bionetics, Inc., 1977)
Mutation Frequency x 10
Negative Control
Positive Control0
AN
Negative Control13
Positive .Control0
AN
Dosage
0.01
0.005
0.001
0.0005
0.03
Nonactivation
11.8
223.0
23.5
13.3
9.8
7.0
0.1
196.0
10.2
Activation
(mouse liver)
14.5
257.0
21.5
11.4
10.3
4.5
14.2
272.7
34.2
computed by dividing the numbers of clones formed in BUdR-selection medium
by number found in medium without BUdR
solvent in which test compound was dissolved
"dosage 0.1% ethylmethanesulfonate (EMSF) for nonactivation tests
dosage 1.0% dimethyInitrosamine (DMNA) for activation tests
179
-------
tion. Forty-three controls received 2 ml/kg of water alone. Rats were
sacrificed on day 21 of gestation.
I'latevnal Effects. Maternal effects were clearly dose-related. For
rats receiving the highest dose (65 mg AN/kg) significant changes were
noted compared to control: decreased weight gain; increased liver weight
(both relative and absolute); decreased food intake on days 6-8 of gesta-
tion only; increased water consumption throughout days 6-20 of gestation;
fewer visible implantation sites.
For rats receiving 25 mg AN/kg the only adverse effect was a signifi-
cantly lowered food intake on days 6 to 8 of gestation. Rats receiving
10 mg AN/kg were unaffected. At all doses there was no significant effect
on litter size, fetal sex ratio, or the incidence or distribution of re-
sorptions.
Fetal Effects. External, soft tissue and skeletal examination re-
vealed significant dose-related effects (Table 51).
.65 mg/kg - lower fetal body weight, lower crown-rump length;
increased frequency of acaudate fetuses; increased frequency of missing
vertebrae (other than a single thoracic and single lumbar vertebra) ;in-
creased incidence of fetuses missing more than one pair of ribs; delayed
ossification of the 5th sternebrae; split 2nd ster.nebrae; missing centra
of cervical vertebrae.
25 mg/kg - The incidence of either soft tissue or skeletal al-
terations was not significantly different from control although some of
the same malformations were observed at the higher dose (Table 51).
10 mg/kg - no adverse effects noted.
180
-------
Table 51
Incidence of Fetal Alterations Observed During the
Soft Tissue or Skeletal Examination Among Litters
ceiving Acrylonitrile by Gavage (Murray et al.
External,
of Rats Re-
, 1976)
Dose Level of Acrylonitrile, mg/kg/day
EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
SKELETAL EXAMINATION
SKULL BONE FORMATION
EXTERNAL EXAMINATION
Acaudate
Acaudate or short tail
Short trunk
Imperforate anus
SOFT TISSUE EXAMINATION
Right-sided aortic arch
Ovaries, anteriorly dis-
placed
Missing kidney.
unilateral
Dilated renal pelvis,
unilateral
Dilated ureter, left
SKELETAL EXAMINATION
Vertebrae - 12 thoracic &
5 lumbar (normal # is
13 T and 6 L)
- missing vertebrae
other than 1 thoracic
lumbar0
-missing centra of cer-
vical vertebrae (other
than GI and G£)
Ribs
-missing 13th pair only
-missing more than 1 pair
Sternebrae
-delayed ossification,
5th
-missing, 5th
-split, 5th
-split, 2nd
V
Fb
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
0
443
154
443
289
0
0.2(1)
0
0
0
0
KD
0
0
2(7)
j
0.2(l)a
5(23)
2(7)
0
2(9)
0
1(4)
0
10
No . Fetuses
388
135
388
253
% Affected (No
0
0
0
0
0
0
0
0
0
% Affected (No.
0
0
8(30)
0
0
3(13)
0
1(3)
0
25
Examined
312
111
312
201
. Affected)
0.6(2)
0.6(2)
0
0
1(1)
A
Kl)d
0
2(2)
1(1)
Affected)
2(7)
j
0.6(2r
10(31)
2(7)
l(2)d
4(13)
1(2)
1(3)
0
65
212
71
212
141
2(4)c
4(8)c
l(3)c>d
l(2)d
j
Kl)d
A
Kir
j
id)d
0 .
1(1) d
0
J
4(8)c'd
34(71) c
0
2(4)c»e
15(31)c
1(2)
4(8)
2(4)c
181
-------
Table 51 (cont'd)
Incidence of Fetal Alterations Observed During the External,
Soft Tissue or Skeletal Examination Among Litters of Rats Re-
ceiving Acrylonitrile by Gavage (Murray et al., 1976)
*
Dose Level of Acrvlonitrile, mg/kg/day
10 25 65
% Affected (No. Affected)
SKULL BONE EXAMINATION
-delayed ossification
any skull bone F 7(21) 6(15) 6(12) 4(5)
Acrylonitrile was given by gavage on days 6-15 of gestation; additional
data and incidence of alterations in litters given in reference
F = fetuses
Significantly different from control by a modified Wilcoxon test, p < 0.05
(This alteration occurred only in fetuses with a short or missing tail at
this dose level.
182
-------
The authors suggest the malformations are not the effect of maternal
toxicity alone, implying acrylonitrile was somehow acting directly on the
embryo or fetus.
Some animals in both the experimental and control groups developed
sialodacryodenitis (rat mumps). As shown in Table 51, some control rats
also developed gross terata, but at a lower level. T. Collins, a pharma-
cologist at the FDA, suggests the possibility that there may have been an
interaction between the viral infection and the chemical stress which may
have caused some of the terata at the 2 highest dose levels. He concludes,
however, that acrylonitrile was frankly (i.e., structurally, visibly)
teratogenic at the two highest levels administered (Collins, 1977).
Scheufler (1976) described acrylonitrile as embryotoxic to pregnant
mice (AB Jena-Halle, CS7B1, and DBA). Acrylonitrile was administered in-
traperitoneally at several unspecified doses. About 200-300 mice were
tested for acrylonitrile and each of several other compounds.
Svirbely and Floyd (1961) carried out reproduction studies in rats.
They reported their findings only briefly in a meeting paper. Sprague-
Dawley rats given 500 ppm in the drinking water showed decreased fertility,
gestation and viability. At this dose, females also developed a progres-
sive muscular weakness in the hind limbs about 16 to 19 weeks after the
weaning of the second litter.
D. Carcino genicity
Recent data have implicated acrylonitrile as a carcinogen. Preliminary
results of an epidemiclogical study at an E. I. DuPont de Nemours and
Company textile plant (Camden, S.C.) revealed more than twice the expected
183
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incidence of cancer among workers exposed to acrylonitrile as discussed in
detail previously (Section III-A-2-d; O'Berg, 1977).
Preliminary findings of long-term inhalation and feeding studies,
sponsored by the Manufacturing Chemists Association, indicate an increase
of tumors in rats exposed to acrylonitrile. Rats consuming 100 or 300 ppm
(mg/1) AN in the drinking water for 1 year developed tumors of the stomach,
central nervous system (CNS), and Zymbal gland of the ear canal (Quast
et al., 1977). Some rats receiving 35 mg/1 developed CNS tumors (Clark,
1977). In rats exposed to an atmosphere containing 80 ppm AN for 6 hours/day
for 5 days/week for 2 years there was an increase in the incidence of tumors
of the gastrointestinal tract, ear canal, mammary region and brain. Exposure
to 20 ppm resulted in an increase in subcutaneous masses of the mammary
region and in brain tumors (Clark, 1978). These studies are discussed in
more detail elsewhere (III-B-3-c). A final report on the two-year drinking
water study is expected by May, 1978. Although interim or preliminary data
are not usually considered appropriate for a carcinogenic evaluation
"immediate concern" is warranted, particularly because the brain and stomach
tumors do not occur spontaneously at the rates observed (Squire, 1978).
Maltoni et al. (1977) conducted carcinogenicity bioassays on Sprague-
Dawley rats (initially 12 weeks old) ingesting or inhaling AN for 2 years.
All animals were kept under observation until spontaneous death. The
authors concluded AN showed a "border-line oncogenic effect."
For the ingestion experiments, AN was administered in olive oil by
gavage at a dose of 5 mg/kg body weight, 3 times per week for 52 weeks.
Controls received olive oil alone. For the inhalation experiments, rats
were exposed to 40, 20, 10, or 5 ppm AN (86.8, 43.4, 21.7 or 10.8 mg/m3)
184
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for 4 hours/day, 5 days per week for 52 weeks. The number and type of tumors
after 131 weeks (end of experiment) for both the ingestion and inhalation
experiments appear in Table 52.
The most frequent types of tumors were: i) mammary tumors - moderate
increase in both experimental and controls; no clear-cut dose-response
relationship; ii) Zymbal gland carcinomas - incidence in treated rats not
considered significant; iii) Forestomach papillomas and acanthomas - "moderate
increase" under both experimental conditions compared to controls; iv) En-
cephalic tumors - found in both treated groups and ingestion (olive oil)
controls. The authors point out that of 3 tumors observed in animals ex-
posed by inhalation, these occurred at the 2 highest doses of AN. They
also stress that the incidence of tumors in the olive oil controls was
"surprisingly high"; v) Skin carcinomas - a few observed among rats treated
by inhalation; vi) Uterine carcinomas - no significant differences between
treated and control rats.
Maltoni et al. (1977) state that these results indicate a "border-line
oncogenie effect" and stress the need for further research.
Szabo et al. (1977) found elevated hepatic glutathione levels in rats
ingesting acrylonitrile for 21 days. They pointed out that similar in-
creases in glutathione have been described previously for chemical car-
cinogens, but caution that it is unknown whether such changes correlate
with carcinogenicicy.
Milvy and Wolff (1977) found acrylonitrile to be mutagenic in the
Ames test (see Section IV-A-3) and suggest the need for careful carcino-
genic testing.
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Table 52
Car cinogeni city Bioassays on Rats
Maltoni et al. (1977); Results After 131 Weeks
A. Ingestion of 5 mg AN/kg, 3 times/week for 52 weeks
Treated
Female Male
Total Na 40 40
Mammary Tumors (%) 52.5 5.0
x Tumors/rat 1.4 1.0
Fibroadenomas and fibromas(%) 18 2
Carcinomas (%) 5.0
Fibroadenomas and carcinomas (%) 2.5
Zymbal Gland Carcinomas (%) - 2.5
Forestomach Papillomas and
Acanthomas (%) 10.0 2.5
Encephalic Tumors (%) 2.5 -
Others (%) 12.5 10.0
B. Inhalation in air at 40, 20, 10, 5 ppm (86.8,
for 4 hr/day, 5 days /week for 52 weeks
Treated
Dose (ppm) 40 20
Sex F M F M
Total Na 30 30 30 30
Mammary Tumors (%) 23.3 13.3 23.3 13.3
x Tumors/rat 1.4 1.0 1.0 1.0
Fibroadenomas and
fibromas (%) 16.6 10.0 30.0 6.6
Carcinomas (%) 6.6 3.3 3.3 6.6
Zymbal Gland Carcinomas (%) - - 3.3
Forestomach Papillomas
and Acanthomas (%) - 10.0 3.3
Encephalic Tumors (%) - 6.6 3.3
Skin Carcinomas (%) 3.3 3.3 3.3
Uterine Carcinomas (%) 3.3 - 6.6
Others (%) - 16.0 13.3 23.3
Control
Female Male
75 74
44.0 2.7
1.4 1.0
26 2
5.3
4.0
1.3
1.3
5.3 1.4
12.0 6.7
43.4, 21.7 and 10.8
10 5
F M F M
30 30 30 30
23.3 3.3 33.3 -
1.4 1.0 1.2 -
23.3 3.3 20.0 -
13.3 -
3.3 3.3
6.6 6.6 3.3 3.3
_ _
3.3 - 13.3 -
3.3 - 10.0 -
23.3 23.3 10.0 -
mg/m3)
Control
0
F M
30 30
16.6 3.3
1.0 1.0
13.3 6.6
3.3 3.3
- -
— _
-
-
3.3 -
13.3 13.3
acorrected number; this represents the no. of rats alive after 28 weeks, when
the first tumor was observed. Percentages developing tumors calculated using
corrected number.
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During 1977, the Environmental Protection Agency's Office of Air
Quality Planning and Standards (EPA/OAQPS) officially requested that EPA's
Carcinogen Assessment Group (EPA/GAG) do a risk assessment on acrylo-
nitrile (Anon. 1977n).
The National Cancer Institute Carcinogenesis Testing Program recognizes
AN as carcinogenic to experimental animals and has no plans to further test
the compound as a potential carcinogen (Cueto, 1978).
Monsanto is sponsoring two animal-feeding studies to establish a no-
effect level for AN. In one study, rats are being fed AN at 1 and 100
ppm in the drinking water. In the second study, 1,3,10, and 100 ppm AN are
being administered by gavage (Anon, 1977p).
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V. REGULATIONS AND STANDARDS
A. Federal Regulations
1. Occupational Safety and Health Administration
Prior to January 17, 1978, occupational exposure to acrylonitrile
had been limited by the Occupational Safety and Health Administration
(OSHA; P.L. 91-596) to an 8-hour time weighted average of 20 ppm (- 45
mg/m3) (Table Z-l; 29 CFR 1910.1000). This was the level recommended by
the American Conferenca of Governmental Industrial Hygienists (ACGIH, 1971)
on the basis of animal exposure data and by analogy with the 10 ppm thres-
hold limit value (TLV) for hydrogen cyanide. On January 17, 1978 OSHA
issued an Emergency Temporary Standard (ETS) which reduced the permissible
exposure to 2 ppm, with a ceiling level of 10 ppm for any 15 minute period
during the 8-hour day. The standard also includes an action level of 1 ppm
as an 8-hour time-weighted average (TWA). A permanent standard will be
issued by July, 1978. Three sets of permissible exposure limits are under
consideration for the permanent standard: 2 ppm AN as an 8-hr TWA; with a
10 ppm ceiling limit over any 15 min period; 1 ppm TWA with a 5 ppm ceiling;
and a 0.2 ppm TWA with a 1 ppm ceiling limit. Enviro Control (1978) con-
ducted an economic assessment of these proposed levels. A public hearing
on the proposed standard began on March 21, 1978. The proposed levels
represent concentrations achievable by engineering controls. There is no
implication that these levels are necessarily safe for worker exposure.
As background to the issuance of the Emergency Temporary Standard,
this course of events occurred: On June 29, 1977 OSHA issued a notice re-
questing information on acrylonitrile stating that the current regulation
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for worker exposure may not be sufficiently protective and that the is-
suance of an Emergency Temporary Standard was being considered (42 FR 33043)
Such action was based on information recently released from the Manu-
facturing Chemists Association (interim report on long-term feeding and
inhalation studies; teratogenicity study) and DuPont (epidemiology study
indicating cancer risks). Based on these and other studies, the National
Institute for Occupational Safety and Health (NIOSH) called for handling
acrylonitrile in the workplace as if it were a human carcinogen (Finklea,
1977). On September 29, 1977 NIOSH recommended in a Criteria Document
sent to OSHA that workplace exposure to acrylonitrile be limited to 4 ppm
of air or 8.7 mg/m3 as determined by a 4-hour sample collected at 0.2
1/min (see section on Detection Methods).
The Emergency Temporary Standard of 2 ppm issued by OSHA was parti-
cularly in response to the carcinogenic potential of acrylonitrile. The
standard applies to workers engaged in the manufacture of acrylic and
modacrylic fibers, ABS and SAN plastics and resins, nitrile rubber,
specialty polymers, plastic and polyurethane intermediates, and polymer
solutions. Related activities such as packaging, repackaging, storage,
transportation and disposal of acrylonitrile are also covered. Many pro-
cesses where acrylonitrile is present in only small amounts are excluded
from the standard.
2. Department of Transportation
Requirements for the transportation of acrylonitrile are contained
in the Hazardous Materials Transportation Act (PL 93-633), specifically,
the Hazardous Materials Table (49 CFR 172.101). Acrylonitrile is classi-
fied as a flammable liquid. Requirements for the packaging of flammable
liquids are contained in 49 CFR 173.119.
The outside packaging for acrylonitrile must contain these labels
for flammable liquids and poisons:
18Q
-------
Any motor vehicle, rail car, or freight container transporting acrylo-
nitrile must display placards on the outside of the vehicle identifying
the cargo as flammable. Labeling regulations are currently in force,
but the placarding compliance date has been extended to July 1, 1978
(42 FR 58522).
The transport of acrylonitrile in a passenger-carrying aircraft,
rail car or cargo vessel is prohibited. When shipped by cargo-only air-
craft, a maximum of 1 quart of acrylonitrile may be contained in each
package shipped. For cargo vessels, acrylonitrile may be stowed "on
deck" or "under deck".
3. Environmental Protection Agency
a. Federal Insecticide, Fungicide, and Rodenticide Act
Under authority of the Federal Insecticide, Fungicide and Rodenticide
Act (FIFRA) (PL 94-140, PL 92-516) acrylonitrile (in a fumigant formulation
with carbon tetrachloride) is classified for restricted use by the Environ-
mental Protection Agency (Costle, 1978). The criteria influencing re-
striction were the hazard and accident history of both acrylonitrile and
carbon tetrachloride. Procedures to be followed by registrants when using
restricted use pesticides are set forth in the Federal Register of February
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9, 1978 (43 FR 5782), about 5 months after proposed procedures were pub-
lished .(Sept. 1, 1977, 42 FR 44170; Costle, 1977).
There are 4 federally registered products containing acrylonitrile:
i) Stauffer Acritet 34-66-Fumigant
ii) ACRON 35
iii) SMCP Tetra-Fumigant
iv) B & G Fumi-ban
(Anon., 1978d). The manufacturers of these products have voluntarily can-
celled these formulations according to the EPA Office of Special Pesticide
Reviews. However, there are two manufacturers in Florida formulating an
AN-CCl^ fumigant.
b. Clean Air Act (PL 95-95)
As of January, 1978 acrylonitrile is not regulated under the Clean
Air Act. A decision awaits information from EFA's Cancer Assessment Group
and from Midwest Research Institute's Monitoring program (Anon., 1977n).
c. Federal Water Pollution Control Act
Acrylonitrile is one of 65 "Consent Decree" substances which are to be
regulated under Section 307 of the Federal Water Pollution Control Act
(PL 92-500). As a result of civil action, the EPA signed a consent agree-
ment in June 1976 to establish effluent limitations for the discharge of
these 65 substances. A water quality criteria is being drafted for acrylo-
nitrile. This criterion is due to be published on June 20, 1978 and will
provide for water to be of fishable and swimmable quality.
Effluent limitation guidelines for discharges associated with
acrylic resin, acrylic fiber,and ABS and SAN manufacture (40 CFR 416)
were suspended at 40 FR 21731.
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d. Federal Water Pollution Control Act as Amended by the
Clean Water Act of 1977 (P.L. 95-217)
Section 53. Under this section the EPA must establish effluent
limitations for the 65 "Consent Decree" substances, which includes AN, no
later than July, 1980. Other chemicals are also under consideration;
EPA is working from a list of 129 "Priority Pollutants", which includes
aeryloni trile.
Section 311. The EPA has designated 271 substances, including
AN, as hazardous under Section 311 and subject to spill control effective
June 12, 1978 (Costle, 1978b). Acrylonitrile (also 60 of the other sub-
stances) is considered "nonremoveable" from water after discharge. Also
established was the "harmful quantity" for each substance, based primarily
on LDso values, when discharged into water; for AN, this was determined
to be 100 pounds. In addition, civil penalties were established for dis-
charge of each substance in "harmful quantities" or greater. For acrylo-
nitrile the approximate rate of penalty is $8.80 per pound of spilled mater-
ial. The penalty rate takes into account the "harmful quantity" as well as
a physical/chemical/dispersal factor (whether the substance floats, sinks,
mixes, precipitates or is miscible when discharged).
Section 504. Section 504 gives the Administrator of the E.P.A.
emergency powers to take action in the event of a release of any pollutant
into any media. The potential exists, therefore, for action in the event
of a spill of acrylonitrile.
e. Solid Waste Act as Amended by the Resource Conservation
and Recovery Act (Oct. 21, 1976)
Draft regulations of the amended Solid Waste Act call for the control
of hazardous wastes. Criteria are being drawn up to regulate solid waste
from specific industrial processes, with an effective date projected for
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mid-1979. In all likelihood, control of acrylonitrile will be affected
under these process lists. Waste substances will be subject to toxicity
and mutagenicity testing; control of acrylonitrile may also be affected
as a result of this testing program.
4. Food and Drug Administration
The Food and Drug Administration regulates the use of acrylonitrile
polymer and copolymer products when they are to be used in contact with
food under 21 CFR 174-180.
The Food and Drug Administration amended food additive regulations
(21 CFR 177.1020; 177.1030; 177.1040; 177.1050 and 177.1480) to eliminate
the use of acrylonitrile copolymers to fabricate beverage containers
(42 FR 48528-48544; Kennedy, 1977). The commissioner of Food and Drugs,
Donald Kennedy, upheld an administrative law judge's decision that acrylo-
nitrile copolymers used to fabricate beverage containers are food addi-
tives and have not been shown to be safe. The FDA ban on acrylonitrile
went into effect on December 22, 1977. Monsanto has filed a petition for
judicial review of FDA's decision'(Anon., 1977o).
Acrylonitrile polymers and copolymers, which are considered indirect
food additives, can be used in other non-beverage food contact uses in-
cluding use in the following: adhesives; coatings; polyolefin films;
paper and paperboard components (in contact with aqueous and fatty foods
as a size promoter and retention aid; in contact with dry food); polymers
and elastomers as components of single and repeated use food contact sur-
faces; and semi-rigid and rigid vinyl chloride plastics (21 CFR).
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B. State Regulations
Agencies in 15 selected states (including those containing pro-
duction and major end-use sites) were contacted about state-level regula-
tions; responses appear in Table 53-56.
1. Workplace Standards
Of states responding to information requested on workplace exposure,
all enforce the standards set by the Occupational Safety and Health Ad-
ministration (Table 53).
2. Use as a Pesticide
States responding indicated acrylonitrile for fumigant use must be
registered with the appropriate state office (e.g., in Ct., Pesticide
Compliance Unit; in Missouri, Dept. of Agriculture; in Tenn., Division
of Plant Industries). New Jersey, New York and Connecticut specifically
indicated that acrylonitrile appears on state lists of restricted use
pesticides (Table 54).
3. Water Quality
In most states, acrylonitrile is indirectly limited by general water
quality standards (Table 55).
4. Air Emissions
Some states have established weight rate emission limitations (Table
55). For example, in Ohio, acrylonitrile is considered photochemically
reactive, and as such, emissions are limited to 8 Ibs./hour and 40 Ibs./day
per equipment, machine or article. However, if the source has a control
device that is at least 85% efficient, the mass emission requirement is
waived. In New York State, acrylonitrile is considered a toxic air con-
taminant when emissions exceed 1 Ib./hour. In Texas, acrylonitrile is
classified as a volatile carbon compound, with restrictions for volatile
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Table 53
Regulations for Acrylonitrile Food Contact and Work-
place Standards in Selected States; Asterisks(*) In-
dicate that Federal Standards are Followed, while
Dashes Indicate no Response from State Agencies
Food Contact Workplace Standards
California * *
Connecticut * *
Delaware * *
Kentucky
Louisiana - -
Missouri
New Jersey * *
New York *
Ohio
Pennsylvania - *
South Carolina * *
Tennessee - *
Texas
^federal standards followed; dashes indicate no response
Table 54
Pesticide Restrictions for Acrylonitrile in Selected States
S tate S tandard
California no response
Connecticut follows federal guidelines; AN is a restricted use
pesticide in Conn.; user must be licensed by
Pesticide Compliance Unit of Conn. Dept. Env. Prot.
Delaware follows federal guidelines
Louisiana no response
Missouri requires registration with Missouri Dept. of Agriculture
New Jersey AN is on N.J. Restricted Use list; user must have a
N.J. Pesticide Applicator certification
New York AN is a Restricted Pesticide under authority of N.Y.
Environmental Conservation Law and Markets Law
Ohio no response
Pennsylvania registered under Pa. Pesticide Control Act
South Carolina follows federal guidelines
Tennessee all pesticides must be registered with the Division
of Plant Industries
Texas no response
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Table 55
Water Standards for Acrylonitrile in Selected States
State
S tandard
California
Connecticut
Delaware
Kentucky
Louisiana
Missouri
New Jersey
New York
Ohio
Pennsylvania
South Carolina
Tennessee
Texas
no response
no specific water quality standards or regulations;
subject to case-by-case technical permit review by
Water Compliance and Hazardous Substance Unit
not specifically controlled
no response
case-by-case permit review
no specific regulations
comply with Federal discharge requirements under
FWPCA
no water quality standards for AN
general water quality standards apply; State
Law: OAC-3745-1
general water quality standards apply
indirectly limited by general water quality criteria
general standards for toxic substances and organics
apply
no response
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Table 56
Air Standards for Acrylonitrile in Selected States
State
S tandard
California
Connecticut
Delaware
Kentucky
Louisiana
Missouri
New Jersey
no response
emissions restricted to 8 lb/hr., 40 Ibs/day for
organic solvents; State Law: Section 19-508-20f(2)
general air quality standards apply; State Law:
Reg. 1-XX111 of Dept. Nat. Res. & Env. Control
(for air pollution)
no response
no specific emission regulations
no specific regulations
general restrictions for volatile organic
substances apply and ambient air quality standaxis;
State Law: NJEPA N.J. Adm. Code Title 7, Chp. 27
New York
Ohio
Pennsylvania
South Carolina
Tennessee
Texas
AN considered at toxic air contaminant when
emissions exceed 1 lb/hr.; State Law: Industrial
Process Air Pollution Control Rule, part 212
considered photochemically reactive (PR) by the
Ohio Environmental Protection Agency. Emission
requirements for PR materials is 8 Ibs/hour
and 40 Ibs./day per equipment, machine or article.
However, if the source has a control device (that
is at least 85% efficient) the mass emission re-
quirement is waived; State Law: OAC 3745-21-01(C)
no weight rate emission limitations for AN; standards
for organic compounds apply for storage and loading;
State Law: Pa. Air Pollution Control Act
no specific regulations
general process emission standards; State Law:
1200-3-7-.07
regulated as a volatile carbon compound; State
Law: Reg. V
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carbon storage, loading, and waste gas disposal listed in Regulation V
of the Texas Air Control Board.
5. Food Contact
States responding indicated reliance on the regulations of the
U.S.D.A. and F.D.A. (Table 52).
C. Foreign Countries
Agencies in several -countries were contacted about acrylonitrile
regulations. Their responses are summarized below (standards in U.S.S.R.
and Bulgaria are from the literature).
1. United Kingdom
The workplace standards for acrylonitrile currently in force in the
United Kingdom are:
TLV 20 ppm (45 mg/m3) TLV = threshold limit value
S.TEL 30 ppm (68 mg/m3) STEL =» short-term exposure limit
The United Kingdom is currently re-evaluating acrylonitrile as a
suspected carcinogen. In general, they follow closely the standards
recommended by the American Conference of Governmental Industrial Hygien-
ists (ACGIH) . There are no water quality or air emission standards in
the U.K. for acrylonitrile.
2. Canada
In Canada, occupational health falls under provincial, not federal,
jurisdiction, so that in theory there could be 11 different standards.
In general, provincial standards reflect ACGIH and/or OSHA recommendations.
There are no tolerance limits for acrylonitrile coming into contact
with food, but Canadian studies are currently in progress to measure the
extent of migration into food.
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3. West Germany
In the Federal Republic of Germany, acrylonitrile is listed as a
cancer-causing agent. No acceptable workplace standards can be set for
such substances.
In waste gas, acrylonitrile cannot exceed 20 mg/m3 (when flow rate
is 0.1 kg/hr or more). There are no specific water quality standards for
acrylonitrile.
4. Belgium
Acrylonitrile can be used as a fumigant only by persons who are li-
censed.
5. U.S.S.R. and Bulgaria
The mean acceptable concentration for acrylonitrile in the workplace is
0.5 mg/m3 (1.1 ppm) in the U.S.S.R. and Bulgaria (Zotova, 1975; Spassovski, 1976)
D. Other Standards - Threshold Limit Value
The American Conference of Governmental Industrial Hygienists (ACGIH,
1971) recommended an & hour time weighted average of 20 ppm on the basis
of animal exposure data and by analogy with the 10 ppm threshold limit
value (TLV) for hydrogen cyanide. This had been the limit used by OSHA,
until exposures were reduced to 2 ppm by the issuance of an Emergency
Temporary Standard.
E. Current Handling Practices
1. Handling, Storage and Transport (American Cyanamid , 1974)
Because acrylonitrile presents health and fire hazards, caution must
be exercised in its handling. Acrylonitrile drums should be stored on
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end no more than two high with the bungs up. To reduce the possibility of
fire, acrylonitrile should be grounded electrically when being withdrawn
from storage equipment. Top unloading is recommended for withdrawing
acrylonitrile from tank cars or trucks.
Storage tanks are usually large enough to receive the entire contents
of a tank car plus a working reserve (10 to 50%). American Cyanamid
recommends that tanks be located above ground, resting on and anchored
to concrete saddles surrounded by concrete or a padded earth dike. The
dike should be large enough to contain the entire contents of the tank
in case of tank failure. Insulation is not required (boiling pt. 77°C;
freezing pt.-83°C).
Storage or handling containers should be thoroughly cleaned, as
contaminated containers may initiate polymerization or decomposition. In
particular, strong alkali or strong oxidizers (especially bromine) will
initiate violent, exothermic polymerization.
Handling of acrylonitrile should be in a cool well-ventilated area,
away from ignition sources.
•
Acrylonitrile is shipped by rail (40.4%), barge (1.7%) and truck
(56.5%) (OHM-TADS, n.d.). Containers used for shipping have been de-
scribed elsewhere in this report (II-C-4).
2. Personnel Exposure
American Cyanamid (1974) has suggested that the following protective
equipment be available to workers: safety harness and life line, gas-tight
safety goggles; industrial gas mask; neoprene or butyl rubber gloves, apron
and boots; safety showers; fire extinguishers; and first-aid kit.
By authority of an Emergency Temporary Standard, OSHA requires that
respiratory protection, protective clothing, and protective equipment
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(i.e., goggles) be available to employees (Bingham, 1978). Table 57
lists respiratory protection available for AN. OSHA also prescribed hy-
giene practices and medical surveillance necessary for compliance with the
Emergency Temporary Standard. Workers exposed to AN must undergo a train-
ing and information program. Warning signs must be posted.
3. Accident Procedures
NIOSH suggested removing workroom spills by vacuum cleaning or by
another method which does not increase the concentration of airborne
acrylonitrile (NIOSH, 1977).
American Cyanamid (1974) suggests that small amounts of waste acrylo-
nitrile resulting from leaks or spills can be removed to a remote loca-
tion, poured onto dry sand or earth (preferably in a pit) then ignited.
Such burning must comply with air pollution regulations.
The EPA Office of Hazardous Materials (OHM/TADS; n.d.) and the
Coast Guard (DOT, 1974) suggested procedures to follow for larger spills.
Fire and air authorities should be notified. The immediate area should
be evacuated (EPA) or at least have restricted access (DOT). The Civil
Defense should be warned of a potential explosion.
Carbon or peat may be used to adsorb acrylonitrile. Alkali solu-
tion will suppress HCN evolution and will help convert AN to the less toxic
cyanate, but should be used with caution. EPA recommends leaving acrylo-
nitrile in the nitrile form. Water containing less than 50 mg/1 is sub-
ject to biological degradation.
The 0 and H Materials, Inc. (Finley, Ohio) drilled wells to pump
acrylonitrile from contaminated groundwater to clean up a spill of 36,000
gallons in Gilford, Indiana (Manganaro, 1977, pers. comm.). This same
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Table 57
Respiratory Protection for Acrylonitrile
(Bingham, 1978)
Concentration of AN or
Condition of Use
Respirator Type
(a) Less than or equal to 20 ppm
(b) Less than or equal to 100 ppm
(c) Less than or equal to 4,000 ppm
(d) Less than or equal to 20,000 ppm
(e) Emergency entry into unknown
concentrations or fire fighting.
(f) Escape
(1) Any chemical cartridge respira-
tor with organic vapor cartridge
and half-mask; or
(2) Any supplied air respirator with
half-mask.
(1) Any organic vapor gas mask; or
(2) Any supplied air respirator
with full facepiece; or
(3) Any self-contained breathing
apparatus with full facepiece.
(1) Supplied air respirator in
positive pressure mode with
full facepiece, helmet, hood,
or suit.
(1) Supplied air respirator and
auxiliary self-contained full
facepiece in positive pressure
mode; or
(2) Open circuit self-contained
breathing apparatus with full
facepiece in positive pressure
mode.
(1) Any self-contained breathing
apparatus with full facepiece in
positive pressure mode.
(1) Any organic vapor gas mask; or
(2) Any self-contained breathing
apparatus with full facepiece.
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company adsorbed AN onto both peat moss and activated carbon to clean up
a spill of 500-600 gallons in Benson, Kentucky (Patterson, 1977, pers:
connn.). .
Harsh (1978) described a method successfully used by the Ohio EPA to
neutralize a spill of acrylonitrile. A tank car containing 133,300 pounds
of acrylonitrile punctured and caught fire. The fire was put out and the
next day most of the remaining acrylonitrile was pumped into a tank car
and removed from the scene. However, samples of residual puddles near the
spill site contained up to 7,231 mg/1 AN. To prevent contamination of the
groundwater the Ohio EPA began a neutralization process to act on the
cyanide portion of the AN molecule. This process involved raising the pH
of the AN contaminated area above 10 with lime, and then spraying chlorine
over the area. Four days after the spill, lime (^ 9600 pounds) was spread
over the area using a bulldozer and shovels. That evening, 900 pounds of
dry granular sodium hypochlorite were mixed with 1700 gallons of water and
applied to the area. Samples taken after 2-4 days showed removal of 90 to
97+ percent of the acrylonitrile. Data for samples taken appear below:
Location AN (mg/1) AN (mg/1) Removal (%)
before treatment after treatment
Puddle north side of tracks 2,203 62.5 97+%
Puddle south side of tracks 7,231 13.1 99+%
Pool in woods 82-471 24 90-96%
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VI. EXPOSURE AND EFFECTS POTENTIAL
Concern about the environmental exposure potential of acrylonitrile
is warranted, especially in light of its potential carcinogenic effects.
As discussed previously, environmental exposure can result during produc-
tion, transport, end-use, and waste handling. For humans, the highest
esposure potential is in the workplace ; risks will be reduced substan-
tially with compliance to the recently promulgated Emergency Temporary
Standard.
Occupationally, up to 12,000 workers in the U. S. come into contact
with acrylonitrile during the most dangerous phases of its use. However,
considering all uses-, about 125,000 workers are exposed (Anon, 1978c).
OSHA described several processes where employee contact to acrylo-
nitrile would be most severe (Bingham, 1978) . In the manufacture of
acrylic fibers, exposure is greatest during wet-spinning when, after the
fibers have coagulated, residual AN is driven off from'the solvent.
Potential exposure to acrylonitrile occurs at several points during
ABS resin manufacture, including: conveyance of AN from storage tanks;
the blending, flocculation and drying areas; suspension and solution
polymerization.
In nitrile rubber manufacture, risks occur especially when the poly-
merization product (with butadiene) is transferred to a tank where
residual monomers are stripped. The resulting latex still contains high
levels of unreacted monomer, thus exposure is also likely during the coagu-
lation, washing and drying processes.
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OSHA also assessed Che risks to workers who produce products containing
acrylonitrile. Handling of fibers is not a likely source of exposure.
However, processing polymer latex is a potential source due to the high
levels of unreacted monomer present.
In addition to occupational exposure, the possibility exists for
general population exposure to acrylonitrile. However, no data are cur-
rently available to adequately assess this risk. On-going monitoring studies
at producer and user facilities by the Midwest Research Institute will con-
tribute information needed to perform a general population risk assessment
(see section II-C). Based on limited monitoring data and estimates, losses
of acrylonitrile to the atmosphere appear to be several times higher during
polymerization operations ("* 4100 tons AN emitted/yr) than monomer produc-
tion (Mascone, 1978). During monomer production, small amounts of AN
(0.00042-0.82 g AN/kg AN produced) have been identified from the absorber
vent, incinerator stack, flare stack, product loading and storage facilities
and from fugitive emissions (Table 15). Acrylonitrile is volatile and re-
active so would not be expected to persist in the atmosphere; however, no
studies were available on the atmospheric reactivity of AN.
Low level population exposure is possible from end-product use. OSHA
indicates that there is no risk of residual acrylonitrile monomer migrating
from finished acrylic or modacrylic fibers (Bingham, 1978). A. T. Kearney
Inc. (1978) indicate little migration from finished consumer products.
However, migration from SAN/ABS resins has been shown (summarized in Kennedy,
1977). The possibility exists for environmental contamination from resins
of other finished products. The range of products made from acrylonitrile
is large; the extent of acrylonitrile migration varies from product to
product. Therefore, a general acceptable level of migration cannot be set
205
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(Bingham, 1978). A possible source of aquatic contamination is from residual
AN leaching from acrylamide used in water treatment and soil consolidation.
However, no studies are available which assess this potential risk. Residual
AN is about 1 ppm in polyacrylamide (Kearney, 1978) and 50-100 ppm in acryl-
amide monomer (Am. Cyanamid, 1977).
Transportation spills are another source of potential human contact
with acrylonitrile. Human exposure at the scene of a spill would likely
•ause signs and symptoms known to occur in the workplace-e.g., headache,
mucous membrane irritation, vertigo, nausea, vomiting, and incoordination
and dermatitis. Contamination of the drinking water might lead to central
nervous system impairment, liver injury and hematological alterations.
Based on a study of A. D. Little (1974) and on actual reported spill
incidents (Table 17) spills of acrylonitrile are most likely to occur along
a rail route than by truck or barge transport. Monitoring data from actual
spills are sparse. Acrylonitrile persisted for about a year or more in
monitoring wells located near (within 100 feet) a tank car spill of 20,000
gallons of AN (Table 20). Initial levels of up to 35,000 mg AN/1 were de-
tected. No attempt at clean-up or containment was made until 108 days
after the spill occurred; at that time 46-3520 mg AN/1 were detected in
monitoring wells. Levels decreased after some contaminated soil and ground-
water was removed (Illinois EPA). In another spill (36,000 gallons onto
farmland) the levels of AN in the groundwater increased for several months
after each rainfall, indicating some short-term persistence. In a differ-
ent spill, residual puddles initially contained up to 7,231 mg AN/1 but a
neutralization process reduced levels by 90% or more (Harsh, 1978).
206
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The high levels of AN resulting from large spills are likely lethal
to most microorganisms, severely hampering biodegradation and thus increas-
ing persistence. Smaller levels (up to 50 mg AN/1), however, have been
shown to be broken down biologically in laboratory tests. Unfortunately,
no studies are available on the fate of AN under environmental conditions.
The potential for release of AN from deep wells, into which AN
production wastewaters are injected, has not been assessed.
207
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TECHNICAL SUMMARY
Acrylonitrile, CH2CHCN, is a-reactive, volatile chemical inter-
mediate used mainly in the manufacture of fibers, resins, and synthetic
rubber. A minor amount of AN is also used as a fumigant. More than 1.5
billion pounds of AN are produced annually, with a growth rate of 8-10% pro-
jected for the next few years (Anon, 1977b). Production occurs at six
sites by four manufacturers (American Cyanamid Co.; E. I. DuPont de
Nemours and Co., Inc.; Monsanto Co.; Vistron Corporation). All produce
acrylonitrile by the catalytic vapor phase oxidation of propylene and
ammonia (ammoxidation of propylene); by-products include acetonitrile
and hydrogen cyanide.
Small amounts of acrylonitrile enter the environment during several
phases of its production. Other sources of potential environmental con-
tamination include transportation losses, end-product manufacture and
end-product use.
Limited data on environmental exposure indicate that up to 50 mg
AN/1 (highest level tested) in aqueous systems are subject to biological
degradation, particularly if the microorganisms are acclimated. Due to
its chemical reactivity and biodegradability, acrylonitrile is expected
to have a short residence time in the environment (Nat'l. Acad. Sci.,
1975).
208
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Recent evidence indicates that acrylonitrile exposure may present
increased carcinogenic, teratogenic, and mutagenic risks. A preliminary
study by DuPont revealed excess cancer incidence and cancer mortality
among workers exposed to acrylonitrile at a fiber plant in Camden, S. C.
(O'Berg, 1977). In rats, preliminary data from, two studies sponsored by
the Manufacturing Chemists Association, show that prolonged exposure to
acrylonitrile results in higher tumor incidence (including carcinomas)
(Norris, 1977; Clark, 1977 and 1978). In one study rats were exposed to
vapor levels of 20 or 80 ppm AN 6 hours/day for 5 days/week; in another
study rats consumed 35, 100 or 300 mg/1 (ppm) AN in the drinking water.
Interim sacrifices after one year revealed tumors of the stomach, central
nervous system and Zymbal gland of the ear canal in rats receiving AN in
the drinking water at 100 or 300 mg/1. Rats exposed to 80 ppm AN vapor
for 2 years developed tumors of both the central nervous system and ear
canal and mammary region masses; at 20 ppm, there was an increase in sub-
cutaneous masses of the mammary region. Maltoni et al. (1977) found AN
to have a "borderline oncogenie effect" in rats ingesting (5 mg/kg, 3x/wk)
or inhaling (87, 43, 22, or 11 mg/m3, 4 hr/day, 5-days/wk) the compound
for 52 weeks.
In another study, maternal and fetal toxicity occurred in gravid rats
receiving 25 or 65 mg AN/kg orally during gestation (Murray et al., 1976).
Embryotoxic effects have been shown for mice (Scheufler, 1976). Acrylo-
nitrile was positively mutagenic in some bacterial assays, but not others
(e.g., SRI, 1976; Litton Bionetics, 1975; Milvy and Wolff, 1977; Venitt
et al., 1977).
209
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Acrylonitrile is toxic in humans by inhalation, ingestion, and skin
contact. Several cases of acrylonitrile intoxication have been reported
for industrial exposure in synthetic rubber manufacture and polymerization
(Wilson, 1944; Wilson et al., 1948), and for accidental exposure (Dudley
and Neal, 1942; Sartorelli, 1966), including fumigant use (Grunske, 1949;
Badimer et al., 1974). Acute vapor exposure can cause headache, mucous
membrane irritation, vertigo, vomiting and incoordination. A few cases of
anemia and jaundice have been attributed to acrylonitrile (Wilson, 1944).
Fumigant exposure has resulted in toxic epidermal necrolysis and, in a
few cases, death. Direct skin contact results in irritation and diffuse
erythema. Russian and Japanese epidemiological studies indicate that
long-term exposure may result in hematological alterations, mild liver in-
jury, and central nervous system impairment (Sakurai and Kusumoto, 1972;
Zotova, 1975; Shustov, 1968).
In mammals, lethal doses of acrylonitrile generally result in altered
breathing, incoordination, weakness, convulsions, and coma, followed by
death. There has been some disagreement about whether breathing is ini-
tially stimulated before becoming shallow (as occurs in cyanide poisoning)
(c.f. Dudley and Neal, 1942; Paulet et al., 1966). Depending on the dose
and route, death usually occurs within 24 hours. At low doses, recovery
is usually complete, without apparent after effects. Signs vary less be-
between routes of administration than between dose and species. In laboratory
mammals, acute oral LDgo values range from 25 to 128 mg AN/kg while acute
parenteral values range from 15 to 130 mg AN/kg. By both route, mice are
most sensitive; guinea pigs, and rats are generally least sensitive. In-
halation studies show dogs to be most sensitive to acrylonitrile (Dudley and
Neal, 1942). Direct skin contact results in erythema. Dermal LDso values
range from 25 to 128 ml AN/kg for guinea pigs and rabbits.
210
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Predominant effects of acute doses of acrylonitrile to laboratory
animals include: central and peripheral nervous system damage (Hashimoto
and Kanai, 1965; Paulet et al., 1966); bilateral adrenal apoplexy and
necrosis (Szabo and Selye, 1971; Szabo et al., 1976); lowered levels of
nonprotein sulfhydryl content of the kidney (Wisniewska-Knypl et al., 1970;
Szabo et al., 1977),. liver (Dinu and Klein, 1976; Vainio and MSkinen, 1977), lung
(Szabo et al., 1977) and brain (Hashimoto and Kanai, 1972); and hemorrhagic
areas of the lungs and liver (e.g., Dudley and Neal, 1942; Jedlicka et al.,
1958).
Long-term effects of acrylonitrile have been described for rats and
dogs. ,Rats ingesting acrylonitrile in the drinking water (35, 85, 210,
or 500 lmg/1. / AN) for 90 days showed no treatment-related pathologic al-
terations; decreased body weight gain and increased liver to body weight
ratios occurred among rats receiving the two higher doses (Humiston et al.,
1975). Incorporation of 0.05 or 0.2% AN in the drinking water of
rats for 21 to 60 days affected mineralcorticoid and glucocorticoid pro-
ducing cells of the adrenal cortex (Szabo et al., 1976). Subacute ingestion
of low levels of acrylonitrile in rats caused dose dependent increases in
liver glutathione levels (Szabo et al., 1976). Subacute injection and
inhalation may adversely affect the nervous system, liver, and kidneys and
retard growth, depending on the dose.
Rats ingesting acrylonitrile for 13 months (35-300 mg/1 AN in the
drinking water) showed decreased water consumption, but normal blood chem-
istry and cell levels. At the higher doses, food consumption and body
weight gain were reduced. Dogs also showed reduced food and water consumption
211
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when given acrylonitrile in the drinking water (200 or 300 mg/1 for up to
6 mo.)- Most dogs at these levels either died spontaneously or were euth-
anized, showing terminal depression, lethargy, weakness, emaciation and
pneumonia.
In laboratory organisms, acrylonitrile is broken down to cyanide
(which is oxidized to thiocyanate) and reacts with sulfhydryl groups by
cyanoethylation. Minor pathways are either unconfirmed or not positively
identified. The metabolism of acrylonitrile appears to be species,.route
and dose dependent (Gut et al., 1975; Young et al., 1977). The toxic ac-
tion of acrylonitrile may be due partly to cyanide formation but is also
probably due to the direct action of acrylonitrile. However, there may
be substantial species differences (i.e., cyanide-mediated toxicity is
likely in mice but doubtful in rats). There has been considerable dis-
agreement about the mechanism of action.
Acrylonitrile is toxic to fish and other aquatic species. The 24-hour
median tolerance limit values for several species of freshwater fish ranges
from 25-45 mg AN/1 (ppm) . Concentrations lethal to shrimp, aquatic insect
larvae and insects are known (~ 1-50 mg/1).
The current workplace exposure is limited by the Occupational Safety
and Health Administration to 2 ppm (a time-weighted average over 8 hours).
Acrylonitrile is classified as a restricted use pesticide.
212
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Szabo, S., Reynolds, E. S., Komanicky, P., Moslen, M. T. and Melby,
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228
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230
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CONCLUSIONS AND RECOMMENDATIONS
Limited data on environmental fate and the absence of monitoring
data make it difficult to assess the effects of environmental contamination
by acrylonitrile at the present time. However, potential contamination is
possible during production, transport, end-use and waste-handling. With
the projected growth of acrylonitrile markets, concomitant increases in
potential hazards can be expected. The need for additional environmental
evaluation studies of acrylonitrile is apparent. Studies sponsored by the
EPA for AN are currently underway at and near production sites. Research
on the biodegradability of acrylonitrile is ongoing at several universities,
e.g., University of Texas and Rutgers University. Additional research,
however, on chemical breakdown (particularly in the atmosphere), transport
and persistence of AN in the environment would be desirable. Presently it
can only be speculated, based on physical-chemical properties and very
limited data, that small quantities of acrylonitrile will not persist or
bioconcentrate.
The effects of large acrylonitrile spills on ecosystems have not been
investigated. Controlled studies and intensive monitoring of actual spills
would be desirable.
The toxic effects of acrylonitrile to mammals are well known, parti-
cularly for acute exposures. Ongoing studies sponsored by the Manufactur-
ing Chemists Association will contribute to long-term assessment of toxic
and carcinogenic effects in rats. There is a paucity of data of effects
on terrestrial microorganisms and plants. Without such information the
effects of acrylonitrile on ecosystems cannot be fully known.
231
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' As more data emerge, assessment of the environmental exposure to
acrylonitrile will become more precise. Implementation of pending regula-
tions should reduce levels of acrylonitrile in some environmental media.
232
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Appendix A
Summary of Sources Employed
References used in this report were selected from searches of auto-
mated information retrieval systems, indices, standard reference works,
journals, books, etc. Manufacturers, researchers, and federal and state
agencies, among others, were contacted directly.
The following is a list of on-line systems searched:
Cancerline
Chemical Abstracts Condensates
Chemical Industry Notes
Economic Information System
Enviroline
Federal Index
Federal Index Weekly
Food Science and Technology Abstracts
Marketing Abstracts
Marketing Abstracts Weekly
National Technical Information System
Office of Hazardous Materials Technical
Assistance Data System
Pollution Abstracts
Smithsonian Science Information Exchange
Science Citation Index
Toxline
Toxback
Water Resources Abstracts
Also the Technical Information Center data base was searched by the National
Institute of Occupational Safety and Health.
Manually searched indices included:
Biological Abstracts (1959-1977)
Chemical Abstracts (1957-1971)
Excerpta Medica
Cancer (1953-1977)
Pharmacology and Toxicology (1965-1977)
Developmental Biology and Teratology (1965-1976)
Environmental Health and Pollution Control (1972-1976)
Occupational Health and Industrial Medicine (1971-1976)
Index Medicus (1957-1977).
233
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Appropriate books and compendia were examined. In addition, current
journals were screened. The literature search is considered complete
through April 1978.
234
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TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
1. REPORT NO.
EPA 56Q/2-78-QQ3
3. RECIPIENT'S ACCESSION NO.
4. TITLE AND SUBTITLE
Investigation of Selected Potential Environmental
Contaminants: Acrylonitrile
5. REPORT DATE
May 1978
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
Lynne M. Miller and Jon E. Villaume
8. PERFORMING ORGANIZATION REPORT NO,
FIRL 80G-C4807-01
9. PERFORMING ORGANIZATION NAME AND ADDRESS
Science Information Services Organization
Franklin Institute Research Laboratory
20th and Race Streets
Philadelphia, Pa. 19103
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
EPA 68-01-3893
12. SPONSORING AGENCY NAME AND ADDRESS
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C. 20460
13. TYPE OF REPORT AND PERIOD COVERED
Final Report
14. SPONSORING AGENCY CODE
15. SUPPLEMENTARY NOTES
Technical Advisor- Patricia Hilgard , E.P.A.
literature on acrylonitrile. Major
exposure, chemistry, production and
Acrylonitrile is used in a wide variety
billion pounds of acrylonitrile are
air, and ammonia. Low levels of
16. ABSTRACT
This report is a survey and summary of the
aspects of its biological effect?.environmental
use, and regulations are reviewed and assessed.
of plastics, fibers, and elastomers. About 1.5
produced annually by the reaction of propylene,
acrylonitrile enter the environment during production, storage, end-product manufacture,
and end-use, although extensive monitoring data are not available. Recent evidence
shows acrylonitrile to be carcinogenic in animals and possibly carcinogenic in humans.
It resulted in birth defects when fed to pregnant rats and caused mutations in some type
of bacteria. Short-term exposure to humans causes headache, mucus membrane irritation,
dizziness, vomiting and incoordination. 'Several fatalities have resulted from fumigant
use. Direct skin contact produces blisters resembling second-degree burns. In laborator
mammals,- signs of acrylonitrile intoxication include altered breathing, incoordi nation,
weakness, convulsions, and coma. Signs are especially variable between species and the
dose administered. Effects may include central and peripheral nervous system damage;
hemorrhaging of the lungs, adrenals, or liver; and depressed sulfhydryl content of the
kidneys, liver, or lungs. Long-term administration of acrylonitrile may affect growth,
food and water intake, adrenal function, and the central nervous system, depending on
the dose.
17.
KEY WORDS AND DOCUMENT ANALYSIS
a.
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS
u. COSATI Field/Group
Acrylonitrile
Carcinogens
Chemical Industry
Environmental Engineering
Regulations
Toxicology
Biological & Med.
Sciences
- biology
- clinical medici
- toxicology
18. DISTRIBUTION STATEMENT
Document is available to the public through
the National Technical Information Service,
Springfield, Virginia 22151
19. SECURITY CLASS (This Report)
21. NO. OF PAGES
234 pp.
20. SECURITY CLASS (This page)
22. PRICE
EPA Form 2220-1 (Rev. 4-77) PREVIOUS EDITION is OBSOLETE
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
DATE: September 5, 1978
SUBJECT: Acrylonitrile Report - Errata
FROM: Frank Letkiewicz, Project Officer
OTE/Assessment Division
TO: Laura Akgulian
OPII, CID
Please inform NTIS that the following reference was omitted from
the bibliography of EPA 560/2-78-003, "Investigation of Selected Potential
Environmental Contaminants: Acrylonitrile":
Maltoni, C., Cilberti, A., and DiMaio, V. (1977), "Carcinogenicity
Bioassay on Rats of Acrylonitrile Administered by Inhalation and by
Ingestion," Estratto da La Medicina del Lavoro, 68:401-411.
Thank You.
cc: Pat Hilgard
EPA FORM J320-6 (REV. 3-76)
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