ACRYLONITRILE
Ambient Water Quality Criteria
Criteria and Standards Division
Office of Water Planning and Standards
U.S. Environmental Protection Agency
Washington, D.C.
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CRITERION DOCUMENTS
ACRYLONITRILE
CRITERIA
Aquatic Life
For acrylonitrile the criterion to protect freshwater aquatic
life as derived using the Guidelines is 130 ug/1 as a 24-hour
average and the concentration should not exceed 300 ug/1 at any
time.
For acrylonitrile the criterion to protect saltwater aquatic
life as derived using procedures other than the Guidelines is 130
ug/1 as a 24-hour average and the concentration should not exceed
290 ug/1 at any time.
Human Health
For the maximum protection of human health from the potential
i
carcinogenic effects of exposure to acrylonitrile through inges-
tion of water and contaminated aquatic organisms, the ambient
water concentration is zero. Concentrations of acrylonitrile
estimated to result in additional lifetime cancer risks ranging
from no additional risk to an additional risk of 1 in 100,000 are
presented in the Criterion Formulation section of this document.
The Agency is considering setting criteria at an interim target
risk level in the range of 1Q~$, io~6, or 10~7 with corresponding
criteria of 0.08 ug/1/ 0.008 ug/1/ and 0.0008 ug/1, respectively.
If water alone is consumed, the water concentration should be less
than 0.16 ug/1 to keep the lifetime cancer risk below 10~5.
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ACRYLONITRILE
Introduction
Acrylonitrile is an explosive, flammable liquid having a
normal boiling point of 77°C and a vapor pressure of 80 torr
(20°C). The toxic effects of acrylonitrile are similar to
cyanide poisoning although not identical. The chemical
structure of acrylonitrile, CH2=CHCN, resembles that of vinyl
chloride, a material known to cause human cancer.
At present 1.6 billion pounds per year of acrylonitrile
are manufactured in the United States. The major use of
acrylonitrile is in the manufacture of copolymers for the
production of acrylic and modacryclic fibers by copolymeriza-
to. *
tion with methyl acrylate, methyl methacrylate, vinyl ace-
tate, vinyl chloride, or vinlyidene chloride (Natl. Inst.
Occup. Safety Health, 1977). Other major uses of acryloni-
trile include the manufacture of acrylonitirile-butadiene-
styrene (ABS) and styrene-acrylonitrile (SAN) resins (used to
produce a variety of plastic products), nitrile elastomers
and latexes, and other chemicals (e.g., adiponitrile, acryla-
mide). Acrylonitrile has been used as a fumigant; however,
all U.S. registrations for this use were voluntarily with-
drawn as of August 8, 1978 (43 FR 35099). The U.S. Food and
Drug Administration has recently banned the use of an acry-
lonitrile resin for soft drink bottles (Chem. Eng. News,
1977, 1978), but its use is still allowed in other food pack-
aging. The National Institute for Occupational Safety and
Health estimates that 125,000 persons are potentially exposed
to acrylonitrile in the workplace (Natl. Inst. Occup. Safety
Health, 1977).
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AcryJ.onitrile has been reported as acutely toxic to fish
at concentrations as low as 10,100 ug/1 and to the inverte-
brate, Daphnia magna, at 7,550 ug/1. Chronic toxic effects
were not seen in D. magna at concentrations up to and includ-
ing 3,600 ug/1. The bluegill, Lepomis macrochirus, concen-
trated .acrylonitrile in its tissues by a factor of 48. The
only available datum for a saltwater organism is a 96-hour
LC50 of 24,500 ug/1 for the pinfish, Lagodon rhomboides (U.S.
EPA, 1978).
At present the body of evidence produced in both toxic-
ity studies on laboratory animals and occupational epidemio-
logic studies on man suggests that acrylonitrile may be a hu-
man carcinogen. Thus, NIOSH has recently voiced,its opinion .
that "acrylonitrile must be handled in the workplace as a
suspect human carcinogen" (Natl. Inst. Occup. Safety Health,
4-
1978). This judgment of NIOSH is based primarily on (1) a
preliminary epidemiologic study of E.I. de Pont de Nemours
1
and Co., Inc. on acrylonitrile polymerization workers from
».
one particular textile fibers plant (Camden, S.C.); in this
study, it was ascertained that a substantial excess risk
* *
(doubling1 over expected) of lung and colon cancers occurred
between 1969 and 1975 in a cohort exposed between, 1950.and
1955 (O'Berg, 1977); (2) interim results from ongoing 2-year
studies on laboratory rats performed by Dow Chemical Co., and
reported jsy the Manufacturing Chemists Association (April,
1977) (as- cited in Federal Register) in which, by either
drinking 'water or inhalation routes of acrylonitrile expo-
sure, laboratory rats developed CNS tumors and zymbal gland
A-2
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carcinomas, not evident in control aminals. Mammary region
masses were also in excess upon exposure to 80 ppm (Chem.
Eng. News, 1978; Norris, 1977; Quast, et al. 1977).
Aside from suggestive evidence of carcinogenicity in man
and animals, numerous workers have reported on the other
genotoxic characteristics of acrylonitrile (embryotoxicity,
mutagenicity, and teratogenicity) in laboratory animals
(Venitt, et al. 1977; Milvey and Wolff, 1977; Murray, et al.
1976). Even though there is some controversy over the
chronic effects of acrylonitrile (Shaffer, 1975), the acute
toxicity of acrylonitrile is well known and the compound ap-
pears to exert part of its toxic effect through the release
of inorganic cyanide (Fassett, 1963; Wilson, 1944).
A-3
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REFERENCES
Chem. Eng. News. Sept. 12, 1977.
Chem. Eng. News. Jan. 23, 1978.
Fassett, D.W. 1963. Cyanides and nitriles. In Industrial
hygiene and toxicology. Vol. II. Interscience Publishers,
New York.
Federal Register. Vol. 43. No. 192, p. 45764, Tuesday,
Oct. 3, l'978.
Milvey, P., and M. Wolff. 1977. Mutagenic studies with
acrylonitrile. Mutat. Res. 48: 271.
Murray, F.J. , et al. 1976. Teratologic evaluation of acrylo-
nitrile monomer given to rats by gavage. Rep. Toxicol. Res.
Lab. Dow Chemical Co., Midland, Mich.
National Institute for Occupational Safety and Health. 1977.
Current intelligence bulletin: Acrylonitrile, July 1. Dep.
Health Edu. Welfare, Rockville, Md.
National institute for Occupational Safety and Health. 1978.
A recommended standard for occupational exposure to acryloni-
trile. DHEW Publ. No. 78-116. U.S. Government Printing
Office, Washington, D.C.
A-4
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Norris, J.M. 1977. Status report on two-year study incorpor-
ating acrylonitrile in the drinking water of rats. Health
Environ. Res. Dow Chemical Co.
O'Berg, M. 1977. Epidemiologic studies of workers exposed to
acrylonitrile; preliminary results. E.I. Dupont de Nemours &
Co.
Quast, J.F., et al. 1977. Toxicity of drinking water con-
taining acrylonitrile in rats: Results after 12 months.
Toxicol. Res. Lab., Health Environ. Res. Dow Chemical Co.
Shaffer, C.B. 1975. Toxicology of acrylonitrile. In F.A.
Ayer, ed. Environmental aspects of chemical use rubber pro-
cess operations. Conf. Proc.
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. U.S. Environ. Prot.
Agency. Contract No. 68-01-4646.
Venitt, S., et al. 1977. Mutagenicity of acrylonitrile (cya-
noethylane) in Escherichia coli. Mutat. Res. 45: 283.
Wilson, R.H. 1944. Health hazards encountered in the manu-
facture of synthetic rubber. Jour. AMA 124: 701.
A-5
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AQUATIC LIFE TOXICOLOGY*
FRESHWATER ORGANISMS
Introduction
No acute or chronic effects of acrylonitrile on freshwater
aquatic life were observed at concentrations below approximately
2,600 ug/1. The 96-hour LC50 values for three fish species and
the 48-hour EC50 for Daphnia magna range from 7,550 to 33,500
ug/l» which indicates that the probable range of sensitivity be-
tween fish and invertebrate species is not great.
Acute Toxicity
The sensitivity of fathead minnows to acrylonitrile has been
tested under different test conditions and water quality
(Henderson, et al. 1961). The pH values were 8.2 for hard water
and 7.4 for soft water. These water quality characteristics ap-
parently do not affect the toxicity of acrylonitrile. Flowthrough
and static test conditions, using measured concentrations, were
compared, and the unadjusted LC50 value was lower for the flow-
through test (10,100 ug/D than for the static test (18,000 ug/1.
*The reader is referred to the Guidelines for Deriving Water Qual-
ity Criteria for the Protection of Aquatic Life [43 FR 21506 (May
18, 1978) and 43 FR 29028 (July 5, 1978)] in order to better
understand the following discussion and recommendation. The fol-
lowing tables contain the appropriate data that were found in the
literature, and at the bottom of each table are the calculations
for deriving various measures of toxicity as described in the
Guidelines.
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The 96-hour unadjusted LC50 values were 14,300 and 18,100 ug/1 at
hardness .concentrations of 380 and 29 mg/1 as CaCOs, respec-
tively (Table 1). After adjustment for test conditions, the
static LC50 is 12,851 ug/1. The adjusted 96-hour LC50 values for
the bluegill, fathead minnow, and guppy (Henderson, et al. 1961)
vary from 8,378 to 23,785 ug/1. The Final Pish Acute Value calcu-
lated from these data is 3,100 ug/1-
The only datum for freshwater invertebrate species is the
48-hour EC50 of 7,550 ug/1 for Daphnia magna (Table 2). The Final
Invertebrate Acute Value is 300 ug/lr and since this concentration
is lower than the comparable value for fish, it also becomes the
Final Acute Value for acrylonitrile.
Chronic Toxicity
Daphnia magna has been exposed for its life cycle and the
results indicate no adverse effects at concentrations as high as
3,600 ug/1 (Table 3). This concentration is only about 0.5 of the
48-hour EC50 (7,550 ug/1) for the same species under comparable
conditions (U.S. EPA, 1978). This small difference between acute
and chronic effects for Daphnia magna is unlike that relationship
between acute and chronic effects for the fathead minnow. Hender-
son, et al. (1961), using flow-through methods and measured con-
centrations, observed a 96-hour LC50 of 10,100 ug/1 (Table 1), and
when that test was continued, the 30-day LC50 was 2,600 ug/1
(Table 5) .
The Final Invertebrate Chronic Value is greater than 710
ug/1, which is derived by dividing the chronic value for Daphnia
magna by the sensitivity factor of 5.1 (Table 3).
B-2
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Residues
The bluegill was exposed for 28 days to 14C-acrylonitrile
with thin layer chromatography being used to verify exposure and
tissue concentrations (U.S. EPA, 1978). The bioconcentration fac-
tor for whole body was 48 with a half-life in the tissues of be-
tween four and seven days (Table 4).
Miscellaneous
As stated earlier/ the 30-day LC50 for fathead minnows under
flow-through conditions was 2,600 ug/1 (Table 5), a result that is
about one-fourth of the comparable 96-hour LC50 of 10,100 ug/1.
Intermediate LC50 values were 6,900 ug/1 after 10 days and 4,200
ug/1 after 20 days. These data suggest that mortality would con-
tinue to occur even after 30 days. Henderson, et al. (1961) also
exposed adult bluegill to 5,000 ug/1 for 1 to 4 weeks and prepared
the fish for a taste study panel (Table 5). No flavor impairment
was detected at that concentration, which was almost one-half of
the 96-hour LC50 value for the bluegill as determined by the same
investigators. It is therefore unlikely that acrylonitrile will
impair the flavor of freshwater fish.
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CRITERION FORMULATION
Freshwater-Aquatic Life
Summary of Available Data
The concentrations below have been rounded to two significant
figures.
Final Fish Acute Value = 2,500 ug/1
Final Invertebrate Acute Value = 300 ug/1
Final Acute Value = 300 ug/1
Final Fish Chronic Value - not available
Final Invertebrate Chronic Value = greater than 710 ug/1
Final Plant Value = not available
Residue Limited Toxicant Concentration » not available
Final Chronic Value = greater than 710 ug/1
0.44 x Final Acute Value = 130 ug/1
The maximum concentration of acrylonitrile is the Final Acute
Value of 300 ug/1 and the 24-hour average concentration is 0.44
times the Final Acute Value. No important adverse effects on
freshwater aquatic organisms have been reported to be caused by
concentrations lower than the 24-hour average concentration.
CRITERION: For acrylonitrile the criterion to protect fresh-
water aquatic life as derived using the Guidelines is 130 ug/1 as
a 24-hour average and the concentration should not exceed 300 ug/1
at any time.
B-4
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Tatie i. Freshwater fish acute values for acrylonitrile
CD
i
•
in
Bioaeeay Test
Or q an isn Method- Cone.**
Fathead minnow, S U
Pimephales pror.elas
Fathead minnow, S U
Pimephales pro.Telas
Fathead minnow, FT U
Pimephales promelas
Guppy, S U
Lebistes reticulatus
Blueglll. S U
Lepomis macrochirus
Bluegill, S U
Lepomis macrochirus
Tine
Ihral
96
96
96
96.
96
96
LC50
tuq/lL
14,300
18,100
10.100
33.500
11.800
10.100
Adjusted
LCiO
lua/ll
7.818
9.895
7.777
18.314
6,451
5,522
heter fence
Henderson, et al.
Henderson, et al.
Henderson, et al.
Henderson, et al.
Henderson, et al.
U.S. EPA. 1978
1961
1961
1961
1961
1961
* S - static. FT - flow-through
** U - unmeasured, M • measured
-9-71S
Geometric mean of adjusted values - 9.735 wg/l • j-| • 2.500 ng/1
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2. Freshwater invertebrate acute values for acrylonitrile (U.S. EPA. 1978)
Adjusted
bicassay Test ti*e L£&0 LCiO .. • -
-• £g£S*** tf-ts) . juii/ij luu/ti
Cladoceran,. S U 48 7.550 6,395
Daphnia magna
* S • static
** U • unaieasured
Geometric mean of adjusted values » 6.395 ng/1 ^T22 " ^0 "S/1
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00
I
Tatle 3. Freshwater invertebrate chronic values for acrylonitrile (U S. EPA. 1978)
organism
Cladoceran,
Daphnia magna
Cnzonic
Limits Value
rest* luw/n iya^il.
LC >3,600 >3.600
* LC = life cycle or partial life cycle
Geometric mean of chronic values »
Lowest chronic value « >3,600 pg/1
Geometric mean of chronic values » >3,600 pg/1 * *-. = >710 pg/1
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Tatle 4. Freshwater residues for acrylonitrile (U.S. EPA, 1978)
Tiftre
Organism Eioconceiitration Factoi (uays;
Bluegill. A8 28
Lepomis macrochirus
CO
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00
I
Table S. Other freshwater data for acrylonitrile
Organism
Fathead minnow,
Ptmephales promelas
Bluegill,
Lepomts macrochirus
Test
Duration
30 days LCSO
1-4 wks No detectable flavor
impairment of tissues
Bluegill (fingerlings), 96 hrs 100% survival
Lepomis macrochirus
Result
juq/ll
2,600
5,000
10,000
peterence
Henderson, et al. 1961
Henderson, et al. 1961
Buzzell, et al. 1968
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SALTWATER ORGANISMS
Introduction
The only datum for the effect of acrylonitrile on saltwater
organism's is a* 96-hour LC50 for the pinf ish.
Acute foxicity
The 96-hour LC50 value for the pinf ish af.ter use of the
Guidelines adjustment factors is 8,840 ug/1 (Table 6). The Final
Fish Acute Value calculated from this result is 2,400'- ug/1. The
comparable value for freshwater fish is 3,100 ug/1, and based on
this minimum amount of data, the sensitivity of freshwater and
saltwater fish species may be similar.
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CRITERION FORMULATION
Saltwater-Aquatic Life
Summary of Available Data
The concentrations below have been rounded to two significant
figures.
Final Fish Acute Value = 2,400 ug/1
Final Invertebrate Acute Value = not available
Final Acute Value = 2,400 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = not available
Residue Limited Toxicant Concentration = not available
Final Chronic Value = not available
0.44 x Final Acute Value = 1,100 ug/1
No saltwater criterion can be derived for acrylonitrile
using the Guidelines because no Final Chronic Value for either
fish or invertebrate species or a good substitute for either
value is available.
However, results obtained with acrylonitrile and freshwater
organisms indicate how a criterion may be derived.
For acrylonitrile and freshwater organisms, 0.44 times the
Final Acute Value is less than the Final Chronic Value that is
derived from results of a life cycle test with Daphnia magna.
Therefore, it seems reasonable to estimate a criterion for
acrylonitrile and saltwater organisms using 0.44 times the Final
Acute Value. Both a Final Fish Acute Value and a Final Inverte-
brate Acute Value are available for acrylonitrile and freshwater
organisms, and the Final Acute Value is based on the invertebrate
B-ll
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value sihce it is the lower of the two* For saltwater organisms,
only a Final Fish Acute Value is available. For freshwater or-
ganisms, the Final Invertebrate Acute Value divided by the Final
f
Fish Acute Value is 300 - 2,500 ug/1 » 0.12. Multiplying this
value times the saltwater Final Fish Acute Value for acrylonit-
rile results in an estimated saltwater Final Invertebrate Acute
Value of 0.12 x 2,400 ug/1 « 290 ug/1. Thus the estimated Final
Acute Value for acrylonitrile is 290 ug/1. Multiplying the Final
Acute Value of 290 ug/1 by 0.44 gives 130 ug/1.
The maximum concentration of acrylonitrile is the Final
Acute Value of 290 ug/1* and the 24-hour average concentration is
0.44 times the Final Acute Value. No important adverse effects
on saltwater aquatic organisms have been reported to be caused by
concentrations lower than the 24-hour average concentration.
CRITERION: For acrylonitrile the criterion to protect salt-
water aquatic life as derived using procedures other than the
Guidelines is 130 ug/1 as .a 24-hour average and the concentration
should not exceed 290 ug/1 at any time.
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09
I
+-•
u>
Table 6. Marine fish acute values for acrylonitrile (Daughercy & GarreCC, 1951)
Organism
Pinfish (juvenile).
Lagodon rhomboides
Bioasaay Test Time
Method* Cone.** thre)
24
LCSO
lug/11
Adjusted
LCSO
(ug/i)
24.500 8.840
* S = static
** U - unmeasured
Geometric mean of adjusted values = 8,840 yg/1
= 2.400 ug/1
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ACRYLONITRILE
REFERENCES
, J,C.,, «t al. 1968. Behavior of organic chemicals in
the aquatic environment. Part II, behavior in dilute systems,
Washington* B.C. Manufact,. Chem. Assoc.
Daugherty, F-M. Jr., and J.T, Garrett. 1951. Toxicity levels
of hydrocyanic acid and some industrial by-products. Tex.
Jour. SQi. 3: 391.
Henderson, C., et al. 196,1. The effect of some organic cya-
nides (nitrile.s) on fish. Eng,. Bull. Ext. Ser. Purdue Univ.
No. 106: 130.
i
U.S. EPA. 197-8. In-depth studies on health and' environmental
impacts of seclected water pollutants. U.S.., Environ. Prot.
Agency, Contract No. 68-01-4646.,
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ACRYLONITRILE
Mammalian Toxicology and Human Health Effects
EXPOSURE
Introduction
Acrylonitrile is an explosive, flammable liquid having
a normal boiling point of 77°C and a vapor pressure of 80
torr (20°C). The toxic effects of acrylonitrile are similar
to cyanide poisoning although not identical. The chemical
structure of acrylonitrile, CHj^CHCN, resembles that of
vinyl chloride, a material known to cause human cancer.
Synonyms for acrylonitrile include cyanoethylene, 2-pro-
penenitrile, VCN, and vinyl cyanide. Polymerization grade
acrylonitrile contains a number of impurities and additives,
namely, dimethylformamide, hydrogen peroxide, hydroxyani-
sole, methyl acrylate, phenyl ether-biphenyl mixture, sodium
metabisulfite, sulfur dioxide, sulfuric acid, and titanium
dioxide. (O'Berg letter, 1977).
At the present time 1.6 billion pounds per year of
acrylonitrile are manufactured in the United States by the
reaction of propylene with ammonia and oxygen in the pres-
ence of a catalyst. (A number of other processes are used
outside the United States.) Current domestic producers
of acrylonitrile are American Cyanamid Company (New Orleans,
Louisiana), E. I. de Pont de Nemours Company, Inc. (Beau-
mont, Texas and Memphis, Tennessee), Monsanto Company (Choco-
late Bayou, Texas), and The Standard Oil Company (Lima,
Ohio).
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The major use of acrylonitrile is in the manufacture
of copolymers for the production of acrylic and modacrylic
fibers by copolymerization with methyl acrylate, methyl
methacrylate, vinyl acetate/ vinyl chloride, or vinylidene
chloride. Acrylic fibers, marketed under tradenames including
Acrilan, Creslan, Orion, and Zefran, are used in the manufac-
ture of apparel, carpeting, blankets, draperies and uphol-
stery. Some applications of modacrylic fibers are synthetic
furs .and hair wigs; tradenames for modacrylic fibers in-
clude Acrylan, Elura, SEP, and Verel. Acrylic and/or mod-
acrylic fibers are manufactured from acrylonitrile by Amer-
ican Cyanamid Company (Milton, Florida), Dow Badishe Company
(Williamsburg, Virginia), E. I. de Pont de Nemours and Com-
pany, Inc. (Camden, South Carolina and Waynesboro, Virgin-
ia) , Eastman Kodak Company (Kingsport, Tennessee), and Mon-
santo Company (Decatur, Alabama) (NIOSH, 1977).
Other major uses of acrylonitrile include the manufac-
ture of acrylonitrile-butadiene-styrene (ABS) and styrene-
acrylonitrile (SAN) resins (used to produce a variety of
plastic products), nitrile elastomers and latexes, and other
chemicals (e.g., adiponitrile, acrylamide). Acrylonitrile
has been used as a fumigant; however, all U.S. registrations
for .this use were voluntarily withdrawn as of August 8,
*
1978 (Federal Register, Vol. 43, p.35099). The 13.S. Food
and Drug Administration has recently banned the use of an
acrylonitrile resin for soft drink bottles (Chem. Eng.
News, Sept. 12, 1977; Jan. 23, 1978), but its use is still
allowed in other food packaging. NIOSH estimates that 125,000
persons are potentially exposed to acrylonitrile in the
workplace. (NIOSH, 1977). ^2
-------
At the present time, the body of evidence produced
in both toxicity studies on laboratory animals and occupa-
tional epidemiologic studies on man suggests that acryloni-
trile may be a human carcinogen. Thus, NIOSH has recently
voiced its opinion that "acrylonitrile must be handled in
the workplace as a suspect human carcinogen." (NIOSH, 1978).
This judgment of NIOSH is based primarily on (1) a prelimi-
nary epidemiologic study of E. I. de Pont de Nemours and
Company, Inc. on acrylonitrile polymerization workers from
one particular textile fibers plant (Camdens- South Carolina) ;
in this study, it was ascertained that a substantial ex-
cess risk (doubling over expected) of lung and colon cancers
occurred between 1969 and 1975 in a cohort exposed between
1950 and 1955 (O'Berg, 1977); (2) interim results from on-
going 2-year studies on laboratory rats performed by Dow
Chemical Company, and reported by the Manufacturing Chemists
Association (April, 1977) in which, by either drinking water
or inhalation routes of acrylonitrile exposure, laboratory
rats developed CNS tumors and zymbal gland carcinomas, not
evident in control animals. Mammary region masses were
also in excess upon exposure to 80 ppm (Chem. Eng. News,
Jan. 23, 1978. Norris, 1977; Quast, et al. 1977)
/
Aside from suggestive evidence of carcinogenicity in
man and animals, numerous workers have reported on the other
genotoxic characteristics of acrylonitrile (ernbryotoxicity,
mutagenicity and teratogenicity) in laboratory animals (Venitt,
et al. 1977; Milvey and Wolff, 1977; Murray, et al. 1976).
Even though there is some controversy over the chronic ef-
fects of acrylonitrile (Shaffer, 1975), the acute toxicity
C-3
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of agrylonitrile is well known and the compound appears
to exert part of its toxic effect through the release of
inorganic cyanide (Fassett, 1963; Wilson, 1944).
In this compilation of the human health effects and
hazard evaluation of acrylonitrile, several reviews were
consulted (Grahl, 1970; Fassett, 1963; NIOSH, 1978). Much
of the literature relating to occupational exposure and
epidemiology is either Russion or East European in origin
and, for the most part, only abstracts of these works were
consulted.
With regard to the contamination of water supplies
with acrylonitrile, most of the work available on this sub-
ject is in the foreign literature and deals primarily with
either the use of polyacrylonitrile for filtration of indus-
trial wastes or the biological treatment of waste effluents
from acrylonitrile plants (Verkhovykh, et al. 1975; Skaki-
hara, et al. 1976; Pradt and Meidl, 1976). Research regarding
the monitoring of acrylonitrile in drinking water was not
available for consideration. This is not unexpected because
of the fact that only recently have the possible genotoxic
effects of acrylonitrile come to light.
Acrylonitrile is the most extensively produced aliphatic
nitrile and ranks 45th on the list of high volume chemicals
produced in the United States (Chem. Eng. News, May 1,
1978). The 1976 production of acrylonitrile was 1.6 billion
pounds (Chem. Eng. News, May 1, 1978) which is approximately
7 times the 1960 production volume.
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Approximately 125,000 individuals in the United States
are exposed to acrylonitrile monomer during its manufacture
and polymerization or during its molding to acrylonitrile-
based polymers including Dralong T, Barex 210, Lopac, buta-
diene-acrylonitrile and polyacrylonitrile (NIOSH, 1977).
Disposal of acrylic polymers, including polyacrylonitrile,
by burning results in the release of acrylonitrile monomer
(Rumber, 1971). Residual amounts of acrylonitrile monomer
are released from fabrics such as underwear made of poly-
acrylonitrile fiber (Rapoport, et al. 1974), and from furni-
ture and other items made of polyacrylonitrile plastics
Volskii, 1973). The public may also be exposed to acryloni-
trile by ingestion of food products which have leached resid-
ual acrylonitrile monomer from polyacrylonitrile packaging
materials, such as commercial plastic wraps for foods. (Chem
Eng. News, Feb. 28, 1977). This problem of acrylonitrile
monomer leaching has led the Food and Drug Administration
to ban the use of polyacrylonitrile plastic for beverage
containers (Chem. Eng. News, April 2,6, 1976 and Feb. 21,
1977). Cigarette smoke has been shown by gas chromatographic
analysis to contain aliphatic nitriles including acryloni-
trile, propionitrile and methacrylonitrile (Izard and Testa,
1968). The presence of aliphatic nitriles in cigarette
smoke may explain why Mallette (1943) found higher values
of thiocyanate (a known metc.bolic product of acrylonitrile)
in the blood and urine of acrylonitrile works who were smokers
compared to non-smokers.
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In brief, in addition to occupational exposure of those
involved in the manufacture and processing of aliphatic
nitriles., the public is exposed to acrylonitrile from the
breakdown of the acrylonitrile-based polymers to monomers
when the polymers are burned for disposal/ by release of
residual monomer from acrylic fibers and plastics, by leaching
of monomer from food packaging, and from cigarette smoke.
Some environmental monitoring for acrylonitrile has
been reported by the Midwest Research Institute (1978).
Limited analyses of air, water, and soils at several sources
and ambient locations throughout the United States resulted
in the occasional finding of acrylonitrile. The values
obtained are summarized in Table 1.
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TABLE 1
Location
(Source)
Fortier, Louisiana
(American Cyanamid)
Linden, New Jersey
(American Cyanamid)
Texas City, Texas
(Monsanto)
Decatur , Alabama
(Monsanto)
Camden, S. Carolina
(DuPont)
Waynesboro, Virginia
(Du Pont)
Washington, West Virginia
(Borg-Warner)
Air-
(Mg/nf
13.6
15.9
8.9
4.2
1.1
7.0
325
Maximum
Acrylonitrile Concentrations*
, Water** Soil**
J) (Mg/1) (Mg/kg)
0.1
0.8
0.4
3,600
20
none detected
1.5
0.5***
50
none detected
none detected
none detected
none detected
none detected
**
Analysis were performed at various time intervals.
Values given are maximum values. Some samples at the
same location may be lower or non-detectable.
Source of water or soil samples not indicated.
*** Only one sample was found where acrylonitrile was at
the detection limit of 0.5 mg/kg. All others were
below detection.
**** TOO low for GC/MS confirmation.
C-7
-------
from witter
While fio data on monitoring of water supplies for the
presence of acrylonitrile were found in the literature/
potential problems may exist. Because toxic manifestations
in animals have been elicited by this route of administra-
tion, this source of exposure is potentially an important
one,
There are limited data on the fate of acrylonitrile
in the aqueous environment. It is known that acrylonitrile
is hydrated readily at 100°C by 84.5 percent sulfuric acid
to produce acrylamide sulfate (Kirk and Othmer , 1967, p.
340). Whether this reaction occurs in the natural environ-
ment is unknown.
Acrylonitrile is known to undergo photodegradation
to saturated derivatives. When left standing, especially
in the presence of light, a yellow color may develop, poss-
t
G-8
-------
TABLE 2
Solubility of Acrylonitrile in Water as a Function of
Temperature (From Kirk and Othmer, 1967, pp. 338-350)
Solubility of
Q Acrylonitrile in
Temperature, C Water (grams/deciliter)
0 7.2
20 7.35
40 7.9
60 9.1
ibly due to polymerization (Kirk and Othmer, 1967). Acryloni-
trile is also subject to biodegradation (Kuchinskii, et
al. 1977; Panova, et al. 1977; Anon, 1977; Schnee, et al.
1977; Kato and Yamamura, 1976; Mikami, et al. 1974). Measure-
ment of biochemical oxygen demand has shown 25-70 percent
>
degradation within 10 days (Hann and Jensen, 1970). Zabe-
zhinskaya, et al. (1962) studied the persistence of acryloni-
trile in the water column, noting that at an initial concen-
tration of 10 mg/1, only 46 percent remained after 24 hours,
19 percent after 48 hours, and 5 percent after 96 hours.
This would tend to minimize the entry of acrylonitrile by
th,is route of exposure. It would be of great value to have
detailed data on the persistence of acrylonitrile in various
aqueous environments. A study by Midwest Research Institute
(1977) investigated the stability of 10 ppm acrylonitrile
in distilled water and Mississippi River water. Little
decomposition occurred after 23 days in distilled water.
In river water, however, total decomposition occurred by
day 6. Adjusting to a pH of 4 had a stabilizing effect
in that 67 percent of acrylonitrile was present at 23 days.
C-9
-------
Adjusting to a pH of 10 delayed decomposition up to 6 days
but total decomposition occurred by day 23.
Possible sources of acrylonitrile in the aqueous environ-
ment - either surface water, ground water or drinking water
- are: (a) dumping of chemical wastes, (b) leaching of wastes
$
from industrial landfills or holding lagoons, (c) leaching
of monomers from polymeric acrylonitrile, (d) precipitation
from atmospheric rain, and (e) loss during transfer and
transport. (Hardy, et al. 1973). The first four sources
listed are worthy of additional comment, and are discussed
below. '"
<
a) Dumping of chemical wastes: Acrylonitrile monomer
waste products are dumped by industrial companies directly
into surface waters or sewage. Acrylonitrile has been used
as a fumigant for stored food stuffs either alone or in
i
a mixture with carbon tetrachloride, (Fishbein, 1976), methyl-
bromide' (Dumas and Bond, 1977) and other chemicals (Heuser
and Scudamore, 1968). Though no longer in use, stored quanti-
ties of these fumigants may be being dumped by the former
manufacturers or the users.
The questions of biotransformations of acrylonitrile
in waste water, its effect on bacteria and particularly
on biological sewage treatment processes such as the acti-
vated sludge treatment process are poorly understood. How-
ever, Chekhovskaya, et al. (1966) have observed the effect
on saprophytic microorganisms and on ammonification and
nitrification of acrylonitrile and related compounds found
in the waste waters from acrylonitrile production. It was
found that acrylonitrile was utilized by saprophytic micro-
C-10
-------
organisms in concentrations of 150 mg/1 (ppm). Acryloni-
trile in a concentration of 50 mg/1 inhibited nitrification.
This suggests that acrylonitrile, entering an activated
sludge process in concentrations of 50 ppm or greater, may
inhibit certain bacterial processes such as nitrification.
Cherry, et al. (1956) reported that microbial activity could
substantially reduce acrylonitrile concentrations of 10,
25 and 50 ppm. They noted also that while the two lower
concentrations supported a mixed population of microorgan-
isms, the 50 ppm concentrations favored the growth of fungi.
This observation supports the findings of Chekhovskaya,
et al. (1966) on inhibition of nitrification at 50 ppm and
above. Other workers have shown similar reductions of acry-
lonitrile content in wastewater by microorganisms (Mikami,
et al. 1974; Kato and Yamamura, 1976).
b) Leaching of wastes from industrial landfills or holding
lagoons: Industrial chemical or pesticide wastes, placed
in holding tanks or lagoons, may spill over into surface
waters as a result of excessive rainfall. These same wastes
may be buried in industrial landfills. If the buried con-
tainers are damaged, rainfall may leach out the acryloni-
trile and providing that the soil is permeable, permit its
movement into proximal ground water.
c) Leaching of monomers from polymeric acrylonitrile:
It is well known that residual amounts of monomers are com-
monly retained in polymers; for example, vinyl chloride
is leached out of PVC pipes and into drinking water (Dress-
man and McFarren, 1978). Russian investigators have reported
that acrylonitrile and other monomers in finished polymers
C-ll
-------
were detected in the range of 30-3000 ppm (Klescbeva, et
al. 1970). Therefore, the acrylonitrile monomer can be
leached from waste polymers buried in landfills in the man-
ner described in
-------
Although PDA has banned the use of polyacrylonitrile.
plastic in soft drink bottles (Chemical and Engineering
News, 1977), attempts to lift this ban by the producing
companies are in progress. The FDA has restricted the mono-
mer residue to about 80 ppm in the finished products and
a restriction to 11 ppm was pending as of 1976. (Federal
Register, 1974, 1975, 1976; The National Resources Defense
Council, 1976). The currently produced soft drink container
includes about 20 ppm acrylonitrile of which as much as
0.3 ppm acrylonitrile and 0.2 ppm HCN are reported to leach
into hot water. (National Resources Defense Council, 1976).
A bioconcentration factor (BCF) relates the concentration
of a chemical in water to the concentration in aquatic organ-
isms, but BCF's are not available for the edible portions
of all four major groups of aquatic organisms consumed in
the United States. Since data indicate that the BCF for
lipid-soluble compounds is proportional to percent lipids,
BCF's can be adjusted to edible portions using data on percent
lipids and the amounts of various species consumed by Americans,
A recent survey on fish and shellfish consumption in the
United States , (Cordle, et al. 1978) found that the per capita
consumption is 18.7 g/day. From the data on the nineteen
major species identified in the survey and data on the fat
content of the edible portion of these species (Sidwell,
et al. 1974), the relative consumption of the four major
groups and the weighted average percent lipids for each
group can be calculated:
C-13
-------
Consumption Weighted Average
Group (Percent) Percent Lipids
Freshwater fishes 12 4.8
Saltwater fishes 61 2.3
Saltwater molluscs 9 1.2
Saltwater decapods 18 1.2
Using the percentages for consumption and lipids for each
of these groups, the weighted average percent lipids is
2.3 for consumed fish and shellfish.
A measured steady-state bioconcentration factor of
48 was obtained for acrylonitrile using bluegills containing
about one, percent lipids (U.S. EPAr 1978). An adjustment
factor of 2.3/1.0 =2.3 can be used to adjust the measured
BCF from the 1.0 percent lipids of the bluegill to the 2.3
percent lipids that is the weighted average for consumed
fish and shellfish. Thus, the weighted average bioconcentra-
tion factor for acrylonitrile and the edible portion of
all aquatic organisms consumed by Americans is calculated
to be 48 x 2.3 = 110.
Inhalation
The current estimate in the U.S. for the number of
'A
individuals involved in the manufacture and polymerization
of acrylonitrile is 125,000 (NIOSH, 1978). Therefore, a
considerable population is at high risk to occupational
exposures, particularly through inhalation. Analyses of
atmospheric air from an acrylic fiber plant in which a large
fraction of the coworkers complained of symptoms of illness,
revealed concentrations of acrylonitrile of 3-20 mg/m (Orusev,
et al. 1973).
C-±4
-------
Workers involved in acrylonitrile synthesis or its
polymerization are not the only occupational groups subject
to acrylonitrile exposure; workers in plastic (polyacryloni-
trile) molding factories are similarly at risk (Scupakas,
196$). Scupakas (1968) studied the working conditions in
an old factory producing thermosetting plastics by molding,
and noted various toxic manifestations in employees including
dermatitis, disorders of CNS, chronic upper respiratory
tract irritation, and other symptomatology when the acryloni-
trile concentration in the in-plant environment was 1.4
mg/m . However, various other compounds were present in
the in-plant atmosphere including phenol, formaldehyde,
ammonia, HC1, butyl phthalate and carbon monoxide. Timofiev-
skaya (1968), and Duvall and Rubey (1973) reported that
various types of acrylonitrile polymers underwent decomposi-
tion to various nitriles, NO , unsaturated hydrocarbons,
A
etc. either under molding conditions (40-400°C) or heating
i »
(40-80°C) and/or burning (200-600°C). The nature of the
products formed were highly dependent on combustion condi-
tions and contained significant amounts of highly toxic
compounds. Some of the polymers studied included Dramalon
T; polyacrylonitrile fiber; Barex 210 (3:1 acrylonitrile-
methylacrylate copolymer); Lopac (9:1 methacrylonitrile-
styrene copolymer); and 1,3 butadiene-nitrile rubber. It
is clear that burning of acrylic polymers, including poly-
acrylonitrile, represents a great potential occupational
and/or environmental hazard due to the release of high concen-
trations of acrylonitrile, other substituted vinyl compounds,
HCN, NO , and other undetermined compounds (Table 3).
A
C-15
-------
TABLE 3
pyrplysis pf Lopac as a Function of Temperature
Using Porapak N Column
(Monsanto, 1973)
Pyrolysis Q
Temperature( C) Pyrolysis Products
116 no compound observed
188 NH7 (trace)
230 NH.f
260 NH,
260 NH, >
290
330 NH3; HCN (trace); acrylonitrile
500 Air; CO; CO2; C2H2; NH3, HCN;
acetonitrile, acrylonitrile,
propionitrile; pyrrole
570 Air; CO; CO2; C2H4; C2H2; NH3; HCN; acetonitrile;
acrylonitrile; pyrrole
740 Air; CO; CO2; C2H4; C2H2; NH3; HCN; acetonitrile;
acrylonitrile; pyrrole
In addition, it is likely that various significant inter-
actions between the compounds occur (Hilado, et al. 1976;
Le Moan and Chaigneau, 1977).
Though data are unavailable,on monitoring the ambient
atmosphere for the presence of acrylonitrile; the stack
gases from synthesis and polymerization plants for acryloni-
trile may well be discharging significant amounts into the
atmosphere. As noted above, another potentially significant
ambient source of acrylonitrile and related compounds in
air is the outside burning of acrylonitrile polymers. While
it is known that aerylonltrile reacts photochemically in
i
the vapor phase (Kirk and Othmer', 1967) , no detailed data
were available to the authors on.the actual reactivity (t,)
T
of acrylonitrile in the atmosphere in ppm or ppb- concentra-
tions.
C-M
-------
Vol'skii, et al. (1973) have noted that the amount
of plastic and synthetic rubber furniture on boats must
be limited to 10.8 kg of LKF-2 plastic/m air to avoid
an accumulation of monomers such as acrylonitrile vaporizing
under the influence of the unusual combination of living
conditions (humidity, heat, and light). The authors recom-
mend adequate ventilation. Undoubtedly, the same findings
apply to homes. In a recent report, Rapoport, et al. (1974)
have indicated that traces of acrylonitrile were detected
in the air surrounding underwear made from polyacrylonitrile
fibers. Acrylonitrile, and a variety of other nitriles,
have been found by gas chromatography to be components of
cigarette smoke; the amounts were not quantified. (Izard
and Testa, 1968).
Inhalation has been reported to'be the major route
of exposure in lethal cases of acrylonitrile poisoning (Rad-
imer, et al. 1974). When man breathes air containing 20
ug acrylonitrile/liter (20,000 jug/m ) the average retention
of acrylonitrile vapors was found to be 46 percent (Rogac-
zewska and Piotrowsky, 1968). A later study by Young, et
al. (1977) found with rats that retention was greater than
90 percent (see Pharmacokinetics).
Dermal
Acrylonitrile has exhibited toxic effects on experi-
mental animals by skin absorption (Hashimoto and Kanai,
1965; Egorov, et al. 1976). Anton'ev, et al. (1970) have
reported that skin contact is one of the most important
routes for acrylonitrile absorption in plant workers and
that the absorption of acrylonitrile applied to the forearm
C-17
-------
PREDICTED SOURCES OF HUMAN EXPOSURE
TO ACRYLONITRILE
FOOD
(Pesticide residue
and monomer from
wrapping plus
bkxxcumulatibn in
fish from water)
AMBIENT
AIR DRINKING WATER
(Acrylonitrile vcpor (Dissolved Acrylonitrile)
plus adsorbed layer
on suspended
particulate)
SMOKING
other nitrites in
cigarette smoke)
and
EXPOSURE
TO
MAN
(
OCCUPATIONAL
(From aarylonitrile,
polyacrylonitrile,
manufacturing plants,
fiber production,
molding, etc.)
COMBUSTION OF
SYNTHETIC POLYMERS
(Acrylonitrile and other
toxic products in
vapors and particulate)
OTHER SOURCES
(Acrylonitrile monomer from
clothing, furniture, dental
materials, etc. )
Figure 1. Predicted Sources of Human Exposure,
C-18
-------
skin averaged 0.6 mg/cm2-hr. Egorov, et al. (1976) have
determined the threshold doses for dermal absorption of
acrylonitrile and other compounds in terms of a one-time
application to the skin as well as a four-month long chronic
application. The value for acrylonitrile was estimated
to be 0.11 mg/kg body weight. The maximum permissible contam-
ination level for the skin of the hands of workers was deter-
mined to be 0.7 mg of acrylonitrile» It is not clear from
the abstract whether the experiment was done on laboratory
animals and extrapolated to man or performed directly on
man. Dermatologic conditions including contact allergic
dermatitis, occupational eczema, and toxodermia in acryloni-
trile workers have been discussed by Dovzhanskii, (1976),
Balda (1975), Malten (1973), and Anton'ev, et al. (1970)
and show the importance of the dermal route in occupational
exposure. That there is a hypersensitivity response to
acrylonitrile has been discussed by Dovzhanskii, (1976),
Balda (1975) and Khromov (1974).
Because of the paucity of data available on acryloni-
trile, it is difficult to assess quantitatively the contribu-
tion of each route of exposure to the total dose in man;
it is likely that the greatest contribution comers via inhala-
tion, particularly in an occupational setting. The next
most likely route is dermal and the least likely is inges-
tion. Figure 1 is a schematic representation of the various
modes of exposure of man to acrylonitrile.
0-19
-------
PHARMACOKINETICS
Absorption and Distribution
Attempts were not made to separate these categories
due to the limited data available at the time of document
preparation. Subsequently, a study on the pharmacokinetics
of 1- C labelled acryloniltrile became available from the
Manufacturing Chemists Association. Details of this study
are included at the end of this chapter.
Blood concentrations of acrylonitrile and cyanide as
a function of time after exposure have been studied in rela-
tion to toxicity (Hashimoto and Kanai, 1965). In the rabbit
at a sublethal dose (30 mg/kg, LD50=75 mg/kg) a typical
blood concentration versus time curve was observed. Acryloni-
tr ile rapidly disappeared with 1 ppm of acrylonitrile remaining
4 hours after exposure. Thiosulfate accelerated the urinary
excretion of SCN~ as a metabolite and somewhat reduced the
toxicity of acrylonitrile; however, the blood concentration
versus time curve was not changed (Hashimoto and Kanai,
1965). L-cysteine administered prior to acrylonitrile resul-
ted in 80 percent reduction of acrylonitrile peak blood
levels and 30 percent reduction of its toxicity. Unchanged
acrylonitrile was detected in the urine of the rabbit 72
hours after exposure and in expired air 1 hour after dosing.
In guinea pig urine, acrylonitrile was detected 24 hours
after administration by gavage to 15 mg/kg (Hashimoto and
Kanai, 1965). Urinary and expiratory excretion of unchanged
acrylonitrile accounted respectively for only 3 and 10 per-
cent of the dose (15 mg/kg) while urinary thiocyanate ac-
counted for 14 percent of the dose (Hashimoto and Kanai,
C-20
-------
1965) . The remainder was probably metabolized via direct
enzymatic or non-enzymatic conjugation with nucleophilic
compounds such as, cysteine, glutathione, free or conjugated
basic amino acids. Alternatively, the remainder may undergo
enzymatic oxidation or reduction. A detailed metabolic
study is required to elucidate the toxicokinetics of acryloni-
trile.
Fat tissue accumulation of acrylonitrile may also occur.
While the high solubility of acrylonitrile in water (7.35
percent at 20°C, Kirk and Othmer, 1967) would permit the
excretion of the unchanged compound in the urine, the uri-
nary detection 72 hours after exposure in the rabbit strongly
suggests either fat storage or reversible protein binding.
Czajkowska (1971) has studied the excretion of metabolites
after a single i.p. dose (60-70 rag/kg) of acrylonitrile
in rats. The main urinary metabolite in rats was SCN~;
its excretion within 72 hours amounted to 8.5 percent of
acrylonitrile intake. The SCN~ excretion half-life was
13 hours. No cyanide was detected in rat urine within 24
hours following the single dose, while only traces of acrylon-
itrile were observed.
Metabolism
Earlier reports (Giacosa, 1883; Meurise, 1900) indi-
cated that most aliphatic nitriles are metabolized to cya-
nide which is then detoxified to thiocyanate. Levels of
cyanide and thiocyanate were elevated in the blood and pre-
sent in the urine of acrylonitrile-treated animals. Brieger,
et al. (1952) observed elevated levels of cyanide, thiocya-
nate (SCN~) and cyanomethemoglobin in the blood of animals
C-21
-------
treated with acrylonitrile. It was concluded that acryloni-
trile exerts its toxicity by the metabolic release of cya-
nide ion, and that the relative ability of various species
to convert CN~ to SCN~ determined their susceptibility to
?
the toxic action of acrylonitrile (Brieger, et al. 1952).
It was found that the urinary excretion of thiocyanate 'after
acrylonitrile administration ranged from 4-25 percent of
the administered dose (Brieger, et al. 1952; Czajkowska,
1971; Gut, et al. 1975; Efremov, 1976; Paulet and Oesnos,
1961; Benes and Cerna, 1959; Dudley and Neal, 1942; Hash-
imoto and Kanai, 1965). Brieger, et al. (1952) noted that
in dogs (a species particularly susceptible to acrylonitrile),
the relative concentration of cyanomethemoglobin increased
with length of exposure, with most of the available methemo-
globin converted to cyanomethemoglobin by the end of. the
lethal exposure period.
Using Wistar rats, albino mice and Chinese hamsters,
Gut, et al. (1975) found that the extent of conversion of
acrylonitrile to cyanide was dependent on the route of admini-
stration, decreasing in the following order: oral ( 20%)
i.p. = S.C.(2-4%) i.v. (1%) (See Table 4). Thus,
the more slowly acrylonitrile enters the system, the more
extensively it is converted to cyanide. This suggests that
conversion of acrylonitrile to cyanide involves metabolic
processes competing with blood protein binding and non-enzy-
matic cyanoethylation. Pretreatment of rats with phenobar-
bital, SKF 525A, cysteine, or dimercaprol (BAL) did not
significantly influence elimination of SCN~ in the urine
C-22
-------
after acrylonitrile administration; however, simultaneous
administration of thiosulfate and acrylonitrile signifi-
cantly increased the metabolized portion (thiocyanate) of
acrylonitrile given to rats by two-fold and mice by 3-fold.
Pretreatment with Aroclor 1254 was found to greatly enhance
the toxicity of acrylonitrile, and to cause a 3-fold increase
in the cyanide level in the blood of treated rats; Gut,
et al. (1975) found acrylonitrile to be strongly bound in
blood. Acrylonitrile was metabolized to SCN~ more effec-
tively by mice than by rats following oral, i.p., and i.v.
administration. Possible differences in the mechanism of
acrylonitrile toxicity in rats and mice are indicated by
the greater metabolism of acrylonitrile to SCN~ and the
larger decrease in its acute toxicity by thiosulfate in
mice compared with rats. Gut, et al. (1975) concluded that
cyanide may play a more important role in the toxicity of
acrylonitrile in mice than it does in rats.
TABLE 4
Influence of the Route of Administration of Acrylonitrile,
40 mg/kg (0.75 mM/kg) on Thiocyanate Elimination in Urine
of Female Wistar Rats in Percent of Dose. (Data of Gut, et al. 1975)
Expt. No.
I
I
II
II
IV
Oral
14.
23.
33.
21.
6
0
4
4
± 3'
± 3-
± 4«
± 1-
0*
2*
0*
6*
i.
5.
5.
2.
2.
p.
2
7
2
9
± °
± °
± °
± °
s.c. i.v.
.4 4.6 + 0.2 1.2 + 0.5**
.4
.1
.5
All results represent Mean + S.E.M., N = 5 to 6. Significantly different
by Student's t test, p 0.05~from: *i.p., s.c. and i.v. administration;
** i.p. and s.c. administration.
C-23
-------
In their study, Gut, et al. (1975) offered no explana-
tion for ths role of eysteine on the acrylonitrile SCN~
balance, nor do they explain cysteine*s protective mechanism
against aerylonitrile toxicity. If cysteine is protecting
tfte animal by reaction with acrylonitrile via formation
of eyanoethylcysl^eine, thiocyanate levels should decrease,
and ig it enhances cyanide metabolism, thiocyanate levels
should increase* However, pretreatment with cysteine had
no effect on thiocyante levels.'
In vitro, it was implicated that acrylonitrile was
conjugated with glutathione (GSH) via a GSH transferase
enzyme. (The conjugate of this reaction was not detected;
rather conjugation was measured indirectly by disappearance
of the GSH substrate) (Boyland and Chasseaud, 1967). Al-
though uptake of aerylonitrile gives rise to a slight in-
crease in cyanometheraoglobin, combined therapy with nitrite
and thiosulfate affords partial protection against its toxic
action. These fact^s suggest that acrylonitrile toxicity
is due in part to the acrylonitrile molecule itself or other
unknown metabolite(s) rather than just the cyanide functional
group. Only traces of unchanged acrylonitrile were detected
in the urine of ac.rylonitrile-treated rats (Czajkowska,
1971). This suggests that the major portion of the com-
pound is altered in the body to other metabolites, or conju-
gates such as indicated in the following scheme proposed.
Proposed pathways for acrylonitrile biotransformation
are presented in Figure 2. (A. Ahmed, personal communica-
tion). Cyanoethylated products (top pathway) of cell macro-
molecules and of circulating nucleophiles can be recovered
C-24
-------
R-CMj-CHjCN
1 f*icl«c ocitf*NH,OH)
JSWogtcal Neuroma
b)S«nMMi e)V-<
4oltMr nucltopMk
xCOOH
CHj-Cft-NHCOCHj
Fiqure 2. Proposed Pathways for Acrylonitrile Biotransformation,
C-25
-------
in tissue fractions and in biologic, fluids. If the proposed
pathway -is correct cyanoethylated glutathione conjugates
should be recoverable in bile and urine. One, in fact,
has been found - cyanoethylated mercapturic acid (Ahmed,
personal communication). Oxidation by the mixed function
oxidases or another enzyme system could lead to an epoxide
which could be enzymically hydrated, could rearrange, or
be acted upon by glutathathione transferase. In either
case, soluble oxidized products would be produced and cya-
nide would be liberated. Products of the proposed oxidation
pathways, including glyoxalic acid, oxalic acid, acetic
acid, cyanoacetic acid, and cyanide are soluble and should
be detectable in blood or urine.
Most recently, Young, et al. (1977) published the results
14
of a comprehensive radiotracer study in which 1 - C label-
led a^crylonitrile was used in male Sprague-Dawley Rats to
determine dose and route dependency of the pharmacokinetics
of this compound. The position of the radiotag allowed
tracking of the three carbon chain metabolites as well as
the one carbon cyano moeity. Three major routes of administra-
tion were used with the following dose variations:
i
Route Doses
Ingestion via single oral dose of aqueousO.l mg/kglO mg/kg solution,
Inhalation of 6 hours'
duration from a
"noge only" 5 ppm 100 ppm
chamber Calc. mean dose = 0.7 mg/kg 10.2 mg/kg
Intravenous injection10 mg/kg=
C-26
-------
The major conclusions of this study are highlighted in the
following:
Absorption: When orally administered to rats, essentially
all of the acrylonitrile is absorbed and metabolized. Only
5 percent of the dose is excreted with the feces in the
form of metabolites.
Metabolism: Qualitatively four metabolites, A, C, E and
C02 were identified in the rat. Three of these (A,C,E)
were excreted primarily in the urine, while CO2/ was primar-
ily exhaled with breath. Chemical identities of compounds
A, C, and E were not elucidated, but contrary to prior suspi-
cion none of these were acrylamide. Metabolite C predomi-
nated at low doses followed by compound A while molecule
E was present in trace quantities. This ratio changed at
high dose when A drastically increased. Recovery of total
radioactivity in metabolites, A, C, E and CO2 exceeded 94
percent.
Distribution: The metabolites of acrylonitrile were rapidly
distributed to all tissues. Plasma concentration of radio-
activity remained at similar levels without regard to route
or dose. Metabolites E and C were reabsorbed from the small
intestine and metabolite E underwent enterohepatic circu-
lation. The enterogastric and enterohepatic phenomena could
account for the retention of the radioactivity in the body.
Metabolite E was found in the erythrocytes, where its half-
life was significantly longer than in other storage sites.
This latter observation suggests that metabolite E forms
adducts with red cell constituents. This in turn may imply
C-27
-------
tb£t the red cell serves as an accumulator of chronic acrylon-
itrile insult in the body, and therefore may be used for
Biological monitoring of exposure. Independently of dose
01? route o£ administration metabolite E was selectively
accumulated in the stomach (glandular and non-glandular
p'orfcioh of the stomach wall) .
14
Even after the total body burden of C declined and
after the C concentration of stomach contents diminished,
the stomach uptake remained at a positive slope. This finding
reinforces phenomena previously observed in rats, namely
the emergence of gastric papillomas even though the route
of exposure was other than oral.
In a similar fashion the skin accumulated acrylonitrile
metabolites which rose to 2-3 fold over plasma levels.
Possible interfering effects Of skin absorption from the
exogeheous gas phase must be discounted because the investi-
gators used a "nose only" type of inhalation chamber. While
the mechanism of skin absorption is unknown, it is plausible
that the abundance of the sulfhydryl groups in the skin
protein matrix may be responsible for the effects seen.
Dose dependency of metabolism: Metabolite C was found to
be the main liver metabolite, which after bile excretion
was readily re-absorbed from the small intestine and "excreted
in the urine. Only a very small portion of the total dose-
load appeared in the form of compound A. After administra-
tion of high doses however, compound A strikingly increased.
The formation of metabolite E was time dependent and did
not occur significantly in the first eight hours aftex admini-
stration. An ir\ vitro study using rat liver homogenate
C-28
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(9000xg) supernate indicated that the liver is not the chief
site for the formation of compound E. In addition, the
very early appearance of metabolite E in the red cells sug-
gests extrahepatic sites (perhaps a red cell enzyme) for
the formation of this molecule.
The fourth metabolite, CO2 could arise as a product
of cyanate metabolism. Although thiocyanate was shown to
be the main product of cyanide metabolism (Boxer and Richards,
1952) these authors have shown that cyanide can be meta-
bolized to carbon dioxide via the cyanate ion. In fact,
this study demonstrated a strong dose dependence of cyanide
metabolism in dogs. It is plausible that the dose depen-
dence of acrylonitrile pharmacokinecs may result in part
from differences in the fate of the cyanide formed.
Excretion
The dose and route dependent variations in the meta-
bolic fate of acrylonitrile are most likely due to shifts
in metabolic pathways associated with hepatic and extrahep-
atic origin. Therefore the authors conclude: "extrapolation
of the results of toxicological studies conducted by one
route to expected toxicity at the same dosage by another
route (a common practice) may not be valid for acrylonitrile
because of its route dependent fate; likewise, extrapolation
from toxicological data at one dose level to a different,
untested, dose levels cannot be done with confidence because
of the dose dependent fate of acrylonitrile in the body".
This conclusion creates some uncertainty in the use
of the linear non-threshold model for calculating the accep-
table risk concentration in water for man exposed to acryloni-
029
-------
trile (see section on Carcinogenicity, Criteria Formulation).
However,-'-the data presented by Young, et al. (1977) did
not indicate that the metabolites whose fate was dose-depen-
dent was necessarily the cancer inducing material. There-
fore, until these data are experimentally developed the
i
linear model can still be applied.
EFFECTS
Acute, Subacute and Chronic Toxicity
Dudley and Neal (1942) reported that a 4 hour exposure
by inhalation to 635 ppm acrylonitrile was fatal to rats,
while a 4 hour exposure to a lower level, 100 ppm, was fatal
to dogs^. Subsequent animal experiments have shown that
acrylonitrile is acutely toxic by all routes of administra-
tion including inhalation, oral, subcutaneous and cutaneous
exposure. (Toxic Substances List, 1977).
Table 5 lists the toxic effect levels for different
species. (Toxic Substances List, 1977). Acrylonitrile
toxicity varies between species (Wilson and McCormick, 1949).
Mice are very sensitive to acrylonitrile and suffer a severe
decrease in body weight with a slight change in blood pic-
ture (Hashimoto, 1962). Benes and Cerna (1959) observed
that rats have higher resistance to acrylonitrile exposure;
they developed delayed symptoms and high levels of thiocya-
nate in urine and blood. Dudley, et al. (1942) reported
that inhalation exposure of rats to 56 ppm x 4 hours, 5
days a week, for 8 weeks resulted in irritation of the respir-
atory mucous membrane with hyperemia, lung edema, alveolar
thickening and hemosiderosis of the spleen. Central nervous
system disorders were also observed.
C-30
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TABLE 5
Toxic Levels of Acrylonitrile for Different Species
(From Toxic Substances List, 1977)
Species
Man
Rat
Mouse
Dog
Cat
Rabbit
Guinea Pig
»
Route
Inhalation
Oral
Inhalation
S.C.
Oral
Inhalation
I. P.
Inhalation
Inhalation
Oral
Inhalation
Skin
Oral
Inhalation
Skin
Effect
TCLo
LD50
LCLo
LD50
LD50
LCLo
LCLo
LCLo
LCLo
LD50
LCLo
LD50
LD50
LC50
LD50
Dose
16 ppm/20 min
82 mg/kg
500 ppm/4 hr
96 mg/kg
27 mg/kg
784 ppm/hr
15 mg/kg
120 mg/kg/4hr
600 ppm/4 hr
43 mg/kg
258 ppm/4hr
280 mg/kg
50 mg/kg
576 ppm/4hr
250 mg/kg
C-31
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A 90-day toxicity study, conducted by Dow Chemical
Company incorporating 200 and 300 ppm of acrylonitrile in
the drinking water of rats resulted in the animals' death
before the end of the study (National Resources Defense
Council, 1976). Knobloch, et al. (1972) observed a percep-
tible change in peripheral blood pattern, functional dis-
orders in the respiratory and cardiovascular systems and
!
the execretory nephron system as well as signs of neuronal
lesion- in the CNS of rats and rabbits breathing acryloni-
trile (50 mg/m air) for 6 months. In addition, they reported
irritation of the mucosa when acrylonitrile concentration
in the air was increased to 250 mg/m . Graczyk, et al.
(1973) reported that i.v. administration of 13-110 mg acrylon-
itrile decreased the pressor effects of epinephrine, norepine-
phrine and acetylcholine. when injected s.c. at 0.5 mg/rat/day
for 10 days, acrylonitrile decreased the rate of 02 uptake
and increased that of glycolysis in brain (Solov'ev, et
al. 1972). Acrylonitrile did not effect the levels of ATP
or creatinine phosphate. Solov'ev, et al. also reported
an increase in the activity of phosphofructokinase and a
decrease in the glycogen level in cerebral tissue.
Knobloch, et al. (1971) reported that the LDSO's of
acrylonitrile in rats were 80 and 100 ,mg/kg when given s.c.
and i.p., respectively, and 34 mg/kg when given s.c. to
mice. When inhaled with air over three weeks, the LCSO's
of acrylonitrile were 0.3, 0.47 and 0.99 mg/1 in mice, rats
and 'guinea pigs, respectively (Knobloch, et al. 1971).
They also- reported that acrylonitrile caused congestion
C-32
-------
and damage to the CNS, lungs, liver and kidneys. I.p. injec-
tions of 50 mg acrylonitrile/kg daily for 3 weeks to adult
rats resulted in body weight loss, leukocytosis, functional
disturbances in liver and kidneys, slight damage to the
neural cells of the brain stem and cortex and parenchymal
degeneration of the liver and kidneys (Knoblock, et al.
1971). Krysiak and Knobloch (1971) reported that acryloni-
trile (20 mg/kg/day for 6 weeks or 40 mg/kg/day for 4 weeks)
caused disturbances in the central nervous system of rats
as evidenced by misperformance in the labyrinth test. In
that test acrylonitrile caused marked impairment of food-
conditioned reflexes and learning ability. Babanov, et
al. (1972) reported that inhalation of acrylonitrile vapor
(0.495 mg/m , 5 hours/day, 6 days/week) for 6 months resul-
ted in CNS disorders and an abnormal blood picture (increased
erythrocyte count and decreased leukocyte count) in rats.
It also resulted in increased total protein catalase and
peroxidase content, decreased ascorbic acid content of blood
serum and increased number of free sulfhydryl groups in
the liver and blood serum. Acrylonitrile given orally in
a dose of 80 mg/kg increased the content of several amino
acids in the brain (Movsumzade, 1970). In the same study
Movsumzade reported that, in the liver, various pools of
basic amino acids levels were decreased to traces. He re-
lated these observations to the damage of synthetic function
of the liver and to damage of the blood-brain barrier.
Takagi, et al. (1968) studied the effect of administration
of vitamins B, or Bj plus cysteine to rats exposed to acrylon-
C-33
-------
itrile vapor over a long period. They observed that urinary
excretion of thiocyanate decreased with this treatment.
They reported that exposure to acrylonitrile caused enlarge-
ment of liver, kidney, heart and spleen and a decline of
alcohol dehydrogenase activity in the liver; alleviation
of these symptoms occurred upon administration of Vitamin
B, or B2 plus cysteine. A single s.c. administration to
rats of acrylonitrile at two times the LD50 dose decreased
the liver and kidney glutathione level greatly and increased
levels of lactic acid (Dinu and Rodica, 1976). These authors
also reported that catalase activity was slightly increased
but onTy in the liver. They concluded that the decrease
of glutathione levels rendered the glutathione peroxidase
ineffective, and the increase of lactic acid concentration
concomitantly inhibited a compensatory increase in catalase
activity. The resulting increase in peroxide level damaged
the tissue. Oinu (1975) reported that similar doses of
acrylonitrile administered orally to rats increased the
hepatic levels of malonaldehyde, glutathione peroxidase
and catalase, which she concluded, indicate lipid peroxidation.
Tissue protein and non-protein sulfhydryl decreased
in guinea pigs and rabbits following a single dose of acrylon-
itrile (Hashimoto and Kanai, 1965; Szabo, et al. 1977; and
Dinu, 1975). Prior treatment with thiol compounds such
as cysteine, confers some protection against the toxic action
of acrylonitrile (Paulet, et al. 1966; Hashimoto and Kanai,
i
1965). An increase in the number of free sulfhydryl groups
was also observed in the liver and serum of rats chronically
C-34
-------
treated with acrylonitrile (Babanov, et al. 1972). In vitro
inhibition of potassium-stimulated respiration of brain
/
cortex was observed at a 10 M acrylonitrile concentration;
little effect on liver respiration was observed. (Hashimoto
and Kanai, 1965). Tarkowski (1968) reported that cytochrome
oxidase was inhibited in liver, kidney, and brain tissue
taken from rats 2 hours after i.p. administrations of 100
mg/kg acrylonitrile. In Tarkowski's in vitro experiments
with similar tissues, inhibitions of 18-30 percent, 45-55
-4 -3 -2
percent and 75-85 percent with 10 , 10 and 10 M acry-
lonitr ile, respectively, were obtained. Since acrylonitrile
did not change the spectrum of cytochrome oxidase in the
same manner as KCN, Tarkowski concluded that the toxic ef-
fect of acrylonitrile could not be attributed to generation
of cyanide. Minami, et al. (1973) reached just the opposite
conclusion. They reported what they thought to be a high
degree of similarity between the response of rabbits poi-
soned by acrylonitrile and rabbits poisoned by cyanide;
the blood pO2, pCO^, pH, hemoglobin and hemotocrit values
were correlated with the, concentration of cyanide and thiocyanate,
Wilson and McCormick (1949) reported that acrylonitrile
shows large variations in toxicity between species. In
rabbits, extensive damage in the four phases of the brain
nervous system was observed. Other symptoms were shivering,
tearing, redness of the ears and hyperemia (Benes and Cerna,
1959). Dudley, et al. (1942) reported that guinea pigs
treated with acrylonitrile (1.25 mg/1) developed strong
interstitial nephritis, bronchopneumonia and inflammatory
035
-------
lung irritation. Dogs were the most sensitive experimental
animals to acrylonitrile (Grahl, 1970). Thiocyanate levels
in serum and urine of dogs treated with 100 ppm acryloni-
trile were ten times higher than those of rats receiving
the same dose (Lawton, et al. 1943 and Lindgren, et al.
1954). Liver and kidney damage was less pronounced in the
dogs than in rats (Brieger, et al. 1952). In monkeys, anoxia,
brain damage and death by suffocation were observed upon
administration of acrylonitrile (Grahl, 1970). Acryloni-
trile intoxication in cats resulted in the early onset of
liver injury (Dudley, et al. 1942). Pathologic examination
of animals following acute acrylonitrile exposure revealed
all animals had edema (Dudley and Neal, 1942; Szabo and
Selye, 1971); histologic changes in the brain, particularly
the cortex, characteristic of anoxia (Brieger, et al. 1952);
blood that was unusually dark red and liquid (Dudley and
Neal, 1942; Brieger, et al. 1952); and liver and kidney
damage (Knobloch, et al. 1972) . Pathologic examination
following repeated acrylonitrile administration revealed
slight damage to the neural cells of the brain stem and
cortex, and parenchymal cell degeneration of the liver (Knob-
loch, et al. 1971). Repeated acrylonitrile administration
was also associated with weight loss, leukocytosis and func-
tional disturbances of liver, kidney and adrenal cortex
(Knobloch, et al. 1971; Szabo, et al. 1976). Szabo and
Selye (1971) reported that adrenal apoplexy and necrosis
were produced in rats by administration of a single oral
dose of acrylonitrile (100-200 mg/kg), 100 percent mortality
C-36
-------
was observed. The adrenals of the dead animals showed
hemorrhages in the cortex and necrosis in the inner cortical
zones. Acrylonitrile induced-adrenal apoplexy, and morta-
lity in female rats were both prevented by pretreatment
with phenobarbital and adrencorticotrophic (ACTH) hormones
(Szabo and Selye, 1971 and 1972). Szabo and Selye (1972)
also reported that the adrenal lesion was abolished by the
potent glucocorticoid, betamethason. Estradiol prevented
adrenal apoplexy in approximately half the animals treated
with a single lethal dose of acrylonitrile (Szabo and Selye,
1972). The mechanism by which these drugs interfered with
the acrylonitrile induced injury is not clear (Szabo and
Reynolds, 1975).
Few human studies, other than cancer epidemiology,
were found for U.S. workers. Therefore, the majority of
studies cited are from the foreign literature. Complete
details of these studies were not available at the time
of writing.
The human threshold of smell to acrylonitrile lies
between 8-40 mg/m (3.7-18.5 ppm), and a quick tolerance
is always developed after repeated inhalation (Fairhall,
1957). A point of unbearability was reached at 800-1000
mg/m (370-460 ppm) sometime after 70 seconds of exposure
(Grahl, 1970). The high threshold of smell and the high
absorptive capacity of environmental objects (such as tex-
tiles, wood, food and grain) to acrylonitrile acts to mini-
mize the perception of acrylonitrile and so intensify the
degree of exposure, and consequently the toxicity.
C-37
-------
Goncharova, et al« (1977) reported that examinations
of 689 persons engaged in the production of acrylonitrile
in the USSR evidenced effects of acrylonitrile upon the
heart. In their studies Shirshova, et al. (1975) indicated
that workers with long service records in the acrylonitriie
polymer industry showed decreases in hemoglobin level and
a trend to leukopenia and relative lymphocytosis. Stamov,
et al. (1976) studied the working environment and health
state of workers involved in the production of polyacryloni-
trile fibers (Burgas, Bulgaria) where dimethylformamide
was also present. Their studies indicated that in exposed
workers there is a tendency towards diseases of the peri-
pheral nervous system, stomach, duodenum and skin.
In an epidemiologic study of health impairment among
acrylonitrile workers in Japan, Sakarai and Kasumoto (1972)
studied 576 workers exposed over a 10-year period (from
1960 to 1970) to acrylonitrile in concentrations of 5-20
ppm. The cohort was studied with respect to: a) age and
length of exposure to acrylonitrile; b) subjective complaints
as well as; c) objective symptoms. They found increased
incidences of subjective complaints including headache,
fatigue, nausea and weakness; as well as clinical symptoms
of anemia, jaundice, conjunctivitis and abnormal values
of specific gravity of whole blood, blood serum and cholines-
terase values, urobilimogen, bilirubin, urinary protein
and sugar. These clinical values were found to vary direc-
tly with length of exposure to acrylonitrile and differences
were significantly different from normals. Sakarai and
C-38
-------
Kasumoto (1972) concluded that acrylonitrile exposures at
these levels caused mild liver injury and probably a cumula-
tive general toxic effect.
The working conditions and health status of operators
engaged in the production of acrylonitrile were studied
by Ostrovskaya, et al. (1976), where the working area atmos-
phere was polluted by acrylonitrile as well as other chem-
icals. In those workers, changes in the heart and circula-
tion, blood methemoglobin content, and increased excretion
of glucuronic acid occurred during working hours.
Zotova (1975) in the U.S.S.R. reported that the concen-
tration of acrylonitrile in the air of the plant he studied,
exceeded by 5-10 fold the "maximal permissible concentra-
tion" (i.e., hygienic goal; 0.435 mg/m ) and he recommended
the enforcement of lower levels for the compound. He reported
the blood of workers in contact with acrylonitrile, when
compared with control values, had a lower content of erythro-
cytes, leukocytes, hemoglobin and sulfhydryl groups.
Shustov and Mavrina (1975) reported that medical examina-
tion of 340 workers and clinical studies of the blood and
other biological fluids of 50 workers in polyacrylonitrile
production plant showed symptoms of poisoning in the major-
ity of the workers. They found that workers complain of
headaches, vertigo, fatigue, insomnia, and skin itching..
The clinical studies show that the majority of the workers
have functional disorders of the central nervous system,
cardiovascular and hemopoietic systems. The degree of patho-
logical change increased with years of service in the plant
(Shustov and Mavrina, 1975).
C-39
-------
Dovzhanskii (1976a, 1976 b) , Khromov (1974) and Balda
(1975) reported contact allergic dermatitis and changes
in immune-globulin levels upon direct contact with acryloni-
trile and other acrylate components of synthetic fabrics.
Mavrina and ll'ina (1974) reported that students of an indus-
trial training school, who came in contact with acrylates
(mainly acrylonitrile), at atmospheric levels of 0.8-1.8
mg/m showed disturbed immunological reactivity and sensitiza-
tion. The positive allergic reactions in persons not having
signs of allergic diseases indicated latent allergy (premor-
bid phase) developing at various times after contact with
acrylonitrile. Because of the considerable sensitivity
of young people/ sensitization by these substances can develop
within several days after the start of the training (Mavrina
and ll'ina, 1974).
Recently Radimer, et al. (1974) reported four cases
in which toxic epidermal necrosis developed 11-21 days after
patients returned to houses fumigated with a 2:1 mixture
of carbontetrachloride and acrylonitrile; this mixture was
once widely used as a pesticide in Florida homes (Radimer,
et al. 1974). In these cases, four patients were hospita-
lized with blisters covering almost the entire skin sur-
face and mucous membranes. Administration of antibiotics,
corticosteroids, fluids and electrolytes produced no improve-
ment in the three adult female patients. These three patients
died of septic shock and gastrointestinal hemorrhage 3-4
weeks after exposure (Radimer et al. 1974). They also reported
that the ten-year-old son of one of these patients developed
widespread pruritic eruptions, but survived with topical
C-40
-------
and parenteral corticosteroid application. The possibility
that carbon tetrachloride rather than acrylonitrile, was
the responsible agent for the observed toxicity cannot be
excluded absolutely (Radimer, et al. 1974). Hardy, et al.
(1972) reported an impaired pulmonary function following
a railroad accident in which a crew of four railroad engin-
eers suffered an intense single exposure to unknown amounts
of acrylonitrile. After the exposure, weakness was the
chief symptom followed by dyspnea on exertion when the workers
returned to normal activity. Pulmonary function testing
done seven years after exposure indicated that lung damage
was still present in all four workers and had probably origi-
nated at the time of the accident (Hardy, et al. 1972).
Two additional cases of mortality following acute acryloni-
trile exposure have been reported. Both involved children,
one treated with acrylonitrile for scalp lice and the other
sleeping in a room fumigated with acrylonitrile (Grunske,
1949).
Toxicological studies give no clear insight into the
possible mechanisms of acute and subacute acrylonitrile
toxicity. Although Tarkowski (1968) proposed some evidence
favoring a cyanide-mediated effect, there is also evidence
against it (Paulet, et al. 1966). Earlier reports indicated
that cyanide liberation is responsible for acrylonitrile
toxicity (Desgrez, 1911 and Wagner-Jauregg, et al. 1948) .
Mediation of acrylonitrile toxicity by cyanide was consi-
i
dered because of the following observations noted upon acry-
lonitrile administration: (a) increased blood and urine
C-41
-------
thiocyanate concentration (Mallette, 1943; Wilson, et al.
1948; Lawton, et al. 1943); (b) appearance of free cyanide
a cyanomethemoglobin in blood (Hashimoto and Kanai, 1965;
Brieger, et al. 1952); (c) slight similarities to the toxi-
city symptoms and histopathologic results produced by admini-
stration of hydrocyanic acid and its salts; (d) successful
use of some cyanide antidotes in treatment of some toxic
symptoms resulting from acrylonitrile administration (Dud-
ley, et al. 1942; Hashimoto and Kanai, 1965; Levina, 1951;
Yoshikawa, 1968) . Other hypotheses have attributed the
toxicity of acrylonitrile to the intact molecule (Schwa-
necke, 1966; Paulet, et al. 1966; Ghiringhelli, 1954; Des-
grez, 1911; Graham, 1965; Magos, 1962; Benes and Cerna,
1959) . Support for these hypotheses comes from the following
observations: (a) no correlation between acrylonitrile
toxicity in guinea pigs or rats with either blood levels
of cyanide ions and cyanomethemoglobin or the amount of
thiocyanate excreted in urine (Ghiringhelli, 1954 and 1956;
Magos, 1962); (b) no free cyanide ions detected in the blood
of guinea pigs exposed to acrylonitrile (Dudley and Neal,
1942 and Dudley, et al. 1942); (c) histopathologic aberra-
tions after acrylonitrile exposure not explicable as cyanide
action (Dudley, et al. 1942; Benes and Cerna, 1959); (d)
controversial reports on the action of specific cyanide
antidotes, e.g., hydroxycobalamine, sodium nitrites and
sodium thiosulfate in treatment of acrylonitrile poisoning
(McOmie, 1943; Ghiringhelli, 1954; Magos, 1962; Hashimoto
and Kanai, 1965).
C-42
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Benes and Cerna (1959) postulated that in acrylonitrile
sensitive animal species, quick decomposition of the entire
acrylonitrile molecule to cyanide ion takes place and a
typical cyanide toxicity is produced. However, Brieger,
et al. (1952) reported that high SCN/CN ratios were observed
in acrylonitrile sensitive animals.
Paulet, et al. (1966) reported that the toxic action
of acrylonitrile in rabbits and guinea pigs is only partial-
ly due to cyanide liberation. It has been suggested that
additional biotransformation may contribute partially to
acrylonitrile's acute toxicity (Paulet, et al. 1966; Benes
and Cerna, 1959). Desgrez (1911) in his earlier studies
suggested a role for the conjugated double bond in acryloni-
trile toxicity.
A number of other hypotheses have been developed to
describe the mechanism of acrylonitrile toxicity (Hashimoto
and Kanai, 1965; Ghiringhelli, 1954; and Magos, 1962).
They suggest the blocking by cyanoethylation of important
sulfhydryl group containing enzymes. This hypothesis was
supported by the excellent antidotal action of cysteine
and glutathione in guinea pigs and mice (Paulet, 1966; Mc-
Laughlin, et al. 1976). A general blocking effect upon
cell metabolism together with irreversible inhibition of
the respiratory enzymes have also been described as possible
mechanisms of acrylonitrile toxicity (Ghiringhelli, 1954
and 1956). Acrylonitrile is known to deplete hepatic gluta-
thione (Szabo, 1977). Dinu (1976) suggested that a decrease
in hepatic glutathione levels renders the glutathione peroxi-
dase ineffective, and the resulting increase in the peroxide
levels damages the hepatic cells.
C-43
-------
Synergism and/or Antagonism
Standard antidotes against cyanide poisoning have been
used in attempts to abate the acute toxicity of acryloni-
trile. Dudley and Neal (1942) found that neither sodium
thiosulfate nor methylene blue afforded any protection against
acrylonitrile lethality/ while injection of sodium nitrite
had a protective and antidotal action against the severity
pf symptoms (particularly the respiratory distress) and
the lethality if given immediately before or after acryloni-
trile exposure. This protective and antidotal action was
observed for dogs, rats and rabbits but not for guinea pigs.
Ghiringhelli (1954) found that guinea pigs were not protected
against acrylonitrile toxicity by the anticyanide treatments
tested: glucose, sodium thiosulfate and nitrite. Using
another antidote for cyanide poisoning, hydroxycobalamin,
Graham (1965) found that prior treatment of mice or dogs
reduced the immediate (2 hours) lethality of acrylonitrile
but increased the lethality at 24 hours. McLaughlin, et
al. (1976) found that the combination of sodium nitrite
with sodium thiosulfate was not effective against acryloni-
trile lethality for mice, dogs and rats and only moderately
effective in. rabbits, while sodium thiosulfate alone was
very effective rats and less effective for rabbits. Cysteine
hydrochloride was the most effective of all antidQtes against
acrylonitrile lethality in all species tested by McLaughlin,
et al. (1976).
C-44
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Other kinds of treatments have been reported to affect
the acute toxicity of acrylonitrile. Jaeger, et al. (1974)
reported that acrylonitrile's LC50 for fasted rats was approx-
imately three times lower than that for fed rats (150 vs
425 ppm x 4 hours). Szabo and Selye (1972) reported phenobar-
bital pretreatment diminished the acute adrenal apoplexy
caused by acrylonitrile, and Paulet, et al. (1966) reported
the same treatment delayed its lethality. HCN and CO were
found to enhance acrylonitrile toxicity in experimental
animals (Yamamoto, 1976) as well as in workers engaged in
the acrylonitrile production (Ostarovskaya, et al. 1976).
Teratogenicity
Murray, et al. (1976) reported that their studies on
Sprague-Dawley rats demonstrated a potential for acryloni-
trile to cause fetal malformation when it was given to preg-
nant rats by gavage at high dose levels (65 mg/kg/day or
approaching the LD50) on gestational days 6-15. Though
sialodacryoadenovirus infection (murine mumps) occurred
in both experimental and control animals, it is unlikely
that this had an effect on the teratogenicity findings.
At administration of 65 mg acrylonitrile/kg/day Murray,
et al. (1976) found significant maternal toxicity and in-
creased fetal malformations, including acaudea, short-tail,
short trunk, missing vertebrae, and right-sided aortic arch.
Other signs of embryo toxicity or fetotoxicity at this dose
level were: increased frequency of early resorption sites
(as detected by sodium sulfide stain), decreased fetal body
weight and crown-rump length, and increased incidences of
minor skeletal variants. At the time of Cesarean section,
C-45
-------
observations were made which are included in Table 5. The
apparent pregnancy rate, i.e., the proportion of bred rats
with visible implantation sites at the time of Cesarean
section was significantly lower among rats given 65 mg acry-
lonitrile/kg/day than among the control rats. Administra-
tion of acrylonitrile had no significant effect on the lit-
ter size, the fetal sex ratio or the incidence or distri-
bution of resorptions. At 65 mg/kg/day, the fetal body
and crown-rump length were significantly lower than control
values. No statistically significant effect was observed
at the doses 10 and 25 mg/kg/day.
In Table 6 the incidence of external or soft tissue
alterations among litters of rats given various doses of
acrylonitrile by gavage is indicated. At 65 mg/kg/day the
frequency of acaudate fetuses among litters was significant-
ly higher than the control incidence. Also at this dose
level, a statistically significant increase in the combined
incidence of acaudate and short-tailed fetuses was observed.
There were no statistically significant differences in the
frequency of either of these tail anomalies alone or com-
bined among litters of rats given the lower doses levels
(10 or 25 mg/kg/day).
The soft tissue examination indicated right-side aortic
arch in single fetuses at both 25 and 65 mg/kg/day (Table 7).
The incidence of skeletal alterations among litters
of rats given acrylonitrile by gavage is summarized in Table
8. The incidence of skeletal alterations among litters
of rats receiving 10 or 25 mg acrylonitrile/kg/day were
C-46
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TABLE 6
Observations Made at the Time of Cesarean Section of Rats Receiving Acrylonitrile by Gavage
Murray, et al. 1976
Dose Level of Acrylonitrile, mg/kg/dayc
-------
TABLE 6 (Continued)
LEGEND
aAcrylonitrile was given by gavage on days 6-15 of gestation.
No. of females with visible implantation sites at the »time of cesarean section or necropsy/total
no. of bred females.
°A female which delivered her litter on day 20 of gestation was included in the calculation
of the pregnancy rates. The litter was not examined for fetal alterations.
Significantly different from control by Fisher's exact probability test, p 0.05.
eNo. of females with implantation sites as observed either visually at the time of cesarean
section or after staining the uterus with sodium sulfide stain/total no. of bred females.
No. of females with implantation sites detected only after staining the uterus with sodium
sulfide stain/total no. of females with implantation sites.
n gMean + S.D.
i h
£ Data from the four females in which implantation sites were detected only after sodium
sulfide staining of the uterus were not included in these calculations.
Mean of litter means + S.D.
-'significantly different from control mean by Dunnett's test, p 0.05.
-------
TABLE 7
Incidence of Fetal Alterations Observed During the External or Soft Tissue Examination Among Littei
of Rats Receiving Acrylonitrile by Gavage, Murray, et al. 1976
Dose Level of Acrylonitrile, mg/kg/dayc
o
i
^
VO
EXTERNAL EXAMINATION
SOFT TISSUE EXAMINATION
EXTERNAL EXAMINATION
Acaudate F
Acaudate or
short tail F
L
Short trunk F
L
Imperforate anus F
L
SOFT TISSUE EXAMINATION
Right-sided aortic F
arch L
Ovaries, anteriorly F
displaced L
Missing kidney, F
unilateral L
Dilated renal pelvis,
unilateral L
Dilated ureter,
left F
L
0
443/38
154/38
0
0.2(1)
3(1)
0
0
0
0
0
0
0
0
KD
3(1)
F
0
0
0
10
No. Fetuses/No
388/35
135/35
% Affected
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
25
. Litters Examined
312/29
111/29
(No. Affected)
0.6(2)
0.6(2)
7(2)
0
0
0
0
KD
3(1)
KDd
3d)
0
0
0
7(2)
KD
3(1)
65
212/17
71/17
2(4)c
4(8)C
35(6)
l(3)C'd
18(3)
K2)d
12(2)
KDd
6(1)
KDd
6(1)
KDd
6(1)
2(2)
0
d
1(1)°
6(1)
-------
o
I
TABLE 7 (Continued)
aAcrylonitrile was given by gavage on days 6-15 of gestation.
F = fetuses; L = litters.
f*
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.
-------
TABLE 8
Incidence of Skeletal Alterations Among Litters of Rats Receiving Acrylonitrile by Gavage
Murray, et al. 1976
Dose Level of Acrylonitrile, mg/kg/daya
SKELETAL EXAMINATION
SKULL BONE EXAMINATION
SKELETAL EXAMINATION
Vertebrae - 12
thoracic and 5
lumbar (normal no.
n is 13 T and 6 L)
i
£ -missing vertebrae
other than 1
thoracic and 1
lumbar0
-missing centra
of cervical
vertebrae (other
than C, and C2)
Ribs -missing 13th
pair only
-missing more
than 1
pair9
»__
Fb
L
F
L
F
L
F
L
F
L
0
443/38
289/37
2(7)
3(1)
0.2(l)d
3d)
-
5(23)
29(11)
2(7)
3(1)
0
0
10
No. Fetuses/No
388/35
253/34
% Affected
0
0
0
0
8(30)
46(6)
0
0
0
0
25
. Litters Examined
312/29
201/24
(No. Affected)
2(7)
7(2)
0.6(2)d
7(2)
10(31)
46(13)
a
2(7)
7(2)
K2)d
7(2)
65
212/17
141/17
0
0
4(8)d'e'
35(6)
34(71)e
88(15)
0
0
2(4)d'e
24(4)
-------
TABLE 8 (Continued)
Dose Level of Acrylonitrile, mg/kg/daya
o
i
ro
Sternebrae -
delated ossifi-
cation, 5th
-missing, 5th
-split, 5th
-split, 2nd
SKULL -BONE EXAMINATION
-delayed ossifi-
cation any skull
bone
F
L
F
L
F
L
F
L
F
L
0
2(9)
16(6)
0
0
1(4)
10(4)
0
0
7(21)
30(11)
10
3(13)
23(8)
0
0
1(3)
9(3)
0
0
,- u
-
6(15)
26(9)
25
4(13)
34(10) .
1(2)
7(2)
1(3)
10(3)
0
0
..,
6(12)
29(7)
65
15(31)®
59(10)
1(2)
12(2)
4(8)
30(5)
2(4)e
24(4)
4(5)
18(3)
Acrylonitrile was given by gavage on days 6-15 of gestation.
F - fetuses; L - litters.
f+
The actual number of thoracic/ lumbar and sacral vertebrae of each of the affected
fetuses were as follows (normal no. is 13 T, 6 L, 4 S): Control - 12T, 2L, OS;
25 mg/kg/day - 2T, OL, OS, 2T, 1L, IS; 65 mg/kg/day -13T, 3L, OS; 3T, OL, )S;
13T, 6L, 2S; 7T, 3L, OS; 13T, 3L, OS; 2T, OL, OS; 3T, OL, OS; 13T, 5L, 4S.
This alteration occurred only among fetuses with short or missing tail at this dose
level.
eSignificantly different from control by a modified Wilcoxon test, p 0.05.
This alteration occurred only among fetuses with 12 thoracic and 5 lumbar vertebrae.
gThe affected fetuses exhibited 0-7 pairs of ribs (normal no. is 13).
-------
not significantly different from control litters. At 65
ing/kg/day, a significant increase was seen in the frequency
of fetuses missing vertebra(e) other than a single thoracic
and single lumbar vertebra. Also at this dose, each acau-
date or short-tailed fetus (and only these fetuses) had
this defect/ ranging in severity from missing a single lum-
bar vertebra to missing 12 thoracic, all lumbar and all
sacral vertebra. In addition, the incidence of fetuses
missing more than one pair of ribs was significantly higher
than control litters (Table 9).
An additional study by Murray, et al. (1978) concluded
that when Sprague-Dawley rats were exposed to 0, 40, or
80 ppm of acrylonitrile by inhalation, teratogenic effects
in the offspring of pregnant rats were suggested at 80 ppm
but not 40 ppm. Significant maternal toxicity was found
at both 80 and 40 ppm.
A second generation progress report from Litton Bione-
tics to MCA (Beliles, et al. 1977) summarizes results of
a three generation reproduction study of rats receiving
acrylonitrile in drinking water. Based on the FQ and F,
generations the authors conclude the followings:
1. Acrylonitrile at 500 ppm reduced body weight gain
and food intake of the first generation parent
rats (FQ);
2. At 100 and 500 ppm water consumption was reduced
in F rats;
C-53
-------
TABLE 9
Status Report (13 Months) on 2-Year Study Incorporating
-Acrylonitrile in the Drinking Water of Rats, Norris, 1977
- Observation of Palpable Masses in Mammary Gland Region -
Norris, 1977
o
1
Ul
**
CONTROLS
35 PPM
100 PPM
300 PPM
aNorris, 1977
J?_
4/73e
0/44
3/46
3/41
MALES
j£_
0/10
0/10
0/10
0/10
TOTAL
jsL
1/7
0/3
1/1
0/7
NO,
5/90
0/57
4/57
3/58
J A
5.5 12/79
0/0 11/45
7,0 9/42
5,2 11/32
FEMALES
B
2/10
0/10
3/10
1/10
TOTAL
C
0/1
3/4
3/5
8/15
No.
14/fQ
14/59
15/57
20/57
%
15.5
23.7
2.6,3
35.1
A - Alive at 13 months (12/21/76).
•*
'B - Interim sacrifice animals after 12 months, on study.
3C - Dead at 13 months (12/21/76).
'No. mass bearing animals/No, animals in group A, B, or C.
-------
3. At 500 ppm the pup survival in both matings of
the first generation was reduced. Reducing the
litters and fostering the pups onto untreated
mothers lessened mortality of the pups, suggesting
a maternal effect;
4. In the second generation the body weights (500
ppm) of the pups at day 21 of lactation were reduced
at both matings;
5. Gross observations, as yet unconfirmed by histopath-
ologic evaluation, suggested a tumorigenic effect
in female rats held 20 weeks after the second
litter (about 8 months of age); and
6. The survival of the pups at the 100 ppm concen-
tration was reduced in one mating of each genera-
tion; because of this inconsistency the toxico-
logic significance has not yet been assessed.
Recent verbal communication from Beliles provided fur-
ther expansion on the findings of this ongoing study: The
effects seen at 500 ppm are quite consistent and responsible
with respect to prenatal viability of the pups. Most of
the delerious effects on the pups appear in late lactation,
which may be due either to maternal/toxic phenomena, or
to insufficient fluid intake by the lactating mothers.
Beliles verbally confirmed significant tumorigenic
effects in the dams. The verified occurrence of zymbal
gland carcinomas were seen as in other studies (see Carceno-
gensis; Morris, 1977; Quast, et al. 1977). Only partial
histopathology is available at this time, final report on
the whole study is anticipated early 1979.
C-55
-------
Mutagenieity
The mutagenicity of acrylonitrile to various organisms
has been described by several investigators. Behes and
Aram (1969) noted only weak effects in Drosophila melano-
gaster and concluded that acrylonitrile toxieity towards
!
the species limited the testing. Milvy and Wolff, (1977)
reported that in various strains of Salmonella typhimurium
activated by mouse liver homogenate, acrylonitrile is muta-
genic in the TA 1535 tester strain that is sensitive to
base substitution, as well as strains TA 1538 and TA 1978,
which are sensitive to frameshift mutagens. No dose-response
data were obtained, however, and high reversion rates were
seen in the controls. Milvy and Wolff reported that the
presence of the activating system and NADPH cofactor is
a prerequisite for acrylonitrile-induced mutagenes/is (Milvy
and Wolff, 1977).
In a comprehensive study Venitt, et al. (1977) concluded
that acrylonitrile is a mutagen for Excherichia coli strains
WP2, WP2 uvrA, and WP2 urvApolA. Acrylonitrile caused a
slight dose-related increase in the number of revertant
colonies compared with untreated bacteria in three of the
four strains. WP2 lexA was not detectably reverted by acry-
!
lonitrile. Of the three strains showing a statistically
significant mutagenic response, WP2 was slightly more sensi-
tive to the mutagenic effect of acrylonitrile, showing a
4-fold increase over the spontaneous levels compared with
a 3-fold increase for WP2 uvrA and a 2-fold increase for
WP2 uvrApolA. Doses above 150 umol per plate caused a de-
056
-------
cline in mutagenic response, concomitant with increasing
toxicity as shown by a dose-related reduction in the density
of the bacterial lawn. An important observation reported
by Venitt, et al. (1977) was that the addition of a mixed
function metabolizing system in vitro (S-9 mixture prepared
from the liver of Aroclor 1254-induced CB hooded male rats)
had no detectable effect on the mutagenic action of acryloni-
trile. Therefore/ they concluded that acrylonitrile is
a directly acting mutagen in these strains of E. coli.
The differential response of the tested strains to
the mutagenic action of acrylonitile suggests that acryloni-
trile causes non-excisable DNA damage. (Venitt, et al.
1977 and Green and Moriell, et al. 1976). Acrylonitrile
has been shown to cyanoethylate ring nitrogen atoms of cer-
tain minor tRNA nucleosides and ribothymidine and thymidine
(Ofengand, 1971 and 1976). Accordingly, Venitt, et al.
(1977) suggested that acrylonitrile might react with thymine
residues in DNA.
Carcinogenicity
The most pertinent animal carcinogenesis studies are
two studies conducted by the Dow Chemical Company, Toxico-
logy Research Laboratory, Midland, Michigan under the admini-
stration of The Manufacturing Chemists Association. Both
studies are 2-year studies concerned with long-term effects
of acrylonitrile in the drinking water of rats. The fol-
lowing discussion of the first study (Norris, 1977) is based
on a 13-month interim report. Discussion of the second
study (Quast, et al. 1977) is based on a 12-month interim
report. (Updated data were not accessible at the time of
C-57
-------
this document's preparation, but will be available for subse-
quent iterations).
In both studies, concentrations of acrylonitrile in
the drinking water of the rats were 0, 35, 100 and 300 mg/1.
The concentrations were equivalent to daily dosages of approx-
imately 4, 10, and 30 mg/kg body weight, respectively.
The Quast, et al. (1977) study used Sprague-Dawley rats,
spartan substrain, while the Norris study did not explicitly
mention the strain of rat employed. Both studies utilized
both males and females.
Norris (1977) noted a statistically significant dose-
related decrease in water consumption by the rats at all
concentrations of acrylonitrile, as well as lowered food
consumption by rats at the highest concentration and lowered
food consumption by the female rats at the intermediate
concentration. The decreased food and water consumption
resulted in a statistically significant decrease in body
weight of animals at the two higher concentrations (100
and 300 mg/1). The body weight of the animals at the lowest
concentration was also decreased, although not by a statis-
tically significant amount when compared with controls.
Urinalysis showed an increase in specific gravity in the
urine of rats of both sexes at the 300 mg/1 concentration
throughout the study and in the females at the 100 mg/1
concentration in the 12th month of the study. The effect
is probably due to lower water intake. As of 13 months,
there was a higher incidence of a) subcutaneous masses in
the mammary region of females at all concentrations of acry-
lonitrile (Table 8) b) masses of the ear canal among both
C-58
-------
sexes at the highest concentration and in females only at
the intermediate concentration (Table 10) c) proliferative
lesions of the brain at the highest and next to higher concen-
tration in males only (Norris, 1977).
Gross pathologic examination of some of the rats that
died spontaneously and of those rats that were sacrificed
after one year of administration of acrylonitrile displayed
focal areas of hyperplasia and/or polyp formation in the
non-glandular portion of the stomach of several animals
at the two higher concentrations. At the lowest concentra-
tion no gross pathologic changes were observed in the stom-
achs of the rats.
Upon microscopic examination of the brains of animals
sacrificed at the 12-month interim kill, proliferative lesions
were observed in rats on the 300 and 100 ppm concentrations.
These lesions were not observed on gross examination. A
similar lesion was noted in the spinal cord of one rat on
the 100 ppm concentration (Table 10). A summary of the
findings of the 13-month interim report of Norris (1977)
appears in Table 11.
Quast, et al. (1977) obtained data on appearance, demeanor,
body weights, food and water consumption, routine hemato-
logy, clinical chemistry determinations (serum urea, alka-
line, phosphatase and SGPT activity), routine urinalysis,
organ weights, organ-to-body weight ratios, and gross and
microscopic pathologic examination of tissues.
C-59
-------
o
1
o
TABLE 10
Status Report (13 Months) on 2-Year Study Incorporating
Acrylonitrile in the Drinking Water of Rats, Morris, 1977
- Ear Canal Masses -
Norris, 1977
CONTROLS
35 PPM
100 PPM
300 PPM
Ab
l/73e
1/44
0/46
4/41
MALES
B°
0/10
0/10
0/10
1/10
TOTAL
cd
0/7
0/3
0/1
1/7
No.
1/90
1/57
0/57
6/58
% A
1.1 1/79
1.7 0/45
0 0/42
10.3 4/32
FEMALES
B
0/10
0/10
2/10
1/10
"TOTAL
C
0/1
0/4
1/5
4/15
No.
1/90
0/59
3/57
9/57
%
1.1
0
5.3
15.8
Norris, 1977
3A - Alive at 13 months {12/21/76).
•»
'B - Interim sacrifice animals after 12 months on study.
3C - Dead at 13 months ,(12/21/76).
;No. mass bearing animals/No, animals in group A, B, or C.
-------
TABLE 11
Status Report (13 Months) on 2-Year Study Incorporating
Acrylonitrile (AN) in the Drinking Water of Rats
- Proliferative Lesions in Brain of Rats Sacrificed After 12 Months -
CONCENTRATION OF
ARCYLONITRILE IN
DRINKING WATER (PPM) MALES FEMALES
CONTROL 0/10 0/10
35 0/10 0/10
100 0/10 3/10 (Plus 1 spinal cord lesion)
300 1/10 2/10
aNot Observed Grossly.
o
i
at
-------
Rats ingesting 100 or 300 rag/1 of acrylonitrile showed
a poorer overall body condition, being smaller and having
an unthrifty condition. In these two treatment groups,
a greater number of rats, compared with the controls either
died or were selected for autopsy, assumedly because they
were moribund or had palpable tumors, prior to the scheduled
12-month sacrifice. This was particularly true in female
rats ingesting 300 mg/1 acrylonitrile where 4 out of the
10 rats were selected for autopsy prior to the 12-month
scheduled sacrifice. In all treatment groups, there was
a dose-related decrease in water consumption, food consump-
tion and body weight gains. Approximate amounts of acryloni-
trile ingested by rats at the three concentrations were
computed to be 4, 10 or 30 mg acrylonitrile/kg/day. Increased
specific gravity of urine was observed in males and females
ingesting 300 mg/1 acrylonitrile and in females ingesting
100 mg/1 acrylonitrile. The 300 mg/1 group of females showed
an elevated serum alkaline phosphatase activity.
Gross and miqroscopic pathologic changes of both a
nontumorous and tumorous nature were detected with greater
frequency in rats in the 100 and 300 mg/1 acrylonitrile
groups than in the 35 mg/1 and control groups. There was
an increased occurrence of tumors in the stomach, nervous
system, and zymbal gland of the ear canal region in rats
ingesting 100 or 300 mg acrylonitrile/1 compared with the
control and 35 mg/1 groups. These tumors are considered
treatment-related. Other types of tumors also occurred
more frequently in these rats than in controls, but their
relationship to treatment is uncertain due to their low
C-62
-------
TABLE 12
Status Report on 2-Year Study Incorporating Acrylonitrile
in the Drinking Water of Rats
- Summary of Findings as of 13 Months -
Statistically significant decreased water consumption at
all dose levels.
Decreased food consumption at 300 ppm in males and females
and at 100 ppm in females.
Statistically significant decreased body weights of males
and females at 300 and 100 ppm and a nonstatistically signi-
ficant decrease at 35 ppm.
Increased specific gravity of urine of males and females
at 300 ppm and in females at 100 ppm.
Increased incidence of masses in the mammary region in females
at all dose levels.
Polyps in stomach of some male and females at 300 ppm and
females at 100 ppm.
Increased incidence of ear canal masses in males and females
at 300 ppm and in females at 100 ppm.
Proliferative lesions in central nervous system of males
and females sacrificed after 12 months at 300 and 100 ppm.
Increased mortality among females at 300 ppm.
C-63
-------
incidence and the small size of the groups. Marked nontum-
orous morphologic changes reflecting toxicity were detected
in various organs in rats ingesting 100 or 300 mg/1. Signi-
ficant increases were observed in the organ weight/body
weight ratio of heart,- liver, and brain. Also, the relative
brain weight:body weight ratio was increased in male rats
receiving 100 mg acrylonitrile/1. Relative liver and kidney
weight: body weight ratios were significantly increased
in female rats at the 300 mg/1 dose. The absolute and rela-
tive organ weight changes in male and female rats were asso-
ciated with decreased fasting body weights.
To summarize the study of Quast, et al. (1977), male
and female rats maintained on water containing 35 mg acryloni-
trile/1 for 12 months exhibited signs of toxicity charac-
terized by slightly decreased water and food consumption
and body weight gain, without a noticeable tumorigenic re-
sponse. When the dose was increased to 100 or 300 mg acrylon-
itrile/1 in drinking water, the rats showed marked signs
of toxicity in addition to a tumorigenic response involving
stomach, nervous sytem, and Zymbal gland of the ear canal.
(Tables 13 and-14). It should.be noted that zymbal gland
tumors were also verbally reported by Beliles (personal
communication) to be present in rats during a 3 year reproduc-
tive study (Beliles, Murray 1977) (see section or Teratology).
In further support of the above data, a letter transmit-
ted by the Manufacturing Chemists Association dated February
22, 1978, includes a summary of preliminary findings of
a study by Dow Chemical U.S.A. indicating a higher incidence
of brain tumors at 80 and 20 ppm in drinking water when
compared to historic control data.
C-64
-------
TABLE 13
Results of Histopathologic Examination of Tumorous Changes
in Male Rats Maintained on Water Containing Acrylonitrile for 12 Months'
Microscopic Findings
Number of rats in the group
Kidney
Hemangioma - unilateral
Stomach
'Focal squamous cell papilloma(s)
Central nervous system
Microtumor suggestive of
Conc«
0
10
0
0
0
jntration of acrylonitrile
in the water (ppm)
35
10
0
0
0
100
10
1
1
2
300
10
0
7
1
mesodermal origin
Histopathologic diagnosis of the following tumors based upon those grossl;.
recognized at autopsy.
Small intestine
Mucinous cystadenocarcinoma 001 0
without metastasis
Large intestine
Well-differentiated polyploid 0 0,0, 1
adenocarcinoma without metastasis
Ear canal tumor
Zymbal gland carcionoma without 000 1
metastasis
Total number of tumors 0 0 5 10
*Quast, et al. 1977
Data are listed as number of rats affected in the group.
C-65
-------
TABLE 14
Results of Hisfcopathologte Examination of Tumorous Changes
iri Female gats Maintained ott water Containing AN for 12 Months
Concentration of aCrylonitrile
irt the .water
Mj. c f PS clop i c F i rid j hg s.._„ , ,0 ,35 100 3.00
Number of rats iri the group 9 9 10 10
S tomacjh
Focal squamous cell papilioma(s^) 000 5
Central nervous., system
Microtumor suggestive of 0042
mesodermal origin
Histopathologic diagnosis of the following tumors based upon those grossly
recognized at autopsy.
Pituitary glarid
Adenoma 1 0 0 0
Ear canal tumor
Zymbal gland carcinoma Without 0 0 2 1
metastasis
Subcutaneous tumogjs).
Mammary gland adenbcardinoma 201 0
without metastasis
Mammary gland adenocarcinoma with 000 1
pulmonary metastasis '
Mammary gland fibroadenoina
: One per rat with tumor
Three per rat with tumor
Uterus
Endometrial polyp
Leiomyoma
Uterocervix fibroma
Total number of tumor's
0
0
\
'0
0
5
0 1
0 l(3,)c
0 2
fo *o
1 12
1 14
2
0
1
1
1
14
f*Quast, et al. 1977
are listed as numfeer of rats affected in the ^roup.
A single rat in this group had 3 mammary gland f ibroa<3'en'omas.
C-66
-------
Maltoni, et al. (1977) have recently reported the results
of long-term carcinogenicity bioassays of acrylonitrile,
lasting more than 130 weeks. The monomer has been tested
in Sprague-Dawley rats by inhalation (40, 20, 10, and 5
ppm, 4 hours daily, 5 times weekly for 52 weeks) and by
ingestion (5 mg/kg body weight in olive oil by stomach tube,
once daily, 3 times weekly for 52 weeks). A slight enhance-
ment of the incidence of some tumors has been reported -
- mammary tumors, fore-stomach papillomas and acanthomas,
skin carcinomas, and encephalic tumors, particularly gliomas.
It should be noted that only one dose was used in the
ingestion studies, so that no-dose response relationship
could be obtained. Data from the inhalation studies are
presented on mammary tumors and Zymbal gland carcinomas
and on encephalic tumors (particularly gliomas), uterine
carcinomas and others (Table 15).
As an additional note it should be pointed out that
possible impurities found in the acrylonitrile used by var-
ious investigators might possibly affect the determination
of carcinogenic effect. The role of these impurities has
not yet been determined.
A recent preliminary epidemiological study from E.
I. de Pont de Nemours and Company on its Camden, South Caro-
line textile fibers plant showed that persons exposed to
acrylonitrile at the plant are at greater risk of developing
cancer, as compared with company, national and regional
experience (O'Berg, 1977). This preliminary retrospective
study analyzes the cancer experience of the cohort of 1343
C-67
-------
TABLE 15
Results of Inhalation Study by Maltoni, et al. 1977.
o
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(»J^S)
(c)
94.4
IJ0.7
IOb.0
110.7
48.0
99. J
102. J
114.0 .
10J.7
9J.O
-
9J.O
9J.O
-
9J.O
£••111 Mo.
or
CUAoura/
animal
1.4
1.0
1.2
1.0
1.0
1.0
1.4
1.0
1.4
1.J
-
1.3
1.0
-
1.0
Carcinonas
No.
2
1
J
l
2
J
'-
-
-
4
-
4
1
1
2
* (0)
6.6
J.J
5.0
J.J
6.6
5.0
-
-
-
U.J
-
6.6
J.J
J.J
J.J
fcveraf 4
latency
time
(necka)
(c)
77.0
58.0
70.7
76.0
J5.0
49.J
-
-
-
91.0
-
91.0
98.0
U5.0
116.5
*«tn Ho.
OI
tuaoura/
anneal
1.5
1.0
I.J
1.0
1.0
1.0
-
-
-
1.0
1.0
1.0
1.0
1.0
«.>•?!.* f and
cariinjv>3
So.
-
-
-
V 1
-
1
1
1
2
-
-
-
-
-
-
1 10)
-
-
-
J.J
-
1.6
J.J
J.J
3.)
-
-
-
-
-
-
»^v'J^^, ••
' itin'y
t.-ii-
,* 'UKS)
(c)
-
-
-
77
-
77
101.0
104. C
102.,
-
-
-
-
*
-
(a) Alive animjls after 2 weeks, when (he first tumour (a mamnury carcinoma) was observed
(b) The p«.rcentjges are referred to the corrected number.
(c) The launcy time of mammary tumours is given as age, the latency time of the other tumours is given as period from the start of the experiment
-------
workers who were exposed to acrylonitrile between 1950 and
1967. It considers no latency/ 15-year latency and 20-year
latency periods for cancer development. About 36 percent
of the 1343 employees are presently lost to follow-up.
In this study, mortality rates were analyzed for active
employees and retirees, and cancer diagnoses and deaths
for active employees were analyzed using company and national
referent rates to determine expected numbers. The most
sensitive analysis, using du Pont referent rates (correcting
for the "healthy worker effect") and a 20-year induction
for cancer (which narrows down the cohort to 470) indicated
eight observed deaths compared with 4.0 expected. The du
Pont Registry data revealed 16 cases of cancer compared
to 5.8 expected. The difference was found to be highly
significant. (See Tables 16 and 17).
The author of the study notes that the results presented
are preliminary-, and that additional follow-up of persons
who quit or were laid off is required. In the cohort, the
losses to follow-up represent a significant percentage (36
percent). About one-third of the losses have had short-
term exposure (less than six months). The acrylonitrile
exposure levels were only qualitatively reported (on the
basis of the job and its potential for exposure) as 3 (lowest
exposure), 2 (moderate exposure) or 1 (highest exposure).
Times at each level were estimated for each cancer morta-
lity. Excess cancer was observed when considering all sites;
individual sites with excess cancer mortality were lung,
large intestine and possibly prostate. (See Tables 16 and
17). The excess cancer in the cohort is distributed among
C-69
-------
TABLE 16
Observed and Expected Numbers of Cancer Deaths* for an
Acrylonitrile Cohort with Six Months or Greater Exposure, Based on du Pont
Company Rates for 196901975, 20-Year Latency (O'Berg, 1977)
All sites
Lung
Large Intestine
Prostate
Observed
7
4
2
1
Male Wage
Expected
3.2
1.2 '
0.2
0.1
Male Salary
P-Value Observed Expected
0.04 1
0.03 0
0
0
0.6
0.2
0.0
0.0
TABLE 17
Observed and Expected Numbers of Cancer Cases* for an
Cohort with Six Months or Greater Exposure, Based on du Pont
Company Rates for 1969-1975, 20-Year Latency (O'Berg, 1977)
All sites
Lung
Large Intestine
Prostate
Observed
13
5
3
1
Male Wage
Expected
4.4
1.2
0.4
0.3
Male Salary
P-Value
.0006
.008
.008
Observed
2
1
Expected
0.8
0.2
0.1
0.0
*Source: Cancer Registry Entries (active employees only).
C-70
-------
many anatomical sites although lung and intestinal cancer
predominate. Significant excess overall cancer mortality
cannot be entirely attributable to these primary sites.
Because an excess of lung cancer occurs in this cohort,
cigarette smoking must be considered as a possible agent
or cofactor; smoking histories were not available for this
interim report however (O'Berg, 1977). Another consider-
ation should also be mentioned; the du Pont cohort had in
common exposure to the following chemicals besides acryloni-
trile: dimethylformamide, hydrogen peroxide, hydroxyani-
sole, methyl acrylate, phenylether-biphenyl mixture, sodium
metabisulfite, sulfur dioxide, sulfuric acid and titanium
dioxide. (O'Berg, 1977 letter). A tabulated list of all
cancer cases 'appear in Table 18 (O'Berg, 1977).
Monson (1977) , analyzed the cancer mortality (and morbi-
dity) experience of 355 white male United Rubber Workers
Union members who had potential exposure to acrylonitrile
in the polymerization recovery and laboratory areas of B.F.
Goodrich plant #3, Akron (Table 19). The mortality exper-
ience of this cohort between 1-1-40 and 7-1-76 was compared
to that of the U.S. general population. Person-years of
follow-up were determined in 5-year age-time groupings and
expected numbers were calculated by multiplying these person-
years by age-time-cause specific mortality rates for U.S.
white males. The cancer registries of the four Akron area
hospitals were reviewed between 1964 and 1974.
Determination was also made of any B.F. Goodrich employee
who developed cancer between these years. In addition,
persons who had cancer as the secondary cause of death on
the death certificate were identified. Based on these data,
C-71
-------
TABLE 18
An Cohort Cancer Cases and/or Deaths, 1969-1975, Duration of Exposure (O'Berg, 1977)
o
~j
to
Date of Total Years of Exposure
First Rounded to Nearest Whole
Cancer Site
Lung
Lung
Lung
Lung
Lung
Lung
Large Intestine
Large Intestine
Large Intestine
Prostate
Prostate . . _
Lymphosarcoma
Hodgkins
Penis
Thyroid
Nasopharynx
Bladder
Pancreas
Exposure
1950
1950
1950
1950
1952
1952
1951
1951
1952
1950
1952
1951
1951
1952
1952
1950
1950
1952
Year
26
20
7
4
5
4
13
5
5
14
5
1
13
12
14
7
3
6
18 gr,
5 yr.
1 yr.
5 yr.
1 yr.
5 yr.
5 yr.
5 yr.
2 yr.
3 yr.
6 yr.
1
»
1 mo.
2 mo.
1 mo.
2 mo.
3 mo.
8 mo.
1 mo.
Time at Severity
2 3
8 yr.
20 yr.
1 yr. 4 mo. 2 mo.
1 yr. 2 mo. 2 yr. 1 mo.
3 yr. 4 mo.
13 yr. 1 mo.
6 mo.
13 yr. 9 mo.
4 mo.
12 yr. 9 mo.
8 mo. 11 yr.
1 yr. 8 mo. 10 yr.
7 yr. 4 mo.
*20-year latent period assumed.
-------
n
i
•~j
Ul
TABLE 19
Observed and Expected Deaths for 355 white Male
Union Members Who Ever Worked in Departments 5570 - 5579
Monson, 1977
ICD No. §
140-205
150-159
153
160-164
177-181
200-205
-
330-334
400-468
470-527
530-581
590-637
800-999
~
Cause of death
All causes
Malignant neoplasms
Digestive
Large intestine
Respiratory
Genitourinary
Lymphatic & Hematopoietic
Residual cancer
Cerebrovascular disease
Circulatory disease
Respiratory disease
Digestive disease
Genitourinary disease
External causes
Residual
Observed
64
20
4
1
9
2
3
2
5
22
5
2
1
5
4
Expected
83.1
15.6
4.6
1.3
5.2
1.7
1.6
2.2
5.1
37.5
4.3
4.5
1.3
8.8
10.5
SMR**
77
128
88
74
175
117
186
94
97
59
117
44
77
57
38
* International Classification of Diseases. 7th Revision.
** Standardized Mortality Ratio: 100 x observed/expected.
-------
Monson (1977) compared cancer morbidity rates in men who
worked in departments with potential exposure to acryloni-
trile with unexposed male workers.
According to this study Monson (1977) reported that
among the male cohort who had some exposure to acrylonitrile
as well as other chemical exposure in the cohort (such as
butadrene), the most significant findings was an excess
-------
exposed to other chemicals. Finally, Monson (1977) concluded
that although proof does not exist that the current levels
of acrylonitrile and other chemical exposures (such as buta-
dien) are harmful, it would be prudent to reduce further
exposure to the chemical. No quantitative exposures of
acrylonitrile are listed in the report. Monson (1977) notes
that his data at Goodrich conflicts with O'Berg's (1977)
du Pqnt study in which an excess of intestinal cancer was
observed. Aside from difference in other chemical exposures
suffered by the two cohorts, Monson (1977) did not assume
a 20 year latency period (providing greater sensitivity)
while O'Berg (1977) did.
C-75
-------
TABLE 20
Observed and Expected Deaths from all Cancers and
Lung Cancer According to Selected Characteristics
Characteristic
Age started working*
Year started working
Age at death
Year of death
Category
(years)
35
35-44
45
1940
1940-49
1950
65
65
1960
1960-69
1970
All
Obs.
5
5
10
0
12
8
11
9
3
9
8
Cancers
Exp.
4.9
4.7
6.0
0.6
7.9
7.1
11.1
4.5
2.6
6.2
6.8
Lung
Obs.
2
1
6
0
3
6
5
4
0
4
5
Cancer
Exp.
1.2
1.8
1.8
0.2
2.3
2.3
3.5
1.3
0.6
1.9
2.3
Age and year refer to entrance into 5570-5579.
C-76
-------
CRITERION FORMULATION
Existing Guidelines and Standards
The Existing Standards for acrylonitrile in various
countries and various years appear in Table 21.
It is evident that at this time, the Russian standard
is substantially less (two order of magnitude) than the
American and West European standards. The work of Scupakas
(1968) indicates, however, that the standard may be exceeded
significantly. The study of Orusev and Popovski (1973)
of a Yugoslavian acrylic fiber plant indicated that their
in-plant concentrations of acrylonitrile begin to approach
the TLV in the U.S.A. Other investigators have noted that
the air standards are often exceeded (Schwanecke, 1966;
Thiede and Franzen, 1965; Babanov, 1960), although it is
unlikely that higher concentrations occur throughout the
day.
Almost twenty years ago, it was advocated by Elkins
(1959) in the U.S.A. that the "MAC" be reduced to 10 ppm
(corresponding to that of HCN). According to Babanov (1960)
an acute danger exists even from 0.85-6.1 mg/m (0.4 - 2.8
ppm) in working areas.
In January, 1978, the Occupational Safety and Health
Administration (OSHA) announced an emergency temporary stan-
dard to reduce sharply worker exposure to acrylonitrile.
OSHA director, Dr. Eula Bingham, said that, effective imme-
diately, employee exposure to acrylonitrile must be reduced
to 2 ppm averaged over an eight-hour period (TLV). Dr.
Bingham noted that the Emergency Temporary Standard was
necessary because of data from studies of workers previously
C-77
-------
Year
TABLE 21
Standards for Arcylonitrile Air Exposure Levels
in Various Countries (between 1970-1974)
Country
Air
pptn
Standard
mg/m
Kind of
Standard
Reference
1970
1970
1970
1974
U.S.S.R.
0.2
Federal Republic 20.0
of Germany
England
U.S.A.
20.0
20.0
0.435
43.5
43.5
43.5
MAC Grahl, 1970;
("Hygenic goal") Schwanecke, 1966;
Babanov, 1960;
Pokrokovsky, 1951;
Thiede and Franzen,
1965
MAK
MAC
TLV
Grahl, 1970;
Thiede and Franzen/
1965; Lefaux, 1966
Grahl, 1970;
Thiede and Franzen,
1965; Lefaux, 1966
Threshold Limit
Values, 1974;
Grahl, 1970;
Mallette, 1943;
Dudley and Neal,
1942; Stokinger,
et al. 1963
C-78
-------
exposed to acrylonitrile and laboratory tests, both'of which
established "exposure to acrylonitrile poses a potential
carcinogenic risk to humans." While OSHA's position is
that there is no way to determine a safe level of exposure
to a carcinogen, in this case "a level was chosen to immedi-
ately minimize the hazard to the greatest extent possible
within the confines of feasibility (Chemical and Engineering
News, Jan. 23, 1978)."
The recent action of OSHA is, in fact, based upon studies
done by the chemical industry itself. In March, 1977, the
Manufacturing Chemists Association (MCA) reported interim
results from a study of the chronic toxicity of acryloni-
trile ingestion on rats. Findings were that ingestion of
100 and 300 ppm of acrylonitrile in drinking water produced
tumors of the CNS and ear canal. In April, 1977, there
were similar tumors reported among rats ingesting 35 ppm
of the substance. (Norris, 1977). Confirming the labora-
tory results, du Pont informed OSHA of preliminary results
of an epidemiological study of workers exposed to acryloni- -
trile at its textile fibers plant in Camden, S.C. (Chemical
and Engineering News, Jan. 23, 1978; O'Berg, 1977). (See
Human Carcinogenicity Studies under Effects).
Current Levels of Exposure
Indices of exposure, apart from very unspecific symp-
toms (such as spirographic examination of the lung) in the
case of chronic exposure (Possner, 1965) include the determin-
ation of increased blood SCN~ level (Mallette, 1943; Wilson,
et al. 1948; Lawton, et al. 1943) and elevated urinary
SCN~ level (Mallette, 1943; Sax, 1957; Elkins, 1959; Lawton,
et al. 1943).
C-79
-------
It must be recognized that smoking presents a problem
in ascertainment of occupational and other exposure because
of the presence of nitriles in cigarette smoke. Thus, smokers
may have a blood level of approximately 3 mg percent SCN~
in blood; the urinary SCN~ level of heavy smokers may normal-
ly reach 9 mg KSCN/1 in contrast to a normal urinary level
for non-smokers of 0.2 mg/1 and for occasional smokers a
normal urinary level of 1.2 mg KSCN/1 (Elkins, 1959). Con-
sequently, in testing for occupational or other exposure,
if it is not known whether a person is a smoker, values
of urinary KSCN _ 10 mg/1 cannot be considered to result
from occupational exposure. Sax (1957) suggests that it
is advisable for the purposes of screening for exposure
to have liver function tests if urinary analysis proves
to be negative. In addition, another suggested method of
screening is that of the spectrophotometric determination
of cyanomethemoglobin in blood (Ullmanns, 1960; Magos, 1962).
The existing occupational standards have already been
mentioned. It has also been noted that these standards
are often exceeded. The production of significant amounts
of acrylonitrile and HCN from thermal decomposition of poly-
acrylonitrile products has already been noted. For example,
overheating of 1 kg of a polyacrylonitrile plastic about
15 g of HCN can be formed. Thus, the amont of HCN formed
in a 30 m room from 100-200 g of polyacrylonitrile fibers
corresponds to 10-15 times the MAC values (Schwanecke, 1966;
Thiede and Franzen, 1965; Mallette, 1943) and this under-
lines a special hazard of polyacrylonitrile plants. The
possible synergism of acrylonitrile and HCN has already
been alluded to.
C-80&O81
-------
There are few data on monitoring of ambient air and
drinking water levels of acrylonitrile. A notable exception
is the analysis of in-plant air emission from a propylene-
based acrylonitrile manufacturing plant by Hughes and Horn
(1977). This lack of data prevents us from predicting most
actual exposures of the public except for certain groups
at high risk such as occupational workers. At the present,
Emergency Air Standard, 2 ppm of acrylonitrile = 4.35 mg/m /day,
the acrylonitrile intake of a worker at threshold level
= 0.90 (4.35 mg/m3) (20 m3/day) = 78.3 mg/day, where 0.90
is the average retention of acrylonitrile (Young, et al.
1977) . Thus, depending on the half-life of acrylonitrile,
a substantial body burden in occupationally exposed indivi-
duals can result.
As indicated under Sources of Exposure, some additional
environmental monitoring data is becoming available (Midwest
Research Institute, 1977 and 1978). However, to data this
information is preliminary in nature and conclusions on
possible human exposures cannot be drawn.
Other groups at risk are listed in the next section.
Due to a lack of data, it is impossible to calculate the
actual intakes of acrylonitrile for these groups.
Special Groups at Risk
Shown below are various groups at varying degrees of
risk to acrylonitrile exposure, with attached references,
wherever feasible. It should be recalled that NIOSH has
estimated that at least 125,000 individuals are exposed
occupationally (NIOSH, 1977).
C-82
-------
Occupational
1. Plastic
Acrylonitrile Manufacturers
Polymer Manufacturers
Polymer Molders
Polymer Combustion Workers
Furniture Makers
2. Fabrics
Fiber Manufacturers
Clothing Sewers
3. Biological Product Manufacturing
Dental Polymer Manufacturers
Contact Lens Fabricators
Blood Filter Fabricators
4. Water Treatment and
Manufacturers
5. Pesticide and Fumigant
Manufacturers
Sprayers
Farmers
(NIOSH, 1977)
(NIOSH, 1977)
(NIOSH, 1977)
(Scupakas, 1968)
(Rumberg, 1971;
Duvall and Rubey,
1973)
(Vol'skii, et al.
1973)
(Rapaport, et al.
1974)
(Orusev and Popov-
ski, 1973; Valic
and Zuskin, 1977)
(Fedorchuk, 1973)
(Crapper, et al.
1978)
(Stoy, et al. 1976)
(Lindsay, et al.
1977)
(Sato, et al. 1977)
(Radimer, et al.
1974)
(Radimer, et al.
1974)
(Radimer, et al.
1974)
C-83
-------
Non-Occupational
1. Accidental
Exposure to Liquid from Trans-
portational spill
Combustion and Fire (firemen
and domestic personnel)
(Hardy, et al. 1972)
(Duvall and Rubey,
1973; Michal,
1976; Hilado, et
al. 1977)
Ingestion of Contaminated Water (Chudy and Crosby,
1978;
or Food . Vettorazzi, 1977)
Respirations of Contaminated Air (environmental
exposure to acrylonitrile or polyacrylonitrile plants)
2. Non-accidental
Cigarette smokers
Wearers of acrylic dentures
Wearers of acrylic underwear,
diapers, and sanitary napkins
Ingestion of food wrapped in
polyacrylonitrile wrapping
Exposure to acrylonitrile
(Izard and Testa,
1968)
(Crapper, et al.
1978)
(Rapoport, et al. 1974;
Harada and Shimodi, 1976)
(Federal Register, 1974, 1975,
1976)
(Vol'skii, et al. 1973)
vapors from polyacrylonitrile furniture.
Basis and Derivation of Criterion
The animal carcinogenicity studies of Norris (1977),
Quast, et al. (1977), and Maltbni, et al. (1977) and the
epidemiological studies of O'Berg (1977) and Monson (1977)
were considered to be the most pertinent data for the determi-
nation of a water quality criterion for the protection of
human health. Although the epidemiological studies showed
excesses of various cancers in man, neither study had quanti-
tative exposure data of the workers to acrylonitrile and
hence could not be utilized for calculation of a safe level.
C-84
-------
The criterion was therefore developed from the animal carcino-
genicity data by utilizing the linear non-threshold model
(see Appendix A). The rat carcinogenicity studies, in general,
showed a tumorigenic response to acrylonitrile whether expo-
sure was by ingestion or inhalation. These data support
the findings of the epidemiological studies.
To select data for the evaluation of an acceptable
risk concentration, studies having the following attributes
were chosen:
1. There was an increase in frequency of tumors in
treated rats over control rats.
2. There was a low frequency of tumors in control
rats.
3. Several dosage levels were tested so dose-response
relationships could be interpreted.
To use the linear dose-response non-threshold model
in calculating a water concentration that results in a risk
of a carcinogenicity incidence of 1/100,000, the following
assumptions were made for all calculations:
1. A maximum bioaccumulation factor of 110 for acryloni-
trile, as determined for the bluegill sunfish
(EPA report, Duluthf Mn.)n
2. Consumption of water per person per day is 2 1
over a period of 70 years.
3. Average consumption of fish per person per day
is 18.7 grams.
4. Average life span for test rats is 730 days.
C-85
-------
Specialized assumptions for converting inhalation dose
to an equivalent ingestion dose were made with the Maltoni,
et a»l. (1977) study as follows (also see Appendix B for
sample calculation):
1. The average rat respiration rate is 0.61 1/min.
kg (Guyton, 1947; Cro'sf ill and Widdiconbe, 1961) .
2. The average weight for male rats is 500 g and
female rats 300 g.
3. The absorption efficiency is 90 percent (Young,
et al. 1977).
4. Since the duration of the experiment was 1001
days, the average life span of the rat was assumed
to be 1001 days due to constraints of the equa-
tions in the linear model.
5. The data of Young, et al. (1977) (see Pharmacoki-
netics) suggests that extrapolation from one dosage
route to another may not be valid. Further verifi-
cation of this data is needed, however, and the
data of Maltoni's inhalation study was included
for comparison with the water ingestion studies.
C-86
-------
The results of the application of the linear non-thres-
hold model to the selected data are summarized below:
Reference . Route
Norris, 1977 water
ingestion
Location of
tumor-
Sex
proliferative female
lesions in brain
mammary gland female
ear canal
masses
female
male
Dose Acceptable risk
(mg/kg) concentration in
water (mg/1)
12.45 1.2 x 10
-4
4.7 1.6 x 10
-4
12.45 9.8 x 10
23.8 8.8 x 10
-5
Quast, et al. water
1977 ingestion
stomach
central
nervous
system
zymbal
gland
female 27.45 1.5 x 10
-4
male 23.8 8.8 x 10
female 11.4 8.3 x 10
-5
-5
male 9.6 1.9 x 10
female 11.4 1.9 x 10
-4
-4
Maltoni, et inhalation gliomas
al. 1977
mammary
gland
male
female
4.1* 18.1 x 10
-4
1.0* 0.6 x 10
male 4.1* 5.6 x 10
Calculated ingestion dose converted from inhalation (Appendix B)
-4
C-87
-------
In spite of the differences between the data sets,
the application of linear non-threshold model results in
relatively similar calculated acceptable risk concentrations
for water in each case. Due to the numerous assumptions
necessary for the Maltoni study1 as well as the potential
inability to convert between dosage routes, the data from
this study were not weighed as -heavily as the others. There-
fore, the value of 0.8 x 10 m'g/1 was selected as the recom-
mended criterion for acrylonitrile in water. It must be
emphasized that this level is based on data from a 12-month
interim report and is, therefore, preliminary in nature.
Under the Consent Decree in NRDC vs. Train, criteria
are to state "recommended maximum permissible concentrations
(including where appropriate, zero) consistent with the
protection of aquatic organisms, human health, and recreation-
al activities." Acrylonitrile is suspected of being a human
carcinogen. Because there is no recognized safe concentration
for a human carcinogen, the recommended concentration of
acrylonitrile in water for maximum protection of human health
is zero.
Because attaining a zero concentration level may be
infeasible in some cases and in order to assist the Agency
and States in the possible future development of water quality
regulations, the concentrations of acrylonitrile corresponding
to several incremental lifetime cancer risk levels have
been estimated. A cancer risk level provides an estimate
of the additional incidence of cancer that may be expected
in an exposed population. A risk of 10 for example, indi-
C-88
-------
cates a probability of one additional case of cancer for
every 100,000 people exposed, a risk of 10~ indicates one
additional case of cancer for every million people exposed,
and so forth.
In the Federal Register notice of availability of draft
ambient water quality criteria, EPA stated that it is con-
sidering setting criteria at an interim target risk level
of 10~5, 10~6 or 10~7 as shown in the table below.
Exposure Assumptions Risk Levels and Corresponding Criteria '
re «»«™™^™^^^^^^^^^^^™^^™^^^^^^™^^^^^™^^^^^«™^^^^^^«^^™»««^^^w^^^^^^^™^«^»««»M«^^^w^^^*»
0 Kf7 1G!~6 1£~5
2 liters of drinking water 0*008 x 0.08 x 0.8 x
and consumption of 18.7 , n-4 n , n-4 n .. . n-4
grams of fish and shellfish (2)
10 * ng/1 10 * ng/1 10 * ng/1
Consumption of fish 0.016 x 0.16 x 1.6 x
and shellfish only. 1Q-4 ng/1 1Q-4 ng/1 1Q-4 ng/1
(I) Calculated by applying a modified "one hit" extrapo-
lation model described in the Methodology Document
to the animal bioassay data presented in Appendix
III. Since the extrapolation model is linear
to low doses, the additional lifetime risk is
directly proportional to the water concentration.
Therefore, water concentrations corresponding
to other risk levels can be derived by multiplying
or dividing one of the risk levels and corresponding
water concentrations shown in the table by factors
such as 10, 100, 1,000, and so forth.
C-89
-------
(2) Fifty one percent of the acrylonitrile exposure
results f-rom the consumption of aquatic organisms
which exhibit an average bioconcentration potential
of 110-fold. The remaining 49 percent of the
acrylonitrile exposure results from drinking water.
Concentration levels were derived assuming a lifetime
exposure to various amounts of acrylonitrile (1) occurring
from the consumption of both drinking water and aquatic
\
life grown in water containing the corresponding acrylonitrile
concentrations and, (2) occurring solely from the consumption
of aquatic life grown in the waters containing the correspond-
, /
ing acrylonitrile concentrations. Because data indicating
other sources of exposure and the contribution to total
body burden are inadequate for quantitative use, the criterion
reflects the increment to risks associated with ambient
water exposure only.
C-90
-------
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of acrylonitrile and their influence on the worker's (health).
Gig. Tr. Prof. Zabol. 8: 8.
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APPENDIX I
Carcinogenicity Risk Assessment by Extrapolation from
Laboratory Animal Toxicity Tests
An assessment of health risks associated with exposures
of a general environmental nature requires prediction of ef-
fects from low level exposures of lifetime duration. Carcin-
ogenic risks effects from environmental exposures must nor-
mally be estimated from animal data obtained at much higher
levels because of the difficulty in detecting a small in-
crease in tumor induction resulting from long-term low level
exposure. Because the carcinogenic process is generally be-
lieved to be irreversible, self-replicating, and often orgin-
ating from a single somatic cell mutation, assumptions of
threshold levels of effect are believed to be invalid for
many, if not all, cancer-causitive compounds. Although many
models have been proposed for extrapolation from animal data
to human risk assessment, the one utilized here was chosen to
facilitate uniform treatment of the variety of chemical com-
pounds that are discussed in the development of those water
criterion documents which deal with animal carcinogens.
It is recognized that the process of evaluating existing
studies and resultant data in preparation for application of
mathematical methods involves a high level of professional
judgment. Many questions will necessarily arise due to the
unique characteristics of the specific compounds under dis-
cussion and the tremendous variability in completeness and
compatability among the available studies.
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A general explanation of the evaluation and extrapola-
tion procedures to be used are as follows;
1. Since the compounds discussed are known, or suspect,
carcinogensf, emphasis was placed on those studies
with carcinogenic or mutagenic endpoints. In par-
ticular, those studies dealing with mammaliam
species.
2. The extrapolation method employed is a mathematical
procedure which uses a single dose and observed re-
sponse of a toxicologic experiment to estimate a
dose level for humans that will not increase the
risk of tumors by more than a specified level (1 in
100,000) (Personal communication, Dr. Todd Thors-
land, GAG, U.S. EPA, Washington, B.C.). Clearly
this method is predicated on sound toxicologic test
procedures. Hence, each included study was evalu-
ated for adherence to sound toxicological and sta-
tistical principles.
3. Judgment was exercised in prioritizing the signifi-
cance of toxicologic studies that use different
routes of administration. In general, the preferred
route of exposure is oral (food, water, or gavage)
followed by intraperitoneal, intravenous, inhala-
tion, or dermal routes of administration for the
same species. However, in some instances, consider-
ation of absorption rates required that other routes
be evaluated.
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The NCI's Ad Hoc Committee on the Evaluation of Low
Levels of Environmental Chemical Carcinogens out-
lined two conditions that would render the extra-
polation of animal carcinogenesis to man inappro-
priate. This committee reported to the Surgeon
General as follows:
"Any substance which is shown conclusively
to cause tumors in animals should be con-
sidered carcinogenic and therefore a poten-
tial hazard for man. Exceptions should be
considered only where the carcinogenic ef-
fect is clearly shown the results from phy-
sical rather than chemical induction or
where the route of administration is shown
to be grossly inappropriate in terms of
conceivable human exposure."
4. After selection of the sound toxicologic studies
that form the basis for development if a recom-
mended criteria, a single dose and observed re-
sponse was selected for the most "sensitive" sex
(if both males and females were tested) accord-
ing to the following method: Select the lowest
dose which yields a tumor response rate that is
greater than the control rate. If the standard
controls and media control response rates are
not significantly different (a<0.05), a combined
rate was calculated from controls.
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5. The extrapolation methods were applied independently
to each selected dose and response pair. The lowest
projected dose was selected as the "safe level"
based on the available toxicologic studies, if judg-
ment indicated equal confidence in the various dose-
response pairs.
6. The calculated safe dose was evaluated along with
the results from human studies to develop a recom-
mended criteria.
Calculation of Estimated Safe Levels for Humans:
The specific data analyses performed along with required
input data are described following in Mathematical Descrip-
tion of Extrapolation Method. This model provides the addi-
tional risk associated with ingestion of 2 liters of water
per day and contaminated aquatic foods. Any other risks as-
sociated with air, food, or other exposure are not addressed
by this model. A copy of the working data sheet is also in-
cluded.
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Mathematical Description of Extrapolation Method
A. Necessary information:
Nt = No. of animals (males or females) exposed to
selected dose that developed tumors (all sites
combined unless tumors appear to be related to
route of administration, e.g., peritoneal tu-
mors would not be included if intraperitoneal .
injection method is used).
Nt = Total number of animals (males or females) ex-
posed to selected dose level.
nc = Number of control animals (males or females)
with tumors.
NC = Total number of control animals (males or fe-
males) .
Le = Actual maximum lifespan for test animals.
le = Length of exposure (no. of hours, days, weeks,
etc.).
d = Average dose per unit of time (mg/kg).
w = Average weight of test animals (kg).
B. Necessary information from general literature:
70 kg = Average weight of man.
L * Theoretical average length of life for test
species, unless specified in article. (See
attached table for appropriate values).
F = Average weight of fish consumed per day, assumed
18.7 grams.
C. Necessary ecological information:
R = Bioaccumulation factor for edible portions of
fish (Supplied by Environmental Research Labora-
tory, Duluth).
(Note: If a bioaccumulation factor is provided
for the total fish or for some part
other than the total edible portion
(such as the fat) an attempt should be
made to estimate factor for edible por-
tion. )
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D. Mathematical Model: p-
Pt = PC + (1-Pc) 1 - e -t3BD
Where:
Pt = nt f Nt = Proportion of test animals with tumors.
PC = nc 7- NC = Proportion of control animals with tumors.
D = L ~ Lifespan weighted average dose level
(mg/kg)/(unit of Time).
n Ji^H- - Pt|\.. C .3! ,KQ>.^ ,. lifespan for test animals Le
B *t b " P4* L ^Jwhere t = lengtg of life for species = IT
B = B \^l— (Note: It is assumed that average weight of man = 70 kg.)
Njw
If and only if B < 0.1 then
10~" x 70
SL = p. /0.p p,- Safe level (mg/1) for man
•D ( 2. +KXr )
If B 2 0-1
SL = -B' ° - " x 70 = Safe level
(Note: It is assumed average .daily consumption of water is
2 liters/day.
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Appendix II
Conversion of Inhalation Dosage to Ingestion Dosage for
the Study of Maltoni, et al. (1977).
The following procedure was utilized to convert the
inhalation dosage of Maltoni, et al. (1977) to equivalent
ingestion dosage. The example uses a dose of 10 ppm; simi-
lar to calculations were made for the specific doses uti-
lized by Maltoni.
1. Conversion of ppm to mg/m was done by using the
/
molecular weight of acrylonitrile and determining
a conversion factor such that
mg/m = ppm x 2.18
Therefore 10 ppm = 21.8 mg/m
2. The inhalation rate of the rat was assumed to
be 0.61 1/min. kg. Correcting for the number
of exposure hours per day the volume of respired
air was determined.
total air = 0.61 1 x 60 min x 4 hour x m^ = 0.1464m
daymin.kg hr day1000 1 kg.day
3. Combining the results of 1. and 2. the air dose
was determined.
mg/kg.d = 21.8mg/m3 x 0.1464m = 3.1915 mg
kg.day kg.day
4. A figure of 90 percent absorption was taken from
Young, et al. (1977). This study was more detailed
and felt to be more precise than that of Rogac-
zewska and Piotrowsky (1968) which indicated 46
percent. The absorption figure was used to con-
vert inhaled dose to the retained dose which was
assumed to be equivalent to ingested dose.
3.1915 mg x 0.90 = 2.872 mg ingested dose
kg.day kg.day
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Because dosing was for only 5 days/week the value
in 4. was corrected to a 7 days/week exposure.
equivalent
weekly dose = 2.872mg x 5 = 2.051mg
kg.d 7 kg.d
Therefore, an inhalation dosage of 10 ppm is esti-
mated to be equivalent to an ingested dosage of
2.051 mg
kg.day
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APPENDIX III
Summary and Conclusions Regarding the
Carcinogenicity of Acrylonitrile (AN) *
Acrylonitrile has a molecular structure (CH2=CH-CN),
which resembles that of vinyl chloride (CH2=CH-C1), a chemical
known to cause animal and human cancer. Principally, it
is used as an intermediate in the manufacture of a wide
variety of acrylic fibers, plastics, and in synthetic rubber.
Acrylonitrile is mutagenic in the Ames Salmonella typhi-
murium strains TA1535, TA1538, and TA1978 in the presence
of mammalian metabolic activation which indicates both base-
pair substitution and frameshift mechanisms of action.
It is also reported positive in Drosophila.
There is strong preliminary evidence that acrylonitrile
is likely to be a human carcinogen. This conclusion is based
on the following studies. 1) two preliminary reports of
the Dow Chemical Co. bioassay of acrylonitrile given in
drinking water to Sprague-Dawley rats, 2) carcinogenicity
of acrylonitrile in Sprague-Dawley rats by Maltoni, adminis-
tered via inhalation. In these three studies, acrylonitrile
has induced excess tumor incidence of the central nervous
system as compared to the controls, 3) in addition, a prelim-
inary epidemiologic study by E.I,, Dupont de Nemours and
Co., Inc. indicated an excess of lung and colon cancer
incidence among active employees in the company working
with acrylonitrile as compared to that of the national experi-
ence.
*This summary has been prepared and approved by the Carcinogens
Assessment Group of U.S. EPA on June 15, 1979.
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In summary, carcinogenic responses have been induced
in Sprague-Oawley rats and humans. These results, together
with the positive mutagenic response, constitute clear evidence
that acrylonitrile is likely to be a human carcinogen.
The water quality criterion for acrylonitrile is based
on tumor incidence of the central nervous system at the
100 ppm dose level in female Sprague-Dawley rats observed
and reported by the Dow Chemical Co. (interim report by
Quast, et al. 1977). It is concluded that the water concen-
tration of acryloitrile should be less than 0.084 jug/1 in
order to keep the lifetime cancer risk below 10~ .
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Summary of Pertinent Data
The water quality criterion for acrylonitrile is derived
from the tumorigenic effect observed in the central nervous
system of female Sprague-Dawley rats given 100 ppm acryloni-
tr ile in drinking water. The time weighted average dose
of 11.4 mg/kg/day was given for 52 weeks, and ten animals
of each group were then sacrificed (interim). The incidence
of brain tumors was 0/9 and 4/10 in the control and the
treated groups, respectively. Assuming a fish bioconcentra-
tion of 110, the criterion is calculated from the following
parameters:
n. = 4 d = 11.4 mg/kg/day
Nfc » 10 R - 110
n = 0 L = 730 days
c
N = 9 w = 0.350 kg
o
le = 368 days F = 0.0187 kg/day
Le = 368 days
Based on these parameters, the one-hit slope BH is
2.0455 (mg/kg/day)" . The resulting water concentration
of acrylonitrile calculated to keep the individual risk
below 10 is 0.084 jag/1. It must be emphasized that this
concentration level is based on data from a 12-month interim
report and is, therefore, likely to be modified when the
final report becomes available.
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