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Acrylonitrile
CASRN 107-13-1
Contents
0206
Acrylonitrile; CASRN 107-13-1
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Acrylonitrile
File On-Line 09/30/1987
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data 07/01/1993
Inhalation RfC Assessment (I.B.) on-line 12/01/1991
Carcinogenicity Assessment (II.) on-line 01/01/1991
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Acrylonitrile
CASRN -- 107-13-1
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Acrylonitrile
CASRN -- 107-13-1
Last Revised -- 12/01/1991
The inhalation Reference Concentration (RfC) is analogous to the oral RfD and
is likewise based on the assumption that thresholds exist for certain toxic
effects such as cellular necrosis. The inhalation RfC considers toxic effects
for both the respiratory system (portal-of-entry) and for effects peripheral
to the respiratory system (extrarespiratory effects). It is expressed in
units of mg/cu.m. In general, the RfC is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily inhalation exposure of the
human population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Inhalation RfCs
were derived according to the Interim Methods for Development of Inhalation
Reference Doses (EPA/600/8-88/066F August 1989) and subsequently, according to
Methods for Derivation of Inhalation Reference Concentrations and Application
of Inhalation Dosimetry (EPA/600/8-90/066F October 1994). RfCs can also be
derived for the noncarcinogenic health effects of substances that are
carcinogens. Therefore, it is essential to refer to other sources of
information concerning the carcinogenicity of this substance. If the U.S. EPA
has evaluated this substance for potential human carcinogenicity, a summary of
that evaluation will be contained in Section II of this file.
___I.B.1. INHALATION RfC SUMMARY
Critical Effect Exposures* UF MF RfC
-------------------- --------------------------- ----- --- ---------
Degeneration and NOAEL: None 1000 1 2E-3
inflammation of nasal mg/cu.m
respiratory epithelium; LOAEL: 43 mg/cu.m (20 ppm)
hyperplasia of mucous LOAEL(ADJ): 7.7 mg/cu.m
secreting cells LOAEL(HEC): 1.9 mg/cu.m
Rat 2-Year Inhalation
Study
Quast et al., 1980
*Conversion Factors: MW = 53.06. Assuming 25C and 760 mmHg, LOAEL (mg/cu.m)
= 20 ppm x 53.06/24.45 = 43. LOAEL(ADJ) = 43 mg/cu.m x 6 hours/24 hours x 5
days/7 days = 7.7 mg/cu.m. The LOAEL(HEC) was calculated for a
gas:respiratory effect in the ExtraThoracic region. MVa = 0.33 cu.m/day, MVh
= 20 cu.m/day, Sa(ET) = 11.6 sq. cm., Sh(ET) = 177 sq. cm. RGDR(ET) =
(MVa/Sa) / (MVh/Sh) = 0.252. LOAEL(HEC) = LOAEL(ADJ) x RGDR = 7.7 mg/cu.m x
0.252 = 1.9 mg/cu.m.
___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC)
Quast J.F., D.J. Schwetz, M.F. Balmer, T.S. Gushow, C.N. Park and M.J.
McKenna. 1980. A two-year toxicity and oncogenicity study with acrylonitrile
following inhalation exposure of rats. Dow Chemical Co., Toxicology Research
Laboratory, Midland, MI.
Sprague-Dawley rats (100/sex/concentration) were exposed 6 hours/day, 5
days/week for 2 years to concentrations of 0, 20 or 80 ppm acrylonitrile
(duration-adjusted concentrations of 7.7 and 31 mg/cu.m). The control group
was exposed only to air. Additional animals were included for interim
sacrifices at 6 months (n=7/sex/dose) and 12 months (n=13/sex/dose). A
significant decrease in mean body weight was observed in the rats exposed to
80 ppm acrylonitrile. Less significant, but similar weight changes were noted
in the 20-ppm females after approximately 1 month. A treatment-related effect
on mean body weight was not observed in the 20-ppm males.
A statistically significant increase in mortality (p<0.05) was observed
within the first year in both male and female rats administered 80 ppm and in
the 20-ppm females during the last 10 weeks of the study. The apparent
increase in reported mortality for the 20-ppm females was principally due to
early sacrifice of rats with large, benign, mammary gland tumors (Quast,
1991). In Sprague-Dawley rats, these tumors occur spontaneously at a high
rate, but in this experiment the tumors were observed earlier and more
frequently, and became larger in exposed animals.
Exposure to acrylonitrile during the first 6-8 months resulted in a
concentration-related increase in water consumption by both males and females.
Urine specific gravity, which was repeatedly evaluated during this time
interval, was usually decreased among rats exposed to 80 ppm. The authors
noted increased pathologic changes to the heart and lungs of male rats of both
groups, but indicated that they were identical to effects in the control rats
that are usually associated with chronic renal disease. Microscopic analysis
of the kidneys indicated a slight, nonstatistically significant increase in
the incidence of spontaneously occurring advanced chronic renal disease.
However, this slight increase could have been due to increased demand on the
kidneys resulting from the increased water consumption seen earlier in the
study.
Occasional significant deviation of the packed cell volume (PCV), and in
the RBC, hemoglobin, and WBC counts were noted. However, the authors
interpreted them as secondary changes associated with decreased growth, tumor
formation, and hemorrhaging resulting from exposure to acrylonitrile.
Urinalysis, hematology, and clinical chemistry were monitored. No other
microscopic findings attributable to acrylonitrile exposure were observed. No
adverse effects were observed on the bone marrow or liver function in rats in
either sex exposed to 80 ppm.
Based on gross and histopathologic evaluation of tissues from over 40
different organs (including the respiratory tract and nasal turbinates), the
two tissues which exhibited a treatment-related adverse effect due to
acrylonitrile exposure were the nasal respiratory epithelium (4 transverse
sections of the nasal turbinates were cut and examined) and the brain (9
sections through the CNS were cut and examined). Gross pathologic
observations revealed significantly increased lung changes suggestive of
pneumonia in 20-ppm male rats. Acute suppurative pneumonia was observed in
the lungs of 10 male rats in the 80-ppm group between 7 and 12 months; it was
occasionally observed in a single rat from the 20-ppm group. There were no
indications of pneumonia in female rats of either exposure group. These
changes are presumed to have been secondary effects related to the stress
associated with the exposure.
A significant increase (p<0.05) in focal gliosis and perivascular cuffing
was observed in the brains of high-concentration males (1/100 controls; 7/100
exposed) and females (0/100 controls; 8/100 exposed), but not in low-
concentration rats. The incidence of glial cell tumors (astocytomas) was
significantly increased in the 80-ppm group over controls for both males
(15/99 vs. 0/100 in controls) and females (16/100 vs. 0/100 in controls). The
incidence of proliferative glial cell lesions suggestive of early tumors was
significantly increased in the 80-ppm males (7/100 vs. 0/100 in controls), but
not in the females at any level (4/100 at 80 ppm; 4/100 at 20 ppm; 0/100 in
controls). Collectively, proliferative changes in the glial cells (i.e.,
tumors and early proliferation suggestive of tumors), were significantly
increased in the 20-ppm (8/100) and 80-ppm (20/100) females over female
controls (0/100), and in the 80-ppm males (22/99), but not in the 20-ppm males
(4/99) when compared with male controls (0/100). NOAEL(HEC) and LOAEL(HEC)
for noncarcinogenic, extrarespiratory effects are 20 ppm (7.7 mg/cu.m) and 80
ppm (31 mg/cu.m), respectively.
There were significant degenerative and inflammatory changes (p<0.05; one-
sided Fisher's Exact test) in the respiratory epithelium of the nasal
turbinates at both exposure concentrations (20 and 80 ppm) which are
interpreted to be treatment-related irritation of the nasal mucosa. In the
male 20-ppm group, there was a slight but not statistically significant
increase in the incidence of respiratory epithelium hyperplasia in the nasal
turbinates (0/11 in controls; 4/12 at 20 ppm; 10/10 at 80 ppm) and a
statistically significant increase in hyperplasia of the mucous secreting
cells (0/11; 7/12; 8/10). In the 20-ppm females there was a slight but not
statistically significant increase in focal inflammation in the nasal
turbinates (2/11; 6/10; 7/10) and a statistically significant increase in
flattening of the respiratory epithelium of the nasal turbinates (1/11; 7/10;
8/10). In the 80-ppm group, effects were more severe and were characterized
by suppurative rhinitis, hyperplasia, focal erosions, and squamous metaplasia
of the respiratory epithelium. No treatment-related effects in the olfactory
epithelium, trachea, or lower respiratory system were observed in either males
or females at either concentration. In this study, 20 ppm (HEC = 1.9 mg/cu.m)
is considered a LOAEL for pathological alterations in the respiratory
epithelium of the extrathoracic region of the respiratory system.
___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC)
UF -- The uncertainty factor of 1000 reflects a factor of 10 to protect
unusually sensitive individuals and 3 to adjust from a minimally adverse LOAEL
to a NOAEL. An uncertainty factor of 3 for interspecies variability is used
because the use of the dosimetric adjustments account for part of this area of
uncertainty. An additional factor of 10 is applied due to an incomplete data
base, or more specifically, the lack of an inhalation bioassay in a second
species, and the lack of reproductive data by the inhalation route with the
existence of an oral study showing reproductive effects.
MF -- None
___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC)
Several epidemiology studies have examined the morbidity and mortality of
workers exposed to acrylonitrile. Mortality due to noncancer endpoints,
including respiratory disease, have been investigated (O'Berg, 1980; Ott et
al., 1980; Werner and Carter, 1981; O'Berg et al., 1985; Chen et al., 1987).
No significant excess mortality has been noted for any noncarcinogenic
endpoint. For further discussion of these cancer assessment studies see
Section II.
Workers in a synthetic rubber manufacturing plant exposed to
concentrations of 16 to 100 ppm acrylonitrile for 20 to 45 minutes experienced
mucous membrane irritation, headaches, nausea, feelings of apprehension and
nervous irritability. Low grade anemia, leukocytosis, kidney irritation and
mild jaundice were also apparent; these effects subsided with exposure
cessation (Wilson et al., 1948). Human volunteers exposed acutely (8 hours)
to acrylonitrile at concentrations of 5.4-10.9 mg/cu.m (2.4-5.0 ppm) exhibited
no deleterious effects (Jakubowski et al., 1987).
No statistically significant increases (p<0.05) in adverse health effects
attributable to acrylonitrile were detected by clinical examination in a
cross-sectional investigation of Japanese workers (n=102) when compared with
matched controls (n=62) employed in 6 different acrylic fiber factories for a
minimum of 5 years (Sakurai et al., 1978). Arithmetic mean exposure levels
at the different factories (as determined by personal sampling) ranged from
0.1-4.2 ppm. Significantly higher exposure levels (arithmetic mean = 4.2 ppm,
geometric mean = 3.7, geometric standard deviation = 1.7) and exposure
durations (mean, 12.6 years; stand. dev., 2.1 years) were reported for workers
from one factory (n=18). While a slight increase in reddening of conjunctiva
and pharynx (3/10 controls; 9/18 exposed) was reported in these workers, it
was not statistically significant (Z test with Yates' correction and Fisher's
Exact test used). Palpable liver was also elevated in this high exposure
group, but was not statistically significant, and blood chemistry evaluations
did not indicate liver damage. These study results are inconclusive due to
the small size of the cohort, examiner bias (i.e., the medical examiner was
not blind to the exposure status of each subject), and shift bias (i.e., the
study required shift workers; less fit workers may have transferred to day
work). However, it is worth noting that the HEC value for the only exposure
level that appears to show any effects (4.2 ppm), HEC = 4.2 x (53.06/24.45) x
(10/20) x (5/7) = 3 mg/cu.m, is consistent with the LOAEL(HEC) calculated from
Quast et al. (1980).
The death of a child (age 3) who was sleeping in a room fumigated with
acrylonitrile has been described by Grunske (1949). Respiratory malfunction,
lip cyanosis, and tachycardia were among the symptoms described prior to
death. Five adults who spent the night and much of the day in the room
complained only of eye irritation or showed no signs of acrylonitrile
poisoning. The concentration of acrylonitrile in the air was not given.
Several other instances of death in children with only mild irritation in
adults were reported by Grunske (1949), but not described in detail.
In a subchronic inhalation experiment, repeated 4-hour exposures (5
days/week) at various concentrations and durations resulted in moderate
toxicity to guinea pigs (265 ppm or 575 mg/cu.m, 8 weeks), rats (100 ppm or
217 mg/cu.m, 8 weeks) and rabbits (100 ppm or 217 mg/cu.m, 8 weeks), and more
severe toxicity (including mortality) to cats (153 ppm or 332 mg/cu.m, 8
weeks), dogs (56 ppm or 122 mg/cu.m, 4 weeks) and monkeys (153 ppm or 332
mg/cu.m, 4 weeks) (Dudley et al., 1942). The moderately toxic effects
included irritation of the eyes and nose, gastrointestinal disturbances, and
weakness of the hind legs. The animals recovered from these effects following
exposure cessation. This study is of limited value due to the small number of
animals tested, the lack of statistical analyses, and the lack of concurrent
controls.
Sprague-Dawley rats (30/sex/concentration) were exposed to 0, 5, 10, 20
and 40 ppm 4 hours/day, 5 days/week for 52 weeks (duration-adjusted
concentrations of 0, 1.3, 2.6, 5.2, and 10.4 mg/cu.m, respectively) (Maltoni
et al., 1977; Maltoni et al., 1988) and at 60 ppm, 4-7 hours/day, 5 days/week
for 104 weeks (Maltoni et al., 1988). Although histopathologic examinations
were performed on various organ systems including the lungs, brain, kidney,
and liver, no noncarcinogenic effects were reported. The exposures did not
have affect on body weight gain. No mortality data were reported.
Beliles et al. (1980) evaluated reproductive capacity in three generations
of male (15/generation) and female (30/generation) Charles River rats exposed
to mean acrylonitrile concentrations of 0, 106 and 522 ppm in drinking water
ad libitum. All three generations of parents were exposed for 100 days and
throughout a 6 day mating period, gestation and lactation. Parents were
examined daily for signs of neurotoxicity. Body weights were obtained every 2
weeks; food consumption was measured weekly; water consumption was measured
twice a week. Offspring were examined on days 0, 4 and 21 of lactation. All
litters were reduced to 10 pups on day 4 to achieve an equal sex ratio. Body
weights were obtained on day 4 (litter) and day 21 (individual). Exposure to
522 ppm acrylonitrile in drinking water (70 mg/kg/day) resulted in reduced
viability and lactation indices (p<0.05) in all generations. Dams of all
generations were reported to have decreased water intake through the lactation
period. Cross-fostering of pups on untreated dams lessened pup mortality.
There were no changes in reproductive capacity at 106 ppm relative to
controls.
One developmental study conducted in rats examined both oral and
inhalation exposure routes. Rats (30/concentration) were exposed to 0, 40 or
80 ppm acrylonitrile vapors 6 hours/day during gestational days 6 to 15. In
accordance with current EPA policy, these values are not duration adjusted.
The group exposed to 80 ppm exhibited a significant increase (p=0.06) in fetal
malformations which include short tail, missing vertebrae, short trunk,
omphalocele and hemivertebra. Mean number of implantations, live fetuses and
resorptions were not significantly altered by exposure to 40 or 80 ppm.
Maternal toxicity was reported at both concentration levels tested, as
evidenced by decreased weight gain, but no effects on fetal body size were
evident (Murray et al., 1978). No evidence of embryotoxicity or
teratogenicity was discerned in rats administered 40 ppm via inhalation. This
study identifies a NOAEL(HEC) = 15.5 mg/cu.m and a LOAEL(HEC) = 31 mg/cu.m
(with maternal toxicity).
___I.B.5. CONFIDENCE IN THE INHALATION RfC
Study -- Medium
Data Base -- Medium
RfC -- Medium
The critical study is given medium confidence, because although it was a
well-conducted chronic study in an appropriate number of animals
(100/sex/concentration), it was performed on only one species, did not
identify a NOAEL, was confounded by the early sacrifice of rats with large
mammary gland tumors and the target organ (nasal turbinates) was only examined
at the end of the study in relatively few animals (10-12/sex/concentration).
Confidence in the data base can be considered medium to low due to a lack of
chronic or subchronic inhalation data in a second species, the lack of
reproductive data by the inhalation route and the existence of an oral study
showing reproductive effects. Confidence in the RfC can also be considered
medium to low.
___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC
Source Document -- This assessment is not presented in any existing U.S. EPA
document.
Other EPA Documentation -- U.S. EPA, 1983
Agency Work Group Review -- 12/19/1990, 08/15/1991
Verification Date -- 08/15/1991
___I.B.7. EPA CONTACTS (INHALATION RfC)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Acrylonitrile
CASRN -- 107-13-1
Last Revised -- 01/01/1991
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- B1; probable human carcinogen
Basis -- The observation of a statistically significant increase in incidence
of lung cancer in exposed workers and observation of tumors, generally
astrocytomas in the brain, in studies in two rat strains exposed by various
routes (drinking water, gavage, and inhalation) forms the basis for this
classification.
___II.A.2. HUMAN CARCINOGENICITY DATA
O'Berg (1980) observed 25 cases of cancer, including eight cases of
respiratory cancer, in 1345 male textile workers exposed to acrylonitrile
and followed for 10 or more years. Estimated levels of exposure were 5-20
ppm acrylonitrile. All of the cancer cases, except for one nonrespiratory
cancer, occurred among 1128 workers with 6 or more months exposure (SIR=126,
SMR=113). A trend of increased cancer incidence was seen with increased
duration of exposure and increased length of follow-up time. The excess of
respiratory cancer was statistically significant and remained so upon
evaluation of the contribution of smoking (five observed vs. 1.6 expected).
Three other studies reported a statistically significant increased
incidence of lung cancer from exposure to acrylonitrile. All suffer from
problems with methodology (e.g., exposure to other carcinogens, no smoking
history, exposure not quantified). Delzel and Monson (1982) studied 327
male workers at a rubber manufacturing plant and reported a statistically
significant increase in lung cancer among workers employed 5 or more years.
Thiess et al. (1980) studied 1469 workers employed 6 months or more in
acrylonitrile processing. A statistically significant increase in lung
cancer and cancer of the lymph system was seen. Werner and Carter (1981)
studied 934 men employed at least 1 year in polymerization of acrylonitrile
and spinning of acrylic fiber. A statistically significant increase was
seen for stomach cancer in all age groups and for pulmonary cancer in the
15-44 year age group. One other study reported a statistically
nonsignificant increase in deaths from cancer from exposure to acrylonitrile
(Monson, 1978), but workers were also exposed to other carcinogens. Five
additional studies reported no evidence of increased risk, but all suffer
from deficiencies in design or methodology.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Quast et al. (1980a) administered acrylonitrile in drinking water at
dose levels of 35, 100, and 300 ppm to 48 Sprague-Dawley rats/sex for 2
years. A statistically significant increase in tumors was observed in the
CNS (astrocytomas), Zymbal gland, stomach, tongue, and small intestine for
both sexes and in the mammary gland of female rats. In general, the
increase was dose-dependent.
Biodynamics (1980a) administered acrylonitrile in drinking water at
doses of 0, 1, and 100 ppm to 100 Sprague-Dawley rats/sex/group. Interim
necropsies were performed at 6, 12, and 18 months (10/sex/group). The study
was terminated early because of low survival rates. There was increased
incidence of astrocytomas of the brain and spinal cord, carcinomas and
adenomas of the Zymbal gland or ear canal, and squamous cell carcinomas and
papillomas of the forestomach in high-dose animals.
A second study was conducted by Biodynamics (1980b) wherein acrylonitrile
was administered in drinking water to 100 Fischer 344 rats/sex/group at dose
levels of 1, 3, 10, 30, and 100 ppm and to a control group of 200/sex.
Interim necropsies were performed at 6, 12, and 18 months (10/sex/ exposed
group and 20/sex/control group). The study was terminated early because of
the low survival rate. Increased incidence of tumors (astrocytomas of the
brain and spinal cord, and carcinomas of the Zymbal gland) was seen in dose
groups of 3 ppm or higher, and the incidence was dose-dependent. An increased
incidence of mammary gland tumors was seen in females at the 100 ppm dose
level. In a three-generation reproductive study in rats [CRL:COBS CD (SD) BR]
were exposed to acrylonitrile in drinking water. The second generation showed
an increased incidence of cancer (astrocytoma and Zymbal gland) at the 500 ppm
exposure level (Beliles, 1980).
Maltoni et al. (1977) administered acrylonitrile in olive oil 3 times/week
for 52 weeks to Sprague-Dawley rats in doses of 0 ppm to 75 rats/sex and 5 ppm
to 40 rats/sex. Increased incidence of tumors of the mammary gland and
forestomach was observed in female rats. In another study (Biodynamics,
1980c), acrylonitrile was administered at doses of 0, 0.10, and 10.0 mg/kg/day
for 5 days to 70 Sprague-Dawley rats/sex/group. The study was terminated at
20 months. Statistically significant increased incidences of brain
(astrocytoma) and Zymbal gland tumors were observed in the high-dose group. A
statistically significant increased incidence of stomach and intestinal tumors
was observed in males and of the mammary gland in females.
In a second study by Quast et al. (1980b), acrylonitrile was administered
by inhalation at 0, 20, and 80 ppm to 100 male and female Sprague-Dawley rats
for 6 hours/day, 5 days/week for 2 years. A statistically significant
increase was observed in tumors of the CNS and other sites.
Acrylonitrile was also administered by inhalation at lower doses of 0, 5,
10, 20, and 40 ppm, 4 hours/day, 5 days/week for 12 months to 30 Sprague-
Dawley rats/sex/group by Maltoni et al. (1977). This resulted in a
statistically significant increase of mammary tumors in males and skin
carcinomas in females.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Acrylonitrile can cause mutations in both Salmonella typhimurium (Venitt
et al., 1977) and Escherichia coli (De Meester et al., 1978). It did not
cause chromosomal aberrations in bone marrow cells of rats and mice (Rabello-
Gay and Ahmed, 1980; Leonard et al., 1981) or in peripheral blood lymphocytes
of exposed workers (Thiess and Fleig, 1978). Acrylonitrile did induce an
increase in sister-chromatid-exchange (SCE) in CHO cells (Ved Brat and
Williams, 1982), and has also been shown to bind to DNA (Guengerich et al.,
1981). A metabolite, 2,3-epoxy-propionitrile, is mutagenic in Salmonella
(Kier, 1982). Acrylonitrile has been shown to transform Syrian hamster embryo
cells and to enhance transformation of these cells infected with an oncogenic
virus (Parent and Casto, 1979).
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
___II.B.1. SUMMARY OF RISK ESTIMATES
Oral Slope Factor -- 5.4E-1 per (mg/kg)/day
Drinking Water Unit Risk -- 1.5E-5 per (ug/L)
Extrapolation Method -- Linearized multistage procedure, extra risk
Drinking Water Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- -------------
E-4 (1 in 10,000) 6E+0 ug/L
E-5 (1 in 100,000) 6E-1 ug/L
E-6 (1 in 1,000,000) 6E-2 ug/L
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Tumor Type -- brain and spinal cord astrocytomas, Zymbal gland carcinomas and
stomach papillomas/carcinomas
Test Animals -- rats (see table)
Route -- drinking water
Reference -- Biodynamics, 1980a,b; Quast et al., 1980a
Administered Dose Human Equivalent Tumor
(ppm) (mg/kg)/day Dose (mg/kg)/day Incidence Reference
----- ----------- ---------------- --------- ---------
Rats/Spartan Sprague-Dawley, males
0 0.00 0.00 6/100 Biodynamics,
1 0.09 0.02 6/98 1980a
100 7.98 1.36 36/98
Rats/Fischer 344, males
0 0.00 0.00 5/200 Biodynamics,
1 0.11 0.02 4/100 1980b
3 0.25 0.04 5/100
10 0.81 0.14 7/100
30 2.49 0.43 20/100
100 8.15 1.39 34/100
Rats/Sprague-Dawley, males
0 0.00 0.00 4/80 Quast et al.,
35 3.42 0.58 18/47 1980a
100 8.53 1.46 36/48
300 21.18 3.62 45/48
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
The quantitative estimate is a geometric mean of these three slope
factors: 4.0E-1 (Biodynamics, 1980a), 4.0E-1 (Biodynamics, 1980b) and 9.9E-1
per (mg/kg)/day (Quast et al., 1980a). The overall risk of tumors was
determined from the number of animals having tumors that were statistically
significant at any site.
The unit risk should not be used if the water concentration exceeds 600
ug/L, since above this concentration the unit risk may not be appropriate.
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
Relatively large numbers of animals were treated and observed and a dose-
response effect was observed in all studies. The slope factors derived from
data on male rats (Quast et al., 1980a; Biodynamics, 1980a,b) were similar
[9.9E-1, 4.0E-1, and 4.0E-1 per (mg/kg)/day] and within a factor of 3. The
slope factors based on the three female rat studies [9.2E-1, 3.7E-1, and 2.9E-
1 per (mg/kg)/day] were similar to those of the respective male rat studies,
as was their geometric mean (4.6E-1 per (mg/kg)/day. In two of the studies
(Biodynamics, 1980a,b) the increases reported could vary considerably since
interim necropsies were included with the final sacrifice.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
___II.C.1. SUMMARY OF RISK ESTIMATES
Inhalation Unit Risk -- 6.8E-5 per (ug/cu.m)
Extrapolation Method -- Average relative risk
Air Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- ---------------
E-4 (1 in 10,000) 1E+0 ug/cu.m
E-5 (1 in 100,000) 1E-1 ug/cu.m
E-6 (1 in 1,000,000) 1E-2 ug/cu.m
___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE
Tumor Type -- respiratory cancer
Test Animals -- humans
Route -- inhalation
Reference -- O'Berg, 1980
The unit risk (BH) was calculated from a relative risk model adjusted
for smoking and based on a continuous lifetime equivalent of occupational
exposure
BH = PO(R-1)/X
= 1.5E-4/ppb x 0.45 ppb/ug/cu.m
= 6.8E-5 per (ug/cu.m)
where: PO = 0.036 = background lifetime probability of death from
respiratory cancer
R = 5.0/1.6 = 3.1 = relative risk of respiratory cancer adjusted
for smoking (O'Berg, 1980)
X = 500 ppb = continuous equivalent lifetime exposure when 9 years
= estimated average exposure duration, and 60 years = estimated
maximum possible age at end of observation period.
___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
The excess incidence of respiratory cancer in the O'Berg (1980) study
was adjusted for smoking. An exposure of 15 ppm was assumed to be the
8-hour TWA with an average exposure duration of 9 years. The maximum possible
age at the end of the observation period was assumed to be 60 years.
The unit risk should not be used if the air concentration exceeds 1E+2
ug/cu.m, as above this concentration the unit risk may not be appropriate.
___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE)
The cohort was sufficiently large and was followed for an adequate time
period. A dose-response relationship was seen for the increased cancer
risk. The increased risk remained after adjustment for smoking. Exposure
levels were estimated by company representatives. The unit risk based on
the Quast et al. (1980b) rat inhalation study was 1.5E-5 per (ug/cu.m).
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1983
The values in the 1983 Health Assessment Document for Acrylonitrile have
received both Agency and outside review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 02/11/1987
Verification Date -- 02/11/1987
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Acrylonitrile
CASRN -- 107-13-1
Last Revised -- 11/01/1991
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfD REFERENCES
Beliles, R.P., H.J. Paulin, N.G. Makris and R.J. Weir. 1980. Three-
generation reproduction study of rats receiving acrylonitrile in drinking
water. Chemical Manufacturers Association, Washington, DC, LBI Project No.
2660, February.
Chen, J.L., J. Walrath, M.T. O'Berg, C.A. Burke and S. Pell. 1987. Cancer
incidence and mortality among workers exposed to acrylonitrile. Am. J. Ind.
Med. 11:157-163.
Dudley, H.C., T.K. Sweeny and J.W. Miller. 1942. Toxicology of acrylonitrile
(vinly cyanide). II. Studies of effects of daily inhalation. J. Ind. Hyg.
Toxicol. 24(9): 255-258.
Grunske, F. 1949. Health care and occupational medicine. Ventox and ventox
intoxication. Dtsch. Med. Wochenschr. 74: 1081-1083.
Jakubowski, M., I. Linhart, G. Pielas and J Kopecky. 1987. 2-
Cyanoethymercapturic acid (CEMA) in the urine as a possible indicator of
exposure to acrylonitrile. Br. J. Ind. Med. 44: 834-840.
Maltoni, C., A. Ciliberti, and V. Di Maio. 1977. Carcinogenicity bioassays
on rats of acrylonitrile administerd by inhalation and by ingestion. Med.
Lav. 68(6): 401-411.
Maltoni, C., A. Ciliberti, G. Cotti and G. Perino. 1988. Long-term
carcinogenicity biosassays on acrylonitrile administered by inhalation and by
ingestion to Sprague-Dawley rats. Ann. NY Acad. Sci. 534: 179-202.
Murray, F.J., B.A. Schwetz, K.D. Nitschke, J.A. John, J.M. Norris and P.J.
Gehring. 1978. Teratogenicity of acrylonitrile given to rats by gavage or by
inhalation. Food Cosmet. Toxicol. 16(6): 547-52.
O'Berg, M.T. 1980. Epidemiologic study of workers exposed to acrylonitrile.
J. Occup. Med. 22(4): 245-252.
O'Berg, M.T., J.L. Chen, C.A. Burke CA, J. Walrath and S. Pell. 1985.
Epidemiologic study of workers exposed to acrylonitrile: An update. J. Occup.
Med. 27(11): 835-840.
Ott, M.G., R.C. Kolesar, H.C. Scharnweber, E.J. Schneider and J.R. Venable.
1980. A mortality survey of employees engaged in the development or
manufacture of styrene-based products. J. Occup. Med. 22: 445-460.
Quast, J.F. 1991. DOW Chemical Company, Midland MI. Letter to Dr. Jeffrey
Gift, U.S. EPA, Research Triangle Park, NC. Results of the 2-year rat
inhalation study on acrylonitrile performed by DOW Chemical Company.
February 4.
Quast, J.F., D.J. Schuetz, M.F. Balmer, T.S. Gushow, C.N. Park and M.J.
McKenna. 1980. A two-year toxicity and oncogenicity study with acrylonitrile
following inhalation exposure of rats. Dow Chemical Co., Toxicology Research
Laboratory, Midland MI.
Sakurai, H., M. Onodera, T. Utsunomiya, H. Minakuchi, H. Iwai and H.
Matsumura. 1978. Health effects of acrylonitrile in acrylic fibre factories.
Br. J. Ind. Med. 35: 219-225.
U.S. EPA. 1983. Health Assessment Document for Acrylonitrile. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Research Triangle Park, NC. October, 1983.
Werner, J.B. and J.T. Carter. 1981. Mortality of United Kingdom
acrylonitrile polymerisation workers. Br. J. Ind. Med. 38: 247-253.
Wilson, R.H., G.H. Hough and W.E. McCormick. 1948. Medical problems
encountered in the manufacture of American-made rubber. Ind. Med. 17(6):
199-207.
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Beliles, R.P., H.J. Paulin, N.G. Makris and R.J. Weir. 1980.
Three-generation reproductive study of rats receiving acrylonitrile in
drinking water. Prepared by Litton Bionetics, Inc., Kensington, MD, for the
Chemical Maufacturers Association, Washington, DC. Available from: CMA,
Washington, DC.
Biodynamics, Inc. 1980a. A twenty-four month oral toxicity/carcinogenicity
study of acrylonitrile administered to Spartan rats in the drinking water,
Vol. 1-2. Prepared by Biodynamics Inc., Division of Biology and Safety
Evaluation, East Millstone, NJ, for Monsanto Company, St. Louis, MO.
Biodynamics, Inc. 1980b. A twenty-four month oral toxicity/carcinogenicity
study of acrylonitrile administered in the drinking water to Fischer 344 rats,
Vol. 1-4. Prepared by Biodynamics Inc., Division of Biology and Safety
Evaluation, East Millstone, NJ, for Monsanto Company, St. Louis, MO.
Biodynamics, Inc. 1980c. A twenty-four month oral toxicity/carcinogenicity
study of acrylonitrile administered by intubation to Spartan rats, Vol. 1-2.
Prepared by Biodynamics Inc., East Millstone, NJ, for Monsanto Company, St.
Louis, MO.
Delzell, E. and R.R. Monson. 1982. Mortality among rubber workers. VI. Men
with exposure to acrylonitrile. J. Occup. Med. 24(10): 767-769.
De Meester, C., F. Poncelet, M. Roberfroid and M. Mercier. 1978. Mutagenicity
of acylonitrile. Toxicology. 11: 19-27.
Guengerich, F.P., L.E. Geiger, L.L. Hogy and P.L. Wright. 1981. In vitro
metabolism of acrylonitrile to 2-cyanoethylene oxide, reaction with
glutathione, and irreversible binding to proteins and nucleic acids. Cancer
Res. 41: 4925-4933.
Kier, L.D. 1982. Ames/Salmonella mutagenicity assay of acrylonitrile.
Monsanto Company, St. Louis, Report No: MSL-2063.
Leonard, A., F. Garny, F. Poncelet and M. Mercier. 1981. Mutagenicity of
acrylonitrile in mouse. Toxicol. Lett. 7: 329-334.
Maltoni, C., A. Ciliberti and V. DiMaio. 1977. Carcinogenicity bioassays on
rats of rats of acrylonitrile administered by inhalation and by ingestion.
Med. Lavoro. 68(6): 401-411.
Monson, R.R. 1978. Mortality and cancer morbidity among chemical workers
with potential exposure to acrylonitrile. Report to the B.F. Goodrich Company
and to the United Rubber Workers. Prepared for submission in the post hearing
comment period to the OSHA Acrylonitrile Hearing.
O'Berg, M. 1980. Epidemiologic study of workers exposed to acrylonitrile.
J. Occup. Med. 22: 245-252.
Parent, R.A. and B.C. Casto. 1979. Effect of acrylonitrile on primary Syrian
golden hamster embryo cells in culture: Transformation and DNA fragmentation.
J. Nat. Cancer Inst. 62(4): 1025-29.
Quast, J.F., C.E. Wade, C.G. Humiston, R.M. Carreon, E.A. Hermann, C.N. Park
and B.A. Schwetz. 1980a. A two-year toxicity and oncogenicity study with
acrylonitrile incorporated in the drinking water of rats. Prepared by the
Toxicology Research Laboratory, Health and Environmental Sciences, Dow
Chemical USA, Midland, MI, for the Chemical Manufacturers Association,
Washington, DC. Available from: CMA, Washington DC.
Quast, J.F., D.J. Schuetz, M.F. Balmer, T.S. Gushow, C.N. Park and M.J.
McKenna. 1980b. A two-year toxicity and oncogenicity study with
acrylonitrile following inhalation exposure of rats. Prepared by the
Toxicology Research Laboratory, Health and Environmental Sciences, Dow
Chemical USA, Midland, MI, for the Chemical Manufacturing Association,
Washington, DC.
Rabello-Gay, M.N. and A.E. Ahmed. 1980. Acrylonitrile: In vivo cytogenic
studies in mice and rats. Mutat. Res. 79: 249-255.
Thiess, A.M. and I. Fleig. 1978. Analysis of chromosomes of workers exposed
to acrylonitrile. Arch. Toxicol. 41(2): 149-52.
Thiess, A.M., R. Frentzel-Beyme, R. Link and H. Wild. 1980. Mortalitats
studie Bei Chemiefacharbeitern Verchiedener Produktionsbetriebe Mit Exposition
Auch Gegenuber Acrylonitrile. Zentralbl. Arbeitsmed. 30: 359-267.
U.S. EPA. 1983. Health Assessment Document for Acrylonitrile. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Research Triangle Park, NC.
Ved Brat, S. and G.M. Williams. 1982. Hepatocyte-mediated production of
sister chromatid exchange in cocultured cells by acrylonitrile: Evidence for
extra-cellular transport of a stable reactive intermediate. Cancer Letters.
17: 213-216.
Venitt, S., C.T. Bushell and M. Osborne. 1977. Mutagenicity of acrylonitrile
(cyanoethylene) in Escherichia coli. Mutat. Res. 45(2): 283-88.
Werner, J.B., and J.T. Carter. 1981. Mortality of United Kingdom
acrylonitrile polymersation workers. Br. J. Ind. Med. 38: 247-253.
_VII. REVISION HISTORY
Substance Name -- Acrylonitrile
CASRN -- 107-13-1
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
03/01/1988 II.B.4. Confidence statement revised
02/01/1989 II.D.3. Secondary contact's phone number corrected
07/01/1989 II. Citations for Quast et al. clarified
07/01/1989 VI. Bibliography on-line
06/01/1990 IV.A.1. Area code for EPA contact corrected
06/01/1990 IV.F.1. EPA contact changed
01/01/1991 I.B. Inhalation RfC now under review
01/01/1991 II. Text edited
01/01/1991 II.C.1. Inhalation slope factor removed (global change)
11/01/1991 I.B. Inhalation RfC summary on-line
11/01/1991 VI.B. Inhalation RfC references added
12/01/1991 I.B. Text edited
01/01/1992 IV. Regulatory actions updated
04/01/1992 IV.A.1. CAA regulatory action withdrawn
08/01/1992 I.A. Oral RfD now under review
07/01/1993 I.A. Work group review date added
VIII. SYNONYMS
Substance Name -- Acrylonitrile
CASRN -- 107-13-1
Last Revised -- 09/30/1987
107-13-1
ACRITET
ACRYLNITRIL
ACRYLON
Acrylonitrile
ACRYLONITRILE MONOMER
AKRYLONITRYL
CARBACRYL
CIANURO DI VINILE
CYANOETHYLENE
CYANURE DE VINYLE
ENT 54
FUMIGRAIN
MILLER'S FUMIGRAIN
NITRILE ACRILICO
NITRILE ACRYLIQUE
PROPENENITRILE
2-PROPENENITRILE
RCRA WASTE NUMBER U009
TL 314
UN 1093
VCN
VENTOX
VINYL CYANIDE
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0206.HTM
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