r
TECHNICAL REPORT DATA
(ftfttt retd liaauetioiu on the mtnt be fort compfenngj
1. REPORT NO.
LPA/6QO/8-88/014
3. RECIPIENT'S ACCESSION NO.
PB88-179411/AS
4. TITLE AND SUBTITLE
6. REPORT DATE
Health Effects Assessment for Acrylonitrile
6. PERFORMING ORGANIZATION CODE
'7. AUTHOR(S)
I. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
13. TYPE OF REPORT AND PERIOD COVERED
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
14. SPONSORING AGENCY CODE
EPA/600/22
s. SUPPLEMENTARY NOTES
6. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfDs or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would,not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qj*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS C. COSATl Field/Group
8. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (Ttus Report)
Unclassified
21. NO. OF PAGES
20. SECURITY CLASS
Unclassified
22. PRICE
EPA ?•*» 2220-t {*•». 4-77) PREVIOUS EDITION is OMOLETK
-------
EPA/600/8-88/014
July, 1987
HEALTH EFFECTS ASSESSMENT
FOR ACRYLONITRILE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
U g TSnvirormental Protection Agency
-------
DISCLAIMER
This document has been reviewed 1n accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
-------
PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with tin and
compounds. All estimates of acceptable Intakes and carcinogenic potency
presented 1n this document should be considered preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-line literature searches of the
TOXLINE and the CHEMFATE/DATALOG data bases. The basic literature searched
supporting this document 1s current up to Hay, 1986. Secondary sources of
Information have also been relied upon In the preparation of this report and
represent large-scale health assessment efforts that entail extensive peer
and Agency review. The following Office of Health and Environmental Assess-
ment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Hater Quality Criteria for
Acrylon1tr1le. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Water Regulations and Standards,
Washington, DC. EPA 440/5-80-017. NTIS PB81-117285.
U.S. EPA. 1983a. Health Assessment Document for Acrylonltrlle.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Research Triangle
Park, NC. EPA-600/8-82-007F. NTIS PB84-149152.
U.S. EPA. 1983b. Reportable Quantity Document for Acrylonltrlle.
Prepared by tdhe Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1985. Health and Environmental Effects Profile for
Acrylonltrlle. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency
Response, Washington, DC.
The Intent In these assessments Is to suggest acceptable exposure levels
for noncarclnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD§ (formerly AIS) or subchronlc reference dose, Is
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
111
-------
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants In ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfDsj) and oral (RfD$g)
exposures.
The RfD (formerly AIC) Is similar In concept and addresses chronic
exposure. It Is an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfD Is route-specific and estimates acceptable exposure for either oral
{RfDo) or Inhalation (RfDi) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development Is explained In U.S.
EPA (1984).
For compounds for which there Is sufficient evidence of carclnogenlclty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer Is a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-j*s have been computed, If appro-
priate, based on oral and Inhalation data 1f available.
1v
-------
ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
Acrylonltrlle has been demonstrated to be carcinogenic In rats exposed
In drinking water (Quast et al., 1980a; B1o/dynam1cst Inc., 1980a,b,c) or by
Inhalation (Quast et al., 1980b). An ep1dem1olog1cal study (O'Berg, 1980)
associated Increased Incidences of cancer, particularly lung cancer, with
occupational exposure to acrylonHMle. U.S. EPA (1983a) derived a potency
slope q-|* of 5.4X10"1 (mg/kg/day)"1 [corresponding to an upper limit
unit risk of 1.5xlO~5 (wg/4)"1] for oral exposure to acrylonUMle
based on the Incidence of tumors at various sites In rats from the Quast et
al. (1980a) and B1o/dynam1cs, Inc. (1980a,b) studies. A potency slope of
0.24 (mg/kg/day)"1, corresponding to a unit risk of 6.8xlO~5 (yg/m3)"1, was
calculated for Inhalation exposure from the Incidence of total cancers In
occupationally exposed humans (O'Berg, 1980). Acrylonltrlle Is classified
by EPA as Group Bl: a probable human carcinogen.
-------
ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Or. Christopher OeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents 1n this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and Kim Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
-------
TABLE OF CONTENTS
1.
2.
3.
4.
5.
ENVIRONMENTAL FATE AND TRANSPORT
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1.
2.2.
ORAL
INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
TOXICANT INTERACTIONS
CARCINOGENICITY
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
Paqe
... 1
... 3
... 3
... 3
... 4
4
... 4
4
. , 5
. . . 5
. . . 7
. . . 7
. . . 7
, , 8
. . . 9
. . . 10
, , 10
. . . 10
. . . 10
. . . 12
. . . 12
. . . 18
. . . 18
. . . 18
. . . 22
vll
-------
TABLE OF CONTENTS (cont.)
Page
6. RISK ASSESSMENT 23
6.1. SUBCHRONIC REFERENCE DOSE (RfDs) 23
6.2. REFERENCE DOSE (RfD) 23
6.3. CARCINOGENIC POTENCY (q^) 23
6.3.1. Oral. 23
6.3.2. Inhalation. . 24
7. REFERENCES 25
APPENDIX 33
vlll
-------
LIST OF TABLES
No. Title Page
1-1 Selected Physical and Chemical Properties and Half-lives
for Acrylon1tr1le 2
3-1 Toxlcologlcal Findings In Rats Orally Exposed to
Acrylonltrlle 6
4-1 Observed and Expected Cancer Incidences, Based on DuPont
Company Incidence Rates for Hale Employees Exposed for
>6 Months 11
4-2 Tumor Incidence 1n Sprague-Dawley Rats Treated for 24 Months
with Acrylonltrlle of High Purity 1n Drinking Water 13
4-3 Tumor Incidence 1n Spartan Rats Treated with 100X Pure
Acrylonltrlle 1n Drinking Water . 15
4-4 Tumor Incidence In Fisher Rats Treated with 100% Pure
Acrylonltrlle In Drinking Water 16
4-5 Tumor Incidence In Male and Female Sprague-Dawley Rats
Exposed by Inhalation for 24 Months to Acrylonltrlle
of High Purity 19
1x
-------
LIST OF ABBREVIATIONS
CAS Chemical Abstract Service
CNS Central nervous system
ONA Deoxyrlbonuclelc acid
NOAEL No-observed-adverse-effect level
ppb Parts per billion
ppm Parts per million
RfO Reference Dose
RfD$ Subchronlc Reference Dose
TLV Threshold limit value
TWA Time-weighted average
-------
1.. ENVIRONMENTAL FATE AND TRANSPORT
Selected physical and chemical properties of acrylonltrlle (CAS No.
107-13-1) are reported In Table 1-1. Synonyms for acrylonltrlle are
2-propenen1tr1le, vinyl cyanide, cyanoethylene, AcMtet, Fumlgraln and
Ventox. In air, acrylonltrlle Is predicted to be removed predominantly by
oxidation reactions with photochemically generated hydroxyl radicals. The
half-lives reported In Table 1-1 are based on experimental data and an
assumed hydroxyl radical concentration of 1x10* molecules/cm3. The
aquatic half-lives reported In Table 1-1 are for volatilization only; thus,
the half-life of acrylonltrlle may vary greatly depending upon the charac-
teristics of the aquatic system (U.S. EPA, 1979, 1983a). The half-life of
acrylonltrlle In soil could not be located 1n the available literature.
Based on Us relatively high water solubility, however, acrylonltrlle 1s
expected to be highly mobile In moist soils. The high vapor pressure Indi-
cates that evaporation from dry soil surfaces 1s expected to occur rapidly.
0064h -1- 10/28/86
-------
TABLE 1-1
Selected Physical and Chemical Properties and
Half-Lives for AcrylonHMle
Property
Value
Reference
Chemical class:
Formula:
Molecular weight:
Specific gravity:
Melting point:
Boiling point:
Vapor pressure:
Water solubility:
Log octanol/water
partition coefficient:
Bloconcentratlon factor;
Half-lives In:
A1r:
Water:
cyanogenated oleflnlc
hydrocarbon
CH2=CHCN
53.06
0.8
-83.5°C
77.3°C at 760 mm Hg
85.5 mm Hg at 20°C
73.5 mg/i at 20°C
0.25
48 1n blueglll sunflsh
2-9 days
0.6-0.8 hours (relatively
rapid flowing shallow
streams); -13 hours
(1 m deep, estimated)
ACGIH, 1986
ACGIH, 1986
ACGIH. 1986
Weber et al.. 1981
U.S. EPA, 1979
Hansch and Leo, 1985
U.S. EPA. 1985
U.S. EPA. 1985;
Edney et al., 1983
Cadena et al., 1984;
U.S. EPA. 1983a
0064h
-2-
10/28/86
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Young et al. (1977) administered single oral doses of 0.1 or 10 mg/kg
l4C-acry1on1tr1le to male rats. Excreta were collected for 72 hours. At
the lower dose, the total recovery of radioactivity was 82.4% with 5.4%
appearing In the feces, while at the higher dose the total recovery of
radioactivity was 104.0% with 5.2% appearing In the feces. These data
Indicate that >95% of orally administered acrylonltrUe Is absorbed from the
gastrointestinal tract.
2.2. INHALATION
Male rats exposed to 5 or 100 ppm (11 or 217 mg/m3) l*C-acrylo-
nltrlle for 6 hours excreted most of the absorbed radioactivity 1n the urine
(Young et al., 1977). The Investigators estimated total absorbed doses of
0.7 and 10.2 mg/kg for 5 and 100 ppm group rats, respectively. These data
suggest that absorption following Inhalation exposure 1s rapid and substan-
tial, and Indicate that "41% and -30% of Inhaled radioactivity Is absorbed
at 5 and 100 ppm exposure levels, respectively.
0064h -3- 10/27/86
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3. TOXICITY IN HUNANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. In the only available subchronlc oral toxldty study of
acrylonUrlle (Quast et al., 1975), four dogs/sex were exposed to 0, 100,
200 or 300 ppm (mg/i) acrylonltrlle 1n drinking water for 6 months, which
corresponded to 10, 16 and 18 mg/kg/day for male dogs, and 8, 17 and 18
mg/kg/day for females, respectively. Administration of either the 200 or
300 ppm (mg/i) concentrations caused morbidity and death. Deaths were due
to food asplratlonrelated bronchopneumonla, and the esophageal walls of
affected dogs were ulcerated. At 100 ppm, female dogs had sporadically
lower water consumption and consistently lower food consumption; these
findings were not observed 1n a supplemental part of the study using the
same experimental design. Relative kidney weights were also Increased In
the 100 ppm males, although there were no remarkable renal lesions, and no
other adverse effects were noted. The equivalent dose of 8-10 mg/kg/day can
be considered a NOAEL for oral exposure.
3.1.2. Inhalation. In rats and rabbits exposed to 50 mg/m3 acrylo-
nltrlle for 6 months, for an unspecified number of hours per day, Knobloch
et al. (1972) not?d peripheral blood pattern changes and respiratory,
cardiac, renal and neuronal dysfunction. CMS disorders and a variety of
biochemical and hematologlcal changes were observed by Babanov et al.
(1972), who exposed rats to 0.495 mg/m3 acrylonltrlle vapor, 5 hours/day,
6 days/week, for 6 months. Hematologlcal changes Included Increased
erythrocyte and decreased leukocyte counts. Increased total protein and
peroxldase content,, and decreased blood ascorbic acid content. Further
details were not available.
0064h -4- 07/07/87
-------
3.2. CHRONIC
3.2.1. Oral. The carclnogenlclty studies discussed In Section 4.2.1.
provide some data on nonneoplastlc effects of chronic exposure to acrylo-
nltrlle. In the studies by Bio/dynamics, Inc. (1980a,b,c), groups of 100
male and 100 female Spartan or Fischer 344 rats were treated with acrylo-
nltrlle In drinking water at concentrations of 1-300 ppm or by gavage at 0.1
or 10.0 mg/kg/day, 5 days/week for 19-26 months. The equivalent doses 1n
the drinking water studies and the treatment-related gross and clinical
observations of all three studies are given 1n Table 3-1.
The consistently observed Increased mortality In rats Ingesting acrylo-
nltrlle at 8-10 mg/kg/day resulted from the debilitating effects of tumors.
The only other effects observed, decreased body weight and changes In
hematologlcal and urine values, were not severe and In many cases could be
attributed to the decreased food and water consumption. Relative organ
weights of the liver and kidney {organ-to-body weight ratio) were Increased
In.the high-dose males and females; however, the absolute organ weights were
either the same as control values or only slightly Increased. Similar
Increases In relative and absolute organ weights were noted for the heart In
the high-dose groups 1n two of the studies {Bio/dynamics, Inc., 1980b,c).
The lack of pair-fed controls makes Interpretation of these observations
difficult.
Quast et al. (1980a) exposed rats to acrylonltrlle In the drinking water
for 2 years. The concentrations used were 35, 85 and 210 ppm for 21 days,
followed by 35, 100 and 300 ppm, for the duration of the study. The U.S.
EPA (1985) stated that the amounts of acrylonltrlle Ingested were equivalent
to 3.42, 8.53 and 21.18 mg/kg/day or 4.36, 10.76 and 24.97 mg/kg/day, for
male or female rats, respectively. Early mortality was noted for males and
0064H -5- 08/11/86
-------
TABLE 3-1
lexicological Findings 1n Rats Orally Exposed to AcrylonHMle*
Consumption
Dose
(mg/kg/day)
7.98
0.093
10.69
OJ46
8.37
2.49
0.84
0.25
0.08
10.89
3.65
1.25
0.36
0.12
1C.O
0.1
10.0
0.1
Sex
H
H
F
F
H
H
H
M
H
F
F
F
F
F
H
H
F
F
Mortality
Increase
ND
Increase
NO
Increase
ND
Increase
NO
ND
Increase
Increase
ND
Increase
ND
Increase
ND
Increase
ND
Body Weight
(% change)
Decrease (10%)
ND
Decrease (8%)
ND
Decrease (12%)
Decrease (<5%)
ND
ND
ND
Decrease (12%)
ND
ND
ND
ND
Decrease (<6%)
ND
ND
ND
Food
Decrease
ND
Decrease
ND
Decrease
ND
ND
ND
NO
Decrease
ND
ND
ND
ND
Decrease
ND
ND
ND
Water
Decrease
ND
Decrease
ND
Decrease
ND
ND
ND
ND
Decrease
ND
ND
ND
ND
ND
ND
Increase
ND
*So'jrc>: B1o/dynam1cs, Inc., 1980a.b,c
ND = No difference from control values
0064h
-6-
07/28/86
-------
females at the highest concentration. Although the U.S. EPA (1985) stated
that treatment of females with the two lowest concentrations also resulted
In early mortality, this finding may have been due to an abnormally low
mortality rate In control females. The only nonneoplastlc hlstopathologlcal
lesions observed were hyperplasla of the stomach and mammary gland and gllal
proliferation In the brain.
3.2.2. Inhalation. In a 10-year study of a population of 576 workers
exposed to 5-20 ppm acrylonUMle, headache, fatigue, nausea and weakness
were frequently reported (Sakaral and Kuslmoto, 1972). Clinically, the
workers had anemia, jaundice and abnormal serum enzyme and urlnalysls
values, the extent of which was directly related to duration of exposure.
Quast et al. (1980b) exposed rats to 0, 20 or 80 ppm acrylonltrlle
vapor, 6 hours/day, 5 days/week, for 2 years. These concentrations corre-
spond to 0, 43 and 174 mg/m3, respectively. The low concentration was
associated with the early onset of chronic renal disease, possibly because
of Increased water consumption. Early mortality apparently masked the
appearance of renal disease at the high concentration.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Hurray et al. (1978) exposed gravid rats to 0, 10, 25 or 65
mg/kg/day by gavage In water, on days 6-15 of gestation. Dams exposed to 25
mg/kg/day had slight maternal toxldty, whereas those given 65 mg/kg/day had
decreased body weight, thickening of the nonglandular stomach and Increased
liver weight. There were no treatment-related effects on the number of
litters. Implants or live fetuses/Utter. Administration of the high dose
led to decreased fetal body weight and Increased crown-rump length. There
were dose-related effects on the Incidence of Utters with fetuses having
0064h -7- 08/11/86
-------
short tails or trunks, Imperforate anus and missing vertebrae. The Investi-
gators concluded that the adverse effects were directly on the fetus rather
than secondary to maternal toxlclty.
Bellies et al. (1980) performed an extensive 3-generat1on reproductive
study on rats with 0, 100 or 500 ppm acrylonltrlle In drinking water. The
parents of the first generation showed some adverse effects of treatment In
the 500 ppm group, with food and water consumption and body weights signifi-
cantly lower than those of control rats (other generations were not moni-
tored for these parameters). Reproductive toxlclty was observed 1n the two
ma tings of the first generation, manifested as an Increased number of deaths
during the lactation period among pups of rats that had been treated at the
500 ppm level. These deaths may have been a result of acrylonltrlle's
effect on the dams, since pups fostered by untreated dams had normal
survival. In the other generations, reproductive capacity and pup survival
were within the normal range. The only adverse effect observed In pups that
survived treatment was a decrease 1n body weight 1n the 500 ppm group. Poor
weight gain In the pups may have been caused by poor lactation 1n the dams,
which was due to the decreased water consumption. Ten weanlings of each sex
from the control and high-dose groups of the F_. Utter were sacrificed
for comprehensive hlstopathologlcal evaluation. No adverse findings were
noted In tissues taken routinely for hlstologlcal evaluation. Acrylonltrlle
appeared to have Uttle direct effect on the development of the embryo and
pup up to the time of weaning.
3.3.2. Inhalation. Hurray et al. (1978) exposed groups of gravid rats to
40 or 80 ppm (87 or 174 mg/m3) acrylonltrlle, 6 hours/day on gestation
days 6-15. Treatment did not Increase the number of specific Individual
0064h -8- 08/11/86
-------
fetal malformations; however, when considering total malformations, exposure
to 80 ppm Increased the number of Utters containing abnormal fetuses,
although not significantly (p«0.06).
3.4. TOXICANT INTERACTIONS
Hydrogen cyanide and carbon monoxide have been found to enhance the
toxlclty of acrylonltrlle (Yamamoto, 1976; Ostlrovskaya et al., 1976). A
number of researchers (Dudley and Neal, 1942; GhlMngheTM, 1954; Graham,
1965; Mclaughlin et al., 1976) have found that the traditional antidotes for
cyanide poisoning, Including sodium thlosulfate, methylene blue, sodium
nitrite and hydroxycobalamlne, were only minimally effective or Ineffective
In cases of experimental acrylonltrlle poisoning.
0064h .9. 07/28/86
-------
4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding the carclnogenldty In humans of
oral exposure to acrylonltrlle were not located 1n the available literature.
4.1.2. Inhalation. Although a number of occupational studies regarding
the carcinogenic risks of acrylonltrlle exposure were available, only one
study (O'Berg, 1980) estimated actual exposure levels. A cohort of 1345
male employees In a textile plant was studied over a 16-year exposure period
(1950-1966), with a minimum 10-year follow-up. Levels of exposure to
acrylonltrlle, as documented by U.S. EPA (1983a), were designated as "high"
(20 ppm, -41 mg/m3), "medium" (10 ppm, -20 mg/m3) or "low" (5 ppm, -10
mg/m3) with a mean of 15 ppm (-30 mg/m3). Considering all employees, 25
cases of cancer were found, compared with 20.5 expected cases (based upon
company records). Eight of these cancers were of the respiratory system,
vs. 4.4 expected cases. Table 4-1 shows the significantly elevated cancer
Incidences 1n workers exposed for >6 months, who were subjected to the
highest exposure concentrations. After adjustment for smoking patterns, the
U.S. EPA (1983a) concluded that the excess risk for lung cancer In long-term
workers was probably related to acrylonltrlle. Smoking was not completely
ruled out as a contributing factor, however.
Although several other ep1dem1olog1cal studies (Oelzell and Honson,
1982; Thless et a!., 1980; Werner and Carter, 1981) reported positive
evidence for lung, lymphatic or stomach cancer associated with acrylonltrlle
exposure, these studies contained a number of methodological flaws, Includ-
ing poor follow-up procedures and exposure to multiple compounds, and will
not be considered further 1n this document.
0064h -10- 08/11/86
-------
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10/27/86
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4.2. BIOASSAYS
4.2.1. Oral. Quast et al. (1980a) found treatment-related Increases 1n a
variety of tumor types In rats exposed to acrylonHMle In the drinking
water (Table 4-2). In males, these tumors Included Zymbal gland carcinomas,
squamous cell tumors of the tongue and forestomach, paplllomas of the
stomach, and gllal cell proliferation and tumors of the CMS. Females had
treatment-related Increases In neoplasla at all these sites, In addition to
tumors of the mammary gland and small Intestine.
B1o/dynam1cs, Inc. (1980a) found Increases In several tumor types (Table
4-3) In both male and female rats exposed In the drinking water to 1 or 100
ppm acrylonltrlle for 19-22 months. Surviving females were sacrificed at 19
months and surviving males at 22 months.
In a more extensive study, B1o/dynam1cs, Inc. (1980b) found similar
tumor types In rats exposed In drinking water to 1, 3, 10, 30 or 100 ppm
acrylonltrlle, for 23-26 months (Table 4-4). Interim sacrifices were
performed at 6, 12 and 18 months. In another study (B1o/dynam1cs, Inc.,
1980c), Spartan rats (100 males and 100 females/group) were given acrylo-
nltrlle In delonlzed water by gavage at 0.1 and 10.0 mg/kg/day, 5 days/week;
however, the study was terminated at 19 and 20 months because of excessive
mortality In the high-dose groups. H1stopatho1og1cal evaluation revealed
Increased Incidences of tumors of the brain and ear canal (Zymbal gland) 1n
high-dose males and females. Stomach tumors were observed only In high-dose
males, and mammary gland tumors were observed 1n high-dose females.
In the 3-generat1on rat study described 1n Section 3.3.1. (Bellies et
al., 1980), second-generation high-dose (500 ppm) offspring had higher
Incidences of astrocytomas and Zymbal gland tumors than did either control
or FQ rats, providing further evidence for acrylonltrile-lnduced carclno-
genlcHy.
0064h -12- 10/27/86
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4.2.2. Inhalation. Quast et al. (1980b) has shown that chronic exposure
to acrylonltrlle vapors 1s tumorlgenlc In rats (Table 4-5).
4.3. OTHER RELEVANT DATA
Information regarding the mutagenldty of acrylonltrlle has been summa-
rized by U.S. EPA (1985). Variable responses for reverse mutations have
been observed 1n plate Incorporation assays using Salmonella typhlmurlum
(DeMeester et al., 1978). In. v1t.ro. acrylonltrlle was shown to be trans-
formed to a reactive epoxlde, which binds Irreversibly to nucleic acids and
proteins (Guengerlch et al., 1981), and Is directly mutagenlc toward j>.
typhlmurlum (Cerna et al., 1981). Positive results have been obtained with
EscheMchla coll (VenHt et al., 1977). Acrylonltrlle was Ineffective 1n
Inducing clastogenlc events In mouse bone marrow cells (Leonard et al.,
1981) and In lymphocytes of exposed human workers (Thless and Flelg, 1978);
however, the compound did Increase the frequency of sister chromatld
exchange (Perocco et al., 1982), unscheduled DNA synthesis In cultured human
lymphocytes (Perocco et al., 1982) and DNA single strand breaks In cultured
Syrian golden hamster cells (Parent and Casto, 1979).
4.4. WEIGHT OF EVIDENCE
IARC (1979) did not have sufficient data to allow classification of the
carcinogenic potential of acrylonltrlle. The U.S. EPA (1980a) Indicated
that, based on then newly available preliminary evidence, acrylonltrlle was
"likely" t.o be a human carcinogen. In 1983, on the basis of subsequent
ep1dem1o1og1ca1 and animal experimentation, U.S. EPA stated that using IARC
criteria the level of animal evidence should be considered "sufficient," and
that the level of human data 1s between "sufficient" and "limited."
0064h -18- 01/27/87
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Therefore, acrylonltrlle was considered by the EPA to be an IARC Group 2A
carcinogen (U.S. EPA. 1983a). For the same reasons, the EPA classification
has been designated 81, a probable human carcinogen (U.S. EPA, 1985). An
EPA classification of Bl signifies that the available animal evidence on
carc1nogen1c1ty may be sufficient and human evidence Is limited (U.S. EPA,
1986). The available animal evidence Is sufficient and would also yield a
weight of evidence classification of B (B2 specifically). Thus, by both
human and animal data acrylonltrlle Is considered to be a probable human
carcinogen. No additional Information that would alter these
classifications was available.
0064h -21- 07/10/87
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5. REGULATORY STANDARDS AND CRITERIA
U.S. EPA (1980a) derived a criterion of 0.58 yg/l for acrylonltrlle,
based upon excess cancer risk associated with the Increased Incidence of
astrocytomas In the CNS of female rats In the chronic drinking water
bloassay by Quast et al. (1980a).
The ACGIH (1985) adopted a TLV-THA of 2 ppm (-4.5 mg/m3) for acrylo-
nltMle, accompanied by a "skin" notation. The compound 1s classified by
»' *
EPA as "Probable Human Carcinogen," Group Bl based upon limited epldemlo-
loglcal evidence and demonstration of cardnogenesls In several animal
species. The ACGIH (1986) based the TLV-TWA upon the "consistent production
of tumors In rats and the suspicion of cancer In humans raised by the
[O'Berg (1980)] study."
The current OSHA (1985) standards for acrylonltrlle are an 8-hour TWA of
2 ppm (~4 mg/m3) and a 15-mlnute celling limit of 10 ppm (-22 mg/m3).
The U.S. EPA (1983a) classifies acrylonltrlle In Group Bl, a probable
human carcinogen, based on sufficient animal evidence and limited human
evidence of carclnogenlclty.
0064h -22- 07/10/87
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfO$)
Sufficient evidence exists to Indicate that acrylonltrlle Is carcino-
genic by the oral and Inhalation routes. It Is. therefore. Inappropriate to
derive RfO» values for oral or Inhalation exposure.
6.2. REFERENCE DOSE (RfO)
Sufficient evidence exists to Indicate that acrylonltrlle Is carcino-
genic by the oral and Inhalation routes. It Is, therefore, Inappropriate to
derive RfO values for oral or Inhalation exposure.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. The U.S. EPA (1983a, 1985} calculated q * values from
three drinking water studies In rats (Bio/dynamics, Inc., 1980a,b; Quast et
al., 1980a), using the multistage linearized model adopted by the U.S. EPA
(1980b). In the B1o/dynam1cs, Inc. (1980a,b) studies, U.S. EPA (1983a,
1985) combined Incidences of CMS astrocytomas, Zymbal gland carcinomas and
forestomach tumors. In the Quast et al. (1980a) study, U.S. EPA (1983a,
1985) considered the total number of tumors described In Section 4.2.1.,
except for female mammary gland tumors. The geometric mean of the q, *s
from these three studies was calculated to be 5.4xlO"4 (mg/kg/day)'1
from data In males and 4.6X10"1 (mg/kg/day)'1 from data 1n females (U.S.
EPA, 1983a). Since the value derived from the data In males was higher and
would result In a more protective estimate for humans, the U.S. EPA (1983a,
1985) adopted It as the estimate of lifetime risk to humans from oral
exposure. In the absence of more recent cardnogenldty data, 1t would be
prudent to retain the q,* value of 5.4X10'1 (mg/kg/day>'*, correspond-
ing to an upper limit unit risk of 1.5xlO~5 (vg/i.)'1, which was
calculated by U.S. EPA (1983a) and subjected to extensive peer review, as
the estimate of oral carcinogenic potency for the purposes of this document.
0064h -23- 07/10/87
-------
6.3.2. Inhalation. The U.S. EPA (1983a) calculated a unit risk, repre-
senting the Increased probability of cancer associated with a unit Increase
In the concentration of chemical of 1.5xlO~4 (ppb)"1 or 6.8xlO"5
(vg/in*)"1 for acrylonltrlle In air, based upon the epldemlologlcal
data of O'Berg (1980). Time weighted average exposure level of 15 ppm (-31
mg/m3) was estimated for occupational exposure. Assuming a reference
human body weight of 70 kg and an Inhalation rate of 20 m3 of air dally
(U.S. EPA, 1980b), the Increased probability of lung cancer with each unit
Increase of acrylonltrlle may be expressed as 0.24 (mg/kg/day)"1.
The U.S. EPA (1983a) also derived an Inhalation unit risk of 3.35xlO"a
(ppm)"1, equivalent to a unit risk of l.SxlO"2 (mg/m3)'1, from the
Incidence data of tumors of the Zymbal gland, brain and spinal cord In
female rats from the Quast et al. (1980b) Inhalation study, using the
linearized multistage model outlined by U.S. EPA (1980b). The potency
slope, q,*, which may be expressed as 5.3xlO~2 (mg/kg/day)"1, 1s lower
than the q,* calculated from the human epldemlologlcal data from the
O'Berg (1980) study [0.24 (mg/kg/day )""*]. Therefore, to avoid the uncer-
tainties associated with Interspedes extrapolation, the more conservative
q,* value, equivalent to 0.24 (mg/kg/day)'1. Is chosen as the estimate
of carcinogenic potency to humans of Inhalation exposure to acrylonltrlle.
The Appendix contains the appropriate summary Information for oral and
Inhalation exposure.
0064h -24- 07/10/87
-------
7. REFERENCES
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ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986.
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concentration factor 1n an Industrial environment. Tokslkol. G1g. Prod.
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Bellies, R.P., H.J. Paulln, N.G. Makrls and R.J. Weir. 1980. Three-genera-
tion reproductive study of rats receiving acrylonltrlle In drinking water.
Prepared by LHton B1onet1cs, Inc., Kensington,: MD, under LBI Project No.
2660 for the Chemical Manufacturers Association, Washington, DC. (Cited In
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B1o/dynam1cs, Inc. 1980a. A 24-month oral tox1c1ty/carc1nogen1c1ty study
of acrylonltrUe administered to Spartan rats 1n the drinking water. Final
Report. Vol. 1 and 2. Prepared by Bio/dynamics, Inc., Division of Biology
and Safety Evaluation, East Millstone, NJ, under Project No. 77-1745 for
Monsanto Company, St. Louis, MO. (CHed In U.S. EPA, 1983a)
0064h -25- 01/27/87
-------
Bio/dynamics, Inc. 1980b. A 24-month oral toxIdty/cardnogenlcUy study
of acrylonHrlle administered In drinking water to Fischer 344 rats. Final
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Safety Evaluation, East Millstone, NJ, under Project No. 77-1744 (BDN-77-27)
for Monsanto Company, St. Louis, MO. (Cited In U.S. EPA, 1983a)
Bio/dynamics, Inc. 1980c. A 24-month oral tox1c1ty/carc1nogen1c1ty study
of acrylonltrlle administered by Intubation to Spartan rats. Final Report.
Vol. 1 and 2. Prepared by B1o/dynam1cs, Inc., Division of Biology and
Safety Evaluation, East Millstone, NJ, under Project No. 77-1746 for
Monsanto Company, St. Louis, MO. (Cited In U.S. EPA, 1983a)
Cadena, F., G.A. EIceman and V.J. Vandlver. 1984. Removal of volatile
organic pollutants from rapid streams. J. Water Pollut. Control. Fed. 56:
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Cerna, M., J. Koclsova, I. Kodytkova, J. Kopecky and R.J. Sram. 1981.
Mutagenlc activity of ox1ranecarbon1tr1le (glyc1don1tr1le). in: Ind.
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Oelzell, E. and R.R. Monson. 1982. Mortality among rubber workers. VI.
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0064h -26- 01/27/87
-------
Dudley, H.C. and P.A. Neal. 1942. Toxicology of acrylonHMle. I. A study
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Gh1r1nghellV L. 1954. AcrylonHMle toxlclty and mechanism of action.
Med. Lavoro. 45: 305. (Hal.) (Cited 1n U.S. EPA, 1980a)
Graham, J.D.P. 1965. Hydroxycobalamlne as an antidote to acrylonltrlle.
Toxlcol. Appl. Pharmacol. 1: 367. (Cited 1n U.S. EPA, 1980a)
Guengerlch, P.P., I.E. Gelger, L.L. Hogy and P.L. Wright. 1981. In vitro
metabolism of acrylonltrlle to 2-cyanoethylene oxide, reaction with gluta-
thlone and Irreversible binding to proteins and nucleic adds. Cancer Res.
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Hansch, C. and A.J. Leo. 1985. HedChem Project. Issue No. 26. Pomona
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IARC (International Agency for Research on Cancer). 1979. IARC Monographs
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0064h -27- 01/27/87
-------
Knobloch. K., S. Szendzlkowskl and T Czajkowskl. 1972. Chronic toxlclty
of acrylonltMle. Med. Pr. 23(3): 243-257. (CA 78:12332h) (Cited 1n U.S.
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poisoning. Toxlcol. Appl. Pharmacol. 37: 133. (Abstract) (Cited In U.S.
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Gehrlng. 1978. Teratogenldty of acrylonltrlle given to rats by gavage or
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O'Berg, H. 1980. Ep1dero1olog1c study of workers exposed to acrylonltrlle.
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Ostlrovskaya, R.S., et al. 1976. Health status of workers currently
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0064h -28- 01/27/87
-------
Parent, R.A. and B.C. Casto. 1979. Effect of acrylonUHle on primary
Syrian golden hamster embryo cells 1n culture. Transformation and DNA
fragmentation. J. Natl. Cancer Inst. 62(4): 1025-1029.
Perocco, P., G. Pane, S. Bolognesl and H. Zannottl. 1982. Increase of
sister chromatld exchange and unscheduled synthesis of deoxyrlbonuclelc acid
by acrylonUrlle 1n human lymphocytes \n_ vitro. Scand. J. Work Environ.
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Quast, J.F., C.G. Humlston, B.A. Schwetz, L.A. Frauson, C.E. Wade and J.M.
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the drinking water of purebred beagle dogs. Prepared by the Toxicology
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Quast, J.F., C.E. Wade, C.G. Humlston, et al. 1980a. A 2-year toxlclty and
oncogenlclty study with acrylonltrlle Incorporated In the drinking water of
rats. Prepared by the Toxicology Research Laboratory, Health and Environ-
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turers Association, Washington, DC. (Cited 1n U.S. EPA, 1983a, 1985)
Quast, 3.F., D.J. Schwetz, M.F. Balmer, T.S. Gushow, C.N. Park and M.J.
McKenna. 1980b. A 2-year toxlclty and oncogenlclty study with acrylo-
nltrlle following Inhalation exposure of rats. Prepared by the Toxicology
Research Laboratory, Health and Environmental Sciences, Dow Chemical USA,
Midland, MI, for the Chemical Manufacturers Association, Washington, DC.
(Cited In U.S. EPA. 1983a, 1985)
0064h -29- 01/27/87
-------
Sakaral, H. and M. Kuslmoto. 1972. Ep1dem1olog1c study of health Impair-
ment among AN workers. Rodo Kagaku. 48: 273. (Cited 1n U.S. EPA, 1980a)
Thless, A.M. and I. Flelg. 1978. Analysis of chromosomes of workers
exposed to acrylonltrlle. Arch. Toxlcol. 41(2): 149-52. (Cited In U.S.
EPA, 1983a, 1985)
Thless, A.M., R. Frentzel-Beyme, R. Link and H. Wild. 1980. MortalHats-
studle 8e1 ChemlefacharbeHern Verschledener Produkt1onsbetr1ebe M1t Exposi-
tion Auch Gegenuber Acrylonltrlle. Zentralbl. Arbeltsmed. 30: 267-359.
(Ger.) (Cited 1n U.S. EPA, 1983a)
U.S. EPA. 1979. Water-related environmental fate of 129 priority pollu-
tants. Vol. 2. Office of Water Planning and Standards, Office of Water and
Management, Washington, DC. EPA 440/4-79-0298.
U.S. EPA. 1980a. Ambient Water Quality Criteria for Acrylonltrlle.
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Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regu-
lations and Standards, Washington, DC. EPA 440/5-80-017. NTIS PB81-117285.
U.S. EPA. 1980b. Guidelines and Methodology Used 1n the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
0064h -30- 02/05/87
-------
U.S. EPA. 1983a. Health Assessment Document for AcrylonUMIe. Prepared
by the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Research Triangle Park, NC. EPA 600/8-82-007F. NTIS
PB84-H9152.
U.S. EPA. 1983b. Reportable Quantity Document for Acrylonltrlle. Prepared
by the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH for the Office of Emergency and
Remedial Response. Washington, DC.
U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity
Determination Based on Chronic Toxldty Data. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1985. Health and Environmental Effects Profile for Acrylonltrlle.
Prepared by the Office of Health and Environmental Assessment, Environmental
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and Remedial Response, Washington, DC.
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Register. 51(185): 33992-34003.
Venltt, S., C.T. Bushel 1 and M. Osborne. 1977. Hutagenlclty of acrylo-
n1tr11e (cyanoethylene) In Escherlchla coll. Hutat. Res. 45(2): 283-288.
0064h -31- 07/07/87
-------
Weber, R.C.. P.A. Parker and N. Bowser. 1981. Vapor pressure distribution
of selected organic chemicals. U.S. EPA, Cincinnati, OH. EPA-600/2-81-021.
39 p.
Werner, J.B. and J.T. Carter. 1981. Mortality of United Kingdom acrylo-
nltrlle polymersatlon workers. Br. J. Ind. Med. 38: 247-253. (Cited 1n
U.S. EPA, 1983a)
Yamamoto, K. 1976. Acute combined effects of HCN and CO, with the use of
combustion products from PAN (polyacrylonltrlle)—gauze mixtures. I.
Rechtsmed. 78: 303. (Cited 1n U.S. EPA, 1980a)
Young, J.D., R.W. Slauter and R.J. Karbowskl. 1977. The pharmacoklnetlc
and metabolic profile of 14C-acrylonHr11e given to rats by three routes.
Prepared by the Toxicology Research Laboratory, Health and Environmental
Research, Dow Chemical USA, Midland, MI, for the Chemical Manufacturers
Association, Washington, DC.
0064h -32- 02/05/81
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