TECHNICAL REPORT DATA
(futt read /lutnicrioiu on tH« revcru before completing]
1. REPORT NO.
2.
3. RECIPIENTS ACCESSION NO.
PB88-179502
4. TITLE AND SUBTITLE
8. REPORT DATE
Health Effects Assessment for Acetonitrile
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
. PERFORMING ORGANIZATION REPORT NO.
. PERFORMING ORGANIZATION NAME AND AOORESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME ANO AOORESS
13. TYPE OF REPORT ANO 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
IS. SUPPLEMENTARY NOTES
e. 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 32991 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, RfD£ 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, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS ANO DOCUMENT ANALYSIS
DESCRIPTORS
b.lOENTIFIERS/OPEN ENDED TERMS
c. COSATi Field/Croup
ft. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (This Report)
Unclassified
21. NO. Of PASES
20. SECURITY CLASS (ThlJpage/
Unclassified
22. PRICE
EPA F«r« 2220-1 (R««. 4-77)
COITION is OMOV.ETC
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EPA/600/8-88/012
June, 1987
HEALTH EFFECTS ASSESSMENT
FOR ACETONITRILE
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.S. Environmental Protection
Y;c,;Lon 5, Library (5PL-1S)
;.-;'-:u .".-. Dsartorn Street, uoc-n 1670
Cbieaso, IL 60604
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DISCLAIMER
This document has been reviewed In 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
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with aceto-
nltrlle. All estimates of acceptable Intakes and carcinogenic potency
presented In this document should be considered as preliminary reflecting
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 Is 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. 1983a. Reportable Quantity Document for AcetonHrlle.
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. 1985a. Health and Environmental Effects Profile for
Acetonltrlle. 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, OC.
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 1n
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 chemical(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s 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).
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 (RfD$i) and oral (RfO$o)
exposures.
111
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The RfD (formerly AIC) 1s 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 (1980) for a discussion of this concept]. The
RfD Is route-specific and estimates acceptable exposure for either oral
(RfDg) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncarclnogens 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 (1983).
For compounds for which there Is sufficient evidence of cardnogenlclty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980). Since cancer 1s a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data If available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n 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.
The RfDso (4.6 mg/day) and RfDg (0.5 mg/day) values for acetonltrlle
were based on a mouse NOAEL of 39 mg/kg/day derived from a 92-day Inhalation
study (Coate. 1983a).
The RfD$i (9.1 mg/day) and RfDj (0.91 mg/day) values were derived
from same study. The Inhalation values are higher than the oral values
because applications of an absorption factor Is necessary 1n extrapolation
from Inhalation to oral exposure. A CS of 26 was based on teratogenldty
and fetotoxldty In hamsters treated with a single oral dose of 200 ing/kg of
acetonltrlle on day 8 of gestation (W1llh1te, 1983).
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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 DeRosa 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, OC.
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 Haste
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
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
ENVIRONMENTAL CHEMISTRY AND FATE
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
. . . 5
. . . 5
. . . 5
5
. . . 8
. . . 8
. . . 8
. . . 8
. . . 8
. . . 11
. . . 12
14
. . . 14
. . . 14
. . . 14
14
. . . 14
. . . 14
. . . 14
. . . 15
. . . 16
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TABLE OF CONTENTS
Page
6. RISK ASSESSMENT 17
6.1. SUBCHRONIC REFERENCE DOSE (RfOs) 17
6.1.1. Oral (RfDso) 17
6.1.2. Inhalation (RfDSi). . 17
6.2. REFERENCE DOSE (RfD) 18
6.2.1. Oral (RfDo) 18
6.2.2. Inhalation (RfDj) 19
6.3. CARCINOGENIC POTENCY (q-|*) 20
7. REFERENCES 22
APPENDIX: Suwnary Table for AcetonltrUe 28
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LIST OF ABBREVIATIONS
AOI Acceptable dally Intake
BUN Blood urea nitrogen
bw Body weight
CAS Chemical abstract service
CS Composite score
Ig Immunoglobulln
Koc Soil sorptlon coefficient standardized
with respect to organic carbon
LCso Concentration lethal to SOX of recipients
(and all other subscripted dose levels)
LDso Dose lethal to SOX of recipients
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
ppm Parts per million
RBC Red blood cell chollnesterase
RfD Reference dose
RfDj Inhalation reference dose
RfDg Oral reference dose
RfD$ Subchronlc reference dose
RfDgi Subchronlc Inhalation reference dose
RfO$o Subchronlc oral reference dose
STEL Short-term exposure level
TLV Threshold limit value
TSH Thyroid stimulating hormone
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected physical and chemical properties and environmental fate of
acetonltrlle are listed In Table 1-1.
In the atmosphere, acetonltrlle should exist primarily In the vapor
phase and 1s expected to react with ozone and photochemically-generated
hydroxyl radicals. The atmospheric half-life listed In Table 1-1 1s based
on the contribution from both ozone and hydroxyl radical reactions. It 1s
based on an ozone reaction rate constant of <1.5xlO~19 cm3/molecule-sec,
an ambient ozone concentration of 101S molecule/cm3, a hydroxyl reaction
rate constant of ~5xlO~14 cmVmolecule-sec at 25°C and an ambient
hydroxyl concentration of 8.0x10* molecule/cm3. In moderately polluted
air, the hydroxyl reaction rate 1s 10 times faster than 1n typical air, and
a half-life of <20 days has been calculated. The complete water solubility
of acetonltrlle suggests that dissolution Into clouds and rain droplets may
occur, with subsequent removal by rainfall (U.S. EPA, 1985a). In water,
mlcroblal degradation and volatilization appear to be the significant fate
and transport processes. At 20-25°C, the half-life In natural waters can be
estimated to be -1-2 weeks from blodegradatlon study data In river water and
from volatility estimations (U.S. EPA, 1985a). Adsorption to suspended
solids and sediments and bloaccumulatlon In aquatic organisms should not be
significant. The half-life of acetonltrlle In soil could not be located 1n
the available literature. Laboratory data Indicate that acetonltrlle 1s
susceptible to significant mlcroblal degradation. Significant evaporation
from soil surfaces may also occur. Estimated K values ranging from 2-15
suggest that acetonltrlle would be highly mobile and, therefore, would
easily leach In soil (U.S. EPA. 1985a).
0104h -1- 12/10/86
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TABLE 1-1
Selected Physical and Chemical Properties and Half-Lives for Aceton1tr1le*
Property
Value
CAS number:
Chemical class:
Molecular weight:
Vapor pressure at 20°C:
Water solubility:
Log octanol/water
partition coefficient:
B1oconcentrat1on factor:
Soil adsorption coefficient:
Half-lives:
Air
Water
Soil
75-05-8
alky! nltrlle
41.05
74 mm Hg
completely mlsclble
-0.34
0.3 (estimated)
2-15 (estimated)
-42 days(estlmated)
-1-2 weeks
NA
'Source: U.S. EPA. 1985a
NA - Not available
0104h
-2-
12/10/8e»
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Quantitative data regarding the absorption of acetonltrlle after oral
exposure could not be located 1n the available literature. Several pharma-
coklnetlc studies (Ahmed and Farooqul, 1982; Silver et al., 1982) and toxlc-
1ty studies (Pozzanl et al., 1959a; Ulllhlte, 1983), however. Imply that
some acetonltMle Is absorbed after Ingestlon. Ahmed and Farooqul (1982)
Identified cyanide In the liver, kidney and brain of rats after oral
treatment with 2460 mg/kg of acetonltrlle 1n saline. Silver et al. (1982)
reported that 11.8X of the dose administered orally to rats was excreted as
thlocyanate In the urine within 24 hours after Ingestlon. The toxlclty
studies, discussed In Chapter 3, resulted In adverse effects after oral
exposure to acetonltrlle.
2.2. INHALATION
Quantitative data regarding the absorption of acetonltrlle In humans
after Inhalation exposure are available (Dalhamn et al., 1968a,b). In a
group of 16 human subjects who were cigarette smokers, an average of 74%
absorption of acetonltrlle was measured when the smoke was held In the mouth
for 2 seconds and was not Inhaled. When the subjects were classified by the
number of cigarettes smoked/day, a slight but statistically significant
(p<0.05) Inverse correlation was noted between the smoking rate and the
extent of acetonltrlle absorption (Dalhamn et al., 1968a). When the
cigarette smoke was Inhaled Into the lungs, absorption of acetonltrlle
Increased to 91X (Oalhamn et al., 1968b).
0104h -3- 10/24/86
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The only other quantitative study on absorption Is that conducted by
Pozzanl et al. (1959a), In which three beagle dogs were exposed for 4 hours
to acetonltrlle vapor at an air concentration of 16,000 ppm (27,000
mg/m3). After ~1 hour, blood cyanide concentrations were 33-53 yg/100
ml blood. Blood cyanide levels peaked after -3 hours (305-433 yg/100
ml blood) and were somewhat reduced at the end of the 4-hour exposure
period (266-291 yg/100 ml blood). The authors did not discuss this
pattern of absorption but noted one "analytical artifact" during the elimi-
nation phase of this study. Given the small number of animals used 1n this
study and possible problems In the analytical technique, these data cannot
be used to derive a rate coefficient for absorption. Nonetheless, the data
Indicate qualitatively that acetonltrlle Is absorbed rapidly upon Inhalation
and suggest that the dogs may have been nearlng steady-state blood concen-
trations at 3-4 hours after exposure.
0104h -4- 10/24/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Pertinent data regarding the toxldty of acetonltMle after
oral exposure could not be located 1n the available literature.
3.1.2. Inhalation. Pozzanl et al. (1959a) Investigated the toxldty of
acetonltrlle 1n subchronlc Inhalation experiments In rats, dogs and monkeys.
Wlstar rats (15/sex/exposure level plus two sets of controls of 15/sex) were
exposed to 0, 166 ppm (279 mg/m3), 330 ppm (554 mg/m3) and 655 ppm (1100
mg/m3) acetonltrlle 7 hours/day, 5 days/week for 90 days. At the 166 or
330 ppm levels, no statistically significant changes were observed In body
weights, organ weights or hlstologlcal appearance of selected major organs.
At 655 ppm, 10/27 males and females had pulmonary lesions as evidenced by
"alveolar capillary congestion and/or focal edema, often accompanied by
bronchial Inflammation, desquamatlon and hypersecretlon of mucus." Central
cloudy swelling of the liver and tubular cloudy swelling of the kidney were
observed In 7/27 and 8/27 rats, respectively. These results were statisti-
cally significant (p<0.05) relative to controls. Although no lesions were
found 1n the adrenals, pancreas, spleen, testes and trachea, 1/5 brains
examined In the 655 ppm exposure group had focal cerebral hemorrhage, an
effect similar to that reported In monkeys at <655 ppm acetonltrlle.
As a preliminary Inhalation experiment, Pozzanl et al. (1959a) exposed
one or two rhesus monkeys/exposure levels to 330 ppm (554 mg/m3), 660 ppm
(1110 mg/m3) and 2510 ppm (4210 mg/m3) acetonltrlle for 7 hours/day for
up to 99 days. No air-exposed controls were maintained. The monkey exposed
to 2510 ppm died with severe pulmonary effects after the second day of
exposure, and two monkeys exposed to 660 ppm died after 23 and 51 days.
0104h -5- 10/24/86
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Brain hemorrhages, adverse changes In the lung (e.g.. atelectasls and pneu-
monltls) and cloudy swelling of the renal convoluted tubules were reported
In the monkeys exposed to acetonltrlle at 660 ppm for >2 days. The monkey
exposed to 330 ppm survived until sacrifice at 99-days, but had chronic
pneumonltls as evidenced by diffuse proliferation of alveolar septa.
monocytlc Infiltration and pleural adhesions. Pozzanl et al. (1959a) also
exposed three adult male mixed breed dogs and three adult male rhesus
monkeys to 350 ppm (588 mg/m3) acetonUrlle, 7 hours/day, 5 days/week for
91 days. Both the monkeys and dogs had pulmonary abnormalities. The dogs
exhibited a transient depression In hematocrH and hemoglobin values but no
significant deviation In erythrocyte counts. Brain hemorrhages were
observed In all three monkeys and cloudy swelling of the convoluted kidney
tubules was noted In two of the three exposed monkeys. The monkeys also
exhibited excitability and over-extension reflexes.
Groups of 10 male and 10 female Fischer 344 rats and 10 male and 10
female B6C3F1 mice were exposed to 0, 25. 50, 100, 200 or 400 ppm (0, 42.
84, 168, 336 or 672 mg/m3) of acetonltrlle vapor 6 hours/day, for 65 days
during a 92-day experimental period (Coate, 1983a,b). Parameters evaluated
Included body and organ weight, clinical chemistry, hematology. Immune
functions after 10 days of exposure (mice), sperm count, motlllty and
morphology, vaginal cytology, levels of serum, T. or TSH or both, urinary
cyanide levels and the histology of the major organs from the control group
and the 400 ppm exposure group, the I1v<>r from the 100 and 200 ppm exposure
groups and the nasal turblnates from all exposure groups. The only statis-
tically significant effects observed 1r rats were decreased mean leucocyte
counts In males exposed to >100 ppm of acetonltrlle and females exposed to
400 ppm of acetonltrlle. Body weights were slightly Increased during the
0104h -6- 12/10/86
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study In Females exposed to >100 ppm and males exposed to 400 ppm, but there
were no statistically significant differences In terminal body weights
between test and control rats. The biological significance of the decreased
leucocyte counts Is unclear. Males exposed to 400 ppm of acetonltMle had
slightly Increased heart-to-body weight ratios, but no cardiac hlstopatho-
loglcal alterations. Hepatocyte vacuollzatlon was observed In all groups
evaluated Including controls, but the Intensity of the vacuollzatlon was
slightly greater In the female rats exposed to 400 ppm of acetonUMle. No
other hlstopathologlcal alterations were reported.
The statistically significant effects In the mice Included decreased BUN
levels, RBC counts and hematocrUs In females exposed to 200 or 400 ppm of
acetonltrlle. Hepatic vacuollzatlon and hypertrophy were observed at all
dose levels evaluated Including controls, but the Intensity of the hepatic
lesions appeared greater In male and female mice exposed to 200 or 400 ppm
of acetonltrlle. Elevated relative liver weights were observed In males at
400 ppm and In females at 100 and 200 ppm. A dose-related decrease In
leucocyte count and serum IgG levels occurred, but did not appear to Indi-
cate specific T- or 8-lymphocyte dysfunction, and the biological signifi-
cance of these findings 1s unclear.
Immuquest Labs, Inc. (1984) exposed groups of unspecified numbers of
female B6C3F1 mice to acetonltrlle at 0, 100, 200 or 400 ppm (0, 168, 336 or
672 mg/m3) 6 hours/day, 5 days/week for 90 days. There were no effects on
physical appearance, body weights or gross appearance at necropsy. Mice 1n
the 200 and 400 ppm groups had atrophy of the thymus, which was noted upon
hlstopathologlcal examination. Slight vacuollzatlon of hepatocytes accom-
panied by hydropic degeneration was also observed at 400 ppm. There were no
treatment-related effects on selected clinical chemistries, but mice at 200
0104h -7- 12/10/86
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and 400 ppm had dose-related decreases In hematocrUs, blood hemoglobin con-
centration, and erythrocyte and leucocyte counts. Changes In hematologlcal
parameters were not significant at 100 ppm. No significant effects on organ
weights were observed, but the Investigators noted a trend toward depressed
thymus weights at 200 and 400 ppm.
After 14 days, Immuquest Labs, Inc. (1984) evaluated Immune function In
mice exposed by the same protocol. A significant dose-related depression of
serum concentration of IgG was observed 1n all exposed mice, but no effects
were observed on the Cunningham plaque-forming response to sheep erythro-
cytes, the lymphocyte blastogenesls test, delayed hypersensHlvlty response
or susceptibility to challenge with PYB6 tumor cells.
3.2. CHRONIC
3.2.1. Oral. Pertinent data regarding the systemic toxldty of aceto-
nltrlle after chronic oral exposure could not be located 1n the available
literature.
3.2.2. Inhalation. Pertinent data regarding the systemic toxlclty of
acetonltrlle after chronic Inhalation exposure could not be located 1n the
available literature.
3.3. "ERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. W1llh1te (1983) studied the teratogenlclty of acetonltrlle
In groups of 6-12 female Syrian Golden hamsters. The hamsters were exposed
to acetonltrlle In distilled water by oral Intubation on day 8 of gestation
(the early primitive streak stage of embryogenesls) at levels of 100, 200,
300 and 400 mg/kg. Controls were treated with distilled water. At the 400
mg/kg dose level, signs of maternal toxlclty were evident after 2.5 hours.
There was a statistically significant (p<0.05) Increase In the Incidence of
malformed offspring at the 300 and 400 mg/kg doses. These malformations
0104h -8- 12/10/86
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Included exencephaly, encephalocele and rib abnormalities. In addition, 2/5
Utters produced by dams treated with 100 mg/kg of acetonltrlle had single
pups with an encephalocele; however, this was apparently not significantly
different from control Incidence. At 200 or 400 mg/kg, there was a
statistically significant (p<0.05) Increase In fetal resorptlons. At all
dose levels, a statistically significant decrease (p<0.05) In average fetal
body weight was found.
In a range-finding teratogenldty study by IRDC (1980), groups of five
mated Charles River COBS CD rats were treated with acetonltrlle 1n distilled
water by gavage at 0, 200, 375, 750, 1500 or 3000 mg/kg/day on days 6-19 of
gestation. Day 0 of gestation was defined as the day 1n which evidence of
mating, a sperm positive vaginal smear or the presence of a copulatory plug,
was observed. Dams were sacrificed on gestation day 20. Parameters of
toxldty evaluated Included mortality, appearance, behavior and body weights
of dams, the numbers and location of viable fetuses, early and late resorp-
tlons, corpora lutea and total Implantation. Gross appearance at necropsy
was recorded at sacrifice and at time of death for those that did not
survive to termination. Treatment-related mortality occurred 1n three dams
receiving 375 mg/kg/day and In all dams at >750 mg/kg/day. Rats In these
groups also had staining of halrcoats, abnormal ocular and nasal discharge
and marked, dose-related mean body weight losses. No adverse maternal
effects were observed at 200 mg/kg/day. Meaningful pregnancy data were
obtained only for the 200 and 375 mg/kg/day groups because of mortality at
higher doses. No adverse effects were observed at 200 mg/kg/day. A marked
Increase 1n early resorptlons was observed In both dams surviving at 375
mg/kg/day, compared with controls.
0104h -9- 01/26/87
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In the definitive teratogenlcHy study performed by IROC (1981), groups
of 25 Charles River COBS rats were treated by gavage with 0, 125, 190 and
275 mg/kg/day of acetonltHle 1n water on days 6-19 of gestation (day 0 =
day on which there was evidence of mating). On day 20 of gestation, the
dams were sacrificed. At the 275 mg/kg/day dose level, two dams died, while
there was reduced body weight gain and emaciation In two others. Increases
In the mean number of early resorptlons and postlmplantatlon losses, and a
decrease 1n the mean number of viable fetuses were also observed at the 275
mg/kg/day treatment level. These effects were not statistically significant
when compared with concurrent controls, but were significant when compared
with historic controls. At the 125 or 190 mg/kg/day dose levels, these
differences were not observed. There was no Increased Incidence of fetal
anomalies, but there was a slight Increase 1n the Incidence of unosslfled
sternebrae In all treated groups as compared with concurrent but not
historic controls.
Pregnant rabbits appear to be more sensitive than rats to the toxlclty
of acetonltHle. Argus Research Laboratories, Inc. (1984) administered
acetonltrlle In delonlzed water by gavage to groups of 25 artificially
Inseminated rabbits on days 6-18 of gestation at 0. 2.0, 15.0 or 30.0
mg/kg/day. Dams were sacrificed on gestation day 29. Five maternal deaths
and two abortions attributed to acetonltrlle occurred at 30.0 mg/kg/day.
These effects were not observed at lower doses. High-dose dams had a
significant (p<0.01) decrease In body weight, accompanied by anorexia during
the treatment period that was followed by a rebound phenomenon during the
posttreatment period so that terminal body weights were higher than controls
on gestation days 19-24. Although body weights at 15.0 mg/kg/day were not
significantly depressed during the treatment period, this group also
0104h -10- 12/10/86
-------
exhibited the rebound phenomenon. A significant (p=0.011) decrease In the
average number of live fetuses/Utter was observed at 30.0 mg/kg/day,
accompanied by a slight but not significant Increase In the Incidence of
resorptlons. There were no treatment-related effects on the Incidence of
pregnancy, number of corpora lutea, Implantations, fetal body weight or sex
ratio. No treatment-related fetal malformations were observed, but an
Increase 1n the Incidence of an extra ossification site 1n the parietal
bones was observed In four fetuses In two high dose Utters (p=0.015), which
was not significant when expressed In terms of Incidences among Utters.
3.3.2. Inhalation. W1llh1te (1983) exposed groups of 6-12 Syrian golden
hamsters to acetonHMle at 0, 1800, 3800, 5000 or 8000 ppm (0, 3022, 6380,
8395 or 13,431 mg/m3) for 60 minutes on day 8 of gestation. Inhalation of
1800 ppm did not Induce fetal malformations or signs of toxldty In the
dams. One dam exposed to 3800 ppm showed dyspnea, tremors, hypersaHvatlon,
ataxla and hypothermia after 60 minutes of exposure, and died 3 hours later.
The other five hamsters showed no signs of Intoxication at this exposure
level and their offspring were normal. At 5000 ppm, all animals were
Irritated and salivated excessively. One hamster had dyspnea, hypothermia
and tremors after 60 minutes exposure, and died 5 hours later. Six abnormal
fetuses were found In two Utters taken from other hamsters exposed at this
level. Malformations seen were exencephaly, encephalocele and Mb fusions.
Four hamsters exposed for 60 minutes to 8000 ppm (13.431 mg/m3) showed
signs of acute toxlclty and three died 1.5 hours after termination of
exposure. H1stopatholog1cal studies failed to reveal any changes 1n liver,
kidney and lungs. Offspring of these dams were afflicted with severe axial
skeletal disorders In five of the nine surviving Utters. Average fetal
body weights were also decreased when compared with litters from dams
0104h -11- 10/24/86
-------
exposed only to chamber air. One fetus showed extrathoraclc ectopla cordls
with accompanying defects In the sternum (a rare syndrome). A significant
Increase was seen In the number of abnormal fetuses at the 5000 (8395
mg/m3) or 8000 (13,431 mg/m3) ppm level when compared with control
animals exposed to chamber air. In addition, there was a significant
Increase In the number of malformed offspring at 5000 ppm (8395 mg/m3)
when compared with the lower level of exposure [3800 ppm (6379 mg/m3)],
which was also true when 8000 (13,431 mg/m3) and 5000 (8395 mg/m3) ppm
levels were compared.
No adverse effects were observed In sperm motllUy and morphology or In
vaginal cytology of F344 rats or B6C3F1 mice exposed to <400 ppm of aceto-
nltrlle, 6 hours/day, 5 days/week for 13 weeks (Coate, 1983a,b) (see Section
3.1.2.).
3.4. TOXICANT INTERACTIONS
In a study designed to assess toxicant Interactions based on the assump-
tion of dose addltlvUy, Pozzanl et al. (1959b) determined the oral LD5Qs
and Inhalation LC5Qs of binary mixtures of acetonUrlle with acetone,
carbon tetrachlorlde, toluene, propylene oxide or eplchlorohydrln. Greater
than additive potency was noted with mixtures of acetonltrlle and acetone
for both oral (3.6 times greater) and Inhalation (2.7 times greater) toxlc-
Ity. In a similar study, Smyth et al. (1969) reported greater than additive
potency for mixtures of acetonltrlle with either acetone (3.6 times greater)
or dloxane (3.2 times greater) based on determinations of oral LD^s.
Carbon tetrachlorlde pretreatment may reduce the acute toxic potency of
acetonltrlle. After carbon tetrachlorlde pretreatment. mice that were
subsequently exposed to 5000 ppm (8395 mg/m3) acetonltrlle by Inhalation
for 1 hour or 575 mg/kg by the Intraperltoneal route showed sharply reduced
0104H -12- 10/24/86
-------
fatalities (UlllhUe, 1981; Ulllhlte and Smith, 1981). Without carbon
tetrachlorlde pretreatment, deaths From Inhalation exposure were 10/10; with
pretreatment. deaths were reduced to 2/10. With the Injection dose, after
pretreatment, deaths were 0/10; without carbon tetrachlorlde pretreatment,
deaths were 7/10. Sodium thlosulfate was also protective, and sodium
nitrite was less protective (M111h1te, 1981). Tan 11 and Hashimoto (1984)
found that an oral dose of 9.96 nmol/kg bw of acetonUrlle (1n water) killed
8/10 mice pretreated with olive oil, whereas 0/10 mice pretreated with
carbon tetrachlorlde died. Arbuzov (1975) reported that acetonltrlle-
Induced lung edema was prevented by compounds that blocked N-chollno-
receptors or by glucocortlcolds or SH group donors, but sodium nitrite and
sodium thlosulfate did not prevent edema.
Tan 11 and Hashimoto (1986) reported that ethanol treatment enhanced the
acute toxldty of acetonltrlle U» vivo when administered orally to mice.
0104h -13- 10/24/86
-------
4. CARCINOGENICITY
4.1. HUNAN DATA
4.1.1. Oral. Pertinent data regarding the cardnogenldty of aceto-
nltrlle In humans after oral exposure could not be located 1n the available
literature.
4.1.2. Inhalation. Pertinent data regarding the cardnogenldty of
acetonltrlle In humans after Inhalation exposure could not be located In the
available literature.
4.2. 8IOASSAYS
4.2.1. Oral. Pertinent data regarding the carclnogenlclty of Ingested
acetonltrlle could not be located In the available literature.
4.2.2. Inhalation. A preliminary subchronlc Inhalation study for
acetonltrlle 1s In progress using rats and mice (NTP, 1986).
4.3. OTHER RELEVANT DATA
Florin et al. (1980) tested acetonltrlle on four strains of Salmonella
typhlmurlum and noted no mutagenlc activity. U.S. EPA (1982) reported that
the National Toxicology Program 1s conducting additional mutagenlclty tests
on acetonltrlle. Published reports of these studies could not be located 1n
the literature.
Brown and Donelly (1984) reported mutagenlc activity In acidic, basic
and neutral extracts from a waste stream of a petrochemical plant where
acetonltrlle was being purified. The waste stream contained 3.46% aceto-
nltrlle, 0.92% acetamide, 0.09% "R-OH" and 0.5X "heavy ends.* The chemical
composition of the latter two fractions were not Identified.
Acetonltrlle has been found to be unacceptable as a solvent for use In
mutagenlclty assays (Arlmoto et al., 1982; Kawalek and Andrews, 1980; Maron
et al., 1981).
0104H -14- 12/10/86
-------
4.4. WEIGHT OF EVIDENCE
According to U.S. EPA (1986) guidelines, acetonltHle should be placed
In Group 0, which Indicates that there are Insufficient data to allow any
conclusion regarding the carclnogenlclty of acetonltrlle. IARC has not
classified acetonltrlle, but an IARC classification of 3, cannot be classi-
fied, seems most appropriate.
0104h -15- 01/26/87
-------
5. REGULATORY STANDARDS AND CRITERIA
NIOSH (1978) recommended a TWA-TLV of 20 ppm (34 mg/ma) for aceto-
nltrtle, while OSHA (1985) listed an acceptable occupational exposure level
of 40 ppm (70 mg/m3) for acetonltrlle.
The ACGIH (1985, 1986) has recommended a TLV of 40 ppm (70 mg/m3},
with a STEL of 60 ppm (105 mg/m3) for acetonltrlle to protect against
organic cyanide poisoning and Injury to the respiratory system based on the
human studies of Pozzanl et al. (1959b) and by analogy to the more toxic
chemical, acrylonltrlle. Acetonltrlle Is designated by the skin notation
Indicating the potential contribution of dermal absorption.
0104h -16- 12/10/86
-------
6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfO$)
6.1.1. Oral (RfDgg). Data regarding subchronlc oral toxlclty of
acetonltrlle could not be located In the available literature. In Section
6.2.1., an RfDQ of 6.5xlO~3 mg/kg/day or 0.45 mg/day for a 70 kg human
was derived by applying an uncertainty factor of 1000 and a modifying factor
of 3 to a NOAEL of 19.3 mg/kg/day resulting from Inhalation exposure of mice
to 100 ppm (168 mg/m3), 6 hours/day, 5 days/week (Coate, 1983b).
An RfDSQ of 6.5xlO~2 mg/kg/day (4.6 mg/day) can be derived by
dividing the NOAEL of 19.3 mg/kg/day by a modifying factor of 3 and an
uncertainty factor of 100 rather than 1000.
6.1.2. Inhalation (RfDSI). Subchronlc Inhalation experiments with
acetonltrlle Include a 90-day experiment In rats, dogs and monkeys (Pozzanl
et a!., 1959a), a 92-day study using rats (Coate, 1983a) and mice (Coate,
1983b) and a 90-day study using mice (Immuquest Labs, Inc., 1984). Pozzanl
et al. (1959a) determined NOAELs using rats at 166 and 330 ppm (279 and 554
mg/m3) 7 hours/day, 5 days/week. At 330 ppm for 7 hours/day, monkeys
developed lesions of chronic pneumonltls and at 350 ppm (588 mg/m3), 7
hours/day for 91 days, dogs developed pulmonary Irregularities and monkeys
developed brain hemorrhages and lung and kidney lesions. The Investigators
concluded that monkeys were more sensitive than rats to the toxic effects of
acetonltrlle. Coate (1983a) observed elevated relative heart weight In male
rats and Increased Intensity of hepatocellular hypertrophy 1n female rats at
400 ppm (672 mg/ma), 6 hours/day on 65/92 days. No adverse effects were
observed at 200 ppm (336 mg/m3). In mice, however, 200 ppm was associated
with decreased erythrocyte counts and hematocMts In females and Increased
Intensity of hepatocytlc vacuollzatlon and hypertrophy (Coate, 1983b). No
0104h -17- 06/08/87
-------
adverse effects In mice were noted at 100 ppm (168 mg/m»). The 90-day
Inhalation study by Immuquest Labs, Inc. (1984) confirms that 100 ppm Is a
NOAEL In mice.
Mice appear to be more sensitive than rats to the effects of aceto-
nltHle. Although monkeys and dogs may be more sensitive than mice, these
species were only examined 1n preliminary evaluations utilizing few animals
at a single exposure level. In addition, rabbits were shown to be more
sensitive than rodents In teratology evaluations. Considering all of the
evidence, the most appropriate basis for an RfDSI 1s the mouse NOAEL of 39
mg/kg/day (Coate, 1983b). The mg/kg/day dose was calculated as follows:
168 mg/m3 x 0.039 ma/24 hours (mouse ventllatory volume, U.S. EPA, 1980)
x 6 hours/24 hours x 5 days/7 days * 0.03 kg.
In developing an RfDSI, a modifying factor of 3 Is applied to account
for the data that suggests that the mouse may not be the most sensitive
species. In addition, an uncertainty factor of 100 1s applied to account for
Interspecles and Interlndlvldual variability resulting In an RfOCT of 0.13
*>1
mg/kg/ day or 9.1 mg/day for a 70 kg human.
6.2. REFERNCE DOSE (RfD)
6.2.1. Oral (RfDQ). ho oral data appropriate for RfD estimation were
located. In the absence of oral data, Inhalation data may be utilized.
This was the approach taken In U.S. EPA (1985a); however, U.S. EPA (1985a)
did not have access to the studies of Coate (1983a,b) nor that of Argus
Research Laboratories, Iric. (1984). These data Indicate that rats are not
only apparently less sensitive to acetonltrlle than monkeys or dogs, but
also appear to be less sensitive than mice or rabbits. The available
Inhalation studies are reviewed 1n Section 6.1.2. As described 1n that
section, the mouse Inhalation NOAEL of 39 mg/kg/day 1s chosen as the most
appropriate basis to estimate an RfDQ. An absorption efficiency of SOX 1s
0104h -18- 06/08/87
-------
utilized to estimate an oral NOAEL resulting 1n an equivalent oral estimate
of 19.5 mg/kg/day. Applying a modifying factor of 3 to account for concerns
that adequate toxlclty evaluations have not been conducted In what appear to
be the most sensitive species, and an uncertainty factor of 1000 (10 to
estimate an RfDQ from subchronlc data, 10 for Interspecles variability and
10 for Intraspecles variability) results In an RfDQ estimate of 6.5xlO~3
mg/kg/day or 0.46 mg/day for a 70 kg human.
The only oral experiments that provided data suitable for calculation of
CSs were the developmental toxlclty studies using hamsters (Wlllhlte, 1983),
rats (IROC, 1981) and rabbits (Argus Laboratories, Inc., 1984). Wlllhlte
(1983) noted a significant Increase In malformations 1n hamsters given a
single oral dose of 200 mg/kg on day 8 of gestation and IRDC (1981) noted
maternotoxlc and fetotoxlc effects 1n rats treated orally with 275 mg/kg/day
during organogenesls. CSs for these effects are calculated and presented In
Table 6-1. These CSs differ somewhat from those calculated by U.S. EPA
(1985a) primarily because of differences In reference body weights for
hamsters; however, the study of W1lh1te (1983) still yields the highest CS.
6.2.2. Inhalation (RfD.). Chronic Inhalation toxlclty data were not
available for acetonltrlle. The most appropriate RfDj Is derived,
therefore, by applying an uncertainty factor of 10 to the RfDg. of 0.13
mg/kg/day (9.1 mg/day) based on the NOAEL of 39 mg estimated for mice
exposed to 100 ppm (168 mg/m3) In the subchronlc study by Coate (1983b).
The resulting RfD, 1s 1.3xlO~* mg/kg/day or 0.91 mg/day for a 70 kg
human.
The effects of subchronlc Inhalation exposure of rats, dogs, monkeys and
mice (Pozzanl et al., 1959a; Coate, 1983a,b), as well as the teratogenlc and
fetotoxlc effects In hamsters of Inhaling acetonltrlle during gestation
0104h -19- 06/08/87
-------
(Wlllhlte, 1983;}, are suitable for calculation of Inhalation CSs. The data
used to calculate MEOs and CSs are presented In Table 6-1. The values for
the MEDs differ somewhat from those reported by U.S. EPA (1985a) primarily
because the default values currently recommended by the U.S. EPA (1985b)
differ from the values used In the preparation of the previous document;
however, the highest CS is still associated with an oral,, not an Inhalation,
study.
6.3. CARCINOGENIC POTENCY (q.,*)
Data are not sufficient for estimation of the carcinogenic potential of
acetonltHle after oral or Inhalation exposure.
0104H -20- 01/12/87
-------
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7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1985.
Threshold Limit Values for Chemical Substances and Physical Agents In the
Workroom Environment with Intended Changes for 1986. Cincinnati, OH. p. 9.
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Documentation of the Threshold Limit Values, 5th ed. Cincinnati, OH.
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Ahmed, A.E. and M.Y.H. Farooqul. 1982. Comparative toxlcltles of aliphatic
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Arbuzov, E.E. 1975. Pathogenesls of toxic lung edema In rats caused by
acetonltrlle. Farmakol. Tokslkol. Nov. Prod. Khlm. S1nt., Hater. Resp.
Konf., 3rd Meeting Date 1974. p. 155-156. (CA 86:134455m)
Argus Research Laboratories, Inc. 1984. Embryofetal toxlclty and terato-
genlclty study of acetonltrlle In New Zealand white rabbits (Segment II
evaluation). Office of Toxic Substances submission. Microfiche No. OTS
507279.
Arlmoto, S., N. Nakano, Y. Ohara. K. Tanaka and H. Hayatsu. 1982. A
solvent effect on the mutagenlclty of tryptophan-pyrolyzate mutagens In the
Salmonella/mammalian mlcrosome assay. Mutat. Res. 102(20): 105-112.
0104h -22- 01/12/87
-------
Brown, K.W. and K.C. Donnelly. 1984. Hutagenlc activity of the liquid
waste from the production of acetonHrlle. Bull. Environ. Contain. Toxlcol.
32(6): 742-748.
Coate, H.B. 1983a. 90-Day subchronlc toxlclty study of acetonHrlle In
Fischer 344 rats. Final Report (revised). Submitted to National Toxicology
Program by Hazleton Laboratories America, Inc.
Coate, W.8. 1983b. 90-Day subchronlc toxlclty study of acetonUMle In
B6C3F1 mice. Final Report (revised). Submitted to National Toxicology
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Dalhamn, T., N.L. Edfors and R. Rylander. 1968a. Mouth adsorption of
various compounds In cigarette smoke. Arch. Environ. Health. 16(6):
831-835.
Dalhamn, T., M.L. Edfors and R. Rylander. 1968b. Retention of cigarette
smoke components 1n human beings. Arch. Environ. Health. 17: 746-748.
Florin, I., L. Futberg, M. Curvall and C.R. Enzell. 1980. Screening of
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Immuquest Labs, Inc. 1984. Limited toxlclty of Inhaled acetonHrlle on the
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0104H -23- 01/12/87
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IROC (International Research and Development Corporation). I960. Pilot
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IROC (International Research and Development Corporation). 1981. Aceto-
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Kawalek, J.C. and A.M. Andrews. 1980. The effect of solvents on drug
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NIOSH (National Institute for Occupational Safety and Health). 1978.
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NTP (National Toxicology Program). 1986. Management Status Report. June,
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OSHA (Occupational Safety and Health Administration). 1985. Permissible
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0104h -24- 01/12/87
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Pozzanl, U.C., C.S. Well and /P./Carpenter. 1959b. The toxlcologlcal
basis of threshold limit values: 5. The experimental Inhalation of vapor
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siderations In the metabolism of nltrlles to cyanide |£ vivo. Drug Metab.
Olspos. 10(5): 495-498.
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toxldty of nltrlles In mice. Arch. Toxlcol. 55(1): 47-54.
Tanll, H. and K. Hashimoto. 1986. Influence of ethanol on the In vivo and
1n vitro metabolism of nltrlles In mice. Arch. Toxlcol. 58(3): 171-176.
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Effect Assessment Chapters of the Ambient Water Quality Criteria Documents.
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U.S. EPA. 1982. AcetonltMle; Response to the Interagency Testing
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0104h -25- 06/08/87
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U.S. EPA. 1983a. Reportable Q\ajt1ty Document for Acetonltrlle. 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. 1983b. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Tox1c1ty 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. 1985a. Health and Environmental Effects Profile for Aceto-
nltrlle. 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. 1985b. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington,
DC.
U.S. EPA. 1986. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
W11lh1te, C.C. 1981. Inhalation toxicology of acute exposure to aliphatic
n1tr1les. CUn. Toxlcol. 18(8): 991-1003.
0104h -26- 06/08/87
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WlllhHe. C.C. 1983. Development toxicology of acetonltrlle In the Syrian
golden hamster. Teratology. 27(30: 313-325.
HlllhUe. C.C. and R.P. Smith. 1981. The role of cyanide liberation In the
acute toxlclty of aliphatic nltrlles. Toxlcol. Appl. Pharmacol. 59(3):
5W-W2,
-------
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en
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M1llh1te, C.C. 1983. Development toxicology of acetonVtrlle In the Syrian
golden hamster. Teratology. 27(30: 313-325.
WHlhUe, C.C. and R.P. Smith. 1981. The role of cyanide liberation In the
acute toxlclty of aliphatic nltrlles. Toxlcol. Appl. Pharmacol. 59(3):
589-602.
TT,5- Environmental Pro-bentlon Apericy
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