United States
Environmental Protection
1=1 m m Agency
EPA/690/R-10/017F
Final
9-27-2010
Provisional Peer-Reviewed Toxicity Values for
Methyl Acetate
(CASRN 79-20-9)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Nina Ching Y. Wang, Ph.D.
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Dan D. Petersen, Ph.D., DABT
National Center for Environmental Assessment, Cincinnati, OH
Martin W. Gehlhaus, III, M.H.S
National Center for Environmental Assessment, Washington, DC
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300)
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	iii
BACKGROUND	4
HISTORY	4
DISCLAIMERS	4
QUESTIONS REGARDING PPRTVS	5
INTRODUCTION	5
REVIEW 01 PERTINENT DATA	6
HUMAN STUDIES	6
ANIMAL STUDIES	6
Oral Exposure	6
Inhalation Exposure	7
Toxicokinetics	9
Genotoxicity	10
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RfD
VALUES FOR METHYL ACETATE	10
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC INHALATION
RfC VALUES FOR METHYL ACETATE	10
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR METHYL ACETATE	10
WEIGHT-OF-EVIDENCE DESCRIPTOR (WOE)	10
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK	10
REFERENCES	11
APPENDIX A. DERIVATION OF A SCREENING VALUE for METHYL ACETATE	14
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COMMONLY USED ABBREVIATIONS
BMC
Benchmark Concentration
BMD
Benchmark Dose
BMCL
Benchmark Concentration Lower bound 95% confidence interval
BMDL
Benchmark Dose Lower bound 95% confidence interval
HEC
Human Equivalent Concentration
HED
Human Equivalent Dose
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
POD
point of departure (oral)
RfC
reference concentration (inhalation)
RfD
reference dose
UF
uncertainty factor
UFa
animal to human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete to complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL to NOAEL uncertainty factor
UFS
subchronic to chronic uncertainty factor
WOE
weight of evidence
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
METHYL ACETATE (CASRN 79-20-9)
BACKGROUND
HISTORY
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1)	EPA's Integrated Risk Information System (IRIS).
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in EPA's Superfund
Program.
3)	Other (peer-reviewed) toxicity values, including
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's IRIS. PPRTVs are developed according to a Standard
Operating Procedure (SOP) and are derived after a review of the relevant scientific literature
using the same methods, sources of data, and Agency guidance for value derivation generally
used by the EPA IRIS Program. All provisional toxicity values receive internal review by a
panel of EPA scientists and external peer review by three independently selected scientific
experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multiprogram
consensus review provided for IRIS values. This is because IRIS values are generally intended
to be used in all EPA programs, while PPRTVs are developed specifically for the Superfund
Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
DISCLAIMERS
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
Methyl acetate appears as a colorless liquid with a fruity or sweet ester odor. It can be
used as a solvent in fast drying paints such as lacquers, a solvent for waste film in the production
of cellulosic adhesives, and is a perfume solvent. Additionally, it is a reaction solvent in dye
production. The empirical formula for methyl acetate is C3H5O2 (see Figure 1). A table of
chemico-physical properties is provided below (see Table 1).
H,C
X
,CH„
Figure 1. Chemical Structure of Methyl Acetate
Table 1. Physical Properties Table (Methyl Acetate)3
Property (unit)
Value
Boiling point (°C)
55.8
Melting point (°C)
-98
Density (g/cirf)
0.9342
Vapor pressure (mm Hg)
216
pH (unitless)
-
Solubility in water (g/L at 20 °C)
2.43 x 105
Molecular weight (g/mol)
74.08
Octanol/water partition coefficient (unitless)
0.18
aHazardous Substances Data Bank (HSDB, 2005)
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No RfD, RfC, or carcinogenicity assessment for methyl acetate (see Figure 1 for
chemical structure of methyl acetate) is available on IRIS (U.S. EPA, 2010) or in the Drinking
Water Standards and Health Advisories list (U.S. EPA, 2006). The HEAST (U.S. EPA, 1997)
lists subchronic and chronic RfDs of 10 and 1 mg/kg-day, respectively, derived in a Health and
Environmental Effects Profile (HEEP) for methyl acetate (U.S. EPA, 1986). These RfDs were
derived by analogy to methanol based on in vivo evidence for metabolic hydrolysis of methyl
acetate to methanol and acetic acid in rabbits (Tambo, 1973) and humans (Tada et al., 1974).
The adjustment across chemicals was made by multiplying the EPA RfD for methanol
(0.5 mg/kg-day) by the ratio of molecular weights for methanol and methyl acetate. The RfD for
methanol, which is currently available on the IRIS database (U.S. EPA, 1993, 2010) but is
currently undergoing reassessment, was based on a NOEL of 500 mg/kg-day as a point of
departure (POD) for serum chemistry and decreased brain weight in rats given gavage doses for
90 days (Toxicity Research Laboratory, 1986) and adjusted by a composite uncertainty factor
(UF) of 1000, including a factor of 10 for extrapolation from subchronic-to-chronic duration.
The LOAEL is 2500 mg/kg-day. The HEEP did not include derivation of RfC values for methyl
acetate.
The Chemical Assessment and Related Activities (CARA) list (U.S. EPA, 1994a, 1991)
includes no other documents for methyl acetate except for the previously mentioned HEEP
(U.S. EPA, 1986). No Environmental Health Criteria document (WHO, 2009) is available. The
chronic toxicity and carcinogenicity of methyl acetate have not been assessed by the
International Agency for Research on Cancer (IARC, 2009), the National Toxicology Program
(NTP, 2009, 2005), ATSDR (2009), or Cal EPA (2009a,b,c). The American Conference of
Governmental Industrial Hygienists (ACGIH, 2008, 2001) recommends a Threshold Limit Value
of 200 ppm (606 mg/m3) derived by analogy to methanol. The National Institute for
Occupational Safety and Health (NIOSH, 2009) Recommended Exposure Limit and
Occupational Safety and Health Administration (OSHA, 2009) Permissible Exposure Limit are
also 200 ppm (606 mg/m3).
Literature searches were conducted from 1960s through August 2010 for studies relevant
to the derivation of provisional toxicity values for methyl acetate. The databases searched
include MEDLINE, TOXLINE (with NTIS), BIOSIS, TSCATS/TSCATS2, CCRIS, DART,
GENETOX, HSDB, RTECS, Chemical Abstracts, and Current Contents (previous 6 months).
REVIEW OF PERTINENT DATA
HUMAN STUDIES
No oral or inhalation studies of methyl acetate in humans were located.
ANIMAL STUDIES
Oral Exposure
No oral studies of subchronic or chronic toxicity of methyl acetate in animals were
located.
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Inhalation Exposure
Groups of Sprague-Dawley rats (10/sex/group) were subjected to nose-only inhalation
exposures of 0, 75, 350, or 2000-ppm methyl acetate (>99.5% pure) for 6 hours/day,
5 days/week, for 28 days (Hofmann, 1999). These exposures equate to 0, 227, 1060, or
"3
6060 mg/m . Clinical observations were performed daily, while body weights and food
consumption were measured twice weekly. Hematological (counts of red blood cells [RBCs],
white blood cells [WBCs, differential], platelets, reticulocytes, and Heinz bodies; hemoglobin
[Hgb] and hematocrit [Hct] levels; mean corpuscular volume, corpuscular hemoglobin, and
corpuscular hemoglobin concentration; and coagulation time), clinical chemistry (serum levels of
sodium, potassium, inorganic phosphorus, uric acid, bilirubin, creatinine, glucose, urea, calcium,
chloride, triglycerides, albumin, total lipids, and proteins, and activity levels of aspartate
aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], and
gamma-glutamyltranspeptidase [GGT]), and urinalysis (appearance, color, volume, specific
weight, pH, hemoglobin, protein, glucose, bilirubin, ketone bodies, and sediment) were
performed at the end of the study. After sacrifice, organ weights were measured, observations
were made for gross abnormalities, and histopathological examinations were performed on the
following tissues: adrenal glands; brain; diaphragm; esophagus; ileum; knee joint; iliac and
mandibular lymph nodes; sciatic nerve; pancreas; rectum; skeletal muscle; cervical, lumbar, and
thoracic spinal cord; spleen; thymus; trachea; larynx; aorta; cecum; duodenum; eye and optic
nerve; jejunum; liver; nasoturbinates and nasopharynx; pituitary glands; salivary glands; skin
(with mammary glands); stomach; thyroid (with parathyroid); urinary bladder; sternal bone
marrow; colon; epididymides; heart; kidneys; lung; medulla oblongata; ovaries; prostate gland;
seminal vesicles; vagina; testes; tongue; and uteri. Statistical comparisons were performed on
observed endpoints.
No deaths or exposure-related clinical signs were observed. Statistically significant
(Mest; p < 0.05) changes in the following endpoints were generally seen only at the high
exposure level of 2000 ppm (see Table 2). Daily average food consumption was statistically
significantly decreased (p < 0.05) in males (-17%) and females (-9%) relative to controls. In
both sexes, body weights were reduced throughout most of the study. Terminal body weight was
statistically significantly reduced by 10% in males (p < 0.05). In females, the decrease in
terminal body weight (-3%) was not statistically significant. Small, statistically significant
increases (p < 0.05) in RBC counts (+5%), Hgb (+5—6%), and Hct (+4—5%) were observed in
both sexes, possibly due to hemoconcentration. Statistically significant larger decreases
(p < 0.05) in WBC counts (-25—33%) were also observed in both sexes at the highest dose,
although with no significant changes in WBC differential in either sex in lower doses. Serum
chemistry changes were generally unremarkable; the only consistent, dose-related changes
observed in both sexes were increases in serum calcium (+2-3%) and decreases in serum
cholesterol (-19—22%). Although decreases in serum cholesterol were also statistically
significant (p < 0.05) in low- and mid-level females, the researchers reported that the observed
cholesterol levels in these groups were similar to contemporary female control groups.
Urinalysis revealed no marked treatment-related effects.
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Table 2. Selected Changes in Sprague Dawley Rats Exposed to Methyl
Acetate by Nose-Only Inhalation for 6 Hours/Day, 5 Days/Week, for 28 Days

Exposure in ppm (mg/m3)
Control
75 (227)
350 (1060)
2000 (6060)
Males
Number of animals examined
10
10
10
10
Terminal body weight (g)
277.7 ± 18.3a
275.3 ± 16.9
280.3 ± 19.0 (9)
249.5 ± 16.3b
Average daily food intake (g)
20.2 ± 1.44 (80)
20.0 ± 1.51 (80)
20.5 ± 1.63 (79)
16.7 ± 1.75 (80)°
Hematology
RBC (1012/L)
8.39 ±0.21
8.37 ± 0.26 (9)
8.29 ±0.35 (8)
8.87 ± 0.27 (8)b
Hemoglobin (g/L)
158 ±4
161 ±4 (9)
160 ± 7 (8)
169 ± 5 (8)b
Hematocrit (fraction)
0.46 ±0.01
0.46 ±0.01 (9)
0.46 ± 0.02 (8)
0.48 ±0.01 (8)b
WBC (109/L)
11.6 ± 1.7
9.9 ± 1.6(9)
11.3 ±2.9 (8)
7.7 ± 2.2 (8)b
Clinical chemistry
Calcium (mmol/L)
2.46 ± 0.07
2.48 ±0.06
2.43 ±0.05
2.53 ± 0.06b
Cholesterol (mmol/L)
2.36 ±0.15
2.31 ±0.23
2.29 ±0.24
1.90 ± 0.18b
Organ weights
Adrenal, absolute (g)
0.0428 ± 0.0079
0.0384 ±0.0052
0.0400 ± 0.0052 (9)
0.0508 ±0.0081 (9)b
Adrenal, relative (%)
0.016 ±0.003
0.014 ±0.002
0.014 ± 0.002 (9)
0.020 ± 0.003 (9)b
Nonneoplastic lesions




Degeneration of olfactory
epithelium (incidence)
0/10d
0/10
0/10
10/10be
Females
Number of animals examined
10
10
10
10
Terminal body weight (g)
204.6 ± 10.6a
204.9 ± 10.4
204.6 ±9.9
198.9 ±8.5
Average daily food intake (g)
15.0 ±0.81 (80)
15.3 ± 1.03 (80)
15.2 ±0.85 (80)
13.6 ± 1.13 (80)b'°
Hematology
RBC (1012/L)
7.87 ±0.23
8.04 ± 0.20
7.85 ±0.20
8.29 ± 0.34b
Hemoglobin (g/L)
148 ±3
152 ±4
149 ±4
156 ± 4b
Hematocrit (fraction)
0.42 ±0.01
0.43 ± 0.02
0.42 ±0.01
0.44±0.01b
WBC (109/L)
9.6 ± 1.6
9.9 ± 1.8
8.9 ± 1.4
7.2 ± 1.5b
Clinical chemistry
Calcium (mmol/L)
2.52 ±0.05
2.53 ±0.05
2.49 ±0.05
2.56 ± 0.06b
Cholesterol (mmol/L)
2.22 ±0.09
2.07 ± 0.23b
2.01 ± 0.1 lb
1.73 ± 0.32b
Organ weights




Adrenal, absolute (g)
0.0530 ±0.0065
0.0537 ±0.0094
0.0611 ±0.0080b
0.0640 ± 0.0063b
Adrenal, relative (%)
0.2600 ± 0.0373
0.2624 ± 0.0454
0.2993 ± 0.0428b
0.3222 ±0.0337b
Thymus, absolute (g)
0.288 ± 0.067
0.266 ± 0.087
0.247 ± 0.085
0.212 ±0.080b
Thymus, relative (%)
0.140 ±0.032
0.130 ±0.038
0.120 ±0.040
0.108 ±0.041b
Nonneoplastic lesions
Degeneration of olfactory
epithelium (incidence)
0/10d
0/10
0/10
9/10be
aMean ± standard deviation (n. if different from group size).
bSignificantly different from control atp< 0.05.
Statistical analysis performed for this review (t-test atp< 0.05).
dNumber affected/number examined.
Statistical analysis performed for this review (Fisher exact test at p< 0.05).
Source: Hofmann (1999).
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Organ weight changes were generally consistent with the observed decrease in body
weight (small, scattered decreases in absolute weight and/or increases in relative weight in a
number of organs), except for larger (approximately 20%) increases in absolute and relative
adrenal weights in both sexes (mid-dose and high-dose in females) and decreases in absolute and
relative thymus weight in females. The researchers considered it likely that the increased adrenal
weights reflected stress in the exposed animals. No gross pathology was observed.
Histopathological examination revealed no marked changes in the adrenals, thymus, or other
tissues, except for degeneration of the olfactory epithelium (Grade 3 indicating moderate
change), which was observed in nearly all high-dose animals in both sexes but not in lower-dose
animals (see Table 2). For this study, a LOAEL of 2000 ppm (6060 mg/m3) and a NOAEL of
"3
350 ppm (1060 mg/m ) are identified for reduced body weight and food consumption, changes in
organ weights, hematology and clinical chemistries, and olfactory epithelial degeneration in rats.
Toxicokinetics
There are very few data available describing the absorption, distribution, metabolism, or
elimination of methyl acetate in humans or animals. None of the available data are sufficient for
estimating rates of chemical uptake or elimination (via excretion or metabolism), or extent of
hydrolysis. Methyl acetate is hydrolyzed to methanol, as was shown for glycol ether acetates
that are hydrolyzed to their parent alcohols in aqueous solution (Miller et al., 1984, 1983;
Nagano et al., 1979). In vitro hydrolysis of methyl acetate is a reversible reaction; two products
are methanol and acetic acid as follows (Mizunuma et al., 1992):
MeAc + H20 ~ HAc + MeOH (aq.)
Henderson and Haggard (1943; also cited in ACGIH, 2001) suggested that the methanol formed
by hydrolysis of methyl acetate in the human body might be responsible for its toxicity: "Methyl
acetate is the most soluble of the series [of esters of organic acids]. Its hydrolysis in the body
yields methyl alcohol. The concentration inhaled for prolonged periods should, therefore, be
regulated with the toxicity of methyl alcohol in mind." Acute physiological action includes mild
irritation and some anesthetic effects. The authors claimed that the "vapors on absorption, and
probably to some extent on surface tissues as well, are largely hydrolyzed, with the liberation of
the acid and the primary alcohol. Any anesthetic effects developed are due to the alcohol."
Two studies in humans and rabbits, respectively, indicate that methanol is produced in
both species (human and rabbit) following exposure to methyl acetate. Tada et al. (1974, also
cited in U.S. EPA, 1986) exposed two volunteers (33 and 48 years old) to 200 ppm (606 mg/m3)
methyl acetate for 2 hours twice daily for 4 days. Urine samples were collected throughout the
4-day study and analyzed for methanol. Urinary methanol, measured in the two subjects for
27 days prior to exposure, ranged from approximately 0.5 to 4.5 mg/L. Peak urinary methanol
levels occurred each day following the second exposure, ranging from 10 to 15 mg/L. In rabbits,
oral administration (dose unknown, article in Japanese) of methyl acetate resulted in hydrolysis
to methanol and acetic acid (Tambo, 1973, also cited in U.S. EPA, 1986). Tambo (1973)
concluded, "Occurrence of alcohol became cause of [tjhinner drunkenness. Occurrence of acetic
acid in blood became cause of acidosis." They also stated that paint thinner, which contains
methyl acetate, "evaporates at mean temperature and is readily absorbed into the lung."
However, acidosis is only of concern by acetic acid at very high doses, and the half-life of acetic
acid is short at low doses.
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Genotoxicity
Zimmerman et al. (1985) reported that methyl acetate induces chromosomal aneuploidy,
but not recombination or point mutations, in the diploid yeast, Saccharomyces cerevisiae. No
other studies are identified for in vitro or in vivo genotoxic effects of methyl acetate in animal or
humans.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL
RFD VALUES FOR METHYL ACETATE
Due to a lack of data, no chronic or subchronic p-RfDs are developed. However, the
appendix of this document contains a screening p-RfD based on an analog treatment, which may
be useful in certain instances. Please see Appendix A for details.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC INHALATION
RFC VALUES FOR METHYL ACETATE
Because the toxicity data based on a Toxic Substances Control Act (TSCA) study
(Hofmann, 1999) are not peer reviewed, no chronic or subchronic p-RfCs are developed.
However, the appendix of this document contains a screening subchronic p-RfC that may be
useful in certain instances. Please see Appendix A for details.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR METHYL ACETATE
WEIGHT-OF-EVIDENCE DESCRIPTOR (WOE)
No human or animal data are available to inform on the carcinogenicity of methyl
acetate. The database for methyl acetate does not contain a chronic bioassay sufficient for
derivation of an oral cancer slope factor or inhalation unit cancer risk. In addition, the 1993 IRIS
summary for methanol (U.S. EPA, 1993) did not conduct a qualitative cancer assessment.
According to the EPA (2005) Guidelines for Carcinogen Risk Assessment, there is "Inadequate
Information to Assess Carcinogenic Potential" for methyl acetate.
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK
Derivation of quantitative estimates of cancer risk for methyl acetate is precluded by the
lack of available data. In addition, because the 1993 IRIS summary for methanol (U.S. EPA,
1993) did not provide a quantitative cancer assessment, a screening p-OSF cannot be derived
based on analogy to methanol for methyl acetate.
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9724-F1F6-975E-7FCE50709CB4C932 (accessed September 15, 2009).
NTP (National Toxicology Program). (2009) Management status report. Available online at
http://ntp. niehs.nih.gov/index.cfm? obi ectid=78CC7E4C-FlF6-975E-72940974DE301C3F
(accessed September 15, 2009).
OSHA (Occupational Safety and Health Administration). (2009) OSHA Standard 1915.1000 for
air contaminants. Part Z, toxic and hazardous substances. Available online at
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table ST WDARDS&p id=102
86 (accessed September 15, 2009).
Tada, O; Nakaaki, K; Fukabori, M. (1974) Method of evaluating the exposure to methanol and
methyl acetate. Rogo Kagaki 50:239-245 (Japanese; Abstract in English) (also cited in
U.S. EPA, 1986).
Tambo, S. (1973) Toxicity hazards of paint thinners with particular emphasis on the metabolism
and toxicity of acetate esters. Nichidal Igaku Zasshi 32:349-360 (Japanese; Abstract in English)
(also cited in U.S. EPA, 1986).
Toxicity Research Laboratory. (1986) Rat oral subchronic toxicity study with methanol. Office
of Solid Waste, U.S. Environmental Protection Agency (as cited in U.S. EPA, 1986).
U.S. EPA (Environmental Protection Agency). (1986) Health and environmental effects profile
for methyl acetate. Prepared by the Office of Health and Environmental Criteria and
Assessment, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC. ECAO-CIN-P205.
U.S. EPA (U.S. Environmental Protection Agency). (1988) Recommendations for and
documentation of biological values for use in risk assessment. Cincinnati, OH.
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U.S. EPA (Environmental Protection Agency). (1991) Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC.
U.S. EPA (Environmental Protection Agency). (1993) Integrated Risk Information System
(IRIS). IRIS Summary of Methanol (CASRN 67-56-1). Office of Research and Development,
National center for Environmental Assessment, Washington, DC. Available online at
http://www.epa.gov/iri s/. (Accessed January 2010).
U.S. EPA (Environmental Protection Agency). (1994a) Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC.
U.S. EPA (Environmental Protection Agency). (1994b) Methods for derivation of inhalation
reference concentrations and application of inhalation dosimetry. Office of Research and
Development. Washington, DC. EPA/600/8-90/066F.
U.S. EPA (Environmental Protection Agency). (1997) Health Effects Assessment Summary
Tables (HEAST). FY-1997 update. Prepared by the Office of Research and Development,
National Center for Environmental Assessment, Cincinnati OH for the Office of Emergency and
Remedial Response, Washington, DC. EPA/540/R-97/036. NTIS PB97-921199.
U.S. EPA (Environmental Protection Agency). (2005) Guidelines for carcinogen risk assessment.
Risk Assessment Forum, Washington, DC; EPA/630/P-03/001F. Federal Register 70(66):
17765-17817.
U.S. EPA (Environmental Protection Agency). (2006) 2006 Edition of the drinking water
standards and health advisories. Office of Water, Washington, DC. EPA 822-R-06-013.
Washington, DC. Available online at http://www.epa.gov/waterscience/drinkine/standards/
dwstandards.pdf (accessed September 15, 2009).
U.S. EPA (Environmental Protection Agency). (2010) Integrated Risk Information System
(IRIS). Office of Research and Development, National Center for Environmental Assessment,
Washington, DC. Available online at http://www.epa.gov/iris/ (accessed January 12, 2010).
WHO (World Health Organization). (2009). Online catalogs for the Environmental Health
Criteria series. Available online at
http://www.who.int/ipcs/publications/ehc/ehc alphabetical/en/index.html (accessed September
15, 2009).
Zimmerman, FK; Mayer, VW; Schell, I; et al. (1985) Acetone, methyl ethyl ketone, ethylacetate,
acetonitrile, and other polar aprotic solvents are strong inducers of aneuploidy in Saccharomyces
cerevisiae. MutatRes 149:339-351.
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APPENDIX A. DERIVATION OF A SCREENING VALUE
FOR METHYL ACETATE
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for methyl acetate. However, information is available for this chemical, which,
although insufficient to support derivation of a provisional toxicity value, under current
guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health Risk
Technical Support Center (STSC) summarizes available information in an appendix and
develops a "screening value." Appendices receive the same level of internal and external
scientific peer review as the PPRTV documents to ensure their appropriateness within the
limitations detailed in the document. Users of screening toxicity values in an appendix to a
PPRTV assessment should understand that there is considerably more uncertainty associated
with the derivation of an appendix screening toxicity value than for a value presented in the body
of the assessment. Questions or concerns about the appropriate use of screening values should
be directed to the STSC.
ORAL STUDIES
Screening Provisional Reference Dose (p-RfD)
No oral data are available for subchronic or chronic exposure of animals or humans to
methyl acetate. However, methyl acetate can be extensively hydrolyzed to methanol in the body
(in aqueous phase). Formation of methanol from methyl acetate has been observed in humans
(Tada et al., 1974) and in rabbits (Tambo, 1973). Oral data for methanol are available and have
been used previously by EPA to develop an assessment for methyl acetate. Previously, EPA
(1986) derived a chronic RfD of 1 mg/kg-day for methyl acetate by analogy to methanol. This
was accomplished by multiplying an RfD of 0.5 mg/kg-day for methanol by the methyl
acetate-to-methanol molecular weight ratio of 74.08 g/mol ^ 32.04 g/mol = 2.312 (U.S. EPA,
1986). The critical effect is based on increased serum alkaline phosphatase (SAP) and serum
glutamic pyruvic transaminase (SGPT), and decreased brain weight (U.S. EPA, 1993).
In the 1993 IRIS summary for methanol, the POD (500 mg/kg-day) was divided by a
composite UF of 1000, which includes a 10-fold UF for interspecies extrapolation, a 10-fold UF
for intraspecies variability, and a 10-fold UF for extrapolation from subchronic-to-chronic
duration, and the chronic RfD (0.5 mg/kg-day) for methanol was derived (U.S. EPA, 1993).
Because of the similar toxicity profiles between methyl acetate and methanol as shown in
occupational and in vivo studies (e.g., Tada et al., 1974; Tambo, 1973; Henderson and Haggard,
1943) and by hydrolysis reaction (1 mol of methyl acetate plus 1 mol of water can be converted
into one mol of methanol and 1 mol of acetic acid), a screening chronic p-RfD for methyl acetate
can be derived by analogy to methanol by molecular weight adjustment as follows:
Screening Chronic p-RfD =	IRIS RfD (methanol) x (MWmethyi acetate ^ MWmethanoi)
(methyl acetate) =	0.5 mg/kg-day x (74.08 g/mol ^ 32.04 g/mol)
=	0.5 mg/kg-day x 2.312
=	1 mg/kg-day
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Because the screening chronic p-RfD for methyl acetate was derived explicitly from
those of methanol, the uncertainties associated with the POD for methanol and confidence in the
principal study and database for methanol all contribute to uncertainty for methyl acetate as well.
For methanol, the confidence in the study, database, and RfD are medium, low, and medium,
respectively. According to EPA (1993):
The principal study was well-designed and provided adequate toxicological
endpoints, but the method of administration was not ideal. The overall database
is weak, lacking data on reproductive, developmental, or other toxicological
endpoints. The RfD is given a medium confidence rating because of the strengths
of the principal study.
Notably, a UF for database deficiency was not applied at time. For methyl acetate, based on the
1993 IRIS summary, there is additional uncertainty due to the reliance on data for methanol to
obtain an assessment. Therefore, the overall confidence in the screening chronic p-RfD for
methyl acetate is low.
INHALATION STUDIES
Screening Provisional Reference Concentration (p-RfC)
No human toxicity studies of methyl acetate are available. The only available animal
study is for nose-only inhalation exposure of rats to 0, 75, 350, or 2000 ppm (0, 227, 1060, or
6060 mg/m3) for 6 hours/day, 5 days/week, for 28 days (Hofmann, 1999) (see Table 2). This
study was submitted to TSCA and has not been peer-reviewed. In this study, no toxicologically
relevant changes were seen at <350 ppm (1060 mg/m ). Systemic effects, including changes in
body weight, food consumption, hematology, clinical chemistries, and organ weights, occurred at
2000 ppm (6060 mg/m ). In this report, body-weight decrease is considered both biologically
and statistically significant (p < 0.05) with a 10% decrease at the highest dose in male rats
-3
(6060 mg/m ). Degeneration of the nasal epithelium was seen in 10/10 males and 9/10 females
at this same exposure level.
Unlike the systemic effects, changes to the nasal epithelium are considered
portal-of-entry effects. For this reason, human equivalent concentrations (HECs) were
calculated differently for nasal epithelium degeneration versus systemic effects, as described by
EPA (1994b). Table A-l shows the HECs for both the nasal and systemic effects.
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Table A-l. Summary of Inhalation Study of Methyl Acetate in Animals
Species and Study
Type
(«/sex/group)
Exposure
NOAEL
LOAEL
Responses at the LOAEL
Reference
Rats
Subacute
Nose-only
Inhalation
Groups of male and
female Sprague-
Dawley rats
(10/sex/group)
exposed to 0, 75,
350, or 2000 ppm,
6 hrs/d, 5 d/wk, for
4 wks
350 ppm
(1060 mg/m3)
HEC: 189 mg/m3
(for systemic effects)
HEC: 31 mg/m3
(for nasal effects)
2000 ppm
(6060 mg/m3)
HEC: 1082 mg/m3
(for systemic effects)
HEC: 180 mg/m3
(for nasal effects)
Reduced body-weight gain and food
consumption, and changes in organ weights and
hematology and clinical chemistry endpoints at
2000 ppm.
Degeneration of the olfactory epithelium at
2000 ppm.
Hofmann, 1999
HEC for systemic effects derived using EPA (1994b) equations for a Category 3 gas:
NOAELhec = NOAELadj x[(Hb/g)A (Hb/g)H],
where NOAELadj = NOAEL x (6 hours ^ 24 hours) x (5 days ^ 7 days) and
(Hb/g)A (Hb/g)H, the ratio of animal to human blood:air partition coefficients, is set to 1 by default (see text).
HEC for respiratory effects derived using EPA (1994b) equations for a Category 1 gas:
NOAELhec = NOAELadj x [(Ve/SAEt )a"=" (Ve/SAEt)hL
where NOAELadj = NOAEL x (6 hours ^ 24 hours) x (5 days ^ 7 days) and
(Ve/SAEt )a (VE /SA|.:t)||. the ratio of animal and human inhalation minute volumes (VE in L/min), normalized to tissue surface area of the
extrathoracic region (SAET, cm2), is 0.166 (see text for calculation).
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For degeneration of the nasal epithelium,
NOAELadj = NOAEL x (6 hours ^ 24 hours) x (5 days ^ 7 days)
NOAELhec,cati = NOAELadj x [(Ve ^ SAet)a ^ (Ve ^ SAet)h]
where NOAELheccati was calculated as the dosimetric adjustment from the NOAELadj in
animals (189 mg/m ) to a NOAEL in humans based on treatment of methyl acetate as a
Category 1 gas exhibiting extrathoracic effects. This was accomplished by multiplying the
NOAELadj by the ratio of animal and human inhalation minute volumes (VEin L/minute),
normalized to tissue surface area of the extrathoracic region (SAET in cm2) (U.S. EPA, 1994b).
The minute volume used for humans was 13.8 L/minute (U.S. EPA, 1994b). For rats, the minute
volume was calculated as
ln(VE) = b0 + b,ln(BW)
For rats, bo equals -0.578, bi equals 0.821, and a reference body weight of 0.236 kg (average for
male and female Sprague-Dawley rats in a subchronic study; U.S. EPA, 1988) was used,
resulting in a Ve value of 0.171 L/minute. The values used for surface area for extrathoracic
tissues of rats and humans were 15 and 200 cm , respectively (U.S. EPA, 1994b). Thus, using a
NOAEL of 6060 mg/m3, the NOAELhec,cati is calculated as follows:
NOAELhec,cati = 189 mg/m3 x [(0.171 mg/m3 - 15) - (13.8 - 200)]
NOAELhec,cati =31 mg/m3
Similarly, for systemic effects:
NOAELHec,cat3 = NOAELadj x [(Hb/g)A ^ (Hb/g)n)]
where NOAELhec,cat3 is calculated as the dosimetric adjustment from the NOAELadj in
animals to a NOAEL in humans based on treatment of methyl acetate as a Category 3 gas
exhibiting remote, extrarespiratory effects. This was accomplished by multiplying the
NOAELadj by the ratio of animal and human blood:gas (air) partition coefficients (Hb/g)
(U.S. EPA, 1994b). Blood:air partition coefficients were measured by Kaneko et al. (1994) for
methyl acetate in humans (90.1) and rats (100). Because the ratio of rat and human blood:air
partition coefficients is 100 90.1 > 1.0, the default value of 1 is applied to the NOAELadj-
Thus, the NOAELhec,cat3 is equal to the NOAELadj of 189 mg/m .
The NOAELhec,cati for nasal lesions of 31 mg/m is approximately 7-fold lower than the
NOAELHec,cat3 of 189 mg/m3 for systemic effects. In addition, examination of the data on
body-weight decrease in male rats (see Table 2) shows that the change rises deeply from 0.8% at
227 mg/m3 to 0.9% at 1060 mg/m3 to 10% at 6060 mg/m3 (LOAEL). Because there is a lack of
dose-response at lower doses and only a biological response at 10% at the highest dose,
benchmark dose (BMD) modeling was not conducted on this data set. Therefore, degeneration
of nasal epithelium from the 28-day exposure in rats (Hofmann, 1999) was selected as the critical
effect for inhaled methyl acetate.
Similarly, examination of the data on nasal lesions in rats (see Table 2) shows that the
incidence rises steeply from 0/10 in the control, low-, and mid-dose groups to 9/10 or 10/10 for
females and males, respectively at the LOAEL. Because there is no exposure level at which the
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incidence of this effect is significantly less than 100% (lack of dose-response at lower doses),
BMD modeling was not conducted on this data set. Thus, a LOAEL/NOAEL approach was used
to derive the screening subchronic p-RfC for methyl acetate, using the NOAELhec,cati of
31 mg/m3 for nasal lesions in rats as the POD.
The screening subchronic p-RfC for methyl acetate is derived as follows:
Screening Subchronic p-RfC = NOAELhec UF
= 31 mg/m3 300
= 0.1 or 1 x 10"1 mg/m3
The composite UF of 300 is composed of the following:
•	UFh: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because data for evaluating susceptible human response are
insufficient.
•	UFa: A factor of 3 is applied to account for interspecies extrapolation
(toxicodynamic portion only) because a dosimetric adjustment was made.
•	UFd: A factor of 10 is applied for database deficiencies because data for
inhalation developmental and multigeneration reproduction studies are not
available. The database also lacks any neurotoxicological studies for potential
neurotoxicity.
•	UFl: A factor of 1 is applied for use of a NOAELhec as the POD for derivation of
the RfC.
•	UFs: A factor of 1 is applied for subchronic-to-chronic extrapolation because a
short-term study was used for deriving a subchronic p-RfC.
Confidence in the principal study is medium. The study of Hofmann (1999) is a
well-designed toxicity study in which data for multiple endpoints of toxicity, including
histological examination of a variety of tissues, were provided for rats. However, the study was
only 4 weeks in duration. Confidence in the database is low. The 28-day study of Hofmann
(1999) is the only inhalation toxicity study available. The rat is the only species for which
inhalation toxicity data exist. No subchronic, chronic, reproductive, or developmental toxicity
data in animals are available. Given medium confidence in the principal study and low
confidence in the database, confidence in the screening subchronic p-RfC is low.
A screening chronic p-RfC for methyl acetate is not derived due to lack of subchronic or
chronic inhalation data.
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