United States
Environmental Protection
1=1 m m Agency
EPA/690/R-13/013F
Final
5-06-2013
Provisional Peer-Reviewed Toxicity Values for
Ethyl Acetate
(CASRN 141-78-6)
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
Carrie R. Fleming, PhD
National Center for Environmental Assessment, Cincinnati, OH
CONTRIBUTOR
Jason C. Lambert, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Audrey Galizia, DrPH
National Center for Environmental Assessment, Washington, DC
Suryanarayana V. Vulimiri, BVSc, PhD, DABT
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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CONTENTS
COMMONLY USED ABBREVIATIONS ii
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVS 1
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) 4
HUMAN STUDIES 7
Oral Exposures 7
Inhalation Exposures 7
ANIMAL STUDIES 7
Oral Exposures 7
Inhalation Exposures 8
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 13
Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity 17
DERIVATION 01 PROVISIONAL VALUES 20
DERIVATION OF ORAL REFERENCE DOSES 21
Derivation of Subchronic Provisional RfD (Subchronic p-RfD) 21
Derivation of Chronic RfD (Chronic RfD) 24
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 24
Derivation of Subchronic Provisional RfC (Subchronic p-RfC) 24
Derivation of Chronic Provisional RfC (Chronic p-RfC) 26
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR 29
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 29
Derivation of Provisional Oral Slope Factor (p-OSF) 29
Derivation of Provisional Inhalation Unit Risk (p-IUR) 29
APPENDIX A. PROVISIONAL SCREENING VALUES 30
APPENDIX B. DATA TABLES 31
APPENDIX C. BMD OUTPUTS 32
APPENDIX D. REFERENCES 33
l
Ethyl acetate
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMCL
benchmark concentration lower bound 95% confidence interval
BMD
benchmark dose
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
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
POD
point of departure
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
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
ETHYL ACETATE (CASRN 141-78-6)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database flittp://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (www.epa.eov/iris). the respective PPRTVs are removed
from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents and appropriate use of this PPRTV assessment should
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).
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INTRODUCTION
Ethyl acetate (CASRN 141-78-6)—also known as acetic acid, ethyl ester—is a clear,
volatile, flammable liquid having a characteristic fruity odor and a reportedly pleasant taste when
diluted. Ethyl acetate is a naturally occurring constituent of plants and is found in a wide variety
of commonly consumed fruits, such as apples, bananas, and nectarines. It is used industrially as
a solvent for lacquers, paints, and inks, and as an inert ingredient in pesticides as a solvent,
cosolvent, or attractant. It is also used by the pharmaceutical industry as a flavoring agent. Ethyl
acetate is included in 21 CFR 182.60 (U.S. FDA, 2010) as a "substance generally recognized as
safe." The structure of ethyl acetate is shown in Figure 1, and selected physicochemical
properties of ethyl acetate are provided in Table 1.
O
Figure 1. Ethyl Acetate Structure
Table 1. Physicochemical Properties of Ethyl Acetate (CASRN 141-78-6)
Property (unit)
Value
Molecular formula
C4H802a
Boiling point (°C)
77. ia
Melting point (°C)
-83.6a
Density (g/cm3 at 20°C)
0.902b
Vapor pressure (mm Hg at 25°C)
93.2a
pH (unitless)
ND
Solubility in water (mg/L at 25°C)
8.0 x 104a
Relative vapor density (air =1)
3.04b
Molecular weight (g/mol)
88.1 lb
aNLM (2011).
bU.S. EPA (2006).
ND = no data.
A summary of available health-related values for ethyl acetate from U.S. EPA and other
agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for Ethyl Acetate (CASRN 141-78-6)
Source/Parameter"
Value
(Applicability)
Notes
Reference
Date Accessed
Noncancer
ACGIH
TLV-TWA:
1440 mg/m3
(400 ppm)
To provide "an occupational
exposure value with a significant
safety factor from the standpoint of
adverse health effects."
ACGIH, 1991
9-26-2012
ATSDR
NV
NA
ATSDR, 2011
9-26-2012
CalFPA
NV
NA
CalEPA. 2008,
2009a
9-26-2012
NIOSH
REL-TWA:
1440 mg/m3
(400 ppm)
IDLH: 10,000 ppm
(35,963 mg/m3)
NA
NIOSH, 2005
9-26-2012
OSHA
PEL-TWA:
1440 mg/m3
(400 ppm)
NA
OSHA, 2011
9-26-2012
IRIS
RfD:
9 x 10 1 mg/kg-d
Based on mortality and body-weight
loss
U.S. EPA, 1988
9-26-2012
Drinking water
NV
NA
U.S. EPA, 2011a
9-26-2012
HEAST
Subchronic RfD:
9 x 10° mg/kg-d
NA
U.S. EPA, 2003
9-26-2012
CARA HEEP
NV
A profile was available in an earlier
version of HEEP (U.S. EPA, 1986a)
U.S. EPA, 1994a
9-26-2012
WHO
NV
NA
WHO, 2011
9-26-2012
Cancer
IRIS
NV
NA
U.S. EPA, 1988
9-26-2012
HEAST
NV
NA
U.S. EPA, 2003
9-26-2012
IARC
NV
NA
IARC, 2011
9-26-2012
NTP
NV
NA
NTP, 2011
9-26-2012
CalEPA
NV
NA
CalEPA (2009b)
9-26-2012
aSources: Integrated Risk Information System (IRIS) database; Health Effects Assessment Summary Tables
(HEAST); International Agency for Research on Cancer (IARC); National Toxicology Program (NTP); California
Environmental Protection Agency (CalEPA); American Conference of Governmental Industrial Hygienists
(ACGIH); Agency for Toxic Substances and Disease Registry (ATSDR); National Institute for Occupational Safety
and Health (NIOSH); Occupational Safety and Health Administration (OSHA); Chemical Assessments and Related
Activities (CARA) list; Health and Environmental Effects Profile (HEEP); World Health Organization (WHO).
IDLH= immediately dangerous to life or health; NA = not applicable; NV = not available; PEL-TWA = permissible
exposure level-time weighted average; REL-TWA = recommended exposure level-time weighted average;
TLV-TWA = threshold limit value-time weighted average.
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Literature searches were conducted on sources published from 1900 through
September 2012, for studies relevant to the derivation of provisional toxicity values for ethyl
acetate, CASRN 141-78-6. Searches were conducted using U.S. EPA's Health and
Environmental Research Online (HERO) database of scientific literature. HERO searches the
following databases: AGRICOLA; American Chemical Society; BioOne; Cochrane Library;
DOE: Energy Information Administration, Information Bridge, and Energy Citations Database;
EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government Printing Office;
Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR: Mathematics
& Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through the National
Service Center for Environmental Publications (NSCEP) and National Environmental
Publications Internet Site (NEPIS) database); PubMed: MEDLINE and CANCERLIT databases;
SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET (Toxicology Data Network):
ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP,
GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER, LactMed, Multi-Database Search,
NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI, and TSCATS; Virtual Health Library; Web
of Science (searches Current Content database among others); World Health Organization; and
Worldwide Science. The following databases outside of HERO were searched for health-related
values: ACGM, AT SDR, CalEPA, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA HEEP,
U.S. EPA OW, U.S. EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 3 provides an overview of the relevant database for ethyl acetate and includes all
potentially relevant repeated short-term-, subchronic-, and chronic-duration studies. The term
"significance" used throughout the document indicates ap-walue of <0.05, unless otherwise
indicated.
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Table 3. Summary of Potentially Relevant Data for Ethyl Acetate (CASRN 141-78-6)
Category
Number of Male/Female,
Strain, Species, Study
Type, Study Duration
Dosimetry"
Critical Effects
NOAEL"
BMDL/
BMCLa
LOAEL"
Reference
(Comments)
Notesb
Human
1. Oral (mg/kg-d)a
Acute0
ND
Short-termd
ND
Long-term6
ND
Chronicf
ND
2. Inhalation (mg/m3)a
Acute0
1 male, 39-yr-old, case
study, duration unknown
NDr
Mortality
NDr
NDr
NDr
Coopman et al.
(2005)
PR
Short-termd
ND
Long-term0
ND
Chronicf
ND
Animal
1. Oral (mg/kg-d)a
Subchronic
30/30 S-D rats, gavage
(7d/wk), 93 d
Interim sacrifice of
10/10 rats at 44-45 d
0, 300, 900, or
3600 mg/kg-d
(Adjusted)
Clinical signs, including increased
salivation, irregular breathing, and
lethargy in both sexes
900
DU
3600
American
Biogenics Corp.
(1986)
PS,
IRIS,
NPR
Chronic
ND
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
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Table 3. Summary of Potentially Relevant Data for Ethyl Acetate (CASRN 141-78-6)
Category
Number of Male/Female,
Strain, Species, Study
Type, Study Duration
Dosimetry"
Critical Effects
NOAEL3
BMDL/
BMCLa
LOAEL3
Reference
(Comments)
Notesb
2. Inhalation (mg/m3)a
Short-term
10/5 CD rat, whole-body
inhalation, 6 h/d, 5 d/wk,
2 wk
0, 959, 1973, or
3877 mg/m3
Decreased food consumption (both
sexes)
NDr
DU
959
Burleigh-Flayer
etal. (1995)
NPR
Subchronic
12 or 18 S-D rats/sex, 6 h/d,
5 d/wk, 13 wk, with a 4-wk
recovery period
0, 209, 448, or
896 mg/m3
Decreased body weights, body-weight
gains, food efficiency, and startle
response (both sexes), and decreased
food consumption (males)
209
DU
448
Christoph et al.
(2003)
PS, PR
Subchronic
10/0 S-D rats, whole-body
inhalation, 6 h/d, 5 d/wk,
89 d for a total of
65 exposures
0, 225, 483, or
965 mg/m3
Animals were evaluated specifically for
alterations in operant behavior. Changes
in operant testing results were not clearly
treatment related
965
DU
NDr
Christoph (1997)
and
Christoph et al.
(2003)
PR
Subchronic
3 Guinea pigs (number/sex
not specified), 4 h/d,
6-7 d/wk, duration not
reported (total of
65 exposures)
1030 mg/m3
None
1030
DU
NDr
Smyth and Smyth
(1928)
PR
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
""Dosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to an adjusted daily dose (ADD in mg/kg-d) for oral noncancer effects and a human equivalent
concentration (HEC in mg/m3) for inhalation noncancer effects. All long-term exposure values (4 wk and longer) are converted from a discontinuous to a continuous
(weekly) exposure. Values from animal developmental studies are not adjusted to a continuous exposure.
HECexresp = (ppm x MW ^ 24.45) x (hours per day exposed ^ 24) x (days per week exposed ^ 7) x blood:air partition coefficient.
bNotes: IRIS = Utilized by IRIS, 1988; PS = principal study, PR = peer reviewed, NPR = not peer reviewed.
0 Acute = Exposure for 24 hours or less (U.S. EPA, 2002).
dShort-term = Repeated exposure for >24 h <30 d (U.S. EPA, 2002).
"Long-term = Repeated exposure for >30 d <10% lifespan (based on 70 years typical lifespan) (U.S. EPA, 2002).
fChronic = Repeated exposure for >10% lifespan (U.S. EPA, 2002).
DU = data unsuitable, NA = not applicable, NV = not available, ND = no data, NDr = not determinable, NI = not identified, NP = not provided, NR = not reported,
NR/Dr = not reported but determined from data, NS = not selected, S-D = Sprague-Dawley.
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HUMAN STUDIES
Oral Exposures
No studies were identified.
Inhalation Exposures
No inhalation exposure studies were found on the short-term, long-term, or chronic
toxicity of ethyl acetate in humans. An acute study was presented by Coopman et al. (2005).
Acute Exposure
Coopman et al., 2005
Coopman et al. (2005) presented a case study of the distribution of ethyl acetate and
ethanol in the tissues of a 39-year-old man following an acute fatal intoxication. The victim was
found dead lying on his abdomen in the interior of a tank containing ethyl acetate. Atmospheric
concentrations of ethyl acetate were not reported. Low ratios of ethyl acetate concentration to
ethanol concentration in tissue samples suggested rapid in vivo hydrolysis of ethyl acetate to
ethanol; a police investigation indicated that the victim had not consumed alcohol within
24 hours of his death. Results regarding tissue distribution of ethyl acetate were confounded by
postmortem penetration through the body surface and possible redistribution.
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure of animals to ethyl acetate were evaluated in one
subchronic-duration study (American Biogenics Corp., 1986).
Subchronic-duration Studies
American Biogenics Corp., 1986
The study by American Biogenics Corp. (1986) is selected as the principal study for
the derivation of the subchronic p-RfD value; it is also the principal study for the chronic
RfD available from IRIS (U.S. EPA, 1988). The original American Biogenics Corp. (1986)
study report could not be obtained; however, study summaries are available in both IRIS
(U.S. EPA, 1988) and HEEP (U.S. EPA, 1986a). Peer-review status of the original study report
is unknown. Tabular data could not be obtained, and standard deviations were not provided.
The following information was indicated in the more detailed HEEP study summary (U.S. EPA,
1986a). The study authors administered ethyl acetate (99.9% purity) in corn oil to
30 Sprague-Dawley rats/sex/group by daily gavage at doses of 0, 300, 900, or 3600 mg/kg-day
for up to 93 days. An interim sacrifice of 10 rats/sex/group was performed on Days 44-45; the
remaining rats were euthanized on Days 91-93. Systemic evaluations including mortality,
clinical signs of toxicity, body-weight gain, food consumption, hematology, clinical chemistry,
urinalysis, and ophthalmoscopic examinations were performed before the interim and terminal
sacrifices. All rats were subjected to a gross necropsy, and major organs (not specified) were
weighed. Comprehensive histological examinations were performed on all control and
3600-mg/kg-day rats that died or were euthanized at study termination. Histological
examinations of the 300- and 900-mg/kg-day rats that died or were euthanized at study
termination were limited to the heart, kidneys, liver, and gross lesions.
Prior to scheduled termination, 2/30 rats died at 900 mg/kg-day, and 7/30 rats died at
3600 mg/kg-day (sex not specified). It was stated that "the deaths of several high-dose rats were
due to pulmonary accident or gavaging trauma" (U.S. EPA, 1986a); therefore, the reported
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mortalities are not considered treatment related. At 3600 mg/kg-day, significantly increased
incidences of salivation, irregular breathing, and lethargy were observed in both sexes, and
significantly reduced body-weight gains were noted in the males. Additionally at this dose,
significant organ-weight changes were observed as follows: in males, decreased absolute spleen
weight, decreased absolute and relative (to brain) kidney weights, decreased absolute and relative
(to body and brain) liver weights, and increased relative (to body) testes weight; and in females,
decreased relative (to body) liver weight. It cannot be determined from the information available
whether the observed decreases in organ and body weights were treatment related or attributable
to the early accidental deaths (for which body and organ weights were recorded at the time of
death). No other changes were described in the available summaries (U.S. EPA, 1986a, 1988).
A LOAEL of 3600 mg/kg-day and a corresponding NOAEL of 900 mg/kg-day is
identified based on clinical observations of toxicity, including increased salivation, irregular
breathing, and lethargy in both sexes.
Chronic-duration Studies
No studies were identified.
Developmental Studies
No studies were identified.
Reproductive Studies
No studies were identified.
Carcinogenicity Studies
No studies were identified.
Inhalation Exposures
The effects of inhalation exposure of animals to ethyl acetate have been evaluated in one
short-term study (Burleigh-Flayer et al., 1995) and two subchronic-duration studies
(Christoph et al., 2003; Smyth and Smyth, 1928).
Short-term Studies
Burleigh-Flayer et al., 1995
In a nonpeer-reviewed study, Burleigh-Flayer et al. (1995) exposed groups of CD rats
(10 males/5 females per group) to ethyl acetate (>99% purity) by whole-body inhalation at
nominal concentrations of 0, 1500, 3000, or 6000 ppm (analytical concentrations: 0, 1491, 3066,
and 6024 ppm) for 6 hours/day, 5 days/week for 2 weeks. Analytical concentrations have been
converted to human equivalent concentrations (HECs) based on the following equation:
CONChec = CONCppm x (molecular weight ^ 24.45) x (hours exposed ^ 24 hours) x (days
exposed ^ 7 days) x Blood: Air Partition Coefficient Ratio. The values for the human and rat
blood:air partition coefficients are unknown, so the default ratio of 1 was applied. The applied
concentrations of 0, 1491, 3066, and 6024 ppm correspond to HECs of 0, 959, 1973, and
3877 mg/m , respectively. The male rats were further subdivided into two groups of five rats
each to undergo separate feeding regimens: either ad libitum or on a restricted basis to maintain
their body weight at approximately 300 g. All females were fed ad libitum. The results
presented below are from the animals fed ad libitum only. A functional observational battery
(FOB) and motor activity testing were performed prior to the start of exposure and at the end of
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the first and second weeks of exposure. Clinical signs, body weights, food consumption, and
water consumption were reported at several time points during the exposure period. All rats
received a complete necropsy at study termination, and absolute and relative (to body) organ
weights were reported for liver, kidneys, lungs, heart, spleen, brain, adrenal glands, testes, and
ovaries.
All animals survived to scheduled termination (Burleigh-Flayer et al., 1995). Clinical
"3
signs were observed at 1973 and 3877 mg/m ; they included hypoactivity, blepharospasm
(abnormal contraction or twitch of the eye), and a lack of a startle reflex. In males, body weights
were decreased in a concentration-dependent manner but were only statistically significant on
Day 12 at 1973 (8% change) and 3877 (12% change) mg/m3. In females, no statistically
significant effect was observed on body weights. Significant decreases in food consumption
were observed at all concentrations in males and females; average daily food consumption over
the duration of the study was decreased by 11-22% in males and 16—21% in females. Increased
water consumption was noted in males at 3877 mg/m3 throughout the study but was only
statistically significant during Days 12-13; there appeared to be a concentration-related trend
toward increased water consumption with increased concentration. In the males, absolute spleen
"3
weights were significantly decreased at 1973 and 3877 mg/m , and absolute liver weights were
significantly decreased at 3877 mg/m3; however, there were no statistically significant changes
in relative (to body) weights for these organs. In the females, absolute and relative ovary
weights were significantly decreased at 3877 mg/m3 (21% change in relative ovary weight), and
relative brain weights were increased (8-11%) at all concentrations. Motor activity was also
decreased in females in a concentration-dependent trend, with a statistically significant decrease
"3
at the high-exposure concentration (3877 mg/m ). No statistically significant changes in mean
motor activity were noted in the males, and the data suggested a trend toward increased activity
at the low concentration rather than decreased. The study authors indicated an increased
incidence of several of the endpoints from the FOB. However, these changes were not
statistically significant; importantly, the small sample size may have limited the ability to detect
changes in incidence of observations from the FOB. No treatment-related gross lesions were
noted at necropsy.
A LOAELhec of 959 mg/m is identified based on decreased food consumption in both
sexes. A NOAEL cannot be determined under the conditions of this study. Due to the limited
exposure period (10 days), this study is not considered adequate for derivation of a subchronic
p-RfC.
Subchronic-duration Studies
Christoph et al., 2003
The study by Christoph et al. (2003) is selected as the principal study for the
derivation of the subchronic and chronic p-RfC values. In this peer-reviewed study,
Christoph et al. (2003) exposed Sprague-Dawley rats (Crl:CD®BR; Charles River Laboratories,
Raleigh, NC) to ethyl acetate (99.9% purity) by whole-body inhalation at concentrations of 0
(n = 18/sex), 350 (n = 12/sex), 750 (n = 12/sex), or 1500 (n = 18/sex) ppm for 6 hours/day,
5 days/week for 13 weeks (0, 225, 483, and 965 mg/m HEC, respectively). This exposure
pattern was interrupted for neurobehavioral testing as detailed below; however, rats were
exposed into Week 14 as necessary to ensure that each rat received 65 exposures. Performing
duration adjustment based on 65 doses in 14 weeks instead of 13 weeks results in the following
conservative estimates of the HEC: 0, 209, 448, and 896 mg/m . Mean analytical concentrations
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-3
were equivalent to nominal values when expressed to two significant figures. Three 0.75-m
stainless steel and glass chambers (209, 448, and 896 mg/m3) and one 1.0-m3 chamber (0 mg/m3)
were used for the exposures. Test compound concentrations were determined every 30 minutes
by gas chromatography, and homogeneity of the test atmospheres was confirmed by sampling at
nine locations in the exposure chambers.
Christoph et al. (2003) recorded body weights, food consumption, and food efficiency
(body-weight gain per amount of food consumed) at least once per week throughout exposure.
During each exposure session, startle responses to a sharp sound were scored every 2 hours. An
observer (not blinded to treatment group) made a visual judgment of the vigor of the group
response (excessive, normal, diminished, or no response). Additionally, standard clinical
observations were recorded immediately after each exposure and at weekly intervals prior to
exposure to identify any enduring signs. Neurobehavioral testing was performed prior to study
initiation and during Weeks 4, 8, and 13. The animals were not exposed on the day of
neurobehavioral testing, but at least one exposure day always preceded a neurobehavioral testing
day. Neurobehavioral testing included an FOB, which included subjectively scored observations
made while the rat was inside a cage, being handled, and in an open field arena, and a motor
activity test in which the number of movements and time spent in motion was recorded for each
rat. After the final exposure, six randomly selected rats from each group were prepared for
neuropathological examination of the brain (forebrain, cerebrum, midbrain, pons, medulla, and
cerebellum), spinal cord (cervical and lumbar), sciatic nerve, tibial nerve, gasserian ganglia,
cervical and lumbar dorsal root fibers and ganglia, cervical and lumbar ventral root fibers, and
gastrocnemius muscle. Remaining rats from the 209- and 448-mg/m3 groups were euthanized,
"3
while 12 rats/sex from the control and 896-mg/m groups were monitored for an additional
4-week recovery period; neurobehavioral testing was performed on these animals at the end of
this period (Week 18). No necropsies were performed. A separate experiment involving operant
behavioral training and testing was performed and is discussed below.
Body weights, body-weight gains, food consumption, and food efficiency were analyzed
with Bartlett's test for homogeneity of variance, followed by an analysis of variance (ANOVA)
and a post hoc Dunnett's test to identify treatment groups that differed significantly from the
controls. Although it was not stated whether this study was conducted in compliance with good
laboratory practice (GLP) standards, a separate report detailing the operant behavioral training
and testing only was GLP-compliant (Christoph, 1997).
Body weights were decreased in a concentration-dependent manner and were statistically
significantly lower than controls at >448 mg/m3 in both sexes (Christoph et al., 2003). Body
weights were presented only graphically, but data were digitized from the graph using GetData
Graph Digitizer. The estimated body weights from this digitization are presented in Table B. 1.
Body weights at the end of dosing were 6, 8, and 15% lower than controls in the 209-, 448-, and
896-mg/m3 males, respectively. In females, 4, 10, and 10% reductions were observed. Over the
entire treatment period, body-weight gains were significantly reduced in all treatment groups in
both sexes (decreased 12, 17, and 28% in the males, and 11, 25, and 30% in the females,
respectively; presented by the study authors in text only) compared to the controls. Food
consumption and food efficiency were reported in text only as percent change from control.
Overall (Weeks 0-13) food consumption was significantly decreased by 9 and 13% in the 448-
and 896-mg/m3 males, respectively, and by 8% in the 896-mg/m3 females. Similarly, food
"3
efficiency was significantly decreased by 9, 8, and 17% in the males at 209, 448, and 896 mg/m ,
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"3
respectively, and by 20 and 25% in the females at 448 and 896 mg/m , respectively. The study
authors stated that some evidence of recovery was noted in these parameters in the 896 mg/m3
rats during the 4-week postexposure period.
Exposure to 448 and 896 mg/m resulted in diminished startle responses to unexpected
auditory stimuli during the exposure period, suggesting an acute sedative effect. No signs of
acute intoxication were observed during clinical observations 30 minutes after the exposures
ended. In the neurobehavioral testing performed on nonexposure days, the principal behavioral
effect was reduced motor activity in the 896-mg/m3 females; this effect was no longer present
after a 4-week recovery period. During Week 13, the mean total duration of movements for the
896-mg/m3 females was decreased by 22% (statistically significant) compared to controls, and
the number of movements was decreased (not statistically significant, magnitude of decrease not
reported). All other neurobehavioral parameters and motor activity measurements were similar
to controls, and no nervous system lesions were observed during the neuropathological
examinations.
The small decreases in body-weight gain and food efficiency at 209 mg/m are not
considered biologically significant. The LOAELhec is 448 mg/m3, based on decreased body
weights, food efficiency, and startle response in both sexes, and decreased food consumption in
the males. The NOAELhec is 209 mg/m3.
Christoph et al. also performed operant behavior testing on groups of male
Sprague-Dawley rats in a sub chronic-duration inhalation study Christoph (1997) and
Christoph et al. (2003). Ten male rats/concentration received training to press a lever on a
multiple fixed ratio-fixed interval schedule of reinforcement for 8 weeks, with the fixed ratio and
fixed interval portions of the schedule being indicated by an illuminated light and a continuous
tone, respectively. In order to motivate the rats to perform the behavioral task, these animals had
limited access to food with a target weight range of 280-313 g. The rats were exposed by
whole-body inhalation to ethyl acetate concentrations of 0, 350, 750, or 1500 ppm (0, 225, 483,
or 965 mg/m HEC) for 6 hours/day, 5 days/week, over a period of 89 days for a total of
65 exposures. Operant testing was performed in the morning prior to each exposure session and
continued during a 2-week postexposure evaluation period. The only difference noted between
treated and control groups in the operant testing was a change in the fixed interval response rate;
the response rate drifted down over time in control animals and up over time in all the treated
groups, and results in all three treated groups were similar. Comparison of the 1500-ppm group
to laboratory historical controls revealed that the pattern of increasing fixed interval response
rate over time was typical of control animals from this laboratory. Results for controls and
treated animals were similar for all other endpoints measured in the operant testing. The study
authors concluded that there was no evidence that subchronic-duration exposure to ethyl acetate
"3
at concentrations of up to 1500 ppm (965 mg/m HEC) caused any persistent neurotoxic effects
in rats.
Smyth and Smyth (1928)
In a peer-reviewed study, Smyth and Smyth (1928) exposed three guinea pigs (strain not
provided) to ethyl acetate (purity not specified) by inhalation at a concentration of 2000 ppm
(1030 mg/m3 HEC) for a total of 65 exposures in "gassing jars" (additional details not provided).
It was stated that during the first 2 weeks, the animals were exposed daily, and then "almost
always for 4-hour periods each day for 6 days a week." As the majority of the exposures were
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performed in this fashion, the HEC is calculated using a 4-hour per day, 6-days per week
paradigm. Body weights were recorded at approximately weekly intervals, and blood counts
(erythrocyte count, hematocrit, and absolute and differential lymphocyte counts reported) and
urine examinations (specific gravity reported) were performed every 2 weeks. It was stated that
all three animals "continued in good condition and showed no definite evidence of harm for a
period of 65 exposures." A LOAEL was not observed; the NOAELhec was 1030 mg/m3. This
study was not considered adequate for derivation of a subchronic p-RfC due to deficiencies in
study design and reporting, especially the insufficient description of dosing techniques.
Chronic-duration Studies
No studies were identified.
Developmental Studies
No studies were identified.
Reproductive Studies
No studies were identified.
Carcinogenicity Studies
No studies were identified.
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OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Other studies that are not appropriate for selection of a point of departure (POD) for ethyl acetate and the determination of p-RfD,
p-RfC, provisional oral slope factor (p-OSF), or provisional inhalation unit risk (p-IUR) values may provide supportive data for hazard
identification or dose-response analysis. These studies may include genotoxicity (see Table 4A), as well as metabolism and mechanistic
studies (see Table 4B).
Table 4A. Summary of Ethyl Acetate Genotoxicity Studies
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without
Activation
With
Activation
Genotoxicity studies in prokaryotic organisms
Reverse
mutation
Salmonella typhimurium strains TA92, TA1535,
TA100, TA1537, TA94, and TA98 were
preincubated with ethyl acetate in the presence
of Kanechlor KC-400-induced Fischer rat
S9 liver microsomes, plated, and incubated
overnight.
5 mg/plate
NA
Ethyl acetate was not mutagenic in this
test system.
Ishidate et al.
(1984)
SOS repair
induction
ND
Genotoxicity studies in nonmammalian eukaryotic organisms
Mutation
ND
Recombination
induction
ND
Chromosomal
abberation
ND
Chromosomal
malsegregation
Ethyl acetate was evaluated in Saccharomyces
cerevisiae D61.M yeast cells. The cells were
exposed to the test compound while culturing at
28°C for 4 h, then incubating in an ice bath for
17 h, and finally growing at 28°C again.
2.44%
+
NA
Ethyl acetate induced mitotic aneuploidy.
There was no change in the frequency of
point mutation or mitotic recombination.
Zimmermann
et al. (1985)
Mitotic arrest
ND
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Table 4A. Summary of Ethyl Acetate Genotoxicity Studies
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without
Activation
With
Activation
Genotoxicity studies in mammalian cells—in vitro
Mutation
ND
Chromosomal
aberrations
Ethyl acetate was evaluated using a Chinese
hamster fibroblast cell line. The cells were
exposed to the test compound at three different
doses for 24 and 48 h, with no metabolic
activation.
9.0 mg/mL
maximum
NA
+, 11% at
48 h
(equivocal
at 24 h)
D20 (calculated dose at which structural
aberrations, including gaps, were
detected in 20% of the metaphases
observed) = 15.8; translocation (TR)
value (indicates the frequency of cells
with exchange-type aberrations per unit
dose in mg/mL) = 0.3.
Ishidate et al.
(1984)
Sister chromatid
exchange (SCE)
ND
DNA damage
ND
DNA adducts
ND
Genotoxicity studies in mammals—in vivo
Chromosomal
aberrations
Ten male and female Chinese hamsters
(number/sex not specified) were administered
ethyl acetate in corn oil by intraperitoneal
injection. The number of micro nucleated
erythrocytes was counted. An additional
10 animals were administered ethyl acetate by
gavage, and the number of micronucleated
erythrocytes was counted.
473 mg/kg
intraperitoneal
injection
2500 mg/kg
gavage
NA
Ethyl acetate did not induce micronuclei
in the bone marrow cells of treated
hamsters by either route of
administration.
Basler (1986)
Sister chromatid
exchange (SCE)
ND
DNA damage
ND
DNA adducts
ND
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Table 4A. Summary of Ethyl Acetate Genotoxicity Studies
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without With
Activation Activation
Mouse
biochemical or
visible specific
locus test
ND
Dominant lethal
ND
Genotoxicity studies in subcellular systems
DNA binding
ND
aLowest effective dose for positive results, highest dose tested for negative results.
b+ = positive, ± = equivocal or weakly positive, - = negative, T = cytotoxicity, DU = data unsuitable, NA = not applicable, NV = not available, ND = no data, NDr = not
determinable, NI = not identified, NP = not provided, NR = not reported, NR/Dr = not reported but determined from data, NS = not selected.
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Carcinogenicity—
intraperitoneal (i.p.)
administration
A/He mice were dosed i.p. with 24 doses of 150 or
750 mg/kg ethyl acetate in tricaprylin (3 doses/wk for
8 wk). Mice were killed 24 wk after the first injection.
The lungs were removed, fixed, and examined grossly
and microscopically; liver, kidney, spleen, thymus,
intestine, salivary gland, and endocrine glands were
examined grossly.
There was no increase in pulmonary tumors.
Ethyl acetate is
not carcinogenic
in this assay
system.
Stoner et al.
(1973)
Carcinogenicity—
dermal application
Female CD-I mice (n = 8) were exposed to ethyl acetate
as solvent controls in an initiation/promotion
carcinogenicity study. Mice were initiated by applying a
single 0.2 mL dose of test compound to shaved dorsal
skin. Four days later, mice were exposed to promoter
chemicals twice weekly for 22 wk. In this case, ethyl
acetate was applied in place of the initiator and the
promoter.
Ethyl acetate-treated mice did not develop papillomas
after 22 wk of treatment.
Ethyl acetate is
not carcinogenic
in this assay
system.
Lindenfelser et
al. (1974)
Metabolism/
toxicokinetic
In a metabolism study, male S-D rats were dosed with
[14C]-ethyl acetate to determine the rate of hydrolysis.
Rats were given intravenous bolus doses of either 10 or
100 mg/kg; radiolabeled metabolites were measured in
blood and brain samples from 30-540 seconds after
dosing. An in vitro blood kinetic study was also
performed.
Intravenously administered ethyl acetate was rapidly
distributed and equilibrated and then very rapidly
eliminated from blood and brain tissue, primarily by
hydrolysis to ethanol and acetate. The in vitro blood
hydrolysis proceeded at a significantly slower rate
indicating that systemic organ carboxyesterase
activity was predominant in the in vivo hydrolysis of
ethyl acetate
Ethyl acetate is
rapidly converted
to ethanol and
acetate following
in vivo
administration to
rats.
Deisinger and
English (1998)
Metabolism/
toxicokinetic
In a metabolism study, male S-D rats were used to
determine the hydrolysis of ethyl acetate by whole blood
in vitro, in vivo by rats injected intraperitoneally with
ethyl acetate in corn oil, and in vivo by rats exposed to
ethyl acetate by inhalation.
Whole blood hydrolyzed ethyl acetate with a half-life
of 65-70 min, producing ethanol. Intraperitoneal
injection of ethyl acetate resulted in high ethanol
blood concentrations within 5 min. Animals exposed
to over 2000 ppm ethyl acetate by inhalation steadily
accumulated ethanol in the blood during exposure.
Ethyl acetate is
hydrolyzed to
ethanol more
rapidly by in vivo
exposure than in
vitro.
Gallaher and
Loomis (1975)
S-D = Sprague-Dawley.
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Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity
The genotoxicity of ethyl acetate has been investigated in various studies including
Ishidate et al. (1984a,b), Zimmermann et al. (1985), and Basler (1986). Ishidate et al. (1984)
preincubated Salmonella typhimurium strains TA92, TA1535, TA100, TA1537, TA94, and
TA98 with ethyl acetate in the presence of an S9 liver fraction from Fischer rats pretreated with a
polychlorinated biphenyl mixture (Kanechlor KC-400). Ethyl acetate was not mutagenic up to a
concentration of 5 mg/plate.
Zimmermann et al. (1985) investigated the induction of mitotic chromosomal
malsegregation by ethyl acetate in Saccharomyces cerevisiae D61.M yeast cells. Efficient
induction of aneuploid cells was only observed when growing cells were exposed to ethyl acetate
during a growth period of 4 hours at 28°C followed by incubation in ice for 17 hours and then
another growth period at 28°C for at least 1 hour. At an exposure concentration of 2.44% ethyl
acetate, mitotic aneuploidy was observed, but the frequency of point mutation or mitotic
recombination was not increased. The study authors suggested that the most likely target
producing the malsegregation was the spindle apparatus.
Ishidate et al. (1984) evaluated the potential of ethyl acetate to induce chromosomal
aberrations in a Chinese hamster fibroblast cell line using methodology typical of these assays.
The cells were exposed to the test compound at three different doses for 24 and 48 hours, with no
metabolic activation. At the maximum dose of 9.0 mg/mL, ethyl acetate was weakly genotoxic,
with an 11% total incidence of cells with structural aberrations at 48 hours (equivocal at
24 hours). A positive result was designated by a value of 10% or above. The D20 (the calculated
dose at which structural aberrations, including gaps, would be detected in 20% of the metaphases
observed) was 15.8, while the translocation (TR) value (indicates the frequency of cells with
exchange-type aberrations per unit dose in mg/mL) was 0.3. The study authors stated that TR
values for chemicals that show carcinogenic potential in animals are relatively high; the value for
ethyl acetate was low.
Basler (1986) investigated the genotoxic potential of ethyl acetate in Chinese hamsters.
Animals were dosed with ethyl acetate in corn oil either by gavage at a dose level of 2500 mg/kg
or by intraperitoneal injection at a dose level of 473 mg/kg. Micronucleus tests counting the
number of micronucleated erythrocytes were negative for both routes of exposure.
Carcinogenicity—Intraperitoneal Administration
Stoner et al. (1973) administered ethyl acetate in purified tricaprylin by intraperitoneal
injection to groups of male and female A/He mice (15/sex/dose group) at dose levels of either
150 or 750 mg/kg three times per week for 8 weeks. The study was terminated 24 weeks after
the first injection. At necropsy, the liver, kidney, spleen, thymus, intestine, salivary gland, and
endocrine glands were examined grossly for abnormalities, and suspicious tissues were examined
microscopically. The lungs were removed and fixed in Tellyesniczky's fluid. After fixation, any
nodules on the lung surface were counted, and some were examined microscopically. The lungs
themselves were examined grossly and microscopically. One male and 2 females dosed at
150 mg/kg and 2 females dosed at 750 mg/kg died prior to study termination; these deaths were
considered incidental to treatment. At 150 mg/kg, 1 male and 1 female were observed to have
one lung tumor each; at 750 mg/kg, 4/15 males and 3/13 females were observed to have at least
one lung tumor each (one of the males had two lung tumors). These results were not
significantly different from untreated mice (in which incidence of mice with lung tumors was
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22% in males and 17% in females); therefore, the study authors did not consider ethyl acetate to
be a carcinogen under these study conditions.
Carcinogenicity—Dermal Application
Lindenfelser et al. (1974) treated eight female CD-I mice with ethyl acetate by dermal
application according to a standard initiation/promotion protocol, in which ethyl acetate was
used as a solvent control. For initiation, a single administration of 0.2 mL of ethyl acetate was
applied to shaved dorsal skin. After 4 days, the mice were treated twice weekly for 22 weeks;
the number of papillomas were recorded weekly, and body weights were recorded every
2 weeks. None of the eight mice treated with ethyl acetate developed papillomas; therefore, the
study author did not consider ethyl acetate to be a carcinogen under these study conditions.
Metaholism/Toxicokinetic Studies
Deisinger and English (1998) investigated the rate of hydrolysis of ethyl acetate both in
vivo and in vitro. Groups of five male Sprague-Dawley rats were dosed with [14C]-ethyl acetate
(>99% chemical and radiochemical purity) in saline (3.75 mL/kg) at 10 or 100 mg/kg via a
femoral vein cannula for an in vivo blood kinetics study. Serial blood samples were collected
from a jugular vein cannula at eight time points ranging from 30-540 seconds postdosing and
deproteinized. Groups of four male Sprague-Dawley rats were dosed with [14C]-ethyl acetate in
saline (3.75 mL/kg) at 100 mg/kg via a femoral vein cannula for an in vivo brain kinetics study.
The rats were euthanized by exsanguination under CO2 anesthesia at each of four time points
from approximately 30-300 seconds postdosing, and the brain was excised, homogenized, and
deproteinized. For both studies, concentrations of [14C]-ethyl acetate, [14C]-ethanol,
[14C]-acetaldehyde, and [14C]-acetic acid in deproteinized blood and/or brain homogenates were
determined by high-performance liquid chromatography (HPLC) using a radiochemical
flow-through detector. Total [14C] concentrations in whole and deproteinized blood and whole
and deproteinized brain homogenates were determined by liquid scintillation counting (LSC). In
an in vitro blood kinetics study, untreated Sprague-Dawley rat whole blood samples were spiked
with [14C]-ethyl acetate in saline at approximately the highest concentration (400 jug/g) seen in
the blood after administration of the 100-mg/kg dose in the in vivo blood kinetics study. The
spiked samples were incubated at 37°C, and aliquots were removed from 2-120 minutes after
spiking. Concentrations of [14C]-ethyl acetate, [14C]-ethanol, and [14C]-acetic acid in
deproteinized and whole blood were determined by HPLC; total [14C] concentrations in whole
and deproteinized blood were determined by LSC. In the in vivo blood kinetics study,
distribution and equilibration of the doses was rapid, followed by very rapid elimination of ethyl
acetate. First-order elimination rate constants of 0.0208/second and 0.0188/second, and
elimination half-lives of 33.4 seconds and 36.9 seconds were estimated for the 10 and 100 mg/kg
doses, respectively. The similar rates indicated that the elimination pathway (carboxyesterase)
was not saturated at 100 mg/kg. In the in vivo brain kinetics study, total brain [14C]
concentrations were approximately 75% of those seen in the blood following the 100-mg/kg
dose. Ethyl acetate in the brain was rapidly hydrolyzed, with an elimination rate constant of
0.0285/second, and the resulting ethanol was rapidly eliminated. In the in vitro blood kinetics
study, the estimated elimination rate constant was 0.0005/second, indicating that systemic organ
carboxyesterase activity is the predominant pathway for in vivo hydrolysis of ethyl acetate.
Gallaher and Loomis (1975) investigated the hydrolysis of ethyl acetate both in vivo and
in vitro using male Sprague-Dawley rats. For the in vitro analysis, an aqueous solution of ethyl
acetate was mixed with whole blood to yield an initial concentration of 0.20 g/100 mL and then
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incubated at 37°C for 5 hours. Aliquots were withdrawn at regular intervals, and ethyl acetate
and ethanol concentrations were measured. Hydrolysis of ethyl acetate in whole blood produced
ethanol, with a calculated half-life of 65-70 minutes. In a separate in vivo experiment, four rats
were given intraperitoneal injections of a 25% solution of ethyl acetate in corn oil at a dose level
of 1.6 mL/kg (calculated to produce an approximate blood concentration of 0.20 g/100 mL).
Blood samples were obtained at regular intervals and analyzed as above. High concentrations of
ethanol were detected in the blood within 5 minutes of dosing, while concentrations of ethyl
acetate were low (<0.02 g/100 mL) for the first 20 minutes and undetectable thereafter
(measurements were taken up to 5 hours after dosing). The half-life in vivo was estimated to be
approximately 5-10 minutes. A third kinetic study examined ethyl acetate metabolism following
inhalation exposure. Rats were exposed to ethyl acetate vapor via endotracheal tube at
concentrations of 500-10,000 ppm. Blood samples were obtained at regular intervals and
analyzed as above. Accumulation of ethanol occurred only when the rats were exposed to
concentrations above 2000-ppm ethyl acetate. At 5000 ppm, there was a steady accumulation of
ethanol in the blood throughout the exposure period, while at 10,000 ppm, ethanol accumulated
more rapidly (to over 100 mg/100 mL 4-5 hours after dosing), resulting in severe respiratory
depression. No appreciable accumulation of ethyl acetate was observed (<0.01 g/100 mL). The
study authors concluded that because ethyl acetate is hydrolyzed to ethanol more rapidly in vivo
than in vitro, it was doubtful that blood enzymes were solely responsible for the hydrolysis.
Additionally, blood ethanol accumulation could be expected to occur in humans if the ambient
concentration of inhaled ethyl acetate was high enough.
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DERIVATION OF PROVISIONAL VALUES
Tables 5 and 6 present a summary of noncancer and cancer reference values, respectively. IRIS data are indicated in the table, if
available.
Table 5. Summary of Noncancer Reference Values for Ethyl Acetate (CASRN 141-78-6)
Toxicity Type (units)
Species/Sex
Critical Effect
p-Reference
Value
POD
Method
PODhed/hec
UFC
Principal
Study
Subchronic p-RfD
(mg/kg-d)
Rat/M+F
Clinical signs, including increased salivation,
irregular breathing, and lethargy in both sexes
7 x KT1
NOAEL
216
300
American
Biogenics
Corp. (1986)
Chronic RfD (mg/kg-d)
IRIS (U.S. EPA, 1988)
Rat/M+F
Mortality and body-weight loss
9 x KT1
NOAEL
900
(unadjusted
by IRIS)
1000
American
Biogenics
Corp. (1986)
Subchronic p-RfC
(mg/m3)
Rat/M+F
Decreased body weights, body-weight gains,
food efficiency, and startle response (both
sexes), and decreased food consumption (males)
7 x KT1
NOAEL
209
300
Christoph et
al. (2003)
Chronic p-RfC (mg/m3)
Rat/M+F
Decreased body weights, body-weight gains,
food efficiency, and startle response (both
sexes), and decreased food consumption (males)
7 x 1(T2
NOAEL
209
3000
Christoph et
al. (2003)
Table 6. Summary of Cancer Values for Ethyl Acetate (CASRN 141-78-6)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF
ND
p-IUR
ND
ND = no data.
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DERIVATION OF ORAL REFERENCE DOSES
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)
The study by American Biogenics Corp. (1986) is selected as the principal study for
the derivation of the subchronic p-RfD value. This is the only available study of subchronic
duration by the oral route of exposure. The original study report was not obtainable; however,
study summaries are available in both IRIS (U.S. EPA, 1988) and HEEP (U.S. EPA, 1986a).
Although it could not be determined if this study was performed according to GLP regulations,
this study did meet standards of design and performance with respect to inclusion of an adequate
number of animals and examination of a variety of endpoints. Systemic parameters evaluated
included mortality, morbidity, clinical signs of toxicity, body-weight gain, food consumption,
hematology, clinical chemistry, urinalysis, ophthalmoscopic examinations, gross necropsy, organ
weights, and histological examinations. This study was selected for development of an RfD by
IRIS (U.S. EPA, 1988) and is deemed adequate for development of a subchronic p-RfD.
As detailed in the section "Review of Potentially Relevant Data," clinical signs, including
increased salivation, irregular breathing, and lethargy, in rats of both sexes occurred at the
highest dose level of 3600 mg/kg-day. Tabular data could not be obtained, and standard
deviations were not provided; therefore, benchmark dose (BMD) modeling was not possible, and
the POD is selected using the NOAEL/LOAEL method. The POD selected is a NOAEL of
900 mg/kg-day based on the above-mentioned clinical signs at a LOAEL of 3600 mg/kg-day.
No dosimetric adjustment was necessary because this was a continuous exposure.
In EPA's Recommended Use of Body Weight3/4 as the Default Method in Derivation of
the Oral Reference Dose (U.S. EPA, 201 lb), the Agency endorses a hierarchy of approaches to
derive human equivalent oral exposures from data from laboratory animal species, with the
preferred approach being physiologically based toxicokinetic modeling. Other approaches may
include using some chemical-specific information, without a complete physiologically based
toxicokinetic model. In lieu of chemical-specific models or data to inform the derivation of
human equivalent oral exposures, EPA endorses body-weight scaling to the 3/4 power (i.e.,
BW3 4) as a default to extrapolate toxicologically equivalent doses of orally administered agents
from all laboratory animals to humans for the purpose of deriving an RfD under certain exposure
conditions. More specifically, the use of BW3 4 scaling for deriving an RfD is recommended
when the observed effects are associated with the parent compound or a stable metabolite but not
for portal-of-entry effects or developmental endpoints.
A validated human physiologically based pharmacokinetic (PBPK) model for ethyl
acetate is not available for use in extrapolating doses from animals to humans. The selected
critical effect of clinical signs, including increased salivation, irregular breathing, and lethargy
(in both sexes) was associated with the parent compound or a stable metabolite. Furthermore,
these aforementioned clinical signs are not portal-of-entry or developmental effects. Therefore,
scaling by BW3 4 is relevant for deriving human equivalent doses (HEDs) for these effects.
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Following U.S. EPA (201 lb) guidance, the POD for clinical signs in adult animals is
converted to an HED through application of a dosimetric adjustment factor (DAF)1 derived as
follows:
DAF = (BWa1/4 - BWh1/4)
where
DAF = dosimetric adjustment factor
BWa = animal body weight
BWh = human body weight
Using a BWa of 0.25 kg for rats and a BWh of 70 kg for humans (U.S. EPA, 1988), the
resulting DAF is 0.24. Applying this DAF to the NOAEL identified for the critical effect in
mature rats yields a NOAELhed as follows:
NOAELhed = NOAEL (mg/kg-day) x DAF
= 900 (mg/kg-day) x 0.24
= 216 mg/kg-day
The subchronic p-RfD for ethyl acetate, based on the NOAELhed of 216 mg/kg-day for
clinical signs, including salivation, irregular breathing, and lethargy, in male and female
Sprague-Dawley rats (American Biogenics Corp., 1986), is derived as follows:
Subchronic p-RfD = NOAELhed + UFC
= 216 mg/kg-day300
= 7 x 10_1 mg/kg-day
:As described in detail in Recommended Use of Body Weight4 as the Default Method in Derivation of the Oral
Reference Dose (U.S. EPA, 2011), rate-related processes scale across species in a manner related to both the direct
(BW1'1) and allometric scaling (BW3 4) aspects such that BW3 4 ^ BW11= BW converted to a
DAF = BWa'74 - BWhI/4.
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Tables 7 and 8, respectively, summarize the UFs and the confidence descriptors for the
subchronic p-RfD for ethyl acetate.
Table 7. Uncertainty Factors for Subchronic p-RfD of Ethyl Acetate
UF
Value
Justification
ufa
3
A UFa of 3 (10°5) has been applied to account for uncertainty in characterizing the
toxicodynamic differences between rats and humans following oral ethyl acetate
exposure. The toxicokinetic uncertainty has been accounted for by calculation of a
human equivalent dose (HED) through application of a dosimetric adjustment factor
(DAF) as outlined in the EPA's Recommended Use of Body Weight3,4 as the Default
Method in Derivation of the Oral Reference Dose (U.S. EPA, 2011).
ufd
10
A UFd of 10 has been applied because there are no acceptable two-generation
reproductive toxicity or developmental toxicity studies.
UFh
10
A UFh of 10 has been applied for inter-individual variability to account for human-to-
human variability in susceptibility in the absence of quantitative information to assess
the toxicokinetics and toxicodynamics of ethyl acetate in humans.
ufl
1
A UFl of 1 has been applied for LOAEL-to-NOAEL extrapolation because the POD is
aNOAEL.
UFS
1
A UFS of 1 has been applied because a subchronic-duration study was selected as the
principal study.
UFC
300
The confidence of the subchronic p-RfD for ethyl acetate is low, as explained in Table 8.
Table 8. Confidence Descriptors for Subchronic p-RfD for Ethyl Acetate
Confidence Categories
Designation3
Discussion
Confidence in study
L
The study is given low confidence. It was well designed and
well conducted, and several appropriate parameters were
evaluated; however, the original study could not be obtained
for review, limiting interpretation.
Confidence in database
L
The database is given a low confidence because there are no
additional subchronic-duration studies, and no developmental
or reproductive studies are available.
Confidence in subchronic
p-RfDb
L
The overall confidence in the subchronic p-RfD is low
because there are no oral developmental or reproductive
toxicity studies available, and there are no studies in a second
species.
aL = low, M = medium, H = high.
bThe overall confidence cannot be greater than lowest entry in table.
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Derivation of Chronic RfD (Chronic RfD)
A chronic RfD of 9 x 1CT1 mg/kg-day is available in IRIS (U.S. EPA, 1988), based on an
oral subchronic-duration study in the rat (American Biogenics Corp., 1986). This chronic RfD
was derived based on a NOAEL of 900 mg/kg-day for mortality and body-weight loss in rats and
included a UFC of 1000. The IRIS database should be checked to determine if any changes have
been made.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
Derivation of Subchronic Provisional RfC (Subchronic p-RfC)
The Christoph et al. (2003) study is selected as the critical study for the derivation of
a subchronic p-RfC. This study is published and peer-reviewed. It was limited in scope to
examination of body weights, food and water consumption, behavioral endpoints, and
neuropathology, and did not examine other endpoints. Christoph et al. also examined operant
behavior in male rats exposed by inhalation to ethyl acetate but found no association between
subchronic whole-body exposure and alterations in operant behavior (Christoph, 1997;
Christoph et al., 2003). There was only one other subchronic-duration study identified (Smyth
and Smyth, 1928) and it did not provide sufficient information to determine the average daily
dose administered and is, therefore, not suitable for derivation of toxicity values. The database
also contains one short-term (2-week) study (Burleigh-Flayer et al., 1995), which, although not
of sufficient duration to support derivation of a subchronic p-RfC, was more comprehensive than
the study by Christoph et al. (2003) and provides support for the findings in that study.
As detailed in the section "Review of Potentially Relevant Data," statistically significant
changes in the study by Christoph et al. (2003) included decreased body weights, body-weight
gains, food efficiency, and startle response in both sexes, and decreased food consumption in the
-3
males at 448 mg/m and above. This decreased food consumption is not thought to be related to
palatability as dosing was performed by inhalation, but may be a result of irritation; however,
appropriate tissues were not examined to verify this. In support of these findings, the most
sensitive effect in a 2-week inhalation study (Burleigh-Flayer et al., 1995) was decreased food
consumption, with decreased motor activity also observed at higher doses. Tabular data could
not be obtained for the effects at the LOAEL in the Christoph et al. (2003) study, and standard
deviations were not provided; therefore, BMD modeling was not possible, and the POD was
selected using the NOAEL/LOAEL method. The POD selected is a NOAELhec of 209 mg/m3
for changes including decreased body weights, body-weight gains, food efficiency, and startle
response in both sexes and decreased food consumption in males occurring at a LOAELhec of
448 mg/m3.
The metabolism study by Gallaher and Loomis (1975) demonstrated that
Sprague-Dawley rats inhaling ethyl acetate vapors rapidly hydrolyzed the test compound to
ethanol, and that ethyl acetate concentrations of 5000 ppm caused an accumulation of ethanol in
the blood. As humans appear to hydrolyze ethyl acetate in a similar fashion (Coopman et al.,
2005), ethyl acetate is considered a Category 3 gas and, thus, has effects peripheral to the
respiratory system (U.S. EPA, 2009). Because Category 3 gases cause extrarespiratory effects,
the concentrations in the study were converted to adjusted doses (to account for continuous
exposure) and then to HEC concentrations utilizing a default blood:air partition coefficient of 1
because the actual value is unknown.
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The following dosimetric adjustments were made for all inhalation exposure doses in
adjusting for continuous exposure and then HECs. As described in the "Review of Potentially
Relevant Data" section, this study dosed for 6 hours/day on an interrupted schedule, resulting in
65 doses applied over 13 to 14 weeks. The dosimetric adjustments for continuous exposure were
performed with the assumption that 65 doses were applied over 14 weeks. The dosimetric
adjustment for 350 ppm is presented below.
1) Exposure concentration adjustment for continuous exposure
CONCadj = CONC x (molecular weight + 24.45) x
(hours exposed + 24 hours) x (days exposed + 98 days)
= 350 ppm x (88.11 g/mol 24.45) x (6 h 24 h) x (65 d 98 d)
= 350 x 3.60 x 0.25 x 0.66
209 mg/m
2) HEC conversion
CONChec = CONCadj x BloodrAir Partition Coefficient
= 209 mg/m3 x 1
= 209 mg/m3
The subchronic p-RfC for ethyl acetate, based on the ratNOAELnEc, is derived as
follows:
Subchronic p-RfC
NOAELhec UFc
= 209 mg/m - 300
= 7 x 10 1 mg/m3
Table 9 summarizes the UFs for the subchronic p-RfC for ethyl acetate.
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Table 9. Uncertainty Factors for Subchronic p-RfC of Ethyl Acetate
UF
Value
Justification
ufa
3
A UFa of 3 (10°5) has been applied to account for uncertainty in characterizing the
toxicodynamic differences between rats and humans following inhalation exposure to
ethyl acetate. The toxicokinetic uncertainty has been accounted for by calculation of a
human equivalent concentration (HEC) as described in the RfC methodology
(U.S. EPA, 1994b).
ufd
10
A UFd of 10 has been applied because there are no acceptable two-generation
reproductive toxicity or developmental toxicity studies.
UFh
10
A UFh of 10 has been applied for inter-individual variability to account for human-to-
human variability in susceptibility in the absence of quantitative information to assess
the toxicokinetics and toxicodynamics of ethyl acetate in humans.
ufl
1
A UFl of 1 has been applied for LOAEL-to-NOAEL extrapolation because the POD is
aNOAEL.
UFS
1
A UFS of 1 has been applied because a subchronic-duration study was selected as the
principal study.
UFC
300
The confidence in the subchronic p-RfC for ethyl acetate is low, as explained in Table 10
below.
Table 10. Confidence Descriptors for Subchronic p-RfC for Ethyl Acetate
Confidence Categories
Designation3
Discussion
Confidence in study
L
The study is given low confidence. It was well designed
and well conducted; however, it was not comprehensive
and only examined neurological effects, body weight, and
food and water intake.
Confidence in database
L
The database is given a low confidence because no
developmental or reproductive studies are available.
Confidence in subchronic
p-RfCb
L
The overall confidence in the subchronic p-RfC is low
because no inhalation developmental or reproductive
toxicity studies are available and because the critical study
only examined one organ system.
"L = low, M = medium, H = high.
bThe overall confidence cannot be greater than lowest entry in table.
Derivation of Chronic Provisional RfC (Chronic p-RfC)
The Christoph et al. (2003) study is selected as the critical study for the derivation of
a chronic p-RfC. There are no available studies of chronic duration by the inhalation route of
exposure. As discussed above in the "Derivation of a Subchronic Provisional RfC (Subchronic
p-RfC)" section, the study by Christoph et al. (2003) is the only suitable study of subchronic
26
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duration by the inhalation route of exposure. It is supported by a short-term (2 week) study by
Burleigh-Flayer et al. (1995).
The POD selected is a NOAELhec of 209 mg/m for changes including decreased body
weights, body-weight gains, food efficiency, and startle response in both sexes, and decreased
"3
food consumption in males occurring at the LOAELhec of 448 mg/m . Further discussion of the
selection of this critical effect is provided in the "Derivation of a Subchronic Provisional RfC
(Subchronic p-RfC)" section.
As previously stated, ethyl acetate is considered a Category 3 gas and, thus, has effects
peripheral to the respiratory system (U.S. EPA, 2009). Because Category 3 gases cause
extrarespiratory effects, the concentrations in the study were converted to adjusted doses (to
account for continuous exposure) and then to HEC concentrations utilizing a default blood:air
partition coefficient of 1 because the actual value is unknown.
Identically to that presented above for derivation of the subchronic p-RfC, the following
dosimetric adjustments were made for all inhalation exposure doses in adjusting for continuous
exposure and then HECs.
1) Exposure concentration adjustment for continuous exposure
CONCadj = CONC x (molecular weight + 24.45) x
(hours exposed + 24 hours) x (days exposed + 98 days)
= 350 ppm x (88.11 g/mol - 24.45) x (6 h - 24 h) x (65 d - 98 d)
= 350 x 3.60 x 0.25 x 0.66
209 mg/m3
2) HEC conversion
CONChec = CONCadj x BloodrAir Partition Coefficient
= 209 mg/m3 x 1
= 209 mg/m3
The chronic p-RfC for ethyl acetate, based on the rat NOAELhec, is derived as follows:
Chronic p-RfC = NOAELhec-UFC
= 209 mg/m3 - 3000
= 7 x 10 2 mg/m3
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Table 11 summarizes the UFs for the chronic p-RfC for ethyl acetate.
Table 11. Uncertainty Factors for Chronic p-RfC of Ethyl Acetate
UF
Value
Justification
ufa
3
A UFa of 3 (10°5) has been applied to account for uncertainty in characterizing the
toxicodynamic differences between rats and humans following inhalation exposure to
ethyl acetate. The toxicokinetic uncertainty has been accounted for by calculation of a
human equivalent concentration (HEC) as described in the RfC methodology
(U.S. EPA, 1994b).
ufd
10
A UFd of 10 has been applied because there are no acceptable two-generation
reproductive toxicity or developmental toxicity studies.
UFh
10
A UFh of 10 has been applied for inter-individual variability to account for human-to-
human variability in susceptibility in the absence of quantitative information to assess
the toxicokinetics and toxicodynamics of ethyl acetate in humans.
ufl
1
A UFl of 1 has been applied for LOAEL-to-NOAEL extrapolation because the POD is
aNOAEL.
UFS
10
A UFS of 10 has been applied because a subchronic-duration study was selected as the
principal study.
UFC
3000
The confidence in the chronic p-RfC for ethyl acetate is low, as explained in Table 12
below.
Table 12. Confidence Descriptors for Chronic p-RfC for Ethyl Acetate
Confidence Categories
Designation3
Discussion
Confidence in study
L
The study is given low confidence. It was well designed
and well conducted; however it was not comprehensive and
only examined neurological effects, body weight, and food
and water intake.
Confidence in database
L
The database is given a low confidence because no
developmental or reproductive studies are available.
Confidence in chronic p-RfCb
L
The overall confidence in the chronic p-RfC is low because
no inhalation chronic, developmental, or reproductive
toxicity studies are available and because the critical study
only examined one organ system.
aL = low, M = medium, H = high.
bThe overall confidence cannot be greater than lowest entry in table.
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CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
Table 13 identifies the cancer WOE descriptor for ethyl acetate. No carcinogenicity
studies in animals by the oral or inhalation routes have been found. The carcinogenicity of ethyl
acetate was investigated in a mouse dermal application study (Lindenfelser et al., 1974) and in a
mouse pulmonary tumor study (Stoner et al., 1973) using intraperitoneal injection as the route of
exposure. No evidence of carcinogenic potential was observed in either of these studies;
however, these studies were not by the inhalation or oral route of administration, and animals
were not treated for the majority of their life spans. These studies do not provide sufficient data
to designate a cancer WOE descriptor other than "Inadequate Information to Assess
Carcinogenic Potential."
Table 13. Cancer WOE Descriptor for Ethyl Acetate
Possible WOE Descriptor
Designation
Route of Entry (oral,
inhalation, or both)
Comments
"Carcinogenic to Humans "
NA
NA
No human cancer studies are
available.
"Likely to Be Carcinogenic
to Humans "
NA
NA
No animal cancer studies are
available.
"Suggestive Evidence of
Carcinogenic Potential"
NA
NA
There are no data available to
suggest that there is a carcinogenic
potential.
"Inadequate Information
to Assess Carcinogenic
Potential"
Selected
Both
There is not adequate information
available to assess carcinogenic
potential.
"Not Likely to Be
Carcinogenic to Humans "
NA
NA
No strong evidence of
noncarcinogenicity in humans is
available
NA = not applicable.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of Provisional Oral Slope Factor (p-OSF)
No human or animal studies evaluating the carcinogenicity of ethyl acetate following oral
exposure have been located. Therefore, derivation of a p-OSF is precluded.
Derivation of Provisional Inhalation Unit Risk (p-IUR)
No human or animal studies examining the carcinogenicity of ethyl acetate following
inhalation exposure have been located. Therefore, derivation of a p-IUR is precluded.
29
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APPENDIX A. PROVISIONAL SCREENING VALUES
There are no provisional screening values for ethyl acetate.
30
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APPENDIX B. DATA TABLES
Table B.l. Estimated Body Weight" (g) of Sprague-Dawley Rats Exposed to Ethyl Acetate
by Inhalation for 13-14 Weeks and Then Allowed to Recover for 4 Weeks
Day
0 ppm
350 ppm (209 mg/m3)
750 ppm (448 mg/m3)
1500 ppm (896 mg/m3)
Male
Female
Male
Female
Male
Female
Male
Female
2
303
192
296
192
296
187
287
192
5
323
201
316
196
309
192
298
196
9
348
212
339
208
330
203
318
205
12
366
219
359
215
345
208
327
212
19
404
235
391
228
382
221
361
224
26
431
242
415
230
406
228
384
233
33
458
253
440
239
429
235
404
242
40
479
262
458
248
447
242
420
244
47
497
266
476
251
465
246
438
247
54
517
271
492
257
481
251
454
255
61
531
278
508
262
490
253
463
260
68
546
282
519
266
504
260
474
264
75
555
289
528
271
510
262
481
264
82
574
291
540
278
526
266
492
266
89
585
296
549
278
535
269
501
269
96
592
300
555
287
544
271
506
269
103
614
298
NMb
NM
NM
NM
517
273
110
628
300
NM
NM
NM
NM
544
278
117
639
303
NM
NM
NM
NM
558
289
124
646
305
NM
NM
NM
NM
562
294
aBody weights are estimated based on digitization of Figure 1 from CMstoph et al. (2003).
bNM = not measured. Body weights after exposures ended (week 96) were only measured in the 0- and 1500-ppm
exposure groups.
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APPENDIX C. BMD OUTPUTS
There are no BMD modeling outputs for ethyl acetate.
32
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