United States
Environmental Protection
1=1 m m Agency
EPA/690/R-10/014F
Final
9-22-2010
Provisional Peer-Reviewed Toxicity Values for
Ethyl Methacrylate
(CASRN 97-63-2)
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
Scott C. Wesselkamper, 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
Q. Jay Zhao, Ph.D., M.P.H., 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	ii
BACKGROUND	1
HISTORY	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	2
INTRODUCTION	2
REVIEW 01 PERTINENT DATA	3
HUMAN STUDIES	3
ANIMAL STUDIES	3
Oral Exposure	3
Inhalation Exposure	5
OTHER STUDIES	6
Toxicokinetics	6
Acute or Short-term Studies	7
Other Routes	8
Genotoxicity	9
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RfD
VALUES I OR ETHYL METHACRYLATE	10
SUBCHRONIC p-RfD	10
CHRONIC p-RfD	10
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC INHALATION
RfC VALUES I OR ETHYL METHACRYLATE	10
SUBCHRONIC p-RfC	10
CHRONIC p-RfC	12
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR ETHYL
METHACRYLATE	13
WEIGHT-OF -E VIDEN CE DESCRIPTOR	13
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK	13
REFERENCES	13
APPENDIX A. DERIVATION OF A SCREENING VALUE FOR ETHYL
METHACRYLATE	17
APPENDIX B. DETAILS OF BENCHMARK DOSE MODELING FOR THE
PROVISIONAL RfCs	19
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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
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
NOAELrec
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
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 METHACRYLATE (CASRN 97-63-2)
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 six 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.
No RfD, RfC, or cancer assessment for ethyl methacrylate (see Figure 1 for the chemical
structure of ethyl methacrylate; molecular weight = 114.5) is included on IRIS (U.S. EPA, 2009)
or on the Drinking Water Standards and Health Advisories (DWSHA) list (U.S. EPA, 2006).
The HEAST (U.S. EPA, 1997) reported a value of 0.09 mg/kg-day for both subchronic and
chronic oral RfDs based on increased relative kidney weight in a 2-year drinking water study of
rats exposed to the related compound, methyl methacrylate (Borzelleca et al., 1964). The methyl
methacrylate no-observed-effect-level (NOEL) of 7.5 mg/kg-day was divided by an uncertainty
factor (UF) of 100, and then adjusted by multiplying the ratio of molecular weights for ethyl
methacrylate and methyl methacrylate (114.5/100.13). The HEAST cited a Health and
Environmental Effects Profile (HEEP) for ethyl methacrylate (U.S. EPA, 1986a) as the source
for the RfD values. No RfC values are reported in the HEAST or derived in the HEEP. Other
than the HEEP (U.S. EPA, 1986a), the Chemical Assessments and Related Activities (CARA)
list (U.S. EPA, 1994a, 1991a) do not include any relevant documents. The toxicity of ethyl
methacrylate has not been reviewed by ATSDR (2009) or the World Health Organization
(WHO, 2009). CalEPA (2009a,b) has not derived toxicity values for exposure to ethyl
methacrylate.
INTRODUCTION
CH.
CH,
'3
0
Figure 1. Chemical Structure of Ethyl Methacrylate
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No occupational exposure limits have been derived for ethyl methacrylate by the
American Conference of Governmental Industrial Hygienists (ACGIH, 2009), the National
Institute of Occupational Safety and Health (NIOSH, 2009), or the Occupational Safety and
Health Administration (OSHA, 2009). A safety assessment of ethyl methacrylate reviewed by
the Cosmetic Ingredient Review Expert Panel was published in 2002, but no occupational
exposure limits were presented in this document.
A cancer assessment for ethyl methacrylate is not available on IRIS (U.S. EPA, 2009),
the DWSHA list (U.S. EPA, 2006), or in the HEAST (U.S. EPA, 1997). Using the 1986
Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986b), the HEEP (U.S. EPA, 1986a)
assigned ethyl methacrylate to weight-of-evidence Group D (Not Classifiable as to Human
Carcinogenicity). Ethyl methacrylate has not been evaluated under the 2005 guidelines
(U.S. EPA, 2005). The International Agency for Research on Cancer (IARC, 2009) has not
reviewed the carcinogenic potential of ethyl methacrylate. Ethyl methacrylate has not been
evaluated for potential carcinogenicity by the National Toxicology Program (NTP, 2009a) and is
not included in the 11th Report on Carcinogens (NTP, 2005). CalEPA (2009b) has not prepared
a quantitative estimate of carcinogenic potential for ethyl methacrylate.
Literature searches were conducted from 1960s through August 9, 2010 for studies
relevant to the derivation of provisional toxicity values for ethyl methacrylate. Databases
searched included MEDLINE, TOXLINE (with NTIS), BIOSIS, TSCATS/TSCATS2, CCRIS,
DART, GENETOX, HSDB, RTECS, Chemical Abstracts, and Current Contents.
REVIEW OF PERTINENT DATA
HUMAN STUDIES
In a case-control study, Hiipakka and Samimi (1987) measured airborne exposure to
ethyl methacrylate (used in nail-sculpting products) in six different sculptured nail salons.
Health symptoms data were collected on 20 female nail sculptors and 20 matched controls using
standardized, self-administered questionnaires on a range of potential effects including irritation,
headaches and dizziness, and neurological signs of clinical adversity. Mean time-weighted
average (TWA) concentrations of ethyl methacrylate were estimated to be 4.5 ppm. The only
statistically significant (p < 0.05 by Chi-Square analysis) health finding was an increase in
reporting of throat irritation. Although consistent increases in nose and skin irritation,
drowsiness, dizzy spells, and trembling of the hands were reported by sculptors as compared
with controls, the differences were not statistically significant. However, these findings could
not be attributed solely to ethyl methacrylate because co-occurring exposures to airborne particle
dust and other organic vapors, including butyl acetate and toluene, also occurred in the work
environment.
ANIMAL STUDIES
Oral Exposure
Data on oral exposure to ethyl methacrylate are available from one subchronic drinking
water study by Abou-Donia et al. (2000). Male Sprague-Dawley rats (8/group) were given ethyl
methacrylate (99% purity) in drinking water for 60 days at concentrations of 0, 0.1, 0.2, or 0.5%,
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(prepared fresh daily). For this assessment, default parameters for drinking water consumption
rate and body weight (U.S. EPA, 1988) were used to estimate daily doses of 139, 277, and
693 mg/kg-day for the low-, mid-, and high-dose groups, respectively. Control animals were
given untreated water. Animals were observed cage-side daily for mortality and clinical signs of
toxicity; observations included overall activity, posture, balance, breathing rate, and evidence of
diarrhea. Group-based qualitative observations were recorded weekly. Body weight was also
monitored weekly. Following termination of exposure, animals were euthanized, and the brain,
spinal cord, and sciatic nerve were removed and examined for histopathology. No other
toxicological evaluations were conducted. In addition to administering ethyl methacrylate in
drinking water, a subchronic neurotoxicity evaluation was also performed via daily
intraperitoneal (i.p.) doses (see summary in "Other Studies" below).
No mortality occurred when ethyl methacrylate was administered in the drinking water
(Abou-Donia et al., 2000). Animals in the mid-dose group (277 mg/kg-day) exhibited lethargy,
and those in the high-dose group (693 mg/kg-day) showed gait alterations, suggesting an
increase in severity of clinical symptoms with increasing dose. No differences in clinical
symptoms were observed between low-dose and control animals. Morphological alterations
were observed in cross-sections of brain, spinal cord, and sciatic nerve in all treated groups.
Major histopathological findings that were statistically significantly (p < 0.05) different from
control at all doses were (1) an increase in the number of clusters of enlarged axons (>0.05 mm
in diameter), primarily at internodal segments, throughout the dorsal, ventral, and lateral
columns of the spinal cord; and (2) a reduction in the number of neurons in sections of the
ventral horns of the spinal cord. However, the magnitude of these effects was not clearly
dose-dependent. Data were only presented in graphical form. Based on visual inspection, the
mean numbers of clusters of enlarged axons were approximately 16, 14, and 23 in the low-,
mid-, and high-dose groups, respectively, as compared with 0 in the control group. Similarly,
based on visual inspection, the numbers of neurons in the ventral horns of a cross-section of the
spinal cord were approximately 11, 15, and 13 in the low-, mid-, and high-dose groups,
respectively, as compared with 22 in the control group.
Other abnormalities were reported to occur in all treated groups, but neither raw data nor
statistical significance was presented (Abou-Donia et al., 2000). These included (1) spongiform
alterations in myelin and clusters of enlarged axons in white matter tracts in the brainstem and
forebrain (fornix, cerebral peduncles, and internal capsule); and (2) shrunken axons with
separated myelin lamellae and large axons with thinner-than-normal myelin sheaths dispersed
throughout the sciatic nerve. The study authors concluded that daily administration of ethyl
methacrylate in drinking water to rats for 60 days produces clinical signs of neurotoxicity and a
range of adverse neuropathological effects consistent with the induction of myelinopathy rather
than a primary axonopathy. They also suggested that neuronal loss, as indicated by decreased
neuronal density, may be either secondary to demyelination or a primary effect of ethyl
methacrylate treatment. The study authors do not identify effect levels. Based on the
neuropathology findings, a lowest-observed-adverse-effect level (LOAEL) of 139 mg/kg-day,
the lowest dose tested, is identified. A no-observed-adverse-effect level (NOAEL) could not be
identified.
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Inhalation Exposure
An inhalation developmental toxicity study (Saillenfait et al., 1999) was the only
inhalation study located for ethyl methacrylate. Nulliparous mated female Sprague-Dawley rats
(23-27 bred rats; 19-25 pregnancies) were exposed to ethyl methacrylate (99% purity) for
6 hours/day, on gestation days (GDs) 6-20, at airborne concentrations of 0, 600, 1200, 1800, or
2400 ppm (equivalent to 0, 2800, 5600, 8400, and 11,200 mg/m3, respectively). For ethyl
methacrylate exposures, the pregnant rats were placed in stainless-steel wire mesh exposure
cages that were moved into 200-L glass/stainless-steel inhalation chambers with dynamic and
adjustable laminar airflow. Control animals were exposed concurrently to filtered room air in an
adjacent chamber identical to those of the exposure groups. Chamber concentrations of ethyl
methacrylate were monitored continuously by gas chromatography. Food and water were
provided ad libitum but not during exposures. Maternal body weights were recorded on GDs 0,
6, 13, and 21. Food consumption was measured for the intervals: GDs 6-13 and 13-21.
Following euthanasia of dams on GD 21, the uterus was removed and weighed. The numbers of
corpora lutea, implantation sites, resorptions, and dead and live fetuses were recorded. Uteri
with no visible implantation sites were stained with 10% ammonium sulfide to detect very early
resorptions. Live fetuses were weighed, sexed, and examined for external anomalies, including
those of the oral cavity. Half of the live fetuses from each litter were preserved in Bouin's
solution and examined for internal soft-tissue changes. The other half were fixed in ethanol
(70%>), eviscerated, and examined for skeletal abnormalities following staining with alizarin
red S. The litter was used as the basis for analysis of fetal variables.
Saillenfait et al. (1999) did not observe mortality during the study. Clinical signs of
toxicity during treatment and any neurotoxicity findings were not reported. Table 1 presents
statistically significant changes in maternal body-weight gain and food consumption, as well as
fetal body weight on a per-litter basis. Maternal body-weight gain was significantly reduced
between GDs 6 and 13 at concentrations >5600 mg/m3, and between GDs 13 and 21 at
11,200 mg/m3. Overall weight gain between GDs 6 and 21 was significantly decreased at
concentrations >5600 mg/m3, and there was a concentration-related reduction in corrected
(adjusted for gravid uterine weight) weight gain relative to controls (see Table 1). Maternal food
consumption was significantly less than controls between GDs 6 and 13, between GDs 13 and
21, and for the entire exposure period (between GDs 6 and 21) at concentrations >5600 mg/m3.
With the exception of fetal body weights, no reproductive or developmental effects were
observed for any measured endpoint. Mean fetal body weight per litter was significantly
reduced in males at concentrations >5600 mg/m3, and in females and both sexes combined at
concentrations >8400 mg/m3 (see Table 1). The percent decreases in mean fetal body weight
relative to controls were 5.2, 7.6, and 7.1%> at 5600, 8400, and 11,200 mg/m3, respectively, for
males; 5.1 and 5.6%> at 8400 and 11,200 mg/m3, respectively, for females; and 6.4 and 6.4%> at
8400 and 11,200 mg/m3, respectively, for males and females combined. The study authors
concluded that inhalation exposure to ethyl methacrylate did not produce evidence of
embryolethality or teratogenicity in any treatment group. Decreases in mean fetal body weight
on a per-litter basis were only observed at maternally toxic doses, as measured by significant
decreases in dam bodyweight gain, absolute body weight, and decreased food consumption. The
study authors do not identify maternal effect levels. Based on statistically significant (p < 0.05)
reduced body-weight gain, a maternal NOAEL of 2800 mg/m3 and a LOAEL of 5600 mg/m3 are
identified. Based on a significant decrease in mean male fetal body weight per litter, the study
authors identified a developmental NOAEL of 2800 mg/m3 and a LOAEL of 5600 mg/m3.
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Table 1. Statistically Significant Changes in Female Sprague-Dawley Rats and Their
Litters Treated with Ethyl Methacrylate via Inhalation on GDs 6-20

Exposure Concentration in mg/m3 (ppm)
Parameter
Control
(0 ppm)
2800
(600 ppm)
5600
(1200 ppm)
8400
(1800 ppm)
11,200
(2400 ppm)
HECa
0
HEC
700
HEC
1400
HEC
2100
HEC
2800
Number of animals treated
25
24
25
24
24
Number of dams/litters examined
23/25b
22/24
20/25
23/24
19/24
Body weight on GD 6 (g)
261 ± 18°
264 ± 20
259 ± 20
260 ± 19
264 ± 19
Body-weight gain (g)

GDs 6-13
29 ±9
24 ±6
19 ± 6d
16 ± 5d
9 ± 7d
GDs 13-21
96 ±22
103 ± 14
89 ± 15
85 ± 13
68 ± 18d
GDs 6-21
125 ± 26
127 ± 15
107 ±18d
101±14d
77 ± 21d
Absolute weight gain (g)e
28 ± 14
19 ±9
13 ± 12d
4 ± 9d
-7 ± 18d
Food consumption (g)

GDs 6-13
21 ± 2
20 ±2
17 ± 2d
17 ± 2d
15 ± 2d
GDs 13-21
25 ±2
25 ±2
22 ± 2d
22 ± 2d
20 ± ld
GDs 6-21
24 ±2
22 ± 1
20 ± 2d
19 ± 2d
18 ± ld
Average fetal body weight per litter (g)

Males
5.79 ±0.26
5.65 ±0.28
5.49 ± 0.35d
5.35 ± 0.34d
5.38 ± 0.41d
Females
5.43 ±0.32
5.34 ±0.20
5.24 ±0.34
5.14 ± 0.35d
5.10 ± 0.44d
Males and females
5.61 ±0.28
5.49 ±0.22
5.37 ±0.32
5.25 ± 0.32d
5.25 ± 0.42d
aHEC = Human Equivalent Concentration in mg/m3 (see RfC derivation text for calculation)
bNumber examined/number treated
°Mean ± SD
dSignificantly different from control atp< 0.05 by Dunnett's test
e(Day 21 body weight) - (gravid uterus weight) - (Day 6 body weight)
Source: Saillenfait et al. (1999).
OTHER STUDIES
Toxicokinetics
No standard toxicokinetic studies have been conducted with ethyl methacrylate.
However, metabolic studies of the acrylate esters (primarily conducted on ethyl and methyl
acrylates) in male Holtzman rats demonstrate that they are hydrolyzed by carboxylases to acrylic
acid and the corresponding alcohol (Silver and Murphy, 1981).
Toxicokinetic data are available for methyl methacrylate, a closely related structural
analog of ethyl methacrylate. Methyl methacrylate is rapidly absorbed following oral,
inhalation, and dermal administration, and it is metabolized to methanol and methacrylic acid,
and, eventually, to C02 via the citric acid cycle (reviewed by U.S. EPA, 1998). Similar
toxicokinetics have been observed with intravenous administration. Very little parent compound
is retained in the body. According to EPA (1998), exposure duration did not affect tissue
concentrations, suggesting that methyl methacrylate does not bioaccumulate. In rats,
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metabolism was observed to occur in the blood, with the rate of disappearance of parent
compound showing a first-order dose dependency and suggesting a simple serum enzymatic
reaction involving esterase-catalyzed hydrolysis to methanol and methacrylic acid (U.S. EPA,
1998). Substrate saturation can occur at elevated doses and several studies suggest that, in the
absence of available carboxylesterases, binding of parent compound with nonprotein sulfhydryl
compounds can occur. In in vitro experiments with methyl methacrylate, the enzymatic
substrate-saturation curve was reduced by the addition of inhibitors of nonspecific
carboxylesterase (U.S. EPA, 1998). In an in vivo study by Silver and Murphy (1981),
pretreatment with tri-o-cresyl phosphate (a carboxylesterase inhibitor) potentiated the acute
toxicity and reduced the level of tissue nonprotein sulfhydryls following a 4-hour inhalation
exposure of rats to either methyl or ethyl acrylate (Silver and Murphy, 1981). Methyl
methacrylate is also metabolized to methacrylic acid by carboxylesterase enzymes in the upper
respiratory tract of rats (primarily in olfactory tissue) following inhalation exposure and can
induce in situ toxicity (U.S. EPA, 1998). However, the rate of metabolism of ethyl methacrylate
may differ from methyl methacrylate, and the possibility of formation of other metabolite(s)
cannot be excluded.
Acute or Short-term Studies
Deichman et al. (1941) reported oral LD50 values for ethyl methacrylate ranging from
12.70 to 14.51 g/kg for rats and from 3.63 to 5.44 g/kg for rabbits.
To investigate structure-toxicity relationships and mechanisms, Ghanayem et al. (1985b)
tested the comparative gastric toxicities of methyl and ethyl acrylates and their substituted esters,
methyl methacrylate and ethyl methacrylate (99% purity), in male Fischer 344 rats (15/dose
group). A previous study in the same laboratory (Ghanayem et al., 1985a) had shown that single
or repeated gavage dose administration of ethyl acrylate caused extensive gastric toxicity in both
the forestomach and glandular stomach. In the Ghanayem et al. (1985b) study, the results of a
single dose of ethyl acrylate treatment were the same as in Ghanayem et al. (1985a). However,
an equimolar concentration (2 mmol/kg dissolved in corn oil) of ethyl methacrylate did not
induce gastric toxicity, as measured by an increase in the size of the stomach and forestomach
edema and changes in the flattening of the glandular stomach rugae 4 hours following dosing.
The study authors concluded that the methyl substitution at Carbon 2 decreases the direct
toxicity of ethyl acrylate, likely due to an increase in the chain length, which alters the polarity
and/or detoxification process of ethyl methacrylate.
Lawrence and Autian (1972) investigated whether ethyl methacrylate (used as a volatile
ingredient of dental products) might affect response to sedatives used in dentistry. Male ICR
mice (10/dose group) were exposed to vapors of ethyl methacrylate (purity not reported) in an
inhalation chamber at a target concentration of 84.79 mg/m3. The duration of exposure was
3.85, 7.70, or 19.25 minutes. Control mice were placed in the inhalation chamber for the longest
exposure time, but they received only air. Following treatment, mice were given a standard dose
of sodium pentobarbital (route not reported but, presumably, via injection), and the length of
sleeping time was monitored. Mean sleeping time was increased only in the group with
19.25 minutes of exposure as compared with controls (94.93 versus 50.63 minutes, respectively).
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Other Routes
In a subchronic neurotoxicity study, ethyl methacrylate (99% purity) was administered
(neat) to male Sprague-Dawley rats (10/dose group) via daily i.p. doses of 0, 100, 200, 400, or
800 mg/kg, 7 days/week, for 60 days (Abou-Donia et al., 2000). The volume of injected
compound varied with body weight and dose, and ranged from 0.02 to 0.16 mL/rat at the
beginning of the experiment and from 0.04 to 0.32 mL/rat at the end. Control animals received
0.1 mL/kg saline daily. Animals were monitored daily for mortality and clinical signs of
toxicity. Body weight was recorded weekly. In the control, 100-, 200-, and 400-mg/kg groups,
motor activity was assessed at the end of the exposure period and was followed by evaluation of
spatial memory in the Morris water maze. Behavioral testing was conducted by a single trained
observer who was blind to treatment. No other toxicological evaluations were conducted.
Motor activity was measured using sets of photobeam devices, placed strategically to
detect both horizontal and vertical movements, with computer data collection. Photobeam
interruptions were recorded at 5-minute intervals and subsequently summed over the 1-hour test
session. In the circular Morris water maze, a closed-circuit video camera was mounted above
the tank to track and transmit images of the swimming rat to a television monitor as well as to a
computer for data analysis. The image of the pool was divided into four separate quadrants, and
a submerged hidden Plexiglas platform was randomly placed in one of the quadrants. Each
animal was released into the pool from one of the quadrants not containing the platform and
allowed to swim for 60 seconds or until it located and climbed onto the escape platform. Rats
were given five trials per day with a 1-minute rest period between each trial. Animals were
trained daily until they successfully found the escape platform within 60 seconds on the last
four trials of a given day or until they had reached the 25th trial (5 days). Escape latencies were
then summed across the number of trials required to meet the designated criterion or through the
25th trial (Abou-Donia et al., 2000).
Significant mortality occurred in all treatment groups >200 mg/kg but was not
dose-dependent (Abou-Donia et al., 2000). Clinical signs of toxicity were increased in a
dose-dependent manner at doses of >200 mg/kg. Body-weight gains varied across treatment
groups, but the differences from control were sporadic, transient, and unrelated to dose. In the
motor activity test, a statistically significant, dose-dependent decrease in both horizontal and
vertical activity was observed in the 100-, 200-, and 400-mg/kg groups as compared with
controls. The effect of trial was also significant, but there was no significant interaction between
trial and treatment. In the Morris water maze, a significant decrease in escape latency was
observed across the 5 days of treatment, demonstrating that the platform location was being
learned. The effect of treatment was significant only in the 400-mg/kg group, with a significant
interaction between day and treatment on Test Days 3 and 5. The study authors concluded that
subchronic i.p. administration of ethyl methacrylate can produce dose-dependent clinical
abnormalities and impairment of motor activity, as well as disruption of spatial memory at the
highest dose tested (400 mg/kg).
Singh et al. (1972) examined the developmental toxicity of ethyl methacrylate and other
methacrylates administered intraperitoneally on GDs 5, 10, and 15 in female Sprague-Dawley
rats (5/dose group) following successful mating with untreated males. Single administered doses
of ethyl methacrylate (purity not mentioned) were 0.122, 0.245, and 0.408 mL/kg (equivalent to
0.111, 0.224, and 0.373 mg/kg, respectively) in the low-, mid-, and high-dose groups,
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respectively. No diluent was used. An untreated group of rats was maintained as controls. For
comparative purposes, cottonseed oil, distilled water, or normal saline were administered to
other groups of rats at a dose of 0.822 mL/kg to test the effects of various vehicles. Five female
rats were housed with a single male, and the onset of gestation was established by the presence
of sperm in the vaginal smear (designated as GD 0). Data on maternal toxicity were not
presented. Statistical tests used for data analysis were not reported; however, the fetus, rather
than the litter, was the unit of analysis. Endpoints examined were number of resorptions,
stillbirths, gross (external) and skeletal malformations, and mean fetal body weight. All dosed
groups showed a small, but statistically significant, increase in the number of fetal resorptions
(p < 0.05) relative to untreated controls. However, there did not appear to be significant
differences in this endpoint relative to the number of resorptions occurring in rat treated with
only distilled water or normal saline vehicle. A small—but statistically significant—increase in
the number of fetuses with gross abnormalities (e.g., hemangiomas on various parts of the fetus,
twisted hind legs, no tail) was reported to occur in all treated groups relative to pooled controls
(3/51, 5/42, and 8/48 in the low-, mid-, and high-dose groups, respectively, versus 0/59, 0/36,
1/50, and 1/50 in untreated, distilled water, normal saline, and cottonseed oil groups,
respectively). No effects on skeletal abnormalities were observed. Mean fetal body weights
were significantly decreased in the mid- and high-dose groups as compared with untreated, but
not vehicle, controls; the mean fetal body weights of all vehicle control groups were also
statistically significantly decreased relative to untreated controls. The numerous limitations of
this study preclude interpretation of the findings. No data on maternal toxicity, including
mortality, were given. Statistical methodology was not reported, and the litter was not used as
the unit of statistical analysis, so it is possible that the observed effects occurred only in a single
litter. Additionally, the sample size was small (5/dose group). Finally, similar effects on
resorption and mean fetal body weight were observed in vehicle controls, suggesting that these
findings were associated, at least in part, with i.p. injection procedures. Thus, the observed
effects could not be clearly attributed to ethyl methacrylate treatment.
Genotoxicity
Ethyl methacrylate was negative in the Ames bacterial mutagenicity assay using
Salmonella typhimurium tester strains TA98, TA100, TA1535, TA1537, and TA1538, with and
without Aroclor 1254- or phenobarbital-induced S9 mix (Zeiger et al., 1987; Waegemaekers and
Bensink, 1984). Preincubation of cell cultures prior to treatment also produced negative findings
with and without metabolic activation (Zeiger et al., 1987).
Ethyl methacrylate was also evaluated for mutagenicity and clastogenicity without
exogenous activation in L578Y mouse lymphoma cells at concentrations ranging from 900 to
2100 |ig/mL (Moore et al., 1988). A weakly positive response (approximately twice the
background rate) was induced at cytotoxic concentrations >1000 |ag/m L and then only at
10-20% survival rates. The dose-response curve was nonlinear, and the study authors attribute
these findings to possible induction of chromosomal aberrations rather than point mutations. A
weakly positive clastogenic response (less than twice the background rate) was also observed in
cell cultures treated separately for analysis of chromatid and chromosomal aberrations
(Moore et al., 1988).
In in vitro genotoxicity testing using Chinese hamster ovary (CHO) cells, ethyl
methacrylate was negative for chromosomal aberrations at plate concentrations ranging from
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1000 to 3000 |ig/mL with and without exogenous rat liver S9 activation (NTP, 2009b). Ethyl
methacrylate was positive for sister chromatid exchanges (SCEs) at plate concentrations ranging
from 1000 to 4000 |ig/mL, with cytotoxicity occurring at higher doses (NTP, 2009b). No
information on genotoxicity endpoints examined in animals treated with ethyl methacrylate in
vivo was located in the available literature.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR ETHYL METHACRYLATE
SUBCHRONIC p-RfD
Oral toxicity data are limited to a single neurotoxicity study (Abou-Donia et al., 2000) in
which ethyl methacrylate was administered in drinking water to male Sprague-Dawley rats for
60 days. However, if this study were to be used as the principal study for the derivation of the
subchronic RfD, the composite UF would be 10,000. Based on current guidelines and SOPs, a
composite UF >3000 cannot be considered for reference value derivation. As such, while a
subchronic p-RfD cannot be derived here, Appendix A of this document contains an oral
"screening value" that may be useful in certain instances. Please refer to Appendix A for details.
CHRONIC p-RfD
There are no chronic oral studies of ethyl methacrylate. A subchronic neurotoxicity
study using only one species (rat) and sex (male) has been conducted, and this study did not
identify a NOAEL. Data for evaluating systemic effects other than neurotoxicity and
reproductive/developmental toxicity via i.p. exposure are not available nor are any oral
toxicological data in another species or in female animals. Due to these database deficiencies,
the data do not support the derivation of a chronic p-RfD.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR ETHYL METHACRYLATE
The only available inhalation study of ethyl methacrylate is a developmental toxicity
study (Saillenfait et al., 1999) in Sprague-Dawley rats. Table 1 summarizes the results of this
study. The only treatment-related effects were large, statistically significant decreases in
maternal body-weight gain (both before and after adjustment for gravid uterine weight) at
exposure concentrations >5600 mg/m3 and decreases in male fetal body weight (on a per-litter
basis) at >5600 mg/m3, and in female and combined male and female fetal body weights at
>8400 mg/m3. No other effects on reproductive and developmental parameters were observed.
SUBCHRONIC p-RfC
Dose-response modeling was performed for corrected (adjusted for gravid uterine
weight) body-weight gain in dams and for mean fetal body weight per litter in males
(Saillenfait et al., 1999). For fetal males, the data were modeled on a per-litter basis as the litter
is considered to be the experimental unit in developmental toxicity studies (U.S. EPA, 1991b).
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Exposure concentrations were adjusted for intermittent dosing (as per guidance provided
by U.S. EPA, 2002) and human equivalent concentrations (HECs) were determined prior to
modeling. The maternal and developmental NOAELrec of 700 mg/m3 was calculated from the
rat NOAEL of 2800 mg/m3 using EPA (1994b) methodology for an extrarespiratory effect
produced by a Category 3 gas, as follows:
NOAELadj = 2800 mg/m3 x 6 hours 24 hours
= 700 mg/m3
NOAELhec = NOAELadj x (Hb/g)A ^ (Hb/g)H
= 700 mg/m3 x 1
= 700 mg/m3
where:
(Hb/g)A ^ (Hb/g)H = the ratio of the blood:gas (air) partition coefficient of the
chemical for the laboratory animal species to the human
value. In the absence of data for ethyl methacrylate, the
default value of 1 was used, as specified in EPA (1994b)
guidance.
Appendix B contains details of the BMD modeling. For maternal data, a benchmark
response (BMR) of 1 standard deviation (SD) from the mean was used. The BMCrec and
BMCLrec associated with the best fitting model for this data set were 1103 and 854 mg/m3,
respectively.
For male fetal body-weight data, a BMR of a 5% change from the control mean (relative
deviation) was used. This BMR level is considered to be less sensitive to background variability
in fetal body weight than a change of 1 SD from the control mean and yields a BMD that more
closely approximates a NOAEL (Allen et al., 1996; Kavlock et al., 1995). The BMCosHEcand
BMCL05hec associated with the best-fitting model were 1794 and 1386 mg/m3, respectively.
The lowest BMCLrec value of 854 mg/m3 (Saillenfait et al., 1999) was selected as the
point of departure (POD) for derivation of a subchronic p-RfC because it is protective of both
fetal and maternal toxicity. This BMCLrec was divided by a composite UF of 300 to derive a
subchronic p-RfC for ethyl methacrylate, as follows:
Subchronic p-RfC = BMCLrec ^ UF
= 854 mg/m3 -300
= 3 mg/m3 or 3 x 10° mg/m3
The composite UF of 300 is composed of the following UFs:
• UFa: A factor of 3 (10°5) is applied for animal-to-human extrapolation because
derivation of a HEC from the animal data partially adjusts for interspecies sensitivity
(U.S. EPA, 1994b).
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•	UFd: The database contains a developmental toxicity study in one species. However,
because subchronic, chronic, developmental toxicity in a second species, and
multigeneration reproductive toxicity studies have not been conducted, the
identification of more sensitive endpoints from ethyl methacrylate inhalation could
have been potentially missed. Thus, a factor of 10 is applied for database limitations.
•	UFh: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because data for evaluating a susceptible human response are
insufficient.
•	UFl: A factor of 1 is applied for extrapolation from a LOAEL to a NOAEL because a
BMCL was used as the POD.
Confidence in the principal study (Saillenfait et al., 1999) is high. This study included
24-25 animals per group and five exposure levels, utilized appropriate statistical methodology,
assessed litter effects, investigated a suitable range of endpoints, and established both a NOAEL
and LOAEL. Confidence in the database is, however, low. Subchronic, chronic, and
multigeneration reproductive toxicity studies have not been conducted and developmental
toxicity data in a second species are also lacking. Low confidence in the subchronic p-RfC
value follows.
CHRONIC p-RfC
To derive the chronic p-RfC using the POD of 854 mg/m3 for decreased maternal
body-weight gain in the developmental toxicity study (Saillenfait et al., 1999), a composite UF is
applied that includes the same areas of uncertainty enumerated above for the subchronic p-RfC,
as well as an additional 10-fold UF, as follows:
•	UFS: A factor of 10 is applied for using data from a less-than-lifetime study to assess
potential effects from chronic exposure.
This results in a composite UF of 3000 for derivation of the chronic p-RfC.
A chronic p-RfC for ethyl methacrylate is derived from the BMCLhec of 854 mg/m3
(Saillenfait et al., 1999) as follows:
Chronic p-RfC = BMCLhec - UF
= 854 mg/m3 - 3000
= 0.3 mg/m3 or 3 x 10_1 mg/m3
As discussed for the subchronic p-RfC, confidence in the principal study is high,
confidence in the database is low, and overall confidence in the chronic p-RfC is low.
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PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR ETHYL METHACRYLATE
WEIGHT-OF-EVIDENCE DESCRIPTOR
Under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), there is
"Inadequate Information to Assess [the] Carcinogenic Potential" of ethyl methacrylate. No
information was located on the potential carcinogenicity of ethyl methacrylate in either humans
or animals. A limited number of in vitro studies suggest that ethyl methacrylate is not mutagenic
but may be weakly genotoxic. In bacterial mutagenicity assays conducted in two different
laboratories, ethyl methacrylate was not observed to be mutagenic with or without exogenous
metabolic activation in all S. typhimurium strains tested (Zeiger et al., 1987; Waegemaekers and
Bensink, 1984). In L5178Y mouse lymphoma cells, ethyl methacrylate was weakly positive for
both mutagenicity and clastogenicity at cytotoxic plate concentrations with 10-20% cell survival
rates (Moore et al., 1988). In CHO cells, ethyl methacrylate was negative for chromosomal
aberrations and positive for SCE (NTP, 2009b). No in vivo genotoxicity studies are available
for ethyl methacrylate.
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK
Derivation of quantitative estimates of cancer risk for ethyl methacrylate ether is
precluded by the lack of available data.
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Abou-Donia, MB; Abdel-Rahman, AA; Kishk, AM; et al. (2000) Neurotoxicity of ethyl
methacrylate in rats. J Toxicol Environ Health A 59(2):97-118.
ACGIH (American Conference of Governmental Industrial Hygienists). (2009) Threshold limit
values for chemical substances and physical agents and biological exposure indices.
Cincinnati, OH.
Allen, BC; Strong, PL; Price, CJ; et al. (1996) Benchmark dose analysis of developmental
toxicity in rats exposed to boric acid. Fundam Appl Toxicol 32(2): 194-204.
ATSDR (Agency for Toxic Substances and Disease Registry). (2009) Toxicological profile
information sheet. U.S. Department of Health and Human Services, Public Health Service.
Available online at http://www.atsdr.cdc.gov/toxpro2.html (accessed September 2, 2009).
Borzelleca, JF; Larson, PS; Hennigar, GS; et al. (1964) Studies on the chronic oral toxicity of
monomeric ethyl acrylate and methyl methacrylate. Toxicol Appl Pharmacol 6:29-35.
CalEPA (California Environmental Protection Agency). (2009a) Search chronic RELs. Office
of Environmental Health Hazard Assessment. Available online at http://www.oehha.ca.gov/air/
chronic_rels/index.html (accessed September 2, 2009).
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CalEPA (California Environmental Protection Agency). (2009b) Search toxicity criteria
database. Office of Environmental Health Hazard Assessment. Available online at
http://www.oehha.ca.gov/risk/ChemicalDB/index.asp (accessed September 2, 2009).
Cosmetic Ingredient Review Expert Panel. (2002) Amended final report on the safety
assessment of ethyl methacrylate. Int J Toxicol 21(Suppl. l):63-79.
Deichman W. (1941) Toxicity of methyl, ethyl and n-butyl methacrylate. J Ind Hyg Toxicol
23:343.
Ghanayem, BI; Maronpot, RR; and Matthews, HB. (1985a) Ethyl acrylate-induced gastric
toxicity. I. Effects of single and repetitive dosing. Toxicol Appl Pharmacol 80:323-335.
Ghanayem, BI; Maronpot, RR; and Matthews, HB. (1985b) Ethyl acrylate-induced gastric
toxicity. II. Structure-toxicity relationships and mechanism. Toxicol Appl Pharmacol
80:336-344.
Hiipakka, D; Samimi, BH. (1987) Exposure of acrylic fingernail sculptors to organic vapors and
methacrylate dusts. J Am Ind Hyg Assoc 48(3):230-237.
IARC (International Agency for Research on Cancer). (2009) IARC monographs on the
evaluation of carcinogenic risks to humans. Available online at http://monographs.iarc.fr/ENG/
Monographs/allmonos90.php (accessed September 2, 2009).
Kavlock, RJ; Allen, BC; Faustman, EM; et al. (1995) Dose-response assessments for
developmental toxicity. Fundam Appl Toxicol 26:211-222.
Lawrence, WH; Autian, J. (1972) Possible toxic effects from inhalation of dental ingredients by
alterations of drug biologic half-life. J Dental Res 41(3): 878-879.
Moore, MM; Amtower, A; Doerr, CL; et al. (1988) Genotoxicity of acrylic acid, methyl acrylate,
methyl methacrylate, and ethyl methacrylate in L5178 mouse lymphoma cells. Environ Molec
Mutagen 11:48-63.
NIOSH (National Institute for Occupational Safety and Health). (2009) NIOSH pocket guide to
chemical hazards. Index by CASRN. Available online at http://www2.cdc.gov/nioshtic-
2/nioshtic2.htm (accessed September 2, 2009).
NTP (National Toxicology Program). (2005) 11th Report on carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Available online at http://ntp-server.niehs.nih.gov/ (accessed
September 2, 2009).
NTP (National Toxicology Program). (2009a) Management Status report. Available online at
http://ntp.niehs.nih.gov/index.cfm?objectid=78CC7E4C-FlF6-975E-72940974DE301C3F
(accessed September 2, 2009).
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NTP (National Toxicology Program). (2009b). Ethyl methacrylate. Testing status of agents at
NTP. Available online at http://ntp.mehs.nih.gov/index.cfm?objectid=BD609C4B-123F-7908
=7B217137FBB991D9 (accessed July 13, 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=STANDARDS&p_id=999
2 (accessed September 2, 2009).
Saillenfait, AM; Bonnet, P; Gallissot, F; et al. (1999) Developmental toxicities of methacrylic
acid, ethyl methacrylate, n-butyl methacrylate, and allyl methacrylate in rats following inhalation
exposure. Toxicol Sci 50(1): 136-145.
Silver, EH; Murphy, SD. (1981) Potentiation of acrylate ester toxicity by prior treatment with
the carboxylesterase inhibitor triorthotolyl phosphate (TOCP). Toxicol Appl Pharmacol
57:208-210.
Singh, AR; Lawrence, WH; Autian, J. (1972) Embryonic-fetal toxicity and teratogenic effects of
a group of methacrylate esters in rats. J Dent Res 51(6): 1632-1638.
U.S. EPA (U.S. Environmental Protection Agency). (1986a) Health and Environmental Effects
Profile (HEEP) for ethyl methacrylate. Environmental Criteria and Assessment Office; Office of
Health and Environmental Effects, Cincinnati, OH. ECAO-CIN-P173.
U.S. EPA (U.S. Environmental Protection Agency). (1986b) Guidelines for carcinogen risk
assessment. Prepared by the Risk Assessment Forum, U.S. Environmental Protection Agency.
Washington, DC.
U.S. EPA (U.S. Environmental Protection Agency). (1988). Recommendations for and
Documentation of Biological Values for Use in Risk Assessment. Environmental Criteria and
Assessment Office; Office of Health and Environmental Effects, Cincinnati, OH.
U.S. EPA (U.S. Environmental Protection Agency). (1991a) Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC.
U.S. EPA (U.S. Environmental Protection Agency). (1991b) Guidelines for developmental
toxicity risk assessment. Risk Assessment Forum, U.S. Environmental Protection Agency,
Washington, DC. EPA/600/FR-91/001.
U.S. EPA (U.S. Environmental Protection Agency). (1994a) Chemical Assessments and Related
Activities (CARA). Office of Health and Environmental Assessment, Washington, DC.
U.S. EPA (U.S. Environmental Protection Agency). (1994b) Methods of derivation of inhalation
reference concentrations and application of inhalation dosimetry. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC.
EPA/600/8-90/066F.
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U.S. EPA (U.S. Environmental Protection Agency). (1997) Health Effects Assessment Summary
Tables. 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 (U.S. Environmental Protection Agency). (1998) Toxicological review of methyl
methacrylate. Available online at http://www.epa.gov/ncea/iris/toxreviews/1000-tr.pdf
(accessed September 2, 2009).
U.S. EPA (U.S. Environmental Protection Agency). (2002) A review of the reference dose and
reference concentration processes. Risk Assessment Forum, U.S. Environmental Protection
Agency, Washington, DC. EPA/630/P-02/002F.
U.S. EPA (U.S. 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 (U.S. 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/drinking/standards/
dwstandards.pdf (accessed September 2, 2009).
U.S. EPA (U.S. Environmental Protection Agency). (2009) 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 September 2, 2009).
Waegemaekers, THJM; Bensink, MPM. (1984) Nonmutagenicity of 27 aliphatic acrylate esters
in the Salmonella microsome test. Mutat Res 137(2-3):95-102.
WHO (World Health Organization). (2009) Online catalogs for the Environmental Health
Criteria Series. Available online at http://www.who.int/ipcs/publications/ehc/ehc_numerical/en/
index.html (accessed September 2, 2009).
Zeiger, E; Anderson, B; Haworth, S; et al. (1987) Salmonella mutagenicity tests: III. Results
from the testing of 255 chemicals. Environ Mutagen 9(Suppl. 9): 1-110.
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APPENDIX A. DERIVATION OF A SCREENING VALUE
FOR ETHYL METHACRYLATE
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for ethyl methacrylate. 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 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. Hazard identification and dose-response information contained in an Appendix
receives the same level of internal and external scientific peer review as the main body of
PPRTV documents, to ensure their appropriateness within the limitations detailed in the
document. In the OSRTI hierarchy, screening values are considered to be below Tier 3, "Other
(Peer-Reviewed) Toxicity Values."
Screening values are intended for use in limited circumstances when no Tier 1, 2, or
3 values are available. Screening values may be used, for example, to rank relative risks of
individual chemicals present at a site to determine if the risk developed from the associated
exposure at the specific site is likely to be a significant concern in the overall cleanup decision.
Screening values are not defensible as the primary drivers in making cleanup decisions because
they are based on limited (e.g., scope, depth, validity, etc.) information. Questions or concerns
about the appropriate use of screening values should be directed to the Superfund Health Risk
Technical Support Center.
SCREENING SUBCHRONIC ORAL VALUE
As noted earlier, oral toxicity data are limited to a single neurotoxicity study
(Abou-Donia et al., 2000) in which ethyl methacrylate was administered in drinking water to
male Sprague-Dawley rats for 60 days. The endpoints measured were limited to mortality,
clinical signs of toxicity, body weight, and histopathology of the brain, spinal cord, and sciatic
nerve. Dose-dependent clinical signs of neurotoxicity were observed at the two highest doses,
and significant central nervous system histology was observed at all treatment levels (p < 0.05).
The major histopathological findings were as follows: (1) a statistically significant increase in
the number of clusters of enlarged axons (>0.05 mm in diameter), primarily at internodal
segments, throughout the dorsal, ventral, and lateral columns of the spinal cord; and (2) a
statistically significant reduction in the number of neurons in sections of the ventral horn of the
spinal cord.
Abou-Donia et al. (2000) presented no raw data. Therefore, benchmark dose-response
modeling could not be conducted and, consequently, the lowest-observed-adverse-effect level
[LOAEL] of 139 mg/kg-day for neurotoxicity was selected as the point of departure (POD) for
derivation of a screening subchronic p-RfD (a no-observed-adverse-effect level [NOAEL] was
not identified in this study). No adjustment was needed for exposure duration as ethyl
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methacrylate was administered continuously in drinking water for 60 days. This LOAEL was
divided by a composite uncertainty factor (UF) of 10,000 to derive a screening subchronic
p-RfD for ethyl methacrylate, as follows:
Screening Subchronic p-RfD = LOAEL UF
= 139 mg/kg-day ^ 10,000
= 0.01 mg/kg-day or 1 x 10~2 mg/kg-day
The composite UF of 10,000 is composed of the following UFs:
•	UFa: A factor of 10 is applied for animal-to-human extrapolation because the data
for evaluating relative interspecies sensitivity are insufficient.
•	UFd: A subchronic neurotoxicity study using only one species (rat) and sex (male)
has been conducted. Data for evaluating systemic effects other than neurotoxicity
and reproductive/developmental toxicity via i.p. exposure are not available. A
developmental study by inhalation exposure was conducted in only one species (rats).
A factor of 10 is applied for database inadequacies because the data for evaluating
systemic toxicity and developmental and reproductive toxicity are insufficient.
•	UFh: A factor of 10 is applied for extrapolation to a potentially susceptible human
subpopulation because the data for evaluating a susceptible human response are
insufficient.
•	UFl: A factor of 10 is applied for extrapolating from a LOAEL to a NOAEL.
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APPENDIX B. DETAILS OF BENCHMARK DOSE MODELING
FOR THE PROVISIONAL RfCs
MODEL-FITTING PROCEDURE FOR CONTINUOUS DATA
The benchmark dose (BMD) modeling for continuous data was conducted with the
EPA's BMD software (BMDS). The original data were modeled with all the continuous models
available within the software employing a BMR of 1 SD. An adequate fit was judged based on
three criteria: (1) the goodness-of-fitp value (p > 0.1), (2) magnitude of scaled residuals in the
vicinity of the benchmark response (BMR), and (3) visual inspection of the model fit. In
addition to the three criteria forjudging the adequate model fit, whether the variance needed to
be modeled, and if so, how it was modeled also determined final use of the model results. If a
constant variance model was deemed appropriate based on the statistical test provided in the
BMDS (i.e., Test 2), the final BMD results were estimated from a constant variance model. If
the test for constant variance was rejected (p< 0.1), the model was run again while modeling the
variance as a power function of the mean to account for this nonconstant variance. If this
nonconstant variance model did not adequately fit the data (i.e., Test 3; />value < 0.1), the data
set was considered unsuitable for BMD modeling. Among all models providing adequate fit, the
lowest BMCL was selected if the BMCLs estimated from different models varied >3-fold;
otherwise, the BMCL from the model with the lowest Akaike's Information Criterion (AIC) was
selected as a potential point of departure (POD) from which to derive an RfD.
MODEL FITTING RESULTS FOR CORRECTED WEIGHT GAIN IN DAMS
All available continuous models in the BMDS (version 2.1.1) have been fit to the
corrected weight gain in Sprague-Dawley dams treated with ethyl methacrylate via inhalation on
Gestation Days (GDs) 6-20 (Saillenfait et al., 1999) (see Table B-l). BMD modeling has been
performed using the calculated human equivalent concentrations (HECs). A BMR of 1 SD from
the control mean was used in the BMD modeling. No adequate model fits were provided with
constant and nonconstant variance. However, visual inspection of the dose-response curve
suggested that the dose-response relationship is better characterized in the low-dose region.
Thus, the highest dose was removed from the analysis for statistical and biological
considerations. Again, no adequate model fits were provided with constant variance after
removing the highest dose, but an adequate fit to the means was provided with nonconstant
variance for all of the continuous models. The linear and power models were determined to be
the best fitting models based on AIC, and the BMCisdhec and BMCLisdhec are predicted to be
1103 and 854 mg/m3, respectively (see Table B-l and Figure B-l).
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Table B-l. BMD Modeling Results Based on Corrected Body-Weight Gain (g) in
Sprague-Dawley Dams Treated with Ethyl Methacrylate via Inhalation on GDs 6-20
Model
Test 2
Test 3
Goodness-of-Fit
p-Value
AIC
BMCisdhec
(mg/m3)
BMCLisdhec
(mg/m3)
All Doses
Linear3'b
0.0048
0.0019
0.8248
654.098
1025.99
853.15
Polynomial3'13
0.0048
0.0019
0.7943
655.656
1172.92
866.05
Powerb'c
0.0048
0.0021
<0.0001
650.347
1119.84
N/A
Hillbc
0.0048
<0.0001
<0.0001
751.228
N/A
N/A
Four Doses (without the highest dose group)
Lineara'b
0.0855
0.1777
0.7208
514.559
1103.36
854.33
Polynomial3'13
0.0855
0.1777
0.4184
516.559
1103.77
854.33
Powerb'c
0.0855
0.1777
0.7208
514.559
1103.36
854.33
Hillbc
0.0855
0.1777
0.4177
516.561
1092.27
846.36
aRestrict betas < 0
bNonconstant variance
°Restrict power > 1
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Linear Model with 0.95 Confidence Level
dose
11:11 02/102010
BMCs and BMCLs indicated are HECs associated with a change of 1 SD from the
control and are in units of mg/m3.
Figure B-l. Fit of Linear Model (Nonconstant Variance) to Data (Without the
Highest Dose Group) on Corrected Weight Gain (g) in Sprague-Dawley Dams
Treated with Ethyl Methacrylate via Inhalation on GDs 6-20
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Linear Model. (Version: 2.13; Date: 04/08/2008)
Input Data File: C:\USEPA\BMDS21\Data\lin_Et_Meth_Weight_Gain_Lin-
ModelVariance-BMRlStd.(d)
Gnuplot Plotting File: C:\USEPA\BMDS21\Data\lin_Et_Meth_Weight_Gain_Lin-
ModelVariance-BMRlStd.pit
Wed Feb 10 11:11:02 2010
BMDS Model Run
The form of the response function is:
Y[dose] = beta 0 + beta l*dose + beta 2*dose/s2 + ...
Dependent variable = Mean
Independent variable = Dose
The polynomial coefficients are restricted to be negative
The variance is to be modeled as Var(i) = exp(lalpha + log(mean(i)) * rho)
Total number of dose groups = 4
Total number of records with missing values = 0
Maximum number of iterations = 25 0
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
lalpha =	4.83126
rho =	0
beta_0 =	27.7
beta 1 = -0.0111429
Asymptotic Correlation Matrix of Parameter Estimates
lalpha
rho
beta_0
beta 1
lalpha
1
-0.96
-0.0084
0. 014
rho
-0. 96
1
0. 0085
-0.014
beta_0
-0.0084
0.0085
1
-0.84
beta_l
0.014
-0.014
-0.84
1
Interval
Variable
Limit
lalpha
4.92283
rho
0.756466
beta_0
31.8281
Parameter Estimates
95.0% Wald Confidence
Estimate	Std. Err.	Lower Conf. Limit Upper Conf.
3.85113	0.546795	2.77943
0.353818	0.205436	-0.0488302
27.7234	2.09431	23.6186
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beta_l	-0.0111892	0.00141385	-0.0139603
0.00841809
Table of Data and Estimated Values of Interest
Dose	N Obs Mean	Est Mean Obs Std Dev Est Std Dev Scaled Res.
0 23	28	27.7	14	12.3	0.107
700 22	19	19.9	9	11.6	-0.359
1400 20	13	12.1	12	10.7	0.395
2100 23	4	4.23	9	8.85	-0.122
Model Descriptions for likelihoods calculated
Model A1:	Yij = Mu(i) + e(ij)
Var {e (i j ) }AugustlO = SigmaA2
Model A2:	Yij = Mu(i) + e(ij)
Var{e(ij)} = Sigma(i)A2
Model A3:	Yij = Mu(i) + e(ij)
Var{e(ij)} = exp(lalpha + rho*ln(Mu(i)))
Model A3 uses any fixed variance parameters that
were specified by the user
Model R:	Yi = Mu + e(i)
Var{e(i)} = Sigma/S2
Likelihoods of Interest
Model
A1
A2
A3
fitted
R
Log(likelihood)
-254.528637
-251.224514
-252.952258
-253.279623
-276.957118
# Param's
5
8
6
4
2
AIC
519.057274
518.449028
517.904516
514.559245
557.914236
Explanation of Tests
Do responses and/or variances differ among Dose levels?
(A2 vs. R)
Are Variances Homogeneous? (A1 vs A2)
Are variances adeguately modeled? (A2 vs. A3)
Does the Model for the Mean Fit? (A3 vs. fitted)
Test 1:
Test 2
Test 3
Test 4
(Note: When rho=0 the results of Test 3 and Test 2 will be the same.)
Tests of Interest
Test -2*log(Likelihood Ratio) Test df	p-value
Test 1
Test 2
Test 3
Test 4
51.4652
6.60825
3.45549
0.654729
<.0001
0. 08549
0.1777
0.7208
The p-value for Test 1 is less than .05. There appears to be a
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difference between response and/or variances among the dose levels
It seems appropriate to model the data
The p-value for Test 2 is less than .1. A non-homogeneous variance
model appears to be appropriate
The p-value for Test 3 is greater than .1. The modeled variance appears
to be appropriate here
The p-value for Test 4 is greater than .1. The model chosen seems
to adeguately describe the data
Benchmark Dose Computation
Specified effect
1
Risk Type
Estimated standard deviations from the control mean
Confidence level
0. 95
BMD
1103.36
BMDL
854.334
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MODEL-FITTING RESULTS FOR AVERAGE FETAL BODY WEIGHT PER LITTER
IN MALES
All available continuous models in the BMDS (version 2.1.1) have been fit to the average
fetal body weight in male offspring of Sprague-Dawley dams (on a per-litter basis) treated with
ethyl methacrylate via inhalation on GDs 6-20 (Saillenfait et al., 1999) (see Table B-l). BMD
modeling has been performed using the calculated HECs. For this data set, a BMR of a 5%
change from the control mean (relative deviation) was used. All of the continuous models
provided an adequate fit to the means. The difference between the BMCLs from these models
was less than 3-fold, so the best fitting model was determined using the AIC. The linear,
polynomial, and power models all converged on the same result with the lowest AIC. Thus, the
BMCosHEcand BMCL05HEcare 1794 and 1386 mg/m3, respectively (see Table B-2 and
Figure B-2).
Table B-2. BMD Modeling Results Based on Changes in Average Fetal Body Weight (g) in
Male Offspring of Sprague-Dawley Dams (on a Per-Litter Basis) Treated with Ethyl
Methacrylate via Inhalation on GDs 6-20
Model
Test 2
Test 3
Goodness-of-Fit
/?-Value
AIC
BMCoshec
(mg/m3)
BMCLqshec
(mg/m3)
Lineara'b
0.1689
0.1689
0.3989
-143.243
1794.43
1385.69
Polynomiarb
0.1689
0.1689
0.3989
-143.243
1794.43
1385.69
Powerb'c
0.1689
0.1689
0.3989
-143.243
1794.43
1385.69
Hillbc
0.1689
0.1689
0.4463
-141.617
1251.34
725.78
aRestrict betas < 0
bConstant variance
°Restrict power > 1
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Linear Model with 0.95 Confidence Level
dose
11:32 02/10 2010
BMCs and BMCLs indicated are HECs associated with a BMR of 5% change from the
control (relative deviation) and are in units of mg/m3.
Figure B-2. Fit of Linear Model (Constant Variance) to Data on Average Fetal
Weight per Litter in Male Offspring of Dams Treated with Ethyl Methacrylate
via Inhalation on GDs 6-20
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Linear Model. (Version: 2.13; Date: 04/08/2008)
Input Data File: C:\USEPA\BMDS21\Data\lin_Et_Meth_Fetal_BW_Lin-
ConstantVariance-BMR05.(d)
Gnuplot Plotting File: C:\USEPA\BMDS21\Data\lin_Et_Meth_Fetal_BW_Lin-
ConstantVariance-BMR05.pit
Wed Feb 10 11:32:07 2010
BMDS Model Run
The form of the response function is:
Y[dose] = beta 0 + beta l*dose + beta 2*dose/s2 + ...
Dependent variable = Mean
Independent variable = Dose
rho is set to 0
The polynomial coefficients are restricted to be negative
A constant variance model is fit
Total number of dose groups = 5
Total number of records with missing values = 0
Maximum number of iterations = 25 0
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
alpha =	0.110177
rho =	0 Specified
beta_0 =	5.756
beta 1 =	-0.00016
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -rho
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
alpha	beta_0	beta_l
alpha	1 -3.8e-011	2.9e-011
beta_0 -3.8e-011	1	-0.81
beta 1	2.9e-011	-0.81	1
Parameter Estimates
95.0% Wald Confidence
Interval
Variable	Estimate	Std. Err.	Lower Conf. Limit Upper Conf.
Limit
alpha	0.10825	0.0138601	0.0810853
0.135416
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beta_0
5.85706
beta_l
0.00010142
5.75649
-0.000160399
0. 0513143
3.0092e-005
5.65591
-0.000219378
Table of Data and Estimated Values of Interest
Dose
Obs Mean
Est Mean Obs Std Dev Est Std Dev Scaled Res.
0
700
1400
2100
2800
25
24
25
24
24
5.79
5. 65
5.49
5.35
5.38
5.76
5 . 64
5.53
5.42
5.31
0.26
0.28
0.35
0.34
0.41
0.329
0.329
0.329
0.329
0.329
0.509
0.0862
-0.637
-1. 04
1. 08
Model Descriptions for likelihoods calculated
Model A1:	Yij = Mu(i) + e(ij)
Var{e(ij)} = SigmaA2
Model A2:	Yij = Mu(i) + e(ij)
Var{e(ij)} = Sigma(i)^2
Model A3:	Yij = Mu(i) + e(ij)
Var{e(ij)} = Sigma^
Model A3 uses any fixed variance parameters that
were specified by the user
Model R:	Yi = Mu + e(i)
Var{e(i)} = Sigma/S2
Likelihoods of Interest
Model
A1
A2
A3
fitted
R
Log(likelihood)
76.098410
79.316053
76.098410
74 . 621747
61.850991
# Param's
6
10
6
3
2
AIC
-140.196821
-138.632106
-140.196821
-143.243495
-119.701982
Explanation of Tests
Test 1: Do responses and/or variances differ among Dose levels?
(A2 vs. R)
Test 2: Are Variances Homogeneous? (A1 vs A2)
Test 3: Are variances adeguately modeled? (A2 vs. A3)
Test 4: Does the Model for the Mean Fit? (A3 vs. fitted)
(Note: When rho=0 the results of Test 3 and Test 2 will be the same.)
Tests of Interest
Test
Test 1
Test 2
Test 3
-2*log(Likelihood Ratio) Test df
34.9301
6.43529
6.43529
p-value
<.0001
0.1689
0.1689
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Test 4
2.95333
3
0.3989
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose levels
It seems appropriate to model the data
The p-value for Test 2 is greater than .1. A homogeneous variance
model appears to be appropriate here
The p-value for Test 3	is greater than .1. The modeled variance appears
to be appropriate here
The p-value for Test 4	is greater than .1. The model chosen seems
to adeguately describe the data
Benchmark Dose Computation
Specified effect
0. 05
Risk Type
Relative risk
Confidence level
0. 95
BMD
1794.43
BMDL
1385.69
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