FINAL DRAFT
tKss ECAO-C1N-P228
environmental Protection Hciy, 1987
Agency
xe/EPA Research and
HEALTH AND ENVIRONMENTAL EFFECTS PROFILE
FOR ETHYL ACRYLATE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It is being circulated for comments
on its technical accuracy and policy implications.
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DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
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PREFACE
Health and Environmental Effects Profiles (HEEPs) are prepared for the
Office of Solid Waste and Emergency Response by the Office of Health and
Environmental Assessment. The HEEPs are Intended to support listings of
hazardous constituents of a wide range of waste streams under Section 3001
of the Resource Conservation and Recovery Act (RCRA), as well as to provide
health-related limits for emergency actions under Section 101 of the Compre-
hensive Environmental Response, Compensation and Liability Act (CERCLA).
Both published literature and Information obtained from Agency program
office files are evaluated as they .pertain to potential human health,
aquatic life and environmental effects of hazardous waste constituents. The
literature searched and the dates of the searches are Included 1n the
section titled "Appendix: Literature Searched." The literature search
material 1s current through November, 1985.
Quantitative estimates are presented provided sufficient data are
available. For systemic toxicants, these Include Reference doses (RfOs) for
chronic exposures. An RfD 1s defined as the amount of a chemical to which
humans can be exposed on a dally basis over an extended period of time
(usually a lifetime) without sufferings deleterious effect. In the case of
suspected carcinogens, RfDs are not estimated in this document series.
Instead, a carcinogenic potency factor of q-|* is provided. These potency
estimates are derived for both oral and Inhalation exposures where possible.
In addition, unit risk estimates for air and drinking water are presented
based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxlcity and carcino-
genlclty are derived. The RQ is used to determine the quantity of a hazard-
ous substance for which notification 1s required 1n the event of a release
as specified under CERCLA. These two RQs (chronic toxlcity and cardnogen-
1city) represent two of six scores developed (the remaining four reflect
IgnitabilHy, reactivity, aquatic toxidty and acute mammalian toxlcity).
The first draft of this document was prepared by Syracuse Research
Corporation under EPA Contract No. 68-03-3228. The document was subse-
quently revised after rev.iews by staff within the .Office of Health and
Environmental Assessment: Carcinogen Assessment Group, Reproductive Effects
Assessment Group, Exposure Assessment Group, and the Environmental Criteria
and Assessment Office in Cincinnati.
The.HEEPs will become part of the EPA RCRA and CERCLA dockets.
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EXECUTIVE SUMMARY
Ethyl acrylate 1s a colorless liquid with an. acrid odor (Wlndholz,
1983). It Is soluble In alcohol, ether and chloroform, and 1s reasonably
soluble in water (Heast, 1985; Wlndholz, 1983). It Is a monomer used In the
production of a variety of polymers, such as flexible resins for latex
paints, textile, paper and leather-finishing resins, and solution polymers
for metal finishing and for the production of acrylic fibers (Celanese Chem-
ical Co., 1982; IARC, 1979b). In 1984, three U.S. manufacturers reported
production of 306.4 million pounds of ethyl acrylate (USITC, 1985).
Currently, four manufacturers at five locations produce this chemical In the
United States (SRI. 1986).
Ethyl acrylate 1s likely to undergo polymerization to an Innocuous resin
1f released to the environment In a spill-type situation (U.S. EPA-NIH»
1986); however, the diluted concentrations, which may be encountered In the
environment, are unlikely to polymerize significantly. If released to
water, volatilization and Indirect photooxldatlon (by hydroxyl radicals) are
expected to be Important removal mechanisms. The role of direct photolysis
cannot be assessed with the data currently available. Ethyl acrylate has
been shown to be significantly biodegradable In two BOD studies (Sasaki,
1978; Price et al., 1974), which suggests that . blodegradatlon 1n the
environment .Is possible. Adsorption onto sediment, bloconcentratlpn and
hydrolysis (except if pH>9) are not expected to be Important In the aquatic
environment. If released to the atmosphere, ethyl acrylate 1s expected to
remain in the vapor-phase and react rapidly with HO radical and ozone, with
an estimated half-life of 6.5 hours (U.S. EPA, 1986). If released to soil,
ethyl acrylate is expected to be highly mobile based on estimated K
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values; therefore, significant leaching 1n soil may occur. Ethyl acrylate
may volatilize slgnlflearnt-ly from soil "surfaces". In moist alkaline soils
(pH>9), hydrolysis Is potentially Important.
Pertinent ambient air or water monitoring data regarding ethyl acrylate
could not be located In the available literature as died 1n the Appendix.
It Is possible that ethyl acrylate will be emitted to the atmosphere or to
water from effluents produced during Us Industrial manufacture or use.
Leaching of residual monomer from polymer products, which have been land-
filled, may be possible. Ethyl acrylate has been reported to be a volatile
component of pineapple concentrate (Naf-Muller and Wlllhalm, 1971). Polymer
products made from ethyl acrylate are permitted for various food contact
uses (U.S. EPA, 1977), suggesting that leaching of residual monomer Into
foods may be possible. Incineration of acrylate polymers may be a source of
atmospheric release.
The Information concerning toxlclty of ethyl acrylate to aquatic biota
1s very limited. LC... values of 0.74 and 12 mg/8. were reported for
gupples (Hermens and Leeuwangh, 1982) and brine shrimp (Price et al., 1974),
respectively.
Pertinent data regarding the extent and rate of absorption of ethyl
acrylate are limited. In rats given a single oral dose of 200 mg/kg ethyl
acrylate, there was no parent compound detected In Intraocular blood 15-60
minutes post-administration, but there were detectable portal blood levels
15-30 minutes after dosing. These results suggest that ethyl acrylate 1s
absorbed by the gastrointestinal tract. .
Stott and McKenna (1984). estimated that 30-70% of an .Inhaled concen-
tration of ethyl acrylate was absorbed Into the bloodstream by the upper
respiratory tract of rats. The NTP (1986a) found half-lives of 53-76
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minutes In male rats and 66-96 minutes 1n females for metabolism of ethyl
acrylate In Individual tiomogenates of the forestomach, glandular stomach and
stomach contents. In. vitro blood half-lives were 1.1.8 and 14.0 minutes for
female and male rats, respectively. Nonproteln thlol concentrations were
reduced In the Isolated stomachs of rats following oral dosing with ethyl
acrylate. Rat lung, kidney and liver homogenates hydrolyzed ethyl acrylate
to acrylic add by tissue carboxylesterase (Miller et al., 1981; Silver and
Murphy, 1981). In rat blood, however, no acrylic add was formed, but ethyl
acrylate was bound to nonproteln sulfhydryl groups (Miller et al., 1981).
Inhibition of carboxylesterase activity In rats Increased the conjugation
reactions 1n the lungs, blood, liver and kidneys (Silver and Murphy, 1981).
Thus, ethyl acrylate can be hydrolyzed to acrylic add or conjugated to non-
protein sulfhydryl .groups, presumably glutathlone, 1n competitive pathways.
Pertinent data regarding the exc.retlon of ethyl acrylate were not located.
An NTP (1986a) report of the potential cardnogenldty of ethyl acrylate
after oral (gava.ge) administration 1n F344 rats and B6C3F1 mice of both
sexes Indicated that ethyl acrylate Induced squamous cell carcinomas or
paplllomas (or both) of the forestomach 1n both spedes. For both species,
dose levels were 0, 100 and 200 mg/kg, 5 days/week for 103 weeks.
No evidence of cardnogenldty was found In rats given up to 2000 ppm In
drinking water for 2 years (Borzelleca et al., 1964).
Miller et al. (1985) found no evidence of cardnogenldty 1n B6C3F1 mice
and F344 rats exposed by Inhalation to. up to 75 ppm (307 mg/m3) ethyl
acrylate, 6 hours/day, 5 days/week, for 27 months, or In rats and mice
exposed to 225 ppm (921 mg/m3), 6 hours/day, 5 days/week for. only 6
months, then maintained for 21 months until terminal sacrifice.
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DePass et al. (1984) found no Increase 1n epidermal tumor Incidence In
C3H/Hej male mice s*1n-painted with 23 mg/mouse ethyl acrylate, 3 times/week
for 2 years.
A causal relationship for Increased Incidences of cancer of the colon
and rectum from occupational exposure to ethyl acrylate/methyl methacrylate
was suggested 1n a historic perspective epidemiology study; however, a
causal relationship could not be confirmed when further studies at other
Rohm and Haas Company plants with less exposure and latency to the same
agents were considered (Rohm and Haas Co., 1981, 1984, 1986a,b;. Mantel,
1986). Moreover, exposure to ethyl acrylate and methylacrylate could not be
separated.
Ethyl acrylate has been found to be nonmutagenlc 1n standard reverse
mutation assays with and without metabolic activation (NTP, 1986a; Haworth
et al., 1983; Waegemakers and Benslnk, 1984). Principally at cytolethal
doses, ethyl acrylate was mutagenlc to CHL cells (Ishldate et al., 1981) and
mouse lymphoma cells (Litton Blonetlcs, 1984) 1n culture. Przybojewska et
al. (1984) demonstrated genotoxlclty of ethyl acrylate In the mlcronucleus
test using Balb/c mice.
Murray et al. (1.981) demonstrated that Inhalation exposure of rat dams
to 50 or 150 ppm (205 or 614 mg/m3) ethyl acrylate, 6 hours/day, from days
6-15 of gestation, had no effect upon reproductive performance 1n dams
although weight gain was significantly Inhibited at the high concentration.
There were no fetal malformations at 0 or 50 ppm. At 150 ppm, pups from
3/29 treated litters had multiple (primarily skeletal) malformations. The
Incidence of fetuses with hypoplastlc tails was higher than historical
controls but not statistically significantly higher than concurrent controls.
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Although this Incidence was not statistically different from control rats,
— _. »
1n a second reproductive study, Pletrowlcz et al. (1980) stated 1n an
abstract that treatment of rat dams by an unspecified route with 25-400
mg/kg ethyl acrylate during gestation was associated with decreased body and
placental weight gains, Increased numbers of resorptlons and skeletal
abnormalities.
In the 2-year gavage study by NTP (1986a), rats and mice had dose-
related Increases In forestomach hyperplasla, hyperkeratosls, Inflammation
or ulceratlon at >100 mg/kg, 5 days/week. The only effect 1n rats treated
with ethyl acrylate in the drinking water at concentrations up to 2000 ppm
or dogs treated orally by capsule with up to =931 ppm (TWA) was decreased
body weight gain 1n high-dose female rats (Borzelleca et al., 1964).
In F344 rats given 0-110 mg/kg ethyl acrylate by gavage 5 times/week for
13 weeks, there were no treatment-related effects on body weight gain,
longevity or clinical signs .(NTP, 1986a). The only prominent hlstopatho-
loglcal change, occurring In the high-dose males, was an occasional'reddened
duodenum or pronounced stomach vasculature. Administration of up to 100
mg/kg ethyl acrylate to male and female B6C3F1 mice on the same treatment
schedule had no effects on longevity, body weight gain or gross or micro-
scopic hlstopathology (NTP, 1986a). Similar results were obtained by Treon
et al. (1949) 1n two rabbits given 31.5 mg/kg ethyl acrylate orally, 5
times/week for 7 weeks. In a series of 14-day oral studies, the NTP (1986a)
determined that gavage administration of 100 mg/kg/day ethyl acrylate 1n
rats and 200 mg/kg/day ethyl acrylate 1n mice led to abdominal adhesions,
thickened forestomach muccsa and nonulceratlve Inflammation. Administration
of higher doses resulted 1n ulcers and more severe Inflammation. Oral
LD50 values ranging from 0.35-1.8 g/kg have been reported (Tanil and
Hashimoto, 1982; Pozzanl et al., 1949; Treon et al., 1949).
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In the chronic Inhalation study, nonneoplastlc lesions of the nasal
mucosa (e.g., hy-perp-lasla, mineralization, Inflammation, metaplasia)
occurred 1n mice and rats at exposures >25 ppm (>102 mg/m3), 6 houcs/day,
5 days/week for up to 27 months (Miller et al., 1985). Exposure to 5 ppm, 6
hours/day, 5 days/week had no effect.
Inhalation exposure to lethal concentrations (1090 mg/m3, 7 hours/day
for 28 days) of ethyl acrylate led to weight loss and severe signs of
mucosal Irritation 1n rats, guinea pigs, rabbits and In one monkey (Treon et
al., 1949); these signs Included conjunctivitis, lethargy and diarrhea.
Examination of poisoned rats, guinea pigs and rabbits revealed multlorgan
Involvement and a variety of edematous and degenerative changes. These
changes were found to be reversible 1n survivors that were sacrificed 2
months after termination of exposure. Exposure at 70 ppm (287 mg/m3) for
7 hours/day 1n rabbits, guinea pigs, rats and monkeys was without adverse
effects (Pozzanl et al., 1949; Treon et al., 1949). Lomonova and Kllmova
(1979) determined 1C,- of 16,200 and 7500 mg/m3 for unspecified
durations for mice and rats, respectively.
Ethyl acrylate 1s a potent skin Irritant (Pozzanl et al., 1949; Treon et
al., 1949) Inducing • erythema, edema, cellular necrosis and abscesses.
Cornea! necrosis after ocular application In' rabbits was observed by Pozzanl
et al. (1949).
A q,* of 4.8xlO"2 (mg/kg/dayJ"1 was derived based on the Incidence
of squamous cell paplllomas/carclnomas of the forestomach 1n male rats In
the NTP (1986a) study. The concentration of ethyl acrylate 1n drinking
water associated with Increased lifetime risk of cancer at levels of 10~5,
10"6 and 10"7 are 7.3xlO~3, 7.3xlO~4 and 7.3xlO"s mg/l, assuming
that a 70 kg man consumes 2 8. water/day. An F factor of 2.16X10"1
(mg/kg/day)~a was also derived from the tumor response data 1n male rats.
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Since the F factor is <1, ethyl acrylate 1s placed In Potency Group 4.
Since there was sufficient evidence that ethyl acrylate is carcinogenic 1n
animals, but suggestive evidence that "it is carcinogenic 1n humans, ethyl
acrylate Is classified as a U.S. EPA Group B2 chemUal at this time, that
1s. a probable human carcinogen. However, this chemical is currently under
Agency review. This additional evidence, expected In a few weeks, may
necessitate a re-evaluation upward to a Bl chemical. A Potency Group 4 and
U.S. EPA Group B2 chemical has a LOW hazard ranking under CERCLA.
An RQ of 1000 was derived based on the observation of respiratory
metaplasia In mice In the chronic inhalation study by Miller et al. (1985).
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TABLE OF CONTENTS
1. INTRODUCTION. . - 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 3
2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES 4
2.1. WATER 4
2.1.1. Hydrolysis 4
2.T.2. Oxidation .... 4
2.1.3. Photolysis 5
2.1.4. Mlcroblal Degradation 5
2.1.5. Volatilization 6
2.1.6. Adsorption 6
2.1.7. Bloconcentratlon 6
2.2. AIR . 7
2.3. SOIL •••'-. 7
2.3.1. Mlcroblal Degradation 7
2.3.2. Adsorption 7
2.3.3. Volatilization 8
2.3.4. Hydrolysis 8
2.4. SUMMARY. . 8
3. EXPOSURE 10
3.1. HATER 10
3.2. FOOD 10
3.3. INHALATION 10
3.4. DERMAL 11
3.5. SUMMARY 11
4. PHARMACOKINETCS 13
4.1. ABSORPTION 13
4.2. DISTRIBUTION ...... . . . 13
4.3. METABOLISM 13
4.4. EXCRETIOK. . . . 15.
4.5. SUMMARY 15
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TABLE OF CONTENTS (cont.)
Page
5. EFFECTS , . 17
5.1. CARCINOGENICITY 17
5.2. MUTAGENICITY 32
5.3. TERATOGENICITY 34
5.4. OTHER REPRODUCTIVE EFFECTS 35
5.5. CHRONIC AND SUBCHRONIC TOXICITY 36
5.6. OTHER RELEVANT INFORMATION 44
5.7. SUMMARY 47
6. AQUATIC TOXICITY 52
6.1. ACUTE 52
6.2. CHRONIC 52
6.3. PLANTS ' 52
6.4. RESIDUES 52
6.5. OTHER RELEVANT INFORMATION 52
6.6. SUMMARY 52
7. EXISTING GUIDELINES AND STANDARDS . 53
7.1. HUMAN. . 53
7.2. AQUATIC. 53
8. RISK ASSESSMENT . . 54
9. REPORTABLE QUANTITIES 60
9.1. REPORTABLE QUANTITY (RQ) RANKING BASED ON CHRONIC
TOXICITY 60
9.2. WEIGHT OF EVIDENCE AND POTENCY FACTOR (F = 1/ED-|0)
FOR CARCINOGENICITY 60
10. REFERENCES 68
APPENDIX: LITERATURE SEARCHED 80
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LIST OF TABLES
No. Title _ Page
5-1 Forestomach Squamous Cell Tumors 1n Hale and Female
F344 Rats and B6C3F1 Mice Given 9954 Pure Ethyl Acrylate
In Corn 011 by Gavage 5 Days/Week for 103 Weeks and
Sacrificed After 104-105 Weeks 18
5-2 Incidence of FolUcular Thyroid Adenomas/Adenocardnomas
In Male and Female F344 Rats and B6C3F1 Mice Exposed by
Inhalation to >99% Pure Ethyl Acrylate Vapors 6 Hours/Day,
5 Days/Week for up to 27 Months 23
5-3 Observed and Expected Deaths from Selected Causes Among White
Male Hourly Employees, Texas Cohort Study 26
5-4 Observed and Expected Deaths (1933-1981) from Selected
Causes Among Bristol Plant Hourly Employees Hired
Before 1946 27
5-5 Mutagenlclty Testing of Ethyl Acrylate 33
8-1 Cancer Data Sheet for Derivation of q-|* 59
9-1 Toxldty Summary for Ethyl Acrylate . , 61
9-2 Inhalation Composite Scores for Ethyl Acrylate Using
the Mouse 63
9-3 Ethyl Acrylate: Minimum Effective Dose (MED) and
Reportable Quantity (RQ). . . ...... 64
9-4 Derivation of Potency Factor (F) for Ethyl Acrylate ..... 67
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LIST OF ABBREVIATIONS
BOD Biological oxygen demand
BOOT Biological oxygen demand theoretical
BUN Blood urea nitrogen
CHL Chinese hamsters lung
CNS Central nervous system
CS Composite score
GRAS Generally recognized as safe
LC5Q Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
1050 Dose lethal to 50X of recipients
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
PCV Packed cell volume
PEL Permissible exposure Tevel
ppm Parts per million
RQ Reportable quantity
RV
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1. INTRODUCTION
1.1. STRUCTURE AND CAS" NUMBEk
Ethyl acrylate Is the common name . for the compound 2-propeno1r add,
ethyl ester (Chemical Abstract Service designation). Synonyms for ethyl
acrylate Include ethyl 2-propenoate, ethoxycarbonylethylehe and acrylic
add, ethyl ester. The structure, molecular weight, empirical formula and
CAS number for ethyl acrylate are as follows:
0
II
CH2=CH-C-0-CH2-CH3
Molecular weight: 100.12
Empirical formula: C5H_Op
CAS number: 140-88-5
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Ethyl acrylate 1s a colorless liquid with an acrid odor (Wlndholz,
1983). It 1s soluble in alcohol, ether and chloroform. (Weast, 1985).
Selected physical properties are as follows:
Melting point: -71.2°C Weast, 1985
Boiling point: 99.8°C Weast, 1985
Density: 0.9234 g/cm3 (20/4°C) Weast. 1985
Refractive Index: 1.4068 (20°C) Weast, 1985
Water solubility
at 20°C: 2.0 g/100 ms. water Wlndholz, 1983
at 2f°C: 1.8 g/10? c w'ate- Kleir, 1981
Vapor pressure
at 20°C: 31 mm Hg Union Carbide, 1979
at 26°C: 40 mm hg Perry and Green, 1984
Log Kow: 1.33 Hansch and Leo, 1985
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Vapor density: 3.45 Wlndholz, 1983
(air = 1)
Flash point: 15°C (open cup) Wlndholz, 1983
Conversion factors: 1 mg/m3 = 0.24 ppm Verschueren, 1983
(air) 1 ppm = 4.16 mg/m3
Ethyl acrylate easily polymerizes on standing (Wlndholz, 1983); the
commercial material may contain from 15-200 ppm hydroqulnone monomethyl
ether or 1000 ppm hydroqulnone as an Inhibitor (IARC, 1977). Polymerization
1s accelerated by heat, light and peroxides (Wlndholz, 1983). Ethyl
acrylate Is flammable and can be a dangerous fire and explosion hazard
(Hawley, 1981).
1.3. PRODUCTION DATA
Commercial production of ethyl acrylate was first reported In the United
States In 1944 (IARC, 1979b). In 1984, three U.S. manufacturers (Celanese,
Rohm and Haas, and Union Carbide) reported production of 306.4 million
pounds (USITC, 1985). The current U.S. manufacturers of ethyl acrylate
Include Badlsch Corp. (Freeport.'TX), Celanese Corp. (Clear Lake, TX; Pampa,
TX), Rohm and Haas Co. (Deer Park, TX) and Union Carbide (Taft, LA) (SRI,
1986).
Ethyl acrylate Is manufactured. 1n the United States by a propylene
oxidation process (SRI, 1986). In this process, acroleln 1s first formed by
the catalytic oxidation of propylene vapor at high temperatures In the
presence of steam and then oxidized with 0? to yield acrylic add (K1ne
and Novak. 1978K The acrylic acid 1s then esterVfled with ethyl alcohol.
1.4. USE DATA
Ethyl acrylate is the most w1dei> useo acrylale ester (Celariese Chemical
Co., 1981) and 1s used as a monomer 1n the production of a variety of
polymer products (IARC, 1979b). It 1s used to produce flexible resins for
0863p -2- 03/23/87
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water-based paints and adheslves, textile, paper and leather-finishing
resins, and has wide usage In Industrial metal finishing with solution
polymers (Celanese Chemical Co., 1981). Ethyl acrylate Is a major component
of acrylic emulsion polymers used In latex paints for exterior house and
trim, and Interior wall semi-gloss and trim. It 1s also used for. the
production of acrylic fibers (IARC, 1979b).
1.5. SUMMARY
Ethyl acrylate Is a colorless liquid with an acrid odor (Wlndholz,
1983). It 1s soluble In alcohol, ether and chloroform, and Is reasonably
soluble (-2% by weight) In water (Weast, 1985; Wlndholz, 1983). It 1s a
monomer used 1n .the production of a variety of polymers, such as flexible
resins for latex paints, textile, paper and leather-finishing resins, and
solution polymers for metal finishing and .for the production of acrylic
fibers (Celanese Chemical Co., 1981; IARC, 1979b). In 1984, three U.S.
manufacturers reported production of 306.4 million pounds of ethyl acrylate
(USITC. 1985). Currently, four manufacturers at five locations produce this
chemical 1n the United States (SRI, 1986).
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2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES
If released to water or soil as In" the case of a spill, ethyl aerylate
Is likely to undergo polymerization to an Innocuous resin (U.S. EPA-NIH,
1986). The polymerized aerylate 1s Insoluble and will sink In water. The
fate processes discussed below relate to dilute concentrations of ethyl
acrylate, which may be encountered In the environment; these dilute concen-
trations are unlikely to experience significant polymerization.
2.1. HATER
2.1.1. Hydrolysis. The hydrolysis half-life for ethyl acrylate at 25°C
and pH 7 has been reported to be 3.5 years (Habey and Mill, 1978). Based on
the add- and base-catalyzed hydrolysis rate constants reported by Mabey and
Mill (1978),. hydrolysis In environmentally addle waters will be even
slower. Hydrolysis 1n alkaline waters will be accelerated, however; at pH 8
and 25°C, the half-life will be on the order of 100 days, while at pH 9, the
half-life will be -10 days. Therefore, hydrolysis will not be Important 1n
environmental waters at pH <9. The hydrolysis products, should hydrolysis
occur, will be acrylic add and ethanol.
2.1.2. Oxidation. Experimental data specific to the oxidation of ethyl
acrylate In water could not be located 1n the available literature as dted
In the Appendix; however, oxidation of. unsaturated compounds by photocheml-
cally produced oxldants such as singlet oxygen and HO radical 1s potentially
an Important removal mechanism (Mill and Mabey, 1985). The half-life for
the reaction of singlet oxygen with ethyl acrylate In the gas phase has been
reported to be >1.54x10* M"1 sec"1 (Datta and Rao, 1979). Assuming
that the reactivity of acrylate monomers in water is similar to that in the
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gas phase and that the concentration of singlet oxygen 1n natural water 1s
10~12 K (Mill and---habey...... 1985), the - ha if-1 He ' for this reaction is
estimated to be >1 year.
The half-life of oleflns In water from reaction with HO radical Is on
the order of 13-14 days (Hill and Habey, 1985). The olefIn-structured
acrylate monomers may again be susceptible to this oxidation process.
Oxidation of oleflns with R0? radical 1n water has a reported half-life
>200 years; therefore, this oxidation reaction 1s not Important.
2.1.3. Photolysis. In cyclohexane, acetonltrlle and methanol solvents,
the ethyl and methyl esters of acrylic and methacryllc adds do not absorb
light strongly 1n the UV spectrum -290 nm (Brunn et al., 1976). Based on
the absorption spectrum of acroleln (U.S.EPA, 1979), ethyl acrylate may have
moderate UV absorption at wavelengths >300 nm. This suggests that direct
photolysis In water may occur, although the significance of this process
cannot be predicted unless more photolytlc data are available.
2.1.4. MlcrobVal Degradation. Price et al. (1974) measured the b1o-
degradabllUy of ethyl acrylate In BOO tests using an acclimated and non-
acclimated sewage seed 1n freshwater and a nonaccllmated sewage seed 1n
synthetic seawater. In the freshwater, 5-day and 20-day BOOTs of 28 and
35%, respectively, were observed with the nonaccllmated seed, while respec-
tive BODTs of 66 and 79% were observed with the acclimated seed. In the
synthetic seawater, 5-day and 20-day BODTs of 11 and . 53% were observed,
respectively. .
Ethyl acrylate was confirmed to be significantly biodegradable (bio-
oxidation was >30% after 2 weeks of Incubation) by the 3apanese MITI test
(Sasaki, 1978). Thorn and Agg (1975) have reported that ethyl ac^ylate
should be degradable by biological sewage treatment provided suitable
acclImatization. can be achieved.
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Chou et al. (1979) used an anaerobic reactor with an upflow filter to
determine that etny-1 aery-late ai a concentration of 500 mg/s. was xoxic at
least to some microorganisms. At a concentration of 100 mg/i, however,
ethyl acrylate was 95% utilized. Speece (1983) suggested that ethyl
acrylate should be amenable to anaerobic biodegradatlon under Industrial
wastewater treatment conditions.
2.1.5. Volatilization. Based on a vapor pressure of 31 mm Hg (Union
Carbide, 1979) and a water solubility of 20 g/i (Windholz. 1983) at 20°C,
the Henry's Law constant for ethyl acrylate can be estimated to be 2xlO~*
atm-mVmol. This value of Henry's Law constant indicates that volatiliza-
tion will be significant from all environmental waters (Lyman et al., 1982).
Using the method of Lyman et al. (1982), the volatilization half-life from a
river 1 meter deep flowing 1 m/sec with a wind velocity of 3 m/sec Is
estimated to be 7.2 hours. The volatilization half-life from a river 10 m
deep is estimated to be 7.6 days.
2.1.6. Adsorption. Based on a water solubility of 20 g/8, at 20°C
(Windholz, 1983) and a log KQW of 1.33 (Ha'nsch and Leo, 1985), partition-
ing from the water column to partlculate organic matter and sediment Is not
expected to be important.
2.1.7. Bioconcentration. The following two equations have been used for.
estimating the BCF (Lyman et al., 1982):
log BGF = 0.76 log KQW - 0.23 (2-1)
log BCF = 2.791-0.564 log WS (in ppm) (2-2)
Based on a log K of 1.33 and a water solubility of 20 g/l at 20°C, the
BCF values estimated from Equations 2-1 and 2-2 for ethyl acrylate are 6 and
2, respectively. These values suggest that bioaccumulation of ethyl
acrylate in aquatic organisms will not be significant.
0863p -6- 03/23/87
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2.2. AIR
Because of its -r.ela-tl-yely high vapor pressure, ethyl acrylate that Is
released to the atmosphere Is expected-to remain In the vapor-phase and not
become associated with participate matter.
The rate constants for the vapor-phase atmospheric reaction of ethyl
acrylate with HO radical and with ozone have been estimated to be
2.7xlO~ia cm3 molecule-sec (HO radical) and 1.3xlO~16 cmVmolecule-
sec (0 ) (U.S. EPA, 1986). Assuming average atmospheric concentrations of
BxlO5 HO radical molecules/cm3 and &X1011 P3 molecules/cm3, the
half-life of ethyl acrylate (with respect to the combined effect of HO
radical and 0 ) has been estimated to be 6.5 hours (U.S. EPA, 1986). The
*J
half-lives with respect to only HO radical or 0~ can be calculated to be
8.9 and 24.7 hours, respectively.
The significance of direct photolysis In determining the fate of atmo-
spheric ethyl acrylate cannot be assessed because of the lack of relevant
data.
2.3. SOIL
2.3.1. M1crob1al Degradation. Pertinent data regarding the mlcroblal
degradation of ethyl acrylate In soil could not be located 1n the available
literature as cited 1n the Appendix. Since ethyl acrylate has been shown to
be degradable 1n -various BOD tests (see Section 2.1..4.), mlcroblal degrada-
tion 1n soil 1s possible.
2.3.2. Adsorption. K values can be estimated using the following two
regression equations (Lyman et al., 1982):
log K = 3.64 - 0.55.log WS (In ppm) (2-3)
log K = 0.544 log K *• 1.377 (2-4)
0863p -7- 03/23/8T
-------
The K values calculated from Equations 2-3 and 2-4 for ethyl acrylate
(log KQW of 1.33; water- sulublHty of 2t),000 ppm) are 19 and 126, respec-
tively. These estimated K values predict high to very high soil-mobil-
ity (Swann et al., 1983). Therefore, ethyl acrylate appears susceptible to
significant leaching 1n soil.
2.3.3. Volatilization. The vapor pressure of ethyl acrylate (31 mm Hg at
20°C) Indicates that H will volatilize from dry surfaces quite rapidly. In
moist soils, volatilization may be significant since ethyl acrylate Is
expected to significantly volatilize from water (see Section 2.1..5.).
2.3.4. Hydrolysis. The aqueous hydrolysis of ethyl acrylate Is not
expected to become environmentally Important until the pH Is >9 (see Section
2.1.1.). In moist alkaline soils (pH>9), hydrolysis 1s potentially
Important.
2.4. SUMMARY
Ethyl acrylate Is likely to undergo polymerization to an Innocuous resin
If released to the environment In a spill-type situation (U.S. EPA-NIH,
1986); however, the diluted concentrations, which may be encountered In the
environment, are unlikely to polymerize significantly. If released to
water, volatilization and Indirect photooxldatlon (by hydroxyl radicals) are
expected to be Important removal mechanisms. The role of direct photolysis
cannot be assessed with the data currently available. Ethyl. acrylate has
been shown to be significantly biodegradable In two BOD studies (Sasaki,
1978; Price et al., 1974), which suggests that blodegradatlon In the
environment 1s possible. Adsorption onto sediment, bloconcentratlon and
hydrolysis (except 1f pH>9) are not expected to be Important 1n the aquatic
environment. If released to the atmosphere, ethyl acrylate 1s expected to
remain 1n the vapor-phase and react rapidly with HO radical and ozone, with
0863p -8- 03/23/87
-------
an estimated half-life of 6.5 hours (U.S. EPA, 1986). If released to soil,
ethyl acrylate Is -expected to be highly mobile based on estimated K
values; therefore, significant leaching" in soil may occur. Ethyl acrylate
may volatilize significantly from soil surfaces. In moist alkaline soils
(pH>9), hydrolysis is potentially Important.
0863p -9- . 10/30/86
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3. EXPOSURE
3.1. HATER
Pertinent monitoring data regarding methyl acrylate In water could not
be located 1n the available literature as cited 1n the Appendix. The U.S.
EPA STORET database contained no postings for the compound.
It 1s possible that ethyl acrylate may be discharged with wastewater
effluents generated during Us manufacture and use operations. Small
amounts of residual ethyl acrylate monomer have been found 1n polyethyl
acrylate (Brunn et al., 1975) and 1n polymer latexes used 1n the paper and
textile Industries (BolUnl et al., 1975). Leaching of residual monomer
from polymer products, which have been landfllled, may be possible, although
no monitoring data 1s available to confirm this suggestion.
3.2. FOOD
Ethyl acrylate has been reported to be a volatile component of pineapple
concentrate (Naf-MulTer and Wlllhalm, 1971).
The U.S. Food and Drug Administration (1977) considers ethyl acrylate to
be a GRAS adjuvant 1n food and polymers, and copolymers made from ethyl
acrylate are permitted for various contact uses with foods. Residual
monomer 1n these polymers and copolymers may leach Into the contacted foods;
however, no data are available to confirm this.
3.3. INHALATION
Pertinent monitoring data regarding ethyl acrylate 1n ambient air could
not be located In the available literature as cited In the Appendix;
however, ambient atmospheric emissions may result from Us manufacture and
use. Ethyl acrylate was Identified 1n an effluent gas stream from a company
Involved 1n painting and printing In Japan (Yasuhara et al., 1984).
0863p -10- 04/30/87
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Klselev et al. (1983) detected ethyl acrylate 1n the volatile emissions
from a plastic mater 1a~l -(-Acronal 800) 'used 1n the building construction
Industry 1n the USSR.
Samiml and Falbo (1982) detected mean TWA ethyl acrylate concentrations
of
-------
products made from ethyl acrylate are permitted for various food contact
uses (U.S. FDA, l^??),- suggesting that' leaching of residual monomer Into
foods may be possible. Incineration of acrylate polymers may be a source of
atmospheric release.
0863p -12- 04/30/87
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4. PHARMACOKINETICS
4.1. ACSORPTION
NTP (1986a) gave three male and., three female Fischer 344 rats 20Q mg/kg
ethyl acrylate as a 4% solution 1n corn oil by gavage. At 15, 30 and 60
minutes postadmlnlstratlon, 50 vi samples of Intraocular blood were taken.
Venepuncture of the exposed portal vein was done 15 and 30 minutes post-
administration and 50 yl samples were withdrawn. Determination of ethyl
acrylate content was made on both sets of samples by gas chromatography.
The NTP (1983) -found no ethyl acrylate in the Intraocular samples at any
time (detection limit = 1 pg/mi). but did detect 4-27 pg/mj. In the
portal blood at 15 minutes and -1-18 pg/ma at 30 minutes after dosing.
Although the results do not provide sufficient data regarding the extent or
rate of absorption, they suggest that gastrointestinal absorption of ethyl
acrylate does occur after oral administration.
Stott and McKenna (1984) studied ethyl acrylate vapor absorption In
Isolated preparations of upper and lower rat respiratory tracts and in the
intact rat. The Investigators estimated that 30-70'/. of the Inhaled ethyl
acrylate was absorbed by the upper respiratory tract. Similar percentages
were absorbed by the lower respiratory tract and the Intact rat.
4.2. DISTRIBUTION
Data regarding the distribution of ethyl acrylate are limited. Treon et
al. (1949) reported that the odor of ethyl acrylate was noticeable in all
tissues and especially 1n the stomachs of rabbits given single oral doses
>420 mg/kg.
4.3. METABOLISM
In the NTP (1983) experiments, groups of six F344 rats were given either
100 or 200 mg/kg ethyl acrylate 1n corn oil by gavage. The rats were killed
0863p -13- 03/23/87
-------
at 30 or 120 minutes after dosing and the stomachs removed. Nonproteln
thlc"! concentration:: were.-found to be reduced, relative to control values,
both 1n the glandular stomach and,.especially, 1n the forestomach. _Reduc-
tlon of forestomach concentrations was slightly greater after the I20-m1nute
kill, and at the higher dose. The percentages of parent compound remaining
In the stomach were 29-40% after 30 minutes.
The forestomachs and glandular stomachs, Including contents, were
removed from six untreated F344 rats (three males and three females) for
determination of j_n vitro- metabolism (NTP, 1986a). After removal of the
stomach contents, all three components were homogenized, and 5 ma allquots
of each homogenate were Incubated with 150 pg ethyl acrylate. Between 5
and 65 minutes after the onset of Incubation, 200 pi allquots were trans-
ferred to vials, where an Internal standard was added. After mixing, a
1 vl aliquot was withdrawn and gas chromatographed. Blood samples for
determination of ethyl, acrylate half-lives were taken from anesthetized
rats, and the Incubation processes were conducted (with 500 pg ethyl
acrylate) similarly to those of the stomach tissues. Allquots were removed
for chromatographlc analysis at 1.5-2.5 minutes after the onset of Incu-
bation.
Metabolism of ethyl acrylate , was first order In homogenates of the
forestomach, glandular stomach and stomach contents. Half-lives for the
disappearance of the parent compound from the forestomach, glandular stomach
and stomach contents 1n male rats were 76, 67 and 53 minutes, respectively,
ana In female rats were 96, 6b ano 73 minutes, respectively. I_n vitro
metabolism 1n blood was much faster; the average half-lives 1n three males
was H.O minutes and tne average in females was 11.8 minutes. Tnese experi-
ments Indicate that metabolism of ethyl acrylate can take place In the
stomach and 1n the blood.
0863p -14- 03/23/87
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Silver and Murphy (1981) showed that rat lung, kidney and liver homo-
genates were capable .of _hy.drolyz1ng ethyl acrylate to acrylic acid by tissue
carboxylesterase. Pretreatment with 5-125 mg/kg TOTP, a carboxylesterase
Inhibitor, 1n Independent groups of rats reduced hydrolysis 36-97% 1n these
tissues. After pretreatment with 125 mg/kg TOTP, rats exposed by Inhalation
for 4 hours to 300-1000 ppm (1228-4095 mg/m3) ethyl acrylate had signifi-
cantly decreased lung, blood, kidney and liver nonproteln sulfhydryl levels,
relative to rats given a corn oil pretreatment. These results suggest the
Importance of the carboxylesterase-medlated ethyl acrylate metabolism and
the shift to a conjugation reaction when that mechanism 1s Inhibited.
Miller et al. (1981) observed hydrolysis of ethyl acrylate to acrylic
acid In rat liver, lung and kidney homogenates. When added to blood J_n
vitro, however, acrylic acid formation was not apparent. Rather, the parent
ester was found to bind to nonproteln sulfhydryl groups.
4.4. EXCRETION
Pertinent data regarding the excretion of ethyl acrylate could not be
located In the available literature as cited 1n the, Appendix.
4.5. SUMMARY
Pertinent data regarding the extent and rate of absorption of ethyl
acrylate are/limited. In rats given a single oral dose of 200 mg/kg ethyl
acrylate, there wa'.s no parent compound detected In Intraocular blood 15-60
minutes postadmlnlstratlon, but there were detectable portal blood levels
15-30 minutes after dosing. These results suggest that ethyl acryTate Is
absorbed by the gastrointestinal tract.
Stott and McKenna (1984) estimated that 30-70% of an Inhaled concentra-
»
tlon of ethyl acrylate was absorbed into the bloodstream by the upper respi-
ratory tract of rats. The NTP (1986a) found half-lives of 53-76 minutes
0863p -15- 03-/23/87
-------
In male rats and 66-96 minutes 1n females for metabolism of ethyl acrylate
in individual homog_enates..of the forestomach, glandular stomach and stomach
contents. Ir\ vitro blood half-lives were 11.8 and 14.0 minutes for^female
and male rats, respectively. Nonproteln thiol concentrations were reduced
1n the Isolated stomachs of rats following oral dosing with ethyl acrylate.
Rat lung, kidney and liver homogenates hydrolyzed ethyl acrylate to acrylic
add by tissue carboxylesterase (Miller et a!., 1981; Silver and Murphy,
1981). In rat blood, however, no acrylic acid was formed, but ethyl
acrylate was bound to nonproteln sulfhydryl groups (Miller et al., 1981).
Inhibition of carboxylesterase activity In rats Increased the conjugation
reactions In the lungs, blood, liver and kidneys (Silver and Murphy, 1981).
Thus, ethyl acrylate can be hydrolyzed to acrylic add or conjugated to non-
protein sulfhydryl groups, presumably glutathlone, In competitive pathways.
Pertinent data regarding the excretion of ethyl acrylate could not be
located 1n the available literature as cited 1n the Appendix.
0863p -16- 03/23/87
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5. EFFECTS
5.1. CARCINOGENICITY
5.1.1. Experimental Studies. The _NTP (1986b) has listed a. 2-year
carclnogenlcHy bloassay of oral ethyl acrylate In F344/N rats and B6C3F1
mice, which is 1n final printing. In this study groups of 50 male and 50
female F344/N rats and B6C3F1 mice received >99% pure ethyl acrylate In corn
oil by gavage, 5 days/week for 103 weeks. Dose levels were 0, 100 and 200
mg/kg. All animals were weighed weekly for the first 12 weeks and monthly
thereafter and were observed twice dally for mortality and morbidity. Gross
and comprehensive histologlcal examinations were performed on all animals
that died, were killed when moribund or were killed 1-2 weeks after the
treatment was discontinued.
There were no significant differences In survival for treated rats and
mice compared with controls. Survival was 64-84% for rats and 52-72% for
mice. The most prominent aeoplastlc lesions were found In the forestomach
(Table 5-1). By the Life Table, Incidental Tumor and Fisher Exact tests,
administration of the high dose significantly (p<0.001) Increased the
Incidences of squamous cell papllloma, carcinoma and combined papllloma/
carcinoma In the forestomachs of male rats over control values. Incidences
of squamous cell papllloma and papllloma/carclnoma were significantly
Increased (p<0.001) at 100 mg/kg doses; administration of the low dose
Increased the Incidence of squamous cell carcinoma at p<0.05, by all three
methods of statistical analysis. For the three forestomach tumor classifi-
cation?, the Cocr.ra- -Amitage, Lift Table anc1 Incident^ Turner tests for
trends were statistically significant ' for males (p<0.001). Forestomach
tumor incidence was l.esr pronounced in treated female rats. Administration
of the high dose led to statistically significant Increases 1n the Inci-
dences of squamous cell papillomas and combined paplllomas/carclnomas
0863p -17- 05/19/87
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TABLE 5-1
Forestomach Squamaus_ Cell Tumors In. Male and Female F344 Rats and
B6C3F1 H1ce Given 99% Pure Ethyl Acrylate 1n Corn 011 by Gavage
5 Days/Week for 103 Weeks and Sacrificed After 104-105 Weeks3
Species/Strain Sex Dose
(rug/kg)
Rat/F344 H 0
100
200
0
100
200
0
100
200
Rat/F344 F 0
100
200
0
100
200
0
100
200
Mouse/B6C3Fl H 0
100
200
M 0
100
200
H 0
TOO
200
Tumor Type
papl lloma
carcinoma
combined
papllloma/
carcinoma
papllloma
carcinoma
combined
papllloma/
carcinoma
papllloma
carcinoma
combined
papil loma/
carcinoma
Tumor Incidence
(p value )b-c
1/50 (p<0.001)
15/50 (p<0.001)
29/50 (p<0.001)
0/50 (p<0.001)
5/50 (p=0.028)
12/50 (p<0.001)
1/50 (p<0.001)
18/50 (p<0.001)
36/50 (p<0.001)
1/50 (p=0.008)
6/50 (p=0.056)
9/50 (p=0.008)
0/50 (p=0.095)
0/50
2/50 (p=0.247)
1/50 (p=0.002)
6/50 (p=0.056)
11/50 (p=0.002)
0/48 (p=0.002)
4/47 (p=0.056)
9/50 (p=0.002)
0/48 (p=0.019)
2/47 (p=0.242)
5/50 (p=0.031)
0/48 (p<0.001)
5/47 ^p=(j.ocoj
12/50 (p<0. 001)
0863p
-18-
10/30/86
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TABLE 5-1 (cont.)
Species/Strain Sex Dose
(mg/kg)
Mouse/B6C3Fl F 0
TOO
200
F 0
100
200
F 0
100
200
Tumor Type
papll "loma
carcinoma
combined
papllloma/
cardmona
Tumor Incidence
(p value)0-0
1/50
4/49
5/48
0/50
1/49
2/48
. 1/50
5/49
7/48
(p=0.072)
(p=0.175)
(p=0.093)
(p=0.135)
(p=0.495)
(p=0.237)
(p=0.022)
(p=0.098)
(p=0.026)
Strengths of Study:
QUALITY OF EVIDENCE
Adequate number of animals for a lifetime bloassay.
Multiple h1stopatholog1cal endpolnts explored.
Appropriate dose levels used. Oral route of exposure.
Weaknesses of Study: Neoplastlc response may be secondary to mucosal
Irritation Induced by gavage administration.
Comments:
Adequate
aSource: NTP, 1986a
bProbab111ty level for control groups represents dose-related trend by the
Cochran-Armltage test
Probability level for treated groups represents treated vs. control com-
parison by Fisher Exact test.
0863p
-19-
03/23/87
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(p<0.05 by the Life Table, Incidental Tumor and Fisher Exact tests), but not
in the Incidence of_ squ.amous cell carcinomas. The occurrences of papllloma
and papHlomas/cardnomas In the 100 mg/kg dose group were significant by
the Incidental tumor test (p=0.034 1n both cases), but not by the Fisher
Exact or Life Table tests. Finally, the Cochran-ArmHage, Life Table and
Incidental Tumor trend tests were statistically significant (p<0.01) for
paplllomas and papHlomas/carclnomas.
Low-dose male rats were found to have Increased Incidences of pancreatic
aclnar cell tumors (p=0.041) and mononuclear cell leukemia (p=0.035) by the
Life Table test. No aclnar cell tumors and only 1/49 mononuclear cell
leukemia were observed In high-dose males; therefore, because of the absence
of a dose-response, the Investigators did not place any biological signifi-
cance upon these findings. They also did not consider findings of negative
dose-related trends 1n the Incidences of basal cell tumors of the skin and
testlcular Interstitial cell tumors to be toxlcologlcally significant. A
negative dose-related trend for the Incidence of benign adrenal pheochromo-
cytomas 1n male rats (controls 15/50; low dose, 13/49; high dose 5/50),
statistically significant by the Cochran-ArmHage test (p=0.011) was con-
sidered by the authors to be treatment-related but the mechanism for reduced
tumor Incidences 1s unknown.
As with the rats, the Incidences of-squamous cell paplllomas and carci-
nomas of the forestomach 1h mice were dose-related (see Table 5-1). Life
Table, Cochran-ArmHage and Incidental Tumor tests for trend, were signifi-
cant (p<0.03j for paplllomas, carcinomas and comoineo papiViomas/carcmomas.
At 100 mg/kg, the Fisher Exact test showed that the 100 mg/kg group had
significantly greater (p=0.026) forestomacr, pap"" lorna^/carcinomas man
0863p -20- 03/23/87
-------
controls; no other comparison at this dose level was statistically signifi-
cant. For the h1gh,-dose -males, there were Increased (p<0.05) Incidences of
squamous cell paplllomas, carcinomas and combined papHlomas/carclnojnas by
all three statistical tests (Fisher, Life Table and Incidental Tumor tests).
In females, there were nonstatlstlcally significant (p>0.05) trends toward
dose-related Increases 1n squamous cell paplllomas and carcinomas, when each
tumor type was analyzed separately. When analyzed as combined papHloma/
carcinoma occurrences, the Cochran-Armltage, Life Table and Incidental Tumor
tests for trend were significant (p~0.02). The combined .tumor Incidence was
Increased 1n the low-dose group, but not significantly; In high-dose
females, the Incidence was statistically significantly Increased (p<0.05 by
the Fisher, L.1fe Table and Incidental Tumor tests). The separate tumor
Incidences were not significantly Increased .above controls 1n either treated
group by any test.
Significant negative trends for hepatocellular tumors, folUcular cell
tumors of the thyroid, lymphocytlc lymphoma 1n male .mice and significantly
lower Incidences of pituitary adenomas In female mice compared with controls
were considered to be treatment-related, but the mechanism Is unknown.
NTP (1986a) concluded that ethyl acrylate was carcinogenic In rats and
mice.
.In a 2-year study, Borzelleca et al. (1964) exposed groups of 25 male
and 25 female Wlstar rats to ethyl acrylate 1n the drinking water at concen-
trations of 0, 6, 60 or 2000 ppm. During the 5th month, the 6 and 60 ppm
levels were raiseo to 7 and 70 ppm. There was no efffect on survival. No
evidence of carcinogenldty was found upon sacrifice of the 2-year survivors
and hlstological examination of heart, lung, "liver, kidney, urinary bladder,
spleen, gastroenterlc. skeletal muscle, bone marrow, skin, brain, thyroid,
adrenal, pancreas, pituitary and gonads.
0863p -21- 03/23/87
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Miller et al. (1985) exposed male and female B6C3F1 mice and F344 rats
to 0, 25, 75 or 225 ppra.. (0, 102, 307- or 921 mg/m3) >99.5% pure ethyl
acrylate vapors for 6 hours/day, 5 darys/week (excluding "holidays''^- For
the 225 ppm group, exposure was discontinued after 6 months and survivors
were maintained for an additional 21 months. Interim sacrifices were per-
formed at 3, 6, 12 and 18 months for rats and 6, 12 and 18 months for mice.
The remaining 60 rats and 60 mice of each sex were maintained as controls
and 75 rats and 75 mice of each sex were used 1n the treated groups. Except
for the high-dose group, all rats and mice were treated for 27 months.
Surviving rats and mice were examined monthly for palpable masses. Rats and
mice that died during the 27-month exposure period, or killed when moribund,
were examined grossly. At the end of 27 months, survivors were sacrificed
and gross pathologies performed on ~50 tissues. Hlstological examinations
of all these tissues (except female mammary tissue and rectum), were
performed for rats and mice in the control and 75 ppm groups. Hlstological
examinations of .a more limited set. (-15) of tissues were performed on rats
and mice exposed to 25 and 225 ppm. In all groups, nasal cavities were
processed and examined at four cross-sectional levels. Only observations on
tissues that were examined histologically were analyzed statistically.
Ethyl acrylate exposure did not affect the longevity of either sex of
mice, or rats.. In addition, there were no significant differences in
Incidences of palpable masses throughout the study. The major pathological
effects found 1n both rats and mice were nonneoplastic changes 1n the
olfactory epithelium (Section 5.5.). In the male rats, Fisher's Exact tests
revealed no significant Increases 1n total benign or total malignant tumor
incidence that were due to treatment,'although (as shown in Table 5-2) tnere
was a statistically significant (p<0.05) Increase in follicular thyroid
adenorna/adenocardnomas, compared with combined control data, at 25 ppm.
0863p -22- 03723/87
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TABLE 5-2
Incidence of Fqlllcular Thyroid Adenomas/Adenocarclnomas In Male and
Female F344 Rats and B6C3F1 Mice Exposed by Inhalation to >99.5% Pure
Ethyl Acrylate Vapors 6 Hours/Day,-5 Days/Week for up to 27 Months3
Species/Strain Sex
Dose
(ppm)
Tumor Incidence
(p value)b
Rat/F344
Mouse/B6C3Fl
0
0
25
75
225d
0 (A)
0 (B)
25
75
225
0 (A)
0 (B)
25
75
225
0 (A)
0 (B)
25
75
225
QUALITY OF EVIDENCE
1/60
0/60
5/76 (p<0.05)
2/75 (NS)
3/71 (NS)
0/59
0/62
1/77 (NS)
1/78 (NS)
0/70 (NS)
1/60
1/61
1/75 (NS)
0/76 (NS)
7/69 (p<0.05)
13/64
12/61
7/78 (NS)
7/76 (NS)
5/66 (p<0.05)(N)9
Strengths of Study:
Weakness of Study:
Overall Adequacy:
Chronic Inhalation exposure 1n a sufficient number of
rats and mice/group. Adequate concentration range, good
control data. Multiple h1stolog1cal endpoVnts examined.
Short dally exposure sessions.
Adequate
aSource: Miller et al. ; 1985 .
^Fisher Exact Test statistic for comparison with combined control groups.
cTwo Independent control groups used for each sex and species
^Exposed for 6 months to 225 ppm then held for 21 more months.
eMale mouse data for "thyroid adenoma" only
^Female mouse data for "thyroid adenomas/adenocarcinomas" only
9S1gn1ficantly lower Incidence 1n treated group compared with controls.
NS = Not significant
0863p
-23-
03-/23/87
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This effect was not found at either higher exposure concentrations or in
female rats. Cocb.ran-_Armitage tests indicated significant dose-related
trends in male rats, only for total - benign and total malignant ' tumors.
Because there was no consistent pattern of primary tumorlgenesis in the
males, the investigators considered these results to be a statistical
anomaly resulting from random variation.
Miller et al. (1985) noted a statistically significant (p<0.05) increase
in thyroid adenomas in the male mice exposed to 225 ppm and a decrease
(p<0.05) in thyroid adenomas/adenocarclnomas in female mice exposed to this
concentration. The authors noted that the spontaneous Incidence of thyroid
tumors was highly variable in B6C3F1 mice. In male B6C3F1 mice, the histor-
ical control Incidence of thyroid folUcular cell adenomas or carcinomas,
after gastric incubation in corn oil, ranged from 0/50 to 5/47 (NTP, 1986a).
Data on rats or on female mice were not provided 1n the NTP (1986a) bio-
assay. Miller et al. (1985) found no other treatment-related Increases In
the Incidences of neoplasla.
Forty male C34/Hej mice were skin painted 3 times/week with 25 vi 9954
pure ethyl acrylate (-23 mg/mouse) 1n acetone (DePass et al., 1984). The
mice were 74-79 days old al the start of the study and were treated for
their entire llfespan. Each mouse was examined dally for tumor development
and complete necropsies were performed on mice that died or, were sacrificed
when moribund. After sectioning and straining, the dorsal skin and all
gross lesions were examined histologlcally. Forty male mice given either 20
mg/mbuse acetone (negative control) or 0.02 mg/mouse o-meinylcholanthrene
(positive control) on the same treatment schedule were also used. DePass et
al. (1984) found no ethyl acrylate or acetone-induced epidermal tumors.
Ethyl acrylate administration also did not affect longevity. Of the mice
treated with 3-methylcholanthrene, 39 developed epidermal tumors.
0863p -24- 03723/87
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5.1.2 EpIdemlologUal Studies
A series of. retrospective epidemiology studies were conducted by Rohm
and Haas (1981, 1984, 1986a,b) to determine .the effect of exposure to ethyl
acrylate and methyl methacrylate on male workers employed at plastics
manufacturing plants 1n Deer Park, TX, Bristol, PA and Knoxvllle, TN.
Mortality among white males employed at the Texas plant was compared
with that for the U.S. white male population (Rohm and Haas, 1981). All
white males, based on the year of their hire, were assigned to one of six
5-year cohorts than spanned the years 1948-1977'. The total of 1849 white
males was followed until December 31, 1978. Vital status was. compiled for
96% of the white male employees both hourly and salaried. At the end of the
follow-up period 89.9% of the cohort were alive, 3.8% status unknown and
6.3% .had died. Of the 1372 hour.ly employees, 90.6% were alive, 3.3% status
unknown and 6.1% were dead.
As summarized 1n Table 5-3, total deaths from all causes showed no
significant excesses of observed over .expected. Observed cancer deaths (20)
were 86.6% of the expected (23.1) (SMR=87). Observed number of respiratory
cancers tend to be .numerically higher than expected for hourly men with <5
years work exposure, but this difference was not statistically significant.
When all hourly, employees were grouped together by year of hire, there Is a
significant excess of other and unspecified cancers and 1n lymphatl.c
cancers. All other sites showed no significant Increased Incidence.
The results of a mortality study' among Bristol, PA plant employees (Rohm
and Haas., 1984) are summarized In Table 5-*. The study population Included
all white hourly employed workers hired between January 1, 1933 and December
31, 1945. Of the 3934 hourly employees, 39% (1528) were dead, 12%.(481)
status unknown and 49% .(1920) were alive. Table 5-4 lists the causes of
death from al-1 diseases for all employees and for those who held Jobs.
0863p -25- 05/19/87
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a
CO
CJ
•o
TABLE 5-3
Observed and Expected Deaths from Selected Causes Among White Male Hourly Employees'
Texas Cohort Study
o
tn
oo
Cause of
All causes
All malignant
Buccal cavity
pharynx
Digestive
Respiratory
Genital
Urinary
Leukemia
Lymphatic
Other cancers
*Source: Rohm
0 = Observed
All
Hourly
Employees
Hourly Employees with >10
Death Any Hourly Work Duration
0
84
neoplasms 20
and 0
3
7
0
1
1
2
6
and Haas Co. , 1981
deaths ; E = expected
E
1.21
23.
0.
6-
8.
0.
1.
1.
1.
3.
deaths
Note: A relatively youthful population
0/E
0.
T 0.
8 0.
65 0.
28 0.
96 0.
09 0.
06 0.
74 1.
55 1.
69
87
00
53
85
00
92
94
15
69
; 0/E = ratio
In which
not
Any Hourly
0
54
15
0
2
6
0
1
1
2
3
E
84.
17.
0.
4.
6.
0.
0.
0.
1.
2.
of observed to
much
Work Duration
6
9
64
44
93
72
88
67
12
52
expected
0/E
0.64
0.84
0.00
0.45
0.87
0.00
1.14
1.49
1.79
1.19
deaths
Years
of Observation
>5 Years Work
0
34
8
0
1
2
0
0
1
2
2
site-specificity Is exhibited;
E
59.9
12.7
0.46
3.10
4.94
0.46
0.62
0.47
0.80
1.82
an addlt
Duration
t
0/E
i
0.57
0.63
0.00
0.-32
0.40
0,00
0.00
2.13
2.50
1.10
lonal 10
to 20-year observation period Is needed.
-------
o
CO
TABLE 5-4
Observed and Fxpected Deaths (1933-1981) from Selected Causes Among Bristol Plant Hourly Employees
Hired Before 1946a
,
IVJ
-J
1
o
tn
10
\
CO
Deaths
All causes
Disease of the:
Circulatory system
Heart disease
Cerebrovascular
AH cancers
Lung cancer
Colorectal
Respiratory disease
Ace 1 dents
Entire
Ob
1528
859
625
108
323
107
52
81
54
Plant Employees Employees Ever In Ethyl Acrylate/Methyl Hethacrylate Jobs
Ec
1869.2
1016.0
685.5
147.5
351.8
104.3
31.2
114.3
101.6
SMRd
82
85
91
73
92
103
167e
71
53
0
1020
558
407
67
223
67
51
57
38
E
1215.9
647.8
447.0
89.1
234.9
72.5
29.8
73.4
70.5
SHR
84
86
91
75
95
93
171e
78
54
^Source: Rohm and Ha
-------
involving exposure to ethyl acrylate/methyl methacrylate. The results are
similar for both groups of employees. Observed cancer deaths were 92 which
1s 95% of the predicted value. Lung, cancer, the most frequent cause of
cancer-related deaths was not significantly Increased in either group of
employees; however, cancers of the large Intestine and rectum were sig-
nificantly higher than expected [52 observed vs. 31.2 expected, SHR=167
(p<0.01); 51 observed vs. 29.8 expected, SMR=171 (p<0.01)].
When employee mortality was further analyzed based on years of exposure,
age of employee or estimated accumulated dose, the results were Inconclusive
according to the authors. Risk of colorectal cancers among ethyl
acrylate/methyl methacrylate workers did not Increase with accumulated dose
when compared with number .of years between first exposure and death. Also
when colorectal cancers were examined for only those workers with the
"highest" exposure levels, the group with the more "Intense" exposure had a
lower, although significant, Increased Incidence of colorectal cancers than
the overall ethyl acrylate/methyl methacrylate exposed population.
According to the author, the excess risk of colorectal cancer did not fH
the pattern that would be expected If monomer exposure were actually causing
the excess and the excess was biologically difficult to explain. The
validity of such a conclusion can be questioned because of absence of exact
exposure data, smaller cohort (lack of statistical power) and flawed study
design.
Since no clear causal relationship between ethyl acrylate/methyl meth-
acrylate and increased relative risk-of colorec.tal cancer was established,
Rohm and Haas (1986a,b) conducted further analyses and studies among Bristol
plant hourly employees hired after 1945 and among workers at the Knoxville.
0863p -28- 05/19/87
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TN plant. The mortality rates among Bristol plant employees hired after
1945 were examined for all white males from January 1946 through December
31. 1982. A total of 6667 men (4035 hourly, 2632 salaried) were Included In
the study population. As In earlier studies, expected deaths were
calculated from mortality rates among U.S. white males. Although potential
for exposure to ethyl acrylate was present 1n the jobs examined, It was
considered to be minor exposure relative to methyl methacrylate that
constituted the major occupational exposure In all ethyl acrylate/methyl
methacrylate workers from 1933-1982. Vital status was verified for 91% of
the 6667 white males, status of remaining 9% unknown; 701 deaths were
Identified (821 expected, SHR=85). Among those deaths from cancers, -no
significant excess of site-specific cancers occurred. No cases of rectal
cancer were found and cancers of the large Intestine were similar 1n number
to those expected (13 observed vs. 13.2 expected). When salaried employees
were excluded from analysis, the cancer Incidence of the 4035 hourly
employees was very, similar to that reported for the whole plant population.
No specific cancer site was significantly elevated and deaths from all
cancers were equivalent to predicted values (110 observed vs. 107.8
predicted). Among hourly employees 65.5% (2644) held Jobs that Involved
potential exposure to ethyl acrylate/methyl methacrylate, 60%'had a >20-year
latency per.lod from first exposure. Deaths from cancer were equivalent to
expected values (73 vs. .72.2'); 6 colorectal cancers were observed versus 7.7
expected. Relative risk of colorectal cancer did not1 Increase 'with
Increasing exposure ,to ethyl acrylate/methyl methacrylate, whether exposure
was assessed as a cumulative "dose" or simply as length of time exposed,
although Mantel (1986) criticized the methodology used to establish "dcse".
This 1s discussed later.
0863p -29- 05/19/87
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A similar separate study was conducted at the Knoxvllle plant (Rohm and
Haas, 1986b). The study population Included all white males (3381) employed
during the period January 1, 1943 through December 31. 1982. Vlta.l status
for 91% of the 3381 white male employees was ver1Med, status of remaining
9% was listed as unknown. Overall deaths from all causes were 858, 175 of
which .were cancer related. Cancers of the digestive tract Including
colorectal cancers were significantly lower than that predicted (28 observed
vs. 51.6 expected). Respiratory cancer mortality rates were significantly
elevated when compared with U.S. men (87 vs.63.3; SMR=167); however, when
the standard mortality rate among employees was compared wHh the SMR for
respiratory cancer for white males 1n Knox County, TN, the SMR was still
elevated but somewhat reduced (87 vs. 78.8; SMR=110). When salaried.
employees were excluded from analysis, mortality rates among hourly
employees whether analyzed by cumulative exposure or by years exposed on the
job, showed no Increased risk of. cancer at any site. Colorectal cancers
were not elevated (9 vs. 16.6). A total of 1271 white males held jobs that
were judged to Involve potential exposure to polymer partlculates. No
association was found between cumulative exposure "dose" and risk of
respiratory cancer or digestive cancers Including colorectal cancers.
Workers were assessed 1n groups of <10, 10-19 and 20+ years from first
exposure.
Rohm and Haas (1986a,b) summarized their findings of the four epide-
miology studies as follows:
1. The 1933-1945 Bristol plant study found, that cancers of the colon and
rectum were significantly higher than expected among hourly employees
who had worked for at least 1 year 1n acrylate/methacrylate operations.
»
2. The excess of colorectal cancers found among employees with primarily
mixed exposures to methyl methacrylate and low levels of ethyl acrylate
did not fH the pattern that would be expected 1f monomer exposure were
actually cans-Ing the excess.
0863p -30- 05/19/87
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3. A mortality study of 1372 hourly employees at the Deer Park, TX plant
(1948-1977) found no signs of digestive cancer among employees handling
ethyl acrylate/meth-yT-methacrylate monomers but exposures In this plant
were much lower than those at the Bristol plant.
4. Contrary to the findings at the Bristol plant for workers hired before
1946, workers hired after 1945 and followed through December 1982 at the
same site, the number of cancers of the large Intestine and rectum was
not greater than expected (reduced exposure and less latency).
5. A separate study of similar processes at the Knoxvllle plant from
1943-1982, that included heavier production exposures as well as lower
recent exposures than those present at the Bristol plant, found no
excess of colorectal cancers among ethyl acrylate/methyl methacrylate
workers and no association of these cancers with either monomer vapor or
polymer particulates. The explanation for the presence of an excess of
cancers of the colon and rectum in ethyl acrylate/methyl methacrylate
workers hired before 1945 and the absences of an excess among those
hired later is not clear. Latent periods of <10, 10-19 and 20+ years
from first exposure were used.
Rohm.and Haas (1986a) concluded from these studies that no convincing cause
for the colorectum cancers was found In the earlier group and the
observations do not support an association between ethyl acrylate or
methacrylate exposure and an Increased Incidence of colorectal cancers. The
problems of the Knoxvllle and Deer Park plant studies can be summarized as
follows: lower exposure, shorter duration in follow-up, ill-defined
nosology, "death due to ill defined causes", and finally, lack of
consistency. Cohorts in different plants did not disprove a positive
finding.
In a review of the Rohm and Haas (1984) cohort mortality study, Mantel
(1986) has pointed out several weaknesses In the design of this study and
the analyses performed and questions the validity of the Rohm and Haas
conclusions. Mantel (1986) found that exposure to ethyl acrylate or methyl
methacrylate was not scored in any specific fashion. Attention was focused
on comparison with external controls either the general U.S. white male
population or regional males (Pennsylvania and New Jersey), disregarding
internal data. The Rohm and Haas study showed certain SMRs for the entire
086JL -31- 05/19/87
-------
plant and for employees ever In ethyl acrylate/methyl methacrylate-related
jobs; this tended to reflect a healthy-corker bias (1f adjustment had.been
made for latent factors, this could .be eliminated) and therefore- these
ratios are characteristically below unity. Mantel (1986) also pointed out
that when comparisons are made using workers with at least 1 year of employ-
ment an SMR=210 was obtained by Rohm and Haas for latency of at least 10
years. However, by dlffencinq this population by exposure and duration,
Mantel (1986) derived an SMR=312. While the Rohm and Haas study does take
into account accumulative exposure to workers, the duration of exposure was
not kept constant over the dosing period thereby diluting any. dose-response
effect. Mantel also pointed out that the lack of dose-response effect
Indicated by the decrease in SMRs with Increasing latency periods is an
artifact of the design because of Increasing background rates. If 1n fact
age cutoffs are used in analyzing this data, SMR ratios Increase. Mantel
concluded that the data .in the Rohm and Haas (1984) study has shown that
occupational exposure to ethyl acrylate/methyl methacrylate Increased the
relative risk of colorectal cancer among workers 3-fold.
5.2. MUTAGENICITY
Ethyl acrylate was found not to be mutagenic 1n plate incorporation
assays (Table 5-5) of Salmonella typhimurlum strains TA98, TA100, TA1537 or
TA1538 (NTP, 1986a; Haworth et al., 1983; Waegemakers and Benslnk, 1984).
Results were the same with or without metabolic activation. Ishldate et al.
(1981) detected .chromosomal aberrations 1n 20% of all metaphases of a lung
flbroblast culture from Chinese hamsters at a dose of 9.8 pg/mi ethyl
acrylate in the absence of S-9. An increased Incidence of mutations at the
thymidlne kiriase locus 1n a mouse lymphoma assay was reported by Litton
B1onet1cs (1980), after treatment of cells with cytolethal doses of ethyl
0863p -32- 05/19/S7
-------
0
00
I
u>
1ABLE 5-5
Hutagcnlclty Testing of Ethyl Acrylate
Assay
R'iyei se
iT'iin! Ion
Rrv?i se
n'.-'l at Ion
C!M «»;".)somal
al'iTi allon
1 :n w-31 d
ni"i .1 1 Ion
HuuXc
crlM cnucleus
1 1"; I
Indicator/
Organism
Salmonella
typhlrr.ur Im
TA98. 1A100.
1A1535. TA1T.37
S. typhlmur Iro
TA98. 1A100.
IA1535. 1A1537
1A1538
OIL cells, lung
flbroblast line
L51784 mouse
lymphoma cells
male Balb/C
mice
Compound
and/or
Purity
99.75C pure In
OHSO or H^O
>99X In
DNSO
NR
dissolved
In DHSO
dissolved
In distilled
water
Application
plate
. Incorporation
plate
Incorporation
liquid
suspenlon
liquid
suspension
Intraper ttoneal
Injection .
Concentration Activating
or Dose System
33-10.000 »S-9
iig/plate
30-2000 *S-9
ng/plate
9.8 |ig/mi none
0.195-100 fS-9
ni/ml
117.5-1800 NA
nig/kg
Response Comment
Both rat liver and
hamster liver S-9 used
NC
» Dose at which chromosomal
aberrations were detected
In 20X of metaphases
i Increase In mutations
• began at 30 ug/t (-S-9)
and 100-150 Mg/t (»S-9)
» Dose-related Increases In
polychromatic erythrocytes
with mlcronuclel at doses
lethal to some polychromatic
cells
1 •
Reference j
Ha worth et al..
1983; NIP. 19B6a
I
Waegemaekers and
Benslnk. 1984
Ishl.dale et al..'
1981
Litton
Blonetlcs, 1900 '
i
Przybojewska [
et al.. 1984
in1 -: Not reported; NA = not applicable; NC •= no comment
CO
a
CO
-------
acrylate. The response was reduced 1n the presence of S-9. Przybojewska et
al. (1984) Injected- groups..of male Balb/c mice with 112.5-1800 mg/kg intra-
perltoneal ethyl acrylate and subsequently removed the femurs of the -treated
mice for analysis of polychromatic micronuclel. They found that ethyl
acrylate, which exerted a dose-related Increase In polychromatic lethality,
also effected a dose-related Increase In micronuclel.
5.3. TERATOGENICITY
Murray et al..(1981) exposed groups of 33 gravid Sprague-Oawley rats to
0, 50 or 150 ppm (205 or 614 mg/m3) ethyl acrylate vapor, 6 hours/day, on
days 6-15 of gestation. Maternal rats were observed dally for toxic
symptoms; food and water consumption was measured every 3 days beginning on
gestation day 6, and maternal body weights were recorded 7 times during
gestation. On day 21, the pups were removed by Caesarean section, the dams
were sacrificed and their livers weighed; Investigators recorded the
position and number of live, dead and resorbed fetuses, -and the uteri of
nonpregnant rats were stained for examination of early resorptlon sites.
Each fetus was weighed and sexed and the crown-rump length was measured.
One-third of the fetuses In each litter was examined microscopically for
soft tissue anomalies, and" all fetuses were cleaned and stained with
alizarin red-S for analysis of skeletal abnormalities.
, Except for the Initial measurement on day 6, dams exposed to 150 ppm
weighed significantly less than controls throughout the exposure period and
on. days 16 and 18. Most of .the weight gain Inhibition of high-dose females
occurred on gestation days 6 and 7. During exposure, the total amount of
weight gained was decreased by 48% In the high-dose group, which also had a
significant decrease In food consumption and a significant Increase In water
OBe.2p -?-- 05/19/87
-------
consumption. There were no changes In absolute or relative liver weights at
either exposure l«velr "and there wert no exposure-related effects on
parameters of maternal reproductive . performance, or on nonter*togen1c
manifestations of fetal toxUHy.
When the Utter was considered as the unit of analysis, the Incidences
of major malformations 1n the offspring of treated dams were not signifi-
cantly different from control rats (Fisher exact p=0.10 by an Independent
analysis done at SRC), although the Incidence of fetuses with hypoplastlc
tails was higher than historical controls. Three of 338 fetuses from 3/29
litters of dams exposed to 150 ppm had multiple occurrences of major malfor-
mations. The first had a short trunk, hypoplastlc tall, small anal orifice,
ectoplc ovaries, missing ribs, vertebrae and centra, and fused and malformed
Mbs. The. second fetus showed a hypoplastlc tall, small anal orifice and
missing vertebrae and the third had a hypoplastlc tall and missing
vertebrae. The significant decrease In maternal weight, at the high dose
makes, the Interpretation of these effects difficult. None of the control or
50 ppm fetuses was found to have a major malformation.
Gravid rats treated by an unspecified route with 25-400 mg/kg ethyl
acrylate from 7-16 days of gestation had decreased body and placental weight
gains and Increased numbers of resorptlons (Pietrowlcz et al., 1980). The
size and number of live fetuses were not affected by treatment, but the
investigators noted increased numbers of skeletal anomalies in the offspring
of exposed rats. No further details were available and therefore no conclu-
sion's from theis data can be made.
5.4. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding the other reproductive effects of ethyl
acrylate could not be located in the available literature as cited in the
Appendix.
08£3: -25- 05/19/87
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5.5. CHRONIC AND SUBCHRONIC TOXICITY
The NTP (1986b) 1s-currently preparing the final technical report of a
lifetime exposure study, of B6C3F1 mice'and F344 rats. In the 2-year-study,
groups of 50 male and 50 female rats and 50 male and 50 female mice were
given gavage doses of 0, 100 or 200 mg/kg ethyl acrylate 1n corn oil, 5
days/week for 103 weeks. All rats and mice were observed twice dally for
morbidity and mortality; body weights were recorded weekly for 12 weeks and
monthly thereafter. Gross necropsies were performed on all rats and mice
found dead and on those sacrificed at the end of the study. Major tissues
were examined for grossly visible lesions. Hlstopathologlcal analysis of
gross lesions, abnormal lymph nodes, tissue masses and 33-34 other sites was
conducted on nonautolyzed rats and mice of all dose groups.
there were no treatment-related effects upon survival 1n either rats or
mice, or upon growth In either sex of rats. Body weights of male mice were
also unaffected by treatment. Administration of 100 mg/kg to female mice
led to an Inhibition 1n growth, particularly In the latter half of the
study; however, a similar Inhibition In growth rate was not found In the
high-dose females.
Prominent In both species were dose-related Increased Incidences of
forestomach lesions, characterized by Inflammation, epithelial hyperplasla
and hyperkeratosls. Ulceratlon was dose-related In mice. Halrballs and
accompanying Inflammatory reactions were sometimes found 1n the mucosa of
rats.
Two-year studies using dogs and rats given oral ethyl acrylate were con-
ducted by Borzelleca et al. (1964). Groups of 25 male and 25 female Wlstar
rats were initially given either 0, 6, 60 or 2000 p.pm ethyl acrylate in
0863? -36- 05/19/87
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drinking water. During the fifth month, the 6 and 60 ppm levels were raised
to 7 and 70 ppm. -Polarographlc analyst of Independent samples of treated
water revealed only marginal loss of acrylate monomer.
Food and fluid consumptions were evaluated periodically. At 3-month
Intervals, hematocrlt, hemoglobin and total white and differential cell
counts were measured on five rats/sex 1n each treatment group. Semi-quanti-
tative uMnalyses for reducing substances and protein were performed at
3-month Intervals from five rats/sex/treatment group. Upon terminal sacri-
fice at 2 years, organ-to-body weight ratios of the heart, spleen, kidney,
liver and testes were measured. H1stopatholog1cal analysis of 16 major
tissue sites was also performed.
Borzelleca et'al. (1964) found no differences In survival rates that
were due .to treatment.. Administration of the 2000 ppm level significantly
(p<0.05) depressed body weight gain In both sexes during the first year and
continued to. depress female body weight gain In the second year. This level
also significantly decreased overall fluid consumption Vn both sexes of rats
and decreased food consumption In females. There were no treatment-related
effects on hematologlcal, urinary or hlstopathologlcal parameters or on
relative organ-to-body weight ratios.
In the chronic dog study, Borzelleca et al. (1964) administered ethyl
acrylate dissolved 1n corn oil by gelatin capsules. Preliminary Investiga-
tions revealed a dissolution rate of <5% after 5 days. Groups of two male
and two female beagles were given doses equivalent to dietary .concentrations
of 0, 10, 100 or 1000 ppm ethyl acrylate. Dogs receiving 10 or 100 ppm
tolerated administration well; however, all four dogs given 1000 ppm
vomited. Starting on the second week, these dogs tolerated 300 ppm dally;
0863r -37- 05/19/87
-------
this level was raised to 400 ppm at 5 weeks, to 500 ppm at 7 weeks, to 600
ppm at 9 weeks, to_.700_ppm at 12 weeks,-to 800 -ppm at 14 weeks and finally
to 1000 ppm at 16 weeks. The 1000 .ppm-level was maintained for the duration
of the study. Thus, the TWA was 931 ppm.
Hematologlcal tests and urinalyses were performed before dietary admin-
istration, at 2, 4 and 13 weeks after administration, and at 13-week
Intervals thereafter. At sacrifice, organ-to-body weight ratios were
calculated and h1stopatholog1cal studies were made on all tissues. Slight
decreases In body weight gain, correlated with decreased food consumption In
the high-dose dogs, were the only treatment-related effects observed.
The NTP (1986a) conducted 13-week studies of ethyl acrylate administra-
tion using .F344 rats and B6C3F1 mice. Groups of 10 female and 10 male rats
were administered ethyl acrylate In corn oil by gavage, 5 times/week at dose
levels of 0, 7, 14, 28, 55 or 110 mg/kg. Groups of 10 mice/sex were admin-
istered ethyl acryl.ate 1n corn oil by gavage, 5 times/week at dose levels of
0, 1.5, 3, 6, 12 or 25 mg/kg. In a second study, 10 male and 10 female
mice/dose group received 0, 12, 25, 50 or TOO mg/kg ethyl acrylate In corn
oil on the same treatment schedule. All rats and mice were checked for
mortality and morbidity twice dally; those found moribund were sacrificed
and necropsled. Each rat or mouse was clinically examined weekly, and body
\ •
weight measurements were taken. At sacrifice, rats arid mice were necrop-
sled. In the control and high-dose groups only, 29 tissues were examined
histologlcally; no histologlcal examinations were performed on mice and rats
from other dose groups.
Treatment had no effect on the longevity or body weight gain of rats.
There .were no compound-related clinical signs or evidences of histopatho-
logical changes, except for an occasional reddened duodenum or prominent
0863D -38- 05/19/87
-------
vasculature In the stomachs of male rats receiving 110 mg/kg. In the first
subchronlc mouse siudy_ 2/10 females receiving 25 mg/kg and 1/10 females
receiving 6 mg/kg died during the ..exposure period. The cause of death In
these mice was unclear. Mean body weight gains were not affected by treat-
ment. In the second mouse study, there were no dose-related affects on body
weights or mortality rates. No evidence of gross or microscopic tissue
damage from compound administration was apparent 1n either mouse study.
Treon et.al. (1949) orally dosed two rabbits with 31.5 mg/kg ethyl
acrylate, 5 days/week for 7 weeks. Besides a small Inhibition In growth
rate, no overt signs of toxldty were observed. The rabbits were sacrificed
2 months after administration of the last dose, at which time there were no
gross or microscopic changes 1n examined tissues. •
Miller et al. (1985) exposed F344 rats and B6C3F1 mice of both sexes by
Inhalation to 0, 25, 75 or 225 ppm (0, 102, 307 or 921 mg/m3) ethyl
acrylate, 6 hours/day, 5 days/week (excluding holidays) for up to 27 months.
Initially, there were 92 rats/sex 1n each 'Of the two control groups and 115
rats/sex 1n each of the three treatment groups. There were also 84 mice/sex
In each of ,the two control groups and 105 mice/sex In each exposure group.
.Eight rats/sex In each control group and 10 rats/sex In each exposure group
were sacrificed after 3, 6, 12 or 18 months of exposure; 8 mice/sex/control
group and 10 mice/sex/exposure group were sacrificed after 6, 12, or 18
months of exposure. Based upon Interim results, the high-dose rats and mice
were withdrawn from exposure after 6 months and maintained for an additional
21 months.
All groups of rats and mice were observed dally for manifestations of
toxldty. Body weights were measured weekly for the first 3 months,
biweekly during months 4-6 and monthly thereafter. Moribund rats and mice
0863D -39- 05/19/87
-------
were sacrificed and histopathology on nonautolyzed tissue was collected for
hematologUal (erythrocyt.e counts, PCV, Jiemoglob.ln concentration, total and
differential leukocyte counts) and. blood biochemical (alkaline phosphatase
and SGPT activities, BUN, and glucose) assessments. Rats only were also
analyzed for cholesterol, fasting blood sugar, trlglycerldes, total protein,
albumlnum and globulins. UMnalyses on rats evaluated uroblllnogen,
b1Hrub1n, glucose, ketones, blood, pH, protein and specific gravity.
Statistical analyses of organ weights, clinical chemistry and hematology
data were not performed for the rats and mice sacrificed at 27 months,
because of the high Incidence of spontaneous diseases found in aging
animals. At terminal sacrifice (27 months), the liver, kidney and brain
weights were recorded for mice and the liver, kidney, brain, heart, spleen
and testes weights for rats. Approximately 50 tissues were taken from each
rat or mouse for gross and. hlstologlcal examination 1n the control and 75
ppm groups.; 1n the 25 and 225 ppm groups, -15 tissues were examined hlsto-
logically.
No effects on mortality rates were found 1n rats. There were Immediate
and lasting Inhibitions In body weight gain In the'75 and 225 ppm groups,
although the degree of Inhibition was diminished In (the latter group after
exposure ended. Relative brain, Hver and kidney weights of subgroups of
rats serially sacrificed (up to and Including 27 months of exposure) were
unremarkable. Hlstopathologlcal examination of tissues from rats maintained
In the chronic study r'evealed treatment-related nonneoplastVc lesions of the
olfactory portions of. the nasal cavity. Concentration-related Increases in
severity and Incidence of basal cell hyperplasia, Intraeplthellal glands,
"respiratory metaplasia" and multlfocal mineralization were found In rats of
0863p -40- 05/19/87
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both sexes exposed to 25 or 75 ppm. Diffuse atrophy of the olfactory
epithelium was conf_1ned_almost exclusively to the 225 ppm group. At 25 ppm,
the primary manifestation was a decrease 1n .the number of mature neurons In
the mucosa, with compensatory hyperplasla, stratification of basal cells and
an Increase 1n IntraepHhellal glandular elements. In 16 males and 6
females, there was slight to moderate "respiratory metaplasia," or replace-
ment of the olfactory epithelium with a dilated respiratory epithelium
similar to that lining the upper respiratory tract. At 75 ppm, lesions were
similar but more extensive 1n terms of both Incidence and the extent of
nasal cavity affected. Virtually all rats exposed to this concentration had
respiratory metaplasia and multlfocal mineralization of the olfactory
epithelium. At 225 ppm, diffuse atrophy was characterized by a diminished
epithelium consisting of a single layer of support cells and a single layer
of focally hyperplastlc basal cells. Incidences of other lesions, Including
Increased IntraepHhellal glandular elements, respiratory metaplasia and
mineralization, were Intermittent among those of the 25 and 75 ppm groups.
The only other treatment-related pathological change considered by the
Investigators to be of biological significance was a positive concentration-
related trend In males, 1n the Incidences of foci ,of adrenal medullary
hyperplasla. Since these lesions are precursors of medullary neoplasla, and
the number of rats In the 25 and' 75 ppm groups that had adrenal neoplasla
was less than the number of similarly afflicted control rats, Miller et'al.
(1985) concluded that fewer of the prollferatWe' adrenal lesions In the
exposed rats had progressed to the oncogenlc stage.
Longevity of mice was not adversely affected by any treatment concentra-
tion. Mean body weight gains 1n the ,75 and 225 ppm mice of both sexes were
significantly lower than for control groups. Near the end of the study,
0863D -41- 05/19/87
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body weight gains In the 25 ppm mice were also slightly depressed. Relative
brain, liver and k1dney_we1ghts of subgroups of mice serially sacrificed (up
to and Including 27 months) were unremarkable. No adverse effects on
hematology, clinical chemistries or urlnalyses on subgroups of mice sacri-
ficed after 6, 12, 18 or 27 months of exposure were noted. Pathologically,
exposure-related lesions In treated mice were restricted to the nasal
mucosa. Concentration-related Increases In the Incidences of submucosal
hyperplasla and respiratory metaplasia were found In b'oth males and females.
In mice exposed to 225 ppm for 6 months and sacrificed at 27 months, the
extent of area affected, but not the severity of lesion, Increased, No
other exposure-related gross or microscopic changes were observed in any
tissues of mice.
In rats exposed to 25 ppm (102 mg/m3) and . sacrificed after 6 or 12
exposure months, there was very slight focal degeneration of the olfactory
epithelium and very slight Inflammation of the nasal mucosa and submucosa
(Miller et al., 1979a). 'After exposure to 75 ppm for 6 or 12 'months, rats
had slight focal hyperplasla of the basal cells, slight to moderate focal
degeneration of the olfactory epithelium and occasional Infolding of the
mucosal surface. The chief difference between 6 and 12 months exposure was
the extent of area affected. In separate groups of 10 rats/sex exposed to
225 ppm for 6 months and sacrificed 3 or 6 months later, there was evidence
of healing and recovery of olfactory lesions.
Killer et all (1985) also chronically exposed rats and mlc'e to 5 ppm (20
mg/m3) ethyl acrylat.e, 6 hours/day, 5 aays/week for 24 months for deiermY-
natlon of a no-effect level for hlstopathologicaV changes. Eighty rats and
80 mice of each sex served as controls and 90 rats and 90 mice of each sex
were in the treated groups. Subgroups of rats and mice were sacrificed
0863p -42- 05/19/87
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after 6, 12, 18 and 24 months of exposure for analysis of nasal turblnate
lesions only. The Investigators observed no neoplastlc or nonneoplastlc
changes at this concentration and treatment did not affect either mortality
or clinical appearances of rats and mice.
As cited by U.S. EPA (1981), 10 B6C3F1 mice and 10 F344 rats of each sex
were exposed 6 hours/day, 5 days/week to ethyl acrylate vapor at concentra-
tions of 0, 75, 150 or 300 ppm (0, 307, 614 or 1228 mg/m3) for 22 days
(Miller et al., 1979b). The rats and mice were observed dally for signs of
toxldty and were examined for gross pathological lesions. Selected organs
were examined microscopically. At 300 ppm, the mean weight gains of male
rats, male mice and female rats were significantly less than those of
controls. At 150 ppm, the mean body weight gain among male and female rats
was also significantly reduced, relative to controls. Mean kidney-to-body
weight ratios were, significantly Increased 1n the 300 ppm rats of both sexes
and 1n the 150 ppm females. In addition, the absolute and relative liver
weights of mice of both sexes exposed to the two highest concentrations were
significantly lower than control weights. The only hlstopathologlcal effect
Involved lesions of the nasal turblnate tn male mice and rats exposed to the
high concentrations. The .effect Involving principally the dorsomedlal
olfactory epithelium was characterized by Inflammation, degeneration, focal.
necrosis and squamous metaplasia. .
Rozzanl et al. (1949) exposed groups of 15 male and 15 female Sherman
rats and 8 or 9 albino male rabbits by Inhalation to 0, 70 or 300 ppm (0,
287 or "i228 mg/m3), 7 hours/day, 5 days/week for 30 days. Hlstologicai
examinations were performed on the liver, kidney, heart, lung, pancreas,
spleen and adrenal. At 300 ppm, 18/30 rats died before the end of the study
0863p -43- 05/19/87
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and had pneumonic and cloudy swelling of renal tubules and liver. The 300
ppm group rats that survived had decreased body weight gain and Increased
kidney weights, and 3/12 had minor liver or lung lesions. The only effect
at 70 ppm 1n rats was Increased kidney weights of males. At 300 ppm, all 9
rabbits died within 7 days and at 70 ppm, 2/8 died within 30 days compared
with 3/8 controls. Pulmonary Infection was thought to be the cause of death.
Treon et al. (1949) observed no effects on rabbits, guinea pigs, rats or
monkeys exposed to ethyl acrylate 7 hours/day at 99 or 105 mg/m3 for
62-130 times over 199 days, or to 300 mg/m3, 50 times over 72 days. Two
rats, two guinea pigs and one monkey exposed for 28 days to 1090 mg/m3
showed large weight losses and signs of respiratory Irritation, conjuncti-
vitis, lethargy and diarrhea. One guinea pig died as a re.sult of exposure;
four similarly exposed rabbits died within 8-1,7 days of the start of
exposure. Surviving animals removed from the chamber were prostate, ataxU,
convulsive, had oplsthotonos, and had breathing difficulties Indicative of
pulmonary edema. Gross and microscopic examination of poisoned animals
revealed brain, spleen, kidney, lung and liver congestion, dilation of
cardiac chambers, myocardlal degenerations, fatty •. hepatic changes, edema,
pyknosls and karyolysls. No significant changes were found In the tissues
of animals that survived exposure and were sacrificed 2 months later.
5.6. OTHER RELEVANT INFORMATION
Oral LD5Q values for ethyl acrylate of 1.797 g/kg In male ddY mice
(Tanll and Hashimato, 1982), 1.02 g/kg 1n male albino rabbits (Pozzanl et
al., 1949) and -C.35• g/kg in female rabbits (Treon et dl., 1949) have been
/
reported. The NTP (1986a) conducted three 14-day oral studies of ethyl
acrylate in F344 rats and B6C3F1 mice of both sexes. In the first study,
0863p -44- 05/19/87
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administration of 110, 225 or 450 mg/kg ethyl acrylate 1n ethanol led to
thickened forestomach mucosa In rats; after 450 mg/kg adhesion of the spleen
and stomach to the peritoneum occurred. A dose of 900 mg/kg was .fatal to
all rats within 24 hours. In mice, the 450 mg/kg dose led to a thickened,
rough mucosal surface 1n the forestomach and for both males and females, 1/5
mice died shortly after termination of exposure. The dose of 450 mg/kg was
the highest one used; the NTP (1986a) did not discuss hlstopathologlcal
changes at lower doses. In the second study, ethyl acrylate was adminis-
tered In drinking, water at concentrations of 0.025-0.45% (rats) and
0.013-0.22% (mice). The only pathological change noted 1n rats and mice
sacrificed after exposure was a reddening of the duodenal mucosal surface.
Because of the stability of ethyl acrylate In water, faulty sipping tubes,
broken water bottles and spillage, this method of administration was consid-
ered Inappropriate for further testing. Finally, 1n the third 14-day study,
groups of five rats and mice of each sex were administered 0, 100, 200, 400,
600 or 800 mg/kg ethyl acrylate In corn oil dally for 14 consecutive days.
Hlstologlcal examinations were made of the stomachs of rats administered
0-400 mg/kg and of mice given 0-600 mg/kg. In rats, abdominal adhesions and
a thickened stomach wall were observed beginning at 100 mg/kg. Starting at
400 mg/kg, ulceratlve and nonulceratlve forestomach Inflammation, charac-
terized by the presence of neutrophlls, lymphocytes and hlstlocytes 1n the
mucosa and submucosa, were observed. The forestomachs of most mice
receiving 200-800 mg/kg were grossly thickened and abdominal lesions were
oDserved at the high dose. Nonulcerative inflammation was first observed at
200 mg/kg and more severe ulceratlve lesions were first seen at 400 mg/kg.
Administration of up to 800 mg/kg for 14 days did not kill any of the
treated rats or mice.
0863p -45- 05/19/87
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Ghanayem et al. (1985a) studied the dose-response relationship, time
course and effect of joute of administration of ethyl acrylate upon the
stomachs of rats. In male F344 rats dosed singly with 100, 200 or 400 mg/kg
ethyl acrylate 1n corn oil, there was a dose-related Increase In mucosal
congestion and submucosal edema of both the glandular and forestomach, as
well as vacuollzatlon of the tunica muscularls. In rats orally dosed with
200 mg/kg ethyl acrylate In corn oil and sacrificed 2, 4, 8 or 24 hours
after administration, the occurrences and severity of lesions of the
forestomach Increased with time. The Incidences of submucosal edema and
Inflammation were also positively related to time after administration.
Whereas a subcutaneous dose of 200 mg/kg ethyl acrylate was without effect
on stomach histology, 1ntraper1toneal administration of the same dose led to
microscopic submucosal edema and vacuollzatlon of the tunica muscularls of
the forestomach. The congestion and edema observed after IntraperHoneal
administration, however, were of considerably less severity than gastric
signs of toxlcity after oral dosing. Administration of four consecutive
oral doses of 200 mg/kg ethyl acrylate Increased the Incidences of super-
ficial mucosal necrosis of the glandular stomach, as well as erosions,
mucosal hyperplasla and vacuollzatlon of the tunica muscularls of the
forestomach, relative to a single administration. Ghanayem et al. (1985a)
concluded that ethyl acrylate caused an Immediate Inflammatory .response,
typical of irritants, which were more pronounced In the forestomach than 1n
the glandular stomach.
In a fo.iow-up study, Gnanayen et al. (1985o, explored the parameters
responsible for ethyl acrylate-lnduced gastric edema. Using a series of
three acrylete esters (methyl, ethyl and butyl.}. Ghanayem et al. (1985b)
0863p -46- 05/19/87
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demonstrated that the extent of forestomach edema as measured gravimetric-
ally was positively correlated with concentration of ester 1n the vehicle
and polarity of the vehicle and negatively correlated with alkyl chain
length. Equlmolar dosing with acrylic add, ethyl and methyl methacrylates
or the fully saturated ethyl and methyl proplonate failed to Induce edema.
As In the previous study, effects on the glandular stomach were not as
pronounced as were those on the forestomach.
Lomonova and Kllmova (1979) calculated LCSQs of 16,200 and 7500
mg/m3 for unspecified durations for mice and rats, respectively, exposed
by Inhalation to ethyl acrylate vapors. Inhalation of ?010 mg/m3 ethyl
acrylate, 7 hours/day, was lethal to all exposed rabbits In 4 days and all
exposed rats and guinea pigs In 13 days (Treon'et a!., 1949). Similarly,
Inhalation exposure of 4830 mg/m3 for 7 hours/day was lethal 1n 1-2.2 days
to four rabbits, two guinea pigs, two rats and one monkey.
After dermal application of ethyl acrylate, the skin of rabbits was
edematous, necrotlc and erythematous (Pozzanl et a!., 1949; Treon et a!.,
1949). Treon et al. (1949) noted scattered collections of polymorphonuclear
leukocytes, focal abscesses and complete destruction of the. epidermis.
Application of 0.5 ma of the undiluted ester to the corneas of rabbits
produced severe necrosis In 24 hours, whereas 0.1 ml led to a mild
necrosis (Pozzanl et al., 1949). Application of 23 mg ethyl acrylate. to the
shaved backs of C3H/HCJ mice 3 times/week for life led to no gross lesions
(DePass et al., 1984). Microscopically, the treated skin appeared necrotlc
and fibrotic, and the mice had dermatitis ano hyperkeratosis.
5.7. SUMMARY
An NTP (1986a) report of the potential carclnogenicity of ethyl acrylate
after oral (gavage) administration 1n F344 rats and B6C3F1 mice of both
sexes indicated that ethyl acrylate induced squamous cell carcinomas or
0863p -47- 05/19/87
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paplllomas (or both) of the forestomach 1n both species. For both species,
dose levels were 0, 100_and 200 mg/kg, 5 jdays/week for 103 weeks.
No evidence of carclnogenldty was -found. 1n rats given up to 2000 ppm In
the drinking water for 2 years (Borzelleca et al., 1964).
Miller et al. (1985) found no evidence of cardnogenldty 1n B6C3F1 mice
and F344 rats exposed by Inhalation to up to 75 ppm (307 mg/m3) ethyl
acrylate, 6 hours/day, 5 days/week, for 27 months, or In rats and mice
exposed to 225 ppm (921 mg/m3), 6 hours/day, 5 days/week for only 6
months, then maintained for 21 months until terminal sacrifice.
DePass et al. (1984) found no Increase In epidermal tumor Incidence 1n
C3H/hej male mice skin-painted with 23 ing/mouse ethyl acrylate, 3 times/week
for 2 years.
A causal relationship for Increased Incidences of cancer of the colon
and rectum from occupational exposure to ethyl acrylate/methyl methacrylate
was suggested In a retrospective epidemiology study on workers employed at
the Bristol, PA plant before 1946; however, the causal relationship could
not be fully established when relative accumulated total exposure and
latency were considered (Rohm and Haas Co., 1984). Fur.ther analyses and
studies were conducted at .the above plastic manufacturing facility for
employees hired after 1946. In these studies no Incidences of cancer of the
colon and rectum were found (Rohm and Haas, T986a). Similar studies
conducted at manufacturing sites 1n Texas and Knoxyllle, TN, found no signs
of Increased digestive cancers Including colorectal cancers among hourly
employees (Rohm and Haas, 1981, 1986b). A review of the Rohm and Haas
(1984) study has pointed out several weaknesses 1n the study design and
analyses perfomed that may have diluted the dose-response effect reported by
0863p -48- 05/19/87
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Rohm and Haas (1984) and suggests that a causal relationship between ethyl
acrylate/methyl methacrylate exposure and Increased Incidences of colorectal
cancers does exist (Mantel, 1986).
Ethyl acrylate has been found to be nonmutagenic 1n standard reverse
mutation assays with and without metabolic activation (NTP, 1986a; Haworth
et al., 1983; Haegemakers and Benslnk, 1984). Principally at cytolethal
doses, ethyl acrylate was mutagenlc to CHL cells (Ishldate et al., 1981) and
mouse lymphoma cells (Utton Blonetics, 1980) 1n culture. Przybojewska et
al. (1984) demonstrated genotoxldty of ethyl acrylate In the mlcronucleus
test using Balb/c mice.
Murray et al. (1981) demonstrated that exposure of rat dams to 50 or 150
ppm (205 or 614 mg/m3) ethyl acrylate, 6 hours/day, from days 6-15 of
gestation, had no effect upon reproductive performance In dams although
weight gain was significantly Inhibited at the high concentration. There
were no fetal malformations at 0 or 50 ppm. At 150 ppm, pups from 3/29
treated Utters had multiple (primarily skeletal) malformations. Although
this Incidence was not statistically different from control rats. In a
second reproductive study, P1etrow1cz et al. (1980) stated that treatment of
rat dams by an unspecified. route with 25-400 mg/kg ethyl acrylate during
gestation was associated with decreased body and placental weight gains,
Increased numbers of resorptlons and skeletal abnormalities.
In the 2-year gavage study by NTP (1986a), rats and mice had dose-
related Increases 1n forestomach hyperplasia, hyperkeratosls, Inflammation
or ulceration at >100 mg/kg, 5 days/week. The only effect 1n rats treated
with ethyl acrylate 1n the drinking water at concentrations up to 2000 ppm
or dogs treated orally by capsule with up to -931 ppm (TWA) was decreased
body weight gain In high-dose female rats (Borzelleca et al., 1964).
0863p -49- 05/19/87
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In F344 rats given 0-110 mg/kg ethyl acrylate by gavage 5 times/week for
13 weeks, there were _no treatment-related effects on body weight gain,
longevity or clinical signs (NTP, 19B6a). .The only prominent histopatho-
logical change, occurring in the high-dose males, was an occasional reddened
duodenum or pronounced stomach vasculature. Administration of up to 100
mg/kg ethyl acrylate to male and female B6C3F1 mice on the same treatment
schedule had no effects on longevity, body weight gain or gross or micro-
scopic histopathology (NTP, 1986a). Similar results were obtained by Treon
et al. (1949) in two rabbits given 31.5 mg/kg ethyl acrylate orally, 5
times/week for 7 weeks. In a series of 14-day oral studies, the NTP (1986a)
determined that gavage administration of 100 mg/kg/day ethyl acrylate in
rats and 200 mg/kg/day ethyl acrylate in mice led to abdominal adhesions,
thickened forestomach mucosa and nonulcerative inflammation. Administration
of higher doses resulted in ulcers and more severe Inflammation. Oral
LDc« values ranging from 0.35-1.8 g/kg have been reported (Tanii and
Hashimoto,. 1982; Pozzani et al.. 1949; Treon et al., 1949).
In the chronic inhalation study, nonneoplastlc lesions of the nasal
mucosa (e.g., hyperplasia, mineralization, Inflammation, metaplasia)
occurred 1n mice and rats a.t exposures >25 ppm (>102 mg/m3), 6 hours/day,
5 days/week for up to 27 months (Miller et al., 1985). Exposure to 5 ppm, 6
hours/day, 5 days/week had no effect.
Inhalation exposure to lethal concentrations (1080 mg/m3, 7 hours/day
for 28 days) of ethyl acrylate led to weight loss and severe signs of
mucosal irritation In rats, guinea pigs, rabbits anc .r; one monkey (Treon et
al., 1949); these signs included conjunctivitis, lethargy and diarrhea.
Examination of poisoned rats, guinea pigs and raobus revealed multiorgan
0863p -50- 05/19/87
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Involvement and a variety of edematous and degenerative changes. These
changes were found_ to_be reversible lo survivors that were sacrificed 2
months after termination of exposure.- Exposure at 70 ppm (287 mg/m3) for
7 hours/day 1n rabbits, guinea pigs, rats and monkeys was without adverse
effects (Pozzanl et al., 1949; Treon et al., 1949). Lomonova and KHmova
(1979) determined LC,Q of 16,200 and 7500 mg/m3 for unspecified
durations for mice and rats, respectively.
Ethyl acrylate Is a potent skin Irritant (Pozzanl et al., 1949; Treon et
al., 1949) Inducing erythema, edema, cellular necrosis and abscesses.
Corneal necrosis after ocular application' In rabbits was observed by Pozzanl
et al. (1949).
0863p -51- 05/19/87
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6. AQUATIC TOXICITY
6.1. ACUTE
LHtle Information 1s available concerning effects of ethyl acrylate on
aquatic organisms. Hermens and Leeuwangh (1982) determined a 14-day LC...
of 7.4 ymol/9. (0.74 mg/2.) for gupples, PoeclHa retlculata. Price et
al. (1974) reported a 24-hour LC5Q of 12 mg/i for brine shrimp, Artemla
sallna. Paulet and V1del (1975) reported a 3-day LC5Q of 5 mg/i for an
unspecified fish species.
6.2. CHRONIC
Pertinent data regarding chronic toxlclty of ethyl acrylate to aquatic
organisms could not be located 1n the available literature as dted In the
Appendix.
6.3. PLANTS
Pertinent data regarding effects of ethyl acrylate on aquatic plants
could not be located 1n the available literature as dted In the Appendix.
6.4. RESIDUES
Pertinent data regarding residues of ethyl acrylate 1n aquatic biota
could not be located 1n the available literature as cited In the Appendix.
6.5. OTHER RELEVANT INFORMATION
U.S. EPA (1972) reported that 0.6 mg/J. ethyl acrylate was the
threshold for tainting of fish flesh.
6.6. SUMMARY
The Information concerning toxlclty of ethyl acrylate to aquatic biota
1s very limited. LC,-n values of 0.74 and 12 mg/a. were reported for
gupples (Hermens and Leeuwangh, 1982) and brine shrimp (Price et al., 1974),
respectively.
0863p -52- 05/19/87
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
The ACGIH' (1985-1986) has adopted., a TLV-TWA of 5 ppm (-20 mg/m3) for
ethyl acrylate and has also recommended deletion of the STEL of 25 ppm (-100
mg/m3). A "skin" designation was also adopted because of ethyl acrylate's
potent dermal Irritation. The current TLV-TWA Is based upon Inhalation
results by Rohm and Haas (1978), Indicating that rats and mice exposed to 25
ppm ethyl acrylate vapors 6 hours/day. 5 days/week for 6 months had slight
degeneration of the olfactory part of the nasal mucosa (ACGIH, 1986). The
ACGIH (1986) supported the decision of several Industrial producers to lower
the TLV-TWA from 25 to 5 ppm (-20 mg/m3) 1n order to minimize sensory
Irritant effects. It also recommended deletion of the STEL until more
quantifiable toxlcologlcal and Industrial hygiene data were made available.
The U.S. FDA (1983) did not affirm ethyl acrylate as a generally recog-
nized as .safe Indirect human food Ingredient. This agency could not find
evidence that the ester was used In the. manufacture of food-related paper
and paperboard products, except as a component of polymers already covered
by current and prior food additive regulations.
OSHA (1985) has recommended a PEL of 25 ppm (-100 mg/m3) with an
accompanying "skin" designation. The major producers of acrylates Including
Rohm and Haas, Celenese, Union Carbide and Daw Badlsche, agreed on an
Internal TWA concentration of 5 ppm for an 8-hour day 1n an occupational
exposure setting (U.S. EPA, 1981).
7.2. AfybMTiC
Guidelines and standards for the protection of aquatic biota from the
effects of ethyl acrylate could not be located In the available literature
as cited In the Appendix.
0863p -53- 05/19/87
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8. RISK ASSESSMENT
An NTP (1986a) report of the potential cardnogenldty of ethyl .acrylate
after oral (gavage) administration in F344 rats and B6C3F1 mice of both
sexes Indicated that ethyl acrylate Induced squamous cell carcinomas or
paplllomas (or both) of the forestomach In both species. For both species,
dose levels were 0, 100 and 200 mg/kg, 5 days/week for 103 weeks.
No evidence of carclnogenlclty was found 1n rats given up to 2000 ppm In
the drinking water for 2 years (Borzelleca et al., 1964).
Miller et al. (1985) found no evidence of cardnogenlcHy In B6C3F1 mice
and F344 rats exposed by Inhalation to up to 75 ppm (307 mg/m3) ethyl
acrylate, 6 hours/day, 5 days/week, for 27 months, or In rats and mice
exposed to 225 ppm (921 mg/m3), 6 hours/day, 5 days/week for only 6
months, then maintained for 21 months until terminal sacrifice.
OePass et al. (1984) found no Increase In epidermal tumor Incidence In
C3H/Hej male mice skin-painted with 23 mg/mouse ethyl acrylate, 3 times/week
for 2 years.
A series of retrospective ep1dem1olog1cal studies have been conducted by
Rohm and Haas (1981, 1984, 1986a,b) for workers occupatlonally exposed to
ethyl acrylte/methyl methacrylate. A causal relationship for Increased
Incidences of cancer of the colon and rectum has been suggested for workers
exposed to ethyl acrylate/methyl methylacrylate (Rohm and Haas, 1984). The
data as presented by Rohm and Haas (1984) did not fully establish this
causal relationship wnen relative accumulated total exposure ana latency, or
later studies conducted at the same site and other manufacturing facilities
were considered. However, a review by Mantel '(1986) has pointed out several
weaknesses with the study design and analyses performed In the Rohm and Haas
0863p -54- 05/19/87
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(1984) cohort study. Further analyses on this data perfomed by Mantel
(1986) Indicated that a 3-fold Increase^ In colorectal cancer resulted from
occupational exposure to ethyl acrylate/methyl methacrylate.
The data provided by the Rohm and Haas (1981, 1984, 1986a,b) studies and
the Mantel (1986) report are Insufficient to establish a clear causal
relationship for Increased Incidences of cancer of the colon and rectum from
occupational exposure to ethyl acrylate/methyl methacrylate. Moreover, the
role of ethyl acrylate as the causative agent for these cancers cannot be
determined since exposure to ethyl acrylate and methyl methacrylate could
not be separated. However, these studies may provide supportive evidence
when considered with the positive Incidence of squamous cell carcinomas and
papHlomas In rats and mice exposed to ethyl acrylate (NTP, 1986a).
Ethyl acrylate has been found to be nonmutagenlc In standard reverse
mutation assays with and without metabolic activation (NTP, 1986a; Haworth
et al., 1983; Haegemakers and Benslnk, 1984). Principally at cytolethal
doses, ethyl acrylate was mutagenic to CHL cells (Ishldate et al., 1981) and
mouse lymphoma cells (LHton B1onet1cs, 1980) In culture. Przybojewska et
al. (1984) demonstrated genototoxlclty of ethyl acrylate 1n the mlcronucleus
test using Balb/c mice.
Murray et al. (1981) demonstrated that exposure of rat dams to 50 or 150
ppm (205 or 614 mg/m3) ethyl acrylate, 6 hours/day, from days 6-15 of
gestation, had no effect upon reproductive performance 1n dams although
weight gain was significantly Inhibited at the high concentration. There
were no fetal malformations at 0 or 50 ppm. At 150 ppm, pups from 3/29
treated litters had multiple (primarily skeletal) malformations. Although
this Incidence was not statistically different from control rats, 1n a
second reproductive study, Pletrowlcz et al. (1980) stated that treatment of
0863p -55- 05/19/87
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rat dams by an unspecified route with 25-400 mg/kg ethyl acrylate during
gestation was associated with decreased body and placental weight gains,
Increased numbers of resorptlons and skeletal abnormalities.
In the 2-year gavage study by NTP (1986a), rats and mice had dose-
related Increases In forestomach hyperplasla, hyperkeratosls, Inflammation
or ulceratlon at >100 mg/kg, 5 days/week. The only nonneoplastlc effect In
rats treated with ethyl acrylate 1n the drinking water at concentrations up
to 2000 ppm or dogs treated orally by capsule with up to -931 ppm (THA) was
decreased body weight gain In high-dose female rats (Borzelleca et al.,
1964).
In F344 rats given 0-110 mg/kg ethyl acrylate by gavage 5 times/week for
13 weeks, there were no treatment-related effects on body weight gain,
longevity or clinical signs (NTP, 1986a). The only prominent hlstopatho-
loglcal change, occurring In the high-dose males, was an occasional reddened
duodenum or pronounced stomach vasculature. Administration of up to 100
mg/kg ethyl acrylate to male and female B6C3F1 mice on the same treatment
schedule had no effects on longevity, body weight gain or gross or micro-
scopic hlstopathology (NTP, 1986a). Similar results were obtained by Treon
et al. (1949) 1n two rabbits given 31.5 mg/kg ethyl acrylate orally, 5
times/week for 7 weeks. In a series of 14-day oral studies, the NTP (1986a)
determined that gavage administration of 100 mg/kg/day ethyl acrylate In
rats and 200 mg/kg/day ethyl acrylate In mice led to abdominal adhesions,
thickened forestomach mucosa and nonulceratlve Inflammation. Administration
of higher doses resulted In ulcers and more severe Inflammation. Oral
LD5Q values ranging from 0.35-1.8 g/kg have been reported (Tanll and
Hashimoto, 1982; Pozzanl et al., 1949; Treon et al., 1949).
0863p -56- 05/19/87
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In the chronic Inhalation study, nonneoplastlc lesions of the nasal
mucosa (e.g., hyperplasia, mineralization, Inflammation, metaplasia)
occurred 1n mice and rats at exposures >25.ppm (>102 mg/m3), 6 hours/day,
5 days/week for up to 27 months (Miller et al., 1985). Exposure to 5 ppm, 6
hours/day, 5 days/week had no effect.
Inhalation exposure to lethal concentrations (1090 mg/m3, 7 hours/day
for 28 days) of ethyl acrylate led to weight loss and severe signs of
mucosal Irritation in rats, guinea pigs, rabbits and in one monkey (Treon et
al., 1949); these signs Included conjunctivitis, lethargy and diarrhea.
Examination of poisoned rats, guinea pigs and rabbits revealed multiorgan
Involvement and a variety of edematous and degenerative changes. These
changes Were found to be reversible in survivors that were sacrificed 2
months after termination of exposure. Exposure at 70 ppm (287 mg/m3) for
7 hours/day in rabbits, guinea pigs, rats and monkeys was without adverse
effects (Pozzani et a.l., 1949; Treon et al.( 1949). Lomonova and Klimova
(1979) determined LC5-S of 16,200 and 7500 mg/m3 for unspecified
durations for mice and rats, respectively.
Ethyl acrylate is a potent skin irritant (Pozzani et al., 1949; Treon et
al., 1949) Inducing erythema,, edema, cellular necrosis and abscesses.
Corneal necrosis after ocular application in rabbits was observed by Pozzani
et al. (1949). . ..
Since ethyl acrylate was carcinogenic in rats and mice, inducing
squamous cell carcinomas or papillomas (or both) of the forestomach (NTP,
1986a), it is appropriate to derive a q* for etny'i acrylate. According
to U.S. EPA (1984) protocol, combined papilloma/carcinoma incidence should
be considered for risk assessment. Since the highest tumor response was
obtained 1n male rats, these data were selected as the most appropriate.
0863p -57- 05/19/87
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Data used in the calculation of the q,* are presented in Table 8-1. The
transformed doses were Calculated by multiplying the doses by 5 days/7 days
and by 103 weeks/104 weeks. The unadjusted q^ of 8.86xlO~a (mg/kg/
day)"1 was calculated using the computerized multistage model developed by
Howe and Crump (1982). The human q * of 4.8xlO~2 (mg/kg/day)~a was
calculated by multiplying the unadjusted q * by the cube root of the ratio
of the reference human body weight (70 kg) to the weight of the male rats
(0.44 kg, estimated from the growth curve 1n the study).
The human q * can be used to determine the hazardous concentrations
for Increased lifetime cancer risks of 10~5, 10"6 and 10~7 1n drinking
water If It Is assumed that a 70 kg human drinks 2 l of water daily (U.S.
EPA, 1980), Division of each risk level by the human q* and multiplica-
tion of each result by 70 kg/2 8,/day, results In concentrations of
7.3xlO~3, 7.3xlO"4 and 7.3xlO~s mg/8... respectively, for the risk
levels of 10"5, 10"6 and 10"'.
Values for q * could also be derived for the Incidences of squamous
cell papllloma/cardnoma of the forestomach for female rats and male and
female mice, but the resulting q,*s would be lower than that derived from
the male rat data.
0863D -58- OS/19/87
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TABLE" 8-1
Cancer Data Sheet for Derivation of q-|*
Compound: ethyl acrylate
Reference: NTP, 1986a
Species, strain, sex: rat, F344, M
Body weight: 0.44 kg (measured)
Length of exposure: (le) = 103 weeks
Length of experiment: (Le) = 104 weeks
Llfespan of animal: (L) = 104 weeks
Tumor site and type: forestomach, combined papllloma/cardnoma
Route, vehicle: oral gavage, corn oil
Experimental Doses
or Exposures
Q mg/kg, 5 days/week
100 mg/kg, 5 days/week
200 mg/kg, 5 days/week
Transformed Dose
(mg/kg/day)
0
70.7
141.5
Incidence
No. Responding/No.
1/50
18/50
36/50
Tested
Unadjusted q^ from study = 8.8632053xlO"3 (mg/kg/day)'1
Human q-j« = 4.8Q25578xlO~2 (mg/kg/day)~A
0863p -59- 05/19/87
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9. REPORTABLE QUANTITIES
9.1. REPORTABLE QUANTITY (RQ) RANKING B/SED ON CHRONIC TOXICITY
The subchronlc and chronic toxldty of ethyl acrylate were discussed In
Section 5.5. and a teratology study was discussed In Section 5.3. Since the
teratology study was negative and since subchronlc studies did not define
effect levels lower than 1n the chronic studies, only the chronic studies
are considered for the derivation of an RQ for ethyl acrylate. These
chronic studies are summarized 1n Table 9-1. As seen from Table 9-1, the
most severe effect was respiratory metaplasia 1n the chronic Inhalation
study by Miller et al. (1985). The lowest equivalent human dose at which
this effect was observed was 1.8 mg/kg/day, which then multiplied by 70 kg,
yields the MED of 126, corresponding to an RV. of 2.3. Metaplasia without
evidence of organ dysfunction warrants an RV of 6. Multiplying the RV.
by the RV yields the CS of 13.8, which corresponds to an RQ of 1000
(Tables 9-2 and 9-3). Since the other effects were of lesser or equal
severity and occurred at higher doses, there Is no need to calculate CSs for
these effects.
9.2. WEIGHT OF EVIDENCE AND POTENCY FACTOR (F=1/ED]0) FOR CARCINOGENICITY
The carclnogenlclty of e-thyl acrylate was discussed In Section 5.1. The
only positive carclnogenlclty data for ethyl acrylate were described 1n an
NTP (1986a.) draft report. Fifty B6C3F1 mice/sex and 50 F344 rats/sex were
given 0, 100 or 200 mg/kg ethyl acrylate by gavage, 5 times/week for 103
weeks. Comprehensive hlstopathology of sacrificed rats and mice revealed
forestomach lesions (both neoplastlc and nonneoplastlc) as the only con-
sistent dose-related effects. The Increase In Incidence of forestomach
paplllomas/cardnomas after treatment was most evident 1n male rats (see
Table 5-1).
0863p -60- 05/19/87
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1ADI. 1
loxlclty Summary for Ethyl Acrylale
OJ
Monte
f'i ;. 1
(',,-,<
['• .'1
, ('. ., I
C"1
— i
. i
II- ,il-
l)i ,l !
Species/ Ni>. at Average Vehicle/
Strain Sox Slarl Welghla Physical
(kg) Slate
r,it/F344 M 50/group 0.44 corn oil
gavage
ral/F344 F 50/group 0.24 corn oil
mouse/ M 50/grfip 0/045 corn oil ~
BM.3F1 gavage
nouse/ F 50/group 0.037 corn oil
Bf.C3Fl
rat/ F 50 0.26 drinking
Wlslar water
dog/ M.F 2Aex 9.1 dissolved In
beagle corn oil;
administered
In gelatin
capsules
Purity Exposure
99X 100 or 200
mg/kg. 5
days/week.
103 weeks
99X 100 or 200
mg/kg. 5
days/week,
103 weeks
99X TOO or 200
mg/kg, 5
days/week,
103 weeks
99X 100 or 200
mg/kg, 5
days/week.
103 weeks
NR 2000 ppm,
104 weeks
NR 933d ppm,
104 weeks
transformed Equivalent
Animal Dose Human Doseb Response
(mg/kg/day) (mg/kg/day)
'1.4. 142.9 13.2. 26.4 Dose-related foreslonkich
lesions: Inflammation.
hyperplasla. hypcrkeratosls
'1.4. 142.9 10. B. 21.5 Dose-related forestomach
lesions: Inflammation.
hyperplasla. hyperkeratosls
n. 4. 142.9 6.2,. 12.3 Dose-related forestomach
lesions: Inf lamnal ton.
epithelial hyperplasla
and hyperkeratosls
'1.4. 142.9 5.8. 11.6 Dose-related forestomach
lesions: hyperplasla. In-
flammation, hyperkeratosls,
188. 5C 29.2 Depression of body weight
gain
^.1.3e 11.8 Slight depression of
body weight gain
Reference
NIP. !9B6a
NIP. 19H6*
NIP. 19('6a
NIP. 19l'6a
BbrzolU'ca
et al.. 1964
Borzellcca
et al. . 1964
O
Ln
-------
TABLE 9-1 (cont.)
00
w
•o
Species/ No. at Average Vehicle/
Hii'ite Strain Sex Start Weight3 Physical
(kg) State
Mli.i latlon rat/F34« M.F 75/sex 0.27(M) vapor
0.17(F)
i-tn'atlon mice/ M,f 75/sex 0.015 vapor
B6C3F1 (H.F)
Transformed
Purity Exposure ' Animal Dose
(mg/kg/day)
>99.5X 25 ppm(102 1?.6(H)
mg/m8), 6 !4.6(F)f
hours/day, -
5 days/week.
1 16 weeks
>99.5X 25 ppm, (102 H0.4f
mg/m3 ) , 6
hours/day.
5- days/week.
116 weeks
Equivalent
Human. Doseb Response
(mg/kg/day)
2.0IH.F) Inhibition In body weight
gain, olfactory mucosal
hyperplasla, metaplasia.
mineralization. Increase
in Intraeplthellal glands;
adrenal medullary hyper-
plasla (males only)
1.8 Slight Inhibition In body
weight gain; submucosal
hyperplasla, respiratory
metaplasia
Reference
Miller
el al. , 1905
t
Miller
et fil.. 1985
•'< •. I 'mated from growth curves of body weight gain data
!'f-T >< ulated hy multiplying the animal dose by the cube root of the ratio of the animal body weight to the human body weight
'.' -i i' ulaled from water cons'-mptlon a-id body weight data provided In the sl.udy
''•MI/I
".v.Miming a dog consumes a -tally amount of food equal to 2.5X of Its body weight
''Mi'ulated by multiplying 102 mg/m" by 6 hours/24 hou's. 5 days/7 days by the animal Inhalation rate and dividing by the animal body weight. The
iiii'>lal1on rates were ca lr.ulate
-------
TABLE 9-2
Inhalation Composite Score for Ethyl Acrylate Using the Mouse*
Animal Dose
(mg/kg/day)
Chronic
Human MED
(tug/day)
RVd
Effect
RVe . CS
RQ
30.4
126
2.3
respiratory
metaplasia
13.8 1000
"Source: Miller et al.t 1985
0863p .
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Route:
Dose*:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ:
TABLE 9-3
Ethyl Acrylate
Minimum Effective Dose (WED) and Reportable Quantity (RQ)
inhalation
126 mg/day
respiratory metaplasia with possible Increased mortality
Miller et al., 1985
2.3
6
13.8
1000
*Equ1valent human dose
0863p
-64-
05/19/87
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, Three other chronic animal bloassays failed to find neoplastlc changes
after ethyl acrylate exposure. Borzelleca et al. (1964) treated rats with
up to 2000 ppm ethyl acrylate In drinking water and dogs with the equivalent
dietary concentration up to 933 ppm ethyl acrylate 1n gelatin capsules for 2
years. Although the extent of hlstologlcal Investigation was not described
In detail (IARC, 1979a), Borzelleca et al. (1964) noted no Increase 1n tumor
frequency In either species. Groups of 60-75 F344 rats and 60-75 B6C3F1
mice of each sex were exposed to 0, 0, 25 or 75 ppm ethyl acrylate vapors, 6
hours/day, 5 days/week for up to 27 months (Miller et al., 1985). The only
pathological changes consistently noted 1n sacrificed rats and mice were
dose-related Increases In nonneoplastlc olfactory mucosal lesions. Inci-
dences of thyroid foll.lcular cell tumors were sporadically different (both
higher and lower) from control Incidences, possibly because of the high
spontaneous occurrences of these tumors (NTP, 1986a;, MUler. et al. 1985).
Finally, DePass et.al. (1984) found no increases 1n ethyl acrylate-Jnduced
skin tumors 1n mice that were' skin-painted 3 times/week for 2 years with 23
mg/mouse. Administration of 0.02 mg/mouse 3-methylcholanthrene, the
positive control, on the same treatment schedule led to tumor development In
39/40 mice.
A causal relationship for Increased Incidences of colon and rectal
cancer from occupational exposure to ethyl acrylate/methyl methacrylate was
suggested In a retrospective epidemiology study (see Table 5-4); however, a
clear causal relationship could not be. established when further studies were
considered .(Rohm and Haas Co., 1981, 1984, 198ba,D; Mantel, 1986). hore-
over, exposure to ethyl acrylate and methyl methacrylate could not be
separated.
0863p -65- 05/19/87
-------
Ethyl acrylate was not mutagenlc 1n prokaryotlc reverse mutation assays
(NTP, 1986a; Haworth et al., 1983; Waegemakers and Benslnk, 1984). It did
cause chromosomal aberrations 1n a CHL.cell line (Ishldate et al., 1981) and
a mouse mlcronucleus assay (Przykojewska et al., 1984) and also Increased
the number of forward mutations In a mouse lymphoma cell culture (LUton
Blonetics, 1980). Most of the genotoxlc changes observed In mammalian
systems occured at cytolethal doses.
Based upon the data provided by the NTP (1986a), ethyl acrylate can be
considered carcinogenic when given by gavage to experimental rodents. As
discussed 1n Chapter 8, a q * was calculated .using the male rat data.
Using the same data and the multistage model of Howe and Crump (1982). an
unadjusted 1/EP10 of 3.99xlO~2 (mg/kg/day)'1 was calculated (Table
9-4). Adjustment of this value by the cube root of the human ('assumed to be
70 kg) to the rat (0.44 kg) body weight ratio..results 1n an .F-factqr of
2.16X10'1 (mg/kg/day)'1.
According to U.S. EPA (1986b) guidelines, data from the NTP (1986a)
study are sufficient In two species to consider ethyl acrylate a carcinogen.
In the absence of adequate human data, ethyl acrylate should be considered a
U.S. EPA Group B2 carcinogen, Becau.se the F-factor 1s <1, ethyl acrylate 1s
placed In Potency Group 3, which, along with a U.S. EPA .classification of
B2, gives ethyl acrylate a LOW hazard ranking under CERCLA.
0863p -66- 05/19/87
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TABLE.9-4
Derivation of Potency Factor (F) for Ethyl Acrylate
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental doses/exposure (mg/kg):
Transformed doses (mg/kg/day):
Tumor Incidence:
Unadjusted 1/ED10:
Adjusted 1/ED-|0 (F factor):
NTP, 1986a
oral (gavage)
rat
F344
male
corn oil
0.44 kg
103 weeks
104 weeks
104 weeks
forestomach
paplllomas/cardnomas
0 100
0 70.7
1/50 18/50
200
141.5
36/50
3.99049xlO~2 (mg/kg/day)'1
2.162259x10'^ (mg/kg/day)"1
0863p
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05/19/87
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1946-1982. Unpublished report. July 22, 1986.
Rohm and Haas Co. 1986b. Mortality Study of Knoxvllle Plant Employees
Hired 1943-1982. Unpublished report.
Sam1m1, B. and 1. Falbo. 1982. Monitoring of workers exposure to low
levels of airborne monomers 1n a polystyrene production plant. Am. Ind.
Hyg. Assoc. J. 43(11): 858-862..
Sasaki, S. 1978. .The scientific aspects of the chemical substance control
law 1n Japan. I. I_n: Aquatic Pollutants: Transformation and Biological
Effects, 0. Hutzlnger, L.H. von Letyoeld and B.C.J. Zoeteman, Ed. Pergamon
Press, Oxford, UK. p. 283-298.
.Silver, E.H. and S.D. Murphy. 1981. Potent1at1on of acrylate ester toxlc-
Hy by prior treatment with the carboxylesterase Inhibitor trlorthotolyl
phosphate (TOTP). Toxlcol. Appl. Pharmacol. 57(2): 208-219.
0863p -75- 05/19/87
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Speece, R.E. 1983. Anaerobic biotechnology for Industry wastewater treat-
ment. Environ. Sc1. Techno!. 17: 416A-4.27A.
SRI (Stanford Research Institute). 1986. 1986 Directory of Chemical
Producers: United States of America. SRI International, Menlo Park, CA.
p. 636, 446-467.
Stott, W.T. and M.J. McKenna. 1984. The comparative absorption and excre-
tion of chemical vapors by the upper, lower and intact respiratory tract of
rats. Fund. Appl. ToxUol. 4:594-602. (CA 101:205466g)
Swann, R.L,, O.A. Laskowskl. P.J. McCall, K. Vanderkuy and H.J. Dlshburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio, and water solubility. Residue Rev. 85: 17-28.
Szczebara, M., R. Stach, H. Molenda and H. Szoltysek. 1983. Occupational
exposure of workers contacting latex containing acrylic compounds at an
unwoven fabrics division.. Med. Pr. 34(1): 53-58. (Pol.) [CA
99(14):110047x]
Tan11, H. and K. Hashimoto. 1982. Structure-toxlcity relationship of
acrylates and methacrylates. Toxicol. Lett. 11(1-2): 125-129.
Thorn, N.S. and A.R. Agg. 1975. The breakdown of synthetic organic
compounds In biological processes. In: Proc. R. Soc. Lond. B. 189: 3^7-357.
0863p -76- 05/19/87
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Treon, J.F., H. Slgnion, H. Wright and K.V. KHzmlller. 1949. The toxldty
of methyl and ethyl acrylate. J. Indust.^ Hyg. Toxlcol. 31: 317-326.
Union Carbide. 1979. 1979-1980 Chemicals and Plastics Physical Properties.
Union Carbide Corp., New York. p. 16.
U.S. EPA. 1972. Water 'Quality Criteria 1972. A Report of the Committee on
Water Quality Criteria. Washington, DC. PB-236-199.
U.S. EPA. . 1979. Water-related Environmental Fate of 129 Priority Pollu-
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U.S. EPA. 1980. Guidelines and Methodology Used 1n the Preparation of
Health Effects Assessment Chapters of the Consent Decree Water Criteria
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U.S. EPA. 1981. CHIP (Chemical Hazard Information Profile). Ethyl
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U.S. EPA. 1986a. Graphical Exposure Modeling System (GEMS). Fate of
Atmosphere Pollutants (FAP), U.S. EPA., Washington, DC.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
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0863p -77- 05/19/87
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U.S. EPA/NIH (National Institute of Health). 1986. OHM-TADS (Oil and
Hazardous Materials Technical Assistance Data System). On-line: April 8,
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U.S. FDA (Food and Drug Administration). 1977. Food and Drugs. 21 CFR
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178.3790. p. 438-596.
U.S. FDA (Food and Drug Administration). 1983. GRAS status of ethyl
acrylate and methyl aqrylate. Federal Register. 48(32): 6705-6706.
USITC (U.S. International Trade Commission). 1985. Synthetic Organic
Chemicals. U.S. Production and Sales, 1984: USITC Publ. 1745, Washington,
DC. p. 256, 283.
Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemicals,
2nd ed. Van Nostrand Relnhold Co., New York. p. 625.
Haegemaekers, T.H. and M.P. Benslnk. 1984. Non-mutagenlclty of 27
aliphatic acrylate esters In the Salmonella-microsome test. Mutat. Res.
137: 95-102..
Weast, R.C., Ed. 1985. CRC Handbook of Chemistry and Physics, 66th ed.
CRl Press, Inc., boca katfln, FL. p. C-5'7.
Windholz, M.. Ed. 1983. The Merck Index, 10th ed. Merck and Co., Inc.,
Rahway, NJ. p. 546.
0863p -78- 05/19/87
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Yasuhara, A., T. M1zoguch1, K. Fuwa, S. Nakayama and T. Shlguro. 1984.
Identification of odorous compounds 1n air and gas from painting and print-
ing Industries by gas chromatography-mass spectrometry and library search
system. Chemosphere. 13(3): 469-482.
0863p -79- 05/19/87
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APPENDIX
LITERATURE SEARCHED
«
This profile 1s based on data Identified by computerized literature
searches of the following:
GLOBAL
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
CAS online STN International
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal. Register
These searches were conducted 1n April, 1986. In addition, hand searches
were made of Chemical Abstracts (Collective .Indices 6 and 7), and the
following secondary sources were reviewed:
ACGIH (American Conference of Governmental Industrial HygVenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th .ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1985-1986. TLVs: Threshold Limit Values for Chemical Substances
and Physical Agents In the Workroom Environment with Intended
Changes for 1985-1986. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty.'s Industrial
Hygiene and Toxicology, 3rd rev. ed., Vo'i. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
0863p -80- 05/19/87
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Clayton, G.O. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxlcoloay, 3rd rev. ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-511"2.
uraysori, K. and u. EcKroti., Eci. 1978-196o. Klrk-Ctmner Encyclo-
pedia of Chemical Technology, 3rd e'd. John Wiley and Sons, NY. -23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO. IARC, Lyons, France.
Jaber, H.M., W.R. Mabey, S.T. Liu, T.W. Chow and H.L. Johnson.
1984. Data aqulsltlon for environmental transport and fate screen-
Ing for compounds of Interest 1n the Office of Solid Waste. EPA
600/6-84-010. NTIS PB84-243906. SRI International, Menlo Park, CA.
NTP (National Toxicology Program). 1986. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977.. Chemical Week Pesticide
Register. McGraw-Hill Book Co.. NY.
Sax, N.I. 1979. Dangerous Properties of Industrial Materials, 5th
ed. Van Nostrand Relnhold Co., NY.
SRI '(Stanford Research Institute). 1984: Directory of Chemical
Producers; Menlo Park, CA.
U.S. EPA. 1985. Status Report on Rebuttable Presumption Against
Registration (RPAR) or Special Review Process. Registration Stan-
dards and the Data Call 1n Programs. Office .of Pesticide Programs,,
Washington, DC.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic .Substances,
Washington, DC.
USITC (U.S. International Trade Commission). 1983. Synthetic
Organic Chemicals. U.S. Production and Sales, 1982, USITC Publ.
1422, Washington, DC. •
Verschueren, k. 1SS3. . Handbook cf Environments! Data on Organic•
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndhoiz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway', NJ.
Worthing, C.R. and S.6. Walker, Ed. 1983. The Pesticide .Manual.
British Crop Protection Council. 695 p.
0863p -81- 05/19/87
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In addition, approximately 30 compendia of aquatic toxlclty d^/.a were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute ToxIcHy
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Pimental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs; U.S.
[PA, Washington. DC. EPf 540/S-79-OC2. N'TIS DB 80-196876. . •
0863p -82- 05/19/87
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