Ethyl acrylate

Specific investigations: other studies

Administrative data

Endpoint:

biochemical or cellular interactions

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1985

Reference 2

Reference Type:

review article or handbook

Title:

Role of Chemically Induced Cell Proliferation in Ethyl Acrylate-Induced Forestomach Carcinogenesis.

Author:

Ghanayem BI et al.

Year:

1991

Bibliographic source:

In: Chemically Induced Cell Proliferation: Implications for Risk Assessment. John Wiley-Liss, Inc., pp. 337-346

Materials and methods

Principles of method if other than guideline:

In previous studies (see Section 7.7, NTP 1986) Ethyl acrylate had caused squamous cell carcinomas and papillomas in the forestomach (nonglandular portion of the stomach) of both sexes of F344 rats and B6C3F1 mice when administered chronically by gavage. The current studies were undertaken to investigate and characterize the nature of the acute gastric toxicity caused by EA.
1. Dose-response study:
A single dose of 100, 200 or 400 mg/kg bw EtAc was dissolved in corn oil to allow gavage administration of the desired dose in a volume of 5 mL/kg body wt. Four hours later, rats were anesthetized with ether, and the stomachs were removed and processed for toxicity evaluation.
2. Time-course study:
A single dose of 200 mg/kg bw EA was dissolved in corn oil to allow gavage administration of the 200 mg/kg dose in a dose volume of 5 mL/kg bw. Rats were anesthetized with ether 2, 4, 8, or 24 hr after treatment, and the stomachs were removed and processed for toxicity evaluation.
3. Route of administration study:
EA, dissolved in corn oil to allow administration of the 200 mg/kg bw dose in a dose volume of 2.5 mL, was given by gavage, sc, or ip; controls were given 2.5 mL/kg corn oil by the corresponding route of administration. Four hours later, rats were anethetized with ether, and the stomachs were removed and processed for toxicity evaluation.
4. Repeated dosing study:
Rats were treated as follows: Groups (eight rats each) were treated by gavage with 200 mg/kg bw EA given in corn oil vehicle at a dose volume of 5 mL/kg body wt. Rats in group one were given a single dose of 200 mg/kg EA by gavage and were sacrificed 24 hr later. Group two rats were given two doses of EA (200 mg/kg bw) 24 hr apart and were sacrificed 42 hr after the second dose; a third group of rats received a 200 mg/kg bw dose of EA every 24 hr for a total of four days and was sacrificed 24 hr after the last dose. Three groups of rats (three to four each) gavaged with one, two, or four daily doses of corn oil were sacrificed with the respective EA-treated groups and served as vehicle control.

GLP compliance:

not specified

Type of method:

in vivo

Endpoint addressed:

carcinogenicity

Test material

Test material information

Constituent 1

Reference substance name:

Ethyl acrylate

EC Number:

205-438-8

EC Name:

Ethyl acrylate

Cas Number:

140-88-5

Molecular formula:

C5H8O2

IUPAC Name:

ethyl acrylate

Details on test material:

- Name of test material (as cited in study report): Ethyl acrylate
- Analytical purity: 99 %
- Impurities (identity and concentrations): 15 - 20 ppm hydroquinone monomethyl ether (inhibitor)
- Lot/batch No.: 0221MJ
- Supplier: Aldrich Chemical Co.

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratory (Wilmington, Mass.)
- Weight at study initiation: 200 - 230 g

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

EA dissolved in corn oil was previously shown to be stable for 8 days (NTP 1986).

Duration of treatment / exposure:

See "Principle of methods"

Frequency of treatment:

See "Principle of methods"

Post exposure period:

no

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 200, and 400 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

8 (dose group); 11 or 15, respectively (control)

Control animals:

yes, concurrent vehicle

Examinations

Examinations:

Evaluation of gastric toxicity:
The rats were anesthetized with ether. The abdomen was opened and the entire stomach was removed, dissected free of other tissues, and opened along the lesser curvature. The stomach was then carefully pinned to a piece of cardboard with the mucosa up. The opened stomach was rinsed free of contents with 10 % aqueous buffered neutral Formalin and fixed by immersion in 10 % aqueous buffered neutral Formalin. After fixation, the stomach was transversely divided into two pieces: the forestomach and the glandular stomach. Each piece was then serial sectioned (five to seven sections), routinely processed, and embedded in paraffin. Sections were stained with hematoxylin and eosin, coded, and evaluated.

Positive control:

no

Results and discussion

Details on results:

Gavage administration of a single dose of 100, 200, or 400 mg/kg bw EA (in corn oil) to F344 male rats caused dose- and time-dependent mucosal and submucosal edema and vacuolization of the tunica muscularis in the forestomach and mild submucosal edema in the glandular stomach. Equivalent sc or ip doses did not produce similar gastric lesions. After ip administration only mild submucosal edema and vacuolization of the tunica muscularis of the forestomach were seen. Forestomach edema was more diffused in ip treated rats than in those treated by gavage. The authors suggested that these effects were probably due to diffusion of EA from the abdominal cavity into the stomach. Treatment of rats with two or four consecutive oral daily doses (200 mg/kg bw each) of EA caused mucosal edema associated with vesicle formation, mucosal hyperplasia, submucosal edema and inflammation, and vacuolization of the tunica muscularis of the forestomach. Submucosal edema and inflammation were also observed in the glandular stomach and mucosal erosions or ulcers were observed in both portions of the stomach after repeated oral exposure to EA. The absence of systemic toxicity plus the dependency of gastric lesions on the gavage route of administration suggest that the EA-induced gastric lesions may be a consequence of localized hemodynamic changes, specifically those characteristic of a classical immediate inflammatory response to an injurious agent at the site of administration.
Additional studies were undertaken to investigate the structural, metabolic, and physical basis of this chemically induced gastric toxicity. Gavage administration of equimolar doses (2 mmol/kg bw) of methyl or ethyl acrylate in corn oil resulted profound gastric toxicity in male F344 rats, while acrylic acid and n-butyl acrylate were without effect. Furthermore, gavage administration of equimolar doses of methyl propionate or ethyl propionate (saturated analogues of methyl acrylate and ethyl acrylate, respectively) as well as methacrylic acid esters were without gastric toxicity. These results indicate that structural requirements for acrylate esters to cause gastric lesions include an intact ester moiety, a double bond, and no substitution at carbon number 2. Additional studies indicate that gastric toxicity may be attributed to the intact ester molecule or to metabolite(s) other than products of carboxylesterase-mediated hydrolysis (acrylic acid and alcohol) and that gastric toxicity is dependent upon both acrylate ester concentration
in dose vehicle and the lipophilicity of the dose vehicle (corn oil vs water).

Any other information on results incl. tables

Incidence of Histopathologic Lesions in Stomachs from Rats Given Ethyl Acrylate by Gavage: Dose-Response Experiment

Lesion	Ethyl acrylate [mg/kg bw]
	Control	100	200	400
Glandular stomach:
Mucosal congestion	2/15	0/8	3/8	8/8
Submucosal edema	1/15	5/8	8/8	8/8
Forestomach:
Mucosal edema	0/15	7/8	8/8	8/8
Submucosal edema	0/15	6/8	8/8	8/8
Vacuolization of tunica muscularis	0/15	3/8	8/8	8/8

Incidence of Histopathologic Lesions in Stomachs from Rats Given Ethyl Acrylate by Gavage: Time-Course Experiment

Lesion	Time [hr] after 200 mg/kg bw Ethyl acrylate
	Control	2	4	8	24
Glandular stomach:
Mucosal congestion	2/15	6/8	3/8	5/8	1/8
Submucosal edema	1/15	2/8	8/8	8/8	7/8
Submucosal inflammation	0/15	0/8	0/8	3/8	7/8
Forestomach:
Mucosal edema	0/15	1/8	8/8	8/8	8/8
Mucosal edema with vesicles	0/15	0/8	0/8	0/8	8/8
Erosions or ulcers	0/15	0/8	0/8	0/8	1/8
Submucosal edema	0/15	7/8	8/8	8/8	8/8
Submucosal inflammation	0/15	0/8	0/8	2/8	8/8
Vacuolization of tunica muscularis	0/15	2/8	0/8	7/8	3/8

Incidence of Histopathologic Lesions in Stomachs from Rats Given Ethyl Acrylate by Gavage: Route of Administration Experiment

Lesion	Route of administration
	Control	Gavage	sc	ip
Glandular stomach:
Mucosal congestion	2/15	5/8	1/8	1/8
Submucosal edema	1/15	8/8	2/8	2/8
Forestomach:
Mucosal edema	0/15	8/8	0/8	0/8
Submucosal edema	0/15	8/8	0/8	6/8
Vacuolization of tunica muscularis	0/15	8/8	0/8	7/8

Incidence of Histopathologic Lesions in Stomachs from Rats Given Ethyl Acrylate by Gavage: Repeated Dosing Experiment

Lesion	200 mg/kg bw Ethyl acrylate
	Control	One dose	Two doses	Four doses
Glandular stomach:
Mucosal congestion	2/11	1/8	5/8	1/8
Submucosal edema	1/11	7/8	4/8	8/8
Submucosal inflammation	0/11	7/8	4/8	6/8
Submucosal mucosal necrosis	0/11	0/8	0/8	6/8
Forestomach:
Mucosal edema	2/11	8/8	2/8	0/8
Mucosal edema with vesicles	0/11	8/8	3/8	3/8
Erosions or ulcers	0/11	1/8	1/8	8/8
Mucosal hyperplasia	0/11	0/8	8/8	8/8
Submucosal edema	0/11	8/8	7/8	7/8
Submucosal inflammation	0/11	8/8	7/8	8/8
Vacuolization of tunica muscularis	3/11	3/8	3/8	8/8