Ethyl acrylate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

28 Apr 1986 - 25 July 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

OECD guideline study conducted in compliance with GLP regulations, with acceptable restrictions (Since the study was intended to focus on the lesions observed in the stomach of rats in longer term studies, the necropsy and tissue examinations were limited and did not meet guideline specifications. Neither ophthalmological and haematological examinations nor clinical biochemistry were performed.)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1987

Report date:

1987

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

Neither ophthalmological and haematological examinations nor clinical biochemistry were performed. Sensory reactivity was not examined either.

GLP compliance:

yes

Limit test:

no

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: more than 99 %
- Impurities (identity and concentrations): 15 ppm 4- methoxyphenol ( MEHQ-HT)
- Lot/batch No.: 3-23122

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 Laboratories, Kingston N.Y.
- Age at study initiation: 6 weeks
- Weight at study initiation: 107-134 g
- Housing: 2 per cage (stainless steel) for the first 2 days of quarantine and individually thereafter.
- Diet: Purina Certified Chow 05002-Meal; Ralston Purina Co., St Louis MO, ad libitum
- Water: Filtered tap water, ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24
- Photoperiod (hrs dark / hrs light): 12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
Corn oil solutions of ethyl acrylate, 0.4, 2.0 and 4.0 % w/v (corresponding to 4, 20 and 40 mg/ml), were prepared by weighing out the appropriate amount of ethyl acrylate and diluting with corn oil to the appropriate concentration.
Fresh samples were prepared once weekly. Each week during the study samples of the ethyl acrylate solutions were collected and were either submitted for analysis or stored frozen at - 70°C for possible future analysis .

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Solutions of ethyl acrylate in corn oil were analyzed by a capillary Gas Chromatography method.
Analytically measured concentrations were generally at 109 - 110 % of the theoretical values. Thus, effect doses were based on the nominal dose values.

Duration of treatment / exposure:

4 or 13 weeks

Frequency of treatment:

5 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 20, 100, and 200 mg/kg bw/day at 5.0 ml/kg bw.
Basis:
actual ingested

No. of animals per sex per dose:

20 per dose except for the high dose (200 mg/kg bw) which included 30 animals

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: 10 animals of the high dose group received 200 mg/kg bw EA for 4 weeks, then during the following 9 weeks the vehicle only (recovery group).

Examinations

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined: Weekly

OTHER: Liver, kidneys and stomach of each animal were weighed.  

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
The entire stomach was removed, dissected free of other tissues, and opened along the greater curvature. The stomach contents were rinsed with 0 .9 % saline, the stomach was blotted dry, weighed, pinned to a piece of cardboard !mucosa up), and fixed by immersion in 16x buffered formalin.
All organs and  tissues of the abdominal and thoracic cavities were examined and histopathologic examinations were performed on the stomachs from all animals.

Statistics:

Distributions of the following parameters were inspected for normality and homogeneity of variance across treatment groups by examining residual plots : body weights, feed consumption, organ weights. Analysis of variance was used for organ weights, and analysis of covariance was used on body weights, and feed consumption to access the presence or absence of an overall treatment effect. When a significant treatment effect was found, group means were compared using T-test on least square (adjusted) means. Statisical significance was indicated when a p-value was less than 0 .05.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY:
No deaths or clinical signs indicative of systemic toxicity were observed in any treatment group. 


BODY WEIGHT AND WEIGHT GAIN:
Rats in the 200 mg/kg bw group exhibited decreased body weight gain (approximately 7 %) in comparison to controls after 13 weeks of treatment. There were no other toxicologically significant changes in body weight.


FOOD CONSUMPTION:
There were no toxicologically significant changes in mean food consumption with any of the treatment groups during the study. Statistically significant decreases in food consumption were seen sporadically throughout the treatment period (more often in the 200 mg/kg bw/day group) but were not consistant nor of a magnitude to consider them treatment related effects.


ORGAN WEIGHTS:
Compound related changes in stomach weights were observed at 100 and 200 mg/kg bw/day after 4 weeks of treatment and in all treatment groups (except the recovery group) after 13 weeks of treatment. These changes generally occured in a dose-related manner. At the 4 week interval, absolute stomach weights were increased 28 and 41 %, and relative stomach weights were increased 24 and 44 %, respectively at 100 and 200 mg/kg bw/day. At the 13-week interval, absolute stomach weights were increased 7, 26 ard 50 % and relative stomach weights were increased 9, 30 and 63 %, at 20, 100 and 200 mg/kg bw/day, respectively. In contrast, the absolute and relative stomach weights of animals in the recovery group were not different from those of the control group. No treatment related effect on the weights of liver and kidney was observed.


GROSS PATHOLOGY:
Gross changes were limited to the forestomachs (non-glandular portion of the stomach of rats) at 100 and 200 mg/kg bw/day at the four- and thirteen-week intervals. Thickening of the forestomach in 1/10 rats and raised and/or discolored foci or areas in 4/10 rats were observed at 200 mg/kgbw/day at four weeks. Also, prominence of the limiting ridge (the raised edge of the forestomach between the glandular and non-glandular portions of the stomach) occurred in 6/10 rats at 100 mg/kg bw/day and all rats at 200 mg/kg bw/day at four weeks. At thirteen weeks, gross changes in the forestomachs of 200 mg/kg bw/day rats included thickening in 1/10, irregular surface in 1/10, raised plaques in 5/10, and nodules in 2/10. The entire stomach was enlarged and/or thickened in 2/10 rats at 200 mg/kg bw/day. These changes were not observed in other groups. Prominence of the limiting ridge was noted at 100 mg/kg bw/day in 1/10 and at 200 mg/kg bw/day in 9/10 rats. No gross changes were observed in stomachs of recovery group rats.


HISTOPATHOLOGY: NON-NEOPLASTIC:
Compound-related histopathologic changes occurred in the forestomachs of treated rats, generally in a dose-related fashion, at 20, 100 and 200 mg/kg bw/day at both time intervals. No histopathologic changes were noted in the stomachs of the recovery rats at thirteen weeks. Diffuse hyperplasia of the squamous epithelium of the forestomach of rats was observed in a dose-related fashion at 20, 100 and 200 mg/kg bw/day at both time intervals. The diffuse hyperplasia was generally moderate at 200 mg/kg bw/day, mild at 100 mg/kg bw/day, and minimal at 20 mg/kg bw/day, with no apparent difference in severity between four and thirteen weeks. Minimal diffuse hyperplasia was defined as basal cell hyperplasia only. Diffuse hyperkeratosis generally occurred at a comparable severity in conjunction with diffuse hyperplasia at 100 and 200 mg/kg bw/day at both time intervals. Submucosal inflammation was noted at 100 mg/kg bw/day in 2/10 rats (minimal only) and at 200 mg/kg bw/day in 10/10 rats (mild only) at four weeks, and at 200 mg/kg bw/day in 9/10 rats (mild to marked) at 13 weeks. Focal submucosal edema occurred in 5/10 rats at 200 mg/kg bw/day at four weeks and in 1/10 rats at 100 mg/kg bw/day and 9/10 rats at 200 mg/kg bw/day at 13 weeks. Focal papillamatous hyperplasia was observed only at 200 mg/kg bw/day in 5/10 rats (moderate to marked) at four weeks and 9/10 rats (marked to severe) at thirteen weeks. A focal eschar in 1/10 rats, a focal epithelial hemorrhage in 1/10 rats, and focal ulcers of the limiting ridge in 2/10 rats were noted at 200 mg/kg bw/day at four weeks.

Effect levels

Dose descriptor:

LOAEL

Effect level:

20 mg/kg bw/day (nominal)

Sex:

male

Basis for effect level:

other: Based on stomach effects (reversible)

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

The increases in stomach weight and histopathologic changes of the forestomach that were present in the 200 mg/kg bw/day dose group after 3 weeks of treatment, disappeared completely when the group was allowed to recover for nine weeks (recovery group).

No NOAEL could be established based on the stomach effects since they were observed at all dose levels.