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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
28 Apr 1986 - 25 July 1986
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
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 Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Neither ophthalmological and haematological examinations nor clinical biochemistry were performed. Sensory reactivity was not examined either.
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
Ethyl acrylate
EC Number:
EC Name:
Ethyl acrylate
Cas Number:
Molecular formula:
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

Fischer 344
Details on test animals or test system and environmental conditions:
- 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

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

Administration / exposure

Route of administration:
oral: gavage
corn oil
Details on oral exposure:
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:
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
Doses / Concentrations:
0, 20, 100, and 200 mg/kg bw/day at 5.0 ml/kg bw.
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).


Observations and examinations performed and frequency:
- Time schedule: daily

- Time schedule for examinations: weekly

- Food consumption for each animal determined: Weekly

OTHER: Liver, kidneys and stomach of each animal were weighed.  
Sacrifice and pathology:
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.
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
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:
No deaths or clinical signs indicative of systemic toxicity were observed in any treatment group. 

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.

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.

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 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.

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:
Effect level:
20 mg/kg bw/day (nominal)
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.


Applicant's summary and conclusion