Ethyl acrylate

Endpoint summary

Description of key information

In a chronic repeated dose study by the inhalation route a NOAEC of 20 mg/m³ was determined in rats for local effects (nasal irritation). The respective NOAEC for systemic effects was 100 mg/m³ based on body weight decrease. After subchronic exposure by vapour inhalation over 3 months the NOAEC for systemic and toxic effects was 0.1 mg/L, while the respective LOAEC was 0.31 mg/L based on retardation of body weight gain and lesions of the nasal mucosa.
After subchronic exposure by gavage over a test period of 90 days, a NOAEL of 55 mg/kg bw/day was determined in rats based on grosspathological changes of the stomach.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEC

20 mg/m³

Additional information

Repeated dose toxicity: Inhalation

In a chronic inhalation study (IATG 1983, Miller et al. 1985), groups of rats and mice were exposed to ethyl acrylate vapor 6 hours per day, 5 days per week at concentrations of 0, 25, 75 or 225 ppm (0, 0.10, 0.31, or 0.92 mg/L) for 3, 6, 12, 18 or 27 months. Exposure of the animals at the 225 ppm concentration was terminated at the 6-month interim sacrifice because of significant body weight loss. Body weights were monitored routinely and haematology and blood chemistry were measured at the time of the sacrifices. Histopathology was conducted on all tissues for the 0 and 75 ppm exposure groups and limited evaluations were made for the other exposure groups. Dose-dependent lesions in the nasal mucosa with metaplasia or atrophy of the olfactory epithelium and hyperplasia of basal cells and Bowman’s glands were observed at all sacrifice periods. Reduced body weight was observed at the two highest concentrations. No other effects, including survival, clinical pathology, or organ changes were related to ethyl acrylate toxicity. Irritation of the nasal epithelium was observed at all doses in both species. The NOAEC for systemic toxicity was 25 ppm (0.10 mg/L) although nasal irritation, a site of contact effect, occurred at this concentration. The NOAEC for nasal irritation after 2 years of exposure was 5 ppm (see study below). The LOAEC was 75 ppm (0.31 mg/L) based on body weight decrease.

Based on the results of the 3 -month-interim sacrifice, the 90 -d-NOAEC for systemic and local effects was set at 25 ppm (0.1 mg/L) since at this test concentration no adverse effects on the nasal mucosa or on body weight gain were observed. The respective LOAEC both for systemic and local effects after 3 -month exposure to EA vapours was 75 ppm (0.31 mg/L).

In a follow-up study, (IATG 1983, Miller et al. 1985), 80 mice and 80 rats per sex were exposed to 5 ppm (0.02 mg/L) of ethyl acrylate for 24 months. Animals were observed each day for signs of toxicity and body weights were measured monthly. Subgroups of animals were necropsied after 6, 12, 18 and 24 months of exposure and histopathology of the nasal turbinates was performed. The results of this study indicated a lack of effect on the nasal mucosa in male and female rats and mice exposed to 5 ppm (0.02 mg/L) ethyl acrylate after 6, 12, 18 and 24 months, thus establishing 5 ppm as the NOAEC for nasal irritation after chronic exposure to EA vapours.

There are several other studies available on repeated dose toxicity of Ethyl acrylate by the inhalation route which do not add significant information.

Repeated dose toxicity: Oral

Two subchronic studies are considered key for the evaluation of the repeated dose toxicity of ethyl acrylate via the oral route. In the first study (Rohm & Haas, 1987), male Fischer 344/N rats were dosed by gavage with 20, 100, or 200 mg/kg bw/day ethyl acrylate, 5 days per week for 4 or 13 weeks. The control group of rats was dosed with corn oil. The test included 20 animals per group except in the high dose group that included 30 animals. After 4 weeks, 10 rats in each group were sacrificed and examined. In the high dose group, 10 rats were treated for only 4 weeks and observed for the remaining 9 weeks as a "recovery group". The study was designed to evaluate the dose/time relationship of the stomach lesions observed in other studies. Therefore, necropsy and histopathology were limited. Treatment-related effects included decreased body weight in the high dose group after 13 weeks and increased stomach weight in all test groups after 4 and 13 weeks. Dose-related hyperplasia and hyperkeratosis of the squamous epithelium of the stomach were recorded after 4 and 13 weeks. In the recovery group (4 weeks of dosing at 200 mg/kg bw/day followed by 9 weeks of recovery), no changes in stomach weight or histopathology were evident. The LOAEL was considered to be 20 mg/kg bw/day based on effects in the stomach. No NOAEL was established based on these stomach effects.

In the second study (NTP, 1986), groups of 10 rats/sex received ethyl acrylate by gavage at doses of 0, 7, 14, 28, 55 or 110 mg/kg bw/day, 5 days per week for 13 weeks. The control group of rats was dosed with corn oil. The high dose of 110 mg/kg bw/day was selected due to ulcerative and nonulcerative inflammation in the stomach of rats in the 14-day dose range-finding study at a dose of 400 mg/kg bw/day. Tissues, including the prostate/testes (males) and ovaries/uterus (females) were examined histologically from all control and high dose animals. The animals in all test groups survived (10 male and 10 female animals/group in each case). Body weights were similar to controls in all groups. No compound-related clinical signs were noted. In the high dose (110 mg/kg bw), reddening of the duodenal mucosa was observed in 1/10 male rats and increased markings on the cardiac region of the stomach was seen in 2/10 male rats. No clear treatment-related findings were observed in this study. The LOAEL was considered to be 110 mg/kg bw/day based on the changes in the stomach. The NOAEL was 55 mg/kg bw/day.

Several studies have been conducted to evaluate the effects of ethyl acrylate on the forestomach mucosa of rats (see Section 7.9.3 and 7.12 of the IUCLID5 Technical Dossier). Ghanayem et al. (1986) observed submucosal fibrosis and foreign body reaction following 14 daily gavage doses of ethyl acrylate at 100 or 200 mg/kg bw and concluded that these reactions were likely to contribute to the forestomach tumors observed with ethyl acrylate. These authors (Ghanayem et al., 1990, 1991) further showed that hyperplasia of the forestomach occurred following the same doses 5 days/week for 13 weeks and that continued exposure was required to sustain the hyperplasia (the lesion regressing following cessation of dosing). This response was also associated with epithelial cell proliferation in the forestomach that was dose- and time-dependent. Rohm & Haas (1987) and Ghanayem et al. (1991) showed the key role of nonprotein sulfhydryl (NPSH) binding to detoxify ethyl acrylate in the forestomach. The results indicate that repeated gavage dosing of EA results in a significant increase in the detoxification capacity of the forestomach (4-fold at doses of 200 mg/kg bw) that remains insufficient to detoxify bolus EA doses greater than 50 mg/kg bw.

 

In a chronic drinking water study (see Section 7.7 of the IUCLID5 Technical Dossier), groups of rats (25/sex) were exposed to ethyl acrylate at 0, 6, 60 or 2000 ppm for 2 years. The low- and mid-dose levels were raised to 7 and 70 ppm at the start of the fifth month (corresponding to approximately 0.5, 5 and 150 mg/kg bw/day). Body weights, feed consumption, and water consumption were measured routinely and clinical pathology measurements (blood and urine) were made at 3 month intervals. At termination, histopathology was performed on animals from the 0, 70 and 2000 ppm groups. Survival was similar across all groups. A reduction in body weight was observed in animals from the high dose group. No other ethyl acrylate-related toxicity was observed in any measurements or tissues. Therefore, the NOAEL was considered to be 70 ppm (equivalent to ca. 5 mg/kg bw/day) and the LOAEL was 2000 ppm (equivalent to ca. 150 mg/kg bw/day) (Borzelleca et al., 1964).

Repeated dose toxicity: Dermal

No subacute or subchronic repeated dose studies with dermal application are available for Ethyl acrylate. But there are two valid chronic studies in mice following dermal application that are discussed under section 7.7 of the IUCLID5 Technical Dossier. Except for a depression of body weight in the high-dose group (3003 mg/kg bw), no other effects were reported after exposure to undiluted EA for 20 weeks in Tg.AC (v-Ha-ras) transgenic mice (Nylander-French and French, 1998). Lifetime exposure to dermal doses of 1150 mg/kg bw EA in mice lead to local skin irritation effects such as epidermal necrosis, dermal fibrosis, hyperkeratosis, and dermatitis (DePass et al., 1984).

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: nose

Justification for classification or non-classification

EU classification according to Annex VI of Directive 67/548/EEC: no classification required

GHS classification (GHS UN rev.3, 2009):

- Specific Target Organ Toxicity: Repeated Exposure: no classification required