Ethyl acrylate

Carcinogenicity

Description of key information

Lifetime dermal exposure to mice did not result in a positive tumour response. A chronic drinking water study with rats also did not result in evidence of carcinogenicity.

Following chronic inhalation exposure to Ethyl acrylate atmospheres of 25, 75, and 225 ppm, the study authors concluded there was “no indication of an exposure-related oncogenic response in any organ or tissue in male or female rats or mice”. While there was a small statistically significant increase in the incidence of thyroid tumors in EA-exposed male rats and mice, the elevated tumor incidences were within the range of historical controls, were not consistently dose-dependent, and most thyroid tumors in exposed animals were benign (adenomas). Furthermore, studies involving chronic oral exposure of EA to rats and mice (drinking water or by gavage) and dogs (capsules) had no evidence of thyroid neoplasia. The weight of evidence from chronic studies, in vivo and in vitro data, and ToxCastTM/Tox 21 HTPS results does not support genotoxic/mutagenic potential for EA nor is there any evidence of hypothalamic-pituitary-thyroid axis disruption. The weight of evidence suggests that the statistically significant associations between EA exposure and thyroid neoplasia represent chance or random observations rather than a real compound-mediated effect.  

Long-term exposure to ethyl acrylate at high concentrations by gavage administration which induced marked local irritation and cellular proliferation led to forestomach tumours in rats and mice. See "additional information" section regarding lack of relevance of this finding to humans.

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): no classification required

Additional information

Regarding forestomach tumors following oral gavage administration:

The National Toxicology Program (NTP, 2001) has concluded that ethyl acrylate should not be classified as an animal carcinogen or a suspected human carcinogen. Ethyl acrylate had been previously classified as a potential human carcinogen based on an NTP bioassay but was removed from the 9th Report on Carcinogens by the NTP. The following is excerpted from the decision document:

 

Ethyl acrylate is used in various industries as an intermediate in the production of emulsion-based polymers which are then used in paint formulations, industrial coatings, and latex products. It is also used as a synthetic flavouring substance and fragrance adjuvant in consumer products. Human exposure to ethyl acrylate occurs mostly through inhalation of ethyl acrylate vapours, but it may also result from skin contact or ingestion as a food additive or by drinking contaminated water. The Report on Carcinogens review groups considered the data underlying the nomination to remove ethyl acrylate from the Report on Carcinogens where it has been listed as reasonably anticipated to be a human carcinogen since 1989. The basis for this listing was a gavage study which resulted in dose-related benign and malignant forestomach neoplasms in rats and mice. The Basic Acrylic Monomer Manufacturers, Inc. (BAMM), submitted a nomination to remove ethyl acrylate from the Report on Carcinogens based upon the following: 

 

1) negative tumorigenicity results from chronic studies using routes other than gavage in corn oil; 2) research results suggesting that the forestomach carcinogenicity observed in the gavage studies was secondary to a site-specific and concentration-dependent irritating effect of ethyl acrylate; and 3) that significant human exposure to ethyl acrylate monomer is unlikely in light of current manufacturing practices and patterns of usage (see summary of ethyl acrylate carcinogenicity data below). 

 

 The majority opinion of the Report on Carcinogens review group was to recommend that ethyl acrylate be removed from the Report on Carcinogens.  

 

 This was based on the facts that  

 

 1) the forestomach tumors induced in animal studies were seen only when ethyl acrylate was administered by gavage at high concentrations that induced marked local irritation and cellular proliferation, 

 

  2) animal studies by other routes of administration including inhalation were negative, and  3) because significant chronic human oral exposure to high concentrations of ethyl acrylate monomer is unlikely. 

 

 Therefore ethyl acrylate does not meet the criteria to be listed in the Report on Carcinogens as reasonably anticipated to be a human carcinogen. 

 

[Delisting text from Appendix B (NTP, 2001)].  

 

The carcinogenicity studies referenced in the above reclassification statement are summarized below and included in the Robust Study Summaries of the IUCLID5 Technical Dossier. These same data were used in 2019 by IARC to classify ethyl acrylate in category 2B.

 

 

 

 Cancerogenicity Studies 

 

Although mutagenic in some in vitro tests, ethyl acrylate is not genotoxic under in vivo physiological conditions perhaps due to its rapid metabolism to acrylic acid and ethanol by carboxyesterases and detoxification through binding to non-protein sulfhydryls. Target tissue toxicity comprised of irritation has been observed in the skin in a lifetime mouse skin painting study, in the nasal olfactory mucosa in 27-month inhalation studies in rats and mice, and in the forestomach in two-year corn oil gavage studies in rats and mice. Only body weight reduction was observed in a two-year drinking-water study in rats. The forestomach carcinogenicity observed in the corn oil gavage studies represents the only treatment-related tumorigenic response in the various animal studies. The irritation, hyperplasia, and tumour responses in the forestomach were related more to target tissue concentration of ethyl acrylate than to delivered dose in the chronic gavage study. Based upon stop-exposure studies, gavage doses of ethyl acrylate in corn oil sufficient to induce sustained mucosal hyperplasia in the forestomach must be administered for longer than six months to induce forestomach neoplasia.

 

The major route of potential human exposure to ethyl acrylate is inhalation. Therefore, the 27-month inhalation study is considered to be the most definitive evaluation showing a lack of carcinogenicity (IATG 1983, Miller et al. 1985). In this study, male and female Fischer 344 rats were exposed to ethyl acrylate vapour 6 hours per day, 5 days per week for 6 months (high dose) or 27 months (mid and low dose and control). The concentrations were 0, 25, 75 and 225 ppm (corresponding to approx. 0, 0.10, 0.31 and 0.92 mg/L). Due to significantly reduced body weights after six months, the high dose exposures were stopped and the animals maintained without further exposure until 21 months. Body weights were monitored routinely and haematology and blood chemistry were measured at the time of the sacrifices (3, 6, 12, 18 months and termination). Histopathology was conducted on all tissues for the 0 and 75 ppm exposure groups and limited evaluations were made for the other exposure groups. No increase in tumours in the 75 ppm group or in the examined tissues from the other groups was observed. These results were supported by the concurrent 27-month inhalation study in female and male B6C3F1 mice (IATG 1983, Miller et al. 1985).

 

NTP conducted carcinogenesis studies of ethyl acrylate by administering this test chemical in corn oil by gavage to groups of 50 male and 50 female F344/ N rats and B6C3F1 mice at doses of 100 or 200 mg/kg bw. Ethyl acrylate was administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same schedule and served as vehicle controls. Survival of dosed male and female rats and mice was comparable with that of the corresponding vehicle controls. There was no evidence of systemic toxicity in the prechronic or in the 2-year studies. Compound-related increased incidences of hyperkeratosis, inflammation, and hyperplasia of the forestomach were observed in rats and mice in the prechronic as well as 2-year studies. In the 2-year studies, squamous cell papillomas and squamous cell carcinomas of the forestomach occurred at the site of chemical deposition with significant positive trends and increased incidences in dosed groups versus vehicle controls for both sexes of rats and mice. Nonneoplastic and neoplastic forestomach lesion frequencies were related to the concentration of ethyl acrylate in dosing solutions used. Significant negative trends for several common rodent tumours were found in treated animals in the 2-year studies. Under the conditions of these studies, ethyl acrylate was carcinogenic for the forestomach of F344/ N rats and B6C3F1 mice, causing squamous cell carcinomas in male rats and male mice, squamous cell papillomas in male and female rats and male mice, and squamous cell papillomas or carcinomas (combined) in male and female rats and mice. Evidence for carcinogenicity was greater in males than in females. Ethyl acrylate also caused irritation of the forestomach mucosa in male and female rats and mice.

 

A reevaluation of the histological preparations of the forestomach by three independent pathologists confirmed that ethyl acrylate, given via tube as a 4 % solution in corn oil, was carcinogenic for the forestomach of rats with statistical significance, but that in the other dose groups no significant increase in the squamous cells carcinoma could be found) (Smith JM et al. 1986). The tumour formation is probably a result of the lesions which are induced locally by ethyl acrylate and which during the healing process lead to foreign body reactions and  epithelial proliferation (Butterworth BE 1989; Ghanayem BJ et al. 1986; Hoel DG et al. 1988).

 

Ethyl acrylate was added to the drinking water of rats in concentrations of 0, 6-7, 60-70, and 2000 ppm for a period of two years. On the basis of fluid and food consumption observations, these concentrations of the test material were estimated to be equivalent to about 10, 100, and 3000 ppm in the food corresponding to approximately 0.5, 5 and 150 mg/kg bw/day). Mortality was unaffected. Body weights of female rats receiving 2000 ppm of ethyl acrylate in the water were significantly depressed or bordered on this throughout the study, and this concentration also significantly depressed body weights of males through the first year. Fluid consumptions were significantly lower in rats receiving 2000 ppm. Haematologic values and urine concentrations of protein and reducing substances varied within normal limits for all groups of rats. Organ to body weight ratios were comparable for all groups. Histopathologic findings revealed no lesions attributable to the test material (Borzelleca JF et al. 1964).

 

To conduct rapid comparative short-term bioassays, the Tg.AC (v-Ha-ras) transgenic mouse model was used. Insertion of the z-globin promoted v-Ha-ras transgene into the FVB mouse genome (Tg.AC) introduced a defined genetic lesion, which is critical but insufficient by itself to induce benign or malignant tumors in the skin unless activated. Activation and expression of the transgenic ras oncoprotein in this mouse line induces a dose-related increase in papillomas (skin reporter phenotype) within weeks. Starting at 12 wk of age, the agent was administered topically (200 μL of acetone vehicle) 3 times/wk for 20 wk to the shaved dorsal skin of female Tg.AC mice (n = 10/group) at doses of 60, 300, or 600 μmoles/mouse. The positive control induced a dose-related increase in papillomas between 6 and 12 wk of treatment that reached a maximum number of papillomas per mouse between 19 and 20 wk of treatment indicating that the test was valid. In contrast, EA gave a negative response (Nylander-French & French 1998).  

 

This result is supported by a lifetime dermal oncogenicity study in Male C3H/HeJ mice (IATG 1982, DePass et al. 1984).

 

Thus, ethyl acrylate did not show clear evidence of compound-mediated carcinogenicity in rats or mice following chronic inhalation to atmospheres of 75 and 225 ppm, respectively. Lifetime dermal exposure to mice did not result in a positive tumour response. A chronic drinking water study with rats also did not result in evidence of carcinogenicity. When administered by gavage at 100 or 200 mg/kg bw/day, ethyl acrylate caused only tumours of the forestomach in rats and mice.

 

 

 

 Other Information 

 

Under Section 7.9.3 of the Technical IUCLID6 Dossier a number of studies on the structural, metabolic and physical basis of the gastric toxicity caused by EA after gavage administration are presented in more detail. Ghanayem et al. (1985) demonstrated that the formation of mucosal and submucosal edema and vacuolarization of the tunica muscularis in the forestomach of rats caused by gavage administration of EA was time- and dose-dependent. Structure-toxicity relationship studies conducted with ethyl acrylate, methyl acrylate, n-butyl acrylate, and acrylic acid revealed that only acrylate esters with an intact ester moiety, a double bond, and no substitution at carbon 2 caused the described gastric toxicity in rats. This applied to ethyl and methyl acrylate. Acrylic acid caused only a low incidence of mucosal congestion, whereas n-butyl acrylate gave no effect on the forestomach at all. Ghanayem et al. (1986, 1991) conducted stop-studies in which F344 rats were treated with 100 and 200 mg EA/kg bw/day, 5 days/week, for 14 days and 13 weeks, respectively. Rats sacrificed at the end of the treatment regimen had severe epithelial hyperplasia of the forestomach. No lesions were observed in the glandular stomach or liver of EA-treated rats. Forestomach hyperplasia induced by EA included upward and downward cell proliferation. However, forestomachs of rats treated for 13 weeks and sacrificed 8 weeks after the last EA dose exhibited a significant decline in the incidence and severity of forestomach mucosal hyperplasia. Histopathologic evaluation of forestomachs of EA-treated rats (13 weeks) which were allowed a 19-month recovery (with no exposure to EA) showed further decline in the incidence and severity of mucosal cell hyperplasia. These results indicate that gavage administration of EA to rats results in extensive and sustained forestomach mucosal hyperplasia. The sustainability of forestomach hyperplasia is apparently dependent on the continued exposure of rats to ethyl acrylate, and regressed after cessation of dosing. Furthermore, although enough post-treatment time was allowed for tumors to develop after cessation of EA administration, forestomachs exhibited a nearly complete recovery with no increased incidence of papillomas or carcinomas.

 

Evidence from the NTP laboratory and others suggested that EA is hydrolyzed to acrylic acid (AA) and ethanol both in vivo and in vitro. The major metabolites detected in the urine of rats treated with EA were derivatives of the glutathione conjugates of EA and AA. The effects of sulfhydryl-depleting agent (diethylmaleate) and sulfhydryl-containing agents (cysteine and cysteamine) on EA-induced forestomach edema in male Fischer 344 rats were investigated by Ghanayem et al. (1991). The rats were given single doses of EA dissolved in corn oil by gavage at dose levels of 100, 200, or 400 mg/kg bw or were orally treated with 50 or 100 mg/kg bw/d for 14 consecutive days. Some animals were pretreated with cysteamine (150 mg/kg bw i.p. before single dose of ethyl acrylate and 75 mg/kg bw i.p. before 14-day exposure to ethyl acrylate), cysteine (200 mg/kg bw i.p.; single dose groups only), or diethylmaleate (0.6 mL/kg bw s.c.). Pretreatment with the sulfhydryl-containing chemicals potentiated the edema. In contrast, depletion of indigenous sulfhydryls by fasting of rats or pretreatment with dimethyl maleate resulted in a significant reduction of the edema formation. Pretreatment with cysteamine did not effect the incidence of hyperplasia, however, the severity of forestomach mucosal hyperplasia was significantly enhanced by this pretreatment. Thus, these data suggest that modulation of indigenous sulfhydryls play a role in EA-induced forestomach toxicity; however, the exact mechanism underlying this role remains to be characterized.