Ethyl acrylate

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Absorption:

All members of the category, including ethyl acrylate, are expected to be readily absorbed by oral, inhalation and dermal routes based on the experimental data and predictions from physico-chemical properties. The available repeated dose toxicity studies for oral, inhalation and dermal routes show the acrylate esters, either as parents and/or their metabolites, are absorbed based on the systemic effects observed.

Ethyl acrylate (EA) has a relatively small molecular size of 100.1 g/mol and a partition coefficient of 1.18 which is considered in the favourable range for absorption via oral, dermal and inhalation routes. Based on this partition coefficient, there is no concern for bioaccumulation (ECHA guidance R7c. section R.7.12.). The water solubility of Ethyl acrylate is 20 g/L at 20 °C. Ethyl acrylate is a liquids, which favours dermal absorption. The volatile nature of EA limits the rate of dermal absorption due to the loss via evaporation. Ethyl acrylate is a skin sensitiser, which indicates it is likely to be absorbed through the skin. The irritant nature of the acrylate esters may enhance the penetration through the skin.

Dermal absorption

Overall, the small molecular weights with a combination of the moderate to high water solubility and a moderate log P_OW suggests dermal absorption will occur for EA. Dermwin (EPISuite) calculated dermal absorption is as follows:

 

Table 1 -Results of the Dermwin

	CAS No.	Molecular Weight (g/mol)	Log POW (at 25 °C)	Dermwin Kp est. [cm/hr]
EA	140-88-5	100.1	1.18	0.00324
DK-EPA heuristics are used to classify ranges of Kp values: Classifications: <0.001 Very Low; >= 0.001-<0.005 Low; >=0.005-<0.05 Moderate; >= 0.05 High

 

The percutaneous absorption and evaporation of 2,3-14C EA has been studied in vitro with sections of hairless mouse and ratskin. While results from both of these species were generally similar, reported information is limited for experiments in the rat, therefore the mouse data is considered the key study. Using Franz Diffusion Cells, mouse (male CD-1) skin sections were mounted in 15 mm internal diameter cells and bathed from beneath with Tyrode's solution or 6% Volpo 20 at 37°C. The bathing solutions were stirred under gentle vacuum for 30 min before use. Each cell was closed immediately after dose application and remained closed throughout the exposure period. Temperature was maintained at 37°C throughout. At each dose, EA penetrated the skin generally more rapidly and to a greater extent with Volpo as the bathing solution (40 to 55% at 24 hr) compared to Tyrode's (19 to 37%). EA, dissolved in acetone, penetrated more rapidly and to a greater degree than neat (100%) EA. Approximately 23 to 41% of the dose evaporated off the skin and was retained by the charcoal trap in the cap. In the rat experiments, within 15 min after administration 88 % of the applied radioactivity had evaporated from the skin and was trapped in the charcoal, adsorbed onto the glass top cell, or remained as vapour above the skin. During the following 6 h, the test substance was absorbed by the skin or by the charcoal trap. At the end of the 6 h exposure, 66 % of the radioactivity was detected in the charcoal or adsorbed onto the top cell, 6 % was in the skin, and 21 % was detected in the culture medium. Repeating the experiment without the charcoal trap or top cell resulted in evaporation of 95 % of the applied EA. According to the authors, these results indicated that non-occluded dermal exposure to the test substance resulted in very low levels of percutaneous absorption. 

 

The summation of the Dermwin predictions and the available experimental data indicate that dermal absorption will occur but will be limited due to the substance’s volatility.

Toxicokinetics and metabolism

The category of the acrylates is based on the hypothesis that the acrylate esters have similar toxicological propertiesand they have a common rapid metabolism pathway described by two primary routes: carboxylesterase mediated hydrolysis of the ester linkage to acrylic acid and the corresponding alcohol; and conjugation of AA-ester with glutathione. The primary hydrolysis products for the acrylate esters are summarised in Table 2.

 

Table 2- Primary hydrolysis products

Acrylates	Primary Hydrolysis Products
Methyl acrylate (MA)	Acrylic acid and methanol
Ethyl acrylate (EA)	Acrylic acid and ethanol
n-Butyl acrylate (nBA)	Acrylic acid and n-butanol
Isobutyl acrylate (iBA)	Acrylic acid and iso-butanol
tert-Butyl acrylate (tBA)	Acrylic acid and tert-butanol
2-Ethylhexyl acrylate (2EHA)	Acrylic acid and 2-ethylhexanol

The alcohol associated with the EA being formed after hydrolysis is ethanol (CAS No. 64-17-5), for which a harmonized classification exists. The local toxicity of the acrylates limits the uptake of the alcohol;therefore, these alcoholsare not considered to impact on the read-across approach within the category. Due to the rapid metabolism of the EA as demonstrated in thein vitroassays, the systemic toxicity exerted from the parental acrylate ester is considered to be of minimal relevance. However, the available toxicological studies of the category members for systemic toxicity endpoints suggest the similarity in toxicological properties. Therefore, any potential variation intoxicity associated with differences in the ester chain length and/or the presence of the tertiary structure is considered to be negligible. It is therefore concluded that AA is the common product of metabolism that is partly responsible for systemic toxicity for all substances within the category.

The major route of metabolism of acrylate esters, including EA, has been shown to involve the rapid cleavage of the ester bond by carboxylic esterases (Figure 1; ECETOC, 1998; WHO, 1997), resulting in internal exposure to AA. Following carboxylesterase-catalysed hydrolysis to AA and the corresponding alcohol, a subsequent metabolic pathway involves metabolism of AA to carbon dioxide (CO₂) via the propionate degradation pathway. The respective alcohols are metabolised via either a catalase peroxidative pathway or the alcohol dehydrogenase pathway.Acrylate esters are also expected to undergo conjugation with GSH to form thioesters (Fredericket al., 1992), with the main urinary conjugate identified as N-acetyl-S-(2-carboxyethyl)cysteine. Inhibition of the hydrolytic pathway with a carboxylase inhibitor results in increased metabolism via the GSH conjugation route. There is no evidence to suggest that the vinyl moiety undergoes epoxidation. Based on a recentin vitroinvestigation for the hydrolysis and glutathione conjugation rates of the acrylate esters, all substances apart from tBA were metabolised by rat liver microsomes in the presence or absence of β-nicotinamide adenine dinucleotide 2’-phosphate reduced tetrasodium salt hydrate (NADPH) to form AA (ARTF, 2018). It was reported that the hydrolysis of the acrylate esters in rat liver microsomes is mainly mediated by esterases which do not require NADPH. 

The proposed metabolic pathway for acrylate esters in rats can be found in ECETOC, 1994; WHO, 1997

Selected in vivo toxicokinetic studies of EA in mammals:

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Older studies: Toxicokinetic and metabolic studies on rats show that ethyl acrylate is rapidly absorbed after oral and inhalation uptake. The substance is rapidly hydrolysed to acrylic acid and ethanol by unspecific carboxylesterases which e.g. were detected in the liver, kidney, lung, plasma, nasal mucous membrane and stomach (Silver & Murphy, 1981a; Stott & McKenna, 1984; 1985; De Bethizyet al., 1987; Ghanayemet al., 1987; Vodickaet al., 1990). The half-life of ethyl acrylate in rat blood is less than 15 minutes (Milleret al., 1981b). After further metabolism, the substance is mostly exhaled as CO₂ (about 70% of the applied dosage within 24 h) or is eliminated with the urine as 3 -hydroxypropionic acid (De Bethizyet al., 1987; Ghanayemet al., 1987). After uptake, ethyl acrylate is conjugated with non-protein-bound sulfhydryl groups (glutathione) and, following further reaction, is excreted with the urine and faeces in the form of mercapturic acid derivatives (De Bethizyet al., 1987). Because ethyl acrylate is metabolized via acetyl-SCoA, one can assume that C2-fragments originating from ethyl acrylate can be used for the novo-synthesis of body molecules.  

Frederick et al. (1992) developed a physiologically based pharmacokinetic (PBPK) and pharmacodynamic model to describe the absorption, distribution and metabolism of orally dosed ethyl acrylate. The model describes the metabolism of ethyl acrylate in 14 tissues based on in vitro metabolic studies including carboxylesterase-catalyzed ester hydrolysis, conjugation with glutathione, and binding to protein and includes as a key component the steady-state rate of glutathione synthesis in each organ because of the role of glutathione depletion in ethyl acrylate kinetics. In vivo validation of the model was conducted by comparing the model predictions to the results of several gavage dosing experiments with ethyl acrylate, including (1) the time course of glutathione depletion in a variety of tissues up to 98 hr following dosing at three dose levels, (2) the rate and extent of radiolabeled carbon dioxide excretion, and (3) protein binding in the forestomach. The very rapid metabolism predicted by the model was consistent with the observation that ethyl acrylate was metabolized too rapidly in vivo to be detected. The validation data indicated that the model provides a reasonable description of the pharmacokinetics and the pharmacodynamic response of specific rat tissues following gavage dosing of ethyl acrylate. A dose surrogate, or measure of delivered dose, for ethyl acrylate was calculated and correlated with the incidence and severity of contact site toxicity (edema, inflammation, ulceration, and hyperplasia). Thus, the model provides a quantitative approach for evaluating potential contact-site toxicity as well as lack of effects in tissues remote from the dosing site as observed experimentally.

Recent studies: Recent in vivo studies were aimed at investigating the potential of ethyl acrylate (EA) to alter glutathione (GSH) concentrations and redox status of GSH in the mouse and rat forestomach after a single exposure (BAMM and ARTF, 2017).

In the mouse study, groups of five male C57BL/6 mice were administered a single dose of EA by gavage at dose levels of 0, 20, 50, or 100 mg/kg body weight (mg/kg bw) in corn oil. Approximately three hours following dosing, all mice were sacrificed and the forestomach was removed, weighed, flash frozen in liquid nitrogen, and placed on dry ice until analysis for levels of GSH and its oxidized form, glutathione disulfide (GSSG). The levels of GSH and GSSG were substantially decreased in a dose-responsive manner. The average GSH concentration in forestomach of the control animals was 532.4 μg/g tissue and the GSH depletion (% reduction relative to controls) in the 20, 50, and 100 mg/kg groups was 52.7, 63.6, and 71.7%, respectively. The average GSSG concentration in forestomach of the control animals was 34.2 μg/g tissue and the GSSG reduction in the 20, 50, and 100 mg/kg groups was 64.8, 76.8, and 81.3%, respectively, relative to controls. The GSH:GSSG ratio was not appreciably changed in EA treated animals. Based upon these findings, it was concluded that EA substantially decreased GSH and GSSG at the administered dose levels in forestomach in mice within three hours after a single oral administration, although the redox status as measured by GSH:GSSG did not appreciably change. 

In rats, a recentin vivocomparative study was conducted in male F344/DuCrl rats, Methyl Acrylate, EA, n-Butyl acrylate and 2-Ethylhexyl acrylate were dosed at the level equivalent to 0.2 mmol/kg bw in corn oil by gavage (ARTF, 2017e). EA was dosed at a level of 20.0 mg/kg body weight. Approximately three hours following dosing, all rats were sacrificed and the forestomach was removed, weighed, flash frozen in liquid nitrogen, and placed on dry ice until analysis for GSH and GSSG levels. The GSH concentration was decreased in forestomach by the EA. The average GSH and GSSG reductions were 42.9 and 26.0% in EA treated rats, relative to controls. The GSH:GSSG ratio was not substantially altered.

With the understanding that GSH conjugation is a major pathway for EA metabolism and its depletion following oral gavage in rodents at approximately 50 mg/kg/day exemplifies kinetic saturation, this dose should provide a guide for determining the MTD for oral studies examining forestomach effects and the consequent assessment of these effects (Ellis-Hutchings et al., 2018). More broadly speaking, saturation of this redox pathway has been previously demonstrated. The fraction of the metabolites N-acetyl(S-carboxyethyl)cysteine and N-acetyl(S-carboxyethyl)cysteine ethyl ester decreases from 30% of the dosage with the oral application of 2 mg/kg bw to about 5% of the dosage at 200 mg/kg bw (De Bethizy et al., 1987). A consumption of sulfhydryl groups is hereby mostly observed locally at the site of the first contact, i.e. after oral application in the forestomach and less in the glandular stomach (Frederick et al., 1990) and after inhalative application in the lung (Silver & Murphy, 1981). A depletion of non-proteinbound thiols in the liver and kidney occurs first with the saturation of carboxylesterase (De Bethizy et al., 1987).