Ethyl acrylate-induced gastric toxicity. II. Structure-toxicity relationships and mechanism

Earlier studies conducted in this laboratory demonstrated that gavage administration of ethyl acrylate caused pronounced gastric toxicity in rats given single or repeated doses. The current studies were undertaken to investigate the structural, metabolic, and physical basis of this chemically induced gastric toxicity. Gavage administration of equimolar doses (2 mmol/kg) of methyl or ethyl acrylate in corn oil resulted in profound gastric toxicity in male F344 rats, while acrylic acid and n-butyl acrylate were without effect. Furthermore, gavage administration of equimolar doses of methyl propionate or ethyl propionate (saturated analogues of methyl acrylate and ethyl acrylate, respectively) as well as methacrylic acid esters were without gastric toxicity. These results indicate that structural requirements for acrylate esters to cause gastric lesions include an intact ester moiety, a double bond, and no substitution at carbon number 2. Additional studies indicate that gastric toxicity may be attributed to the intact ester molecule or to metabolite(s) other than products of carboxylesterase-mediated hydrolysis (acrylic acid and alcohol) and that gastric toxicity is dependent upon both acrylate ester concentration in dose vehicle and the lipophilicity of the dose vehicle (corn oil vs water).