Key Topics
Characterization Of Mode And Mechanism Of Action Data Related To Ethyl Acrylate-induced Rodent Forestomach Tumors And Their Relevance To Humans. Presented Platform Presentation at SOT (March 11-15, 2018).
Ethyl acrylate (EA) is a chemical monomer intermediate widely used in industrial production of emulsion-based polymers. EA’s utility in polymerization reactions stems from its conjugated α,β-unsaturated ester bond. This reactivity causes strong irritation to all tissues upon contact. High-dose, chronic gavage bioassay studies resulted in benign and malignant forestomach neoplasms in rats and mice. Despite a lack of other systemic effects following subchronic or chronic EA exposure, and a lack of tumor induction in chronic drinking water, inhalation, and dermal studies, the substance has been classified as “possibly carcinogenic to humans” by the International Agency for Research on Cancer (IARC) since 1986. To aid in an evaluation of the relevance of EA-induced forestomach tumors to humans, the available in silico, in vitro, in vivo, mode- and mechanism-of-action data have been comprehensively evaluated with respect to this adverse outcome. Critical early key events include sustained saturation of glutathione conjugation (detoxification) following high-concentration bolus dosing, resulting in cytotoxicity. Subsequent key events include increased inflammation, regenerative cell proliferation, and hyperplasia of forestomach epithelial cells, with forestomach tumors occurring following greater than 6 months of treatment in a non-specific manner, as indicated by lack of activity in in vivo genotoxicity and mutagenicity studies. Collectively, the evaluated mode- and mechanism-of-action data demonstrate that EA-induced epithelial cell tumors in the rodent forestomach occur by a mode of action that is specific to rodents. The requirement for repetitive longterm bolus EA exposure to a rodent-unique organ at sufficiently high concentrations to cause sustained saturation (depletion) of glutathione conjugation are critical early events without relevance to humans. Furthermore, lack of a specific genotoxic and/or mutagenic mechanism of EA for this rodent tumor provides strong evidence that the existing IARC classification should be removed. Publication