title: Development of a category approach to predict the testicular toxicity of chemical substances structurally related to ethylene glycol methyl ether.
abstract: We propose a category approach to assessing the testicular toxicity of chemicals with a similar structure to ethylene glycol methyl ether (EGME). Based on toxicity information for EGME and related chemicals and accompanied by adverse outcome pathway information on the testicular toxicity of EGME, this category was defined as chemicals that are metabolized to methoxy- or ethoxyacetic acid, a substance responsible for testicular toxicity. A Japanese chemical inventory was screened using the Hazard Evaluation Support System, which we have developed to support a category approach for predicting the repeated-dose toxicity of chemical substances. Quantitative metabolic information on the related chemicals was then considered, and seventeen chemicals were finally obtained from the inventory as a shortlist for the category. Available data in the literature shows that chemicals for which information is available on the metabolic formation of EGME, ethylene glycol ethyl ether, methoxy- or ethoxyacetic acid do in fact possess testicular toxicity, suggesting that testicular toxicity is a concern, due to metabolic activation, for the remaining chemicals. Our results clearly demonstrate practical utility of AOP-based category approach for predicting repeated-dose toxicity of chemicals.
authors.affiliation: Chemical Management Center, National Institute of Technology and Evaluation, 2-49-10, Nishihara, Shibuya-ku, Tokyo 151-0066, Japan. Electronic address: yamada-takashi@nite.go.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Chemical Management Center, National Institute of Technology and Evaluation, 2-49-10, Nishihara, Shibuya-ku, Tokyo 151-0066, Japan.
authors.forename: Yushiro
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Chemical Management Center, National Institute of Technology and Evaluation, 2-49-10, Nishihara, Shibuya-ku, Tokyo 151-0066, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Hasegawa
authors.affiliation: Chemical Management Center, National Institute of Technology and Evaluation, 2-49-10, Nishihara, Shibuya-ku, Tokyo 151-0066, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sakuratani
authors.affiliation: Food Safety Commission of Japan, 5-2-20, Akasaka, Minato-ku, Tokyo 107-6122, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamazoe
authors.affiliation: Biological Safety Research Center, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ono
authors.affiliation: Biological Safety Research Center, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Hirose
authors.affiliation: Biosafety Research Center, 582-2, Shioshinden, Iwata, Shizuoka 437-1213, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hayashi
mesh_terms: D000085:Acetates / Q000378:metabolism; D000818:Animals; D016208:Databases, Factual; D005026:Ethylene Glycols / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D051379:Mice; D051381:Rats; D018570:Risk Assessment / Q000379:methods; D013737:Testis / Q000187:drug effects*
chemical_list: D000085:Acetates; D005026:Ethylene Glycols; C034096:ethoxyacetic acid; C005219:methyl cellosolve; C013598:methoxyacetic acid
keywords: Adverse outcome pathway; Category approach; Methoxyacetic acid; Repeated-dose toxicity; Testicular toxicity