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Comparison of the developmental/reproductive toxicity and hepatotoxicity of phthalate esters in rats using an open toxicity data source

Kaori Ambe, Yuko Sakakibara, Aya Sakabe, Hayato Makino, Tatsuya Ochibe, Masahiro Tohkin
Journal of Toxicological Sciences 2019, 44 (4): 245-255
Phthalate esters (PEs) are widely used as plasticizers in various kinds of plastic products. Some PEs have been known to induce developmental and reproductive toxicity (DART) as well as hepatotoxicity in laboratory animals. In some cases of DART, the strength of toxicity of PEs depends on the side chain lengths, while the relationship between hepatotoxicity and side chain length is unknown. Therefore, in this study, we compared DART and hepatotoxicity in rats, focusing on 6 PEs with different side chains. We collected toxicity data of 6 PEs, namely, n-butyl benzyl phthalate (BBP), di-n-butyl phthalate (DBP), di(2-ethylhexyl) phthalate (DEHP), di-isodecyl phthalate (DIDP), di-isononyl phthalate (DINP), and di-n-octyl phthalate (DNOP), from open data source, then, we constructed the toxicity database to comprehensively and efficiently compare the toxicity effects. When we compared DART using the toxicity database, we found that BBP, DBP, and DEHP with short side chains showed strong toxicities against the reproductive organs of male offspring, and the No-Observed-Adverse-Effect Levels (NOAELs) of BBP, DBP, and DEHP were lower than DIDP, DINP, and DNOP with long side chains. Comparing hepatotoxicities, the lowest NOAEL was shown 14 mg/kg/day for DEHP, based on liver weight gain with histopathological changes. However, as BBP and DBP showed higher NOAEL than the other 3 PEs (DIDP, DINP, and DNOP), we conclude that hepatotoxicity does not depend on the length of side chain. Concerning side chain length of PEs, we effectively utilized our constructed database and found that DART and hepatotoxicity in rats showed different modes of toxicities.


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