title: Uterotrophic assay, Hershberger assay, and subacute oral toxicity study of 4,4'-butylidenebis(2-tert-butyl-5-methylphenol) and 3-(dibutylamino)phenol, based on the OECD draft protocols.
abstract: We performed a uterotrophic assay, the Hershberger assay, and a 28-day repeated-dose toxicity study [enhanced Organization for Economic Co-operation and Development (OECD) test guideline No. 407] of 4,4'-butylidenebis(2-tert-butyl-5-methylphenol) and 3-(dibutylamino)phenol, based on the OECD draft protocols. In the uterotrophic assay of 4,4'-butylidenebis(2-tert-butyl-5-methylphenol), female SD rats were subcutaneously injected with the chemical at doses of 0, 100, 300, and 1,000 mg/kg on each of 3 days from postnatal day 20 to day 22, and no changes were observed. In the Hershberger assay of 4,4'-butylidenebis(2-tert-butyl-5-methylphenol), the test chemical was orally administered to castrated male SD rats at doses of 0, 50, 200, and 1,000 mg/kg/day for ten consecutive days beginning on postnatal day 56, and no changes were observed. When this chemical was orally administered at doses 0, 5, 25, and 125 mg/kg/day for at least 28 days in the subacute oral toxicity study, an increase in thyroid weight was observed in the female rats in the 125 mg/kg group, an increase in serum thyroid-stimulating hormone (TSH) values in the male and female rats in the 125 mg/kg group, and a decrease in serum T3 and T4 values in the male rats in the 125 mg/kg group, and thyroid follicular epithelial cell hypertrophy was observed in some of the female rats in the 125 mg/kg group. These findings were concluded to be the result of endocrine-mediated effects of the chemical on thyroid function. In addition, increased liver weight, abnormal histological findings in the liver, and abnormal biochemical parameters related to liver function were observed in male and/or female rats in 5 mg/kg group and higher dose groups. The no-observed-effect level for 4,4'-butylidenebis(2-tert-butyl-5-methylphenol) was concluded to be <5 mg/kg/day. In the uterotrophic assay of 3-(dibutylamino)phenol, female SD rats were subcutaneously injected with the chemical at doses of 0, 100, 300, and 1,000 mg/kg on each of 3 days from postnatal day 20 to day 22, and no changes were observed. In the Hershberger assay of 3-(dibutylamino)phenol, the test chemical was orally administered at doses of 0, 50, 200, and 400 mg/kg/day to castrated male SD rats for ten consecutive days beginning on postnatal day 56, and no changes were observed. On the other hand, when this test chemical was orally administered at doses 0, 30, 100, and 300 mg/kg/day for at least 28 days in the subacute oral toxicity study, thyroid weight increased in the male rats in the 300 mg/kg group, thyroid follicular epithelial cell hypertrophy was observed in a small number of male rats in the 300 mg/kg group, serum T3-values decreased in the female rats in the 300 mg/kg group, and a tendency for TSH-values to increase was observed in the male and female rats in the 300 mg/kg group. Therefore, 3-(dibutylamino)phenol was also concluded to have slight anti-thyroid acting effects as the endocrine-mediated effects. On the other hand, increased hemosiderin deposition in the spleen, increased spleen weight, hematological abnormalities, and squamous epithelial hyperplasia of the forestomach were detected in male and/or female rats in the 100 and/or 300 mg/kg groups, and thus the no-observed-effect level for 3-(dibutylamino)phenol was concluded to be 30 mg/kg/day.
authors.affiliation: Chemicals Evaluation and Research Institute, 3-822 Ishii, Hita, Oita, Japan. yamasaki-kanji@ceri.jp
authors.forename: Kanji
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Katusi
authors.initials: K
authors.lastname: Miyata
authors.forename: Keiji
authors.initials: K
authors.lastname: Shiraishi
authors.forename: Takako
authors.initials: T
authors.lastname: Muroi
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Higashihara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Oshima
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Minobe
mesh_terms: D000284:Administration, Oral; D000818:Animals; D052244:Endocrine Disruptors / Q000633:toxicity*; D005260:Female; D005837:Genitalia, Male / Q000187:drug effects / Q000254:growth & development; D017408:Guidelines as Topic; D006485:Hemosiderin / Q000378:metabolism; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size; D010636:Phenols / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013963:Thyroid Hormones / Q000097:blood; D014599:Uterus / Q000187:drug effects / Q000254:growth & development
chemical_list: D052244:Endocrine Disruptors; D010636:Phenols; D013963:Thyroid Hormones; D006485:Hemosiderin