title: Combined repeated-dose and reproductive/developmental toxicity screening test of 1-tert-butoxy-4-chlorobenzene in rats.
abstract: We have carried out animal toxicity tests of chemicals for a chemical safety program implemented by the Ministry of Economy, Trade, and Industry of Japan. Here, we tested 1-tert-butoxy-4-chlorobenzene in a combined repeat-dose and developmental and reproductive toxicity test. The test chemical was administered daily by gavage to 9-week-old Crl:CD (SD) rats at doses of 0, 20, 100, and 500  mg/kg/d. Males were treated for 42 d beginning 14 d before mating. Females were treated from 14 d before mating to day 4 of lactation. Decreased spontaneous locomotion, decreased respiratory rate, and incomplete eyelid opening were observed at 500 mg/kg/d (both sexes), but resolved within 30 min of administration, suggesting central nervous system depression. No notable changes were observed in body weight, food consumption, functional battery tests, or blood test. Increased liver weight with centrilobular or diffuse hepatocyte hypertrophy was observed at 100 and 500 mg/kg/d (both sexes). There were no biochemical or histopathological changes related to hepatotoxicity. Increased kidney weight with basophilic tubules, tubule dilatation, and increased hyaline droplets were observed in males dosed at 100 and 500 mg/kg/d. Immunohistochemical staining indicated α2u-globulin nephropathy, a male rat-specific toxicity. Although kidney weight was also increased in females dosed at 500 mg/kg/d, it was not considered to be an adverse effect because there were no histopathological changes. Pup weights on postnatal day 0 were decreased at 500 mg/kg/d and still decreased on postnatal day 4. Our data indicated the no-observed-adverse-effect-level for repeated-dose and reproductive/developmental toxicity for 1-tert-butoxy-4-chlorobenzene was 100 mg/kg/d.
authors: a CERI Hita, Chemicals Evaluation and Research Institute , Hita-shi , Oita , Japan.
authors: Yasuhiro
authors: Y
authors: Tsubokura
authors: b Chemical Biotesting Center, Chemicals Evaluation and Research Institute , Bunkyo-ku , Tokyo , Japan , and.
authors: Ryuichi
authors: R
authors: Hasegawa
authors: a CERI Hita, Chemicals Evaluation and Research Institute , Hita-shi , Oita , Japan.
authors: Sunao
authors: S
authors: Aso
authors: a CERI Hita, Chemicals Evaluation and Research Institute , Hita-shi , Oita , Japan.
authors: Toshio
authors: T
authors: Kobayashi
authors: a CERI Hita, Chemicals Evaluation and Research Institute , Hita-shi , Oita , Japan.
authors: Takayuki
authors: T
authors: Koga
authors: a CERI Hita, Chemicals Evaluation and Research Institute , Hita-shi , Oita , Japan.
authors: Satsuki
authors: S
authors: Hoshuyama
authors: a CERI Hita, Chemicals Evaluation and Research Institute , Hita-shi , Oita , Japan.
authors: Yutaka
authors: Y
authors: Oshima
authors: a CERI Hita, Chemicals Evaluation and Research Institute , Hita-shi , Oita , Japan.
authors: Katsumi
authors: K
authors: Miyata
authors: a CERI Hita, Chemicals Evaluation and Research Institute , Hita-shi , Oita , Japan.
authors: Yuji
authors: Y
authors: Kusune
authors: a CERI Hita, Chemicals Evaluation and Research Institute , Hita-shi , Oita , Japan.
authors: Takako
authors: T
authors: Muroi
authors: c CERI Kurume, Chemicals Evaluation and Research Institute , Kurume-shi , Fukuoka , Japan.
authors: Naoki
authors: N
authors: Hashizume
authors: c CERI Kurume, Chemicals Evaluation and Research Institute , Kurume-shi , Fukuoka , Japan.
authors: Yoshiyuki
authors: Y
authors: Inoue
authors: a CERI Hita, Chemicals Evaluation and Research Institute , Hita-shi , Oita , Japan.
authors: Shozo
authors: S
authors: Ajimi
authors: a CERI Hita, Chemicals Evaluation and Research Institute , Hita-shi , Oita , Japan.
authors: Kotaro
authors: K
authors: Furukawa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D002722:Chlorobenzenes / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005260:Female; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D009928:Organ Specificity; D018812:Paternal Exposure / Q000009:adverse effects*; D010647:Phenyl Ethers / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D018675:Toxicity Tests
chemical_list: C000622234:1-tert-butoxy-4-chlorobenzene; D002722:Chlorobenzenes; D010647:Phenyl Ethers
keywords: central nervous system depression; hepatocyte hypertrophy; probabilistic approach; α2u-Globulin nephropathy