期刊
TOXICOLOGICAL SCIENCES
卷 136, 期 2, 页码 392-401出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kft211
关键词
propylparaben; parahydroxybenzoic acid ester; spermatogenesis; endocrine disruptor; puberty; sulfotransferase
类别
资金
- Bristol-Myers Squibb
- Orphan Europe
- Pfizer
- Reckitt Benckiser Healthcare
- Sanofi Aventis
- Servier
Parabens are in widespread use as preservatives in drugs. In the late 1990s, concerns were raised about their capacity to disrupt endocrine function based on in vitro data and in vivo uterotrophic tests. Studies in juvenile male rats provided conflicting results on pospubertal sperm production. In an exploratory pharmacokinetic study, Wistar male rats received a single dose of propylparaben (PP) at 3, 10, 100, or 1000mg/kg, orally on postnatal day (PND) 31. Plasma PP concentrations were quantifiable up 8h after dosing with a mean T-max value of 15min. Distribution was 4.8 l/kg, the plasma elimination half-life was 47min, and clearance was 4.20 (l/h)/kg at 10mg/kg. A sulfoconjugated metabolite was detected. In the juvenile toxicology study, PP was orally administered by gavage to 20 Wistar male rats at doses of 3, 10, 100, or 1000mg/kg/day in 1% hydroxyethylcellulose for 8 weeks starting on PND21. A first subgroup of 10 males/dose was necropsied immediately after the 8-week exposure period; a second subgroup of 10 males/dose was necropsied after a 26-week washout period. Blood samples were taken from additional satellite animals after dosing on PND21 and PND77 for toxicokinetic analysis. There was no evidence of an effect of PP on the weight of the male reproductive organs, epididymal sperm parameters, hormone levels, or histopathology. The dose of 1000mg/kg/day was the no-observed adverse effect level, corresponding to a maximum plasma concentration of 12 030ng/ml and exposure to 47 760 ngh/ml (AUC(08 h)) at the end of the treatment.
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