Potential teratogenicity of di-n-butyltin dichloride and other dibutyltin compounds.

摘要

The developmental toxicity of di-n-butyltin dichloride (DBT-dC) was evaluated in Wistar rats following oral administration. No maternal toxicity, embryotoxicity, or malformations were observed at 1, 2.5, or 5 mg DBT-dC/kg body weight. Signs of maternal toxicity, including decreased food consumption, body weight gain, and thymus weight, were observed at 10 mg/kg body weight DBT-dC. At this dose, no evidence of embryotoxicity, including such measures as total resorptions, viable fetuses, or fetal weights, was noted in any litter data. There was a slightly increased frequency of total malformations at the 10 mg/kg dose level of 4/262 treated vs. 1/269 control fetuses. All defects occurred singly with no clustering nor organ system pattern of occurrence, which would be indicative of a teratogenic effect. The no-observed-adverse-effect-level (NOAEL) for prenatal as well as maternal toxicity was considered to be 5 mg DBT-dC/kg body weight. The interpretation and utility of previously published studies on the developmental toxicity of dibutyltin compounds are confounded by dose regimen and data reporting deficiencies. These studies suggest that, after oral administration during days 6-17 of pregnancy, the NOAEL for malformations in rats of different strains ranges from 1.7 to 5 mg/kg body weight. In these studies, the maternal LD50 was reported to be about 8 mg/kg body weight in one study but at greater than 15 mg/kg in others. Thus, the NOAEL for teratogenicity may be roughly estimated to be from one-tenth to one-third of the maternal LD50. When evaluated, thymus involution, a typical but reversible effect of di- and tri-butyltin compounds, was also observed at 5-10 mg/kg body weight. The most susceptible time for inducing teratogenic effects is reported to be days 7-9 of pregnancy, but malformations have also been found with dosing over longer duration at lower doses. It is doubtful that the findings of malformations at highly toxic doses in animals has any health hazard significance, especially when human exposure to dibutyltins typically occurs at several orders of magnitude lower than the doses used in these studies. Further comparative pharmacokinetic studies would be necessary in order to refine the hazard characterization. Copyright 2001 Wiley-Liss, Inc.