Evaluation of developmental toxicity of β-thujaplicin (hinokitiol) following oral administration during organogenesis in rats

The objective of this study was to evaluate the developmental toxicity of beta-thujaplicin (TP) in rats. Pregnant rats were given TP by gastric intubation at 15, 45, or 135 mg/kg on days 6-15 of pregnancy. The maternal body weight gain during administration at 45 and 135 mg/kg and after administration at 136 mg/kg and adjusted weight gain at 45 and 135 mg/kg were significantly reduced. A significant decrease in food consumption during and after administration was found at 45 and 135 mg/kg. A significant increase in the incidence of postimplantation loss was found in pregnant rats given TP at 135 mg/kg. A significantly lower weight was found in female fetuses at 45 and 135 mg/kg and in male fetuses at 135 mg/kg. Although a significantly increased incidence of fetuses with skeletal variations and decreased degree of ossification were found at 135 mg/kg, no significant increase in external, skeletal and internal malformations was detected after administration of TP. The data demonstrated that TP had adverse effects on embryonic/fetal survival and growth only at maternal toxic doses. No adverse effects on morphological development were found in rats fetuses. Based on the significant decreases in maternal body weight gain and weight of female fetuses at 45 mg/kg and higher, it is concluded that the no-observed-adverse-effect levels (NOAELs) of TP for both dams and fetuses are considered to be 15 mg/kg in rats. (C) 2003 Elsevier Ltd. All rights reserved.