Ema Makoto, Fujii Sakiko, Matsumoto Mariko, Hirose Akihiko, Kamata Eiichi
Division of Risk Assessment, Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Tokyo, Japan.
Reprod Toxicol. 2006 Nov;22(4):672-8. doi: 10.1016/j.reprotox.2006.05.003. Epub 2006 May 16.
Pregnant rats were given 1,3-di-o-tolylguanidine (DTG) by gavage at 0, 10, 20 or 40 mg/kg bw/day on days 6-19 of pregnancy and the pregnancy outcome was determined on day 20 of pregnancy. At 40 mg/kg bw/day, deaths were observed in four out of 24 females. The incidences of females showing mydriasis at 20 and 40 mg/kg bw/day and showing decreased locomotor activity at 40 mg/kg bw/day were significantly increased. Alopecia, bradypnea, prone position and tremor were also observed at mg/kg bw/day. The maternal body weight gain at 20 and 40 mg/kg bw/day and food consumption at 40 mg/kg bw/day were significantly reduced. A significantly decreased weight of the gravid uterus, increased incidence of postimplantation loss, decreased number of live fetuses, and lowered weights of fetuses and placentae were found at 40 mg/kg bw/day. The incidences of the total number of fetuses with external malformations at 40 mg/kg bw/day and with skeletal malformations at 20 and 40 mg/kg bw/day were significantly increased. Significantly higher incidences of fetuses with brachydactyly and short tail and defects of caudal vertebrae, phalanges and metacarpals were observed at 40 mg/kg bw/day. Delayed ossification was also noted at 40 mg/kg bw/day. The data indicate that DTG is teratogenic at maternal toxic doses and the NOAELs of DTG for maternal and developmental toxicity are 10 mg/kg bw/day in rats.
在妊娠第6至19天，给怀孕大鼠经口灌胃给予1,3-二邻甲苯基胍（DTG），剂量分别为0、10、20或40mg/kg体重/天，并在妊娠第20天确定妊娠结局。在40mg/kg体重/天的剂量下，24只雌性大鼠中有4只死亡。在20和40mg/kg体重/天剂量下出现瞳孔散大以及在40mg/kg体重/天剂量下出现运动活性降低的雌性大鼠发生率显著增加。在该剂量下还观察到脱毛、呼吸缓慢、俯卧姿势和震颤。在20和40mg/kg体重/天剂量下母体体重增加以及在40mg/kg体重/天剂量下食物摄入量显著减少。在40mg/kg体重/天剂量下，发现妊娠子宫重量显著降低、着床后丢失发生率增加、活胎数量减少以及胎儿和胎盘重量降低。在40mg/kg体重/天剂量下出现外部畸形的胎儿总数发生率以及在20和40mg/kg体重/天剂量下出现骨骼畸形的发生率显著增加。在40mg/kg体重/天剂量下，观察到短指、短尾以及尾椎、指骨和掌骨缺陷的胎儿发生率显著更高。在40mg/kg体重/天剂量下还注意到骨化延迟。数据表明，DTG在母体中毒剂量下具有致畸性，大鼠中DTG对母体和发育毒性的无观察到有害作用水平为10mg/kg体重/天。
