Prenatal developmental toxicity study of the basic rubber accelerator, 1,3-di-o-tolylguanidine, in rats.
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.
Ema
Makoto
M
Division of Risk Assessment, Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Tokyo, Japan. ema@nihs.go.jp
Fujii
Sakiko
S
Matsumoto
Mariko
M
Hirose
Akihiko
A
Kamata
Eiichi
E
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities / Q000187:drug effects; D002972:Cleft Palate / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects; D005865:Gestational Age; D006146:Guanidines / Q000633:toxicity*; D006228:Hand Deformities, Congenital / Q000139:chemically induced; D008098:Litter Size / Q000187:drug effects; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D015878:Mydriasis / Q000139:chemically induced; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012408:Rubber / Q000737:chemistry / Q000633:toxicity*; D012744:Sex Ratio; D015430:Weight Gain / Q000187:drug effects; D015431:Weight Loss / Q000187:drug effects
D006146:Guanidines; D012408:Rubber; C050232:1,3-ditolylguanidine