Reproductive and developmental toxicity screening test of basic rubber accelerator, 1,3-di-o-tolylguanidine, in rats.
Twelve male and female rats per group were exposed to the rubber accelerator 1,3-di-o-tolylguanidine (DTG) by gavage at 0, 8, 20 or 50 mg/kg bw/day. Males were dosed for a total of 49 days beginning 14 days before mating. Females were dosed for a total of 40-49 days beginning 14 days before mating to day 3 of lactation throughout the mating and gestation period. At 50 mg/kg bw/day, deaths were observed in two males and three females. Lowered body weight gain and food consumption were noted in males at 50 mg/kg bw/day and females at 20 and 50 mg/kg bw/day. Mydriasis, decreased locomotor activity, bradypnea, prone position, tremor and/or salivation were observed in males and females at 20 and 50 mg/kg bw/day. No effects of DTG were found on the estrous cyclicity, precoital interval, copulation, fertility and gestational indices, numbers of corpora lutea and implantations, or gestation length. A significant decrease in the number, body weight and viability of offspring and increase in the incidence of fetuses with external malformations were found at 50 mg/kg bw/day. Oligodactyly, anal atresia and tail anomalies were observed. These data suggest that DTG may be teratogenic. The NOAELs of DTG for general and developmental toxicity in rats are 8 and 20 mg/kg bw/day, respectively.
Ema
Makoto
M
Division of Risk Assessment, Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan. ema@nihs.go.jp
Kimura
Eisuke
E
Matsumoto
Mariko
M
Hirose
Akihiko
A
Kamata
Eiichi
E
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity; D001006:Anus, Imperforate / Q000139:chemically induced; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D007441:Intubation, Gastrointestinal; D008098:Litter Size / Q000187:drug effects; D008297:Male; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D012472:Salivation / Q000187:drug effects; D012744:Sex Ratio; D014034:Toes / Q000002:abnormalities; D018675:Toxicity Tests / Q000379:methods*; D015431:Weight Loss / Q000187:drug effects
D000927:Anticonvulsants; D006146:Guanidines; C050232:1,3-ditolylguanidine