Takafumi Itami

Teratogenic evaluation of di-n-butyl phthalate in rats

Pregnant rats were given di-n-butyl phthalate (DBP) by gastric intubation at a dose of 0, 0.5, 0.63, 0.75 or 1.0 g/kg on days 7-15 of pregnancy. A significant decrease in the maternal body weight gain after treatment with DBP was found at a dose of 0.63 g/kg and above. Maternal death and complete resorption of implanted embryos in all the surviving dams were observed in the 1.0 g/kg group. Significantly increased incidence of postimplantation loss and decreased fetal weight were detected at doses of 0.63 and 0.75 g/kg. The incidence of fetuses with malformations was higher in the 0.63 and 0.75 g/kg groups than in the control group, and the difference was significant in the 0.75 g/kg group. Cleft palate were predominantly observed.

Teratogenic phase specificity of butyl benzyl phthalate in rats

Pregnant rats were given butyl benzyl phthalate (BBP) by gastric intubation at a dose of 0.6, 0.75 or 1.0 g/kg on days 7-9, 10-12 or 13-15 of pregnancy. While treatment with BBP on days 7-9 or 13-15 at doses of 0.75 and 1.0 g/kg was significantly teratogenic, no evidence of teratogenicity was detected when BBP was given on days 10-12. The incidence of malformed fetuses was proportional to the dose of BBP. Treatment on days 7-9 with BBP at doses of 0.75 g/kg and above caused a significant increase in the number of skeletal malformations, such as fusion of the cervical vertebral arches and deformity of the thoracic vertebrae, but neither external nor internal malformations. Treatment on days 13-15 with two higher doses of BBP resulted in a significantly increased incidence of fetuses with external and skeletal malformations such as cleft palate and fusion of the sternebrae. The highest incidence of malformed fetuses occurred after treatment with BBP on days 13-15. It could be concluded that the susceptibility to the teratogenicity of BBP varies with the developmental stage at the time of administration.

Behavioral effects of acute exposure to tributyltin chloride in rats.

The behavioral effects of a single acute exposure to nonlethal doses of tributyltin chloride (TBTCl) were studied in male Wistar rats. The rats were given TBTCl by oral gavage at doses of 0, 6.3, 12.5, 25.0 or 50.0 mg/kg, and spontaneous motor activity (SMA) and acquisition of conditioned avoidance responses in a shuttle box were monitored. Body weight gain in the 50.0-mg/kg group was significantly lowered, but weight gain in the 6.3-, 12.5- and 25.0-mg/kg groups was comparable to that in the control group. TBTCl caused a dose-related decrease in SMA during the dark phase. The 24-h total daily and 12-h nocturnal activity was decreased at doses of 12.5 mg/kg and above. The acquisition of shock avoidance responses was inhibited in all TBTCl-treated groups in a dose-dependent manner, and the difference was significant for rats given TBTCl at doses of 25.0 mg/kg and above. The data indicate that an acute exposure to TBTCl can cause significant changes in rat behavior and suggest that SMA can serve as a sensitive index for detecting its toxicity.

Teratogenic Evaluation of Tributyltin Chloride in Rats Following Oral Exposure

The teratogenicity of tri-n-butyltin chloride (TBTC1) was examined in Wistar rats. The pregnant rats were administered orally 25, 15, 9, 5 and 0(Control) mg of TBTC1/kg of body weight/day from day 7 to 15 of pregnancy. Maternal toxicity, as evidenced by both of decreased body weight gain and food consumption was observed at 25, 15 and 9 mg/kg/day dose group. However, only in the 25 mg/kg/day dose group some clinical signs of toxicity (sedation, diarrhoea and salivation) were observed and 70 percent of the dams were dead. In the 25 mg/kg/day dose group, all fetuses were dead. Statistically significant reductions in the female fetal body weight were observed in 9 and 5 mg/kg/day dose groups. In all groups treated with TBTC1 except the 25 mg/kg/day dose group, no significant differences in the numbers of live fetuses and intrauterine death (dead fetuses and resorptions) or sex ratios of fetuses were found between the TBTC1-treated and control groups. Fetal external, skeletal and internal malformations were not observed at any of the dose levels. However, several types of skeletal and internal variations including delayed ossifications were observed in some groups treated with TBTC1, but the incidences were not significantly different from controls. Also, two fetuses with dilatation of the renal pelvis were found in 9 and 5 mg/kg/day dose group. Statistically significant increases of placental weight in all TBTC1-treated groups were observed when compared to that of control group. In conclusion, TBTC1 administered orally to Wistar rats during days 7-15 of pregnancy produced related signs of fetal toxicity but no evidence of teratogenicity and induced a marked increase in placental weight.

Susceptible period for the teratogenicity of di-n-butyltin dichloride in rats

Pregnant rats were given di-n-butyltin dichloride (DBT) by gastric intubation at a dose of 20 mg/kg on days 7-9, 10-12 or 13-15 of pregnancy or at a dose of 20 or 40 mg/kg on day 6, 7, 8 or 9 of pregnancy. While treatment with DBT on days 7-9 was significantly and highly teratogenic, no evidence of teratogenicity was detected when DBT was given on days 10-12 or 13-15. Treatment on day 7 or 8 with both doses of DBT, but neither on day 6 or 9, resulted in an increased incidence of fetuses with malformations. The highest incidence of malformed fetuses occurred after treatment on day 8. The incidence of malformed fetuses was proportional to the dose of DBT. Anomaly of tail, anal atresia, club foot, omphalocele, deformity of the vertebral column, defect of the ribs and anophthalmia or microphthalmia were predominantly observed. It could be concluded that, following maternal exposure to DBT in rats, developing offspring are not susceptible to teratogenic effects of DBT on day 6 and that day 7 is the earliest susceptible period, day 8 is the highest susceptible period and day 9 is no longer a susceptible period for teratogenesis of DBT.

Changes of Spontaneous Motor Activity of Rats After Acute Exposure to Tributyltin Chloride

The effects of a single acute exposure to tributyltin chloride (TBTCl) on spontaneous motor activity (SMA) in home cage were studied in male Wistar rats. The rats were given TBTCl intraperitoneally at a dosage of 0, 1.6 or 3.3 mg/kg, and the SMA was measured for five days after administration of TBTCl. Body weight gain in the 3.3 mg/kg group was significantly lowered, but that in the 1.6 mg/kg group was comparable to that in the control group. The SMA during light phase was not affected by TBTCl treatment. However, the SMA during dark phase was decreased in both of the TBTCl-treated groups. These decreases in SMA gradually returned to the control levels. The 24-hr total daily and 12-hr nocturnal activity in the TBTCl-treated groups were decreased in a dose-dependent manner. These data indicate that TBTCl possesses behavioral toxicity and suggest that the decreased nocturnal SMA is a sensitive index for detecting toxicity of chemicals in rats.

TERATOLOGY STUDY OF DIETHYLENE GLYCOL MONO-n-BUTYL ETHER IN RATS

The teratogenicity of diethylene glycol mono-n-butyl ether (DEGMBE) was studied in Wistar rats. The pregnant rats were fed a diet containing DEGMBE from day 0 through day 20 of pregnancy. The dietary concentrations of DEGMBE were 0, 0.04, 0.2 and 1% and the daily intakes of DEGMBE were 0, 25, 115 and 633 mg/kg, respectively. In the DEGMBE-treated groups, the maternal body weight gain during pregnancy was significantly reduced, but neither decrease in food consumption during pregnancy nor any clinical sign of toxicity was observed. No significant differences between the DEGMBE-treated groups and the control group were found in the pre- and postimplantation losses, the number of live fetuses per litter, the sex ratio of live fetuses, the fetal body weight and the placental weight. External, skeletal and internal examinations of the fetuses revealed no evidence of teratogenesis. In the postnatal development of the offspring from the dams given DEGMBE, a high survival rate and good growth of the offspring were noted. It could be concluded that DEGMBE has no adverse effects on the pre- and postnatal development of the offspring in rats.

Teratology Study of Tween 60 in Rats

The teratogenicity of Tween 60 was studied in Wistar rats. Pregnant rats were given Tween 60 at a dose of 0, 0.1, 1.0 or 10% in the diet from day 7 to day 14 of pregnancy. Daily intakes of Tween 60 were 99 mg/kg for the 0.1% group, 960 mg/kg for the 1.0% group and 7693 mg/kg for the 10% group. No change induced by Tween 60 was detected in the number, sex ratio and body weight of live fetuses. External, skeletal and internal examinations of the fetuses revealed no evidence of teratogenesis. It could be concluded that Tween 60 has no harmful effects on the prenatal development of the rat offspring at doses employed in the present study.

Teratogenic evaluation of p-tert-butylphenol formaldehyde resin (novolak type) in rats following oral exposure.

The teratogenicity of p-tert-butylphenol formaldehyde resin, novolak type, (PTBP-FR) was examined in Wistar rats. Pregnant rats were fed diets containing 0, 2.5, 5 or 10% of PTBP-FR ad libitum from day 6 to day 15 of pregnancy. Maternal toxicity, as evidenced by a decreased maternal body weight gain and food consumption, was observed in the 5 and 10% dose groups. However, treatment-related clinical signs were not observed. No significant reductions in the fetal body or placental weights were observed in any dose group. There were no significant differences in the number of live fetuses, intrauterine deaths (dead fetuses and resorptions), or fetal sex ratios found between the PTBP-FR-treated and control groups. Although external and internal malformations including short tail, dilatation of the cerebral ventricle and the renal pelvis and dextrocardia, and some skeletal variations were observed in fetuses at some groups treated with PTBP-FR, the incidences of these morphological alterations were not statistically different from controls. In conclusion, PTBP-FR administered orally to Wistar rats during days 6-15 of gestation produced no related signs of developmental toxicity.

Evaluation of Teratogenic Potential of Sodium Sulfite in Rats

The teratogenicity of sodium sulfite was examined in Wistar rats. The pregnant rats were fed diets containing 5, 2.5, 1.25, 0.63 or 0.32% of sodium sulfite heptahydrate(Na2SO3.7H2O) ad libitum from day 8 to 20 of pregnancy. Maternal toxicity, as evidenced by decreased body weight gain and decreased food consumption was observed at the 5% group, but no clinical signs of toxicity were observed. A significant reduction in the fetal body weight of both sexes was observed in all dose groups except 2.5% group. No significant differences in the numbers of live fetuses and intrauterine death (dead fetuses and resorptions) or sex ratios of fetuses were found between the sodium sulfite-treated and control groups. Fetal external, skeletal and internal malformations were not observed at any dose level. However, several types of skeletal and internal variations as well as delayed ossifications were observed in some groups treated with sodium sulfite, but the incidences were not significantly different from controls. Also, some fetuses with dilatation of the renal pelvis and the lateral ventricle were found in all groups except 1.25% group, but there was no dose-response. The live birth index and survival rate of offspring within 4 weeks and their body weight gain at 3 weeks after birth were not affected by sodium sulfite-treatment. In conclusion, sodium sulfite (0, 0.32, 0.63, 1.25, 2.5 or 5.0% as Na2SO3.7H2O) administered in the diet to Wistar rats during days 8-20 of pregnancy produced related signs of fetal toxicity but no evidence of teratogenicity.