T. R. Hanley

Ethylene Glycol Monomethyl Ether II. Reproductive and Dominant Lethal Studies in Rats

Groups of male and female Sprague-Dawley (CD) rats were exposed to 0, 30, 100, or 300 ppm ethylene glycol monomethyl ether (EGME) vapor 6 hours/day, 5 days/week for 13 weeks. The 0 and 30 ppm groups each contained 30 rats/sex and the 100 and 300 ppm groups each had 20 rats/sex. Following the exposure period, males were bred to unexposed females to evaluate reproductive capability and dominant lethality. Additional matings of control and 300 ppm exposed males were performed during the post-exposure period in order to evaluate the recovery of fertility. Exposed females were bred with unexposed males to assess reproductive parameters. Results of the present study indicate a potential for inhaled EGME to completely suppress fertility in male rats at the 300 ppm level. Fertility of these rats was partially restored at 13 weeks post-exposure. Body weights of animals in the 300 ppm group were reduced as a result of the exposures. No dominant lethal effect or impaired fertility was observed in male rats exposed to 30 or 100 ppm EGME. Treatment-related pathologic alterations were observed only in male rats at the 300 ppm level and induced decreased testicular size and atrophic seminiferous tubules. Female rats tolerated up to 300 ppm EGME without any adverse reproductive effects. Based on these results, it was concluded that the no-adverse effect level of EGME for fertility and reproduction was 100 ppm in rats.

Teratogenic potential of inhaled dichlorobenzenes in rats and rabbits.

Orthodichlorobenzene (ODCB) and paradichlorobenzene (PDCB) were evaluated for teratogenic potential in rats (ODCB only) and rabbits. Groups of bred rats and inseminated rabbits were exposed to 0, 100, 200, or 400 ppm of ODCB; groups of inseminated rabbits were exposed to 0, 100, 300, or 800 ppm of PDCB. Animals were exposed for 6 hr/day on Days 6 through 15 (rats) or 6 through 18 (rabbits) of gestation. Maternal toxicity, as evidenced by a significant decrease in body weight gain, was observed in all groups of ODCB-exposed rats and liver weight was significantly increased in the 400-ppm ODCB-exposed group. Slight maternal toxicity was observed in groups of rabbits exposed to 400 ppm ODCB or 800 ppm PDCB as indicated by significantly decreased body weight gain during the first 3 days of exposure. Inhalation of up to 400 ppm of ODCB was not teratogenic or fetotoxic in rats, and neither ODCB nor PDCB was teratogenic or fetotoxic in rabbits at exposure levels up to 400 or 800 ppm, respectively.

Teratologic Evaluation of Inhaled Propylene Glycol Monomethyl Ether in Rats and Rabbits

Pregnant Fischer 344 rats and New Zealand White rabbits were exposed via inhalation to 0, 500, 1500, or 3000 ppm of propylene glycol monomethyl ether (PGME) for 6 hr/day on Days 6 through 15 (rats) or 6 through 18 (rabbits) of gestation. Initial exposure to 3000 ppm of PGME produced signs of mild central nervous system depression which were more pronounced and of a longer duration in rats than in rabbits. Postexposure recovery was rapid and accomodation to the test atmosphere developed following subsequent exposures. Rats and rabbits exposed to 3000 ppm had decreased weight gains over the exposure period and rats had decreased food consumption during the first 3 days of exposure. Fetal examination revealed no embryotoxic or teratogenic effects among rats or rabbits in any exposure group. Slight fetotoxicity among rats, in the form of delayed sternebral ossification, was observed at 3000 ppm. Thus, it was concluded that PGME was not teratogenic at exposure levels up to 3000 ppm.

Inhalation teratology study on monochlorobenzene in rats and rabbits.

The embryotoxic and teratogenic potential of inhaled monochlorobenzene (MCB) was evaluated in rats and rabbits. Bred Fischer 344 rats and inseminated New Zealand White rabbits were exposed to 0, 75, 210, or 590 ppm of MCB via inhalation for 6 hr/day during the period of major organogenesis. Exposure to 590 ppm caused elevated liver weights in both species and decreased body weight gain and feed consumption in rats. Inhalation of MCB vapors during gestation was not embryotoxic or teratogenic in rats. In rabbits, a few MCB-exposed fetuses exhibited visceral malformations which were not observed among concurrent controls, though no dose-related increase in malformations occurred. To further evaluate the effects of MCB in rabbits, additional groups were exposed to 0, 10, 30, 75, or 590 ppm. This subsequent study did not result in any increase in malformations in the MCB-exposed groups. Fetal effects were limited to a slight delay in skeletal development which occurred only in rats exposed to 590 ppm, a maternally toxic concentration.

Teratology and Reproduction Studies with Triclopyr in the Rat and Rabbit

Triclopyr (3,5,6-trichloro-2-pyridyloxyacetic acid), being developed as a new herbicide for use on brush and weeds, was evaluated for its potential effects on reproduction, and embryonal and fetal development. Pregnant Sprague-Dawley rats were given doses of 0, 50, 100, or 200 mg/kg/day by gavage on Days 6 through 15 of gestation. Dose-related signs of maternal toxicity were observed during the treatment period. No teratogenic effects were observed at any dose level, though slight fetotoxicity, possibly secondary to maternal toxicity, occurred at the high dose level (200 mg/kg/day). Pregnant New Zealand White rabbits were given doses of 0, 10, or 25 mg/kg/day by gavage on Days 6 through 18 of gestation which produced transient, dose-related decreases in maternal body weight gain. However, there were no indications of any treatment-related effects on fetal growth and development among rabbits. Male and female Sprague-Dawley rats maintained on diets supplying 0, 3, 10, or 30 mg/kg/day over three generations exhibited no consistent treatment-related effects on reproductive performance, pregnancy, parturition, or neonatal survival. These data indicated that triclopyr had little or no potential for teratogenic or reproductive toxicity even when the level of exposure approached that which elicited maternal toxicity.

Teratologic evaluation of inhaled epichlorohydrin and allyl chloride in rats and rabbits.

Pregnant Sprague-Dawley rats and New Zealand white rabbits were exposed to vapors of epichlorohydrin (ECH) at concentrations of 0, 2.5 or 25 ppm or to allyl chloride (AC) at concentrations of 0, 30, or 300 ppm. Exposures were for 7 hr/day on days 6 through 15 (rats) or 6 through 18 (rabbits) of gestation. Maternal effects including decreased body weight and food consumption were observed among rats inhaling 25 ppm of ECH. No evidence of an adverse effect to the embryo or fetus was observed among rats or rabbits following exposure to ECH. In the AC study maternal toxicity occurred in both rats and rabbits treated at 300 ppm. These consisted of depressed weight gain during gestation and increases in liver weight (both species) and kidney weights (rats only). Fetuses from rats exposed to 300 ppm of AC had a slight delay in skeletal development but there were no other signs of embryotoxicity. Thus, ECH and AC were not teratogenic or embryolethal in rats or rabbits following inhalation exposure to concentrations which induced effects in the maternal animals.

Metabolism and disposition of ethylene carbonate in male fischer 344 rats

Ethylene carbonate (EC) has a toxicity profile which resembles that of ethylene glycol (EG). To determine whether the toxicity of EC could be explained on the basis of its metabolism to EG, male Fischer 344 rats were given 200 mg/kg of uniformly labeled [14C]EC in water by gavage and the disposition of the radiolabel was then followed for 72 hr. EC was rapidly metabolized, with approximately 57 and 27% of the administered dose eliminated in the expired air as 14CO2 and in the urine, respectively; the remainder was found in the carcass. Separation of the urinary metabolites using liquid chromatography revealed a single radioactive peak. This metabolite was unequivocally identified as ethylene glycol via gas chromatography-mass spectrometry with the aid of 13C enrichment of the EC dose. Measurement of whole blood levels of EC and EG in rats given 200 mg/kg of EC by gavage revealed blood levels of EG approximately 100-fold higher than the levels of EC in these same animals, with a half-life of EG in blood of 2 hr, indicating rapid conversion of EC to EG. In a separate group of animals administered an equimolar dose of [14C]EG (141 mg/kg), approximately 37% of the dose was expired as 14CO2 and 42% was excreted in the urine as parent compound. When expressed on the basis of the ethanediol moiety, the disposition of EC was identical to that of EG. In view of the rapid and extensive biotransformation of EC to EG and the similarity of the existing (though limited) toxicity data base of EC compared to EG, utilization of the extensive EG systemic toxicity data base for assessing the safety of EC appears justified.

Embryotoxicity and fetotoxicity of orally administered tridiphane in mice and rats

Tridiphane [2-(3,5-dichlorophenyl)-2-(2,2,2-trichloroethyl)oxirane], a broad-leaf herbicide, was evaluated for its potential effects on mouse and rat embryonal and fetal development. Pregnant CF-1 mice were given 0, 25, 75, or 250 mg tridiphane/kg/day on Days 6 through 15 of gestation. Significant maternal toxicity was observed in both the 75- and 250-mg/kg/day dose groups. An increased percentage of females given 250 mg/kg/day showed implantation sites only after staining of the uterus, suggesting a toxic effect on the embryo during the early stages of development, possibly secondary to maternal toxicity. Increases in some skeletal variants were noted at the 75-mg/kg dose level; however, a teratogenic effect was not observed. An additional group of mice was given 250 mg/kg/day on Days 8 through 15 of gestation. Maternal toxicity was also observed among these mice as manifested by significantly elevated (+50%) liver weight; however, there was a substantial increase in the number of females with full-term litters following this shorter dosing period. An increase in the occurrence of cleft palate in these offspring associated with low fetal body weights was also observed. Pregnant Sprague-Dawley rats were given 0, 30, 100, or 200 mg/kg/day of tridiphane on Days 6 through 15 of gestation. Maternal toxicity was observed among rats given 200 mg/kg. Increased incidences of two minor skeletal variants, lumbar spurs and extra ribs, were observed in the 200-mg/kg/day dose group, and an increase in lumbar spurs was observed at 100 mg/kg/day. Thus, tridiphane was embryotoxic and induced cleft palate in mice only at the maternally toxic dose level of 250 mg/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Teratologic evaluation of orally administered nitrapyrin in rats and rabbits.

Pregnant Fischer 344 rats and New Zealand White rabbits were orally administered 0, 5, 15, or 50 mg nitrapyrin/kg/day on Gestation Days 6 through 15 (rats) or 0, 3, 10, or 30 mg/kg/day on Gestation Days 6 through 18 (rabbits). In rats, 50 mg/kg/day produced slight histopathologic changes in the livers of pregnant females. Fetal examination revealed no evidence of fetotoxicity or teratogenicity among rats at dose levels up to 50 mg/kg/day. Among rabbits, a significant depression in maternal weight gain and increased absolute and relative liver weights were observed at 30 mg/kg/day. An increased incidence of crooked hyoid bone among fetal rabbits in the 30 mg/kg/day dose group was considered indicative of fetotoxicity but not teratogenicity. Thus, administration of nitrapyrin was not teratogenic at dose levels up to 50 mg/kg/day in rats and 30 mg/kg/day in rabbits.