J.A. John

Embryotoxicity and fetotoxicity of orally administered chlorpyrifos in mice

Abstract Pregnant CF-1 mice were given 0, 1, 10, or 25 mg/kg/day of chlorpyrifos by gavage on Days 6 through 15 of gestation. Severe maternal toxicity was observed among pregnant mice given 25 mg/kg of the test compound. Plasma and erythrocyte cholinesterase levels were significantly reduced among maternal mice at all dosages. Fetotoxicity was noted among litters of mice given 25 mg/kg of chlorpyrifos as evidenced by decreased fetal body measurements and an increased incidence of minor skeletal variants. An increase in the incidence of exencephaly was observed among litters of mice at the lowest dosage, 1 mg/kg/day, but not at 10 or 25 mg/kg. Additional groups of mice were given 0, 0.1, 1, or 10 mg chlorpyrifos/kg/day on Days 6 through 15 of gestation. Plasma and erythrocyte cholinesterase levels were significantly decreased among maternal mice at 1 and 10 mg/kg but not at the lowest dosage, 0.1 mg/kg. No evidence of a teratogenic response was observed in these mice. Thus, since exencephaly was not repeatable and was not found at 10- and 25-fold higher dose levels in the original study, chlorpyrifos was not teratogenic in mice at dose levels up to 25 mg/kg/day.

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.

The effects of maternally inhaled vinyl chloride on embryonal and fetal development in mice, rats, and rabbits.

Abstract These studies evaluated the effects of inhaled vinyl chloride on mouse, rat, and rabbit embryonal and fetal development. Groups of pregnant CF-1 mice, Sprague-Dawley rats and New Zealand white rabbits were exposed to 500 ppm of vinyl chloride 7 hr daily during the period of major organogenesis. Subsequently, other groups of mice were similarly exposed to 50 ppm of vinyl chloride and rats and rabbits were exposed to 2500 ppm of vinyl chloride. While maternal toxicity was observed, vinyl chloride alone did not cause significant embryonal or fetal toxicity and was not teratogenic in any of the species at the concentrations tested. Maternal toxicity was more prominent among mice than among rats and rabbits. Simultaneous exposure of some of the pregnant animals to vinyl chloride by inhalation plus 15% ethanol in the drinking water resulted in toxic effects greater than those associated with exposure to vinyl chloride alone in the three species. The maternal toxicity was enhanced to an extent greater than the embryotoxicity.

Inhalation toxicity of epichlorohydrin: Effects on fertility in rats and rabbits

The effects of inhaled epichlorohydrin (ECH) on the fertility of Sprague-Dawley rats and New Zealand white rabbits were studied. Groups of 10 male rabbits, 30 male rats, and 30 female rats were exposed to 0, 5, 25, or 50 ppm of ECH vapor for 6 hr/day, 5 days/week for 10 weeks, and were held for a 10-week postexposure females. Exposed male rats were mated with unexposed females at several intervals during and after the exposure period. In addition, female rats which had been exposed for the 10-week period were mated with unexposed males and allowed to deliver their young. Exposure to 50 ppm of ECH vapor for 10 weeks resulted in transient infertility in the male Sprague-Dawley rats; recovery of fertility in rats occurred during the second week after termination of exposure. Male rats exposed to 25 ppm of ECH were able to impregnate unexposed females; however, fewer implantations were observed in these females than in the females mated to control males suggesting that fertility was adversely affected in this group as well. This effect also was reversed by the second week following termination of exposure. The incidence of resorptions in the unexposed female rats which were bred to the exposed males was not adversely affected. Among female rats exposed to ECH, no adverse effects were observed on estrus cycle, pregnancy rate, parturition, or the number and viability of the offspring. No discernible effects were noted on the volume of the ejaculate or on the motility, viability, concentration, or fertility of spermatozoa from male rabbits exposed to up to 50 ppm of ECH. Histologic examination of tissues from an interim and final termination of the exposed animals indicated that the most severely affected organ following inhalation exposure to 25 or 50 ppm of epichlorohydrin in both rats and rabbits was the nasal turbinates. These lesions, interpreted to be a result of irritation from the test material, were no longer present in animals which were held for the 10-week postexposure period. No adverse effects were observed among rats or rabbits exposed to 5 ppm of ECH for 10 weeks.

Embryo- and fetotoxicity of inhaled methyl ethyl ketone in rats☆

Abstract Pregnant Sprague-Dawley rats inhaled 0, 400, 1000, or 3000 ppm methyl ethyl ketone (MEK) for 7 hr/day on Days 6 through 15 of gestation. Maternal toxicity, as evidenced by decreased weight gain and increased water consumption, was observed among rats exposed to 3000 ppm MEK. Slight fetotoxicity was observed among litters of rats exposed to 3000 ppm MEK as evidenced by an increased incidence of two minor skeletal variants. The results of this study duplicate the increased incidence of skeletal variants observed in an earlier study by B. A. Schwetz, B. K. J. Leong, and P. J. Gehring (1974, Toxicol. Appl. Pharmacol. 28, 452–464), and do not indicate that inhaled MEK causes either an embryotoxic or teratogenic response in rats 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.

Teratogenic Effects of Vitamin a Palmitate in Fischer 344 Rats

Prior to employing the Fischer 344 rat in teratology studies, it was considered necessary to establish the responsiveness of this strain to teratogenic agents. Bred Fischer 344 rats were administered 0, 3.2, 32, or 128 mg/kg/day (approximately 1,000, 10,000, or 40,000 USP units per animal) of vitamin A palmitate by gavage on days 6 through 15 of gestation. Maternal toxicity, as evidenced by decreased body weight gain, and decreased food and water consumption, was observed at the 128 mg/kg/day dose level. This dosage level was embryolethal and teratogenic in the Fischer 344 rat. The incidence of fetal resorptions was statistically significantly increased as compared to controls. Among the surviving fetuses, malformations observed included cleft palate, exencephaly, microphthalmia, anophthalmia, hydronephrosis, brachygnathia, pinna anomalies, and great vessel and heart anomalies. Based on these findings, it is concluded that the Fischer 344 rat responded to a known teratogenic agent and hence is appropriate for use in studies designed to evaluate the teratogenic potential of test agents.

Teratological evaluation of inhaled ethyl acrylate in rats

Abstract Pregnant Sprague-Dawley rats (33 per group) were exposed to 0, 50, or 150 ppm of ethyl acrylate for 6 hr/day during Days 6 through 15 of gestation (the period of major organogenesis). Maternal toxicity as evidenced by decreased body weight gain, decreased food consumption, and increased water consumption was noted among rats exposed to 150 ppm of ethyl acrylate. In the presence of maternal toxicity at 150 ppm, a slight but not statistically significant increase in malformed fetuses was observed. At 50 ppm, there was neither maternal toxicity nor an adverse effect on the developing embryo or fetus in rats. Based on these data, inhalation of the ethyl acrylate vapors by rats at a concentration of 50 or 150 ppm during major organogenesis was not considered to be teratogenic.

Teratologic evaluation of 3,6-dichloropicolinic acid in rats and rabbits

3,6-Dichloropicolinic acid (clopyralid), a new herbicide, was evaluated for teratogenic potential in Fischer 344 rats and New Zealand White rabbits. Rats were given 0, 15, 75, or 250 mg clopyralid/kg/day by gavage on Days 6-15 of gestation while rabbits were given 0, 110, or 250 mg clopyralid/kg/day on Days 6-18 of gestation. Maternal toxicity, as evidenced by decreased body weight gain, was observed among pregnant rats in the 250-mg/kg/day group. No evidence of maternal toxicity was observed among treated rabbits. A teratogenic effect was not detected in either species.