Developmental toxicity of 1,2-dichloropropane (PDC) in rats and rabbits following oral gavage.

1,2-Dichloropropane (PDC) was evaluated for its potential to cause embryonal/fetal toxicity and teratogenicity in pregnant rats and rabbits. PDC was administered via oral gavage at dose levels of 0, 10, 30, or 125 mg/kg/day on Days 6 through 15 of gestation (rats) or 0, 15, 50, or 150 mg/kg/day on gestation Days 7 through 19 (rabbits). Fetuses were examined on Gestation Day 20 (rats) or Day 28 (rabbits). Maternal toxicity was observed in both rats and rabbits at the high dose levels. Rats given 125 mg/kg/day of PDC showed clinical signs of toxicity and decreased body weight and body weight gain. Rabbits given 150 mg/kg/day PDC showed changes in hematologic parameters and decreased body weight gain. Although maternal toxicity was apparent, no indication of teratogenicity was observed in rat or rabbit fetuses at any dose level. Significant increases in the incidence of delayed ossification of skull bones, considered secondary to decreased maternal body weight gain, were observed in rats given 125 mg/kg/day and in rabbits given 150 mg/kg/day. No maternal or developmental effects were observed in rats given 10 or 30 mg/kg/day or in rabbits given 15 or 50 mg/kg/day of PDC. Based on the results of these studies the maternal and developmental NOELs in rats and rabbits were 30 and 50 mg/kg/day, respectively.

Neurological consequences of congenital hypothyroidism in Fischer 344 rats.

Congenital hypothyroidism was induced in rat pups by treating pregnant and lactating dams with an antithyroid drug, methimazole. Methimazole (0.00, 0.01, 0.03 or 0.10 mg/ml) was added to the drinking water of female Fischer 344 rats from gestational day 17 through lactational day 10. The same animals as pups and adults were evaluated with a developmental neurotoxicological test battery. Pups were evaluated for physical measures of maturation, thermoregulation, flash evoked potential (FEP), motor activity, and morphology of brain, thyroid and kidneys. Parameters evaluated in the same animals as adults were body weight, functional observational battery, grip strength, body temperature, and neurological tests (FEP, auditory brainstem response to 4 and 16 kHz tone pips (ABR4, ABR16) and clicks (ABRc), somatosensory evokes potentials recorded from the somatosensory cortex (SEP-S) and the cerebellum (SEP-C), and caudal nerve action potential to single and paired stimuli (CNAP). Treatment-related findings in pups included slightly decreased body weight, slightly increased kidney weights, altered thyroid morphology, delayed incisor eruption, decreased thermoregulation, and FEP changes. Although a pup no effect level was not determined, effects at 0.01 mg/ml were minimal. Adult ABR4 and ABR16 waveforms were slower than controls and had altered shapes; ABRc, SEP-S, and SEP-C waveforms exhibited reduced power, increased latency and altered shape. Effects were detected in adults at all doses and thus, the neurological characteristics of rat congenital hypothyroidism were clearly detected with this developmental neurotoxicological test battery. The effects on body weight, kidney weight and thyroid morphology, however, suggest a general developmental effect and nervous system function did not appear to be preferentially affected.

Teratogenic evaluation of a polybromodiphenyl oxide mixture in New Zealand white rabbits following oral exposure.

Polybromodiphenyl oxide (PBDPO), a potential flame retardant additive in thermoplastics and thermosets, was tested for its embryo/fetal toxicity and teratogenicity in pregnant rabbits. PBDPO was orally administered to groups of 26 New Zealand White rabbits at dose levels of 0 (corn oil, vehicle control), 2, 5, or 15 mg/kg/day in a dose volume of 1 ml/kg body weight on Days 7 through 19 of gestation. The offspring were then examined on Day 28 of gestation. No evidence of teratogenicity was observed at any dose level tested. Pregnant rabbits in the 15 mg/kg/day dose group showed evidence of maternal toxicity as exhibited by significant increases in absolute and relative liver weights and decreased body weight gain during gestation Days 7 through 20 and Days 7 through 28. Slight fetal toxicity accompanied the maternal toxicity at the high dose level, as demonstrated by an increase in the incidence of delayed ossification of the sternebrae.

1,3-dichloropropene: two-generation inhalation reproduction study in Fischer 344 rats.

This study evaluated the effects of inhaled technical-grade 1,3-dichloropropene (DCPT) on reproduction and neonatal growth and survival. Groups of 30 male and 30 female Fischer 344 rats, approximately 6 weeks of age, were exposed via inhalation to 0, 10, 30 or 90 ppm DCPT for 6 hr/day, 5 days/week, for two generations. The parental f0 and f1 generations were each bred twice. Reproductive and neonatal parameters evaluated included indices of fertility and pup survival, gestation length, litter size, pup body weight, and pup sex ratio. Gross and histologic examinations were concluded on all f0 and f1 adults. In addition, randomly selected f1b and f2b weanlings were given gross examinations. Parental effects were limited to rats exposed to 90 ppm DCPT and included decreased body weights and histopathologic effects on the nasal mucosa of adult male and female rats. The histopathologic effects consisted of slight, focal hyperplasia of the respiratory epithelium and/or focal degenerative changes in the olfactory epithelium. No adverse effects on reproductive parameters or neonatal growth or survival were observed in the f1a, f1b, f2a, or f2b litters even at an exposure concentration which produced effects in adult animals. Based on these results, it is concluded that inhalation exposure of rats up to 90 ppm DCPT for two successive generations did not adversely affect the reproductive and neonatal parameters evaluated.

Quantitative measurement of water consumption patterns in lactating female and neonatal Fischer 344 rats employing [14C]methylcellulose.

Lactating female and neonatal Fischer 344 rats were given water containing [14C]methylcellulose, a nonabsorbed marker, over a 24-hr interval on Days 13, 15, 18, 21, 24, and 27 postpartum. The amount of water consumed was calculated based on the 14C activity recovered in the feces and gastrointestinal tract. Maternal water consumption during the first 28 days postpartum, when expressed as g/kg/day, averaged 2.5 times the level consumed by nonlactating female rats. Maternal water consumption peaked on Day 21 postpartum at 3.3 times the level measured in nonlactating female rats of comparable age. Neonatal water consumption began on Day 18 postpartum and by Day 28 postpartum was 1.9 times the level observed in nonlactating females. Average neonatal water consumption between Days 21 and 28 postpartum was 1.3 times the level for nonlactating female rats. These data indicate that when the test material is administered via the drinking water the dose levels received by the maternal and neonatal rats have been routinely underestimated, and that conclusions concerning the dose-response relationship or increased sensitivity during this period must be tempered by these results.

Teratogenic evaluation of diglycidyl ether of bisphenol A (DGEBPA) in New Zealand white rabbits following dermal exposure.

Diglycidyl ether of bisphenol A (DGEBPA) was tested for its potential to cause embryo/fetal toxicity and teratogenicity in pregnant rabbits. DGEBPA was applied daily to the clipped skin of New Zealand White rabbits for approximately 6 hr/day at dose levels of 0 (polyethylene glycol 400, vehicle control), 30, 100, or 300 mg/kg body weight/day on Days 6 through 18 of gestation. Fetuses were examined for external, visceral, and skeletal alterations on Day 28 of gestation. Maternal toxicity was observed among pregnant rabbits in the 300 mg/kg/day dose group as evidenced by moderate to severe erythema, fissures, hemorrhage, and slight edema at the exposure site. Similar, but less severe skin lesions were observed in pregnant rabbits in the 100 mg/kg/day exposure group. A slight erythema at the site of application was observed in dams in the 30 mg/kg/day dose group. The erythema in rabbits from the low dose group was indistinguishable from the erythema caused by the occlusive bandages/jackets used to hold the test material in place and, thus, was not considered toxicologically significant. No evidence of embryo/fetal toxicity or teratogenicity was observed at any dose level. Thus, the embryo/fetal no-observed-effect level for dermally applied DGEBPA was 300 mg/kg body weight/day, the maximum tolerated dose.

Effect of inhaled propylene oxide on reproductive parameters in Fischer 344 rats.

Reproductive parameters in Fischer 344 rats were evaluated following inhalation of propylene oxide (PO) for two successive generations. Thirty male and 30 female rats were exposed to 0, 30, 100, or 300 ppm PO for 6 hr/day, 5 days/week for 14 weeks and then mated to produce the f1 litters. After weaning, 30 randomly selected f1 pups/sex/group were exposed to PO for 17 weeks and subsequently mated to produce the f2 litters. Reproductive parameters examined included fertility, litter size and neonatal growth, and survival. All adults and selected weanlings were examined for gross and histologic lesions. Toxicity due to PO was demonstrated by decreased body weights of parental f0 and f1 rats at 300 ppm. No treatment-related effects on fertility (mating or conception) were observed in either f0 or f1 matings. Neonatal survival indices for f1 or f2 litters revealed no treatment-related effects. Litter size was decreased in the f1 rats exposed to 100 ppm PO. However, the litter size in the 300 ppm group was comparable to the control group, and no effect on litter size was shown in PO-exposed f2 litters. Pup weights were unaffected by parental exposure to PO in either generation. Pathologic examination of adults and weanlings revealed no changes considered due to PO. Based on these results, it is concluded that inhalation exposure to PO at levels up to 300 ppm over two generations did not produce any adverse effects on reproductive function.