Prenatal developmental toxicity of decabromodiphenyl ethane in the rat and rabbit.

BACKGROUND: The potential embryotoxic and teratogenic effects of decabromodiphenyl ethane (DBDPEthane; CASRN 84852-53-9) were evaluated in prenatal developmental studies using rats and rabbits and performed in accordance with international guidelines and Good Laboratory Practice standards. Preliminary dose-range-finding studies were conducted, which indicated doses up to 1,250 mg/kg-day were well tolerated by both rats and rabbits. METHODS: For the developmental studies, animals were administered DBDPEthane via gavage at dosage levels of 0, 125, 400, or 1,250 mg/kg-day from gestation day (GD) 6 through 15 for rats and GDs 6 through 18 for rabbits. All female rats and rabbits were sacrificed on GD 20 or GD 29, respectively, and subjected to cesarean section. Fetuses were individually weighed, sexed, and examined for external, visceral and skeletal abnormalities. RESULTS: No treatment-related mortality, abortions, or clinical signs of toxicity were observed during the study. Body weights, body weight gain, and food consumption were not affected by treatment. No significant internal abnormalities were observed in either species on necropsy. Cesarean section parameters were comparable between control and treated groups. No treatment-induced malformations or developmental variations occurred. CONCLUSIONS: Based on these results, no evidence of maternal toxicity, developmental toxicity, or teratogenicity was observed in rats or rabbits treated with DBDPEthane at dosage levels up to 1,250 mg/kg-day.

Developmental toxicity studies of methyl ethyl ketoxime (MEKO) in rats and rabbits.

The developmental toxicity of methyl ethyl ketoxime (MEKO), an industrial antioxidant used primarily as an antiskinning agent in alkyd paint, was investigated in rats and rabbits. Following preliminary dose range finding studies, groups of 25 pregnant rats or 18 pregnant rabbits were dosed by gavage with aqueous solutions of MEKO at 0, 60, 200, or 600 mg/kg (rats) or 0, 8, 14, 24, or 40 mg/kg (rabbits) on gestation days 6-15 or 6-18, respectively. In rats, dose-dependent clinical signs of maternal toxicity including reduced body weight gains were noted at 200 and 600 mg/kg. At 60 mg/kg and above enlarged spleens were observed at necropsy. The preliminary study found methemoglobin formation and reticulocytosis indicative of anemia at these dose levels. No treatment-related gestational effects, malformations or developmental variations were observed in the rats. In rabbits, 3 females aborted and 8 females were found dead at 40 mg/kg between gestation days 11 and 24. Clinical signs of maternal toxicity were present in surviving doses at this dose level. Body weight gains were reduced at 24 and 40 mg/kg. The preliminary study indicated maternal hematological effects in the rabbits similar to the rats at dose levels as low as 10 mg/kg. MEKO was not considered to have produced any treatment-related gestational effects, malformations or developmental variations in the rabbit at dose levels at or below 24 mg/kg. Because of excessive maternal mortality and abortions at the 40 mg/kg dose level, only 6 rabbits produced litters. The severe maternal toxicity and limited number of litters precluded a full assessment of developmental toxicity at 40 mg/kg. Nonetheless, MEKO did not appear to be teratogenic to the rabbit at this dose level.

Embryo-fetal developmental and reproductive toxicology of vinyl chloride in rats.

Vinyl chloride (VC) exposure is primarily via inhalation in the workplace. The primary target organ of VC toxicity is the liver and occupational exposure to VC leads to hepatic angiosarcoma. However, based on epidemiological studies, researchers have been unable to ascertain the effect of occupational VC exposure on embryo-fetal development or reproductive function. A limited number of animal studies available in the literature have examined the effect of VC on embryo-fetal development, however, there are no published studies on the effect of VC exposure on reproductive capability. The current study was designed to assess the potential maternal and/or embryo-fetal developmental and 2-generation reproductive toxicity of inhaled VC in CD(R) Sprague-Dawley rats at exposure levels of 0, 10, 100, and 1100 ppm. In the embryo-fetal/developmental toxicity study, the female rats were exposed to VC daily from gestation day (GD) 6 through 19. In the reproductive toxicity study, the F(0) generation male and female rats were exposed to VC for a 10-week premating and 3-week mating periods. The F(0) generation male rats were exposed to VC until terminal euthanasia. The F(0) generation female rats were exposed from GD 0 through GD 20 and lactation day (LD) 4 through LD 25. Our results indicate that up to 1100 ppm VC exposure did not adversely affect embryo-fetal developmental or reproductive capability over 2 generations in rats. The primary target organ of VC, the liver, was affected as evidenced by an increase in liver weight and/or histologically identified cellular alterations, such as centrilobular hypertrophy at 100 and 1000 ppm. Based on the results of these studies, the no observed adverse effect level (NOAEL) for embryo-fetal/development is 1100 ppm, and the NOAEL for reproduction is 1100 ppm. The results from the current studies, which are a more comprehensive embryo-fetal/developmental and reproduction study, may be incorporated into future risk assessments of occupational exposure to VC where concerns regarding the effects of VC exposure remain.