Oral repeat dose and reproductive toxicity of the chlorinated flame retardant Dechlorane Plus.

This study consisted of a 28-day oral repeat dose (repeat dose toxicity [RDT]) phase and a developmental and reproductive (developmental and reproductive toxicity [DART]) phase with rats. Rats were treated with Dechlorane Plus at doses of 0, 750, 1500, or 5000 mg/kg by gavage. For the RDT phase, no effects were observed on in-life parameters or clinical or anatomic pathology. In the DART phase, no effects were observed on reproductive or fertility indices, or fetal development through lactation day (LD) 4. No effects were noted on gestation day (GD) 20 implantation data, fetal indices, or external and visceral examinations. Mortalities occurred across all dose groups, although these were gavage-related errors and not compound related. Microscopic evidence of gavage-related errors included adhesions, inflammation, and fibrosis in the thoracic and pleural cavities. These findings were not test article related as they were observed only in animals with evidence of gavage injury. The no-observable-effect level (NOEL) in both phases of study was 5000 mg/kg.

Developmental toxicity associated with receptor tyrosine kinase Ret inhibition in reproductive toxicity testing.

BACKGROUND: Urogenital abnormalities are among the most common of all human birth defects. In developmental toxicity studies with the Syk kinase inhibitor R788, a spectrum of findings, including renal agenesis, were observed. R788 has also been found to inhibit the receptor tyrosine kinase Ret. Ret kinase is known to be an essential component in the signaling pathway required for renal organogenesis and ureteric duct formation. Previously known is that mutant mice without the c-ret gene, develop urogenital malformations including renal agenesis. METHODS: In GLP developmental toxicity studies, gravid rabbits were treated orally with R788 at doses of 0, 10, 22, and 50 mg/kg/day (gestation days 7-19) and gravid rats received 0, 5, 12.5, and 25 mg/kg/day (gestation days 6-17) by the same route. The activity of R406 against Ret kinase was assessed in biochemical and cell-based assays. RESULTS: A dose-dependent increase in malformations, including renal and ureteric agenesis and a specific major vessel anomaly, retroesophageal right subclavian artery, was observed in both the rat and rabbit. R788 proved to be a potent inhibitor of Ret kinase. CONCLUSIONS: R788 promoted a spectrum of developmental toxicity, including renal and ureteric agenesis and a specific major vessel abnormality, retroesophageal right subclavian artery, in two different species. These effects are likely the result of inhibition of Ret kinase given its importance in the normal ontogeny of the urogenital and cardiovascular systems across species.

Developmental toxicity study with 3-(methylthio)propionaldehyde vapor by whole-body exposure of Sprague-Dawley rats.

Time-mated Sprague-Dawley rats were exposed whole body to analytically measured 3-(methylthio) propionaldehyde (3-MTP) vapor concentrations of 0 (air controls), 9.87, 58.3 and 127.8 ppm over gestational days (gd) 6-15 for 6 h day(-1). There was an exposure concentration-related maternal toxicity (clinical signs, body weight change and food consumption) that was marginal at 9.87 ppm. No effects on gestational parameters, fetal numbers and sex ratio or fetal body weights were noted. There was no increase in the incidence of either malformations or variations (total, external, visceral or skeletal). Thus, the no-observed-adverse-effect level (NOAEL) for development toxicity for exposure to 3-MTP vapor was 127.8 ppm.

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.