Oral (Drinking Water) Developmental Toxicity Studies of Bromodichloromethane (BDCM) in Rats and Rabbits

Abstract

Crl:CD(SD)IGS BR VAF/Plus (Crl SD) rats and Hra(NZW) SPF rabbits were tested for potential developmental toxicity from bromodichloromethane (BDCM) provided continuously in the drinking water during gestation (gestation days [GDs] 6 to 21 in rats and GDs 6 to 29 in rabbits). Concentrations of 0, 50, 150, 450, or 900 ppm of BDCM were used for rats; 0, 15, 150, 450, or 900 ppm were used for rabbits (in dose range-finding studies, 1350 ppm was excessively maternotoxic to both species). Investigated maternal parameters included viability, clinical signs, water and feed consumption, and body weights. Maternal gross lesions, gravid uterine weights, abnormal placentas, and numbers of corpora lutea, implantation sites, live and dead fetuses, and early and late resorptions were observed at time of Caesarean sectioning (GD 21 in rats; GD 29 in rabbits). Body weights, sex ratios, and morphological abnormalities (external, soft tissue, and skeletal) were noted in the fetuses. Mean consumed doses of BDCM were calculated to be 0, 2.2, 18.4, 45.0, or 82.0 mg/kg/day for the rats, and 0, 1.4, 13.4, 35.6, or 55.3 mg/kg/day for the rabbits (approximate human intake is 0.8 microg/kg/day [0.0008 mg/kg/day] in adults). In pregnant rats, toxicologically important, statistically significant effects included reduced absolute (g/day) and relative (g/kg/day) water consumption values at > or =50 ppm (2.2 mg/kg/day) and reduced body weight gains (also when corrected for gravid uterine weight) and absolute (g/day) and relative (g/kg/day) feed consumption values at >450 ppm (45.0 mg/kg/day). These parameters were also significantly reduced at > or =450 ppm (35.6 mg/kg/day) in pregnant rabbits (significant weight loss occurred in the rabbits at 900 ppm, i.e., 55.3 mg/kg/day). Thus, the maternal no-observable-adverse-effect level (NOAEL) for BDCM was 150 ppm, i.e., 18.4 and 13.4 mg/kg/day in rats and rabbits, respectively. No adverse effects on embryofetal viability, growth, sex ratio, gross external, soft tissue, or skeletal morphology occurred at 900 ppm in rats or rabbits. Minimal delays in the ossification of forepaw phalanges and hindpaw metatarsals and phalanges occurred in rat fetuses at 900 ppm; delays were considered marginal, reversible, and associated with severely reduced maternal weight gain. Therefore, the developmental NOAEL for rats was 450 ppm (45.0 mg/kg/day), whereas in rabbits it was 900 ppm (55.3 mg/kg/day). These NOAELs are 56,250 and 69,120 times the human adult exposure level of 0.0008 mg/kg/day, respectively. Based on the results of these studies, BDCM should not be identified as a risk to development of human conceptuses.

Disinfection By-Product Exposures and the Risk of Specific Cardiac Birth Defects

“…Stronger associations (aOR = 1.62; 95% CI: 1.04, 2.51) have also been reported for CVDs and THM4 ≥ 130 versus < 60 μg/L in an Australian population using heavily brominated water ( Chisholm et al 2008 ). Studies with rats exposed to brominated THMs were negative for CVDs ( Christian et al 2001 ; Ruddick et al 1983 ); however, one study examining monobromoacetic acid (MBAA) exposure reported increased incidence of CVDs ( Randall et al 1991 ). Another study in rats reported CVDs [e.g., ventricular septal defect (VSD), levocardia, right-sided aortic arch, and ductus arteriosus] following exposure to bromochloroacetonitrile ( Christ et al 1995 ).…”

Drinking water treatment is not associated with an observed increase in neural tube defects in mice

“…Rats exposed to 0, 50, 150, 450, or 900 mg/kg and rabbits exposed to 0, 15, 150, 450, or 900 mg/kg of BDCM did not significantly exhibit any embryotoxic effects (Christian et al 2001). Rats treated with BDCM on gestational days 6–10 at 75 mg kg −1 day −1 exhibited full litter resorption; however, exposure on gestational days and 11–15 at 75 or 100 mg kg −1 day −1 had no effect (Bielmeier et al 2001).…”