The potential toxicity of bromoacetonitrile was evaluated using a short-term reproductive and developmental toxicity screen. This study design was selected to identify the process (development; female reproduction; male reproduction; various somatic organs/processes) that is the most sensitive to bromoacetonitrile exposure.
The dose-range finding study initially used concentrations of 625-5000 ppm. This study was suspended after five days due to significant reductions in body weight, and feed and water consumption. The second dose-range finding study was conducted at concentrations of 0, 30, 100, 200, and 500 ppm of BAN in the drinking water for two weeks. The 500 ppm animals were euthanized after 8 days as a result of sharp decreases in body weight, and feed and water consumption. Based on dose-related decreases in mean body weight and water consumption, concentrations of 0, 5, 30, and 100 ppm were selected for the main study, which utilized one group of male rats (10 per dose level) and two groups of female rats designated as Group A (peri-conception exposure, 10 per dose level) and Group B (gestational exposure, 13 per dose level). Control animals received deionized water, the vehicle.
During the treatment period, all animals survived to the scheduled necropsy and there were no clinical signs of general toxicity noted at any dose level. The male body weights were comparable across dose groups, while both the 30 and 100 ppm Group A and B females body weights showed a slight (p greater than 0.05), but consistent decrease of 7-8% and 2-7% by SD 33 and GD 20, respectively, as compared to the controls. The 5 ppm Group A females body weight also showed a decrease (p greater than 0.05) of 5% by SD 33. Feed consumption in all treated groups was generally decreased by less than or equal to 23%. Over the course of the study and during treatment, water consumption was decreased in the 100 ppm animals by 30-52%, as compared to the controls. Although not always significant, water consumption was reduced in the 30 ppm animals by 12-34% and in the 5 ppm Group A females by 9-18%, as compared to the controls. The overall average calculated consumption of BAN for the 5, 30, and 100 ppm groups was 0.5, 2.4, and 6.0 mg/kg/day, respectively.
There were no statistically significant changes in female reproductive parameters; however, there were several indications that female reproductive effects may have resulted from BAN. There was a small but consistent increase in post-implantation loss in both the Group A and B females: 38% and 33% increase in the 30 and 100 ppm Group A females, respectively, and 31%, 30%, and 57% increase in the 5, 30, and 100 ppm Group B females, respectively. In addition, the 100 ppm Group A females had an increase in pre-implantation loss of 147% and the 100 ppm Group B females had an increase in resorptions of 70%. These increases in pre- and post implantation losses and resorptions were largely the result of one or two dams in each group, although these females could not statistically be considered outliers.
The blood urea nitrogen level of the 100 ppm males was increased by 19%, a small but biologically significant indicator of mild renal damage. However, this may be attributable to decreased fluid consumption, and therefore, the effects cannot be separated from dehydration.
Male and female clinical observations, gross findings, organ weights, organ-to-body-weight ratios, and hematology endpoints were comparable across dose groups.
Results of this study indicate that there was significant aversion to BAN in the water and suggest that BAN may be a possible mild renal toxicant at 100 ppm (approximately 7 mg/kg/d), as evidenced by an increase in BUN; and a potential reproductive toxicant at 100 ppm, as evidenced by increased (p greater than 0.05) post-implantation loss.