Short-Term Reproductive and Developmental Toxicity Study of Dibromochloroacetic Acid (CAS No. 5278-95-5) Administered to Sprague Dawley Rats in the Drinking Water
Report Date: Jan. 14, 2000
The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings were not evaluated in accordance with the levels of evidence for reproductive or developmental toxicity criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.
The potential toxicity of Dibromochloroacetic acid was evaluated using a short-term reproductive and developmental toxicity screen. This study design was selected to identify the physiologic process (development; female reproduction; male reproduction; various somatic organs/processes) that is the most sensitive to DBCA exposure.
The first range-finding study was conducted at concentrations of 0, 30, 100, 300, and 500 ppm of DBCA in the drinking water for two weeks, with no significant test-article related effects observed at any dose level including 500 ppm. Following two weeks of a wash-out period, the second range-finding study was conducted at concentrations of 0, 750, 1000, and 1500 ppm of DBCA in the drinking water for two weeks. Based on decreases in water consumption, dose levels of 0, 500, 1000, and 1500 ppm (Groups 1, 2, 3, and 4, respectively) were selected for the main study. The main study utilized two groups of male rats designated as A males (Main study, non-BrdU treated, 10 per group in Groups 1-4) and B males (Main study, BrdU treated, 5 animals in Groups 1, 2, and 3, and 8 animals in Group 4), and three groups of female rats designated as A females (peri-conception exposure, 10 per group in Groups 1-4), Group B (gestational exposure, 13 per group in Groups 1-4), and Group C (peri-conception exposure, BrdU-treated, 5 animals in Groups 1, 2, and 3, and 8 animals in Group 4). Control animals received deionized water, the vehicle.
During the treatment period, all animals survived to the scheduled necropsy. Body weights were 10-14% less than controls in the 1500 ppm A and C females. Water consumption was decreased at several of the intervals for the 1000 and 1500 ppm dose groups. Water consumption was decreased by 12-49% at 1000 and 1500 ppm in both males and females throughout the course of the study. The overall calculated mean consumption of DBCA for Groups 2, 3, and 4 was 51, 89, and 112 mg/kg body weight/day, respectively.
There were no treatment-related findings noted in male clinical pathology parameters, female reproductive parameters, gross visceral observations, or male reproductive parameters except for a decrease of 11% in sperm velocity and ALH max in the 1500 ppm A males.
Necropsy organ weights and organ-to-body weight ratios were evaluated in A and B males, and the ratios were comparable to the controls in both A and B males. Gross findings and histopathologic findings were comparable across all groups in both males and females. The BrdU Labeling Index for the liver of the B males, and liver and kidney of C females, was significantly increased at 1500 ppm dose level. Although not statistically significant, LI was increased in the kidney of C females at 500 and 1000 ppm dose levels. The LI for the 500, and 1000 ppm groups was generally increased with a corresponding increase in water consumption, however, the LI for the 1500 ppm group was increased as compared to the controls with similar or decreased water consumption. The nature of the response suggests a mitogenic mode of action for DBCA, although, histopathologic evaluation did not identify any changes which would result from the cell proliferative effects observed in the liver and kidney of B males and C females.
Results of this study indicate that DBCA at doses at and above 1000 ppm produced consistent decreases in food and water consumption in both sexes, but did not result in any female reproductive toxicity or any visceral malformation or variations in any pups. In the male reproductive data, a decrease of 11% in the male sperm velocity samples and in the male ALH max were observed in the 1500 ppm A male; no changes in fertility were noted. From these data, DBCA is: taste-aversive, a possible mitogen and a general toxicant in both male and female rats Æ 1500 ppm, and a male reproductive toxicant at 1500 ppm.