The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings may not have been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. For more information, see the Explanation of Levels of Evidence for Developmental Toxicity. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.
1,1,1-Trichloroethane (TCEN), a saturated lipophilic trichlorinated hydrocarbon was evaluated for postnatal effects in COBS CD® (SD)BR outbred albino rats. This study was designed to assess the repeatability of a report (Dapson et al., 1984) that 10 ppm TCEN in drinking water caused cardiac malformations in rats. TCEN was administered in the drinking water at nominal concentrations of 3, 10 and 30 ppm, using 0.05% Tween 80® as an emulsifying agent. Two control groups, one receiving deionized/filtered water and the other receiving a vehicle control solution containing 0.05% Tween 80® and 0.9 ppm 1,4-dioxane, a stabilizing agent found in the bulk chemical, were also included. Male and female breeders were exposed to the control solutions or test compound for 14 consecutive days prior to cohabitation and for up to 13 days during the cohabitation phase. Sperm-positive females continued to be exposed to the formulations throughout gestation, and females delivering live litters received treatment to the end of lactation on postnatal day (pnd) 21. The following results were obtained:
- A minimal dose-related decrease in water consumption and slight dose-related increase in weight gain for males during the premating period.
- A minimal dose-related decrease in water consumption for females during the premating period.
- Average TCEN consumption based on time-weighted averages of TCEN concentration in the formulations during the premating period was 267, 792, or 2388 mg/kg/day for males, and 313, 994, or 2956 mg/kg/day for females in the 3, 10, or 30 ppm dose groups .
- No effect of treatment on any measure of maternal weight gain, food, or water consumption during the gestational period. Average maternal TCEN consumption from gestational day (gd) 0 to parturition was 348, 1162, or 3504 mg/kg/day for the 3, 10, or 30 ppm dose groups, respectively.
- No effect on fertility or length of gestation.
- At 30 ppm TCEN, a small but significant decrease in maternal weight gain during the postnatal period, that was not accompanied by any significant perturbation of maternal food or water intake. Average maternal consumption of TCEN from pnd 1-21 was 605, 1987, or 5922 mg/kg/day for the 3,10, or 30 ppm groups, respectively.
- No effect of treatment on pup body weight or survival from pnd 1 to pnd 21, or sex ratio of live litters. At 30 ppm, a slight but significant increase in mortality from conception to pnd 1 was observed. An increase in mortality from conception to pnd 4 was also noted in the 30 ppm group but was not significantly different from the vehicle control.
- No evidence of a dose-related increase in cardiac or other malformations in pups culled on pnd 4, or those examined at scheduled sacrifice on pnd 21.
- TCEN-containing drinking water solutions were difficult to formulate and were unstable. These problems seriously limited attempts to estimate the true level of exposure of the animals to the test chemical. Thus, it was necessary to calculate TCEN consumption based on time-weighted averages of TCEN concentration in the formulations.
- A pharmacokinetic model predicted that blood concentrations of TCEN would be less than 5 ng/ml. Using an analytical method with a 5 ng/ml limit of detection, we were unable to detect TCEN in the majority of samples from adult male and female rats, and pups on pnd 21.
Continuous exposure to TCEN in the drinking water at nominal concentrations up. to 30 ppm caused only minimal toxicity in the parental generation and the 21 day old pups. Based on the time-weighted average concentrations of TCEN in the formulations, the average exposure levels over the entire study were 2.7, 8.5, or 27.1 ppm TCEN for the 3, 10, or 30 ppm groups, respectively. Although a documented exposure level higher than that reported by Dapson et al. (1984) was used in the present study, no abnormalities of the ductus arteriosus or atrium were observed.