rats. The lowest-observed-adverse-effect level (LOAEL) of GD was 0.0175 mg/kg per day in a subchronic toxicity study (Bucci et al. 1992). In that study, male and female rats were administered GD by gavage 5 days a week for 13 weeks. Because of the discontinuous exposure regimen, ORNL adjusted the LOAEL (LOAELadj) for continuous exposures by multiplying 0.0175 mg/kg per day by a factor of 5/7 (i.e., 5 days/7 days) to yield a LOAELadj of 0.0125 mg/kg per day. The RfD for GD was calculated to be 4 × 10-6 mg/kg per day by dividing the LOAELadj by 2,700, the product of the uncertainty factors and the modifying factor selected by ORNL.

APPROPRIATENESS OF THE CRITICAL STUDY

The critical study used by ORNL for deriving the RfD for GD was a subchronic toxicity study (Bucci et al. 1992) in which Caesarian-derived Sprague-Dawley rats (12 males and 12 females per group) were administered GD by gavage at doses of 0.0175, 0.035, and 0.07 mg/kg per day for 5 days a week for 13 weeks and then sacrificed and necropsied. Plasma-ChE and red-blood-cell (RBC)-acetylcholinesterase (AChE) measurements, as well as several other blood measurements, were taken before dosing and at the end of weeks 1, 3, 7, and 13. Significant depression in plasma ChE was observed in male and female rats of the high-dose group at weeks 1 and 7 and in mid-dose males at week 7 compared with control values. No significant effect on RBC-AChE concentrations were observed. ORNL reanalyzed the data with analysis of variance and Dunnett's and Scheffe's comparisons and reported that at week 3 in females and week 7 in males, RBC-AChE concentrations of all dose groups were significantly lower than those of controls, but no dose-response relationship was found. In females during week 1, RBC-AChE concentrations in the controls and in all dose groups were inexplicably increased relative to baseline values (measurements taken before exposure). With regard to plasma ChE, a dose-related significant decrease relative to controls was observed at weeks 1 and 7 for male and female rats. In comparison with baseline values, plasma-ChE concentrations of the mid- and high-dose groups were significantly reduced at weeks 1, 3, 7, and 13 for males and females (with the exception of high-dose females at week 3). The lowest dose of 0.0175 mg/kg per day was considered by ORNL to be the LOAEL for the study because the reduction in plasma



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