These changes tended to occur at a higher overall incidence in high dose males and in females at all dose levels, but without a dose response relationship. Ocular find ings were not considered by the panel to be related to test material, but were instead manifestations of abnormalities typically associ ated with the Fisher 344 rat used in these studies, as well as viral infection. When the remaining clinical signs were evaluated for consistency with dehydration, based on the B. Gadagbui et al. / Regulatory Toxicology and Pharmacology 57 220 234 231 nature of the effects as well as dose response and temporal pat terns, the clinical signs were considered to be most consistent with dehydration as the underlying cause.

Nearly all effects occurred during the first two weeks of the study, when water consumption was markedly lower, as water consumption MLN8237 returned to normal, these clinical signs abated. Thus, the high doses in the drinking water study of 20,000 ppm, 896 mg/kg day and 1108 mg/ kg day, were considered to be NOAELs for clinical signs. Gastric hyperplasia and eosinophilic inclusion were observed in male and females in a 28 day rat dietary study for alachlor OXA at the high dose of 20,000 ppm. No such effects were observed in the corresponding 90 day studies for the alachlor degradates. The panel concluded that it is likely that this observa tion is dose related, since the 28 day studies tested higher doses than the 90 day studies. The finding could also be attributed to lo cal irritation, which would be consistent with exposure to high doses of alachlor OXA due to its acidity.

The investigators consid ered the gastric changes to have been the SNDX-275 result of altered mucus production in the epithelium of the glandular stomach. These observations were examined critically in light of the finding that chronic dietary treatment of rats with the parent chemical, ala chlor caused gastric tumors in the rat. However, gastric histopathological changes observed in this 28 day study with alachlor OXA are different than those that are associated with the development of gastric tumors in the rat stomach after treatment with the parent alachlor. Based on the available data, the panel concluded that the observed changes with alachlor OXA represent an adverse treat ment related effect consistent with a local toxicity associated with high dietary doses of an acidic chemical, rather than a general sys temic effect.

Thus, these effects were not considered as an appro priate basis for the RfD. 3. 2. Step 2: choice of appropriate species, study, and point of departure A detailed critical examination of each potential key study as well as the array Protease of endpoints described above led the panel to con clude that decreased body weight was a treatment related adverse effect in some studies for the degradates. No consistent treatment related adverse effects were observed on the thyroid for these degradates. Hematological findings observed in the drinking water study for alachlor ESA were marginal, not of clinical significance, and may have been related to changes in drinking water intake. No treatment related adverse effects on reproductive or developmental endpoints were identified for these degradates.

Table 4 shows the critical PI-103 effects and the point of departure for each degradate. For alachlor ESA, several differences were noted but no statistically significant effects were judged to be adverse after an extensive review of individual animal data, including clin ical signs and chemistries in either a 91 day drinking water study or in a 90 day feeding study. The high dose in the 90 day dietary study serves as the appropriate NOAEL and the basis of the RfD, since it is lower than the high dose used in the drinking water study. For alachlor OXA, the highest dose was judged as the appropriate NOAEL, because only minimal changes in body weight were ob served in the 90 day dietary study without statistically significant differences between controls and treated animals.

The critical effects for acetochlor ESA are decreased body weight gain, decreased food consumption, and decreased food uti lization noted in the 90 day dietary study, with NOAELs at the mid dose. For acetochlor OXA, NOAELs at the mid dose were identified for decreased body weight gain and decreased food utilization in the 90 day dietary study. Endpoints with statistically significant FDA changes or trends were also chosen for modeling using U. S. EPAs Benchmark Dose Soft ware 1. 4. However, BMD runs did not re sult in values that were more reliable than identified NOAELs and LOAELs, due principally to the lack of a clear dose response. In some cases, where acceptable fit to the data was achieved, the Benchmark Dose was not judged as an appropriate point of departure because the maximum effect observed at the highest dose was substantially less than the typical Benchmark Response of 10% decrease in body weight rela tive to controls.