The panel acknowledged that the specific ocular ef fect observed for alachlor would not have been detectable in the rat strain used in the alachlor ESA study. However, this data gap was not considered critical in light of the likely differences in the mode of action between the parent chemicals and these degradates and the fact that uveal degeneration in rats induced by alachlor were not critical effect for the alachlor RfD. A second potential data gap was considered based on data indi cating potential for neurotoxic effects in several acetochlor rat and dog studies. However, there was no indication of a neurotoxic potential for acetochlor degradates. The panel concluded that since no such effects were observed even at limit doses in subchronic studies, these degradates are not likely to be neurotoxic.

Absence of a longer duration systemic toxicity study PDE Inhibitors in a sec ond species was also considered in selecting the appropriate data base uncertainty factor, since only rat studies were available for the degradates. The panel discussed whether a 1 year dog study was needed, since some data for the parent chemicals suggest that the dog is the more sensitive species and effects that occur at 1 year are not found in the 90 day studies. However, the U. S. EPA no longer requires a chronic dog study as part of the required data set for pesticide registration, rather a 13 week study is deemed sufficient. The U. S. EPA Science Advisory Panel recently analyzed the value added by con ducting a 1 year study in the dog and found that the longer dura tion study in dogs does not add significantly to the ability to identify the critical adverse effect level.

The European Food Safety Authority PDE Inhibitors Panel on Plant Protection Products reached a similar conclusion that extension of a dog toxicity study beyond a 13 week duration provides little additional information. The panel compared effect levels from studies of rats versus dogs and for studies of different durations for the parent chemicals to evaluate the importance of missing studies for the degradates. These comparisons were only used as a qualitative guide because of the potential differences in mode of action for the degradates versus the parent chemicals. Similar data were also reviewed for the effect levels for various species and study durations for metola chlor, and its ESA degradate, for which a subchronic dog study was B.

Gadagbui et al. / Regulatory Toxicology and Pharmacology 57 220 234 233 available. This analysis HDAC-42 did not indicate that the subchronic dog study would warrant a greater UF D factor than con sidered by the panel. In no case of the parent chemicals did repro ductive or developmental toxicity drive the assessment, and in all three cases, dog and rat effect levels were roughly quantitatively similar, at the same study exposure length. Given that the four degradates are less reactive, absorbed to a lesser extent, and less metabolized when compared with the parent compounds, greater variability in toxicity among these degradates is not expected than observed with their parent compounds.

A combined value of 10 fold was recom mended by the panel for uncertainties in both the lack of certain studies to determine the critical effect and the lack of a chronic study as a basis of the RfD. This latter factor was considered by the panel to be best Ponatinib judged as 10, although it could be as high as 30, 2 because the available toxicology data for the parent compound suggest only a modest, if any, change between subchronic and chronic NOAELs, and the available information suggests that neither developmental nor reproductive toxicity is the critical effect. More over, the panel concluded that the same UF can be used for develop ing a safe dose for each degradate, because the chemical structures and data bases are similar and all have a similar spectrum of toxicity based on the available array of studies. Furthermore, no data were available that would suggest significant mode of action differences.

Thus, the panel considered that a PARP composite UF of 1000 for each degradate was reasonable. A composite UF of less than 1000 was not considered appropriate. 3. 5. Mode of action data to justify a cumulative risk assessment approach The potential for a cumulative risk assessment for these degra dates was evaluated based on potential commonalities in critical effects and their underlying modes of action. The panel concluded that the data are inadequate to identify the mode of action for any of the observed effects of the degradates, except perhaps for the proposed effect of irritation and the gastric effects observed in the 28 day study for alachlor OXA. In the absence of such data on mode of action, a cumulative risk assessment approach would not be supported for the four degradates.