Given the WOE how likely is it that 1,3-D poses a genotoxic risk to humans at the exposure levels encountered by humans (see lines 1114-1122 and 1135-1151, including Table 31, for a description of exposures encountered by the general population). Why? To what extent do you think that the Tox21 recently being developed can be applied to better understand the potential for human genotoxic risk with respect to carcinogenicity (e.g., OECD AOP program https://www.oecd.org/chemicalsafety/testing/adverse-outcome-pathways-molecular-screening-and-toxicogenomics.htm)?

I would see this a very unlikely, and this is where it circles back to 6.2. If no direct DNA reactivity is to be expected there is very likely a threshold involved and this is where MoA information can help (plus a state of the art micronucleus in vivo, to remove that vulnerability)

I do not think that 1,3D poses a genotoxic risk to humans at the exposure levels encountered by humans, as the exposure levels are are at least 10 fold below the population adjusted dose. I think high throughput and computational models models for genotoxicity such as those in Tox21 will be very valuable for evaluating chemicals in development and prioritizing chemicals already in the environment for animal testing. Results will have to be modified after effects of metabolic activation have been analyzed. I'm not sure how, but other than the bioavailability program in tox21 and the In Vitro Chemical Disposition program, some method of better extrapolating from experimental animals to humans still needs to be developed.

Genotoxicity is always triggered by definition at appropriate dose-levels due to the intrinsic features of the available genotoxicity studies. However, although it is recognized that thresholds below which genotoxic effects do not occur, likely exist for both DNA-reactive and DNA-nonreactive substances, it is also noted that small increments of the spontaneous level of DNA damage/mutations, cannot be unequivocally excluded by experimental measurement or by mathematical modelling (McGregor et al., Mutation Research 783 (2015) 55-65). On this basis, genotoxic risk to humans at the exposure levels for humans reported in the white paper cannot be strictly established.
In my opinion, application of Tox21 is at present of limited support to better understand the potential for human genotoxic risk with respect to carcinogenicity