Please provide one question you would like to have the genotoxicity expert panel members answer (please be sure to put your response in the form of a question).

Would the panel members comment on the wide range of their opinions on question 2.6 (Is 1,3-D mutagenic?)? The White Paper authors mention the external review draft of an EPA framework for weighing evidence for a mutagenic mode of action (MOA), although they didn't apply the framework. How did the panelists define mutagenic? Question may have been re-phrased in several ways; such as, "was 1,3-D mutagenic in vivo in tests relevant to human carcinogenicity?".

Is it possible that exposure of a fetus, via a pregnant mother could lead to genotoxic effects in the fetus? Should in vitro tests for genotoxic effects of 1,3-D be carried out in human cells?

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)?

NOTE TO SciPi BUT NOT TO THE OTHER REVIEWERS - ARE THERE ESTIMATES FOR EXPOSURE TO 1,3-D FOR MIXER/LOADER, APPLICATOR OR OTHER EXPOSED POPULATIONS? IF SO I WOULD PROVIDE THOSE ESTIMATES FOR EACH OF THESE EXPOSED SUBPOPULATIONS AS SUBCATEGORIES FOR THIS QUESTION AND ASK WHAT IS YOUR OPINION OF THE GENOTOXIC RISK FOR EACH OF THESE SUBPOPULATIONS AND HOW COULD TOX21 APPROACHES HELP AS WELL

Limitations were noted in the study design of the mouse bone marrow micronucleus test (Gallapudi, 1985) by the peer review. Two reviewers considered the evidence for overall clastogenicity to be equivocal, and one judged it as positive, although the test itself was considered to be negative by all three. Two of the reviewers consider this test to be clearly or slightly relevant. One reviewer raised the concern of the limited utility of this test for haloalkanes and haloakenes.

Question: Please comment on whether the negative mouse micronucleus assay (inhalation) has any utility as part of the weight of evidence assessment to address the in vivo clastogenic potential of 1,3-D, and comment on what further information you would want to clarify the mouse miconucleus test and to address the concern for potential chromosomal effects?

Is the rationale for suggesting that 1,3-d has some genotoxic potential (as indicated in some panel member responses) based on results that represent exceedances of the the KMD or is it just the limits and inherent uncertainty of the data that lead some to take that position?

“Since, unlike bioassay rodents, humans are never exposed to a single substance in isolation, how would ‘knowing’ that a particular substance is nongenotoxic change the estimate of the additional cancer risk that would be associated with a given additional exposure to that substance?”