With the available information from genotoxicity studies, and with the pattern of tumor results from the cancer bioassays, what is your overall conclusion on the aneugenic potential of 1,3-D in humans following in vivo exposure (please explain)?

no state-of-the art data available to prove the absence of a clastogenic and/or aneugenic effect

Aneugenicity is normally assessed from the evaluation of micronuclei, both in vitro and in vivo using the immunochemical labeling of kinetochores (CREST method) or using DNA pericentromeric sequence probes in combination with fluorescent in situ hybridization (FISH techniques) to mark centromeres. In the present case, my feeling is that 1,3-D does not bear an aneugenic potential. However, since no data on the induction of micronuclei in vitro and no reliable data in vivo on the induction of micronuclei are available, this end-point remains undetermined.

There are several suggestive positive results in the last 2 tables of the white paper, although they all have some questions. These have been detailed in the other reviewers’ responses. I do not think that the use of DMSO as a solvent necessarily disqualifies a test, as DMSO reacts with 1,3-D epoxide and not 1,3-D, and in some cases it is not known if the epoxide was present in the 1,3-D. The studies cited above cannot rule out an aneugenic response and the question asks about the aneugenic potential of 1,3-D. The results cited indicate that 1,3-D is certainly not strongly aneugenic, but some aneugenic potential has not been ruled out by the tests in experimental animals or in vitro. However, as the aneugenic potential of 1,3-D is so low in such tests and the doses are so much higher than those humans would be exposed to I believe it highly unlikey that 1,3-D is aneugenic in humans.