The review sponsor concluded that due to presence of epichlorhydrin, a known mutagen and carcinogen, which is not representative of manufactured 1,3-D since 1985, the NTP bioassays are considered not relevant to assess the carcinogenicity of 1,3-D. In addition, there are four cancer bioassays via oral route that tested the modern 1,3-D and they are GLP and test guideline compliant studies, thus are adequate for assessing 1,3-D’s tumorigenicity. Please indicate the degree to which you agree or disagree with this conclusion. (please explain)

Just a comment, both the old and new formulations of 1,3 D are called Telone II. It has not been informed if old Telone II and new Telone II formultions have the same concentration of 1,3D. It is also not known what is the concentration of 1,3 D in DD92, which has been used in rat experiments. Could anyone inform this, please?

We could also discuss about the potency of epichlorohydrin. Are you aware of any carcinogenesis study with epichlorohydrin alone?

The white paper includes a reference on a study with epichlorohydrin. I am aware that epichlorohydrin was used as a stabilizer in other chemicals that were tested by NTP in the 1970s (eg. trichloroethene). It could help to check doses of epichlorohydrin in these studies and correlate to tumor response in the target liver.

Information on composition of the different Telone II formulations including impurities would be helpful to interpret the inconsistent results in the newer studies (Scott et al., and Kelly et al.)

To users 477751 [Expert 11] and 915125 [Expert 6] : my (long) comment on Topic 5.5 (WOE subpanel) presents cancer slope factor estimates from the bioassays of epichlorohydrin alone, and in my opinion STRONGLY suggests that the 1% impurity was far too small an amount to account for the excesses in tumors in the NTP bioassays of 1,3D-- *especially* the female bladder carcinomas, since epichlorohydrin has never been found to increase this tumor type.

I appreciate the comment by 37600 [Expert 2] to the effect that a 1% concentration of epichlorohydrin was too small to have resulted in the tumor incidences observed in the NTP studies. However, we don't know anything about the potential interaction between the 1% contaminant and the 1,3-D. In addition, we have other bioassays in which there was no possible interaction between these substances. Why would we not believe the results of these unconfounded bioassays as opposed to speculating about the possible contribution of the 1% contaminant in the NTP bioassays.

To user-750802 [Expert 9] -- you raise a good question but I think one logical answer is "because positive findings have more weight than negative ones, unless/until the positive findings are EXPLAINED satisfactorily." If all we needed to dismiss, say, an epidemiology study with a relative risk of 5 is another one with a RR of 1 (or 0.5), then we would have failed to act on many "known" causes of human disease. You're correct that it's possible that all the positive findings in the NTP bioassays are explained by the impurity, but I'm just pointing out how weak that explanation seems to me-- especially w/respect to the female mouse bladder tumors.