Answer Explanations 4

Considered but with less weight
Expert 5
From the limited metabolism studies, it appears that epoxidation of 1-3D, although a minor pathway does occur when metabolic activation is present – perhaps at several percent yield. Since some epoxide will be formed. It seems unreasonable to discard results with 1-3D containing around 1% epichlorohydrin. One could estimate the contribution of say, 1% epichlorohydrin to the genotoxicity of purified 1,3-D by comparing the genotoxic effects of the pure compounds (e.g. if epichlorohydrin is 100x more potent than 1,3-D could it account all of the observed genotoxic effects?). In practice this might be difficult (but maybe not impossible) as conditions for assaying the pure compounds would have to be very similar. Without this information there is no way to know if contaminated samples should be discarded. However, in cases where no metabolic activation is present (e.g., Ames test without S-9 fraction), results containing contaminated 1,3-D are not reliable.
Expert 4
(Please add the following to the Comments Section. I can’t figure out to do that) Consider on a case-by-case basis focused on an evaluation of the likelihood that the amount of epichlorohydrin used in the study contributed to the tumors observed.
Ignored
Expert 14
Yes, at least for the in vitro studies where epichlorohydrin is a clear genotoxic agent. However, for the in vivo genotoxicity studies the presence of epichlorohydrin as stabilizer for 1,3-D does could not represent a confounder factor since it has been shown in a number of cytogenetic studies a negative outcome in mice and rats at dose-levels up to 200 mg/kg bw (Rossi et al., 1983; Tsuchimoto and Matter, 1981; Kirkhat, 1981; Salamone et al., 1981; Terada et al., 1992; Asita et al., 1992; Dabney et al., 1979; Sram et al., 1981).
Considered fully
Expert 1
This is a difficult question. If there was a choice saying 'case by case' then I would have checked that box. I belive that the White paper and Zeiger make this sound a bit too simplistic - known mutagen and carcinogen - yes, but in my view the question to ask is its relevance towards the outcome of these studies. Did check for epichlorohydrin data and found, for example, a 2018 NTP micronucleus study that was clearly negative (tested up to 200 mg/kg. Even if it was positive at such high doses - how could a presence of a 1% impurity (i.e., 1% of the respective top dose tested in these assays) explain the positive results in the described studies?
0
Expert 5
04/18/2019 15:43

Perhaps one could estimate the contribution of say, 1% epichlorohydrin to the genotoxicity of purified 1,3-D by comparing the genotoxic effects of the pure compounds (i.e. if epichlorohydrin is 100x more potent than 1,3-D could it account all of the observed genotoxic effects?). In practice this might be difficult (but maybe not impossible) as conditions for assaying the pure compounds would have to be very similar. Without this information there is no way to know if contaminated samples should be discarded.

1 vote 1 0 votes
Expert 14
04/19/2019 03:47

Independently by the potential confounding role of epichlorohydrin, particularly for the outcome of the in vivo studies, I think that this is not a real issue. The studies with a positive outcome for genotoxicity in the presence of epichlorohydrin (e.g. bone marrow micronucleus test by Shelby,1993; Kevekordes, 1996; Alkaline elution by Kitchin, 1994) are not relevant for risk assessment due to significant limitations and shortcomings as also pointed out in “Result 2.8”.
For the bone marrow micronucleus test by Shelby (1993) considered by the author as positive at 150 mg/kg, the negative historical control data were not considered and the frequency of micronucleated PCE (Mn-PCE) observed at 150 mg/kg (0.31 %) is usually found in negative control animals. In addition, no evidence of target tissue exposure is present.
For the bone marrow micronucleus test by Kevekordes (1996), in addition to an inadequate study design (single animals in negative controls), it bears unrealistic values of PCE/NCE ratios which invalidate directly the study.
For the alkaline elution by Kitchin (1994) it should be noted that this test has never been fully validated.

1 vote 1 0 votes
Expert 1
04/21/2019 19:31

It seems like none of the reviewers is now providing clear support anymore for simply excluding studies for the presence of epichlorohydrin . While I agree with most of the statements from reviewer 617591 [Expert 14] regarding limitations of 'non-standard' studies I do not believe that this disqualifies them for any consideration in the risk assessment. If there was a state-of-the-art micronucleus/clastogenicity in vivo study available then that would be an easier call

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