Answer Explanations 4

Expert 4
Change my comment for this question to: I agree with user 553126 [Expert 5] that while 1,3-D may pose a hazard, the risk is negligible at realistic conditions.
Most likely aneugenic
Expert 5
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.
Most likely NOT aneugenic
Expert 14
This, however, is only a guess since no reliable in vitro data are available and the relevant in vivo data (bone marrow micronucleus test) bear limitations. An in vitro micronucleus test, OECD TG 487 compliant, would not only provide relevant and robust information on the clastogenicity of the compound but also information on the aneugenic potential (FISH extended) in case of positive results for induction of micronuclei. The additional use of GSH would possibly provide further useful information.
Clearly NOT aneugenic
Expert 1
no evidence of aneugenicty
1 vote 1 0 votes
Expert 5
04/18/2019 14:08

There are several suggestive positive results in the last 2 tables of the white paper, although they all have some questions. 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 the 1,3-D and in some cases it is not known if the epoxide was present in the 1,3-D. As the question asks about potential I would say likely, but the risk under realistic conditions is negligible.

0
Expert 14
04/18/2019 15:22

To user 553126 [Expert 5] : Among the studies present in the last 2 tables of the white paper and technically relevant for aneuploidy (bone marrow micronucleus test), none of them can establish whether 1,3-D is aneugenic or not for the following different reasons:
1) Micronucleus-bone marrow (Gollapudi 1985). The result is negative but the strength of the study is not sufficient to exclude either aneugenicity or clastogenicity since no evidence of target tissue exposure is present and the statistical sample (1000 PCE/animal) is limited. In addition, an unjustified difference in the percentage of PCE in the negative control group between male and female animals (56.8 and 68.8 respectively at the 24 hour sampling time) and within female animals at 24 and 48 hour sampling times (68.8 and 61.5, respectively) is present. Overall, this study cannot be considered adequate for risk assessment at present.
2) Micronucleus-bone marrow (Shelby 1993): Positive >150 mg/kg. In my opinion this study is not positive because the frequency of Mn-PCE observed at 150 mg/kg (0.31 %) is usually found in negative control animals. Here, the negative historical control data would have helped. In addition, as also noted before, no evidence of target tissue exposure is present. Overall not reliable for both aneugenicity and clastogenicity;
3) Micronucleus-bone marrow (Kevekordes 1996): Positive. In my opinion, this study, in addition to an inadequate study design (single animals in negative control), bears unrealistic values of PCE/NCE ratios which invalidate directly the study.
Overall, these studies cannot rule out the concern for both aneugenicity and clastogenicity.

0
Expert 1
04/21/2019 19:36

This question 2.8 and the variability in views will likely resolve if there was a clean (presumed to be negative) recent OECD 474 study available (a negative would also negate aneugenic effects)

0 votes -1 1 vote
Expert 4
04/22/2019 10:19

I agree with user-553126 [Expert 5] that while 1,3-D may pose a hazard that at realistic conditions the risk is negligible.

Comments are closed for this page.