How do you interpret the in vivo genotoxicity studies for 1,3-D summarized in the white paper?

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  Expert 14

  	clearly negative	slightly negative	equivocal	slightly positive	clearly positive
  Mouse bone marrow micronucleus test (Gallapudi, 1985)	1	0	0	0	0
  Dominant lethal assay (Gallapudi, 1998)	1	0	0	0	0
  Big Blue mouse assay (Gallapudi, 1997)	1	0	0	0	0
  32P Post-labelling assay (Stott, 1997)	1	0	0	0	0
  Big Blue rat assay via oral route (Young, 2018)	1	0	0	0	0

  1) I judged the results of the mouse bone marrow micronucleus test (Gollapudi et al. 1985) clearly negative. However, no evidence of target tissue exposure is overall evident, based on the data on %PCE available. In any case some shortcomings and inconsistencies are present in this parameter. There is 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). In addition, the statistical sample (1000 PCE) which was considered adequate at the time, is nowadays judged insufficient.
  2) Technically, the dominant lethal assay (Gollapudi, 1998) is clearly negative and essentially complies, with the relevant 478 OECD Guideline.
  3) The Big Blue mouse assay (Gollapudi, 1997) is clearly negative and essentially complies, with the relevant 488 OECD Guideline with the exception that the administration period was 14 days instead of 28 days requested for slow proliferating tissues/organs (e.g. liver).
  4) The 32P Post-labelling assay (Stott, 1997) is clearly negative.
  5) The Big Blue rat assay via oral route (Young, 2018) is clearly negative

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  Expert 5

  	clearly negative	slightly negative	equivocal	slightly positive	clearly positive
  Mouse bone marrow micronucleus test (Gallapudi, 1985)	1	0	0	0	0
  Dominant lethal assay (Gallapudi, 1998)	1	0	0	0	0
  Big Blue mouse assay (Gallapudi, 1997)	0	0	1	0	0
  32P Post-labelling assay (Stott, 1997)	0	0	1	0	0
  Big Blue rat assay via oral route (Young, 2018)	1	0	0	0	0

  Taken together, the results indicate that 1,3-D is not a strong genotoxin, but the evidence so far has not ruled out a weak genotoxic activity.

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  Expert 1

  	clearly negative	slightly negative	equivocal	slightly positive	clearly positive
  Mouse bone marrow micronucleus test (Gallapudi, 1985)	1	0	0	0	0
  Dominant lethal assay (Gallapudi, 1998)	0	1	0	0	0
  Big Blue mouse assay (Gallapudi, 1997)	1	0	0	0	0
  32P Post-labelling assay (Stott, 1997)	0	1	0	0	0
  Big Blue rat assay via oral route (Young, 2018)	1	0	0	0	0

  Gallapudi 1985: see this as a clear negative despite the 8-fold increase for females at 48h vs control in the high dose. Reason is that the corresponding 24h negative control was at comparable level (and no scientific reason why the 24 and 48h controls should differ), so likely this is caused by an unusually low neg control at 48 h. Ideally historical neg control data should be available/added
  Gallapudi 1998: Neg for implants, but there seems a dose-response for the observed resorptions (3 and 4). Also wondering if the increase from 1.7% to 7.7% is not stat significant? To note, I am not an expert in this assay
  Gollapudi 1997: Clear neg
  Scott 1997: Difficult to judge without the original report. Detection limit for postlabeling seems low, at least for the lower range (1/million) given.
  Young 2018: Clean negative. Belive the dose selection should be described more clearly, could be critical