With the available information, what is your overall conclusion on the clastogenic potential of 1,3-D (please explain)?

Answer Explanations

• Most likely NOT clastogenic

  Expert 1

  As described above I don't see that the 'epichlorohydrin' studies can just plainly be discounted. This is also true for what is described as 'fragmentation assays' which in fact are DNA strand break assays. Their results have not suficiently been discussed. On the 'negative' side there is no fully guidline compliant study available to confirm the absence of a clastogenic potential in vivo.
  My choice of 'equivocal' is admittedly influenced by the knowlege that pesticides are looked at very critically by regulatots and therefore an attempt to support improvments to the dataset/White paper.

• Equivocal

  Expert 14

  This view is based on the fact that concern for clastogenicity and aneugenicity is not ruled out neither in vitro nor in vivo. As previously mentioned, the bone marrow micronucleus test is not an adequate in vivo follow-up assay for IARC carcinogenic haloalkanes and haloakenes which are genotoxic in vitro as shown by Morita et al. (1997), Mutation Research 389,3–122.
  In addition, the relevance of the quoted mouse bone marrow micronucleus test by Gollapudi (1985), is further limited by several shortcomings which include:
  • an unjustified difference in the percentage of PCE in the negative control group between male and female animals and within female animals at 24 and 48 hour sampling times;
  • no clear demonstration of target tissue exposure (no reduction of %PCE);
  • a limited statistical sample (1000 PCE/animal).
  In this frame, I would mention the positive results observed in different organs in the alkaline single cell gel electrophoresis (comet) assay after treatment with these classes of compounds (Sasaky et al., 2000). In this study 1,3-D, injected intraperitoneally to mice, induced marked and statistically significant increases in DNA breakage in the stomach, liver, kidney, blood, lung, brain and bone marrow three hours after treatment. Histopathological observation excluded the presence of signs of necrosis in the organs in which DNA damage was observed. This last observation is further strengthened by the negative findings observed in the same organs at the 24 hour sampling time. Notably, the effect observed in bone marrow, though significantly different from the untreated control was marginally affected compared to the other organs/tissues.

• Most likely clastogenic

  Expert 5

  The bone marrow micronucleus test is likely the most relevant to this question, and it suffers from a number of shortcomings; perhaps the most serious of which is the lack of evidence that 1,3-D or its metabolites reaches the bone marrow. Although there is no unequivocal evidence indicating clastogenic potential, it cannot be ruled out.