Expert 10

60 and 150 ppm would have exceeded the KMD, and thus the protective mechanism of GSH conjugation.

Expert 13

Yes, the doses used in the two above mentioned studies included 60 and 150 ppm that would have exceeded the KMD. Prolonged inhalation exposure of male B6C3F1 mice to a high concentration (60 ppm) of 1,3-D is associated with an increased incidence of only benign adenomas in the lung only. This is the only tumor type related to 1,3-D treatment and was not observed in female mice or in either sex of rats. The potential of 1,3-dichloropropene (1,3-DCP) to induce dominant lethal mutations in the germ cells of male CD rats following inhalation exposure was investigated by Gollapudi et al., (Environ Mol Mutagen., 1998). Groups of 11-week-old males (30 animals/group) were exposed to 1,3-DCP vapors by inhalation at targeted concentrations of 0 (negative control), 10, 60, and 150 ppm for 10 weeks (6 hr/day, 7 days/week). Based on these results, it was concluded that 1,3-DCP is not mutagenic to the male germ cells of CD rats at exposure levels < or = 150 ppm, the highest concentration tested. Rats and mice excrete approximately 80% of even relatively high oral dosages within 24 hr, primarily as breakdown products of a glutathione conjugate or as carbon dioxide. These products reflect the primary routes of metabolism of DCP, via GSH-conjugative and hydrolytic pathways. An additional pathway based upon the epoxidation of DCP has also been proposed, but this does not appear to occur to any toxicologically significant degree in the presence of normally occurring GSTs. Direct evidence of the latter pathway is only been obtained at dosages of DCP in excess of the reported LD50. Humans also appear to rapidly metabolize DCP and excrete its metabolites. Subchronic toxicity studies of relatively pure DCP in rats and mice via oral or inhalation routes have resulted in portal-of-entry tissue effects that reflect the irritant properties of this chemical to nasal and gastric mucosa. At higher exposure levels in mice, however, toxicity was also identified in a remote tissue, the urinary bladder. Toxicity in dogs ingesting DCP was limited to the formation of a regenerative hypochromic, microcytic anemia. No teratological or reproductive effects were observed in rats or rabbits inhaling DCP vapors (Stott et al., Rev Environ Contam Toxicol. 2001). Fischer 344 rats and B6C3F1 mice were administered 1, 3-dichloropropene (1,3-D) via their diets for up to 2 years, at dose levels of 0, 2.5, 12.5, or 25 mg 1,3-D/kg body wt/day for rats and 0, 2.5, 25, or 50 mg 1,3-D/kg body wt/day for mice. There were no effects on survival or clinical pathology parameters for rats or mice. Histopathologic effects attributed to treatment in rats consisted of basal cell hyperplasia of the non-glandular mucosa of the stomach in males and females given 12.5 or 25 mg/kg/day for 12 and 24 months and an increased number of hepatocellular adenomas in males given 12.5 or 25 mg/kg/day and females given 25 mg/kg/day for 24 months (Stebbins et al., Regulatory Toxicol Pharmacol., 2000). The above findings are generally supportive of each others.

Expert 12

I confirm that the mutation occurred at exposure higher than the assumed KMD. I also confirm that the metabolic profiles seems to be sex, route and species invariant.
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Expert 13
04/19/2019 17:40

No more comment from my side.

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Expert 10
04/23/2019 10:52

nothing to add.

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Expert 12
04/24/2019 09:51

No more comment.

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