Expert 12

This seems valid, however, please see my responses detailed in the items 7.1, 7.2, 7.4 and 7.6 where I believe that additional uncertainty factors might be applied in the current toxicological risk assessment to cover some remaining uncertainty and variability in the calculation of the margin of exposure (MOE), or alternatively used a more conservative KMD of 10 ppm based on Figure 5.

Expert 10

We are given very little information on the elimination rate of 1,3 D. The provided text tells us that 1-3-D is eliminated rapidly from the rodent bloodstream with an half life in initial phase of 4-7 min and followed by a slower phase with 22-43 min of half-life. Although no data is provided in the White paper for human either from in vivo or in vitro metabolism, a EPA tox review document (https://cfpub.epa.gov/ncea/iris/iris_documents/documents/toxreviews/0224tr.pdf) provide information from a human clinical study (Waechter et al 1992) where elimination half lives are 12.3±1.4 for the terminal phase of the cis isomer and 17.1 hours for the trans. more than 93% of chemical is expected to be eliminatoin after 4 half-lives (in this case 68 h). It therefore seems to be eliminated somewhat slower in humans. We are missing information on the GST isoenzymes that are involved in rodent and human . Are they the same? For question 5) we need info on mechanism explaining non-linearity (i.e., GSH depletion or GST saturation), and we need information mentioned in 7.1. To much information is missing to conclude that a KMD will be observed at same levels in humans. If we are to extrapolate from animal data, an uncertainty factor should be used.

Expert 13

1. Based on the available reports/literature we could say with confidence that 1,3-Dichloropropene that inhalation and oral exposure studies in animals have shown that 1,3-dichloropropene is readily absorbed, conjugated with glutathione (GSH) via glutathione S-transferase (GST), and rapidly excreted in the urine. Elimination rates were quite rapid, with half-lives of 5-12 min. 2. Time course evaluations of 1,3-D levels in mice exposed to 20, 60 or 120 ppm showed steady-state concentrations of parent compound were achieved by the end of the 6 hr exposure interval (Hackett 2018). No accumulation of test material was found between exposure days. 3. Toxicokinetics following oral and inhalation are comparable. Waechter et al. (1992) showed that the major metabolites after inhalation in humans, cis- and trans-3CNAC, were identical to those found in rats after oral exposure. 4. 1,3-Dichloropropene toxicokinetics in humans appear to be similar to those observed in rodents in terms of uptake, detoxification and formations of major metabolites. 5. The available results show that exposure to 60 ppm and higher 1,3-D in air affords systemic exposures that are 3-4 times above dose-proportionality, which is consistent with saturation of metabolic clearance between 20 and 60 ppm. With the lower dose range expanded, it is clear to see that supralinear increases in 1,3-D concentrations are evident even at 20 ppm. This nonlinearity is quite consistent with the depletion of glutathione between 10-30 ppm reported previously and indicates that the non-dose proportional systemic levels of this compound are related to saturation of glutathione-based metabolic clearance. 6. The available evidence also strongly suggests that the kinetically-derived maximum dose for repeated exposures is at or below 30 ppm. 3-Parameter piecewise linear (hockey-stick) model of 1,3-D Toxicokinetics following repeated exposures to B6C3F1 mice was presented in . With the lower dose range expanded, it is clear to see that supralinear increases in 1,3-D concentrations are evident even at 20 ppm. This nonlinearity is quite consistent with the depletion of glutathione between 10-30 ppm (Bartels Report, 2018).
3 votes 3 0 votes
Expert 13
04/17/2019 11:36

I agree with user # 850922 [Expert 10] that the information available is limited but based on literature review I am of the opinion that 1,3-D does not get accumulated and is rapidly excreted in urine resulting in a short biological half-life.

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Expert 11
04/18/2019 05:34

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Expert 2
04/18/2019 09:49

The debate under question 7.1 concerns part (4) of this question above-- and so far I don't see much on this page that addresses the interspecies (and the human intraspecies) concern here. User 432123 [Expert 13] states that humans and rodents have the same metabolic pathways and isoenzymes, but assuming that's true, this provides no basis for QUANTITATIVE interspecies (or intraspecies) extrapolation for risk assessment purposes.

1 vote 1 0 votes
Expert 12
04/23/2019 06:30

I agree with the two other reviewers. We knows already lot things but some additional uncertainty factors could be needed. First, a greater unbound fraction (most active form) of the compound in human plasma versus rodent would not be protective for human. Since we do not have this information, the interspecies scaling factor could be adjusted. And I also agree that the toxicological risk assessment should be refined since it is too simple from now.; at least a scaling factor based on species and/or interindividual differences in the amount of Glutathione would be relevant. However, as said, the current MOE are already large (safe).

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Expert 10
04/23/2019 10:47

There is no human information to estimate a KMD value for humans. If animal data are to be used, I agree that uncertainty factors will be needed, as mentioned by user-292467 [Expert 12] .

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Expert 4
04/24/2019 04:52

I agree with the points raised here and think that the key point is raised by user-292467 [Expert 12] who notes that that the current MOE are already large (safe).

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Expert 2
04/24/2019 08:01

See also the discussion in Topic 7.4 below about the possible relationship between "large MOEs" and hazard classification.

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Expert 12
04/24/2019 09:46

No more comment. I agree.

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