Based on the available data, what inhalation concentration in mice do you think is a kinetically-derived maximum dose (KMD)?

See my comments to the previous question 3.3. Based on the figure 5 of the whither paper, it might be that the real KMD (systemic dose nonlinearity) is rather observed between 10 and 20 ppm, not 20 ppm exactly. However, the reviewer agrees that it is close to 20 ppm (but might be 15 ppm). In the white paper, the assumed KMD of 30 ppm or below has been derived from the dataset on the ratios cis/trans of 1,3-D in blood. However, the figures 5 and 6 suggest a KMD closer to the 15 ppm range. Therefore, it is stated that doses ≥20 ppm would be expected to provide quantifiable levels of the cis-isomer (which might only be due to analytical limitations), which might explain an assumed higher KMD of 30 ppm. However, this does not mean that a non-linearity of the GSH depletion might not occur significantly below 30 ppm (e.g., 15 ppm) as observed in the Figures 5 and 6. More discussions should be presented on that aspect to explain why 30 ppm only has been chosen as the upper limit of the KMD versus potentially 15 ppm in the Figures 5 and 6.

Dose response curves for 1,3-D blood clearance

a KMD is by definition the point of departure from linearity. According to figures 5 of white paper, the blood concentrations data clearly departs from linearity at 20 ppm exposures . The KMD should there before between 10 and 20 ppm.

It is evident from the available reports/publications that the increase in levels of the 1,3-D isomers in circulating blood was observed at exposure concentrations ≥30 ppm. Based on the data, a Kinetically- derived maximum dose (KMD) for 1,3-D in mice for repeated exposures should be at or below 30 ppm. 21-30 ppm could be considered a reasonable range although a small amount of biologic variability might be expected..