Please comment on the White paper interpretation of the inhalation chronic bioassays by Stott 1987 (mice) and Lomax 1987 (rats). In your response, please comment on whether the increase incidence of bronchioavleolar tumors in male mice should be regarded as treatment related. If the your response is treatment-related, do you agree it is a weak response at the highest dose tested in males only. Please comment on whether this response should be considered as relevant or not for human health risk assessment.

A point to discuss is the conclusion that the lung tumors occur at concentrations that induces non-linear plasma kinetics. I do not think that this argument can be made since plasma concentrations of 1,3-D may not reflect target tissue concentrations in the lung. This should be related to exposure concentration. Metabolism in the target cells could be saturated, but would this would only be reflected in plasma concentrations if there is a significant 1st-pass in the lung ?

I am not a PK expert and I hope others contribute to the discussion on this point. But the PK issue would not change my view that the slight increase in lung ademonas via inhalation in a highly susceptible strain/sex does NOT provide a basis for a concern in humans. Also as stated in comments above, there was no evidence of carcinogenicity in female mice and in either sex of the rat in the inhalation bioassays. Slight increase likely due to growth of spontaneous lesions and ability to score as adenomas because of size.

An honest question out of possible ignorance: how is it possible to ignore lung tumors **by inhalation** as a "portal of entry effect"? How is this different from ignoring melanoma among lifeguards as a "portal of entry effect"? Naively, perhaps, one would think that the first site of contact with a carcinogen would be more, rather than less, important than distal sites.

User-37600 [Expert 2] asks an important question. Should we rule out "portal of entry effects" as irrelevant for human risk assessment? Do we ignore UV-induced melanomas in humans? The answer is no. However, if a compound given by daily oral gavage causes forestomach tumors in a rodent model, should we conclude that the compound would be carcinogenic in humans exposed by inhalation? Not necessarily. Since inhalation is the primary route of human exposure to 1.3-D, I would not rule out the importance of lung tumors in an inhalation study.

The point is not ignoring portal of entry effect. I am questioning the arguments regarding relevance of the non-linear plasma kinetics to discuss away the lung effects. I do not think that this is logic since the conc. of 1,3-D in the respiratory tract is depending on the air conc. Plasma kinetics may indicate saturation of liver biotransformation. I would not rule out portal of entry effects in any assessment

I agree, simply because a response is port of entry, is not a basis for disregarding. My point is given the high variable background and susceptibility, and that this benign tumor response was slightly outside of HCs, it is not convincing evidence of carcinogenicity. Some of the statements in the White paper should be revised so as not to imply that port of entry is a basis for downplaying or dismissing.

Agree with user-232578 [Expert 7]

agree with user 477751 [Expert 11] and user 232578 [Expert 7]

just flagging that in Section 8.6 below, there is a more complete discussion of the (not-agreed-upon) issue of whether the lung adenomas are in fact "slightly outside" of historical control rates or are completely different from historical control rates.

answering to users 37600 [Expert 2] and 750802 [Expert 9] , if to consider portal of entry for respiratory system, the nasal cavity would be the selected one, and not the lungs.