General Comments

Based on discussion at the meeting, there was agreement among the committee members to use an interspecies uncertainty factor (UF) of 3 to derive the values for AEGL-2 and -3, because the physiologically based pharmacokinetic (PBPK) model used accounted for the oversensitivity of the animals in the experiment compared to humans.

The committee also recommended that a statement and a specific citation to the standard operating procedures (SOP) (including the specific section) should be added to explain why an intraspecies UF of 3 was selected, for both AEGL-2 and -3.

The committee recommended that new language should be added to describe why a “correction” factor was used to derive AEGL-2 and -3 values.

The committee also agreed with the approach used by the authors for time extrapolation and dose extrapolation and supported their findings and recommendations relative to the modeling. The committee believes that the methods used are accepted in the modeling community. However, since PBPK modeling is notorious for visualizing the uncertainties in dose-response relationships, further clarification is needed regarding how to handle the concept of “adequate fit,” “model validation,” and “poor fit.” In addition, new text needs to be added describing how the specific PBPK model used to derive the AEGL values was evaluated and why it is considered to be a “valid” model for application in the derivation of AEGL values for xylenes.

Specific Comments

Page 41, lines 13-15. Eye irritation is not a sensory irritation (for example, bad smell is a sensory irritation to the olfactory system and glaring light is a sensory irritation to the vision).

Page 44, lines 25-32. Contradiction? Was an exposure of rats to 2,800 parts per million (ppm) xylene for 4 hours (h) a no-observed-effect level (NOEL) for prostration (lines 25-26), or did it produce prostration (line 32)? Or does “NOEL” in line 25 refer to death only and not to “reversible prostration”?

Editorial Comments

Page 5, line 9. Delete “age” (or “years old”).

Page 31, Table 10. Add units (hours) to the Duration column.

Page 37, Section 4.3.2. Intraspecies Differences. The discussion of the two- to threefold range in humans is discussed in the SOP, but no references are provided here. Because this is an important point, add a reference to the SOP here so the reader understands that the basis for this statement is documented in the SOP. Add NRC 2001 (SOP manual) as a reference either at the end of the first or second paragraphs.

Page 48, line 35. Spell out what “EEL” stands for.

Scientific Comments in Response to the Initial Comments on Xylenes Discussion

Page 3, lines 12-15. This statement and consequent calculation is not justified. An elderly person being at greater risk for pharmacodynamic reasons (maximal sensitivity in newborn, pregnant, and

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