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In many instances, the systemic endpoint of concern observed in the test animal was from oral dose (as from a feeding study). Yet even when a reliable absorption rate can be obtained to extrapolate absorbed dose from an applied dermal dose, there is still an uncertainty about the exact impact of this dermally absorbed dose compared to the toxicity (reference) dose absorbed via the oral route. Ross et al. (2000) provide a fair discussion on the potential overestimation from bolus (oral) dose to nonbolus (dermal) dose.

Human dermal (and even inhalation) acquisition typically takes places incrementally over the entire (work)day, whereas an oral absorbed dose can be completely acquired by test animals in minutes to less than an hour. In addition to this slower dermal acquisition, the rate of dermal absorption is typically lower than that of oral absorption. As Rozman and Klaassen (1996) point out, this absorption difference is due in part to the fact that absorption by the dermal route requires a chemical to pass through several densely packed epidermis cells. In contrast, the intestine's large number of villi and microvilli increases the oral absorption surface area approximately 600-fold. Rozman and Klaassen also assert that it is the concentration of a chemical at the site of action, not the total (absorbed) dose, that ultimately determines toxicity. Complicating these acquisition and absorption incompatibilities further is the possibility that a dermal dose might not undergo the same series of critical metabolic pathways as an oral dose does.