Chemical exposure to skin remains an important route by which systemic toxicity may occur. However, chemicals are seldom contacted singly in neat form and generally are present as a mixture. A total of 56 8-hr isolated perfused porcine skin flap (IPPSF) topical experiments were used to study the percutaneous absorption and cutaneous distribution of binary mixtures (solute/solvent) of 14C-labeled phenol vs p-nitrophenol (PNP) at two concentrations (4 micrograms/cm2 vs 40 micrograms/cm2) in two vehicles (acetone vs ethanol) under occluded vs nonoccluded dosing conditions. Pertinent comparisons were made to determine if dose, vehicle, or occlusion had a significant effect on absorption, localization of the test compounds, or total recoveries. Total recoveries were much greater in all cases for PNP than phenol. Absorption, penetration into tissues, and total recoveries of phenol were greater under occluded conditions than nonoccluded. Absorption and penetration of phenol into tissues were greater with ethanol than with acetone under nonoccluded conditions, but the opposite was observed under occluded conditions. Percentage of applied dose penetration into tissues was greater from low-dose phenol in acetone than high-dose, suggesting a fixed absorption rate. This was also seen for PNP, but only under occluded conditions. Neither phenol dose,vehicle, or occlusion had any significant effect on the labeled phenol seen in the stratum corneum or on time of peak flux, a finding which limits the usefulness of noninvasive stratum corneum sampling to assess topical penetration. There was greater absorption and penetration into tissues of PNP from acetone than from ethanol. PNP dose had a significant effect on time of peak dose, with low-dose PNP taking longer to reach its peak. Neither PNP dose, vehicle, nor occlusion had any significant effect on total recovery of labeled PNP. The results suggest that comparative absorption of phenol and PNP are vehicle-, occlusion-, and penetrant-dependent. These factors must be considered when comparing absorption data between studies. These findings suggest that single chemical data (the compound applied neat) is not predictive of even binary mixtures and that exposure conditions further modulate disposition.