Pharmacokinetics of 2-ethyl-1,3-hexanediol. III. In vitro skin penetration comparisons using the excised skin of humans, rats, and rabbits.

Excised skin from Fischer 344 rats, New Zealand White rabbits, and human females (obtained from mammoplasty patients) were compared for their in vitro skin penetration potential with 2-[14C]-ethyl-1,3-hexanediol (EHD). EHD was applied as both an undiluted dose and a 3% v/v aqueous dose using a flowthrough skin penetration chamber design and was analyzed over 0-6 hr. The undiluted dose was equivalent to a 150 mg/kg dose used in vivo with rats (Frantz et al., Drug Metab. Dispos. 20(1), 6-18, 1992), but normalized on a per cm2 surface area basis, and applied under occluded conditions (covered as for in vivo studies). Undiluted applications of EHD did not substantially penetrate skin, with effluent recoveries of approximately 0.9% of the applied dose for human skin, 2-4% for rat skin, and 3-6% for rabbit skin. By comparison, nonoccluded human skin showed lower effluent radioactivity (0.6%), which was attributed to EHD evaporation from skin. With undiluted EHD, approximately 97% of the recovered 14C was an unabsorbed dose for human skin, with 94% for rat skin and 85% for rabbit skin (expressed as a percentage of the recovered dose). Based on HPLC analysis of effluent samples, 99-100% of the undiluted [14C]EHD penetrated rat, rabbit, and human skin in the unmetabolized form. In contrast, approximately 5% of the applied aqueous dose was recovered in the effluents for human skin, while 6-9% appeared in effluents for rat skin; rabbit skin was not evaluated for aqueous doses. The fraction of unabsorbed aqueous EHD dose totaled 53% of the applied dose for human skin and 63% for rat skin. Evaporative loss of undiluted [14C]EHD was also measured (captured on activated charcoal) in separate experiments and compared with a known standard chemical, N,N[14C]diethyl-m-toluamide (DEET). Evaporation of EHD was clearly a competing factor with penetration, particularly for human skin preparations, and evaporative losses were similar to those seen in previous studies. Penetration of skin was also greater for both EHD and DEET when evaporation was not permitted (stopped chamber). Permeability constant (kp) values were calculated using the pseudo steady-state slopes from plots for cumulative mg/cm2 penetration vs time. For undiluted EHD, human skin had the slowest penetration rate, while rabbit skin kp values were the largest. The kp values for water solutions of EHD on rat and human skin demonstrated a slightly higher penetration, with values of the same order of magnitude as that observed for a concurrently run [14C]ethanol control. The minimal skin penetration observed in vitro in this study, taken together with in vivo percutaneous pharmacokinetic studies (Frantz et al., 1992) and the known percutaneous toxicology of EHD, suggests that penetration through human skin and systemic adverse effects should be minimal.