Dermal penetration and metabolism of five glycidyl ethers in human, rat and mouse skin

1. Glycidyl ethers (GE), an important class of industrial chemicals, are co nsidered to be potentially mutagenic in vivo because some GE have been show n to be direct mutagens in short-term in vitro tests. 2. The percutaneous penetration and metabolism of representatives of differ ent classes of GE was studied in the fresh, full-thickness C3H mouse, and d ermatomed human and Fisher 344 rat skin to determine the apparent permeabil ity constants, lag times and metabolic profiles. 3. Five different GE, the diglycidyl ethers of bisphenol A (BADGE), 4,4'-di hydroxy-3,3',5,5'-tetramethylbiphenyl (Epikote YX4000) and 1,6-hexanediol ( HDDGE) and the GE of 1-dodecanol (C(12)GE) and o-cresol (o-CGE), were synth esized by reaction of their alcohols with epichlorohydrin. Their radiolabel led analogues were synthesized with a C-14- label using [U-C-14]-epichloroh ydrin. 4. There was a large variation (four orders of magnitude) in percutaneous p enetration between the five GE. In general, penetration through full-thickn ess mouse skin was higher than through dermatomed rat skin, whereas dermato med human skin was the least permeable. The permeability increased in the o rder YX4000 < BADGE < C(12)GE < o-CGE < HDDGE. 5. The relative skin permeability of the five GE could be explained for a s ignificant part by the lipophilicity, expressed as log P-o/w, in combinatio n with the molecular weight of the compounds. 6 . During skin penetration, all GE were extensively metabolized to their cor responding (bis-)diols. Virtually no YX4000, and only very small amounts of C,,GE and BADGE, penetrated the skin unchanged, but significant amounts of HDDGE and o-CGE penetrated the skin unchanged. For o-CGE, but none of the other GE, the percentage of the applied dose that penetrated the skin uncha nged increased over time. 7. The large variation in response observed with the five selected GE indic ates that GE should not be considered as a single class of compounds but ra ther on the basis of their individual properties.