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 considered to be potentially mutagenic in vivo because some GE have been shown to be direct mutagens in short-term in vitro tests. 2. The percutaneous penetration and metabolism of representatives of different classes of GE was studied in the fresh, full-thickness C3H mouse, and dermatomed human and Fisher 344 rat skin to determine the apparent permeability constants, lag times and metabolic profiles. 3. Five different GE, the diglycidyl ethers of bisphenol A (BADGE), 4,4'-dihydroxy-3,3',5,5'-tetramethylbiphenyl (Epikote YX4000) and 1,6-hexanediol (HDDGE) and the GE of 1-dodecanol (C12GE) and o-cresol (o-CGE), were synthesized by reaction of their alcohols with epichlorohydrin. Their radiolabelled analogues were synthesized with a 14C-label using [U-14C]-epichlorohydrin. 4. There was a large variation (four orders of magnitude) in percutaneous penetration between the five GE. In general, penetration through full-thickness mouse skin was higher than through dermatomed rat skin, whereas dermatomed human skin was the least permeable. The permeability increased in the order YX4000 < BADGE < C12GE < o-CGE < HDDGE. 5. The relative skin permeability of the five GE could be explained for a significant part by the lipophilicity, expressed as log P(o/w), in combination with the molecular weight of the compounds. 6. During skin penetration, all GE were extensively metabolized to their corresponding (bis-)diols. Virtually no YX4000, and only very small amounts of C12GE 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 unchanged increased over time. 7. The large variation in response observed with the five selected GE indicates that GE should not be considered as a single class of compounds but rather on the basis of their individual properties.
Boogaard
P J
PJ
Department of Molecular Toxicology, Shell Research and Technology Center, Shell International Chemicals BV, Amsterdam, The Netherlands. Peter.J.Boogaard@opc.shell.com
Denneman
M A
MA
Van Sittert
N J
NJ
D000818:Animals; D001559:Benzhydryl Compounds; D001713:Biphenyl Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D001940:Breast / Q000187:drug effects / Q000378:metabolism; D002273:Carcinogens / Q000737:chemistry / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003408:Cresols / Q000737:chemistry / Q000493:pharmacokinetics; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009153:Mutagens; D010539:Permeability; D051381:Rats; D011916:Rats, Inbred F344; D012588:Scintillation Counting; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D001713:Biphenyl Compounds; D002273:Carcinogens; D003408:Cresols; D004852:Epoxy Compounds; D009153:Mutagens; C414960:epikote YX4000; C020344:glycidyl ethers; C414962:1,6-hexanediol diglycidyl ether; C046242:cresyl glycidyl ether; C414961:1-dodecyl glycidyl ether; C019273:bisphenol A diglycidyl ether; D000098826:Bisphenol A Compounds