title: Risk assessment of topically applied products.
abstract: The human risk of harmful substances in semisolid topical dosage forms applied topically to normal skin and broken skin, respectively, was assessed. Bisphenol A diglycidyl ether (BADGE) and three derivatives of BADGE previously quantified in aqueous cream and the UV filters 3-BC and 4-MBC were used as model compounds. Tolerable daily intake (TDI) values have been established for BADGE and derivatives. Endocrine disruption was chosen as endpoint for 3-BC and 4-MBC. Skin permeation of the model compounds was investigated in vitro using pig skin membranes. Tape stripping was applied to simulate broken skin associated with various skin disorders. BADGE and derivatives had a tendency to permeate pig skin membranes in vitro with higher fluxes in the tape stripped membranes compared to the non-treated membranes. Data from the in vitro skin permeation study and from the literature were used as input parameters for estimating the risk. The immediate human risk of BADGE and derivatives in topical dosage forms was found to be low. However, local treatment of broken skin may lead to higher exposure of BADGE and derivatives compared to application to normal skin. 3-BC permeated skin at higher flux than 4-MBC. Both UV filters are endocrine disrupting compounds with 3-BC being the more potent. UV filters in sunscreen are often present in high concentrations, which potentially may lead to high systemic exposure dosages. Thus, the risk associated with use of 3-BC and 4-MBC containing sunscreen with regards to endocrine disrupting effects was found to be high and more data is urgently needed in order to fully assess the human risk of 3-BC and 4-MBC in commercial sunscreen.
authors.affiliation: Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 [corrected] Copenhagen [corrected] Denmark. tus@dkma.dk
authors.forename: Tue
authors.initials: T
authors.lastname: Søeborg
authors.forename: Line Hollesen
authors.initials: LH
authors.lastname: Basse
authors.forename: Bent
authors.initials: B
authors.lastname: Halling-Sørensen
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001559:Benzhydryl Compounds; D001593:Benzyl Compounds / Q000633:toxicity*; D002164:Camphor / Q000031:analogs & derivatives* / Q000633:toxicity; D004304:Dosage Forms; D004852:Epoxy Compounds / Q000633:toxicity*; D006801:Humans; D066298:In Vitro Techniques; D019055:No-Observed-Adverse-Effect Level; D018570:Risk Assessment; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption; D013473:Sunscreening Agents / Q000633:toxicity*; D013552:Swine; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D001593:Benzyl Compounds; D002164:Camphor; D004304:Dosage Forms; D004852:Epoxy Compounds; D013473:Sunscreening Agents; C511303:3-benzylidene camphor; C038939:enzacamene; C019273:bisphenol A diglycidyl ether; D000098826:Bisphenol A Compounds