title: Investigation of the skin sensitizing properties of 5 osmolytic prodrugs in a weight-of-evidence assessment, employing in silico, in vivo, and read across analyses.
abstract: The amino acid esters ethyl glycinate (EG), DL-α-tocopheryl-(mono-)betainate hydrochloride (TMB), DL-α-tocopheryl-(mono-)glycinate hydrochloride (TMG), DL-α-tocopheryl-(mono-)prolinate hydrochloride (TMP), and DL-α-tocopheryl-(mono-)sarcosinate hydrochloride (TMS) were previously shown to exert an osmoprotective function to human skin in vitro. Based on literature data, the parent compounds α-tocopherol (vitamin E) and the amino acids glycine, betaine (trimethylated glycine), proline, and sarcosine (N-methylated glycine) are not considered to be sensitizers. To investigate skin sensitizing properties of the esters, EG, TMG, and TMP were tested in the Local Lymph Node Assay (LLNA). Remaining esters were assessed by read across analysis considering structural similarities and mechanistic aspects. The LLNA results were consistent with in silico outcomes from ToxTree 2.5.0 indicative for protein binding; EG was negative; TMG and TMP were positive. Since TMB and TMS showed structural similarities to TMG and TMP and were also positive in ToxTree, it was concluded that both TMB and TMS can also be expected to have a skin sensitizing potential and therefore animal testing was waived.
authors.affiliation: Department of Toxicology, Henkel AG & Co. KGaA, Duesseldorf, Germany. julia.scheel@henkel.com
authors.forename: Julia
authors.initials: J
authors.lastname: Scheel
authors.forename: Detlef
authors.initials: D
authors.lastname: Keller
mesh_terms: D000818:Animals; D001622:Betaine / Q000494:pharmacology; D017449:Dermatitis, Allergic Contact / Q000209:etiology / Q000503:physiopathology*; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D023441:Local Lymph Node Assay; D051379:Mice; D009995:Osmosis / Q000187:drug effects*; D011355:Prodrugs / Q000494:pharmacology*; D011392:Proline / Q000494:pharmacology; D012521:Sarcosine / Q000494:pharmacology; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D024502:alpha-Tocopherol / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D011355:Prodrugs; D001622:Betaine; C022010:glycine ethyl ester; D011392:Proline; D024502:alpha-Tocopherol; D005998:Glycine; D012521:Sarcosine