title: In vitro penetration and subchronic toxicity of alpha-methyl-1,3-benzodioxole-5-propionaldehyde.
abstract: alpha-Methyl-1,3-benzodioxole-5-propionaldehyde (methyl-3,4-methylene-dioxy-hydrocinnamic Aldehyde, MMDHCA) is a widely used commercially available fragrance material. Because of the wide range of product availability, there is dermal exposure associated with its use. The objective of this study was to determine the in vitro human skin absorption of (14)C MMDHCA and subchronic toxicity of the material. Twenty mL of a 1% solution of radiolabeled MMDHCA in ethanol was applied to the surface of epidermal membranes isolated from full thickness human skin samples and placed in diffusion cells. Samples of the receptor fluid (50% ethanol/water) were harvested at 2, 8, 24, and 48 h and analyzed by liquid scintillation chromatography to assess dermal absorption. At 24 and 48 h, respectively, 42% and 50% of the applied dose of MMDHCA had permeated the human skin in vitro. Only 67% of the applied dose was recovered by 48 h. For the subchronic toxicity, MMDHCA was applied dermally once daily to male and female Sprague-Dawley rats (15/sex/group) at 50, 150, or 300 mg/kg/day (0.043, 0.129, or 0.259 mL/kg/day applied neat to 5 cm(2) dorsal skin) for at least 90 consecutive days. A control group (15/sex) was given vehicle (reverse osmosis water) at 0.259 mL/kg/day for a similar duration. Rats were necropsied at the end of treatment (10/sex/group) or following a 4-week recovery period (5/sex/group). The following parameters were evaluated: dermal irritation, estrous cycle, ophthalmologic examinations, body weight, feed consumption, hematology, blood coagulation, serum chemistry, organ weights, macroscopic and histopathologic examinations, and male reproductive assessment. No test article-related mortalities or effects on, estrous cycles, ophthalmic exams, mean body weights, mean body weight change, feed consumption, absolute or relative organ weights, macroscopic observations, or male reproductive morphology/function were observed. MMDHCA-related dermal irritation was observed across all dose levels with increased incidence and severity at 300 mg/kg/day. Dermal irritation that initially ranged from slight to marked improved to slight or resolved completely during the recovery phase. Based on the findings in this study, it can be concluded that (1) MMDHCA exhibits moderately high human skin permeation; (2) the NOEL for dermal irritation is below 50mg/kg/day when applied undiluted to 5 cm(2) dorsal skin and (3) the NOEL for systemic toxicity is greater than 300 mg/kg/day. During the 4-week recovery period of the 90-day study, the animals had largely recovered from MMDHCA induced dermal irritation and the associated microscopic findings.
authors.affiliation: Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. amapi@rifm.org <amapi@rifm.org>
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Api
authors.forename: Aurelia
authors.initials: A
authors.lastname: Lapczynski
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Isola
authors.forename: I
authors.initials: I
authors.lastname: Glenn Sipes
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001774:Blood Chemical Analysis; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D002853:Chromatography, Liquid / Q000662:veterinary; D004148:Dioxolanes / Q000493:pharmacokinetics* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D030762:Estrous Cycle / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D010476:Perfume / Q000493:pharmacokinetics / Q000633:toxicity; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012869:Skin Absorption / Q000187:drug effects; D012871:Skin Diseases / Q000139:chemically induced* / Q000473:pathology; D036401:Toxicity Tests, Chronic
chemical_list: D002250:Carbon Radioisotopes; D004148:Dioxolanes; D010476:Perfume; C512486:alpha-methyl-3,4-methylene-dioxyhydrocinnamic aldehyde