title: Introduction of a methoxymethyl side chain into p-phenylenediamine attenuates its sensitizing potency and reduces the risk of allergy induction.
abstract: The strong sensitizing potencies of the most important primary intermediates of oxidative hair dyes, p-phenylenediamine (PPD) and p-toluylenediamine (PTD, i.e. 2-methyl-PPD) are well established. They are considered as the key sensitizers in hair dye allergic contact dermatitis. While modification of their molecular structure is expected to alter their sensitizing properties, it may also impair their color performance. With introduction of a methoxymethyl side chain we found the primary intermediate 2-methoxymethyl-p-phenylenediamine (ME-PPD) with excellent hair coloring performance but significantly reduced sensitizing properties compared to PPD and PTD: In vitro, ME-PPD showed an attenuated innate immune response when analyzed for its protein reactivity and dendritic cell activation potential. In vivo, the effective concentration of ME-PPD necessary to induce an immune response 3-fold above vehicle control (EC3 value) in the local lymph node assay (LLNA) was 4.3%, indicating a moderate skin sensitizing potency compared to values of 0.1 and 0.17% for PPD and PTD, respectively. Finally, assessing the skin sensitizing potency of ME-PPD under consumer hair dye usage conditions through a quantitative risk assessment (QRA) indicated an allergy induction risk negligible compared to PPD or PTD.
authors: The Procter & Gamble Co., Central Product Safety and Communications, Darmstadt, Germany. Electronic address: goebel.c.1@pg.com.
authors: Carsten
authors: C
authors: Goebel
authors: The Procter & Gamble Co., Central Product Safety, Cincinnati, OH, USA.
authors: John
authors: J
authors: Troutman
authors: Dept. of Environmental Toxicology, Trier University, Trier, Germany.
authors: Jenny
authors: J
authors: Hennen
authors: The Procter & Gamble Co., Central Product Safety and Communications, Darmstadt, Germany.
authors: Helga
authors: H
authors: Rothe
authors: The Procter & Gamble Co., Central Product Safety and Communications, Darmstadt, Germany.
authors: Harald
authors: H
authors: Schlatter
authors: The Procter & Gamble Co., Central Product Safety, Cincinnati, OH, USA.
authors: G Frank
authors: GF
authors: Gerberick
authors: Dept. of Environmental Toxicology, Trier University, Trier, Germany.
authors: Brunhilde
authors: B
authors: Blömeke
mesh_terms: D000818:Animals; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D017449:Dermatitis, Allergic Contact / Q000276:immunology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006202:Hair Dyes / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D023441:Local Lymph Node Assay; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008808:Mice, Inbred CBA; D010655:Phenylenediamines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D018570:Risk Assessment; D012867:Skin / Q000187:drug effects / Q000276:immunology
chemical_list: D051940:B7-2 Antigen; D006202:Hair Dyes; D010655:Phenylenediamines; C587181:2-methoxymethyl-p-phenylenediamine; C029728:4-phenylenediamine
keywords: 2,4-dinitrochlorobenzene; 2-Methoxymethyl-p-phenylenediamine; 2-methoxymethyl-p-phenylenediamine; Alternative methods; DC; DMSO; DNCB; HE-PPD; HRP/P; Hair dyes; Innate immune response; LLNA; ME-PPD; MEL; NESIL; PPD; PTD; QRA; SCCS; SI; Scientific Committee on Consumer Safety; Skin metabolism; Skin sensitization; WoE; dendritic cell; dimethylsulfoxide; horseradish peroxidase and hydrogen peroxide; hydroxyethyl-PPD; local lymph node assay; measured exposure level; no expected sensitization induction level; p-phenylenediamine; p-toluylenediamine; quantitative risk assessment; stimulation index; weight-of-evidence