Hydroxyethyl-3,4-methylenedioxyaniline HCl

EU 1223/2009 Annex III — SCCS opinion: Opinion on Hydroxyethyl-3

EU 1223/2009 Annex III — SCCS opinion: Assessment Strategies for Hair Dyes

EU 1223/2009 Annex III — SCCS opinion: Opinion on the Use of Permanent Hair Dyes and Bladder Cancer Risk

EU 1223/2009 Annex III — SCCS opinion: Opinion on Personal Use of Hair Dyes and Cancer Risk

EU 1223/2009 Annex III — SCCS opinion: Opinion concerning Use of Permanent Hair Dyes and Bladder Cancer - Updated 2004

Definition and Structure Hydroxyethyl-3,4-Methylenedioxyaniline HCl (CAS# 94158-14-2) is the bicyclic, ammonium salt that conforms to the structure in Figure 1.1 Figure 1. Hydroxyethyl-3,4-Methylenedioxyaniline HCl Hydroxyethyl-3,4-Methylenedioxyaniline HCl is used as an oxidative hair coloring “precursor” ingredient.2,6 In a 2009 SCCS report, an industry submission indicated that this oxidative coloring precursor and a developer (hydrogen peroxide) were mixed at ratios ranging from 1:1 to 1:3.2 However, Hydroxyethyl-3,4-Methylenedioxyaniline HCl was also listed as a “coupler” in a different SCCS report from 2010.3 No reaction scheme was found in the literature. In a typical formulation, a precursor is activated via an oxidant, such as peroxide. The resultant activated precursor proceeds to react with a coupler to form in-situ a product that is purported to be the actual dye that colors hair in these types of oxidative hair dyes. Physical and Chemical Properties Hydroxyethyl-3,4-Methylenedioxyaniline HCl is a beige crystal.2 It is soluble in water, acetone/water, dimethyl sulfoxide (DMSO), and ethanol (Table 1). Method of Manufacture There were no method of manufacture data identified in the literature for Hydroxyethyl-3,4-Methylenedioxyaniline HCl. Impurities and Nitrosation Impurities that may be present in Hydroxyethyl-3,4-Methylenedioxyaniline HCl include 3,4-methylenedioxy-aniline (114 to 1097 ppm in 5 batches tested), 1,3-benzodioxol (below limit of detection [35 ppm] in 5 batches tested), and 1,2-methylenedioxy-4- nitrobenzene (below limit of detection [8 ppm] in 5 batches tested).2 The following residual solvents were not identified at a 100 ppm … [kırpıldı — bölüm toplam 13221 karakter]

A non-GLP study was conducted in Pirbright White (SPF) guinea pigs (n=10 females) evaluating 2% (water vehicle) Hydroxyethyl- 3,4-Methylenedioxyaniline HCl.2 A single, 0.1 ml application of the test substance was instilled into the conjunctival sac of the right eye, and the left eye served as the control; the eyes were not rinsed following application. Eyes were examined 0.5, 1, 2, 3, 4, 6, and 7 hours after the instillation of the test substance. At 24 hours following treatment, a fluorescein-instillation reading was performed. Edema, slight conjunctival redness, and corneal opacity were observed in 2 animals 3 hours post-instillation. The SCCS report indicates that 2% Hydroxyethyl-3,4-Methylenedioxyaniline HCl caused transient irritation to guinea pig eyes. EPIDEMIOLOGY STUDIES Hydryoxyethyl-3,4-Methylenedioxyaniline HCl is used as an oxidative (permanent) hair dye ingredient. While the safety of individual hair dye ingredients is not addressed in epidemiology studies that seek to determine links, if any, between hair dye use and disease, such studies do provide broad information. Currently available epidemiology studies provided insufficient evidence to support a causal association between personal hair dye use and a variety of tumors and cancers. A detailed summary of the available hair dye epidemiology data is available at http://www.cir-safety.org/cir-findings.

Irritation Animal A non-GLP study was conducted in female, Pirbright White (SPF) guinea pigs (n=15) to evaluate the effect of Hydroxyethyl-3,4- Methylenedioxyaniline HCl through dermal exposure.2 A 5% aqueous solution of Hydroxyethyl-3,4-Methylenedioxyaniline HCl (purity not specified) was applied (non-occlusive) to a 12 cm2 area of clipped flank skin one time per day for 5 consecutive days. The skin was examined for signs of irritation 5 hours following each application and on the third day following the final application. The results indicated that the test substance was non-irritating. Sensitization Animal A local lymph node assay (LLNA) was performed in accordance with OECD TG 429 and GLP.2 To examine skin sensitization potential, the cell proliferation in the draining lymph nodes was measured in CBA/J mice (n=5 females/ concentration) following dermal exposure to Hydroxyethyl-3,4-Methylenedioxyaniline HCl (99.7% purity). Twenty-five microliters of 0 (vehicle only), 0.5, 1.5, 5, and 10% Hydroxyethyl-3,4-Methylenedioxyaniline HCl (in DMSO, or in a 3:1 mixture of water/acetone (1:1) and olive oil) were applied to the ear skin of mice for 3 consecutive days. A hair dryer was used to dry the ears after application. At the 1.5% test concentration (DMSO vehicle), slight-to-severe skin desquamation on the ears was observed in all animals by day 5, and erythema was noted in one animal. The authors attributed these effects to the low pH of the test solution.2 The stimulation indices for all the test concentrations in either vehicle were greater than 3 (dose-dependent with DMSO vehicle), and an EC3 (“equal to the concentration inducing a stimulation index of 3”) was not estimated. Positive controls performed as expected. The results using either vehicle indicated that dermally applied Hydroxyethyl-3,4-Methylenedioxyaniline HCl has strong sensitization potential in mice. QSAR … [kırpıldı — bölüm toplam 3961 karakter]

There were no carcinogenicity studies for Hydroxyethyl-3,4-Methylenedioxyaniline HCl found in the literature, and unpublished data were not provided.

Provided below is a summary of genotoxicity studies that are presented in detail in Table 3. Experiments examining Hydroxyethyl-3,4-Methylenedioxyaniline HCl were conducted in vitro. An Ames test using Salmonella typhimurium was negative for genotoxicity up to 5000 µg/plate.2 A mammalian cell gene mutation assay using mouse lymphoma cells was non-mutagenic during a 4-hour incubation with concentrations up to 1100 µg/ml with metabolic activation and up to 1650 µg/ml without activation. In an in vitro micronucleus test performed in human peripheral blood lymphocytes, there was a statistically significant, concentration-dependent increase in relevant micronucleated binucleate cells in the presence of metabolic activation. This indication of chromosomal damage resulted from a 3-hour treatment (at concentrations up to 2177 µg/ml) performed 48 hours after mitogen stimulation (cells were harvested 96 hours after mitogen stimulation); cytotoxicity (13% to 65%) was noted at concentrations ranging from 700 to 2177 µg/ml in several of the micronucleus experiments. Palpebral closure and lethargy were observed 1 hour post-administration in an in vivo bone marrow micronucleus test conducted in mice that were intraperitoneally exposed to Hydroxyethyl-3,4-Methylenedioxyaniline HCl (up to 250 mg/kg). 2 No chromosomal aberrations or damage to the mitotic apparatus in bone marrow cells were observed from treatment with the test substance.

EPA ToxValDB skin/eye data — endpoint: skin sensitisation: in vivo (LLNA), classification: High Frequency of Sensitization, species: mouse, study: skin sensitization, guideline: according to OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay), year: 2004. Caveat: this is an aggregated record; dose, species and route of exposure must be considered together.