Hair cosmetics: dyes.

Hair plays a significant role in body image, and its appearance can be changed relatively easily without resort to surgical procedures. Cosmetics and techniques have therefore been used to change hair appearance since time immemorial. The cosmetics industry has developed efficient products that can be used on healthy hair or act on concomitant diseases of the hair and scalp. Dyes embellish the hair by bleaching or coloring it briefly, for temporary periods of longer duration, or permanently, depending on the composition of a dye (oxidative or nonoxidative) and its degree of penetration of the hair shaft. The dermatologist's knowledge of dyes, their use, and their possible side effects (contact eczema, cancer, increased porosity, brittleness) can extend to an understanding of cosmetic resources that also treat hair and scalp conditions.

Contact dermatitis to hair dye: an update.

Exposure to hair dyes has long been known as a significant risk factor for development of allergic contact dermatitis among the exposed population as these lead to severe eczema of face and upper trunk in the consumer and hand eczema in hair-dressers. Currently, para-phenylenediamine (PPD) is the main ingredient used in permanent hair color products in the market and is the most important allergen. Prevalence of PPD sensitization is high in patients with contact dermatitis across all continents, with hair dye use being the commonest cause. In order to decrease the burden of disease, use of alternative natural dyeing agents among consumers and use of barrier neoprene gloves among hairdressers should be encouraged apart from stringent legislation to reduce the amount of PPD reaching the consumer.

The challenge of testing chemicals for potential carcinogenicity using multiple short-term assays: an analysis of a proposed test battery for hair dyes.

Recent reports of the association of hair dyes usage with increased bladder cancer risk in women with the slow NAT-2 acetylator phenotype have resulted both in attempts to identify the putative carcinogen as well as in devising batteries of tests that could be used to screen for such putative carcinogens in hair dye formulations, their intermediates and final products. Analytical studies have reported the presence of traces ( approximately 0.5 ppm) of the carcinogen 4-aminobiphenyl in some hair dye preparations. In parallel, SCCNFP (Scientific Committee on Cosmetic and Non-Food Products Intended for Consumers) has suggested the deployment of a battery of six in vitro assays followed by an in vivo assay. The practicality of deploying and interpreting such a battery is analyzed herein as it is expected to result in 64 and 128 possible test results and SCCNFP does not provide detailed guidance of how the test results are to be interpreted. In this study we have applied a previously described Bayesian approach which takes advantage of the known predictive performances of individual assays, to analyze the possible outcomes of the 6-7 test batteries. While the SCCNFP battery is clearly risk-averse, it is shown that performing all of the assays is not always necessary and moreover it does not necessarily improve predictive performance. Finally, based upon the reported mutagenicity of 4-aminobiphenyl, it is doubtful that this "impurity" would be detected by the test battery.

Testing strategies in mutagenicity and genetic toxicology: an appraisal of the guidelines of the European Scientific Committee for Cosmetics and Non-Food Products for the evaluation of hair dyes.

The European Scientific Committee on Cosmetics and Non-Food Products (SCCNFP) guideline for testing of hair dyes for genotoxic/mutagenic/carcinogenic potential has been reviewed. The battery of six in vitro tests recommended therein differs substantially from the batteries of two or three in vitro tests recommended in other guidelines. Our evaluation of the chemical types used in hair dyes and comparison with other guidelines for testing a wide range of chemical substances, lead to the conclusion that potential genotoxic activity may effectively be determined by the application of a limited number of well-validated test systems that are capable of detecting induced gene mutations and structural and numerical chromosomal changes. We conclude that highly effective screening for genotoxicity of hair dyes can be achieved by the use of three assays, namely the bacterial gene mutation assay, the mammalian cell gene mutation assay (mouse lymphoma tk assay preferred) and the in vitro micronucleus assay. These need to be combined with metabolic activation systems optimised for the individual chemical types. Recent published evidence [D. Kirkland, M. Aardema, L. Henderson, L. Müller, Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens. I. Sensitivity, specificity and relative predictivity, Mutat. Res. 584 (2005) 1-256] suggests that our recommended three tests will detect all known genotoxic carcinogens, and that increasing the number of in vitro assays further would merely reduce specificity (increase false positives). Of course there may be occasions when standard tests need to be modified to take account of special situations such as a specific pathway of biotransformation, but this should be considered as part of routine testing. It is clear that individual dyes and any other novel ingredients should be tested in this three-test battery. However, new products are formed on the scalp by reaction between the chemicals present in hair-dye formulations. Ideally, these should also be tested for genotoxicity, but at present such experiences are very limited. There is also the possibility that one component could mask the genotoxicity of another (e.g. by being more toxic), and so it is not practical at this time to recommend routine testing of complete hair-dye formulations as well. The most sensible approach would be to establish whether any reaction products within the hair-dye formulation penetrate the skin under normal conditions of use and test only those that penetrate at toxicologically relevant levels in the three-test in vitro battery. Recently published data [D. Kirkland, M. Aardema, L. Henderson, L. Müller, Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens. I. Sensitivity, specificity and relative predictivity, Mutat. Res. 584 (2005) 1-256] suggest the three-test battery will produce a significant number of false as well as real positives. Whilst we are aware of the desire to reduce animal experiments, determining the relevance of positive results in any of the three recommended in vitro assays will most likely have to be determined by use of in vivo assays. The bone marrow micronucleus test using routes of administration such as oral or intraperitoneal may be used where the objective is extended hazard identification. If negative results are obtained in this test, then a second in vivo test should be conducted. This could be an in vivo UDS in rat liver or a Comet assay in a relevant tissue. However, for hazard characterisation, tests using topical application with measurement of genotoxicity in the skin would be more appropriate. Such specific site-of-contact in vivo tests would minimise animal toxicity burden and invasiveness, and, especially for hair dyes, be more relevant to human routes of exposure, but there are not sufficient scientific data available to allow recommendations to be made. The generation of such data is encouraged.

Ranking of hair dye substances according to predicted sensitization potency: quantitative structure-activity relationships.

Allergic contact dermatitis following the use of hair dyes is well known. Many chemicals are used in hair dyes and it is unlikely that all cases of hair dye allergy can be diagnosed by means of patch testing with p-phenylenediamine (PPD). The objectives of this study are to identify all hair dye substances registered in Europe and to provide their tonnage data. The sensitization potential of each substance was then estimated by using a quantitative structure-activity relationship (QSAR) model and the substances were ranked according to their predicted potency. A cluster analysis was performed in order to help select a number of chemically diverse hair dye substances that could be used in subsequent clinical work. Various information sources, including the Inventory of Cosmetics Ingredients, new regulations on cosmetics, data on total use and ChemId (the Chemical Search Input website provided by the National Library of Medicine), were used in order to identify the names and structures of the hair dyes. A QSAR model, developed with the help of experimental local lymph node assay data and topological sub-structural molecular descriptors (TOPS-MODE), was used in order to predict the likely sensitization potential. Predictions for sensitization potential were made for the 229 substances that could be identified by means of a chemical structure, the majority of these hair dyes (75%) being predicted to be strong/moderate sensitizers. Only 22% were predicted to be weak sensitizers and 3% were predicted to be extremely weak or non-sensitizing. Eight of the most widely used hair dye substances were predicted to be strong/moderate sensitizers, including PPD - which is the most commonly used hair dye allergy marker in patch testing. A cluster analysis by using TOPS-MODE descriptors as inputs helped us group the hair dye substances according to their chemical similarity. This would facilitate the selection of potential substances for clinical patch testing. A patch-test series with potent, frequently used, substances representing various chemical clusters is suggested. This may prove useful in diagnosing PPD-negative patients with symptoms of hair dye allergy and would provide some clinical validation of the QSAR predictions.

Final report on the safety assessment of 6-Amino-m-Cresol, 6-Amino-o-Cresol, 4-Amino-m-Cresol, 5-Amino-4-Chloro-o-Cresol, 5-Amino-6-Chloro-o-Cresol, and 4-Chloro-2-Aminophenol.

Each of these ingredients function as hair colorants. 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol are identified as oxidative hair dyes, that is, they are combined with an oxidizing agent before being applied to the hair. 6-Amino-m-Cresol, 6-Amino-o-Cresol, 4-Amino-m-Cresol, and 5-Amino-4-Chloro-o-Cresol are used in oxidative hair dyes, but it is not known if they are also used in nonoxidative (semipermanent) hair dyes. No toxicologically significant impurities are present with these two ingredients. To supplement the safety test data on these ingredients, available data on related ingredients (4-amino-2-hydroxytoluene and p-,m-, and o-aminophenol) previously found safe as used by the Cosmetic Ingredient Review (CIR) Expert Panel were summarized. 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol do not absorb significant ultraviolet radiation in the UVB region and none in the UVA region, although 4-Amino-m-Cresol had a symmetrical UV absorption peak at 300 nm. Percutaneous penetration of 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol alone was significant, but when combined with oxidative developer, skin absorption was extremely low. Both of these dyes are excreted rapidly via the urine. Repeated exposure of animal skin to 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol failed to produce any cumulative irritation and single exposures up to 10%were not irritating to animal skin. 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol combined with oxidizer were not sensitizers in guinea pig maximization tests. Ocular irritation resulted from exposure of animals to undiluted 5-Amino-4-Chloro-o-Cresol, but not to a 5%solution. Only minor irritation was observed with 5%5-Amino-6-Chloro-o-Cresol. Subchronic toxicity testing in animals using 5-Amino-4-Chloro-o-Cresol, 5-Amino-6-Chloro-o-Cresol, and 4-Amino-m-Cresol did not yield any adverse reactions. 6-Amino-m-Cresol and 4-Amino-m-Cresol were generally not mutagenic in in vitro and in vivo tests. Exposure to 5-Amino-4-Chloro-o-Cresol, 5-Amino-6-Chloro-o-Cresol, 6-Amino-m-Cresol and 4-Amino-m-Cresol from cosmetics were several orders of magnitude below developmental toxicity no-observed-adverse effect levels (NOAELs). Although irritation data on several ingredients are absent, products containing these ingredients must include a caution statement and patch test instructions for determining whether the product causes skin irritation. The Expert Panel expects that following this procedure would identify individuals who would have an adverse reaction and allow them to avoid significant exposures. These compounds, when tested alone, are moderate skin sensitizers, but when combined with the developer, these ingredients are not sensitizers in animal tests. This information, coupled with the available animal test data, supports the safety of these ingredients in oxidative hair dyes. In the absence of systemic toxicity data, however, the available data are insufficient to support the safety of 6-Amino-o-Cresol and 4-Chloro-2-Aminophenol in semipermanent hair dyes. The types of data required for these two ingredients for this use include (1) physical and chemical properties, including the octanol/water partition coefficient; (2) impurities data, especially regarding the presence of m-cresol, other organic molecules, and heavy metals; (3) data demonstrating that the metabolism is similar to that of 4-amino-2-hydroxytoluene and/or p-,m-, and o-aminophenol, or 28-day dermal toxicity with histopathology, dermal reproductive toxicity data, and an in vitro genotoxicity study for 6-Amino-o-Cresol and one genotoxicity study in a mammalian system; if positive, a 2-year dermal carcinogenicity study using National Toxicology Program methods may be needed.

Hair dye use and risk of adult acute leukemia.

Certain chemicals in hair dyes are known animal carcinogens. Darker, more permanent, and earlier dye formulations may be more carcinogenic than other dye types. For 769 adult acute leukemia cases and 623 population-based controls in a US and Canadian case-control study in 1986-1989, the authors asked separately about use of permanent and nonpermanent (semipermanent and temporary) hair dye use. Use was reported by 45% of women and 6% of men. There was a modest positive association for ever use of permanent dyes (odds ratio = 1.5, 95% confidence interval: 1.0, 2.1), which was stronger for long duration (15 or more years) of use (odds ratio = 1.8, 95% confidence interval: 1.0, 3.1). The greatest odds ratio was for 15 or more years of using hair dyes up to six times per year (odds ratio = 2.4, 95% confidence interval: 1.0, 5.8); the corresponding odds ratio for use six or more times a year was lower, suggesting the possibility of misclassification of dye type among frequent users, since nonpermanent dyes tend to be used more frequently than permanent dyes. Nonpermanent dyes were not associated with risk. Long duration of permanent dye use may have a larger impact on the risk of adult acute leukemia and other hematopoietic cancers than prior epidemiologic data suggest.

Hair dye use and other risk factors for leukemia and pre-leukemia: a case-control study. Italian Leukemia Study Group.

A case-control study was carried out to examine the relation of three subtypes of leukemia cells and refractory anemia with excess of blasts to selected behavioral and environmental factors. Cases aged 15 years or older were recruited in three hospitals located in Rome, Bologna, and Pavia, respectively. Outpatients who were either normal or had nonneoplastic hematologic disorders and were seen in the same hospitals as the cases were enrolled as controls. Two hundred fifty-two patients with acute myeloid leukemia, 100 with acute lymphocytic leukemia, 111 with refractory anemia with excess of blasts, 156 with chronic myeloid leukemia, and 1,161 controls were included in the study. Refractory anemia with excess of blasts and chronic myeloid leukemia were included because they are regarded as forms of pre-leukemia. Odds ratio estimates were generally imprecise, but associations were suggested between specific case subtypes and exposure to dark hair dye, selected occupations (shoemaker, painter, electrician, child care), residence in houses built with tuff, and smoking. Although the exploratory nature of the study and its limited statistical power preclude firm conclusions, its results are consistent with those of previous studies, and are in general biologically plausible.

Use of hair coloring products and the risk of lymphoma, multiple myeloma, and chronic lymphocytic leukemia.

OBJECTIVES: Hair coloring products are widely used and contain components that are mutagenic and carcinogenic. An association between occupational exposure to hair coloring products and hematopoietic cancers has been reported, but the risk for these cancers among users has not been carefully evaluated. METHODS: We conducted a population-based, case-control study with telephone interviews from 385 with telephone interviews from 385 non-Hodgkin's lymphoma cases, 70 Hodgkin's disease cases, 72 multiple myeloma cases, 56 chronic lymphocytic leukemia cases, and 1432 controls. RESULTS: Among women, use was associated with odds ratios of 1.5 for non-Hodgkin's lymphoma, 1.7 for Hodgkin's disease, 1.8 for multiple myeloma, and 1.0 for chronic lymphocytic leukemia. Risk was higher for permanent hair coloring products than for semi- or nonpermanent products, particularly for dark colors. Long duration and early age of first use tended to increase risk, but the patterns were inconsistent. Use was much less common in men and did not significantly increase risk. CONCLUSIONS: The use of hair coloring products appears to increase the risk of non-Hodgkin's lymphoma. Multiple myeloma and Hodgkin's disease were also associated, although based on far fewer subjects. If these results represent a causal association, use of hair coloring products would account for 35% of non-Hodgkin's lymphoma cases in exposed women and 20% in all women.