Safety Assessment of Basic Red 76 as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of Basic Red 76, which is reported to function in cosmetics as a hair colorant and hair-conditioning agent. The Panel reviewed the available data to determine the safety of this ingredient. The Panel concluded that Basic Red 76 is safe for use as a hair dye ingredient in the present practices of use and concentration described in the safety assessment.

Hair dyes: a systematic review of pertinent in vivo human studies.

What is the safety of hair dyes in human use? To address this, the penetration of hair dyes into human bodies must be quantified. This article provides a critical overview to update work published in the area of in vivo hair dye penetration in humans. Studies are in humans, with one including rhesus monkey and one including in vitro human skin. MEDLINE, PubMed, Embase, Scopus, Web of Science, and Google Scholar databases were searched from 2004 to October 2019 for articles with experimental methodology on in vivo percutaneous absorption of hair dyes in humans and six studies were included. Findings indicate that percutaneous penetration occurs with hair dye use, with less absorbed in hairdressers. However, much remains unknown about the penetration of the over 200 commercially available hair dyes. A major void exists in data confirming or denying the completeness of excretion once absorbed.

Safety Assessment of 2-Amino-3-Hydroxypyridine as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of 2-Amino-3-Hydroxypyridine, which is reported to function as an oxidative hair dye ingredient. The Panel reviewed relevant animal and human data provided in this safety assessment, and concluded that 2-Amino-3-Hydroxypyridine is safe in the present practices of use and concentration for use in oxidative hair dye formulations.

The Bio-Safety Concerns of Three Domestic Temporary Hair Dye Molecules: Fuchsin Basic, Victoria Blue B and Basic Red 2.

Hair-coloring products include permanent, semi-permanent and temporary dyes that vary by chemical formulation and are distinguished mainly by how long they last. Domestic temporary hair dyes, such as fuchsin basic, basic red 2 and Victoria blue B, are especially popular because of their cheapness and facile applications. Despite numerous studies on the relationship between permanent hair dyes and disease, there are few studies addressing whether these domestic temporary hair dyes are associated with an increased cancer risk. Herein, to ascertain the bio-safety of these temporary hair dyes, we comparatively studied their percutaneous absorption, hemolytic effect and cytotoxic effects in this paper. Furthermore, to better understand the risk of these dyes after penetrating the skin, experimental and theoretical studies were carried out examining the interactions between the dyes and serum albumins as well as calf thymus (CT)-DNA. The results showed that these domestic temporary hair dyes are cytotoxic with regard to human red blood cells and NIH/3T3 cell lines, due to intense interactions with bovine serum albumin (BSA)/DNA. We conclude that the temporary hair dyes may have risk to human health, and those who use them should be aware of their potential toxic effects.

Investigation of hair dye deposition, hair color loss, and hair damage during multiple oxidative dyeing and shampooing cycles.

Color fastness is a major concern for consumers and manufacturers of oxidative hair dye products. Hair dye loss results from multiple wash cycles in which the hair dye is dissolved by water and leaches from the hair shaft. In this study, we carried out a series of measurements to help us better understand the kinetics of the leaching process and pathways associated with its escape from the fiber. Hair dye leaching kinetics was measured by suspending hair in a dissolution apparatus and monitoring the dye concentration in solution (leached dye) with an ultraviolet-visible spectrophotometer. The physical state of dye deposited in hair fibers was evaluated by a reflectance light microscopy technique, based on image stacking, allowing enhanced depth of field imaging. The dye distribution within the fiber was monitored by infrared spectroscopic imaging of hair fiber cross sections. Damage to the ultrafine structure of the hair cuticle (surface, endocuticle, and cell membrane complex) and cortex (cell membrane complex) was determined in hair cross sections and on the hair fiber surface with atomic force microscopy. Using differential scanning calorimetry, we investigated how consecutive coloring and leaching processes affect the internal proteins of hair. Further, to probe the surface properties of hair we utilized contact angle measurements. This study was conducted on both pigmented and nonpigmented hair to gain insight into the influence of melanin on the hair dye deposition and leaching processes. Both types of hair were colored utilizing a commercial oxidative hair dye product based on pyrazole chemistry.

The use of personal hair dye and its implications for human health.

Hair dye products now represent one of the most rapidly growing beauty and personal care industries as both men and women commonly change hair color to enhance youth and beauty and to follow fashion trends. Irrespective of economic and education status, people dye their hair to emphasize the importance given to appearance. Despite adverse reactions, many people continue dyeing mainly for cosmetic purposes. This paper provides a comprehensive review on various aspects of hair dying products, especially with respect to the hair-coloring process, classification, chemical ingredients, possible human health impacts, and regulations. Permanent hair dye, which is the most commonly used product type, is formed by an oxidative process involving arylamines to bring about concerns with long-term exposure. Hence, significant efforts have been put to understand the possible side effects of such exposure including cancer risk. However, hair dyes and their ingredients are mainly identified to have moderate to low acute toxicity such as the cause of allergic contact dermatitis. Although some hair dye components are reported to be carcinogenic in animals, such evidence is not consistent enough in the case of human studies. Consequently, further research is desirable to critically address the significance of this issue, especially with respect to the safety of hair dye ingredients.

Suitability of the in vitro Caco-2 assay to predict the oral absorption of aromatic amine hair dyes.

Oral absorption is a key element for safety assessments of cosmetic ingredients, including hair dye molecules. Reliable in vitro methods are needed since the European Union has banned the use of animals for the testing of cosmetic ingredients. Caco-2 cells were used to measure the intestinal permeability characteristics (Papp) of 14 aromatic amine hair dye molecules with varying chemical structures, and the data were compared with historical in vivo oral absorption rat data. The majority of the hair dyes exhibited Papp values that indicated good in vivo absorption. The moderate to high oral absorption findings, i.e. ≥60%, were confirmed in in vivo rat studies. Moreover, the compound with a very low Papp value (APB: 3-((9,10-dihydro-9,10-dioxo-4-(methylamino)-1-anthracenyl)amino)-N,N-dimethyl-N-propyl-1-propanaminium) was poorly absorbed in vivo as well (5% of the dose). This data set suggests that the Caco-2 cell model is a reliable in vitro tool for the determination of the intestinal absorption of aromatic amines with diverse chemical structures. When used in combination with other in vitro assays for metabolism and skin penetration, the Caco-2 model can contribute to the prediction and mechanistic interpretation of the absorption, metabolism and elimination properties of cosmetic ingredients without the use of animals.

Extrapolation of systemic bioavailability assessing skin absorption and epidermal and hepatic metabolism of aromatic amine hair dyes in vitro.

Approaches to assess the role of absorption, metabolism and excretion of cosmetic ingredients that are based on the integration of different in vitro data are important for their safety assessment, specifically as it offers an opportunity to refine that safety assessment. In order to estimate systemic exposure (AUC) to aromatic amine hair dyes following typical product application conditions, skin penetration and epidermal and systemic metabolic conversion of the parent compound was assessed in human skin explants and human keratinocyte (HaCaT) and hepatocyte cultures. To estimate the amount of the aromatic amine that can reach the general circulation unchanged after passage through the skin the following toxicokinetically relevant parameters were applied: a) Michaelis-Menten kinetics to quantify the epidermal metabolism; b) the estimated keratinocyte cell abundance in the viable epidermis; c) the skin penetration rate; d) the calculated Mean Residence Time in the viable epidermis; e) the viable epidermis thickness and f) the skin permeability coefficient. In a next step, in vitro hepatocyte Km and Vmax values and whole liver mass and cell abundance were used to calculate the scaled intrinsic clearance, which was combined with liver blood flow and fraction of compound unbound in the blood to give hepatic clearance. The systemic exposure in the general circulation (AUC) was extrapolated using internal dose and hepatic clearance, and Cmax was extrapolated (conservative overestimation) using internal dose and volume of distribution, indicating that appropriate toxicokinetic information can be generated based solely on in vitro data. For the hair dye, p-phenylenediamine, these data were found to be in the same order of magnitude as those published for human volunteers.

Ethosomes in hair dye products as carriers of the major compounds of black tea extracts.

OBJECTIVES: This study describes a novel carrier, the ethosome-based system, which is composed of non-ionic surfactants, ethanol, and water. METHODS: Brij(®) 52 (non-ionic surfactants), soya phosphatidylcholine (PC), cholesterol, and the major compounds (caffeine and gallic acid) of black tea extracts were dissolved in the ethanolic phase. The aqueous phase containing Paragon III was heated to 60 °C and mixed with the previous solution. Finally, 3.4 ml NaOH (6.5 N) was added to adjust the pH level to 4.05. The mixture was centrifuged at 2000 g for two minutes, and the precipitate was taken as the end product. Black tea extracts were applied in ethosome-based formulations, and the efficacy of these formulations in penetrating nude mouse skin and in dyeing white hairs was investigated. RESULTS: Compared with an ethanolic solution and black tea extracts, the non-ionic ethosomal delivery system dramatically enhanced the adsorption of black tea extracts onto hair surfaces in vitro. The non-ionic ethosomal system was much more efficient in delivering and facilitating the adsorption of black tea extracts to the hair surface than hydroalcoholic black tea extracts. CONCLUSIONS: This formulation may have potential for development as a hair dye and protective agent.

Artificial membranes as models in penetration investigations.

BACKGROUND/AIMS: In vitro methods used in the research of transepidermal transport of active substances generally rely on the penetration rate of test compounds through standard membranes. Models typically used in penetration experiments are specially prepared human or animal skin samples or synthetic membranes. The objective of this study was to establish if the test results for an artificial liposome membrane can be extrapolated to determine the actual bioavailability of active substances. METHODS: Tests were conducted in a side-by-side diffusion cell. As model membranes, a liquid-crystal lipid membrane (LM), phospholipid membrane (PM) and pig skin sample were used. The test compounds were eight synthetic dyes used in hair colouring products. RESULTS/CONCLUSION: Research findings reveal that membranes composed of lipids, identical to those present in the epidermis and forming analogical liquid-crystal structures provide a close approximation of the actual bioavailability of active substances (correlation between the results obtained for pig skin and LM was significant: R = 0.95 and R = 0.93 in the presence of a 1% Sodium dodecyl sulphate in donor system). Unlike biological membranes, intercellular cement does not contain phospholipids. The observed correlation between penetration coefficients through the PM and pig skin was not significant (R = 0.82). The experiments confirm that the PM constitutes a less credible model for the studies of transepidermal transport in real life conditions.

Permanent hair dye-incorporated hyaluronic acid nanoparticles.

We prepared p-phenylenediamine (PDA)-incorporated nanoparticles using hyaluronic acid (HA). PDA-incorporated HA nanoparticles have spherical shapes and sizes were less than 300 nm. The results of FT-IR spectra indicated that PDA-incorporated HA nanoparticles were formed by ion-complex formation between amine group of PDA and carboxyl group of HA. Furthermore, powder-X-ray diffractogram (XRD) measurement showed that intrinsic crystalline peak of PDA disappeared by formation of nanoparticle with HA at XRD measurement. These results indicated that PDA-incorporated HA nanoparticles were formed by ion-complex formation. At drug release study, the higher PDA contents induced faster release rate from nanoparticles. PDA-incorporated nanoparticles showed reduced intrinsic toxicity against HaCaT human keratinocyte cells at MTT assay and apoptosis assay. We suggest that PDA-incorporated HA nanoparticles are promising candidates for novel permanent hair dye.

Hair dye-incorporated poly-γ-glutamic acid/glycol chitosan nanoparticles based on ion-complex formation.

BACKGROUND: p-Phenylenediamine (PDA) or its related chemicals are used more extensively than oxidative hair dyes. However, permanent hair dyes such as PDA are known to have potent contact allergy reactions in humans, and severe allergic reactions are problematic. METHODS: PDA-incorporated nanoparticles were prepared based on ion-complex formation between the cationic groups of PDA and the anionic groups of poly(γ-glutamic acid) (PGA). To reinforce PDA/PGA ion complexes, glycol chitosan (GC) was added. PDA-incorporated nanoparticles were characterized using field-emission scanning electron microscopy, Fourier- transform infrared (FT-IR) spectroscopy, dynamic light scattering, and powder X-ray diffractometry (XRD). RESULTS: Nanoparticles were formed by ion-complex formation between the amine groups of PDA and the carboxyl groups of PGA. PDA-incorporated nanoparticles are small in size (<100 nm), and morphological observations showed spherical shapes. FT-IR spectra results showed that the carboxylic acid peak of PGA decreased with increasing PDA content, indicating that the ion complexes were formed between the carboxyl groups of PGA and the amine groups of PDA. Furthermore, the intrinsic peak of the carboxyl groups of PGA was also decreased by the addition of GC. Intrinsic crystalline peaks of PDA were observed by XRD. This crystalline peak of PDA was completely nonexistent when nanoparticles were formed by ion complex between PDA, PGA, and GC, indicating that PDA was complexed with PGA and no free drug existed in the formulation. During the drug-release experiment, an initial burst release of PDA was observed, and then PDA was continuously released over 1 week. Cytotoxicity testing against HaCaT human skin keratinocyte cells showed PDA-incorporated nanoparticles had lower toxicity than PDA itself. Furthermore, PDA-incorporated nanoparticles showed reduced apoptosis and necrosis reaction at HaCaT cells. CONCLUSION: The authors suggest that these microparticles are ideal candidates for a vehicle for decreasing side effects of hair dye.

Determination of 2,5-toluylenediamine (2,5-TDA) and aromatic amines in urine after personal application of hair dyes: kinetics and doses.

The personal use of hair dye products is currently under discussion due to the potentially increased risk of bladder cancer among long-time users described in epidemiological literature. In order to investigate the dermal absorption of aromatic diamines as well as aromatic amines possibly present as contaminants in hair dye formulations, we conducted a biomonitoring study under real-life conditions and calculated kinetics and doses for the urinary excretion. Urine samples of two female subjects were collected for a time period of 48 h after personal application of a hair dye cream and analysed for aromatic diamines as well as o-toluidine and 4-aminobiphenyl using highly specific GC/MS-methods. 2,5-Toluylenediamine (2,5-TDA) as active ingredient of hair dyes is rapidly absorbed dermally. After a distribution phase of 12 h, 2,5-TDA is excreted with a half-time of 8 h. Excretion was 90% complete within 24 h after application. The doses of 2,5-TDA excreted within 48 h were 700 µg for application of a brown-reddish hair dye cream and 1.5 mg for the application of a brown-black hair dye cream. Urinary 4-aminobiphenyl as well as contaminations with other aromatic diamines were not detectable in our study. Due to the artifactual formation of o-toluidine in the presence of high concentrations of urinary 2,5-TDA, our results could not prove an increased internal exposure of humans to carcinogenic amines after personal application of hair dyes.

Internal exposure of hairdressers to permanent hair dyes: a biomonitoring study using urinary aromatic diamines as biomarkers of exposure.

PURPOSE: To determine whether the occupational exposure of hairdressers to permanent hair dyes can be quantified by the use of biological monitoring of urinary aromatic diamines as one of the main constituents and to compare these levels to those recently determined in persons after personal application of hair dyes. METHODS: Fifty-two hairdressers (40 female and 12 male) from 16 hairdresser salons in and around the city of Aachen took part in this field study. Subjects were asked to document all operations associated with possible exposure to permanent hair dyes like mixing colour, application of colour, washing after dyeing, and cutting of freshly coloured hair. Excretion of aromatic diamines 2,5-toluylene diamine (2,5-TDA) and p-phenylene diamine (p-PDA) as main constituents of commercially available hair dyes was measured in urine samples using a highly specific and accurate GC/MS-method. Urine samples were taken at 5 points of time during the work week: pre-shift before the start of the work week, pre- and post-shift on the third day of the work week and finally pre- and post-shift on the last day of a work week in order to meet different workloads and possible accumulative effects over the week. Nineteen persons matched for age served as a control group and gave spot urine samples. RESULTS: Although the levels were generally low, we could determine a significantly higher internal exposure to 2,5-TDA in hairdressers (medians ranged from <0.2 µg/g creatinine up to 1.7 µg/g creatinine at various sampling times, with a maximum of 155.8 µg/g creatinine) compared to the control group (median <0.2 µg/g creatinine, maximum 3.33 µg/g creatinine). At the same time, p-PDA was detectable only in selected cases in the group of hairdressers but not in the control group. Overall, there was neither an intra-shift effect seen nor an effect across the work week. There was also no significant difference in urinary excretion of participants who reported wearing protective gloves compared to those who reported not wearing protective gloves. CONCLUSION: The internal exposure to aromatic diamines in hairdressers using permanent hair dyes can be determined using biological monitoring. The extent of exposure is low compared to subjects after personal application of hair dyes, who excreted more than 200 times higher amounts of aromatic diamines. This slight work-related exposure might be reduced by the strict adherence to the use of suitable gloves as well as long-sleeved clothing.

Dermal penetration and metabolism of p-aminophenol and p-phenylenediamine: application of the EpiDerm human reconstructed epidermis model.

To address the provision of the 7th Amendment to the EU Cosmetics Directive banning the use of in vivo genotoxicity assays for testing cosmetic ingredients in 2009, the 3D EpiDerm reconstructed human skin micronucleus assay has been developed. To further characterise the EpiDerm tissue for potential use in genotoxicity testing, we have evaluated the dermal penetration and metabolism of two hair dye ingredients, p-aminophenol (PAP) and p-phenylenediamine (PPD) in this reconstructed epidermis model. When EpiDerm tissue was topically exposed to PAP or PPD for 30 min (typical for a hair dye exposure), the majority (80->90%) of PAP or PPD was excluded from skin tissue and removed by rinsing. After a 23.5h recovery period, the PAP fraction that did penetrate was completely N-acetylated to acetaminophen (APAP). Similarly, 30 min topical application of PPD resulted in the formation of the N-mono- and N,N'-diacetylated metabolites of PPD. These results are consistent with published data on the dermal metabolism of these compounds from other in vitro systems as well as from in vivo studies. When tissue was exposed topically (PAP) or via the culture media (PPD) for 24h, there was good batch-to-batch and donor-to-donor reproducibility in the penetration and metabolism of PAP and PPD. Overall, the results demonstrate that these two aromatic amines are biotransformed in 3D EpiDerm tissue via N-acetylation. Characterising the metabolic capability of EpiDerm tissue is important for the evaluation of this model for use in genotoxicity testing.

Amended safety assessment of sodium picramate and picramic acid.

Sodium picramate is the sodium salt of picramic acid, a substituted phenolic compound. Sodium picramate and picramic acid function as hair colorants; they are reportedly used in 31 and 3 hair-dye products, respectively. No concentration-of-use data were available for sodium picramate, but picramic acid was reported to be used at 0.6%. The Cosmetic Ingredient Review Expert Panel recognized that adding picramic acid to a hair-dye formulation likely results in formation of a salt such as sodium picramate, which suggested that safety test data for one ingredient would be applicable to the other. Hair dyes containing these ingredients bear a caution statement and patch test instructions for determining whether the product causes skin irritation. The panel finds that the available data support the safety of these colorants in hair dyes and expects that sodium picramate would be used at concentrations comparable to those reported for picramic acid.

Final report on the safety assessment of amino nitrophenols as used in hair dyes.

2-Amino-3-nitrophenol, 2-amino-4-nitrophenol, 2-amino-5-nitrophenol, 4-amino-3-nitrophenol, 4-amino-2-nitrophenol, 2-amino-4-nitrophenol sulfate, 3-nitro-p-hydroxyethylaminophenol, and 4-hydroxypropylamino-3-nitrophenol are substituted aromatic compounds used as semipermanent (nonoxidative) hair colorants and as toners in permanent (oxidative) hair dye products. All ingredients in this group except 2-amino-4-nitrophenol sulfate, 2-amino-5-nitrophenol, and 4-amino-2-nitrophenol have reported uses in cosmetics at use concentrations from 2% to 9%. The available toxicity studies for these amino nitrophenol hair dyes did not suggest safety concerns except for the potential carcinogenicity and mutagenicity of 4-amino-2-nitrophenol. 2-Amino-3-nitrophenol, 2-amino-4-nitrophenol, 2-amino-4-nitrophenol sulfate, 2-amino-5-nitrophenol, 4-amino-3-nitrophenol, 3-nitro-p-hydroxyethylaminophenol, and 4-hydroxypropylamino-3-nitrophenol are safe as hair dye ingredients in the practices of use and concentration as described in this safety assessment, but the data are insufficient to make a safety determination for 4-amino-2-nitrophenol.

Human percutaneous absorption of a direct hair dye comparing in vitro and in vivo results: implications for safety assessment and animal testing.

Although in vitro skin absorption studies often detect small residues of applied test material in the epidermis/dermis, it is uncertain whether the residue is within the living skin. We studied the dermal absorption of a hair dye hydroxyanthraquinone-aminopropyl methyl morpholinium methosulphate (HAM) in human skin in vivo and in vitro. In vivo, skin (back and scalp) received 0.5% HAM in a commercial formulation at 20microg/cm2 After 0.5 or 48h, skin was tape stripped, followed by cyanoacrylate biopsies (CAB). Sebum from scalp sites was collected for 48h. In vitro, skin was treated with 20mg/cm2 dye for 0.5h, penetration determined after 24h. In vivo, at 0.5h, total recovery (back) was 0.67microg/cm2 (tape strips+CAB). Fluorescence microscopy showed HAM in the hair follicle openings (HFO). At 0.5h, scalp tape strips contained 1.80microg/cm2, HFO 0.82microg/cm2. At 48h, HFO contained 0.21microg/cm2, sebum 0.80microg/cm2. In vivo, skin residues were in the non-living skin and eliminated via desquamation and sebum secretion. In vitro, the SC contained 1.50microg/cm2, epidermis/dermis 0.86microg/cm2, receptor fluid<0.04microg/cm2, a total of 0.90microg/cm2 was considered to be bioavailable. In vitro epidermis/dermis residues were nearly identical to those located in non-living skin in vivo. In conclusion, in vitro percutaneous penetration studies may produce seemingly bioavailable material , which raises the need for a Threshold of Skin Absorption (TSA) addressing a negligible dermal absorption in order to avoid unnecessary in vivo toxicity studies on substances that produce no significant human systemic exposure.

Final report on the safety assessment of Basic Blue 99.

Basic Blue 99 is a direct, nonoxidative hair colorant used in temporary and semipermanent hair dyes. According to current reported usage data, Basic Blue 99 is used at concentrations from 0.004% to 2% and the most often reported use is in hair tints. Hair dyes containing Basic Blue 99, as "coal tar" hair dye products, are exempt from the principal adulteration provision and from the color additive provision of the Federal Food, Drug, and Cosmetic Act of 1938 when the label bears a caution statement and "patch test" instructions for determining whether the product causes skin irritation. Preliminary testing on or by individuals should be done using an open patch test that is evaluated at 48 h after application of the test material. Users, therefore, would be able to determine their individual reactions to hair dye products containing Basic Blue 99. Basic Blue 99 dye is approximately 60% to 63% dye, whereas the remainder of the mixture is composed of sugar ( approximately 25.7%), volatile matter/water crystallization ( approximately 1.8%), and inorganic salts (bringing the mixture to 100%). The dermal absorption of Basic Blue 99 is low in both rats and humans. The LD(50) values of Basic Blue 99 in mice and rats were 2.7 g/kg and between 1.0 g/kg and greater than 2.0 g/kg, respectively. Mice and rats orally administered Basic Blue 99 for 90 days did not show any indications of cumulative toxicity. Discoloration of organs involved in the elimination of Basic Blue 99 from the animals was noted in both test species. In rabbits, Basic Blue 99 did not cause ocular irritation, but some discoloration was noted. Basic Blue 99 caused minimal dermal irritation in rabbits. Sensitization occurred in animals exposed to Basic Blue 99 in a DMSO vehicle, but not in a water vehicle in guinea pigs and mice. Basic Blue 99 administered by gavage did not cause developmental toxicity in rats. Basic Blue 99 was a weak mutagen with and without metabolic activation in the Ames test, producing both reverse and frameshift mutations, but did not induce mutations in Escherichia coli or in any mammalian cells tested. In a modified repeated-insult patch test (RIPT), no volunteers had any reaction to Basic Blue 99 after a 1-h occlusive challenge. Case reports have documented positive patch test results to 1% Basic Blue 99 in three patients. A current review of the hair dye epidemiology literature identified that use of direct hair dyes, although not the focus in all investigations, appears to have little evidence of an association with cancer or other adverse events. The Panel recognizes that hair dye epidemiology studies do not address the safety of individual hair dyes. Based on the available safety test data on Basic Blue 99, however, the Panel determined that this ingredient would not likely have carcinogenic potential as used in hair dyes. The Cosmetic Ingredient Review Expert Panel concluded that Basic Blue 99 is safe as a hair dye ingredient in the practice of use and concentration as described in this safety assessment.

Final report on the safety assessment of HC Yellow No. 5.

HC Yellow No. 5 is a direct hair dye. Hair dyes containing HC Yellow No. 5, as "coal tar" hair dye products, are exempt from the principal adulteration provision and from the color additive provision of the Federal Food, Drug, and Cosmetic Act of 1938 when the label bears a caution statement and "patch test" instructions for determining whether the product causes skin irritation. Preliminary testing on or by individuals should be done using an open patch test that is evaluated at 48 h after application of the test material. Users, therefore, would be able to determine their individual reactions to hair dye products containing HC Yellow No. 5. Absorption of HC Yellow No. 5 is minimal through skin (< 0.2%). The oral LD(50) for rats is 555.56 mg/kg. No significant toxic effects were observed after chronic oral exposure of HD Yellow No. 5 to dogs. Mild dermal irritation, but no dermal sensitization or ocular irritation was observed in laboratory animals. Results of fertility and reproductive performance, teratology, and developmental studies were negative. HC Yellow No. 5 was found to be nonmutagenic and noncytotoxic in standard laboratory assays. A current review of the hair dye epidemiology literature identified that use of direct hair dyes, although not the focus in all investigations, appears to have little evidence of an association with cancer or other adverse events. Based on the available safety test data on HC Yellow No. 5, the Panel determined that this ingredient likely would not have carcinogenic potential as used in hair dyes. The Cosmetic Ingredient Review (CIR) Expert Panel concluded that HC Yellow No. 5 is safe as a hair dye ingredient in the practices of use and concentration as described in this safety assessment.