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IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Some Aromatic Amines, Organic Dyes, and Related Exposures. Lyon (FR): International Agency for Research on Cancer; 2010. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 99.)
1.1. Introduction
Throughout history and across cultures, women as well as men have felt the need to change the natural colour of their skin, lips and hair, or to restore the colour of greying hair. For thousands of years, cosmetic dyes have been a part of all human cultures. The use of hair dyes can be traced back at least 4000 years; evidence from royal Egyptian tombs suggests the use of henna for dyeing of hair and fingernails. Henna contains the dye Lawsone (2-hydroxy-1,4-naphthoquinone), which, in its pure form, is also used as a synthetic direct (semi-permanent) hair dye. In the days of the Roman Empire, grey hair was darkened by combing it with lead combs dipped in vinegar. Interestingly, it has recently been shown that this application produces darkening of grey hair by deposition of lead sulfide nanoparticles (diameter of about 5 nm) on the surface of the hair (Walter et al., 2006; Nohynek et al., 2004a). Traditional, lead acetate-based products for darkening grey hair are still found on the international market, although their importance is minor.
Today, millions of consumers use a large variety of cosmetic dyes and pigments to change the appearance of their skin, lips, nails or hair. Hair dyeing has become a common practice in modern industrialised societies; the hair-dye industry has estimated (unpublished data) that between 50 and 80% of women have used hair dyes in the USA, Japan and the European Union. During the last century, synthetic dyes have taken a pivotal role in hair colouration. Their chemistry, use and safety have been reviewed (Corbett 1999, 2000; Corbett et al., 1999; Nohynek et al., 2004a; Zviak & Millequant 2005a,b).
1.2. Composition of modern hair dyes
Modern hair dyes may be classified into the following categories: oxidative (permanent) dyes, direct (temporary or semi-permanent) dyes, and natural dyes.
In the frequently used code system introduced by the European Cosmetic Association (COLIPA), hair-dye ingredients are classified into classes A, B or C: class A includes ingredients of oxidative hair dyes, class B those of semi-permanent hair dyes, and Class C those of temporary hair dyes (see examples in Tables 1.4, 1.5, 1.6).
Table 1.4.
Approximate total (North America, Latin America, EU, rest of the world) annual (2005) worldwide use (metric tonnes) of oxidative hair-dye ingredients. Data were collected by the international hair-dye industry and cover approximately 90% of the world (more...)
Table 1.5.
Approximate annual (2005) worldwide use (metric tonnes) of semi-permanent hair-dye ingredients. Data were collected by the major international hair-dye industry and cover approximately 90% of the world market.
Table 1.6.
Approximate annual (2005) worldwide use (metric tonnes) of major temporary hair-dye ingredients. Data were collected by the international hair-dye industry and cover approximately 90% of the world hair-dye market.
1.2.1. Oxidative (permanent) hair dyes
(a) Composition
Oxidative (permanent) hair dyes are the most important group and have a market share in the EU or the USA of approximately 80% (Corbett et al., 1999).
Oxidative (permanent) hair dyes consist of two components that are mixed before use and generate the dye within the hair by chemical reactions. Their chemistry and use has recently been reviewed (Corbett et al., 1999; Zviak and Millequant, 2005b). Modern oxidative dyes contain several ingredients with different functions (examples in 507 Table 1.1) as follows:
- Primary intermediates: arylamines (para-phenylenediamine (PPD), para-toluenediamine (PTD), substituted para-diamines), para-aminophenols (para-aminophenol, 4-amino-meta-cresol), 4,5-diaminopyrazole and pyrimidines. Oxidation of these substances and their chemical coupling with modifier (coupler) molecules result in coloured reaction products.
- Couplers or modifiers: these include meta-substituted aromatic derivatives (m-phenylenediamines, meta-aminophenols, resorcinol), pyridines and naphthols. Couplers determine the final shade by reaction with the oxidized form of primary intermediates, followed by further oxidative coupling reactions.
- Oxidants: hydrogen peroxide, urea peroxide, sodium percarbonate, perborate.
- Alkalinising agents: ammonia, monoethanolamine or aminomethylpropanol.
Table 1.1.
Examples of dye-substance classes used in modern oxidative hair dyes (from Corbett, 1999 and 2000; Hair-dye industry data, 2007).
(b) Relative concentration of the components
The actual colouring mixture is prepared extemporaneously, before application to the hair, by mixing, generally weight by weight, a solution containing the precursors and the other components of the formula with a solution containing hydrogen peroxide called developer. Each of these two solutions amounts in general to 50 g per use, but it is not uncommon to use 40 g of a colourant formula mixed with 60 g of developer. With non-lightening oxidative colouring the amount of developer may be twice the amount of colourant formula. The final mixture applied to the hair amounts to about 100 g but can vary according to the amount of hair to be treated.
Given that it is diluted by the developer, if the original concentration of a precursor (base or coupler) is X, its concentration in the final mixture coming into contact with the hair, is, at most X/2.
In practice, the initial concentration X used lies between 0.006% and 7%. This range of concentrations corresponds to a spectrum of shades from very pale blond to black This is how the 20–70 shades of an oxidation-dye formulation are built up. It is worth noting that in the market:
- About 50% of shades contain no more than 0.5% precursors or colourants as a whole;
- About 25% of shades contain between 0.5% and 0.75% overall precursors or colourants; and
- About 25% of shades contain more than 0.75% of total precursors or colourants, with even fewer shades with a concentration reaching or exceeding 3.5% before mixing the developer.
The concentrations mentioned above represent the total content of precursors or dyestuffs (sometimes as many as 10) that is necessary to achieve the desired shade. More precisely, oxidation-dye products consist of a mixture of two or three bases, four or five couplers and sometimes one or two direct colourants (see below) (Zviak & Millequant, 2005b).
The shade/colour achieved on the hair depends on the ingredients and their concentrations. Given the number of ingredients and the different resulting colour tones, a clear correlation of hair-dye shade with the concentration of the primary intermediate and coupler cannot be made. The dye shade, however, permits an estimation of the ingredient concentrations: dark hair dyes tend to contain the highest concentration of ingredients, whereas light (blond) shades tend to contain lower concentrations.
1.2.2. Direct hair dyes
Direct hair dyes include semi-permanent (resisting several shampooing processes) or temporary (resisting one or few shampooing processes) hair dyes. Direct hair dyes represent the second category of economically important hair colorants.
Semi-permanent colouring agents contain low-molecular-weight dye molecules, such as nitro-phenylenediamines, nitro-aminophenols, and some azo or anthraquinone dyes. These dyes may be used on their own in semi-permanent hair dyes or in combination with oxidative hair dyes in permanent hair-dye products to improve the tone of the final colour on the hair.
Temporary dyes represent the third class of hair colours. Temporary colouring agents are relatively large molecules and include azo-, triphenylmethane-, indophenol- or indamine-type dyes (Zviak & Millequant, 2005a) that are less resistant to washing and may be rinsed off by a single or a few shampooing processes. Typical formulations of semi-permanent hair dye are presented in Table 1.2.
Table 1.2.
Ingredients of typical semi-permanent hair-colouring products.
1.2.3. Natural hair dyes
The majority of natural dyes use henna (produced by extraction of the leaves of a North African shrub (Lawsonia inermis) or the pure dye ingredient of henna, i.e. Lawsone (2-hydroxy-1,4-naphthoquinone). Henna has a long history of widespread use as a natural hair and body dye; however, a warning was raised against Lawsone by the Scientific Committee on Consumer Products (SCCP) of the European Commission (SCCNFP 2004). In addition, the reported increase in the use of Henna mixed with synthetic dye molecules, such as para-phenylenediamine (Black Henna) or other aromatic amines as a direct hair dye or body paint is of concern (Onder, 2003; Arranz Sánchez et al., 2005).
Other natural dyes include extracts of Chamomile, indigo and various woods, barks or flowers (Zviak and Millequant, 2005a).
Natural dyes extracted from plants are of relatively small but growing economic importance.
1.2.4. Trends in composition over time
The invention, history and use of oxidative hair dyes and their ingredients has been reviewed (Corbett, 1999). The components of oxidative hair dyes have considerably changed since their introduction at the end of the 19th century. In the early phase, aromatic amines (primary intermediates, para-diamines, para-aminophenols) were used on their own in combination with hydrogen peroxide. During the period up the 1920s it was found that primary intermediates (para-diamines, para-aminophenols) may be combined with coupler molecules (resorcinol, meta-diamines, meta-aminophenols) to form coloured end products on oxidation. Thus in the early 1930s, the principal primary intermediates and couplers used today were already on the market. From the 1930s up to the 1970s there was little innovation in the components of oxidative and direct hair dyes; in the 1960s most manufacturers used a basic palette of 10–15 typical dye components; substances used in the period between the early 1930s to the 1970s are shown in Table 1.3.
Table 1.3.
Some dye components used in typical oxidative and direct hair dyes in the period 1930s–1970s. US data (Corbett, 1999b).
In the 1970s and 1980s, major changes took place in the composition of direct and oxidative hair dyes. First, numerous innovative dyes were discovered, and several new direct and oxidative substances were introduced on the market. Second, in 1975, the positive results of mutagenicity tests in Salmonella typhimurium (Ames test) initiated a long-lasting controversy about the genotoxic and/or carcinogenic potential of some hair dyes, when Ames et al. suggested that nearly 90% of oxidative hair-dye ingredients were mutagenic in Salmonella typhimurium and might therefore pose a carcinogenic risk to consumers (Ames et al., 1975).
On the basis of a worldwide survey coordinated by the EU, US and Japanese Cosmetic Associations during late 2007/early 2008, there would currently be 50 ingredients of oxidative, 43 ingredients of semi-permanent, and 88 ingredients of temporary hair dyes on the international market (EU, North- and Latin-America, Asia).
1.3. Production volumes
The major ingredients in oxidative hair dyes and their approximate annual worldwide tonnage of use (2005) are shown in Table 1.4. These data suggest that the bulk of substances used in oxidative hair dyes (total worldwide use at 50 to 250 tonnes) consist of traditional ingredients, such as resorcinol, para-phenylenediamine, 2,5-diaminotoluene and 4-amino-2-hydroxytoluene, para- and meta-aminophenol, 2-methyl-5-hydroxyethyl-aminophenol and 4-amino-meta-cresol. A few other ingredients are used at an annual tonnage of 10 to 50 tonnes, whereas most oxidative hair-dye ingredients are used at relatively minor amounts at 5 tonnes or less.
The estimated worldwide annual (2005) use of semi-permanent hair dyes is shown in Table 1.5. These data reveal a tonnage significantly lower than that of oxidative hair dyes and reflect their lesser economic importance. With the exception of two nitro-phenol-type semi-permanent dye ingredients (2-amino-6-chloro-4-nitrophenol and 4-hydroxypropyl-amino-3-nitrophenol), which are used at 5 to 15 tonnes per year, most substances are below 5 tonnes, whereas three substances are below 0.5 tonnes per year.
The estimated worldwide annual (2005) use of temporary hair dyes is shown in Table 1.6. The total annual use of most of these dyes is < 5 tonnes, except for Acid Violet 43 and Acid Red 33, which are used at 5 to 10 tonnes per year.
1.4. Application and formation of hair dyes
1.4.1. Application of hair dyes
Oxidative and direct hair dyes are applied to the hair in aqueous solutions or as a gel at a maximal concentration of 2.0 to 3.0% of the primary dye ingredient (dark-shade hair dyes) or < 0.05% (light-shade hair dyes) (see paragraph 1.2.1). After a contact time varying from a few to approximately 30 min permitting the hair-dyeing process to take place, the dye is rinsed off, and the hair is shampooed, rinsed, cut and dried. Detailed modern hair-dyeing techniques were recently reviewed (Zviak & Millequant, 2005a and 2005b).
1.4.2. Reaction products of hair dyes
Taking into account the standard volume of 80 mL of commercial hair-dye formulations, human external exposure during hair colouring would be in the range of 40 to 2400 mg. The frequency of hair-dye use varies between once per month (temporary hair dyes) to once per 6–8 weeks (oxidative hair dyes).
An analytical methodology based essentially on HPLC was developed, which allowed the study of the kinetics of oxidative hair-dye coupling chemistry under conditions reflecting consumer usage, i.e. colour formation over 30 min (SCCNFP 2004, opinion 0941/05; Rastogi et al., 2006). The methodology was applied to 11 different combinations of hair-dye precursors and couplers, and demonstrated that the amount of colour formed increases with time, while the amounts of free precursors and couplers decrease. Only the expected reaction products – based on the chemistry of the oxidative coupling of precursors and couplers – were formed, and no significant additional reactions or unexpected products were detected. Self-coupling products (such as Bandrowski’s base) or transient intermediates were not detected in the hair-dye formulations.
During the dyeing process, the consumer is exposed to the precursor(s), the coupler(s) and the expected reaction product(s). The kinetics of colour formation also revealed that the exposure of the consumer to the reaction product (hair dye) is much less than the exposure to the precursor and coupler over the whole application time. The total concentrations of unreacted precursors and couplers in various experiments were 12–84% of the applied dose. The typical concentration of reaction products in the formulations after 30 min varied from 0.02% to 0.65%. A worst-case scenario for the exposure from hair dyes in the dyeing process was derived from the data: the maximum content of a hair dye formed in the formulation 30 min after application was 0.65%. In a 70-ml (= 70-g) formulation this equals to 455 mg of hair dye formed.
1.5. Personal use of hair colourants
The main route of exposure to hair-dye components during personal use of hair colourants is dermal. Several studies have measured dermal and systemic exposure to hair-dye components, mainly by use of para-phenylenediamine (PPD) or [14C]-labelled PPD.
In a study from the USA, seven hair dyes (oxidative and direct) were [14C]-labelled and applied onto volunteers (Wolfram & Maibach, 1985). The extent of scalp penetration was slightly higher for direct dyes but in neither case did it exceed 1% of the applied dose.
In a study on percutaneous absorption of PPD during an actual hair-dyeing procedure, urinary levels of PPD metabolites were monitored during 24 or 48 hours after the dye had been applied (Goetz et al., 1988). The fraction of the applied dose found in the urine 24 hours after application ranged from 0.04% to 0.25%. This study also showed a five- to ten-fold decrease in PPD penetration when the scalp was protected with clay before applying the dye.
In a study from Taiwan, China (Wang & Tsai, 2003), five volunteers dyed their own hair with various dye products containing different concentrations of PPD (2.2–3.2% or 1.1–1.6 g). The PPD excretion in the urine after 48 hours was 0.02–0.45% of the total dose.
Eight volunteers (Hueber-Becker et al., 2004) received an oxidative hair-dye application containing [14C]-PPD. The dye remained on the hair and scalp for 30 min. In the urine samples collected afterwards, 0.50±0.24% of the total applied radioactivity was recovered. The mean systemic dose was calculated to be approximately 0.09±0.04mg [14C]-PPD-equivalents/kg body weight. In an in-vitro human skin study, a total of 2.4±1.6% of the applied radioactivity was absorbed (found in epidermis, dermis and receptor fluid), corresponding to an absorption rate of 10.6±6.7 µgeq/cm2. In the same eight volunteers, specific PPD metabolites were measured: five different metabolites were found, mainly N-mono-acetylated and N, N′-diacetylated PPD (Nohynek et al., 2004b).
1.5.1. Estimation of the internal dose to the user of hair-dye ingredients
According to its “Notes of Guidance”, the Scientific Committee for Consumer Products (SCCP) assesses hair dyes based on data of percutaneous absorption, mainly from in-vitro studies with human or pig skin. In a typical study, 20 mg of a representative hair-dye formulation per cm 2 is applied onto the skin. Following a 30-min contact time, the amount of hair dye in the epidermis (stratum corneum excluded), dermis and the receptor fluid after 24 hours is determined and summed-up to provide a worst-case value for the systemic (internal) dose. Taking the commercially important hair dye para-phenylenediamine (PPD) as an example, and using a worst-case scenario for a 60-kg adult person, the systemic exposure dose was estimated to be 0.052 mg/kg bw, calculated as follows:
A maximum concentration of 4.0% of PPD is mixed before use with H2O2. Thus the usage volume of 100 ml contains at maximum 2.0% PPD. Assuming the highest penetration (0.00447 mg/cm2) and a typical human body weight (60 kg) and exposed scalp area (700 cm2), this would give a systemic exposure dose of 0.00447 mg/cm2 x 700 cm2/60 kg = 0.052 mg/kg body weight. (source: SCCP’s “Notes of Guidance” for the testing of cosmetic ingredients and their safety evaluation, 6th revision, adopted by the SCCP during the 10th plenary meeting of 9 December 2006).
1.6. Occupational exposure as a hairdresser and barber
Occupational exposure studies in hairdressers have mainly focused on airborne exposure. Only few studies have measured dermal and systemic exposure of hairdressers to certain chemicals.
1.6.1. Airborne exposure in hairdressing salons
In addition to hair dyes, hairdressers can be exposed to a wide variety of chemicals. Studies to measure the airborne occupational exposure of hairdressers are summarized in Table 1.7. In these studies, ethanol is generally used as a marker for solvent exposure, and para-phenylenediamine (PPD) is often used as a marker for dye exposure.
Table 1.7.
Airborne occupational exposure levels in hairdressing salons.
The exposure to organic solvents is generally highest in the hairdressers’ breathing zone during the mixing and application of chemicals to the hair. The exposure time is usually short, varying from tens of seconds (hair sprays) to tens of minutes (permanent solutions and dyes) (Leino, 2001), but these tasks may be repeated many times a day. Several studies showed that local exhaust ventilation can significantly reduce airborne exposure (Hollund & Moen, 1998; Leino, 2001), but also indicated that it is seldom used.
The exposure of hairdressers to oxidative hair dyes was measured under controlled conditions. Three separate phases of hair dyeing were monitored: (1) dye preparation/hair dyeing, (2) rinsing/shampooing/conditioning, and (3) cutting/drying/styling, on eighteen hair dressers working for six hours with a dark-shade oxidative hair dye containing 2% of [14C]-para-phenylenediamine (PPD). The detected PPD-equivalents in personal air samples (charcoal cartridges) were higher during the hair-dyeing phase than during the other phases, and ranged from <0.25 µg (detection limit) to 0.88 µg with a mean exposure time of ~30 min (Hueber-Becker et al., 2007).
1.6.2. Dermal and systemic exposure
In a study from Sweden (Lind et al., 2005) the dermal exposure of 33 hairdressers was assessed with a hand-rinse method (Lind et al., 2004). Samples were taken in the hairdressing salons during normal working hours: before the hair-dyeing procedure, after the application of the hair dye, and after cutting of the newly dyed hair. The samples were analysed for five different compounds used in common commercial hair-dye products in Sweden: 1,4-phenylenediamine (PPD), toluene-2,5-diaminesulphate (TDS), 3-aminophenol (MAP), resorcinol (RES), and 2-methyl-resorcinol (MRE). The results are shown in Table 1.8. The maximum levels detected after application of hair dyes were: 939 nmol per hand for PPD, 244 for MAP, 741 for TDS, 773 for RES and 187 for MRE. Positive findings were also reported for samples taken before mixing hair-dye cream with oxidizing cream. This exposure may derive from previous hair-dyeing activities on the same day or from background exposure from contaminated surfaces. Hand exposure was not significantly lower in hairdressers working with gloves compared with hairdressers not using gloves while dyeing hair. It was noted, however, that gloves were often re-used and could be a source of contamination.
Table 1.8.
Amounts of hair-dye compounds in hand rinse from professional hair dressers.
In a later study, the penetration of PPD, TDS, and RES through protective gloves during hairdressing was investigated: when properly used, all the tested gloves gave considerable protection against permeation of the hair-dye components studied (Lind et al., 2007).
A study among 18 hairdressers in controlled conditions using radioactive PPD (2%) in hair dyes measured systemic exposure to PPD (Hueber-Becker et al., 2007). No radioactivity above the limit of detection (< 10 ng PPDeq/ml) was found in blood samples. Several urine samples contained no measurable or quantifiable radioactivity. Using the detected urinary levels and the urine volume, the mean urinary excretion across all hairdressers during the working-day was calculated to be < 25 ± 5.2 µg [14C]-PPDeq.
1.7. Regulations and guidelines
The legislation of cosmetics and the regulation of ingredients in hair-dye formulations in the EU and the USA differ. During the 1980s, several putative carcinogenic hair-dye substances were banned in the EU, but not in the USA. Furthermore, in April 2003 the EU Scientific Committee on Consumer Products (SCCP) started a strategy to ensure the safety of hair-dye products. The SCCP foresees banning of all permanent and non-permanent hair dyes for which industry has not submitted a safety file for the substances involved, and of those on which the SCCP has issued a negative opinion. Table 1.9 gives the list of ingredients that are currently not permitted in hair-dye products in the European Union. A substantial number of those banned substances were of limited commercial interest.
Table 1.9.
List of 135 hair-dye substances banned by the European Union (updated September 2007).
The Japanese regulation of cosmetics is the most restrictive. All cosmetic products are considered equivalent to drugs and are thus subject to premarket approval by the Ministry of Health and Welfare, and may contain only those ingredients included in the Comprehensive Licensing Standards of Cosmetics by Category (CLS); these ingredients must be conform certain defined specifications. Other Asian countries (e.g. Republic of Korea and China) have developed regulatory requirements for hair dyes and their ingredients similar to those in Japan (Corbett et al. 1999; Nohynek et al. 2004a).
In response to occupational safety concerns, i.e. the risk for developing contact dermatitis, international hair-dye label warnings recommend that hairdressers wear protective gloves during the hair dyeing and rinsing processes (Wilkinson and Shaw, 2005).
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