446 JOURNAL OF COSMETIC SCIENCE Synthetic colorants have established specifications for impurities that can be generated through an analysis of synthetic processes and degradation products that may occur during further processing. Each country has set purity requirements for colorants to pro- tect its consumers against unsafe products, adulteration, and fraud. During the synthesis of synthetic colorants, organic and inorganic impurities are determined by the degree of purity of the starting materials, reactants, and solvent. Therefore, it is important to use pure substances during the synthesis to reduce side reactions. Residual starting materials, intermediate products, by-products, and decomposed products are considered organic impurities. Metals included in the substances or used as a catalyst during the synthe- sis are considered inorganic impurities. Specially, impurities known to damage human health must meet the acceptance criteria or they are banned. Because certain levels of impurities may remain in a product, the manufacturing process should be fully under- stood to recognize the diverse sources of impurities. Authorities in each country have established the quality requirements in the specifica- tions for synthetic colorants to ensure consumers’ safety. Specially, the EU and the United States have exemplary criteria for purity tests. The specifications can be broadly catego- rized as either identification tests or purity tests. Identification tests are experiments to prove the presence of the desired compound. Usually, organic structures are determined quickly by spectrophotometric tests that compare the absorption value of infrared (IR) and/or ultraviolet (UV) radiation with that of reference standards. In contrast, purity tests are experiments to determine the purity of the desired compound. To satisfy the purity tests, impurities must be carefully controlled during the synthesis of synthetic colorants. In the next section, synthetic colorants are classified in terms of their chemical structure, and we discuss a representative group of useful dyes. First, azo dyes represent the largest share of the dye industry today. The advantage of this dye is that it is synthesized in only two steps, and various shades of colors can be expressed by simply changing the substit- uents. Second, xanthene dyes are important for their brilliant shades between greenish yellow and purple (23). They are also known to be the most abundant, widely distributed class of fluorescent molecules (24). Third, quinophthalone dyes were chosen because the EU and the United States have different definitions of the colorant. The distinct differ- ence between each country’s specifications also are described. Azo Dyes. Azo dyes, which are characterized by the presence of an azo bond (-N = N-), are the most important colorant and comprise over 50% of world dyestuff production (21). “Azo” group refers to two nitrogen atoms joined by a double bond. Azo dyes can have one or more azo groups in the compound. Azo dyes are simply synthesized in the sequential reaction of diazotization and azo coupling. The diazotization of an aromatic amine starts when it is treated with nitrous acid made from sodium nitrite (NaNO 2 ) and hydrogen chloride (HCl) at 0–5°C. Diazonium salt (a compound containing the N 2 + group) reacts with other nucleophiles such as phenols or amines to yield azo colorants. The greatest advantage of this scheme is that it can produce a wide range of shades by only coupling readily available aromatic amines with phenols or naphthols. Another advantage of this process is that the reaction is carried out in water, which offers economic and environ- mentally friendly benefits. When an azo dye contains a group such as carboxylic acid (-CO 2 – ) or sulfonic acid (-SO 3 – ) in a molecule, it improves the dye’s solubility. It has been

447 COSMETIC COLORATION: A REVIEW reported that azo dyes may be degraded by the cleavage of the azo bond to form aromatic amines (e.g., aniline, o-toluidine, and benzidine) in the presence of reducing species at higher temperatures (25). Here, we discuss in more detail the different types of specifications applied in each country. Allura Red AC (AR CI 16035, FD&C Red No. 40) is a red dye that is authorized for use in cosmetics in the four entities. It is prepared by coupling diazotized cresidine-p-sulfonic acid 1 with Schaeffer’s salt 2 as shown (Figure 1) (20). Usually, the requirements for synthetic colorants’ purity are much greater than those of natural colorants. A comparison of the four entities specifications is shown in Table III. Concerning purity, AR must contain more than 85% of the total coloring matter. Specified impurities include subsidiary coloring matters and organic compounds other than coloring matters. Subsidiary coloring matters are compounds produced during the manufacturing process in addition to principal coloring matters (26). Organic compounds other than coloring matters are uncolored impurities such as uncombined intermediate starting materials (26). Subsidiary coloring matters are restricted in the EU by their total concentration and are restricted in three specified sections in the United States’ regulatory framework (27). The higher/lower degree of sulfonation products (tri- and monosulfonated components of AR) are included in the subsidiary coloring matters. Generally, impurities from the residual starting material in the raw material are restricted except in Korea. During the synthesis of AR dye, the starting material, cresidine-p-sulfonic acid (4-amino-5- methoxy-o-toluenesulfonic acid) and the coupling reagent of 6-hydroxy-2-naphthalene sulfonic acid, sodium salt (Schaeffer’s salt) are regulated to 0.2% and 0.3%, respectively. Schaeffer’s salt may react with another Schaeffer’s salt to produce another by-product— 6,6-oxybis(2-naphthalene-sulfonic acid)—which has a maximum content limitation of 1.0%. Moreover, the EU and China require the primary aromatic amine content to be less than 0.01%. Xanthene Dye. German von Bayer first synthesized xanthene dye in 1871 by condensing resorcinol and phthalic anhydride (28). Fluorescein (CI 45350, D&C Yellow No. 7) is one of the typical xanthene dyes. Xanthene 3 is a tricyclic compound of two benzene rings connected by a central pyran (oxygen-containing) ring. Fluorescein consists of a hydroxyl substituted xanthene ring connected to a benzene ring. The main characteristic of fluorescein is that it displays significant fluorescence. The fluorescence is widely seen in colorants in MeO H2N SO 3 H HCl, NaNO 2 H2O MeO N 2 SO3H Cresidine-p-sulfonic acid, 1 HO SO3 Na + H 2 O or ROH SO3 MeO N N HO SO 3 Na + Na + Schaeffer's salt, 2 Allura Red AC Figure 1. Synthesis of Allura red AC.