450 JOURNAL OF COSMETIC SCIENCE electron-­withdrawing groups (halogen) nearby is more acidic than the carboxylic acid (pKa 4.95) (32). As the acidity of the molecules increases because of halogen substitution, the zwitterionic form seems highly implausible (30). TBF exists in two tautomeric forms in a neutral solution: an open quinoid form, which has a yellowish-red color and fluorescence, and a closed lactone form, which is colorless with no fluorescence (30). A comparison of the four entities’ specifications is shown in Table IV. TBF may contain lower halogenated subsidiary coloring matters as an impurity. In the specifications, the EU and China control the limits of fluorescein and monobrominated fluorescein to 1% and 2%, respectively. The United States has more intense standard limits: fluorescein, sum of mono- and difluorescein, and trisbromofluo- rescein are restricted to 0.2%, 2%, and 11%, respectively. However, the four entities’ legislation does not specify the exact position of the halogens on the substituted mole- cule. In the United States, the criteria for residual starting materials must be satisfied as well. Quinophthalone Dye. Quinophthalone dye is made from quinaldine and phthalic anhydride and was first synthesized by Jacobsen in 1882 (34). It has a yellow to red shade and shows good lightfastness (35). It is typically synthesized by the condensation of quinolone with phthalic anhydride or phthalic acid in the presence of zinc chloride (22). Condensation products are sulfonated to produce a water-soluble dye. Quinoline Yellow SS (CI 47000, D&C Yellow No. 11) and Quinoline Yellow WS (QY CI 47005, D&C Yellow No. 10) fall into the category of nonsulfonated and sulfonated products. When being sulfonated, oil-­soluble Quinoline Yellow SS converts to water-soluble QY. Quinophthalone dye may exist as three tautomers: enaminone, keto-enol, and zwitterion forms (a compound con- taining both positive and negative charges Figure 5). The enaminone form has been shown to be the most stable (36). Despite the quinophthalone structure’s having been clarified, the conventional chemical structure [2-(2-quinolyl) indan-1,3-dione] is still widely used (Figure 5) (37). As for the sulfonation, it favors substitution in positions 6’- and 8’- positions in the quinoline ring and 4- and 5- positions in the indandione ring (37). Because current regulations simply name mono- and disulfonates of quinophthalones, O HO O CO2H O HO OH O O neutral open quinoid form (yellowish-red) neutral closed lactone form (colorless) O O O CO2H monoanion Phenolate O O O CO 2 dianion O HO OH CO2H cation +H+ -H+ +H+ -H+ +H+ -H+ Br Br Br Br Br Br Br Br Br Br Br Br Br Br Br Br Br Br Br Br 2' 4' 5' 7' Figure 4. Structures of tetrabromfluorescein by the pH of the medium. Adapted from Cooksey et al. (30)

451 COSMETIC COLORATION: A REVIEW Table IV Purity Specification Comparison of Tetrabromfluorescein Purity Specification EU United States China Korea Name CI 45380 D&C Red No. 21 CI 45380 Red 223 Solubility — — — Clear in EtOH Insoluble matter — — — ≤ 1.0% Soluble matter — — — ≤ 0.5% Chlorides and sulfates — — — ≤ 3.0% Loss on drying — — — ≤ 7.0% Organic compounds other than coloring matter 2-(3,5-dibromo-2,4-dihydroxybenzoyl) benzoic acid — ≤ 0.5% — — Phthalic acid — ≤ 1% — — Brominated resorcinol — ≤ 0.4% — — Heavy metals ≤ 20 ppm Arsenic — ≤ 3 ppm — ≤ 2 ppm Lead — ≤ 20 ppm — — Mercury — ≤ 1 ppm — ≤ 1 ppm Zinc — — — ≤ 200 ppm Total color — ≥ 90% — — Disodium salt of 2′,4′,5′,7′- tetrabromofluorescein — ≥ 87% — (90.0–101.0)% Subsidiary coloring matters Fluorescein 2-(6-hydroxy-3-oxo-3H-xanthen-9-y1) benzoic acid ≤ 1% ≤ 0.2% ≤ 1% — Monobromofluorescein (2-(bromo-6-hydroxy-3-oxo-3H-xanthen- 9-yl) benzoic acid) ≤ 2% ≤ 2% ≤ 2% — Dibromofluoresceins — — — Tribromofluoresceins — ≤ 11% — — 2′,4′,5′,7′-Tetrabromoflurorescein, ethyl ester — ≤ 1% — — Abbreviation : ‘—’ : does not have a criteria N H O O Enaminone form N O HO Ketoenolform N H O O Zwitterion form 2-(2-quinolyl) indan-1,3-dione (Quinophthalone from E104) N O O 6' 8' 5 4 wrong structure most stable preferential postions of sulfone group Figure 5. Structures of Quinophthalone. Adapted from Han et al. (36) and Weisz et al. (37).