The most com mon photo allergens are considered to be BP-3 and BP-4. Over the 3-year period, between January 2003 and December 2005, 1,693 patients underwent patch testing to extended British Contact Dermatitis Society standard series 553 of these patients (33%) were also patch-tested to an extended facial/cosmetic series that included a selection of chemical UV fi lters supplied by Trolab (Hermal, Reinbek, Germany) and Chemotechnique (Crawford Pharmaceuticals, Milton Keynes, UK). BP-4 was the most frequently positive chemical UV fi lter that was tested (13 patients). It also pro- duced the third most frequently positive patch test results overall. Of the 13 patients who patch-tested positively to BP-4, fi ve were male and eight were female. None of the other UV fi lters that we added, for this study, gave any appreciable numbers of positive results. BP-3, which previously had been routinely patch-tested in the British Contact Dermatitis Society facial/cosmetic series, gave positive results in three patients (0.5%) (52,53). P-Aminobenzoate Derivatives. One of the most widely used and commercially promoted UV fi lters, worldwide, is the UVB fi lter, 4-aminobenzoic acid (PABA) (54). Never- theless, it was proven that not only PABA but also its derivatives could cause photo- allergic reactions (55,56). In the year 2008, PABA was prohibited in the EU, as a UV fi lter in cosmetic products. Similarly, the use of ethylhexyl dimethyl p-aminobenzoic acid (padimate O) has also been limited and almost been replaced by different UV fi lters. Salicylate Derivat ives. This group of ana logues is typically characterized by two UVB fi lters, EHS and homosalate. Salicylate derivatives are not strong UVB absorbers, but they are able to enhance other UVB fi lters, as they are highly water resistant, because of their water insolubil- ity. Salicylates used in cosmetics are known to cause no allergic or photoallergic reactions, while at the same time, they do not permeate into the skin (57). Photostability and solubility make EHS a particularly suitable ingredient of sunscreens. In addition, triethanolamine sa- licylate, a water-soluble UV absorber, acts typically as a photo-protective agent in haircare products (58). Camphor Derivatives . The camphor deriva tives, 3-benzylidene camphor and 4-MBC, were widely used, for a long time, because of their perfect photostability, as UVB fi lters. In 1994, almost 30% of sunscreen products contained 4-MBC. During 2004–2006, 4-MBC was still widely used in sunscreen products. However, mainly because of their endocrine potential, the camphor derivatives have been strongly criticized in the past years. Produced and patented by L’Oréal (Paris, France) in 1982 and approved by the EU in 1991, terephthalylidene dicamphor sulphonic acid (TDSA, Mexoryl SX) has been found to be an effective UV fi lter. The use of Mexoryl SX in the sunscreen “Anthelios SX” was approved by the FDA in 2006. TDSA exhibits suffi cient sun protection against the nega- tive effect of UVA rays, including pigmentation, epidermal hyperplasia, and even the limitation of skin hydration and elasticity. Also, TDSA is photostable and not percutane- ously absorbed (59-61). A study was designed to i nvestigate the systemically absorbed dose of Mexoryl SX in humans after topical application of a typical sunscreen emulsion. In addition, to assess the correlation with in vitro experiments, the percutaneous absorption of this UVA fi lter through isolated human skin was measured under identical exposure conditions. When applied in vivo for a period of 4 h, 89–94% of the applied radioactivity was recovered from the wash-off samples. In urine samples, the radioactivity slightly exceeded background JOURNAL OF COSMETIC SCIENCE 310
levels and corresponded maximally to 0.014% of the topically applied dose. No radioac- tivity was measured in blood or feces sampled up to 120 h after application. In vitro, 24 h after a 4-h application, Mexoryl SX remained primarily on the skin surface. The mean in vitro absorption over 24 h, adding up the amounts found in the dermis and receptor fl uid, was 0.16% of the applied dose. It was concluded from the in vivo pharmacokinetic results that the systemically absorbed dose of Mexoryl SX was less than 0.1%. This study dem- onstrated that, under realistic exposure conditions, the human systemic exposure to this UVA fi lter is negligible and poses no risk to human health (62). Cinnamate Derivatives. Hu man exposure to ethylh exyl (octyl) methoxycinnamate (EHMC/ OMC) is signifi cant, and it can pose a risk for human health. EHMC has been found to be absorbed through the skin, and it was detected in human biomatrices, such as urine, blood, and human breast milk. Several studies have proven the toxic potential of EHMC, such as endocrine-disrupting effect in vitro and in vivo. However, it is reported and estab- lished that EHMC experiences degradation by two primary pathways, photolysis and photoisomerization. One of the products of photoisomerization is also cis-EHMC. When EHMC is exposed to sunlight, the commonly present trans-EHMC may be transferred to cis-EHMC (cis/trans isomerization, also called geometric isomerization). The isomeric form in which EHMC appears may impact its toxicity potential. Researchers studied the s kin permeation of the parental trans-EHMC and its cis-isomer. The trans-EHMC geometric isomer along with its laboratory-produced cis-EHMC coun- terpart was added in a commercial sunscreen lotion, which was applied on the skin (fore- arm) of two volunteers (2 mg cm-2). The combined product was left on the skin for 8 h, and then tape stripping was used to remove the horny layer. A total protein assay was applied, and the thickness of the given SC was measured spectrophotometrically. The HPLC-DAD method was used to estimate the concentration of the isomers present in the extracted SC. The kinetic parameters [diffusion coeffi cient (D), partition coeffi cient (K), and permeability coeffi cient (k)] were calculated from the measured depth-concentration profi le in six replicates (six application sites on the skin) with the use of Fick’s second law [D cis-EHMC = 1.62 ± 0.83 × 1014 (m2 s-1), D trans-EHMC = 1.58 ± 0.84× 1014 (m2 s-1)]. The values of calculated diffusion coeffi cients and permeability coeffi cients of cis-EHMC were slightly higher than those of trans-EHMC. However, the Wilcoxon nonparametric test showed no statistical difference in either k or D of both isomers (p 0.05). Although the Wilcoxon nonparametric test showed no statistical difference in dermatotoxicokinetic parameter of both isomers (p 0.05), the studies by Necasova et al. and Sharma et al. (63,64) showed that the cis-EHMC can cause more signifi cant risk than trans-EHMC in the scenario of female population exposure (ages 16–65) after daily application of several kinds of personal cosmetic products. Even though the permeation of both isomers seems to be similar, the emergent cis-EHMC causing greater DNA damage can be more harmful than trans-EHMC in the same depth of SC. In vitro genotoxic effects of trans- and cis- EHMC on adult human liver stem cells HL1–hT1 and human-derived lymphoblastoid cells TK-6 using a high-throughput comet assay were studied. TK-6 cells treated with cis-EHMC showed a high level of DNA damage when compared with untreated cells in concentrations 1.56–25 μgmL-1. Trans-EHMC showed genotoxicity after exposure to the two highest concentrations, 12.5 and 25 μgmL-1. It still remains crucial to conduct diffe rent toxicological studies of isomeric forms and defi ne their dermatotoxicokinetic parameters to decipher the risks imposed on the human skin (65). DISTRIBUTION OF UV FILTERS ON THE SKIN 311
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