Photocontact Allergen Research Articles

Ultraviolet filter contact and photocontact allergy: consumer exposure and risk assessment for octocrylene from personal care products and sunscreens.

Octocrylene (OCT) is an ultraviolet (UV) filter used in personal care products (PCPs) to prevent sun-related skin damage. OCT is photostable and has the ability to photostabilize other UV filters, which has recently led to its increased use in PCPs. Emerging clinical and experimental studies indicate that OCT is both a contact and a photocontact allergen. To quantify OCT exposure via PCPs, including aggregate exposure that arises from concurrent use of multiple PCP categories, for use in an exposure-based quantitative risk assessment (QRA). Probabilistic modelling of exposure was performed at an individual level simulating 1 day of concurrent and single PCP use. PCP use data obtained via a questionnaire were linked to OCT concentrations gained from chemical analyses of PCPs used by the questionnaire respondents from the German-speaking part of Switzerland (n = 1196; ages ≤ 1-97 years). Acceptable exposure levels (AELs) were calculated for OCT and compared with the computed exposure estimates. Overall, 19%, 33% and 79% of respondents were exposed to OCT via hand cream, face cream and sunscreen, respectively. Sunscreen was the most prevalent exposure source and largest contributor to aggregate exposure. For the study population, the overall mean and median exposure to OCT via sunscreen alone exceeded the QRA-predicted AEL of 4·9 μg cm(-2). Use of OCT in PCPs at levels greater than the threshold for induction of skin sensitization might lead to an increased number of sensitized individuals. It is therefore desirable to perform a new safety assessment of OCT.

Clinical and experimental studies of octocrylene's allergenic potency

Reports of positive patch test and photopatch test reactions to the chemical ultraviolet filter octocrylene have increased during the last decade. Little is known about the reason for octocrylene's allergenic activity. To present and discuss the results of patch tests and photopatch tests with octocrylene, and to investigate the possible cause of its allergenic properties. Results of patch tests and photopatch tests with octocrylene in patients with adverse skin reactions to sunscreen products and/or ketoprofen were collected. The allergenic potency of octocrylene was investigated in the murine local lymph node assay (LLNA). Chemical reactivity assays were used to mimic octocrylene's interaction with biomolecules. We report 23 cases of positive test reactions to octocrylene (5 patch test and 18 photopatch). Notably, many of these patients also had positive photopatch test reactions to ketoprofen and benzophenone-3. Octocrylene was shown to be a moderate sensitizer in the LLNA, and it reacted with amines such as lysine, but not with thiols such as cysteine. The clinical studies show that octocrylene is both a photocontact allergen and a contact allergen. Octocrylene's ability to cause contact allergy is probably attributable to its reactivity towards lysine. To be able to understand why octocrylene causes photocontact allergy, further studies are needed.

Evaluation of photopatch test allergens for Indian patients of photodermatitis: Preliminary results

There is a strong need to develop a photopatch test tray suitable for Indian patients of photodermatitis as European/Scandinavian photopatch test trays may not be wholly relevant for them. We carried out this study using photoallergens relevant in the Indian context to determine their relevance in patients of photodermatitis. Thirty patients (M:F, 23:7) between 19 and 76 years of age of photodermatitis and 10 controls were patch- and photopatch tested with 20 common photoallergens. In addition, the patients were also (photo) patch tested with articles of daily use as and when these were suspected to be the cause. Forty-three positive reactions to one or more antigens were seen in 22 (74%) patients. Fourteen positive photopatch tests to seven allergens were observed in 10 (33%) patients, and nine (30%) of them had a definite relevance. The most common contact allergen was fragrance mix (FM) (30%), followed by p-phenylenediamine (20%) and Parthenium hysterophorous (17%). The definite relevance of the patch- and photopatch tests could be correlated in 47% of these patients. FM is the most common contact and photocontact allergen among the various photopatch test antigens. Although differences in technique and evaluation make direct comparison between different centers difficult, still photopatch testing remains an integral part and gold standard for the work-up of the photosensitive patients.

Safety studies of topical imiquimod 5% cream on normal skin exposed to ultraviolet radiation

Background: Imiquimod 5% topical cream is an immune response modifier that induces interferon alpha and interleukin-12, and exhibits antiviral and tumor-inhibiting properties. It is currently available for treatment of genital and perianal warts. Three randomized, open-label or assessor-blinded, placebo-controlled studies were carried out to assess its safety on normal white skin exposed to ultraviolet radiation (UVR). Methods: Healthy white volunteer adult subjects between the ages of 18 and 60 years with skin types I, II or III (Fitzpatrick Scale, US Federal Register 43:38260, 1978) were invited to participate. Imiquimod 5% cream (each dose ∼0.1–0.2 ml) was compared with placebo cream. Two preliminary studies assessed the potential photosensitizing properties of the drug, and the third study added measurement of sunburn cell counts (SBC) and deoxyribonucleic acid (DNA) pyrimidine dimer (PD) formation. The three studies were: a 6-week standard photocontact allergenicity bioassay; a 4-day standard phototoxicity bioassay; and a 4-week photodamage study using biopsy sample analyses to determine SBC or PD frequency. Results: Imiquimod had no detectable potential for inducing either photocontact allergy ( n=115) or phototoxicity ( n=20). The final study further assessing photodamage potential of imiquimod included 44 subjects. There were no significant differences between imiquimod vs. the control (no drug+UVB) for SBC counts (mean 0.88 vs. 0.93), or PD frequency (mean 60.86 vs. 70.03). Conclusions: Results from the two preliminary safety studies suggest that imiquimod 5% cream does not possess a detectable photosensitizing potential in humans. Furthermore, topical imiquimod did not enhance UVR-induced damage to epidermal cells or DNA.

An Integrated Model for the Differentiation of Chemical-Induced Allergic and Irritant Skin Reactions

Contact and photocontact allergic as well as irritant and photoirritant skin reactions represent a major problem in clinical dermatology and during the development of new pharmaceuticals. Furthermore, there is a lack ofin vitroandin vivoassays that provide a clear differentiation between allergic and irritant skin reactions. Here, we describe an integrated model to differentiate between chemical-induced allergic and irritant skin reactions by measuring objective and easy-to-determine parameters within both skin and skin-draining lymph nodes. Dose–response studies with standard contact and photocontact allergens as well as irritants and photoirritants revealed that irritants predominantly induced skin inflammation, which in turn stimulated draining lymph node cell proliferation. In contrast, the induction phase of contact or photocontact allergy was characterized by marginal skin inflammation, but a marked activation and proliferation of skin-draining lymph node cells. Therefore, a differentiation index (DI) was defined describing the relation between skin-draining lymph node cell activation (lymph node cell count index) and skin inflammation (ear swelling). A DI > 1 indicates an allergic reaction pattern whereas DI < 1 demonstrates an irritant potential of a chemical. Experiments with the contact allergen oxazolone, the photocontact allergen TCSA + UVA, the irritant croton oil, and the photoirritant 8-methoxypsoralen + UVA confirmed the predictive value of DI. Furthermore, flow cytometric analysis of lymph node-derived T- and B-cell subpopulations revealed that contact sensitizer, but not irritant, induced the expression of CD69 on the surface of I-A+cells. In conclusion, further studies with a broad range of irritants and allergens will be required to confirm general applicability.

Final Report on the Safety Assessment of Octyl Palmitate, Cetyl Palmitate and Isopropyl Palmitate

The Palmitates used in cosmetic products are esters of palmitic acid and octyl, cetyl, or isopropyl alcohol. The acute oral LD50 is estimated from studies with rats to be greater than 14.4 g/kg for Cetyl Palmitate and greater than 64.0 g/kg for Octyl and Isopropyl Palmitates. Acute studies with rabbits showed no evidence of dermal toxicity for any of the Palmitates. Isopropyl Palmitate was “well tolerated” and Octyl Palmitate was nontoxic in separate subchronic dermal studies. Rabbit skin tests with the Palmitates showed that they are nonirritating and nonsensitizing. Also, Draize rabbit eye irritation tests on the Palmitates produced either no or only very slight ocular irritation. One of three formulations containing Octyl Palmitate at concentrations between 40% and 50% produced mild irritation. Formulations containing Cetyl Palmitate at concentration of 2.7% were minimally irritating and produced no signs of sensitization, phototoxicity, or photo contact allergenicity. A formulation containing 45.6% Isopropyl Palmitate produced no signs of irritation, sensitization, phototoxicity, or photo contact allergenicity. From the available information, it is concluded that Octyl Palmitate, Cetyl Palmitate, and Isopropyl Palmitate are safe as cosmetic ingredients in the present practices of use and concentration.

Final Report on the Safety Assessment of Carbomers-934, -910, -934P, -940, -941, and -962

The Carbomers are synthetic, high molecular weight, nonlinear polymers of acrylic acid, cross-linked with a polyalkenyl polyether. The Carbomer polymers are used in cosmetics and emulsifying agents at concentrations up to 50%. Acute oral animal studies showed that Carbomers-910, -934, -934P, -940, and -941 have low toxicities when ingested. Rabbits showed minimal skin irritation and zero to moderate eye irritation when tested with Carbomers-910 and -934. Subchronic feeding of rats and dogs with Carbomer-934 in the diet resulted in lower than normal body weights, but no pathological changes were observed. Dogs chronically fed Carbomer-934P manifested gastrointestinal irritation and marked pigment deposition within Kupffer cells of the liver. Clinical studies with Carbomers showed that these polymers have low potential for skin irritation and sensitization at concentrations up to 100%. Carbomer-934 demonstrated low potential for phototoxicity and photo-contact allergenicity. On the basis of the available information presented and as qualified in the report, it is concluded that the Carbomers are safe as cosmetic ingredients.

Use of the occlusive patch to evaluate the photosensitive properties of chemicals in guinea-pigs

Guinea-pig tests were conducted on a known photocontact allergen, tetrachlorosalicylanilide (TCSA), a known phototoxin, 8-methoxypsoralen, two reportedly weak photoallergens, musk ambrette and 6-methylcoumarin, and a negative control, octylphenoxy polyethoxyethanol (Triton X-15). The data show that under the test conditions used, photosensitivity responses can be produced, and combinations of these as well as the other biological responses can be readily defined. The results indicate that musk ambrette is photoallergenic, that 8-methoxypsoralen is phototoxic and that Triton X-15 is only a slight irritant. On the other hand, results with TCSA suggest that it is a strong contact allergen and photoallergen, while 6-methylcoumarin would be considered to be a weak contact allergen with weak phototoxic properties. Previous reports that barrier destruction or adjuvanticity is necessary to produce photoallergy to musk ambrette were not confirmed; by ensuring occlusion using standard methods, the photoallergic nature of the response to this material was clearly demonstrated. A device described elsewhere (Newmann & Parker, Fd Chem. Toxic. 1985, 23, 683) has made it possible to develop methods that can be used to differentiate clearly among the possible biological responses that can occur in guinea-pigs when photoreactive materials are applied to their skin and irradiated. The probable biological responses that need to be defined, under the above conditions, are primary irritation, delayed contact hypersensitivity, phototoxicity and/or photoallergenicity.

5 Final Report on the Safety Assessment of Propylene Glycol Stearate and Propylene Glycol Stearate Self-Emulsifying

Propylene Glycol Stearates (PGS) are a mixture of the mono- and diesters of triple-pressed stearic acid and propylene glycol and are used in a wide variety of cosmetic products. Studies with 14C-labeled PGS show that it is readily metabolized following ingestion. In rats, the acute oral LD50 has been shown to be approximately 25.8 g/kg. The raw ingredient produced no significant dermal toxicity, skin irritation, or eye irritation in acute tests with rabbits. Subchronic animal studies produced no evidence of oral or dermal toxicity. Propylene glycol monostea-rate was negative in in vitro microbial assays for mutagenicity. In clinical studies, PGS produced no significant skin irritation at concentrations up to 55% nor skin sensitization on formulations containing 2.5%. Photo-contact allergenicity tests on product formulations containing 1.5% PGS were negative. From the available information, it is concluded that Propylene Glycol Stearates are safe as cosmetic ingredients in the present practices of use.

Final Report on the Safety Assessment of Cetearyl Octanoate

Cetearyl Octanoate is the esterification product of 2-ethylhexanoic acid and cetearyl alcohol. The acute oral LD50 for Cetearyl Octanoate is estimated from studies with rats to be greater than 8.0 ml/kg. The ingredient produced no significant acute, subchronic or dermal skin or eye irritation when tested in rabbits. The ingredient produced no evidence of skin sensitization in the guinea pig. Similar studies with product formulations containing Cetearyl Octanoate confirmed these results, as well as indicated the ingredient was not phototoxic. In clinical studies, four of 100 subjects showed slight to moderate irritation with undiluted Cetearyl Octanoate. Product formulations containing between 0.2% and 30% Cetearyl Octanoate were tested on a total of 644 subjects with no signs of skin sensitization, photocontact allergenicity, or phototoxicity. From the available information, it is concluded that Cetearyl Octanoate is safe as a cosmetic ingredient in the present practices of use.

Final Report on the Safety Assessment of Myristyl Myristate and Isopropyl Myristate

Acute oral and dermal toxicity tests indicated that Myristyl Myristate is nontoxic to rats. This cosmetic ingredient produced minimal to mild skin irritation, minimal eye irritation in rabbits, and no sensitization in guinea pigs. Studies with rabbits indicated that undiluted Isopropyl Myristate was a mild irritant after 24 h and moderate to severe when applied for three consecutive days. Isopropyl Myristate was minimally irritating to the rabbits' eye, and was not a skin sensitizer in studies with guinea pigs. In limited studies, Isopropyl Myristate was not carcinogenic on the skin of mice, but a mixture of Isopropyl Myristate and isopropyl alcohol significantly accelerated the carcinogenic activity of benzo(a)pyrene on the skin. Human studies with Isopropyl Myristate indicated that it was not a human skin irritant or sensitizer when applied in a product formulation containing 15-58% of the ingredient. A product containing 43% Isopropyl Myristate produced no phototoxicity and no photo-contact allergenicity in human studies. From the available information, it is concluded that Myristyl Myristate and Isopropyl Myristate are safe as cosmetic ingredients in the present practices of use.

Predictive animal testing for photocontact allergenicity.

The purpose of this investigation was to establish a standardized animal model to predict the photoallergenic potential of new chemical compounds. In a first series of experiments the main factors influencing the induction of photoallergenicity were evaluated (induction concentration, pH of the test solution, pretreatment of the irradiation site with sodium lauryl sulphate, additional use of adjuvant injections and routes of administration). Osram Ultravitalux lamps were utilized for these studies. In a second series of experiments a Xenon 6000 W radiation source was used. Positive results were obtained with well known photosensitizers, as, for instance, the halogenated salicylanilides, as well as with so-called weak photoallergens (e.g. bithionol, sulphanilamide) by stimulating the animals' immune system with Freund's complete adjuvant. The photoallergenic compounds were at the same time tested for their contact allergenic potential in the optimization test. A standard procedure for the predictive photoallergenicity assay in guinea-pigs is proposed.

Regulatory issues concerning AETT and 6-MC.

Acetylethyltetramethyltetralin, a widely used synthetic fragance material, was found to cause neurotoxic effects in animals. 6-Methylcoumarin, another fragance material, was determined to be a photocontact allergen. Insufficient information on their usage, consumer exposure and likely hazard to human health under conditions of use impair regulatory decisions. FDA's ability to protect consumers against a health hazard is greatly influenced by the availability of such data.

Photocontact allergy to 6-methylcoumarin.

A proprietary sunscreen-induced photosensitivity reactions in a small number of users. Laboratory study revealed that the reactions were of the photoallergic type and were due to the presence of a synthetic fragrance, 6-methylcoumarin. By photomaximization testing 6-methylcoumarin was found to be a potent photocontact allergen.