Final report on the safety assessment of BHT(1).

BHT is the recognized name in the cosmetics industry for butylated hydroxytoluene. BHT is used in a wide range of cosmetic formulations as an antioxidant at concentrations from 0.0002% to 0.5%. BHT does penetrate the skin, but the relatively low amount absorbed remains primarily in the skin. Oral studies demonstrate that BHT is metabolized. The major metabolites appear as the carboxylic acid of BHT and its glucuronide in urine. At acute doses of 0.5 to 1.0 g/kg, some renal and hepatic damage was seen in male rats. Short-term repeated exposure to comparable doses produced hepatic toxic effects in male and female rats. Subchronic feeding and intraperitoneal studies in rats with BHT at lower doses produced increased liver weight, and decreased activity of several hepatic enzymes. In addition to liver and kidney effects, BHT applied to the skin was associated with toxic effects in lung tissue. BHT was not a reproductive or developmental toxin in animals. BHT has been found to enhance and to inhibit the humoral immune response in animals. BHT itself was not generally considered genotoxic, although it did modify the genotoxicity of other agents. BHT has been associated with hepatocellular and pulmonary adenomas in animals, but was not considered carcinogenic and actually was associated with a decreased incidence of neoplasms. BHT has been shown to have tumor promotion effects, to be anticarcinogenic, and to have no effect on other carcinogenic agents, depending on the target organ, exposure parameters, the carcinogen, and the animal tested. Various mechanism studies suggested that BHT toxicity is related to an electrophillic metabolite. In a predictive clinical test, 100% BHT was a mild irritant and a moderate sensitizer. In provocative skin tests, BHT (in the 1% to 2% concentration range) produced positive reactions in a small number of patients. Clinical testing did not find any depigmentation associated with dermal exposure to BHT, although a few case reports of depigmentation were found. The Cosmetic Ingredient Review Expert Panel recognized that oral exposure to BHT was associated with toxic effects in some studies and was negative in others. BHT applied to the skin, however, appears to remain in the skin or pass through only slowly and does not produce systemic exposures to BHT or its metabolites seen with oral exposures. Although there were only limited studies that evaluated the effect of BHT on the skin, the available studies, along with the case literature, demonstrate no significant irritation, sensitization, or photosensitization. Recognizing the low concentration at which this ingredient is currently used in cosmetic formulations, it was concluded that BHT is safe as used in cosmetic formulations.

Final report on the safety assessment of EDTA, calcium disodium EDTA, diammonium EDTA, dipotassium EDTA, disodium EDTA, TEA-EDTA, tetrasodium EDTA, tripotassium EDTA, trisodium EDTA, HEDTA, and trisodium HEDTA.

EDTA (ethylenediamine tetraacetic acid) and its salts are substituted diamines. HEDTA (hydroxyethyl ethylenediamine triacetic acid) and its trisodium salt are substituted amines. These ingredients function as chelating agents in cosmetic formulations. The typical concentration of use of EDTA is less than 2%, with the other salts in current use at even lower concentrations. The lowest dose reported to cause a toxic effect in animals was 750 mg/kg/day. These chelating agents are cytotoxic and weakly genotoxic, but not carcinogenic. Oral exposures to EDTA produced adverse reproductive and developmental effects in animals. Clinical tests reported no absorption of an EDTA salt through the skin. These ingredients are likely, however, to affect the passage of other chemicals into the skin because they will chelate calcium. Exposure to EDTA in most cosmetic formulations, therefore, would produce systemic exposure levels well below those seen to be toxic in oral dosing studies. Exposure to EDTA in cosmetic formulations that may be inhaled, however, was a concern. An exposure assessment done using conservative assumptions predicted that the maximum EDTA dose via inhalation of an aerosolized cosmetic formulation is below that shown to produce reproductive or developmental toxicity. Because of the potential to increase the penetration of other chemicals, formulators should continue to be aware of this when combining these ingredients with ingredients that previously have been determined to be safe, primarily because they were not significantly absorbed. Based on the available data, the Cosmetic Ingredient Review Expert Panel found that these ingredients are safe as used in cosmetic formulations.

Final report on the safety assessment of sorbitan caprylate, sorbitan cocoate, sorbitan diisostearate, sorbitan dioleate, sorbitan distearate, sorbitan isostearate, sorbitan olivate, sorbitan sesquiisostearate, sorbitan sesquistearate, and sorbitan triisostearate.

Sorbitan fatty acid esters are mono-, di-, and triesters of fatty acids and sorbitol-derived hexitol anhydrides. They function as surfactants in cosmetic formulations. Previously, the Cosmetic Ingredient Review (CIR) Expert Panel had reviewed the safety of several of these sorbitan fatty acid esters (Sorbitan Laurate, Sorbitan Oleate, Sorbitan Palmitate, Sorbitan Sesquioleate, Sorbitan Stearate, Sorbitan Trioleate, and Sorbitan Tristearate). This safety assessment is an addendum to that report that includes Sorbitan Caprylate, Sorbitan Cocoate, Sorbitan Diisostearate, Sorbitan Dioleate, Sorbitan Distearate, Sorbitan Isostearate, Sorbitan Olivate, Sorbitan Sesquiisostearate, Sorbitan Sesquistearate, and Sorbitan Triisostearate. Although concentrations of these ingredients up to 25% have been reported to be used, most commonly they are used at less than 10%. These esters may be hydrolyzed to the fatty acid and anhydrides of Sorbitol. Fatty Acids are absorbed and metabolized. Sorbitan fatty acid esters were relatively nontoxic via ingestion in acute and long-term studies. They were generally minimal to mild skin irritants in animal studies, except that Sorbitan Isostearate applied to the skin was a moderate irritant in one rabbit study and when injected intradermally caused mild to severe irritation in guinea pigs. Sorbitan fatty acid esters did not sensitize guinea pigs. The fatty acid component, tested alone, typically caused only slight irritation and sensitization, and was not photosensitizing. Sorbitan fatty acid esters were not ocular irritants. Fatty acids are normal components of diet for which no data were available concerning reproductive or developmental toxicity, but Sorbitol had no adverse effects on the reproduction of CD rats during a multigeneration feeding study and was not a reproductive toxin at doses of 3000 to 7000 mg/kg/day for 2 years. Overall these esters and their corresponding fatty acids were not mutagenic, but Sorbitan Oleate was reported to reduce DNA repair following ultraviolet radiation exposure in human lymphocytes in culture. Sorbitan Laurate and Sorbitan Trioleate were cocarcinogens in one mouse study, but Sorbitan Trioleate and Sorbitan Oleate were not tumor promoters in another study. In clinical tests, Sorbitan fatty acid esters were generally minimal to mild skin irritants and were nonsensitizing, but Sorbitan Sesquioleate did produce an allergic reaction in fewer than 1% of patients with suspected contact dermatitis and addition of Sorbitan Sesquioleate to the components of a fragrance mix used in patch testing increased both irritant and allergic reactions to the fragrance mix. Careful consideration was made of the data on the cocarcinogenesis of Sorbitan Laurate and Sorbitan Trioleate, but the high exposure levels, high frequency of exposure, and absence of a dose-response led to the conclusion that there was not a cocarcinogenesis risk with the use of these ingredients in cosmetic formulations. Accordingly, these ingredients were considered safe for use in cosmetic formulations under the present practices of use.