Final report on the safety assessment of Hexamidine and Hexamidine Diisethionate.

Hexamidine Diisethionate functions as a biocide in cosmetics at concentrations of 0.03% to 0.1% in 38 cosmetic products. Hexamidine functions as a biocide and preservative in cosmetics, but is not in current use in cosmetics, but it is used in over-the-counter (OTC) drug products. Hexamidine was poorly absorbed by human cadaver skin when in water-oil formulations or in a gel that simulated a cosmetic product formulation. Hexamidine Diisethionate was poorly absorbed by the skin of live rats and was not stored in any tissue type. Hexamidine Diisethionate given to rats intravenously was rapidly metabolized to Hexamidine. Excretion was primarily via the feces, with a small amount excreted in the urine. Acute oral LD(50) values of Hexamidine Diisethionate were 0.71 to 2.5 g/kg in mice and 0.75 g/kg in rats. Dermal exposure to 4 g/kg Hexamidine Diisethionate in rats or up to 9.4 ml/kg of a 0.1% Hexamidine Diisethionate solution under occlusion in rabbits produced no mortality or other signs of toxicity. The no-observed-effect level (NOEL) for oral subchronic toxicity of Hexamidine Diisethionate in rats was 50 mg/kg/day. No signs of toxicity were observed with 2% Hexamidine Diisethionate in subchronic studies using rabbits. Application of 0.1 ml of 0.11% Hexamidine Diisethionate in aqueous solution to the eyes of rabbits produced transient reactions; 0.05% produced no reactions. Slight erythema was observed with 0.10% Hexamidine Diisethionate applied to the abraded skin of 1/11 albino rabbits. A 40% solution of Hexamidine Diisethionate applied to 10% of the body surface of rats produced slight erythema, slight edema, and scabbing in some animals at varying times after treatment. Hexamidine Diisethionate was not a sensitizer in the guinea pig maximization test or in an intracutaneous guinea pig sensitization test. Hexamidine Diisethionate was not a photosensitizer in albino rabbits. Hexamidine Diisethionate was not mutagenic in a bacterial reverse mutagenicity assay or clastogenic in mammalian cells. Hexamidine Diisethionate at 0.10% did not provoke primary irritation, inflammation, or sensitization in a clinical test of 200 human subjects. One case report of photosensitivity to Hexamidine and one of contact sensitivity to Hexamidine were reported. There were nine case reports of contact sensitivity to Hexamidine Diisethionate. A European safety assessment recommended a limit of 0.1% Hexamidine Diisethionate in leave-on and rinse-off cosmetic products. In considering the available data, the Cosmetic Ingredient Review (CIR) Expert Panel acknowledged the lack of carcinogenicity and reproductive/developmental toxicity data. Because genotoxicity studies were negative, and there were no structural alerts, the Panel concluded that it was unlikely that these ingredients would be carcinogenic. Because the rate of absorption of Hexamidine and Hexamidine Diisethionate is slow, there is no tissue accumulation, and excretion is rapid and complete, and there was no toxicity in a subchronic study, the Panel concluded that dermal exposures would not likely present a risk of reproductive/developmental toxicity. The Panel noted that a guinea pig maximization study using Hexamidine Diisethionate produced no dermal reactions and that a clinical test at 0.1% produced no irritation or sensitization. The Panel also expressed concern regarding the possible presence of 1,4-dioxane as an impurity, and stressed that the cosmetic industry should continue to use the necessary purification procedures to remove these impurities from the ingredient before blending into cosmetic formulations. The Panel noted that there are no data for concentration of use for eye makeup and baby products, and was concerned that there should not be unrestricted concentration levels in these product categories. Although there are gaps in knowledge about product use, the overall information available on the types of products in which these ingredients are used and at what concentration indicate a pattern of use. Within this overall pattern of use, the Expert Panel considers all ingredients in this group to be safe at concentrations up to and including 0.1%.