4: Final Report on the Safety Assessment of Hydroquinone and Pyrocatechol

Abstract

Hydroquinone and Pyrocatechol, two benzenediol isomers, are used as couplers in oxidative hair dyes at concentrations of less than 1.0%. Both compounds are absorbed from the gastrointestinal tract; Pyrocatechol is also readily absorbed through the skin. Both compounds are excreted in the urine, mainly as the ethereal sulfate. In acute oral studies Hydroquinone is practically nontoxic to moderately toxic; the data from subchronic feeding studies of Hydroquinone indicated that it was not toxic at 1% but was at higher concentrations. Pyrocatechol was moderately toxic in acute studies. Subchronic oral studies of Pyrocatechol at 0.25% produced hepatic cell hyperplasia in rats. Hydroquinone was a weak depigmenter but not an irritant when tested at 1.0%. Theingredient was a sensitizer when injected at 2.0%. The acute dermal LD50 of Pyrocatechol was 0.8 g/kg. Pyrocatechol did not depigment rabbit skin at 1.0% but did at 3.0%; skin irritation was observed at 5.0%. Guinea pigs were sensitized when Pyrocatechol was injected at concentrations above 0.2 μM. Undiluted product formulation containing 2.0% Hydroquinone produced mild conjunctivitis in 3 of 6 animals; undiluted Pyrocatechol is an extreme ocular irritant. Hydroquinone was not teratogenic in three separate studies. The results of mutagenesis assays of Hydroquinone varies with the assay system used. In four Salmonella typhimurium strains, both with and without activation, the mutagenesis assay was negative. Hydroquinone produced positive results both with and without activation in the HeLa DNA synthesis test but was not considered mutagenic in assays using Chinese hamster cells. Hydroquinone induced SCE and delayed cell-turnover time in human lymphocyte studies. Oral doses of Hydroquinone did not inhibit testicular DNA synthesis in male mice, and was nonmutagenic in the mouse sperm-head abnormality test. In multigeneration studies with rats, topically applied hair dyes containing 0.2% Hydroquinone had no effect on reproduction; the dye was neither embryotoxic or teratogenic. Dermally applied hair dyes containing Hydroquinone were not carcinogenic. Hydroquinone when applied topically was neither a tumor promoter nor a cocarcinogen in mice. The mutagenicity of Pyrocatechol also varies with the test system used. In most studies, Pyrocatechol was nonmutagenic, both with and without metabolic activation, in the Ames' assay. The compound was negative in the Escherichia coli DNA polymerase assay, but was positive in the yeast, Saccharomyces cerevisiae. Pyrocatechol was negative in the HeLa DNA synthesis test and with Chinese Hamster V79 cells. The compound increased the numbers of chromatid breaks and exchanges in Chinese hamster ovary cells and induced SCE and delayed cell turnover time in human lymphocyte cultures. The compound given by intraperitoneal injection to mice was negative in the sperm-head abnormality test but was positive in the bone marrow assay. In three studies in mice, topically applied Pyrocatechol was not a tumor promotor. However, topically applied Pyrocatechol was a cocarcinogen for mouse skin in two other studies. Positive sensitization reactions to Hydroquinone were reported in 8.9% of 536 dermatologic patients. Two of 38 patients treated with an ointment containing 5.4% Hydroquinone became sensitized. A cosmetic formulation containing 2% Hydroquinone produced one or more mild irritation reactions in 69 of 90 subjects in the induction phase of a sensitization test; 22 of the 69 subjects were mildly sensitized when challenged. The use of ointments containing 2, 3, and 5% Hydroquinone produced at least minimal depigmentation in white but not black subjects. It is concluded that Hydroquinone and Pyrocatechol are safe for cosmetic use at concentrations of ≤ 1.0% in formulations that are designed for discontinuous, brief use followed by rinsing from the skin and hair.