International Journal of Toxicology

Hydroxyethylcellulose, Hydroxypropylcellulose, Methylcellulose, Hydroxypropyl Methylcellulose, and Cellulose Gum are modified cellulose polymers that are used in cosmetic products at concentrations up to 10%. The cellulose derivatives pass essentially unchanged through the gastrointestinal tract following oral administration. They are practically nontoxic when administered by inhalation or by oral, intraperitoneal, subcutaneous, or dermal routes. Subchronic and chronic oral studies indicate that the cellulose derivatives are nontoxic when administered to laboratory animals. No significant teratogenic or reproductive effects have been demonstrated. Ocular and dermal irritation studies show that the cellulose derivatives are, at most, minimally irritating to rabbit eyes and nonirritating to slightly irritating to rabbit skin when tested at concentrations up to 100%. No mutagenic activity of theseingredients was demonstrated. The cellulose derivatives at concentrations up to 100% were nonirritating to mildly irritating, nonsensitizing, and nonphotosensitizing when evaluated in clinical studies. It is concluded that theingredients reviewed are safe as cosmeticingredients in the present practices of use and concentration.

Quaternium-15 is used as an antimicrobial preservative in cosmetic products at concentration ranges from ≤0.1 to 1%. The cosmeticingredient is not absorbed through human skin in significant amounts. Animal toxicity studies indicate that Quaternium-15 is mildly to moderately toxic depending on animal species, concentration, and route of exposure. Testicular atrophy and decreased spermatogenesis in immature rabbits were reported in one subchronic dermal study. Orally administered Quaternium-15 was teratogenic in rats when given by gavage to pregnant dams in doses ≥25 mg/kg per day. No teratogenic effects were observed at doses of 5 mg/kg per day. Dermally applied Quaternium-15 did not produce maternal toxicity, fetal toxicity, or fetal abnormalities at doses up to and including 500 mg/kg per day. No testicular effects were produced by Quaternium-15 in three subsequent studies on mature rabbits. Quaternium-15 was a moderate skin irritant in test animals at concentrations above 5%. Quaternium-15 was not a significant eye irritant in rabbits. Animal sensitization studies with Quaternium-15 produced conflicting results depending on the test methodologies used. Quaternium-15 does not appear to possess significant mutagenic activity. Primary irritation studies on Quaternium-15 in inert vehicles and formulations indicate that Quaternium-15 is not a primary skin irritant in humans. Quaternium-15 in inert vehicles may be a human sensitizer in some clinical patients. The sensitization potential of the preservative was much less pronounced when cosmetic products were tested on nonclinical subjects. Quaternium-15 may exhibit cross-sensitization with formaldehyde. Quaternium-15 is not a significant photosensitizing agent. Although Quaternium-15 is a potential skin sensitizer, it is concluded that Quaternium-15 is safe as a cosmeticingredient at concentrations not exceeding those presently in use.

In cosmetic products, Coconut Oil is used as a cleanser, foaming agent, or stabilizer at concentrations up to 50%. Acute, chronic, and subchronic oral toxicity studies indicate that Coconut Oil and Hydrogenated Coconut Oil are relatively nontoxic byingestion. Neither compound produced significant skin or eye irritation in laboratory animals. No sensitization was reported. Clinical assessment of cosmetic products containing Coconut Oil produced very minimal skin irritation reactions. There was no indication that theseingredients were primary irritants, sensitizers, or phototoxic compounds following human testing. It is concluded that Coconut Oil, Coconut Acid, Hydrogenated Coconut Oil, and Hydrogenated Coconut Acid are safe for use as cosmeticingredients.

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.

2-Methylresorcinol and Resorcinol are most frequently used in cosmetic hair dye formulations at concentrations between 1 and 5%. The results of cutaneous and oral feeding studies have indicated that both 2-Methylresorcinol and resorcinol are readily absorbed by rodents and are rapidly eliminated. Acute oral toxicity studies indicate that 2-Methylresorcinol is moderately toxic and Resorcinol is slightly to moderately toxic. Subchronic feeding and dermal studies of bothingredients produced no significant effects. A chronic dermal study was uneventful. Significant skin effects were observed in mice, but not in rabbits, following dermal application of Resorcinol at 5%. A 10% Resorcinol solution was not irritating to guinea pigs. A 2.5% 2-Methylresorcinol solution was classified as a primary irritant in rabbits, but 10% 2-Methylresorcinol was not irritating to guinea pigs. 2-Methylresorcinol was not an ocular irritant at 2.5%, but irritation was produced at 5% concentration in unwashed rabbit eyes. Neither 2-Methylresorcinol at 5% nor Resorcinol at 3% produced sensitization in guinea pigs. 2-Methylresorcinol was not photoallergenic to guinea pigs but was a sensitizer at 10%. Resorcinol was not photoallergenic to guinea pigs but was a sensitizer at 10%. Resorcinol and 2-Methylresorcinol were nonmutagenic in microbial and tissue culture assays for mutagenicity. Topically applied hair dyes containing 2-Methylresorcinol and Resorcinol were negative for carcinogenicity. Resorcinol showed no cocarcinogenic potential when tested on mice and rats. 2-Methylresorcinol at 3% concentration produced no evidence of irritation or sensitization in human subjects. Resorcinol was a mild skin irritant and rare sensitizer in clinical testing, but not when tested on nonclinical groups. On the basis of the available animal and clinical data, it is concluded that 2-Methylresorcinol and Resorcinol are safe as cosmeticingredients in the present practices of use and concentrations.

Disperse Black 9 is a monoazo dye used in hair dyes at a concentration not exceeding 0.4%. In acute toxicity studies, Disperse Black 9 was slightly toxic to practically nontoxic when administered orally and practically nontoxic when administered intraperitoneally. At a concentration of 100% the dye was nonirritating to rabbit eyes and was nonirritating to both the intact and abraded skin of rabbits at concentrations up to 0.38%. Disperse Black 9 at 25% did not produce either irritation or sensitization in guinea pigs. In subchronic oral studies Disperse Black 9 was toxic at 1% but not at 0.1 %. There were no signs of local or systemic toxicity at concentrations up to 0.24% in formulations. In chronic studies, dye containing 0.13% Disperse Black 9 was nontoxic to dogs. A hair dye formulation containing 0.5% Disperse Black 9 produced no significant toxicological effects when applied dermally to mice for 20 months. Disperse Black 9 (0.13% in a dye composite) produced neither teratogenic nor reproductive effects in rats or rabbits. Disperse Black 9 was nonmutagenic in four different assay systems. Disperse Black 9, 0.5% in a hair dye, was not carcinogenic when dermally applied to mice. A 3% suspension of the dye produced no irritation or sensitization in human subjects. On the basis of the available data, it is concluded that Disperse Black 9 is safe for use as a cosmeticingredient.

Cosmetic grade Petroleum Distillate consists predominantly of C₁₀-C₁₆ paraffinic, naphthenic, and isoparaffinic hydrocarbons. The Distillate is used in a variety of cosmetic products at concentrations up to 50%. Undiluted Petroleum Distillate had an acute oral LD₅₀ in rats of >25 ml/kg. Subchronic animal tests on a formulation containing 41.75% Petroleum Distillate were uneventful. Moderate skin irritation and mild, transient eye irritation were observed in rabbits following a single exposure to undiluted Petroleum Distillate. Cosmetic formulations containing 29.2–55% Petroleum Distillate were generally nonirritating, nonsensitizing, and nonphotosensitizing to human skin. It is concluded that Petroleum Distillate, as characterized in the report, is safe as a cosmeticingredient at the current concentrations of use.