6 Final Report on the Safety Assessment of Methylisothiazolinone and Methylchloroisothiazolinone

Abstract

Methylisothiazolinone and Methylchloroisothiazolinone (MI/MCI) are heterocyclic organic compounds that are used in cosmetics as a broad spectrum preservative system. MI/MCI was absorbed after oral administration and then was excreted in the urine or feces; storage in the tissues was minimal. Up to 62% of a single percutaneous dose was bound to the site of application 24 hours after exposure. The MI/MCI-CG bound to the skin had a 13.1-day half-life. MI/MCI was moderately to highly toxic to rats, and highly toxic to rabbits when administered orally, and moderately toxic when applied dermally. MI/MCI was not a cumulative ocular irritant when tested at 55 ppm. The dermal irritation of MI/MCI was concentration dependent but nonirritating to rabbit skin at 560 ppm concentrations; this nonirritating concentration is well above the maximum recommended use concentration. No treatment-related effects were observed in rats which received MI/MCI in oral doses up to 24.4 mg/kg/day for 2 weeks. Doses of MI/MCI up to 2.8 mg/kg/day applied dermally to rabbits, 5 days per week for 3 weeks, produced moderate irritation at the application site but no systemic toxicity. Dermal application of MI/MCI at doses up to 0.4 mg/kg/day for 3 months produced no systemic toxicity in rabbits. No toxicologically significant treatment-related effects were observed in rats or dogs at doses up to 30 and 28 mg/kg/day, respectively. The result of genotoxic testing of MI/MCI varied with the assay used. Dermal application of 400 ppm MI/MCI-CG, 3 times per week for 30 months, had no local or systemic tumorigenic effect in male mice. MI/MCI administered by gavage to pregnant rabbits and rats at doses up to 13.3 mg/kg/day was toxic to the dam, embryo, and fetus; the compound was not teratogenic. MI/MCI is a sensitizer however, the concentration of MI/MCI in cosmetic products which produced sensitization varies. The available human sensitization test data at concentrations of 50 ppm and above are not in agreement. MI/MCI-CG was not a sensitizer or photosensitizer at a concentration of 15 ppm. It is concluded that Methylisothiazolinone/Methylchloroisothiazolinone may be safely used in “rinse-off” products at a concentration not to exceed 15 ppm and in “leave-on” cosmetic products at a concentration not to exceed 7.5 ppm. The stated safe use concentration refers to a mixture containing 23.3% Methylisothiazolinone and 76.7% Methylchloroisothiazolinone.