Cosmetics are a part of everyday life for people of all ages around the world. People use cosmetics to maintain their personal hygiene or to care for their personal appearance. Cosmetics contain many ingredients with various functionalities. As the use of cosmetics has expanded, the safety issues of cosmetic ingredients have drawn extensive attention. Therefore, certain cosmetic ingredients are under regulation, requiring that human health be safe when using cosmetics under normal or predictable conditions of use. Drometrizole is categorized as an ingredient of sunscreen and is known to be used in various cosmetics and non-cosmetics. The purpose of this review is to investigate the toxicological data and risk assessment of drometrizole using the available published data.[1]

Physical and chemical properties

Drometrizole (CAS no. 2440-22-4) called 2-(2′-hydroxy-5′-methylphenyl) benzotriazole, is an odorless benzotriazole compound that appears as an off-white to yellow crystalline powder with a structure as shown. It is also known as 2-(2H-benzotriazol-2-yl)-4-methylphenol, 2-(2H-benzotriazol-2-yl)-p-cresol, benazol P, and tinuvin P. Molecular weight is 225.25. Its melting point is 131°C to 133°C and its boiling point is 225°C. The Log P (octanol/water) of drometrizole is 4.31 and it is soluble in organic solvents such as acetone, chloroform, dioctylphthalate, ethanol, ethyl acetate, but insoluble in water.

Cosmetic use

Drometrizole is used in a variety of cosmetics and personal care products in addition to non-cosmetic products. In cosmetics, drometrizole is categorized as a sunscreen ingredient and used as a UV light absorber and stabilizer. It prevents the deterioration of cosmetics and personal care products because it absorbs, reflects, and scatters UV rays (9). It is also used as a fragrance ingredient in consumer goods by International Fragrance Association-affiliated members. According to the US Food and Drug Administration (FDA), in 1981, drometrizole was used in the following cosmetics: bath, fragrances, coloring and noncoloring hair care, manicuring, shaving, skin care, and suntan preparations. Of the 217 reported drometrizole use cases, 77% were used in nail polishes and enamels, and 11% were used in noncoloring hair shampoos. According to voluntary industry reports to the US FDA in 2005, there were two uses of drometrizole: in noncoloring shampoos and in other noncoloring hair preparations. In 2006, the International Cosmetic Ingredient Dictionary and Handbook indicated the uses of drometrizole in nail polishes and enamels. Based on the list of cosmetics ingredients reported by manufacturers to the Ministry of Food and Drug Safety (MFDS) in 2015, drometrizole was used in 184 products of the 100,190 products manufactured in Korea. Most of these are nail care products while it is not used as the main ingredient of sunscreens in Korea.[2]

In non-cosmetic products, drometrizole is used as a UV absorber and stabilizer in plastics, polyesters, celluloses, acrylates, dyes, rubber, synthetic and natural fibers, waxes, detergent solutions, and orthodontic adhesives. Because of its high degree of environmental stability, it is used in polymerization or compounding of plastics. Due to its stability in the presence of light and heat, it may be used in agricultural applications as a UV absorber to prevent leaf burn and apple peel spot. It is formulated in insecticides as a stabilizer. In addition, it has antioxidant and stabilizing effects and is approved as an indirect food additive. It is used as a UV absorber in food packaging. According to the Global Cosmetic Ingredient Information database, drometrizole is regulated to be used up to 7% in cosmetics other than those washed immediately after use, such as soap or shampoo in Japan.

Acute toxicity

Mice and rats were administered 5.0 or 10.0 g/kg of drometrizole in sunflower oil by stomach tube intubation. After body weight and behavior were monitored for 3 weeks, acute toxicity of drometrizole was evaluated to be low. The oral lethal dose (LD50) of drometrizole in mice was reported to be 6.5 g/kg and > 5.0 g/kg by Labor Hygiene and Occupational Diseases. Oral toxicity was evaluated in rats for nail care cosmetics containing 1%, 0.3% and 0.03% of drometrizole. The LD50 of products containing 1% of drometrizole was > 15.0 g/kg. LD50 of products containing 0.3% and 0.03% of drometrizole was > 5.0 g/kg. No acute toxicity was observed in these treatments.

Tif:Ralf (SPF) rats were orally treated with 4,640, 7,750, or 10,000 mg/kg of drometrizole suspended in polyethylene glycol (PEG) 400. Rats were observed for clinical symptoms and mortality for 14 days after treatment. Rats showed sedation, dyspnea, curved position, and ruffled fur within 2 hr after administration. Two females of 10,000 mg/kg group died within one week and all other animals recovered within 10 days after treatment. The animals showed no symptoms associated with administration at necropsy. The Environmental Protection Agency (EPA) concluded that the oral LD50 of drometrizole in rats was > 10,000 mg/kg. Five male and five female Charles River rats were exposed to drometrizole/air mixture at 1,420 mg/m3 for 4 hr. Drometrizole aerosol was produced through a Ferris wheel dust system. The animals showed no clinical signs, toxicity, or mortality for 14 days after exposure. There were no effects or changes related to exposure at necropsy. Thus, LC50 (4 hr) of drometrizole was evaluated to be > 1,420 mg/m3. A nail product containing 0.3% drometrizole was applied under occlusive patches to the clipped skin of 10 rabbits for 24 hr. After application, the animals were observed for 14 days. Dermal LD50 was estimated to be > 2 g/kg. Nail polish products containing 1% drometrizole were applied to six albino guinea pigs under occlusive patches at 3.0 g/kg doses for 24 hr. There were no toxic effects or mortality for 14 days after treatment.

Phototoxicity

A three-year clinical therapeutic trial was performed to evaluate the light-protective effect of UV light-absorbing preparations containing drometrizole in 145 patients with light dermatoses and light sensitivity. An ointment containing 5% drometrizole or a lacquer containing 1.5 parts by weight of drometrizole was tested with radiation of an OsramUltra Vitalux lamp or sunlight. Drometrizole was proven to be highly effective in 445 applications with only two cases of hypersensitivity reactions. Two suntan oils, each containing 0.1% drometrizole were applied on the backs of human subjects (2 males and 8 females) for phototoxicity evaluation. An occlusive patch containing 0.2 mL samples was applied for 24 hr and the oil was reapplied after the patch was removed. The test site was irradiated with 1 minimal erythema dose (MED) of UVB followed by exposure to UVA for 12 min. The scores measured at 15 min, 24 hr, and 48 hr, were all zero. None of the products used in the tests showed phototoxicity.[3]

A prophetic patch test was performed to evaluate phototoxicity of a nail product containing 0.03% drometrizole. Single induction and challenge patches with UV exposure were applied to 99 human subjects. The test scores were all zero.A repeat insult patch test (RIPT) with UV exposure was performed to evaluate phototoxicity of nail product containing 0.03% drometrizole in 48 human subjects. Ten induction patches and a single challenge patch with UV exposure were applied. Five cases with score 1 (max. = 3) and one case of score 2 were observed in the induction phase. One case of score 1 at challenge was reported. In addition, one case was noted at challenge with UV exposure. In conclusion, the nail product containing 0.03% drometrizole was evaluated as nonirritating, nonsensitizing, and nonphotosensitizing.

References

[1] EU. Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on Cosmetic Products. Official Journal of the European Union. 2009;59:1.

[2] Hughes TM, Martin JA, Lewis VJ, Stone NM. Allergic contact dermatitis to drometrizoletrisiloxane in a sunscreen with concomitant sensitivities to other sun screens. Contact Derm. 2005;52:226–227

[3] Hald M, Bergendorff O, Isaksson M, Johansen JD. Allergic contact dermatitis caused by plastic items containing the ultraviolet absorber drometrizole. Contact Derm. 2018;79:110–112.