J. Cosmet. Sci., 70, 223–234 (September/October 2019) 223 Titanium Dioxide and Zinc Oxide Nanoparticles in Sunscreens: A Review of Toxicological Data MAJA VUJOVIC and EMILIJA KOSTIC , Faculty of Medicine, Department of Pharmacy, University of Nis, 18000 Nis, Serbia (M.V., E.K.), Institute of Forensic Medicine in Nis, 18000 Nis, Serbia (M.V., E.K.) Accepted for publication June 24, 2019 . Synopsis The positive effects of sunlight have been known for many years, and the negative ones, too. Sunscreens are physical and chemical UV absorbers. Nanotechnology has developed nanoparticles of physical blockers: titanium dioxide (TiO2) and zinc oxide (ZnO). Their smaller diameter and increased bioreactivity are the focus of many toxicological studies. The usage of sunscreens has increased around the world, so all toxicological aspects should be carefully considered. There are in vitro and in vivo studies: studies on animal and human skin investigations of potential genotoxicity and cytotoxicity generation of reactive oxygen species penetration skin irritation acute, subchronic, and chronic toxicity and carcinogenesis. The experimental conditions of these studies differ from study to study, but most authors agree that there is no penetration of nanoparticles into viable skin layers. Risk-benefi t analysis of TiO2 and ZnO nanoparticles (NPs) usage in sunscreens strongly indicates that potential risks are vastly outweighed over the benefi ts. Because of the results of some authors indicating possible penetration through damaged skin, further studies should be conducted, primarily addressed on skin penetration mechanisms. INTRODUCTION UV radiation can cause harmful effects on the skin. UVC, and partly UVB, can be absorbed by molecular oxygen to produce ozone. Stratospheric ozone absorbs UV rays below 290 nm, but UVB and UVA rays reach the human skin and cause metabolic and biological reactions (1). Although many patients and physicians believe that regular use of sunscreens provides protection from skin cancer, this protective effect has been confi rmed only in the cases of squamous cell carcinoma and actinic keratoses, but for basal cell carcinoma and malig- nant melanoma, the results are inconclusive (2–4). In the United States, skin cancer is the most common form of cancer. Annually, more than one million cases are diagnosed in the form of squamous cell and basal cell carcinoma, both associated with UV radiation. The incidence of melanoma is rising signifi cantly. Address all correspondence to Maja Vujovic at majavujovic1@gmail.com and Emilija Kostic at emilija293@gmail.com.

JOURNAL OF COSMETIC SCIENCE 224 More people are diagnosed with skin cancer each year in the United States than all other cancers combined (5,6). SUNSCREENS The negative effects of sunlight, sunburns, photoaging, and skin cancers are reduced by the use of sunscreens. Sunscreens should provide protection against the adverse effects of both UVB and UVA radiation. Compounds that have the ability to protect from UV radiation are classifi ed into two groups: organic and inorganic blockers. Minerals such as zinc oxide (ZnO) and titanium dioxide (TiO2) are often used as inorganic physical sun blockers. TiO2 and ZnO have been used as ingredients for sunscreen formulations for more than 20 years. Their mechanism of actions involves absorption, refl ection, and refl ecting and the scattering of UV sunlight (7). The disadvantage of microsized ZnO and TiO2 particles is their poor dispersive proper- ties, resulting in a white color that is not cosmetically appealing (8). NANOPARTICLES The rapid development of nanotechnology has resulted in an increasing number of nano- material-based products. Because of their physicochemical properties, nanomaterials have found an important role in cosmetics. When particles become smaller than 100 nm (the optimal light scattering size), visible light is transmitted across the particles. This avoids the cosmetically undesired opaqueness of inorganic sunscreens and makes the application of cosmetic products based on nanoparticles (NPs) commercially attractive, without re- ducing UV-blocking effectiveness (9). Possible adverse effects have been considered. Because the surface area to volume ratio of particles increases as the particle diameter decreases, NPs may be more (bio) reactive than normal bulk materials. This is the reason why safety of cosmetic products containing NPs has been frequently discussed. Many scientists and research institutes mainly focus on various kinds of toxicological and skin penetration studies. However, safety also concerns the physicochemical properties of sunscreen ingredients to be taken up by the skin in both the absence and presence of light. With the widespread use and the potential for TiO2 or ZnO NPs exposure, concerns have focused on their possible resorption. COSMETIC REGULATION International Cooperation on Cosmetic Regulation defi nes a nanomaterial in cosmetics as an insoluble intentionally manufactured ingredient with one or more dimensions ranging from 1 to 100 nm in the fi nal formulation. In addition, the nanomaterial must be suffi - ciently stable and persistent in biological media to disable potential interactions with biosystems (10). In 2012, the International Organization for Standardization underlined that the physico- chemical characterization of nanomaterials was critical for the identifi cation of test mate- rials before toxicological assessment (11).