On the other hand, the U.S. Food and Drug Administration (FDA) in their Final Administrative Order on Sunscreen Drug Products posted in September 2021 still accepts titanium dioxide up to 25% in the list of Generally Recognized As Safe and Effective (GRASE) in the main document, without further clarification on what kind or size of particles [9]. However, on page 24 (Sunscreen containing nanomaterials) FDA clearly “distinguish nanomaterials from other forms of these ingredients'' (zinc oxide and titanium dioxide) and ask for comments on “any particular nanomaterials that you believe should not be permitted for use in OTC sunscreen products”. To the best of our knowledge, this Agency did not ban the use of nanoparticulate titanium dioxide in any form, even though it is mentioned on page 34 that the anatase form is the more photoactive one, due to the lack of evidence with real sunscreens OTC (over the counter) in vivo. Moreover, other regulations in Latin America (MERCOSUR agreement, 2006) do not state clearly their position on the use of nanoparticulate TiO₂NPs [10].

Exposure to titanium dioxide in utero and in breastfeeding children

FAQ – EFSA 2021 safety assessment of titanium dioxide (E171)

Titanium dioxide (TiO₂) is considered as an inert and safe material and has been used in many applications for decades. However, with the development of nanotechnologies TiO₂ nanoparticles, with numerous novel and useful properties, are increasingly manufactured and used. Therefore increased human and environmental exposure can be expected, which has put TiO₂ nanoparticles under toxicological scrutiny. Mechanistic toxicological studies show that TiO₂ nanoparticles predominantly cause adverse effects via induction of oxidative stress resulting in cell damage, genotoxicity, inflammation, immune response etc. The extent and type of damage strongly depends on physical and chemical characteristics of TiO₂ nanoparticles, which govern their bioavailability and reactivity. Based on the experimental evidence from animal inhalation studies TiO₂ nanoparticles are classified as “possible carcinogenic to humans” by the International Agency for Research on Cancer and as occupational carcinogen by the National Institute for Occupational Safety and Health. The studies on dermal exposure to TiO₂ nanoparticles, which is in humans substantial through the use of sunscreens, generally indicate negligible transdermal penetration; however data are needed on long-term exposure and potential adverse effects of photo-oxidation products. Although TiO₂ is permitted as an additive (E171) in food and pharmaceutical products we do not have reliable data on its absorption, distribution, excretion and toxicity on oral exposure. TiO₂ may also enter environment, and while it exerts low acute toxicity to aquatic organisms, upon long-term exposure it induces a range of sub-lethal effects.

Understanding the Wholesale Lithopone Pigment Pricelist

This constant high rate of ROS production leads rapidly to extreme macromolecular oxidation, here it is observed in the AOPP and MDA detected after 3 h in samples treated with bare P25TiO₂NPs (Fig. 6, Fig. 7). Macromolecular oxidation includes, among others, both protein and lipid oxidation. The ROS causes protein oxidation by direct reaction or indirect reactions with secondary by-products of oxidative stress. Protein fragmentation or cross-linkages could be produced after the oxidation of amino acid side chains and protein backbones. These and later dityrosine-containing protein products formed during excessive production of oxidants are known as advanced oxidation protein products (AOPP). They absorb at 340 nm and are used to estimate the damage to structural cell amino acids. Lipid oxidation is detected by the conjugation of oxidized polyunsaturated lipids with thiobarbituric acid, forming a molecule that absorbs light at 532 nm. Polyunsaturated lipids are oxidized as a result of a free-radical-mediated chain of reactions. The most exposed targets are usually membrane lipids. The macromolecular damage could represent a deadly danger if it is too extensive, and this might be the case. Moreover, it could be observed that cellular damage continues further and becomes irrevocable after 6 h and MDA could not be detected. This may be due to the fact that the lipids were completely degraded and cells were no longer viable. Lipids from the cell membrane are the most prone to oxidation. In fact, lipid peroxidation biomarkers are used to screen the oxidative body balance [51]. At the same time, AOPP values are up to 30 times higher for bare nanoparticles in comparison to the functionalized ones.