Recently, Yanagisawa et al. reported that the transdermal exposure (mimicking skin-barrier dysfunction or defect) of NC/Nga mice to TiO₂ NPs (15, 50, or 100 nm), in combination with allergen, aggravated atopic dermatitis-like lesions through a T-helper type 2 (Th2) dominant immune response. The study also indicated that TiO₂ NPs can play a role in the initiation and/or progression of skin diseases, since histamine was released, even in the absence of allergen.

The lack of clear regulations and controls explains that P25TiO₂NPs are still found in many of the commercialized sunscreens in the market. Some of them are coated to reduce the photoactivity of the anatase form, which is known to be responsible for tissue damage, but not enough studies were made on these coated forms. The anatase photoactivity could trigger the production of reactive oxygen species (ROS) generation, as it was stated before. The ROS are chemically reactive species containing oxygen, such as peroxides, superoxide, hydroxyl radical, and singlet oxygen. They are regularly produced in the biological milieu and counterbalanced by physiological antioxidant defense mechanisms. However, an abrupt increase of ROS may result in non-reversible damage to the skin cells. The effects of coated and uncoated P25TiO₂NPs need therefore to be studied, and articles on this topic present different conclusions. [11], [12], [13] Recent literature on this topic found that TiO₂NPs inhalation provokes serious genotoxicity and DNA damage [14], [15], [16], [17]. On the other hand, some studies in rats have reported no significant harm to genetic material [18], [19], [20], [21], [22].

In a study published in the journal Environmental Toxicology and Pharmacology in 2020, researchers examined the effects of food additives titanium dioxide and silica on the intestinal tract by grouping and feeding mice three different food-grade particles — micro-TiO2, nano-TiO2, and nano-SiO2.  With all three groups, researchers observed changes in the gut microbiota, particularly mucus-associated bacteria. Furthermore, all three groups experienced inflammatory damage to the intestine, but the nano-TiO2 displayed the most pronounced changes. The researchers wrote: “Our results suggest that the toxic effects on the intestine were due to reduced intestinal mucus barrier function and an increase in metabolite lipopolysaccharides which activated the expression of inflammatory factors downstream. In mice exposed to nano-TiO2, the intestinal PKC/TLR4/NF-κB signaling pathway was activated. These findings will raise awareness of toxicities associated with the use of food-grade TiO2 and SiO2.”

Regarding flavoring substances, JECFA concluded that there is no safety concern and established specifications for 21 agents across three classes: aliphatic primary alcohols, aldehydes, carboxylic acids, acetals, and esters containing additional oxygenated functional groups; linear and branched-chain aliphatic, unsaturated and unconjugated alcohols, aldehydes, acids, and related esters; and saturated aliphatic acyclic linear primary alcohols, aldehydes, and acids.