Titanium dioxide (TiO₂) is a chemical compound, a white pigment that creates a white or opaque color.

It is now present in many applications: cosmetics, paints, papers, sunscreens, pharmaceutical additives.

We frequently find it in the coatings of medicinal tablets, beverages, in sunscreens as anti-UV filter.

Widely used as an additive in the food industry as a bleaching agent (E171).

Titanium dioxide has so far been considered safe and inert.

A brief history on the evolution of scientific studies on the safety of this chemical component.

 2011 - 2016

Titanium dioxide in our everyday life; is it safe? The answer is cautious : "we do not have reliable data on its absorption, distribution, excretion and toxicity on oral exposure." (1).

Some studies recognize a positive value in the biomedical applications of titanium dioxide (2).

Other studies do not reveal any toxicological problems (3).

In 2016, EFSA provides an opinion with a review of the safety of titanium dioxide (TiO₂, E171) when used as a food additive.
The present Opinion deals with the re‐evaluation of the safety of titanium dioxide (TiO₂, E 171) when used as a food additive. From the available data on absorption, distribution and excretion, the EFSA Panel on Food Additives and Nutrient Sources added to Food concluded that the absorption of orally administered TiO₂ is extremely low and the low bioavailability of TiO2 appears to be independent of particle size. The Panel concluded that the use of TiO2 as a food additive does not raise a genotoxic concern. From a carcinogenicity study with TiO₂ in mice and in rats, the Panel chose the lowest no observed adverse effects levels (NOAEL) which was 2,250 mg TiO₂/kg body weight (bw) per day for males from the rat study, the highest dose tested in this species and sex. The Panel noted that possible adverse effects in the reproductive system were identified in some studies conducted with material which was either non‐food‐grade or inadequately characterised nanomaterial (i.e. not E 171). There were no such indications in the available, albeit limited, database on reproductive endpoints for the food additive (E 171). The Panel was unable to reach a definitive conclusion on this endpoint due to the lack of an extended 90‐day study or a multigeneration or extended‐one generation reproduction toxicity study with the food additive (E 171). Therefore, the Panel did not establish an acceptable daily intake (ADI). The Panel considered that, on the database currently available and the considerations on the absorption of TiO₂, the margins of safety (MoS) calculated from the NOAEL of 2,250 mg TiO2/kg bw per day identified in the toxicological data available and exposure data obtained from the reported use/analytical levels of TiO₂ (E 171) would not be of concern. The Panel concluded that once definitive and reliable data on the reproductive toxicity of E 171 were available, the full dataset would enable the Panel to establish a health‐based guidance value (ADI) (4).

 2017 - 2019

Since 2017, some studies carried out using ultramodern nano techniques (European Synchrotron of Grenoble) attribute to genotoxide genotoxic characteristics.

If the Titanium Dioxide is inlaid into the skin, as in the case of tattoos,  additional laboratory-based mass spectrometric methods demonstrated simultaneous transport of organic pigments, heavy metals and titanium from skin to regional lymph nodes. The toxicity of TiO₂depends on its speciation (crystal structure) which can be either rutile or the more harmful photocatalytically active anatase. The contribution of tattoo inks to the overall body load on toxic elements, the speciation of TiO₂, and the identities and size ranges of pigment particles migrating from subepidermal skin layers towards lymph nodes have never been analytically investigated in humans before. The average particle size in tattoo inks may vary from 1 µm. Therefore most tattoo inks contain at least a small fraction of particles in the nano range (5).

The deposit of particles leads to chronic enlargement of the respective lymph node and lifelong exposure. With the detection of the same organic pigments and inorganic TiO₂ in skin and lymph nodes, we provide strong analytical evidence for the migration of pigments from the skin towards regional lymph nodes in humans. So far, this only has been assumed to occur based on limited data from mice and visual observations in humans (6).

This study by 19 researchers at the University of Toulon notes with concern that the daily intake of TiO2 nanoparticles, as they overcome the normal defenses of the human body, is associated with an increased risk of chronic intestinal inflammation and carcinogenesis (7).

This 2018 study confirms the relationship between titanium dioxide nanoparticles and the EMT process in colorectal cancer cells (8).

In 2019 this study suggests that ocean acidification would enhance the accumulation of titanium dioxide nanoparticles in edible bivalves and may therefore increase the health risk for seafood consumers (9).

2019 - The French law prohibits the use of titanium dioxide (LOI n° 2018-938 du 30 octobre 2018) in the food sector.

11-6-2020 I wrote to the European Directorate for Health and Food Safety (DG SANTE) reiterating doubts about the safety of parabens and E171 titanium dioxide. Finally, also from this body came the answer that clarifies all doubts:

"Regarding the use of methyl- and propylparaben as excipients in oral medicinal products for human use, I would advise you to look at the information provided by the European Medicines Agency at https://www.ema.europa.eu/en/use-methyl-propylparaben-excipients-human-medicinal-products-oral-use This discussion paper deals with methyl- and propylparaben, as these are the parabens predominantly used in oral pharmaceutical formulations. The focus of this paper is on possible endocrine disrupting effects in humans.

Regarding titanium dioxide, the European Food Safety Authority published its opinion on May 6, 2021 and concluded that, based on all available evidence, a concern for genotoxicity cannot be ruled out, and given the many uncertainties, E 171 can no longer be considered safe when used as a food additive. As mentioned in a tweet on the same day, following EFSA's new scientific opinion on the food additive E171, we will propose to ban its use in the EU. https://twitter.com/food_eu/status/1390347410476523521

Regarding medicinal products, the Commission has asked the European Medicines Agency to assess the effect on the use of TiO2 in medicinal products and the feasibility of alternatives to replace TiO2, if possible, without impact on the quality, safety and efficacy of medicinal products. A decision will be made by the Commission based on the analysis provided by the Agency."

Now, how long will it be before these ingredients are permanently removed from our medicines?

 Bibliografia_____________________

(1) Skocaj M, Filipic M, Petkovic J, Novak S. Titanium dioxide in our everyday life; is it safe? Radiol Oncol. 2011 Dec;45(4):227-47. doi: 10.2478/v10019-011-0037-0.

(2) Fei Yin Z, Wu L, Gui Yang H, Hua Su Y. Recent progress in biomedical applications of titanium dioxide. Phys Chem Chem Phys. 2013 Feb 28. 

(3) Naya M, Kobayashi N, Ema M, Kasamoto S, Fukumuro M, Takami S, Nakajima M, Hayashi M, Nakanishi J. In vivo genotoxicity study of titanium dioxide nanoparticles using comet assay following intratracheal instillation in rats. Regul Toxicol Pharmacol. 2012 Feb;62(1):1-6. doi: 10.1016/j.yrtph.2011.12.002.

(4) Re-evaluation of titanium dioxide (E 171) as a food additive. EFSA Journal 2016;14(9):4545 [83 pp.].

(5) Ines Schreiver, Bernhard Hesse, Christian Seim, Hiram Castillo-Michel, Julie Villanova, Peter Laux, Nadine Dreiack, Randolf Penning, Remi Tucoulou, Marine Cotte & Andreas Luch Synchrotron-based ν-XRF mapping and μ-FTIR microscopy enable to look into the fate and effects of tattoo pigments in human skin Scientific Reports 7, Article number: 11395 (2017) https://doi.org/10.1038/s41598-017-11721-z

(6)  Lehner K, Santarelli F, Vasold R, Penning R, Sidoroff A, König B, Landthaler M, Bäumler W. Black tattoos entail substantial uptake of genotoxicpolycyclic aromatic hydrocarbons (PAH) in human skin and regional lymph nodes. PLoS One. 2014 Mar 26;9(3):e92787. doi: 10.1371/journal.pone.0092787. eCollection 2014.

(7) Sarah Bettini, Elisa Boutet-Robinet, Christel Cartier, Christine Coméra, Eric Gaultier, Jacques Dupuy, Nathalie Naud, Sylviane Taché, Patrick Grysan, Solenn Reguer, Nathalie Thieriet, Matthieu Réfrégiers, Dominique Thiaudière, Jean-Pierre Cravedi, Marie Carrière, Jean-Nicolas Audinot, Fabrice H. Pierre, Laurence Guzylack-Piriou and Eric Houdeau Food-grade TiO2 impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon  Sci Rep. 2017; 7: 40373. Published online 2017 Jan 20. doi: 10.1038/srep40373

(8) Setyawati MI, Sevencan C, Bay BH, Xie J, Zhang Y, Demokritou P, Leong DT. Nano-TiO2 Drives Epithelial-Mesenchymal Transition in Intestinal Epithelial Cancer Cells. Small. 2018 Jul 2:e1800922. doi: 10.1002/smll.201800922.

(9) Shi W, Han Y, Guo C, Su W, Zhao X, Zha S, Wang Y, Liu G.  Ocean acidification increases the accumulation of titanium dioxide nanoparticles (nTiO2) in edible bivalve mollusks and poses a potential threat to seafood safety.  Sci Rep. 2019 Mar 5;9(1):3516. doi: 10.1038/s41598-019-40047-1.