Titanium dioxide (TiO₂) is a polycrystalline chemical compound, titanium oxide obtained from titanium minerals such as rutile, anatase, ilmenite by chlorination, sulphation or pyrolysis. 

The name describes the structure of the molecule:

• Titanium is a chemical element with the symbol Ti and the atomic number 22. It is a bright transition metal with a silver color, low density and high strength. Titanium is resistant to corrosion in seawater, aqua regia and chlorine.
• Dioxide indicates that there are two oxygen atoms in the compound. Dioxides are a type of oxide in which oxygen atoms form bonds with another element.

The chemical chlorination process has replaced the obsolete sulphuric acid process. Titanium dioxide must not only be chemically extracted, but also purified, which is done at high temperature.

The synthesis process takes place in different steps:

• Extraction of titanium ore. Titanium dioxide is typically extracted from titanium ore, such as rutile or ilmenite, through mining.
• Purification. Titanium ore is purified, typically through a process known as the chloride process or sulfate process. In the chloride process, the ore is converted to titanium tetrachloride (ticl4) by chlorination in the presence of carbon. Titanium tetrachloride is then oxidized by air or oxygen at high temperatures to produce titanium dioxide. In the sulfate process, the mineral is treated with sulfuric acid to produce a titanium sulfate, which is then hydrolyzed to produce titanium dioxide.
• Grinding. The resulting titanium dioxide is then ground to reach the desired particle size for use as a pigment. It can also be produced in its most dangerous form for human health: in nanoparticles.

It occurs in the form of a liquid or ultra-fine white crystalline powder, high specific surface area, odourless, tasteless, stable at room temperature. Good thermal and chemical stability, good catalytic and photocatalytic efficiency, photoactive under UV radiation, anatase structure. In silicone elastomers it has a thermostructuring effect. Its particles have regular arrangements with a reticular structure.

What it is used for and where

White pigment that creates a white or opaque colouration. It is present in many applications: cosmetics, paints, paper, sunscreens, pharmaceutical additives and is often found in the coatings of medicinal tablets, beverages, and the anti-UV filter in sunscreens.

Cosmetics

It is a restricted ingredient as IV/143 VI/27 VI/27a (nano) a Relevant Item in the Annexes of the European Cosmetics Regulation 1223/2009.

It has the following INCI functions:

Colorant. This ingredient has the function of colouring the solution in which it is inserted in a temporary, semi-permanent or permanent manner, either alone or in the presence of the complementary components added for colouring.

Opacifying agent. It is useful into formulations that may be translucent or transparent to make them opaque and less permeable to light.

UV absorber. It acts by intercepting ultraviolet light before it can cause damage by reducing its energy through dissipation and returning it to a lower energy state.

UV filter. It is the defining ingredient in sun creams that can mitigate the sun's ultraviolet (UV) radiation, which is a high risk factor for the development of skin cancer, erythema and photo-ageing. 

Medicine

Unfortunately, we find it frequently in the coatings of medicinal tablets.

Food

It is widely used as an additive in the food industry as a bleaching agent as E171.

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 gave an opinion with a review on the safety of titanium dioxide (TiO₂, E171) when used as a food additive.
Present Opinion has dealt 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 also 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 rats, the Panel chose the lowest non-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 - 2021

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

If Titanium Dioxide is inlaid in 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 the skin to regional lymph nodes. The toxicity of TiO₂  depends 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 can provide strong analytical evidence for the migration of pigments from the skin towards regional lymph nodes in humans. So far, this has only 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 were coincerned that the daily intake of TiO₂ nanoparticles, as they overcame the normal defenses of the human body, was associated with an increased risk of chronic intestinal inflammation and carcinogenesis (7).

This 2018 study confirmed 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 might therefore increase the health risk to seafood consumers (9).

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

2020 - French law. Order of December 21, 2020 suspending the marketing of food products containing the additive E 171 (titanium dioxide - TiO₂).(Arrêté du 21 décembre 2020 portant suspension de la mise sur le marché des denrées contenant l'additif E 171 (dioxyde de titane - TiO₂) - Légifrance (legifrance.gouv.fr) )

The results of this 2021 study indicated long-time dietary intake of TiO₂ particles could induce element imbalance and organ injury. The liver displayed more serious change than other organs, especially under the treatment with TiO₂ NPs. Further research on the oral toxicity of TiO₂ NPs should pay more attention to the health effects of element imbalances using realistic exposure methods (10).

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 EMA (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?

7-2-2022 The use of Titanium Dioxide (TiO2 - E171) as a food additive has been banned and is no longer permitted in the EU as a result of Commission Regulation (EU) 2022/63 amending Annexes II and III of Regulation (EC) No. 1333/2008.

The transition period is 6 months and ends on 7 August 2022. Until the end of this transitional period, food produced in accordance with the rules applicable before 7 February 2022 may continue to be placed on the market. After 7 August 2022, foods containing TiO2 may no longer be placed on the EU/NI market, however, foods already on the market may remain on the market until they reach the minimum durability or expiry date.

Unfortunately, titanium dioxide (TiO2 - E171) continues to be permitted as additive in pharmaceuticals. Unacceptable  decision!

Titanium dioxide studies

Optimal typical characteristics of the commercial product Titanium dioxide

• Molecular Formula: TiO₂ o O₂Ti
• Molecular Weight : 79.865 g/mol
• CAS : 13463-67-7   1317-80-2   1317-70-0   98084-96-9
• UNII    15FIX9V2JP
• EC Number: 236-675-5
• DSSTox Substance ID: DTXSID3021352    DTXSID9050432    DTXSID6052827
• MDL number  MFCD00011269
• PubChem Substance ID   24882641
• InChI=1S/2O.Ti
• InChI Key    GWEVSGVZZGPLCZ-UHFFFAOYSA-N
• SMILES     O=[Ti]=O
• IUPAC dioxotitanium
• ChEBI    32234

Synonyms :

 [TiO2] 100292-32-8 101239-53-6 1025343-79-6 116788-85-3 12000-59-8 12036-20-3 1205638-49-8 1236143-41-1 12701-76-7 12767-65-6 12789-63-8 1309-63-3 1317-70-0 1317-80-2 1344-29-2 13463-67-7 1377807-26-5 1385RN 59 1393678-13-1 1400974-17-5 158518-86-6 1700 White 185323-71-1 185828-91-5 188357-76-8 188357-79-1 195740-11-5 221548-98-7 224963-00-2 234DA 246178-32-5 252962-41-7 37230-92-5 37230-94-7 37230-95-8 37230-96-9 39320-58-6 39360-64-0 39379-02-7 416845-43-7 494848-07-6 494848-23-6 494851-77-3 494851-98-8 500HD 55068-84-3 55068-85-4 552316-51-5 62338-64-1 63B1 White 767341-00-4 859528-12-4 861455-28-9 861455-30-3 866531-40-0 97929-50-5 98084-96-9 A 200 (pigment) A 330 (pigment) AC1L1AA6 Aerolyst 7710 Aerosil P 25 Aerosil P 25S6 Aerosil P 27 Aerosil T 805 Aeroxide® P25 A-Fil A-Fil Cream A-FN 3 AI3-01334 AK 15 (pigment) AKOS015913799 Amperit 780.0 AMT 100 AMT 600 AN-49054 Anatase Anatase (TiO2) Anatase titanium dioxide Atlas white titanium dioxide AUF 0015S austiox Austiox R-CR Austiox R-CR 3 B 101 (pigment) Bayer R-FD 1 bayeri tian Bayertitan Bayertitan A Bayertitan AN 3 Bayertitan R-FD 1 Bayertitan R-FK 21 Bayertitan R-FK-D Bayertitan R-KB 2 Bayertitan R-KB 3 Bayertitan R-KB 4 Bayertitan R-KB 5 Bayertitan R-KB 6 Bayertitan R-U 2 Bayertitan R-U-F Bayertitan R-V-SE 20 Bayertitan T Baytitan bis(oxido)titanium Bistrater L-NSC 200C Blend White 9202 BR 29-7-2 Brookite C 97 (oxide) C.I. 77891 C.I. Pigment White 6 Cab-O-Ti Calcotone White T CCRIS 590 CCRIS 9317 CCRIS 9325 CG-T CHEBI:32234 CI 77891 CI Pigment white 6 CL 310 component of A-Fil Cosmetic Hydrophobic TiO2 9428 Cosmetic Micro Blend TiO2 9228 Cosmetic White C47-5175 Cosmetic White C47-9623 CTK5H9706 C-Weiss 7 C-Weiss 7 [German] D01931 DB09536 dioxido de titanio dioxotitanium dioxyde de titane DTXSID3021352 E 171 EC 215-282-2 EC 236-675-5 EINECS 215-280-1 EINECS 215-282-2 EINECS 236-675-5 Flamenco FT-0645791 Hombikat hombita n Hombitan Hombitan R 101D Hombitan R 610K Horse head a-410 Horse head a-420 Horse head r-710 HSDB 869 I14-43300 I14-43301 I14-45012 J-006053 JR 600A KH 360 KH360 Kronos Kronos 1002 Kronos 2073 Kronos CL 220 Kronos RN 40P Kronos RN 56 Kronos titanium dioxide Levanox White RKB LS-144047 LS-19300 LS-194104 LS-785 MC 50 (oxide) MFCD00011269 NCGC00187590-01 NCI-C04240 NCI-C0424O NSC 15204 NSC15204 NSC-15204 NT 100 (oxide) O2Ti Octahedrite Octahedrite (mineral) Orgasol 1002D White 10 Extra Cos oxido de titanio(IV) P 25 P 25 (oxide) Pigment white 6 R 680 R 830 (mineral) Rayox RO 2 ru na arh 200 Runa ARH 20 Runa ARH 200 Runa rh20 Rutile Rutile (TiO2) Rutile titanium dioxide Rutiox CR S 150 (oxide) s212 Sagenite T-3875 Tichlor Tin dioxide dust Tinoc M 6 TiO2 Tiofine tiona t.d Tiona t.d. Tiona td Tioxide Tioxide AD-M Tioxide A-DM Tioxide A-HR Tioxide R XL Tioxide R.XL Tioxide R-CR Tioxide RHD Tioxide RSM Tioxide R-SM Tipaque Tipaque R 820 Ti-Pure ti-pure r 101 ti-pure r 90 0 Ti-Pure R 900 Ti-Pure R 901 ti-pure r 915 Titafrance Titan White Titandioxid Titandioxid (sweden) Titandioxid [Swedish] Titania Titania paste, reflector Titania paste, transparent Titanic acid anhydride Titanic anhydride Titanic oxide Titanii dioxidum Titanium (IV) oxide TITANIUM DIOXIDE (ANATASE) Titanium dioxide (TiO2) Titanium dioxide (USP) Titanium dioxide [USP] Titanium dioxide P25 Titanium Dioxide Rutile Titanium oxide (JP17) Titanium oxide (TiO2) Titanium oxide (VAN) Titanium oxide, TiO2 Titanium peroxide titanium peroxide Titanium peroxide (TiO2) Titanium White Titanium( cento) oxide Titanium(IV) oxide Titanium(IV) oxide, rutile Titanium(IV)Dioxide Titanox Titanox 2010 Titanox RANC Trioxide(s) Tronox Unitane Unitane 0-110 Unitane 0-220 Unitane o-110 Unitane o-220 Unitane OR Unitane OR 450 unitane or 572 Unitane OR 650 Unitane or-150 Unitane or-340 Unitane or-342 Unitane or-350 Unitane or-540 Unitane or-640 Uniwhite AO Uniwhite KO Uniwhite OR 450 Uniwhite OR 650 WLN: TI O Zopaque Zopaque LDC 

References___________________________________________________________________

(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  Article | OPEN | Published: 12 September 2017 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.  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;14(30):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.

(10) Duan SM, Zhang YL, Gao YJ, Lyu LZ, Wang Y. The Influence of Long-Term Dietary Intake of Titanium Dioxide Particles on Elemental Homeostasis and Tissue Structure of Mouse Organs. J Nanosci Nanotechnol. 2021 Oct 1;21(10):5014-5025. doi: 10.1166/jnn.2021.19351.