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.

and is also used as:

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.

Titanium dioxide has for years 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 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 :

 Titanium oxide, E171, CI 77891, Pigment White 6, PW6, Titanium(IV) oxide, Rutile, titanium white, dioxotitanium

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. 

Abstract. Background: Titanium dioxide (TiO(2)) is considered as an inert and safe material and has been used in many applications for decades. However, with the development of nanotechnologies TiO(2) nanoparticles, with numerous novel and useful properties, are increasingly manufactured and used. Therefore increased human and environmental exposure can be expected, which has put TiO(2) nanoparticles under toxicological scrutiny. Mechanistic toxicological studies show that TiO(2) 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 TiO(2) nanoparticles, which govern their bioavailability and reactivity. Based on the experimental evidence from animal inhalation studies TiO(2) 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 TiO(2) 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 TiO(2) 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. TiO(2) 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.

(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. 

Abstract. As one of the most common chemical materials, titanium dioxide (TiO2) has been prepared and widely used for many years. Among all the applications, the biomedical applications of TiO2 have motivated strong interest and intensive experimental and theoretical studies, owing to its unique photocatalytic properties, excellent biocompatibility, high chemical stability, and low toxicity. Advances in nanoscale science suggest that some of the current problems of life science could be resolved or greatly improved through applying TiO2. This paper presents a critical review of recent advances in the biomedical applications of TiO2, which includes the photodynamic therapy for cancer treatment, drug delivery systems, cell imaging, biosensors for biological assay, and genetic engineering. The characterizations and applications of TiO2 nanoparticles, as well as nanocomposites and nanosystems of TiO2, which have been prepared by different modifications to improve the function of TiO2, are also offered in this review. Additionally, some perspectives on the challenges and new directions for future research in this emerging frontier are discussed.

(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) Schreiver I, Hesse B, Seim C, Castillo-Michel H, Villanova J, Laux P, Dreiack N, Penning R, Tucoulou R, Cotte M, Luch A. Synchrotron-based ν-XRF mapping and μ-FTIR microscopy enable to look into the fate and effects of tattoo pigments in human skin. Sci Rep. 2017 Sep 12;7(1):11395. doi: 10.1038/s41598-017-11721-z. 

Abstract. The increasing prevalence of tattoos provoked safety concerns with respect to particle distribution and effects inside the human body. We used skin and lymphatic tissues from human corpses to address local biokinetics by means of synchrotron X-ray fluorescence (XRF) techniques at both the micro (μ) and nano (ν) scale. Additional advanced mass spectrometry-based methodology enabled to demonstrate simultaneous transport of organic pigments, heavy metals and titanium dioxide from skin to regional lymph nodes. Among these compounds, organic pigments displayed the broadest size range with smallest species preferentially reaching the lymph nodes. Using synchrotron μ-FTIR analysis we were also able to detect ultrastructural changes of the tissue adjacent to tattoo particles through altered amide I α-helix to β-sheet protein ratios and elevated lipid contents. Altogether we report strong evidence for both migration and long-term deposition of toxic elements and tattoo pigments as well as for conformational alterations of biomolecules that likely contribute to cutaneous inflammation and other adversities upon tattooing.

(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.

Abstract. Hundreds of millions of people worldwide have tattoos, which predominantly contain black inks consisting of soot products like Carbon Black or polycyclic aromatic hydrocarbons (PAH). We recently found up to 200 μg/g of PAH in commercial black inks. After skin tattooing, a substantial part of the ink and PAH should be transported to other anatomical sites like the regional lymph nodes. To allow a first estimation of health risk, we aimed to extract and quantify the amount of PAH in black tattooed skin and the regional lymph nodes of pre-existing tattoos. Firstly, we established an extraction method by using HPLC-DAD technology that enables the quantification of PAH concentrations in human tissue. After that, 16 specimens of human tattooed skin and corresponding regional lymph nodes were included in the study. All skin specimen and lymph nodes appeared deep black. The specimens were digested and tested for 20 different PAH at the same time.PAH were found in twelve of the 16 tattooed skin specimens and in eleven regional lymph nodes. The PAH concentration ranged from 0.1-0.6 μg/cm2 in the tattooed skin and 0.1-11.8 μg/g in the lymph nodes. Two major conclusions can be drawn from the present results. Firstly, PAH in black inks stay partially in skin or can be found in the regional lymph nodes. Secondly, the major part of tattooed PAH had disappeared from skin or might be found in other organs than skin and lymph nodes. Thus, beside inhalation and ingestion, tattooing has proven to be an additional, direct and effective route of PAH uptake into the human body.

(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

Abstract. Food-grade titanium dioxide (TiO2) containing a nanoscale particle fraction (TiO2-NPs) is approved as a white pigment (E171 in Europe) in common foodstuffs, including confectionary. There are growing concerns that daily oral TiO2-NP intake is associated with an increased risk of chronic intestinal inflammation and carcinogenesis. In rats orally exposed for one week to E171 at human relevant levels, titanium was detected in the immune cells of Peyer's patches (PP) as observed with the TiO2-NP model NM-105. Dendritic cell frequency increased in PP regardless of the TiO2 treatment, while regulatory T cells involved in dampening inflammatory responses decreased with E171 only, an effect still observed after 100 days of treatment. In all TiO2-treated rats, stimulation of immune cells isolated from PP showed a decrease in Thelper (Th)-1 IFN-γ secretion, while splenic Th1/Th17 inflammatory responses sharply increased. E171 or NM-105 for one week did not initiate intestinal inflammation, while a 100-day E171 treatment promoted colon microinflammation and initiated preneoplastic lesions while also fostering the growth of aberrant crypt foci in a chemically induced carcinogenesis model. These data should be considered for risk assessments of the susceptibility to Th17-driven autoimmune diseases and to colorectal cancer in humans exposed to TiO2 from dietary sources.

(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.

Abstract. Large amounts of anthropogenic CO2 in the atmosphere are taken up by the ocean, which leads to 'ocean acidification' (OA). In addition, the increasing application of nanoparticles inevitably leads to their increased release into the aquatic environment. However, the impact of OA on the bioaccumulation of nanoparticles in marine organisms still remains unknown. This study investigated the effects of OA on the bioaccumulation of a model nanoparticle, titanium dioxide nanoparticles (nTiO2), in three edible bivalves. All species tested accumulated significantly greater amount of nTiO2 in pCO2-acidified seawater. Furthermore, the potential health threats of realistic nTiO2 quantities accumulated in bivalves under future OA scenarios were evaluated with a mouse assay, which revealed evident organ edema and alterations in hematologic indices and blood chemistry values under future OA scenario (pH at 7.4). Overall, this study suggests that OA would enhance the accumulation of nTiO2 in edible bivalves and may therefore increase the health risk for seafood consumers.

(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. 

Abstract. Background: Titanium dioxide (TiO₂), consisting of nanoparticles and sub-microparticles, were widely used as food additive and consumed by people every day, which has aroused a public safety concern. Some studies showed TiO₂ can be absorbed by intestine and then distributed to different tissues after oral intake, which is supposed to affect the content of various elements in the body whereas led to tissue damage. However, knowledge gaps still exist in the impact of TiO₂ on the disorder of elemental homeostasis. Thus, this study aimed to explore the oral toxicity of TiO₂ by assessing its influence on elemental homeostasis and tissues injury. Method: ICR mice were fed with normal feed, TiO₂ nanoparticles (NPs)-mixed feed or TiO₂ submicron particles (MPs)-mixed feed (1% mass fraction TiO₂ NPs or MPs were mixed in commercial pellet diet) for 1, 3, and 6 months. Particles used in this study were characterized. The distribution of Ti and other 23 elements, the correlation among elements, and pathological change in the liver, kidney, spleen and blood cells of the mice was determined. Result: Ti accumulation only appeared in blood cells of mice treated with TiO₂ MPs-mixed feed for 6 months, but TiO₂ cause 12 kinds of elements (boron, vanadium, iron, cobalt, copper, zinc, selenium, sodium, calcium, magnesium, silicon, phosphorus) content changed in organ tissue. The changed kinds of elements in blood cells (6 elements), liver (7 elements) or kidney (6 elements) were more than in the spleen (1 element). The TiO₂ NPs induced more elements changed in blood cells and liver, and the TiO₂ MPs induced more elements changed in kidney. Significantly positive correlation between Ti and other elements was found in different organs except the liver. Organ injuries caused by TiO₂ NPs were severer than TiO₂ MPs. Liver exhibited obvious pathological damage which became more serious with the increase of exposure time, while kidney and spleen had slight damages. Conclusion: These results 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.