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French Agency for Food, Environmental and Occupational Health & Safety

Titanium dioxide in nanoparticle form: ANSES defines a toxicity reference value (TRV) for chronic inhalation exposure

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News of 02/04/2019

Titanium dioxide in nanoparticle form (TiO2-NP) is used in many industrial and commercial applications. ANSES was asked to define a toxicity reference value (TRV) for this substance as part of its national mission to develop health reference values. Following an in-depth analysis of all the available toxicity data, the Agency is recommending a chronic TRV by inhalation for the P25 form of TiO2-NP of 0.12 µg/m-3. This reference value will be used when conducting health risk assessments as part of the management of industrial facilities and sites in France. It is also the first TRV developed for a nanomaterial in France.

TiO2 can occur in a wide variety of forms depending on its physico-chemical characteristics, in particular nanoparticle forms with a size of less than 100 nm. Depending on its form, it is used for its ultraviolet-ray absorption properties and whitening qualities in many industrial and commercial applications: as a food additive, or in cosmetics, pigments and paints. In France, amounts of nanoparticle substances produced, imported or distributed in excess of a minimum quantity of 100 g must be declared in the R-Nano online database managed by ANSES. The data recorded in R-Nano indicate that many industrial sites in France use TiO2-NP, constituting a source of exposure for workers and potentially for local populations. 

In order to address the challenges of managing industrial facilities and sites in France, ANSES was asked to define a chronic TRV by inhalation for TiO2-NP (respiratory exposure). A TRV is a toxicological indicator used as a benchmark for assessing risks to human health. Below this value, it is considered that exposure to the substance does not present a health risk.


Toxicological profile of TiO2-NP and critical effect

Following an exhaustive review of the scientific literature and based on all the data on the toxicity of TiO2-NP, the experts established a toxicological profile for TiO2-NP and determined its critical effect for inhalation exposure.

Analysis of the data showed that TiO2-NP causes an inflammatory phenomenon following inhalation exposure that may be accompanied by an increase in the number and/or volume of lung cells. Other experimental data have also shown that TiO2-NP induces effects on foetal development and on other organs, especially the cardiovascular system, brain, liver and kidneys. The TRV of TiO2-NP is based on the pulmonary effect, which is the effect occurring at the lowest exposure level.


Chronic TRV by inhalation

ANSES is proposing a chronic TRV of 0.12 µg/m3 for TiO2-NP in the P25 form (anatase/rutile 80/20; 21 nm), which is the best documented form in the literature to date. In addition, given the very limited data on TiO2-NP, it was not possible to reach any conclusion on potential differences between the hazard profiles of the various existing forms of TiO2-NP. According to current knowledge, therefore, it cannot be said that TiO2-P25 is the most toxic form of TiO2-NP by the respiratory route. ANSES will examine the feasibility of extending this TRV to other forms of TiO2-NP.

In addition, in view of the data collected and analysed for this work, the Agency confirms the need to classify TiO2-NP as carcinogenic by inhalation. This is because TiO2-NP has intrinsic properties specific to certain forms, such as its high surface reactivity, the production of highly oxidising reactive oxygen species, and photocatalytic reactions. TiO2 cannot therefore be regarded as a poorly soluble, low toxicity (PSLT) dust. TiO2 is currently being proposed for classification as a Category 2 carcinogen by the Committee for Risk Assessment of the European Chemicals Agency (ECHA). 

The expert appraisal also revealed that most of the experimental studies available on TiO2-NP only explored the pulmonary effects. ANSES therefore emphasises the need to conduct additional studies to assess the influence of different physico-chemical factors on the toxicity of TiO2-NP, taking all the physiological parameters into account and not only pulmonary toxicity.

It should be noted that this expert appraisal took place within the broader context of the Agency's work on TiO2, which includes the ongoing assessment process under the REACh Regulation and the assessment of the toxicity of the additive E171 in nanoparticle form in the context of oral exposure (ingestion).