Titanium oxide sulphate

Endpoint summary

Description of key information

According to column 2 in the table given in REACH Annex IX, studies on repeated dose toxicity need not to be conducted if a substance undergoes immediate disintegration and there are sufficient data on the cleavage products (both for systemic effects and effects at the site of uptake). This deems to be the case as target chemical titanium oxide sulphate hydrolyses easily when in contact with wet material at around the environmentally and physiologically relevant pH range. Repeated dose toxicity studies on the final hydrolysis product titanium dioxide reveal that the substance needs not to be classified for repeated dose toxicity. Concerning the other final hydrolysis product sulphuric acid, its corrosiveness is not of relevance in this case, as the acidic effect is not to be considered as a true toxic effect.

Additional information

General assessment applicable to all three routes of exposure:

According to column 2 in the table given in REACH Annex IX, studies on repeated dose toxicity need not to be conducted if a substance undergoes immediate disintegration and there are sufficient data on the cleavage products (both for systemic effects and effects at the site of uptake). This deems to be the case as target chemical titanium oxide sulphate hydrolyses easily when in contact with wet material at around the environmentally and physiologically relevant pH range. Repeated dose toxicity studies on the final hydrolysis product titanium dioxide reveal that the substance needs not to be classified for repeated dose toxicity (for more details see "addendum on inhalation route of exposure" below). Concerning the other final hydrolysis product sulphuric acid, its corrosiveness is not of relevance in this case, as the acidic effect is not to be considered as a true toxic effect.

Addendum on repeated dose toxicity dermal route of exposure:

Even though dermal exposure to an aqueous solution of titanium oxide sulphate, or even exposure to solid titanium oxide sulphate, basically might be conceivable, the effect of corrosiveness in the first place would be down to the final hydrolysis product sulphuric acid. Its corrosiveness is not of relevance in this case, as the pH effect is not to be considered as a true toxic effect. Dermal exposure to final hydrolysis product titanium dioxide particles might also be considered as basically possible, however the intrusion of detrimental titanium compounds through the skin is not probable. This is also supported by the absence of any adverse effects in the skin irritation and skin sensitisation studies on titanium dioxide.

Addendum on repeated dose toxicity inhalation route of exposure:

In addition to what is being summarised above under "general assessment", an exposure to aerosols containing titanium oxide sulphate, or to solid particles of titanium oxide sulphate, basically still might be conceivable. However, based on the phys.-chem. properties of the substance (and mixtures containing the substance) and on its anticipated handling and use, the exposure by inhalation route is being considered unlikely. In addition, according to column 2 of the table given in REACH Annex IX, testing by the inhalation route of exposure only "is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size".

Concerning final hydrolysis product TiO2, chronic studies with the rat basically would indicate that a GHS classification as Specific Target Organ Systemic Toxicity (Repeated Exposure) STOT RE 2 might be applicable. However this classification for effects on the lung is not justified under GHS, as the rat is a uniquely sensitive species in its pulmonary responses to subchronic or chronic exposures to high doses of inhaled low solubility dusts, leading to inflammation, the development of fibroproliferative effects, and eventually lung tumor formation. These responses are not observed or measured in similarly exposed mice or hamsters. The pulmonary effects observed in rats, including inflammatory and fibrotic responses, are also not observed in large mammals such as nonhuman primates and humans. It has also been clearly demonstrated through epidemiology studies of TiO2-exposed workers that there is no causal link between TiO2 exposure and the risk of non-malignant respiratory disease in humans. (Statement on TiO2 quoted from: TITANIUM DIOXIDE MANUFACTURERS ASSOCIATION (TDMA), European Chemical Industry Council, Brussels, Belgium; "Evaluation of the Classification of Titanium Dioxide for Specific Target Organ Toxicity according to the UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS)" (May 2009).

Justification for classification or non-classification

No classification of the unstable compound titanium oxide sulphate as to its repeated dose toxicity properties.

Concerning final hydrolysis product TiO2, chronic studies with the rat basically would indicate that a GHS classification as Specific Target Organ Systemic Toxicity (Repeated Exposure) STOT RE 2 might be applicable. However, classification of TiO2 under the GHS Specific Target Organ Systemic Toxicity (Repeated Exposure) for effects on the lung is not justified, as the rat is recognized as a uniquely sensitive species in its pulmonary responses to inhaled low solubility dusts such as TiO2 under conditions of pulmonary particle overload. The pattern of pulmonary effects in the rat following such exposures include inflammation and fibrotic responses that are not observed in other rodent species, nonhuman primates or humans under similar exposure conditions. Overall, the epidemiological evidence from well-conducted investigations has shown no causal link between TiO2 exposure and the risk of non-malignant respiratory disease in humans (Statement on TiO2 quoted from: TITANIUM DIOXIDE MANUFACTURERS ASSOCIATION (TDMA), European Chemical Industry Council, Brussels, Belgium; "Evaluation of the Classification of Titanium Dioxide for Specific Target Organ Toxicity according to the UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS)" (May 2009).

Concerning classification of the final hydrolysis product titanium dioxide, further see the following discussion:

According to regulation (EC) 1272/2008, a classification for specific target organ toxicity – repeated exposure shall be taken into account only when reliable evidence associating repeated exposure to the substance with a consistent and identifiable toxic effect demonstrates support for the classification. These adverse health effects include consistent and identifiable toxic effects in humans, or, in experimental animals, toxicologically significant changes which have affected the function or morphology of a tissue/organ, or have produced serious changes to the biochemistry or haematology of the organism and these changes are relevant for human health.

The following observations have been made in experimental animals and in human epidemiological studies (inhalation route):

(i) No systemic toxicity was shown to result from chronic inhalation exposure in rats to high concentrations of pigment grade titanium dioxide

(ii) Particle overload is observed for insoluble particles such as titanium dioxide, whereby the rat is the most sensitive species studied, and species-specific differences are demonstrated in various mechanistic animal studies. It has been demonstrated with reasonable certainty that lung overload conditions are not relevant for human health and, therefore, results based on these data do not justify classification.

(iii) It has also been clearly demonstrated through epidemiological studies of titanium dioxide -exposed workers that there is no causal link between titanium dioxide exposure and the risk of non-malignant respiratory disease in humans

For the reasons presented above, no classification for specific target organ toxicant (STOT) – repeated exposure, inhalation is required.