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Carcinogenicity

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Description of key information

The conduct of carcinogenicity studies direct on the unstable target compound titanium oxychloride is technically not feasible. Read-across with studies on the final hydrolysis products titanium dioxid and hydrochloric acid is being proposed. Evidence for the production of carcinogenic lesions was obtained in the repeated dose toxicity study on titanium dioxide (described under repeated dose toxicity: inhalation). The substance however is not subject to classification.

Key value for chemical safety assessment

Justification for classification or non-classification

TiCl4 as well as its hydrolysis products TiOCl2, TiO2 and HCL are non-mutagenic.

HCL has been tested negative for carcinogenic potential.

TiO2 induces lung cancer in rats , but this effect is unique to rats and only seen at concentrations leading to lung overload by overwhelming the lung clearance mechanisms. It is inappropriate to base the evaluation of titanium dioxide as a suspect carcinogen solely on the observation that rats develop lung tumours under condition of “lung particle overload”, since such tumours induced in rats by inert poorly soluble particles such as titanium dioxide are widely considered as unreliable predictors of hazard to humans.

TiCl4 has caused lung carcinomas in rats but like TiO2 only at concentrations where the combination of the caustic action of HCl and the formation of TiO2 particles overwhelmed the mucociliar clearance of the lung. TiCl4 all in all was judged not to be carcinogenic, and the same is proposed for its intermediate hydrolysis product titanium oxychloride.

Overall, the epidemiological evidence from well-conducted investigations has not shown that exposure to titanium dioxide is correlated to any detectable carcinogenic potential for humans. Therefore, neither under CLP nor under the EU classification system, a classification is warranted given that the mechanism of tumour formation has been clearly identified, with good evidence that this process cannot be extrapolated to man.

Additional information

Target compound titanium oxychloride is an unstable chemical intermediate which results from the hydrolysis of parent compound titanium tetrachloride.

1. step: TiCl4 + H2OTiOCl2 + 2 HCl

2. step: TiOCl2 + H2OTiO2 + 2 HCl

Summary reaction: TiCl4 + 2 H2OTiO2 + 4 HCl

In water this reaction takes place immediately.

As can be seen from above shown chemical equations, target compound titanium oxychloride only can occur and be stabilised in the chemical equilibrium when hydrochloric acid is being added. Therefore the conduct of carcinogenicity studies direct on the target compound titanium oxychloride is technically not feasible. For this reason, read-across with studies on the final hydrolysis products titanium dioxid and hydrochloric acid is being proposed.

Evidence for the production of carcinogenic lesions was obtained in the repeated dose toxicity inhalation study on hydrolysis product titanium dioxide. It was concluded that three of the lesions should be diagnosed as squamous metaplasia and the other two as proliferative keratin cysts. Additionally, parent compound titanium tetrachloride was not carcinogenic in rats. Most probably the formation of carcinomas was induced by the combination of the caustic action of HCl formed in the lung from the hydrolysis of TiCl4 and the overload with TiO2 particles that overwhelmed the mucociliar clearance of the (already damaged) tissue. No carcinoma formation was seen at a concentration level (0.1 mg/m³) where no significant irritation/corrosion effects in the lung occurred.

In the evaluation of the carcinogenicity of TiO2 it has been determined that the rat is uniquely sensitive to the effects of titanium dioxide lung overload and that therefore TiO2 is not to be classified as human carcinogen.

Citation from the TiO2 dossier:

“The rat is uniquely sensitive to the formation of lung tumours when exposed under conditions of particle overload to titanium dioxide (TiO2) and other poorly soluble low-toxicity particles. Although particle overload is observed in other experimental species, such as the mouse, it is only in the rat that a sequence of events is initiated that leads to fibroproliferative disease, septal fibrosis, hyperplasia and eventually lung tumours. Similar pathological changes are not observed in other common laboratory rodents, in non-human primates, or in exposed humans. Detailed epidemiological investigations have shown no causative link between titanium dioxide exposure and cancer risk in humans. At workplace exposure concentrations, no lung cancer hazard has been observed. Thus, a carcinogen rating for titanium dioxide is not warranted.”

HCl as the second hydrolysis product of TiCl4 was negative in a 2 year rat bioassay.

Citation from the HCl dossier:

“Hydrochloric acid did not evoke a carcinogenic response in treated rats.”

In addition TiCl4 as well as its hydrolysis products TiO2 and HCl are deemed not to be mutagenic.

No correlation between TiO2 exposure and lung cancer in humans was seen in the above mentioned epidemiologic study.

Based on these results neither parent compound titanium tetrachloride, nor target compound TiOCl2, nor final hydrolysis product titanium dioxide are deemed to be carcinogenic.

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