Registration Dossier

Administrative data

Description of key information

No studies have been conducted focussing on carcinogenicity. Evidence for the production of carcinogenic lesions was noted in the original report of the repeated dose toxicity study described under repeated dose toxicity: inhalation (Tobia 1986). Nevertheless a re-assessment of the histopathological data by a panel of 4 toxicologists came to the conclusion that all questionalble are not of carcinogenic nature.

Key value for chemical safety assessment

Additional information

Evidence for the production of carcinogenic lesions was obtained in the repeated dose toxicity: inhalation (Tobia 1986). The lesions were recently re-examined by a panel of four pathologists. They concluded that three of the lesions should be diagnosed as squamous metaplasia and the other two as proliferative keratin cysts. Additionally, in the opinion of the three pathologists conducting this re-examination, 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 (Levy, 1995). 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 TiCl4 exposure and lung cancer in humans was seen in the above mentioned epidemiologic study.

Based on these results TiCl4 is deemed not to be carcinogenic and does not need to be classified.

Justification for classification or non-classification

TiCl4 as well as its hydrolysis products 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. TiO2 is therefore not classified as carcinogen. 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. A panel of 3 pathologists re-examining the test results have judged TiCl4 not be carcinogenic.