Titanium

Endpoint summary

Description of key information

Titanium dioxide did not show adverse effects in a chronic oral repeated dose toxicity study in rats with a NOAEL of 3500mg/kg bw/day.
Titanium dioxide is not absorbed to any relevant extent through human skin, thus no toxic effects can be expected via the dermal route of exposure.
Titanium it not inhalable at any relevant extent, thus conduct of repeated dose toxicity studies via the inhalation route is considered dispensable.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

3 500 mg/kg bw/day

Study duration:

chronic

Species:

rat

Additional information

Titanium is a transition-metal and is subject at its surface to passivation by the formation of a passive and protective oxide (i. e. titanium dioxide) coating that effectively protects it from further reaction. In particular for titanium metal and granules, the oxide layer will form a quantitatively continuous layer to envelop the entire particle irrespective of product form. The reaction kinetics have been investigated and reported in various references (Uhlig, 1979; Schmets et al. 1953; Andreeva, 1964; Burleigh, 1989; El Din et al., 1988), indicating that the oxide layer is formed immediately after the interaction of the clean surface with the air atmosphere. Any melt processing of titanium metal has to be conducted under an inert atmosphere or vacuum to protect the metal from instant oxidation. Similarly the use of solid titanium at elevated temperatures is restricted due to its propensity for rapid oxidation.

 

Furthermore, transformation/dissolution testing according to “OECD 29 Environmental Health and Safety Publications, Series on testing and assessment, Guidance document on transformation/ dissolution of metals and metal compounds in Aqueous media” has shown that titanium metal compared to titanium dioxide has a similar release rate of titanium ions (please refer to the respective entry under the endpoint water solubility).

 

In view of this, it may be assumed that human exposure towards titanium metal is secondary to that of titanium dioxide.

Thus, unlimited read-across for repeated dose toxicity is considered justified.

Repeated dose toxicity, oral

Male and female F344 rats (8-weeks old, 50 animals per group) were fed a diet containing 2% corn oil and 25,000 or 50,000 ppm titanium dioxide for 103 weeks (7 days per week). Groups of male and female B6C3F1 mice (36 days old, 50 animals per group) were fed analogously. With the exception of white faeces, there was no other clinical sign that was judged to be related to titanium dioxide exposure (for detailed information please refer to the endpoint study records reported under section carcinogenicity).

In a 28 -days study male rats were exposed by oral gavage for 29 days to 24,000 mg/kg titanium dioxide particles (test items: H-27201, H-27203), or the vehicle. Under the conditions of this study, the no-observed-effect level for titanium dioxide was 24,000 mg/kg/day for male rats, based on the lack of any adverse effects at this dose.

Repeated dose toxicity, dermal

Titanium dioxide was tested in various percutaneous absorption tests which have been reviewed by the Scientific Committee on cosmetic products and non-food products (SCCNFP/0005/98, 2000) and which concluded “extensive tests for percutaneous absorption, mostly in vitro, indicate that absorption does not occur, either with coated or uncoated material; one experiment found some evidence that a little of the material could be found in the openings of the follicles. [...] The toxicological profile of this material does not give rise to concern in human use, since the substance is not absorbed through the skin. In view, also, of the lack of percutaneous absorption, a calculation of the margin of safety has not been carried out.”

Repeated dose toxicity, inhalation

The conduct of a repeated-dose toxicity study via inhalation is unjustified as inhalation of the substance is considered negligible, based on the outcome of the dustiness testing according to the modified Heubach method, as reported under section particle size distribution (granulometry). Based on the results of the MPPD model only about 0.01 % or less of inhaled material is predicted to be deposited in the pulmonary region (PU), whereas the material deposited in the tracheobronchial (TB) and the extrathoracic region (Head) may be assumed to be cleared to the GI tract (i.e., by mucociliary escalation and subsequent swallowing) (cf. Annex VIII section 8.6.1 Column 2 of regulation (EC) 1907/2006).

References

H.H. Uhlig (1979) Passivity in Metals and Alloys, Corrosion Science, Vol. 19, pp. 777-791

J. Schmets and M. Pourbaix (1953) Equilibrium Potential-pH Diagram for the System Ti-H2O, Corrosion of Titanium, Technical Report RT. 4, CEBELCOR, pp. 167-179

V.V. Andreeva (1964) Behavior and Nature of Thin Oxide Films on Some Metals in Gaseous Media and in Electrolyte Solutions, Corrosion, Vol. 20, No. 2, pp. 35-47

T.D. Burleigh (1989) Anodic Photocurrents and Corrosion Currents on Passive and Active-Passive Metals, Corrosion, Vol. 45, No. 6, pp.464-472

A.M. Shams El Din and A.A. Hammoud (1988) Oxide Film Formation and Thickening on Titanium in Water", Thin Solid Films, Vol. 167, No. 1, pp. 269-280

Justification for classification or non-classification

Repeated dose toxicity, oral

The reference National Cancer Institute (1979) is considered as the key study for repeated dose toxicity via oral application and will be used for classification. Rats were dosed at 3500 mg/kg bw/day orally via feed. Based on the lack of any adverse effects, the no observed adverse effect level (NOAEL) via oral application for titanium dioxide was established at 3500 mg/kg bw/day

(for detailed information please refer to the endpoint study records reported under section carcinogenicity).

The classification criteria according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – repeated exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and the no observed adverse effect level (NOAEL) via oral application is above the guidance value for a Category 1 classification of 10 mg/kg bw/day and above the guidance value for a Category 2 classification of 100 mg/kg bw/day. For the reasons presented above, no classification for specific target organ toxicant (STOT) – repeated exposure, oral is required.

 

Repeated dose toxicity, dermal

Titanium dioxide was tested in various percutaneous absorption tests which have been reviewed by the Scientific Committee on cosmetic products and non-food products (SCCNFP/0005/98, 2000) and which concluded “extensive tests for percutaneous absorption, mostly in vitro, indicate that absorption does not occur, either with coated or uncoated material; one experiment found some evidence that a little of the material could be found in the openings of the follicles. [...] The toxicological profile of this material does not give rise to concern in human use, since the substance is not absorbed through the skin. In view, also, of the lack of percutaneous absorption, a calculation of the margin of safety has not been carried out.”

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

 

Repeated dose toxicity, inhalation

The conduct of a repeated-dose toxicity study via inhalation is unjustified as inhalation of the substance is considered negligible, based on the outcome of the dustiness testing according to the modified Heubach method, as reported under section particle size distribution (granulometry). Based on the results of the MPPD model only about 0.01 % or less of inhaled material is predicted to be deposited in the pulmonary region (PU), whereas the material deposited in the tracheobronchial (TB) and the extrathoracic region (Head) may be assumed to be cleared to the GI tract (i.e., by mucociliary escalation and subsequent swallowing) (cf. Annex VIII section 8.6.1 Column 2 of regulation (EC) 1907/2006).

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