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Diss Factsheets

Administrative data

Description of key information

No reliable results are available for repeated dose toxicity of synthetic rutile. Therefore, read-across is proposed to available data on TiO2.
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.
Synthetic rutile is 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

Read across concept

Synthetic rutile consists primarily of a titanate phase (solid solution) most of which is titanium in an oxidised form. Upon ingestion, a low rate of dissolution in the GI tract is assumed, based on the experimental verified inertness of the material. Any material being released from Synthetic rutile under physiological conditions will be in the form of ionic titanium, which is similarly the case for titanium dioxide, thus read-across from repeated dose oral toxicity data on titanium dioxide is considered feasible without any restrictions.

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 synthetic rutile compared to titanium dioxide has a similar release rate of titanium ions (please refer to the respective entry under the endpoint water solubility).

 

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 method EN 15051/ DIN 33897-2, as reported under section particle size distribution (granulometry). The results demonstrate that synthetic rutile has a limited ability to be inhaled by humans: 0.025 % of airborne material is estimated to be inhalable, whereas about 0.002 % or less of inhaled material is predicted to be deposited in the pulmonary region (PU), i.e. respirable fraction. 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).

For the reasons presented above, the conduct of a repeated dose toxicity study via inhalation is considered dispensable.

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.

It is considered that these conclusions can be read across to Synthetic Rutile.

 

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.

It is considered that these conclusions can be read across to Synthetic Rutile.

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 method EN 15051/ DIN 33897-2, as reported under section particle size distribution (granulometry). The results demonstrate that synthetic rutile has a limited ability to be inhaled by humans: 0.025 % of airborne material is estimated to be inhalable, whereas about 0.002 % or less of inhaled material is predicted to be deposited in the pulmonary region (PU), i.e. respirable fraction. 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).

For the reasons presented above, the conduct of a repeated dose toxicity study via inhalation is considered dispensable.

It is considered that these conclusions can be read across to Synthetic Rutile.