Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

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).

 

There are no guideline-conform studies or other relevant studies available on reproductive toxicity of titanium dioxide (TiO2).

Annex X of the REACH Regulation (EC No. 1907/2006) lays down the standard information requirements for substances manufactured or imported in quantities of 1000 tonnes or more. These require the conduct of studies on the reproduction toxicity endpoint “fertility” as follows:

• two-generation reproduction study (according to EC B.35 / OECD TG 416) in the rat.

 

However, according to column 2 specific rules (see Annex X) for adaptation to the standard information requirements it is stated that such studies need not be conducted if:

• the substance is known to be a genotoxic carcinogen and appropriate risk management measures are implemented or

• the substance is known to be a germ cell mutagen and appropriate risk management measures are implemented or

• the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant route of exposure (e.g. plasma/blood concentrations below the limit of detection using a sensitive method and absence of the substance and of metabolites of the substance in the urine, bile or exhaled air) and there is no or no significant human exposure.

 

Whereas the first and second provisions do not apply to TiO2, the registrant is of the opinion that the conduct of a two-generation reproduction toxicity study is not required because the following criteria are met:

1. Other existing data from animal experiments do not demonstrate adverse effects on the reproductive organs of rats and mice.

2. Toxicokinetic data indicate that TiO2 has a negligible absorption from the gastrointestinal tract of rats thus any systemic toxicity is not expected.


Short description of key information:
No reliable results are available for effects on fertility of synthetic rutile. Therefore, read-across is proposed to available data on TiO2. Based on the weight of evidence from the available long-term toxicity/carcinogenicity studies in rodents and the relevant information on the toxicokinetic behaviour in rats it is concluded that TiO2 does not present a reproductive toxicity hazard.

Effects on developmental toxicity

Description of key information
No reliable results are available for developmental toxicity / teratogenicity of synthetic rutile. Therefore, read-across is proposed to available data on TiO2. Based on the weight of evidence from the available long-term toxicity/carcinogenicity studies in rodents and the relevant information on the toxicokinetic behaviour in rats it is concluded that TiO2 does not present a reproductive toxicity hazard.
Additional information

There are no guideline-conform studies or other relevant studies available on developmental toxicity of titanium dioxide (TiO2). Annex X of the REACH Regulation (EC No. 1907/2006) lays down the standard information requirements for substances manufactured or imported in quantities of 1000 tonnes or more.

These require the conduct of studies for the reproduction toxicity endpoint “developmental toxicity” as follows:

• prenatal developmental toxicity study (according to EC B.31 / OECD TG 414) in the rat as favoured species. The need for a developmental study (according to OECD TG 414) in a second species should be considered based on the outcome of the first test and all other relevant available data,

 

However, according to column 2 specific rules (see Annex X) for adaptation to the standard information requirements it is stated that such studies need not be conducted if:

• the substance is known to be a genotoxic carcinogen and appropriate risk management measures are implemented or

• the substance is known to be a germ cell mutagen and appropriate risk management measures are implemented or

• the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant route of exposure (e.g. plasma/blood concentrations below the limit of detection using a sensitive method and absence of the substance and of metabolites of the substance in the urine, bile or exhaled air) and there is no or no significant human exposure.

 

Whereas the first and second provisions do not apply to TiO2, the registrant is of the opinion that the conduct of a developmental toxicity study is not required because the following criteria are met:

1. Other existing data from animal experiments do not demonstrate adverse effects on the reproductive organs of rats and mice.

2. Toxicokinetic data indicate that TiO2 has a negligible absorption from the gastrointestinal tract of rats thus any systemic toxicity is not expected.

Justification for classification or non-classification

Based on the weight of evidence from the available long-term toxicity/carcinogenicity studies in rodents and the relevant information on the toxicokinetic behaviour in rats, it is concluded that titanium dioxide does not present a reproductive toxicity hazard. There is evidence from the animal chronic toxicity/carcinogenicity studies in rats and mice that the intake of high amounts of titanium dioxide or inhalation to high concentrations of titanium dioxide was not associated with adverse effects on the reproductive organs.

The results of a toxicokinetic study demonstrate that no relevant systemic absorption occurs via the oral exposure route as indicated by the titanium concentrations in whole-blood and urine which were below the limit of quantification (<0.04 mg/l). Tissue titanium concentrations in liver, kidney and muscle were below the limit of detection (<0.1 - <0.2 mg/kg wet weight) indicating no substantial accumulation of titanium in the body. Furthermore, any metabolism of the inorganic material whatsoever can be excluded.

For the reasons presented above, conducting a developmental toxicity study or a two-generation reproduction toxicity study would therefore not provide any further insights in the toxicity of titanium dioxide. Because of the lack of absorption and systemic distribution, any quantitatively relevant exposure of reproductive organs in male and female mammalian species to titanium dioxide is unlikely, so that any specific effects on reproduction are not to be expected. Therefore, it is scientifically not justified to conduct either a developmental toxicity study or a two-generation reproduction study in rats which complies with the 3R-rules and the principles of animal welfare.

For the reasons presented above, no classification for reproductive toxicity is required.

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