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Key value for chemical safety assessment

Effects on fertility

Additional information

UGI (Upgraded Ilmenite) consists primarily of a titanate phase (solid solution) most of which is Ti in an oxidised form. Upon uptake into the body, a low rate of dissolution in the respiratory or gastrointestinal tracts is assumed, based on the experimental verified inertness of the material in artificial physiological media. Any material being released from UGI under physiological conditions will thus be in the form of ionic Ti, which is similarly the case for titanium dioxide: more specifically, the results from in vitro bioaccessibility testing in such fluids demonstrate a similar dissolution pattern of UGI and titanium dioxide (see summary reported under point 7.1.1 basic toxicokinetics), thus read-across for reproduction toxicity data from titanium dioxide to UGI is considered principally feasible without any restrictions.

Considering that guideline-conform studies or other relevant studies are not available for reproduction toxicity of titanium dioxide (TiO2), the following waiving argument has been put forward in agreement with Annex X of the REACH Regulation (EC No. 1907/2006), which lays down the standard information requirements for substances manufactured or imported in quantities of 1000 tonnes or more. These require the conduct of a study on the reproduction toxicity endpoint “fertility” in the form of a 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 explicitly 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 routes 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 conduct of a two-generation reproduction toxicity study is not required because the following criteria are met: (i) other existing data from animal experiments do not demonstrate adverse effects on the reproductive organs of rats and mice, and (ii) toxicokinetic data indicate that TiO2 has a negligible absorption from the gastrointestinal tract of rats thus any systemic toxicity is not expected.

In conclusion, given the chemical composition of UGI and similar bioaccessibility in simulated physiological fluids of UGI and titanium dioxide, the above derogation argument is considered to apply also to UGI without any restrictions.

Effects on developmental toxicity

Additional information

UGI (Upgraded Ilmenite) consists primarily of a titanate phase (solid solution) most of which is Ti in an oxidised form. Upon uptake into the body, a low rate of dissolution in the respiratory or gastrointestinal tracts is assumed, based on the experimental verified inertness of the material in artificial physiological media. Any material being released from these oxidic slag phases under physiological conditions will thus be in the form of ionic Ti, which is similarly the case for titanium dioxide: more specifically, the results from in vitro bioaccessibility testing in such fluids demonstrate a similar dissolution pattern of UGI and titanium dioxide (see summary reported under point 7.1.1 basic toxicokinetics), thus read-across for reproduction toxicity data from titanium dioxide to UGI is considered principally feasible without any restrictions.

Considering that guideline-conform studies or other relevant studies are not available for reproduction toxicity of titanium dioxide (TiO2), the following waiving argument has been put forward in agreement with Annex X of the REACH Regulation (EC No. 1907/2006), which lays down the standard information requirements for substances manufactured or imported in quantities of 1000 tonnes or more. These require the conduct of a study on “developmental toxicity” in the form of a 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 explicitly 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 conduct of a developmental toxicity study is not required because the following criteria are met: : (i) other existing data from animal experiments do not demonstrate adverse effects on the reproductive organs of rats and mice, and (ii) toxicokinetic data indicate that TiO2 has a negligible absorption from the gastrointestinal tract of rats thus any systemic toxicity is not expected.

In conclusion, given the chemical composition of UGI and similar bioaccessibility in simulated physiological fluids of UGI and titanium dioxide, the above derogation argument is considered to apply also to UGI without any restrictions.

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.

Additional information