potassium titanium oxide (K2Ti6O13)

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Data waiving:

exposure considerations

Justification for data waiving:

the study does not need to be conducted because relevant human exposure can be excluded as demonstrated in the relevant exposure assessment

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING

Potassium titanium oxide is an inorganic, particulate, crystalline substance. It is inert, with very low water solubility, a high melting point and does not contain any oxidising groups. Some particles, including fibres, are inhalable and respirable generating concern about the inhalation hazard associated with both fibres and fine particulates. Acute oral toxicity studies have shown it to be practically non-toxic (LD50>2000 mg/kg) while acute inhalation data for this particulate solid show it to be well tolerated (LD50>1.9 g/m3; Annex V method). The key study for repeated dose toxicity consisted of particles of respirable size. Exposure was via the inhalation route, 90 days duration (6 hours per day, 5 days per week). The changes seen were confined to the lung and are consistent with local reactions to deposition of dust particles and clearance or attempted clearance of particles from the lung. There was no other reported systemic change in any other organ (Battelle, 2000b). An additional study in which the biopersistence of the particulates and the progression of local tissue reactions was investigated is consistent with the Battelle study (Tanaka, 2008). The NOAEL of 500mg/m3 was the top dose in the Battelle study. The local findings in the lung and the absence of any systemic change (including change to reproductive organs) coupled with an absence of genotoxicity with or without metabolic activation and absence of skin and eye irritation hazard are evidence that the adsorption, systemic exposure, systemic toxicity and biological reactivity of potassium titanium oxide are very low. Like potassium titanium oxide, titanium dioxide (TiO2; EC 236-675-5; CAS13463-67-7) is also an insoluble, inert particulate solid. While the morphology of TiO2 particles is different from potassium titanium oxide (fibres are very unlikely to be present) the particle sizes of the various forms of potassium titanium oxide on the market, (including TOFIX SNR, SS and LL) are generally larger or equivalent to those of TiO2 as tested (below). 93.7% of the TiO2 is <10µm in diameter. A repeated dose 28-day oral toxicity study of TiO2 in rats did not identify any adverse effect in any organ at a high dose of 24,000 mg/kg bw/day (Mayer, 2006). Repeated inhalation exposure to TiO2 for up to 2 years revealed only adverse effects associated with local inflammatory responses and particle overload in the respiratory tract of mice, hamsters and rats (Bermudez, 2002 and 2004; Lee, 1985; Warheit, 1997). There were no other target organs. More specifically, there is evidence from the long-term (2 year) inhalation studies of toxicity/carcinogenicity in rats and mice, in which the animals were exposed to high concentrations of TiO2, that the exposure is not associated with adverse effects on the reproductive organs, (Bermudez, E et al , 2002). This is consistent with the Battelle study. The results of a toxicokinetic study with TiO2 demonstrate that no systemic absorption occurred 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. The lack of absorption (and hence systemic toxicity) of TiO2 via the inhalation route is consistent with this observation. In addition, any metabolism of the inorganic material can be excluded (Langford-Pollard, 2003). Given their similar properties (insoluble, inert, particulate solid) and the similar responses to exposure via the inhalation route, it can be anticipated that the systemic absorption of potassium titanium oxide, including the various forms of TOFIX, will be similarly low by any relevant route. For the reasons presented above, conducting a screening test for reproductive/developmental toxicity (OECD 421 or 422) would not provide any further insights into the toxicity of potassium titanium oxide. It is considered that the absorption potential of TiO2 is sufficiently similar to those of potassium titanium oxide, including TOFIX, to enable read-across regarding the lack of systemic exposure and toxic effects to be justified. It is concluded that it is scientifically unjustified to conduct a reproductive screening study in rats which complies with the 3R-rules and the principles of animal welfare (in accordance with Annex X, section 8.7, column 2 of regulation (EC) 1907/2006).

In accordance with the last paragraph of the preamble text to Annex IX; "When, for certain endpoints, information is not provided for other reasons than those mentioned in column 2 of this Annex or in Annex XI, this fact and the reasons shall also be clearly stated"; studies in developmental toxicity / teratogenicity are not conducted based on the lack of bioavailability. Based on the existing sub-chronic inhalation study and toxicokinetic properties of the substance, the substance is not absorbed via inhalation and no significant systemic effects were observed at any dose level tested in the repeat dose inhalation studies. The effects observed in the 90day repeated dose study was considered to be due to the material being phagocytosed by alveolar macrophages and that the material accumulates in these macrophages, and that is the limit to systemic exposure. (Section 7.5.3 Repeated dose toxicity: inhalation). Therefore, there is no value in conducting studies to examine reproductive toxicity (pre-natal development toxicity and two-generation reproductive toxicity) - the results will not be influenced by systemic toxicity. The attached chemical safery report demonstrates that potential health risks from acute and long-term occupational inhalation exposure to the substance are adequately controlled under the conditions of use given in the respective exposure scenarios . The fibre-based and dust-based risk characterisation ratios for potential adverse health affects that may arise from such exposure are all well below 1 for all identified uses.

Materials and methods

Test animals

Species:

rat