potassium titanium oxide (K2Ti6O13)

Endpoint summary

Description of key information

Acute and sub-chronic inhalation studies and an oral toxicity study in rats showed no evidence of systemic toxicity. The effects seen in both inhalation studies were attributable to local effects in the lung and upper respiratory tract. Although the molecular weight does not preclude absorption, the substance has very low solubility in water (<2.4E-04 g/l)  (even when placed in boiling water for a period of 18 weeks there is no dissolution of potassium. (Filler Society of Japan (1994) Application Encyclopaedia of Fillers; Taiseisha; p 131, Table 4)) and organic solvents.

Additional information

TOXICOKINETIC BEHAVIOUR: General comments

Acute and sub-chronic inhalation studies and an oral toxicity study in rats showed no evidence of systemic toxicity. The effects seen in both inhalation studies were attributable to local effects in the lung and upper respiratory tract. Although the molecular weight does not preclude absorption, the substance has very low solubility in water (<2.4E-04 g/l) and organic solvents. Even when placed in boiling water for a period of 18 weeks there is no dissolution of potassium. (Filler Society of Japan (1994) Application Encyclopeadia of Fillers; Taiseisha; p131, Table 4).

In view of this low water solubility and the toxicity study results, it is unlikely that any signifcant systemic absorption of this substance would occur, although transport of sufficiently small fibres, by phagocytic cells into the lymphatic circulation is possible.

Since it is unlikely that any significant absorption could occur, discussion of distribution, metabolism and excretion is largely irrelevant for this inorganic substance.

Fibres entering the lymphatic system would be unlikely to dissolve and become bioavailable due to the very low water solubility. These factors may, however, result in the potential biopersistence of fibres deposited in the respiratory tract.

The results of thein vitrobacterial and mammalian genotoxicity studies did not show any evidence that the addition of the metabolic system either enhanced or diminished the activity of the substance.

Poorly water soluble products (the substance also has a very low water solubility of less than 2.4E-04g/l), are not favourable for urinary excretion. Any test material that is not absorbed will be excreted in the faeces.

TOXICOKINETIC BEHAVIOUR BY INHALATION ROUTE

Di potassium titanate (Potassium titanium oxide) is an inorganic particulate material.

Inhalation the relevant route of exposure. Some particles, including fibres, are inhalable and respirable generating concern about the inhalation hazard associated with insoluble particulates. Retention of the particles in the lung and the inability to clear the lung were key concerns in the toxicological evaluation of dipotassium titanate.

In an intratracheal installation study (Tanaka 2007), the biological half-life of TOFIX-S (one variant of dipotassium titanate) in the rat lung after a single intra-tracheal instillation was found to be 2.3 months, consistent, the author noted, with particulate materials having little biological effect. No production of 8-hydroxydeoxyguanosine (an indicator of oxidative damage caused by active oxygen species) was observed, no significant differences in gene expression of TIMP-2 (Tissue Inhibitors of MetalloProteins) was found (suggesting that the substance has little effect on inflammation and fibrosis), and no significant changes were noted in histopathological examination of the lungs.

In the Tanaka 2007 study, fibres were defined as fibre shaped particles with an aspect ratio (length to diameter) of > 3:1. According to the counting rules adopted, anything with a diameter of > 0.2 µm was counted. It was calculated that 9.8% of the particles counted were fibres according to these rules. The geometric mean diameter and geometric mean length were 1.4 µm (SD 1.5) and 6.2 µm (SD 1.8) respectively. The number of fibrous and non- fibrous particles counted was 124 and 1136 respectively.

In the 90 day study on pulmonary fibrosis and carcinogenicity by the inhalation route (Tanaka 2008) the same material was used, although an additional particle size analysis was carried out. The substance had a geometric mean aerodynamic diameter of 4.9 µm (SD 1.8), indicating that TOFIX-S is a respirable dust. The number of fibrous and non-fibrous particles counted was 108 and 1120 respectively. Indicating that 9.6% of the particles counted were fibrous. The substance used in the inhalation toxicity study is therefore consistent with that used in the intratracheal installation study and the particles would have reached the alveolar region of the lung. No biological effects were noted.

The results of the two studies strongly suggest that Potassium titanium oxide, when inhaled, is not distributed systemically. This would be expected for an inert, low solubility particulate substance.

A 90 day study (Battelle 2000) in which rats were exposed to 5, 50, or 500 mg/m3 potassium titanium oxide for 6 hours per day, 5 days per week also gave rise to no systemic effects. None of the particles met the criteria for WHO fibre.

Finally, the results of a toxicokinetic study with TiO2, a similar inert, low solubility particulate substance, demonstrated 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, (Lee, K.P. et al. 1985). In addition, any metabolism of the inorganic material can be excluded (Langford-Pollard, 2003).

The repeat dose inhalation study on potassium titanium oxide and on the TOFIX-S variant, taken together with the results of the toxicokinetic study for titanium dioxide, a similar inert particulate and the similar responses to exposure via the inhalation route strongly suggest that the systemic absorption of dipotassium titanate, including the various forms of TOFIX, will be low by any relevant route, inhalation, dermal and oral.