Bis(ethyl acetoacetato-O1',O3)bis(2-methylpropan-1-olato)titanium

Endpoint summary

Description of key information

Repeated toxicity testing was considered unnecessary since this substance undergoes immediate disintegration and there are sufficient data on cleavage product. The intrinsic properties of this substance, after repeated administration, are related to the most hazardous degradation product Isobutanol. NOAEC was identified to be 1000 ppm (=3030 mg/m3). 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

3 030 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

3 030 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated oral toxicity

Weight of evidence approach was used to evaluate the testing needs of this endpoint as there are no studies available from the bis(ethylacetoacetato‐O1',O3")bis(2-methyl propan-1-olato)titanium. In order to avoid unnecessary animal testing, further investigations were considered scientifically unjustified since the substance undergoes immediate disintegration and there are sufficiently data on cleavage products.

Bis(ethylacetoacetato‐O1',O3")bis(2-methyl propan-1-olato)titanium hydrolyses rapidly (< 10 min) when it comes in contact with water or moisture (Brekelmans, M. J. C., 2013). After hydrolysis no significant reaction products other than Isobutyl alcohol, ethyl acetoacetate (EAA) and titanium dioxide (TiO2) exist. Thus, the intrinsic properties of the target substance are most likely related to these decomposition products.

2-methylpropanol is the most relevant decomposition product of the target substance for CSA. However, oral route is not likely route of human exposure, since a vapor pressure of 10 hPa at 20.9 °C indicates that 2-methylpropanol will exist solely as a vapor in the ambient atmosphere. There is sufficient information available from a subchronic inhalation study conducted for 2-methylpropanol by Li et al. (1999) to conclude that this alcohol has low toxicity after repeated exposure (NOAEC 1000 ppm =3030 mg/m3).

TiO2 exists as solid insoluble precipitate having low bioavailability and possessing very low acute and long-term toxicity (US EPA, 1994; WHO, 1982).

Ethyl acetoacetate (EAA) has not demonstrated any relevant toxic effects in oral repeated studies in rats up to 1 000 mg/kg bw/day (European Chemicals Bureau, 2002).

Based on these facts, it can be concluded that for the target substance the most appropriate route of administration is inhalation regards to the likely route of human exposure, and there is no need to investigate further repeated oral toxicity of this substance.

Repeated inhalation toxicity

Weight of evidence approach was used to evaluate the testing needs of this endpoint as there are no studies available from the Bis(ethylacetoacetato‐O1',O3")bis(2-methyl propan-1-olato)titanium. In order to avoid unnecessary animal testing, further investigations were considered scientifically unjustified since the substance undergoes immediate disintegration and there are sufficiently data on cleavage products.

Bis(ethylacetoacetato‐O1',O3")bis(2-methyl propan-1-olato)titanium hydrolyses rapidly (< 10 min) when it comes in contact with water or moisture (Brekelmans M. J. C. 2013). Due to the instability of the target substance evaluation of the inhalation toxicity of the substance is not possible. After hydrolysis no significant reaction products other than 2 -methylpropanol, ethyl acetoacetate (EAA) and titanium dioxide (TiO2) exist.

2-methylpropanol is a volatile substance, and therefore the most relevant substance to cause the intrinsic repeated dose toxicity of this substance via inhalation. One high quality guideline-compliant repeated dose inhalation study is available for 2-methylpropanol (Li, A.A. et al., 1999). In this study rats and mice were exposed for 6 hours per day for 13 week to 2-methylpropanol vapour at concentrations of 0, 250, 1000, 2500 ppm. There were no morphological of behavioral effects indicative of a persistent or progressive effect of 2-methylpropanol on the nervous system at exposure concentrations of up to 2500 ppm. A slight reduction in responsiveness to external stimuli occurred in all treated groups during exposure. However, there was no difference from the control animals with respect to responsiveness during non-exposure periods. No effects were noted during the FOB examinations. Therefore, the slight decrease in responsiveness is likely transient effect from acute exposure to 2-methylpropanol. There was a slight (but statistically significant) increase in red blood cell counts, hematocrit, and hemoglobin parameters in the 2500 ppm female rats when compared to the control female rats. Although these effects were considered related to treatment and considered for the derivation of the NOAEL, they were of questionable biological significance due to the slight nature of the effects. There were no changes in ophthalmology, serum chemistry, organ weights, or gross or microscopic pathology that were attributed to 2-methylpropanol exposure.

For ethyl acetoacetate (EAA) no repeated inhalation studies are available, but repeated oral exposure has not demonstrated any relevant toxic effects (European Chemicals Bureau, 2002).

Titanium dioxide is the solid insoluble precipitate of this substance. Therefore, inhalation is not the appropriate route of administration of this decomposition product and unlikely route of human exposure to be further considered in CSA.

Repeated dermal toxicity

No valid repeated dermal study identified for bis(ethylacetoacetato-O1’, O3”) bis(2-methyl propan-1-olato) titanium. Testing is not necessary since skin contact in use and production is not likely since the adequate RMMs are in use (see sections 9&10 of CSR).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Not likely exposure route

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
No study available for the substance itself. Based on the read-across data from the most hazardous decomposition product as the target substance is hydrolytically unstable with half-life of < 10 minutes (Brekelmans, M. J. C, 2013).

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
No study available for the substance itself. Based on the read-across data from the most hazardous decomposition product as the target substance is hydrolytically unstable with half-life of < 10 minutes (Brekelmans, M. J. C, 2013).

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Not likely exposure route.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Not likely exposure route.

Justification for classification or non-classification

The intrinsic properties of bis(ethylacetoacetato‐O1',O3")bis(2 -methyl propan-1 -olato)titanium are related to the most hazardous degradation product; 2 -methylpropanol. Based on the observations made after the subchronic exposure of 2 -methylpropanol in rats Abby et al (1999) which were indicative for CNS depression which is common for alcohols, there is no need for classification of the substance based on the effects after repeated exposure in accordance with the criteria of CLP Regulation 1272/2008 and the EU directive 67/548/EEC.