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Description of key information

As titanium tetraisopropanolate hydrolyses rapidly when contact with water or moisture the bioaccumulation potential is related to the main degradation products, not the substance itself.
The key information of the hazardous degradation product:
Absorption: little absorption through intact skin, readily absorbed by oral and inhalation exposure
Distribution: widely distributed to the tissues with no obvious accumulation in any tissues studied
Metabolism: acetone has been identified as the primary metabolite of IPA
Excretion: excretion was rapid and the exhaled breath was the predominant route for excretion of IPA and its metabolites
In conclusion, as IPA is metabolized and excreted rapidly the substance is not expected to have bioaccumulation potential.
The key information of the non-hazardous degradation product:
As titanium dioxide is not soluble and is eliminated mainly unabsorbed this substance is not expected to have bioaccumulation potential.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

No studies on titanium tetraisopropanolate relating to toxicokinetics have been conducted. The assessment of the toxicokinetic behaviour is based on available information on the physical and chemical properties of the substance and the data obtained from the degradation products.

The substance is hydrolytically unstable. When it comes in contact with water or moisture, a complete hydrolysis will take place with no significant reaction products other than isopropanol (IPA) (CAS no 67 -63 -0) and hydrated titanium dioxide (CAS no 13463 -67 -7). These degradation products were determined by using OECD 111 method under Good Laboratory Practice (GLP) (Scholz, T. 2010). The hydrolysis reaction of titanium tetraisopropanolate is rapid; the half-life is less than 3 minutes under physiological conditions. Thus, the toxicokinetic behaviour of IPA and titanium dioxide instead of the target substance is focused in CSA. As the substance is hydrolyzed and the hazardous degradation product, IPA is metabolized and excreted rapidly the substance is not expected to have bioaccumulation potential.

Toxicokinetics of the hazardous degradation product

In the study report by Slauter et al. 1994, rats were exposed via inhalation to isopropanol vapor at concentration of 500 and 5000 ppm for 6 hrs. There were no obvious organs in which IPA or its metabolites were retained after exposures, although the liver and kidney had slightly elevated concentrations of substances relative to the blood. IPA is metabolized predominantly to acetone which is then exhaled or excreted in the urine. Finally acetone is oxidized to carbon dioxide which is exhaled. IPA itself accounts for the next largest fraction of the compounds excreted. In addition, a small fraction (3.5%) of the total dose is metabolized to glucuronide conjugate and excreted in the urine. The half-life of elimination from the blood is predicted by one-compartment model and is shown to be in the range of 0.6-2 hr. There was no bioaccumulation observed for single administration of IPA (Slauter, R. W. et al. 1993).

Clear signs of central nervous system (CNS) depression (reduced reaction to external stimuli and pain, ataxia and reduced muscle tone) have been reported after administration of the titanium tetraisopropanolate in acute oral toxicity study (Billmeier, J. et al. 1978). Based on these results it can be concluded that following test item ingestion, IPA is released eliciting observed CNS effects. This study also indicates that no accumulation of test item or its metabolites accumulate since the clinical signs observed after the target substance administration resolved within 1-2 days.

Further information on toxicokinetics of IPA is available in numerous well documented studies. These indicate that IPA is readily absorbed (80% within 30min) following ingestion over a wide range of doses in animals and man (Ellenhorn, 1988 cited in WHO, 1990). However, skin absorption of IPA is relatively low and absorption through intact skin occurs only on prolonged exposure (Martinez, 1986 cited in WHO, 1990). There is evidence for a delay in absorption through the gastrointestinal (GI) tract at high dose levels and an extension in half life suggesting limited metabolic capability. IPA is rapidly distributed throughout the body and has been shown to cross the blood/brain barrier. Two hours are required for complete tissue distribution fop (Ellenhorn, 1988 cited in WHO, 1990).

Elimination from the blood follows first order kinetics. Approximately 64 - 84 % of an intravenous dose has been shown to be oxidized to acetone in rabbit (WHO, 1990). Elimination of IPA is retarded by ethanol and it has been shown that IPA is a poorer substrate for alcohol dehydrogenase than ethanol. Excretion occurs mainly through the expired air either as unchanged IPA or as acetone. Quantities of acetone and IPA are excreted in the urine together with the glucuronide conjugate of IPA. There is evidence in man that sulphonation may occur.

Toxicokinetics of the non-hazardous degradation product

Titanium dioxide is insoluble in water and most ingested titanium is eliminated unabsorbed. In rats, about 95 % ingested dose of titanium dioxide is recovered from feces indicating that the most ingested titanium is not absorbed from gastrointestinal tract by blood (Patty, F. 1965). However, detectable amounts of titanium can be found in the blood, brain and parenchymatous organs of individuals in the general population (Friberg, L. et al.1986). Based on average titanium concentrations found in human urine of about 10 µg/liter, it can be calculated that the absorption is about 3 % (WHO, 1982).

After chronic inhalation exposure totitanium dioxide, accumulation of the substance was shown in the lungs. Titanium was also present in the lymph nodes adjacent to the lung (HSDB, 2012). However, quantitative information on absorption through inhalation is lacking.