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

Endpoint summary

Description of key information

The key information of the hazardous degradation product 2-methylpropanol:
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:  isobutyraldehyde and isobutyric acid were identified as the primary metabolites of 2-methylpropanol
Excretion: excretion was rapid and the exhaled breath was the predominant route for excretion of 2-methylpropanol and its metabolites
In conclusion, as 2-methylpropanol is metabolized and excreted rapidly the substance is not expected to have bioaccumulation potential.
The key information of the non-hazardous degradation products:
As titanium dioxide is not soluble and is eliminated mainly unabsorbed this substance is not expected to have bioaccumulation potential.
As ethyl acetoacetate is readily absorbed, and finally metabolized to CO2, the substance is not expected to have bioaccumulation potential.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No studies on bis(ethylacetoacetato-O1’,O3”) bis(2-methyl propan-1-olato)titanium 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 2-methylpropanol (CAS no 78 -83-1) and non-hazardous degradation products; hydrated titanium dioxide (TiO2), (CAS no 13463-67-7) and ethyl acetoacetate (EAA), (CAS no 141-97-9).

These degradation products were determined by using OECD 111 method under Good Laboratory Practice (GLP) (Brekelmans M. J. C., 2013). The hydrolysis reaction of Bis(ethylacetoacetato-O1’,O3”) bis(2 -methyl propan-1-olato)titanium is rapid; the half-life is less than 10 minutes under physiological conditions. Thus, the toxicokinetic behaviour of 2-methylpropanol, TiO2 and EAA instead of the target substance is focused in CSA.

Toxicokinetics of the hazardous degradation product

Respiratory bioavailability studies conducted with 2-methylpropanol have correlated airborne 2-methylpropanol levels with internal blood levels of 2-methylpropanol and isobutyric acid (Poet, 2003). Inhalation of 2,000 ppm (6,060 mg/m3 ) 2-methylpropanol in a closed chamber resulted in 2-methylpropanol levels up to 278 µM and isobutyric acid levels up to 93 µM. Blood levels of 2-methylpropanol decreased to 155 µM by ninety minutes and isobutyric acid levels were not detectable. The clearance of 2-methylpropanol in rats was investigated using intraperitoneal injections (Hedlund and Kiessling; 1969). Clearance of 2-methylpropanol was very rapid. Oral administration of 2-methylpropanol to rabbits was reported by Saito (1975), with blood and urinary analysis for 2-methylpropanol and metabolites. The metabolism proceeded as expected although the analytical procedures employed detected a urinary metabolite that coeluted with isovaleric acid but was not fully characterized.

 The Class I Alcohol Dehydrogenase (ADH) isozymes appear to be the most active for 2-methylpropanol metabolism. The alcohol dehydrogenase reaction was studied further in rat and chick embryo liver homogenates (Sinclair, et al., 1990). The clearance of 2-methylpropanol in rats was investigated using in situ liver perfusions and in vitro liver homogenates (Hedlund and Kiessling; 1969). Clearance of 2-methylpropanol was very rapid in both test systems.

Excretion occurs mainly through the expired air either as unchanged 2-methylpropanol or as isobutyraldehyde and isobutyric acid Quantities of metabolites and 2-methylpropanol are excreted in the urine together with the glucuronide conjugate of 2-methylpropanol.

 

Toxicokinetics of the non-hazardous degradation products

TiO2 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, about 10 µg/liter, it can be calculated that the absorption is about 3 % (WHO, 1982). After chronic inhalation exposure to titanium 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. Titanium dioxide is released from bis(ethylacetoacetato-O1’,O3”) bis(2 -methyl propan-1-olato)titanium as hydrated form and thus human exposure via inhalation is not relevant.

Absorption of ethyl acetoacetate (EAA) via the oral route is demonstrated in animals (European Chemical Bureau, 2002). It may be anticipated that EAA is partially cleaved already in the gastrointestinal tract due to acidic pH values or by bacterial activity. In a first metabolic step the absorbed portion of ethyl acetoacetate will be hydrolyzed into 3-oxobutanoic acid (also called diacetic acid) and ethanol by the unspecific esterases of the blood. Also, absorption via the lungs can be assumed due to the vapor pressure of EAA (1 hPa at 20°C).

The diacetic acid is an endogenous product of fat metabolism and is further metabolized predominantly to carbon dioxide and water; ethanol will be metabolized on known pathways (European Chemicals Bureau, 2002). It is anticipated, that the stability (half-life) of systemically available ethyl acetoacetate is clearly higher in humans than in rats since esterase activities in human plasma are generally lower than in those in the rat (McCracken et al., 1993). The main route of elimination of EAA and its metabolites is urinary excretion or exhalation of the metabolic product carbon dioxide in the breath.

As bis(ethylacetoacetato-O1’,O3”) bis(2-methyl propan-1-olato)titanium hydrolyses rapidly when in contact with water or moisture, the bioaccumulation potential is related to the main degradation products, not the substance itself.