Titanium tetrakis(2-ethylhexanolate)

Endpoint summary

Description of key information

As titanium tetrakis(2-ethylhexanolate) hydrolyses rapidly when in 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 (2-ethylhexanol):
Rapid absorption, metabolism and excretion of 2-EH as oxidized metabolites predominantly in urine was observed following oral ingestion. Bioaccumulation is unlikely due to virtually complete excretion within 28 hrs.
Dermal absorption of 2-EH by rat skin is slow and bioavailability is low. Metabolism and excretion show no differences compared to the oral route.
 
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 tetrakis(2-ethylhexanolate) 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-ethylhexanol (2-EH) (CAS 104-76-7) and hydrated titanium dioxide (CAS 13463-67-7). These degradation products from hydrolysis study were determined by using OECD 111 method under Good Laboratory Practice (GLP) (Brekelmans, M. J. C., 2013). The hydrolysis reaction of Titanium tetrakis(2-ethylhexanolate) is rapid; the half-life is less than 10 minutes under physiological conditions. Thus, the toxicokinetic behaviour of 2-ethylhexanol (2-EH) and titanium dioxide (TiO2) instead of the target substance is focused in CSA. As the substance is hydrolyzed, and the hazardous degradation product 2-ethylhexanol is metabolized and excreted rapidly, the substance is not expected to have bioaccumulation potential.

Toxicokinetics of the hazardous degradation product

Toxicokinetics of 2-ethylhexanol was investigated by Albro, P.W. (1975). The test substance was efficiently absorbed following oral administration to rats. 14C associated with 2-ethyl[1-14C]-hexanol was rapidly excreted in respiratory CO2 (6-7%), faeces (8-9%) and urine (80-82%), with essentially complete elimination by 28 h after administration. There was no difference between the low or high dose (9 µg/kg bw and 278 mg/kg bw, resp.). The major metabolite is 2-ethylhexanoic acid, which appears in urine; alternatively it may also be further metabolized by either ß-oxidation or omega and omega-1 oxidation. Only 3% of the 2-ethylhexanol are excreted unchanged.

2-EH is a good substrate for mammalian dehydrogenases which leads to 2-ethylhexanoic acid which can be conjugated or further metabolized via partial ß-oxidation, or omega- and omega-1 oxidation, followed by conjugation (Albro, 1975).

2-EH inhibits the mitochondrial ß-oxidation of fatty acids in-vitro and in-vivo, which results in decreased levels of plasma ketones, and increased levels of hepatic total lipids and triglycerides. In contrast, the peroxisomal oxidation pathways are not inhibited by 2 -EH (Badr, 1990).

Overall, 2-EH was rapidly absorbed, metabolized, and excreted mainly via urine within 28 hours following the oral administration to rats. Accumulation of 2-EH or its metabolites is unlikely to 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, in humans detectable amounts of titanium can be found in the blood, brain and parenchymatous organs (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 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 released from titanium tetrakis(2 -ethylhexanolate) exists as hydrated form and thus human exposure via inhalation is not relevant.

Dermal absorption

2-EH was only slowly absorbed following dermal application of 1g/kg bw in the rat as less than 7% of the dose was absorbed within 6 hours of skin contact. The absorbed dose underwent rapid oxidative metabolism and glucuronidation followed by rapid excretion, predominantly in the urine. The absorption rate was 0.57 mg/cm²/h.