Titanium(4+) ethanolate

Endpoint summary

Description of key information

As titanium(4+) ethanolate 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 (ethanol):
Absorption: 21% maximum absorption (worst case). Real life absorption typically ~1-2%. Evaporation half life around 12 seconds from skin.
Distribution: widely distributed to the tissues with no obvious accumulation in any tissues.
Metabolism: final metabolic products of ethanol are carbon dioxide and water
Excretion: excretion is rapid, mainly eliminated by metabolism, only 2-5% is eliminated unmetabolised in breath, urine and sweat. 
In conclusion, as ethanol 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(4+) ethanolate 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 ethanol (CAS 64-17-5) and hydrated titanium dioxide (CAS no 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(4+) ethanolate is rapid; the half-life is less than 5 minutes under physiological conditions. Thus, the toxicokinetic behaviour of ethanol and titanium dioxide instead of the target substance is focused in CSA. As the substance is hydrolyzed, and the hazardous degradation product ethanol is metabolized and excreted rapidly, the substance is not expected to have bioaccumulation potential.

Toxicokinetics of the hazardous degradation product

Ethanol has a low molecular weight (46.07) and is highly soluble in both water and lipid, allowing absorption across the surface of the gastrointestinal (GI) tract, the lungs and skin. Following ingestion, absorption of ethanol begins immediately with greater than 90% of the consumed dose being absorbed by the GI tract. The consumption of two alcoholic beverages (approximately 20g ethanol) results a maximum ethanol concentration in blood of approximately 300 mg/L within one hour; the concentration of ethanol in blood then rapidly declines, reaching endogenous levels after several hours.

In a study to assess the skin penetration potential of ethanol, an in vitro study was carried out using excised pig skin and radiolabeled ethanol (Pendlington, 2001). Ethanol penetration was greater under occlusive conditions than non-occlusive conditions, as might be expected. Absorption rates were around 21% and 1% of applied doses respectively. In a study to help understand the skin penetration potential of ethanol, an in vitro study was carried out to assess the evaporation rate of radiolabeled ethanol from excised pig skin (Pendlington, 2001). The evaporation half life was found to be 11.7 seconds, suggesting that systemic doses of ethanol resulting from skin absorption following single exposures to ethanol will, under practical conditions, be very low due to rapid evaporation.

Ethanol can also be absorbed by inhalation. A recent study using lower levels of ethanol exposure (25 – 1000 ppm) reported a value of between 70 to 80 % absorption (Tardif, 2004), which may be representative of occupational exposure levels. Once absorbed by this route, the degree of ethanol retention is generally low due to the ‘wash-in-wash out effect observed with water soluble chemicals. Seeber et al., (1994) exposed 24 volunteers to ethanol at 80, 400 and 800 ppm for 4 hours with resulting blood ethanol levels of 0.25, 0.85 and 2.1 mg/l respectively.

Irrespective of the route of exposure, following absorption into the blood stream, ethanol is distributed throughout the body with the final volume of distribution close to that of total body water, estimated as 50 – 60 % of lean body weight in adults. Ethanol perfuses organs with the greatest blood supply most quickly (brain, lungs and liver) and equilibrium between tissues and blood is generally achieved within 1 – 1.5 hr after ingestion (Bevan, et al. 2009).

Once absorbed, ethanol is metabolised, principally by the liver, which accounts for 92-95% of capacity with minor amounts metabolised in other tissues such as the kidney and lung (Crabb et al., 1987; Lieber & DeCarli, 1977). A number of metabolic paths are available but only one is relevant to the low blood ethanol concentrations likely to result from either inhalation or dermal exposure. Ethanol metabolism in the liver is carried out in three steps, (i) oxidation of ethanol to acetaldehyde (AcH), (ii) conversion of AcH to acetate and (iii) oxidation of acetate to carbon dioxide and water.

The majority of absorbed ethanol is eliminated from the body by metabolism (95 – 98 %; Norberg et al., 2003). The maximum amount of ethanol that can be metabolised per hour has been estimated to be between 83 – 127 mg/kg/hr, or 8 – 9 g ethanol/hr.  Elimination rates can be influenced by both environmental and genetic factors leading to intraspecies variation in rates (Jones, 1984). A small concentration of ethanol (2 – 5 %) is also eliminated unmetabolised in breath, urine and sweat (Norberg et al., 2003).

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(4 +) ethanolate exists as hydrated form and thus human exposure via inhalation is not relevant.