(ethyl acetoacetato-O1',O3)(pentane-2,4-dionato-O,O')[propane-1,3-diolato(2-)-O,O']titanium

Endpoint summary

Description of key information

No toxicokinetic studies are available; however a theoretical assessment of the toxicokinetic properties of the substance ((ethyl acetoacetato-O1',O3)(pentane-2,4-dionato-O,O')[propane-1,3-diolato(2-)-O,O']titanium) is made based on the available structural, chemical, physiochemical and toxicological data according to the requirements of the REACH Regulation.

In conclusion, the substance will be rapidly hydrolysed under physiological conditions; consequently systemic exposure to the intact substance is not predicted. Absorption of some of the hydrolysis products is likely following oral, dermal and inhalation exposures and may be significant following oral and inhalation exposure. In the absence of reliable quantitative estimates of absorption, default assumptions can be made for each route of exposure for the purposes of the risk assessment.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

General observations

The substance is of moderate molecular weight (352.2), is reported to be of relatively low water solubility (measured at 1.01 g/L at pH 4) and has a moderate LogP value (estimated value 2.28). Water solubility was measured experimentally on the basis of soluble titanium; however other observations made in this study indicate that the substance undergoes hydrolysis or alternative transformation mechanism. It will be assumed that the water solubility decreases with an increasing pH value. In preliminary water solubility investigations conducted within the ecotoxicological tests (with fish, daphnia and algae) a limit of water solubility of approximately 3.5 mg/L at a pH value of about 7.5 was obtained. A hydrolysis test was not conducted. No evaluation of the hydrolytic stability of the test item in aqueous media was possible. This was due to the absence of a suitable substance specific analytical method with which to evaluate the intact test item chelate.

The substance is an organotitanium substance. Based on the findings in the water solubility study with this substance and on knowledge from structurally-related organotitanium substances (Table 1), the substance is assumed to be hydrolytically unstable and will therefore be subject to rapid hydrolysis in aqueous conditions. The water solubility study reports the formation of a white precipitate, consistent with hydrolysis and the formation of hydrated titanium oxides.

Table 1                Hydrolysis of structurally-related organotitanium substances (Source: REACH registration dossiers disseminated on the ECHA web page)

EC Name	CAS	Hydrolysis
Bis(2-ethylhexan-1-olato)bis(pentane-2,4-dionato-O,O')titanium	94233-27-9	<= 30 min at pH 10 and 30°C
Bis(ethyl acetoacetato-O1',O3)bis(2-methylpropan-1-olato)titanium	83877-91-2	<= 10 min at pH 4, 7 and 9 at 25°C
Bis(ethyl acetoacetato-O1',O3)bis(propan-2-olato)titanium	27858-32-8	<= 10 min at pH 4, 7 and 9 at 25°C
Bis(pentane-2,4-dionato-O,O')bis(propan-2-olato)titanium	17927-72-9	1.491h at 25°C
Butyl (dialkyloxy(dibutoxyphosphoryloxy))titanium(trialkyloxy)titanium phosphate	109037-78-7	readily hydrolysable
Ethoxybis(pentane-2,4-dionato-O,O')(propan-2-olato)titanium	68586-02-7	<= 30 min at pH 1.2, 4, 7 and 10 at 30°C
Tetrakis(2-ethylhexane-1,3-diolato)titanium	5575-43-9	<= 10 min at pH 4, 7 and < 5 minutes at pH 9 at 25 °C
Tris(isooctadecanoato-O)(propan-2-olato)titanium	61417-49-0	<=1hr
Titanium tetra(octanolate), branched and linear	83897-91-0	<= 10 min at pH 7 and pH 9, and < 5 min at pH 4 at 25 °C
Titanium, diethylene glycol ethylene glycol triisopropanolamine complexes	68784-47-4	<= 30 min at pH 4.4 at 25°C

Absorption

Oral absorption

The substance is assumed to be hydrolytically unstable and will therefore be subject to rapid hydrolysis in the mammalian gastrointestinal tract. Systemic exposure to the intact substance is therefore unlikely; however systemic exposure to the hydrolysis products may occur. Based on the structure of the molecule, the hydrolysis products are predicted to be acetylacetone, ethyl acetoacetate, 1,3-propanediol and hydrated titanium oxides. Titanium oxides are of very low water solubility and are not absorbed from the gastrointestinal tract (1). The other hydrolysis products (acetylacetone, ethyl acetoacetate, 1,3-propanediol) are low molecular weight and water-soluble, and are therefore likely to be absorbed from the gastrointestinal tract to a significant extent.

The OECD 422 screening study reports some findings (reduced weight gain, decreased serum T4 concentration) at the highest dose level of 750 mg/kg bw/d that are consistent with systemic exposure (and therefore oral absorption). The associated range-finding toxicity study reports signs of toxicity (noisy respiration) consistent with systemic toxicity at dose levels of 350, 700 and 1000 mg/kg bw/d. Other signs reported in the range-finding (post-dose salivation) are likely to represent a local response to dosing. Bodyweight effects were also apparent at dose levels of 700 and 1000 mg/kg bw/d. Clinical signs consistent with systemic toxicity (hunched posture, lethargy, noisy and laboured respiration, piloerection and dehydration) are reported in the acute oral toxicity study at a dose level of 2000 mg/kg bwbut not at 300 mg/kg bw. These findings therefore indicate systemic exposure to the test material; although based on the predicted hydrolytic behaviour of the substance, any systemic exposure is likely to be the hydrolysis products (or metabolites of the hydrolysis products) at higher dose levels.

Dermal absorption

The dermal absorption of the substance cannot be excluded on the basis of its physicochemical properties, although absorption is likely to be limited due to the molecular weight and low water solubility. The acute dermal toxicity study does not provide any evidence of systemic exposure. Hydrolysis of the substance may also occur on dermal contact. Dermal absorption of the titanium hydroxide formed by hydrolysis is unlikely based on its very low water solubility (the REACH Registration Dossier for titanium dioxide reports water solubility in the range 0.04 to 0.287 µg/L); however dermal absorption of the other (low molecular weight and water-soluble) hydrolysis products may occur.

Inhalation absorption

The substance may also undergo hydrolysis in the respiratory tract. Absorption of the essentially insoluble titanium oxide formed by hydrolysis is unlikely; this will be subject to mucociliary clearance. Absorption of the other (low molecular weight and water-soluble) hydrolysis products is likely to be significant. However inhalation exposure to the parent substance is unlikely to occur due to the low volatility of the substance and its irritant properties.

Distribution

Based on the behaviour of the substance in aqueous environments, the intact substance is unlikely to be distributed beyond the site of contact; however some of its hydrolysis products are likely to be absorbed.

There is no direct evidence of distribution to specific organs or tissues from relevant (haematological, clinical chemistry or histopathological) parameters measured in the OECD 422 screening study; there is no indication of a target of toxicity. Serum T4 concentration was significantly reduced in males dosed with 750 mg/kg bw/d in this study. In the absence of histopathology this finding may reflect increased T4 metabolism secondary to liver enzyme induction. An increased incidence of small pups is reported in this study at 750 mg/kg bw/d. This finding is likely to be secondary to the lower maternal bodyweight seen at the end of gestation in this group, and does not strongly indicate trans-placental distribution of the hydrolysis products. Similarly, the reduced pup weight gain seen at 750 mg/kg bw/d is associated with lower maternal bodyweight and reduced maternal food consumption and is therefore likely to be a secondary effect rather than representing distribution of the hydrolysis products to the breastmilk. 

The hydrolysis products of the substance that are absorbed following oral exposure are likely to be subject to extensive metabolism; post-hepatic distribution may therefore be limited at realistic levels of exposure. The clinical signs seen at higher dose levels, however, indicate that the hydrolysis products may be distributed around the body at high levels of exposure.

Metabolism

The substance is likely to be rapidly hydrolysed in aqueous environments to form acetylacetone, ethyl acetoacetate, 1,3-propanediol and hydrated titanium oxides. The metabolism of these hydrolysis products is considered, in turn, below.

Titanium oxides

Information for titanium dioxide (1) indicates that this hydrolysis product is not absorbed and is not subject to further metabolism.

Ethyl acetoacetate

Ethyl acetoacetate is subject to hydrolysis by non-specific plasma esterase enzymes, with the formation of 3-oxobutanoic (acetoacetic) acid and ethanol (2). 3-oxobutanoic acid is a normal product of metabolism and, consequently, is likely to be incorporated into normal metabolic pathways and ultimately metabolised in the citric acid cycle to carbon dioxide and water. Ethanol is sequentially metabolised to acetaldehyde (predominantly by alcohol dehydrogenase, but potentially also involving cytochrome P450 2E1 and catalase) and acetic acid (by aldehyde dehydrogenases). Acetic acid is used in the formation of acetyl-CoA and is incorporated into the citric acid cycle, ultimately being metabolised to carbon dioxide and water (3).

Acetoacetate

Acetoacetic (3-oxobutanoic) acid is a normal product of metabolism and, consequently, is likely to be incorporated into normal metabolic pathways and ultimately metabolised in the citric acid cycle to carbon dioxide and water.

1,3-propanediol

The metabolic pathway for 1-3-propanediol has not been experimentally elucidated but is likely to follow that for other simple alcohols, in which alcohol dehydrogenase and aldehyde dehydrogenase enzymes act sequentially, with the formation of 3-hydroxypropionaldehyde, malondialdehyde or 3-hydroxypropionic acid, malonic semi-aldehyde and malonic acid. The majority of these substances are likely to be incorporated into normal metabolic pathways and ultimately metabolised to carbon

Excretion

Based on the hydrolysis of the substance and the behaviour of its hydrolysis products, it is concluded that following oral absorption, the hydrolysis product titanium dioxide will be excreted in the faeces. Small amounts of ethanol (formed from the hydrolysis product ethyl acetoacetate) may be excreted in the urine or expired air (3); however this and the other hydrolysis products are likely to be incorporated into normal metabolic reactions and excreted predominantly in the form of carbon dioxide and water.

Bioaccumulation

Based on the likely toxicokinetic properties of the substance, bioaccumulation is not predicted.

References

(1) Winkler HC, Notter T, Meyer U & Naegeli H (2018).Critical review of the safety assessment of titanium dioxide additives in food. J Nanobiotechnology 16:51

(2) European Commission Joint Research Centre (2002). EU Risk Assessment Report: ethyl acetoacetate. Special Publication I.02.75.

(3) Holford NH (1987). Clinical pharmacokinetics of ethanol. Clinical Pharmacokinetics 13(5): 273-92.