Bis(2-ethylhexan-1-olato)bis(pentane-2,4-dionato-O,O')titanium

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

According to hydrolysis test results, this substance is hydrolytically unstable with hydrolysis rate estimated to be several minutes. The hydrolysis products have been identified to be 2-ethylhexanol, acetylacetone and titanium dioxide. The discussion of toxicokinetics is based on the hydrolysis/degradation products.

Reason / purpose for cross-reference:

data waiving: supporting information

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Objective of study:

other: ADME and kinetics

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

female

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

1) single dose exposure
2) repeated dose exposure, 14 days

Dose / conc.:

50 mg/kg bw/day (actual dose received)

Dose / conc.:

500 mg/kg bw/day (actual dose received)

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on absorption:

2-EH was rapidly absorbed after oral administration of 50 and 500 mg/kg bw; evidenced by the rapid excretion (approx. 50% of the dose within
8 hrs). 95-97% of the dose were excreted within 96 hrs.

Details on distribution in tissues:

Distribution into tissues is of minor relevance, due to rapid excretion, mainly as polar conjugates in urine. Bioaccumulation is unlikely to occur, as excretion was virtually complete (>95%) within 96 hrs.

Details on excretion:

2-EH was rapidly absorbed after oral administration of 50 and 500 mg/kg bw; evidenced by the rapid excretion (approx. 50% of the dose within 8 hrs). 95-97% of the dose were excreted within 96 hrs, mainly as polar conjugates in urine. Bioaccumulation is unlikely to occur, as excretion was virtually complete within 96 hrs.

Metabolites identified:

yes

Details on metabolites:

The majority of the oral and dermal doses were eliminated as glucuronides of oxidized metabolites of 2-ethylhexanol (2-EH). Major metabolites:
glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid, 5-hydroxy-2-ethylhexanoic acid, and 6-hydroxy-2-ethylhexanoic acid. Only trace amounts of the unchanged 2-ethylhexanol were detected in urine.

Conclusions:

No bioaccumulation potential based on study results.
1. Excretion balance studies were conducted with 2-ethylhexanol (2-EH) in female Fischer 344 rats following single high (500 mg/kg) and low (50 mg/kg) oral doses of 14C labeled 2-EH, following repeated oral dosing with unlabelled 2-EH at the low level, following dermal exposure for 6h with a 1 g/kg applied dose of [14C]2-EH, and following a 1 mg/kg i.v. dose of [14C]2-EH.
2. The high, low and repeated low oral dose studies with 2-EH showed similar excretion balance profiles of [14C], with some evidence of metabolic saturation at the high dose.
3. No evidence of metabolic induction was seen following the repeated low oral dosing.
4. All of the oral doses were eliminated rapidly, predominantly in the urine during the first 24 h following dosing.
5. T h e dermal dosing resulted in only about 5% absorption of the 1 g/kg dose, with the major portion of the dose recovered unabsorbed from the dermal exposure cell at 6 h.
6 . Urinary metabolites eliminated following the oral and dermal doses were predominately glucuronides of oxidized metabolites of 2-EH, including glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid, 5-hydroxy-2-ethylhexanoicacid and 6-hydroxy-2-ethylhexanoic acid.

Executive summary:

As the target substance hydrolyses rapidly (half-life < 30 minutes) the intrinsic properties are related to hydrolysis products of the target substance. This information is used as a supporting evidence on the toxicity of the target substance in CSA.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

other:

Principles of method if other than guideline:

Intravenous study: The substance was given to four adult male Fischer 344 rats per dose by single intra-venous injection. Target radioactivity was 2 – 5 mCi. Blood was collected at appropriate intervals from a lateral tail vein until 30 hr post dosing. At 48 hr a cardiac puncture was performed for a final blood sam-ple with all groups. Urine and feces were. For airborne collections, room air was drawn through the me-tabolism cages at approximately 500 ml/min. Expired 14CO2 was trapped.

Inhalation study: A total of fifty animals were exposed 6 hours nose-only to a target concentration and serial groups of 3 animals were removed at the blood sampling intervals during the absorption phase. Included was a group of 4 rats which were monitored by plethysmography during exposure to ensure that there was no excessive peripheral sensory irritation with consequent changes in minute volume. Respira-tory rate was measured. After exposure the animals were transferred to metabolism cages.

GLP compliance:

yes

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male

Route of administration:

other: inhalation: dust; intravenous

Vehicle:

other: physiol. saline for intravenous, unchanged for inhalation

Duration and frequency of treatment / exposure:

IV: single exposure
Inhalation: single 6h exposure

Dose / conc.:

400 ppm

Remarks:

Inhalation

Dose / conc.:

4.3 mg/kg bw/day (nominal)

Remarks:

I.V

Dose / conc.:

43 mg/kg bw/day (nominal)

Remarks:

I.V.

Dose / conc.:

430 mg/kg bw/day (nominal)

Remarks:

I.V

Dose / conc.:

148.5 mg/kg bw/day (nominal)

Remarks:

I.V.

No. of animals per sex per dose / concentration:

I.V.: 4
Inhalation: 50

Conclusions:

Low bioaccumulation potential based on study results.

2,4-PD is readily absorbed during a 6 hr exposure to 400 ppm, and biexponentially eliminated from plasma postexposure. However, even at 48 hr postexposure, radioactivity derived from 14C-2,4-PD is still present. The majority of the dose is eliminated as CO2 and in urine, with at least 7 metabolites being detected in urine. Although there is no preferential tissue accumulation of 14C-2,4-PD-derived radioactivity, the plasma elimination profiles and the detection of some radioactivity in many tissues at 48 hr postexposure, indicates a potential for cumulative effects. The only definitive repeated exposure known toxicity, and with a latency to expression, is central neurotoxicity and 14C could still be detected in the brain 48 hr after a single exposure. The urinary elimination profiles suggest that biological monitoring might best be undertaken using a metabolite as marker. (from Frantz 1998).

Executive summary:

As the target substance hydrolyses rapidly (half-life < 30 minutes) the intrinsic properties are related to hydrolysis products of the target substance. This information is used as a supporting evidence on the toxicity of the target substance in CSA.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No studies were conducted on the target substance,Reaction product of Titanium tetrakis(2-ethylhexan-1-olato) and pentane-2,4-dione. As the target substance hydrolyses rapidly (half-life < 30 minutes) the intrinsic properties are related to hydrolysis products of the target substance. The hydrolysis products include 2-ethylhexanol, pentane-2,4-dione, and non-hazardous titanium dioxide. This information is used as a supporting evidence on the toxicity of the target substance in CSA.

Toxicokinetics of 2-ethylhexanol

Human data
No studies on toxicokinetics in humans in vivo are available. In a diffusion experiment by
Barber et al. (1992), the absorption rate of human skin in vitro was 38 µg per cm2 and hour.

Animal data

No quantitative data on the absorption by inhalation exposure are available. The occurrence of systemic toxic effects after inhalation exposure shows the efficient absorption by this route.

Absorption

The toxicokinetics of EH in female rats were studied by Deisinger et al. (1994). After oral gavage of 50 or 500 mg/kg the absorption rate was about 80%, independent of the administered dose. No differences in absorption were likewise observed following repeated exposures. The dermal absorption rate after exposure to 1000 mg/kg was reported to be about 5% in this study. In a diffusion experiment by Barber et al. (1992), the absorption rate of rat skin in vitro was 215 µg per cm2 and hour, i.e. about five times higher than in human skin.

Metabolism

In the study by Deisinger et al. (1994), the metabolism of EH was similar after oral and dermal exposure. The main metabolites in urine of orally treated rats were 2-ethylhexanoic acid, 5-hydroxy-2-ethylhexanoic acid, 6-hydroxy-2-ethylhexanoic acid and 2-ethyl-1,6-hexane diacid. Together, they represented 37 - 45% of the administered dose. Minor metabolites were 5-hydroxy-2-ethylhexanoic acid as well as lactones of 5-hydroxy-2- ethylhexanoic acid and 2-ethyl-5-hexanoneacid. They represented 3 - 5% of the administered dose. About 1% of the administered dose was recovered as 2-ethylhexanol. All these compounds were predominantly excreted as glucuronides (Deisinger et al., 1994). Albro (1975) reported the formation of about 50% 2-ethylhexanoic acid following a single oral exposure of rats to 275 mg/kg.

Excretion

After gavage to rats, 95% of EH was eliminated within 96 h (mostly within 24 h). About 70% of the administered dose was excreted in urine, 13% in faeces and 11% in expired air. A similar elimination pattern was found after dermal exposure, with lower absolute amounts due to lower absorption following dermal exposure. Older studies in mice and rats support the results of the most detailed study by Deisinger et al. (1994). (Cited and modified from SCOEL/SUM/158 ).

Toxicokinetics of pentane-2,4-dione (2,4-PD)

No studies are available concerning the mode of action of the substance. It is known, however, that 1,3-diketones unfold metal chelating properties in vivo which may lead to inhibition of enzymatic activity of metal containing enzymes such as peroxidases or cytochrome P450 without concomitantly lowering protein contents. In an inhalation study conducted in male Fischer 344 rats it could be shown that 14C-labeled-2,4-PD was readily absorbed by the inhalation route. Nose-only exposure to 400 ppm 14Clabeled-2,4-PD resulted in a rapid increase in plasma radioactivity during the first 3 hours of exposure, with a tendency to plateau toward the end of the 6 hour exposure period. Plasma unmetabolized 14C-labeled-2,4-PD was present throughout the whole of the exposure phase, but was significantly less than total 14C. Immediately postexposure, radioacivity was present in all tissues examined, but on a concentration basis (µg equivalents/g) there was no preferential accumulation of 14C in any tissue or organ. On a total organ basis, highest contents were in liver and kidneys. Post-exposure, plasma unmetabolized 14C-labeled-2,4-PD declined rapidly to undetectable concentrations by 12 hours. Elimination of 14C from plasma followed a biphasic pattern with a terminal half-life (beta t½) of 30.72 hours. Excretion over 48 hours of 14C was approximately equivalent between urine (37.6 %, mainly not identified metabolites) and expired 14 CO2 (36.3 %), which the most part of the radioactivity was eliminated in the first 12 hours. Expired volatiles, feces, tissues and carcass accounted for 2.29, 2.78, 1.66 and 17.15 % of the total administered radioactivity dose 48 hours postdosing, respectively (Frantz et al. 1998). (Cited from OECD SIDS, pentane-2,4-dione)

 

Toxicokinetics of Titanium dioxide

 

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 faeces 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).

Titanium dioxide released from target substance exists as hydrated form and thus human exposure via inhalation is not relevant.