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

Basic toxicokinetics

Administrative data

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

Data source

Reference

Reference Type:

publication

Title:

Metabolism of 2-ethylhexanol administered orally and dermally to the female Fischer 344 rat.

Author:

P. J. Deisinger, R. J. Boatman & D. Guest

Year:

1994

Bibliographic source:

Xenobiotica. 1994 May;24(5):429-40

Materials and methods

Objective of study:

other: ADME and kinetics

Test material

Test material information

Constituent 1

Reference substance name:

2-ethylhexan-1-ol

EC Number:

203-234-3

EC Name:

2-ethylhexan-1-ol

Cas Number:

104-76-7

Molecular formula:

C8H18O

IUPAC Name:

2-ethylhexan-1-ol

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

female

Administration / exposure

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

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

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

Doses / concentrations 2

Dose / conc.:

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

No. of animals per sex per dose / concentration:

4

Control animals:

no

Results and discussion

Toxicokinetic / pharmacokinetic studies

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.

Metabolite characterisation studies

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.

Applicant's summary and conclusion

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.