Ethoxybis(pentane-2,4-dionato-O,O')(propan-2-olato)titanium

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

2-propanol and triethanolamine are two main hydrolysis prodcuts of the target substances.

Data source

Reference

Reference Type:

publication

Title:

Disposition and Pharmacokinetics of Isopropanol in F-344 Rats and B6C3F1 Mice

Author:

Slauter, R.W., et al

Year:

1994

Bibliographic source:

Fundam. Appl. Toxicol. 23, 407-420 (1994)

Materials and methods

Objective of study:

excretion

metabolism

toxicokinetics

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

no

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Propan-2-ol

EC Number:

200-661-7

EC Name:

Propan-2-ol

Cas Number:

67-63-0

Molecular formula:

C3H8O

IUPAC Name:

propan-2-ol

Details on test material:

- Name of test material (as cited in study report): IPA, 2-propanol
- Physical state: liquid

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Administration / exposure

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

single exposure for 6 hr

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

500 ppm

Remarks:

low dose group

Doses / concentrations 2

Dose / conc.:

5 000 ppm

Remarks:

high dose group

No. of animals per sex per dose / concentration:

4

Control animals:

no

Positive control reference chemical:

none

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

rapid absorption

Main ADME results 2

Type:

distribution

Results:

widely distributed without any accumulation

Main ADME results 3

Type:

metabolism

Results:

major metabolites were acetone and carbon dioxide

Main ADME results 4

Type:

excretion

Results:

predominant elimination pathway is exhaled breath

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The concentration of radiolabel in the blood increased rapidly following the initiation of inhalation exposure at either concentration. The concentration of radiolabel appeared to still be rising at the end of the exposure to 500 ppm but appeared to have plateaued by the end of the exposure to 5000 ppm IPA.

Details on distribution in tissues:

Widely distributed among the tissues following nose only inhalation exposure to nominal concentrations of 500 and 5000 ppm. No evidence was observed to indicate that IPA or its radiolabeled metabolites accumulated in any tissue with the possible exception of kidney and liver, which had slightly elevated concentrations of radiolabel relative to the blood.

Details on excretion:

Following nose only inhalation of IPA the breath is, by far, the predominant route of excretion of radiolabel by both sexes. The excretion of the absorbed dose was rapid, with greater than 90% of the absorbed radiolabel being excreted from the breath, urine, and feces within 72 h of the beginning of the inhalation exposure. Exhalation in the breath accounted for a total of about 83% of the absorbed dose at the low exposure level while it accounted for just under 88% following the high exposure level. Even though total excretion of radiolabel in the breath was practically the same following either inhalation exposure, the distribution of radiolabel that appeared in the breath was dramatically different. Following exposure to 500 ppm males and females exhaled an average of 49% of the absorbed radiolabel as carbon dioxide in the breath. Following exposure to 5000 ppm, only 22% of the radiolabel present in the exhaled breath was found to be 14CO2. While the exhaled breath was the major route of excretion following both exposure levels, urine was a minor route of elimination of radiolabel and excretion in the feces was negligible.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Acetone was found to be the primary radiolabeled metabolite of IPA. In the exhaled breath acetone accounted for 75-100% of the radiolabeled organic volatile compounds being exhaled. The balance of the exhaled radioactivity was accounted for by CO2 and IPA itself. A third radiolabeled metabolite (accounting for less than 5% of the total dose) was found when the urine was analyzed by HPLC; this urinary metabolite was identified as isopropyl glucuronic acid.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

not reported.

Applicant's summary and conclusion

Conclusions:

No bioaccumulation potential of 2-propanol based on the test results.
Pharmacokinetics of propan-2-ol (IPA) was studied in rats. Animals were exposed by inhalation for 6 hours to IPA vapor. Total exhalation of radiolabel (as CO2, acetone, propan-2-ol) was 83%-87% of the administered dose. Urine and feces accounted for excretion approximately 7% and 1%, respectively. No single tissue contained greater than 1.6% of recovered dose.