Isopropyl acetate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Objective of study:

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Isopropyl acetate is believed to be rapidly hydrolysed in vivo to the parent alcohol isopropanol. This study uses two single iv doses of non-radiolabelled isopropyl acetate and the rise and decay of the parent ester and the hydrolysis product isopropanol followed by taking blood samples for up to 4 hours post dosing.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Isopropyl acetate

EC Number:

203-561-1

EC Name:

Isopropyl acetate

Cas Number:

108-21-4

Molecular formula:

C5H10O2

IUPAC Name:

isopropyl acetate

Constituent 2

Reference substance name:

isopropyl acetate

IUPAC Name:

isopropyl acetate

Details on test material:

Material re-purified in laboratory before use to a molar purity of 99.99% (molar percent)

Specific details on test material used for the study:

Source: INEOS nv, Antwerp, Belgium
Purity: to be confirmed

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Administration / exposure

Route of administration:

intravenous

Vehicle:

physiological saline

Duration and frequency of treatment / exposure:

Single dose. Volume given 10mL.kgbw.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

5 mg/kg bw (total dose)

Doses / concentrations 2

Dose / conc.:

50 mg/kg bw (total dose)

No. of animals per sex per dose / concentration:

4

Control animals:

no

Positive control reference chemical:

no

Details on dosing and sampling:

- Tissues and body fluids sampled: blood
- Time and frequency of sampling: Collection periods 1, 2, 3, 5, 10, 15, 20, 30, 60, 120, 240 minutes. Number of samples limited to 11 for ethical reasons.
- From how many animals: (samples pooled or not): measurements of individual animals
- Method type(s) for identification: See 'any other information for details of method"
- Limits of detection and quantification: To be confirmed in final report but all key metabolites well above LOD/LOQ.

Statistics:

Mean and standard deviation calculated

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:

Recovery of dose material exceeded 95% at all dose levels leading to conclusion that almost all the substance is excreted by this route.

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 2.9 mins

Remarks:

Standard deviation 0.87min. Average of the results from the 3 animals tested at a dose of 5mg/kgbw. Mean residence time 4.1 mins.

Toxicokinetic parameters 2

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: 2.4 mins

Remarks:

Standard deviation 0.4min. Average of the results from the 4 animals tested at a dose of 5mg/kgbw. Mean residence time 3.5 mins.

Metabolite characterisation studies

Metabolites identified:

yes

Remarks:

isopropanol

Any other information on results incl. tables

All data points from animal #1 in the low dose group indicated a half life of 82 mins. However, the data points were rather scattered, particularly the last two. A plotted line through all the data points was not statistically significant (R=0.42). Discarding the last two data points did produce a statistically significant result indicating a half life of 6-7 mins (still significantly above the other results). This result was discarded as an outlier. Further information on a possible cause for this erroneous result may be available in the full study report.

Applicant's summary and conclusion

Conclusions:

The half life for in vivo hydrolysis of isopropyl acetate to isopropanol is 2-3 minutes and is independent of dose over the tested range of 5-50mg/kgbw.

Executive summary:

An in vivo hydrolysis study was carried out in rats to determine the rate of hydrolysis of isopropyl acetate to isopropanol. Groups of four male rats were dosed iv with isopropyl acetate in physiological saline in two dose groups of 5 and 50mg/kgbw. Blood was sampled from the tail over a period of 60 minutes for analysis of isopropyl acetate, with sampling biased towards the initial part of the study period. The half life was determined to be in the range 2 -3 minutes with no difference between the two dose groups.