2-isopropoxyethanol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1970

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

Non-guideline non-GLP study, with adequate and well described methods and results.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1970

Reference 2

Reference Type:

publication

Title:

The metabolism of isopropyl oxitol in rat and dog

Author:

Hutson, D.H. and Pickering, B.A.

Year:

1971

Bibliographic source:

Xenobiotica, 1, 105-119.

Materials and methods

Objective of study:

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-isopropoxyethanol

EC Number:

203-685-6

EC Name:

2-isopropoxyethanol

Cas Number:

109-59-1

Molecular formula:

C5H12O2

IUPAC Name:

Propan-2-ol

Details on test material:

- Name of test material (as cited in study report): O-Isopropyl [1,2-14C] ethanediol/ [1,2-14C]isopropyl oxitol.
- Specific activity (if radiolabelling): 9.6 uCi/mg

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

other: Carworth Farm E strain

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Carworth Farm E strain
- Weight at study initiation: 200-250g body wt.
- Housing:The rat were housed for four days in Jencons all-glass metabolism cages as described by Wright, et al.(1965) and had free access to food and water
- Individual metabolism cages: yes

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

physiological saline

Duration and frequency of treatment / exposure:

Single exposure

Doses / concentrations

Dose / conc.:

0.933 other: mg

Remarks:

9.55uCi in 0.5 ml of 0.9% sterile saline.

No. of animals per sex per dose / concentration:

6

Control animals:

not specified

Details on study design:

Respired air from each animal was drawn (400ml/min) through a trap containing 500ml 5M NaOH. These traps were changed every 24 hrs for 4 days. After 4 days the animals were killed by ether anaesthesia and were skinned (the feet, muzzle and tail remaining with the skin). The alimentary tracts, from anus to oesophagus, were then removed for separate analysis.

Details on dosing and sampling:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): Urine and faeces were collected daily. All samples were stored at - 20 degrees C until required for assay. Daily urine samples were directly assayed for radioactivity by scintillation counting. Faeces and tissues were homogenized with water and duplicate samples combusted in oxygen, the resulting CO2 being absorbed directly into scintillator solution. The CO2 content of the NaOH traps was determined by releasing CO2 from 1 mL duplicate samples of soln. by the addition of 5M-H2SO4, and trapping the released gas in 5 mL of phenylethylamine. The other components of the scintillator were then added to the phyeylethylamine and the sample assayed for radioactivity.
- Measurement of radioactivity: Aliquots of solution to be assayed for radioactivity were blended with 15ml of phenyl ethylamine scintillator solution based on that devised by Dobbs (1963) and the radioactivity determined using a Packard Tricarb Liquid Scintillation Scpectrometer (Model 3003).
- Method type(s) for identification: The 0-24h urine from the rats was pooled and analysed directly by t.l.c. in comparison with 2-isopropoxyethanol and isopropoxyacetic acid.

Results and discussion

Preliminary studies:

-In a preliminary experiment with one animal, the respired air was drawn through acetone at -20 degrees C in order to trap respired radioactive metabolites, if any. After 12h, the acetone was radioassayed. An amount of radioactivity corresponding to less than 0.2% of the dose was recovered in the trap.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

No data

Details on distribution in tissues:

Skin: 3.4% of administered radioactivity (4.4% males, 2.4% females)
Gut: 0.7% of administered radioactivity (0.8% males, 0.6% females)
Carcass: 6.1% of administered radioactivity (7.2% males, 5.0% females)

Details on excretion:

The metabolism of 2-isopropoxyethanol was similar in the dog and the rat. In the rat, this material was rapidly metabolized and 88% was excreted from the body in 24h (average for male and female), 73% via the urine, and 14% via the lungs as carbon dioxide. See Table 1 in Remarks.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The major urinary metabolites were isopropoxyacetic acid (30% of urinary radioactivity), N-isopropoxyacetylglycine(46% of urinary radioactivity), and ethylene glycol (13% of urinary radioactivity). Only the first two metabolites were identified in the urine from beagle hound treated with this glycol ether. The occurrence of the glycine derivative of isopropoxyacetic acid was unexpected and suggests conjugation of the acid within the mitochondrion by glycine N-acylase. Based on these results, the authors suggest the metabolic scheme shown in Figure 1 for the rat.

Any other information on results incl. tables

There was no difference between results calculated by gaseous transfer of the carbon dioxide traps and results calculated by direct sampling of the traps,thus all radioactivity exctreted via the lungs was [14C]carbon dioxide, and no other volatile metabolite was excreted.

Table 1. Daily levels of radioactivity in urine, faeces, and respired air after the administration of [14C]isopropyl oxitol to rats

 

Period	Males			Females
	Urine	Faeces	CO2	Urine	Faeces	CO2
0-24 h	65.5 (3.28)	4.3 (1.64)	10.1 (0.44)	76.1 (4.87)	4.6 (2.59)	7.9 (0.47)
24-48 h	1.2 (0.23)	0.1 (0.07)	4.0 (0.30)	2.1 (0.41)	0.1 (0.06)	2.9 (0.22)
48-72 h	0.4 (0.04)	0.1 (0.08)	1.4 (0.04)	0.6 (0.08)	0.1 (0.03)	1.0 (0.07)
72-96 h	0.3 (0.03)	0.3 (0.06)	0.8 (0.06)	0.4 (0.08)	0.2 (0.06)	0.4 (0.04)
Totals	67.4 (3.1)	4.8 (1.7)	16.3 (0.4)	79.2 (4.4)	5.0 (2.6)	12.2 (0.6)

Results expressed as % of the administered radioactivity and (S.E.M. values are shown in parenthesis).

Applicant's summary and conclusion

Conclusions:

low bioaccumulation potential based on study results. The test substance is rapidly metabolised and 88% excreted within 24 hrs

Executive summary:

In this study a single intraperitoneal injection of [1,2-14C]isopropyl oxitol was administered to rats and its metabolism and excretion determined. The material was rapidly metabolised and 88% was excreted from the body within 24hrs in the rat, 71% through kidneys, and 12% via the lungs as carbon dioxide. Radioactivity found in the animal tissues at the end of the experiment accounted for 10% of the adminstered dose. The major urinary metabolites were isopropoxyacetic acid (30% of urinary radioactivity), N-isopropoxyacetylglycine(46% of urinary radioactivity), and ethylene glycol (13% of urinary radioactivity).