Isobutyl acetate

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:

other: Well-documented report, which meets basic scientific principles

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Investigation of the respiratory bioavailability of a series of alcohols and acetate esters in rats using combined gas uptake inhalation measurements, plethysmography and a blood sampling system

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Isobutyl acetate

EC Number:

203-745-1

EC Name:

Isobutyl acetate

Cas Number:

110-19-0

Molecular formula:

C6H12O2

IUPAC Name:

isobutyl acetate

Details on test material:

- Name of test material (as cited in study report): isobutyl acetate (purchased from Acros Organics, Los Angeles, CA, USA)
- Analytical purity: 98%
- Impurities (identity and concentrations): no data
- Lot/batch No.: I4025000
- Stability under test conditions: no data
- Storage condition of test material: no data

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hilltop Lab Animals Inc., Scottsdale, PA, USA
- Age at study initiation: no data
- Weight at study initiation: 270 - 350 g
- Fasting period before study: no data
- Housing: housing according to good husbandry practice
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): PMI 5002 Certified Rodent Diet from Animal Specialties Inc., Hubbard, OR, USA
- Water (e.g. ad libitum): deionized water from reverse osmosis
- Acclimation period: no data
- other: animals were provided with indwelling jugular cannulas

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1.5
- Humidity (%): 50 ± 20
- Air changes (per hr): 15 - 20
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

TYPE OF INHALATION EXPOSURE: head only

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: closed, recirculating, 8-L gas uptake exposure chamber with whole-body plethysmograph (plethysmograph from Buxco Electronics Inc. Sharon, CT, USA
- Method of holding animals in test chamber: tubular shaped plethysmograph chamber with neck seal to separate the exposed head of the animal from the body chamber.
- Source and rate of air: no data
- Method of conditioning air: no data
- System of generating particulates/aerosols: injection of a known volume of test material into the exposure chamber via a heated injector port to achieve the target exposure concentration
- Method of particle size determination: not determined
- Treatment of exhaust air: no data

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: not investigated

ANALYTICAL VERIFICATION OF TEST MATERIAL CONCENTRATONS
- Brief description of analytical method used: gas chromatographic analysis using a Hewlett Packard 5890 Series II GC with FID detection
- Samples taken from breathing zone: no data
- Sampling schedule: samples were analysed approx. every 7 min via automatic injection of about 1 mL of chamber air into the GC

Duration and frequency of treatment / exposure:

2 hour single exposure

Doses / concentrations

Remarks:

Doses / Concentrations:
Target exposure concentration: 2000 ppm
Measured concentrations declined from 1911.54 ± 115.79 ppm at time 0 to 144.85 ± 41.08 ppm at 2 hours (n=7).

No. of animals per sex per dose / concentration:

7 male animals

Control animals:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood by indwelling jugular cannula
- Time and frequency of sampling: prior to exposure and at 5, 10, 15, 20, 25, 30, 40, 50, 60, 90 min after injection of the test material into the chamber. Isobutyl acetate, isobutanol and isobutyric acid were analyzed.

Results and discussion

Any other information on results incl. tables

Non specific chamber loss rate

During a 2 hour period, chamber concentrations decreased without a live rat from 2148 to 823 ppm (n=2) of isobutyl acetate. The non specific chamber loss was initially (first 45 minutes) more rapid than in a the final phase.

 

Chemical exposure

During exposure of animals to isobutyl acetate, the decline in chamber concentrations was substantial over the 2 hour exposure period. Experiments with 7 animals resulted in a decrease of chamber exposure concentrations from 1912 to 145 ppm (mean value, n=7).

 

Blood concentrations

Isobutyl acetate, isobutanol, and isobutyric acid were analyzed in blood samples of 4 to 6 animals.

 

Data are shown in the following table.

 

 

Time [min]	n	Isobutyl acetate [µM]		Isobutanol [µM]		Isobutyric acid [µM]
		mean	SD	mean	SD	mean	SD
0	6	0.0	0.0	0.0	0.0	0.0	0.0
5	6	16.1	15.0	35.4	22.2	5.99	0.90
10	6	31.5	29.1	86.5	57.9	7.97	3.43
15	5	18.0	10.3	74.3	40.9	11.66	5.25
20	5	16.5	8.6	101.6	42.4	12.52	7.39
25	6	16.4	6.0	77.9	27.1	8.57	2.92
30	5	21.4	12.3	70.8	22.0	11.11	3.58
40	6	24.9	14.9	59.2	35.5	11.40	5.02
50	6	19.9	10.9	51.0	37.1	8.57	5.46
60	5	11.6	2.5	28.9	15.3	4.85	1.16
90	4	7.6	NA	10.6	5.2	6.20	1.31

 

NA     not applicable (only two values)

 

The blood concentrations of the parent isobutyl acetate were found to be 16.1 µM at 5 min and 7.6 µM at 90 min with maximal concentrations of 31.5 and 24.9 µM at 10 and 40 min respectively. For the hydrolysis product isobutanol, higher blood levels were determined. The blood concentrations of isobutanol were 35.4 µM at 5 min and 10.6 µM at 90 min with peak concentrations of 86.5 and 101.6 µM at 10 and 20 min. Isobutyric acid, the oxidation product of isobutanol, showed lower blood levels (6.99 µM at 5 min, 6.2 µM at 90 min, peak concentration 12.52 µM at 20 min).

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Isobutyl acetate is readily absorbed from the respiratory tract. Maximum blood concentrations are reached at 10 and 40 minutes. After 90 min a substantial decrease in blood concentrations can be observed. During the complete observation/exposure period, the levels of the hydrolysis product isobutanol were higher then the levels of the parent isobutyl acetate (1.5 to 6 fold). Isobutyric acid (oxidation product of isobutanol) was found at lower levels (approximately half of the peak exposure of isobutyl acetate).

Executive summary:

The respiratory bioavailability of isobutyl acetate was studied in rats in a combined gas uptake inhalation measurements, plethysmography and a blood sampling experiment. Male SD rats with jugular vein-implanted cannulas exteriorized through a gas uptake inhalation chamber were individually exposed for 2 hrs to a targeted initial concentration of 2000 ppm of isobutyl acetate while simultaneously monitoring respiratory rates with a body-only plethysmograph (head-only exposures). Exposure was performed in a closed, recirculating 8 L gas uptake exposure chamber.

Blood samples (10) were collected during each exposure for 90 minutes for analysis of isobutyl acetate as parent compound and isobutanol and isobutyric acid as metabolites.

Maximum blood levels of isobutylacetate were reached after 10 minutes (31.5 µM = 3.66 mg/L) with a second peak at 40 minutes (24.9 µM = 2.89 mg/L). At 90 minutes blood concentrations had declined to 7.6 µM (0.88 mg/L) (OPP/ACC 2004).

Analyzed metabolites were isobutanol and isobutyric acid. The maximum blood concentration of isobutanol were 86.5 µM (6.41 mg/L) and 101.6 µM (7.53 mg/L) measured at 10 and 20 min respectively. Until the end of the observation period (90 min) blood levels decreased to 10.6 µM (0.79 mg/L).

Blood levels of isobutyric acid were lower with 5.99 µM (0.53 mg/L) at 5 min, 12.52 µM (1.1 mg/L) at 20 min (peak concentration) and 6.2 µM (0.55 mg/L) at 90 min.