2-methylbutan-2-ol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1977-5-25 to 1981-04-15

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: acceptable publication

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1992

Report date:

1981

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Deviations:

not applicable

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-methylbutan-2-ol

EC Number:

200-908-9

EC Name:

2-methylbutan-2-ol

Cas Number:

75-85-4

Molecular formula:

C5H12O

IUPAC Name:

2-methylbutan-2-ol

Radiolabelling:

no

Test animals

Species:

other: mice, rats and dogs

Strain:

other: CD1-mice, Fischer rats and beagle dogs

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Sex: Mice and rats: males and females; dogs: males
- Source:
mice: Charles River Breeding Laboratories, Wilmington, MA, USA;
rats: Charles River Breeding Laboratories, Portage, MI, USA;
dogs: Laboratory Research Enterprises, Kalamazoo, MI, USA
- Age at study initiation:
mice: app. 4 weeks
rats: app. 5 weeks;
dogs: app. 10 months
- Fasting period before study: no
- Housing:
mice: 5 / cage
rats: 3-4 / cage
dogs: 2 / run
- Individual metabolism cages: yes
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: mice and rats 1 month each, dogs 3 months

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not specified (monitored during exposure only)
- Humidity (%): not specified (monitored during exposure only)
- Air changes (per hr): not specified (monitored during exposure only)
- Photoperiod (hrs dark / hrs light): 12h light / 12h dark

Administration / exposure

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

Exposures in 4.1 cubic meter stainless steel chambers under dynamic arflow. Total airflow through the chambers about 750 L/min. Vapors were generated by metering liquid tertiary amyl alcohol at a controlled rate into a heated (180°C) vaporization flask. Compressed air was used to sweep the vapors from the flask into the main chamber airflow where they were mixed and diluted with tempered air (about 22°C & 50% humidity) before entering the chamber. Control animals were not placed in a chamber but were kept in an animal room during the exposure period.
Temperature and relative humidity in the chambers and the animal room were recorded at least once each exposure day.

HOMOGENEITY AND STABILITY OF TEST MATERIAL:
- Stability of test item: measured prior to and following completion by flame ionisation-gas chromatography
- Homogeneity: not tested

CHAMBER CONCENTRATION.
- The analytical chamber concentration was monitored with a infrared spectrophotometer. The chamber concentration were analysed at least 3 times per day for each exposure level.

Duration and frequency of treatment / exposure:

59 to 61 days, for 6 hours per day

Doses / concentrations

Remarks:

Doses / Concentrations:
nominal: 50; 225; 1000 ppm (0.18; 0.81; 3.6 mg/L)
measured: 50.5 +/- 1.9; 227.6 +/- 8.4 or 990.4 +/- 25.6 ppm

No. of animals per sex per dose / concentration:

10 male and female CD-1 mice;
10 male and female Fischer 344 rats;
4 male beagle dogs.

4 additional male Fischer 344 rats and up to 18 male CD-1 mice, from the same shipment of animals, were added to each treatment group except control and used to define the clearance of 2-Methylbutan-2-ol from the plasma.

Control animals:

yes

Details on dosing and sampling:

Blood samples were collected during the second month of the study following 5 consecutive daily 6 hour exposures.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 29 min (mouse, exposed to 1000 ppm)

Toxicokinetic parameters 2

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: 47 min (rat, exposed to 50 ppm)

Toxicokinetic parameters 3

Test no.:

#3

Toxicokinetic parameters:

half-life 1st: 69 min (dog, exposed to 50 ppm)

Any other information on results incl. tables

The lowest plasma concentrations were found in the mouse and the highest concentrations were found in the dog. Half an hour after the end of the high concentration exposure the mean concentrations found in the plasma of mice, rats and dogs were 42 +/- 15, 98 +/- 5 and 341 +/- 189 µg/ml, respectively. The post-exposure plasma concentration time-profiles suggests that the observed differences in plasma concentrations were in part due to differences in the ability of these species to eliminate 2-methyl-2-butanol. Following the low concentration exposure, 2-methyl-2-butanol was cleared from the plasma of the rat and dog in a first-order manner (elimination not saturated). Following the high concentration exposure, 2-methyl-2-butanol was cleared from the plasma of mice in a first-order manner but was better described by assuming Michaelis-Menten or saturation kinetics in both rat and dog. The apparent half-life for the elimination of tertiary amyl alcohol in the mouse (t1/2 = 29 min) exposed to high concentration was less than in either the rat (t1/2 = 47 min) or dog (t1/2 = 69 min) exposed to low concentration.