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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Link to relevant study record(s)

Reference
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:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
metabolism
Principles of method if other than guideline:
In an effort to understand the elimination kinetics of aliphatic alcohols found in alcoholic beverages, research was conducted with human subjects.
Test subjects consumed isobutanol in an ethanol/water vehicle over a two hour time period. Blood and urine samples were collected prior to consumption, at the end of the two-hour consumption period, at one, two, eight (urine only), and nine hours after the end of the exposure period.
GLP compliance:
not specified
Specific details on test material used for the study:
- Name of test material (as cited in study report): Isobutanol
Species:
human
Strain:
not specified
Sex:
not specified
Route of administration:
oral: drinking water
Vehicle:
other: orange juice
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Orange juice was prepared containing 40 % (v/v) ethan-1-ol and 3.75 mg/l 2-methylpropan-1-ol
Duration and frequency of treatment / exposure:
2 hours followed by 9 hours of post exposure
No. of animals per sex per dose / concentration:
not specified
Control animals:
not specified
Metabolites identified:
yes
Details on metabolites:
isobutyraldehyde and isobutyric acid

The blood concentrations of isobutanol, isobutyraldehyde, and isobutyric acid were approximately 4, 4, and 17 µmol/L at the end of the consumption period, clearly demonstrating that isobutyric acid was the major metabolite of isobutanol metabolism. While the addition of ethanol to the test beverage definitely altered the rate of isobutanol metabolism (via a competition for metabolic enzymes), the presence of ethanol did not affect how isobutanol was metabolized. Blood levels of isobutanol decreased over the next two hours while the isobutyraldehyde levels slowly increased in the blood. Isobutyric acid levels also decreased after the end of the consumption period. Urinary concentrations of isobutanol peaked at the one-hour postexposure time point. Urinary levels of isobutyraldehyde peaked at the eight hour post-exposure time point. Urinary levels of isobutyric acid peaked at the end of the two-hour exposure period. Urinary levels of propionaldehyde roughly followed those for isobutyraldehyde with peak levels of approximately 8 µmol/L. Urinary levels of propionic acid rose after the exposure period ended with plateau levels between 2 and 8 hours of approximately 60 µmol/L. Urinary levels of succinic acid roughly followed the propionic acid urinary elimination curve with peak levels of approximately 30 µmol/L. A diagram was provided in the paper describing the further metabolism of isobutyric acid, ending with propionic acid. The formation of succinic acid from propionic acid is proposed based on the known intermediate metabolism of propionic acid via the citric acid cycle.

Description of key information

Short description of key information on bioaccumulation potential result: 
Absorption
Rapid absorption after inhalative exposition in rats (measurable blood levels after 5 min; Poet 2003) and after oral exposition in rabbits (Saito et al. 1975).
Metabolism
Rapid metabolism to isobutyric acid in rats (blood level of the metabolite peaked 10 min after isobutanol; Poet 2003).
Class I Alcohol Dehydrogenase (ADH) isozymes appear to be the most active for isobutanol metabolism in animals and humans (Sinclair et al. 1990)
Isobutyric acid, isobutyraldehyde and a not fully characterized urinary metabolite coeluted with isovaleric acid were known metabolites of isobutanol (several authors, i.e. Rüdell et al. 1983)
Excretion
Rapid excretion after inhalative exposition in vivo in rats (blood level peaked after 15 min; Poet 2003) and in rabbits (Saito et al. 1975) and in situ/ in vitro (Hedlund and Kiessling 1969) in rats.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Isobutanol is rapidly absorbed following oral administration and inhalation exposures. Isobutanol is metabolised to isobutyraldehyde and isobutyric acid in rats and humans, primarily by alcohol and aldehyde dehydrogenases.

Discussion on bioaccumulation potential result:

Non-human information

In vitro Studies

The Class I Alcohol Dehydrogenase (ADH) isozymes appear to be the most active for isobutanol metabolism. The alcohol dehydrogenase reaction was studied in rat and chick embryo liver homogenates (Sinclair et al., 1990). The clearance of isobutanol in rats was investigated using in situ liver perfusions and in vitro liver homogenates (Hedlund and Kiessling 1969; Val. 4). Clearance of isobutanol was very rapid in both test systems.

In vivo Studies

Respiratory bioavailability studies conducted with isobutanol have correlated airborne isobutanol levels with internal blood levels of isobutanol and isobutyric acid (ACC, 2003). Inhalation of 2000  ppm (ca. 6.0  mg/L) isobutanol in a closed chamber resulted in isobutanol levels up to 278 µM after 15 min and isobutyric acid levels up to 93 µM after 25 min. Blood levels of isobutanol decreased to 155 µM by ninety minutes and isobutyric acid levels were not detectable. The clearance of isobutanol in rats was investigated using intraperitoneal injections (Hedlund and Kiessling; 1969). Clearance of isobutanol was very rapid. Oral administration of isobutanol to rabbits was reported by Saito et al. (1975), with blood and urinary analysis for isobutanol and metabolites. The metabolism proceeded as expected although the analytical procedures employed detected an urinary metabolite that coeluted with isovaleric acid but was not fully characterized. Plapp (2015) investigated the kinetics of ADH in rats and stated, that isobutanol was eliminated with zero-order kinetic at a dose of 10 mmol/kg.

 

Human information

In vitro Studies

Metabolism of isobutanol to isobutyraldehyde and isobutyric acid is via the alcohol and aldehyde dehydrogenase enzymes (as was demonstrated in vitro by Ehrig et al., 1988). The Class I ADH isozymes appears to be the most active for isobutanol metabolism. The kinetic constants for the alcohol dehydrogenase reaction was determined to have a Km of 0.04 - 0.11 µM and a Vmax of 0.68 - 0.86 µmol min-1 g wet wt.-1 in human liver homogenates (Sinclair, et al., 1990).

In vivo Studies

Studies in humans demonstrated that isobutanol was rapidly metabolized to isobutyric acid (main metabolite) and isobutyraldehyde; the renal elimination of isobutanol and its main metabolite isobutyric acid peaked within one hour after dosing (Ruedell et al. 1983). Isobutanol is rapidly absorbed and eliminated from blood following oral administration to humans (Bilzer et al., 1990).

Furthermore, volunteers that were exposed via breathing masks to concentrations up to 200 ppm n-butanol for 2 hours did not feel adverse effects (Astrand et al. 1976).

 

Summary

Isobutanol is rapidly absorbed following oral administration and inhalation exposures. Isobutanol is metabolised to isobutyraldehyde and isobutyric acid in rats and humans, primarily by alcohol and aldehyde dehydrogenases.