Butan-1-ol

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:

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

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Fate of n-Butanol in Rats after Oral Administration and its uptake by dogs after inhalation or skin application

Author:

DiVincenzo GD, Hamilton ML

Year:

1979

Bibliographic source:

Toxicology and Applied Pharmacology 48: 317-325

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1978

Report date:

1978

Materials and methods

Objective of study:

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

n-[1-14C]Butanol was mixed with corn oil and administered by gavage to male Charles River CD (SD) rats in doses of 4.5, 45, or 450 mg/kg bw. The excretion of the n-[1-14C]Butanol was examined.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Butan-1-ol

EC Number:

200-751-6

EC Name:

Butan-1-ol

Cas Number:

71-36-3

Molecular formula:

C4H10O

IUPAC Name:

butan-1-ol

Test material form:

liquid

Specific details on test material used for the study:

- Specific activity (if radiolabelling): 1.71 mCi/mmol
- Locations of the label (if radiolabelling): n-[1-14C]Butanol

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River
- Weight at study initiation: 200-250 g
- Fasting period before study: 16 hours
- Housing: individually
- Individual metabolism cages: yes
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
no data

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
[1-14C]-n-butanol was diluted with carrier and mixed with corn oil; a 1 mL mixture was administered by gavage at single doses of 4.5, 45 and 450 mg/kg bw. Each rat received between 0.224 and 28.4 µCi of radioactivity

VEHICLE
- Justification for use and choice of vehicle (if other than water): none given
- Concentration in vehicle: 1 mL mixture was administered by gavage at single doses of 4.5, 45 and 450 mg/kg bw
- Amount of vehicle: 1 mL

Duration and frequency of treatment / exposure:

single oral application

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

4.5 mg/kg bw (total dose)

Doses / concentrations 2

Dose / conc.:

45 mg/kg bw (total dose)

Doses / concentrations 3

Dose / conc.:

450 mg/kg bw (total dose)

No. of animals per sex per dose / concentration:

All animals were male.
It is not stated how many animals were used. It is stated that radioactivity recovery was calculated for 2 animals treated with 4.5 and 45 mg/kg bw and for 4 animals treated with 450 mg/kg bw.

Control animals:

no

Positive control reference chemical:

no data

Details on dosing and sampling:

Animals were placed individually into metabolism chambers after treatment for sample collection.

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, carcass, blood, CO2, organs: liver, kidney, lung, heart, brain, adrenal glands, fat
- Time and frequency of sampling: urine and faeces 24 hours after dosing; air traps at 4, 8, 12 and 24 after dosing; blood, fat and organs after 4, 8 and 24 hours

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, breath and plasma
- Time and frequency of sampling: breath: air traps were changes at 4, 8, 12 and 24 after dosing; blood: 0.5, 1, 2, 4 and 8 h after dosing with 450 mg/kg bw; urine: 24 h after dosing
- From how many animals: breath and blood: individual; urine: pooled from 4 animals (pH adjusted to 7.0)
- Method type(s) for identification:GC-FID, TLC

Statistics:

If 4 animals were evaluated the mean and standard deviation were calculated.

Results and discussion

Main ADME results

Main ADME results 1

Type:

distribution

Results:

highest concentrations: liver 3.88 % at 8 h, blood 0.74 % at 8 h, kidney 0.24 % at 4 h, other tissue < 0.12 %

Main ADME results 2

Type:

excretion

Results:

Elimination of administered dose 450 mg/kg bw: > 44 % within 4 h, 69.3 % at 8 h, 83.3 % at 24 h

Main ADME results 3

Type:

other: remaining radioactivity in carcass

Results:

at 4 h: 42.2 %; at 8 h: 27.2 %; at 24 h: 12.3 %

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

Values are expressed as the percentage of the dose for four rats.
The highest concentrations of radioactivity were found in the liver (3.88 %) and blood (0.74 %) at 8 h and the kidney (0.24 %) at 4 h. The overall distribution of radioactivity in other tissues (0.12 % and less) was relatively low.

Details on excretion:

Radioactivity was eliminated rapidly in expired air as 14C02. In rats dosed with 450 mg/kg bw over 44 % of the administered dose was eliminated within 4 h; 69.3 and 83.3 % were eliminated at 8 and 24 h, respectively. Urinary radioactivity accounted for 4.4 % of the dose at 24 h. Fecal radioactivity was negligible at 4 and 8 h and was less than 1.0 % of the dose at 24 h.
The radioactivity remaining in the carcass was 42.2 % at 4 h, 27.2 % at 8 h, and 12.3 % at 24 h. The overall recovery of 14C was 86.7% at 4 hr, 99.6 % at 8 h, and 101 % at 24 h. Unchanged n-butanol in expired air accounted for less than 1.0 % of the dose. Rats dosed with 4.5 or 45 mg/kg bw showed a similar excretion pattern to that of rats dosed with 450 mg/kg bw.
The concentration of n-butanol in the plasma of rats dosed with 450 mg/kg bw was examined. The highest concentration of n-butanol was 70.9 µg/ml at 1 h. n-Butanol disappeared from the plasma rapidly and at 4 h was below the limit of detection.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Pooled 24 h urine collections from rats dosed with 450 mg/kg bw were treated with 3 N hydrochloric acid or beta-glucuronidase and then extracted with diethyl ether. The extract was counted and analyzed by gas chromatography. About 75 % of the radioactivity was detected as n-butanol, presumably both as an O-sulfate (44.4 %) and as an O-glucuronide (30.7 %). Urea accounted for the remainder of the radioactivity.
Less than 1 % of the administered dose was excreted unchanged.