Butanone

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

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 Type:

publication

Title:

Dose-dependent kinetics of inhaled methylethylketone in man

Author:

Liira, J., Johanson, G., & Riihimaki, V.

Year:

1990

Bibliographic source:

Toxicology letters, 50(2-3), 195-201

Materials and methods

Study type:

study with volunteers

Endpoint addressed:

basic toxicokinetics

Principles of method if other than guideline:

- Principle of test: Inhalation kinetics in human volunteers
- Short description of test conditions: volunteers were exposed for 4 hours on three separate days at least one week apart. Volunteers were exposed to MEK alone, or to MEK before or after ingestion of alcohol.
- Parameters analysed / observed: blood concentration was measured during and after three 4-hour exposure periods. Exhaled air was sampled during and after exposure. Urine samples were obtained every two hours during and every four hours after the exposure period. Analysis: methyl ethyl ketone (MEK), ethanol and the reversible intermediate metabolite 2-butanol in blood. MEK and the metabolite 2,3-butanediol (2,3-BD) in urine. MEK in exhaled air. Area under the curve (AUC) and clearance were calculated.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Butanone

EC Number:

201-159-0

EC Name:

Butanone

Cas Number:

78-93-3

Molecular formula:

C4H8O

IUPAC Name:

butan-2-one

Method

Type of population:

other: Healthy students

Subjects:

- Number of subjects exposed:
- Sex: Male
- Number: 5.
- Race: no information
- Demographic information: all were students; no other demographic information
- Known diseases: all were healthy

- Age: 22 - 24 years (mean 23),
- Weight 63 to 77 kg (mean 70.2),
- Height 165 to 185 cm (mean 180)
- Mean minute ventilation in sedentary activity: approximately 11 litres/min (assumed, based on Liira, 1988)

Ethical approval:

confirmed and informed consent free of coercion received

Remarks:

"The principles of the Declaration of Helsinki concerning human medical studies were strictly followed and the study program was accepted by the ethical committee of the Institute Of Occupational Health. The study subjects gave their informed consent."

Route of exposure:

inhalation

Reason of exposure:

intentional

Exposure assessment:

measured

Details on exposure:

- Route of administration: inhalation: vapour
- Duration and frequency of treatment / exposure: 4-hour exposure period on three separate days at least 7 days apart
- Concentration: 200 ppm, 8.2 mmol/m³, equivalent to 592 mg/m³ based on m. wt 72.1057. Mean measured concentration 203 ± 3, range 178-227

Examinations:

- Urine analysis: yes, analysed for test substance methyl ethyl ketone (MEK) and metabolite 2,3-butanediol (2,3-BD)
- Haematology: yes, analysed for test substance, methyl ethyl ketone (MEK) and reversible intermediate metabolite 2-butanol

Medical treatment:

None

Results and discussion

Outcome of incidence:

The pulmonary retention of MEK in the lungs remained constant throughout exposures with or without exercise.
The relative uptake varied between 46.0% and 55.8%
Blood concentration of MEK increased from approximately 12 µmol/l to approximately 60 µmol/l from start to end of the 4-hour exposure, returning to approximately 5 µmol/l at 8 hours after end of exposure.
Blood concentration of 2-butanol, a reversible metabolite of MEK, increased from approximately 0.5 µmol/l to approximately 2 µmol/l from start to end of the 4-hour exposure, returning to approximately 5 µmol/l 4 hours after the end of exposure.
Blood concentration of 2,3-BD reached a maximum of approximately 50 µmol/l one to three hours after the end of the 4-hour exposure, returning to approximately 2 to 3 times initial levels 8 hours after end of exposure.
Less than 1% of the absorbed dose of MEK was eliminated by exhalation.
Less than 1% of the absorbed dose of MEK was eliminated in the urine, as most MEK is metabolised to 2,3-butanediol (2,3-BD).
Excretion of 2,3-BD increased for more than 4 hours after the end of exposure, then decreased over the next 16 hours.

Any other information on results incl. tables

Mean toxicokinetic parameters (mean ± SD unless otherwise indicated)

Parameter	Value
Pulmonary retention (%)*	55.8 ±9.1
Pulmonary uptake of MEK (mmol)*	12.0 ± 2.0
AUC (µmol x min/l)*	23400 ± 8300
Apparent clearance (l-min)*	0.60 ± 0.31
Pulmonary excretion of MEK (mmol)**	0.34 ± 0.16 (2.8%)
Urinary excretion of MEK (µmol) **	26.7 ± 9.6 (0.2%)
Urinary excretion of 2,3-butanediol (pooled samples) (µmol) **	426 (3.5%)

* Exposure to 200 ppm MEK for four hours

** Excretion of MEK and 2,3-BD over 24 hours during and after exposure to 200 ppm MEK for four hours. Figures in parentheses are in percentages of total pulmonary uptake of MEK.

Applicant's summary and conclusion

Conclusions:

The relative uptake of MEK in human volunteers exposed via inhalation for 4 hours at 200 ppm was 55.8%.
Metabolism: 2-Butanol is a reversible intermediate metabolite of MEK. 2,3-butanediol (2,3-BD) is the final metabolite.
Excretion of MEK via inhalation: less than 1% of absorbed dose.
Excretion of MEK via urine: less than 1% of absorbed dose.
Excretion of 2,3-BD via urine: 3.5% of absorbed dose.