Acetone

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: Study meets generally accepted scientific principles, sufficiently documented, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Uptake of highly soluble gases in the epithelium of the conducting airways

Author:

Schrikker ACM, de Vries WR, Zwart A, Luijendijk SCM

Year:

1985

Bibliographic source:

Pflügers Archiv (Europ J Physiol ) 405: 389-394

Materials and methods

Objective of study:

other: absorption and excretion via airways

Principles of method if other than guideline:

Absorption and excretion in expired air during short-term wash-in phase and wash-out phase measured by mass spectrometry

Test material

Test material information

Constituent 1

Reference substance name:

Acetone

EC Number:

200-662-2

EC Name:

Acetone

Cas Number:

67-64-1

Molecular formula:

C3H6O

IUPAC Name:

propan-2-one

Test animals

Species:

human

Strain:

other: healthy unexposed volunteers

Sex:

male

Details on test animals or test system and environmental conditions:

TEST PERSONS
4 male subjects without a history of lung disease, 25-38 years of age

Administration / exposure

Route of administration:

inhalation: vapour

Details on exposure:

TYPE OF INHALATION EXPOSURE: mouth only

GENERATION OF TEST ATMOSPHERE
- Exposure apparatus: Subjects breath through a mouthpiece with unidirectional valves. The inlet of this mouthpiece is connected to a Douglas bag containing air with 0.01 vol% acetone (capacity 200 L) during washin. During washout the outlet of the mouthpiece is connected successively to a pneumotachograph and an open mixing box with room air. The connecting metal tubes, the mouth piece and the sampling system was kept at a constant temperature of 40 °C to avoid loss of expired acetone in condensed water vapour.

Duration and frequency of treatment / exposure:

twelve breaths (wash-in phase) followed by a post-exposure of ten breaths (wash-out phase); subjects at rest or exercise on bicycle ergometer with increasing workloads of 50, 100, and 150 W

Doses / concentrations

Remarks:

Doses / Concentrations:
0.01 vol% corresponding to 100 ppm or 237 mg/m3

No. of animals per sex per dose / concentration:

The 4 subjects experienced all types of exposure scenarios

Positive control reference chemical:

CO2 as reference gas with well-known washout characteristics

Details on study design:

- Experimental phases:
Conditioning time before data acquisition: 2 min
Washin phase during exposure: 2 breaths of room air followed by twelve washin breaths of the acetone atmosphere
Washout phase after termination of exposure: ten washout breaths

- Physical activity:
subjects were sitting on a bicycle ergometer
resting group: without pedalling
exercise groups: pedalling at a rate of about 70 cycles per minute with increasing workloads of 50, 100, and 150 W

Details on dosing and sampling:

Sampling of acetone atmospheres during inhalation and post-inhalation:
During washout the outlet of the mouthpiece was connected successively to a pneumotachograph and an open mixing box with room air.
Air samples were taken at two different locations in the experimental set-up:
- inspired/expired acetone concentrations during washin: immediately behind the connection to the mouth-piece during the first 6 breaths during the washin period
- expired acetone concentrations during washout: immediately behind the connection to the mouth-piece during the washout breaths
- mixed expired acetone concentrations: sampling from the mixing box during the last 3 breaths during the washin period

Quantitative determination of acetone concentrations:
by means of a quadropole mass spectrometer with a short time constant of 45 msec, sample time 10 msec, measuring time interval 40 ms

Determination of expired volume from integrated flow signal from the pneumotachograph, sampling time every 40 msec

Evaluations:
- Expiratory concentration-time curves during washout for determination of the moment of the beginning of phase II and the slope of the alveolar plateau. The CO2 concentration time curve was used as a standard to determine the time interval during which the slopes of the alveolar plateaus could be calculated.
- Excretion values: determined from mixed expired and the inspired gas concentrations during washin

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

during inspiration in wash-in phase: dissolution of acetone in mucous membranes of conducting airways with concentration in proximal airways > distal airways; acetone concentration in airstream decreases continuously during passage down the airways, amount in alveolar space negligible as acetone is drained away very efficiently by perfusing blood, blood/gas partition coefficient 341
during inspiration in wash-out phase: after termination of exposure the concentration maximum of acetone in airway surrounding tissues continuously moves to the distal airways due to evaporation from the mucous membranes into inspired air
during inspiration in wash-in phase: dissolution of acetone in mucous membranes of conducting airways with concentration in proximal airways > distal airways; acetone concentration in airstream decreases continuously during passage down the airways, amount in alveolar space negligible as acetone is drained away very efficiently by perfusing blood, blood/gas partition coefficient 341
during inspiration in wash-out phase: after termination of exposure the concentration maximum of acetone in airway surrounding tissues continuously moves to the distal airways due to evaporation from the mucous membranes into inspired air

Details on excretion:

during expiration in wash-in phase: dissolved acetone evaporates from mucous membranes during passage of the airstream from the alveolar space to the upper airways: effect in distal > proximal airways
during expiration in wash-out phase: the alveolar gas takes up acetone from tissues in distal airways with a relatively high acetone concentration, but will then lose acetone to proximally located tissue where the concentration is relatively low now; the concentration maximum in the mucous membranes continuously moves up the airways so that the amount of expired acetone increases continuously during the later washout phase

Any other information on results incl. tables

Phase I of washout breaths (phase preceeding the beginning of phase II characterized by a steep increase of expired gas concentration):

total expired volume (mean value obtained in 20 experiments with 4 subjects under 5 different workload conditions):

- CO2 (reference): constant volume of about 50 ml

- acetone: continuous increase from 20 ml for the first expiration up to about 35 ml for the ninth expiration

Phase II of washout breaths (phase of increased expiration of gases):

Characterization of expiration by two sub-phases (data for first expiration in washout):

- CO2: sub-phase 1: initial steep increase of expired CO2 concentration corresponded to 20 % of the total duration of phase II; followed by subphase 2 (corresponding to 80 % of the total duration of phase II): phase of slow increase with calculated slope of +11.7 % per sec

- acetone: sub-phase 1: increase of expired concentration appearing earlier and steeper than for CO2 expiration; the acetone concentration was already halfway to its maximal level at the beginning of phase II for CO2; sub-phase 2: slow decline of expired acetone with a negative slope of -20.9% per sec

Slope of the alveolar plateau (mean value):

- CO2: ca. +12% per sec for all washout breaths of the different experimental conditions

- acetone: -20% per sec for the first expiration during wash-out, rapid increase to ca. -5 % per sec up to 3rd expiration, followed by gradual increase up to ca. +5 % up to the 9th expiration

Washin phase - inspiration:

During inspiration acetone is dissolved in the mucous membranes of the conducting airways. The poorly perfused tissue lining of the proximal airways is the first to be exposed to and to retain acetone. As the airflow approaches the distal airways acetone is contained in a lower concentration as compared with inspired gas and as a result, less acetone can be absorbed by the tissue lining the distal airways. At the end of the wash-in period, tissue lining in proximal airways will contain higher concentrations of acetone than in distal airways. The alveolar space will contain only a negligible amount of acetone because it is drained away very efficiently by the perfusing blood due to the large blood solubility of acetone based on a blood/gas partition coefficient of 341.

Washin phase - expiration:

The expired alveolar gas resumes acetone during its passage through the conducting airways as acetone dissolved in the mucous membranes evaporates again during expiration. The concomitant loss of acetone, especially from superficial airway tissue, leads to gradually less acetone being taken up by the expired gas as it continues its passage through the airways. This explains the negatively sloping alveolar plateau for acetone during washin and early washout.

Washout phase - inspiration:

During washout, this process of evaporation from the tissue lining starts at the upper airways were fresh air enters during each inspiration. Inspired air takes up acetone from the tissue of proximal airways and this acetone is thereafter dissolved in the tissue of distal airways where the concentration of acetone is low. As a result, the concentration maximum of acetone in the airway surrounding tissues will continuously move to the distal airways and an area will be created proximal to that maximum where the concentration of acetone is relatively low.

Washout phase - expiration:

Excretion of contaminant gases via the airstream is characterized by a first phase with a relatively low concentration in the airstream (phase I) followed by a second phase with a steep increase of concentration (phase II). The difference in excretion profiles of the reference gas CO2 and of acetone are due to the exchange of acetone between airstream and tissue lining of the airways. During expirations in the washout phase, the alveolar gas first takes up acetone from tissues in distal airways with a relatively high acetone concentration, but will then lose acetone to proximally located tissue where the concentration is relatively low now. Consequently, during phase I the total expired volume of acetone was low with a value of 20 ml for the first expiration increasing up to about 35 ml for the ninth expiration. In contrast, the expired volume was constantly at 50 ml for carbon dioxide. Acetone expired in phase II of washout is due to acetone that is removed from the tissue lining of the upper and larger airways, including the oral cavity. However, during the washout phase the concentration in the proximal tissue will steadily increase and this will involve a continuous increase in the acetone concentration in expired gas resulting in a positive slope of the alveolar plateau in later washout (increase from -20% per sec for the first expiration, rapid increase to ca. -5 % per sec up to 3rd expiration, followed by gradual increase up to ca. +5 % up to the 9th expiration).

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: The time course of uptake and excretion of acetone is characterized by dissolution and resolution processes in the epithelial tissue lining the conducting airways.
A physiological basis for the deviating excretion behaviour of acetone as a highly soluble vapour was detected based on the exhalation profile of short-term inhalation (12 breaths). During exposure (washin phase) acetone is dissolved in the mucous membranes of the airways due to its high water solubility so that the concentration in the airstream decreases more and more during its passage down the respiratory tract. Acetone concentration in the alveolar region is negligible, also because acetone is drained away by the perfusing blood. On its passage up the respiratory tract the expired airstream resumes acetone that evaporates from the lining tissues. After termination of exposure (washout phase), the zone of high tissue concentrations in the proximal poorly perfused airways gradually moves down to the lower respiratory tract as fresh air is inspired. This process is reversed during expirations in later washout, leading to a continuous increase in expired acetone that evaporates from the lining tissues of the upper respiratory tract. Consequently, acetone in expired air originates from the epithelial tissue lining the conducting airways.

Executive summary:

To detect a physiological basis for the deviation of the excretion behaviour of acetone as a highly water soluble vapour, short duration washin and washout experiments were carried out in four male subjects in the presence of 100 ppm (237 mg/m³) acetone at rest or at physical exercise under workloads of 50 -150 W . The washin phase included 12 breaths of acetone atmosphere, the washout phase 10 breaths of fresh air during which acetone concentrations were continuously recorded in expired air. Subjects were also exposed to CO₂ as reference gas with well-known washout characteristics. The differences in excretion profiles of the reference gas CO₂ and of acetone are due to the exchange of acetone between airstream and tissue lining of the airways due to its high water solubility.

During exposure (washin phase), acetone is dissolved in the mucous membranes of the airways. In this way, the concentration in the airstream decreases more and more during its passage down the respiratory tract. Acetone concentration in the alveolar region is negligible, also because acetone is drained away by the perfusing blood due to a blood/gas partition coefficient of 341. However, on its passage up the respiratory tract the expired airstream resumes acetone that evaporates from the lining tissues.

After termination of exposure (washout phase), the zone of high tissue concentrations in the proximal, poorly perfused airways gradually moves down to the lower respiratory tract as fresh air is inspired. This process is reversed during expirations in later washout, as the alveolar gas first takes up acetone from tissues in distal airways with a relatively high acetone concentration, but will then lose acetone to proximally located tissue where the concentration is relatively low now.

During washout concentrations in expired air are characterized by a phase of low concentration, termed phase I, followed by a steep increase of acetone concentration, termed phase II. During phase I the total expired volume of acetone was low with a value of 20 ml for the first expiration increasing up to about 35 ml for the ninth expiration. In contrast, the expired volume was constant at 50 ml for carbon dioxide. Acetone expired in phase II of washout is due to acetone that is removed from the tissue lining of the upper and larger airways, including the oral cavity. As the concentration in the proximal tissue increases steadily this involves a continuous increase in the acetone concentration in expired gas indicated by a positive slope of the alveolar plateau in later washout (increase from -20% per sec for the first expiration, rapid increase to ca. -5 % per sec up to 3rd expiration, followed by gradual increase up to ca. +5 % up to the 9th expiration).

Consequently, acetone in expired air originates from the epithelial tissue lining the conducting airways.