Citric acid

Exposure related observations in humans: other data

Administrative data

Endpoint:

exposure-related observations in humans: other data

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

publication

Title:

Importance of Inspiratory Flow Rate in the Cough Response to Citric Acid Inhalation in Normal Subjects

Author:

Barros, M.J., Zammattio, S.J., Rees, J.P.

Year:

1990

Bibliographic source:

Clinical Science, 78 (5), p 521-525

Materials and methods

Type of study / information:

Experiment in human volunteers

Endpoint addressed:

respiratory irritation

other: assessment of tussigenic potential (cough induction)

Principles of method if other than guideline:

Measurement of cough response and inspiratory flow rate after exposure to nebulised solution of substance

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Citric acid

EC Number:

201-069-1

EC Name:

Citric acid

Cas Number:

77-92-9

Molecular formula:

C6H8O7

IUPAC Name:

2-hydroxypropane-1,2,3-tricarboxylic acid

Method

Ethical approval:

confirmed, but no further information available

Details on study design:

The cough response to citric acid is produced mainly by irritation of the larynx and trachea. Variations in the inspiratory flow rate might lead to changes in deposition of the drug, and consequently in the cough threshold.
The effect of inspiratory flow rate was studied in 11 healthy non-smoking volunteers aged 23 to 29 years (9 male, 2 female).
The test substance was administered by inhalation of a nebulised solution via apparatus which limited and measured the inspiratory flow rate to 50, 100 and 150 l/minute of increasing concentrations of citric acid.
The test was finished when a cough was produced after each inhalation at one concentration (cough threshold) or the maximum concentration was reached. Each concentration was given at three different flow rates. The exposures were repeated on 3 days at least 48 hours apart.

Exposure assessment:

estimated

Details on exposure:

TYPE OF EXPOSURE: inhalation

TYPE OF EXPOSURE MEASUREMENT: not stated

EXPOSURE LEVELS: 2.5, 5.0, 10, 20, 40, 80, 160, 320 and 640 mg/l

EXPOSURE PERIOD: Three inhalations (residual volume to total capacity) at each concentration, 1 minute apart. A 3-minute interval separated concentrations.

POSTEXPOSURE PERIOD: All coughs up to 30 seconds after the beginning of each inhalation were registered.

DESCRIPTION / DELINEATION OF EXPOSURE GROUPS / CATEGORIES: flow rates limited to 50, 100 and 150 l/min.

Results and discussion

Results:

The mean (SD) inspiratory flow rates achieved were 51.4 (5.3). 86.2 (16.6) and 134.4 (22.9) l/minute.
The geometric mean (97% confidence intervals) cough threshold:
21 (9-54) mg/l at an inspiratory flow rate of 50 l/min and 43 (13-141) mg/l at 150 l/min (P<0.05).
The amount of substance tolerated before the cough threshold was achieved:
5.2 (2.0-13.8) mg at an inspiratory flow rate of 50 l/min and 11.6 (3.4-39.8) mg at 150 l/min (P<0.05).
The number of coughs per inhalation:
1.6 (1.1-2.0) at an inspiratory flow rate of 50 l/min and 1.1 (0.7-1.5) at 150 l/min (P< 0.05).

Applicant's summary and conclusion

Conclusions:

When healthy, non-smoking human volunteers were challenged with nebulised citric acid solution, a greater cough stimulus was observed at lower inspiratory flow rates. It is concluded that inspiratory flow rate should be controlled when cough challenges with citric acid are performed.

Executive summary:

A study was conducted to evaluate the effect of inspiratory flow rate on the cough response to citric acid (Barros et.al., 1990.) It is considered by the authors that the cough response to citric acid is produced mainly by irritation of the larynx and trachea. Variations in the inspiratory flow rate might lead to changes in deposition of the drug, and consequently in the cough threshold.

The effect of inspiratory flow rate was studied in 11 healthy non-smoking volunteers aged 23 to 29 years (9 male, 2 female). The test substance was administered by inhalation of a nebulised solution via apparatus which limited and measured the inspiratory flow rate to 50, 100 and 150 l/minute of increasing concentrations of citric acid.

The test was finished when a cough was produced after each inhalation at one concentration (cough threshold) or the maximum concentration was reached. Each concentration was given at three different flow rates. The exposures were repeated on 3 days at least 48 hours apart.

The mean cough threshold was determined to be 21 (±9-54) mg/l at an inspiratory flow rate of 50 l/min and 43 (±13-141) mg/l at 150 l/minute. It was concluded that inspiratory flow rate should be controlled when cough challenges with citric acid are performed.