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Toxicological information

Sensitisation data (human)

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Administrative data

Endpoint:
sensitisation data (humans)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
other: not rated
Rationale for reliability incl. deficiencies:
other: Well and detailed documented study.

Data source

Reference
Reference Type:
publication
Title:
The Roles of pH and Ionic Species in Sulfur Dioxide- and Sulfite-Induced Bronchoconstriction.
Author:
Fine, J.M. et al.
Year:
1987
Bibliographic source:
Am. Rev. Respir. Dis. 136: 1122-1126

Materials and methods

Type of sensitisation studied:
respiratory
Study type:
study with volunteers
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
A study was performed to access the relative brochoconstriction potency of the different chemical forms of sulfite at various pH values. 10 asthmatic subjects inhaled sodium sulfite aerosols through a mouthpiece in 6 concentrations (0.03, 0.1, 0.3, 1.0, 3.0 and 10.0 mg/ml) at 3 levels of pH (pH 4.0, 6.6 and 9.0) for 1 min in 10 min intervals. The different pH levels were tested on 3 subsequent days. Concentration-response curves of specific airway resistance before and after inhalations were performed. Furthermore, the role of acidity was determined by buffered acetic acid aerosols.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): sodium sulfite

Method

Type of population:
other: general, only asthmatics
Ethical approval:
confirmed, but no further information available
Subjects:
- Number of subjects exposed: 10 nonsmoking volunteers
- Sex: males and females
- Age: 22 – 34 years old
- Race: North American
- Other:
Clinical history:
- all subjects had asthma, as defined by a history of recurrent episodes of wheezing, chest tightness, and reversible airway obstructions
- no subject took theophylline or sympathomimetric drugs within 12 h or consumed caffeine within 4 h before any experiment.
- no subject gave a history suggestive of sensitivity to ingest sulfite preservative
Controls:
no data
Route of administration:
inhalation
Details on study design:
- first, the effects of inhaled sodium sulfite were compared delivered at 3 different levels of pH: pH 9 was chosen to study the effects of sulfite ion (SO32-) in the absence of significant amounts of SO2 or bisulfite (HSO3-); pH 6.6 was chosen to study the effects of bisulfite – in addition pH 6.6 is the recorded pH of human airways; pH 4, since SO2 generation increases by more than 2 orders of magnitude compared to pH 6.6.
- To test the role of change in airway pH as would be induced by release of hydrogen ions by dissolved SO2 and sulfites, the bronchoconstriction effects of buffered acetic acid aerosol matched with sulfite pH 4 were also studied.
- each subject was tested on 7 separate days; concentration response curves were performed to methacholine on the first day and to inhaled sodium sulfite aerosol at the three different pHs on 3 subsequent days- the buffered acetic acid aerosol was tested on another day
- the challenges were performed in single-blind fashion
- to exclude “specific sulfite sensitivity” an oral metabisulfite challenge was also performed on each subject – sensitivity to SO2 was also tested
- the subjects inhaled increasing concentrations of aerosolized Na2SO3 at each pH during 1 min of tidal breathing
- bronchoconstrictor response was assessed by measuring specific airway resistance (SRaw) before and after each challenge

A detailed method description is provided in the original paper.

Results and discussion

Results of examinations:
-9/10 subjects developed significant bronchoconstriction (SRaw > 100 % above baseline) after sulfite inhalation at all 3 levels of pH during increasing concentrations; a 100 % increase in SRaw occurred at the lowest sulfite concentration at pH 4 and at the highest concentration at pH 9
- the mean values for PC100 (100 % increase in Sraw) were 0.17 mg/mL at pH 4, 0.49 mg/mL at pH 6.6 and 2.10 mg/mL at pH 9.0 and were significantly different. The bronchoconstriction effects were clearly pH-dependent.
- The one who did not develop bronchoconstriction at any pH was also the only one who did not develop bronchoconstriction after inhaling as much as 8 ppm SO2

Applicant's summary and conclusion

Conclusions:
The results of this study confirm that inhaled sulfite aerosols are a stimulus to bronchoconstriction in subjects with asthma. The bronchoconstrictor effects of sodium sulfite aerosols were clearly pH-dependent, with the greatest effect occurring at the most acid pH (pH 4). However the acidity itself seems not to be the stimulus in this study. Between the two ionic forms of sulfite the results suggest that bisulfite is either the more potent or the only bronchoconstrictor stimulus.