Registration Dossier

Toxicological information

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
between 1982 and 1988
Reliability:
other: not rated
Rationale for reliability incl. deficiencies:
other: Well-reported test with clinical patients. However test substance not clearly defined: cation was not stated.

Data source

Reference
Reference Type:
publication
Title:
Aspirin, Salicylate, Sulfite and Tartrazine induced Bronchoconstriction safe doses and case definition in Epidemiological Studies.
Author:
Corder, E.H.; Buckley, C. E.
Year:
1995
Bibliographic source:
J. Clin. Epidemiol. 48, 1269-1275

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
immunotoxicity
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
A tertiary referral clinic population was used in the study to estimate safe exposure doses for epidemiological studies. 2046 patients were tested in an oral challenge test with metabisulfite (cation not stated). The oral challenge consisted of administration of sequential increasing doses of the test compound followed by measurement of air volume and flow 30-40 minutes later until a positive test was detected or the highest dose (0.02, 0.2 and 2.0 mM) in the test sequence had been administered. A 15% decrease in the amount of air expired in one second was defined as a positive response.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): metabisulfite
- Molecular formula (if other than submission substance): HSO3-

Method

Type of population:
other: tertiary referral clinic population
Subjects:
- Number of subjects exposed: 2046 exposed to metabisulfite, 1442 exposed to tartazine, 632 exposed to aspirine, 307exposed to salicylate
- Sex: 72. 7 % females
- Age: mean 52.9, SD 17.8, range 13-85
- Race: 89.6 % white
- Demographic information:
- Known diseases:
- Other: Patients were asked not to use inhaled or oral bronchodilators and theophylline on the day of the test
Ethical approval:
confirmed, but no further information available
Route of exposure:
oral
Reason of exposure:
intentional
Exposure assessment:
not specified
Details on exposure:
The test compound was administered orally in capsules.
Examinations:
- During the interval between 1983 until 1990 sham placebo challenges with 2 or more doses of encapsulated d-sorbitol were requested in 273 patients. The placebo challenges were used to estimate the maximum contribution of false positive reactions to the oral chemical challenges.

Oral chemical challenges:
- Baseline measurements of air volume and flow were made before ingestion of the first test capsule using standard spirometric methods.
- Patients were encouraged to inhale deeply and exhale completely as fast as possible during forced expiration. The best of 3 or more efforts was recorded. Air volume and flow were expressed as a percentage of that expected for persons of the same age, weight, sex and height, the predicted normal (PN).
- The oral challenge consisted of administration of sequential increasing doses of the test compound followed by measurement of air volume and flow 30 – 40 min later until a positive test was detected or the highest dose in the test substance had been administered.
- A four dose sequence with 0.01, 0.1, 1.0 and 2.0 mM of the test compound was used initially until experience with the safety of the test method revealed that a 0.02, 0.2, and 2.0 mM dose sequence could be used.
- All challenge tests were completed within 4 h.
- The fraction of the forced expired volume in one second (FEV1) and the time needed to exhale between 25 and 75 % of the forced expired volume (FEF25-75) were measured. Percent changes from baseline were calculated as %=100% x [(Post-challenge measurement/baseline measurement) – 1.0], where each measurement is a percentage of the PN. A test was considered positive if there was at least a ≥15% drop in FEV1 from baseline at the highest dose tested.

Results and discussion

Results of examinations:
-236 (11.5 %) oral challenges with metabisulfite were positive.
- median effective dose and 95 % confidence limits for metabilsulfite [mM]: (i) FEV1 covariate: ED50 = 0.193; confidence interval = 0.135 – 0.274; (ii) FEF25-75 covariate ED50 = 0.188; confidence interval = 0.131 – 0.269
- Interestingly, the use of this method and model for metabisulfite revealed a significant lack of fit when applied without a simultaneous evaluation of a measure of baseline respiratory function. Inclusion of either the baseline FEV1 or FEF25-75 yielded models with good fit. Specification of higher and lower false positive rates resulted in similar median dose estimates for metabisulfite [mM]: (i) 0 % false positives: ED50 = 0.155; confidence interval = 0.104 – 0.232; (ii) 12 % false positives: ED50 = 0.215; confidence interval = 0.153 – 0.302
- The compound doses needed to provoke acute changes in the air ways in the most susceptible patients (ED5) and in almost all apparent reactors (ED95) are for metabisulfite (n=236): i) ED5: 4.6 mg; 0.026 mM; confidence interval = 0.012 – 0.055 mM; (ii) ED95: 255.8 mg;1.440 mM; confidence interval = 0.970 – 2.110
- The median effective dose of metabisulfite was inversely related to the magnitude of decrement in the FEV1. A highly significant decrease in median effective dose (increased sensitivity) for each percent increase in severity of the FEV1 response to the compound was revealed. The baseline pulmonary function was typically lower among patients with 10-14 % induced decrements (91 %PN FEV1, 70 % PN FEF25-75) than on patients with a 20 % or greater induced decrement (98 % PN FEV1, 79 % PN FEWF25-75).

Applicant's summary and conclusion

Conclusions:
Doses to which the most sensitive (5%) and practically all (95 %) susceptible persons might respectively respond are: metabisulfite 4.6 mg, 255.8 mg.