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Acute Toxicity: inhalation

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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
npt specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Entry adopted from the OECD SIAR on sulfur dioxide without modification. Study meets generally accepted scientific principles, sufficient documentation; specific investigation on time-course of airway hyperreactivity and inflammatory changes in BAL after exposure to high concentration; study acceptable for assessment.

Data source

Reference
Reference Type:
publication
Title:
Acute transient SO2-induced airway hyperreactivity: effects of nedocromil sodium
Author:
Jackson D. M. & Eady R. P.
Year:
1988
Bibliographic source:
J Appl Physiol 65: 1119 - 1124.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Study meets generally accepted scientific principles,sufficient documentation; specific investigation on time-course of airway hyperreactivity and inflammatory changes in BAL after exposure to high concentration; study acceptable for assessment
GLP compliance:
not specified
Test type:
other: inflammatory changes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
gas
Details on test material:
- Name of test material (as cited in study report): Sulphur dioxide
- Physical state: gaseous

Test animals

Species:
dog
Strain:
other: beagle
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: ca. 10 kg

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure:
other: endotracheally intubated, artificially respired
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Palmer constant-volume pump, intubation tube
- Method of holding animals in test chamber: anesthetized and laying supine
- Source and rate of air: artificially respiration (12 mL/kg at a rate of 20 breaths/min)

TEST ATMOSPHERE
- Brief description of analytical method used: air flow measured with a Fleisch pneumotachograph (type 0:1 mm H2O) and a Furness Controls micromanometer (1-0-1 cm H2O). Tidal volume was obtained by electrical integration of flow signal. An esophageal ballon was used to estimate intrapleural pressure and transpulmonary pressure was measured with a Furness Controls micrometer (10-0-10 cm H2O).
- Total lung resistance and dynamic lung compliance were measured by a manual graphic method.
- Samples taken from breathing zone: yes, air SO2-air mixture was analysed with a Drager gas sampling system
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
2 h
Concentrations:
400 ppm SO2 in the air (12 mL/kg at a rate of 20 breaths/min)
No. of animals per sex per dose:
4
Control animals:
yes
Details on study design:
- dogs were sedated with thiopental sodium (5-10 mg/kg iv), the anesthetized with chloralose (80 mg/kg iv), intubated (0-mm tube). Supplementary chloralose was given when required. Lung reactivity was assessed using histamine aerosols. A section of the right lung was lavaged. 100 breaths of an aerosol generated from either saline or 2 % nedocromil sodium were given. 15 min after that, SO2 air mix was administered. 15 min after dosing again 100 breaths of one of the aerosols was given to the dogs. After lung recovery a lavage at the same site as before was performed. Lungs were tested for reactivity and a lavage was performed at 1, 2, 3 and 4 h after exposure to SO2. Atropine was given on the peak of bronchoconstriction induced by histamine aerosol at 4 h to assess the atropine-sensitive component of the bronchoconstriction.
- Duration of observation period following administration: 4 h
- Necropsy of survivors performed: yes, the dogs were killed after the last histamine challenge with pentobarbital sodium
- Other examinations performed: bronchoscopy, lung lavage (tube in the third an d fourth generation bronchus), measurement of lung reactivity, lungs and trachea were blocked into wax and cut into slices and stained. Sections were evaluated for the infiltration of macrophages, polymorhonuclear leukocytes and lymphocytes into the alveoli and the epithelium, lamina propria and submucosa of the large and small airways, general histological assessment

- no further details stated
Statistics:
A two tailed Student's t test for independent values was used to test the significance of the difference in mean values between the two groups (saline treated vs. nedocromil treated). Differences that produced P<0.05 were accepted as significant.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LC0
Effect level:
> 400 ppm
Based on:
test mat.
Exp. duration:
2 h
Mortality:
- no mortality during 4 h post exposure
Clinical signs:
other: - SO2 exposure caused an immediately but transient increase in lung reactivity to histamine aerosol - lungs were most reactive immediately after exposure and after 2 h lung reactivity had returned to control level - immediately after exposure to SO2 total
Body weight:
not specified
Gross pathology:
not specified
Other findings:
- Histopathology: moderate to severe damage to airway epithelium in all animals; the larger airways were more severely affected than the smaller ones

Any other information on results incl. tables

Table 1: Cell counts in lung lavages, Values are means, expressed as no. of cells x 1000/ml of lavage fluid recovered

.

.

Lymphocytes

Macrocytes

Eosinophils

Goblet Cells

Mast Cells

Control

Saline

5±3.5

25±8

2±1

1.2±12

0.4±0.2

Nedocromil sodium

8±3

30±13

5±5

0

0

0.25 h

Saline

4±2

24±8

7±6

18.5±14

16±12

Nedocromil sodium

3±1

19±7

30±24

0

0

1 h

Saline

11±3

64±18

25±15

1.7±1

1.5±1

Nedocromil sodium

12±6

58±18

73±46

0

1.4±1

2 h

Saline

22±9

67±23

40±26

2±1

5±4

Nedocromil sodium

8±4

38±12

54±27

0

2±1

3 h

Saline

0

83±35

19±19

2±2

0

Nedocromil sodium

2±3

39±26

44±64

0

0

4 h

Saline

6±6

120±55

5±3

0

0

Nedocromil sodium

10±13

74±65

20±22

0

0

- Respiratory function parameters: total lung resistance increased, dynamic lung compliance decreased at termination of exposure
- Airway reactivity: increased reactivity to histamine challenge up to 1 h post exposure, fully reversible within 2 h
- Pulmonary inflammation (cells in lung lavage at different timepoints post exposure): significant increases of total cells and neutrophils:immediate increase, continuously rising with maximum at 3-4 h, neutrophils representing 90 % of cells; significant increases of epithelial cells: maximum increase up to 1 h, reversible within 3 h

Exposure of dogs to 400 ppm sulfur dioxide for 2 hours caused an immediate increase of bronchial responsiveness to histamine that lasted for about 2 hours post-exposure. Cell numbers in BAL were increased up to 1 hour for epithelial cells and from 1-4 hours for neutrophils. There was no significant change of lymphocytes, macrophages, eosinophils, goblet cells, or mast cells in lavages.

Applicant's summary and conclusion

Conclusions:
Exposure of dogs to 400 ppm sulfur dioxide for 2 hours caused an immediate increase of bronchial responsiveness to histamine that lasted for about 2 hours post-exposure. Cell numbers in BAL were increased up to 1 hour for epithelial cells and from 1-4 hours for neutrophils. There was no significant change of lymphocytes, macrophages, eosinophils, goblet cells, or mast cells in lavages.