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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
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.Test procedure in accordance with generally accepted scientific standards, old study described in sufficient detail, specific investigation of concentration and time-dependence of retention of sulfur dioxide; study acceptable for assessment
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Pulmonary dynamics and retention od toxic gases.
Author:
Leong, K.J. and MacFarland, H.N.
Year:
1965
Bibliographic source:
Arch. Environ. Health 3: 668-675

Materials and methods

Objective of study:
other: specific investigation of retention in the respiratory tract
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Test procedure in accordance with generally accepted scientific standards, old study described in sufficient detail, specific investigation of concentration and time-dependence of retention of sulfur dioxide; study acceptable for assessment
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
no details stated

Test animals

Species:
rat
Strain:
Wistar
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 190-210 g
no further information stated

Administration / exposure

Route of administration:
inhalation
Vehicle:
other: air
Details on exposure:
TYPE OF INHALATION EXPOSURE: head only (muzzle)

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: a specially designed apparatus for the measurement of minute volume and analytical device for the continouos measurement of sulphur dioxide
- System of generating particulates/aerosols: The main gas supply tube, through which the animal breathes, is fed at a constant rate with air containing a known concentration of the toxicant. Pure air and air containing about 8000 ppm of SO2 are proportioned through two by-pass flow regulators and the final mixture is metered by means of a third regulator directly into the main gas tube. In this manner, a steady flow of SO2 in air in concentration range 0 to 1000 ppm is readily obtained.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): not stated
Duration and frequency of treatment / exposure:
Physiological and analytical data were recorded simultaneous for a period of two hours.
Doses / concentrations
Remarks:
Doses / Concentrations:
Gas concentrations ranging from 40 to 750 ppm. Measured concentration: 41 +/- 2 ppm, 64 +/- 4 ppm, 83 +/- 2 ppm, 145 +/-1 ppm, 231 +/- 3 ppm, 426 +/- 4 ppm and 751 +/- 17 ppm.
No. of animals per sex per dose:
Seven groups of ten rats were exposed.
Control animals:
yes
Details on study design:
The values for percent retention of sulfur dioxide by an individual rat at designated time-points (after 1, 5, 10, 30, 60, 90, 120 min.) were calculated. These values together with the minute volume, respiratory rate, and the calculated tidal volume (minute volume divided by respiratory rate) at the corresponding time-point, were then subjected to an analysis of variance and a range test for significant differences shown in treatment and time effects.
Experimental procedure: After all instruments were calibrated, the experimental animal was inserted into the holder with its muzzle projecting through a face mask. The animal was allowed to rest for a short time before the mask outlet was coupled onto the main gas supply tube.
Histological Method: At the end of the tow-hour exposure, following a short period of observation, the animals were anesthetised with pentobarbital and the lungs were removed for histological examination. Lungs from all animals in each trial were prepared as follows: the anterior portion of the trachea was tied off and the lungs distended to normal size by injection of Bouin's fixative. The trachea was then tied again below the point of injection. After embedding and cutting, the sections were stained with Harris' hematoxylin and eosin, and mounted slides were prepared according to standard procedure.

Results and discussion

Preliminary studies:
Respiratory pattern in those animals exposed to 40 to 400 ppm of SO2 was occasionally rather erratic. The respiration of animals undergoing an inhalation exposure to the high concentration (750 ppm) of the irritant became grievously laboured.

Retention of sulfur dioxide (difference between sulfur dioxide concentration in inspired and exspired airstream determined as percentage of inhaled dose):
Concentration-dependence: decrease from 60.2% at 41 ppm to 34.6% at 751 ppm (measured after 1 minute).
Time-dependence: maximum retention at the beginning of exposure (1 min); with increasing time there was a tendency to a slight decrease of retention: at 41 ppm 60.2% retention at 1 min, 51.8% at 120 min; at 751 ppm 34.6% retention at 1 min, 27.2% at 120 min exposure

Histological findings: a positive correlation between the frequency of occurence of pulmonary damage and the concentration of SO2. 70% to 80% of the lungs from rats exposed respectively to 426 to 751 ppm of the gas showed various degrees of pulmonary edema. 10% to 30% of the specimens from groups of animals subjected to low levels (60 to 200 ppm) of SO2 demonstrated similar types of lesions. Non of the lungs of the animals from 40 ppm and the control groups had observable adverse histological changes.
Main ADME results
Type:
other: retention
Results:
The experimental data suggested an exponential relationship allowing extrapolation of retention for lower sulfur dioxide concentrations.

Metabolite characterisation studies

Metabolites identified:
no

Any other information on results incl. tables

Table 1: Mean values of percent retention with standard deviations of rats exposed to different concentrations of sulphur dioxide.

SO2 concentration (ppm)

Time (min)

1

5

10

30

60

90

120

A - 41 ± 2

60.2 ± 6.2

52.7 ± 14.2

57.8 ± 11.5

52.3 ± 8.7

53.4 ± 7.8

54.5 ± 8.6

51.8 ± 11.6

B - 64 ± 4

55.8 ± 11.8

52.1 ± 11.1

53.3 ± 12.2

52.5 ± 9.1

47.6 ± 12.6

45.9 ± 15.5

45.3 ± 19.4

C - 83 ± 2

51.9 ± 7.8

47.8 ± 10.9

48.9 ± 8.2

45.3 ± 7.9

47.7 ± 8.6

39.9 ± 10.4

37.5 ± 12.6

D - 145 ± 1

44.1 ± 7.2

38.9 ± 8.8

39.6 ± 7.7

37.8 ± 14.7

38.9 ± 13.0

37.9 ± 11.5

38.3 ± 8.4

E - 231 ± 3

39.5 ± 16.4

39.7 ± 12.6

39.9 ± 12.0

40.8 ± 13.3

33.2 ± 13.3

35.5 ± 6.3

36.7 ± 7.3

F - 426 ± 4

36.4 ± 12.3

37.7 ± 8.7

33.3 ± 8.7

37.4 ± 12.1

29.2 ± 12.3

33.4 ± 11.1

27.9 ± 7.5

G - 751 ± 7

34.6 ± 9.9

33.4 ± 11.0

30.9 ± 10.2

27.8 ± 9.7

25.0 ± 9.7

27.2 ± 11.6

27.2 ± 11.8

Applicant's summary and conclusion

Conclusions:
The capacity of the respiratory system of rats to retain sulfur dioxide was inversely related to the exposure concentration (range 41 to 751 ppm). Decreasing retention in the lower concentration range was suggested to correlate with increasing bronchoconstriction changing the absorptive conditions. The experimental data suggested an exponential relationship allowing extrapolation of retention for lower sulfur dioxide concentrations. Based on this extrapolation retention at the 1 ppm level would be anticipated to be about 93%.
In contrast, at high concentrations the absorptive processes may be interfered by significant accumulation of bronchial secretions and development of pulmonary edema. These mechanisms may also play a role for the observed slight diminution of retention with exposure time increasing up to 120 min.