Registration Dossier

Toxicological information

Repeated dose toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Entry adopted from the OECD SIAR on sulfur dioxide without modification.Concerning the investigated endpoints the study is comparable to a guideline study: well documented, adequate number of exposed animals, appropriate exposure and post-exposure periods; specific investigation of body and lung weight, histopathology of lung and nose and particle clearance at a single low concentration; study acceptable for assessment.

Data source

Reference
Reference Type:
publication
Title:
Effects of repeated inhalation exposures to 1-nitropyrene, benzo[a]pyrene, Ga2O3, particles and SO2 alone and in combinations on particle clearance, bronchoalveolar lavage fluid composition, and histopathology.
Author:
Wolff, R.K. et al.
Year:
1989
Bibliographic source:
J Toxicol Environ Health 27: 123 - 138.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Concerning the investigated endpoints the study is comparable to a guideline study: well documented, adequate number of exposed animals, appropriate exposure and post-exposure periods; specific investigation of body and lung weight, histopathology of lung and nose and particle clearance at a single low concentration; study acceptable for assessment.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): sulfur dioxide

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: from the Institute's breeding colony
- Age at study initiation: 7-8 weeks
- Housing: Rats were housed and maintained in two types of facilities. Before and after inhalation exposure periods they were hosed one or two per cage in polycarbonate cages with hardwood chip bedding and filter caps.
- Diet: ad libitum, Lab Blox, Allied Mills, Chicago
- Water: ad libitum
- Acclimation period: 1-2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 30-50
- Photoperiod: 12 hours dark/light cycle

No further details are given.

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
nose only
Vehicle:
other: air
Remarks on MMAD:
MMAD / GSD: no data
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Method of holding animals in test chamber: For the conduct of all inhalation exposures, rats were maintained in carcinogen exposure units, which each contained both wire mesh caging for housing up to 80 rats and an 80-port nose-only exposure chamber. For the majority of the time, rats were resident in the wire mesh cages with food available ad libitum. Water was also available, ad libitum, from automatic water valves.
- System of generating particulates/aerosols: SO2 was generated by dilution in air of 1% SO2 delivered from a compressed gas cylinder and metered by a mass flow controller.
- Method of particle size determination: Particle exposure concentrations were detremined by weighing filter samples taken throughout each 2-hour exposure.
No further details are given.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations were monitored continuously with a Beckman SO2 analyser.
Duration of treatment / exposure:
4-week exposure
Frequency of treatment:
2 hours/day, 5 days/week
Doses / concentrations
Dose / conc.:
5.2 ppm (analytical)
Remarks:
SD: ± 0.6 ppm
No. of animals per sex per dose:
Groups of 3 male and 3 female rats were exposed.
Control animals:
yes
Details on study design:
Groups of rats were exposed to atmospheres of pure 1-nitropyrene (NP) aerosol (7.5 mg/m^3) and to these same compounds adsorbed to Ga2O3 particles (27 mg/m^3) both with and without co-exposure to 5 ppm SO2. Rats were also exposed to SO2 alone.
There were 80 rats per exposure group (equal numbers of males and females). The SO2 concentration was set at 5 ppm. This is the short-term industrial threshold limit value (American Conference of Governmental Industrial Hygienists, 1987).
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations:

FOOD CONSUMPTION: No data

FOOD EFFICIENCY: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER: Lung weight
Sacrifice and pathology:
HISTOPATHOLOGY: Yes
Groups of rats were sacrificed for histopathologic evaluations 1 day, 2 weeks, 2 months, 6 months and 12 months after the exposure period by exsanguination while under halothane anesthesia. The right lung was examined and then taken for lung analysis of the gallium oxide burden. The left lung was intratracheally perfused to normal inflation with fixative. Nasal sections were examined because they were also an initial deposition site. Trimmed tissues were embedded in paraffin, sectioned at 5 µm, and stained with haematoxylin and eosin. Slides were examined by light microscopy. Morphologic changes were identified and graded for their severity in each rat.

GROSS PATHOLOGY: No data
Other examinations:
no data
Statistics:
Analysis of variance using repeated measures and fractional factorial analysis was used to determine if there were significant effects of grouping factors of exposure to SO2 on body weight, lung weight, lung burdens or clearance of radiolabelled tracer particles..
The criterion for statistical significance was p<0.05.

Results and discussion

Results of examinations

Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Details on results:
BODY WEIGHT AND WEIGHT GAIN
There was no significant difference in body weight among the groups either before or at any time after the cessation of the 4-week exposure (data not shown).

ORGAN WEIGHTS
Lung weights of exposed rats were similar to those of controls 12 months after exposure.

HISTOPATHOLOGY:
There were no significant lung lesions in any of the experimental groups at any time after exposure to SO2. No significant lesions were found in the nasal cavities of rats in any of the experimental groups.

No further details are given.

Effect levels

Dose descriptor:
NOAEL
Effect level:
5 ppm
Sex:
male/female
Basis for effect level:
other: overall effects body weight; organ weights: liver weight; histopathology of lung and nose tissue (examination by light microscopy);

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Subacute exposure of rats (4 weeks, 2 hours/day, 5 days/week) to 5 ppm sulfur dioxide by nose-only exposure was without any effect on body or lung weights, histopathology of lung and nose tissue (examination by light microscopy), or particle clearance.