Registration Dossier

Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study conducted according to GLP. The reliability is reduced to a score of 2 because ECHA guidance requires this for read-across substances.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
(1981)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Physical state: solid
- Analytical purity: approx. 99 %
- Lot/batch No.: MS 70037.62
- Expiration date of the lot/batch: 1995-December
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
other: (Tif: RAI f (SPF) hybrids of RII/1 x RII/2)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: CIBA-GEIGY Limited Animal Production, Stein /Switzerland
- Weight at study initiation: 177 - 227 g
- Fasting period before study: at least 5 d
- Housing: Groups of 5 in Makrolon type-4 cages
- Diet (ad libitum): Rat diet Nafag 890
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 55 +/- 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION

- Exposure apparatus:
The exposure apparatus was developed by Battelle Research Center (Geneve/Switzerland). The internal active volume was less than 1 l and the flow in any individual aerosol delivery chamber was standardised to 2 l/min (velocity 1.25 m/s).

- Method of holding animals in test chamber:
For inhalation period rats were placed in Macrolon animal holders.

- Treatment of exhaust air:
The exhaust air was decontaminated by passage through a Pall HDC absolute filter.

VEHICLE:
The test compound tended to form secondary agglomerates. Therefore, it was mixed with inert silica. A 10% mixture of Sipernat 50S with the test article was used in the animal exposure tests.


TEST ATMOSPHERE:
The aerosol concentration was determined gravimetrically five times during exposure period. The Particle size determination was conducted four times during exposure using an eight-stage cascade impactor. In the same intervall temperature, relative humidity and oxygen content of the inhalation chambers were assessed.


The test substance was administered as an aerosol in a nose-only exposure system that ensures uniform exposure and avoids re-breathing of the aerosol. During exposure, the animals were placed in Macrolon animal holders positioned radially around the exposure chamber, so that only the snouts and nostrils were exposed. The aerosol was generated from the solid test material blended with 10 % Sipernat 50S (Degussa, Germany) by means of a brush-feed micronizing jet mill. A cyclone-type classifier ensures that only particles of the desired diameter leave the jet mill.
The control animals were exposed to an inhalation atmosphere of Sipernat 50S at a nominal concentration of 0.48 mg/l under the same conditions as described above.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gravimetrically
Duration of exposure:
4 h
Concentrations:
2.25 mg/l; Due to the properties of the test material, it was not possible to generate higher concentrations of the test compound with the equipment used in this study.
No. of animals per sex per dose:
10 (5 males, 5 females)
Control animals:
yes
Details on study design:
The control animals were exposed to an inhalation atmosphere of Sipernat 50S at a nominal concentration of 0.48 mg/l under the same conditions as treated animals.

- Duration of observation period following administration: 14 days
- Frequency of observations of clinical symptoms and mortality: During and after exposure, therafter daily.
- Frequency of weighing: Body weights were recorded prior to treatment and on day 7 and 14.
- Necropsy of survivors performed: yes, all animals were sacrificed and subjected to gross pathology.
Statistics:
Body weights of treated and untreated animals were compared by analysis of variance.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2.25 mg/L air
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: None of the animals died.
Mortality:
None of the animals died.
Clinical signs:
other: Piloerection, hunched posture and dyspnea were seen in animals exposed to the test material. They recovered within 5 days.
Body weight:
Males exposed to the test substance showed a significantly higher body weight gain during the first and the second observation week as compared to control animals.
Gross pathology:
No macroscopic findings were observed at necropsy.
Other findings:
- Histopathology:
- In all examined tissue samples, the alveolar lumen contained alveolar macrophages (phagocytic cells) filled with brown
pigment, most likely representing the test article. This change was minimal in males and moderate in females. The pneumocytes
type II in the alveolar epithelium of all animals were activated. This activation was minimal and multifocal in
3 males and one female, moderate and multifocal in 2 males and 4 females. The bronchial lymph node of one male and one female
showed moderate brown pigmentation, regarded to represent the test article. In one male the bronchiolar epithelium was
minimally and focally hyperplastic.
- The minimal congestion, the minimal emphysema and the minimal and multifocal bronchiolar dilatation seen in all animals are a common response in rats treated by inhalation. Therefore, it was considered not to be treatment-related.

Any other information on results incl. tables

Table 1: Mean body weights in grams (Dose level: 2.25 mg/l)

Test day

1*

7

14

 

 

 

 

Control males

212 +/-4

246 +/- 12

278 +/-19

Treated males

202 +/-6

254 +/- 7

297 +/- 9

 

 

 

 

Control females

187 +/- 5

199 +/- 4

215 +/- 8

Treated females

186 +/- 6

199 +/- 8

215 +/- 7

*body weights on day 1 were assessed before application of 2.25 mg/l.

Applicant's summary and conclusion