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Diss Factsheets

Administrative data

acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
7 Apr 2008 - 20 May 2008
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was conducted according to OECD and EC guidelines and according to GLP principles.

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guidelineopen allclose all
according to guideline
OECD Guideline 403 (Acute Inhalation Toxicity)
according to guideline
EU Method B.2 (Acute Toxicity (Inhalation))
according to guideline
EPA OPPTS 870.1300 (Acute inhalation toxicity)
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:

Test material

Constituent 1
Details on test material:
- Name of test material (as cited in study report): S-500
- Physical state: yellow powder
- Lot/batch No.: MF1456-2345
- Expiration date of the lot/batch: 18 August 2011
- Storage condition of test material: At room temperature in the dark
- Stability under storage conditions: Stable

Test animals

Details on test animals or test system and environmental conditions:
- Strain: Crl:WI(Han)
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 10 – 12 weeks old
- Weight at study initiation: males 271-372 g, females 186-224 g
- Fasting period before study: no
- Housing:
Before exposure: Group housing of 5 animals per sex per cage in labelled Macrolon cages (type IV; height 18 cm.) containing sterilised sawdust as bedding material and paper as cage-enrichment
After exposure : Group housing, maximally 5 animals per sex per cage in labelled stainless steel wire mesh cages. Four days after exposure the animals of group 1 were housed as described above.

- Diet (e.g. ad libitum): Free access to pelleted rodent diet except during exposure to the test substance.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.

- Temperature (°C): 19.5 – 21.3
- Humidity (%): 31 – 71
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
other: unchanged (no vehicle)
Details on inhalation exposure:
The design of the exposure chamber was based on the flow past nose-only inhalation chamber (Am. Ind. Hyg. Assoc. J. 44(12): 923-928, 1983). The chamber consisted of 3 animal sections with 8 animal ports each. The number of open animal ports was adapted to the air flow in such a way that at each animal port the theoretical air flow was approximately 2.0 L/min, which ensures an adequate oxygen supply to the test animals.

- Method of conditioning air:
- System of generating particulates/aerosols: An aerosol was generated by administering the test substance to a stream of pressurized air by means of a spiral feeder and an air mover. The aerosol was directly led through the exposure chamber.
- Method of particle size determination: Samples for characterization of the particle size distribution were taken twice during the exposure period. In group1 the data of the second sample did not allow an accurate estimate of the Mass Median Aerodynamic Diameter (MMAD) and the Geometric Standard Deviation (GSD). For this reason, on the day after exposure a test atmosphere was generated under identical conditions as during exposure of the animals and a new sample for characterization of the particle size distribution was taken.

- Treatment of exhaust air: From the exposure chamber the test atmosphere was passed through a filter before it was released to the exhaust of the fume hood.
- Temperature, humidity, pressure in air chamber: The temperature and relative humidity were measured with a humidity and temperature indicator and were recorded after the animals were placed in the experimental set-up and at 30 minute intervals after initiation of the exposure. The probe was inserted in a tube mounted in one of the free animal ports of the middle section of the exposure chamber

- Brief description of analytical method used: The actual concentration was determined 9 (group 1) and 8 (group 2) times during the exposure period. Samples were drawn from the test atmosphere through a tube mounted in one of the free animal ports of the middle section of the exposure chamber. Samples were drawn through a glass fiber filter. The collected amount of the test substance in the air sample was measured gravimetrically. Sample volumes were measured by means of a dry gas meter.
Subsequently the mean concentrations and the standard deviations were calculated.
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:
Duration of exposure:
4 h
The mean actual concentrations were 3.2 ± 0.3 and 5.7 ± 0.4 mg/L. The nominal concentrations were 44.8 and 50.9 mg/l. The generation efficiencies (ratio of actual and nominal concentration) were 7.2 and 10.2%.
No. of animals per sex per dose:
Control animals:
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing:
During exposure: Three times during exposure for mortality, behavioural signs of distress and effects on respiration.
Mortality/Viability: Twice daily.
Body weights: Days 1 (pre-administration), 8 and 15 and at death (after day 1).
Clinical signs: Twice (at 1 and at 3 hours after exposure) on the day of dosing (day 1) and once daily thereafter, until day 15. The symptoms were graded according to fixed scales and the time of onset, degree and duration were recorded:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopic examinations
Not performed.

Results and discussion

Effect levels
Dose descriptor:
Effect level:
1 - 5 mg/L air (analytical)
Exp. duration:
4 h
At 5.7 mg/L one male was found dead after approximately 1 hour of exposure, two males were found dead after approximately 3 hours, two females after approximately 2 hours and one female after approximately 3 hours. At 3.2 mg/L two males and one female were found dead on Day 2. No further mortalities occurred.
Clinical signs:
other: During exposure to 5.7 mg/L slightly increased breathing rate was noted among the animals, while one female showed laboured respiration. During exposure to 3.2 mg/L slightly decreased breathing rate was noted in one female. No clinical signs were noted am
Body weight:
During the first week after exposure the males at 5.7 mg/L showed reduced body weight gain, while the females at 5.7 mg/L and all animals at 3.2 mg/L showed body weight loss. The body weight gain during the second week after exposure shown by the animals was considered to be similar to that expected of normal untreated animals of the same age and strain.
Gross pathology:
Macroscopic post mortem examination of all decedents revealed yellowish granular contents in the larynx and yellowish contents in the stomach.

Macroscopic post mortem examination of the surviving animals at termination did not reveal any abnormalities.

Applicant's summary and conclusion

Interpretation of results:
Migrated information Criteria used for interpretation of results: EU
The inhalatory LC50, 4h value of S-500 in Wistar rats was established to be within the range of 1.0 – 5.0 mg/L.

Based on these results and according to the:
- Globally harmonized system of classification of chemicals (GHS), United Nations, New York and Geneva, 2003, S-500 should be classified in Class 4 for acute toxicity by the inhalatory route.
- EC criteria for classification and labelling requirements for dangerous substances and preparations (Council Directive 67/548/EEC), S-500 should be labelled as: harmful by inhalation (R20).