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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:
15 February 2007 to 15 May 2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report date:
2007

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: JMAFF (12 Nousan, Notification No. 8147)
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes

Test material

Constituent 1
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Physical state: solid
- Appearance: grey powder with lumps
- Storage condition of test material: room temperature in the dark

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: ca. 12 weeks
- Housing: prior to expsure animals were housed 5 by sex in Marcolon cages furnished with sterilised sawdust and paper cage enrichment. After the exposure the animals were housed in groups of 5 by sex in labelled stainless steel wire mesh cages.
- Diet: pelleted rodent diet, SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany (ad libitum)
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.2 - 23.1 °C
- Humidity (%): 42 - 65 %
- Air changes (per hr): ca. 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: Milli-U water
Details on inhalation exposure:
TRIAL TEST ATMOSPHERE GENERATION
Trial generations of a test atmosphere revealed that a dry dust aerosol could not be generated at sufficiently high concentrations due to clogging of the aerosol generating equipment by the test material. Trial generations of a test atmosphere with formulations of the test material at concentrations in water were performed. A formulation of 2 g test material in 3 g of water was considered optimal for the 4 -hour exposure of the animals. The mean concentration of 3.2 mg/L achieved during the study was considered to be the highest attainable.

EXPOSURE CHAMBER
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. The inlet of the test atmosphere was located in the top section and the outlet was located in the bottom section. The direction of the flow of the test atmosphere guaranteed a freshly generated atmosphere for each individual animal.

TEST ATMOSPHERE GENERATION
The test material suspension was placed on a magnetic stirrer fed by means of a peristatic pump to a Hospitak nebuliser type 950 operating at an air pressure of 1.9 bar. The mean air flow under these conditions was 15.5 L/minute. Subsequently the aerosol was passed through the exposure chamber. from the exposure chamber the test atmosphere was passed through a filter before it was released to the exhaust of the fume hood.

NOMINAL CONCENTRATION
The nominal concentration was calculated by dividing the amount of test material used by the volume of pressurised air entering the exposure chamber used for exposure of the animals.

ACTUAL CONCENTRATION
The actual concentration was determined 10 times during the exposure period. Samples were drawn from the test atmosphere through a tube mounted in one of the free animals ports in the middle section of the exposure chamber. Samples were drawn through a glass fiber filter. After sampling the filters were dried by passing 5 litres of room air through the filters. The collected amount of test material in the air sample was measured gravimetrically. Sample volumes were measured by means of a dry gas meter.

PARTCILE SIZE CHARACTERISATION
The particle size was characterised twice during the exposure period. the samples were drawn (2 L/min) from the test atmosphere through a tube mounted in one of the free animal ports of the middle section of the exposure chamber. The samples were collected with an 8 stage Marple personal cascade impactor, fiber glass filters and a fiber glass back-up filter. Amounts of test material collected were gravimetrically analysed.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
3.2 ± 1.1 mg/L (mean measured)
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for mortality and viability were performed twice daily. Body weights were recorded on days 1 (pre-administration), 8 and 15. Clinical signs were recorded twice on the day of dosing and once daily thereafter.
- Necropsy of survivors performed: yes (all animals were necropsied at the end of the observation period and subject to gross pathological examination)

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 3.2 mg/L air
Exp. duration:
4 h
Remarks on result:
other: represents the highest test concentration considered to be technically attainable
Mortality:
None of the animals died during the study.
Clinical signs:
other: During and after exposure no clinical signs were noted. No effects on body weight and body weight gain indicative of toxicity were noted.
Body weight:
Between days 1 and 8 slight body weight loss was noted in all males and two females and reduced weight gain was noted in three females. Body weight gain resumed normal values in males and females between day 8 and 15. Weight loss or reduced weight gain during the first days following an acute inhalatory exposure is a common finding hence this finding is not considered to be indicative of test material toxicity.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.

Any other information on results incl. tables

Test atmosphere concentration

The mean actual concentration was 3.2 ± 1.1 mg/L. The nominal concentration was 23.3 mg/L. The generation efficiency was 15%.

Particle size

The mean mass aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were determined twice. The MMAD was 3.0 and 3.2 µm, respectively and the GSD was 2.1 and 2.0, respectively.

Stability monitoring

During the exposure a gradual decrease of the opacity due to a decrease of test material concentration was noted. For this reason a nebulizer was cleaned at regular intervals, after which the opacity showed an instantaneous increase.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute inhalation LC50 of the test material was determined to be in excess of 3.2 mg/L, the highest test concentration considered to be technically attainable.
Executive summary:

The acute inhalation toxicity of the test material was investigated in a study which was conducted under GLP conditions and in accordance with the standardised guidelines OECD 403, EU Method B.2, EPA OPPTS 870.1300 and JMAFF.

During the study the test material was administered by nose-only inhalation, for 4 hours, to one group of five male and five female Wistar rats, followed by a 14 -day observation period. Animals were subject to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice.

The mean actual concentration was 3.2 ± 1.1 mg/L. The nominal concentration was 23.3 mg/L. The generation efficiency was 15%.

The mean mass aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were determined twice. The MMAD was 3.0 and 3.2 µm, respectively and the GSD was 2.1 and 2.0, respectively.

Under the conditions of the study no mortality occurred and no clinical signs were noted. No effects on body weight and body weight gain indicative of toxicity were noted. Furthermore, no abnormalities were found at macroscopic post mortem examination.

The acute inhalation LC50 of the test material was determined to be in excess of 3.2 mg/L, the highest test concentration considered to be technically attainable.

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