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Toxicological information

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:
1991-10-02 to 1991-11-13
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Guideline study without restrictions Minor deviations: - According to the guideline, the weight variation in animals or between groups used in a test should not exceed +/- 20 % of the mean weight. The males of the group with the 2.42 mg/l air concentration were slightly outside this weight range. - According to the guideline, the relative humidity should be between 30 - 70 % in the animal room. In this study the relative humidity was slightly higher (60 +/- 20 %). -According to the guideline, animals should be tested with inhalation equipment designed to sustain a dynamic air flow of 12 to 15 air changes per hour. In this study in the high concentration group the air flow was 29.4 changes per hour. - According to the guideline, the duration of exposure should be at least 4 hours after equilibration of the chamber concentration. It was not stated if the 4 hours started after equilibration of the chamber concentration. - According to the guideline, weight changes should be calculated and recorded when survival exceeds one days. This is missing in this study. -The GSD for the MMAD is missing. - The 95 % confidence level for the females is missing.

Data source

Reference
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:
adopted 12 May 1981
Deviations:
yes
Remarks:
see "rational for reliability"
GLP compliance:
yes (incl. certificate)
Remarks:
The study report stated that the study was performed according to "Good Laboratory Practice" Regulations of the EEC enacted in Germany in the "Chemikaliengesetz" dated March 14th, 1990, BGBL I, pp. 521, 1990.
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Divanadium pentaoxide analytical grade pulverised (V2O5)
- Physical state: beige solid powder
- Analytical purity: Vanadium: 56.05 % (Calculated V2O5: 97.86%)
- Stability under test conditions: Stable during course of study
- Storage condition of test material: Dry, in closed containers at room temperature
- Median particle size: 3.0 - 3.9 µm
No further significant information on test material was stated.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Lippische Versuchstierzucht HAGEMANN GmbH, D-4923 Extertal 1
- Age at study initiation: 52-69 days
- Weight at study initiation: 188 - 270 g (males; 164 - 206 g (females)
- Fasting period before study: approx. 16 hours
- Housing: Animales were kept in groups of two or three in Makrolon cages (type III). Granulated textured wood (type 2, supplied by Johannes Brandenburg, D-4937 Goldenstedt) was used as bedding material.
- Diet (ad libitum): Standardized diet for rats ALTROMIN 1324 (supplied by: ALTROMIN GmbH, D- 4937 Lage/Lippe)
- Water (ad libitum): tap water
- Quarantine period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 °C +/- 3 °C (maximum range)
- Relative humidity: 60 % +/- 20 % (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12
No further significant information on test animals was stated.

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
other: air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus & Exposure chamber volume: : The study was carried out using a dynamic inhalation apparatus with a nose only exposure of the animals according to KIMMERLE & TREPPER (Rhema-Labortechnik, D-6238 Hofheim/Taunus). The apparatus consists of a cylindrical exposure chamber (volume 40 l) which holds a maximum of 20 animals in pyrex tubes at the edge of the chamber in a radial position.

- Source and rate of air: At the bottom of the exposure chamber the air was sucked off at the similar rate as created by the dust generator in order to produce a homogenous distribution in the exposure chamber. Air-flow meters (Rotameter, ROTA Apparate- und Maschinenbau, D-7867 Wehr 2/Baden) were used to control the constant supply of compressed air and vacuum. Flow rates were checked at least once/hour and corrected if necessary. Air flow was 480 l/h for the low and medium concentration, and 1175 l/h for the high concentration. The air change was 12.0 changes per hour for the low and medium concentration, and 29.4 changes per hour for the high concentration.

- System of generating particulates/aerosols: The dust was generated with a dust generator and dosing apparatus (BURGHART, D-2000 Wedel/Holstein). The generator was fed with compressed air from a compressor.

- Method of particle size determination: An analysis of the particle size distribution was carried out twice during the exposure period using a cascade impactor according to MAY (1975).
The impactor is a device that classifies particles present in a sampleof air or gas into known size ranges. It does this by drawing the air sample through a cascade of progressively finer nozzles. The air jets from these impact on plane sampling surfaces (slides) covered with adhesive tape. Each stage represents an aerodynamic size range. The dust from the exposure chamber was sucked through the cascade impactor for 1.5 to 5 minutes at a constant flow rate of 5 l/min. The slides were removed from the impactor and were weighed on an analytical balance (SARTORIUS, type 1601004, precision 10µg).
Respirable amount (particle size <= 4 µm)
Dose level 0.90 mg/l air:0.61 mg/l air
Dose level 2.42 mg/l air:2.01 mg/l air
Dose level 4.72 mg/l air: 3.52 mg/l air
The sample supplied had a particle size distribution of 55.9 % in the particle size range of 2.4 to 5.0 µm.

- Temperature, humidity: The temperature (GTH 1200 Digital Thermometer, Fa. Greisinger Electronic GmbH) and humidity (Sekunden-Hygrometer Typ 6100, Testoterm) was continuously monitored close to the nose of the animals in the inhalation chamber. The temperature was 19 °C - 21 °C and the relative humidity was 60 % - +/- 20 %.

TEST ATMOSPHERE (Test substance concentration)
- Brief description of analytical method used: The dust concentration in the inhalation chamber was measured with an air sample filter (Minisart SM 17598) and pump (water jet air pump controlled by a rotameter). Dust samples were taken during the first half and during the second half of the exposure. The Minisart SM 17598 filters were placed close to the animals' nose and sucked through with a constant flow of air of 300 l/h for 1 to 3 minutes. The filters were weighed before and after sampling (accuracy 0.01 mg).

TEST ATMOSPHERE
- Particle size distribution: The sample supplied had a particle size distribution of 55.9 % in the particle size range of 2.4 to 5.0 µm measured with a Malvern particle sizer.
Particle size (µm) and mean (concentration 0.90 mg/l air):
<0.5 µm: 1.33 %
0.5 µm: 12.80 %
1 µm: 22.25 %
2 µm: 52.36 %
4 µm: 68.25 %
8 µm: 75.84 %
16 µm: 90.17 %
>= 32 µm: 99.90 &
Particle size (µm) and mean (concentration 2.42 mg/l air):
<0.5 µm: 0.0 %
0.5 µm: 5.18 %
1 µm: 17.19 %
2 µm: 52.89 %
4 µm: 83.10 %
8 µm: 87.50 %
16 µm: 93.73 %
>= 32 µm: 100.01 %
Particle size (µm) and mean (concentration 4.72 mg/l air):
<0.5 µm: 1.87 %
0.5 µm: 8.85 %
1 µm: 31.02 %
2 µm: 69.52 %
4 µm: 74.59 %
8 µm: 78.18 %
16 µm: 91.77 %
>= 32 µm: 100.0 %
- MMAD:
Dose level 0.90 mg/l air: 2.44 µm
Dose level 2.42 mg/l air: 2.32 µm
Dose level 4.72 mg/l air: 2.01µm
No further significant information on inhalation exposure was stated.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
see "details on inhalation exposure" above.
Duration of exposure:
4 h
Remarks on duration:
Exposition started by locating the rats into the exposure chamber.
Concentrations:
mean actual concentration 0.90 +/- 0.39 (nominal concentration: 1.9 mg/l air), 2.42 +/- 0.38 (nominal concentration: 7.4 mg/l air), 4.72 +/- 1.45 (nominal concentration: 8.6 mg/l air) mg V2O5 analytical grade pulverised/l air. 4.72 mg/l air was the highest concentration that could be generated in the inhalation chamber.
No. of animals per sex per dose:
5 males /5 females
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: During and following espoxure, observations were made. A careful clinical examination was made at least once each day until all symptoms subsided, thereafter each working day. Observations on mortality were made at least once daily with appropriate actions taken to minimize loss of animals to the study. Individual body weights of the animals were determined before the exposure, after 1 week and at study termination.
- Necropsy of survivors performed: Yes, Necropsy of all animals was carried out and all gross pathological changes were recorded. From animals which survived 24 hours or longer a microscopic examination of all organs which showed evident lesions was performed after preparation of paraffin sections and HE-staining..
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: Cageside observations included, but were not limited to, changes in the skin and fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, and somatomotor activity and behaviour pattern. Particluar attention was directed to observation of tremors, convulsions, salivation, diarrhoea. lethargy, sleep and coma.
No further significant information on study design was stated.
Statistics:
The mass median aerodynamic diameter (MMAD) was estimated by means of nonlinear regression analysis (LICHFIELD & WILCOXON). The 32 mm particle size range was not included in the determination of the MMAD in order not to give undue weight to this value.
The LC50 (24 hours/14days) was calculated by regression analysis (if possible according to FINNEY).

Results and discussion

Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LC50
Effect level:
11.09 mg/L air
95% CL:
> 0.68 - < 180.68
Exp. duration:
4 h
Remarks on result:
other: Slope: 1.783; LC50 was calcualted according to Finney (probit analysis)
Sex:
female
Dose descriptor:
LC50
Effect level:
4.29 mg/L air
Exp. duration:
4 h
Remarks on result:
other: Slope: 20.14; LC50 was calculated by regressiong analysis.
Mortality:
Death at 2.42 mg/l in males and 4.72 mg/l in females.
At the dose-level of 2.42 mg/l prematurely deceased animal (1/5 males) died 4 days after start of exposure.
At the dose level of 4.72 mg/l prematurely deceased animals (1/5 males; 4/5 females) died 2 days after start of exposure.
Clinical signs:
Dose level and toxic signs:
0.90 mg/l: no signs of systemic intolerance (males and females)
2.42 mg/l: Except for mortality no signs of systemic intolerance (males and females)
4.72 mg/l: except for mortalitiy no signs of systemic intolerance (males and females)
Body weight:
There was no inhibition of body weight gain in males or females.
Gross pathology:
Autopsy of deceased animals:
lungs haemorrhagic: 4.72 mg/l (1/1 males; 3/4 females). All further deceased animals showed no pathological findings.
Autopsy of surviving animals:
lungs haemorrhagic: 2.42 mg/l air (2/4 males; 1/5 females)
Lungs haemorrhagic and light dark coloured: 4.72 mg/l air (1/4 males)
All further scarificed animals showed no pathological findings.
The histopathological changes found in the lungs were:
2.42 mg/l air: vascular congestion (2/2 males); oedema (1/2 males) and (inital) haemorrhagic bronchopneumonia (2/2 males)
4.72 mg/l air: vascular congestion (2/2 males; 3/3 females); oedema (1/2 males; 2/3 females) and (inital) haemorrhagic bronchopneumonia (2/2 males; 3/3 females)
These changes can be regarded as unspecific effects which can normally occur after the administration of a dust.

Applicant's summary and conclusion

Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
According to the EEC-Commission directive of July 29th, 1983 on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances (83/467/EEC) and the results obtained under the present test conditions V2O5 analytical grade pulverised can be classified as harmful in an acute inhalation toxicity test in the rat.