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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:
disregarded due to major methodological deficiencies
Study period:
2010-03-02 to 2011-06-01
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Remarks:
According to Annec VIII of Regulation 1907/2006, the studies on acute toxicity do not generally need to be conducted if the substance is classified as corrosive to the skin. Vanadium oxide sulphate pentahydrate is a strong acid (pH< 2) and meets the classification criteria of Regulation (EC) No 1272/2008 for Skin Corr. 1A and Serious eye damage (H314: Causes severe skin burns and eye damage.) Hence, any effects observed may represent the corrositivity of the substance and not its intrinsic toxicity. In addition, the substance was administered in ASTM water. However, based on bioaccessibility testing, stability in water is not expected so that it is unknown what the animals were exposed to.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report date:
2011

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Version / remarks:
2009-09-07
Deviations:
yes
Remarks:
Please refer to "Principles of method if other than guidelines" below.
Principles of method if other than guideline:
The limit test of this study (2 mg/L) was conducted in compliance with the requirements of the following test guidelines with the exception that body weights were not obtained 1 and 3 days after exposure: 1) US EPA Health Effects Testing Guideline, OPTTS 870.1300, entitled Acute Inhalation Toxicity, 1998 and 2) OECD test guideline 403 (1981). In order to reduce animal use and to provide an acute inhalation toxicity estimate and information for the Global Harmonized System (GHS) of classification and labelling for the test substance, all subsequent exposures were conducted in compliance with OECD test guideline 436 (2009) (with exception that body weights were not obtained 1 and 3 days after exposure). The initial subsequent exposures were determined by the study director in conjunction with the sponsor and any subsequent exposures were determined according to the scheme in Annex 3c of the OECD 436 test guideline.
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Vanadium oxide sulphate
EC Number:
248-652-7
EC Name:
Vanadium oxide sulphate
Cas Number:
27774-13-6
Molecular formula:
VOSO4
IUPAC Name:
vanadium oxide sulphate
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study report): Vanadyl sulfate (received from GfE Metall und Materialien GmbH, Nuremberg, Germany)
- Physical state: blue granular powder
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature in the original container

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories (Raleigh, NC)
- Age at receipt: 51 and 56 days
- Weight at receipt: 16 to 28 g
- Housing: animal were double-housed and then after randomization, single-housed, in stainless steel cages suspended over absorbent paper cage boards
- Diet (ad libitum, except during inhalation exposure): Certified Rodent Chow 5002 meal (PMI Nutrition International, Inc., Brentwood, MO)
- Water (ad libitum, except during inhalation exposure): City of Chicago water
- Quarantine period: approx. one week
During quarantine the mice were observed daily for signs of disease and general unthriftiness.
To condition the animals to placement and restraint in the nose-only holding tubes (CH Technologies, U.S.A., Westwood, NJ) and to reduce stress during the exposure phase, the animals were placed in the holding tubes over three days according to the following schedule: one hour on Day 1, two hours on Day 2 and three hours on Day 3 prior to their exposure.

ENVIRONMENTAL CONDITIONS
- Temperature: 18.0 to 22.0°C
- Relative humidity: 30 to 43%
- Air changes: minimum of 10 air changes per hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: water
Mass median aerodynamic diameter (MMAD):
>= 1.68 - <= 1.93 µm
Geometric standard deviation (GSD):
>= 1.61 - <= 2.93
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus/Method of holding animals in test chamber: a 52-port, flow-past nose-only inhalation exposure chamber (Lab Products Inc., Seaford, DE) was used. The animals were restrained in nose-only exposure animal holding tubes (CH Technologies, U.S.A., Westwood, NJ). Each tube was placed in a pre-designated port of the inhalation exposure chamber.

- System of generating particulates/aerosols: the test atmosphere was created by generating an aerosol (with filtered air) of the test substance using a 6-Jet Collison Nebulizer (BGI Incorporated, Waltham, MA) positioned in the chamber. The test substance was weighed, dissolved in ASTM water, and poured into the Collison Nebulizer jar. The nebulizer used compressed air to aspirate the solution into a sonic velocity gas jet which impacted against a barrier (the inside of the jar) to remove the larger fraction of droplets. The resulting test atmosphere entered a mixing plenum where it may have been diluted with breathable quality compressed air in order to achieve the target concentration prior to introduction to the nose-only inhalation exposure chamber. The exhaust from the exposure chamber was moved through a high efficiency particulate air (HEPA) filter by a ring compressor and exhausted outside the building. Inlet and exhaust flows to and from the chamber were controlled and continuously monitored by rotometers.

T90 time was assessed to be approximately 30 seconds.

- Temperature, humidity, oxygen percentage in air chamber: oxygen percentage was measured once during the exposure with an Altair Oxygen Sensor and Detector (MSA Instrument Division, Pittsburgh, PA).
Inhalation exposure chamber temperature and relative humidity were monitored with a hand-held thermohygrometer (model # 8721, Control Company, Fisher Scientific, Friendswood, TX) and were recorded at approximately half-hour intervals during exposure.
Temperature (mean ± SD):
2.17 mg/L: 22.9°C ± 0.16
1.09 mg/L: 22.9°C ± 0.23
0.53 mg/L: 22.3°C ± 0.16
0.05 mg/L: 22.5°C ± 0.16
Relative humidity (mean ± SD):
2.17 mg/L: 99.9% ± 0.00%
1.09 mg/L: 99.9% ± 0.00%
0.53 mg/L: 99.9% ± 0.00%
0.05 mg/L: 58.8% ± 2.29
Oxygen (%):
2.17 mg/L: 20.8%
1.09 mg/L: 20.8%
0.53 mg/L: 20.8%
0.05 mg/L: 20.8%

- Method of particle size determination: aerosol particle size was monitored at least once per two hours during the exposure with a quartz crystal microbalance (QCM) Cascade Impactor (California Measurements Inc., Sierra Madre, CA). The mass median aerosol diameter (MMAD) and geometric standard deviation (GSD) were calculated from the mass accumulated on each stage of the QCM.

TEST ATMOSPHERE
- Brief description of analytical method used: the concentration of the test substance in the test atmosphere was monitored gravimetrically by filter-collected samples. One sample was taken from the breathing zone of the animals every hour of exposure. The gravimetric sampling train consisted of a pre-weighed filter in a series with a dry-gas meter connected to a constant flow vacuum pump. The dry-gas meter measured the corresponding volume of chamber air sampled and the weight to volume ratio was determined to obtain the aerosol mass concentration. All filter-collected samples were weighed, and all filters were analysed chemically by ICP-MS for determination of vanadium content and to calculate the test atmosphere concentration.
Aerosol concentration was monitored with a real-time aerosol sensor (model #pDR-1000AN, MIE, Inc. Bedford, MA). The sensors were employed as a real-time indicator of short term changes in aerosol concentration.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.):
2.17 mg/L: 1.93 µm (GSD: 1.61 to 1.88)
1.09 mg/L: 1.81 µm (GSD: 2.39 to 2.44)
0.53 mg/L: 1.84 µm (GSD: 1.73 to 1.92)
0.05 mg/L: 1.68 µm (GSD: 2.75 to 2.93)

A group of five male and five female mice was exposed to an aerosol of vanadyl sulfate in a nose-only inhalation exposure chamber for 4 hours at a concentration of 2.0 mg/L. Due to the mortality observed at the 2.0 mg/L exposure concentration an additional group of three male and three female mice was exposed to an aerosol of vanadyl sulfate in a nose-only inhalation exposure chamber for 4 hours at a concentration of 1.0 mg/L. Due to the mortality observed at the 1.0 mg/L exposure concentration an additional group of three male and three female mice was exposed to an aerosol of vanadyl sulfate in a nose-only inhalation exposure chamber for 4 hours at a concentration of 0.5 mg/L. Due to mortality observed at the 0.5 mg/L exposure concentration a fourth group of three male and three female mice was exposed to an aerosol of vanadyl sulfate in a nose-only inhalation exposure chamber for 4 hours at a concentration of 0.05 mg/L. Surviving animals were observed for a 14-day post-exposure period.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Please refer to the field "Details on inhalation exposure" above.
Duration of exposure:
4 h
Concentrations:
actual concnetrations: 0.05, 0.53, 1.09, and 2.17 mg/L
target concentrations: 0.05, 0.5, 1.0 and 2.0 mg/L
No. of animals per sex per dose:
2.17 mg/L: 5 males / 5 females
1.09 mg/L: 3 males / 3 females
0.53 mg/L: 3 males / 3 females
0.05 mg/L: 3 males / 3 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were observed for signs of toxicity during the exposure, immediately after the exposure and at least once daily during the 14-day post-exposure observation period. Body weights were determined one day after animal receipt, prior to randomization, on Day 1 prior to exposure, and one week after exposure. All surviving animals were weighed on the day of their scheduled necropsy, prior to euthanasia. Body weights of animals found dead were also collected prior to necropsy. Body weight changes were calculated for mice surviving more than 24 hours.

- Necropsy of survivors performed: yes
All exposed animals, including those found dead, were subjected to necropsy. At the end of the observation period, all surviving animals were euthanized and subjected to a necropsy. The necropsy included examination of all body surfaces and openings, and examining the external appearance of the brain, heart, liver, kidneys, lungs (especially any changes in the immediately associated and exposed respiratory tract), gastrointestinal tract, spleen, gonads and the urinary bladder. The gastrointestinal tract and the urinary bladder were opened and examined if lesions were present. Respiratory tracts were saved and fixed, abnormal tissue were also retained for possible pathologic evaluation, when considered needed. All decedents were also subject to the necropsy procedures described above.
Statistics:
The LC50 value was estimated based on the mortality results according to the shceme in Annex 3c of the OECD 436 test guideline (adopted September 2009).

Results and discussion

Preliminary study:
not applicable
Effect levels
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
0.125 other: mg/L (actual conc.)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: LC50 cut off value according to the scheme in Annex 3c of the OECD 436 (2009)
Mortality:
- 2.17 mg/L: all mice, with the exception of one female, died within five days of being exposed to the test substance (four males on the day of exposure [Day 1], one male and one female on Day 2, one female on Day 3, and two females on Day 5).
- 1.09 mg/L: all six mice died within three days of being exposed to the test substance (two males and two females on the day of exposure [Day 1], and one male and one female on Day 3).
- 0.53 mg/L: all six mice died within three days of being exposed to the test substance (two males on the day of exposure [Day 1], one male on Day 2 and three females on Day 3).
- 0.05 mg/L: no animals died after exposure to the test substance
Clinical signs:
other: Wet inguinal fur was seen following exposures on Day 1 for those animals that survived past Day 1. Skin/fur discolouration (blue) was observed in one or two animals on Day 1 following exposure to 1.0 and 0.5 mg/L of the test substance. Other clinical sign
Body weight:
All surviving mice gained weight during the study.
Gross pathology:
- 2.17 mg/L: discoloured lungs (pale pink to dark red, some mottled and some with foci) were observed in all animals, with the exception of one male and one female that had no gross lesions.
- 1.09 mg/L: discoloured lungs (pale pink to dark red, one mottled and one with a red focus) were observed in all animals, with exception of one male that had no gross lesions.
- 0.53 mg/L: mottled and/or discoloured lungs (pale pink to dark red) were observed in all animals, with the exception of one female that had no gross lesions.
- 0.05 mg/L: no gross lesions were observed at necropsy in any animal.

Applicant's summary and conclusion

Interpretation of results:
study cannot be used for classification
Conclusions:
According to Annec VIII of Regulation 1907/2006, the studies on acute toxicity do not generally need to be conducted if the substance is classified as corrosive to the skin. Vanadium oxide sulphate pentahydrate is a strong acid (pH< 2) and meets the classification criteria of Regulation (EC) No 1272/2008 for Skin Corr. 1 and Serious eye damage (H314: Causes severe skin burns and eye damage.) Hence, any effects observed via inhalation may represent the corrositivity of the substance and not its intrinsic toxicity. In addition, the substance was administered in ASTM water. However, based on bioaccessibility testing, stability in water is not expected so that it is unknown what the animals were exposed to.