Vanadyl pyrophosphate

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant study conducted in accordance with internationally recognised test methods

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1994

Report date:

1994

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Version / remarks:

.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Vanadyl pyrophosphate

EC Number:

406-260-5

EC Name:

Vanadyl pyrophosphate

Cas Number:

58834-75-6

Molecular formula:

V2P2O9

IUPAC Name:

divanadium(4+) (phosphonatooxy)phosphonate dioxidandiide

Details on test material:

- Name of test material (as cited in study report): BTN/A
- Chemical name: Vanadyl pyrophosphate
- Chemical formula: (VO)2P207
- Physical state: brown solid
- Lot/batch No.:0001
- Purity: >98%
- Storage condition of test material: Room temperature, prtected from light

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: BRL, Biological Research Laboratory Ltd. CH-4414 Fuellinsdorf, Switzerland
- Age at study initiation: Males 8 - 10 weeks Females 10 - 12 weeks
- Weight at study initiation: Males 180.1 - 199.6 g Females 180.4 - 199.8 g
- Fasting period before study: n/a
- Housing: groups of five of teh same sex in Makrolon type-4 cages (dimensions in mm: 590 x 385 x 200), with standard softwood bedding ("Lignocel", Schi11 AG, CH-4132 Muttenz, SWitzerland).
- Diet (e.g. ad libitum): Animals had ad libitum access to pelleted standard Kliba 343, rat maintenance diet, Batch nos. 86/93 and 87/93 ("Kliba", Klingentalml)ehle AG, CH-4303 Kaiseraugst, SWitzerland).
- Water (e.g. ad libitum): Animals had ad libitum access to community tap water from Geneva.
- Acclimation period:6 days (group 1) or 15 days (group 2)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C,
- Humidity (%): 30-70%
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light: 12 hours light / 12 hours dark.

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

Inhalation exposure was performed according to the method of Sachsse et al. (1973, 1976). The animals were confined separately in Makrolon tubes which were positioned radially around the exposure chamber. The test article stream reached the animal's nose through ports situated at different levels around the axis of the chamber. Each level had ports that could be rotated, allowing clo'se observation of all the animals without interruption .of exposure.The flow-past, nose-only design of the exposure system was based upon the fluid dynamic modeling of the aerosol flow to ensure a uniform test article distribution and provide a constant stream of "fresh" test article to each animal, and preclude rebreathing the exhaled air. The internal active volume of the chamber for exposing up to 24 animals was approximately 0.7 litres. The resulting time for the concentration to reach 99 % of its ultimate value (T99) at an animal port was 7 seconds.

GENERATION OF THE TEST ARTICLE: The test article was generated using a RBG-1000 aerosol. generator (Palas, Germany) connected (fi rst technical test) or not connected (second technical test) to a micronising Jet-mill. As the percentage of particles EXPOSURE SYSTEM MONITORING: Samples for the measurements of the test article concentrations, particle size distribution, oxygen concentration, relative humidity and temperature were collected from a port of the chamber, directly from the feed tube which delivers IIfreshll test article to the animal's nose. Therefore all the measurements were isoax;al and represented exactly what was delivered to the animals.
On-line Monitoring of Concentration:
The relative aerosol concentration was monitored on-line using a RAM-1 light scattering type aerosol device from GCA Corp. Bedford, Massachusett U.S.A
Gravimetric Concentration:
Samples of the test atmosphere were collected (n=6 in group 1, n=5 in group 2) on Ge1man Type AlE, 47 mm diameter glass fiber fi1ters using a stai n1ess steel filter sampling device (Gelman Science Inc., Ann Arbor, Michigan, U.S.A). The mean sampling airflow rates were 1.57 l/min (group 1) and 1.50 l/min (group 2). Gravimetric concentrations were calculated by dividing the weight of the material collected on the filters by the volume of air passing through them during the collection period.
Particle Size Distribution and Mass Median Aerodynamic Diameter:
The particle size of the test atmosphere was determined using a Mercer 7 stagecascade impactor (Model 02-130, In-Tox Products, Albuquerque, New Mexico, U.S.A). The test atmosphere was impacted at each stage onto stainless steel slips which were weighed before and after sampl ing using a model M3 balance (Mettler AG, CH-8604 Volketswil, Switzerland). The airflow rate during sampling was 1 l/min. The amount of test article deposited on each stage repr sents the quantity of aerosol particles obtained for a speci'fied aerodynamic diameter range (def; ned by the stage cutoff diameter and the cutoff diameter of the preceding stage). The values are expressed as a percentage of the total quantity of aerosol deposited in the impactor. These determinations were performed four times in group 1 and 5 times in group 2. Assuming a log-normal distribution, the particle size distribution is described by the mass median aerodynamic diameter (MMAD) and the distribution width, (geometric standard deviation, GSD). The MMAD is derived by plotting the cumulative percentage of particles against the log of the aerodynamic diameter on a log-probability (probit) scale using a software program from Biosoft, Cambridge, U.K. The 50 % intercept of the resulting regression line is the MMAD, and the slope of the 1i ne represents the GSD. The latter is ca1cul ated by diViding the mass median diameter by the diameter where· the 15.9 % (=4 on probit scale) line intercepts the regression line
Oxygen Concentration:
The oxygen concentration was measured once during each exposure using an Oxopac RO device from Draegerwerk AG, CH-8047 Zurich, Switzerland
Relative Humidity and Temperature:
The relative humidity and temperature were determined once during each exposure using a HMI 32, VAISALA humidity and temperature indicator from Kuenzli Elektronik, CH-8006 Zurich, Switzerland.

Duration of exposure:

4 h

Concentrations:

Concentrations (gravimetric) (mean ± SD.)
Group 1: 5.28 ± 0.58 mg/L air (n = 6)
Group 2 5.83 ± 1.46 mg/L air (n =5)

No. of animals per sex per dose:

Number of groups: 2
Number of animals per group: 5 males and 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15d
- Frequency of observations and weighing: on days 1 (before exposure), 8 and 15 of test using a Mettler PM 4000 balance.
- Necropsy of survivors performed: yes. Necropsies were performed by experienced prosectors under the management of a pathologist. All animals were necropsied. All animals were anesthetized by an intraperitoneal injection of sodium pentobarbital (approximately 300 mg/kg b.w.) and exsangui nated. All macroscopi c changes or abnormality es were descri bed and recorded. The lungs, trachea and larynx and nasopharyngeal tissues were collected from all animals and fixed in a neutral phosphate buffered 4 ~ formaldehyde solution. The lungs were instilled with the fixative at a hydrostatic pressure of 30 cm H20. All collected organ/tissues are available for histopathological examination if requested by the Sponsor.
- Other examinations performed:
- clinical signs: once per hour during exposure (only grossly abnormal signs, as the animals were 1n restraint tUbes), once after exposure and at least once daily thereafter.
- body weight.
- mortality: once per hour during exposure, once after exposure on test day 1, and twice daily thereafter.
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical signs - Once / hour during exposure, following exposure on Day 1 and at least daily thereafter for 14 days. Body weight: Weekly (Days 1, 8 and 15)
- Necropsy of survivors performed: Yes

Statistics:

Not applicable

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.83 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No deaths occurred during the exposure nor during the 15-day observation period.

Clinical signs:

other: Restlessness was noted in a few animals of both groups during exposure. Just after exposure, hunched posture and a slight degree of tachypnea were noted in all animals of both groups. Ruffled fur was recorded in all animals except in the males of group 1.

Body weight:

Except for one female (group 2) which did not gain weight between test days 1 and 8, other animals gained weight at a normal rate.

Gross pathology:

Except for 1 male in group 2 and 1 female in group 1, the lungs of all other animals were incompletely collapsed with reddish or gray white foci in three cases.

Other findings:

The percentage of particles

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Acute inhalation toxicity has been investigated in accordance with OECD/EU test methods. Rats were exposed for 4 hours to an atmosphere containing the highest achievable concentration that could be generated. The percentage of particles < 4.6 um was in excess of 60%. The median lethal dose (LC50) in the rat was >5.83 mg/L air.

Executive summary:

Acute inhalation toxicity has been investigated in accordance with OECD/EU test methods. Rats were exposed for 4 hours to an atmosphere containing the highest achievable concentration that could be generated. The percentage of particles < 4.6 um was in excess of 60%. The median lethal dose (LC50) in the rat was >5.83 mg/L air.