Vanadyl pyrophosphate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Experimental data reported in peer reviewed journal

Data source

Reference

Reference Type:

publication

Title:

Short-term Toxicity Studies of Vanadium in Rats

Author:

Domingo JL, llobet JM and Tomas JM

Year:

1985

Bibliographic source:

J. Appl. Toxicol. 5(6): 418-421, 1985

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

Reduced haematology, clinical chemistry and pathology investigations compared with current test guideline

GLP compliance:

not specified

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Sodium metavanadate

EC Number:

237-272-7

EC Name:

Sodium metavanadate

Cas Number:

13718-26-8

IUPAC Name:

Sodium metavanadate

Details on test material:

- Name of test material (as cited in study report): Sodium metavanadate
- Molecular formula (if other than submission substance): O3-V.Na
- Molecular weight (if other than submission substance): 121.9
- Smiles notation (if other than submission substance): [V](=O)(=O)[O-].[Na+]
- InChl (if other than submission substance): 1/Na.3O.V/q+1;;;-1;/rNa.O3V/c;1-4(2)3/q+1;-1
- Structural formula attached as image file (if other than submission substance): see Figure 1 - Sodium metavanadate structure.png

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Biocentre, Barcelona, Spain
- Age at study initiation: No data
- Weight at study initiation: 91.6 +/- 10.8 g
- Housing: Individual metabolism cages
- Diet (e.g. ad libitum): Panlab rodent diet, Barcelona, Spain available ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
No data

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: Solutions prepared in water without heating at pH 7.4 and stored at 21-24 deg C

DIET PREPARATION: Not applicable

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

Continuous exposure via drinking water

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 5, 10 and 50 ppm vanadium
Basis:
nominal in water

No. of animals per sex per dose:

10 males / 10 females

Control animals:

yes, concurrent vehicle

Positive control:

No

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Daily

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: On termination
- Anaesthetic used for blood collection: Yes (ether) followed by exanguination
- Animals fasted: No data
- How many animals: 5/.sex/group
- Parameters examined: GOT, GPT, total protein, bilirubin, urea, uric acid, creatinine, glucose and cholesterol


URINALYSIS: Yes
- Time schedule for collection of urine: Daily
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters examined: Volume

NEUROBEHAVIOURAL EXAMINATION: No data


OTHER: DETERMINATION OF TISSUE VANADIUM CONCENTRATION
- Time schedule for collection of blood: On termination
- How many animals: 5/.sex/group
- Tissues examined: Liver, kidneys, heart, spleen and lungs

Sacrifice and pathology:

GROSS PATHOLOGY: Yes - All animals
HISTOPATHOLOGY: Yes - 3 animals/sex/group. Heart, lungs, liver, kidneys, spleen, stomach, small intestine, large intestine examined

Statistics:

Significance of differences between control and treatment groups examined using Student's t-test

Results and discussion

Results of examinations

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Total protein, urea and uric acid increased at 50 ppm

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Changes in spleen, kidneys and lungs at 50 ppm

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY: No data

BODY WEIGHT AND WEIGHT GAIN: Weight gain significantly increased (P<0.05), relative to controls, in animals treated at 50 ppm during first 2 weeks. Cumulative effects over total duration of study no differant from controls.

FOOD CONSUMPTION: No effects

FOOD EFFICIENCY: No effects

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Consumption increased (but not significantly), relative to controls, in animals treated at 50 ppm during first 4 weeks. Cumulative effects over total duration of study no differant from controls.

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: Total protein, urea and uric acid significantly increased (P < 0.05), relative to controls, in animals treated at 50 ppm.

URINALYSIS: Volume excreted significantly increased (P<0.05), relative to controls, in animals treated at 50 ppm during first 4 weeks

ORGAN WEIGHTS: No effects

GROSS PATHOLOGY: No details reported

HISTOPATHOLOGY - NON-NEOPLASTIC: There were mild histological changes in spleen, lungs and kidneys of all treated animals, more evident in animals treated at 50 ppm. These changes included hypertrophy and hyperplasy in the white pulp of spleen, corticomedullar microhaemorrhagic foci in the kidneys and mononuclear cell infiltration, mostly perivascular, in the lungs.

OTHER FINDINGS - TISSUE VANADIUM CONCENTRATION: Vanadium was not detected in the organs of control animals or in those treated at the lowest concentration investigated, 5 ppm. In the 10 ppm group, vanadium was detected in the kidneys (0.58 microgram/g tissue wet weight) and spleen (0.48 microgram/g tissue wet weight). In the 50 ppm group, measurable vanadium levels were evident in all analysed tissues with the highest concentrations found in the kidneys and the spleen (Liver – 0.30 microgram/g tissue wet weight; Kidneys – 2.92 microgram/g tissue wet weight; heart – 0.30 microgram/g tissue wet weight; spleen – 1.19 microgram/g tissue wet weight and lungs – 0.24 microgram/g tissue wet weight).

Effect levels

1

Dose descriptor:

LOAEL

Effect level:

50 ppm

Based on:

other: vanadium

Sex:

male/female

Basis for effect level:

other: clinical chemistry; histopathology

2

Dose descriptor:

NOAEL

Effect level:

10 ppm

Based on:

other: vanadium

Sex:

male/female

Basis for effect level:

other: overall effects

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Vanadium, administered in the drinking water at concentrations of 5, 10 and 50 ppm for 90 days, was generally well tolerated. There was no significant effect on weight gain, nutrition or organ weights. The only changes evident by blood chemistry investigations on termination of the study were slight increases in urea and uric acid in animals treated at 50 ppm, the authors suggesting that these may suggest some alterations in renal function. Microscopic examination of tissues revealed only mild lesions in the kidneys, spleen and lungs, these dose-dependent. Measurable levels of vanadium was significant only in the highest dose group, the authors commenting that the significance of these results and the potential kinetics of accumulation are not known.

Executive summary:

A sub-chronic study of 90 days duration has been undertaken in the rat using methods similar to OECD test guidelines in place at the time. Vanadium, administered in the drinking water at concentrations approximately 1/100, 1/50 and 1/10 of the oral LD50 were well tolerated, and did not affect weight gain, nutrition or organ weights. The only changes evident by blood chemistry investigations on termination of the study were slight increases in urea and uric acid in animals treated at 50 ppm, the authors suggesting that these may suggest some alterations in renal function. Microscopic examination of tissues revealed only mild lesions in the kidneys, spleen and lungs, these dose-dependent. Measurable levels of vanadium was significant only in the highest dose group, the authors commenting that the significance of these results and the potential kinetics of accumulation are not known.