Divanadyl pyrophosphate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards, well documented and acceptable for assessment.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Divanadyl pyrophosphate

EC Number:

407-130-0

EC Name:

Divanadyl pyrophosphate

Cas Number:

65232-89-5

Molecular formula:

(VO)2P2O7

IUPAC Name:

(phosphonooxy)phosphonic acid dihydrate vanadium

Details on test material:

- Physical state: grey/green powder
- Analytical purity: 96%
- Lot/batch No.: 104
- Storage condition of test material: at 13 °C protected from light.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK)
- Age at study initiation: 32-40 days
- Weight at study initiation: 73-86 g
- Housing: 5 animals per cage
- Diet: LAD1 complete, pelleted laboratory rodent diet (Biosure, UK), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 25 °C
- Humidity (%): 40 - 70 %
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 1% methylcellulose in distilled water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

by atomic adsorption spectrophotometry

Duration of treatment / exposure:

30 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
20, 100, 500 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: on basis of a preliminary study

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: twice weekly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 29
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes, overnight
- How many animals: all
- Parameters examined: packed cell volume, haemoglobin concentration, erythrocyte count, total and differential leucocyte count, platelet count, mean cell haemoglobin, mean cell volume.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 29
- Animals fasted: Yes, overnight
- How many animals: all
- Parameters examined: alkaline phosphatase, alanine amino-transferase, aspartate amino-transferase, urea, creatinine, glucose, bilirubin, total protein, sodium, potassium, chloride, calcium, inorganic phosphorus.

URINALYSIS: Yes
- Time schedule for collection of urine: day 25
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: appearance, volume, pH, specific gravity, protein, glucose, ketones, bilirubin, urobilinogen, nitrite, blood

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, detailed examination of the external features and orifices, the neck and the subcutaneous structures and the cranial, thoracic, pelvic and abdominal cavities and their viscera.

HISTOPATHOLOGY: Yes, abnormalities, adrenals, heart, kidneys, liver, spleen.

Other examinations:

Organ weight from adrenals, heart, kidneys, liver, spleen, testes was recorded.

Statistics:

The following test were used: student`s t-test, Dunnett´s or Fisher-Behrens tests and Fisher Exact Probability test.

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY
One male rat treated at 500 mg/kg/day showed bodyweight loss and was found dead on day 20. One female showed bodyweight loss from the beginning of the study, loose faeces, hunched posture and piloerection on Day 3 and was killed on Day 4 on humane grounds. A further female was hunched, thin and had reduced body temperature and muscle tone, muscle tremor, rapid respiration, piloerection and pallor on Day 21, and was killed on humane grounds on the same day.

Salivation was observed on days 20 to 28 in three females at 500 mg/kg bw and on day 20 in one female at 100 mg/kg bw.

BODY WEIGHT AND WEIGHT GAIN
Females treated with 500 mg/kg bw showed slighly lower body weight gain.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Females treated with 500 mg/kg bw showed slighly lower food consumption, particularly during the first week of treatment.

HAEMATOLOGY
The mean red cell-volumes of rats treated at 500 mg/kg/day were lower than those of the controls. In addition, haemoglobin concentrations and packed cell volumes were slightly lower and red cell numbers slightly higher than those of the controls. Females treated at this dosage had slightly lower lymphocyte and corresponding total leucocyte numbers and slightly higher platelet counts than the female controls.

CLINICAL CHEMISTRY
The plasma alanine amino-transferase activities of male and female rats treated at 500 mg/kg/day and female rats treated at 100 mg/kg/day were slightly higher than those of the controls. The plasma urea concentration of male rats treated at 500 mg/kg/day was marginally higher than that of the male controls and the plasma alkaline phosphatase activity of females treated at this dosage was slightly lower than that of the female controls.

URINALYSIS
Urine was considered to have been unaffected by treatment with.

ORGAN WEIGHTS
There were no differences in organ weight between treated and control animals that could be unequivocally attributed.
Slightly higher liver, kidney and spleen weights relative to bodyweight recorded for female rats treated at 500 mg/kg/bw/day, when compared with control values, were considered to have more likely reflected a difference in growth performance than a direct effect of the test material.

GROSS PATHOLOGY
There were no microscopic findings attributable to treatment. Enlarged lymph nodes were observed in some animals treated at 500 mg/kg bw/day but these were considered unlikely to be related to treatment.

HISTOPATHOLOGY:
Histopathology of the male that died revealed diminished glycogen and congestion in the liver. Histopathology of one female that was sacrificed revealed papillary mineralisation in the right kidney, plasmocytosis and parafollicular hyperplasia in the mesenteric lymph nodes and diminished glycogen and congestion in the liver. The second female that was sacrificed, showed hydronephrosis and vacuolation or degeneration of the right kidney tubules, hepatocytic degeneration and inflammation, diminished glycogen and congestion in the liver and atrophy of the splenic white pulp. In the surviving animals there were no other microscopic changes which were attributed to treatment.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: clinical signs; mortality;

2

Dose descriptor:

NOEL

Effect level:

20 mg/kg diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: clinical chemistry;

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

In conclusion, the oral administration at a dosage of 500 mg/kg/day for four consecutive weeks caused the death of three rats, haematological alterations and changes in blood chemistry. Effects at 100 mg/kg/day were essentially confined to a marginal increase in plasma alanine aminotransferase activity in females. The no observed adverse effect level (NOAEL) under the conditions of the present study was 100 mg/kg bw/day for both sexes.