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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2009-09-24 to 2010-12-20
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study conducted according to OECD Guideline 423: Acute Oral Toxicity-Acute Toxic Class Method, except that the second dose used after 2000 mg/kg was 1373 mg/kg instead of the recommended 300 mg/kg as the purpose of the study was not only to determine the acute oral toxicity of the test substance, but to aid in the classification according to the CLP regulations and to support a read-across strategy for tungsten substances.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report date:
2010

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
The second dose used after 2000 mg/kg was 1373 mg/kg instead of 300 mg/kg.
GLP compliance:
yes
Remarks:
Statement, no certificate
Test type:
acute toxic class method
Limit test:
yes

Test material

Constituent 1
Reference substance name:
Ammonium metatungstate
IUPAC Name:
Ammonium metatungstate
Constituent 2
Chemical structure
Reference substance name:
Hexaammonium wolframate
EC Number:
234-733-4
EC Name:
Hexaammonium wolframate
Cas Number:
12028-48-7
Molecular formula:
[(NH4)6(H2W12O40)*3H2O]
IUPAC Name:
Hexaammonium Wolframate
Details on test material:
- Name of test material (as cited in study report): Ammonium metatungstate
- Physical state: White powder
- Analytical purity: 99.999%
- Storage condition of test material: The test substance was stored at room temperature (~15-30 degrees C).
- Stability under test conditions: Stable for at least 48 hours in water
- Storage condition of test material: Room temperature in the dark

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories (Portage, MI)
- Age at study initiation: 7-8 weeks at arrival
- Weight at study initiation: 170-198 g (bw of first shipment day after arrival), 186-201 g (bw of second shipment day after arrival)
- Fasting period before study: Yes, overnight
- Housing: Rats were individually housed in stainless steel wire cages suspendered over excrement pans. Absorbent pan liners were placed in the pan below the stainless steel mesh floor of each animal cage to absorb liquids.
- Diet (eg ad libitum): Certified Rodent Chow 5002 meal was provided ad libitum, except for an overnight fasting period immediately preceding test substance administration, and 3 to 4 hours after dosing.
- Water (eg ad libitum): Fresh city of Chicago water without additional treatment was available ad libitum.
- Acclimation period: ~1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.4-23.6
- Humidity (%): 31-69
- Air changes (per hr): IITRI does not monitor animal room air changes daily; however, IITRI measures animal room air flow rates annually.
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
Milli-Q
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 100, 150 and 400 mg/ml

MAXIMUM DOSE VOLUME APPLIED: The maximum volume did not exceed 1 ml/100 g body weight.

DOSAGE PREPARATION: The test substance dosing formulations were prepared either one day prior to or on the day of dosing, by dissolving the bulk test substance in Milli-Q water and mixing until dissolved.

Doses:
2000, 1373, and 1000 mg/kg
No. of animals per sex per dose:
3 animals (2000 mg/kg), 6 animals (1373 mg/kg) and 6 animals (1000 mg/kg); See "any other information on materials and method" section.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All animals were observed at least once during the first 30 minutes after dosing, periodically during the first 24 hours (with special attention given during the first 4 hours) and at least once daily thereafter (for all surviving animals). Observations included any changes in skin and fur, eyes and mucous membranes, respiratory, circulatory and autonomic and central nervous systems, and somatomotor activity and behaviour pattern. Special attention was given to observations of tremors, convulsions, salivation, diarrhea, lethargy and coma. Body weights were determined one day after receipt and on the day of randomization to facilitate test subject selection. Body weights for study animals were measured on the day of treatment (prior to dosing), weekly thereafter (for all surviving animals), and at death.
- Necropsy of survivors performed: yes; A limited gross necropsy was performed on all animals which died during the study or were sacrificed at the end of the 14 day observation period. The necropsy on day 15 included examination of all body surfaces and orifices; and the external appearance of the brain, heart, lungs, spleen, liver, kidneys, gastrointestinal tract, urinary bladder and gonads. If external lesions were present, then the stomach and the rest of the gastrointestinal tract and the urinary bladder were opened and examined.
Statistics:
As a vehicle control group was not used, and the number of animals was not sufficient, statistical analyses on clinical observations, body weight and body weight gain were not conducted.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 1 000 - < 1 373 mg/kg bw
Remarks on result:
other: Estimated
Mortality:
The three animals from Group 1, which were dosed at 2000 mg/kg, all died; the six animals in groups 2 and 3, which were dosed at 1373 mg/kg, all died; no animal deaths occurred in groups 4 and 5, which were dosed at 1000 mg/kg.
Clinical signs:
Clinical observations observed during the post dosing periods included:
Group 1 (2000 mg/kg): discolored inguinal fur, discolored urine, rough coat, and redness around nose fur.

Groups 2 and 3 (1373 mg/kg): rough coat, salivation, emaciation, diarrhea, redness around nose fur, hypoactivity, thinness and alopecia.

Groups 4 and 5 (1000 mg/kg): diarrhea, alopecia, rough coat, scant feces, and thinness.

These observations (with the exception of alopecia) were determined to be the result of the test substance.
Body weight:
One animal from group 1 (2000 mg/kg) survived until day 8 and lost 47 g; two animals from Group 2 (1373 mg/kg) survived until day 8 and had a mean body weight loss of 42 g, two animals from Group 3 (1373 mg/kg) had a mean loss of 38 g. The animals in groups 4 and 5 (1000 mg/kg) had mean body weight gains of -10 and 1 g at day 8, respectively; and mean body weight gains of 30 and 17 g at day 15, respectively.
Gross pathology:
Gross necropsy observations seen in animals that died included dark red small intestine, dark red fluid in the stomach, red foci on the stomach, dilated urinary bladder, enlarged cervical lymph node, enlarged and red mesenteric, mandibular and bronchial lymph nodes, pale liver and kidney, and clear fluid in the pleural cavity. The six animals in the 1000 mg/kg group had no gross observations at necropsy.

Any other information on results incl. tables

The dose formulations prepared at 150 mg/ml were within 10% of the target concentration. The dose formulation prepared at 400 mg/ml was found to be 118 % of its target value. Chemical analysis was not performed on the 1000 mg/kg (100 mg/ml) formulation as the standard practice at IITRI is to verify at least two formulations: The results of the formulations analysis (the 400 mg/ml formulation was 18% higher than the target and the 150 mg/ml formulation was 10% higher than the target) would indicate that the 100 mg/ml formulation was prepared within the target range.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The estimated oral LD50 of treated female Sprague Dawley rats was >1000-<1373 mg/kg.