Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2017-08-22 to 2017-09-06
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report Date:
2018

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
17 Dec 2001
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
30 May 2008
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study report): Tungsten zirconium hydroxide oxide
- Physical state: solid
- Appearance: white powder
- Further information on test material confidential
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Controlled room temperature (15-25°C, below 70 RH%).
- Stability under test conditions: Analysis of stability, homogeneity and concentration of the test item under test conditions was not performed as part of this study.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The formulation was homogenised to visually acceptable levels and was stirred up to finishing the treatment to ensure sufficient homogeneity. No correction was made for the purity/composition of the test item.

Test animals

Species:
rat
Strain:
other: Crl:(WI)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 9 weeks old
- Weight at study initiation: 205 - 232 g. Body weight variation did not exceed +/- 20% of the sex mean.
- Fasting period before study: overnight
- Housing: Type II. polypropylene/polycarbonate cages, with Lignocel 3/4-S Hygienic Animal Bedding produced by J. Rettenmaier & Söhne GmbH + CO.KG (D-73494 Rosenberg, Germany) was available to animals during the study. Arbocel crinklets natural produced by J. Rettenmaier & Söhne GmbH + CO.KG (D-73494 Rosenberg, Germany) was available to animals during the study.
- Diet (e.g. ad libitum): Animals received ssniff® SM R/M "Autoclavable complete diet for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest, Germany (Batch number: 262 21592, Expiry date: 31 January 2018), ad libitum.
- Water (e.g. ad libitum): Tap water from the municipal supply, as for human consumption from a 500-mL bottle, ad libitum.
- Acclimation period: At least 12 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.1 – 23.9 °C
- Humidity (%): 32 – 71 %
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): Light-12 hours daily, from 6.00 a.m. to 6.00 p.m.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
methylcellulose
Remarks:
1%
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: The selection of the vehicle was based on trial formulations with the test item. The test item was found to be insoluble in distilled water (the formulation separated immediately to different phases) at a concentration of 200 mg/mL. With 1% methylcellulose aqueous solution, the formulation (suspension) was found to be acceptable for oral gavage.
- Lot/batch no. (if required): 5115851

DOSAGE PREPARATION (if unusual): The test item was freshly formulated at a concentration of 200 mg/mL in the vehicle in the Pharmacy of Citoxlab Hungary Ltd. on the day of administration. The formulation container was magnetically stirred continuously up to the end of dose administration procedures. Formulations were used within 4 hours after preparation.
Doses:
A single dose of 2000 mg/kg bw.
No. of animals per sex per dose:
3 females per group, 2 groups
Control animals:
no
Details on study design:
- Procedure: A single dose of 2000 mg/kg bw was administered by oral gavage (using a stainless steel bulb tipped gastric feeding tube attached to a syringe) in the morning. - Food was withheld overnight for a maximum of 16 hours before treatment, and returned 3 hours after treatment.
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were performed on all animals at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Individual observations were performed on the skin, fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. The body weight was recorded on the day before treatment (Day -1), on the day of the treatment (Day 0), weekly thereafter (Day 7) and at necropsy (Day 14).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopic observations
Statistics:
No statistical analysis was performed (the method used is not intended to allow the calculation of a precise LD50 value).

Results and discussion

Preliminary study:
Initially, three female animals were treated with 2000 mg/kg bw of the test item. No mortality was observed, therefore further 3 animals were treated at the dose level of 2000 mg/kg bw. As no mortality was observed in this second dose group, further testing was not required according to the test guidelines
Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
The test item did not cause mortality at a dose level of 2000 mg/kg bw in any animal.
Clinical signs:
All animals were symptom-free during the observation period at a dose level of 2000 mg/kg bw.
Body weight:
There were no treatment related body weight changes. Body weights were within the range commonly recorded for this strain and age.
Gross pathology:
There was no evidence of macroscopic changes at a dose level of 2000 mg/kg bw in any animal.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, the acute oral LD50 value of the test item tungsten zirconium hydroxide oxide was found to be above 2000 mg/kg bw in female Crl:(WI) rats.
The substance is not classified according to the CLP Regulation.