Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2016-04-27 to 2016-05-12
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report Date:
2016

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: PEGYZ-23
- Expiration date of the lot/batch: 31 March 2021
- Purity: 100%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Controlled room temperature (15-25 ºC, below 70% relative humidity), protected from light.

OTHER SPECIFICS
Description: pink powder (the colour was determined by visual inspection upon arrival at test facility)
Safety precautions: Routine safety precautions (lab coat, gloves, safety glasses, face mask) for unknown materials were applied to assure personal health and safety. Possibly irritative.

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl:(WI) rats
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: female rats (nulliparous and non-pregnant); Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D97633 Sulzfeld, Germany
- Age at study initiation: 9 weeks old
- Weight at study initiation: 203 – 216 g, body weight variation did not exceed +/- 20% of the sex mean
- Fasting period before study: The night before treatment the animals were fasted for a maximum of 16 hours. Food but not water, was withheld overnight.
- Housing: Group housing of 3 animals per cage. Cage type: Type II. polypropylene/polycarbonate. Bedding: “Lignocel 3/4-S Hygienic Animal Bedding” and “Arbocel crinklets natural” nest building material produced by J. Rettenmaier & Söhne GmbH & Co.KG (D-73494 Rosenberg, Germany)
- Diet (e.g. ad libitum): ad libitum, free access to rodent diet
- Water (e.g. ad libitum): ad libitum, free access to tap water
- Acclimation period: 13-14 days before start of treatment under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.6-23.9 °C
- Humidity (%): 26-70%
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 400
Details on oral exposure:
VEHICLE
- Justification for choice of vehicle: The selection of the vehicle was based on trial formulations with the test item. In order of preference, the recommended vehicles were the following: distilled water, 0.5 or 1% methyl cellulose or carboxymethylcellulose, PEG 400, corn oil, sunflower oil or DMSO. Trial formulations with distilled water and 1% methyl cellulose caused noticeably rapidly settling formulations, therefore they were considered as not suitable for treatments. Consequently, PEG 400 was also tried as a vehicle, which resulted in an acceptably stable formulation, suitable for treatments.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION
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 stability and concentration in vehicle was not determined. However, to limit the impact, the formulations were used within 4 hours after adding the vehicle to the test item and the test item preparation was performed with approved procedures and documented in detail. 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.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:
The initial dose level was selected by the Study Director to be that which is most likely to produce mortality in some of the dosed animals. In the lack of any preliminary toxicological information, 2000 mg/kg bw was selected to be the starting dose. The limit dose (= starting dose level) for this study was 2000 mg/kg bw.
Doses:
2000 mg/kg (single dosage). A second test at the same dose level was performed.
No. of animals per sex per dose:
3 females per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days (dosing on day 0)
- Frequency of observations and weighing:
* mortality/viability: not explicitly mentioned
* body weights: on the day before treatment (Day -1), on the day of the treatment (Day 0) and weekly thereafter
* clinical signs: after dosing at 30 minutes, then 1, 2, 3, 4 and 6 hours after the treatment and once each day in the morning for 14 consecutive days thereafter
* individual observations were performed on the skin and fur, eyes and mucous membranes and also 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
- Necropsy of survivors performed: Yes, all animals were subjected to a necropsy and a macroscopic examination. After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed. All gross macroscopic changes were recorded for each animal.

Statistics:
No statistical analysis was performed.

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Erbium gadolinium yttrium zirconium oxide did not cause mortality at a dose level of 2000 mg/kg bw.
Clinical signs:
All animals were symptom free during the study.
Body weight:
Body weight gains of erbium gadolinium yttrium zirconium oxide treated animals during the study showed no indication of a test item-related effect.
Gross pathology:
There was no evidence of the macroscopic observations at a dose level of 2000 mg/kg bw.

Any other information on results incl. tables

Initially, three females (Group 1) were treated at a dose level of 2000 mg/kg bw. As no mortality was observed, a confirmatory group (Group 2) was treated at the same dose level. No mortality was observed in the confirmatory group. Therefore, no further testing was required according to OECD 423 and Commission Regulation (EC) No 440/2008 of 30 May 2008, B.1.Tris.

Deviations from the study plan:

Due to technical reasons, a relative humidity value (minimum of 26%) outside the expected range of 30-70% was once recorded during the acclimatisation period of the study. However, this minor difference of the environmental parameter was considered not to have adversely affected the results or integrity of the study as confirmed by the clinical veterinarian.

During the formulation, the test item was weighed and the formulations were prepared on a weight:volume basis (as (w/v)%) in the Pharmacy, therefore adjustment for specific gravity of the vehicle was not made.

These deviations are considered not to have had an impact on the outcome of the study and interpretation of the results.

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 erbium gadolinium yttrium zirconium oxide was found to be above 2000 mg/kg bw in female Crl:(WI) rats. The study result does not trigger classification under CLP or GHS.