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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
27 April 2016 to 12 May 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Cross-reference
Reason / purpose:
other: read-across target
Reference
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study conducted on read-across material
Justification for type of information:
Read-across to structurally similar substance erbium, gadolinium, yttrium and zirconium oxide (EC 946-001-8). The only difference between the substance being registered and the read-across substance is that the substance to be registered is missing the gadolinium oxide content (about 1.4 %). The absence of this compound at such a low % is considered highly unlikely to affect its properties.
Reason / purpose:
read-across source
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.

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

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl:(WI) rats
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D97633 Sulzfeld, Germany.
- Females nulliparous and non-pregnant: Yes
- 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: Ad libitum, free access to rodent diet.
- Water: 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 air exchanges per hour.
- 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 material. 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
The test material 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 material and the test material 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 material.

CLASS METHOD
- 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, 2 000 mg/kg bw was selected to be the starting dose. The limit dose (= starting dose level) for this study was 2 000 mg/kg bw.
Doses:
2 000 mg/kg (single dosage). A second test at the same dose level was performed.
No. of animals per sex per dose:
Three 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: Recorded on the day before treatment (Day -1), on the day of the treatment (Day 0) and weekly thereafter.
* Clinical signs: Animals were observed individually 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. The method used is not intended to allow the calculation of a precise LD50 value.

Results and discussion

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

Any other information on results incl. tables

Initially, three females (Group 1) were treated at a dose level of 2 000 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.

Applicant's summary and conclusion

Interpretation of results:
other: Not classified according to EU criteria
Conclusions:
Under the conditions of this study, the acute oral LD50 value of the test material was found to be above 2 000 mg/kg bw in female Crl:(WI) rats.
Executive summary:

The acute oral toxicity of the test material was investigated in a study which was conducted in accordance with the standardised guidelines OECD 423, EU Method B.1 Tris and US EPA OPPTS 870.1100, under GLP conditions.

During the study, two groups of three female Crl:(WI) rats were treated with the test item at a dose level of 2 000 mg/kg bw via oral gavage (Group 1 and Group 2).

A single oral treatment was carried out by gavage for each animal after an overnight food withdrawal. The animals were fasted for not more than 16 hours. Food was made available again 3 hours after the treatment. The test material was administered formulated in PEG 400 at a concentration of 200 mg/mL at a dose volume of 10 mL/kg bw.

Initially, three females (Group 1) were treated at a dose level of 2 000 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.

Clinical observations were performed at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Body weight was measured on Days -1, 0 and 7 and before necropsy. All animals were subjected to a necropsy and a macroscopic examination.

None of the animals died and all animals were symptom free during the study. Body weight gains of animals treated with test material showed no indication of a test material-related effect. There was no evidence of the macroscopic observations at a dose level of 2 000 mg/kg bw.

Therefore, under the conditions of the study the acute oral LD50 value of the test material was found to be above 2 000 mg/kg bw in female Crl:(WI) rats.