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Description of key information

Acute Oral Toxicity

Read-across to structurally similar substance erbium, gadolinium, yttrium and zirconium oxide (EC 946-001-8)

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.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

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
Reason / purpose:
other: read-across target
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
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.
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.
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.
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.

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.

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.

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.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

> Acute Oral Toxicity

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. The study was conducted on the read-across 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.

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.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to acute toxicity via the oral route.