Lutetium oxide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

31 August 2016 -13 January 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

yes

Remarks:

Small protocol deviations. These deviations are considered to have no impact on the outcome of the study and interpretation of the results. See "Any other information on materials and methods incl. tables".

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

yes

Remarks:

Small protocol deviations. These deviations are considered to have no impact on the outcome of the study and interpretation of the results. See "Any other information on materials and methods incl. tables".

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

Small protocol deviations. These deviations are considered to have no impact on the outcome of the study and interpretation of the results. See "Any other information on materials and methods incl. tables".

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Lutetium oxide

EC Number:

234-764-3

EC Name:

Lutetium oxide

Cas Number:

12032-20-1

Molecular formula:

Lu2O3

IUPAC Name:

Lutetium oxide

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study report): dilutetium trioxide
- Physical state/Appearance: white solid
- Further information confidential.

Specific details on test material used for the study:

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: On the day of administration, the test item was freshly formulated at a concentration of 200 mg/mL in the vehicle.
- No correction for purity of the test item was applied.

FORM AS APPLIED IN THE TEST (if different from that of starting material) : formulation with polyethylene glycol (PEG 400) at a concentration of 200 mg/mL

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Crl

Sex:

female

Details on test animals or test system 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: young healthy adult rats, 9 weeks old
- Weight at study initiation: 209 - 225 g. Body weight variation did not exceed +/-20% of the sex mean.
- Fasting period before study: Overnight. Food but not water, was withheld during the overnight period before treatment.
- Housing: Group caging (3 animals/cage) in type II. polypropylene/polycarbonate (23*38*18 cm), “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) were available to animals during the study.
- Diet (e.g. ad libitum): 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: 278 5652, expiry date: 30 November 2016), 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: 14-15 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.8 – 25.1ºC
- Humidity (%): 34-75%
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 dark/12 light

IN-LIFE DATES
- From: 2016-08-31 To: 2016-09-14 (females no. 2164, 2165, 2166)
- From: 2016-09-01 To: 2016-09-15 (females no. 2167, 2168, 2169)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

PEG 400

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL (PEG 400)
- Amount of vehicle (if gavage): 10 mL/kg bw
- 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.
- Lot/batch no. (if required): BCBQ0052V

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION: Test item was freshly formulated on the day of administration. The stability and concentration in the vehicle were not determined. 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.

- 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. Based on the 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. 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 (OECD 423, Commission Regulation (EC) No. 440/2008 of 30 May 2008, B.1.Tris).

Doses:

single dose, 2000 mg/kg bw

No. of animals per sex per dose:

2 groups; 3 females/group

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
* 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 except one occasion which was afternoon.
* 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.
* Body weight: The body weight was recorded on the day before treatment (Day -1), on the day of the treatment (Day 0) and weekly thereafter.
- Necropsy of survivors performed: Yes, all animals were subjected to a necropsy and a macroscopic examination. The animals were exsanguinated after verification of narcosis following an injection of pentobarbital sodium (Euthanimal 40%; Lot No.: 1409236-06, Expiry Date: September 2017, Produced by: AlfasanNederland BV, Woerden, Netherlands). 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 item did not cause mortality at a dose level of 2000 mg/kg bw.

Clinical signs:

other: All animals were symptom free during the study.

Gross pathology:

There was no evidence of macroscopic observations at a dose level of 2000 mg/kg bw.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of the study, the acute oral LD50 value of the test item was found to be above 2000 mg/kg bw in female Crl:(WI) rats. According to these results, lutetium oxide needs not to be classified according to CLP criteria.