Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 27 march 2017 to 15 September 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP compliance

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report date:
2017

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
22 September 2015
Test type:
acute toxic class method
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Tris[oxalato(2-)]dilutetium
EC Number:
222-328-5
EC Name:
Tris[oxalato(2-)]dilutetium
Cas Number:
3426-45-7
Molecular formula:
C6Lu2O12
IUPAC Name:
[mu-ethanedioato(2-)-kappaO~1~:kappaO~2~][bis(ethanedioato-kappaO~1~)]dilutetium(2+)
Constituent 2
Chemical structure
Reference substance name:
Water
EC Number:
231-791-2
EC Name:
Water
Cas Number:
7732-18-5
Molecular formula:
H2O
IUPAC Name:
Water
Test material form:
solid: particulate/powder
Details on test material:
Name: Tris[oxalate(2-)]dilutetium
Specific details on test material used for the study:
Correction factor: 1.16

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl:WI
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
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 9 weeks old
- Weight at study initiation: 184 - 212 g
- Fasting period before study: yes
- Housing: Type II polypropylene/polycarbonate
- Diet (e.g. ad libitum): ad libitum, except the night before treatment. 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 no.: 484 14771, expiry date: 30 June 2017).
- Water (e.g. ad libitum): ad libitum. Tap water from the municipal supply, as for human consumption was available from a 500 mL bottle.
- Acclimation period: yes, at least 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.7 – 25.0°C
- Humidity (%): 35 – 58 %
- Air changes (per hr): 15 – 20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.

IN-LIFE DATES: From: 28 March 2017 To: 12 April 2017

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: Prior to animal testing the solubility of the test item was assessed in a trial formulation. The order of the tested vehicles was according to the Study Plan until a suitable vehicle was found, therefore two vehicles, distilled water and 1% methyl cellulose (1% MC) were examined.
Formulation with distilled water resulted in a suspension with rapid sedimentation, thus 1% MC was also tested. Formulation with 1% MC resulted in a suspension with slow sedimentation. As this formulation was acceptable to use via oral gavage, 1% MC was found to be the appropriate vehicle. The formulations were stirred using a magnetic stirrer. The homogeneity of the formulation was assessed by visual inspection.
- Lot/batch no. (if required): 5115851

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION: Test item was freshly formulated at appropriate concentrations in the vehicle in the Pharmacy of CiToxLAB Hungary Ltd. on the day of administration. The formulation was stirred with a magnetic stirrer until completion of treatment.
Correction of the purity was applied as described est item information. The used correction factor for all formulations was 1.16.

CLASS METHOD
- Rationale for the selection of the starting dose: The initial dose level was selected by the Study Director to be that which was most likely to produce mortality in some of the dosed animals. Based on the preliminary toxicological information from the Sponsor, a limit dose of 2000 mg/kg bw was selected as a starting dose.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3 per group
Control animals:
no
Details on study design:
- 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. 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
- Other examinations performed:
* clinical signs: 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.
* necropsy: Macroscopic examination was performed on all animals. After examination of the external appearance, the cranial, thoracic and the abdominal cavities were opened and the organs and the tissues were observed. Macroscopic abnormalities were recorded if they were present.
Statistics:
Not applicable

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
Tris[oxalate(2-)]dilutetium did not cause mortality at a dose level of 2000 mg/kg bw.
Clinical signs:
All animals were symptom-free during the 14-day observation period at a dose level of 2000 mg/kg bw.
Body weight:
There were no effects on body weights or body weight gains that could be attributed to treatment with Tris[oxalate(2-)]dilutetium.
Gross pathology:
There was no evidence of the macroscopic observations in animals dosed at 2000 mg/kg bw and terminated on Day 14.

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 Tris[oxalate(2-)]dilutetium was found to be above 2000 mg/kg bw in female Crl:WI rats.
Executive summary:

The single-dose oral toxicity of Tris[oxalate(2-)]dilutetium was performed according to the acute toxic class method (OECD 423 and Commission Regulation (EC) No 440/2008 of 30 May 2008, B.1.tris) in Crl:WI Wistar rats.

Two groups of 3 female Crl:WI rats were treated with the test item at a dose level of 2000 mg of Tris[oxalate(2-)]dilutetium (active ingredient)/kg body weight (bw) (Group 1 and Group 2).

A single oral treatment was carried out by gavage for each animal after an overnight food withdrawal. Food was made available again 3 hours after the treatment. The test item was formulated in 1% Methyl cellulose 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 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.

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, 7 and 14 (before necropsy). All animals were subjected to a necropsy and a macroscopic examination.

The results of the study were summarized as follows:

Mortality: Tris[oxalate(2-)]dilutetium did not cause mortality at a dose level of 2000 mg/kg bw.

Clinical Observations:All animals were symptom-free during the 14-day observation period at a dose level of 2000 mg/kg bw.

Body Weight and Body Weight Gain: There were no effects on body weights or body weight gains that could be attributed to treatment with Tris[oxalate(2-)]dilutetium.

Necropsy: There was no evidence of the macroscopic observations in animals dosed at 2000 mg/kg bw and terminated on Day 14.

 

Conclusion: Under the conditions of this study, the acute oral LD50 value of the test item Tris[oxalate(2-)]dilutetium was found to be above 2000 mg/kg bw in female Crl:WI rats.

According to the GHS criteria, Tris[oxalate(2-)]dilutetium can be ranked as "Category 5 or Unclassified" for acute oral exposure.