Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From April 30 to May 23, 2008.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted according to internationally accepted testing guidelines and performed according to GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report Date:
2008

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
adopted 17th December 2001
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd.
- Animals: rat, HanRcc: WIST(SPF).
- Age at study initiation: 11 weeks.
- Housing: in groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenzl Switzerland) .
- Diet: ad libitum: pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 12/08 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland).
- Water: ad libitum; community tap water from Fiillinsdorf.
- Acclimation period: under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C, continuously monitored.
- Humidity: between 30-70 % (values above 70 % during cleaning process possible).
- Air changes: 10-15 air changes per hour.
- Photoperiod: light cycle of 12 hours light and 12 hours dark.
- Other: music during the daytime light period.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
VEHICLE
- Vehicle: polyethylene glycol 300 (PEG 300)
- Justification for choice of vehicle: the vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date. This formulation trial is excluded from the statement of compliance.
- Lot/batch no.: 1310049

DOSE FORMULATION
The dose formulations were made shortly before each dosing occasion using a magnetic stirrer, a spatula and/or an Ultra-Turrax (Janke & Kunkel, D-79219 Staufen) as homogenizers.
The test item was weighed into a tarred glass beaker on a suitable precision balance and the vehicle added (weight:volume).
Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.
The test item was diluted in vehicle at a concentration of 0.2 g/ml and administered at a dosing volume of 10 ml/kg.

TREATMENT
The animals received a single dose of the test item by oral gavage administration at 2000 mg/kg body weight after being fasted for approximately 17 to 18 hours (access to water was permitted). Food was provided again approximately 3 hours after dosing.
The dosing volume was 10 ml/kg body weight.
Doses:
Single dose at 2000 mg/kg bw.
No. of animals per sex per dose:
3 females per group; two groups tested.
Details on study design:
OBSERVATIONS
- Duration of observation period following administration: 15 days
- Mortality / Viability: daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.
- Body Weights: on test days 1 (prior to administration), 8 and 15.
- Clinical Signs: daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. All abnormalities were recorded.
- Necropsy: all animals were killed at the end of the observation period by Carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. No organs or tissues were retained.
Statistics:
No statistical analysis was used.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the study.
Clinical signs:
Soft feces were recorded in one animal at the 3-hour observation. Otherwise, no clinical signs were observed during the course of the study.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
No macroscopic findings were recorded at necropsy.

Any other information on results incl. tables

Mortality / Clinical Signs

Dose mg/kg bw Animal N. Sex Signs Test days
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
0.5 1 2 3 5
2000 1 F No clinical signs
2 F No clinical signs
3 F No clinical signs
2000 4 F No clinical signs
5 F No clinical signs
Soft feces
6 F No clinical signs
Key:  √ noted

* Examinations were performed within the first 30 minutes and 1, 2,3 and 5 hours after treatment.

No clinical signs were evident in any animal during the acclimatization period.

Macroscopical findings (scheduled necropsy, 21 May-08, day 15 after treatment)

Group 1:

Animal 1: no findings noted

Animal 2: no findings noted

Animal 3: no findings noted

Group 2:

Animal 4: no findings noted

Animal 5: no findings noted

Animal 6: no findings noted

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information according to the CLP Regulation Criteria used for interpretation of results: EU
Conclusions:
LD50 (female rat): greater than 2000 mg/kg body weight.
Executive summary:

Method

Two groups, each of three female HanRcc:WIST (SPF) rats, were treated with test item by oral gavage administration at a dosage of 2000 mg/kg body weight. The test item was diluted in vehicle (PEG 300) at a concentration of 0.2 g/ml and administered at a dosing volume of 10 ml/kg.

The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs within the first 30 minutes and approximately 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.

Results

All animals survived until the end of the study period. Soft feces were recorded in one animal at the 3-hour observation. Otherwise, no clinical signs were observed during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were recorded at necropsy.

Conclusion

The median lethal dose of test item after single oral administration to female rats, observed over a period of 14 days is:

LD50 (female rat): greater than 2000 mg/kg body weight.