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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
From July 27th to August 19th, 2005
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted according to internationally accepted testing guidelines and performed in compliance with Good Laboratory Practice. Justification for read across approach is given in the endpoint summary and in the read across justification report attached to the Section 13 of this dossier.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report date:
2005

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
adopted 17th December 2001
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
April 29, 2004
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes

Test material

Test animals

Species:
rat
Strain:
other: HanRcc:WIST (SPF))
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services CH-4414 Füllinsdorf / Switzerland.
- Age at study initiation: 11-13 weeks.
- Weight at study initiation: 174.2 - 199.7 g.
- Fasting period before study: the animals received a single dose of the test item after being fasted for approximately 18 to 19 hours (access to water was permitted). Food was provided again 3 hours after dosing.
- Housing: Makrolon type-4 cages with wire mesh tops and standard softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland).
- Diet: pelleted standard Provimi Kliba 3433 rat/mouse mainte-nance diet, batch no. 25/05 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad libitum.
- Water: community tap water from Füllinsdorf ad libitum.
- Acclimation period: under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature: continuously monitored environment with ranges for room temperature 22 ± 3 °C.
- Humidity: between 30-70 % (values above 70 % during cleaning process possible).
- Air changes: 10-15 air changes per hour.
- Photoperiod: automatically controlled 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:
water
Remarks:
purified
Details on oral exposure:
VEHICLE
Purified water was found to be a suitable 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 GLP statement of compliance.

DOSE FORMULATION
Dose levels are in terms of the test item. The dose formulations were made shortly before each dosing occasion using a magnetic stirrer, a spatula and an Ultra-Turrax (Janke & Kunkel, D-79219 Staufen) as homogenizers.
The test item was weighed into a tared 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.

TREATMENT
- Application volume: 10 ml/kg body weight.
- Rationale: oral administration was considered to be an appropriate application method as it is a possible route of human exposure during manufacture, handling and use of the test item.
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
2 goups of 3 female each one.
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: mortality and viability were controlled 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 were recorded on test days 1 (prior to administration), 8 and 15.
- Necropsy of survivors performed: all animals were killed at the end of the observation period by an intraperitoneal injection of Vetanarcol at a dose of at least 2.0 ml/kg body weight (equivalent to at least 324 mg sodium pentobarbitone/kg body weight) and discarded after macroscopic examinations were performed. No organs or tissues were retained.
- Other examinations performed: clinical signs were daily observed 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.
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:
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
0.5* 1* 2* 3* 5*
2000 1 F No clinical signs
2 F No clinical signs
3 F No clinical signs
2001 4 F No clinical signs
5 F No clinical signs
6 F No clinical signs

Key: √ noted

* Examinations were performed approximately 0.5, 1, 2, 3 and 5 hours after treatment.

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

BODY WEIGHTS

Dose mg/kg bw Animal N. Sex Day 1 (treatment) Day 8 Day 15
2000 1 F 180.3 197.9 211.8
2 F 174.2 203.2 214.2
3 F 199.7 222.8 233.2
2001 4 F 176.1 199.7 212.3
5 F 176.1 204.1 218.0
6 F 194.2 218.5 228.3

Body weights are presented in grams.

MACROSCOPIC FINDINGS

Dose mg/kg bw Animal N. Sex Mode of death Findings
2000 1 F Scheduled necropsy No macroscopic findings
2 F Scheduled necropsy No macroscopic findings
3 F Scheduled necropsy No macroscopic findings
2001 4 F Scheduled necropsy No macroscopic findings
5 F Scheduled necropsy No macroscopic findings
6 F Scheduled necropsy No macroscopic findings

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information according to the CLP Regulation (EC 1272/2008) Criteria used for interpretation of results: EU
Conclusions:
LD50 (female rat) > 2000 mg/kg body weight
Executive summary:

Two groups, each of three female HanRcc:WIST (SPF) rats, were treated with the test item by oral gavage administration at a dosage of 2000 mg/kg body weight. The test item was diluted in vehicle (purified water) at a concentration of 0.2 g/ml and administered at a volume dosage 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 at approximately 30 minutes, 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. All animals survived until the end of the study period. 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

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