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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:
31 May 2012 - 16 July 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Compliant to GLP and testing guidelines; adequate consistence between data, comments and conclusions.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Test guidelineopen allclose all
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
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Test material form:
other: liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: breeder: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: approximately 8 weeks old on the day of treatment
- Mean body weight at study initiation: 218 g (range: 203 g to 226 g)
- Fasting period before study: yes, during the night before treatment
- Housing: polycarbonate cages with stainless steel lids
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: at least 5 days before treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h.

IN-LIFE DATES: 12 June 2012 to 10 July 2012.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 and 200 mg/mL
- Justification for choice of vehicle: The vehicle used in this study was selected from the results of solubility assays performed by the CiToxLAB France Pharmacy.
In the absence of recommendation from the Sponsor, the solubility assay first started at the concentration of 200 mg/mL, and the first choice vehicle was drinking water treated by reverse osmosis. As unsatisfactory solubility of the test item was obtained in this vehicle (i.e. heterogeneous emulsion or suspension at the concentration of 200 mg/mL was obtained), another vehicle was chosen from the following organic solvents (in order of preference): 0.5% methylcellulose aqueous solution and corn oil. A homogenous suspension was obtained at the concentration of 200 mg/mL in corn oil.
- Maximum dose-volume applied: 20 mL/kg

DOSAGE PREPARATION (if unusual):
The test item was administered as a homogenous suspension in the vehicle. The test item was mixed with the required quantity of vehicle.
Dose formulations preparations were prepared by the CiToxLAB France Pharmacy extemporaneously on the day of each administration.
The dose formulations were stored in a well ventilated place, at a temperature < 45°C, and delivered to the study room in brown flasks.

CLASS METHOD (if applicable):
- Rationale for the selection of the starting dose:
The starting dose-level was selected in agreement with the Sponsor, based on the following rationale: since no relevant toxicity data are available for the estimation of a lethal dose-level and any existing data were taken into account by the Sponsor, the starting dose-level was 300 mg/kg for animal welfare reasons.
Doses:
300 and 2000 mg/kg.
No. of animals per sex per dose:
3 females per treatment step.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Clinical observations: frequently during the hours following treatment; then, at least once a day.
- Body weight: just before treatment on day 1; then on days 8 and 15.
- Necropsy of survivors performed: yes (macroscopic).
Statistics:
No

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No mortality on 6 females treated with 2000 mg/kg
Mortality:
No unscheduled deaths occurred during the study.
Clinical signs:
Piloerection was observed between 1 and 3 hours and/or 4 hours after treatment in 2/3 females treated at 300 mg/kg. There were no clinical signs observed at the dose-level of 2000 mg/kg.
Body weight:
When compared to CiToxLAB France historical control data, a slightly lower body weight gain was noted in 3/6 females treated at 2000 mg/kg between day 1 and day 8 (+22 g to +36 g vs. +44 ± 4.2 g in control data base) and between day 8 and day 15 (+10 g and +13 g vs. +20 ± 5.7 g in control data base).
A slightly lower body weight gain was also noted in 2/3 females treated at 300 mg/kg between day 1 and day 8 (+28 g and +38 g vs. +44 ± 4.2 g in control data base) and between day 8 and day 15 (+5 g and +12 g vs. +20 ± 5.7 g in control data base).
Gross pathology:
The few macroscopic findings noted (red discoloration in the thymus in two females from group 3) at the end of the observation period were of those commonly recorded in the Sprague-Dawley rat and none were considered to be related to the test item administration.
Other findings:
no

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: CLP Regulation
Conclusions:
The oral LD50 of the test item was higher than 2000 mg/kg in rats.
Therefore, the test item is not classified as toxic or harmful by oral route according to the criteria of CLP Regulation.
Executive summary:

The objective of this study was to evaluate the potential acute toxicity of the test item following a single oral administration (gavage) to rats.

This study was performed according to the international guidelines (OECD No. 423 and Council Regulation No. 440/2008 of 30 May 2008, Part B.1tris) andin compliance with the principles of Good Laboratory Practices.

 

Methods

The test item was administered once by oral route (gavage) to three groups of three fasted female Sprague-Dawley rats under a dosage-volume of 10 mL/kg. The test item was prepared in corn oil.

Since no relevant toxicity data were available for the estimation of a lethal dose-level and any existing data have been taken into account by the Sponsor, the starting dose-level was 300 mg/kg for ethical reasons. After the first assay, the next higher dose-level of 2000 mg/kg was tested. Then, as no toxicity was observed at this higher dose-level, the results were confirmed in other females by using the same dose‑level.

Each animal was observed at least once a day for mortality and clinical signs for 15 days. Body weight was recorded on day 1 and then on days 8 and 15.

On completion of the observation period, the animals were sacrificed and then submitted for a macroscopic post-mortem examination.Macroscopic lesions were preservedin buffered formalin thendestroyed at the finalization of the study report as no microscopic examination was performed.

Results

No unscheduled deaths occurred during the study.

Piloerection was observed between 1 and 3 hours and/or 4 hours after treatment in 2/3 females treated at 300 mg/kg. There were no clinical signs observed at the dose-level of 2000 mg/kg.

When compared to CiToxLAB France historical control data, a slightly lower body weight gain was noted in females treated at 300 or 2000 mg/kg between day 1 and day 15.

The test item administration did not induce any macroscopic changes.

Conclusion

The oral LD50 of the test item was higher than 2000 mg/kg in rats.

Therefore, the test item is not classified as toxic or harmful by oral route according to the criteria of CLP Regulation.