Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 09.Mar.2006 to 06.Apr.2006
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Test inspired from OECD guideline 420, with only one dose tested at 500 mg/Kg bw.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report Date:
2013

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratoires France, Domaine des Oncins, 69592 L'Arbresle Cedex, France
- Age at study initiation: 8-12 weeks at the time of administration
- Weight at study initiation: In each group, individual weights of the animals did not deviate from the group mean weight by more than ± 20%. At the day of administration,weights were 207.8g, 217.3g and 209.3g.
- Fasting period before study: Animals were fasted during the night before treatment but had free access to water. They remained deprived of food for 3-4 hours post-dose.
- Housing: Observations were performed at the time of delivery of the animals and daily during the period of acclimatisation. Animals were housed in cages of standard dimensions with sawdust bedding (SAFE, Reference B8/20). Cages were cleaned according CERB internal SOPs. The animals were placed in an air-conditioned (20-24°C) animal house kept at relative humidity between 45% and 65% (except during the cleaning slot) in which non-recycled filtered air was changed approximately 10 times per hour. The artificial day/night cycle involved 12 hours light and 12 hours darkness with light on at 7.30 a.m.
- Diet (e.g. ad libitum): RM1 (E)-SQC SDS/DIETEX feed (quality controlled/radiation sterilised) was available ad libitum except during the fasting experimental period. The criteria for acceptable levels of contaminants in the feed supplied were within the limits of the analytical specifications established by the diet manufacturer.
- Water (e.g. ad libitum): Drinking water was available ad libitum in polycarbonate feeder bottles with a stainless steel nipple. A specimen of water is obtained every 6 months and sent to the Laboratoire Departemental d'Analyse du Cher - 216, Rue Louis Mallet - 18014 Bourges Cedex, France, for analysis. The criteria for acceptable levels of contaminants in the water supplied were within the limits of the analytical specifications.
- Acclimation period: Minimum of five days in the laboratory animal house where the experiment took place.

IN-LIFE DATES: From day 1, day of administration to D15, day of euthanasia

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 50 mg/mL
- Amount of vehicle (if gavage): 10 mL/Kg
- Justification for choice of vehicle: Sterile water was chosen on the basis of the information provided by the Sponsor
- Lot/batch no. (if required):/
- Purity:/

MAXIMUM DOSE VOLUME APPLIED: 500 mg/Kg body weight.

DOSAGE PREPARATION (if unusual): Each dose was expressed in mg/kg of the test item and adjusted to individual body weight as determined immediately before administration.
Doses:
500 mg/Kg
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality was recorded twice a day, i.e. in the morning and at the end of the working day. All animals including those of the sighting study were examined clinically on the day of treatment, 30 minutes, 2 hours, 4 hours and 6 hours after administration. Thereafter they were examined clinically at least once daily for 14 days. Animals were weighed on the following days:on D1 (day of administration), D7 and D14 during the study, and on D15, day of euthanasia.
- Necropsy of survivors performed: yes, All animals surviving to the end of the 14-day monitoring period were euthanased on D15 by subtotal
exsanguination, after sodium pentobarbital anaesthesia by the intraperitoneal route. All animals were subjected to gross necropsy and their organs (liver, spleen, kidneys, stomach, intestines, gonads/ reproductive tract, lungs, heart and any other organs with obvious abnormalities) were examined macroscopically.
Statistics:
No statistical analysis

Results and discussion

Preliminary study:
During the sighting test, no death occurred from D1 to D14, no clinical sign occurred from D1 to D14 and the body weight gain of the first animal wasnot considered to be affected by the treatment with the test item
Effect levels
Sex:
female
Dose descriptor:
LD0
Effect level:
500 mg/kg bw
Based on:
test mat.
Mortality:
No death occurred from D1 to D14 in the females treated at 500 mg/kg body weight
Clinical signs:
No clinical sign occurred from D1 to D14 in the females treated at 500 mg/kg body weight
Body weight:
During the main test, a slight body weight loss was observed during the first week of the study in one female, but on D14 the overall body weight gain was not considered to be affected by the treatment. In addition, the body weight gain of the last female was higher than the two other ones throughout the study.
This was without toxicological effect.
Gross pathology:
No organ or tissue gross finding was seen at necropsy of the females of the sighting test or of the main test.

Applicant's summary and conclusion

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: other: Based on the observed data
Conclusions:
Under the experimental conditions adopted in this study equivalent to an OECD 420, the maximal non-lethal dose by oral route in rats was 500 mg/kg body weight. Therefore test item was not considered as toxic by oral route according to CLP criteria.
Executive summary:

At the Sponsor's request, the potential acute toxicity of the test item was evaluated after a single dose administration by the oral (gavage) route in the rat inspired by the general requirements of OECD Guideline No. 420 (December 17, 2001) and method B1 of Council Directive No. 67/548/EEC and subsequent amendments (GLP study, scored as validity 2 according to Klimisch criteria). At the Sponsor's request, three females were treated at 500 mg/kg body weight. The test item was administered orally to animals, deprived of food since the previous day, in a volume of 10 mL/kg as a purple solution in sterile water. Animals were monitored daily for 14 days after administration of the test item. Animals were weighed on days D1, D7, D14 and D15.

Under the experimental conditions adopted, oral administration of the test item at 500 mg/kg body weight caused no mortality and no clinical signs during a 14-day period, in female Sprague-Dawley rats. Under the experimental conditions adopted, the maximal non-lethal dose by oral route in rats was 500 mg/kg body weight.