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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline Study according to GLP

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no

Test material

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

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST SYSTEM
Test system: Rat, HanRcc:WIST (SPF)
Rationale: Recognized by the international guidelines as a recommended test system.
Source: RCC Ltd, Laboratory Animal Services, CH-4414 Füllinsdorf / Switzerland
Number of animals per group 3 females
Total number of animals 12 females
Age when treated: 12-13 weeks
Identification: Unique cage number and corresponding color-coded spots on the tail. The animalswere marked at acclimatization start.
Randomization: Selected by hand at time of delivery. No computer generated randomization program.
Acclimatization:
Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

HUSBANDRY
Room no.: 0105 / RCC Ltd, Füllinsdorf
Conditions: Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with ranges for room temperature 22 ± 3 °C and for relative humidity between 30-70 % (values above 70 % during cleaning process possible), automatically controlled light cycle of 12 hours light and 12 hours dark, music during the daytime light period.

Accommodation: In groups of three in 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 maintenance diet, batch nos. 25/05 and 39/05 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad libitum. Results of analyses for contaminants are archived at RCC Ltd.

Water: Community tap water from FOllinsdorf ad libitum. Results of bacteriological, chemical and contaminant analyses are archived at RCC Ltd.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
(purified)
Details on oral exposure:
VEHICLE
The following information was provided by RCC Ltd:
Purified water prepared at RCC Ltd (deionised water which was processed and treated by the PURELAB Option-R unit. This latter links four purification technologies: reverse osmosis,adsorption, ion-exchange and photo oxidation). 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.
Doses:
2
No. of animals per sex per dose:
6 females per dose group
Control animals:
no
Details on study design:
DOSE FORMULATION
Dose levels are in terms of the test item as supplied by the sponsor.
The dose formulations were made shortly before each dosing occasion using a magnetic
stirrer as homogenizer. The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weightvolume). Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.

TREATMENT
The animals received a single dose of the test item by oral gavage administration at 2000 mg/kg or 300 mg/kg body weight after being fasted for approximately 17 to 19 hours (access to water was permitted). Food was provided again approximately 3 hours after dosing. The application volume was 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.

OBSERVATIONS
Mortality / Viability
Body weights
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 (with the clinical signs) and twice daily during days 2-15. On test days 1 (prior to administration), 8 and 15. 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.
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: LD50 given as "cut off value"
Mortality:
2000 mg/kg body weight: 2/6
300 mg/kg body weight: 0/6
Clinical signs:
2000 mg/kg body weight: ruffled fur, hunched posture, sedation
300 mg/kg body weight: no clinical signs of intoxication
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
All animals which died spontaneously during the observation period were necropsied as soon as they were found dead. All surviving animals at the end of the observation period.
Other findings:
MACROSCOPIC FINDINGS
In three animals treated at 2000 mg/kg, liquid contents were found in the stomach and/or duodenum, jejunum, ileum and caecum at necropsy, whereas no macroscopic findings were recorded in the remaining animals.

Applicant's summary and conclusion

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the OECD 423, the LD50 - cut off value of the test substance after single oral administration to female rats, observed over a period of 14 days is:
LD50 - cut off value (female rat) = 2000 mg/kg b.w.
Executive summary:

Four groups, each of three female HanRcc:WIST (SPF) rats, were treated with the test substance by oral gavage administration at a dosage of 2000 mg/kg or 300 mg/kg body weight. The test item was diluted in vehicle (purified water) at a concentration of 0.2 g/mL or 0.03 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. The following animals were treated and percentage of mortality was observed:

6 females treated at 2000 mg/kg 33 %

6 females treated at 300 mg/kg 0 %

Two animals treated at 2000 mg/kg were found dead four or six hours after treatment, whereas all animals treated at 300 mg/kg survived until the end of the study period. Slightly to moderately ruffled fur was observed in five animals treated at 2000 mg/kg from the 30-minute or 1-hour reading to the 2-hour examination and persisted in four of these animals up to the 3- or 5-hour observation or until test day 4. Hunched posture was noted in two animals at the 1-hour reading and persisted in one female until the 2-hour reading, whereas three other animals showed this symptom from the 2- to 3- or 5-hour observation or at the 3-hour examination only. Slight to moderate sedation was noted in four animals at the 1-hour reading and persisted in three of them until two, three or five hours after treatment. Slight to moderate tremor was seen in two animals treated at 2000 mg/kg prior to their spontaneous death three or five hours after treatment. Ventral recumbency was noted in one of these animals at the 5-hour reading. No clinical signs were observed during the course of the study in all animals treated at 300

mg/kg. The body weight of the animals was within the range commonly recorded for this strain and age. In three animals treated at 2000 mg/kg, liquid contents were found in the stomach and/or duodenum, jejunum, ileum and caecum at the unscheduled necropsy, whereas no macroscopic findings were recorded in the remaining animals.