Registration Dossier

Toxicological information

Acute Toxicity: oral

Currently viewing:

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2006-04-04 (date of report to study director and test facility management)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2006
Report Date:
2006
Reference Type:
other: Expert Report
Title:
Unnamed
Year:
2014
Report Date:
2014

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Remarks:
E
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:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: IRA091
- Expiration date of the lot/batch: Unknown
- Purity: 100%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature (20 ± 5 °C), light protected
- Stability under test conditions: Unknown in PEG 300

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: female rats (nulliparous and non-pregnant), HanRCC:WIST (SPF-Quality); RCC Ltd., Laboratory Animal Services
- Age at study initiation: 12 weeks
- Weight at study initiation: 0.177 - 0.197 kg (range of three treatment groups)
- Fasting period before study: animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test item. Water was available ad libitum.
- Housing: 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 (e.g. ad libitum): ad libitum, free access to pelleted rodent diet
- Water (e.g. ad libitum): ad libitum, free access to tap water.
- Acclimation period: at least 5 days before start of treatment under laboratory conditions.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 30-70% (values above 70 % during cleaning process possible)
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: exact dates not reported

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 300
Details on oral exposure:
VEHICLE
- Concentration in vehicle: The test item was diluted in vehicle (PEG 300) at a concentration of 0.03 g/mL and 0.2 g/mL
- Justification for choice of vehicle: The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date. PEG 300 was found to be a suitable vehicle.

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

DOSAGE PREPARATION (if unusual):
- 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, 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.


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: not indicated

TREATMENT
The animals received a single dose of the test item by oral gavage administration at 300 mg/kg body weight or 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.
Doses:
2000 mg/kg, 300 mg/kg (single dosage each)
No. of animals per sex per dose:
3 females per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days (until day 15)
- Frequency of observations and weighing:
mortality/viability: Daily during the acclimatization period, approximately 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: days 1 (pre-administration), 8 and 15.
clinical signs: Daily during the acclimatization period, approximately 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 of survivors performed: The two 2000 mg/kg treated animals and one 300 mg/kg treated animal which died spontaneously approximately 30 minutes or 3 hours after test item administration and the third animal of the 2000 mg/kg treated group which was killed in extremis approximately one hour after treatment were necropsied as soon as they were found dead or killed. The animal sacrificed for ethical reasons was killed by an intraperitoneal injection of Vetanarcol.
All surviving 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 performed.

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Two 2000 mg/kg treated animals were found dead approximately 30 minutes after treatment and the remaining animal treated at the same dose was killed in extremis for ethical reasons approximately 1 hour after treatment. Two out of six 300 mg/kg treated animals were found dead approximately 3 and 6 hour after treatment, respectively.
Clinical signs:
In one animal treated at 2000 mg/kg, slightly ruffled fur with slight sedation were noted at the 30-minute reading and slightly ruffled fur with moderate sedation and moderate tremors as well as ventral recumbency were noted at the one hour reading just before it was killed in extremis for ethical reasons.

In the first group of three animals treated at 300 mg/kg, slightly ruffled fur was noted in all animals from the 30-minute to the 5-hour reading and persisted as slight to moderate ruffled fur in the two surviving animals on test day 2. Slight sedation was also noted in the three animals from the 2- to the 5-hour and persisted as moderate sedation in one surviving animal on test day 2. Half closed to closed eyes were noted in all animals at the 3- and 5-hour reading. Slight tremors were noted at the 5-hour reading in the animal found dead approximately one hour later. Hunche posture was noted in both surviving animals on test day 2. In the second group of animals treated at 300 mg/kg, slightly to moderately ruffled fur was noted in all animals from the 30-minute to the 2-hour reading and persisted in the surviving animals until test day 2. Slight to moderate sedation was also noted in the same animals from the 30-minute to the 2-hour reading and persisted in the two surviving animals until the 5-hour reading and test day 2, respectively. Half closed to closed eyes and hunched posture were noted in all animals the 30-minute or 1-hour reading to the 2-hour reading and persisted in the two surviving animals until the 5-hour reading. Slight poor coordination was noted from the 2- to the 5-hour reading in one animal. Convulsions and tachypnea were noted at the 2-hour reading in the animal which was found dead approximately 3 hours after treatment. Furthermore, each animal was observed sitting individually in a corner of the cage one hour after treatment.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
Liquid contents in the stomach, duodenum, jejunum, and ileum was noted in the two animals treated at 2000 mg/kg at the unscheduled necropsy. Lungs not collapsed were also noted in one of them. Liquid contents in the stomach and ileum and an empty jejunum was also noted in one 300 mg/kg treated animals at the unscheduled necropsy. Due to a technical error of the animal technician, no macroscopic findings were recorded for one 300 mg/kg treated animal.

Any other information on results incl. tables

Number of dead animals in each test group with 3 animals each:

Females 2000 mg/kg: two out of three

Females 300 mg/kg: two out of six (1 out of three in first group, 1 out of three in second group)

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The median lethal dose of T001492 after single oral administration to female rats, observed over a period of 14 days is: 300 mg/kg body weight < LD50 (female rat) < 2000 mg/kg body weight.

T001492 is to be classified as Toxic if swallowed (Category 3) based on a Janssen expert statement following this study conclusion.