Registration Dossier

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: GLP and guideline conform study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report Date:
2000

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
Test type:
acute toxic class method

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age and weight at study initiation: Young adult animals (approx. 7 weeks old) were selected. Body weight variation did not exceed +/- 20% of the sex mean.
- Housing: Accommodation Group housing of 3 animals per sex per cage in labelled polycarbonate cages containing purified sawdust as bedding material (SAWI, Jelu Werk, Rosenberg, Germany).
- Diet (e.g. ad libitum): Free access to standard pelleted laboratory animal diet (from Carfil Quality BVBA, Oud- Turnhout, Belgium).
- Water (e.g. ad libitum): Free access to tap-water. Certificates of quarteriy analysis were examined and then retained in the NOTOX archives.
- Acclimation period: Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.
- Fasting: Food was withheld overnight (for a maximum of 20 hours) prior to dosing until approximately 3-4 hours after administration of the test
substance.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12

IN-LIFE DATES:
Start : 18 January 2000
End : 03 February 2000

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
Oral gavage, using a stainless steel stomach tube. Food was withheld overnight (for a maximum of 20 hours) prior to dosing until approximately 3-4 hours after administration of the test substance

Vehicle: The vehicle was selected based on a pretest performed at NOTOX.

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg (10 ml/kg) body weight.

DOSAGE PREPARATION:
The formulation (w/w) was prepared within 4 hours prior to dosing.
Homogeneity was accomplished to a visually acceptable level.
Adjustment was made for specific gravity of vehicle.

Doses:
Single dosage, on day 1. Dose level (volume) 2000 mg/kg (10 ml/kg) body weight
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
The toxicity of the test substance was assessed by stepwise treatment of groups of 3 animals. The first group was treated at a dose level of 2000 mg/kg body weight. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were to be taken into account for determination of the time interval between the dose groups


- Duration of observation period following administration: 14 days (or other?)
- Frequency of observations and weighing: Twice daily. Weighing: days 1 (pre-administration), 8 and 15.
- Necropsy of survivors performed: yes
At the end of the observation period, all animals were sacrificed by
asphyxiation using an oxygen/carbon dioxide procedure and
subjected to necropsy. Descriptions of all internal macroscopic
abnormalities were recorded.
- Other examinations performed: clinical signs, body weight,organ weights
Statistics:
No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
>= 2 000 mg/kg bw
Mortality:
No mortality occurred.
Clinical signs:
Alopecia was noted in one female on days 3 and 4, and red staining of the nose was noted in one male immediately after dosing. A red skin of various body parts and/or red faeces due to staining by the test substance was noted in all animals during the observation period. No further clinical signs were noted.
Body weight:
The body weight gain shown by the animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.

Applicant's summary and conclusion

Conclusions:
The oral LD50 value of TKP 50048 in Wistar rats was established to exceed 2000 mg/kg body weight.
Executive summary:

TKP 50048 was administered by oral gavage to three Wistar rats of each sex at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (day 15).

No mortality occurred.

Alopecia was noted in one female on days 3 and 4, and red staining of the nose was noted in one male immediately after dosing. A red skin of various body parts and/or red faeces due to staining by the test substance was noted in all animals during the observation period. No further clinical signs were noted. The body weight gain shown by the animals over the study period was considered to be normal.

No abnormalities were found at macroscopic post mortem examination of the animals.

The oral LD50 value of TKP 50048 in Wistar rats was established to exceed 2000 mg/kg body weight.