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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1999-01-12 to 1999-01-28
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report date:
1999

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
1996
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
1996
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1-(3,5-Dihydroxyphenyl)-1-oxo-2-(N-1-(4-methoxyphenyl)isopropylamino)ethane Hydrobromide
EC Number:
928-779-0
Molecular formula:
C18-H21-N-O4 x HBr
IUPAC Name:
1-(3,5-Dihydroxyphenyl)-1-oxo-2-(N-1-(4-methoxyphenyl)isopropylamino)ethane Hydrobromide
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: No details on the source of the test material were provided. Batch number: 323.
- Expiration date of the lot/batch: 16 December 1999 (allocated by testing facility, 1 year after reciept of the test substance).
- Purity test date: No details reported.

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature in the dark.
- Stability under test conditions: Stable
- Solubility and stability of the test substance in the solvent/vehicle: The vehicle was selected based on a pretest performed at the testing facitlity. The stability of the test substance in the vehicle was not indicated.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The formulations were prepared within 4 hours before dosing. Homogeneity was accimplished to a visually acceptable level. Adjustment was made for specific gravity of the vehicle.
- Preliminary purification step (if any): No details reported.
- Final dilution of a dissolved solid, stock liquid or gel: No details reported.
- Final preparation of a solid: No details reported.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Germany
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: Approx. 6 weeks old
- Weight at study initiation: Body weight did not exceed +/- 20% of the sex mean
- Fasting period before study: Overnight prior to dosing until approximately 3-4 hours after administration of the test substance
- Housing: Polycarbonate cages containing purified sawdust as bedding material. 3 animals per sex per cage.
- Diet (e.g. ad libitum): Free access
- Water (e.g. ad libitum): Free access
- Acclimation period: At least 5 days before start of treatment under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C
- Humidity (%): 50%
- Air changes (per hr): 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours dark per day








Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
VEHICLE
- Concentration in vehicle: The concentration of the test substance in vehicle was varied to allow constant dosage volume in terms of ml/kg.
- Justification for choice of vehicle: Propylene glycol (specific gravity 1.036). The vehicle was selected based on a pretest performed at the testing facility.

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg for both dose levels.

Doses:
2000 and 200 mg/kg bw.

No. of animals per sex per dose:
200 mg/kg bw: 3 females and 3 males
2000 mg/kg bw: 3 females
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality/Viability: twice daily. The time of death was recorded as precisely as possible; Body weights: days 1 (pre-administration), 8 and 15;
- Necropsy of survivors performed: Yes (gross pathology only).
- Other examinations performed:Clinical signs performed at periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15.
Statistics:
None (The method used is not intended to allow the calculation of a precise LD 50 value).

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 200 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
The incidence of mortality was as follows:
Dose level Morality Sex
2000 mg/kg 3/3 females
200 mg/kg 0/3 females
200 mg/kg 0/3 males

Of the three female mortalities; one decedant was found dead within 4 hours after dosing. Two animals were killed in moribund approximatley 4.5 hours after dosing.
Clinical signs:
Clinical signs observed during the study period were as follows:
At 2000 mg/kg clinical signs of females: Tonic spasms, tremors, abnormal posture and paddling movements (hindlegs), shallow respiration, hypersensitivity to touch and red discoloured ears and feet of the front- and hind-legs (considered to be caused by vasodilation).
At 200 mg/kg clinical signs of females: Lethargy, abnormal posture of the hindlegs and/or hunched salivation on day 1 only.
At 200 mg/kg clinical signs of males: Lethargy, abnormal posture of the hindlegs and/or hunched posture on day 1 only.
Body weight:
The body weight gain over the study period in the animals treated with 200 mg/kg bw was considered to be similar to that expected in normal untreated animals of the same age and strain.
Gross pathology:
Thickened limiting ridge in the stomach and/or a pale pancreas were found at macroscopic post mortem examination of the animals that were found dead or sacrificed for ethical reasons.
No abnormalities were found at macroscopic post mortem examination of the animals at scheduled necropsy.
Other findings:
No further details reported.

Any other information on results incl. tables

The incidence of mortality was 3/3 females (2000 mg/kg) and 0/3 females and 0/3 males (200 mg/kg). A decedent was found within 4 hours post treatment. Two animals were sacrificed moribund approximately 4.5 hours post-treatment.

Clinical signs observed during the study period were as follows:

 Dose level  Clinical signs
 2000 mg/kg  Females: Tonic spasms, tremors, abnormal posture and paddling movements (hindlegs), shallow respiration, hypersensitivity to touch and red discoloured (considered to be caused by vasodilation) ears and feet of the front- and hind-legs.
 200 mg/kg  Females: Lethargy, abnormal posture of the hindlegs and/or salivation on day 1 only.
 200 mg/kg   Males: Lethargy, abnormal posture of the hindlegs and/or hunched posture on day 1 only.

The body weight gain over the study period shown by the animals treated at 200 mg/kg body weight was considered to be normal.

Thickened limiting ridge in the stomach and/or a pale pancreas were found at macroscopic post mortem examination of the animals that were found dead or sacrificed for ethical reasons. No abnormalities were found at macroscopic post mortem examination of the animals at scheduled necropsy.

The oral LD50 value of the test item in Wistar rats was established 200 -2000 mg/kg body weight.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The oral LD50 value of the substance in Wistar rats was determined to be 200 -2000 mg/kg bw.
Based on the dose effect relationship the LD50 was estimated to be > 300 mg/kg bw, therefore, the test substance is classified as Acute tox Cat. 4 according to CLP.