(4aR*, 8aR*)-1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6H-benzofuro[3a,3,2-ef] [2]benzazepin-6-one hydrochloride (1:1)

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2001-07-18 to 2001-08-08

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Report date:

2001

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

GLP compliance:

yes

Remarks:

: This study was performed in compliance with the Swiss Ordinance relating to Good Laboratory Practice, adopted February 2nd, 2000 [RS 813.016.5].

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

rel-(4aR,8aR)-1-bromo-3-methoxy-4a,5,9,10,11,12-hexahydro-6H-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-one hydrochloride (1:1)

EC Number:

700-867-1

Molecular formula:

C16H16BrNO3.HCl

IUPAC Name:

rel-(4aR,8aR)-1-bromo-3-methoxy-4a,5,9,10,11,12-hexahydro-6H-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-one hydrochloride (1:1)

Test material form:

solid

Details on test material:

- Name of test material (as cited in study reports): T002102
- Physical state: solid
- Appearance: white (SDS)

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: RT002102G4A311
- Expiration date of the lot/batch: 25-MAR-2002
- Purity:99.4%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
- Stability of the test substance in the solvent/vehicle: 2 hours

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: HanBrl:WIST (SPF), RCC Ltd. Biotechnology & Animal Breeding Division, CH-4414 Füllinsdorf, Switzerland
- Age at study treatment: 9 weeks (males); 12 weeks (females)
- Weight at study initiation: males: 229.5-257.7 g; females: 202.3-215.4 g
- Fasting period before study: no data
- Housing: During acclimatization, animals were housed in groups of five per sex in Makrolon type-4 cages with standard softwood bedding. During treatment and observation animals were individually housed in Makrolon type-3 cages with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz).
- Diet: ad libitum, pelleted standard Provimi Kliba 3433, batch no. 72/01 rat maintenance diet
- Water: ad libitum, community tap water from Itingen
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 30-70 %
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12hrs light/12 hrs dark, music during the light period

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

polyethylene glycol

Remarks:

PEG300

Details on dermal exposure:

TEST SITE
- Area of exposure: back of the animals was clipped with an electric clipper. On test day 1, 2000 mg/kg bw evenly on the intact skin with a syringe and covered with a semi-occlusive dressing.
- % coverage: 10 % of the total body surface
- Type of wrap if used: A dressing was wrapped around the abdomen and fixed with an elastic adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The test sites were washed with lukewarm tap water and dried with disposable paper towels.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4 mL volume/body weight
- Concentration (if solution): the test substance was diluted in polyethylene glycol (PEG 300) at a concentration of 0.5 g/mL
- Constant volume or concentration used: yes
- For solids, paste formed: no

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 male/female rats per dose

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing:
- mortality/viability: daily during acclimatization and at least 1, 2, 3 and approximately 5 hours after the test item administration. Twice daily during days 2-15.
- body weight: on test days 1(pre-administration), 8, 15
- clinical signs: daily during acclimatization and at least 1, 2, 3 and approximately 5 hours after the test item administration. Once daily during days 2-15
- Necropsy of survivors performed: At the end of the observation period all animals were sacrificed by intraperitoneal injection of Narcoren at a dose of at least 2.0 mL/kg body weight (equivalent to at least 320 mg sodium pentobarbitone/kg body weight). The animals were examined macroscopically and all abnormalities recorded. Thereafter, they were discarded.

Statistics:

No statistical analysis were used.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred during the study

Clinical signs:

other: No systemic or local signs of toxicity were observed during the study period

Gross pathology:

No macroscopic findings were observed at necropsy

Any other information on results incl. tables

The results of the dose verification analysis were 98.8, 97.7 and 95.8 % of nominal for samples taken from the top, middle and bottom of the mixing container. The individual concentrations varied in the range from -2 % to +1 % of the mean concentrations. Since the concentrations were found to be within the accepted range of 80 - 120 % of the nominal concentration, it was determined that the test substance was homogeneously distributed in the vehicle. The test substance was found to be stable in the vehicle under storage conditions over a period of two hours.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The median lethal dose after a single dermal administration to rats of both sexes, observed over a period of 14 days is greater than 2000 mg/kg body weight. Therefore, the substance should not be considered to be classified according to CLP regulation.