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

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

August 1st, 2001 to August 22nd, 2001

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:

in compliance with the Swiss Ordinance relating to GLP, adopted February 2nd, 2000 [RS 813.016.5] and based on the OECD Principles of GLP, as revised in 1997 and adopted November 26th, 1997 by decision of the OECD Council [C(97)186/Final]

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

439-750-2

EC Name:

-

Cas Number:

183487-56-1

Molecular formula:

Hill formula: C17H19BrClNO3 CAS formula: C17H19BrClNO3

IUPAC Name:

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

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

- Name of test material (as cited in study report): T002113
- Substance type: powder
- Physical state: solid
- Analytical purity: 92.9 %
- Purity test date: no data
- Lot/batch No.: RT002113G3A231
- Expiration date of the lot/batch: 1-dec-2001
- Storage condition of test material: at room temperature (range of 20 +/- 3 °C), away from direct sunlight
- Stability of test item: stable under storage conditions
- Stability of test item in vehicle: 2 hours , the concentration, homogeneity, and stability of T002113 was determined (see further)

Test animals

Species:

rat

Strain:

other: HanBrl: WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: 10 rats (5 males and 5 females), RCC Ltd, Biotechnology & Animal Breeding Division, CH-4414 Füllinsdorf, Switzerland
- Age when treated: 9 weeks for males, 12 weeks for females
- Weight at study initiation: 224.0-245.5 g for males, 201.6-208.1 g for females
- Housing: during acclimatization in groups of 5 per sex in Makrolon type-4 cages with standard softwood bedding. Individually in Makrolon type-3 cages with standard softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz, Switzerland) during treatment and observation.
- Diet (e.g. ad libitum): ad libitum, pelleted standard Provimi Kliba 3433, batch no. 72/01 rat maintenance diet (Provimi Kliba AG, CH-4303 Kaiseraugst). Results of analyses for contaminants are archived at RCC Ltd, Itingen.
- Water (e.g. ad libitum): ad libitum, community tap water from Itingen. Results of bacteriological, chemical and contaminant analyses are archived at RCC Ltd, Itingen.
- Acclimation period: 7 days, 1-aug to 7-aug-2001 (males and females) (under laboratory conditions)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 30-70 %
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs fluorescent light (light period between 6.00 and 18.00), music during light period

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

other: bi-distilled water

Details on dermal exposure:

TEST SITE
- Area of exposure: the back of the animal
- % coverage: approximately 10 % of the total body surface
- Type of wrap if used: semi-occlusive dressing, the dressing was wrapped around the abdomen and fixed with an elastic adhesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the skin was flushed with lukewarm tap water and dried with disposable paper towels
- Time after start of exposure: 24 hrs

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg body weight in 4 ml/kg body weight
- Constant volume or concentration used: yes
- For solids, paste formed: no

VEHICLE
- Amount(s) applied (volume or weight with unit): 4 ml/kg body weight

Duration of exposure:

24 hrs

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

2 x 5 (5 males and 5 females)

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: mortality and viability daily during acclimatization period and twice daily during days 1-15. Body weights on test days 1 (pre-administration), 8 and 15. Clinical signs daily during acclimatization and at least four times on test day 1 after the test item administration. Once daily during days 2-15.
- Necropsy of survivors performed: yes, at the end of the observation period all animals were sacrificed by intraperitoneal injection of NARCOREN (Rhone Merieux GmbH, 0-88471 Laupheim) at a dose of at least 2.0 ml/kg body weight (equivalent to at least 320 mg sodium pentobarbitone/kg body weight).
- All animals were examined macroscopically

Statistics:

No statistical analysis was used.

Results and discussion

Effect levels

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.

Body weight:

other body weight observations

Remarks:

The body weight of the animals was within the range commonly recorded for this strain and age.

Gross pathology:

No macroscopic findings were observed at necropsy.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The median lethal dose of T002113 after single dermal administration to rats of both sexes, observed over a period of 14 days is:
LD50 (rat): greater than 2000 mg/kg body weight