2-[(5A,7A)-17-(CYCLOPROPYLMETHYL)-3,6-DIMETHOXY-18,19-DIHYDRO-4,5-EPOXY-6,14-ETHENOMORPHINAN-7-YL]-3,3-DIMETHYLBUTAN-2-OL

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2006-05-02 to 2006-05-25

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

(2S)-2-[(1S,2R,6S,14R,15R,16R)-3-(cyclopropylmethyl)-11,15-dimethoxy-13-oxa-3-azahexacyclo[13.2.2.1²,⁸.0¹,⁶.0⁶,¹⁴.0⁷,¹²]icosa-7,9,11-trien-16-yl]-3,3-dimethylbutan-2-ol

Cas Number:

16524-65-5

Molecular formula:

C30H43NO4

IUPAC Name:

(2S)-2-[(1S,2R,6S,14R,15R,16R)-3-(cyclopropylmethyl)-11,15-dimethoxy-13-oxa-3-azahexacyclo[13.2.2.1²,⁸.0¹,⁶.0⁶,¹⁴.0⁷,¹²]icosa-7,9,11-trien-16-yl]-3,3-dimethylbutan-2-ol

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study report): JNJ-18163678-AAA (T002713)
- Physical state: solid (powder)
- Appearance: White powder

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material:00477910 RT002713G4A051
- Expiration date of the lot/batch: 2006-06-30
- Purity test date: No data

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature (range of 20+/-5°C), light protected
- Stability under test conditions:stable under storage consitions
- Solubility and stability of the test substance in the solvent/vehicle: unknown in PEG300
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: No data

Test animals

Species:

rat

Strain:

Wistar

Remarks:

HanRcc:WIST

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services,CH-4414 FOllinsdorf I Switzerland
- Age at study initiation: 12 weeks
- Weight at study initiation: 178.9 - 190.4g females
- Fasting period before study: 17-18 hours
- Housing: In groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3433 ratlmouse maintenance diet, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: under laboratory conditions

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

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

PEG300

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0.2 g/mL
- Amount of vehicle (if gavage): not indicated
- Justification for choice of vehicle: not indicated

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg bw

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3 (the test was repeated with another 3 animals)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded at approximately 30 minutes, 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 were recorded on day 1(prior to administration) and on days 8 and 15.
-Necropsy of deaths: no deaths occured
- Necropsy of survivors performed: yes
- Other examinations performed: no

Statistics:

No statistical analysis was used.

Results and discussion

Preliminary study:

see study from Safepharm Laboratories 2005

Effect levels

Key result

Sex:

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: Slightly ruffled fur was noted in all animals from the 3D-minute or 1-hour reading to the 5-hour reading and persisted until test day 2 in two animals and until test day 3 in three animals. Slight sedation was noted in all

Gross pathology:

No macroscopic findings were recorded at necropsy.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute oral toxicity study with rats, T002713 showed LD50 values of >2000 mg/kg bw. According to CLP, the substance is not classified.