Endo-8-isopropyl-8-azabicyclo[3.2.1]octan-3-ol

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

04 April - 06 September 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

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Test material

Test material information

Constituent 1

Reference substance name:

Endo-8-isopropyl-8-azabicyclo[3.2.1]octan-3-ol

EC Number:

222-314-9

EC Name:

Endo-8-isopropyl-8-azabicyclo[3.2.1]octan-3-ol

Cas Number:

3423-25-4

Molecular formula:

C10H19NO

IUPAC Name:

Endo-8-isopropyl-8-azabicyclo[3.2.1]octan-3-ol

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

PREPARATION OF THE TEST ITEM
- In the first and second step 200 mg of the test item N-Isopropylnortropin were solved in 1% Carboxymehylcellu1ose (CMC, Sigma, Lot-No. 36H0738) ad 10 ml.
- In the third and fourth step 2000 mg of the test item were solved in 1 % CMC ad 10 ml. The test substance was freshly mixed prior to application and stirred throughout dose administration to guarantee stability and homogenicity.
- The vehicle was chosen due to its non-toxic characteristics.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
-Male and Female Wistar rats (HsdBr1: WH, Full-Barrier) strain were obtained from Harlan Winkelmann GmbH, D-33178 Borehen.
-The animals were derived from a controlled full barrier maintained breeding
system (spf).
-According to Art. 9.2, NO.7 ofthe German Act on Animal Welfare the animals
were bred for experimental purposes.

- Step 1: Body weight at the commencement of the study: 148 - 158 g.
3 male animals were used.
- Step 2: Body weight at the commencement of the study: 130 - 134 g.
3 female animals were used.
- Step 3: Body weight at the commencement of the study: 160 - 175 g.
3 male animals were used.
- Step 4: Body weight at the commencement of the study: 135 - 148 g.
3 female animals were used.

CONDITIONS
The animals were barrier maintained (semi-barrier) in air conditioned rooms.
- Temperature: 22 ± 3° C
- Rel. humidity: 55 ± 10%
- Artificiallight, lighting regime 12 : 12 hours, light 6.00 - 18.00
- Air change: 10 x / hour.
- Feeding ad libitum, Altromin 1324 maintenance diet for rats and mice, totally-pathogen-free (TPF).
- Free access to tap water (drinking water, municipal residue control,microbiol. controlled periodically).
- The animals were kept in Macrolon cages on Altromin saw fiber bedding.
- Adequate acclimatization period.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

The test item was administered in a single dose by gavage using an intubation cannula.
Volume of application: The test item was applied according to bodyweight at a volume of 10 ml/k:g bw.

Doses:

200 and 2000mg

No. of animals per sex per dose:

3

Control animals:

not specified

Details on study design:

-The starting dose (step 1 and 2) was 200 mg/kg body weight. Since no compound-related mortality was found further testing was required. According to OECD Guideline 423 the next steps (step 3 and 4) were performed at the next higher dose level of 2000 mg/kg body weight. According to the acute toxic class method regime no further testing was required.

-Animals were observed for 14 days after dosing.
-The animals were weighed prior to first application and once a week thereafter.

-A careful clinical examination was made twice a day on the day of dosing and once a day thereafter. Cageside observations included changes in the skin and fur, eyes and mucous membranes. Also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern were examined. Particular attention was directed to observations of tremor, convulsions, salivation, diarrhea, lethargy, sleep and coma.

At the end of the observation period the animals were sacrificed by an overdosage of pentobarbital.
All animals were subjected to gross necropsy. All gross pathological changes were recorded.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

>= 1 000 - <= 1 500 mg/kg bw

Based on:

test mat.

Mortality:

Step 1 and Step 2
-The dosage of 200 mg/kg bw caused neither compound-related mortality in the three male nor in the three female animals within 14 day p. appl.

Step 3
-The dosage of 2000 mg/kg bw caused compound-related mortality in two of three male animals.
All male animals showed reduced spontaneous activity and apathy 10 min after application.
Animal No. 3 was found dead 24 h p. appl. and animal No. 2 was found dead 96 h p. appl.
In animal No. 1 reduced spontaneous activity was visible for 9 days and apathy was found until 4 days after application.
-As three days after application of step 3 only one of the male animals was dead.

Step 4
-The dosage of 2000 mg/kg bw, caused compound-related mortality in all three female animals within 24 h p. appl.

Clinical signs:

other:

Body weight:

other body weight observations

Remarks:

All rats achieved body weight gains during Step 1 and Step 2 (200 mg/kg), But on Step 3 and 4 only one male rat gain its body weight on Day 14, and almost all rats body weight drops during their deaths after application.

Gross pathology:

Step 1 and Step 2
-A careful clinical examination was made once a day. At the end of' the observation period the animals were sacrificed, and necropsy was carried out to record gross pathological changes.
-Beside acute injection of blood vessels in the abdominal region, which· is due to the euthanasia injection no special gross pathological changes were found in animals of step 1 and step 2.

Step 3
-A careful clinical examination was made once a day. At the end of the observation period the surviving animal was sacrificed, and necropsy was carried out to record gross pathological changes.
-Beside acute injection of blood vessels in the abdominal region, which is due to the euthanasia injection no special gross pathological changes were found in animal No 1 of step 3.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Considering the reported data of this toxicity test it can be stated that the test item N-Isopropylnortropin has acute toxic characteristics.
The LD50 was determined to be between approx. 1000 and 1500 mg/kg bw.