Endo-(±)-8-aza-8-isopropylbicyclo[3.2.1]oct-3-yl (hydroxymethyl)phenylacetate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24 August to 29 October 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-aza-8-isopropylbicyclo[3.2.1]oct-3-yl (hydroxymethyl)phenylacetate

EC Number:

244-859-1

EC Name:

Endo-(±)-8-aza-8-isopropylbicyclo[3.2.1]oct-3-yl (hydroxymethyl)phenylacetate

Cas Number:

22235-81-0

Molecular formula:

C19H27NO3

IUPAC Name:

Endo-(±)-8-aza-8-isopropylbicyclo[3.2.1]oct-3-yl (hydroxymethyl)phenylacetate

Test material form:

solid: particulate/powder

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
The Wistar rats were derived from a controlled full barrier-maintained breeding system (spf). Source: Harlan Winkelman GmbH, D-33178 Borchen

Step 1: 3 male animals with body weight range of 154-162 grams
Step 2: 3 female animals with body weight range of 145-149 grams
Step 3: 3 male animals with body weight range of 160-161 grams

ANIMAL HUSBANDRY
The animals were barrier maintained (semi-barrier) in air-conditioned rooms with the following conditions:
- Temperature: 22 +/- 3 degC
- Relative humidity: 55 +/- 10%
- Artificial light, lighting regime 12: 12hrs, light 6.00-18.00
- Air change: 10x per hour

Feeding ad libitum, Altromin 1324 maintenance diet for rats and mice, totally-pathogen-free (TPF)

The animals were kept in Macrolon cages on Altromin saw fiber bedding with free access to tap water (drinking water, municipal residue control, microbiol. controlled periodically).

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

cotton seed oil

Details on oral exposure:

The test item was administered in a single dose by gavage using an intubation cannula. Volume of application was applied according to the body-weight at a volume of 10ml/kg body weight.

Doses:

200 and 2000 mg/kg

No. of animals per sex per dose:

Step 1: 3 male animals, dosed with 200 mg/kg bw
Step 2: 3 female animals, dosed with 200 mg/kg bw
Step 3: 3 male animals, dosed with 2000 mg/kg bw

Details on study design:

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 somamotor activity and behaviour pattern were examined. Particular attention was directed to observations of tremor, convulsions, salivation, diarrhea, lethargy, sleep and coma.

Rats were weighed on Day 0 (day before dosing), Day 7 and 14.

Results and discussion

Effect levels

Key result

Dose descriptor:

LD50

Effect level:

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

Based on:

test mat.

Mortality:

Compound-related mortality of 2 out of 3 animals were observed at step 3 (2000 mg/kg bw).

Clinical signs:

observations of tremors

other:

Any other information on results incl. tables

The acute toxic class method was performed with SCH 1000 / II-III Tropaester NV. It is the principle of the acute toxic class method that, based on a stepwise procedure with the use of a minimum number of animals per step, sufficient information is obtained on the acute toxicity of the test item to enable its classification.

In the first step the test item SCH 1000/ II-III Tropaester NV was given in a dose of 200 mg/kg body weight to a group of 3 male rats (HsdBrl:WH Wistar) in a single exposure via oral gavage. In a second step the test item was given to a group of 3 female rats (HsdBrl:WH Wistar) in a single exposure via oral gavage.

The dosage of 200 mg/kg bw caused no compound-related mortality neitller in the three male nor in the three female animals within 14 days p. appl.. Throughout the 14-days observation period no weight loss was recorded (table 1).

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 re cord gross pathological changes. No clinical signs of toxicity were observed throughout the observation period. 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.

According to the acute toxic class method regime, in a third step the test item SCH 1000 / II-III Tropaester NV was given to a further group of three male animals in a dose of 2000 mg/kg bw.

The dosage of 2000 mg/kg bw caused compound-related mortality in two of three male animals within 24 hours p. appl. with showing clinieal signs as reduced spontaneous activity, apathy, tremor and prone position. No special gross pathological changes were found in this animals.

Since compound-related mortality of two of three animals was observed at step 3 (2000 mg/kg bw) no further testing was required. A careful clinical examination was made once a day with the surviving animal. No clinical signs of toxieity were observed throughout the observation period. At the end of the observation period the animal was sacrificed and necropsy was carried out to record gross pathological changes.

Beside acute injection of blood vessels in the abdominal region at the euthanised animal, which is due to the euthanasia injection, no special gross pathological changes were found.

According to the results obtained the LD50 was determined to be between 500 and 1000 mg/kg bw.

 

Table 1: Weight gain (in g) Step 1 and Step 2 (200mg/kg)

Animal No., sex	Day 0	Day 7	Day 14
1 male	160	196	225
2 male	162	197	241
3 male	154	190	218
1 female	145	168	185
2 female	146	168	178
3 female	149	178	196

Table 2: Weight Gain (in g) Step 3 (2000 mg/kg)

Animal No., Sex	Day 0	Day 7	Day 14
1 male	161	death after 24 hours
2 male	160	death after 30 mins
3 male	160	185	238

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 SCH 1000/ II-III Tropaester NY has acute toxic characteristics.
The LD50 was determined to be between 500 and 1000 mg/kg BW.