(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl methanesulfonate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

17 November 2003 and 08 December 2003.

Reliability:

1 (reliable without restriction)

Justification for data waiving:

other:

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl methanesulfonate

EC Number:

700-367-3

Cas Number:

35130-97-3

Molecular formula:

C9 H17 N O3 S

IUPAC Name:

(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl methanesulfonate

Details on test material:

Sponsor's identification : SB-322065
Description : cream coloured solid with orange coloured pieces
Batch number : MTN-B-07C
Date received : 12 November 2003
Storage conditions : room temperature in the dark

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

Female Sprague-Dawley CD (Crl : CD® (SD) IGS BR) strain rats were supplied by Charles River
(UK) Ltd, Margate, Kent, UK. On receipt the animals were randomly allocated to cages. The
females were nulliparous and non-pregnant. After an acclimatisation period of at least five days
the animals were selected at random and given a number unique within the study by indelible
ink-marking on the tail and a number written on a cage card. At the start of the study the animals
were eight to twelve weeks of age. The bodyweights fell within an interval of ± 20% of the initial
bodyweight of the first treated animal.
The animals were housed in groups of up to four in suspended solid-floor polypropylene cages
furnished with woodflakes. With the exception of an overnight fast immediately before dosing
and for approximately three to four hours after dosing, free access to mains drinking water and
food (Certified Rat and Mouse Diet (Code 5LF2) supplied by International Product Supplies
Limited, Wellingborough, Northants, UK) was allowed throughout the study. The diet, drinking
water and bedding were routinely analysed and were considered not to contain any contaminants
that would reasonably be expected to affect the purpose or integrity of the study.
The temperature and relative humidity were set to achieve limits of 19 to 25°C and 30 to 70%
respectively. Any occasional deviations from these targets were considered not to have affected
the purpose or integrity of the study. The rate of air exchange was at least fifteen changes per
hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00
to 18:00) and twelve hours darkness.
The animals were provided with environmental enrichment items which were considered not to
contain any contaminant of a level that might have affected the purpose or integrity of the study.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

For the purpose of the study the test material was freshly prepared, as required, as a solution in
distilled water.
All animals were dosed once only by gavage using a metal cannula attached to a graduated
syringe. The volume administered to each animal was calculated according to its fasted
bodyweight at the time of dosing.

Doses:

2000 and 300 mg/kg

No. of animals per sex per dose:

one at 2000 and five at 300 mg/kg bw

Control animals:

no

Details on study design:

Following a preliminary test in which the animal treated at a dose level of 2000 mg/kg
died and an animal treated at a dose level of 300 mg/kg survived, an additional four fasted female
animals were given a single oral dose of test material, as a solution in distilled water at a dose
level of 300 mg/kg bodyweight. Clinical signs and bodyweight development were monitored
during the study. All animals were subjected to gross necropsy.

Results and discussion

Preliminary study:

The animal treated at a dose level of 2000 mg/kg was found dead after four hours and no mortality occured in the animal treated at 300 mg/kg.

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 300 - < 2 000 mg/kg bw

Mortality:

The animal treated at a dose level of 2000 mg/kg was found dead four hours after
dosing. There were no deaths noted at a dose level of 300 mg/kg.

Clinical signs:

Signs of systemic toxicity noted in the animal treated at a dose level of
2000 mg/kg were hunched posture, lethargy, decreased respiratory rate, ptosis, occasional body
tremors and hypothermia. There were no signs of systemic toxicity noted in animals treated at a
dose level of 300 mg/kg.

Body weight:

Surviving animals showed expected gains in bodyweight.

Gross pathology:

Abnormalities noted at necropsy of the animal treated at a dose level of 2000 mg/kg
were abnormally red lungs, dark liver, dark kidneys and haemorrhage of the gastric mucosa, nonglandular
region of the stomach and small and large intestines. No abnormalities were noted at
necropsy of animals treated at a dose level of 300 mg/kg.

Applicant's summary and conclusion

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral median lethal dose (LD50) of the test material in the female
Sprague-Dawley CD strain rat was found to be greater than 300 mg/kg bodyweight but less than
2000 mg/kg bodyweight.