(6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone;dihydrate;dihydrochloride

Endpoint summary

Description of key information

Two studies carried out. The first used dose levels of 300mg/kg and 2000mg/kg. Results show that the LD50 lies between the two dose levels. A second study was carried out using a dose level of 450mg/kg. Under the conditions of this test, the LD50 of this substance is estimated to be 450mg/kg.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

10th October 2017 to 30th Oct 2017

Reliability:

1 (reliable without restriction)

Qualifier:

no guideline followed

Principles of method if other than guideline:

This study was intended to provide information on the potential health hazards of the test article with respect to oral exposure. Data from this study may serve as a basis for classification and/or labeling of the test article. The Sprague Dawley rat was chosen as the animal model for this study as it is an accepted rodent species for preclinical toxicity testing by regulatory agencies. The oral route was selected since this is a possible means of exposure in humans. Dose levels were selected to explore the limits of tolerability in this initial assessment of toxicity for LSN584368.

GLP compliance:

not specified

Remarks:

The study was not within the scope of regulations governing the conduct of noncliniical laboratory studies and is not intended to comply with the regulations

Test type:

acute toxic class method

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

The Sprague Dawley rat was chosen as the animal model for this study as it is an accepted rodent species for preclinical toxicity testing by regulatory agencies. A total of 7 male and 7 female Sprague Dawley rats (Rattus norvegicus) were used.

Environmental Conditions
The targeted conditions for animal room environment will be as follows:

Temperature: 68°F to 79°F (20°C to 26°C)
Humidity: 30% to 70%
Light cycle: 12 hours light and 12 hours dark (except during designated procedures)
Ventilation: 10 or more air changes per hour

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

On the day prior to dosing (Day -1) the animals chosen for use on the study were weighed and fasted. On Day 0, the test article was administered orally as a single dose at a dose volume of 10 mL/kg using a syringe attached to a gavage cannula. Individual doses were calculated based on the animal's fasted (Day 0) body weight. Animals were returned to ad libitum feeding after dosing.

Doses:

300mg/kg and 2000mg/kg

No. of animals per sex per dose:

7 males, 7 females

Control animals:

yes

Details on study design:

See below

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Following dose administration to the 2000 mg/kg group on Day 0, 1/3 males and 3/3 females were found dead and 2/3 males were euthanized moribund.

Clinical signs:

other: Adverse test article-related clinical signs in the 2000 mg/kg group consisted of partially closed eyes, shallow breathing, increased respiratory rate, and decreased activity. Salivation was also noted following dosing in the 2000 mg/kg group. This findi

Gross pathology:

A gross necropsy examination was performed for all animals in the 2000 mg/kg group.
Macroscopic observations were limited to abnormal stomach content for all animals, wet material accumulation on the skin for 2/6 animals, dark thymus foci for 2/6 animals, and dark stomach foci for 1/6 animals.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Mortality occurred in the 2000 mg/kg group. Following dose administration on Day 0,
1/3 males and 3/3 females were found dead and 2/3 males were euthanized moribund.
No mortality, clinical signs, or effects on body weight were observed at 300 mg/kg.
Under the conditions of this test, the median lethal dose of LSN584368 is estimated to be
greater than 300 mg/kg and less than 2000 mg/kg.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12th April 2018 to 26 April 2018

Reliability:

1 (reliable without restriction)

Qualifier:

no guideline followed

Principles of method if other than guideline:

The purpose of this study was to assess the short-term toxicity of LSN584368 when administered by gavage as a single oral dose. This study was intended to provide information on the potential health hazards of the test article with respect to oral exposure. Data from this study will serve as a basis for classification and/or labeling of the test article. The Sprague Dawley rat was chosen as the animal model for this study as
it is an accepted rodent species for preclinical toxicity testing by regulatory agencies. The oral route was selected since this is a possible means of exposure in humans. The dose level was selected to be intermediate between those used in a prior acute oral study (Testing Facility Study No. 20134152) in which the median lethal dose of LSN584368 was estimated to be greater than 300 mg/kg and less than 2000 mg/kg.

GLP compliance:

not specified

Remarks:

The study was not within the scope of regulations governing the conduct of noncliniical laboratory studies and is not intended to comply with the regulations

Test type:

acute toxic class method

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Species:Rat
Strain:Crl:CD(SD) Sprague Dawley
Number of Males Ordered:4
Number of Females Ordered:4
Target Age at the Initiation of Dosing:7 to 12 weeks
Target Weight at the Initiation of Dosing: 200 to 300 g (males) 150 to 250 g (females)

Environmental conditions
Temperature: 68°F to 79°F (20°C to 26°C)
Humidity: 30% to 70%
Light cycle: 12 hours light and 12 hours dark (except during designatedprocedures)
Ventilation: 10 or more air changes per hour

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

On the day prior to dosing (Day -1), the animal(s) chosen for use will be weighed and fasted. On Day 0, the test article will be administered orally at a dose volume of 10 mL/kg. The test article will be administered using a syringe attached to a gavage cannula. Individual doses will be calculated based on the animal's fasted (Day 0) body weight. Animals will be returned to ad libitum feeding after dosing.

Doses:

450mg/kg

No. of animals per sex per dose:

3

Control animals:

yes

Details on study design:

See below

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 450 mg/kg bw

Based on:

test mat. (dissolved fraction)

Mortality:

Following dose administration of 450 mg/kg on Day 0, 3/3 females were euthanized in moribund condition. All males survived to scheduled euthanasia on Day 14.

Clinical signs:

other: In males, test article-related clinical observations included decreased activity, hunched posture, partially closed eyes, piloerection, and abnormal gait on Day 0; from Days 1 to 9, only piloerection was observed in males. In females, clinical observatio

Gross pathology:

A gross necropsy examination was performed for all female animals administered 450 mg/kg. There were no gross necropsy findings noted for the females that were euthanized moribund.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Mortality occurred in animals administered 450 mg/kg. Following dose administration
Day 0, 3/3 females were euthanized in moribund condition. Test article-related clinical
observations in male and female rats included decreased activity, tremors (females only),
hunched posture, partially closed eyes, piloerection, abnormal gait, cold to the touch
(females only), and prostration (females only). With the exception of piloerection, all
clinical signs in males resolved by Day 1, and all males survived to scheduled euthanasia.
No treatment-related effects on body weight were observed in males.
Under the conditions of this test, the median lethal dose of LSN584368 is estimated to be
450 mg/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

450 mg/kg bw