4-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile bis sulphate

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

25 July - 16 August 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD Guideline 402 (Acute Dermal Toxicity: Fixed Dose Procedure) (migrated information)

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-(6-{3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

Molecular formula:

C22H24N6O2.[2]H2O4S

IUPAC Name:

4-(6-{3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

Test material form:

solid: particulate/powder

Details on test material:

Batch (Lot) Number: 18-547.25-002
Physical Description: White powder
Storage Conditions: Kept in a room temperature area, protected from light

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS:
- Initial age at dosing: 8 weeks
- Weight range at dosing: Males: 220 g - 261g
Females: 206 g - 237 g
- Fasting period before study: not reported
- Housing: individually housed in polycarbonate cages with bedding and automatic watering valve.
- Diet (e.g. ad libitum): All animals had free access to a standard certified commerical laboratory diet.
- Water (e.g. ad libitum): Municipal tap water, after treatment by reverse osmosis and ultraviolet irradiation, was freely available to each animal via an automatic watering system, except during designated procedures.
- Acclimation period: At least 8 days were allowed between receipt of the animals and the start of treatment to accustom the animals to the laboratory environment.

ENVIRONMENTAL CONDITIONS:
- Average Temperature (°C): 21°C
- Average Humidity Range (%): 52% to 56%
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

IN-LIFE DATES: From: 25 Juy 2019 To: 16 August 2019

Administration / exposure

Type of coverage:

occlusive

Vehicle:

other: Reverse Osmosis Deionized (RODI) Water

Details on dermal exposure:

TEST SITE:
- Area of exposure: The clipped area was approximately 10% of the animal’s body surface area. The region to be dosed included the scapula to the wing of the ilium and halfway down the flank on each side of the animal. Care was taken to avoid abrading the skin during the clipping procedure.
- % coverage: 10% of the body surface area
- Type of wrap if used: The animal was inverted and the gauze dressing, which was backed by plastic wrap (occlusive binding) and an elastic wrap, was applied to the clipped area of the test animal.

REMOVAL OF TEST SUBSTANCE:
- Washing (if done): Residual test article was removed using gauze moistened with Reverse Osmosis (RO) water followed by dry gauze.
- Time after start of exposure: 24 hours

TEST MATERIAL:
- Amount(s) applied (volume or weight with unit): Group 1: 50 mg/kg, Group 2: 200 mg/kg, Group 3: 1,000 mg/kg, and Group 4: 2,000 mg/kg

Duration of exposure:

An apporximate 24-hour exposure period

Doses:

Dose Level: 50 mg/kg, 200 mg/kg, 1,000 mg/kg, 2,000 mg/kg
Adjusted Dose Level:80 mg/kg, 320 mg/kg, 1,600 mg/kg, 3,200 mg/kg

No. of animals per sex per dose:

5/sex/group

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations were made hourly for the first four hours after dosing and twice daily thereafter. Body weights were taken within 24 hours of receipt, just prior to dosing, and at 7 and 14 days. Individual body weights were recorded for all animals at study assignment (Day -3), prior to dosing on Day 0, and on Days 7 and 14.
- Necropsy of survivors performed: A gross-only necropsy was performed on all animals at the time of scheduled euthanasia (Day 14).
- Other examinations performed: dermal observations, mortality/moribundity checks

Statistics:

Data were presented as individual values by animal. The individual data tables also included the means and standard deviations and were calculated separately for males and females.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred during the study

Clinical signs:

other: There were no test article-related clinical observations. Incidental findings consisted of thin fur, stained fur, erected fur, increased vocalization, skin scabs, skin flaking, and pink/red skin.

Gross pathology:

There were no test article-related macroscopic pathology findings.

Other findings:

Test article-related dermal irritation was observed in males and females with dose-dependent incidence and/or severity (minimal to moderate) at ≥ 50 mg/kg.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this test, COM-1079 (Compound 3532670) was considered non-toxic at a topical dose level of 50, 200, 1000, and 2000 mg/kg. The Median Lethal Dose by the dermal route of administration was estimated to be greater than 2000 mg/kg.