N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

4th March 2020 to 16th March 2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2020

Report date:

2020

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: EC 440/2008 part B 'Acute Oral Toxicity, Acute Toxic Class Method'

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: JMAFF Guidelines (2000), including the most recent revisions

Test guideline 4

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

acute toxic class method

Test material

Test material information

1

Reference substance name:

Reference substance 001

Cas Number:

2374827-92-4

Test material form:

solid: particulate/powder

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

At study assignment, each animal was identified using a subcutaneously implanted electronic identification chip. The animals were allowed to acclimate to the Test Facility toxicology accommodation for at least 5 days before the commencement of dosing. Animals were assigned to the study at the discretion of the coordinating biotechnician, with all animals within ± 20% of the sex mean body weights.
Before the initiation of dosing, a health inspection was performed and any assigned animal considered unsuitable for use in the study were replaced by alternate animals obtained from the same shipment and maintained under the same environmental conditions.
The disposition of all animals was documented in the study records.
On arrival and following assignment to the study, animals were group housed (up to 3 animals of the same sex and same dosing group together) in polycarbonate cages (Makrolon MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier &Söhne GmbH+ CO. KG, Rosenberg, Germany) equipped with water bottles. Animals were separated during designated procedures/activities. Each cage was clearly labeled. Target temperatures of 18 to 24°C with a relative target humidity of 40 to 70% were maintained. The actual daily mean temperature during the study period was 20 to 21°C with an actual daily mean relative humidity of 36 to 52. A 12-hour light/12-hour dark cycle was maintained. Ten or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms.
Pelleted rodent diet was provided ad libitum throughout the study, except during designated procedures. Municipal tap-water was freely available to each animal via water bottles.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Doses:

The first group of 3 was treated at a dose level of 300 mg/kg. Based on the results, two additional groups were dosed at 50 mg/kg.
The dose volume for each animal was based on the body weight measurement prior to dosing.
A dose volume of 10 mL/kg body weight was used for each dose.

No. of animals per sex per dose:

3 females

Details on study design:

The toxicity of the test item was assessed by stepwise treatment of groups of 3 females. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 30 - < 300 mg/kg bw

Based on:

test mat.

Mortality:

At 300 mg/kg, two animals were found dead on Day 1 and one animal was found dead on Day 3 post-treatment.

Clinical signs:

other: At 300 mg/kg, clinical signs consisted of hunched posture, erected fur, decreased respiratory rate, eyes partly/completely closed, lying on the side, moderate uncoordinated movements, shallow breathing and decreased activity. At 50 mg/kg, erected fur was

Gross pathology:

No test item related abnormalities were found at macroscopic postmortemexamination of the
animals.
Beginning autolysis was found in one animal that died during the study, at macroscopic post
mortemexamination. Furthermore, macroscopic postmortem examination of the surviving
animals at termination showed an abnormality of the left kidney (smaller) in only one animal,
which was considered to be not toxicologically relevant. Examination of the other animals did
not reveal any abnormalities.

Applicant's summary and conclusion

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The oral LD50 value of PF-06715298 in Wistar Han rats was established to be within the range of 50-300 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 200 mg/kg body weight.
Based on these results:
• According to GHS PF-06715298 should be classified as: Toxic if swallowed (Category 3) for acute toxicity by the oral route.
• According to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments),PF-06715298 should be classified as Category 3 and should be labeled as H301: Toxic if swallowed.

Executive summary:

The objective of this study was to assess the toxicity of the test item when administered in a single dose to female rats at one or more defined dosages. Furthermore, the results of the study allowed the test item to be ranked according to most classification systems, currently in use. This study should provide a rational basis for risk assessment in man.
The study was carried out in compliance with the guidelines described in:
• OECD No.423 (2001) "Acute Oral Toxicity, Acute Toxic Class Method".
• EC No 440/2008, part B: "Acute Oral Toxicity, Acute Toxic Class Method".
Initially,PF-06715298 was administered by oralgavageto three female Wistar Han rats at 300 mg/kg body weight. In a stepwise procedure two additional groups of three females were dosed at 50 mg/kg body weight. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15).
At 300 mg/kg, two animals were found dead on Day 1 and one animal was found dead on Day 3 post-treatment. At 50 mg/kg, no mortality occurred.
At 300 mg/kg, clinical signs consisted of hunched posture, erected fur, decreased respiratory rate, eyes partly/completely closed, lying on the side, moderate uncoordinated movements, shallow breathing and decreased activity. At 50 mg/kg, erected fur was observed in three males on Day 1. Furthermore, hunched posture and severe uncoordinated movements was observed in the other three animals on Days 1 and/or 2. The body weight gain shown by the surviving animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.
No test item related abnormalities were found at macroscopic postmortemexamination of the animals.
The oral LD50 value ofPF-06715298 in Wistar Han rats was established to be within the range of 50-300 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 200 mg/kg body weight.
Based on these results and according to the Globally Harmonized System of Classification and Labelling of
Chemicals (GHS) of the United Nations (2017) (including all amendments), PF-06715298 should be classified as: Toxic if swallowed (Category 3) for acute toxicity by the oral route and should be labeled as H301: Toxic if swallowed.