cis-N-methyl-N-(1H-pyrrolo[2,3-d]pyrimidin4-yl)cyclobutane-1,3-diamine phosphate (1:1)

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

17 Nov 2018 to 18 Dec 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Test guideline 4

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Test type:

acute toxic class method

Test material

Test material information

1

Reference substance name:

(1s,3s)-N1-methyl-N1-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}cyclobutane-1,3-diamine; phosphoric acid

EC Number:

951-920-2

Molecular formula:

C11H15N5* H3PO4

IUPAC Name:

(1s,3s)-N1-methyl-N1-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}cyclobutane-1,3-diamine; phosphoric acid

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Results and discussion

Effect levels

Effect levels 1

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 50 - <= 300 mg/kg bw

Based on:

test mat.

Effect levels 2

Key result

Sex:

female

Dose descriptor:

LD100

Effect level:

>= 300 - <= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

At 2000 and 300 mg/kg all animals were found dead on Day 1 post-treatment.
At 50 mg/kg, no mortality occurred.

Clinical signs:

other: At 2000 mg/kg, piloerection was noted for the animals on Day 1. At 300 mg/kg, lethargy, flat posture, hunched posture, piloerection and/orptosiswere noted on Day 1. At 50 mg/kg, hunched posture, quick breathing, uncoordinated movements, piloerection, ptos

Applicant's summary and conclusion

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The oral LD50 value ofPF-03817968-09 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 the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments),PF03817968-09 should be classified as: Toxic if swallowed (Category 3). According to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments),PF-03817968-09 should be classified as Category 3 and should be labeled as H301: Toxic if swallowed.

Executive summary:

The objective of this study was to determine the potential toxicity of PF-03817968-09, when given by oralgavageat a single dose to rats of a single sex (females) at one or more defined doses to evaluate the potential reversibility of any findings. 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-03817968-09 was administered by oralgavageat a single dose to three female Wistar Han rats at 2000 mg/kg body weight. In a stepwise procedure three additional groups of three females were dosed at 300, 50 and 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 2000 mg/kg and 300 mg/kg, all animals were found dead on Day 1. At 50 mg/kg, no mortality occurred. At 2000 mg/kg, piloerection was noted on Day 1. At 300 mg/kg, lethargy, flat posture, hunched posture, piloerection and/orptosiswere noted on Day 1. At 50 mg/kg, hunched posture, quick breathing, uncoordinated movements, piloerection,ptosisand/or focal erythema (ears, legs, nose, tail and/or general) were noted between Days 1 and 3. 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. Macroscopic abnormalities of the thymus (many, several dark red foci) were found in all animals at 2000 mg/kg that died during the study. Macroscopic postmortemexamination of the other animals that died during the study and of the surviving animals did not reveal any abnormalities. The oral LD50 value ofPF-03817968-09 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), PF03817968-09 should be classified as: Toxic if swallowed (Category 3) according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments) and should be labeled as H301: Toxic if swallowed