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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22nd Nov 2018 - 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:
2019
Report date:
2019

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Qualifier:
according to guideline
Guideline:
other: JMAFF Guidelines (2000), including the most recent revisions
GLP compliance:
yes
Test type:
acute toxic class method

Test material

Constituent 1
Chemical structure
Reference substance name:
cis-N-hydroxy-3-[methyl(1H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino]cyclobutanecarboxamide
EC Number:
951-622-2
Molecular formula:
C12H15N5O2
IUPAC Name:
cis-N-hydroxy-3-[methyl(1H-pyrrolo[2,3-d]pyrimidin- 4-yl)amino]cyclobutanecarboxamide

Test animals

Species:
rat
Strain:
other: Wistar Han
Sex:
female
Details on test animals or test system and environmental conditions:
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 40 to 53%. 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.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
A single dose of test item was administered to the appropriate animals by oral gavage on Day
1, using a syringe with a plastic gavage cannula attached.
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.
The dosing formulations were stirred continuously during dose administration.
Animals were deprived of food overnight (for a maximum of 20 hours) prior to dosing and
until 3-4 hours after administration of the test item. Water was available.
Control animals:
no
Details on study design:
The Wistar Han rat was chosen as the animal model for this study as recognized by
international guidelines as a recommended test system. The test method and number of
animals were based on the test guidelines.
The study plan was reviewed and agreed by the Animal Welfare Body of Charles River
Laboratories Den Bosch B.V. within the framework of Appendix 1 of project license
AVD2360020172866 approved by the Central Authority for Scientific Procedures on
Animals (CCD) as required by the Dutch Act on Animal Experimentation (December 2014).

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
other: Hunched posture and piloerection were noted for all animals on Days 1 and/or 2.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals

Applicant's summary and conclusion

Interpretation of results:
study cannot be used for classification
Conclusions:
The oral LD50 value of PF-07085579 in Wistar Han rats was established to exceed 2000
mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed
5000 mg/kg body weight.
Based on these results, PF-07085579 does not have to be classified and has no obligatory
labelling requirement for acute oral toxicity according to the Globally Harmonized System of
Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all
amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging
of items and mixtures (including all amendments).
Executive summary:

The objective of this study was to determine the potential toxicity of  PF-07085579, when given by oral  gavage  at a single dose to rats of a single sex at one or more defined doses to

evaluate the potential reversibility of any findings.

PF-07085579 was administered by oral  gavage  to two consecutive groups of three female Wistar Han rats at 2000 mg/kg body weight. Animals were subjected to daily observations

and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15). No mortality occurred.

Hunched posture and piloerection were noted for all animals on Days 1 and/or 2. The body weight gain shown by the animals over the study period was considered to be

similar to that expected for normal untreated animals of the same age and strain. No abnormalities were found at macroscopic post  mortem  examination of the animals.

The oral LD50 value of  PF-07085579 in Wistar Han rats was established to exceed 2000 mg/kg body weight. According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed

5000 mg/kg body weight. Based on these results,  PF-07085579 does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of

Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).