(1R,2S,3S,4R)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 2015-09-24 to 2015-10-13

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented study performed according to OECD guideline 423, EU method B1 tris and EPA OPPTS guideline 870.1100, in compliance with GLP. No deviations were noted.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

(2S,3S)-3-({5-fluoro-2-[5-fluoro-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl}amino)bicyclo[2.2.2]octane-2-carboxylic acid

EC Number:

821-185-1

Cas Number:

1777721-63-7

Molecular formula:

C27H25F2N5O4S

IUPAC Name:

(2S,3S)-3-({5-fluoro-2-[5-fluoro-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl}amino)bicyclo[2.2.2]octane-2-carboxylic acid

Test material form:

solid: particulate/powder

Details on test material:

- Name of the test material (as cited in study reports): JNJ-63757109-AAA (T003690)
- Physical state: solid (powder)
- Appearance: white to slightly yellow power

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: female rats (nulliparous and non-pregnant), Wistar strain Crl:WI (Han) (outbred, SPF-Quality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Young adult animals (approx. 8-9 weeks old)
- Weight at study initiation: 149 - 163 grams
- Fasting period before study: animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test item. Water was available ad libitum.
- Housing: group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne GmbH + CO. KG, Rosenberg, Germany) and paper as cage-enrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom)
- Diet (e.g. ad libitum): ad libitum, free access to pelleted rodent diet
- Water (e.g. ad libitum): ad libitum, free access to tap water.
- Acclimation period: at least 5 days before start of treatment under laboratory conditions.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24 °C
- Humidity (%): 40-70 %
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From 2015-09-24 to 2015-10-13

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/ml
- Amount of vehicle (if gavage): no data
- Justification for choice of vehicle: The vehicle was selected based on trial preparations performed at WIL Research Europe and on test item data
supplied by the Sponsor. The vehicle was chosen from (in order of preference): water (Elix) (test item did not dissolve), 1% aq. carboxymethyl cellulose (test item did not dissolve), propylene glycol (spec.gravity 1.036) (turbid solution), polyethylene glycol 400 (spec. gravity 1.125) and corn oil
(spec. gravity 0.92). There was no information available regarding the solubility or stability in vehicle.

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

DOSAGE PREPARATION (if unusual):
- The preparations (w/w) were kept at room temperature and were dosed within 4 hours after adding the vehicle to the test item. Homogeneity was obtained to visually acceptable levels and the formulations were stirred during dosing, which ensures homogeneity sufficient for these kinds of studies.
- Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The toxicity of the test item was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 2000 mg/kg.

Doses:

2000 mg/kg (single dosage)

No. of animals per sex per dose:

3 females per dose group (2 groups)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: mortality/viability: twice daily; body weights: days 1 (pre-administration), 8 and 15; clinical signs: at periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15. The signs were graded according to fixed scales and the time of onset, degree and duration were recorded: maximum grade 4: grading slight (1) to very severe (4); maximum grade 3: grading slight (1) to severe (3); maximum grade 1: presence is scored (1).
- Necropsy of survivors performed: yes, At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.

Statistics:

No statistical analysis was performed

Results and discussion

Effect levels

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 was noted for all animals on Day 1. Additionally, one animal also showed hunched posture on Days 2 and 3. Uncoordinated movements and piloerection were noted for the first three animals treated on Day 1.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of all animals.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 value of JNJ-63757109-AAA (T003690) in Wistar 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, JNJ-63757109-AAA (T003690) does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Regulation (EC) No 1272/2008.