p-fluorophenyl 4-piperidyl ketone hydrochloride

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 2015-09-15 to 2015-10-08

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Report date:

2015

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:

p-fluorophenyl 4-piperidyl ketone hydrochloride

EC Number:

247-070-0

EC Name:

p-fluorophenyl 4-piperidyl ketone hydrochloride

Cas Number:

25519-78-2

Molecular formula:

C12H14FNO.ClH

IUPAC Name:

4-(4-fluorobenzoyl)piperidine hydrochloride

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

- Name of test material (as cited in study report): JNJ-398099-AAC (T001047)
- Substance type: white powder
- Physical state: solid
- Analytical purity: 97.2 % (acid titration)
- Impurities (identity and concentrations): R050110 0.25%, total impurities 0.3%
- Purity test date: no data
- Lot/batch No.: I15DB1484
- Expiration date of the lot/batch: 2017-04-19 (retest date)
- Stability under storage conditions: until 2017-04-19 (retest date)
- Storage condition of test material: at room temperature
- Correction factor: 1.18
- Solubility in vehicle: >300 g/L
- Stability in vehicle: no data

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: 12 female rats (nulliparous and non-pregnant), Wistar strain Crl:WI (Han) (outbred, SPF-Quality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 9-12 weeks old
- Weight at study initiation (day 1): 163 - 204 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 (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- 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, health inspection at least prior to dosing. It was ensured that the animals were healthy and without any abnormality that might affect the study integrity.
- Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study.

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

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30 mg/ml (300 mg eq/kg body weight) and 5 mg/ml (50 mg eq/kg body weight)
- Amount of vehicle (if gavage): 10 ml/kg
- 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) (turbid solution), 1% aq. carboxymethyl cellulose, propylene glycol (spec.gravity 1.036), polyethylene glycol 400 (spec. gravity 1.125) and corn oil (spec. gravity 0.92). There was no information available regarding the stability in vehicle.
- Lot/batch no. (if required): no data
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

DOSAGE PREPARATION (if unusual):
- The preparations (w/w) were dosed within 4 hours after adding the vehicle to the test item. Homogeneity was assessed by visual inspection of the solutions and the formulations were stirred during dosing, which ensures homogeneity sufficient for these kinds of studies.
- A factor 1.18 was used to correct for purity/composition of the test item.
- The concentration of the test item in vehicle was varied to allow constant dosage volume in terms of ml/kg body weight.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: the dose level was selected based on toxicity data (e.g. existing human and animal data, literature, substance data supplied by the Sponsor, analysis of structure activity relationships (SAR) and in vitro, ex-vivo and in vivo tests) of the test item (specified and approved by the Study Director in the study files).

Doses:

300 and 50 mg eq/kg body weight

No. of animals per sex per dose:

3 females per dose

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 and at death (if found dead after day 1);
- 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, the m animals surviving to the end of the observation period were sacrificed by oxygen/carbon dioxide procedure. All animals assigned to the study were subjected to necropsy and descriptions of all internal macroscopic abnormalities recorded.

Statistics:

No statistical analysis was performed

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 50 - < 300 mg/kg bw

Based on:

test mat.

Mortality:

At 300 mg eq/kg, three out of six animals were found dead on day 1 or 2.
At 50 mg eq/kg, no mortality occurred.

Clinical signs:

irregular respiration

lethargy (hypoactivity)

other:

Body weight:

other body weight observations

Remarks:

The mean 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.

Gross pathology:

No toxicologically relevant abnormalities were found at macroscopic post mortem examination of all animals.
Beginning of autolysis was noted for one of the animals that died during the study and was considered not toxicologically significant.

Applicant's summary and conclusion

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

The oral LD50 value of JNJ-398099-AAC (T001047) in Wistar 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 300 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 (2011) (including all amendments),
JNJ-398099-AAC (T001047) 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 substances and mixtures (including all amendments), JNJ-398099-AAC (T001047) should be classified as Category 3 and should be labeled as H301: Toxic if swallowed.