Registration Dossier

Diss Factsheets

Toxicological information

Acute Toxicity: oral

Currently viewing:

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2016-01-19 to 2016-02-23
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2016

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
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

Constituent 1
Chemical structure
Reference substance name:
1-benzhydrylpiperazine
EC Number:
212-667-7
EC Name:
1-benzhydrylpiperazine
Cas Number:
841-77-0
Molecular formula:
C17H20N2
IUPAC Name:
1-(DIPHENYLMETHYL)PIPERAZINE
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study reports): JNJ-130806-AAA (T000750)
- Physical state: solid (powder)
- Appearance: white to slight beige powder
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Janssen Pharmaceutica N.V., M15B1451
- Expiration date of the lot/batch: 30 January 2001
- Purity correction factor: 1

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature
- Stability under test conditions: Analysis of stability, homogeneity and concentration of the test item under test
conditions was not performed as part of this study.
- Solubility and stability of the test substance in the solvent/vehicle:


Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Wistar strain Crl:WI (Han) (outbred, SPF-Quality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 8-10 weeks
- Weight at study initiation: 138 - 182 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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1% aqueous
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL, 300 mg/mL, 5 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 (turbid solution), 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 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.
- No correction was made for purity of the test item as correction factor is 1

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 body weight
300 mg/kg body weight (2 groups)
50 mg/kg body weight (2 groups)
No. of animals per sex per dose:
3 females per group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days (until day 15)
- Frequency of observations and weighing:
- mortality/viability: twice daily.
- body weights: days 1 (pre-administration), 8 and 15 and at death (if found dead or sacrificed 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 moribund animals and 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 2000 mg/kg, all animals were found dead or were sacrificed for humane reasons on Day 1.(3/3)
At 300 mg/kg, two animals were found dead on Day 1 and one animal was found dead on Day 2. No mortality occurred in the remaining three animals. (3/6)
At 50 mg/kg, no mortality occurred. (0/6)
Clinical signs:
At 2000 mg/kg, hunched posture and piloerection were noted for all animals on Day 1. Additionally, the animal sacrificed for humane reasons showed clonic spasms, flat posture, abnormal gait, shallow respiration and hypersensitivity to touch and sound.
At 300 mg/kg, tremors, hunched posture, uncoordinated movements and/or piloerection were noted for all animals between Days 1 and 5.
At 50 mg/kg, tremors, hunched posture, uncoordinated movements and/or piloerection were noted for all animals between Days 1 and 3.
Body weight:
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.
Gross pathology:
At 2000 mg/kg, gray-white discolouration of the stomach contents was noted for all animals at macroscopic examination.
At 300 mg/kg, gray-white discolouration of the stomach contents was noted for one animal at macroscopic examination. No abnormalities were noted for the other animals at this dosage.
At 50 mg/kg, macroscopic post mortem examination did not reveal any abnormalities.
Beginning of autolysis was noted for one of the animals found dead at 300 mg/kg. This was considered not toxicologically relevant.

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The oral LD50 value of T000750 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 (2015) (including all amendments), T000750 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), T000750 should be classified as Category 3 and should be labeled as H301: Toxic if swallowed.

In addition, given the toxicity observed on central nervous system after single exposure (hunched posture, uncoordinated movements and/or piloerection), T000750 should also be classified as STOT SE 1 Category 1 and should be labeled as H370 - Causes damage to organs (Central Nervous System).