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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2016-01-26 to 2016-03-08
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:
yes
Remarks:
test with dose 2000 mg/kg bw performed three times
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-acetyl-4-(4-hydroxyphenyl)piperazine
EC Number:
267-744-8
EC Name:
1-acetyl-4-(4-hydroxyphenyl)piperazine
Cas Number:
67914-60-7
Molecular formula:
C12H16N2O2
IUPAC Name:
1-[4-(4-hydroxyphenyl)piperazin-1-yl]ethan-1-one
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material: JNJ-119379-AAA (T001141)
- Physical state: solid (powder)
- Appearance: white 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. I15FB3131
- Expiration date of the lot/batch: 11-Jun-2017 (retest date)
- 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

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: 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 sufficiently for these kinds of studies. No correction was made for purity of the test item as the correction factor is 1. The concentration of the test item in vehicle was varied to allow constant dosage volume in terms of mL/kg body weight.


Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Crl:WI (Han) (outbred, SPF-Quality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 8-10 weeks
- Weight at study initiation: 139 - 194 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 and 30 mg/mL
- 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).

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.

Doses:
2000 mg/kg body weight (3 groups)
300 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
- Frequency of observations and weighing:
- mortality/viability: twice daily. The time of death was recorded as precisely as possible;
- 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, 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
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 300 - <= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
At 2000 mg/kg, four out of eight animals were found dead on Day 2. (The test was performed three times: 1st test: 2 of 3 animals died (1 animal excluded from interpretation), 2nd test: 0 animals died, 3th test: 3 of 3 animals died
At 300 mg/kg, no mortality occurred.
Clinical signs:
At 2000 mg/kg, lethargy, hunched posture, quick breathing, shallow respiration, piloerection and/or ptosis were noted for all animals on Days 1 and/or 2.
At 300 mg/kg, hunched posture, piloerection and/or ptosis were noted for all animals on Day 1.
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, abnormalities of the body cavities (Thoracic cavity: contains watery-clear fluid) were noted for all animals found dead.
At 300 mg/kg, macroscopic post mortem examination did not reveal any abnormalities.
Autolysis was noted for all animals found dead at 2000 mg/kg. This was considered not toxicologically relevant.
Other findings:
One of the animals (no. 3) that was dosed at 2000 mg/kg and was found dead on Day 2, showed a perforated esophagus at macroscopic post mortem examination. During observations for clinical signs hunched posture, piloerection and ptosis were noted for this animal on Day 1. Further, watery clear fluid in the thoracic cavity and autolysis were noted at macroscopic examination.
Since it could not be excluded that this mortality occurred due to a gavage error the data obtained from this animal were excluded from the study results. However, it was considered that sufficient data were available from the remaining animals for proper evaluation of the study.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
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), T001141 should be classified as: harmful if swallowed (Category 4) 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), T001141 should be classified as Category 4 and should be labeled as H302: Harmful if swallowed.