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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2015-01-13 to 2015-02-03
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 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
Qualifier:
according to guideline
Guideline:
other: JMAFF No 8147, 11/2000
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:
2-chlorophenyl cyclopentyl ketone
EC Number:
229-802-0
EC Name:
2-chlorophenyl cyclopentyl ketone
Cas Number:
6740-85-8
Molecular formula:
C12H13ClO
IUPAC Name:
2-chlorophenyl cyclopentyl ketone
Test material form:
liquid
Details on test material:
- Name of test material (as cited in study reports): JNJ-54582034-AAA (T003642)
- Physical state: liquid
- Appearance: yellow liquid
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. 0020709377
- Expiration date of the lot/batch: 2016-08-31 (retest date)
- Purity/correction factor: 96.1%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- The test substance was dosed undiluted as delivered by the sponsor. No correction was made for the purity/composition of the test substance. Test substance was stirred on a magnetic stirrer during dosing

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, SPFQuality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 11 weeks old
- Weight at study initiation: 156-208 grams
- Fasting period before study: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance. 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): Free access to pelleted rodent diet
- Water (e.g. 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 to 24°C
- Humidity (%): 40 to 70%
- Air changes (per hr): at least 10 air changes/hour
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 1.739 mL/kg

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:
2000 mg/kg (1.739 mL/kg) body weight
300 mg/kg (0.261 mL/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 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, two animals were found dead on Day 3.
At 300 mg/kg, no mortality occurred.
Clinical signs:
At 2000 mg/kg, lethargy, flat posture, hunched posture, uncoordinated movements, laboured respiration, piloerection and/or ptosis were noted for all animals between Days 1 and 6.
At 300 mg/kg, hunched posture 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:
No test substance related abnormalities were found at macroscopic post mortem examination of the animals treated at 2000 or 300 mg/kg.
Advanced autolysis was found in both animals that died during the study, at macroscopic examination. This finding is considered not toxicologically significant.
Fluid in the uterus, found in one animal, is related to a stage in the oestrous cycle and is a normal finding.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The oral LD50 value of T003642 in Wistar rats was established to be within the range of 300-2000 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 1000 mg/kg body weight.
According to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) (including all amendments), T003642 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), T003642 should be classified as Category 4 and should be labeled as H302: Harmful if swallowed.