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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:
2015-05-28 to 2015-06-23
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well-documented, GLP-compliant study, performed according to the OECD test guideline 423, EU method B.1 tris and EPA OPPTS guideline 870.1100. No deviations were recorded

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:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: JMAFF, 12 Nousan, Notification No 8147, Nov 2000
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study report): JNJ-119717-AAA (T001036)
- Physical state: solid
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., A14JB3442
- Expiration date of the lot/batch: 30 September 2016 (retest date)
- Purity: 99.9% (acid titration)

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


Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: rat, Wistar strain Crl:WI (Han) (outbred, SPF-quality); from Charles River Deutschland, Sulzfeld, Germany; female animals (nulliparous and non-pregnant)
- Age at study initiation: approx. 8-10 weeks
- Weight at study initiation:148-192 grams (bodyweights of Day 1 were determined pre-administration of the test item)
- 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 18cm) containing sterilized sawdust as bedding material and paper as cage-enrichment
- 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):18-24°C
- Humidity (%):40-70%
- Air changes (per hr):at least 10 air changes per hour
- Photoperiod (hrs dark / hrs light):12hrs light/12 hrs dark cycle.

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Remarks:
specific gravity 1.036
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 mg/ml , 200 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg bw
- 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), 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.
- Lot/batch no. (if required): no data
- Purity:no data

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg body weight; using plastic feeding tubes

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 the purity 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: no data
Doses:
Stepwise procedure:
initially: 2000 mg/kg bw (1 group of 3 animals)
then: 300 mg/kg bw (2 groups of 3 animals)

frequency: single dosage on Day 1
No. of animals per sex per dose:
3 females/dose group; 3 groups
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. Animals showing pain, distress or discomfort, which was considered not transient in nature or was likely to become more severe, were sacrificed for humane reasons based on OECD guidance document on humane endpoints. 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.
- 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 levelsopen allclose all
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Effect level:
1 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: based on OECD423
Mortality:
At 2000 mg/kg, two animals were sacrificed for humane reasons on day 2.
At 300 mg/kg, no mortality occurred.
Clinical signs:
At 2000 mg/kg, lethargy, flat posture, hunched posture, slow breathing, shallow respiration, piloerection, watery discharge from the eyes, ptosis and/or hypothermia were noted for the animals on days 1 and/or 2.
At 300 mg/kg, lethargy, hunched posture, uncoordinated movements, piloerection and/or ptosis were noted for the animals on days 1 and/or 2.
Body weight:
At 2000 mg/kg, the surviving animal showed reduced body weight gain between days 8 and 15.
At 300 mg/kg, the body weight gain 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, dark red contents of the urinary bladder were found in the two animals sacrificed for humane reasons on day 2.
At 300 mg/kg, no abnormalities were found at macroscopic post mortem examination.
Other findings:
No other findings

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The oral LD50 value of JNJ-119717-AAA (T001036) 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.
Based on the results: -according to the GHS , JNJ-119717-AAA (T001036) 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, JNJ-119717-AAA (T001036) should be classified as category 4 and should be labeled as H302: Harmful if swallowed