Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016-09-22 to 2016-10-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report Date:
2017

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
2001
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
May 2008
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Foresty, and Fisheries
Version / remarks:
12 Nousan, Notification No 8147, November 2000; including most recent revisions
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-7982559-AAA (T001329)
- Physical state: solid (powder)
- Appearance: Grey-brown powder
Specific details on test material used for the study:
Test Material SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Janssen Pharmaceutica N.V., I14IB3639
- Expiration date of the lot/batch: 17 September 2020 (retest date)
- Purity correction factor: 1

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room Temperature
- Solubility and stability of the test substance in the solvent/vehicle: Analysis of test item in vehicle for concentration, stability, homogeneity was not performed, however preparation was performed with approved procedure and documented in detail. Homogeneity was visually inspected prior to use.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Test preparation material was kept at room temperature no more than 4 hours before animals were dosed. Preparations were stirred on magnetic stirrer during dosing. Adjustment was made for specific gravity of the vehicle.No correction was made for purity of the test item as the correction factor is 1.





Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl:WI (Han)(outbred, SPF-Qualtiy)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: 144 - 164 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%; study plan deviation: deviations from the minimum level of daily mean relative humidity occurred. Evaluation: laboratory historical data did not indicate an effect of the deviations. The study integrity was not affected by this deviation.
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Remarks:
1% Aqueous
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Justification for choice of vehicle: The vehicle was selected based on trial preparations performed at Charles River Den Bosch and on test item data supplied by the Sponsor. The vehilce was chosen from: water (Elix) (test item did not dissolve), 1% aq. carboxymethyl cellulose (test item did not dissolve), propylene glycol (spec. gravity 1.036) (turbid solution), 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.
- Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item as the correction factor is 1.

Doses:
2000 mg/kg (single dosage)
No. of animals per sex per dose:
3 females per group (6 total)
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
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, at the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.
Statistics:
No statistical analysis was performed.

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred
Number of dead animals in each test group with 3 animals each:
Females 2000 mg/kg: 0
Females 2000 mg/kg: 0
Clinical signs:
Piloerection, hunched posture and/or uncoordinated movements were noted for the majority of animals on Day 1.
Body weight:
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 abnormalities were found at macroscopic post mortem examination of all animals.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 value of T001329 in Wistar rats was established to exceed 2000 mg/kg body weight. According to OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.

Based on these results, T001329 does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals of the United Nations (2015) and Regulation (EC) No 1272/2008 on classification, labelling and packing of substances and mixtures (including all amendments).