Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2017-08-10 to 2018-08-31
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report Date:
2018

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: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: wax
Details on test material:
Physical state: wax form
Appearance: clear, viscous, wax
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., I17EB1781
- Expiration date of the lot/batch: 26 April 2018 (retest date)
- Purity correction factor: 1.13

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
- Solubility and stability of the test substance in the solvent/vehicle: No data.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: 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 assessed by visual inspection of the solutions and the formulations were stirred during dosing, which ensures homogeneity sufficiently for these kinds of studies. Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item.
Before sampling the test item was heated in a warmth cabinet at 60ºC for approximately 3 days. In order to obtain homogeneity, the test item preparations were heated in a water bath with a maximum temperature of 61.3ºC for a maximum of 16 minutes. The test item formulations were allowed to cool to a temperature of maximally 40ºC prior to dosing.

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Wistar strain Crl:WI (Han) (outbred, SPF-Quality); Charles River Deutschland, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approx. 10-11 weeks old
- Weight at study initiation: 171 - 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 (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; the actual daily mean temperature during the study period was 21 - 22°C
- Humidity (%): 40 to 70; the actualy daily mean relative humidity was 50 - 72%.
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
400
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 174 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg
- 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 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) (test item did not dissolve), polyethylene glycol 400 (spec. gravity 1.125) (yellow clear solution) and corn oil (spec. gravity 0.92) (yellow clear solution).

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 assessed by visual inspection of the solutions 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. Before sampling the test item was heated in a warmth cabinet at 60ºC for approximately 3 days. In order to obtain homogeneity, the test item preparations were heated in a water bath with a maximum temperature of 61.3ºC for a maximum of 16 minutes. The test item formulations were allowed to cool to a temperature of maximally 40ºC prior to dosing.
Doses:
1770 mg/kg bw
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
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, 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:
> 1 770 mg/kg bw
Based on:
test mat.
Mortality:
One animal was found dead on Day 2.
Clinical signs:
Lethargy, flat and hunched posture, uncoordinated movements, piloerection, salivation, and/or ptosis were noted for the animals between Days 1 and 3, with piloerection and hunched posture reappearing on Day 7 for one animal. Additionally, slow breathing, shallow respiration and hypothermia were observed on Day 1 for the animal that died during the study.
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:
Several dark red foci on the thymus were found in the animal that died during the study, at macroscopic post mortem examination. Additionally, beginning autolysis was noted for the animal that died during the study, which was considered not to be test item related. No further macroscopic findings were noted for the animals.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The oral LD50 value of T001597 in Wistar rats was established to exceed 1770 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 (2017) (including all amendments), T001597 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 items and mixtures (including all amendments), T001597 should be classified as Category 4 and should be labeled as H302: Harmful if swallowed.