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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:
2016-09-27 to 2016-10-20
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)
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 No 8147, 11/2000
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 reports): T000836 (JNJ-16250351-AAH)
- Physical state: solid
- Appearance: white powder
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: I16DB2126
- Expiration date of the lot/batch: 2018-04-27 (retest date)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature
- Stability under test conditions: no data
- Solubility and stability of the test substance in the solvent/vehicle: no data

OTHER SPECIFICS:
-Correction factor: 1.3

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: 9 female rats (nulliparous and non-pregnant), Wistar strain Crl:WI (Han) (outbred, SPF-Quality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 8 weeks old
- Weight at study initiation: 138-157 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
- 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 & Sohne GmbH + CO. KG, Rosenberg, Germany) and paper as cage enrichmentitum (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:
water
Remarks:
Elix, Millipore S.A.S., Molsheim, France
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 mg/mL ; 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 vehicle was chosen from (in order of preference): water (Elix) (hazy solution), 1% aq. carboxymethyl cellulose, 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 stability in vehicle.

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 sufficiently for these kinds of studies. Adjustment was made for specific gravity of the vehicle. A factor of 1.3 was used to correct for the purity/composition 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: The toxicity of the test item was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 2000 mg/kg. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups.
Doses:
2000 mg eq/kg
300 mg eq/kg
No. of animals per sex per dose:
3 females per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- 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.
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 other: mg eq/kg bw
Based on:
test mat.
Mortality:
At 2000 mg/kg, all animals were found dead on Day 1.
No further mortality occurred.
Clinical signs:
At 2000 mg/kg, hunched posture was noted for two out of three animals on Day 1.
At 300 mg/kg, hunched posture and piloerection were noted for three out of six 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:
At 2000 mg/kg, dark red colouration of the jejunum and pancreas or several red foci on the thymus were noted.
At 300 mg/kg, macroscopic examination did not reveal any abnormalities.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The oral LD50 value of T000836 in Wistar rats was established to be within the range of 300-2000 mg eq/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 500 mg/kg body weight.
According to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments), T000836 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), T000836 should be classified as Category 4 and should be labeled as H302: Harmful if swallowed.