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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:
From 2016-10-04 to 2016-11-01
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 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:
White to light yellow powder
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: A16FC1793
- Expiration date of the lot/batch: 08 June 2018 (retest date)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature
- Stability under test conditions: No data. The test item was kept at room temperature for a maximum of 4 hours prior to dosing

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 as the correction factor is 1. The concentration of the test item in vehicle was varied to allow constant dosage volume in terms of mL/kg body weight.

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: approx. 8 weeks old
- Weight at study initiation: 144-165 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): 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:
propylene glycol
Remarks:
gravity 1.036
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200, 30, 5 mg/mL
- Amount of vehicle (if gavage): 2000, 300, 50 mg/kg (10 mL/kg) body weight
- 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) (clear solution), 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.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

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.
Doses:
2000, 300, 50 mg/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 (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. 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: 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 levelsopen allclose all
Key result
Sex:
female
Dose descriptor:
LD50 cut-off
Effect level:
200 mg/kg bw
Based on:
test mat.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 50 mg/kg bw
Based on:
test mat.
Remarks:
Range is 50 - 300 mg/kg bw
Mortality:
At 2000 mg/kg, all animals were found dead on Day 1.
At 300 mg/kg, one animal was found dead on Day 1, one animal was found dead on Day 2 and one animal was sacrificed for humane reasons on Day 8.
At 50 mg/kg, no mortality occurred.
Clinical signs:
At 2000 mg/kg, abnormal posture, hunched posture, piloerection and general tremor were noted for all animals on Day 1.
At 300 mg/kg, restless behavior, general tremor, hunched posture, abnormal gait, salivation, lean appearance and/or hypersensitivity to sound were noted for all animals between Days 1 and 8.
At 50 mg/kg, restless behavior, hunched posture, uncoordinated movements and/or piloerection were noted for all animals on Days 1 and/or 2.
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 discoloration of the glandular mucosa of the stomach was noted for one animal.
At 300 mg/kg, a distended stomach (with gas) was noted for one animal.
At 50 mg/kg, no abnormalities were found at macroscopic examination.

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The oral LD50 value of T000841 in Wistar rats was established to be within the range of 50-300 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 200 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 (2015) (including all amendments), T000841 should be classified as: Toxic if swallowed (Category 3) 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),
JNJ-118781-AAA (T000841) should be classified as Category 3 and should be labeled as H301: Toxic if swallowed.