Registration Dossier

Administrative data

Description of key information

Acute oral toxicity:

In an acute oral toxicity study in female Wistar rats, following the acute toxic class method in accordance with the OECD Guideline 423 and EU Method B.1 tris, the LD50 was established to be greater than 2000 mg/kg (Latour, 2016).

Acute inhalation toxicity:

In addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For T003421, a study was considered however not deemed scientifically justified for the dermal route of exposure due to its low potential for a significant rate of absorption through the skin. Based on the fact that the inhalation route of exposure is not considered relevant in the risk assessment for human exposure and the addition of a waiver for the acute dermal toxicity testing, an acute inhalation toxicity study will not be performed.

Acute dermal toxicity

In addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For this substance, an acute dermal toxicity study was considered. However, this can be waived based on the fact that the substance does not meet the criteria for classification for acute toxicity or STOT SE by the oral route, and no systemic toxicity is observed in in vivo studies with dermal exposure.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016-08-04 to 2016-08-31
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
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, Foresty and Fisheries
Version / remarks:
12 Nousan, Notification No 8147, November 2000
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Specific details on test material used for the study:
Test Material SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Janssen Pharmaceuticals N.V., M15KB4494
- Expiration date of the lot/batch: 13-Nov-2016 (retest date)
- Purity correction factor: 1
- Laboratoory Test ID: 206847/A

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.





Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: female rats (nulliparous and non-pregnant), Wistar strain Crl:WI (Han) (outbred, SPF-Quality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: 164, 159, 164, 141, 168, 163 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%
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 04 August 2016
To:31 August 2016
Route of administration:
oral: gavage
Vehicle:
propylene glycol
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). There was no information available regarding the solubility or 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 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.

Doses:
2000 mg/kg (single dosage)
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.
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.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occured
Clinical signs:
Uncoordinated movements, piloerection and/or hunched posture were noted for five 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.

Number of dead animals in each test group with 3 animals each:

Females 2000 mg/kg: 0

Females 2000 mg/kg: 0

Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 value of T003421 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 results, T003421 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).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute oral toxicity:

A K2 non-GLP study with limited information on test conditions and animals was performed according to OECD Guideline 425 (Herlich, 2012).

One fasted female rat received a single oral gavage dose of the test item formulated in 0.5% Hypromellose at a dose level of 175 mg/kg.

As this animal survived, a second fasted female rat was similarly dosed at 550 mg/kg. as this animal survived an additional three fasted female rats were similarly doses at 2000 mg/kg in a sequential manner to complete the study.

There was no mortality, no changes in body weight or body weight gain, or macroscopic findings at necropsy. Two of the three rats administered 2000 mg/kg had pale feces 24 hours after the administration of a single dose.

The acute median lethal dose LD50 of the test item was greater than 2000 mg/kg.

This non-GLP study is used as supporting study.

 

A second acute oral toxicity study with T003421 according to the acute toxic class method in female Wistar rats (GLP, OECD guideline 423 and EU Method B.1 tris) was performed (Latour, 2016). This K1 GLP study is assigned as key study.

T003421 was administered by oral gavage to two subsequent groups of three female Wistar rats at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15).

No mortality occurred.

Uncoordinated movements, piloerection and/or hunched posture were noted for five animals on Day 1.

The mean body weight gain shown by the animals over the study period was considered to be normal.

No abnormalities were found at macroscopic post mortem examination of all animals.

The oral LD50 value of T003421 in Wistar rats was established to exceed 2000 mg/kg body weight.

According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.

 

Acute inhalation toxicity:

In addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For T003421, a study was considered however not deemed scientifically justified for the dermal route of exposure due to its low potential for a significant rate of absorption through the skin. Based on the fact that the inhalation route of exposure is not considered relevant in the risk assessment for human exposure and the addition of a waiver for the acute dermal toxicity testing, an acute inhalation toxicity study will not be performed.

Acute dermal toxicity

In addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For this substance, an acute dermal toxicity study was considered. However, this can be waived based on the fact that the substance does not meet the criteria for classification for acute toxicity or STOT SE by the oral route, and no systemic toxicity is observed in in vivo studies with dermal exposure.

Justification for classification or non-classification

Based on the available data, T003421 does not have to be classified for acute oral toxicity according EU CLP.

No studies were available for acute toxicity via the inhalation and dermal route so no classification could be derived for acute toxicity after exposure to the test item via those exposure routes.