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Description of key information

Acute toxicity: Oral

In two separate acute oral toxicity study in female rats, following the acute toxic class method in accordance with the OECD Guideline 423, the LD50 was established to be greater than 2000 mg/kg (Latour 2017 and Herlich 2012).

 

Acute toxicity: Inhalation

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 T003422, a key study is available for the dermal route of exposure. Therefore, an acute inhalation toxicity study should not be performed.

 

Acute toxicity: Dermal

In an acute dermal toxicity study in male and female Crl:WI (Han) (SPF) rats, following the standard acute method according to OECD Guideline 402 and EC method B.3, the LD50 was established to exceed 2000 mg/kg body weight (Latour, 2016).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
From 7 May 2012 to 30 May 2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
GLP compliance:
no
Test type:
up-and-down procedure
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
- Name of test material (as cited in study report): JNJ-42808415-AAA (Alternate name: T3422)
- Lot/batch No.: RT003422PFP031
Species:
rat
Strain:
not specified
Sex:
female
Details on test animals and environmental conditions:
no data
Route of administration:
oral: gavage
Vehicle:
other: 0.5% hypromellose
Details on oral exposure:
No data
Doses:
175, 550 and 2000 mg/kg
No. of animals per sex per dose:
1 female rat at 175 mg/kg
1 female rat at 550 mg/kg
3 female rats at 2000 mg/kg
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: mortality: once daily; clinical observations: once during the predose period, on dosing days - prior to dosing, at approximately 30 minutes postdose, and three more times throughout the day. Daily thereafter for the subsequent two weeks; body weight: once during the predose period on day 1 (non-fasted). Day 0 prior to dosing (fasted). Days 7 and 14 (non-fasted).
- Necropsy of survivors performed: yes, fourteen days after dose administration
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There was no mortality at any dose.
Clinical signs:
There were no compound-related clinical signs at 175 or 550 mg/kg. Two of three rats administered 2000 mg/kg had pale feces (discolored white to tan) approximately 24 hours after a single dose. This finding is considered compound-related but not toxicologically relevant. All other observed signs were considered incidental.
Body weight:
One female rat administered 2000 mg/kg had a decrease in body weight gain from days 7-14. However, throughout the two weeks (days 1 to 14), the body weight gain of this rat was comparable to other rats, and therefore not considered significant.
Gross pathology:
There were no compound-related gross pathology findings at any dose.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute median lethal oral dose (LD50) of JNJ-42808415-AAA to female rats was > 2000 mg/kg of body weight.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016-09-27 to 2016-10-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reference:
Composition 0
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 Notification No 8147
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material:
I15AB0305
- Expiration date of the lot/batch:
2017-01-23 (retest date)
- Purity test date:
2015-01-24

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:
Stability for at least 6 hours at room temperature under normal laboratory conditions and 26 days in the refrigerator is confirmed over the concentration range 1 to 200 mg/mL, Project 512709

OTHER SPECIFICS: correction factor was 1
Species:
rat
Strain:
Wistar
Remarks:
Crl: WI (Han) (outbred)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
Wistar strain Crl:WI (Han) (outbred, SPFQuality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation:
approx. 8 weeks old
- Weight at study initiation:
143-189 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 cageenrichment (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

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 2000 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 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. No correction was made for purity of the test item as the correction factor is 1.

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/kg (10 mL/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: 15 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; 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.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Lethargy, uncoordinated movements, piloerection and/or hunched posture were noted for all animals on Day 1. Additionally, hunched posture was noted for two animals on Days 2 and 3.
Body weight:
The mean body weight gain shown by the 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.
Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 value of T003422 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.
Based on these results, T003422 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 (GHS) of the United Nations (2015) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
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
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2016-06-21 to 2016-07-06
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: JMAFF Guidesline No 8147
Version / remarks:
November 2000, including the most recent revisions
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Test material information:
Composition 1
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., I15AB0305
- Expiration date of the lot/batch: 23-JAN-2017 (retest date)
-Purity/composition 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: Stability for at least 6 hours at room temperature under normal laboratory conditions and 26 days in the refrigerator is confirmed over the concentration range 1 to 200 mg/mL, Project 512709. Homogeneity was assessed by visual inspection of the solutions.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Preparation was kept at room temperature and dosed within 4 hours after adding the vehicle to the test item. Adjustment was made for specific gravity of the vehicle. Preparations were stirred on a magnetic stirrer during application.


Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: 5 male and 5 female rats (nulliparous and non-pregnant), Wistar strain Crl:WI (Han) (outbred, SPF-Quality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Young adult animals (approx. 12 weeks old)
- Weight at study initiation: 352, 341, 313, 341, 340 grams (males) and 217, 208, 191, 205, 208 grams (females)
- Housing: Individually housed in labeled Makrolon cages (MIII 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. During the acclimatization period the animals were group housed in Makrolon cages (MIV type, height 18 cm).

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24 °C
- Humidity (%): 40-70%. Deviation: Deviation from the maximum level of daily mean relative humidity occurred. Laboratory historical data do not indicate an effect of the deviation.
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 21-JUN-2016
To: 06-JUL-2016
Type of coverage:
occlusive
Vehicle:
propylene glycol
Details on dermal exposure:
TEST SITE
- Area of exposure: on the back of the animal
- % coverage: approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females
- Type of wrap if used: surgical gauze patch (Surgy 1D), successively covered with aluminum foil and Coban elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only.

REMOVAL OF TEST SUBSTANCE
- Washing: after removal of dressing, the skin was cleaned of residual test item using tap water
- Time after start of exposure: 24 h

Dose volumne: 10 mL/kg bw
Duration of exposure:
24 h
Doses:
2000 mg/kg (single dosage) on Day 1
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Preparation of test item:
-The preparation (w/w) was kept at room temperature and 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 as the correction factor is 1.

Treatment of animals and application of test item:
-Method: Dermal application. Test preparation was stirred on a magnetic stirrer during application.
-Clipping: One day before exposure (Day -1) an area of approximately 5x7 cm on the back of each animal was clipped.

Frequency of dosing: Single dosage, on Day 1.

Observation period: until day 15 after treatment
- Mortality/Viability: Twice daily.
- Body weights: Days 1 (pre-administration) and 15. No observation on Day 8 (Deviation Evaluation: Sufficient data was available for evaluation of the study).
- Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The time of onset, degree and duration were recorded and the symptoms graded according to fixed scales:
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: 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.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Chromodacryorrhoea (snout) was noted for four males and two females on Days 1 and/or 2. General erythema, malacute erythema, scales and/or scabs were seen in the treated skin-area of most animals throughout the observation period. These local effects were considered not to have affected the conclusion of the study.
Body weight:
The changes noted in body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
Interpretation of results:
GHS criteria not met
Conclusions:
The dermal LD50 value of JNJ-42808415-AAA (T003422) in Wistar rats was established to exceed 2000 mg/kg body weight. Based on results, test substance does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity according to the:
-Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments),
-Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amentments).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

Acute Oral Toxicity:

An acute oral toxicity study with T003422 according to the acute toxic class method in female rats (OECD guideline 423) was performed (Latour 2017).

The test substance 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.

Lethargy, uncoordinated movements, piloerection and/or hunched posture were noted for all animals on Day 1. Additionally, hunched posture was noted for two animals on Days 2 and 3.

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 T003422 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.

A second study (Herlich 2012) was also performed according the OECD 423 test guideline and established an LD50 greater than 2000 mg/kg bw.

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 T003422, a key study is available for the dermal route of exposure. Therefore, an acute inhalation toxicity study should not be performed.

 

 

Acute Dermal Toxicity:

An acute deral toxicity study with T003422 according to OECD guideline 402 and EU Method B.3 in male and female Crl:WI (Han) (SPF) rats was performed (Latour, 2016).

The test substance was administered to five Wistar rats of each sex by a single dermal application at 2000 mg/kg body weight for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15).

No mortality occurred.

Chromodacryorrhoea (snout) was noted for four males and two females on Days 1 and/or 2.

The mean body weight gain during the observation period was within the range expected for rats used in this type of study.

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

The dermal LD50 value of T003422 in Wistar rats was established to exceed 2000 mg/kg body weight.

Justification for classification or non-classification

Acute Oral Classification:

Based on these results, T003422 does not have to be classified under EU CLP.

 

Acute Inhalation Classification:

No data were available to decide on the classification for the inhalation route.

 

Acute Dermal Classification:

Based on these results, T003422 does not have to be classified under EU CLP.