Registration Dossier

Administrative data

Description of key information

  • Acute toxicity: Oral

In an acute oral toxicity study in female Crl:WI (Han) (SPF) 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 within the range of 300 - 2000 mg/kg. According to the OECD 423 guideline, the LD50 cut-off value was considered to be 1000 mg/kg body weight.

  • Acute toxicity: Inhalation

No reliable acute toxicity study via the inhalation route was available. However, this endpoint is waived as specific data are available for the oral and dermal exposure routes.

  • 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.

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:
2015-05-28 to 2015-06-23
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well-documented, GLP-compliant study, performed according to the OECD test guideline 423, EU method B.1 tris and EPA OPPTS guideline 870.1100. No deviations were recorded
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, 12 Nousan, Notification No 8147, Nov 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:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Janssen Pharmaceutica N.V., A14JB3442
- Expiration date of the lot/batch: 30 September 2016 (retest date)
- Purity: 99.9% (acid titration)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature


Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: rat, Wistar strain Crl:WI (Han) (outbred, SPF-quality); from Charles River Deutschland, Sulzfeld, Germany; female animals (nulliparous and non-pregnant)
- Age at study initiation: approx. 8-10 weeks
- Weight at study initiation:148-192 grams (bodyweights of Day 1 were determined pre-administration of the test item)
- 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 18cm) containing sterilized sawdust as bedding material and paper as cage-enrichment
- 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):18-24°C
- Humidity (%):40-70%
- Air changes (per hr):at least 10 air changes per hour
- Photoperiod (hrs dark / hrs light):12hrs light/12 hrs dark cycle.

IN-LIFE DATES: no data
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Remarks:
specific gravity 1.036
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 mg/ml , 200 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg bw
- Justification for choice of vehicle: The vehicle was selected based on trial preparations performed at WIL Research Europe 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), 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.
- Lot/batch no. (if required): no data
- Purity:no data

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg body weight; using plastic feeding tubes

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 the purity 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: no data
Doses:
Stepwise procedure:
initially: 2000 mg/kg bw (1 group of 3 animals)
then: 300 mg/kg bw (2 groups of 3 animals)

frequency: single dosage on Day 1
No. of animals per sex per dose:
3 females/dose group; 3 groups
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 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 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.
- Necropsy of survivors performed: yes. The moribund animals and 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
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Effect level:
1 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: based on OECD423
Mortality:
At 2000 mg/kg, two animals were sacrificed for humane reasons on day 2.
At 300 mg/kg, no mortality occurred.
Clinical signs:
At 2000 mg/kg, lethargy, flat posture, hunched posture, slow breathing, shallow respiration, piloerection, watery discharge from the eyes, ptosis and/or hypothermia were noted for the animals on days 1 and/or 2.
At 300 mg/kg, lethargy, hunched posture, uncoordinated movements, piloerection and/or ptosis were noted for the animals on days 1 and/or 2.
Body weight:
At 2000 mg/kg, the surviving animal showed reduced body weight gain between days 8 and 15.
At 300 mg/kg, the body weight gain 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 contents of the urinary bladder were found in the two animals sacrificed for humane reasons on day 2.
At 300 mg/kg, no abnormalities were found at macroscopic post mortem examination.
Other findings:
No other findings
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The oral LD50 value of JNJ-119717-AAA (T001036) in wistar rats was established to be within the range of 300-2000 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 1000 mg/kg body weight.
Based on the results: -according to the GHS , JNJ-119717-AAA (T001036) 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, JNJ-119717-AAA (T001036) should be classified as category 4 and should be labeled as H302: Harmful if swallowed
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 000 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 2016-01-21 to 2016-02-04
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented study performed according to OECD guideline 402, in compliance with GLP. No deviations were noted.
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
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
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., A14JB3442
- Expiration date of the lot/batch: 30 September 2016 (retest date)
- Purity: 99.9% (acid titration)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature
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. 10 weeks old)
- Weight at study initiation: 184-304 grams
- Housing:group housed in Makrolon cages (MIV type, height 18 cm) during acclimatisation period; 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
- Health inspection At least prior to dosing. It was ensured that the animals were healthy and that the skin to be treated was intact and free from any abnormality

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 2016-01-21 to 2016-02-04
Type of coverage:
not specified
Vehicle:
propylene glycol
Details on dermal exposure:
TEST SITE
- Area of exposure: approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females
- % coverage: no data
- 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 (if done): after removal of dressing, the skin was cleaned of residual test item using tap water
- Time after start of exposure: 24 h
Duration of exposure:
24 h
Doses:
2000 mg/kg (single dosing)
No. of animals per sex per dose:
5
Control animals:
not specified
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.

Observations:
Observation period: until day 15 after treatment
- 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 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
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Lethargy, hunched posture, piloerection, chromodacryorrhoea (snout) and/or ptosis were noted for all animals on Day 1. General erythema, scales and/or scabs were seen in the treated skin-area of most animals during 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-119717-AAA (T001036) in Wistar rats was established to exceed 2000 mg/kg body weight. Based on these results, JNJ-119717-AAA (T001036) does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity according to the Regulation (EC) No 1272/2008.
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 T001036 according to the acute toxic class method in female Crl:WI (Han) (SPF) rats (OECD guideline 423 and EU Method B.1 tris) was performed (WIL, 2015). Single dosages of 300 mg/kg bw (2 groups of 3 animals) and 2000 mg/kg bw (1 group of 3 animals) were applied. The substance was formulated in propylene glycol at concentrations of 30 mg/ml and 200 mg/ml respectively. The rats received a single oral dose of test item, and were observed during 14 days following administration. Lethality and viability were observed twice daily, and bodyweight was monitored at day 1 (prior to administration), 8 and 15. Clinical signs were observed at periodic intervals on the day of dosing (day 1) and once daily thereafter. Necropsy of survivors and macroscopic examination were also performed. Internal macroscopic abnormalities were recorded. 

At 2000 mg/kg, two animals were sacrificed for humane reasons on day 2. At 300 mg/kg, no mortality occurred. At 2000 mg/kg, lethargy, flat posture, hunched posture, slow breathing, shallow respiration, piloerection, watery discharge from the eyes, ptosis and/or hypothermia were noted for the animals on days 1 and/or 2. At 300 mg/kg, lethargy, hunched posture, uncoordinated movements, piloerection and/or ptosis were noted for the animals on days 1 and/or 2.

At 2000 mg/kg, the surviving animal showed reduced body weight gain between days 8 and 15. At 300 mg/kg, the body weight gain over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.

At 2000 mg/kg, dark red contents of the urinary bladder were found in the two animals sacrificed for humane reasons on day 2. At 300 mg/kg, no abnormalities were found at macroscopic post mortem examination.

The oral LD50 value of JNJ-119717-AAA (T001036) in Wistar rats was established to be within the range of 300-2000 mg/kg body weight. According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 1000 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 this substance 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 dermal toxicity study with T001036 according to the standard acute method in male and female Crl:WI (Han) (SPF) rats (OECD guideline 402 and EU Method B.3 was performed (WIL, 2016). The substance was dissolved in propylene glycol and applied on a clipped area on the back at 2000 mg/kg bw. The test item was then wrapped with a surgical gauze patch (Surgy 1D), successively covered with aluminum foil and Coban elastic bandage. After 24 h hours of exposure remainings of the test item were washed-off. The animals were observed during 14 days. Lethality and viability were observed twice daily, and bodyweight was monitored at day 1 (prior to administration), 8 and 15. Clinical signs were observed at periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15. Necropsy of survivors and macroscopic examination were also performed. Internal macroscopic abnormalities were recorded. 

No mortality occurred. Clinical signs observed were: Lethargy, hunched posture, piloerection, chromodacryorrhoea (snout) and/or ptosis were noted for all animals on Day 1. General erythema, scales and/or scabs were seen in the treated skin-area of most animals during the observation period. These local effects were considered not to have affected the conclusion of the study. No abnormalities were found at macroscopic post mortem examination of the animals.

The dermal LD50 value of JNJ-119717-AAA (T001036) in Wistar rats was established to exceed 2000 mg/kg body weight.

Justification for classification or non-classification

Based on the results showing an LD50 between 300 - 2000 mg/kg bw and according to the criteria laid down in Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures, JNJ-119717-AAA (T001036) should be classified as acute oral toxic category 4 and should be labeled as H302: Harmful if swallowed.

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

Based on the dermal LD50 exceeding 2000 mg/kg bw, JNJ-119717-AAA (T001036) does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity according to the criteria laid down in Regulation (EC) No 1272/2008.