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 exceed 2000 mg/kg. According to the OECD 423 guideline, the LD50 cut-off value was considered to exceed 5000 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:
2015-10-20 to 2015-11-10
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
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
- Llot/batch No.of test material: I15FB2768
- Expiration date of the lot/batch: 01 July 2017 (retest date)
- Purity 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: Analysis of test item in vehicle for solubility was not performed, however preparation was performed with approved procedure and documented in detail. Stability for at least 6 hours at room temperature is confirmed over the concentration range 1-200 mg/mL, WIL Research Project 509922. 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.





Species:
rat
Strain:
Wistar
Remarks:
Wistar strain Crl:WI (Han) (outbred, SPF-Quality)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 8-10 weeks
- Weight at study initiation: 147-192 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
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): No data
- 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 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).

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION:
- The preparations (w/w) 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 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.

Doses:
2000 mg/kg (single dosage)
No. of animals per sex per dose:
3 females per dose group
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, 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 recorded.
Statistics:
No statistical analysis was performed.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred
Females 2000 mg/kg: 0
Females 2000 mg/kg: 0
Clinical signs:
Hunched posture, uncoordinated movements and/or piloerection were noted for the animals between Days 1 and 3.
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.
Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 value of T001325 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 the results, T001325 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 (2011) (including all amendments) 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:
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 2016-02-09 to 2016-02-23
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
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: I15FB2768
- Expiration date of the lot/batch: 2017-07-01 (retest date)
- Purity test date: No data

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature
- Stability under test conditions: No data
- Solubility and stability of the test substance in the solvent/vehicle: Stability for at least 6 hours at room temperature is confirm over the concentration range 1-200 mg/mL, project 509922

OTHER SPECIFICS:
correction factor: 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: 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: 276-296 g (males), 185-203 g (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%
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

In-Life dates: From 2016-02-09 to 2016-02-23
Type of coverage:
semiocclusive
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 (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 dosage)
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
Preparation of test item:
The preparation (w/w) was 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.
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 two male and one female animal on Day 1.
Erythema maculate, scales, scabs and/or brown staining were seen in the treated skin-area of the 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-1806792-AAA (T001325) in Wistar rats was established to exceed 2000 mg/kg body weight. Based on these results, JNJ-1806792-AAA (T001325) 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) 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
Value:
2 000 mg/kg bw

Additional information

  • Acute oral toxicity:

An acute oral toxicity study with T001325 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 (Latour, 2016). Single dosage of 2000 mg/kg bw was applied. The substance was formulated in propylene glycol at a concentration of 200 mg/mL. 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 until day 15. Necropsy of survivors and macroscopic examination were also performed. Internal macroscopic abnormalities were recorded. 

No mortality occurred. Hunched posture, uncoordinated movements and/or piloerection were noted for the animals between Days 1 and 3.

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.

No abnormalities were found at macroscopic post mortem examination.

The oral LD50 value of JNJ-1806792-AAA (T001325) 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 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 T001325 was performed according to the standard acute method in male and female Crl:WI (Han) (SPF) rats (OECD guideline 402 and EU Method B.3 (Latour, 2016). The substance was dissolved in propylene glycol and applied on a clipped area on the back at 2000 mg/kg bw. The preparation was held in contact with the skin with a dressing, consisting of 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: Chromodacryorrhoea (snout) was noted for two male and one female on Day 1. Erythema maculate, scales, scabs and/or brown staining were seen in the treated skin-area of animals during the observation period. These local effects were considered not to have affected the conclusion of the study. 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. No abnormalities were found at macroscopic post mortem examination of the animals.

The dermal LD50 value of JNJ-1806792-AAA (T001325) in Wistar rats was established to exceed 2000 mg/kg body weight.

Justification for classification or non-classification

Based on the oral LD50 exceeding 2000 mg/kg bw, T001325 does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the criteria laid down in Regulation (EC) No 1272/2008.

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

Based on the dermal LD50 exceeding 2000 mg/kg bw, T001325 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.