Registration Dossier

Administrative data

Description of key information

  • Acute oral toxicity:

In an acute oral toxicity study in HanRcc:Wist (SPF) rats, following the acute toxic class method in accordance with the OECD guideline n° 423 and EU Method B.1 tris, the LD50 was determined to be greater than 2000 mg/kg bw for female animals, observed over a period of 14 days. The study has been performed in compliance with GLP principles (Giannini, 2008)

  • Acute inhalation toxicity: 

No study is available. This endpoint is waived based on following justification: A key study is available for the oral and dermal route of exposure. According to the REACH Regulation, for substances other than gasses, only one additional route of exposure should be tested other than the oral route of exposure for acute toxicity (column 2, Annex VIII, section 8.5. Therefore, it is not necessary to perform an acute toxicity study via the inhalation route of exposure.No study is available. This endpoint is waived based on following justification: A key study is available for the oral and dermal route of exposure. According to the REACH Regulation, for substances other than gasses, only one additional route of exposure should be tested other than the oral route of exposure for acute toxicity (column 2, Annex VIII, section 8.5. Therefore, it is not necessary to perform an acute toxicity study via the inhalation route of exposure.

  • Acute dermal toxicity:

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 (WIL, 2016).

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:
From 03/09/2008 to 26/09/2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented GLP study performed according to OECD guideline 423 and EEC method B.1 Tris.
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
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
other: HanRcc: WIST(SPF)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services, Wölferstrasse 4, 4414 Füllinsdorf / Switzerland
- Age at study initiation: 11 weeks
- Weight at study initiation: 182.3 - 199.5 g
- Fasting period before study: approximately 17 to 17,5 hours (access to water was permitted)
- Housing: In groups of 3 in Makrolon type-4 cages with wire mesh tops and standard softwood bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): between 30-70%
- Air changes (per hr): 10 - 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark, music during the daytime light period

Route of administration:
oral: gavage
Vehicle:
other: Polyethylene glycol 300 (PEG 300)
Details on oral exposure:
VEHICLE
- Lot/batch no. : 1349048

The dose formulations were made shortly before each dosing occasion using a magnetic stirrer and a spatula as homogenizers. The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume).

Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.
Doses:
2000 mg/kg
No. of animals per sex per dose:
2 groups of 3 females, one dose tested
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality / Viability: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.
Body weights: On test days 1 (prior to administration), 8 and 15.
Clinical signs: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on day 1. Once daily during days 2 - 15.
- Necropsy of survivors performed: yes: all animals were killed at the end of the observation period by carbon dioxide asphyxiation and discraded after macroscopic examinations were performed. No organs or tissues were retained.
Statistics:
No statistical analysis was used.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the study.
Clinical signs:
No clinical signs were observed during the course of the study.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
No macroscopic findings were recorded at necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
The median lethal dose of T003063 after single oral administration to female rats, observed over a period of 14 days is: LD50 (female rat): greater than 2000 mg/kg body weight.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Acute toxicity: via inhalation route

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 2016-02-18 to 2016-03-03
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: M14KB4863
- Expiration date of the lot/batch: 2017-11-10 (retest date)
- Purity test date: 2015-01-19

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: No data

OTHER SPECIFICS:
correction factor: 1
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: males: mean 310 g std.dev. 11, females: mean 195 g std.dev. 6.
- 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.
- Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study.
- 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).
- 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
- Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.

IN-LIFE DATES: 2016-02-18 to 2016-03-03
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 specified
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 and at death.
- 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: The moribund animal and animals surviving to the end of the observation periodwere 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 test substance related mortality occurred.
One male animal was sacrificed for humane reasons on Day 2. Considering the findings of this animal it was concluded that the animal showed severe effects due to the bandage procedure. Since the cause of death of this animal was not related to the test article, the data obtained from this animal were excluded from the study results.
Clinical signs:
Chromodacryorrhoea was noted for three female animals on Day 1.
Scales, scabs and/or erythema maculate were seen in the treated skin-area and/or cheek 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:
Macroscopic post mortem examination of the animals at termination did not reveal any abnormalities.
Interpretation of results:
GHS criteria not met
Conclusions:
The dermal LD50 value of JNJ-39453193-AAA (T003063) in Wistar rats was established to exceed 2000 mg/kg body weight. Based on these results, the 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) 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

Additional information

  • Acute oral toxicity:

The study aimed to assess the acute oral toxicity of T003063 to the rat using the acute toxic class method in female HanRcc:Wist (SPF) rats, according to the OECD guideline 423 and EU method B.1 tris (EC 440/2008) (Giannini, 2008). The study has been performed in compliance with GLP. The substance was administered by oral gavage at a dosage of 2000 mg/kg bw to female rats, in a dosing volume of 10 mL/kg. The substance was formulated in PEG300 at a concentration of 0.2 g/mL The study aimed to assess the acute oral toxicity of T003063 to the rat using the acute toxic class method in female HanRcc:Wist (SPF) rats, according to the OECD guideline 423 and EU method B.1 tris (EC 440/2008) (Giannini, 2008). The study has been performed in compliance with GLP. The substance was administered by oral gavage at a dosage of 2000 mg/kg bw to female rats, in a dosing volume of 10 mL/kg. The substance was formulated in PEG300 at a concentration of 0.2 g/mL.

Two groups of 3 female rats each received a single oral dose of test item, and were observed during 14 days following administration. The animals were examined daily during the acclimatization period and mortality, viability, and clinical signs were recorded. All animals were examined for clinical signs within the first 30 minutes and approximately 1, 2, 3 and 5 hours after treatment on day 1 and once daily during the test days 2 to 15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 prior to administration and on days 8 and 15. All animals were necropsied and examined macroscopically.

All animals survived until the end of the study period. No clinical signs were observed during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were recorded at necropsy.

The LD50 of T003063 after single oral administration to female rats, observed over a period of 14 days is greater than 2000 mg/kg body weight.

  • Acute inhalation toxicity:

A key study is available for the oral and dermal route of exposure. According to the REACH Regulation, for substances other than gasses, only one additional route of exposure should be tested other than the oral route of exposure for acute toxicity (column 2, Annex VIII, section 8.5. Therefore, it is not necessary to perform an acute toxicity study via the inhalation route of exposure.

  • Acute dermal toxicity:

An acute dermal toxicity study with T003063 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 test substance related mortality occurred. One animal died, which was not related to the test article. Therefore this animal was excluded from the study results. Clinical signs observed: Chromodacryorrhoea was noted for three female animals on Day 1. Scales, scabs and/or erythema maculate were seen in the treated skin-area and/or cheek of the 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 u sed in this type of study and were therefore considered not indicative of toxicity. Macroscopic post mortem examination of the animals at termination did not reveal any abnormalities.

The dermal LD50 value of JNJ-39453193-AAA (T003063) in Wistar rats was established to exceed 2000 mg/kg body weight


Justification for classification or non-classification

Based on the results showing an oral LD50 exceeding 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, (T003063) 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, (T003063) 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.