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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 in the range of 300 - 2000 mg/kg. According to the OECD 423 guideline, the LD50 cut-off value was considered to be 2000 mg/kg body weight (WIL, 2016).

  • 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. (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 2016-01-26 to 2016-03-08
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
test with dose 2000 mg/kg bw performed three times
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
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. I15FB3131
- Expiration date of the lot/batch: 11-Jun-2017 (retest date)
- Purity/correction factor: 1

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature
- Stability under test conditions: Analysis of stability, homogeneity and concentration of the test item under test conditions was not performed as part of this study

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: 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 sufficiently for these kinds of studies. No correction was made for purity of the test item as the correction factor is 1. The concentration of the test item in vehicle was varied to allow constant dosage volume in terms of mL/kg body weight.


Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Crl:WI (Han) (outbred, SPF-Quality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 8-10 weeks
- Weight at study initiation: 139 - 194 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:
CMC (carboxymethyl cellulose)
Remarks:
1% Aqueous
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL and 30 mg/mL
- 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 (turbid solution), propylene glycol (spec.gravity 1.036), polyethylene glycol 400 (spec. gravity 1.125) and corn oil (spec. gravity 0.92).

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.
- No correction was made for purity of the test item.

Doses:
2000 mg/kg body weight (3 groups)
300 mg/kg body weight (2 groups)
No. of animals per sex per dose:
3 females per group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
- mortality/viability: twice daily. 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: 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, 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
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 300 - <= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
At 2000 mg/kg, four out of eight animals were found dead on Day 2. (The test was performed three times: 1st test: 2 of 3 animals died (1 animal excluded from interpretation), 2nd test: 0 animals died, 3th test: 3 of 3 animals died
At 300 mg/kg, no mortality occurred.
Clinical signs:
At 2000 mg/kg, lethargy, hunched posture, quick breathing, shallow respiration, piloerection and/or ptosis were noted for all animals on Days 1 and/or 2.
At 300 mg/kg, hunched posture, piloerection and/or ptosis were noted for all animals on Day 1.
Body weight:
The 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:
At 2000 mg/kg, abnormalities of the body cavities (Thoracic cavity: contains watery-clear fluid) were noted for all animals found dead.
At 300 mg/kg, macroscopic post mortem examination did not reveal any abnormalities.
Autolysis was noted for all animals found dead at 2000 mg/kg. This was considered not toxicologically relevant.
Other findings:
One of the animals (no. 3) that was dosed at 2000 mg/kg and was found dead on Day 2, showed a perforated esophagus at macroscopic post mortem examination. During observations for clinical signs hunched posture, piloerection and ptosis were noted for this animal on Day 1. Further, watery clear fluid in the thoracic cavity and autolysis were noted at macroscopic examination.
Since it could not be excluded that this mortality occurred due to a gavage error the data obtained from this animal were excluded from the study results. However, it was considered that sufficient data were available from the remaining animals for proper evaluation of the study.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Based on these results:
- according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments), T001141 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 (including all amendments), T001141 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
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 2016-02-04 to 2016-02-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute 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. I15FB3131
- Expiration date of the lot/batch: 11-Jun-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: There was no information available regarding the
solubility or stability in vehicle.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The preparations (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 theformulations were stirred during dosing, which ensures homogeneity sufficiently for these kinds of studies.


Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system 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: 185 - 297 grams
- Housing: group housed in Makrolon cages (MIV type, height 18 cm) durign acclimatization 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.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24 °C
- Humidity (%): 40-70%
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
not specified
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1% aqueous
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
- 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:
no
Details on study design:
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 (the method used is not intended to allow the calculation of a precise LD50 value).
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:
No clinical signs of systemic toxicity were noted.
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 T001141 in Wistar rats was established to exceed 2000 mg/kg body weight. Based on these results, T001141 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
Value:
2 000 mg/kg bw

Additional information

  • Acute oral toxicity:

An acute oral toxicity study with T001141 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 2016). Single dosages of 2000 mg/kg bw (3 groups each of 3 animals) and 300 mg/kg bw (2 groups each of 3 animals) were applied. The substance was formulated in 1% aqueous CMC (carboxymethyl cellulose) at concentrations of 200 mg/ml and 30 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, four out of eight animals were found dead on Day 2. (The test was performed three times: 1st test: 2 of 3 animals died [1 animal excluded from interpretation], 2nd test: 0 animals died, 3rd test: 3 of 3 animals died). At 300 mg/kg, no mortality occurred. Clinical signs oberved: At 2000 mg/kg, lethargy, hunched posture, quick breathing, shallow respiration, piloerection and/or ptosis were noted for all animals on Days 1 and/or 2. At 300 mg/kg, hunched posture, piloerection and/or ptosis were noted for all animals on Day 1.

The 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. At 2000 mg/kg, abnormalities of the body cavities (Thoracic cavity: contains watery-clear fluid) were noted for all animals found dead. At 300 mg/kg, macroscopic post mortem examination did not reveal any abnormalities. Autolysis was noted for all animals found dead at 2000 mg/kg. This was considered not toxicologically relevant.

With these results, the oral LD50 value of T001141 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 2000 mg/kg body weight. The study is rated K1 and is selected as key study.

An additional supporting study on acute oral toxicity in rats was performed, and the oral LD50-value of substance T001141 was determined to be > 640 mg/kg bw (J&J PRD).

  • 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 T001141 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 1% aqueous CMC (carboxymethyl cellulose) 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. No clinical signs of systemic toxicity were noted. 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 T001141 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, T001141 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, T001141 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.