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Administrative data

Description of key information

Acute toxicity: Oral

The acute oral toxicity was assessed with a K2 acute toxic class method performed following the OECD Guideline 423 (Sanders, 2004). The LD50 was determined to be greater than 2000 mg/kg bw.

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 T002488, 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
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004-11-10 to 2004-12-09
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
modified on 2001-12-17
Deviations:
yes
Remarks:
: 1) no characterization of the test material; 2) not sufficient data for the animals tested.
GLP compliance:
no
Remarks:
The study was conducted in a facility operating to Good Laboratory Practice within the UK national GLP monitoring programme, but the study report had not been audited by the QA Unit. No formal claim of GLP compliance was made for the study.
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: No data
- Expiration date of the lot/batch: No data
- Purity test date: No data

Species:
mouse
Strain:
other: Outbred albino
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 20-24 g
- Fasting period before study: Yes, fasting period not provided.
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS: no data

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE: no data

MAXIMUM DOSE VOLUME APPLIED:
- no data

DOSAGE PREPARATION (if unusual):
- no data

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: advised in OECD-423 guideline
Doses:
300 mg/kg bw; 2000 mg/kg bw (two groups) stepwise procedure
No. of animals per sex per dose:
3 females/group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: mortality and clinical signs were observed 30 minutes, 1, 2, 3, and 4 hours after dosing, and daily for 14 days after dosing. Body weights were recorded on days 0, 7, and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: mortality, clinical signs, body weight, and macroscopic examinations.
Statistics:
No statistical analysis was used.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortalities were reported for the tested concentrations.
Clinical signs:
No signs of systemic toxicity were reported for the tested concentrations.
Body weight:
The bodyweight was within the normal range of variability.
Gross pathology:
No abnormalities were found during the necropsy observations.
Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 of the test substance in the female outbred albino mouse is estimated to be greater than 2000 mg/kg bodyweight.
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:
study scientifically not necessary / other information available
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
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
Deviations in RH and 2 animalswere excluded from results due to missing bandages on Day 2.
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
yes
Remarks:
Deviations in RH and 2 animals were excluded from results due to missing bandages on Day 2.
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
Deviations in RH and 2 animalswere excluded from results due to missing bandages on Day 2.
Qualifier:
according to
Guideline:
other: Japenese Ministry of Agriculture, Foresty and Fisheries (JMADD)
Version / remarks:
12 Nousan, Notification No 8147, November 2000
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: I15FC2164, Janssen Pharmaceutica N.V.
- Expiration date of the lot/batch: 23-JUN-2017 (retest date)
- Manufacture date: 24-JUN-2015
- Purity/composition correction factor: 1

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature. The characterization and stability of the test item have been performed according to cGMP Guidelines
- Solubility and stability of the test substance in the solvent/vehicle: 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.

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. Preparations were stirred on a magnetic stirrer during application. 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.


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: 346, 326, 331, 347, 353 grams (males) and 195, 201, 193, 195, 199 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).
- 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
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. Two animals were found without bandage on Day 2.
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:
Treatment of animals and application of test item:
Method: Dermal 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 all males and two out of three females on Days 1 and 2. White discoloration and/or scaliness 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.
Two female animals were excluded from interpretation due to a shortened application time. One of these animals showed chromodacryorrhoea on Days 1 and 2. White discoloration and/or general erythema were seen in the treated skin-area of these animals during the observation period.
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 T002488 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
Value:
2 000 mg/kg bw

Additional information

Acute toxicity: Oral

A group of three fasted three females was treated with the test material at a dose level of 300 mg/kg bodyweight. Based on the results from this dose level further groups of fasted females were treated at a dose level of 2000 mg/kg bodyweight. Dosing was performed sequentially. The test material was administered orally as a suspension in arachis oil BP. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

There were no deaths and no signs of systemic toxicity.

The acute oral median lethal dose (LD50) of the test material in the female outbred albino mouse was estimated as being greater than 2000 mg/kg bodyweight.

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

Acute toxicity: Dermal

An acute dermal toxicity study with T002488 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 item 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 all male and two out of three female animals on Days 1 and 2. White discoloration and/or scaliness 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. Two female animals were excluded from interpretation due to a shortened application time. One of these animals showed chromodacryorrhoea on Days 1 and 2. White discoloration and/or general erythema were seen in the treated skin-area of these animals during the observation period. 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 T002488 in Wistar rats was established to exceed 2000 mg/kg body weight.

Justification for classification or non-classification

Acute Oral Classification:

Based on the value of the LD50 determined with the test and the criteria of the DSD and CLP regulations; T002488 should not be classified for acute toxicity by the oral route of exposure.

Acute Inhalation Classification:

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

Acute Dermal Classification:

Based on the results, T002488 does not have to be classified for acute toxicity by the dermal route of exposure.