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Description of key information

Acute oral toxicity: In an acute oral toxicity GLP-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 in the range 300-2000 mg/kg for both females and males (K1, Esposito, 2007)
Acute toxicity via inhalation: No reliable data were available. However, this endpoint is waived as specific data are available for the oral and dermal exposure route.
Acute dermal toxicity: A K1 acute dermal test was performed in male and female HanRcc:WIST (SPF) rats according to OECD Guideline 402 and EC method B3 without deviations. The median lethal dose of the substance after 24-h dermal exposure to rats of both sexes, observed over a period of 14 days is greater than 2000 mg/kg body weight (K1, Esposito, 2007)

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:
2007-02-21 to 2007-03-28
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:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
: certificate issued by Swiss GLP Monitoring Authorities
Test type:
acute toxic class method
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Name of test material (as cited in study report): T002675 (TIC876)
- Physical state: liquid, colorless to yellowish
- Analytical purity: 97.76%
- Lot/batch No.: 603T-1
- Expiration date of the lot/batch: 2007-12-19

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature (range of 20 +/- 5 °C), light protected
- Stability under test conditions: unknown in PEG 300, is excluded from teh statement of compliance

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The dose formulations were made shortly before each dosing occasion using a magnetic stirrer as homogenizer. 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.
Species:
rat
Strain:
other: HanRcc: Wist (SPF)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd., Laboratory Animal Services CH-4414 Füllinsdorf / Switzerland
- Age when treated: 11 weeks
- Weight at study initiation (day 1): 178.1-191.7 g
- Fasting period before study: approximately 18 to 19 hours, access to water was permitted. Food was provided again approximately 2 hours after dosing.
- Housing: in groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding
- Diet (e.g. ad libitum): pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 89/06, ad libitum
- Water (e.g. ad libitum): community tap water from Füllinsdorf, ad libitum
- Acclimation period: 2007-02-21 to 2007-02-27 (females, 2000 mg/kg); 2007-02-23 to 2007-03-05 (females, 300 mg/kg); 2007-03-07 to 2007-03-13 (females, 300 mg/kg)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12, music during light period

IN-LIFE DATES: From: 2007-02-28 To: 2007-03-03 (females, 2000 mg/kg); 2007-03-06 To: 2007-03-20 (females, 300 mg/kg); 2007-03-14 To: 2007-03-28 (females, 300 mg/kg)
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 300
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 0.2 or 0.03 g/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date.
- Lot/batch no. (if required): 130022563006152

MAXIMUM DOSE VOLUME APPLIED:
- 10 mL/kg bw
Doses:
2000 mg/kg bw or 300 mg/kg bw
No. of animals per sex per dose:
3 females/ group,
2 groups at 300 mg/kg bw (6 total)
1 group at 2000 mg/kg bw (3 total)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded; all animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15; mortality/viability was recorded at approximately 30 minutes, 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 were recorded on day 1 (prior to administration) and on days 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: macroscopic examination
Statistics:
No statistical analysis was used.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Remarks on result:
other: no data on confidence level
Mortality:
All the animals treated with 2000 mg/kg died spontaneously 2 or 3 days after treatment. No deaths occurred in the animals treated with 300 mg/kg during the study.
Clinical signs:
The animals treated with 2000 mg/kg all showed a slight to moderate ruffled fur and a slight to moderate sedation from the 30-minute reading until their respective deaths. The animals also had closed eyes between 30 minutes after treatment and the 3-hour reading or their respective deaths. A poor coordination was noted at the 2- and 3-hour readings in the three animals. All of the animals had in addition a hunched posture from the 5 hours or 2 days after treatment, up to test day 3. One animal showed additionally soft feces and deep respiration 3 days after treatment.

The animals treated with 300 mg/kg all showed a slight to moderate ruffled fur, a slight to moderate sedation and a hunched posture. The symptoms were notable from the 30-minute or 1-hour reading to the 5-hour or 2-day reading, respectively.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
One animal from the 2000 mg/kg treatment group which died spontaneously showed a distended stomach, and the jejunum and ileum were empty. No other macroscopic findings were recorded at necropsy.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The LD50 of the test substance after single oral administration to female rats, observed over a period of 14 days was greater than 300 mg/kg bw and less than 2000 mg/kg bw.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
300 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:
2007-03-01 to 2007-03-22
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
GLP compliance:
yes (incl. QA statement)
Remarks:
: certificate issued by Swiss GLP monitoring authorities
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Name of test material (as cited in study report): T002675 (TIC876)
- Physical state: liquid, colorless to yellowish
- Analytical purity: 97.76%
- Lot/batch No.: 603T-1
- Expiration date of the lot/batch: 2007-12-19

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature (range of 20 +/- 5 °C), light protected
- Stability under test conditions: Unknown in PEG 300, is excluded from the statement of compliance

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume). The formulation was prepared shortly before the application using a magnetic stirrer as homogenizer. Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.
Species:
rat
Strain:
other: HanRcc:WIST (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd., Laboratory Animal Services CH-4414 Füllinsdorf / Switzerland
- Age when treated: 11 weeks (female); 8 weeks (male)
- Weight at study initiation (day of treatment): Males: 228.2-254.6 g; Females: 189.4-204.2g
- Fasting period before study: no data
- Housing: during the acclimatization in groups of five per sex in Makrolon type-4 cages with standard softwood bedding, individually in Makrolon type-3 cages with standard softwood bedding during treatment and observation
- Diet (e.g. ad libitum): pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 80/06, ad libitum
- Water (e.g. ad libitum): community tap water from Füllinsdorf, ad libitum
- Acclimation period: 2007-03-01 to 2007-03-07


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


IN-LIFE DATES: From: 2007-03-08 To: 2007-03-22
Type of coverage:
semiocclusive
Vehicle:
polyethylene glycol
Remarks:
PEG 300
Details on dermal exposure:
TEST SITE
- Area of exposure: The backs of animals
- % coverage: approximately 10% of the total body surface was exposed.
- Type of wrap if used: the test item was applied at a dose of 2000 mg/kg bw evenly on the intact skin with a syringe and covered with a semi-occlusive dressing. The semi-occlusive dressing was wrapped around the abdomen and fixed with an elastic adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The skin was flushed with lukewarm tap water and dried with a disposable paper towel.
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4 mL/kg bw
- Concentration (if solution): 0.5 g/mL

VEHICLE
- Amount(s) applied (volume or weight with unit): 4 mL/kg bw
- Concentration (if solution): no data
- Lot/batch no. (if required): 130022563006152
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
one group with 5 males and 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded; all animals were examined for clinical signs at approximately .5, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15; local signs were noted once daily from test day 2 to 15; mortality/viability was recorded at approximately .5, 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 were recorded on day 1 (prior to administration) and on days 8 and 15.
- Necropsy of survivors performed: yes, all surviving animals were killed at the end of the observation period by carbon dioxide asphyxiation
- Other examinations performed: macroscopic examination, no organs or tissues were retained
Statistics:
No statistical analysis was used.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No deaths occurred during the study.
Clinical signs:
No systemic or local signs of toxicity were observed during the study period.
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 observed at necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
The median lethal dose (LD50) of the test substance after single dermal administration to rats of both sexes, observed over a period of 14 days was greater than 2000 mg/kg bw .
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw

Additional information

Acute oral toxicity:

The study aimed to assess the acute oral toxicity of T002675 to the rat using the acute toxic class method in male and female HanRcc:Wist (SPF) rats, according to the OECD guideline 423 and EU Method B.1 tris (K1, Esposito, 2007). The substance was tested at 300 in two groups and 2000 mg/kg in one group. The substance was formulated in polyethylene glycol, at the concentration of 0.03 or 0.2 g/mL, respectively.

3 rats per sex 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 least four times on test day 1 after the test substance administration, and once daily during days 2-15. All abnormalities were recorded. Necropsy of survivors and macroscopic examination were also performed.

The animals treated with 2000 mg/kg showed all a slight to moderate ruffled fur and a slight to moderate sedation from the 30-minute reading until their respective death. The animals had also closed eyes between 30 minutes after treatment and the 3-hour reading or their respective death. A poor coordination was noted at the 2- and 3-hour reading in the three animals. All the animals had in addition a hunched posture from the 5 hours or 2 days after treatment and up to test day 3. One animal showed additionally soft feces and deep respiration 3 days after treatment.

The animals treated with 300 mg/kg showed all a slight to moderate ruffled fur, a slight to moderate sedation and a hunched posture. The symptoms were notable from the 30-minute or 1-hour reading and to the 5-hour or 2-day reading, respectively.

One animal from the 2000 mg/kg treatment group which died spontaneously showed a distended stomach and the jejunum and ileum were empty. No other macroscopic findings were recorded at necropsy.

The median lethal dose of TIC876 (T002675) after single oral administration to female rats, observed over a period of 14 days is in the range 300 - 2000 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:

The study aimed to assess the acute dermal toxicity of T002675 to the rat using semi occlusive coverage of test substance in male and female HanRcc: WIST (SPF) rats, according to the OECD guideline 402 and EU Method B.3. (K1, Esposito, 2007). The dose level tested in this study was 2000 mg/kg for both males and females. The substance was diluted in polyethylene glycol 300 (PEG300), at the concentration of 0.5 g/mL, and then applied on the back of 5 males/females after clipping with an electric clipper. 10% of the total body surface was covered with the test item.

The duration of observation period following 24-h dermal exposure was 14 days. Observations for clinical signs of toxicity were performed daily during acclimatization and at least 1, 2, 3 and approx. 5 hours on test day 1 after test substance administration and once daily during days 2-15. All abnormalities were recorded. Body weights were recorded on test days 1 (pre-administration), 8 and 15.

No deaths occurred during the study and no systemic or local signs of toxicity were observed during the study period.

The median lethal dose after a single dermal administration to rats of both sexes, observed over a period of 14 days is greater than 2000 mg/kg body weight.


Justification for selection of acute toxicity – oral endpoint
Only one reliable study available.

Justification for selection of acute toxicity – inhalation endpoint
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.

Justification for selection of acute toxicity – dermal endpoint
Only one reliable study available.

Justification for classification or non-classification

 Based on the LD50 estimated to be in the range 300-2000 mg/kg bw for the oral route of exposure in rats, T002675 should be classified as Acute tox. Cat 4 for the oral route of exposure (H302) according to the CLP criteria.

With LD50 greater than 2000 mg/kg bw for dermal route of exposure, the substance should not be classified as acute toxic via the dermal route according to the criteria of the DSD and CLP Regulation. No data were available to decide on the classification for the inhalation route.