Registration Dossier

Administrative data

Description of key information

Acute oral toxicity: 

The acute oral toxicity dose (LD50) was considered based on different studies conducted on rats for the test chemical. The LD50 value is >2000 mg/kg bw, for acute oral toxicity. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute oral toxicity.

 

Acute Inhalation Toxicity:

The acute inhalation toxicity study need not be conducted because exposure to humans via inhalation route is not likely taking into account due to the low vapour pressure of the test chemical, which is reported to be 9.54E-13 Pa (7.15E-15 mm Hg). Thus, exposure to inhalable dust, mist and vapour of the chemical is highly unlikely. Therefore this study is considered for waiver. 

 

Acute Dermal toxicity:

The acute dermal toxicity dose (LD50) was considered based on different studies conducted on rats for the test chemical. The studies concluded that LD50 value is >2000 mg/kg bw, for acute dermal toxicity. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute dermal toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
experimental data from various test chemicals
Justification for type of information:
Data is summarized based on the available information from various test chemicals.
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
WoE report is based on 3 acute oral toxicity studies as - WoE 2, WoE 3 and WoE 4.
Acute Oral toxicity test was carried out to study the effects of the test chemicals on rodents.
GLP compliance:
not specified
Test type:
other: not specified
Limit test:
no
Species:
rat
Strain:
other: 1. Sprague-Dawley (Crj: CD (SD) IGS) 2. Sprague-Dawley Crl:CD (SD) BR 3. not specified
Sex:
male/female
Details on test animals and environmental conditions:
1. TEST ANIMALS
- Source: Charles River Japan Co., Ltd.
- Age at study initiation: 4 week old
- Weight at study initiation: The weight range on the administration day was 112 to 127 g for males and 101 to 110 g for
females.
- Fasting period before study: Animals were fasted for about 17 to 18 hours
- Housing: Bracket type metal wire mesh floor cage was divided into groups of 3 or less, after grouping they were kept individually.
- Diet (e.g. ad libitum): solid feed
- Water (e.g. ad libitum): drinking water freely using automatic water supply equipment.
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 to 23 ° C.
- Humidity (%): 50 to 70%
- Air changes (per hr): ventilation frequency of 10 to 15 times/hour
- Photoperiod (hrs dark / hrs light): an illumination time of 12 hours (lighting from 8:00 to 20:00)
2. not specified
3. not specified
Route of administration:
oral: gavage
Vehicle:
other: 1. 0.5% methyl cellulose aqueous solution 2. water 3. not specified
Details on oral exposure:
1. VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg
2. not specified
3. not specified
Doses:
1. 0 and 2000 mg/kg bw
2. 2000 mg/kg bw
3. 5000 mg/kg
No. of animals per sex per dose:
1. Total = 10 animals (5 male and 5 female)
2. Total:10 (5 males + 5 females)
3. not specified
Control animals:
other: 1. yes, 5 male and 5 female 2. not specified 3. not specified
Details on study design:
1. - Duration of observation period following administration: 14 days
- Frequency of observations: The life and death, appearance, behavior and the like of the animals were observed consecutively from immediately after administration on the administration day (0 day after administration) until 1 hour after administration and at 1 hour interval from 2 hours to 6 hours after administration. From day 1 to day 14 post administration, observation was carried out once a day until the autopsy day.
The body weight was measured at 0 (before administration on the administration day), 1, 3, 5, 7, 10 and 14
days after administration (autopsy day), and the body weight gain and the body weight gain rate from day 0 to the 14th day after administration.
- Necropsy of survivors performed: yes, on the 14th day after administration, after observing the external surface table, animals were exsanguinated under ether anesthesia and killed by lethality, and the whole body organs and tissues were observed macroscopically.
2. Details on study design
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed 1, 2and 4 hours after dosing and thereafter daily for 14 days. Body weights were recorded on days 1, 8 and 15 of the study.
- Necropsy of survivors performed: yes
- Other examinations performed: Macroscopic examination of main organs was performed after autopsy. No histological examinations were performed.
3. - Other examinations performed: Animals were observed for mortality and clinical signs.
Statistics:
1. Bartlett 's test for body weight, body weight gain and body weight gain rate was conducted and equi-dispersibility was analyzed. In the case of equi-variance, it is analyzed by one-way analysis of variance and in case of unequal variance it is analyzed by Kruskal-Wallis's test method. As a result of the analysis of the Kruskal-Wallis method, when significant difference was observed, it was analyzed by Mann-Whitney U-test method. In the test between the control group and the test substance-administered group, the significance level was set to 5% in each case.
2. not specified
3. not specified
Preliminary study:
1. In the dose setting test, the test chemical was orally administered to Crj: CD (SD) IGS rats of 3 male and 3 female rats, respectively. As a result, no death was observed, so the OECD Test Method
Guideline (401) 2000 mg/kg and a control group to which only the solvent was administered. The number of animals in one group was 5 for both males and females, and grouping was performed by stratified random extraction method based on the body weight the day before administration.
2. The dose group was selected on the basis of a preliminary range-finding study in which rats were given the test compound in water at dose levels from 100 to 2000 mg/kg bw, one death was reported at 1000 mg/kg bw but the only reported clinical signs were dose-related pink skin tone due to the compound and the death was considered to be unrelated to treatment.
3. not specified
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No mortality was observed
Sex:
not specified
Dose descriptor:
LD50
Effect level:
5 000 mg/kg bw
Based on:
test mat.
Mortality:
1. Dead cases were not observed in both males and females.
2. No mortality was observed
3. 50% mortality was observed at 5000 mg/kg bw.
Clinical signs:
1. No abnormality was observed in both males and females.
2. The only clinical sign was a pink discoloration of the skin, apparent from 1 hour to 7 days after dosing.
3. Behavioral changes such as, somnolence (general depressed activity) and respiratory depression was observed in treated animals.
Body weight:
1. There was no significant difference between the 2000 mg/kg group and the control group in both males and females.
2. Body weight gain was considered normal for the age and strain of rat.
3. not specified
Gross pathology:
1. No abnormal findings were observed in both males and females.
2. At autopsy an orange coloration of the mammary tissue and /or abdominal fat, attributed to the staining properties of the substance and not considered to be a toxic effect
3. not specified
Other findings:
1. not specified
2. The distribution and persistence of staining indicates that the substance has the potential to accumulate, at least at the high dose used in this acute study
3. not specified
Interpretation of results:
other: Not classified
Conclusions:
According to CLP regulation, the test chemical cannot be classified for acute oral toxicity, as the LD50 value is >2000 mg/kg bw.
Executive summary:

In different studies, the given test chemical has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents,

i.e. most commonly in rats for test chemical. The studies are summarized as below –

 

The acute oral toxicity study was conducted by using the given test chemical in 5 male and 5 female per group of Sprague-Dawley (Crj: CD (SD) IGS) ratsat the dose concentration of 2000 mg/kg bw. The given test chemical was dissolved in 0.5% methyl cellulose aqueous solution and administered as 10 mL/kg via oral route. A control group to which only the solvent was administered.

In the dose setting test, the test chemical was orally administered to Crj: CD (SD) IGS rats of 3 male and 3 female rats, respectively. As a result, no death was observed, so the OECD Test Method Guideline (401) 2000 mg/kg and a control group to which only the solvent is present was administered. The number of animals in one group was 5 for both males and females, and grouping was performed by stratified random extraction method based on the body weight the day before administration.

The life and death, appearance, behaviour and the like of the animals were observed consecutively from immediately after administration on the administration day (0 day after administration) until 1 hour after administration and at 1 hour interval from 2 hours to 6 hours after administration. From day 1 to day 14 post administration, observation was carried out once a day until the autopsy day.

The body weight was measured at 0 (before administration on the administration day), 1, 3, 5, 7, 10 and 14 days after administration (autopsy day), and the body weight gain and the body weight gain rate from day 0 to the 14th day after administration. Necropsy of survivors performed. On the 14th day after administration, after observing the external surface table, animals were exsanguinated under ether anaesthesia and killed by lethality, and the whole body organs and tissues were observed macroscopically.

Bartlett’s test for body weight, body weight gain and body weight gain rate was conducted and equi-dispersibility was analyzed. In the case of equi-variance, it is analyzed by one-way analysis of variance and in case of unequal variance it is analyzed by Kruskal-Wallis's test method. As a result of the analysis of the Kruskal-Wallis method, when significant difference was observed, it was analyzed by Mann-Whitney U-test method. In the test between the control group and the test substance-administered group, the significance level was set to 5% in each case.

Dead cases were not observed in both males and females. No abnormality was observed in both males and females. There was no significant difference between the 2000 mg/kg group and the control group in both males and females. No abnormal findings were observed in both males and females.

Under the condition of this, the LD50 value was considered to be >2000 mg/kg bw, when 5 male and 5 female per group Sprague-Dawley (Crj: CD (SD) IGS) rats were treated with the given test chemical via oral gavage route.

 

The above study is supported with another study mentioned in secondary source for the given test chemical as per OECD Guideline 401 (Acute Oral Toxicity) in 5 male and 5 female Sprague Dawley rats at the dose concentration of 2000 mg/kg bw.

The test material dissolved in water and administered via oral gavage route. The dose group was selected on the basis of a preliminary range-finding study in which rats were given the test compound in water at dose levels from 100 to 2000 mg/kg bw. The dose selected for the Limit Test was 2000 mg/kg bw.

The animals were observed 1, 2 and 4 hours after dosing and thereafter daily for 14 days. Body weights were recorded on days 1, 8 and 15 of the study. Macroscopic examination of main organs was performed after autopsy. No histological examinations were performed.

In the preliminary range-finding study, one death was reported at 1000 mg/kg bw but the only reported clinical signs were dose-related pink skin tone due to the compound and the death was considered to be unrelated to treatment.

There were no deaths during the Limit test. The only clinical sign was a pink discoloration of the skin, apparent from 1 hour to 7 days after dosing. Body weight gain was considered normal for the age and strain of rat. At autopsy an orange coloration of the mammary tissue and /or abdominal fat, attributed to the staining properties of the substance and not considered to be a toxic effect. The distribution and persistence of staining indicates that the substance has the potential to accumulate, at least at the high dose used in this acute study.

Under the condition of the study, the acute oral toxicity dose (LD50) value was considered to be >2000 mg/kg body weight, when 10 male and female Sprague Dawley rat, Crl:CD (SD) BR rats were treated with the given test chemical orally.

 

Both the above studies are further supported with the study mentioned in database for the test chemical. The acute oral toxicity study of the given test chemical was conducted in rats at the concentration of 5000 mg/kg bw. Animals were observed for mortality and clinical signs. 50% mortality was observed at 5000 mg/kg bw. Behavioural changes such as, somnolence (general depressed activity) and respiratory depression was observed in treated animals. Hence, the LD50 value was considered to be 5000 mg/kg bw, when rats was treated with the given test chemical via oral route.

 

Thus, based on the above summarised studies on test chemical, it can be concluded that LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute oral toxicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Data is Klimisch 2 and from database.

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
Quality of whole database:
Waiver

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
experimental data from various test chemicals
Justification for type of information:
Data is summarized based on the available information from various test chemicals.
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
WoE report is based on 3 acute dermal toxicity studies as- WoE 2, WoE 3 and WoE 4.
Acute dermal toxicity test was carried out to study the effects of the test chemicals on rodents.
GLP compliance:
not specified
Test type:
other: not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
1. TEST ANIMALS
- Source: National Institute of Biosciences, Pune.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Young adult (8 to 10 weeks old) female rats were used.
- Weight at study initiation: The weight ranges of approximately 223.8 to 246.1 grams at initiation of dosing were used.
Body weights at the start : Female - Mean: 231.32 g (= 100 %); Minimum :223.8 g (- 3.25 %); Maximum : 246.1 g (+ 6.39 %)
- Housing: The rats were individually housed in polycarbonate cages with paddy husk as bedding.
- Identification: Each rat was individually identified by the cage number.
- Diet (e.g. ad libitum): Rodent feed supplied by the Nutrivet Life Sciences, Pune, was provided ad libitum from individual feeders.
- Water (e.g. ad libitum): Water was provided ad libitum from individual bottles attached to the cages. All water was from a local source and passed through the reverse osmosis membrane before use.
- Acclimation period: 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.0 to 22.4 degree centigrade.
- Humidity (%): 53.4% to 58.8%.
- Air changes (per hr): Ten to fifteen air changes per hour.
- Photoperiod (hrs dark / hrs light): An artificial light and dark cycle of 12 hours each was provided to the room.

IN-LIFE DATES: 08-05-2018 to 31-05-2018
2. TEST ANIMALS
- Source: National Institute of Biosciences, Pune.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Young adult (8 to 10 weeks old) female rats were used.
- Weight at study initiation: The weight ranges of approximately 223.8 to 246.1 grams at initiation of dosing were used.
Body weights at the start : Female - Mean: 228.08 g (= 100 %); Minimum :222.8 g (- 2.31 %); Maximum :235.1 g (+ 3.08 %)
- Housing: The rats were individually housed in polycarbonate cages with paddy husk as bedding.
- Identification: Each rat was individually identified by the cage number.
- Diet (e.g. ad libitum): Rodent feed supplied by the Nutrivet Life Sciences, Pune, was provided ad libitum from individual feeders.
- Water (e.g. ad libitum): Water was provided ad libitum from individual bottles attached to the cages. All water was from a local source and passed through the reverse osmosis membrane before use.
- Acclimation period: 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.0 to 22.4 degree centigrade.
- Humidity (%): 53.4% to 58.8%.
- Air changes (per hr): Ten to fifteen air changes per hour.
- Photoperiod (hrs dark / hrs light): An artificial light and dark cycle of 12 hours each was provided to the room.

IN-LIFE DATES: 08-05-2018 to 31-05-2018
3. TEST ANIMALS
- Source: National Institute of Biosciences, Pune.
- Age at study initiation: Young adult male and female rats aged between 6 – 9 weeks were used.
- Weight at study initiation: The weight ranges of approximately 218.4 to 262.2 grams at initiation of dosing were used.
Body weights at the start : Male Mean: 256.40 g (= 100 %); Minimum : 251.3 g (- 1.99 %); Maximum : 262.2 g (+ 2.26 %)
Female Mean: 224.72 g (= 100 %); Minimum : 218.4 g (- 2.81 %); Maximum : 231.5 g (+ 3.02 %)
- Housing: The rats were individually housed in polycarbonate cages with paddy husk as bedding.
- Diet (e.g. ad libitum): Rodent feed supplied by the Nutrivet Life Sciences, Pune, was provided ad libitum from individual feeders.
- Water (e.g. ad libitum): Water was provided ad libitum from individual bottles attached to the cages. All water was from a local source and passed through the reverse osmosis membrane before use.
- Acclimation period: 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Room temperature was maintained at 20.0 to 21.9 degree centigrade.
- Humidity (%): Room humidity was maintained at 56.1% to 58.7%.
- Air changes (per hr): The animal room was independently provided with at least ten to fifteen air changes per hour of 100% fresh air that had been passed through the HEPA filters.
- Photoperiod (hrs dark / hrs light): An artificial light and dark cycle of 12 hours each was provided to the room.

IN-LIFE DATES: 08-11-2016 to 23-11-2016
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
1. TEST SITE
- Area of exposure: Trunk (dorsal surface and sides from scapular to pelvic area)
- % coverage: Approximately 10% of the total body surface area.
- Type of wrap if used: The test item was held in contact with the skin using a porous gauze dressing and non irritating tape around the animal to cover the exposure site. Elizabethan collar was placed on each animal for first 24 hours after application of the test item. These collars prevent ingestion of test item.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The wrapping was removed and the test site wiped free of excess test item. Distilled water was used to remove residual test item.
- Time after start of exposure:24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
2. TEST SITE
- Area of exposure: Trunk (dorsal surface and sides from scapular to pelvic area)
- % coverage: Approximately 10% of the total body surface area.
- Type of wrap if used: The test item was held in contact with the skin using a porous gauze dressing and non irritating tape around the animal to cover the exposure site. Elizabethan collar was placed on each animal for first 24 hours after application of the test item. These collars prevent ingestion of test item.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The wrapping was removed and the test site wiped free of excess test item. Distilled water was used to remove residual test item.
- Time after start of exposure:24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
3. TEST SITE
- Area of exposure: Dorsal surface and sides from scapular to pelvic area.
- % coverage: Approximately 10% of the total body surface area.
- Type of wrap if used: Porous gauze dressing and non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Distilled water was used to remove residual test item.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
Duration of exposure:
1. 24 hours
2. 24 hours
3. 24 hours
Doses:
1. Dose Range Finding Study:
Group I : 200 mg/kg body weight
Group I : 1000 mg/kg body weight
Group I : 2000 mg/kg body weight
Main Study:
Group II : 2000 mg/kg body weight
2. Dose Range Finding Study:
Group I : 200 mg/kg body weight
Group I : 1000 mg/kg body weight
Group I : 2000 mg/kg body weight
Main Study:
Group II : 2000 mg/kg body weight
3. A single dose of 2000 mg of the test item per kilogram of body weight was administered to ten rats (five males and five females).
No. of animals per sex per dose:
1. Dose Range Finding Study:
Group I : 200 mg/kg body weight - 1
Group I : 1000 mg/kg body weight - 1
Group I : 2000 mg/kg body weight - 1
Main Study:
Group II : 2000 mg/kg body weight - 2
2. Dose Range Finding Study:
Group I : 200 mg/kg body weight - 1
Group I : 1000 mg/kg body weight - 1
Group I : 2000 mg/kg body weight - 1
Main Study:
Group II : 2000 mg/kg body weight - 2
3. 10 (5/sex).
Control animals:
not specified
Details on study design:
1. - Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Twice daily
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical Observations and General Appearance: Animals were observed for clinical signs, mortality, until sacrifice. Onset, duration and severity of any sign were recorded. The clinical signs and mortality observations were conducted at 10, 30, 60 minutes, 2, 4 and 6 hours on the day of dosing and once daily thereafter for 14 day. Daily observation was done as far as possible at the same time. The observations included general clinical signs, observations of eyes, mucous membranes, respiratory, circulatory system and behavior pattern.

Evaluation of Dermal Reaction: Dermal reaction was observed daily for study period of 14 days.

Body weights: Individual animal body weights were recorded pre-test (prior to administration of the test item), day 7 and at termination on day 14.

Gross Pathology: Necropsy was performed on animals surviving at the end of the study. Macroscopic examination of all the orifices, cavities and tissues were made and the findings were recorded. All animals surviving the study period were sacrificed by the carbon dioxide asphyxiation technique (day 15).

Histopathology: No gross abnormalities were observed in animals sacrificed terminally hence, no histopathology was performed.
2. - Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Twice daily
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical Observations and General Appearance: Animals were observed for clinical signs, mortality, until sacrifice. Onset, duration and severity of any sign were recorded. The clinical signs and mortality observations were conducted at 10, 30, 60 minutes, 2, 4 and 6 hours on the day of dosing and once daily thereafter for 14 day. Daily observation was done as far as possible at the same time. The observations included general clinical signs, observations of eyes, mucous membranes, respiratory, circulatory system and behavior pattern.

Evaluation of Dermal Reaction: Dermal reaction was observed daily for study period of 14 days.

Body weights: Individual animal body weights were recorded pre-test (prior to administration of the test item), day 7 and at termination on day 14.

Gross Pathology: Necropsy was performed on animals surviving at the end of the study. Macroscopic examination of all the orifices, cavities and tissues were made and the findings were recorded. All animals surviving the study period were sacrificed by the carbon dioxide asphyxiation technique (day 15).

Histopathology: No gross abnormalities were observed in animals sacrificed terminally hence, no histopathology was performed.
3. - Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Twice daily
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical Observations and General Appearance: Animals were observed for clinical signs, mortality, until sacrifice.
Onset, duration and severity of any sign were recorded. The clinical signs and mortality observations were conducted at 10, 30, 60 minutes, 2, 4 and 6 hours on the day of dosing and once daily thereafter for 14 day. Daily observation was done as far as possible at the same time.
The observations were included general clinical signs, observations of eyes, mucous membranes, respiratory, circulatory system and behavior pattern.

Evaluation of Dermal Reaction: Dermal reaction was observed daily for study period of 14 days.

Body weights: Individual animal body weights were recorded pre-test (prior to administration of the test item), day 7 and at termination on day 14.

Gross Pathology: Necropsy was performed on animals surviving at the end of the study. Macroscopic examination of all the orifices, cavities and tissues were made and the findings were recorded. All animals surviving the study period were sacrificed by the carbon dioxide asphyxiation technique (day 15).
Statistics:
1. not specified
2. not specified
3. not specified
Preliminary study:
1. Dose Range Finding Study: A single dose of 200 mg/kg body weight of the test item was administered to 1 female animal. No death or clinical signs of toxicity was observed during first 48 hours, hence, additional 1 female animal was administered at the dose of 1000 mg/kg body weight. Administration of 1000 mg/kg body weight did not reveal any clinical signs of toxicity or death during first 48 hours, hence, additional 1 female animal was administered at the dose of 2000 mg/kg body weight. Administration of 2000 mg/kg body weight did not reveal any clinical signs of toxicity or death during first 48 hours.
2. Dose Range Finding Study: A single dose of 200 mg/kg body weight of the test item was administered to 1 female animal. No death or clinical signs of toxicity was observed during first 48 hours, hence, additional 1 female animal was administered at the dose of 1000 mg/kg body weight. Administration of 1000 mg/kg body weight did not reveal any clinical signs of toxicity or death during first 48 hours, hence, additional 1 female animal was administered at the dose of 2000 mg/kg body weight. Administration of 2000 mg/kg body weight did not reveal any clinical signs of toxicity or death during first 48 hours.
3. not specified
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
1. Dose Range Finding Study: Animals treated at the dose level of 200, 1000 and 2000 mg/kg body weight, survived through the study period of 14 days.
Main Study: Animals treated at the dose level of 2000 mg/kg body weight survived through the study period of 14 days.
2. Dose Range Finding Study: Animals treated at the dose level of 200, 1000 and 2000 mg/kg body weight, survived through the study period of 14 days.
Main Study: Animals treated at the dose level of 2000 mg/kg body weight survived through the study period of 14 days.
3. Sex : Male Group I - Animal treated at the dose level of 2000 mg/kg: All animals survived through the study period of 14 days.
Sex : Female Group I – Animal treated at the dose level of 2000 mg/kg: All animals survived through the study period of 14 days
Clinical signs:
1. Dose Range Finding Study: Animals treated at the dose level of 200, 1000 and 2000 mg/kg body weight, did not result in any signs of toxicity during the study period of 14 days.
Main Study: Animals treated at the dose level of 2000 mg/kg body weight did not result in any signs of toxicity during the study period of 14 days.
2. Dose Range Finding Study: Animals treated at the dose level of 200, 1000 and 2000 mg/kg body weight, did not result in any signs of toxicity during the study period of 14 days.
Main Study: Animals treated at the dose level of 2000 mg/kg body weight did not result in any signs of toxicity during the study period of 14 days.
3. Sex : Male Group I - Animal treated at the dose level of 2000 mg/kg body weight did not result in any signs of toxicity during the study period of 14 days. All animals survived through the study period of 14 days.
Sex : Female Group I - Animal treated at the dose level of 2000 mg/kg body weight did not result in any signs of toxicity during the study period of 14 days. All animals survived through the study period of 14 days.
Body weight:
1. Dose Range Finding Study:
Group I (200 mg/kg) - Percent body weight gain after 7 days and 14 days was found to be 5.63% and 10.99% respectively.
Group I (1000 mg/kg) - Percent body weight gain after 7 days and 14 days was found to be 6.70% and 10.63% respectively.
Group I (2000 mg/kg) - Percent body weight gain after 7 days and 14 days was found to be 6.85% and 10.66% respectively.
Main Study:
Group II (2000 mg/kg) - Percent body weight gain after 7 days and 14 days was found to be 5.29% and 8.66% respectively.
2. Dose Range Finding Study:
Group I (200 mg/kg) - Percent body weight gain after 7 days and 14 days was found to be 5.63% and 10.99% respectively.
Group I (1000 mg/kg) - Percent body weight gain after 7 days and 14 days was found to be 6.70% and 10.63% respectively.
Group I (2000 mg/kg) - Percent body weight gain after 7 days and 14 days was found to be 6.85% and 10.66% respectively.
Main Study:
Group II (2000 mg/kg) - Percent body weight gain after 7 days and 14 days was found to be 5.29% and 8.66% respectively.
3. Sex : Male Group I (2000 mg/kg) - Percent body weight gain after 7 days and 14 days was found to be 9.93% and 20.46% respectively.
Sex : Female Group I (2000 mg/kg) - Percent body weight gain after 7 days and 14 days was found to be 5.18% and 10.21% respectively.
Gross pathology:
1. Gross pathological examination did not reveal any abnormalities in animals from 200 mg/kg, 1000 mg/kg and 2000 mg/kg dose groups from dose range finding study and main study sacrificed terminally.
2. Gross pathological examination did not reveal any abnormalities in animals from 200 mg/kg, 1000 mg/kg and 2000 mg/kg dose groups from dose range finding study and main study sacrificed terminally.
3. Gross pathological examination did not reveal any abnormalities in animals from 2000 mg/kg dose group.
Other findings:
1. - Other observations: Evaluation of Dermal Reaction
Dose Range Finding Study: Animals treated at the dose level of 200, 1000 and 2000 mg/kg body weight, did not result in any skin reaction during the study period of 14 days.
Main Study: Animals treated at the dose level of 2000 mg/kg body weight did not result in any skin reaction during the study period of 14 days.
2. - Other observations: Evaluation of Dermal Reaction
Dose Range Finding Study: Animals treated at the dose level of 200, 1000 and 2000 mg/kg body weight, did not result in any skin reaction during the study period of 14 days.
Main Study: Animals treated at the dose level of 2000 mg/kg body weight did not result in any skin reaction during the study period of 14 days.
3. - Other observations: Evaluation of Dermal Reaction
Sex : Male Group I - Animal treated at the dose level of 2000 mg/kg body weight did not result in any skin reaction during the study period of 14 days.
Sex : Female Group I - Animal treated at the dose level of 2000 mg/kg body weight did not result in any skin reaction during the study period of 14 days.
Interpretation of results:
other: Not classified
Conclusions:
According to CLP regulation, the test chemical cannot be classified for acute dermal toxicity, as the LD50 value is >2000 mg/kg bw.
Executive summary:

In different studies, the given test chemical has been investigated for acute dermal toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents, i.e. most commonly in rats for test chemical. The studies are summarized as below –

 

The reported study was designed and conducted to determine the acute dermal toxicity profile of the given test chemical as per OECD Guideline 402 (Acute Dermal Toxicity) in Sprague Dawley rats.

In the dose range finding study a single dose of 200 mg/kg body weight of the test item was administered to 1 female animal. No death or clinical signs of toxicity was observed during first 48 hours, hence, additional 1 female animal was administered with the dose of 1000 mg/kg body weight. Administration of 1000 mg/kg body weight did not reveal any clinical signs of toxicity or death during first 48 hours, hence, additional 1 female animal was administered at the dose of 2000 mg/kg body weight. Administration of 2000 mg/kg body weight did not reveal any clinical signs of toxicity or death during first 48 hours.

As the dose range finding study revealed no mortality or clinical signs at the maximum dose of 2000 mg/kg, the main study was initiated with two additional animals.  The animals were administered with a dose of 2000 mg/kg body weight in sequential manner at 48 hours intervals.

Animals from dose range finding study treated at the dose levels of 200 mg/kg, 1000 mg/kg and 2000 mg/kg and animals from main study treated at the dose level of 2000 mg/kg exhibited normal body weight gain and revealed no clinical signs of toxicity or mortality during the study period of 14 days. Gross pathological examination did not reveal any abnormalities attributable to the treatment.

Hence, it was concluded that the acute dermal median lethal dose (LD50) of given test chemical, when administered to female Sprague Dawley rats was considered to be >2000 mg/kg body weight. Thus, according to CLP criteria for acute toxicity rating for the chemicals, it infers that the given test chemical does not classify as an acute dermal toxicant.CLP Classification: “Not classified”.

 

The above study is supported with another study conducted on rats for the test chemical. The reported study was designed and conducted to determine the acute dermal toxicity profile of the given test chemical as per OECD Guideline 402 (Acute Dermal Toxicity) in Sprague Dawley rats.

In the dose range finding study a single dose of 200 mg/kg body weight of the test item was administered to 1 female animal. No death or clinical signs of toxicity was observed during first 48 hours, hence, additional 1 female animal was administered with the dose of 1000 mg/kg body weight. Administration of 1000 mg/kg body weight did not reveal any clinical signs of toxicity or death during first 48 hours, hence, additional 1 female animal was administered at the dose of 2000 mg/kg body weight. Administration of 2000 mg/kg body weight did not reveal any clinical signs of toxicity or death during first 48 hours.

As the dose range finding study revealed no mortality or clinical signs at the maximum dose of 2000 mg/kg, the main study was initiated with two additional animals.  The animals were administered with a dose of 2000 mg/kg body weight in sequential manner at 48 hours intervals.

Animals from dose range finding study treated at the dose levels of 200 mg/kg, 1000 mg/kg and 2000 mg/kg and animals from main study treated at the dose level of 2000 mg/kg exhibited normal body weight gain and revealed no clinical signs of toxicity or mortality during the study period of 14 days. Gross pathological examination did not reveal any abnormalities attributable to the treatment.

Hence, it was concluded that the acute dermal median lethal dose (LD50) of given test chemical, when administered to female Sprague Dawley rats was considered to be >2000 mg/kg body weight. Thus, according to CLP criteria for acute toxicity rating for the chemicals, it infers that the given test chemical does not classify as an acute dermal toxicant.CLP Classification: “Not classified”. 

 

Both the above studies are further supported with the study mentioned in report. The reported study was designed and conducted to determine the acute dermal toxicity profile of the given test chemical as per OECD Guideline 402 (Acute Dermal Toxicity) in Sprague Dawley rats.

The test item was applied to shorn skin of 5 male and 5 female animals at 2000 mg/kg body weight. Administration of the test item at 2000 mg/kg did not result in any skin reaction at the site of application during the study period of 14 days. Administration of the test item did not result in any signs of toxicity and mortality during the study period of 14 days. Animals exhibited normal body weight gain through the study period of 14 days. Gross pathological examination did not reveal any abnormalities attributable to the treatment.

Hence, it was concluded that the acute dermal median lethal dose (LD50) of the given test chemical, when administered to male and female Sprague Dawley rats was considered to be >2000 mg/kg body weight. Thus by considering the CLP criteria for acute toxicity rating for the chemicals, it infers that the given test chemical does not exhibit acute toxicity by the dermal route. CLP Classification: “Not classified”.

 

Thus, based on the above summarised studies on test chemical, it can be concluded that LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute dermal toxicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Data is Klimisch 2 and from report.

Additional information

Acute oral toxicity:

In different studies, the given test chemical has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents,

i.e. most commonly in rats for test chemical. The studies are summarized as below –

 

The acute oral toxicity study was conducted by using the given test chemical in 5 male and 5 female per group of Sprague-Dawley (Crj: CD (SD) IGS) ratsat the dose concentration of 2000 mg/kg bw. The given test chemical was dissolved in 0.5% methyl cellulose aqueous solution and administered as 10 mL/kg via oral route. A control group to which only the solvent was administered.

In the dose setting test, the test chemical was orally administered to Crj: CD (SD) IGS rats of 3 male and 3 female rats, respectively. As a result, no death was observed, so the OECD Test Method Guideline (401) 2000 mg/kg and a control group to which only the solvent is present was administered. The number of animals in one group was 5 for both males and females, and grouping was performed by stratified random extraction method based on the body weight the day before administration.

The life and death, appearance, behaviour and the like of the animals were observed consecutively from immediately after administration on the administration day (0 day after administration) until 1 hour after administration and at 1 hour interval from 2 hours to 6 hours after administration. From day 1 to day 14 post administration, observation was carried out once a day until the autopsy day.

The body weight was measured at 0 (before administration on the administration day), 1, 3, 5, 7, 10 and 14 days after administration (autopsy day), and the body weight gain and the body weight gain rate from day 0 to the 14th day after administration. Necropsy of survivors performed. On the 14th day after administration, after observing the external surface table, animals were exsanguinated under ether anaesthesia and killed by lethality, and the whole body organs and tissues were observed macroscopically.

Bartlett’s test for body weight, body weight gain and body weight gain rate was conducted and equi-dispersibility was analyzed. In the case of equi-variance, it is analyzed by one-way analysis of variance and in case of unequal variance it is analyzed by Kruskal-Wallis's test method. As a result of the analysis of the Kruskal-Wallis method, when significant difference was observed, it was analyzed by Mann-Whitney U-test method. In the test between the control group and the test substance-administered group, the significance level was set to 5% in each case.

Dead cases were not observed in both males and females. No abnormality was observed in both males and females. There was no significant difference between the 2000 mg/kg group and the control group in both males and females. No abnormal findings were observed in both males and females.

Under the condition of this, the LD50 value was considered to be >2000 mg/kg bw, when 5 male and 5 female per group Sprague-Dawley (Crj: CD (SD) IGS) rats were treated with the given test chemical via oral gavage route.

 

 

The above study is supported with another study mentioned in secondary source for the given test chemical as per OECD Guideline 401 (Acute Oral Toxicity) in 5 male and 5 female Sprague Dawley rats at the dose concentration of 2000 mg/kg bw.

The test material dissolved in water and administered via oral gavage route. The dose group was selected on the basis of a preliminary range-finding study in which rats were given the test compound in water at dose levels from 100 to 2000 mg/kg bw. The dose selected for the Limit Test was 2000 mg/kg bw.

The animals were observed 1, 2 and 4 hours after dosing and thereafter daily for 14 days. Body weights were recorded on days 1, 8 and 15 of the study. Macroscopic examination of main organs was performed after autopsy. No histological examinations were performed.

In the preliminary range-finding study, one death was reported at 1000 mg/kg bw but the only reported clinical signs were dose-related pink skin tone due to the compound and the death was considered to be unrelated to treatment.

There were no deaths during the Limit test. The only clinical sign was a pink discoloration of the skin, apparent from 1 hour to 7 days after dosing. Body weight gain was considered normal for the age and strain of rat. At autopsy an orange coloration of the mammary tissue and /or abdominal fat, attributed to the staining properties of the substance and not considered to be a toxic effect. The distribution and persistence of staining indicates that the substance has the potential to accumulate, at least at the high dose used in this acute study.

Under the condition of the study, the acute oral toxicity dose (LD50) value was considered to be >2000 mg/kg body weight, when 10 male and female Sprague Dawley rat, Crl:CD (SD) BR rats were treated with the given test chemical orally.

 

 

Both the above studies are further supported with the study mentioned in database for the test chemical. The acute oral toxicity study of the given test chemical was conducted in rats at the concentration of 5000 mg/kg bw. Animals were observed for mortality and clinical signs. 50% mortality was observed at 5000 mg/kg bw. Behavioural changes such as, somnolence (general depressed activity) and respiratory depression was observed in treated animals. Hence, the LD50 value was considered to be 5000 mg/kg bw, when rats was treated with the given test chemical via oral route.

 

Thus, based on the above summarised studies on test chemical, it can be concluded that LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute oral toxicity.

 

Acute Inhalation Toxicity:

The acute inhalation toxicity study need not be conducted because exposure to humans via inhalation route is not likely taking into account due to the low vapour pressure of the test chemical, which is reported to be 9.54E-13 Pa (7.15E-15 mm Hg). Thus, exposure to inhalable dust, mist and vapour of the chemical is highly unlikely. Therefore this study is considered for waiver. 

Acute Dermal Toxicity:

In different studies, the given test chemical has been investigated for acute dermal toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents, i.e. most commonly in rats for test chemical. The studies are summarized as below –

 

The reported study was designed and conducted to determine the acute dermal toxicity profile of the given test chemical as per OECD Guideline 402 (Acute Dermal Toxicity) in Sprague Dawley rats.

In the dose range finding study a single dose of 200 mg/kg body weight of the test item was administered to 1 female animal. No death or clinical signs of toxicity was observed during first 48 hours, hence, additional 1 female animal was administered with the dose of 1000 mg/kg body weight. Administration of 1000 mg/kg body weight did not reveal any clinical signs of toxicity or death during first 48 hours, hence, additional 1 female animal was administered at the dose of 2000 mg/kg body weight. Administration of 2000 mg/kg body weight did not reveal any clinical signs of toxicity or death during first 48 hours.

As the dose range finding study revealed no mortality or clinical signs at the maximum dose of 2000 mg/kg, the main study was initiated with two additional animals.  The animals were administered with a dose of 2000 mg/kg body weight in sequential manner at 48 hours intervals.

Animals from dose range finding study treated at the dose levels of 200 mg/kg, 1000 mg/kg and 2000 mg/kg and animals from main study treated at the dose level of 2000 mg/kg exhibited normal body weight gain and revealed no clinical signs of toxicity or mortality during the study period of 14 days. Gross pathological examination did not reveal any abnormalities attributable to the treatment.

Hence, it was concluded that the acute dermal median lethal dose (LD50) of given test chemical, when administered to female Sprague Dawley rats was considered to be >2000 mg/kg body weight. Thus, according to CLP criteria for acute toxicity rating for the chemicals, it infers that the given test chemical does not classify as an acute dermal toxicant.CLP Classification: “Not classified”.

 

The above study is supported with another study conducted on rats for the test chemical. The reported study was designed and conducted to determine the acute dermal toxicity profile of the given test chemical as per OECD Guideline 402 (Acute Dermal Toxicity) in Sprague Dawley rats.

In the dose range finding study a single dose of 200 mg/kg body weight of the test item was administered to 1 female animal. No death or clinical signs of toxicity was observed during first 48 hours, hence, additional 1 female animal was administered with the dose of 1000 mg/kg body weight. Administration of 1000 mg/kg body weight did not reveal any clinical signs of toxicity or death during first 48 hours, hence, additional 1 female animal was administered at the dose of 2000 mg/kg body weight. Administration of 2000 mg/kg body weight did not reveal any clinical signs of toxicity or death during first 48 hours.

As the dose range finding study revealed no mortality or clinical signs at the maximum dose of 2000 mg/kg, the main study was initiated with two additional animals.  The animals were administered with a dose of 2000 mg/kg body weight in sequential manner at 48 hours intervals.

Animals from dose range finding study treated at the dose levels of 200 mg/kg, 1000 mg/kg and 2000 mg/kg and animals from main study treated at the dose level of 2000 mg/kg exhibited normal body weight gain and revealed no clinical signs of toxicity or mortality during the study period of 14 days. Gross pathological examination did not reveal any abnormalities attributable to the treatment.

Hence, it was concluded that the acute dermal median lethal dose (LD50) of given test chemical, when administered to female Sprague Dawley rats was considered to be >2000 mg/kg body weight. Thus, according to CLP criteria for acute toxicity rating for the chemicals, it infers that the given test chemical does not classify as an acute dermal toxicant.CLP Classification: “Not classified”.

 

 

Both the above studies are further supported with the study mentioned in report. The reported study was designed and conducted to determine the acute dermal toxicity profile of the given test chemical as per OECD Guideline 402 (Acute Dermal Toxicity) in Sprague Dawley rats.

The test item was applied to shorn skin of 5 male and 5 female animals at 2000 mg/kg body weight. Administration of the test item at 2000 mg/kg did not result in any skin reaction at the site of application during the study period of 14 days. Administration of the test item did not result in any signs of toxicity and mortality during the study period of 14 days. Animals exhibited normal body weight gain through the study period of 14 days. Gross pathological examination did not reveal any abnormalities attributable to the treatment.

Hence, it was concluded that the acute dermal median lethal dose (LD50) of the given test chemical, when administered to male and female Sprague Dawley rats was considered to be >2000 mg/kg body weight. Thus by considering the CLP criteria for acute toxicity rating for the chemicals, it infers that the given test chemical does not exhibit acute toxicity by the dermal route. CLP Classification: “Not classified”.

 

Thus, based on the above summarised studies on test chemical, it can be concluded that LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute dermal toxicity.

Justification for classification or non-classification

Based on the above studies on test chemical, it can be concluded that LD50 value is >2000 mg/kg bw, for acute oral and acute dermal toxicity. Thus, comparing this value with the criteria of CLP regulation, the given test chemical cannot be classified for acute oral and acute dermal toxicity. For acute inhalation toxicity wavier was added so, not possible to classify.