Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Acute oral toxicity: 

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

Acute Inhalation toxicity:

For test chemical, acute toxicity testing by the inhalation route was considered for waiver given that the substance has low vapour pressure of 0.00162 Pa at 25 degree C . Thus, exposure by inhalation is also unlikely for test chemical given the comparitively larger size of the particulates.

Acute Dermal toxicity:

The acute dermal toxicity dose (LD50) for test chemical was considered based on experimental study, the value considered to be >2000 mg/kg bw in rabbits. Thus, comparing this value with the criteria of CLP regulation, 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:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Data is from study report
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Principles of method if other than guideline:
The aim of this study was to assess the toxicity potential of test chemical after single oral administration in rats.
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS

- Source:In-House Bred
- Age at study initiation:8- 11 weeks at the time of dosing
- Weight at study initiation: 168-192 g (Individual body weights were within ± 5% prior to treatment after overnight fasting)
- Fasting period:The animals were fasted for minimum 16-18 hours prior to dosing and for 3-4 hours post dosing.
- Housing: The animals were housed individually in polycarbonate cages with corn cobs as bedding in a controlled environment.
- Diet (e.g. ad libitum): Conventional laboratory rodent diet (Nutrivet Life Sciences, Pune), ad libitum
- Water (e.g. ad libitum): Aqua guard filtered tap water, ad libitum
- Acclimation period: Animal numbers 1-3 were acclimatized for five days, and 4-6 for seven days prior to administration of the test item.

ENVIRONMENTAL CONDITIONS
- Temperature (°C):20.40 - 23.10°C
.- Humidity (%):Minimum: 37.40 - 56.00%
- Air changes (per hr): More than 12 changes per hour
- Photoperiod (hrs dark / hrs light): 12-hrs light/12-hrs dark
Route of administration:
oral: unspecified
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage):10 ml
- Justification for choice of vehicle: Corn oil was selected because test item was not miscible in distilled water.
- Lot/batch no. (if required): MKBD4650- Purity: No data av available

MAXIMUM DOSE VOLUME APPLIED:10 ml/kg body weight
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 female rats
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Daily
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical Observation, body weight and mortality.
Statistics:
No data available
Preliminary study:
No data available
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other:
Remarks:
No mortality observed
Mortality:
No mortality was observed in the animals treated with 2000 mg/kg throught out the 14 days observation period post dosing.
Clinical signs:
other: At 2000 mg/kg, animal nos. 1, 2, 3, 4 and 6 were observed normal at 30 minutes, mild to moderate diarrhea at 1, 2, 3 and 4 hours and mild epistaxis at 3 and 4 hours followed by normal clinical sign till day 14. Additionally, animal no. 2 was observed with
Gross pathology:
No external or internal gross pathological changes were seen in all the six animals treated with 2000 mg/kg body weight during terminal sacrifice.

Table 1: Individual Animal Body Weight (g) andBody Weight Changes(%)

Sex:Female

Animal No.

Group/ Dose (mg/kg)

Body Weight (gram)

Body Weight Change (%)

Day 0

Day 7

Day 14

Day

0-7

Day

0-14

1

G1/ 2000

174

193

216

10.92

24.14

2

171

185

210

8.19

22.81

3

168

192

202

14.29

20.24

4

192

205

218

6.77

13.54

5

178

149

178

-16.29

0.00

6

174

189

198

8.62

13.79

 

 

Table 2: Summary of Animal Body Weight (g) and Body Weight Changes (%)

Sex:Female

Group/ Dose (mg/kg)

Rats Body Weight (g)

Body Weight Changes (%)

Day 0

Day 7

Day 14

0-7

0-14

G1/ 2000

Mean

176.17

185.50

203.67

5.42

15.75

SD

8.45

19.10

14.77

10.95

8.91

n

6

6

6

6

6

Keys:SD = Standard Deviation, n = Number of Animals

Table 3: Individual Animal Clinical Signs and Symptoms

Sex:Female

Animal No.

Group/ Dose (mg/kg)

Hours (Day 0)

1/2

1

2

3

4

1

G1/ 2000

1

49++

49+

64+

49+

64+

49+

2

1

49++

49+

64+

49+

64+

49+

3

1

49++

49+

64+

49+

64+

49+

4

1

49+

49++

64+

49++

64+

49+

5

1

1

49+

64+

49+

49+

64+

6

1

49++

49++

64+

49+

49+

64+

Animal No.

Group/ Dose (mg/kg)

Days post dosing

1

2

3

4

5

6

7

8

9

10

11

12

13

14

1

G1/ 2000

1

1

1

1

1

1

1

1

1

1

1

1

1

1

2

182

1

1

1

1

1

1

1

1

1

1

1

1

1

3

1

1

1

1

1

1

1

1

1

1

1

1

1

1

4

1

1

1

1

1

1

1

1

1

1

1

1

1

1

5

1

1

1

1

1

1

1

1

1

1

1

1

1

1

6

1

1

1

1

1

1

1

1

1

1

1

1

1

1

Keys:1 = Normal, 49 = Diarrhoea, 64 = Epistaxis, 182 = Soiled anal region with fecal material,+= Mild,++= Moderate

 

Table 4: Individual Animal Mortality Record

Sex:Female

Animal No.

Group/ Dose (mg/kg)

Day of Observation (Day 0 to 14)

Morning Observations

Evening Observations

1

G1/ 2000

No mortality and morbidity

No mortality and morbidity

2

No mortality and morbidity

No mortality and morbidity

3

No mortality and morbidity

No mortality and morbidity

4

No mortality and morbidity

No mortality and morbidity

5

No mortality and morbidity

No mortality and morbidity

6

No mortality and morbidity

No mortality and morbidity

  

Table 5: Gross Necropsy Observation

 Sex:Female  

Animal No.

Group/ Dose (mg/kg)

Mode of Death

Gross Observation

External

Internal

1

G1/ 2000

Terminal sacrifice

No abnormality detected

No abnormality detected

2

Terminal sacrifice

No abnormality detected

No abnormality detected

3

Terminal sacrifice

No abnormality detected

No abnormality detected

4

Terminal sacrifice

No abnormality detected

No abnormality detected

5

Terminal sacrifice

No abnormality detected

No abnormality detected

6

Terminal sacrifice

No abnormality detected

No abnormality detected

 

 

Interpretation of results:
other: Not classified
Conclusions:
Body weight gain was observed in all the animals treated with 2000 mg/kg body weight, during the 14-day observation period. At 2000 mg/kg, animal number 1, 2, 3, 4 and 6 were observed normal at 30 minutes, mild to moderate diarrhea at 1, 2, 3 and 4 hours and mild epistaxis at 3 and 4 hours followed by normal clinical sign till day 14. Additionally, animal number 2 was observed with soiled anal region with fecal material on day1. Animal number 5 was observed normal at 30 minutes and 1 hour, mild diarrhea at 2, 3 and 4 hours and mild epistaxis at 3 and 4 hours followed by normal clinical sign till day 14. No external and internal gross pathological changes were seen in all the six animals treated with 2000 mg/kg body weight during terminal sacrifice
The acute oral LD50 value for the test chemical was considered to be greater than 2000 mg/kgbw.
Executive summary:

An acute oral toxicity study of test chemical was conducted in female Wistar rats as per OECD No. 423.Six Wistar female rats were for the acute oral toxicity study. Prior to dosing, the animals were fasted for minimum 16-18 hours and for 3-4 hours post dosing, with food withheld but drinking water provided ad libitum. Corn oil was selected as the vehicle because test item was not miscible in distilled water. Three rats of the first group were dosed with starting dose of 2000mg/kgbw and the animals didnot show any mortality so another three rats of the same group were dosed with 2000 mg/kgbw and no mortality was observed. Hence, further dosing was stopped. Body weight gain was observed in all the animals treated with 2000 mg/kg body weight, during the 14-day observation period. At 2000 mg/kg, animal number 1, 2, 3, 4 and 6 were observed normal at 30 minutes, mild to moderate diarrhea at 1, 2, 3 and 4 hours and mild epistaxis at 3 and 4 hours followed by normal clinical sign till day 14. Additionally, animal number 2 was observed with soiled anal region with fecal material on day1. Animal number 5 was observed normal at 30 minutes and 1 hour, mild diarrhea at 2, 3 and 4 hours and mild epistaxis at 3 and 4 hours followed by normal clinical sign till day 14. No external and internal gross pathological changes were seen in all the six animals treated with 2000 mg/kg body weight during terminal sacrifice. The acute oral LD50 value for the test chemical was considered to be greater than 2000 mg/kgbw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Data is klimish 1 and from study report

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size
Clinical signs:
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:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Data is from study report
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Principles of method if other than guideline:
The objective of the study was to assess the dermal toxicity of test chemical after single dose application by dermal route in rats.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: In-House Bred
- Age at study initiation: No data available-
- Weight (Prior to Treatment):Male: 225-245 g ; Female: 215-231 g
- Fasting period before study: No data available
- Housing:The animals were housed individually in polycarbonate cages with corn cob as bedding in a controlled environment
.- Diet (e.g. ad libitum): Conventional laboratory rodent diet (Nutrivet Life Sciences, Pune),ad libitum
- Water (e.g. ad libitum): Aqua guard filtered tap water, ad libitum
- Acclimation period: All animals were acclimatized to the test conditions for 5 days prior to administration of the test item.ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.20-24.40°C
- Humidity (%): 36.60-57.30%
- Air changes (per hr): More than 12 changes per hour
- Photoperiod (hrs dark / hrs light):12-hrs light/:12-hrs dark
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE

- Area of exposure: The test item was applied uniformly over clipped dorsal area of rat skin.
- % coverage: Approximately 10% body surface area of rat.
- Type of wrap if used: Porous gauze dressing and non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The residual test item was removed by using distilled water.
- Time after start of exposure: 24-hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): A limit dose of 2000 mg/ kg body weight of test item was applied.
- Constant volume or concentration used: Yes
- For solids, paste formed: No VEHICLE
- Amount(s) applied (volume or weight with unit): No data available
- Concentration (if solution): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available
Duration of exposure:
24 hours
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
Total: 10 rats 2000 mg/kg: 5 males, 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Daily
- Necropsy of survivors performed: Yes
.- Other examinations performed: Clinical signs, body weight, local signs/skin reactions and mortality.
Statistics:
No statistical analysis was performed since the study was terminated with limit test.
Preliminary study:
No data available
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Non toxic to animals
Mortality:
No mortality was observed at 2000 mg/kg body weight during the 14 day observation period.
Clinical signs:
other: No systemic or local signs of toxicity were observed at 2000 mg/kg body weight during the experimental period.
Gross pathology:
The external and internal gross pathological observation of all terminally sacrificed animals did not show any pathological abnormality.
Other findings:
No data available

Table 1: Individual Animal Body Weight (g) andBody Weight Changes(%)

 

Dose:2000 mg/ kg bodyweight                                                                                                                Density:0.96365

Animal No.

Sex

Dose (ml) Applied*

Body Weight (gram)

Body Weight Change (%)

Day 0

Day 7

Day 14

Day 0-7

Day 0-14

1

Male

0.49

236

243

249

2.97

5.51

2

0.48

231

239

247

3.46

6.93

3

0.47

225

248

274

10.22

21.78

4

0.51

245

270

287

10.20

17.14

5

0.48

233

240

260

3.00

11.59

6

Female

0.45

215

223

215

3.72

0.00

7

0.47

227

231

233

1.76

2.64

8

0.48

231

228

233

-1.30

0.87

9

0.48

231

236

237

2.16

2.60

10

0.45

215

213

217

-0.93

0.93

Key:* = Based on density of test item and day 0 body weight taken prior to dose application.

 

Table 2: Individual Animal Clinical Signs and Symptoms

 

Dose:2000 mg/kg body weight

Animal No.

Sex

Hour(s) - Day 0

Day

1

2

3

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

1

Male

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

2

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

3

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

4

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

5

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

6

Female

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

7

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

8

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

9

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

10

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

Key: 1 = Normal

 

Table 3: Individual Animal Mortality Record

 

Dose:2000 mg/kg body weight

       Animal No.

Sex

Days of Observation (0 to 14)

Morning Observations

Evening Observations

1

Male

No mortality and morbidity

No mortality and morbidity

2

No mortality and morbidity

No mortality and morbidity

3

No mortality and morbidity

No mortality and morbidity

4

No mortality and morbidity

No mortality and morbidity

5

No mortality and morbidity

No mortality and morbidity

6

Female

No mortality and morbidity

No mortality and morbidity

7

No mortality and morbidity

No mortality and morbidity

8

No mortality and morbidity

No mortality and morbidity

9

No mortality and morbidity

No mortality and morbidity

10

No mortality and morbidity

No mortality and morbidity

 

Table 4:Summaryof Animal Body Weight (g) and Body Weight Changes (%)

 

Dose:2000 mg/kg body weight

Sex

Body Weight (gram)

Body Weight Changes (%)

Day 0

Day 7

Day 14

Day 0-7

Day 0-14

Male

Mean

234.00

248.00

263.40

5.97

12.59

SD

7.35

12.79

17.01

3.88

6.86

n

5

5

5

5

5

Female

Mean

223.80

226.20

227.00

1.08

1.41

SD

8.20

8.76

10.20

2.14

1.17

n

5

5

5

5

5

Keys:SD= Standard deviation, n = Number of animals

 

Table 5: GrossNecropsyObservation

 

 Dose:2000 mg/kg body weight                                                                             Mode of Death:Terminal Sacrifice

Animal No.

Sex

Gross Observation

External

Internal

1

Male

No abnormalities detected

No abnormalities detected

2

No abnormalities detected

No abnormalities detected

3

No abnormalities detected

No abnormalities detected

4

No abnormalities detected

No abnormalities detected

5

No abnormalities detected

No abnormalities detected

6

Female

No abnormalities detected

No abnormalities detected

7

No abnormalities detected

No abnormalities detected

8

No abnormalities detected

No abnormalities detected

9

No abnormalities detected

No abnormalities detected

10

No abnormalities detected

No abnormalities detected


 

Interpretation of results:
other: Not classified
Conclusions:
No mortality was observed at 2000 mg/kg body weight during the 14 day observation period. No systemic or local signs of toxicity were observed at 2000 mg/kg body weight during the experimental period. The male and female animals were observed with body weight gain compared to day 0 throughout the experiment. The external and internal gross pathological observation of all terminally sacrificed animals did not show any pathological abnormality. Based on the results, the acute dermal median lethal dose of test chemical was considered to be greater than 2000 mg/kg body weight.
Executive summary:

The acute toxicity of test chemical was determined after single dose application by dermal route in rats. This study was performed according to OECD 402 Guidelines. Five male and five female Wistar rats were treated with test item by a single dermal application at the dose level of 2000 mg/kg body weight and observed for 14 days after treatment. Since no test item related mortality was observed, the study was terminated with limit test only. The test item was applied uniformly over clipped dorsal area of rat skin. The porous gauze dressing was put on the intact skin and wrapped around the abdomen and it was anchored with non-irritating tape. After 24 hour application period, the residual test item was removed by using distilled water. The skin reactions were assessed. The animals were observed daily for clinical signs, mortality. The body weight changes were recorded on day 0 and on day 7 and day 14. All animals were necprosied and examined macroscopically. No statistical analysis was performed since the study was terminated with limit test. No mortality was observed at 2000 mg/kg body weight during the 14 day observation period. No systemic or local signs of toxicity were observed at 2000 mg/kg body weight during the experimental period. The male and female animals were observed with body weight gain compared to day 0 throughout the experiment. The external and internal gross pathological observation of all terminally sacrificed animals did not show any pathological abnormality. Based on the results, the acute dermal median lethal dose of test chemical was considered to be greater than 2000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Data is klimish 1 and from study report

Additional information

Acute oral toxicity:

An acute oral toxicity study of test chemical was conducted in female Wistar rats as per OECD No. 423. Six Wistar female rats were for the acute oral toxicity study. Prior to dosing, the animals were fasted for minimum 16-18 hours and for 3-4 hours post dosing, with food withheld but drinking water provided ad libitum. Corn oil was selected as the vehicle because test item was not miscible in distilled water. Three rats of the first group were dosed with starting dose of 2000mg/kgbw and the animals didnot show any mortality so another three rats of the same group were dosed with 2000 mg/kgbw and no mortality was observed. Hence, further dosing was stopped. Body weight gain was observed in all the animals treated with 2000 mg/kg body weight, during the 14-day observation period. At 2000 mg/kg, animal number 1, 2, 3, 4 and 6 were observed normal at 30 minutes, mild to moderate diarrhea at 1, 2, 3 and 4 hours and mild epistaxis at 3 and 4 hours followed by normal clinical sign till day 14. Additionally, animal number 2 was observed with soiled anal region with fecal material on day1. Animal number 5 was observed normal at 30 minutes and 1 hour, mild diarrhea at 2, 3 and 4 hours and mild epistaxis at 3 and 4 hours followed by normal clinical sign till day 14. No external and internal gross pathological changes were seen in all the six animals treated with 2000 mg/kg body weight during terminal sacrifice The acute oral LD50 value for the test chemical was considered to be greater than 2000 mg/kgbw.

Acute Inhalation toxicity:

For test chemical, acute toxicity testing by the inhalation route was considered for waiver given that the substance has low vapour pressure of 0.00162 Pa

at 25 degrees C. Thus, exposure by inhalation is also unlikely for test chemical given the comparitively larger size of the particulates.

Acute Dermal Toxicity:

The acute toxicity of test chemical was determined after single dose application by dermal route in rats. This study was performed according to OECD 402 Guidelines. Five male and five female Wistar rats were treated with test item by a single dermal application at the dose level of 2000 mg/kg body weight and observed for 14 days after treatment. Since no test item related mortality was observed, the study was terminated with limit test only. The test item was applied uniformly over clipped dorsal area of rat skin. The porous gauze dressing was put on the intact skin and wrapped around the abdomen and it was anchored with non-irritating tape. After 24 hour application period, the residual test item was removed by using distilled water. The skin reactions were assessed. The animals were observed daily for clinical signs, mortality. The body weight changes were recorded on day 0 and on day 7 and day 14. All animals were necropsied and examined macroscopically. No statistical analysis was performed since the study was terminated with limit test. No mortality was observed at 2000 mg/kg body weight during the 14 day observation period. No systemic or local signs of toxicity were observed at 2000 mg/kg body weight during the experimental period. The male and female animals were observed with body weight gain compared to day 0 throughout the experiment. The external and internal gross pathological observation of all terminally sacrificed animals did not show any pathological abnormality. Based on the results, the acute dermal median lethal dose of test chemical was considered to be greater than 2000 mg/kg body weight.

 

Justification for classification or non-classification

Based on the above experimental studies on test chemical indicate that the test chemical is not likely to cause any toxicity when exposed to test organisms via oral, dermal or inhalation route of exposure. Hence, the test chemical can be classified under the category "Not Classified" as per CLP Regulation.