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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
April 17, 2014 to May 12, 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2014
Report date:
2014

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
not specified
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
5-(3-phenylprop-2-ynoyl)-1,3-dihydro-2-benzofuran-1,3-dione
EC Number:
935-606-2
Cas Number:
1329658-14-1
Molecular formula:
C17H8O4
IUPAC Name:
5-(3-phenylprop-2-ynoyl)-1,3-dihydro-2-benzofuran-1,3-dione
Test material form:
solid: particulate/powder
Details on test material:
Short Name: PETA
Long Name: NNEXAMITE™ A56 (PETA)
Chemical Name: Phenylacetylene modified trimellitic anhydride
Lot Number: NEX-X61-A02
CAS Number: 1329658-14-1
Description: Yellow powder
Purity: >99 %
Molecular weight: 276.24
Manufacture date: 04 September 2013
Expiry date: 01 May 2014
Storage conditions: Room temperature (15-25 °C), protected from humidity
Safety Precautions: Routine safety precautions (gloves, goggles, face mask, lab coat) for unknown materials were applied to assure personnel health and safety
Specific details on test material used for the study:
No further details specified in the study report.

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Species: Rat (Rattus norvegicus)
Strain: Wistar
Age/Weight: at Dosing 8 to 9 weeks, Weight (g) Minimum: 167.4, Maximum: 189.5
Source: Animal Breeding Facility, Jai Research Foundation
Total Number of Animals Used: Twelve females
Female rats were nulliparous and non-pregnant.
The study was undertaken in compliance with the 'Guidelines for Laboratory Animals Facility' issued by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), India. These guidelines promote the humane care of animals used in research by providing specifications that will enhance animal well being and experimental quality for the advancement of biological knowledge that is relevant to humans and animals.
Project proposal for the experimentation was approved by Institutional Animal Ethics Committee (IAEC), Jai Research Foundation.
JRF is also accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) that promotes the humane treatment of animals in science.

Acclimatisation
Acclimatisation Period 5 to 9 days
The rats were received into the experimental procedure room and allowed to acclimatise for a period of 5 days for set I rats (rat N° 1, 2 and 3), 7 days for set II rats (rat N° 4, 5 and 6), 9 days for set III rats (rat N° 7, 8 and 9) and 6 days for set IV rats (rat N° 10, 11 and 12) prior to commencement of dosing.

Husbandry Practices
Caging: Polypropylene rat cages covered with a stainless steel grid top were used. Autoclaved clean rice husk was used as the bedding material.
Water Bottle: Each cage was supplied with a polypropylene water bottle with a stainless steel nozzle.
Housing: Three rats per cage.
Room Sanitation: Daily: 1. Rack was cleaned with cloth. 2. Floor of experimental procedure room was swept. 3. All work tops and the floor were mopped with a disinfectant solution.

Animal Identification
Each rat was uniquely numbered on the tail using a tattoo machine. Appropriate labels were attached to the cages indicating the study number, test item code, set number and sex, dose, type of study, cage number and animal numbers.

Feed and Water
The rats were provided with feed (with the exception of overnight fasting prior to dosing and three hours post-dosing) and water, ad libitum. The quality of feed and water is regularly monitored at Jai Research Foundation. There were no known contaminants in the feed and water at levels that would have interfered with the experimental results obtained.
Feed: Teklad certified Global High Fiber Rat/Mice Feed manufactured by Harlan, U.S.A.
Water: UV sterilized water filtered through Kent Reverse Osmosis water filtration system.

Environmental Conditions
Environmental Temperature: 20 to 23 °C
Conditions Humidity: 65 to 66% relative humidity
Air Changes: Minimum 15 air changes/hour
Photoperiod: The photoperiod was 12 hours artificial light and 12 hours darkness, light hours being 06:00 h - 18:00 h, which was maintained through an automatic timer.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
vegetable oil
Details on oral exposure:
The test item formed homogenous suspension in vegetable oil, so the actual dose formulation was prepared using vegetable oil as the vehicle. The required quantity (300 mg for set I and set II and 2000 mg for set III and set IV) was mixed with vegetable oil and the final volume was made up to 10 mL. Gavage solutions were prepared freshly within 2 hours prior to dosing on all occasions.
Doses:
300 mg/kg bw (x 2 dose groups)
2000 mg/kg bw (x 2 dose groups)
No. of animals per sex per dose:
3 per dose group (12 in total)
Control animals:
no
Details on study design:
Dose Administration
Individual dose volume was adjusted according to body weight. All rats were dosed by gavage (day 0) using a metal cannula attached to a BD 1 mL disposable syringe which was graduated up to 1 mL.
Rats were fasted overnight prior to dosing until three hours post-dosing.

Main Study
A first set (set I) of three female rats was given a single dose of 300 mg/kg body weight NEXAMITETM A56 (PETA). No mortality was observed at this dose level so a second set (set II) of three female rats was administered with same dose of 300 mg/kg body weight NEXAMITE TM A56 (PETA). No mortality was observed at this dose level so a third set (set III) of three female rats was administered with a higher dose level of 2000 mg/kg body weightNEXAMITETM A56 (PETA). No mortality was observed at this dose level so a fourth set (set IV) of three female rats was administered with same dose of 2000 mg/kg body weight NEXAMITE TM A56 (PET A). No mortality was observed at this dose level hence the endpoint was achieved and further testing was not required.

Observations
The rats were observed for signs of toxicity and mortality at 0.5, 1, 2, 3, 4 and 6 hours postadministration on the day of dosing. Subsequently, the rats were observed twice a day for morbidity and mortality for a period of 14 days following oral dosing. The clinical signs were recorded once a day.
Individual body weight was recorded prior to dosing on day O and on days 7 and 14.

Necropsy
Surviving rats at the end of the 14-day observation period were euthanised by carbon dioxide asphyxiation and subjected to a gross pathological examination consisting of an external examination and opening of abdominal and thoracic cavities. Gross macroscopic changes, if any, were recorded.
Statistics:
Not specified

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed in rats treated at the dose level of 300 and 2000 mg/kg body weight NEXAMITE™ A56 (PETA).
Clinical signs:
other: No clinical sign was observed in rats treated with 300 and 2000 mg/kg body weight NEXAMITE™ A56 (PETA).
Gross pathology:
External: External examination of terminally sacrificed female rats did not reveal any abnormality of pathological significance.
Internal: Visceral examination of terminally sacrificed rats did not reveal any lesion of pathological significance.
Other findings:
Not specified

Any other information on results incl. tables

Dose, Mortality/Animals Treated

Dose (mg/kg body weight)

Female rats (mortality/total)

300

0/6

2000

0/6

 

Mortality

Sex: Female

Dose (mg/kg body weight)

Set No

Number of Rats Used

Mortality after Dosing

At Hour

On Day

½ - 4

6

1

2

3

4 – 7

8 – 14

300

I

3

0

0

0

0

0

0

0

II

3

0

0

0

0

0

0

0

2000

III

3

0

0

0

0

0

0

0

IV

3

0

0

0

0

0

0

0

 

Individual and Mean Body Weight (g) and Body Weight Change (%)

Sex: Female

Dose

(mg/kg body weight)

Rat No

Body Weight (g) on Day

Percent Body Weight Change on Day

0

7

14

7

14

300

1

171.2

195.7

222.3

14.31

29.85

2

167.4

192.4

213.8

14.93

27.72

3

171.3

194.6

207.3

13.60

21.02

Mean

170.0

194.2

214.5

14.28

26.20

Standard Deviation

±2.2

±1.7

±7.5

±0.67

±4.61

4

178.2

205.1

218

15.10

22.33

5

173.4

198.3

205.3

14.36

18.40

6

171.9

199.8

220.0

16.23

27.98

Mean

174.5

201.1

214.4

15.23

22.90

Standard Deviation

±3.3

±3.6

±8.0

±0.94

±4.82

2000

7

176.0

200.1

212.3

13.69

20.63

8

180.6

204.0

216.4

12.96

19.82

9

168.6

191.6

202.7

13.64

20.23

Mean

175.1

198.6

210.5

13.43

20.23

Standard Deviation

±6.1

±6.3

±7.0

±0.41

±0.41

10

182.8

200.1

218.5

9.46

19.53

11

188.9

210.4

230.8

11.38

22.18

12

189.5

213.8

232.4

12.82

22.64

Mean

187.1

208.1

227.2

11.22

21.45

Standard Deviation

±3.7

±7.1

±7.6

±1.69

±1.68

Key: 0 = Before dosing

 

Individual Clinical Observations

Sex: Female                                                                                      Set I

Dose

(mg/kg body weight)

Rat No

Clinical Signs Observed Post-dosing

At Hour (Day 0)

0.5

1

2

3

4

6

300

1

1

1

1

1

1

1

2

1

1

1

1

1

1

3

1

1

1

1

1

1

 

Dose (mg/kg body weight)

Rat No

Clinical Signs Observed Post-dosing

On Days

1

2

3

4

5

6

7

8

9

10

11

12

13

14

300

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

3

1

1

1

1

1

1

1

1

1

1

1

1

1

1

 

                                                                                                        Set II

Dose

(mg/kg body weight)

Rat No

Clinical Signs Observed Post-dosing

At Hour (Day 0)

0.5

1

2

3

4

6

300

4

1

1

1

1

1

1

5

1

1

1

1

1

1

6

1

1

1

1

1

1

 

Dose (mg/kg body weight)

Rat No

Clinical Signs Observed Post-dosing

On Days

1

2

3

4

5

6

7

8

9

10

11

12

13

14

300

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

Key: 1 = normal

Note: Day 0 = Day of dosing

 

Sex: Female                                                                              Set III

Dose

(mg/kg body weight)

Rat No

Clinical Signs Observed Post-dosing

At Hour (Day 0)

0.5

1

2

3

4

6

2000

7

1

1

1

1

1

1

8

1

1

1

1

1

1

9

1

1

1

1

1

1

 

Dose (mg/kg body weight)

Rat No

Clinical Signs Observed Post-dosing

On Days

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

7

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

9

1

1

1

1

1

1

1

1

1

1

1

1

1

1

 

                                                                                                       Set IV

Dose

(mg/kg body weight)

Rat No

Clinical Signs Observed Post-dosing

At Hour (Day 0)

0.5

1

2

3

4

6

2000

10

1

1

1

1

1

1

11

1

1

1

1

1

1

12

1

1

1

1

1

1

 

Dose (mg/kg body weight)

Rat No

Clinical Signs Observed Post-dosing

On Days

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

10

1

1

1

1

1

1

1

1

1

1

1

1

1

1

11

1

1

1

1

1

1

1

1

1

1

1

1

1

1

12

1

1

1

1

1

1

1

1

1

1

1

1

1

1

Key: 1 = normal

Note: Day 0 = Day of dosing

 

Individual Necropsy Findings

Sex: Female

Dose

(mg/kg body weight)

Set No

Rat No

Mode of Death

External

Internal

300

I

1

Terminal sacrifice

No abnormalities detected

No abnormalities detected

2

Terminal sacrifice

No abnormalities detected

No abnormalities detected

3

Terminal sacrifice

No abnormalities detected

No abnormalities detected

II

4

Terminal sacrifice

No abnormalities detected

No abnormalities detected

5

Terminal sacrifice

No abnormalities detected

No abnormalities detected

6

Terminal sacrifice

No abnormalities detected

No abnormalities detected

2000

III

7

Terminal sacrifice

No abnormalities detected

No abnormalities detected

8

Terminal sacrifice

No abnormalities detected

No abnormalities detected

9

Terminal sacrifice

No abnormalities detected

No abnormalities detected

IV

10

Terminal sacrifice

No abnormalities detected

No abnormalities detected

11

Terminal sacrifice

No abnormalities detected

No abnormalities detected

12

Terminal sacrifice

No abnormalities detected

No abnormalities detected

 

Applicant's summary and conclusion

Interpretation of results:
Category 5 based on GHS criteria
Conclusions:
No mortality was observed in rats treated at the dose level of 300 mg and 2000 mg NEXAMITE™ A56 (PETA)/kg body weight. The acute oral median lethal dose (LD50 cut-off value) of NEXAMITE™ A56 (PETA) in Wistar rats was found to be 5000 mg/kg body weight.
Executive summary:

In an acute oral toxicity study, four sets of fasted Wistar rats (3 females/set) were given a single oral dose of NEXAMITE™ A56 (PETA) at a dose of300 (for each set I and set II) and 2000 (for each set III and set IV) mg/kg body weight and were observed for 14 days.

 

No clinical signs or mortalities were observed in rats treated with 300 mg/kg (set I and set II) and 2000 mg/kg body weight (set III and set IV) NEXAMITE™ A56 (PETA).

 

Normal gain in body weight was observed in all the rats.

 

All the rats at termination were subjected to gross pathological examination. External examination and visceral examination of the terminally sacrificed rats did not reveal any lesion of pathological significance. In the absence of any pathological lesion in terminally sacrificed rats, it is concluded that the test item did not produce any treatment related effect at the dose level used in the present study.

 

"The acute oral median lethal dose (LD50 value) of NEXAMITE™ A56 (PET A) in Wistar rats was found to be >2000 mg/kg body weight" and then follow with "The acute median lethal dose (LD50 cut-off value) of NEXAMITE TM A56 (PETA) in Wistar rats was found to be 5000 mg/kg body weight".

Based on the results of this study, an indication of the classification for NEXAMITE™ A56 (PETA) is as follows:

Globally Harmonized System of Classification and Labelling of Chemicals (GHS 2013): Category 5 or Unclassified