Registration Dossier

Administrative data

Description of key information

The acute oral toxicity of the registration substance was investigated according to the OECD Gudieline 423. Six female rats were treated once with the registration substance at dose of 2000 mg/kg bw. No effect was observed. The LD50 of the registration substance was determined to be higher than 2000 mg/kg bw. No classification is warranted.

The acute dermal toxicity of the registration substance was investigated according to the OECD Gudieline 402. Five female and five male rats were treated once with the registration substance at dose of 2000 mg/kg bw. No effect was observed. The LD50 of the registration substance was determined to be higher than 2000 mg/kg bw. No classification is warranted.

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:
24/05/2016 - 18/07/2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Specific details on test material used for the study:
The test material corresponded to the approximately 45% of the registration substance. The given dose refers to the amount of the registration substance.
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Sainath Agencies, Bapujinagar, Musheerabad, Hyderabad 500 020

- Age at study initiation: 8 - 9 Weeks

- Weight at study initiation: 189.4 to 209.2 g

- Housing:Animals were housed individually in standard polysulfone cages (Size: approximately L 425 x B 266 x H 185 mm), with stainless steel top grill having facilities for pelleted food and drinking water in polycarbonate bottle. Additionally, polycarbonate rat huts were placed inside the cage as an enrichment object and were changed along with the cage at least once a week. Bedding: steam sterilized corn cob was used and changed once a week along with the cage.

- Diet (ad libitum):Hypro Rat & Mice Pellet Feed, manufactured by Pranav Agro Industries Ltd., Pune 411 030, Maharashtra, India, was provided to animals.

- Water (ad libitum):Deep bore-well water passed through activated charcoal filter and exposed to UV rays in Aquaguard on-line water filter-cum-purifier manufactured by Eureka Forbes Ltd, Mumbai 400 001, India was provided to animals in polycarbonate bottles with stainless steel sipper tubes.

- Acclimation period: After physical examination, the animals were acclimatized for five to seven days before treatment. Animals were observed once daily during acclimatization period. Females were nulliparous and non-pregnant.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 to 23°C
- Humidity (%):65 to 67%
- Air changes (per hr):12.9 to 13.1 air changes/hour
- Photoperiod (hrs dark / hrs light):12 hours light and 12 hours dark cycle

IN-LIFE DATES: From: 27 May 2016 To: 17 June 2016
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Remarks:
The dose level of 2000 mg/kg refers to the active ingredient, the registration substance
Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED:2000 mg/kg

DOSAGE PREPARATION : The undiluted test item as supplied by the sponsor was administered based on the density of the test item i.e., 1.05 g/cm3 at 20 ºC (as per TIDS provided by the sponsor) and the dose volume was 4.52 mL/kg body weight, i.e., [1.90 (dose volume as per density) x 2.38 (correction factor)] to attain the dose of 2000 mg/kg body weight (G1-FTS) as oral gavage to overnight fasted (16 to 18 hours) 3 female rats.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: As per the Material Safety Data Sheet provided by the Sponsor, the acute oral LD50 rat is > 2000 mg/kg body weight. Hence the test was started as per Annex 2d of the OECD 423 test guideline. The starting dose was 2000 mg/kg body weight (G1-FTS). No test item-related mortality was observed; hence test was continued with same dose with three additional female rats second step (G1-STS). The subsequent dosing was done at approximately 48 hours after the first dosing
Doses:
Doses: 2000 mg/kg body weight (first treatment step and second treatment step)
No. of animals per sex per dose:
3 females/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed five times on test day 1 (day of administration) i.e. at 30 minutes and four times at hourly intervals and once daily during days 2 to 15 post administration. The body weights were recorded on test day 1 (pre-administration), day 8 (7 days post administration) and day 15 (14 days post administration).

- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology.
Preliminary study:
Body weights, body weight changes and pre-terminal deaths are presented in Table 1.
Individual clinical signs and necropsy findings are presented in Table 2.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
No mortality
Clinical signs:
no clinical signs
Body weight:
Rats increased throughout the observation period
Gross pathology:
No abnormality detected at necropsy
Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral toxicity of the registration substance was investigated according to the OECD Gudieline 423. Six female rats were treated once with the registration substance at dose of 2000 mg/kg bw. No effect was observed. The LD50 of the registration substance was determined to be higher than 2000 mg/kg bw. No classification is warranted.
Executive summary:

The acute oral toxicity of the registration substance was investigated according to the OECD Gudieline 423. Six female rats were treated once with the registration substance at dose of 2000 mg/kg bw. No effect was observed. The LD50 of the registration substance was determined to be higher than 2000 mg/kg bw. No classification is warranted.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
One valid recently performed 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:
27/06/2016-19/07/2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
The test material corresponded to the approximately 45% of the registration substance. The given dose refers to the amount of the registration substance.
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Sainath Agencies, Bapujinagar, Musheerabad, Hyderabad 500 020

- Age at study initiation: 8 - 9 Weeks

- Weight at study initiation: Females: 211.6 to 229.2 g & Males: 235.8 to 266.8 g


- Housing:Animals were housed individually in standard polysulfone cages (Size: approximately L 425 x B 266 x H 185 mm), with stainless steel top grill having facilities for pelleted food and drinking water in polycarbonate bottle. Additionally, polycarbonate rat huts were placed inside the cage as an enrichment object and were changed along with the cage at least once a week. Bedding: steam sterilized corn cob was used and changed once a week along with the cage.

- Diet (ad libitum):Hypro Rat & Mice Pellet Feed, manufactured by Pranav Agro Industries Ltd., Pune 411 030, Maharashtra, India, was provided to animals.

- Water (ad libitum):Deep bore-well water passed through activated charcoal filter and exposed to UV rays in Aquaguard on-line water filter-cum-purifier manufactured by Eureka Forbes Ltd, Mumbai 400 001, India was provided to animals in polycarbonate bottles with stainless steel sipper tubes.

- Acclimation period: After physical examination, the animals were acclimatized for five days for females and seven days for males before treatment. Animals were observed once daily during acclimatization period. Females were nulliparous and non-pregnant.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 to 23°C
- Humidity (%):65 to 67%
- Air changes (per hr):12.9 to 13.1 air changes/hour
- Photoperiod (hrs dark / hrs light):12 hours light and 12 hours dark cycle

IN-LIFE DATES: From: 27 May 2016 To: 17 June 2016
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Remarks:
The applied dose level refers to the active ingredient, the registration substance.
Details on dermal exposure:
TEST SITE
- Area of exposure: approximately 10 x 8 cm
- % coverage: 10%
- Type of wrap if used: Adhesive tape

REMOVAL OF TEST SUBSTANCE
- Washing: with water
- Time after start of exposure: after 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Refer Table 1.
Based on the individual body weight, the undiluted test item at the dose of 2000 mg/kg body weight and dose volume was 4.52 mL/kg body weight
[1.90 mL/kg (dose volume as per density) x 2.38 (correction factor)] was calculated based on the density of the test item i.e., 1.05 g/cm3 (as per TIDS provided by the sponsor). For example, for rat Rm4741, the body weight was 222.4 g, the dose volume administered was 0.87 mL [i.e., body weight of rat 222.4 g x dose volume 4.52 mL/kg / 1000 = 222.4 x 4.52 / 1000 = 1.005 mL rounded off to 1.01 mL]

- Concentration (if solution): Undiluted test item
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 per sex
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed for clinical signs and pre-terminal deaths (mortality) four times (at hourly intervals after application) during day 1 and twice daily on day 2 and 3 and once daily during days 4 to 15. Individual body weights of animals were recorded on test days 1 (Pre-application), 8 (7 days post application), and 15 (14 days post application).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology.
Preliminary study:
Body weights, body weight changes and pre-terminal deaths are presented in Tables 1.
Individual clinical signs of toxicity and necropsy findings are presented in Table 2.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No Mortality
Clinical signs:
Refer Table 2.
There were no clinical signs observed during the study. However, in females, the skin reactions of erythema, edema, scale formation, peeling/desquamation were observed during days 3 to 10 post dose application. The rat numbers Rm4741 and Rm4745 were normal from day 7 onwards, Rm4742 was normal from day 8 onwards, Rm4743 was normal from day 10 onwards and rat Rm4744 were normal from day 11 onwards.
Body weight:
All rats gained body weight throughout the observation period when compared to their initial weight.
Gross pathology:
No abnormalities detected.

Table 1. Individual Body Weight, Body Weight Changes and Pre-Terminal Deaths

Group and

Dose

(mg/kg

body weight)

Rat

No.

S

e

x

Body weight (g)

No. dead /

No. tested

Pre- terminal deaths (%)

Day 1

Initial

(at treatment)

8th  

day

Weight change

(day 8 – Initial)

15th

 day

Weight change

(day 15 – Initial)

 

 

 

 

 

 

 

G1

2000

(4.52 mL/kg)*

 

 

Rm4741

F

222.4

231.6

9.2

239.8

17.4

 

 

 

 

 

 

 

 

0/10

 

 

 

 

 

 

 

 

0

Rm4742

F

229.2

242.3

13.1

247.6

18.4

Rm4743

F

224.6

230.3

5.7

236.9

12.3

Rm4744

F

211.6

218.9

7.3

222.7

11.1

Rm4745

F

218.2

229.5

11.3

238.5

20.3

Rm4746

M

235.8

247.2

11.4

259.4

23.6

Rm4747

M

240.3

251.9

11.6

263.1

22.8

Rm4748

M

266.8

276.9

10.1

287.5

20.7

Rm4749

M

262.2

277.1

14.9

286.5

24.3

Rm4750

M

255.8

272.7

16.9

281.8

26.0

F : Female         M: Male   

 

*: Calculated based on the density of the test item: 1.05 g/cm3(as per TIDS provided by the sponsor), i.e., 1.90 mL/kg (dose volume as per density) x 2.38 (correction factor).

Table 2.        Individual Clinical / Toxic Signs and Necropsy Findings

Rat

No.

Sex

Body weight initial

(g)

Volume

 applied

(mL)

 

Day of Observations

Day 1

2

3

4

5

6

7

1

hour

2

hours

3

hours

4

hours

 

 

 

 

 

 

 

AM

PM

AM

PM

Rm4741

F

222.4

1.01

N

N

N

N

N

N

124(4)

124(4)

124(1)

124(2)

124(2)

N

Rm4742

F

229.2

1.04

N

N

N

N

N

N

124(4)

124(4)

124(1)

124(1)

124(2)

124(2)

Rm4743

F

224.6

1.02

N

N

N

N

N

N

124(4)

124(5)

124(4)

124(5)

124(4)

124(1)

124(1)

124(2)

Rm4744

F

211.6

0.96

N

N

N

N

N

N

124(4)

124(5)

124(4)

124(5)

124(4)

124(1)

124(1)

124(2)

Rm4745

F

218.2

0.99

N

N

N

N

N

N

124(4)

124(4)

124(1)

124(2)

124(2)

N

Rm4746

M

235.8

1.07

N

N

N

N

N

N

N

N

N

N

N

N

Rm4747

M

240.3

1.09

N

N

N

N

N

N

N

N

N

N

N

N

Rm4748

M

266.8

1.21

N

N

N

N

N

N

N

N

N

N

N

N

Rm4749

M

262.2

1.19

N

N

N

N

N

N

N

N

N

N

N

N

Rm4750

M

255.8

1.16

N

N

N

N

N

N

N

N

N

N

N

N

F: Female            M: Male               NAD: No Abnormality Detected      N:                      AM: Ante Meridian      PM: Post    

124(1): Scale formation           124(2): peeling / desquamation              124(4): Erythema           124(5): Edema

 

*: Calculated based on the density of the test item: 1.05 g/cm3(as per TIDS provided by the sponsor), i.e., 1.90 mL/kg (dose volume as per density) x 2.38 (correction factor).

Table 2 contd. Individual Clinical / Toxic Signs and Necropsy Findings

 Group: G1                                                                Dose: 2000 mg/kg body weight (4.52 mL/kg *)

Rat

No.

Sex

Body weight initial

(g)

Volume

 applied

(mL)

 

Days of observation

Necropsy

Findings

 

8

9

10

11

12

13

14

15

 

 

 

 

 

 

 

 

 

Rm4741

F

222.4

1.01

N

N

N

N

N

N

N

N

NAD

 

Rm4742

F

229.2

1.04

N

N

N

N

N

N

N

N

NAD

 

Rm4743

F

224.6

1.02

124(2)

124(2)

N

N

N

N

N

N

NAD

 

Rm4744

F

211.6

0.96

124(2)

124(2)

124(2)

N

N

N

N

N

NAD

 

Rm4745

F

218.2

0.99

N

N

N

N

N

N

N

N

NAD

 

Rm4746

M

235.8

1.07

N

N

N

N

N

N

N

N

NAD

 

Rm4747

M

240.3

1.09

N

N

N

N

N

N

N

N

NAD

 

Rm4748

M

266.8

1.21

N

N

N

N

N

N

N

N

NAD

 

Rm4749

M

262.2

1.19

N

N

N

N

N

N

N

N

NAD

 

Rm4750

M

255.8

1.16

N

N

N

N

N

N

N

N

NAD

 

 F: Female            M: Male               NAD: No Abnormality Detected      N:                      AM: Ante    

  PM: Post Meridian        124(1): Scale formation           124(2): peeling/desquamation          124(4): Erythema           124(5): Edema

 

*: Calculated based on the density of the test item: 1.05 g/cm3(as per TIDS provided by the sponsor), i.e., 1.90 mL/kg (dose volume as per density) x

    2.38 (correction factor).

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results of the present study, the LD50 of the registration substance is determined to be higher than 2000 mg/kg bw.
Executive summary:

The acute dermal toxicity of the registration substance was investigated according to the OECD Gudieline 402. Five female and five male rats were treated once with the registration substance at dose of 2000 mg/kg bw. No effect was observed. The LD50 of the registration substance was determined to be higher than 2000 mg/kg bw. No classification is warranted.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
One valid recently performed study available.

Additional information

Justification for classification or non-classification

No classification is warranted for the endpoints acute toxicity based on the results obtained in the oral acute toxicity study (OECD 423) and dermal acute toxicity study (OECD 402).