Registration Dossier

Administrative data

Description of key information

Oral (OECD 423), rat, LD50 > 2000 mg/kg bw

Dermal (OECD 402), rat, LD50 > 2000 mg/kg bw

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:
10 - 30 Aug 2017
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)
Version / remarks:
17 December 2001
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Slovak National Accreditation Service, Karloveska 63, 840 00 Bratislava 4, Slovak Republic
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dobrá Voda, Slovak Republic
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 180 - 205 g
- Fasting period before study: over night and 3 - 4 h post-administration
- Housing: 3 animals per cage
- Bedding: Lignocel S3/4, Lufa - ITL GmbH, Germany
- Diet: ssniff (Spezialdiäten GmbH, Germany), provided at recommended doses each day approximately at the same time
- Water: tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23.18 ± 0.45
- Humidity (%): 55.40 ± 3
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: To: 15 - 30 August 2017
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
VEHICLE
- Justification for choice of vehicle: Olive oil is a standard vehicle according to OECD 423
- Lot/batch no.: L63417
- Expiry date: 06/2018
- Manufacturer: Oleificio Luca, Italy
- Storage temperature (°C): 20 ± 5

CLASS METHOD (if applicable):
- Rationale for the selection of the starting dose: Available information indicated that the test item is likely to be non-toxic with regard to acute toxicity. Hence, the limit dose of 2000 mg/kg body weight was used as a starting dose.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: immediately after dosing, 0.5, 1, 2 and 4 h after administration
- Frequency of weighing: immediately prior to dosing and weekly thereafter
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross necropsy
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 is cut-off according to OECD 423
Mortality:
All (6/6 females) animals survived the limit dose of 2000 mg/kg body weight.
Clinical signs:
During the observation period, no animals displayed signs of intoxication, change of health, or any other adverse reaction.
Body weight:
The body weight of all animals increased during the study. No body weight losses were observed between the first and second week after administration.
Gross pathology:
During necropsy, no macroscopic findings were observed.

Table 1: Body Weights and Body Weight Differences

 

 

Sex

 

Dose

 

ID

Body Weight (g)

Body Weight Difference (g)

Initial

Week 1

Week 2

Week 1 - Initial

Week 2 - Initial

Week 2 - Week 1

 

 

 

 

 

 

2000 mg/kg

1

205

210

215

5

10

5

2

185

190

200

5

15

10

3

190

190

200

0

10

10

4

190

200

205

10

15

5

5

190

200

210

10

20

10

6

180

210

220

30

40

10

Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Conclusions:
The LD50 of the test item has been determined to be greater than 2000 mg/kg body weight after single oral administration to female Wistar rats.

Based on 'Annex 2d Test Procedure with a Starting Dose of 2000 mg/kg body weight' of OECD 423 it can also be concluded that the LD50 cut-off value is equal to or greater than 5000 mg/kg body weight after single oral administration to Wistar rats.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No. 1907/2006.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 - 31 Aug 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
24 February 1987
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 434 (Acute Dermal Toxicity - Fixed Dose Procedure)
Version / remarks:
Proposal for a New Draft Guideline, May 2004
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Slovak National Accreditation Service, Karloveska 63, 840 00 Bratislava 4, Slovak Republic
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dobrá Voda, Slovak Republic
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8 - 12 weeks
- Weight at study initiation: 195 - 200 g (f), 220 - 230 g (m)
- Housing: 3 animals per cage
- Bedding: Lignocel S3/4, Lufa - ITL GmbH, Germany
- Diet: ssniff (Spezialdiäten GmbH, Germany), provided at recommended doses each day approximately at the same time
- Water: tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23.18 ± 0.45
- Humidity (%): 55.40 ± 3
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: To: 15 - 31 August 2017
Type of coverage:
semiocclusive
Vehicle:
olive oil
Details on dermal exposure:
TEST SITE
- Area of exposure: clipped and shaved dorsal area of trunk
- % coverage: approx. 10% of total body surface area
- Type of wrap if used: semi-occlusive dressing with non-irritating tape

REMOVAL OF TEST SUBSTANCE
- Washing: residual test item was removed with lukewarm water
- Time after start of exposure: 24 h

VEHICLE
- Justification for choice of vehicle: Olive oil is a standard vehicle according to test guideline
- Lot/batch no.: L63417
- Expiry date: 06/2018
- Manufacturer: Oleificio Luca, Italy
- Storage temperature (°C): 20 ± 5

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Available information indicated that the test item is likely to be non-toxic with regard to acute toxicity. Hence, a limit dose of 2000 mg/kg body weight was used as a starting dose.
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: immediately after dosing, 0.5, 1, 2 and 4 h after administration, daily for the next 14 days
- Frequency of weighing: immediately prior to dosing and weekly thereafter
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross necropsy
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All 5/5 females and 5/5 males at the limit dose of 2000 mg/kg body weight survived.
Clinical signs:
Animals lived through observation period without signs of intoxication. Neither change of health nor negative reactions were observed.
Body weight:
The body weight of all females increased during the study, stagnation of body weight in two females between the first and second week was noticed.
Gross pathology:
All animals (5 females and 5 males) were necropsied. During necropsy, no macroscopic changes were noticed.

  Table 1: Body Weights and Body Weight Differences

 

Sex

Dose

ID

Body Weight (g)

Body Weight Difference (g)

Initial

Week 1

Week 2

Week 1 - Initial

Week 2 - Initial

Week 2 - Week 1

 

 

 

 

2000 mg/kg

1

195

205

210

10

15

5

2

200

200

225

0

25

25

3

200

200

215

0

15

15

4

200

220

220

20

20

0

5

195

210

210

15

15

0

 

 

 

 

2000 mg/kg

6

230

250

275

20

45

25

7

230

250

270

20

40

20

8

230

235

250

5

20

15

9

230

245

260

15

30

15

10

220

245

260

25

40

15

Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Conclusions:
The LD50 of the test item has been determined to be greater than 2000 mg/kg body weight after single dermal administration to male and female Wistar rats.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No. 1907/2006.

Additional information

Acute toxicity: oral

The acute toxicity via the oral route was investigated in rats in a study performed according to OECD 423 and in compliance with GLP (hameln, 2017a). A group of 6 female rats was treated with the limit dose of 2000 mg/kg bw of the test substance via oral gavage. The observation period following administration was 14 days. During the study period, no animal died. No clinical signs of toxicity were observed in the surviving animals. All surviving animals showed normal body weight gain. Necropsy did not reveal any macroscopic findings. Thus, the oral LD50 value for female rats was considered to be greater than 2000 mg/kg bw.

Acute toxicity: inhalation

No data on acute inhalation toxicity is required as data on two other routes of exposure, i.e. oral and dermal, are provided.

Acute toxicity: dermal

The acute dermal toxicity was evaluated in rats in accordance with OECD 402 under GLP conditions (hameln, 2017b). Groups of 10 rats (5 males and 5 females) were treated with the test substance dissolved in olive oil at the limit dose of 2000 mg/kg bw under semi-occlusive conditions for 24 h. The animals were observed for a period of 14 days following administration. During the study period, no mortality and no clinical signs of toxicity occurred in any animal. No substance-related findings during necropsy were observed in any animal. No effects on body weight gain were observed with the exception of two females that showed stagnation of body weight between the first and second week. Thus, the dermal LD50 for male and female rats was considered to be greater than the tested limit dose of 2000 mg/kg bw.

Conclusion

Taken together, the available data on oral and dermal acute toxicity do not indicate any relevant acute toxicity.

Justification for classification or non-classification

The available data on acute oral and acute dermal toxicity of the registered substance do not meet the criteria for classification according to Regulation (EC) No. 1272/2008 (CLP) and are, therefore, conclusive but not sufficient for classification. Due to the lacking of suitable data, no assessment with respect to acute inhalation toxicity is possible.