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Administrative data

Description of key information

Oral: LD50 > 2000 mg/kg bw (limit tes), OECD 423, EU Method B.1 tris, Kiss (2012).
Dermal: LD50 > 2000 mg/kg bw (limit test), OECD 402, EU Method B.3, EPA OPPTS 870.1200, JMAFF 2-1-2, Zelenák (2011).

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:
27 September 2011 to 12 October 2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
other: JMAFF 12 Nousan 8147 (2000)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: CRL:(WI)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 9 weeks old.
- Weight at study initiation: 238 – 265 g.
- Fasting period before study: Yes, animals were fasted the day before dosing, food being returned 3 hours after treatment.
- Housing: Animals were housed in groups of 3 in Type II polypropylene/polycarbonate cages.
- Diet: Complete feed for rats and mice, ad libitum.
- Water: Municipal tap water, ad libitum.
- Acclimation period: At least 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 15-20 air exchanges/hour.
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 06:00 to 18:00 hours.
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
DOSAGE PREPARATION: Test material was freshly formulated at a concentration of 200 mg/mL in the vehicle on the day of administration. The formulation container was stirred continuously up to finishing the treatment.

CLASS METHOD
- Rationale for the selection of the starting dose: The initial dose level was selected by the study director to be that which was most likely to produce mortality in some of the dosed animals.

ADMINISTRATION: Group 1 was dosed first at 2000 mg/kg bw . The results were then confirmed by dosing Group 2 in the same manner.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
Six females per dose, tested in two groups of 3 animals.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing:
> Clinical observations were performed at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and then daily until day 14. Observations included assessment of the skin, fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
> Bodyweights were measured on Days -1, 0, 7 and 14 prior to necropsy.
- Necropsy of survivors performed: yes
- Other examinations performed: After examination of the external appearance, the cranial, thoracic and the abdominal cavities were opened and the organs and the tissues were observed. Macroscopic abnormalities were recorded.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed in either Group 1 or 2.
Clinical signs:
Liquid faeces was observed in all animals, treated at a dose level of 2000 mg/kg bw, on the day of dosing. All animals fully recovered and were symptom free from 6 hours after the treatment until the end of the observation period.
Body weight:
No treatment related effects were observed.
Gross pathology:
There was no evidence of treatment related findings at necropsy. Pelvic dilatation of the right kidney was incidentally observed in one animal.

Table1: Clinical Observations

Group

Animal No.

Observations

Observation Days

Frequency

0

1 - 14

30 min

1 h

2 hrs

3 hrs

4 hrs

6 hrs

1

8861

Symptom Free

+

+

+

-

+

+

+

19/20

Faeces liquid

-

-

-

1

-

-

-

1/20

8862

Symptom Free

+

+

+

-

+

+

+

19/20

Faeces liquid

-

-

-

1

-

-

-

1/20

8863

Symptom Free

+

+

+

-

-

+

+

18/20

Faeces liquid

-

-

-

1

1

-

-

2/20

2

8864

Symptom Free

+

+

+

-

+

+

+

19/20

Faeces liquid

-

-

-

1

-

-

-

1/20

8865

Symptom Free

+

+

+

-

+

+

+

19/20

Faeces liquid

-

-

-

1

-

-

-

1/20

8866

Symptom Free

+

+

+

-

+

+

+

19/20

Faeces liquid

-

-

-

1

-

-

-

1/20

Frequency of observations = number of occurrence of observations / total number of observations.

 

Table 2: Bodyweights (g)

Group No.

Animal No.

Body weight (g) on Days

Weight Gain (g)

-1

0

7

14

-1 - 0

0 - 7

7 -14

-1 - 14

1

8861

281

265

296

301

-16

31

5

20

8862

273

256

288

296

-17

32

8

23

8863

269

251

290

304

-18

39

14

35

2

8864

266

249

281

290

-17

32

9

24

8865

257

239

267

277

-18

28

10

20

8866

255

238

257

274

-17

19

17

19

Mean:

266.8

249.7

279.8

290.3

-17.2

30.2

10.5

23.5

Standard Deviation:

9.8

10.3

15.0

12.5

0.8

6.6

4.3

6.0

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study, no signs of acute toxicity were observed, and it can be concluded that the acute oral LD50 is greater than 2000 mg/kg bw.
Executive summary:

The acute oral toxicity of the test material was assessed in study performed under GLP conditions and in line with OECD 423 and EU Method B.1 tris according to the acute toxic class method. Female CRL:(WI) rats were treated with the test material at a dose level of 2000 mg/kg bw in two groups. Initially, three females (Group 1) were treated at a dose level of 2000 mg/kg bw. As no mortality was observed, a confirmatory group (Group 2) was treated at the same dose level.

Under the conditions of the study no mortality was observed in either group. Animals showed normal weight gain. Liquid faeces were observed in all animals on the day of dosing; all animals had fully recovered, and were symptom free, from 6 hours after the treatment until the end of the observation period. There was no evidence of treatment related findings at necropsy. Pelvic dilatation of the right kidney was incidentally observed in one animal. It can therefore be concluded that the acute oral LD50 of the test material is in excess of 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The quality of the dataset is considered to be high.

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:
19 October 2011 to 02 November 2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: JMAFF 2-1-2
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: Young adults.
- Weight at study initiation: 227 - 254 g.
- Housing: Individually in polypropylene/polycarbonate cages.
- Diet: Complete feed for rats and mice, ad libitum.
- Water: Municipal tap water, ad libitum.
- Acclimation period: 6 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30-70%
- Air changes (per hr): 15-20 air charges per hour.
- Photoperiod (hrs dark / hrs light): 12 hours light, from 06:00 to 18:0 hours.

IN-LIFE DATES: From: 19 October 2011 To: 02 November 2011
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: The back of each animal.
- % coverage: The test material was applied to the shaved skin. the test material was moistened with water and distributed as evenly as possible over an area of approximately 10 % of the total body area.
- Type of wrap if used: A gauze pad was placed over the applied test material. The gauze pad was fixed with a hypoallergenic plaster on the skin of the animals. The entire trunk of the animal was then wrapped with semi occlusive plastic wrap.

REMOVAL OF TEST SUBSTANCE
- Washing: After exposure the treated area of skin was washed with water at body temperature.
- Time after start of exposure: 24 hours.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 per sex per dose.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing:
> Clinical Observations: Performed on all animals at 1 and 5 hours after dosing and daily for 14 days thereafter. Observations included the skin and fur, eyes and mucous membranes, the respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
> Bodyweights: Measured prior to dosing on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: Yes. After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed. All macroscopic changes were recorded.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
No clinical signs were observed after the treatment with the test material or during the 14-day observation period. No local signs were observed after the treatment with the test material or during the 14-day observation period.
Body weight:
The body weight and body weight gain of treated animals did not show any test material related effects. Body weights and weight gain can be seen in Tables 1 and 2.
Gross pathology:
There was no evidence of the observations at a dose level of 2000 mg/kg bw at necropsy.
Other findings:
No local dermal signs were observed after treatment with the test material.

Table 1: Male Bodyweight Data (g)

Animal No.

Body weight (g) Days

Body Weight Gain (g)

0

7

14

0-7

7-14

0-14

9407

243

297

340

54

43

97

9408

254

307

351

53

44

97

9409

245

299

348

54

49

103

9410

243

291

339

48

48

96

9411

237

289

340

52

51

103

Mean

244.4

296.6

343.6

52.2

47.0

99.2

Standard Deviation

6.1

7.1

5.5

2.5

3.4

3.5

 

Table 2: Female Bodyweight Data (g)

Animal No.

Body weight (g) Days

Body Weight Gain (g)

0

7

14

0-7

7-14

0-14

9412

229

240

252

11

12

23

9413

237

247

280

10

33

43

9414

227

238

252

11

14

25

9415

237

263

263

26

0

26

9416

245

257

269

12

12

24

Mean

235.0

249.0

263.2

14.0

14.2

28.2

Standard Deviation

7.2

10.8

11.9

6.7

11.9

8.3

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study, no signs of systemic or local toxic effects were observed during the 14 day observation period. The acute dermal LD50 of the test material was determined to be greater than 2000 mg/kg bw in both male and female rats.
Executive summary:

The acute dermal toxicity of the test material was assessed in study performed under GLP conditions and in line with OECD 402, EU Method B.3, EPA OPPTS 870.1200 and JMAFF 2-1-2. A limit test was carried out at 2000 mg/kg bw in both sexes (5 rats/sex). The test material was applied as supplied, moistened with water, as a single dermal 24-hour exposure followed by a 14-day observation period. After the exposure period the residual test material was removed by washing the area with water. Clinical observations were performed on all animals at 1 and 5 hours after dosing and daily for 14 days thereafter. Body weight was measured prior to dosing on Day 0 and on Days 7 and 14. Rats were euthanized and a gross macroscopic examination performed at the end of the 2-week observation period (Day 14).

Under the conditions of the study no mortality was observed at 2000 mg/kg bw. Bodyweights showed normal weight gain. No clinical signs of systemic or local toxic effects were observed during the 14 day observation period. Additionally there was no evidence of treatment related findings at necropsy. Accordingly the acute dermal LD50 of the test material was determined to be in excess of 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The quality of the dataset is considered to be high.

Additional information

Oral Toxicity

In the key study (Kiss, 2011) the acute oral toxicity of the test material was assessed under GLP conditions and in line with OECD 423 and EU Method B.1 tris according to the acute toxic class method. Female CRL:(WI) rats were treated with the test material at a dose level of 2000 mg/kg bw in two groups. Initially, three females (Group 1) were treated at a dose level of 2000 mg/kg bw. As no mortality was observed, a confirmatory group (Group 2) was treated at the same dose level.

Under the conditions of the study no mortality was observed in either group. Animals showed normal weight gain. Liquid faeces were observed in all animals on the day of dosing; all animals had fully recovered, and were symptom free, from 6 hours after the treatment until the end of the observation period. There was no evidence of treatment related findings at necropsy. Pelvic dilatation of the right kidney was incidentally observed in one animal. It can therefore be concluded that the acute oral LD50 of the test material is in excess of 2000 mg/kg bw.

Inhalation Toxicity

In accordance with point 8.5.2, Column 2 (Specific rules for adaptation from Column 1), Annex VIII of Regulation (EC) No. 1907/2006, an acute inhalation study does not need to be performed as the substance has a low vapour pressure (< 0.0015 Pa at 25 °C) and the use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur. The acute toxicity endpoint has been addressed by assessing toxicity via the oral and dermal routes, which are more appropriate when considering the properties of this substance.

Dermal Toxicity

In the key study (Zelenák, 2011) the acute dermal toxicity of the test material was assessed in study performed under GLP conditions and in line with OECD 402, EU Method B.3, EPA OPPTS 870.1200 and JMAFF 2-1-2. A limit test was carried out at 2000 mg/kg bw in both sexes (5 rats/sex). The test material was applied as supplied, moistened with water, as a single dermal 24-hour exposure followed by a 14-day observation period. After the exposure period the residual test material was removed by washing the area with water. Clinical observations were performed on all animals at 1 and 5 hours after dosing and daily for 14 days thereafter. Body weight was measured prior to dosing on Day 0 and on Days 7 and 14. Rats were euthanized and a gross macroscopic examination performed at the end of the 2-week observation period (Day 14).

Under the conditions of the study no mortality was observed at 2000 mg/kg bw. Bodyweights showed normal weight gain. No clinical signs of systemic or local toxic effects were observed during the 14 day observation period. Additionally there was no evidence of treatment related findings at necropsy. Accordingly the acute dermal LD50 of the test material was determined to be in excess of 2000 mg/kg bw.

 


Justification for selection of acute toxicity – oral endpoint
This study was performed under GLP conditions and in accordance with standardised guidelines. It was assigned a reliability score of 1 in accordance with the criteria outlined in Klimisch (1997). It was therefore considered suitable to be the key study for this endpoint.

Justification for selection of acute toxicity – inhalation endpoint
A data waiver has been submitted to address this endpoint.

Justification for selection of acute toxicity – dermal endpoint
This study was performed under GLP conditions and in accordance with standardised guidelines. It was assigned a reliability score of 1 in accordance with the criteria outlined in Klimisch (1997). It was therefore considered suitable to be the key study for this endpoint.

Justification for classification or non-classification

Acute Oral Toxicity:

According to the criteria outlined in Regulation (EC) No. 1272/2008, the test material does not meet the criteria for classification for acute oral toxicity.

Acute Dermal Toxicity:

According to the criteria outlined in Regulation (EC) No. 1272/2008, the test material does not meet the criteria for classification for acute dermal toxicity.