Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Acute oral toxicity:

Key study: OECD 423 and EU method B.1 tris. Klimish score 1. GLP study. The LD50 of the test item is higher than 2000 mg/kg body weight by oral route in the rat. The LD50 cut-off of the test item may be considered to be higher than 5000 mg/kg body weight by oral route in the rat.

Acute dermal toxicity:

Key study: OECD 402 and EU method B.3. Klimish score 1. GLP study. The dermal LD50 of the test item in rats is greater than 2000 mg/kg bw.

Acute toxicity: inhalation.

Data waiving (scientifically not necessary / other information available): In accordance with column 2 of REACH Annex VIII, the study does not need to be conducted because exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols or droplets of an inhalable size.

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:
January 3, 2017 - January 18, 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature

Species:
rat
Strain:
Sprague-Dawley
Remarks:
SPF Caw
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: JANVIER LABS (53940 Legenest St. Isle - France)
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8 weeks old
- Weight at study initiation: 197.3 ± 9.4 g
- Fasting period before study: overnight
- Housing: Groups of three in solid-bottomed clear polycarbonate cages with a stainless steel mesh lid. Each cage contains sawdust bedding which was changed at least 2 times a week. Each cage was installed in conventional air conditioned animal husbandry.
- Diet (e.g. ad libitum): Foodstuff (ENVIGO -2016) ad libitum
- Water (e.g. ad libitum): Tap-water from public distribution system ad libitum. Microbiological and chemical analyses of the water were carried out once every six months by Bureau Veritas- Eurofins (France)
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19ºC - 25ºC. A temperature lower than 19ºC was registered on 3 and 7 of January 2017. The minimum value measured was 22%.
- Humidity (%): 30% - 70%. A relative humidity lower than 30% was registered on 3, 4, 5, 6, 7, 8, 17 and 18 of January 2017. The minimum value measured was 22%.
- Air changes (per hr): 10 changes/hour
- Photoperiod (hrs dark / hrs light): 12 h light (7 - 19 h) / 12 h darkness

IN-LIFE DATES: From: 3 January 2017 To: 18 January 2017
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 0.2 g/mL
- Amount of vehicle (if gavage): 10 mL/kg body weight
- Justification for choice of vehicle: DMSO produced the most suitable formulation at the requested concentration.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/Kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Without preliminary information. The selected starting dose is 2000 mg/kg body weight.
Doses:
2000 mg/kg
No. of animals per sex per dose:
6
Control animals:
yes
Remarks:
Study No. TAO423-2016-004 (see "Other information on results").
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Systemic observations at 30 min, 1h, 3h, 4h, 24h, 48h after adminitrationand daily during 14 days. Weighing: on day Day 0 (just before administering the test item) then on Day 2, Day 7, and Day 14.
- Necropsy of survivors performed: yes. At termination, macroscopic observation was observed. Macroscopic observations were entered on individual autopsy sheets. Only those organs likely to be modified in cases of acute toxicity were examined. Parameters examined: Oesophagus, Stomach, Duodenum, Jejunum, Ileon, Caecum, Colon, Rectum, Spleen, Liver, Thymus, Trachea, Lungs, Heart, Kidneys, Urinary Bladder, Ovaries, Uterus, Treatment Area, Adrenals and Pancreas.
- Other examinations performed:
Clinical signs: Spontaneous activity, Preyer's reflex (noise), Respiratory rate, Convulsions, Tremors, Body temperature, Muscle tone, Palpebral opening, Pupil appearance, Salivation, Lachrymation, Righting reflex, Back hair appearance, Mortality.
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study.
Clinical signs:
No clinical signs related to the administration of the test item were observed during the study.
Body weight:
The body weight evolution of the animals remained normal during the study.
Gross pathology:
The macroscopic examination of the animals at the end of the study did not reveal treatment related changes.

Table 1. Test item at 2000 mg/kg bw. Body weight and weight gain in grams.

FEMALES

D0

D2

D2-D0

D7

D7-D0

D14

D14-D0

Rf 0839

190

212

22

237

47

251

61

Rf0840

199

225

26

243

44

259

60

Rf 0841

182

202

20

222

40

244

62

Rf 0854

204

221

17

245

41

260

56

Rf 0855

206

217

11

239

33

262

56

Rf 0856

203

224

21

243

40

269

66

MEAN

197.3

216.8

19.5

238.2

40.8

257.5

60.2

Standard deviation

9.4

8.7

5.1

8.4

4.7

8.8

3.8

GENERAL APPEARANCE BEFORE AUTOPSY: Normal

Observations: Nothing to report.

Current control Study:

The study identified No. TAO423 -2016 -004 was performed to assess the comportament of the strain of rat used at the laboratory in the environment and to give additional historical data. The method was designed to meet the requirements of the following: OECD Guideline No. 423 (December 17th, 2001) and Method B1 tris of Council regulation No. 440/2008.

Test item : Distilled water

Study dates: 20 September 2016 to 04 October 2016

Results:

- Clinical examinations: Nothing to report. Animal normal (3/3)

- Bodyweight evolution: normal during the test.

- Necropsy: No treatment related changes were observed.

Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 of the test item is higher than 2000 mg/kg body weight by oral route in the rat. The LD50 cut-off of the test item may be considered to be higher than 5000 mg/kg body weight by oral route in the rat.
Executive summary:

The acute oral toxicity of the test ite has been tested in accordance with OECD 423 and EU method B.1 tris, following GLP. The test item was administered to a group of 6 female Sprague-Dawley rats at the dose of 2000 mg/kg body weight by oral gavage. All animals were observed immediately after administration for the onset of any toxic signs and once daily thereafter for 14 days.No mortality occurred during the study and the body weight evolution of the animals remained normal during the study. No clinical signs related to the administration of the test item were observed during the study. The macroscopic examination of the animals at the end of the study did not reveal treatment related changes. No other signs of systemic toxicity were noted. The LD50 of the test item is higher than 2000 mg/kg body weight by oral route in the rat. The LD50 cut-off of the test item may be considered to be higher than 5000 mg/kg body weight by oral route in the rat.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw
Quality of whole database:
Klimish score 1.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
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
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
Study scientifically not necessary / other information available: In accordance with column 2 of REACH Annex VIII, the study does not need to be conducted because exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols or droplets of an inhalable size.
Reason / purpose for cross-reference:
data waiving: supporting information
Reason / purpose for cross-reference:
data waiving: supporting information
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:
May 10, 2017 - May 24, 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
yes
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
Species:
rat
Strain:
Sprague-Dawley
Remarks:
SPF Caw
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: JANVIER LABS (53940 Legenest St. Isle - France)
- Females nulliparous and non-pregnant: yes
- Age at study initiation: males: 7 weeks old; females: 8 weeks old
- Weight at study initiation: males: 257.4 ± 9.1; females: 214.2 ± 5.7
- Fasting period before study: overnight
- Housing: Groups of three in solid-bottomed clear polycarbonate cages with a stainless steel mesh lid. Each cage contains sawdust bedding which was changed at least 2 times a week. Each cage was installed in conventional air conditioned animal husbandry.
- Diet (e.g. ad libitum): Foodstuff (ENVIGO -2016) ad libitum
- Water (e.g. ad libitum): Tap-water from public distribution system ad libitum. Microbiological and chemical analyses of the water were carried out once every six months by Bureau Veritas- Eurofins (France)
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19ºC - 25ºC. A temperature lower than 19ºC was registered on 18 of May 2017. The minimum value measured was 27ºC.
- Humidity (%): 30% - 70%. A relative humidity lower than 30% was registered on 10, 13, 16, 17, 23 and 24 of May 2017. The minimum value measured was 18%.
- Air changes (per hr): 10 changes/hour
- Photoperiod (hrs dark / hrs light): 12 h light (7 - 19 h) / 12 h darkness

IN-LIFE DATES: From: 10 May 2017 To: 24 May 2017
Type of coverage:
other: non-occlusive
Vehicle:
water
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal area of the trunk of the animal
- % coverage: 10% of the body surfade area
- Type of wrap if used: non-occlusive porous gauze dressing (50 mm x 50 mm non woven swab, 4-layer patch, MEDISTOCK) secured in position with a strip of surgical adhesive tape (50 mm wides hypoallergenic micropore TM adhesive tape from 3M)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): after removing the gauze dressings, the treated area was rinsed with destilled water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mL/kg bw
- Concentration (if solution): 0.2 g/ml
- Constant volume or concentration used: yes
- For solids, paste formed: no

VEHICLE
- Amount(s) applied (volume or weight with unit): 10 mL/Kg bw
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5
Control animals:
yes
Remarks:
Study No. TAD-2016-004 (see "Other information on results").
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily observations, the animals were weighed on day 0 (just before administering the test item) then on day 2, day 7, and day 14.
- Necropsy of survivors performed: yes.
At the end of the study, the animals were euthanized with sodium pentobarbital (Dolethal®). Macroscopic observations were entered on individual autopsy sheets. Only those organs likely to be modified in cases of acute toxicity were examined. No organ was removed and preserved in view to microscopic examinations.
Gross pathology: On D14, the animals were anaesthetised with sodium pentobarbital and administration continued to fatal levels. Macroscopic observations were entered on individual autopsy sheets. Only those organs likely to be modified in cases of acute toxicity were examined. Parameters examined: Oesophagus, Stomach, Duodenum, Jejunum, Ileon, Caecum, Colon, Rectum, Spleen, Liver, Thymus, Trachea, Lungs, Heart, Kidneys, Urinary Bladder, Ovaries, Uterus, Treatment Area, Adrenals and Pancreas.
- Other examinations performed:
Clinical signs: Spontaneous activity, Preyer's reflex (noise), Respiratory rate, Convulsions, Tremors, Body temperature, Muscle tone, Palpebral opening, Pupil appearance, Salivation, Lachrymation, Righting reflex, Treatment site, Mortality.

Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred during the study.
Clinical signs:
Neither cutaneous reactions nor systemic clinical signs related to the administration of the test item were observed.
Body weight:
The body weight evolution of the animals remained normal throughout the study.
Gross pathology:
The macroscopic examination of the animals at the end of the study did not reveal treatment-related changes.

Table 1. Test item at 2000 mg/kg bw. Body weight and weight gain in grams.

MALES

D0

D2

D2-D0

D7

D7-D0

D14

D14-D0

Rm 1455

261

266

5

310

49

354

93

Rm 1456

255

261

6

313

58

360

105

Rm 1457

258

262

4

311

53

348

90

Rm 1458

244

256

12

298

54

344

100

Rm 1459

269

280

11

318

49

369

100

MEAN

257.4

265.0

7.6

310.0

52.6

355.0

97.6

Standard deviation

9.1

9.1

3.6

7.4

3.8

9.9

6.0

FEMALES

D0

D2

D2-D0

D7

D7-D0

D14

D14-D0

Rf 1460

211

216

5

231

20

300

89

Rf1461

220

218

-2

238

18

269

49

Rf 1462

218

219

1

240

22

264

46

Rf 1463

206

212

6

216

10

248

42

Rf 1464

216

228

12

239

23

256

40

MEAN

214.2

218.6

4.4

232.8

18.6

267.4

53.2

Standard deviation

5.7

5.9

5.3

10.0

5.2

19.9

20.3

GENERAL APPEARANCE BEFORE AUTOPSY: Normal

Observations: Nothing to report.

Current control Study:

The study identified No. TAD -2016 -004 was performed to assess the comportament of the strain of rat used at the laboratory in the environment and to give additional historical data. The method was designed to meet the requirements of the following: OECD Guideline No. 402 (February 24th, 1987) and Method B.3 of Council regulation No. 440/2008.

 

Test item : Distilled water

Study dates: 20 September 2016 to 04 October 2016

Results:

- Clinical examinations: Nothing to report. Animal normal (10/10)

- Bodyweight evolution: normal during the test.

- Necropsy: No treatment related changes were observed.

Interpretation of results:
GHS criteria not met
Conclusions:
The dermal LD50 of the test item in rats is greater than 2000 mg/kg bw.
Executive summary:

A limit test was performed to determine the acute dermal toxicity of the test item in rats according to OECD 402 and EU method B.3, following GLP. The test item was applied onto the intact skin of 10 Sprague Dawley rats (5 males, 5 females) at a dose of 2000 mg/kg bw. All animals were observed once daily for 14 days, survival and body weight were monitored. There were no mortality and systemic clinical signs related to the administration of the test item during the study. Neither cutaneous reactions nor systemic clinical signs related to the administration of the test item were observed. Normal changes in body weights and none macroscopic findings were found. In conclusion, the test item was found to be non toxic by dermal route, with an LD50 > 2000 mg/kg bw in rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Klimish score 1.

Additional information

Acute oral toxicity:

Key study: The acute oral toxicity of the test item has been tested in accordance with OECD 423 and EU method B.1 tris, following GLP. The test item was administered to a group of 6 female Sprague-Dawley rats at the dose of 2000 mg/kg body weight by oral gavage. All animals were observed immediately after administration for the onset of any toxic signs and once daily thereafter for 14 days. No mortality occurred during the study and the body weight evolution of the animals remained normal during the study. No clinical signs related to the administration of the test item were observed during the study. The macroscopic examination of the animals at the end of the study did not reveal treatment related changes. No other signs of systemic toxicity were noted. The LD50 of the test item is higher than 2000 mg/kg body weight by oral route in the rat. The LD50 cut-off of the test item may be considered to be higher than 5000 mg/kg body weight by oral route in the rat.

Acute dermal toxicity:

Key study: A limit test was performed to determine the acute dermal toxicity of the test item in rats according to OECD 402 and EU method B.3, following GLP. The test item was applied onto the intact skin of 10 Sprague Dawley rats (5 males, 5 females) at a dose of 2000 mg/kg bw. All animals were observed once daily for 14 days, survival and body weight were monitored. There were no mortality and systemic clinical signs related to the administration of the test item during the study. Neither cutaneous reactions nor systemic clinical signs related to the administration of the test item were observed. Normal changes in body weights and none macroscopic findings were found. In conclusion, the test item was found to be non-toxic by dermal route, with an LD50 > 2000 mg/kg bw in rats.

Justification for classification or non-classification

Based on the available information (oral LD50 5000 mg/kg bw, dermal LD50 > 2000 mg/kg bw), the substance is not classified for acute toxicity according to CLP Regulation (EC) no. 1272/2008.