Registration Dossier

Administrative data

Description of key information

LD50 (oral, rat) > 5000 mg/kg bw
LD50 (dermal, rat) > 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:
05 August - 20 August 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP - guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
and EU Method B.1 tris directive 2004/73/EC (Acute Oral Toxicity - Acute Toxic Class Method)
GLP compliance:
yes (incl. certificate)
Remarks:
Groupe Interministeriel des Produits Chimiques
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Elevage JANVIER, Le Genest St Isle, France
- Age at study initiation: 8 weeks
- Weight at study initiation: 189 - 200 g
- Fasting period before study: food was removed one day prior to dosing
- Housing:by groups of three in solid-bottomed clear polycarbonate cages with a stainless steel mesh lid. Each cage contained sawdust bedding which was changed at least 2 times a week. Each cage was installed in conventional air conditioned animal husbandry
- Water (e.g. ad libitum): tap water from public distribution system
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 24
- Humidity (%): 42 - 67
- Air changes (per hr): at least ten changes
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg body weight
Doses:
single dose of 2000 mg/kg body weight
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 and weighing: daily observations, weighing at days 0, 2, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, organ weights
Sex:
female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Mortality:
No deaths occured.
Clinical signs:
No clinical signs observed.
Body weight:
Normal throughout study.
Gross pathology:
No treatment related changes.

Table: Clinical observations (N = normal, No = none)

Observations:

Females

T0 + 30 min.

T0 + 1 Hour

T0 + 3 Hours

T0 + 4 Hours

Rf

Rf

Rf

Rf

Rf

Rf

1100

1101

1102

1106

1107

1108

Spontaneous activity

N

N

N

N

N

N

Preyer’s reflex (noise)

N

N

N

N

N

N

Respiratory rate

N

N

N

N

N

N

Convulsions

No

No

No

No

No

No

Tremors

No

No

No

No

No

No

Body temperature

N

N

N

N

N

N

Muscle tone

N

N

N

N

N

N

Palpebral opening

N

N

N

N

N

N

Pupil appearance

N

N

N

N

N

N

Salivation

N

N

N

N

N

N

Lachrymation

N

N

N

N

N

N

Righting reflex

N

N

N

N

N

N

Back hair appearance

N

N

N

N

N

N

Mortality

0

0

0

0

0

0

Remarks

None

None

Table: Clinical observations continued (N = normal, No = none)

Observations:

Females

D1 to D14

Rf

Rf

Rf

Rf

Rf

Rf

1100

1101

1102

1106

1107

1108

Spontaneous activity

N

N

N

N

N

N

Preyer’s reflex (noise)

N

N

N

N

N

N

Respiratory rate

N

N

N

N

N

N

Convulsions

No

No

No

No

No

No

Tremors

No

No

No

No

No

No

Body temperature

N

N

N

N

N

N

Muscle tone

N

N

N

N

N

N

Palpebral opening

N

N

N

N

N

N

Pupil appearance

N

N

N

N

N

N

Salivation

N

N

N

N

N

N

Lachrymation

N

N

N

N

N

N

Righting reflex

N

N

N

N

N

N

Back hair appearance

N

N

N

N

N

N

Mortality

0

0

0

0

0

0

Remarks

None

None

Table: Body weight and weight gain in grams

Females

D0

D2

D2-D0

D7

D7-D0

D14

D14-D0

Rf 1100

189

205

16

225

36

240

51

Rf 1101

193

215

22

236

43

264

71

Rf 1102

195

226

31

228

33

264

69

Rf 1106

190

213

23

213

41

241

51

Rf 1107

200

223

23

243

43

258

58

Rf 1108

198

217

19

231

33

253

55

Mean

194.2

216.5

22.3

232.3

38.2

253.3

59.2

Standard deviation

4.4

7.5

5.0

6.4

4.8

10.8

8.8

Table: necropsy data females Rf1100 - Rf1102 (X = Euthanasia, at term; N.t.r = nothing to report)

Observed organs

Results

Oesophagus

X

N.t.r.

Stomach

X

N.t.r.

Duodenum

X

N.t.r.

Jejunum

X

N.t.r.

Ileon

X

N.t.r.

Caecum

X

N.t.r.

Colon

X

N.t.r.

Rectum

X

N.t.r.

Spleen

X

N.t.r.

Liver

X

N.t.r.

Thymus

X

N.t.r.

Trachea

X

N.t.r.

Lungs

X

N.t.r.

Heart

X

N.t.r.

Kidneys

X

N.t.r.

Urinary Bladder

X

N.t.r.

Ovaries

X

N.t.r.

Uterus

X

N.t.r.

Treatment Area

-

-

Adrenals

X

N.t.r.

Pancreas

X

N.t.r.

Particulars: none

Table: necropsy data females Rf1106 - 1108 (X = Euthanasia, at term; N.t.r. = nothing to report)

Observed organs

Results

Oesophagus

X

N.t.r.

Stomach

X

N.t.r.

Duodenum

X

N.t.r.

Jejunum

X

N.t.r.

Ileon

X

N.t.r.

Caecum

X

N.t.r.

Colon

X

N.t.r.

Rectum

X

N.t.r.

Spleen

X

N.t.r.

Liver

X

N.t.r.

Thymus

X

N.t.r.

Trachea

X

N.t.r.

Lungs

X

N.t.r.

Heart

X

N.t.r.

Kidneys

X

N.t.r.

Urinary Bladder

X

N.t.r.

Ovaries

X

N.t.r.

Uterus

X

N.t.r.

Treatment Area

-

-

Adrenals

X

N.t.r.

Pancreas

X

N.t.r.

Particulars: none

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
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:
05 August - 19 August 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP - guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
and EU Method B.3 of the directive 92/69/EEC (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Groupe Interministeriel des Produits Chimiques
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Elevage JANVIER, Le Genest St Isle, France
- Age at study initiation: 7 - 8 weeks
- Weight at study initiation: 223 - 237 g (males), 205 - 227 g (females)
- Fasting period before study: no
- Housing: during treatment in individual cage (solid-bottomed clear polycarbonate cages with stainless steel mesh lid; sawdust bedding, changed at least two times a week; conventional air condition); at D3 animals were put into cage by 2 or 3
- Water: tap-water from public distribution
- Acclimation period: at least five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 48 -72
- Air changes (per hr): at least 10 changes
- Photoperiod (hrs dark / hrs light): 12 / 12


IN-LIFE DATES: From: To:
Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
TEST SITE
- Type of wrap if used: porous gauze dressing

REMOVAL OF TEST SUBSTANCE
- Washing (if done): rinsed with distilled water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mL/kg bw test item diluted in distilled water; effective dose of 2000 mg/kg bw
test item
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations daily, weighing on day 0, 2, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
other: No deaths occured. No clinical signs.
Sex:
male/female
Dose descriptor:
other: local NOAEL
Effect level:
>= 11 other: mg/cm²
Remarks on result:
other: No local effects were observed.
Mortality:
none
Clinical signs:
none
Body weight:
normal throughout the study
Gross pathology:
no treatment related changes

Table: clinical observations (N = normal, No = none)

Observations

Males

Females

T0 + 1 Hour

T0 + 3 Hours

T0 + 4 Hours

Rm

Rm

Rm

Rm

Rm

Rf

Rf

Rf

Rf

Rf

1087

1088

1089

1090

1091

1092

1093

1094

1095

1096

Spontaneous activity

N

N

N

N

N

N

N

N

N

N

Preyer’s reflex (noise)

N

N

N

N

N

N

N

N

N

N

Respiratory rate

N

N

N

N

N

N

N

N

N

N

Convulsions

No

No

No

No

No

No

No

No

No

No

Tremors

No

No

No

No

No

No

No

No

No

No

Body temperature

N

N

N

N

N

N

N

N

N

N

Muscle tone

N

N

N

N

N

N

N

N

N

N

Palpebral opening

N

N

N

N

N

N

N

N

N

N

Pupil appearance

N

N

N

N

N

N

N

N

N

N

Salivation

N

N

N

N

N

N

N

N

N

N

Lachrymation

N

N

N

N

N

N

N

N

N

N

Righting reflex

N

N

N

N

N

N

N

N

N

N

Back hair appearance

N

N

N

N

N

N

N

N

N

N

Mortality

0

0

0

0

0

0

0

0

0

0

Remarks

None

None

Table: clinical observations (N = normal, No = none)

Observations

Males

Females

D1 to D14

Rm

Rm

Rm

Rm

Rm

Rf

Rf

Rf

Rf

Rf

1087

1088

1089

1090

1091

1092

1093

1094

1095

1096

Spontaneous activity

N

N

N

N

N

N

N

N

N

N

Preyer’s reflex (noise)

N

N

N

N

N

N

N

N

N

N

Respiratory rate

N

N

N

N

N

N

N

N

N

N

Convulsions

No

No

No

No

No

No

No

No

No

No

Tremors

No

No

No

No

No

No

No

No

No

No

Body temperature

N

N

N

N

N

N

N

N

N

N

Muscle tone

N

N

N

N

N

N

N

N

N

N

Palpebral opening

N

N

N

N

N

N

N

N

N

N

Pupil appearance

N

N

N

N

N

N

N

N

N

N

Salivation

N

N

N

N

N

N

N

N

N

N

Lachrymation

N

N

N

N

N

N

N

N

N

N

Righting reflex

N

N

N

N

N

N

N

N

N

N

Back hair appearance

N

N

N

N

N

N

N

N

N

N

Treatment site

N*

N*

N*

N*

N*

N*

N*

N*

N*

N*

Mortality

0

0

0

0

0

0

0

0

0

0

Remarks

N* = slight green coloration at D1 and D2

Table: body weight and weight gain in grams

Males

D0

D2

D2-D0

D7

D7-D0

D14

D14-D0

Rm 1087

232

238

6

273

41

309

77

Rm 1088

230

237

7

276

46

323

93

Rm 1089

227

231

4

265

38

306

79

Rm 1090

237

245

8

282

45

324

87

Rm 1091

223

231

8

261

38

300

77

Mean

229.8

236.4

6.6

271.4

41.6

312.4

82.6

Standard deviation

5.3

5.8

1.7

8.4

3.8

10.6

7.1

Females

D0

D2

D2-D0

D7

D7-D0

D14

D14-D0

Rf 1092

205

220

15

234

29

257

52

Rf 1093

208

213

5

224

16

254

46

Rf 1094

211

213

2

230

19

242

31

Rf 1095

206

212

6

226

20

250

44

Rf 1096

227

226

-1

242

15

255

28

Mean

211.4

216.8

5.4

231.2

19.8

251.6

40.2

Standard deviation

9.0

6.1

6.0

7.2

5.5

5.9

10.3

Table: necroscopic observations males (X = Euthanasia, at term; N.t.r. = nothing to report)

Observed organs

Results

Oesophagus

X

N.t.r.

Stomach

X

N.t.r.

Duodenum

X

N.t.r.

Jejunum

X

N.t.r.

Ileon

X

N.t.r.

Caecum

X

N.t.r.

Colon

X

N.t.r.

Rectum

X

N.t.r.

Spleen

X

N.t.r.

Liver

X

N.t.r.

Thymus

X

N.t.r.

Trachea

X

N.t.r.

Lungs

X

N.t.r.

Heart

X

N.t.r.

Kidneys

X

N.t.r.

Urinary Bladder

X

N.t.r.

Testicles

X

N.t.r.

Ovaries

-

-

Uterus

-

-

Treatment Area (Skin)

X

N.t.r.

Adrenals

X

N.t.r.

Pancreas

X

N.t.r.

Particulars: none

Table: necroscopic observations females (X = Euthanasia, at term; N.t.r. = nothing to report)

Observed organs

Results

Oesophagus

X

N.t.r.

Stomach

X

N.t.r.

Duodenum

X

N.t.r.

Jejunum

X

N.t.r.

Ileon

X

N.t.r.

Caecum

X

N.t.r.

Colon

X

N.t.r.

Rectum

X

N.t.r.

Spleen

X

N.t.r.

Liver

X

N.t.r.

Thymus

X

N.t.r.

Trachea

X

N.t.r.

Lungs

X

N.t.r.

Heart

X

N.t.r.

Kidneys

X

N.t.r.

Urinary Bladder

X

N.t.r.

Testicles

-

-

Ovaries

X

N.t.r.

Uterus

X

N.t.r.

Treatment Area (Skin)

X

N.t.r.

Adrenals

X

N.t.r.

Pancreas

X

N.t.r.

Particulars: none

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
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 oral toxicity

In the oral toxicity study performed by Seguier (2008) according to OECD 423 and GLP, 6 female Wistar rats were treated with 2000 mg/kg bw of the test substance in water by gavage. After application of the test substance and during the 14 day-observation period, no mortality occured, no clinical signs and no effects on the body weight gain were observed in any animal. Macroscopic examinations at necropsy did not reveal any abnormalities.

According to the acute toxic class method described in the OECD guideline 423, if there is no mortality following administration of 2000 mg/kg bw in two separate steps, the LD50 cut-off limit is 5000 mg/kg bw. Therefore, the LD50 is considered to be 5000 mg/kg bw for female rats.

Acute dermal toxicity 

The acute dermal toxicity of the test substance was investigated in a study performed according to OECD 402 and GLP (Seguier, 2008). A single test substance dose of 2000 mg/kg bw was applied on the skin of five male and five female Sprague-Dawley rats. The treated skin site was covered with a semiocclusive dressing for 24 h. No mortality occurred during the 14 day-observation period. No clinical signs and no changes on body weight were observed and the necropsy revealed no test substance-related findings. Therefore, the LD50 is > 2000 mg/kg bw for male and female rats.


Justification for selection of acute toxicity – oral endpoint
There is only one study available.

Justification for classification or non-classification

The available data on the acute oral and dermal toxicity of the test substance does not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and is therefore conclusive but not sufficient for classification.