Registration Dossier

Administrative data

Description of key information

Oral: LD50 = > 2000 mg/kg bw, female rat, OECD 423, EU Method B.1 tris, Dreher 2013a
Dermal: LD50 = > 2000 mg/kg bw, male/female rat, OECD 402, EU Method B.3, Dreher 2013b

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:
26 November 2012 to 13 December 2012
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:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
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
Limit test:
yes
Species:
rat
Strain:
other: HsdHan:WIST
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 8 - 9 weeks
- Weight at study initiation: 167 - 179 g (on day of dosing)
- Fasting period before study: animals were fasted from the evening of the day prior to dosing (day -1) until approximately 3 hours after dosing
- Housing: animimals were housed in groups up to 5 during the acclimation period and in groups of three from the day prior to dosing. Cages conformed to the Code of Practice for the Housing and Care of Animals Used in Scientific Procedures' (Home Ofice, London, 1989)
- Diet: ad libitum
- Water: mains water, ad libitum
- Acclimation period: 7 - 9 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 32 - 71 %
- Air changes (per hr): 15 - 20 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
TEST MATERIAL FORMULATION
The test material was used as supplied. The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level.
Individual doses were calculated using the fasted body weights of the rats on the morning of dosing and the specific gravity of the neat test material.
Doses:
2000 mg/kg
No. of animals per sex per dose:
3 females per treatment group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: animals were observed for clinical signs of reaction to treatment 15 and 30 minutes and 1, 2, 3 and 4 hours post-dose on day 1, twice daily on days 2, 3 and 4 and once daily thereafter.
- Frequency of weighing: animals were weighed on the day prior to dosing and on days 1, 4, 8 and 15
- Necropsy of survivors performed: yes. A full macroscopic examination was performed and all lesions recorded. The necropsy procedure included inspection of the external surfaces and orifices, all viscera and tissue within the abdominal, thoracic and cranial cavities, free-hand sectioning of the liver and kidneys and examination of representative sections of mucosal surfaces of the stomach, small and large intestines.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
None of the animals died during the study.
Clinical signs:
Clinical signs were confined to decreased activity and hunched posture in three animals two hours after dosing. These signs persisted in two animals three hours after dosing.
Body weight:
All rats achieved body weight gains during the first and second weeks of the study.
Gross pathology:
No abnormalities were noted at necropsy.

Table 1: Individual Body Weights

Animal number

Body weight (g)

day -1

day 1

day 4

day 8

day15

184

187

172

187

189

197

185

188

179

193

198

200

186

174

168

181

186

192

187

182

174

182

190

203

188

174

167

173

181

191

189

174

167

173

180

190

Table 2: Clinical Signs Following Treatment

Animals number

Clinical sign

Sign noted after dosing on day 1 (hours):

Sign noted on day 2 - 15

1

2

3

187

decrease activity

X

X

hunched posture

X

X

188

decrease activity

X

X

hunched posture

X

X

189

decrease activity

X

hunched posture

X

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study the acute oral LD50 of the test material was determined to be in excess of 2000 mg/kg bw.
Executive summary:

The acute oral toxicity of the test material was determined in a GLP study which was conducted in line with standardised guidelines OECD 423 and EU Method B.1 tris. During the study, two groups of three female rats were dosed test material, by gavage, at a dose level of 2000 mg/kg. Following administration, animals were observed for mortality and clinical signs, and body weights were recorded, over a period of 14 days. All animals were sacrificed on day 15 and underwent a full necropsy. None of the animals died during the study and clinical signs were confined to decreased activity and hunched posture in three animals two hours after dosing. These signs persisted in two animals three hours after dosing. All rats achieved body weight gains during the first and second weeks of the study and no abnormalities were noted at necropsy. Under the conditions of the study the acute oral 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 study was performed in line with GLP and accepted standardised guidelines with a high standard of reporting. The study was assigned a reliability score of 1 in accordance with the criteria for assessing data quality as outlined in Klimisch (1997) and considered suitable for assessment as an accurate reflection of the substance.

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:
4 December 2012 to 27 December 2012
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:
yes
Remarks:
The relative humidity reached maximum value of 71 %
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
yes
Remarks:
The relative humidity reached maximum value of 71 %
Principles of method if other than guideline:
The relative humidity reached maximum value of 71 %, 1 % higher than the maximum recommended in the guidelines. This deviations was not considered not to have affected the integrity or outcome of the study.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: HsdHan:WIST
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 8 - 10 weeks
- Weight at study initiation: 236 - 302 g (males); 173 - 202 g (females)
- Housing: in groups up to 5 by sex during acclimation and individually from the day prior to dosing. After completion of the day 3 observations animals allocated to the main study were returned to group housing. Cages conformed to the 'Code of Practice for the Housing and Care of Animals Used in Scientific Procedures' (Home Office, London, 1989)
- Diet: ad libitum
- Water: mains warer, ad libitum
- Acclimation period: 8 to 16 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 45 - 71 %
- Air changes (per hr): 15 - 20 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
Hair from the dorsum was removed with electric clipper on the day before dosing. the dermal site was an area of at least 10 % of the total body surface. The test material was spread evenly across the dermal test site. A dense gauze patch was placed over the treated skin, held in places with and elasticated, open-weave, adhesive compression bandage. this was wrapped securely around the torso of the animal.

REMOVAL OF TEST SUBSTANCE
The dressing was removed approximately 24 hours after application. The dermal test site of each rat was lightly brushed clean of any solid residues and swabbed with water-moistened cotton wool before the animal was returned to the holding cage.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): individual dose volumes were calculated from the body weights of the rats on the morning of dosing (day 1), taking account of the specific gravity of the test material (0.914 g/mL). The dose volume applied to each animal was 2.19 mL/kg (dose level: 2000 mg/kg bw).
Duration of exposure:
24 hours
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5 males and 5 females per group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: clinical signs were recorded immediately post-dose and approximately 15 and 30 minutes, and 1, 2, 3 and 4 hours post-dose on day 1, twice daily on days 2, 3 and 4 and daily thereafter.
- Frequency of weighing: animals were weighed on days -1, 1, 4, 8 and 15
Necropsy of survivors performed: yes. A full macroscopic examination was performed and all lesions recorded. The necropsy procedure included inspection of the external surfaces and orifices, all viscera and tissue within the abdominal, thoracic and cranial cavities, free-hand sectioning of the liver and kidneys and examination of representative sections of mucosal surfaces of the stomach, small and large intestines.
- Other examinations performed: dermal reactions. The condition of the dermal test site was recorded following removal of the dressing on day 2 and once daily thereafter. erythema and oedema were scored according to the Draize scale (Table 1).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mL/kg bw
Based on:
test mat.
Mortality:
None of the animals died during the study.
Clinical signs:
There were no clinical signs of reaction to treatment.
Body weight:
All rats gained weight during the first and second weeks of the study except for one female which showed no change in body weight during the first week.
Gross pathology:
No macroscopic changes were noted at necropsy.
Other findings:
There were no dermal reactions.

Table 2: Individual body weights and weekly increments

Dose level (mg/kg)

Animal number and sex

Body weight (g) at:

Increment (g)

Day -1

Day 1

Day 4

Day 8

Day 15

Day 1

to 8

Day 8

to 15

2000

194M

231

236

241

259

270

23

11

195M

267

271

271

280

301

9

21

196M

297

302

295

312

324

10

12

197M

261

268

266

274

297

6

23

198M

288

296

292

310

332

14

22

2000

203F

183

183

189

194

202

11

8

204F

189

194

191

198

205

4

7

205F

198

202

196

207

218

5

11

206F

185

189

183

189

203

0

14

207F

180

173

175

183

195

10

12

Table 3: Dermal Reactions - Males

Day

Dermal reaction

Animal number and sex

194M

195M

196M

197M

198M

2

Erythema

Oedema
Other

0

0
-

0

0
-

0

0
-

0

0
-

0

0
-

3

Erythema

Oedema
Other

0

0
-

0

0
-

0

0
-

0

0
-

0

0
-

4

Erythema

Oedema
Other

0

0
-

0

0
-

0

0
-

0

0
-

0

0
-

5 to 15

Erythema

Oedema
Other

0

0
-

0

0
-

0

0
-

0

0
-

0

0
-

 

Dermal Reactions - Females

Day

Dermal reaction

Animal number and sex

203F

204F

205F

206F

207F

2

Erythema

Oedema
Other

0

0
-

0

0
-

0

0
-

0

0
-

0

0
-

3

Erythema

Oedema
Other

0

0
-

0

0
-

0

0
-

0

0
-

0

0
-

4

Erythema

Oedema
Other

0

0
-

0

0
-

0

0
-

0

0
-

0

0
-

5 to 15

Erythema

Oedema
Other

0

0
-

0

0
-

0

0
-

0

0
-

0

0
-

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the test, the acute dermal median lethal dose of the test material was estimated to be in excess of 2000 mg/kg to male and female rats.
Executive summary:

The acute dermal toxicity of the test material was determined in a GLP study which was conducted in accordance with standardised guidelines OECD 402 and EU Method B.3. During the study five male and female rats received a single dermal application of 2000 mg/kg of the test material and were assessed daily for the following 14 days for any signs of systemic toxicity. None of the animals died and there were no signs of systemic toxicity. There were no dermal reactions and all animals gained weight during the study. There were no macroscopic abnormalities at examination post mortem. The acute dermal median lethal dose of the test material was estimated to be in excess of 2000 mg/kg to both male and female rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The study was performed in line with GLP and accepted standardised guidelines with a high standard of reporting. The study was assigned a reliability score of 1 in accordance with the criteria for assessing data quality as outlined in Klimisch (1997) and considered suitable for assessment as an accurate reflection of the substance.

Additional information

Oral

The acute oral toxicity of the test material was determined in a GLP study which was conducted in line with standardised guidelines OECD 423 and EU Method B.1 tris. During the study, two groups of three female rats were dosed test material, by gavage, at a dose level of 2000 mg/kg. Following administration, animals were observed for mortality and clinical signs, and body weights were recorded, over a period of 14 days. All animals were sacrificed on day 15 and underwent a full necropsy. None of the animals died during the study and clinical signs were confined to decreased activity and hunched posture in three animals two hours after dosing. These signs persisted in two animals three hours after dosing. All rats achieved body weight gains during the first and second weeks of the study and no abnormalities were noted at necropsy. Under the conditions of the study the acute oral LD50 of the test material was determined to be in excess of 2000 mg/kg bw.

Inhalation

According to point 8.5 of Annex VIII of Regulation (EC) No. 1907/2006, the test for the second acute toxicity study will be performed on the most appropriate route of exposure, taking into account the nature of the substance and the likely route of human exposure. The test substance has very low vapour pressure, so the potential for the generation of inhalable forms is low. Furthermore, the use of this substance will not result in aerosols, particles or droplets of an inhalable size being formed, therefore exposure to humans via the inhalation route will be unlikely to occur. On these bases, no acute inhalation toxicity test was performed.

Dermal

The acute dermal toxicity of the test material was determined in a GLP study which was conducted in accordance with standardised guidelines OECD 402 and EU Method B.3. During the study five male and female rats received a single dermal application of 2000 mg/kg of the test material and were assessed daily for the following 14 days for any signs of systemic toxicity. None of the animals died and there were no signs of systemic toxicity. There were no dermal reactions and all animals gained weight during the study. There were no macroscopic abnormalities at examination post mortem. The acute dermal median lethal dose of the test material was estimated to be in excess of 2000 mg/kg to both male and female rats.


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

Justification for selection of acute toxicity – dermal endpoint
Only one study is available.

Justification for classification or non-classification

In accordance with with criteria for classification as defined in Annex I, Regulation (EC) No. 1272/2008, the test material does not require classification for acute oral, or acute dermal, toxicity as no signs of toxicity were noted during the course of ether of the studies.