Registration Dossier

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Diss Factsheets

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 19 September 2017 - 24 October 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report date:
2018

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
see "Any other information on materials and methods incl. tables" for more details.
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
see "Any other information on materials and methods incl. tables" for more details.
Principles of method if other than guideline:
Hungarian GLP Regulations: 42/2014. (VIII. 19.) EMMI decree of the Ministry of Human Capacities which corresponds to the OECD GLP, ENV/MC/CHEM (98) 17.

EPA Health Effects Test Guidelines (OPPTS 870.1100), United States, EPA 712-C-98-190 (1998)
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Selenium disulphide
EC Number:
231-303-8
EC Name:
Selenium disulphide
Cas Number:
7488-56-4
Molecular formula:
S2Se
IUPAC Name:
selenium disulphide
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
Test item name: Selenium Disulphide
CAS Number: 7488-56-4
Batch/Lot Number: PMC / 285 / 16
Description: Orange/yellow powder
Expiry Date: 24 November 2019
Purity: 100%
Storage Conditions: Room temperature (between 5oC and 30oC), protected from light
Safety precautions: Enhanced safety precautions were applied considering the supplied safety datasheet to assure personnel health and safety.
Hazards: Toxic if inhaled.
Toxic if swallowed.

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Species and strain: Crl:WI Wistar rats
Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld, Germany
Hygienic level at arrival: SPF
Hygienic level during the study: Standard housing conditions
Number of animals: 18 animals, 3 animals/group
Sex: Female, nulliparous and non-pregnant
Age of animals at dosing: Young healthy adult rats, 8-10 weeks old
Body weight at treatment: 186 - 240 g
Acclimatisation period: At least 5 days

Husbandry
Animal health: Only healthy animals were used for the test. The health status was certified by the staff Veterinarian.
Number of animal room: 522/8
Housing: 3 animals/cage
Cage type: Type II. polypropylene/polycarbonate
Bedding: Lignocel 3/4-S Hygienic Animal Bedding produced by J. Rettenmaier & Söhne GmbH + CO.KG (D-73494 Rosenberg, Germany) was available to animals during the study.

Nesting: Arbocel crinklets natural produced by J. Rettenmaier & Söhne GmbH + CO.KG (D-73494 Rosenberg, Germany) was available to animals during the study.
Lighting period: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Temperature: 20.2 – 23.3 °C
Relative humidity: 33 – 80 %
Ventilation: 15-20 air exchanges/hour
Enrichment: Animals were housed by group to allow social interaction and with deep wood sawdust bedding to allow digging and other normal rodent activities.

The temperature and relative humidity were recorded twice daily during the acclimatisation period and throughout the study.

Food and Water Supply
Animals received ssniff® SM R/M "Autoclavable complete diet for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest, Germany (Batch number: 262 21592, Expiry date: 31 January 2018), ad libitum, and tap water from the municipal supply, as for human consumption from a 500 ml bottle, ad libitum. The food is considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.

Water quality control analysis is performed once every three months and microbiological assessment is performed monthly, by Veszprém County Institute of State Public Health and Medical Officer Service (ÁNTSZ, H-8201 Veszprém, József Attila u. 36., Hungary). The quality control results are retained in the archives at CiToxLAB Hungary Ltd.

Animal Identification
Animals were individually identified using numbers written on the tail with an indelible pen. The numbers were given on the basis of CiToxLAB Hungary Ltd.' s Master File, for each animal allocated to the treatment groups. The cages were identified by cards, with information about study code, sex, dose group, cage number and individual animal numbers.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
methylcellulose
Details on oral exposure:
Formulation
The test item was freshly formulated at the concentrations of 5, 30 and 200 mg/mL in the vehicle, in the Pharmacy of CiToxLAB Hungary Ltd. on the day of administration. The formulation container was magnetic stirred continuously up to the end of dose administration procedures.


Procedure
A single oral gavage administration was followed by a 14-day observation period. On the night before treatment, the animals were fasted. The food but not water was withheld during an overnight period. Animals were weighed before treatment. The test item was administered by oral gavage in the morning. The food was returned 3 hours after the treatment.


Justification of the doses:
A limit test was not performed as the toxicity of the test substance was unknown at 2000 mg/kg bodyweight (bw). In agreement with the Sponsor, in the main test a starting dose of 300 mg/kg bw was selected based on the information provided by the Sponsor.

Initially, three females (Group 1) were treated at a dose level of 300 mg/kg bw. As no mortality and no severe symptoms were observed after 24 hours, a confirmatory group (Group 2) was treated at the same dose level.

After the 48-hour observation time point, one animal died unexpectedly in Group 1; however, as this animal was symptom-free before death and other animals were symptom-free also, the next group (Group 3) was treated at the dose level of 2000 mg/kg bw according to OECD 423. As no mortality was observed and only very minor symptoms were seen in the treated groups, a confirmatory group (Group 4) was treated at the dose level of 2000 mg/kg. Due to delayed toxicity, one further animal was found dead in Group 1 and more severe symptoms appeared later in the experiment in other treated animals also: 2 out of 3 animals died in Group 3 and 3 out of 3 animals died in Group 4.

Since 2 out of 3 animals from Group 1 died (delayed death , following the OECD scheme, three further animals were treated at a dose level of 50 mg/kg bw (Group 5). As no mortality was observed, a confirmatory group (Group 6) was treated at the same dose level. No mortality was observed in the confirmatory group; therefore, no further testing was required according to OECD 423 and Commission Regulation (EC) No 440/2008 of 30 May 2008, B.1.tris.
Doses:
50 mg/kg body weight
300 mg/kg body weight
2000 mg/kg body weight
No. of animals per sex per dose:
Six groups of three female Crl:WI rats were treated with the test item at the dose levels of 300 (Group 1 and 2), 2000 (Group 3 and 4) and 50 mg/kg body weight (bw) (Group 5 and 6).
Control animals:
not specified
Details on study design:
Clinical observations
Clinical observations were performed on all animals at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter or until death. Individual observations were performed on 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.

Body Weight Measurement
The body weight was recorded on the day before treatment (Day -1), on the day of the treatment (Day 0), weekly thereafter and at necropsy (Day 14) or at death. Additional measurements were performed on Day 4 in Group 2 and on Day 3 in Group 3.

Necropsy
Macroscopic examination was performed on all animals. The surviving animals were sacrificed by exsanguination under pentobarbital anaesthesia (Euthanimal 40%; Lot No.: 1609291-03, Expiry date: 31 October 2019, produced by: Alfasan International B.V., Kuipersweg 9, 3449 JA Woerden, The Netherlands; and Euthasol 400 mg/ml, Lot No.: 16B095, Expiry date: 31 January 2019, produced by: Produlab Pharma B.V., Forellenweg 16, 4941 SJ Raamsdonksveer, The Netherlands). After examination of the external appearance, the cranial, thoracic and the abdominal cavities were opened and the organs and the tissues were observed.

Evaluation of the results
The method used was not intended to allow the calculation of a precise LD50 value. The test item was ranked into categories of Globally Harmonized Classification System (GHS (rev. 6) 2015). Clinical signs, body weight, body weight gain and gross macroscopic data were tabulated.

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 300 - <= 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality (0/6) occurred at the dose level of 50 mg/kg bw.

2 out of 6 animals died on Day 2 and Day 3 at the dose level of 300 mg/kg bw.

5 out of 6 animals died between Day 1 and Day 7 at the dose level of 2000 mg/kg bw.
Clinical signs:
other: All animals were symptom-free at the dose level of 50 mg/kg bw during the 14-day observation period. At the dose level of 300 mg/kg bw, the following test item related symptoms were observed up to Day 14 or until death: hunched back (6 out of 6 animals),
Gross pathology:
There was no evidence of the macroscopic observations in any animals at the dose level of 50 mg/kg bw.

At the dose level of 300 mg/kg bw, the following macroscopic findings were observed at necropsy: in the found dead animals, dark red discoloration/non-collapsed/collapsed lungs and thymus were agonal or post mortem rather than test item-related. Additionally, incidental thin fur at the right cheek was noted in one animal. There were test item-related gross changes noted in the liver and stomach of 3 out of 4 rats terminated on Day 14. Thickness of the non-glandular stomach mucosa and/or yellowish multifocal discoloration of the liver were seen in these animals. In addition, enlargement of pale discoloured spleen was macroscopically described in one single animal and therefore this change was not ascribed to the administration of test item.

At the dose level of 2000 mg/kg bw, the following macroscopic findings were observed at necropsy: for animal that died relatively soon after treatment (ID 1066), yellow liquid mixed with diet in the digestive content the stomach was observed. For animals that died later (ID 1063 and 1065), discoloration (dark red) of the stomach was observed in 1 out of the 2 animals (ID 1063). Other macroscopic changes including dark red discoloration of the non-collapsed/collapsed lungs and thymus were regarded as agonal or post mortem rather than test item-related. In one surviving animal multifocal thickness/yellow-red discoloration of the non-glandular stomach mucosa, red liquid mixed with diet in the digestive content of the stomach, yellowish multifocal discoloration of the liver and/or yellowish liquid (approximately 5.0 ml) within the abdominal cavity, were regarded as test item-related.
Other findings:
FOUND DEAD - Macroscopic Findings

Dose level of 2000 mg/kg bw

For animal that died relatively soon after treatment (ID 1066), yellow liquid mixed with diet in the digestive content the stomach was observed. For animals that died later (ID 1063 and 1065), discoloration (dark red; yellow-red) of the stomach was observed.

Other macroscopic changes including dark red discoloration of the non-collapsed/collapsed lungs and thymus were regarded as agonal or post mortem rather than test item-related.

Dose level of 300 mg/kg bw

Dark red discoloration/non-collapsed/collapsed lungs and thymus were agonal or post mortem rather than test item-related. Additionally, incidental thin fur at the right cheek was noted in one animal.

Any other information on results incl. tables

CLINICAL OBSERVATIONS

DOSE LEVEL: 300 mg/kg bw, Treatment on Day 0       

SEX: FEMALE

 

Cage No.

Animal Number

 

Observations

Observation days

 

Frequency

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

30'

1h

2h

3h

4h

6h

 

 

 

 

1

 

1057#

Symptom Free

+

+

+

-

-

+

+

 

5/7

Hunched back

-

-

-

+

+

-

-

2/7

Found dead

-

-

-

-

-

-

-

+

 

-

 

1058#

Symptom Free

+

+

+

-

-

+

+

+

 

6/8

Hunched back

-

-

-

+

+

-

-

-

2/8

Found dead

-

-

-

-

-

-

-

-

+

 

-

 

1059

Symptom Free

+

+

+

+

+

+

+

+

+

-

-

-

-

+

+

+

+

+

+

+

16/20

Hunched back

-

-

-

-

-

-

-

-

-

+

-

-

-

-

-

-

-

-

-

-

1/20

Piloerection

-

-

-

-

-

-

-

-

-

+

+

+

+

-

-

-

-

-

-

-

4/20

 

 

 

 

 

 

 

 

 

2

 

 

1060

Symptom Free

+

+

+

+

+

+

+

-

-

-

-

-

-

-

-

-

-

-

-

-

7/20

Activity decreased

-

-

-

-

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

1/20

Hunched back

-

-

-

-

-

-

-

+

+

+

+

+

+

+

+

+

+

+

+

+

13/20

Piloerection

-

-

-

-

-

-

-

+

+

+

+

+

+

+

+

+

+

+

+

+

13/20

Wasted

-

-

-

-

-

-

-

-

-

+

+

+

+

+

+

+

+

+

+

+

11/20

Urine coloured - dark yellow

-

-

-

-

-

-

-

-

-

-

-

-

-

-

+

+

+

+

+

+

6/20

 

 

1061

Symptom Free

+

+

+

-

-

+

+

-

-

-

-

-

-

-

-

-

-

-

-

-

5/20

Activity decreased

-

-

-

-

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

1/20

Hunched back

-

-

-

+

+

-

-

+

+

+

+

+

+

+

+

+

+

+

+

+

15/20

Piloerection

-

-

-

-

-

-

-

+

+

+

+

+

+

+

+

+

+

+

+

+

13/20

Wasted

-

-

-

-

-

-

-

-

-

+

+

+

+

+

+

+

+

+

-

-

9/20

Urine coloured - dark yellow

-

-

-

-

-

-

-

-

-

-

-

-

-

-

+

+

+

+

+

+

6/20

 

 

1062

Symptom Free

+

+

+

-

-

-

+

-

-

-

-

-

-

-

-

-

-

-

-

-

4/20

Activity decreased

-

-

-

-

-

-

-

1

-

-

-

-

-

-

-

-

-

-

-

-

1/20

Hunched back

-

-

-

+

+

+

-

+

+

+

+

+

+

+

+

+

+

+

+

+

16/20

Piloerection

-

-

-

-

-

-

-

+

-

-

-

-

+

+

+

+

+

+

+

+

9/20

Wasted

-

-

-

-

-

-

-

-

-

+

+

+

+

+

+

+

+

+

+

+

11/20

Urine coloured - dark yellow

-

-

-

-

-

-

-

-

-

-

-

-

-

-

+

+

+

+

+

+

6/20

Remarks:

+ = present h = hour (s)

# = Found dead

- = absent ' = minute

Frequency of observation = number of occurrence of observation / total number of observations Severities: 1 = Slight/Small/Few; 2 = Moderate/Medium; 3 = Marked/Large/Many

CLINICAL OBSERVATIONS

DOSE LEVEL: 2000 mg/kg bw, Treatment on Day 0

SEX: FEMALE

 

Cage No.

Animal Number

 

Observations

Observation days

 

Frequency

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

30'

1h

2h

3h

4h

6h

 

 

 

 

 

 

 

 

 

3

 

 

1063#

Symptom Free

+

+

+

+

-

-

-

-

-

-

-

-

 

4/12

Activity decreased

-

-

-

-

-

-

-

1

1

1

1

2

5/12

Hunched back

-

-

-

-

+

+

+

+

+

+

+

+

8/12

Piloerection

-

-

-

-

-

-

+

+

+

+

+

+

6/12

Wasted

-

-

-

-

-

-

-

-

-

-

+

+

2/12

Found dead

-

-

-

-

-

-

-

-

-

-

-

-

+

 

-

 

 

1064

Symptom Free

+

+

+

-

-

+

+

+

-

-

-

-

-

-

-

-

-

-

-

-

6/20

Activity decreased

-

-

-

-

-

-

-

-

1

1

1

1

1

1

-

-

-

-

-

-

6/20

Hunched back

-

-

-

+

+

-

-

-

+

+

+

+

+

+

+

+

+

+

+

+

14/20

Piloerection

-

-

-

-

-

-

-

-

+

+

+

+

+

+

+

+

+

+

+

+

12/20

Wasted

-

-

-

-

-

-

-

-

-

-

-

+

+

+

+

+

+

+

+

+

9/20

Urine coloured - dark yellow

-

-

-

-

-

-

-

-

-

-

-

-

-

+

+

+

+

+

+

+

7/20

 

 

1065#

Symptom Free

+

+

+

+

-

-

-

-

-

-

-

 

4/11

Activity decreased

-

-

-

-

-

-

-

1

1

1

1

4/11

Hunched back

-

-

-

-

+

+

+

+

+

+

+

7/11

Piloerection

-

-

-

-

-

-

+

+

+

+

+

5/11

Wasted

-

-

-

-

-

-

-

-

-

-

+

1/11

Found dead

-

-

-

-

-

-

-

-

-

-

-

+

 

-

 

 

 

 

4

 

1066#

Symptom Free

+

+

-

-

-

-

 

2/6

Hunched back

-

-

+

+

+

+

4/6

Found dead

-

-

-

-

-

-

+

 

-

 

1067#

Symptom Free

+

+

+

-

-

-

-

 

3/7

Hunched back

-

-

-

+

+

+

+

4/7

Found dead

-

-

-

-

-

-

-

+

 

-

 

1068#

Symptom Free

+

+

+

-

-

-

-

 

3/7

Hunched back

-

-

-

+

+

+

+

4/7

Found dead

-

-

-

-

-

-

-

+

 

-

CLINICAL OBSERVATIONS

DOSE LEVEL: 50 mg/kg bw, Treatment  on Day 0       

SEX: FEMALE

 

Cage No.

Animal Number

 

Observations

Observation days

 

Frequency

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

30'

1h

2h

3h

4h

6h

 

5

1098

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

20/20

1099

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

20/20

1100

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

20/20

 

6

1101

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

20/20

1102

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

20/20

1103

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

20/20

Remarks:

+ = present h = hour (s)

' = minute

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

BODY WEIGHT DATA

DOSE LEVEL: 300 mg/kg bw, Treatment on Day 0       

SEX: FEMALE

Cage No.

 

Animal Number

Body weight (g)

Days

Day/Body Weight(g)

Death

Body Weight Gain (g)

-1

0

4

7

14

-1-0

0-7

7- 14

-1 - 14

 

1057#

214

196

/

-

-

2/202

-18

-

-

-

1

1058#

207

193

/

-

-

3/190

-14

-

-

-

 

1059

212

193

/

202

231

-

-19

9

29

19

 

1060

200

187

162

159

170

-

-13

-28

11

-30

2

1061

194

186

167

160

183

-

-8

-26

23

-11

 

1062

203

196

172

160

171

-

-7

-36

11

-32

Mean:

205.0

191.8

167.0

170.3

188.8

-

-13.2

-20.3

18.5

-13.5

Standard deviation:

7.5

4.4

5.0

21.2

28.8

-

5.0

20.0

9.0

23.6

BODY WEIGHT DATA

DOSE LEVEL: 2000 mg/kg bw, Treatment on Day 0       

SEX: FEMALE

Cage No.

 

Animal Number

Body weight (g)

Days

Day/Body

Weight (g) Death

Body Weight Gain (g)

-1

0

3

7

14

-1-0

0-7

7- 14

-1 - 14

 

1063#

211

197

180

153

-

7/153

-14

-44

-

-

3

1064

214

197

183

178

181

 

-17

-19

3

-33

 

1065#

209

196

178

-

-

6/168

-13

-

-

-

 

1066#

195

198

/

-

-

1/184

3

-

-

-

4

1067#

207

189

/

-

-

2/195

-18

-

-

-

 

1068#

202

196

/

-

-

2/186

-6

-

-

-

Mean:

206.3

195.5

180.3

165.5

181.0

-

-10.8

-31.5

3.0

-33.0

Standard deviation:

6.9

3.3

2.5

17.7

-

-

8.0

17.7

-

-

Remarks

- = No data

# = Found dead

/ = No body weight measurement was performed

BODY WEIGHT DATA

DOSE LEVEL: 50 mg/kg bw, Treatment on Day 0       

SEX: FEMALE

CageNo.

 

Animal Number

Body weight (g)

Days

Day/Body

Weight (g) Death

Body Weight Gain (g)

-1

0

 

7

14

-1-0

0-7

7- 14

-1 - 14

 

1098

240

230

/

253

263

-

-10

23

10

23

5

1099

223

214

/

234

246

-

-9

20

12

23

 

1100

254

240

/

261

290

-

-14

21

29

36

 

1101

240

219

/

257

268

-

-21

38

11

28

6

1102

232

220

/

245

255

-

-12

25

10

23

 

1103

233

223

/

241

248

-

-10

18

7

15

Mean:

237.0

224.3

/

248.5

261.7

-

-12.7

24.2

13.2

24.7

Standard deviation:

10.4

9.3

/

10.3

16.3

-

4.5

7.2

7.9

6.9

Remarks

- = No data

/ = No body weight measurement was performed

NECROPSY FINDINGS

DOSE LEVEL: 300 mg/kg bw, Treatment on Day 0       

SEX: FEMALE

Cage

No.

Animal

Number

Necropsy Date/

Necropsy Day

External Observations

Internal Observations

Organ/Tissue

 

 

 

 

 

1

1057#

21 September 2017

Day 2

No external observations recorded

Collapsed

Lungs

 

 

1058#

 

 

22 September 2017

Day 3

 

 

Fur: Thin, cheek, right

Non-collapsed

 

Lungs

Discoloration, dark red, diffuse, all lobes

Discoloration, dark red, diffuse

Thymus

1059

03 October 2017

Day 14

No external observations recorded

No internal observations recorded

Not applicable

 

 

 

 

 

 

 

2

1060

04 October 2017

Day 14

No external observations recorded

Discoloration, yellowish, multifocal, all

lobes

Liver

 

 

 

1061

 

 

 

04 October 2017

Day 14

 

 

 

No external observations recorded

Discoloration, yellowish, multifocal, all

lobes

Liver

Enlargement

 

Spleen

Discoloration, pale, diffuse

Thickness, multifocal, non-glandular

mucosa

Stomach

 

1062

 

04 October 2017

Day 14

 

No external observations recorded

Discoloration, yellowish, multifocal, all

lobes

Liver

Thickness, multifocal, non-glandular

mucosa

Stomach

Remarks

# = Found dead

NECROPSY FINDINGS

DOSE LEVEL: 2000 mg/kg  bw, Treatment on Day 0       

SEX: FEMALE

Cage

No.

Animal

Number

Necropsy Date/

Necropsy Day

External Observations

Internal Observations

Organ/Tissue

 

 

 

 

 

 

 

 

 

 

 

3

 

 

 

1063#

 

 

 

28 September 2017

Day 7

 

 

 

No external observations recorded

Non-collapsed

 

Lungs

Discoloration, dark red, diffuse, all lobes

Discoloration, dark red, diffuse

Thymus

Discoloration, dark red, multifocal, non-

glandular mucosa

Stomach

 

 

 

 

 

1064

 

 

 

 

05 October 2017

Day 14

 

 

 

 

 

No external observations recorded

Liquid material yellowish approx.: 5 ml

Abdominal Cavity

Discoloration, yellowish, multifocal, all

lobes

Liver

Thickness, multifocal, non-glandular

mucosa

 

 

 

Stomach

Discoloration, yellow-red, focal approx.: 30 mm x 10 mm insize non-glandular

mucosa

Digestive content: Liquid material red

mixed with diet

 

1065#

 

27 September 2017

Day 6

 

No external observations recorded

Collapsed

 

Lungs

Discoloration, red, diffuse, all lobes

 

 

 

 

4

 

1066#

 

23 September 2017

Day 1

 

No external observations recorded

Non-collapsed

Lungs

Digestive content: Material liquid yellow

mixed with diet

Stomach

1067#

24 September 2017

Day 2

No external observations recorded

Non-collapsed

Lungs

 

1068#

 

24 September 2017

Day 2

 

No external observations recorded

Non-collapsed

 

Lungs

Discoloration, red, diffuse, all lobes

Remarks

# = Found dead

NECROPSY FINDINGS

DOSE LEVEL: 50 mg/kg bw, Treatment on Day 0

SEX: FEMALE

Cage

No.

Animal

Number

Necropsy Date/

Necropsy Day

External Observations

Internal Observations

Organ/Tissue

 

 

5

1098

18 October 2017

Day 14

No external observations recorded

No internal observations recorded

Not applicable

1099

18 October 2017

Day 14

No external observations recorded

No internal observations recorded

Not applicable

1100

18 October 2017

Day 14

No external observations recorded

No internal observations recorded

Not applicable

 

 

6

1101

24 October 2017

Day 14

No external observations recorded

No internal observations recorded

Not applicable

1102

24 October 2017

Day 14

No external observations recorded

No internal observations recorded

Not applicable

1103

24 October 2017

Day 14

No external observations recorded

No internal observations recorded

Not applicable

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Under the conditions of this study, the acute oral LD50 value of the test item Selenium Disulphide was found to be between 300 and 2000 mg/kg bw in female Crl:WI Wistar rats.

According the Regulation (EC) No 1272/2008 classification of Selenium Disulphide can be ranked as "Category 4" for acute oral exposure.
Executive summary:

The single-dose oral toxicity study with Selenium Disulphide was performed according to the acute toxic class method (OECD 423 and Commission Regulation (EC) No 440/2008 of 30 May 2008, B.1.tris) in Crl:WI Wistar female rats.

Six groups of three female Crl:WI rats were treated with the test item at the dose levels of 300 (Group 1 and 2), 2000 (Group 3 and 4) and 50 mg/kg body weight (bw) (Group 5 and 6).

A single oral treatment was carried out by gavage for each animal after an overnight food withdrawal. Food was made available again 3 hours after the treatment. The test item was administered at the dose levels of 50, 300 and 2000 mg/kg bw.

Initially, three females (Group 1) were treated at a dose level of 300 mg/kg bw. Due to delayed mortality with few or no clinical signs, the selection of dose groups based on mortality in the first 48 hours after dosing resulted in more groups being required than in a standard study.

Clinical observations were performed at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Body weight was measured on Days -1, 0, 7 and before necropsy (Day 14) or at death. Additional measurements were performed on Day 4 in Group 2 and on Day 3 in Group 3. All animals were subjected to a necropsy and a macroscopic examination.

Mortality

No mortality (0/6) occurred at the dose level of 50 mg/kg bw.

2 out of 6 animals died on Day 2 and Day 3 at the dose level of 300 mg/kg bw.

5 out of 6 animals died between Day 1 and Day 7 at the dose level of 2000 mg/kg bw.

Clinical Observations

All animals were symptom-free at the dose level of 50 mg/kg bw during the 14-day observation period.

At the dose level of 300 mg/kg bw, the following test item related symptoms were observed up to Day 14 or until death: hunched back (6 out of 6 animals), piloerection (4 out of 6 animals), slight decreased activity (3 out of 6 animals), dark yellow coloured urine (3 out of 6 animals). 3 out of 6 animals were thin from Day 4 until the end of the 14-day observation period.

At the dose level of 2000 mg/kg bw, the following test item related symptoms were observed up to Day 14 or until death: hunched back (6 out of 6 animals), piloerection (3 out of 6 animals), slightly or moderately decreased activity (3 out of 6 animals) and dark yellow coloured urine (1 out of 6 animals). 3 out of 6 animals were thin from Day 5 or 6 until the end of the 14-day observation period or until death.

Body Weight and Body Weight Gain

At the dose level of 50 mg/kg bw, there were no treatment related body weight changes. Body weights were within the range commonly recorded for this strain and age.

At the dose level of 300 mg/kg bw, slight body weight loss was observed until Day 7 in 3 out of 6 animals. The body weight gain of the surviving animals were normal between Day 7 and Day 14.

At the dose level of 2000 mg/kg bw, slight or moderate body weight loss was observed in 2 out of 6 animals until Day 7 or until death. The body weight gain of the surviving animal was normal between Day 7 and Day 14.

Macroscopic Findings

There was no evidence of the macroscopic observations in any animals at the dose level of 50 mg/kg bw.

At the dose level of 300 mg/kg bw, the following macroscopic findings were observed at necropsy: in the found dead animals, dark red discoloration/non-collapsed/collapsed lungs and thymus were agonal or post mortem rather than test item-related. Additionally, incidental thin fur at the right cheek was noted in one animal. There were test item-related gross changes noted in the liver and stomach of 3 out of 4 rats terminated on Day 14. Thickness of the non-glandular stomach mucosa and/or yellowish multifocal discoloration of the liver were seen in these animals. In addition, enlargement of pale discoloured spleen was macroscopically described in one single animal and therefore this change was not ascribed to the administration of test item.

At the dose level of 2000 mg/kg bw, the following macroscopic findings were observed at necropsy: for animal that died relatively soon after treatment (ID 1066), yellow liquid mixed with diet in the digestive content the stomach was observed. For animals that died later (ID 1063 and 1065), discoloration (dark red) of the stomach was observed in 1 out of the 2 animals (ID 1063). Other macroscopic changes including dark red discoloration of the non-collapsed/collapsed lungs and thymus were regarded as agonal or post mortem rather than test item-related. In one surviving animal multifocal thickness/yellow-red discoloration of the non-glandular stomach mucosa, red liquid mixed with diet in the digestive content of the stomach, yellowish multifocal discoloration of the liver and/or yellowish liquid (approximately 5.0 ml) within the abdominal cavity, were regarded as test item-related.

Conclusion

Under the conditions of this study, the acute oral LD50 value of the test item Selenium Disulphide was found to be between 300 and 2000 mg/kg bw in female Crl:WI Wistar rats.

According the Regulation (EC) No 1272/2008 classification of Selenium Disulphide can be ranked as "Category 4" for acute oral exposure.