Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Acute Toxicity: Oral

LD50 value > 2000 mg/kg bw in female Crl:WI rats.

Acute Toxicity: Dermal

LD50 value >2000 mg/kg bw in male/female Crl:WI rats.

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:
28 March 2017 to 12 April 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)
Version / remarks:
OECD Guidelines for Testing of Chemicals No. 423. Acute Oral Toxicity – Acute Toxic Class Method. Adopted: 17 December 2001
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
Commission Regulation (EC) NO 440/2008 of 30 May 2008, B.1.tris
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
EPA Health Effects Test Guidelines (OPPTS 870.1100), United States, EPA 712-C-98-190 (1998)
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:
No further details specified in the study report.
Species:
rat
Strain:
Wistar
Remarks:
Crl:WI
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: 6 animals, 3 animals/group
Sex: Female, nulliparous and non-pregnant
Age of animals at dosing: Young healthy adult rats, 8 weeks old
Body weight at treatment: 185 – 202 g
Acclimatization period: 5-6 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: 522/4
Housing: 3 animals / cage
Cage type: Type II. polypropylene/polycarbonate
Bedding and nesting: “Lignocel” 3/4-S Hygienic Animal Bedding” and “Arbocel crinklets natural” nesting material produced by J. Rettenmaier & Söhne GmbH + Co.KG (D-73494 Rosenberg, Germany) were available to animals during the study.
Copies of the Certificates of Analysis are retained in the archive at CiToxLAB Hungary Ltd.
Lighting period: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Temperature: 20.4 – 24.4 °C
Relative humidity: 30 – 64 %
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: 484 14771, expiry date: 30 June 2017), 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 A. 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 marker 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.
Route of administration:
oral: gavage
Vehicle:
methylcellulose
Details on oral exposure:
Vehicle: 1% methyl cellulose

Components of the vehicle:
Name: Distilled water
Manufacturer: Hungaro-Gal Kft.
Batch number: 802 0117
Expiry date: 23 July 2017

Name: Methyl cellulose
Manufacturer: Shin-Etsu Chemical Co., Ltd.
Batch number: 5115851
Expiry date: 27 November 2018

Formulation
The test item was freshly formulated at a concentration of 200 mg/mL in the vehicle, in the Pharmacy of CiToxLAB Hungary Ltd. on the day of administration. The formulation container was stirred continuously up to finishing the treatment.

Justification of the dose:
The initial dose level was selected by the Study Director to be that which is most likely to produce mortality in some of the dosed animals. In the lack of any preliminary toxicological information, 2000 mg/kg bw was selected to be the starting dose.

Initially, three female animals were treated with 2000 mg/kg bw of the test item. No mortality was observed, therefore further 3 animals were treated at the dose level of 2000 mg/kg bw. As no mortality was observed in this second dose group, further testing was not required according to the test guidelines (OECD 423, Commission Regulation (EC) NO 440/2008 of 30 May 2008, B.1.tris).
Doses:
The initial dose level was selected by the Study Director to be that which is most likely to produce mortality in some of the dosed animals. In the lack of any preliminary toxicological information, 2000 mg/kg bw was selected to be the starting dose.
No. of animals per sex per dose:
Initially, three female animals were treated with 2000 mg/kg bw of the test item. No mortality was observed, therefore further 3 animals were treated at the dose level of 2000 mg/kg bw. As no mortality was observed in this second dose group, further testing was not required.
Control animals:
no
Details on study design:
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 just before treatment. The test item was administered by oral gavage in the morning. The food was returned 3 hours after the treatment.

OBSERVATIONS
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. 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) and weekly thereafter.

NECROPSY
Macroscopic examination was performed on all animals. The animals were sacrificed by exsanguination under pentobarbital anaesthesia (Release, 300 mg / kg pentobarbital sodium; Lot number: 106075, Expiry date: 31 July 2018, Produced by: Wirtschaftsgenossenschaft deutscher Tierärzte eG, Germany). 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.
Statistics:
Not required
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
6,6’-di-tert-butyl-2,2’-thiodi-p-cresol did not cause mortality at a dose level of 2000 mg/kg bw.
Clinical signs:
There were no systemic clinical signs noted in any animal throughout the study.
Body weight:
There were no treatment related body weight changes. Body weight gains of 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol treated animals during the study showed no indication of a test item-related effect.
Gross pathology:
There was no evidence of the macroscopic observations at a dose level of 2000 mg/kg bw.
Other findings:
No further findings detailed in the study report.

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

7-14

30’

1h

2h

3h

4h

6h

1

7879

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

20/20

7880

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

20/20

7881

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

20/20

2

7882

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

20/20

7883

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

20/20

7884

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: 2000 mg/kg bw, Treatment on Day 0                                       SEX: FEMALE

Cage No.

Animal Number

Body weight (g)

Days

Body Weight Gain (g)

-1

0

7

14

-1 – 0

0 – 7

7 – 14

-1 – 14

1

7879

219

197

226

239

-22

29

13

20

7880

212

200

241

257

-12

41

16

45

7881

212

202

221

229

-10

19

8

17

2

7882

196

185

204

218

-11

19

14

22

7883

196

190

209

229

-6

19

20

33

7884

206

200

224

237

-6

24

13

31

Mean:

206.8

195.7

220.8

234.8

-11.5

25.25

14.0

28.0

Standard deviation:

9.3

6.7

13.2

13.2

5.9

8.7

3.9

10.4

 

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

1

7879

11 April 2017

Day 14

No external observation recorded

No internal observations recorded

Not applicable

 

7880

11 April 2017

Day 14

No external observation recorded

No internal observations recorded

Not applicable

 

7881

11 April 2017

Day 14

No external observation recorded

No internal observations recorded

Not applicable

2

7882

12 April 2017

Day 14

No external observation recorded

No internal observations recorded

Not applicable

 

7883

12 April 2017

Day 14

No external observation recorded

No internal observations recorded

Not applicable

 

7884

12 April 2017

Day 14

No external observation recorded

No internal observations recorded

Not applicable

 

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, the acute oral LD50 value of the test item 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol was found to be above 2000 mg/kg bw in female Crl:WI rats.
According the GHS criteria, 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol can be ranked as "Category 5 or Unclassified" for acute oral exposure.
Executive summary:

The single-dose oral toxicity of 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol 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 rats.

 

Two groups of three female Crl:WI rats were treated with the test item at a dose level of 2000 mg/kg bw (Group 1 and Group 2).

 

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 formulated in 1% methyl cellulose at a concentration of 200 mg/mL at a dose volume of 10 mL/kg bw.

 

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. 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.

 

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 and 7 and 14 (before necropsy). All animals were subjected to a necropsy and a macroscopic examination.

 

RESULTS

Mortality

6,6’-di-tert-butyl-2,2’-thiodi-p-cresol did not cause mortality at a dose level of 2000 mg/kg bw.

 

Clinical Observations

There were no systemic clinical signs noted in any animal throughout the study.

 

Body Weight and Body Weight Gain

There were no treatment related body weight changes. Body weight gains of 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol treated animals during the study showed no indication of a test item-related effect.

 

Macroscopic Findings

There was no evidence of the macroscopic observations at a dose level of 2000 mg/kg bw.

 

CONCLUSION

Under the conditions of this study, the acute oral LD50 value of the test item 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol was found to be above 2000 mg/kg bw in female Crl:WI rats.

 

According the GHS criteria, 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol can be ranked as "Category 5 or Unclassified" for acute oral exposure.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
K1 - GLP accredited laboratory study to OECD Guideline 423 and EU Method B.1 tris

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:
08 August 2017 to 22 August 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:
yes
Remarks:
See "Any other information" for details
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
Commission Regulation (EC) No 440/2008 of 30 May 2008, B.3.Tris
Deviations:
yes
Remarks:
See "Any other information" for details
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
See "Any other information" for details
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
No further details specified in the study report.
Species:
rat
Strain:
Wistar
Remarks:
Crl:WI
Sex:
male/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: 5 animals/sex
Sex: Male and female, female rats were nulliparous and non-pregnant
Age of animals at dosing: Young adult rats
Body weight at treatment: Between 221 g and 255 g
Acclimatisation period: 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: 242/6
Housing: Individual caging
Cage type: Type II. polypropylene/polycarbonate
Bedding and nesting: “Lignocel 3/4-S Hygienic Animal Bedding” and “Arbocel crinklets natural” nest building material 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: 21.1 – 28.2 °C
Relative humidity: 32 – 74 %
Ventilation: 15-20 air exchanges/hour
Enrichment: Rodents were housed 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 A. u. 36., Hungary).

Animal Identification
Animals were individually identified using numbers written on the tail with an indelible marker 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.
Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
Formulation
The test item was administered as a single dose. Sufficient water was used to dampen the test material to ensure good contact with the skin.

Procedure
The back of each animal was shaved (approximately 10% area of the total body surface) approximately 24 hours prior to treatment. The test item was applied as a single dose to the shaved skin and remained in contact with the skin for the 24-hour exposure period. The test material was dampened with sufficient water before application to ensure good contact with the skin. Sterile gauze pads were placed on the skin of rats to cover the test item. These gauze pads were kept in contact with the skin using a patch with adhesive hypoallergenic plaster. The entire trunk of the animal was then wrapped with semi occlusive plastic wrap for 24 hours.
At the end of the exposure period, the area of skin treated with the test item was washed with water of body temperature.
Duration of exposure:
24 hours.
Doses:
A single dermal application was made.
No. of animals per sex per dose:
10 (5 males/5 females)
Control animals:
no
Details on study design:
Clinical Observations
Clinical observations were performed on the day of treatment at 1 and 5 hours after application of the test item and once each day 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.
Skin Irritation:
Adverse skin reactions at the site of application were recorded daily following the removal of the dressing.

Body Weight Measurement
The body weights were recorded on Day 0 (before test item administration) and on Days 7 and 14 just before necropsy.

NECROPSY
Macroscopic examination was performed on all animals. The animals were sacrificed by exsanguination under pentobarbital anaesthesia (Release, 300 mg/mL pentobarbital sodium; Lot number: 106075, Expiry date: 31 July 2018, Produced by: Wirtschaftsgenossenschaft deutscher Tierärzte eG, Germany). 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.
Statistics:
Not specified.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
6,6’-di-tert-butyl-2,2’-thiodi-p-cresol did not cause mortality at the dose level of 2000 mg/kg bw.
Clinical signs:
There were no systemic clinical signs noted in any animal throughout the study.
Body weight:
Body weight gains of 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol treated animals during the study showed no indication of a test item-related effect.
Gross pathology:
There was no evidence of the macroscopic observations at a dose level of 2000 mg/kg bw.
Other findings:
No local dermal signs were observed after treatment with the test item during the 14 days observation period.

CLINICAL OBSERVATIONS

DOSE LEVEL: 2000 mg/kg bw

 

SEX: MALE

Cage No.

Animal No.

Observations

Observation days

Frequency

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

1h

5h

1

357

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

16/16

2

358

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

16/16

3

359

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

16/16

4

360

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

16/16

5

361

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

16/16

 

DOSE LEVEL: 2000 mg/kg bw

 

SEX: FEMALE

Cage No.

Animal No.

Observations

Observations days

Frequency

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

1h

5h

6

362

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

16/16

7

363

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

16/16

8

364

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

16/16

9

365

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

16/16

10

366

Symptom Free

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

16/16

Remarks:             + = present

                         h = hour (s)          Treatment day = Day 0

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

 

BODY WEIGHT DATA

DOSE LEVEL: 2000 mg/kg bw

 

 

 

SEX: MALE

Cage No.

Animal No.

Body weight (g)

Body Weight Gain (g)

Days

0

7

14

0-7

7-14

0-14

1

357

233

297

349

64

52

116

2

358

243

285

319

42

34

76

3

359

247

309

366

62

57

119

4

360

229

288

358

59

70

129

5

361

222

289

247

67

58

125

Mean:

234.8

293.6

347.8

58.8

54.25

113.0

Standard deviation:

10.2

9.7

17.8

9.8

13.1

21.3

 

DOSE LEVEL: 2000 mg/kg bw

 

 

 

SEX: FEMALE

Cage No.

Animal No.

Body weight (g)

Body Weight Gain (g)

Days

0

7

14

0-7

7-14

0-14

6

362

225

264

279

39

15

54

7

363

242

261

276

19

15

34

8

364

255

317

338

62

21

83

9

365

221

240

251

19

11

30

10

366

232

252

257

20

5

25

Mean:

235.0

266.8

280.2

31.8

143.4

45.2

Standard deviation:

13.7

29.6

34.5

18.9

5.9

23.8

 

NECROPSY FINDINGS

DOSE LEVEL: 2000 mg/kg bw

 

 

SEX: MALE

Cage No.

Animal No.

Necropsy Date/ Necropsy Day

External Observations

Internal Observations

Organ/ Tissue

1

357

22 August 2017

Day 14

No external observations

No internal observations

Not applicable

2

358

22 August 2017

Day 14

No external observations

No internal observations

Not applicable

3

359

22 August 2017

Day 14

No external observations

No internal observations

Not applicable

4

360

22 August 2017

Day 14

No external observations

No internal observations

Not applicable

5

361

22 August 2017

Day 14

No external observations

No internal observations

Not applicable

 

DOSE LEVEL: 2000 mg/kg bw

 

 

SEX: FEMALE

Cage No.

Animal No.

Necropsy Date/ Necropsy Day

External Observations

Internal Observations

Organ/ Tissue

6

362

22 August 2017

Day 14

No external observations

No internal observations

Not applicable

7

363

22 August 2017

Day 14

No external observations

No internal observations

Not applicable

8

364

22 August 2017

Day 14

No external observations

No internal observations

Not applicable

9

365

22 August 2017

Day 14

No external observations

No internal observations

Not applicable

10

366

22 August 2017

Day 14

No external observations

No internal observations

Not applicable

 

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, the acute dermal median lethal dose (LD50 value) of the test item 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol was found to be above 2000 mg/kg bw in male and female Crl:WI rats.
According to the GHS criteria, 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol can be ranked as "Category 5 or Unclassified" for acute dermal exposure.
Executive summary:

An acute dermal toxicity study was performed with test item 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol in Crl:WI rats, in compliance with OECD Guideline No. 402.

 

A limit test was carried out at 2000 mg/kg body weight (bw) in both sexes (5 rats/sex). The test item was applied as a single dermal 24-hour exposure followed by a 14-day observation period.

 

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. Gross macroscopic examination was performed on all animals at the end of the 2-week observation period (Day 14).

 

RESULTS

Mortality

6,6’-di-tert-butyl-2,2’-thiodi-p-cresol did not cause mortality at the dose level of 2000 mg/kg bw.

 

Clinical Observations

There were no systemic clinical signs noted in any animal throughout the study.

 

Local dermal signs

No local dermal signs were observed after treatment with the test item during the 14 days observation period.

 

Body weight and body weight gain

Body weight gains of 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol treated animals during the study showed no indication of a test item-related effect.

 

Macroscopic Findings

There was no evidence of the macroscopic observations at a dose level of 2000 mg/kg bw.

 

CONCLUSIONS

Under the conditions of this study, the acute dermal median lethal dose (LD50 value) of the test item 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol was found to be above 2000 mg/kg bw in male and female Crl:WI rats.

 

According to the GHS criteria, 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol can be ranked as "Category 5 or Unclassified" for acute dermal exposure.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
K1 - GLP accredited laboratory study to OECD Guideline 402 and EU Method B.3 tris

Additional information

Acute Toxicity: Oral

Two groups of three female Crl:WI rats were treated with the test item at a dose level of 2000 mg/kg bw (Group 1 and Group 2). 

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 formulated in 1% methyl cellulose at a concentration of 200 mg/mL at a dose volume of 10 mL/kg bw.

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. No mortality was observed in the confirmatory group; therefore no further testing was required.

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 and 7 and 14 (before necropsy). All animals were subjected to a necropsy and a macroscopic examination.

 

RESULTS

Mortality

6,6’-di-tert-butyl-2,2’-thiodi-p-cresol did not cause mortality at a dose level of 2000 mg/kg bw.

Clinical Observations

There were no systemic clinical signs noted in any animal throughout the study.

Body Weight and Body Weight Gain

There were no treatment related body weight changes. Body weight gains of 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol treated animals during the study showed no indication of a test item-related effect.

Macroscopic Findings

There was no evidence of the macroscopic observations at a dose level of 2000 mg/kg bw.

Acute Toxicity: Dermal

An acute dermal toxicity study was performed with test item 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol in Crl:WI rats, in compliance with OECD Guideline No. 402.

 

A limit test was carried out at 2000 mg/kg body weight (bw) in both sexes (5 rats/sex). The test item was applied as a single dermal 24-hour exposure followed by a 14-day observation period.

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. Gross macroscopic examination was performed on all animals at the end of the 2-week observation period (Day 14).

 

RESULTS

Mortality

6,6’-di-tert-butyl-2,2’-thiodi-p-cresol did not cause mortality at the dose level of 2000 mg/kg bw.

Clinical Observations

There were no systemic clinical signs noted in any animal throughout the study.

Local dermal signs

No local dermal signs were observed after treatment with the test item during the 14 days observation period.

Body weight and body weight gain

Body weight gains of 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol treated animals during the study showed no indication of a test item-related effect.

Macroscopic Findings

There was no evidence of the macroscopic observations at a dose level of 2000 mg/kg bw.

Under the conditions of this study, the acute dermal median lethal dose (LD50 value) of the test item 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol was found to be above 2000 mg/kg bw in male and female Crl:WI rats.

Justification for classification or non-classification

Acute Toxicty: Oral

According the GHS criteria, 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol can be ranked as "Category 5 or Unclassified" for acute oral exposure.

Acute Toxicity: Dermal

According to the GHS criteria, 6,6’-di-tert-butyl-2,2’-thiodi-p-cresol can be ranked as "Category 5 or Unclassified" for acute dermal exposure.