Registration Dossier

Administrative data

Description of key information

The acute oral toxicity of substance IFF TM 10-202 is greater than 2000 mg/kg bodyweight according to OECD Test Guideline 423 using the Acute Toxic Class Method.
The acute dermal toxicity potential of the test material, IFF TM 10-202, gave an LD50 of > 2000 mg/kg body weight according to OECD Test Guideline 402, using a fixed dose method.

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:
Testing was conducted between 03 September 2013 and 01 October 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study is considered to be a reliability 1 as it has been conducted according to OECD Test Guideline 423 using the Acute Oral Toxicity-Acute Toxic Class Method in compliance with GLP.
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
On occasions the relative humidity was outside the target range of 30 to 70 %. This was considered not to have affected the purpose or integrity of the study.
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
Animals and Animal Husbandry

Female Wistar (RccHan™:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non pregnant. After an acclimatization period of at least five days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card. At the start of the study the animals were eight to twelve weeks of age. The body weight variation did not exceed ± 20 % of the body weight of the initially dosed animal.

The animals were housed in groups of up to three in suspended solid floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately three to four hours after dosing, free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analyzed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.

The temperature and relative humidity were set to achieve limits of 19 to 25 °C and 30 to 70 % respectively. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

Justification
Rats are the preferred species of choice as historically used for safety evaluation studies and are specified in the appropriate test guidelines.
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
Test Item Formulation and Experimental Preparation

For the purpose of the 2000 mg/kg dose level, the test item was used as supplied. The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level. For the purpose of the 300 mg/kg dose level, the test item was freshly prepared, as required, as a solution in arachis oil BP. Arachis oil BP was used because the test item did not dissolve/suspend in distilled water.

The test item was formulated within two hours of being applied to the test system. It is assumed that the formulation was stable for this duration.

No analysis was conducted to determine the homogeneity, concentration or stability of the test item formulation. This is an exception with regard to GLP and has been reflected in the GLP compliance statement.

In the absence of data regarding the toxicity of the test item, 2000 mg/kg was chosen as the starting dose.
Doses:
Groups of fasted animals were dosed 300 mg/kg with a dose volume of 10 mL/kg. A second dose level of 2000 mg/kg was administered with a dose volume of 2.27 mL/kg and was tested twice.

All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted body weight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each group to confirm the survival of the previously dosed animals.
No. of animals per sex per dose:
3 females rats per dose level
Control animals:
no
Details on study design:
The animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.

Individual body weights were recorded prior to dosing and seven and fourteen days after treatment.

At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities for examination of major organs. The appearance of any macroscopic abnormalities was recorded. No tissues were retained
Statistics:
Data evaluations included the relationship, if any, between the exposure of the animal to the test item and the incidence and severity of all abnormalities including behavioral and clinical observations, gross lesions, body weight changes, mortality and any other toxicological effects.

Using the mortality data obtained, an estimate of the acute oral median lethal dose (LD50) of the test item was made.

The results were also evaluated according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures.
Sex:
female
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
Pilo-erection and/or hunched posture were noted in animals treated at a dose level of 2000 mg/kg. Additional signs of systemic toxicity noted in one animal treated at a dose level of 2000 mg/kg were ptosis, ataxia, lethargy and labored, noisy and gasping respiration.

There were no signs of systemic toxicity noted at a dose level of 300 mg/kg.
Body weight:
Animals showed expected gains in body weight, except for one animal treated at a dose level of 2000 mg/kg which showed body weight loss during the first week but expected gain in body weight during the second week.
Gross pathology:
No abnormalities were noted at necropsy.

Mortality Data

Dose Level mg/kg

Sex

Number of Animals Treated

Deaths During Day of Dosing
(Hours)

Deaths During Period After Dosing
(Days)

Deaths

½

1

2

4

1

2

3

4

5

6

7

8-14

300

Female

3

0

0

0

0

0

0

0

0

0

0

0

0

0/3

2000

Female

3

0

0

0

0

0

0

0

0

0

0

0

0

0/3

Female

3

0

0

0

0

0

0

0

0

0

0

0

0

0/3

Individual Clinical Observations - 300 mg/kg

Dose Level mg/kg

Animal Number and Sex

Effects Noted After Dosing
(Hours)

Effects Noted During Period After Dosing
(Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

300

1-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-1

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-2

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0


0=   No signs of systemic toxicity

Individual Clinical Observations - 2000 mg/kg

Dose Level mg/kg

Animal Number and Sex

Effects Noted After Dosing
(Hours)

Effects Noted During Period After Dosing
(Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

2-0

Female

0

0

H

HP

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-1

Female

0

0

H

H

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-2

Female

0

0

H

HP

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-0

Female

0

H

H

H

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-1

Female

H

H

H

H

0

0

0

0

0

0

0

0

0

0

0

0

0

0

3-2

Female

HRlPt

H

HA

HALRnPt

0

0

0

0

0

0

HP

HP

HPRl

H

HRlRg

HRlRg

HP
RlRg

HP
RlRg


0=   No signs of systemic toxicity

P =   Pilo-erection

H =  Hunched posture

Pt = Ptosis

Rl = Labored

Rn = Noisy respiration

Rg =Gasping respiration

A =  Ataxia

L =  Lethargy

Individual Body Weights and Body Weight Changes - 300 mg/kg

Dose Level

mg/kg

Animal Number
and Sex

Body Weight (g) at Day

Body Weight Gain (g) During Week

0

7

14

1

2

300

1-0 Female

164

174

223

10

49

1-1 Female

154

166

192

12

26

1-2 Female

158

162

194

4

32

Individual Body Weights and Body Weight Changes - 2000 mg/kg

Dose Level

mg/kg

Animal Number
and Sex

Body Weight (g) at Day

Body Weight Gain (g) During Week

0

7

14

1

2

2000

2-0 Female

172

184

199

12

15

2-1 Female

173

183

197

10

14

2-2 Female

164

179

199

15

20

3-0 Female

163

181

187

18

6

3-1 Female

162

187

191

25

4

3-2 Female

166

140

143

-26

3

 

Individual Necropsy Findings - 300 mg/kg

Dose Level
mg/kg

Animal Number
and Sex

Time of Death

Macroscopic Observations

300

1-0 Female

Killed Day 14

No abnormalities detected

1-1 Female

Killed Day 14

No abnormalities detected

1-2 Female

Killed Day 14

No abnormalities detected

Individual Necropsy Findings - 2000 mg/kg

Dose Level
mg/kg

Animal Number
and Sex

Time of Death

Macroscopic Observations

2000

2-0 Female

Killed Day 14

No abnormalities detected

2-1 Female

Killed Day 14

No abnormalities detected

2-2 Female

Killed Day 14

No abnormalities detected

3-0 Female

Killed Day 14

No abnormalities detected

3-1 Female

Killed Day 14

No abnormalities detected

3-2 Female

Killed Day 14

No abnormalities detected


Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was found to be greater than 2000 mg/kg body weight (Globally Harmonized Classification System - Category 5, >2000 - 5000 mg/kg body weight).

The test item does not meet the criteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures.
Executive summary:

The acute oral toxicity of substance IFF TM 10-202 is greater than 2000 mg/kg bodyweight according to OECD Test Guideline 423 using the Acute Toxic Class Method.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

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:
The study was conducted between 30 October 2013 and 13 November 2013.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was considerd to be a reliability 1 as it has been conducted according to OECD Test Guideline 402 using a fixed dose method and in compliance with GLP.
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Five male and five female Wistar (RccHan™:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non-pregnant. After an acclimatization period of at least five days the animals were selected at random and given a number unique within the study by indelible ink-marking on the tail and a number written on a cage card. At the start of the study the animals weighed at least 200 g, and were eight to twelve weeks of age. The weight variation did not exceed ±20% of the mean weight for each sex.
The animals were housed in suspended solid floor polypropylene cages furnished with woodflakes. The animals were housed individually during the 24-Hour exposure period and in groups of five, by sex, for the remainder of the study. Free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analyzed and were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.
The temperature and relative humidity were set to achieve limits of 19 to 25 °C and 30 to 70% respectively. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.
The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
On the day before treatment the back and flanks of each animal were clipped free of hair.
Using available information on the toxicity of the test item, a single group of animals was treated with 2000 mg/kg (specific gravity 0.882; dose volume 2.27 mL/kg).
The calculated volume of test item, as received, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area) using a graduated syringe. A piece of surgical gauze was placed over the treatment area and semi occluded with a piece of self adhesive bandage. The animals were caged individually for the 24-Hour exposure period.
After the 24-Hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with arachis oil BP to remove any residual test item. The animals were returned to group housing for the remainder of the study period.

Test Item Formulation and Experimental Preparation
For the purpose of the study the test item was used as supplied. The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level.
The absorption of the test item was not determined
Duration of exposure:
24 h
Doses:
Single dose
No. of animals per sex per dose:
5/sex/dose
Control animals:
no
Details on study design:
The animals were observed for deaths or overt signs of toxicity 0.5, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.
After removal of the dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation
Any other skin reactions, if present were also recorded.
Individual body weights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.
At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
No signs of systemic toxicity were noted during the observation period.
Body weight:
All animals showed expected gains in body weight over the observation period.
Gross pathology:
No abnormalities were noted at necropsy.
Other findings:
Signs of dermal irritation noted at the treatment sites of four females were very slight to well-defined erythema, very slight edema small superficial scattered scabs and crust formation. Slight desquamation was also noted at the treatment sites of three females.
No signs of dermal irritation were noted at the treatment sites of all males and one female.

Individual clinical observations and mortality data with dose level at 2000 mg/kg

Animal No. & Sex

Effects noted after dosing (hours)

Effects noted during period after dosing

(Days)

0.5

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

1-0 male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-1 male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-2 male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-3 male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-4 male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-0 female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-1 female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-2 female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-3 female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-4 female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0 = No signs of systemic toxicity.

Individual dermal reactions - Males (Dose level 2000 mg/kg)

Animal No & Sex

Observation

Effects noted during period after dosing

(Days)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

1-0 male

Erythema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-1 male

Erythema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-2 male

Erythema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-3 male

Erythema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-4 male

Erythema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0 = No reactions.

Individual dermal reactions - Females (Dose level 2000 mg/kg)

Animal No & Sex

Observation

Effects noted during period after dosing

(Days)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2-0 female

Erythema

0

1

1

1

1

1

0

0

0

0

0

0

0

0

Edema

0

1

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

D

CFSs

CFSs

CFSs

Ss

Ss

0

0

0

0

0

2-1 female

Erythema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-2 female

Erythema

0

2

1

1

1

1

0

0

0

0

0

0

0

0

Edema

0

1

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

DCf

D

D

CfSs

Ss

CfSs

Ss

0

0

0

0

0

0

2-3 female

Erythema

0

1

1

1

1

1

0

0

0

0

0

0

0

0

Edema

0

1

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

0

Ss

Ss

SsCf

Ss

Ss

0

0

0

0

0

2-4 female

Erythema

0

2

1

1

1

1

0

0

0

0

0

0

0

0

Edema

0

1

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

D

D

CfSs

CfSs

CfSs

Ss

0

0

0

0

0

0

0 = No reactions D = Slight desquamation Ss = Small superficial scattered scabs Cf = Crust formation 

Individual body weights and body weight changes (Dose level 2000 mg/kg)

Animal No. & Sex

Body weight (g) at Day

Body Weight Change

0

7

14

1

2

1-0 Male

290

308

332

18

24

1-1 Male

253

262

284

9

22

1-2 Male

275

284

302

9

18

1-3 Male

269

281

300

12

19

1-4 Male

264

286

304

22

18

2-0 Female

230

233

240

3

7

2-1 Female

233

241

246

8

5

2-2 Female

233

237

242

4

5

2-3 Female

224

228

236

4

8

2-4 Female

228

240

244

12

4

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight.
The test item does not meet the criteria for classification according to the Globally Harmonized System of Classification and Labelling of Chemicals.
The test item does not meet the criteria for classification according to the Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures.
Executive summary:

The acute dermal toxicity potential of the test material, IFF TM 10-202, gave an LD50 of > 2000 mg/kg body weight according to OECD Test Guideline 402, using a fixed dose method.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

Justification for selection of acute toxicity – oral endpoint
The study was conducted in vivo in an appropriate test species according to internationally recognised guidelines.

Justification for selection of acute toxicity – dermal endpoint
The study was conducted in vivo in an appropriate test species according to internationally recognised guidelines.

Justification for classification or non-classification

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was found to be greater than 2000 mg/kg body weight (Globally Harmonized Classification System - Category 5, >2000 - 5000 mg/kg body weight; not toxic or harmful via the oral route, 2000 mg/kg body weight according to Directive 67/548/EEC).

The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight. The test item does not meet the criteria for classification according to the Globally Harmonized System of Classification and Labelling of Chemicals.