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Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011-05-23 to 2011-09-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report date:
2011

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
(Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, München, Germany)
Test type:
standard acute method
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Dihydro-3-(tripropenyl)furan-2,5-dione
EC Number:
295-556-6
EC Name:
Dihydro-3-(tripropenyl)furan-2,5-dione
Cas Number:
92077-08-2
Molecular formula:
R-C4H3O3 , whereas R=C8-C10-alkyl-(branched, unsaturated)
IUPAC Name:
3-[(1E)-2-methyloct-1-en-1-yl]oxolane-2,5-dione
Details on test material:
Name: Tripropenyl succinic anhydride
Product: Genopur ASA
CAS No.: 92077-08-2
Batch No.: ESD0010823
Certificate of Analysis: dated 10 September 2011
Chemical Name: dihydro-3-(tripropenyl)furan-2,5-dione
Molecular Weight: ca 220 (calculated value)
pH: 1-2
Physical State at RT: liquid
Density: 1.01 g/cm3 (20°C, DIN 51757)
Colour: yellow to brown
Expiry Date: 01.12.2012
Storage Conditions: at room temperature
Safety Precautions: The routine hygienic procedures were sufficient to assure personnel health and safety.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Full barrier in an air-conditioned room
- Temperature: 22 +/- 3 °C
- Relative humidity: 55 +/- 10%
- Artificial light, sequence being 12 hours light, 12 hours dark
- Air change: 10 x / hour
- Free access to Altromin 1324 maintenance diet for rats and mice (lot no. 1130)
- Free access to tap water, sulphur acidified to a pH value of approximately 2.8 (drinking water, municipal residue control, microbiological controls at regular intervals)
- The animals were kept individually in IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding (lot no. 040311)
- Certificates of food, water and bedding are filed at BSL BIOSERVICE
- Adequate acclimatisation period (at least five days) under laboratory conditions

Administration / exposure

Type of coverage:
semiocclusive
Details on dermal exposure:
Preparation of the Animals:
The animals were marked for individual identification by tail painting.
Approximately 24 hours before the test, the fur was removed from the dorsal area of the trunk using an electric clipper.
Care was taken to avoid abrading the skin, and only animals with healthy intact skin were used.
No less than 10% of the body surface was cleared for the application.
Prior to the application a detailed clinical observation was made of all animals.
Application:
The test item was applied at a single dose, uniformly over an area which was approximately 10% of the total body surface.
The test item was held in contact with the skin by a dressing throughout a 24-hour period.
The dressing consisted of a gauze-dressing and non-irritating tape and was fixed with an additional dressing in a suitable manner.
Duration of exposure:
The test item was held in contact with the skin throughout a 24-hour period.
At the end of the exposure period the residual test item was removed using
aqua ad injectionem (Berlin Chemie, lot no. 0195A191, expiry date: 04/2013).
Doses:
The test item was applied at a single dose of 2000 mg/kg body weight to each animal.
No. of animals per sex per dose:
5 male and 5 female
Control animals:
not required
Details on study design:
Observation period:
All animals were observed for 14 days after dosing

Weight Assessment:
The animals were weighed on day 1 (prior to the application) and on days 8 and 15.

Clinical Examination:
careful clinical examination was made several times on the day of dosing (at least once during the first 30 minutes and with special attention given during the first 4 hours post-dose). As soon as symptoms were noticed they were recorded. Thereafter, the animals were observed for clinical signs once daily until the end of the observation period. All abnormalities were recorded.
Cageside observations included changes in the skin and fur, eyes and mucous membranes. Also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern were examined. Attention was directed to observations of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

Pathology:
At the end of the observation period the surviving animals were sacrificed with an overdosage of pentobarbital injected intraperitoneally (Narcoren®, Merial) at the dosage of approximately 8 mL/kg bw. All animals were subjected to gross necropsy. All gross pathological changes were recorded and in case of findings the tissues were preserved for a possible histopathological evaluation. The preserved tissues of which no histopathological evaluation was made will be discarded 3 months after the release of the final report unless otherwise agreed upon with the sponsor.

Evaluation of Results:
Individual reactions of each animal were recorded at each time of observation.
Toxic response data were recorded by sex and dose level.
Nature, severity and duration of clinical observations were described.
The body weight changes were summarised in a tabular form.
Necropsy findings were described.
On the basis of the test results, the test item may be classified in one of the following classes in conformity with the criteria given in Annex VI to Commission Directive 2001/59/EC:
• Very toxic
Substances and preparations shall be classified as very toxic, and assigned the symbol “T+” and indication of danger “very toxic” in accordance with the criteria specified below:
R27 Very toxic in contact with skin
- LD50 dermal, rat or rabbit: <= 50 mg/kg
• Toxic
Substances and preparations shall be classified as toxic, and assigned the symbol “T” and indication of danger “toxic” in accordance with the criteria specified below. Risk phrases shall be assigned in accordance with the following criteria:
R24 Toxic in contact with skin
- LD50 dermal, rat or rabbit: 50 < LD50 <= 400 mg/kg
• Harmful
Substances and preparations shall be classified as harmful, and assigned the symbol “Xn” and indication of danger “harmful” in accordance with the criteria specified below. Risk phrases shall be assigned in accordance with the following criteria:
R21 Harmful in contact with skin
- LD50 dermal, rat or rabbit: 400 < LD50 <= 2000 mg/kg
On the basis of the test results, the following risk phrases may be assigned in conformity with the criteria given in Annex I of Regulation (EC) 1272/2008:
Category 1: LD50 <= 50 mg/kg. DANGER. Skull and crossbones in diamond. Fatal in contact with skin.
Category 2: LD50 > 50 mg/kg <= 200 mg/kg. DANGER. Skull and crossbones in diamond. Fatal in contact with skin.
Category 3: LD50 > 200 mg/kg <= 1000 mg/kg. DANGER. Skull and crossbones in diamond. Toxic in contact with skin.
Category 4: LD50 > 1000 mg/kg <= 2000 mg/kg. WARNING. Exclamation point in diamond. Harmful in contact with skin.
On the basis of the test results, the following risk phrases may be assigned in conformity with the criteria given in GHS - Globally Harmonized System of Classification and Labelling of Chemicals, third revised edition, July 2009:
Category 1: LD50 <= 50 mg/kg. DANGER. Skull and crossbones in diamond. Fatal in contact with skin.
Category 2: LD50 > 50 mg/kg <= 200 mg/kg. DANGER. Skull and crossbones in diamond. Fatal in contact with skin.
Category 3: LD50 > 200 mg/kg <= 1000 mg/kg. DANGER. Skull and crossbones in diamond. Toxic in contact with skin.
Category 4: LD50 > 1000 mg/kg <= 2000 mg/kg. WARNING. Exclamation point in diamond. Harmful in contact with skin.
Category 5: LD50 > 2000 mg/kg <= 5000 mg/kg. WARNING. No symbol. May be harmful in contact with skin.
Statistics:
According to OECD guidelines, the biological relevance of the results is the criterion for the interpretation of results,
a statistical evaluation of the results is not regarded as necessary.

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality was observed
Clinical signs:
other: No treatment-related effects were observed.
Gross pathology:
No treatment-related effects were observed.
Other findings:
Erythema grade 1 – 2 was observed in all animals.
Oedema grade 1 was observed in 3 of 5 male and all female animals.
Desquamation and eschar were observed in all animals. Scratches were observed in 1 of 5 male animals.
The signs of irritation were not completely reversible within the observation period.

Any other information on results incl. tables

Table Clinical Signs of Systemic Toxicity – Individual Data - Males:

Animal
No. / Sex / Dose

Time of
Observation (Post-Dose)

Observations

(for Signs of Dermal Irritation, see Table 5)

21/ male /
2000 mg/kg bw

during the whole observation period

no signs of toxicity

22/ male /
2000 mg/kg bw

during the whole observation period

no signs of toxicity

23/ male /
2000 mg/kg bw

30 min.,
1 h, 2 h, 3 h, 4 h

no signs of toxicity

1 day

nasal discharge

2 days until the end of the observation period

no signs of toxicity

24/ male /
2000 mg/kg bw

30 min.,
1 h, 2 h, 3 h, 4 h

no signs of toxicity

1 day

nasal discharge

2 days until the end of the observation period

no signs of toxicity

25/ male /
2000 mg/kg bw

30 min.,
1 h, 2 h, 3 h, 4 h

no signs of toxicity

1 day

nasal discharge

2 days until the end of the observation period

no signs of toxicity

Table Clinical Signs of Systemic Toxicity – Individual Data – Females:

Animal
No. / Sex / Dose

Time of
Observation (Post-Dose)

Observations

(for Signs of Dermal Irritation, see Table 5)

26/ female / 2000 mg/kg bw

during the whole observation period

no signs of toxicity

27/ female / 2000 mg/kg bw

30 min.,
1 h, 2 h, 3 h, 4 h

no signs of toxicity

1 day

nasal discharge

2 days until the end of the observation period

no signs of toxicity

28/ female / 2000 mg/kg bw

30 min.,
1 h, 2 h, 3 h, 4 h

no signs of toxicity

1 day

nasal discharge

2 days until the end of the observation period

no signs of toxicity

29/ female / 2000 mg/kg bw

during the whole observation period

no signs of toxicity

30/ female / 2000 mg/kg bw

30 min.,
1 h, 2 h, 3 h, 4 h

no signs of toxicity

1 day

nasal discharge

2 days until the end of the observation period

no signs of toxicity

Table Skin Irritation – Individual Data – Males:

Day after Start of Application

Animal No. 21

Animal No. 22

Animal No. 23

Animal No. 24

Animal No. 25

E/O

Comments

E/O

Comments

E/O

Comments

E/O

Comments

E/O

Comments

day 2

1/1

nsf

1/0

nsf

1/1

nsf

2/1

nsf

1/0

nsf

day 3

1/0

s

1/0

nsf

1/0

nsf

1/1

nsf

1/0

nsf

day 4

1/0

d, es

1/0

d, es

1/0

d

1/1

d

1/0

d, es

day 5

0/0

d

0/0

d, es

1/0

d

1/0

d

1/0

d, es

day 6

0/0

d

0/0

d, es

0/0

d

0/0

d

0/0

d, es

day 7

0/0

d

0/0

d

0/0

d

0/0

d

0/0

d

day 8

0/0

d, es

0/0

nsf

0/0

d, es

0/0

d

0/0

d, es

day 9

0/0

d

0/0

nsf

0/0

d, es

0/0

d, es

0/0

d, es

day 10

0/0

d

0/0

nsf

0/0

d

0/0

nsf

0/0

d

day 11

0/0

d (large area)

0/0

nsf

0/0

d

0/0

nsf

0/0

d

day 12

0/0

d

0/0

nsf

0/0

d

0/0

nsf

0/0

d

day 13

0/0

nsf

0/0

nsf

0/0

nsf

0/0

nsf

0/0

d

day 14

0/0

nsf

0/0

nsf

0/0

nsf

0/0

nsf

0/0

nsf

day 15

0/0

nsf

0/0

nsf

0/0

nsf

0/0

nsf

0/0

nsf

 

Comments:

E = erythema; O = oedema; 1, 2, 3, 4 = scoring system laid down in OECD Guideline 404 (Table 2)

d =desquamation; es = eschar; s = scratches; nsf = no specific findings

 

Table Skin Irritation – Individual Data – Females:

Day after Start of Application

Animal No. 26

Animal No. 27

Animal No. 28

Animal No. 29

Animal No. 30

E/O

Comments

E/O

Comments

E/O

Comments

E/O

Comments

E/O

Comments

day 2

1/1

nsf

1/1

nsf

2/1

nsf

1/1

nsf

2/1

nsf

day 3

1/1

nsf

1/0

nsf

2/0

nsf

2/0

es, fur stuck together

1/0

fur stuck together

day 4

0/0

nsf

1/0

d

1/0

d

1/0

d, es

1/0

d, fur stuck together

day 5

0/0

nsf

1/0

d

0/0

d

1/0

d

1/0

d, al

day 6

0/0

d

0/0

d

0/0

d

0/0

d

1/0

d, al

day 7

0/0

d

0/0

d, es

0/0

d

0/0

d

2/0

d, al, es

day 8

0/0

d, es

0/0

nsf

0/0

d, es

0/0

nsf

2/0

d, al, es

day 9

0/0

d

0/0

d

0/0

nsf

0/0

nsf

0/0

d, al, es

day 10

0/0

nsf

0/0

nsf

0/0

nsf

0/0

nsf

0/0

es (large area), al

day 11

0/0

nsf

0/0

nsf

0/0

nsf

0/0

nsf

0/0

es (large area), al, d

day 12

0/0

nsf

0/0

nsf

0/0

nsf

0/0

nsf

0/0

es (1 cm2), al, d

day 13

0/0

nsf

0/0

nsf

0/0

nsf

0/0

nsf

0/0

es (1 cm2), al, d

day 14

0/0

nsf

0/0

nsf

0/0

nsf

0/0

d

0/0

es (1 cm2), al, d

day 15

0/0

nsf

0/0

nsf

0/0

nsf

0/0

d

0/0

es (1 cm2), al, d

 

Comments:

E = erythema; O = oedema; 1, 2, 3, 4 = scoring system laid down in OECD Guideline 404 (Table 2)

d =desquamation; es = eschar; s = scratches; al = alopecia both flanks where hair were stuck together the day before

 nsf = no specific findings

 

Table Absolute Body Weights in g and Body Weight Gain in %:

Dose: 2000 mg/kg body weight

Animal No. / Sex

g
Day 1

g
Day 8

g
Day 15

%
Day 1-15

21 / male

237

244

273

15

22 / male

236

247

267

13

23 / male

244

257

287

18

24 / male

235

251

289

23

25 / male

240

253

285

19

26 / female

210

205

217

3

27 / female

206

209

213

3

28 / female

210

210

221

5

29 / female

202

207

219

8

30 / female

212

201

216

2

Table Macroscopic Findings - Individual Data – Males and Females:

Dose: 2000 mg/kg bw

Animal No. /
Sex

Organ

Macroscopic Findings

21 / male

-

nsf

22 / male

-

nsf

23 / male

-

nsf

24 / male

-

nsf

25 / male

-

nsf

26 / female

-

nsf

27 / female

-

nsf

28 / female

-

nsf

29 / female

-

nsf

30 / female

-

nsf

Table LD50:

Dose (Unit)

 

Number of Animals Investigated

Number of Intercurrent Deaths

LD50

2000 mg/kg bw

5 males

0

> 2000 mg/kg bw

2000mg/kg bw

5 females

0

> 2000 mg/kg bw

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the present study, single dermal application of the test item Tripropenyl succinic anhydride
to rats at a dose of 2000 mg/kg body weight was associated with neither mortality nor signs of toxicity but signs of irritation.
The dermal LD50 was determined to be > 2000 mg Tripropenyl succinic anhydride / kg body weight.
In conformity with the criteria given in Annex VI to Commission Directive 2001/59/EC the test item
Tripropenyl succinic anhydride has no obligatory labelling requirement for percutaneous toxicity.
According to Annex I of Regulation (EC) 1272/2008 the test item Tripropenyl succinic anhydride
has no obligatory labelling requirement for percutaneous toxicity and is unclassified.
According to OECD-GHS (Globally Harmonized Classification System) the test item
Tripropenyl succinic anhydride has no obligatory labelling requirement for percutaneous toxicity and is unclassified.
Executive summary:

Summary Results

On the basis of the test results given below and in conformity with the criteria given in Annex VI to Commission Directive 2001/59/EC, the substance should be:

classified asvery toxic

 

  

 

classified astoxic

 

 

 

classified as harmful

 

 

 

not classified

X

 

 

limit test

X

On the basis of the test results given below and in conformity with the criteria given in inAnnex I of Regulation (EC) 1272/2008, the substance should be:

classified into category 1

 

  

 

classified into category 2

 

 

 

classifiedinto category 3

 

 

 

classifiedinto category 4

 

 

 

not classified

X

On the basis of the test results given below and in conformity with the criteria given in inOECD-GHS (Globally Harmonized System of Classification and Labelling of Chemicals), the substance should be:

classified into category 1

 

 

 

classified into category 2

 

 

 

classifiedinto category 3

 

 

 

classifiedinto category 4

 

 

 

classifiedinto category 5

 

 

 

not classified

X

LD50:                                                        > 2000 mg /kg bw

Species/strain:                                         WISTAR Crl: WI(Han) rats

Vehicle (moistening):                               no vehicle used

Number of animals:                                  5 male and 5 female

Duration of exposure:                             24 hours

Method:                                                  OECD 402, EC 440/2008, OPPTS 870.1200


 

Results per Step

Sex

Dose
(mg/kg bw)

Number
of Animals

Number
of Intercurrent Deaths

male

2000

5

0

female

2000

5

0

Signs of toxicity related to dose level used, time of onset and duration:

No treatment-related effects were observed.

Effect on organs (related to dose level):

No treatment-related effects were observed.

Signs of irritation:

Erythema grade 1 – 2 was observed in all animals. Oedema grade 1 was observed in 3 of 5 male and all female animals.

Desquamation and eschar were observed in all animals. Scratches were observed in 1 of 5 male animals.

The signs of irritation were not completely reversible within the observation period.

Conclusion

Under the conditions of the present study, single dermal application of the test item Tripropenyl succinic anhydride to rats

at a dose of 2000 mg/kg body weight was associated with neither mortality nor signs of toxicity but signs of irritation.

The dermal LD50 was determined to be > 2000 mg Tripropenyl succinic anhydride/ kg body weight.

In conformity with the criteria given inAnnex VI to Commission Directive 2001/59/EC the test item Tripropenyl succinic anhydride

has no obligatory labelling requirement for percutaneous toxicity.

According to Annex I of Regulation (EC) 1272/2008 the test item Tripropenyl succinic anhydride has no obligatory labelling

requirement for percutaneous toxicity and is unclassified.

According to OECD-GHS (Globally Harmonized Classification System) the test item Tripropenyl succinic anhydride has no obligatory labelling requirement for percutaneous toxicity and is unclassified.