Registration Dossier

Administrative data

Description of key information

Key irritation studies for skin and eye were conducted in rabbits with a test item containing 70% active 
ingredient. Scoring according to Draize demonstrated an overall irritation score of 2.3/4 for skin and
mean 24 -72h scores for cornea, conjuctiva and iris of 14/80,6.3/20 and 1/10, respectively for the eye.
There were various eye changes which were not (fully) reversible within the observation period.
This information resulted in classification for skin irritation (CLP category 2) and severe eye damage
(CLP Category 1).

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1968
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted non-GLP, with limited data on study design, however the study was conducted according to state of the art methods at that time period. The study is considered adequate, reliable and relevant.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
6 animals, 72h observation period
GLP compliance:
no
Species:
rabbit
Strain:
not specified
Details on test animals and environmental conditions:
Not provided
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.5 mL of the product as received
Duration of treatment / exposure:
24 hours
Observation period:
72 hours
Number of animals:
6
Irritation parameter:
other: primary irritation score
Basis:
mean
Time point:
24/48/72 h
Score:
2.3
Max. score:
8
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: no data on 48 h observation
Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
intact skin
Time point:
24/48/72 h
Score:
1.5
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: no data on 48 h observation
Irritation parameter:
erythema score
Basis:
animal #2
Remarks:
intact skin
Time point:
24/48/72 h
Score:
1.5
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: no data on 48 h observation
Irritation parameter:
erythema score
Basis:
animal #3
Remarks:
intact skin
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: no data on 48 h observation
Irritation parameter:
erythema score
Basis:
animal #4
Remarks:
intact skin
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: no data on 48 h observation
Irritation parameter:
erythema score
Basis:
animal #5
Remarks:
intact skin
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: no data on 48 h observation
Irritation parameter:
erythema score
Basis:
animal #6
Remarks:
intact skin
Time point:
24/48/72 h
Score:
1.5
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: no data on 48 h observation
Irritation parameter:
edema score
Basis:
animal #1
Remarks:
intact skin
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: no data on 48 h observation
Irritation parameter:
edema score
Basis:
animal #2
Remarks:
intact skin
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: no data on 48 h observation
Irritation parameter:
edema score
Basis:
animal #3
Remarks:
intact skin
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: no data on 48 h observation
Irritation parameter:
edema score
Basis:
animal #4
Remarks:
intact skin
Time point:
24/48/72 h
Score:
2.5
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: no data on 48 h observation
Irritation parameter:
edema score
Basis:
animal #5
Remarks:
intact skin
Time point:
24/48/72 h
Score:
0.5
Max. score:
4
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: no data on 48 h observation
Irritation parameter:
edema score
Basis:
animal #6
Remarks:
intact skin
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: no data on 48 h observation

Table1. Rabbit skin irritation results

Time,

Hours

Reaction

Rabbit Number, Value

Mean

Value

1

2

3

4

5

6

 

ERYTHEMA

 

 

 

 

 

 

 

24

intact

2

2

2

2

1

2

1.8

72

intact

1

1

2

2

1

1

1.3

24

abraded

2

2

2

2

1

2

1.8

72

abraded

1

1

1

2

1

0

1.0

 

EDEMA

 

 

 

 

 

 

 

24

intact

0

2

2

4

1

1

1.7

72

intact

0

0

0

1

0

1

0.3

24

abraded

0

0

0

4

2

1

1.2

72

abraded

0

0

0

1

0

0

0.2

Structure of the tissue at the site of contact was not destroyed or changed irreversibly in 24 hours or less.

Primary Irritation Score: 2.3 (Sum of the mean values divided by 4)

Interpretation of results:
irritating
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
The Primary Skin Irritation score of the test item Butanedioic acid, sulfo-, 1,4-ditridecyl ester, sodium salt ( 70% active ingredient) was 2.3.
Executive summary:

0.5 mL of Butanedioic acid, sulfo-, 1,4-ditridecyl ester, sodium salt (70% active ingredient) was held under an impervious patch in continuous 24-hour contact with the shaved skin of 6 rabbits. Erythema and edema were observed in all animals on abraded and intact skin at 24 hours, which had not reversed by 72 hours. The overall primary irritation score was 2.3. The structure of the tissue at the site of contact was not destroyed or changed irreversibly within 24 hours.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1968
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted non-GLP, however the study was conducted according to state of the art methods at that time period. The study is considered adequate, reliable and relevant.
Qualifier:
according to
Guideline:
other: FHSA, 16cfr1500.42 CPSC
Deviations:
no
Principles of method if other than guideline:
FHSA: Federal Hazardous Substances Act
CPSC: Consumer Product Safety Commission
GLP compliance:
no
Species:
rabbit
Strain:
not specified
Details on test animals or tissues and environmental conditions:
Not provided
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.1 mL of the product as received was introduced into the conjunctival sac.
Duration of treatment / exposure:
Not provided
Observation period (in vivo):
72 hours
Number of animals or in vitro replicates:
6
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done):No

SCORING SYSTEM:
The scoring system used herein for eye irritation reactions is that of Draize, J.H., Woodward,
G., and Calvery, H.O.: J. Pharmacol. Exptl. Therap.82:377, 1944.
The maximum possible scores for eye irritation reactions (again excluding necrosis) are:
Cornea,80; Iris, 10; Conjunctivae, 20.

TOOL USED TO ASSESS SCORE: Not provided
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
14
Max. score:
80
Reversibility:
not fully reversible within: 72 h
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
1
Max. score:
10
Reversibility:
not fully reversible within: 72 h
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
6.3
Max. score:
20
Reversibility:
not fully reversible within: 72 h
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
26.7
Max. score:
80
Reversibility:
not fully reversible within: 72 h
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
10
Max. score:
80
Reversibility:
not fully reversible within: 72 h
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
20
Max. score:
80
Reversibility:
not fully reversible within: 72 h
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
24/48/72 h
Score:
3.3
Max. score:
80
Reversibility:
fully reversible within: 72 h
Irritation parameter:
cornea opacity score
Basis:
animal #5
Time point:
24/48/72 h
Score:
21.7
Max. score:
80
Reversibility:
not fully reversible within: 72 h
Irritation parameter:
cornea opacity score
Basis:
animal #6
Time point:
24/48/72 h
Score:
3.3
Max. score:
80
Reversibility:
fully reversible within: 72 h
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
10
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
5
Max. score:
10
Reversibility:
not fully reversible within: 72 h
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
10
Irritation parameter:
iris score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0
Max. score:
10
Irritation parameter:
iris score
Basis:
animal #5
Time point:
24/48/72 h
Score:
0
Max. score:
10
Irritation parameter:
iris score
Basis:
animal #6
Time point:
24/48/72 h
Score:
0
Max. score:
10
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
9.3
Max. score:
20
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: Conjunctivae score : sum of conjunctivae redness, chemosis and discharge
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
12
Max. score:
20
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: Conjunctivae score : sum of conjunctivae redness, chemosis and discharge
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
5.3
Max. score:
20
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: Conjunctivae score : sum of conjunctivae redness, chemosis and discharge
Irritation parameter:
conjunctivae score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2.7
Max. score:
20
Reversibility:
fully reversible within: 48 h
Remarks on result:
other: Conjunctivae score : sum of conjunctivae redness, chemosis and discharge
Irritation parameter:
conjunctivae score
Basis:
animal #5
Time point:
24/48/72 h
Score:
4
Max. score:
20
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: Conjunctivae score : sum of conjunctivae redness, chemosis and discharge
Irritation parameter:
conjunctivae score
Basis:
animal #6
Time point:
24/48/72 h
Score:
4.7
Max. score:
20
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: Conjunctivae score : sum of conjunctivae redness, chemosis and discharge
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
9.3
Max. score:
20
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: Conjunctivae score : sum of conjunctivae redness, chemosis and discharge
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
12
Max. score:
20
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: Conjunctivae score : sum of conjunctivae redness, chemosis and discharge
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
5.3
Max. score:
20
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: Conjunctivae score : sum of conjunctivae redness, chemosis and discharge
Irritation parameter:
chemosis score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2.7
Max. score:
20
Reversibility:
fully reversible within: 48 h
Remarks on result:
other: Conjunctivae score : sum of conjunctivae redness, chemosis and discharge
Irritation parameter:
chemosis score
Basis:
animal #5
Time point:
24/48/72 h
Score:
4
Max. score:
20
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: Conjunctivae score : sum of conjunctivae redness, chemosis and discharge
Irritation parameter:
chemosis score
Basis:
animal #6
Time point:
24/48/72 h
Score:
4.7
Max. score:
20
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: Conjunctivae score : sum of conjunctivae redness, chemosis and discharge
Irritant / corrosive response data:
This product is irritating to the eye of the rabbit. Therefore, precautions should be observed to avoid its introduction into or near the eyes.

Table 1.Rabbit eye irritation results

Time,

Hours

Structure

Rabbit Number, Value

Mean

Value

1

2

3

4

5

6

24

CORNEA

20

10

20

5

30

5

15

IRIS

0

5

0

0

0

0

1

CONJUNCTIVAE

10

12

6

8

8

8

9

48

CORNEA

20

10

20

5

30

5

15

IRIS

0

5

0

0

0

0

1

CONJUNCTIVAE

8

14

6

0

4

4

6

72

CORNEA

40

10

20

0

5

0

12

IRIS

0

5

0

0

0

0

1

CONJUNCTIVAE

10

10

4

0

0

2

4

 At the readings made at 24, 48 and 72 hours, there was:

- discernible opacity or ulceration of the cornea other than a slight dulling of the normal luster.

- no inflammation of the iris other than slight deepening of the folds, or slight circumcorneal injection.

- adiffuse, deep-crimson red appearance of the conjunctivae, with individual vessels not easily discernible.

- an obvious swelling of the conjunctivae, excluding cornea and iris, with partial eversion of the lids.

- no destruction or irreversible change of any tissue in 24 hours, or less.

Interpretation of results:
irritating
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Primary Eye irritation: Moderate Eye Irritation
Did not lessen significantly within 72 hours.
Executive summary:

0.1 g Butanedioic acid, sulfo-, 1,4 -ditridecyl ester, sodium salt (70% active) was introduced into the conjunctival sac of 6 rabbits. Scoring according to Draize et al. (1944) demonstrated a mean cornea score of 14/80, a mean iris score of 1/10 and a mean conjuctiva score of 6.3/20. At the readings made at 24, 48 and 72 hours, there was discernible opacity or ulceration of the cornea other than a slight dulling of the normal luster,adiffuse, deep-crimson red appearance of the conjunctivae, with individual vessels not easily discernible, and an obvious swelling of the conjunctivae, excluding cornea and iris, with partial eversion of the lids. It was concluded that the test item containing 70% active ingredient produces  irritation of rabbit eyes. Therefore, precaution should be observed to avoid its introduction into or near the eyes.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

- A key study for skin irritation with registered substance was performed in 6 male rabbits with test item containing 70% active ingredient, applying 0.5 mL under impervious patch for 24 hours on the shaved intact and abraded skin (American Cyanamid Company, 1968c). Erythema and edema were observed in all animals on abraded and intact skin at 24h, which had not reversed by 72h. The overall primary irritation score was 2.3. The structure of the tissue at the site of contact was not destroyed or changed irreversibly at 24h.

- In a second study, a test item was administered as 1cc 50% dispersion in Nujol oil to 3 rabbits under occlusion for 18h, and followed for 10 days (Hazleton, 1950b). Upon removal there was an immediate mild irritation of the area contacted by the solution. Within 48 hours from the time of application the skin appeared toughened and presented a parchment-like appearance. After five to six days the skin again became pliable and at the end of the 10-day observation period appeared entirely normal. The animals were sacrificed after 10 days and no gross pathology was observed. The study was considered as supporting study, confirming the reversible changes.

- In a third study, a test item was administered as 1cc 50% dispersion in S.A.E. 10 oil to 3 rabbits under occlusion for 18h, and followed for 11 days (American Cyanamid Company, 1951c). Mild irritation with some coreacious condition was observed within 48h, but disappeared after 5 days. In spite of the relatively mild reaction, one of three animals died after 6 days and one after 11 days. The study was disregarded based on these unexpected reactions.

- In conclusion, slight to moderate skin irritation was observed in the key and supporting study; reversibility within 10 days was demonstrated in the supporting study, therefore the registered substance is considered to be a skin irritant of CLP 2 classification.

 

Eye irritation

- A key study for eye irritation with registered substance was performed with test item containing 70% active ingredient in 6 rabbits where 0.1 mL of test item introduced in the eye conjuctival sac (American Cyanamid Company, 1968d). Scoring according to Draize et al. (1944) demonstrated a mean cornea score of 14/80, a mean iris score of 1/10 and a mean conjuctiva score of 6.3/20. At the readings made at 24, 48 and 72 hours, there was discernible opacity or ulceration of the cornea other than a slight dulling of the normal luster, a diffuse, deep-crimson red appearance of the conjunctivae, with individual vessels not easily discernible, and an obvious swelling of the conjunctivae, excluding cornea and iris, with partial eversion of the lids. It was concluded that the test item containing 70% active ingredient produces  irritation of rabbit eyes.

- In a second, supporting study, a test item was administered as 0.05 cc 50% dispersion in Nujol oil in the conjuctival sac of 3 rabbits, followed for 13 days (Hazleton, 1950a), resulting in an immediate slight irritation and lacrimation, however this disappeared during the first several hours and thereafter the eyes appeared entirely normal throughout an observation period of 10 to 13 days. The animals were sacrificed and appeared normal at autopsy.

- In a third, also supporting study, a test item administered as 1cc 50% dispersion in S.A.E. 10 oil in the conjunctival sac of 3 rabbits, followed for 72 hours (Hazleton, 1951d). After application there was immediate irritation with lacrimation. The irritation was slight without edema at the one- and six-hour observations and had entirely subsided within 24 hours. Thereafter the eyes remained normal.

- In conclusion, moderate to severe eye irritation was seen in the key study; the opacity and ulceration of the cornea were considered to important adverse findings, therefore the registered substance is considered to be cause severe damage to the eye (CLP class 1).

 

Further information supporting the classification is provided in the read across justification for the Diester subgroup, showing that all substances in the group (except 1 which was not irritating) were irritating for skin and all were group classified to cause severe eye damage (justification with data matrix separately attached in Section 13).

 

Justification for selection of skin irritation / corrosion endpoint: Key study 

Justification for selection of eye irritation endpoint: Key study 

Effects on skin irritation/corrosion: slightly irritating 

Effects on eye irritation: highly irritating

Justification for classification or non-classification

Based on the results the test item containing 70% active ingredient needs to be classified for skin irritation according to the Directive 67/548/EEC, Annex VI with symbol Xi and the indication of danger “irritant”; the following risk phrase shall be assigned: R38 - Irritating to skin.  For the eye, the substance containing 70% active ingredient is classified as irritating to eyes and risk phrase R41- Risk of serious damage to eyes shall be assigned.

According to CLP regulation (No. 1272/2008 of 16 December 2008), the test item containing 70% ingredient is classified as Category 2, with signal word 'Warning' and hazard statement: H315 - Causes skin irritation. For the eye irritation, the substance containing 70% active ingredient is classified as Category 1, with signal word 'Danger' and hazard statement: H319 -Causes serious eye damage.