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Diss Factsheets

Administrative data

Description of key information

When tested in guideline-compliant studies for skin irritation and eye irritation, fumaric acid was a slight or mild skin irritant not requiring classification, and a moderate eye irritant.

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:
25 April to 9 May 1984
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
12 May 1981
GLP compliance:
no
Remarks:
GLP was not yet legally implemented when the study was conducted.
Species:
rabbit
Strain:
other: small white Russian
Details on test animals or test system and environmental conditions:
Male and female rabbits between 1.9 and 2.8 kg were housed in individual stainless steel cages and acclimated for 14 days. Rabbits received K4 single diet for rabbits (Ssniff Special Feed GmbH) and water ad libitum. Room temperature was 20 °C with 60 % relative humidity. Air was exchanged 15 times per hour and a 12 hr light-dark cycle was employed.
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
other: paraffin oil
Controls:
not required
Amount / concentration applied:
0.5 g test material wetted with paraffin oil
Duration of treatment / exposure:
4 hrs
Observation period:
1, 24, 48 and 72 hours as well as 5, 7, 8, 12 and 14 days
Number of animals:
3 males and 3 females
Details on study design:
TEST SITE
- Area of exposure: 6 cm² patch of skin
- Type of wrap if used: Linen cloth (2.5 × 2.5 cm) covered with a polyethylene foil (6 × 6 cm). The application site was secured with an elastic band.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Distilled water

SCORING SYSTEM:

Erythema and eschar formation:
No erythema...0
Very slight erythema (barely perceptible)...1
Well-defined erythema...2
Moderate to severe erythema...3
Severe erythema to slight eschar formation...4

Oedema formation:
No oedema...0
Very slight oedema...1
Slight oedema...2
Moderate oedema...3
Severe oedema...4

Reaction values for redness and swelling were calculated for 1, 24, 48 and 72 hours after patch removal. These absolute values were added together and divided by the number of assessment times (4) to determine the irritation index:
0–0.5 Not irritating
0.6–3.0 Mildly irritating
3.1–5.0 Moderately irritating
5.0–8.0 Highly irritating
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 72 hrs
Score:
0.63
Reversibility:
fully reversible within: 14 days
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
ca. 1
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
ca. 1.67
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
ca. 0.67
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
ca. 1
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
ca. 1
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
ca. 0.33
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
ca. 0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
ca. 0.33
Max. score:
4
Irritant / corrosive response data:
The mean score over 24-72 hours for redness was calculated to be 0.72.
The mean score over 24-72 hours for swelling was calculated to be 0.11.
Neither score warrants classification for skin irritation.

Individual and average redness (R) and swelling (S) values

 Animal number  1 hr    24 hr 48 hr  72 hr
 R  S  R  S  R  S  R  S
 1  0  0  0  0  0  0  0  0
 2  0  0  1  0  1  0  1  0
 3  0  0  *2  0  *1  1  *2  0
 4  0  0  0  0  1  0  1  0
 5  0  0  0  0  0  0  0  0
 6  0  0  0  0  1  0  2  1
Total     0     0.5     0.83     1.17
Average                       2.50/4 = 0.63
*Redness directly on the application surface
Interpretation of results:
GHS criteria not met
Conclusions:
This study supports the conclusion that fumaric acid is a mild skin irritant that does not require classification for dermal irritation according to EU and GHS systems.
Executive summary:

Dermal application of 0.5 g fumaric acid was mildly irritating to the skin of male and female rabbits. Fumaric acid did not elicit dermal reactions that would exceed the threshold for classification in accordance with EU criteria.

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:
25 April 1984 to 16 May 1984
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
no
Remarks:
GLP was not yet legally implemented when the study was conducted.
Species:
rabbit
Strain:
other: small white Russian
Details on test animals or tissues and environmental conditions:
Male and female rabbits between 1.9 and 2.1 kg were housed in individual stainless steel cages and acclimated for 14 days. Rabbits received K4 single diet for rabbits (Ssniff Special Feed GmbH) and water ad libitum. Room temperature was 20C with 60% relative humidity. Air was exchanged 15 times per hour and a 12 hr light-dark cycle was employed.
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.1 g fumaric acid
Duration of treatment / exposure:
The test material was not washed out.
Observation period (in vivo):
1, 24, 48 and 72 hours and 5, 7, 9, 12, 15, 19 and 21 days.
Number of animals or in vitro replicates:
3 males and 3 females
Details on study design:
Test material was applied to the lower conjunctival sac of the right eye by pulling away the lower eyelid. The left eye was treated in one animal.
The contralateral eye served as a concurrent, inherent control.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.28
Max. score:
2
Reversibility:
not reversible
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
2.83
Max. score:
3
Reversibility:
fully reversible within: 19d
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.72
Max. score:
4
Reversibility:
fully reversible within: 19 d
Remarks on result:
positive indication of irritation

Table 1:Cornea evaluation: Degree of opacity (A) × extent of opacity (B) × 5

 

 

1 h

24 h

48 h

72 h

Animal #

Sex

A

B

A × B × 5

A

B

A × B × 5

A

B

A × B × 5

A

B

A × B × 5

1

M

1

4

20

1

4

20

1

4

20

1

4

20

2

M

1

4

20

1

4

20

1

4

20

2

4

40

3

M

2

4

40

2

4+

40

2

4+

40

3

2–

30

4

F

2

4

40

3

2

30

4

2–

40

4

2–

40

5

F

2

4

40

1

4+

20

4

2-

40

3

2–

30

6

F

1

4

20

1

4

20

1

4

20

1

4

20

Mean

 

 

 

30

 

 

25

 

 

30

 

 

30

*) Circular streak (0–4 mm) on the pupil;

+ Spot on the cornea with opacity up to white coloration;

– Remaining surface: reduction in normal clarity

 

Table 2:Iris evaluation: A = Change

 

 

1 h

24 h

48 + 72 h

Animal #

Sex

A

A × 5

A

A × 5

A

A × 5

1

M

0

0

0

0

0

0

2

M

0

0

0

0

0

0

3

M

0

0

0

0

1*

5

4

F

0

0

0

0

0

0

5

F

0

0

1*

5

1*

5

6

F

0

0

0

0

0

0

Mean

 

 

0

 

0.83

 

1.67

*) Circumcorneal injection

 

Table 3:Conjunctive evaluation: Redness (A) + swelling (B) + exudation (C)

 

 

1 h

24 h

48 h

72 h

Animal #

Sex

A

B

C

(A + B + C) × 2

A

B

C

(A + B + C) × 2

A

B

C

(A + B + C) × 2

A

B

C

(A + B + C) × 2

1

M

2

2

2

12

3

2

2

14

3

1

2

12

3

1

1

10

2

M

2

3

2

14

3

2

2

14

2

2

2

12

3–

2

1

12

3

M

2*

3

2

14

2

2

2

12

3–

2

2

14

3–

2

1

12

4

F

2

3

2

14

3+

2

3

16

3

2

3

16

3–

2

2

14

5

F

2*

2

2

12

2

2

2

12

3

1

2

12

3–

1

2

12

6

F

2

2

2

12

3

2

2

14

3

2

2

14

3

1

2

12

Mean

 

 

 

 

13

 

 

 

13.37

 

 

 

13.33

 

 

 

12

*) Necrotic spots on mucous membrane;

+ Skin-like mucous on the cornea;

– White layer is exuded from the mucous membrane

 

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
This study supports the conclusion that fumaric acid is an eye irritant.
Executive summary:

Application of 0.1 g fumaric acid to the eyes of male and female rabbits was considered irritating to the eye and ocular mucous membrane. Fumaric acid is classified as an eye irritant. It is assigned the symbol Xi and the risk-phrase R36 - irritating to the eyes according to Directive 67/548/EEC. It is assigned the pictogram GHS07 with the signal word warning and the hazard statement H319 "causes serious eye irritation".

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Male and female small white Russian rabbits were exposed to 0.5 g fumaric acid wetted with paraffin oil under an occlusive patch for 4 hours. Dermal application of fumaric acid was mildly irritating to the skin of male and female rabbits with an irritation index of 0.63.

Male and female small white Russian rabbits administered 0.1 g fumaric acid by application to the eyelid pocket showed an irritation index of 42.8 after 72 hours. Fumaric acid was considered moderately irritating to the eye and ocular mucous membrane.

Effects on skin irritation/corrosion: slightly irritating

Effects on eye irritation: moderately irritating

Justification for classification or non-classification

Fumaric acid is listed on Annex I of Directive 67/548/EEC as an irritant to eyes (Xi; R36).

The mild skin irritation observed was insufficient to justify classification. Moderate, reversible eye irritation seen in the study discussed above shows that fumaric acid should remain classified for ocular irritation according to current EU criteria.

Fumaric acid is classified as an eye irritant. It is assigned the symbol Xi and the risk-phrase R36 - irritating to the eyes according to Directive 67/548/EEC. It is assigned the pictogram GHS07 with the signal word warning and the hazard statement H319 "causes serious eye irritation".