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EC number: 230-022-8 | CAS number: 6915-15-7
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- Endpoint summary
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- Endpoint summary
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- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
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- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
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- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Eye irritation
Administrative data
- Endpoint:
- eye irritation: in vivo
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 25 April 1984 to 16 May 1984
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Guideline-compliant, proprietary study. For read-across justification see Section 13.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 984
- Report date:
- 1984
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 405 (Acute Eye Irritation / Corrosion)
- GLP compliance:
- yes
Test material
- Reference substance name:
- Fumaric acid/ Fumaril
- IUPAC Name:
- Fumaric acid/ Fumaril
- Reference substance name:
- Fumaric acid
- EC Number:
- 203-743-0
- EC Name:
- Fumaric acid
- Cas Number:
- 110-17-8
- Molecular formula:
- C4H4O4
- IUPAC Name:
- (2E)-but-2-enedioic acid
- Details on test material:
- - Name of test material (as cited in study report): Fumaric acid
- Molecular formula (if other than submission substance): C4 H4 O4
- Molecular weight (if other than submission substance): 116.07
- Smiles notation (if other than submission substance): O=C(O)C=CC(=O)O
- InChl (if other than submission substance): 1S/C4H4O4/c5-3(6)1-2-4(7)8/h1-2H,(H,5,6)(H,7,8)/b2-1+
- Structural formula attached as image file (if other than submission substance): see Fig. Fumaric acid structure.jpg
- Physical state: Solid
- Analytical purity: 99.5%
- odour: odourless
- Impurities (identity and concentrations): benzoic, maleic and phthalic acid <0.05%
- Other: pH 2.1 at 4.9 g/L density 1.63 g/cm3
Constituent 1
Constituent 2
Test animals / tissue source
- 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.
Test system
- Vehicle:
- unchanged (no vehicle)
- Controls:
- other: left eyelid of each animal
- 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
Results and discussion
In vivo
Results
- Irritation parameter:
- overall irritation score
- Basis:
- mean
- Time point:
- other: 72 hrs
- Score:
- 42.8
- Reversibility:
- not fully reversible within: 21 days
- Irritant / corrosive response data:
- The mean values over the 24, 48 and 72 hour post-instillation observations were:
corneal opacity = 2.0
Iris = 0.28
Conjunctival redness = 2.83
conjunctival chemosis = 1.72
Any other information on results incl. tables
Table 1. Cornea Evaluation: Degree of Opacity (A) x Extent of Opacity (B) x 5
Animal number | 1 hr | 24 hr | 48 hr | 72 hr | ||||||||||||
A | B | AxBx5 | A | B | AxBx5 | A | B | AxBx5 | A | B | AxBx5 | |||||
1 | 1 | 4* | 20 | 1 | 4 | 20 | 1 | 4 | 20 | 1 | 4 | 20 | ||||
2 | 1 | 4 | 20 | 1 | 4 | 20 | 1 | 4 | 20 | 2 | 4 | 40 | ||||
3 | 2 | 4 | 20 | 2 | 4+ | 40 | 2 | 4+ | 40 | 3 | 2- | 30 | ||||
4 | 2 | 4 | 20 | 3 | 2 | 30 | 4 | 2- | 40 | 4 | 2- | 40 | ||||
5 | 2 | 4 | 20 | 1 | 4+ | 20 | 4 | 2- | 40 | 3 | 2- | 30 | ||||
6 | 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
Animal number | 1 hr | 24 hrs | 48 + 72 hrs | |||
A | A x 5 | A | A x 5 | A | A x 5 | |
1 | 0 | 0 | 0 | 0 | 0 | 0 |
2 | 0 | 0 | 0 | 0 | 0 | 0 |
3 | 0 | 0 | 0 | 0 | 1* | 5 |
4 | 0 | 0 | 0 | 0 | 0 | 0 |
5 | 0 | 0 | 1* | 5 | 1* | 5 |
6 | 0 | 0 | 0 | 0 | 0 | 0 |
Mean | 0 | 0.83 | 1.67 | |||
*Circumcorneal injection |
Table 3. Conjunctive Evaluation: Redness (A) + Swelling (B) + Exudation (C)
Animal number | 1 hr | 24 hrs | 48 hrs | 72 hrs | ||||||||||||
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 | 2 | 2 | 2 | 12 | 3 | 2 | 2 | 14 | 3 | 1 | 2 | 12 | 3 | 1 | 1 | 10 |
2 | 2 | 3 | 2 | 14 | 3 | 2 | 2 | 14 | 2 | 2 | 2 | 12 | 3- | 2 | 1 | 12 |
3 | 2* | 3 | 2 | 14 | 2 | 2 | 2 | 12 | 3- | 2 | 2 | 14 | 3- | 2 | 1 | 12 |
4 | 2 | 3 | 2 | 14 | 3+ | 2 | 3 | 16 | 3 | 2 | 3 | 16 | 3- | 2 | 2 | 14 |
5 | 2* | 2 | 2 | 12 | 2 | 2 | 2 | 12 | 3 | 1 | 2 | 12 | 3- | 1 | 2 | 12 |
6 | 2 | 2 | 2 | 12 | 3 | 2 | 2 | 14 | 3 | 2 | 2 | 14 | 3 | 1 | 2 | 12 |
Mean | 13 | 13.67 | 13.33 | 12.0 | ||||||||||||
*Necrotic spots on mucous membrane; +Skin-like mucous on the cornea; -White layer is exuded from the mucous membrane |
Applicant's summary and conclusion
- Interpretation of results:
- moderately irritating
- Remarks:
- Migrated information Criteria used for interpretation of results: EU
- Conclusions:
- This study supports the conclusion that fumaric acid and malic are moderate eye irritants requiring classification.
- Executive summary:
Application of 0.1 g fumaric acid to the eyes of male and female rabbits was considered moderately 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".
Read across to fumaric acid is considered valid and malic acid is considerd to exhibit similar properties and require classification as iritating to eyes. It is not considered valid to perform further animal tests on malic acid.
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