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Diss Factsheets

Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The paper provides a comparison of GPMT and LLNA designs for assessment of sensitising potential rather than a method for assessing the sensitisation potential of fumaric acid. Fumaric acid is included as one of the range of test materials under consideration but the results are used to compare the relative merits of the two study designs. The results do supplement other studies that indicate fumaric acid is not a sensitiser.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
GLP compliance:
yes
Type of study:
guinea pig maximisation test

Test material

Constituent 1
Reference substance name:
Fumaric acid
EC Number:
203-743-0
EC Name:
Fumaric acid
Cas Number:
110-17-8
IUPAC Name:
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): C4H4O4
- Smiles notation (if other than submission substance): C(=C/C(=O)O)\C(=O)O
- InChl (if other than submission substance): 1/C4H4O4/c5-3(6)1-2-4(7)8/h1-2H,(H,5,6)(H,7,8)/b2-1+
- Substance type: endogeneous lipid unsaturated
- Analytical purity: 99%
- Impurities (identity and concentrations): not stated
- Composition of test material, percentage of components: not stated

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS: SPF-Hsd Poc: DH guinea pigs
- Source:Harlan Winkelmann,Borchen Germany.
- Age at study initiation: not stated
- Weight at study initiation: 300-500g
- Housing:Group housed in Terlauronmakrolon type cages with saw fibre bedding
- Diet (e.g. ad libitum): Altromin 3122 maintenance diet or Ssniff Ms-H, 4mm V2233-000
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: at least five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3°C
- Humidity (%): 55±10% RH
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: not stated To: not stated

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
cotton seed oil
Concentration / amount:
intradermal induction - 5%
topical induction - 25%
Challenge application - 10%
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
cotton seed oil
Concentration / amount:
intradermal induction - 5%
topical induction - 25%
Challenge application - 10%
No. of animals per dose:
10 test and 5 controls
Details on study design:
RANGE FINDING TESTS: various tests performed to determine suitable dose concentrations foreach phase of the main study

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2 - intradermal and topical
- Exposure period:
- Test groups: 10 guinea pigs exposed to FCA and test material in vehicle on day 1, treated with SLS prior to topical application afte one week, topical induction applied over injection sites and occluded for 48 hours
- Control group: as test group but with test material. only 5 guinea pigs used
- Site:
- Frequency of applications: once on day 1 and 8
- Duration: intradermal injections unlimited, toppical induction exposure for 48 hours
- Concentrations: 5 and 25%

B. CHALLENGE EXPOSURE
- No. of exposures: two
- Day(s) of challenge: day 20 and 28
- Exposure period: 24 hours
- Test groups: ten animals
- Control group: five animals
- Site: dorsum
- Concentrations: 25%
- Evaluation (hr after challenge): 24 and 48 and 72 hours post patch removal

Positive control substance(s):
not required

Study design: in vivo (LLNA)

Statistics:
Not required.

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
10%
No. with + reactions:
1
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 10%. No with. + reactions: 1.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
10%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
10%
No. with + reactions:
1
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 10%. No with. + reactions: 1.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
10%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
other: 3rd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: other: 3rd reading. . Hours after challenge: 72.0. Group: test group. Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
other: 3rd reading
Hours after challenge:
72
Group:
negative control
Dose level:
10%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: other: 3rd reading. . Hours after challenge: 72.0. Group: negative control. Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
10%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: negative control. Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
10%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: negative control. Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 5.0.
Reading:
rechallenge
Hours after challenge:
72
Group:
test chemical
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 72.0. Group: test group. Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
72
Group:
negative control
Dose level:
10%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 72.0. Group: negative control. Dose level: 10%. No with. + reactions: 0.0. Total no. in groups: 5.0.

Any other information on results incl. tables

No signs of systemic toxicity were observed. Fumaric acid caused a grade 1 skin reaction in one animal at 24 and 48 h after patch removal. This animal did not show a reaction when re-challenged.

Applicant's summary and conclusion

Interpretation of results:
not sensitising
Remarks:
Migrated information
Conclusions:
Fumaric acid was non-sensitising in the guinea pig maximisation test.
Executive summary:

Read across to fumaric acid is considered valid and malic acid is concluded to have low toxicity and classification is not required

The rational for read across is that fumaric acid will metabolise in biological systems to malic acid. Fumaric acid is also slightly more fat soluble and is considered more likely to absorb to membranes and increase transport.

It is not considered valid to perform further animal tests on malic acid.

The skin sensitisation potential of one saturated and eight unsaturated lipid biochemicals was tested in a LLNA and guinea pig Maximisation test for comparative purposes to test the hypothesis that chemicals with unsaturated carbon-carbon double bonds may give a higher false positive rate in LLNA results than in the GPMT.

Fumaric acid was non-sensitising in the GPMT.

The relative merits of the two assays are further discussed in the paper but are not directly relevant to the assessment of fumaric acid sensitising potential.