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Diss Factsheets

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
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. For read-across justification see Section 13.
Justification for type of information:
HYPOTHESIS FOR THE ANALOGUE APPROACH
The registered (target) substance, malic acid, plays an important part in the Krebbs Cycle as an intermediary step in the metabolism of sugars and other carboxylic acids. The substance is therefore regarded as producing common breakdown products via biological processes.
The source substance, fumaric acid (fumarate) is metabolised as part of the Krebbs Cycle to malate (malic acid) by the addition of water in the presence of the enzyme fumarase. This is an essential part of metabolism and, since the metabolism of fumaric acid occurs through malic acid in biological systems, the toxicological properties of fumaric acid will most likely reflect the properties of malic acid.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Reported invstigation of false positive responses observed with the LLNA and comparing outcome with "traditional" methods.
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
Route:
intradermal and epicutaneous
Vehicle:
cotton seed oil
Concentration / amount:
intradermal induction - 5%
topical induction - 25%
Challenge application - 10%
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
Statistics:
Not required.
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.

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.

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

The skin sensitisation potential of one saturated and eight unsaturated lipid biochemicals was tested in a LLNA and guinea pig Maximisation test (GPMT) 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.

Read across to fumaric acid is considered valid and malic acid is considered to exhibit similar properties. 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 via membranes and increase transport.

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

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Fumaric acid exhibited no dermal sensitisation potential in both the traditional Maximisation test and the LLNA.

Read across to fumaric acid is considered valid based on the rational 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 via membranes and increase transport. As a result, malic acid is considered to exhibit similar properties.

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


Migrated from Short description of key information:
Dermal sensitisation - Negative; based on read across to malic acid from fumaric acid

Respiratory sensitisation

Endpoint conclusion
Additional information:
Migrated from Short description of key information:
No data available, but not considered to be sensitising based on absence of effects in LLNA

Justification for classification or non-classification

The negative responses observed with a structural analogue of malic acid, fumaric acid, in both the traditional maximisation test and the LLNA are sufficient to justify non-classification according to current EU and GHS criteria.