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Diss Factsheets

Administrative data

Description of key information

Fumaric acid is not considered a skin sensitiser.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
supporting 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.
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
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 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.
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
supporting 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.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
GLP compliance:
yes
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
CBA
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS: SPF-CBA/Ca01aHsd mice
- Source: Harlan Winkelmann,Borchen Germany.
- Age at study initiation: 6-12 weeks
- Weight at study initiation: not stated
- Housing: Group housed in makrolon type cages with saw fibre bedding
- Diet (e.g. ad libitum):Altromin 1324 maintenance diet
- 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

Vehicle:
dimethyl sulphoxide
Concentration:
5, 10 and 25%
No. of animals per dose:
five mice per group
Details on study design:
RANGE FINDING TESTS:
- Compound solubility: three different concentrations tested to detct highest tolerable exosure concentration
- Irritation: local irritatiion measured by ear sweling
- Lymph node proliferation response: not determined in preliminary investigation

MAIN STUDY
ANIMAL ASSIGNMENT AND TREATMENT
- Name of test method: LLNA
- Criteria used to consider a positive response: SI

TREATMENT PREPARATION AND ADMINISTRATION:
In the main test groups of 5 mice were treated by topical applications of 25 µl test or control solution, applied to the entire dorsal surface of the ear. Topical applications were performed once daily for 3 consecutive days. The negative control group was treated with vehicle alone. The positive control group was treated with 1% p-phenylenediamine. On day 6 all mice were injected with 20µCi tritiated methyl thymidine via the tail vein. Approximately 5 hours later the mice were sacrificed and the draining auricular lymph nodes were excised, weighed (right and left) and individually pooled per animal in PBS. The cell suspension was prepared according to standard methods. Tritated thymidine was measured using a scintillation counter and expressed as disintegrations per minute.
The proliferative response of the lymph node cells was expressed as number of disintegrations per node (DPM/node) adjusted for background values. The Stimulation Index was calculated as the ratio of the arithmetic mean of DPM/node values forthe test and control groups
Positive control substance(s):
other: 1% p-phenylenediamine
Statistics:
DPM/node and SI calculated as per standard methods
Parameter:
SI
Remarks on result:
other: SI = 1.3 at 5%; 2.3 at 10% and 1.4 at 25% LNWI - 1.3 at 55; 1.5 at 10% and 1.3 at 25% SI = stimulation index - no linear dose response and no value exceeding 3.0 LNWI = lymph node weight index
Parameter:
other: disintegrations per minute (DPM)
Remarks on result:
other: Individual values not presented in publication

No signs of systemic toxicity were observed. No clinical signs of local irritation were observed by visual inspection of the ears. Fumaric acid gave clear negative results, with SI values below 3. A weak but statistically significant LNWI increase was observed at 10% but not 5% or 25%. As the lymph node weight reaction was weak and lacked a dose-response relationship, the SI result was given precendence and it was concluded that fumaric acid was not sensitising in the LLNA.

Interpretation of results:
not sensitising
Remarks:
Migrated information
Conclusions:
Fumaric acid gave a clearly negative response in the murine LLNA, which supported the conclusion that the GPMT also indicated so sensitising potential for this material and reinforced the conclusion drawn from the key study presented in this data point that no classification is necessary in respect of sensitisation for fumaric acid.
Executive summary:

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.

The results of the LLNA test for fumaric acid, as part of the test series, are presented in this summary. It was concluded that fumaric and succinic acids gave clearly negative LLNA results and that neither material would be classified for hypersensitivity potential based on the results of the GPMT . The relative merits of the two assaysare further discussed in the paper but are not directly relevant to the assessment of fumaric acid sensitising potential.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
GLP compliance:
no
Remarks:
GLP was not yet legally implemented when the study was conducted.
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Study report from 1989 available.
Species:
guinea pig
Strain:
other: Bor: DHPW
Sex:
female
Details on test animals and environmental conditions:
One to five animals were kept in type IV Makrolon cages for an acclimation period of 5-8 days. Average weight of animals was 400 g. G4 general diet for guinea pigs and water were provided ad libitum. Room temperature was 20 °C with 60 % relative humidity. There were 15 air exchanges per hour with a 12 hr light-dark rhythm.
Route:
intradermal and epicutaneous
Vehicle:
corn oil
Concentration / amount:
Induction, intradermal: 0.5%
Induction, epicutaneous: 25% test material
Day(s)/duration:
7
Adequacy of induction:
non-irritant substance, but skin pre-treated with 10% SDS
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
corn oil
Concentration / amount:
Challenge: 25 %
Day(s)/duration:
2
Adequacy of challenge:
not specified
No. of animals per dose:
19 animals per dose
Details on study design:
A total of six intracutaneous injections were made in the right and left shoulder area of animals: a mixture of Freunds Complete Adjuvant and water, 0.5 % test material in corn oil, and 0.5 % test material in a mixture of FCA and corn oil. A patch test was carried out a week later. Twenty-four hours prior to the patch test, the shoulder region was shaved and 10 % SDS prepared in vaseline was massaged into the skin to provoke a mild skin irritation. Filter paper was coated with 25 % test material in corn oil, applied to the injection region and covered with an adhesive bandage. The patch was secured for 48 hrs with an elastic bandage.
Two weeks later, a filter paper patch coated with 25% test substance in corn oil was applied to the left flank of animals and covered with an adhesive bandage. An elastic bandage was used to secure the patch for 24 hours. A patch containing only corn oil was applied to the right flank of animals.
Challenge controls:
A total of six intracutaneous injections were made in the right and left shoulder area of animals: A mixture of Freunds Complete Adjuvant and water, corn oil, and a mixture of FCA and corn oil. A patch test was carried out a week later. Filter paper was coated with corn oil, applied to the injection region and covered with an adhesive bandage. The patch was secured for 48 h with an elastic bandage. Two weeks later, a filter paper patch coated with 25 % test substance in corn oil was applied to the left flank of animals and covered with an adhesive bandage. An elastic bandage was used to secure the patch for 24 hours. A patch containing only corn oil was applied to the right flank of animals.
Positive control substance(s):
not required
Positive control results:
None - not necessary according to guideline.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25 %
No. with + reactions:
0
Total no. in group:
19
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25 %
No. with + reactions:
0
Total no. in group:
19
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
45
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Group:
positive control
Remarks on result:
not measured/tested

Local reactions during experiment

After intracutaneous injection: All injection sites treated with FCA showed intense redness and swelling, as well as necrosis, in both control and treated animals. Mild redness and swelling was also seen in control animals treated with corn oil. Twenty-four hours after patch removal, all injection sites treated with FCA were crusted and scabby.

After patch test of 48 h duration: Intense inflammation, at times bloody, was seen in control and test animals treated with FCA and demineralised water. 24 hours after patch removal: all injections sites treated with FCA were crusted and scabby.

Interpretation of results:
not sensitising
Conclusions:
This study supports the conclusion that fumaric acid is not a skin sensitiser.
Executive summary:

Fumaric acid shows no sensitisation effect on the skin of female guinea pigs according to the Magnusson-Kligman maximization test.

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

A total of six intracutaneous injections were made in the right and left shoulder area of female guinea pigs: a mixture of Freunds Complete Adjuvant and water, 0.5 % fumaric acid in corn oil, and 0.5 % fumaric acid in a mixture of FCA and corn oil. A patch test was carried out a week later with 25 % fumaric acid in corn oil, applied to the injection region and covered with an adhesive bandage. The patch was secured for 48 h with an elastic bandage. Two weeks later, a filter paper patch coated with 25 % fumaric acid in corn oil was applied to the left flank of animals and covered with an adhesive bandage for 24 hours. At 48 h post challenge, none of the animals showed any positive skin reactions. Fumaric acid at a concentration of 25 % showed no sensitization effect on the skin of female guinea pigs according to the Magnusson-Kligman maximization test.

In the LLNA, groups of 5 mice were treated by topical applications of 25 µl test or control solution, applied to the entire dorsal surface of the ear. Topical applications were performed once daily for 3 consecutive days. The negative control group was treated with vehicle alone. The positive control group was treated with 1% p-phenylenediamine. On day 6 all mice were injected with 20µCi tritiated methyl thymidine via the tail vein. Approximately 5 hours later the mice were sacrificed and the draining auricular lymph nodes were excised, weighed (right and left) and individually pooled per animal in PBS. The cell suspension was prepared according to standard methods. Tritiated thymidine was measured using a scintillation counter and expressed as disintegrations per minute.

The proliferative response of the lymph node cells was expressed as number of disintegrations per node (DPM/node) adjusted for background values. The Stimulation Index was calculated as the ratio of the arithmetic mean of DPM/node values for the test and control groups.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Fumaric acid is not classified as a skin sensitiser based on results of a guideline-comparable Magnusson-Kligman maximization study which showed no evidence of skin sensitisation.

No evidence of skin sensitisation was seen in a guideline-compliant Local Lymph Node Assay with fumaric acid.