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Diss Factsheets

Toxicological information

Skin sensitisation

Currently viewing:

Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Evaluation of the skin sensitizing potential of biodegradable magnesium alloys
Author:
Witte, F. et al.
Year:
2007
Bibliographic source:
J. Biomed. Mater. Res. A. 86: 1041-1047.

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
GLP compliance:
not specified
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The guinea pig maximisation test is a well-accepted method (OECD guidelines available). Because this information was already available, a LLNA method was not required.

Test material

Constituent 1
Chemical structure
Reference substance name:
Magnesium
EC Number:
231-104-6
EC Name:
Magnesium
Cas Number:
7439-95-4
Molecular formula:
Mg
IUPAC Name:
magnesium
Specific details on test material used for the study:
4 different magnesium alloys:
(i) AZ31: MgAl(2.4 - 3.6%) Zn(0.5 - 1.5%) Mn(0.15 - 1%) Si 0.1% Cu 0.1% = Mg content between 96.8 - 93.7% (w/w)
(ii) AZ91: MgAl(8.1 - 9.3%) Zn(0.4 - 1%) Mn(0.17 - 0.35%) Si 0.2% = Mg content between 91.1% - 89.2% (w/w)
(iii) WE43: MgLi4Al(3.4 - 4.6%) rare earth(1.8 - 3%) Mn(min.0.25%) Zn (max0.22%) = Mg content between 94.3 - 92% (w/w)
(iv) LAE442: MgY(3.7 - 4.3%) rare earth(2.4 - 4.4%) Zr(0.4 - 1%) Li 0.2% Mn 0.15% = Mg content between 93.2 - 90% (w/w)
Numbers following the letters represent the percentage of the element content in the magnesium alloy displayed in % w/w

The test material AZ31 was achieve from Dead Sea Magnesium, Israel, the remaining alloys were purchased from Magnesium Elektron in UK.

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann, Borchen, Germany
- Weight at study initiation: 400-550g
- Housing: in pairs in clean plastic cages (55 x 32.8 x 19 cm^3) on standard bedding
- Diet: ad libitum, standard pellets
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature: 20 +/- 3°C
- Humidity: humidity of 30-70%
- Photoperiod: 2 hours dark/light cycle

Study design: in vivo (non-LLNA)

Induction
Route:
intradermal and epicutaneous
Vehicle:
other: All test items were tested both in a dissolved and in a solid state. Therefore, the magnesium alloys were dissolved by boiling in 2 mol/L HCl solution and buffered with 1 mol/L NaOH solution at pH 5.5.
Concentration / amount:
The test substances were produced by carefully machining the alloys to small chips. Only chips of less than 0.8 3 0.8 3 0.2 mm3 were selected as substances for epicutaneous tests.
Day(s)/duration:
24 h
Challenge
Route:
epicutaneous, semiocclusive
Vehicle:
other: All test items were tested both in a dissolved and in a solid state. Therefore, the magnesium alloys were dissolved by boiling in 2 mol/L HCl solution and buffered with 1 mol/L NaOH solution at pH 5.5.
Concentration / amount:
100%
Day(s)/duration:
24 h
No. of animals per dose:
20 animals for each test substance; 10 with the solid material and 10 with the dissolved material. 15 animals in the negative control group and 15 animals in the positive control group.
Details on study design:
An intradermal test and an epicutaneous patch test were performed. The skin reaction was interpreted by a qualitative grading of three independent observers immediately and 24 hours after patch removal. For grading of the skin reaction, the erythema classification according to Magnusson-Klingman test was used. A skin reaction graded greater than zero was defined as erythema.

The test site was clipped for intradermal injection.Topical induction was performed by clipping and shaving the area over the former intradermal injection areas. Cellulose patches of 2 x 4 cm2 were saturated with the dissolved test substance and fixed with overlapping non permeable tape, an elastic bandage and adhesive tapes. The patch was removed after 24 h. To get a deeper skin infiltration of the test substance, the shaved area was treated with 10% SLS in petrolatum 24 h before topical induction.

Two weeks later, the epicutaneous challenge was performed by clipping and shaving another area of 5 x 5 cm2 on the left flank. A cellulose patch of 2 x 2 cm2 was saturated with the test substance and covered with overlapping nonpermeable tape, an elastic bandage, and adhesive tapes. The patch was removed after 24 h. Ery- thema was photographed and judged immediately and 24 h after challenging. The procedure for testing the solid test substances was carried out in the same manner as for the dissolved alloys except for the epicutaneous induction procedure. For the epicutaneous induction procedure, solid test substances were mixed with petrolatum for the appli- cation on the patches.
Challenge controls:
Negative control: sodium-lauryl-sulfate
Preliminary test performed with all test items with one animal each; non-irritant concentrations were determined
Positive control substance(s):
yes
Remarks:
hydroxy-cinnamon-aldehyde

Results and discussion

Positive control results:
All guinea pigs exposed to the standard allergen HCA showed persisting erythema for more than 24 h after patch removal. One animal died during the challenge phase for reasons not related to the test and one skin biopsy was lost because of technical problems. The histological analysis showed in 12 (92.3%) of the remaining 13 biopsies all four criteria of allergy such as spongiosis, edema, and dif- fuse as well as perivascular mononuclear infiltrates. The positive control biopsies contained a mean of 52.7 basophile cells/400 leucocyte cells. Furthermore, in biopsies of the positive con- trol group, a significant higher number of basophile cells was found compared to the negative control group and to all tested substances (p = 0.001, ANOVA).

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
dissolved test substance
No. with + reactions:
3
Total no. in group:
10
Clinical observations:
mild skin reactions after 24 hours
Remarks on result:
other: AZ91
Reading:
1st reading
Hours after challenge:
0
Group:
test chemical
Dose level:
dissolved test substance
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
mild clinical skin response immediately after patch removal; 24h after the patch was removed, all erythema had faded.
Remarks on result:
other: AZ31
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
dissolved test substance
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: AZ31
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
not specified
No. with + reactions:
15
Total no. in group:
15
Clinical observations:
persisting erythema
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
not specified
No. with + reactions:
0
Total no. in group:
15
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
dissolved test substance
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: WE43 and LAE442

Any other information on results incl. tables

Between 90% (AZ31) and 100% (AZ91) of the tested skin areas displayed erythema immediately after patch removal. However, after 24 hours the erythema remained in 20% of the AZ91 group and 11% of the LAE442. To identify allergic erythema after 24 hours, dermal biopsies were taken. All biopsies exhibited significantly (p=0.001) less histomorphological criteria of allergenicity compared to the positive control group. In all biopsies no significant differences were found for basophile cells compared to the negative control. In the LAE442 group of the solid test substances, one animal died unrelated to the study conditions. Animals treated with AZ91and LAE442 which still had an erythema 24 hours after patch removal, showed no criteria of allergenicity in histomorphological analysis. No correlation was found between the cell count of eosinophiles and the concentration of aluminium in the test solutions (p>0.05).

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The tested magnesium alloys (with a total magnesium content between 89.2 – 96.8%) provide no sensitising potential compared to the control groups.
Executive summary:

Corroding metals made of magnesium alloys represent a new class of degradable implants for muscu- loskeletal surgery. These implants may be associated with skin sensitizing reactions because of the release of metal ions. This study was conducted to compare the sensitiz- ing potential of four different magnesium alloys (AZ31, AZ91, WE43, and LAE442) to current implant materials such as titanium (TiAl6V4) and a degradable polymer (SR-PLA96). Solutions and solid chips of these materials were prepared and tested in 156 guinea pigs according to the Magnusson–Kligman test. A standard allergen (hydroxy-cinnamon-aldehyde) causing allergic erythema was used as positive control and a standard irritant (so- dium-lauryl-sulfate) causing local skin irritation for less than 24 h was used as negative control. All erythema were graded immediately and 24 h after patch removal

by three independent observers. Histomorphological anal- yses were performed on skin biopsies taken 24 h after patch removal. We found that initial erythema in animals treated with solid chips diminished within 24 h and were caused by local skin irritation. Local skin irritation was also determined in erythema remaining for 24 h after patch removal in animals treated with dissolved test materials. No allergenic reactions according to the histo- morphological criteria were observed in skin biopsies. We conclude that no skin sensitizing potential were detected for standard materials as well as for all tested magnesium alloys by the used methods.