Magnesium 2,3,4,5,6,7-Hexahydroxyheptanoate

Endpoint summary

Description of key information

There is no skin sensitisation study available for Magnesium glucoheptonate. Since magnesium glucoheptonate is expected to dissociate to magnesium and glucoheptonate ions, medical and scientific literature data on skin sensitisation potential of glucoheptonate ion, its structurally related analogue gluconate, and organic and inorganic magnesium salts and compounds have been taken into account to evaluate skin sensitisation potential of Magnesium glucoheptonate. Additionally, toxicological profile of Calcium glucoheptonate can be considered. Calcium glucoheptonate is used for decades in both human and veterinary medicine for treatment of hypocalcaemia to correct calcium deficiency states (EMEA, 1998; Drop and Cullen, 1980). Similarly, Magnesium glucoheptonate is used as antihypomagnaesemic drug and as a nutritional supplement (Pharmacopoeia, 2015 on drugs.com). There is no maximum residue limit established for both Calcium and Magnesium glucoheptonate in foodstuff of animal origin (Commission Regulation, 2009, No. 37/2010). No cases of delayed contact hypersensitivity associated with glucoheptonates have been found in the literature (Dabeer & Chemservice SA, 2015). Glucoheptonates are widely used as imaging agents in nuclear medicine (please refer to read-across statement). No skin sensitisation or other types of allergic reactions due to the use of glucoheptonates are reported in the publically available scientific literature. Glucoheptonic acid is a structural sugar like analogue of an endogenous substance gluconic acid. Calcium gluconate and gluconic acid have been assessed for their safe use in cosmetics (CIR, 2014). "The 2014 Cosmetic Ingredient Review Expert Panel acknowledged that the group of monosaccharides, disaccharides, and their related Ingredients, including calcium gluconate and gluconic acid, are safe for humans at concentrations as used in cosmetics. Based on the clinical experience of the Panel, there is little concern that these ingredients are irritants or sensitizers.” Based on this information, no hypersensitivity reactions can be expected for glucoheptonate ion. Referring to skin sensitisation potential of magnesium ion, different organic and inorganic magnesium salts function as bulking agents, buffering agents and pH adjusters, antioxidants and skin conditioning agents in a wide variety of cosmetic formulations. “The Cosmetic Ingredient Review (CIR) Expert Panel reviewed the safety of magnesium sulfate, is being used at concentrations up to 11% and 25% in leave-on and rinse-off products, respectively. The CIR Expert Panel noted that the extensive clinical experience of the Panel, including the results of numerous patch tests, indicates that magnesium salts do not have the potential to induce sensitization. Anhydrous Magnesium sulfate was found to be non-sensitizer when tested up to a concentration of 50 % in the mouse local lymph node assay, according OECD Guideline 429 (CIR, 2014a). The Panel concluded that magnesium sulfate is safe in the present practices of use and concentration in cosmetics” (CIR, 2014a). Magnesium salts of ascorbic acid (Magnesium Ascorbate and Magnesium Ascorbyl Phosphate) (CIR, 2005), Magnesium aspartate (CIR, 2013) and Magnesium citrate (CIR, 2014b) are evaluated to be safe as used in cosmetic products. The Panel concluded that these magnesium salts are not sensitizing in human subjects. Based on this information, no skin sensitizing potential can be attributed to magnesium ion. As additional evidence on the absence of skin sensitising properties of magnesium ion can serve a skin sensitisation study with magnesium alloys used for implants for musculoskeletal surgery (Witte et al., 2008). The magnesium alloys tested as dissolved and solid materials in guinea pigs according to Magnusson-Kligman (OECD 406) test were all negative at challenge exposure. Based on this information no skin sensitisation potential can be expected for Magnesium glucoheptonate. The substance does not need to be classified and labelled as skin sensitizer.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation

Remarks:

in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented peer-reviewed report.

Qualifier:

no guideline required

Principles of method if other than guideline:

The report describes results of dermal application of creams containing Magnesium Ascorbyl Phosphate to prevent scurvy and dark pigmentation in guinea pigs and humans, respectively. The report concludes safety use of L-ascorbic acid and its magnesium, calcium and sodium salts in cosmetic products.

GLP compliance:

no

Type of study:

other: dermal application of cream containing magnesium ascorbyl phosphate to guinea pigs and humans.

Justification for non-LLNA method:

The study was conducted prior LLNA became as standard information requirement.

Reading:

other: Evaluation of skin sensitisation potential of magnesium compounds in cosmetic formulations.

Group:

test chemical

Dose level:

Cosmetic formulations: 7.5 to 30.0 mg/day/animal or 10 % cream (humans/day)

No. with + reactions:

0

Total no. in group:

34

Clinical observations:

No overt skin reactions related to sensitisation

Remarks on result:

other:

Remarks:

Magnesium salts of ascorbic acid (Magnesium Ascorbate, Magnesium Ascorbyl Phosphate, Sodium Ascorbate) are evaluated to be safe as used in cosmetic products. The Panel concluded that these magnesium salts are not sensitizing in human subjects.

Imai et al. (1967) administered either a stock diet or a scorbutigenic diet and water ad libitum for 10 days to male guinea pigs. Guinea pigs fed the scorbutigenic diet were divided into groups after the 10-day feeding period and were percutaneously given Ascorbic Acid at doses from 3.5 to 14.0 mg/day or Magnesium Ascorbyl Phosphate at doses from 7.5 to 30.0 mg/day, both in a cream. The cream was applied on the clipped skin of the back just posterior to the neck. The cream base consisted of cetyl alcohol 3%, hydrogenated lanolin 4%, vegetable oil such as olive oil 3%, isopropyl myristate 6%, polyethylene glycol 6%, nonionic surface-active agents such as polyoxyethylene stearate and glycerol monostearate 16%, and preservatives. One-third the daily dose of the cream was applied at 8 AM, 12 PM, and 4 PM. After application the animals were observed. The L-Ascorbic Acid dose of 7 mg/animal/day (0.5 g cream/ day) and 15 mg/animal/day of Magnesium Ascorbyl Phosphate (0.5 g cream/day) prevented the development of scurvy; the activity of Magnesium Ascorbyl Phosphate was somewhat weaker than that of L-Ascorbic Acid. Sixteen hours after the last application of cream, the skin of the back (treated) and of the abdomen (non-treated) were examined microscopically. The applied skin of the backs in the treated groups indicated the existence of Ascorbic Acid in the intercellular space of the epithelium, contrasting with the absence of Ascorbic Acid in the control group and in the skin of the abdomen in all groups (Imai et al. 1967).

Magnesium Ascorbyl Phosphate Magnesium Ascorbyl Phosphate (VC-PMG) cream (10%) was applied twice a day to the skin of 34 patients with ephelides, chloasma, senile freckles, nevus of Ota, or healthy skin. The effectiveness of the lightening of the pigmentation was judged by a color-difference meter. The VC-PMG cream was effective or fairly effective in 19 of 34 patients. VC-PMG cream applied to the healthy skin of 25 patients resulted in 1 effective, 2 fairly effective, 8 slightly effective, 12 not effective, and 2 possible darkenings (Kameyama et al. 1996).

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Magnesium salts of ascorbic acid (Magnesium Ascorbate, Magnesium Ascorbyl Phosphate, Sodium Ascorbate) are evaluated to be safe as used in cosmetic products. The Panel concluded that these magnesium salts are not sensitizing in human subjects.

Executive summary:

Magnesium Ascorbate is described as antioxidant and skin conditioning agent and Magnesium Ascorbyl Phosphate is an antioxidant in cosmetic products. The concentration of use in cosmetics is reported to be in the range of 0.001 -3%.

Magnesium Ascorbyl Phosphate (7.5 to 30 mg/animal/day (= 0.5 g cream/day)) administered dermally, prevented the development of scurvy in guinea pigs fed by scorbutigenic diet. No skin sensitisation reactions were reported due to the administration of this magnesium salt in treated animals. Magnesium Ascorbyl Phosphate (10 % as lightening cream) was tested in patients with different skin disorders and in healthy patients. No skin sensitization reactions were reported.

Because of the structural and functional similarities of the ingredients: L-Ascorbic Acid, Calcium Ascorbate, Magnesium Ascorbate, Magnesium Ascorbyl Phosphate, Sodium Ascorbate, and Sodium Ascorbyl Phosphate, the Panel believes that the data on one ingredient can be extrapolated to all of them.

Reference 2

Endpoint:

skin sensitisation

Remarks:

in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented peer-reviewed report.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Result of HRPIT in 210 human volunteers treated with magnesium aspartate (0.1% in face cream) is reported.

GLP compliance:

not specified

Type of study:

other: HRIPT

Justification for non-LLNA method:

The study was conducted prior LLNA became as standard information requirement. Moreover, LLNA is not applicable here, because it is a human study.

Species:

human

Route:

epicutaneous, semiocclusive

Vehicle:

no data

Concentration / amount:

0.1%

Route:

epicutaneous, semiocclusive

Vehicle:

no data

Concentration / amount:

0.1%

Reading:

other: No dermal sensitisation was observed

Remarks on result:

other: Reading: other: No dermal sensitisation was observed.

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Magnesium aspartate is not a skin sensitizer.

Executive summary:

Magnesium aspartate is used as buffering agent and pH adjuster in cosmetic formulations at cncentrations of 0.00005-0.1%. Result of HRPIT in 210 human volunteers treated with magnesium aspartate (0.1% in face cream) showed that the substance is not a skin sensitiser. The Panel concluded that Magnesium aspartate has no safety concerns as used in cosmetics.

Reference 3

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:

other: Acceptable well-documented peer-reviewed reports.

Qualifier:

no guideline available

Principles of method if other than guideline:

Summary of sensitization study results (non-human and human) conducted with monosaccharides, disaccharides, and related Ingredients as used in cosmetics.

GLP compliance:

not specified

Type of study:

patch test

Justification for non-LLNA method:

The study was conducted prior LLNA became as standard information requirement.

Reading:

other: Mono- and disaccharides did not produe hypersensitivity skin reactions when tested in animals and In human repeated insult patch tests (HRIPTs).

Remarks on result:

other: Reading: other: Mono- and disaccharides did not produe hypersensitivity skin reactions when tested in animals and In human repeated insult patch tests (HRIPTs)..

A face and neck formulation containing 2.48% lactose did not produce irritation or hypersensitivity in a 4-wk safety-in use ophthalmological evaluation. Thirty-one subjects participated in the study.

In non-human studies, a 50% aq. solution of gluconic acid was not a dermal irritant and lactitol was not an irritant or sensitizer in rabbits. In human repeated insult patch tests (HRIPTs), formulations containing 10% rhamnose, up to 8% glucose, 5% mannose, 2.48% lactose, and less than 1% isomalt, kefiran, lactitol, sucralose, and xylobiose were not irritants or sensitizers. A formulation containing 10% rhamnose did induce a significant irritation reaction in one subject, and irritation was observed in 16% of the subjects during induction in an HRIPT of a rinse-off hair product containing 29% sucrose (tested as a 50% dilution); no sensitization reactions were reported for this product.

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Calcium gluconate and gluconic acid, structurally similar anlogues to glucoheptonates, have been assessed by the Panel as non-sensitizers in cosmetic formulations.

Executive summary:

"The Panel acknowledged that sucrose and glucose are used in cosmetics at relatively high concentrations, and that data from irritation and sensitization studies at maximum use concentrations of these ingredients are lacking; however, based on the clinical experience of the Panel, there is little concern that these ingredients are irritants or sensitizers".

Reference 4

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented peer-reviewed report.

Qualifier:

according to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Deviations:

no

GLP compliance:

not specified

Type of study:

mouse local lymph node assay (LLNA)

Species:

mouse

Strain:

not specified

Sex:

not specified

Vehicle:

other: yes, not specified

Concentration:

10, 25 and 50%

No. of animals per dose:

5

Parameter:

SI

Remarks on result:

other: SI < 3

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The Cosmetic Ingredient Review (CIR) Expert Panel reviewed the safety of magnesium sulfate, which functions as a bulking agent in cosmetic products and is being used at concentrations up to 11% and 25% in leave-on and rinse-off products, respectively. The CIR Expert Panel noted that the history of safe medical use of magnesium sulfate indicates no significant toxicity concerns relating to systemic exposure to this ingredient. Furthermore, the extensive clinical experience of the Panel, including the results of numerous patch tests, indicates that magnesium salts do not have the potential to induce sensitization. The Panel also noted that results were negative for 50% magnesium sulfate in a mouse skin irritation study and in an in vitro sensitization assay. The Panel concluded that magnesium sulfate is safe in the present practices of use and concentration in cosmetics.

Executive summary:

The skin sensitization potential of anhydrous magnesium sulfate (in propylene glycol) was evaluated using the mouse local lymph node assay, according OECD Guideline 429. Three groups of 5 mice were used, and the dorsal surface of both ears was epidermally treated with the test substance (10%, 25%, and 50%) at a dose volume of 25 μL/ear. A vehicle control group was also included in the study. The animals were then injected i.v. with 3H-methyl thymidine, killed, and the draining auricular lymph node of each ear was excised. Lymph nodes were pooled for each animal, and cell suspensions prepared. The stimulation index (SI) was calculated for each group. The SI is defined as the ratio of the DPM/group compared to the DPM/vehicle control group. Because there was no indication that the test substance elicited an SI of ≥ 3 when tested up to a concentration of 50%, anhydrous magnesium sulfate was considered a non-sensitizer.

Reference 5

Endpoint:

skin sensitisation

Remarks:

in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented peer-reviewed report.

Qualifier:

no guideline required

Principles of method if other than guideline:

The report describes safety assessment of citric acid, its inorganic salts including Magnesium citrate and alkyl citrate esters for their use in cosmetic products.

GLP compliance:

not specified

Type of study:

other: read-across from a whole group of citrates and alkyl citrate esters.

Justification for non-LLNA method:

The studies with magnesium salts of citrates were conducted prior LLNA became as standard information requirement.

Key result

Remarks on result:

other: Magnesium citrate at 0.01 to 2 % concentrations in cosmetic formulations is not sensitising to human skin.

Magnesium citrate is not sensitizing.

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Magnesium citrate is not a skin sensitizer.

Executive summary:

Magnesium citrate functions as skin conditioning agent in cosmetic products at concentrations of 0.01-2%. The Panel concluded that citric acid and the inorganic citrate salts including magnesium citrate and alkyl citrate esters, are safe in the present practices of use and concentration in cosmetic formulations.

Reference 6

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:

other: Acceptable well-documented publication which meets basic scientific principles.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Deviations:

no

Principles of method if other than guideline:

The article describes results of skin sensitisation test with four different magnesium alloys according to Magnusson-Kligman in guinea pigs.

GLP compliance:

not specified

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

The study was conducted prior LLNA became a standard information requirement.

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann Borchen, Germany.
- Age at study initiation: not reported.
- Weight at study initiation: 400-550 g; 600 -700 g at the end of experiment.
- Housing: in pairs in clear plastic cages (55 x 32.8 x 19 cm³) on standard bedding.
- Diet (e.g. ad libitum): ad libitum (standard diet).
- Water (e.g. ad libitum): ad libitum.
- Acclimation period: not reported.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3
- Humidity (%): 30-70
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12

Route:

intradermal and epicutaneous

Vehicle:

physiological saline

Remarks:

Petrolatum was used for epicutaneous induction of solid test substances. For testing of dissolved substances: the implants were dissolved in 2M hydrochloride acid buffered with 1M sodium hydroxide at pH 5.5.

Concentration / amount:

Not applicable. All implant materials were tested both in a dissolved and in a solid state. All implant materials were dissolved by boiling in 2M hydrochloride acid and buffered with 1M sodium hydroxide at pH 5.5. The supernatants were microfiltrated (22 µm) and the ional metal content was confirmed by inductively coupled plasma atomic emission spectrometry (ІСP-AES).

Route:

epicutaneous, occlusive

Vehicle:

physiological saline

Remarks:

Petrolatum was used for epicutaneous induction of solid test substances. For testing of dissolved substances: the implants were dissolved in 2M hydrochloride acid buffered with 1M sodium hydroxide at pH 5.5.

Concentration / amount:

Not applicable. All implant materials were tested both in a dissolved and in a solid state. All implant materials were dissolved by boiling in 2M hydrochloride acid and buffered with 1M sodium hydroxide at pH 5.5. The supernatants were microfiltrated (22 µm) and the ional metal content was confirmed by inductively coupled plasma atomic emission spectrometry (ІСP-AES).

No. of animals per dose:

10 (for solid substances);
10 (for dissolved substances)

Details on study design:

The animals were divided randomly into groups of 20 animals for each test substance. For each test substance, 10 animals were tested with test substances in a solid slate and a dissolved state.

RANGE FINDING TESTS:
In a preliminary study, non irritant concentrations were determined in one animal for each test substance and the reproducibility of the test was confirmed in a positive and a negative control group оf 15 animals each.

PERFORMING the MAGNUSSON-KLIGMAN TEST
An intradermal test and an epicutaneous patch test were performed according to the GPMT.

The skin reaction was interpreted by a qualitative grading of three independent observers immediately and 24 h alter patch removal. For the grading of the skin reaction, the erythema classification according to Magnusson-Kligman test was used (0: no reaction; 1: mild redness, no swelling; 2: moderate and diffuse redness, no swelling; 3: intensive redness and swelling; 4: necrosis). A skin reaction graded greater than zero was defined as erythema.
The test site was clipped with electric clippers for intradermal injection. Per topical application, the hair was clipped and closely shaved. Cellulose filters 2 X 4 cm² and 2 X 2 cm² were used as patches. Applied test patches were covered with overlapping pieces of impermeable plastic tape and fixed with 25 cm long strips of elastic tape bandage which was secured by two 6 cm long pieces of tape.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2
- Exposure period: single intradermal injection on day 0 and 24 hours (topical application on day 7).
- Control group: negative and positive controls as well as standards implant materials titanium (TiAl6V4) and polymeric material (SR-PLA96) were included.
- Site: intradermal injection: back (between shoulders). To prepare the skin for the intradermal induction with dissolved test substances, an area of 4 x 6 cm² was clipped between the shoulders. Topical application: the area over the former intradermal injection areas.
- Test group: A total of six intradermal injections of 0.1 ml each were made in two rows of three injections each. The two cranial injections contained FCA (Freund's Complete Adjuvant™, Sigma-Aldrieh) and physiological saline solution of equal volume parts. The pair of caudal injections contained FCA and test substance in equal volume parts. Seven days later, 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 nun 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.

- Frequency of applications: single applications (1x intradermal injection; 1 x topical application).

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 22+23+24
- Exposure period: 24 hours
- Site: 5 x 5 cm² area on the left flank.
- Evaluation (hr after challenge): 24 hours
Two weeks later, the epicutaneous challenge was performed by clipping and shaving another area of 5 x 5 cm² on the left flank (Fig. 1). 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. Erythema 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 application on the patches.

Positive control substance(s):

yes

Remarks:

Hydroxy-cinnamon-aldehyde (HCA)

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

dissolved test substances

No. with + reactions:

3

Total no. in group:

10

Clinical observations:

Three out of 10 animals tested with AZ91 and TLA16V4 had mild skin reactions after 24 h. Twenty four hours after the patch was removed, all erythema had faded.

Remarks on result:

other: see Remark

Remarks:

Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: dissolved test substances. No with. + reactions: 3.0. Total no. in groups: 10.0. Clinical observations: Three out of 10 animals tested with AZ91 and TLA16V4 had mild skin reactions after 24 h. Twenty four hours after the patch was removed, all erythema had faded..

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

dissolved test substances

No. with + reactions:

1

Total no. in group:

10

Clinical observations:

In AZ31 and SR-PLA96 one out of 10 animals showed a mild clinical skin response immediately after patch removal. Twenty four hours after the patch was removed, all erythema had faded.

Remarks on result:

other: see Remark

Remarks:

Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: dissolved test substances. No with. + reactions: 1.0. Total no. in groups: 10.0. Clinical observations: In AZ31 and SR-PLA96 one out of 10 animals showed a mild clinical skin response immediately after patch removal. Twenty four hours after the patch was removed, all erythema had faded..

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

solid test substances

No. with + reactions:

2

Total no. in group:

10

Clinical observations:

after 24 h the erythema remained in 20% of the AZ91 group

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: solid test substances. No with. + reactions: 2.0. Total no. in groups: 10.0. Clinical observations: after 24 h the erythema remained in 20% of the AZ91 group.

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

solid test substances

No. with + reactions:

1

Total no. in group:

10

Clinical observations:

after 24 h the erythema remained in 11% of the LAE442 group.

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: solid test substances. No with. + reactions: 1.0. Total no. in groups: 10.0. Clinical observations: after 24 h the erythema remained in 11% of the LAE442 group..

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

solid test substances

No. with + reactions:

1

Total no. in group:

10

Clinical observations:

after 24 h the erythema remained in 10% of the TiA16V4 group.

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: solid test substances. No with. + reactions: 1.0. Total no. in groups: 10.0. Clinical observations: after 24 h the erythema remained in 10% of the TiA16V4 group..

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

No erythema was observed in all guinea pigs exposed to the standard irritant SLS.

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No erythema was observed in all guinea pigs exposed to the standard irritant SLS. .

Reading:

1st reading

Hours after challenge:

24

Group:

positive control

No. with + reactions:

10

Total no. in group:

10

Clinical observations:

All guinea pigs exposed to the standard allergen HCA showed persisting erythema for more than 24 h after patch removal.

Remarks on result:

other: see Remark

Remarks:

Reading: 1st reading. . Hours after challenge: 24.0. Group: positive control. No with. + reactions: 10.0. Total no. in groups: 10.0. Clinical observations: All guinea pigs exposed to the standard allergen HCA showed persisting erythema for more than 24 h after patch removal..

Solid test substances

Between 90% (AZ31, SR-PLA96) and 100% (AZ91, WE43, LAE442, and TiA16V4) of the tested skin areas displayed erythema immediately after patch removal. However, after 24 h the erythema remained in 20% of the AZ91 group, 11% of the LAE442 group, and in 10% of the TiA16V4 group (Fig. 3). To identify allergic erythema after 24 h, dermal biopsies were taken. All biopsies exhibited significantly (p = 0.001) less histomorphological criteria of allergenicty compared to the positive control group. Furthermore, 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. However, animals treated with AZ91, LAE442, and TiA16V4 which still had an erythema 24 h after patch removal, showed no criteria of aliergenieity in histomorphological analysis. No correlation was found between the cell count of eosinophiles and the concentration of aluminium in the test solution (p > 0.05, Pearson correlation).

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The clinical and histological results of this study indicate that no skin sensitizing potential was detected for all tested magnesium alloys as well as for titanium and the degradable polymer.

Executive summary:

Corroding implant materials made of different magnesium alloys were tested in a skin sensitisation study according to the Magnusson and Kligman test (Witte et al., 2008). Standard implant materials such as titanium (TiA16V4) and a degradable polymer (SR-PLA96) were used as standards. The test design was similar to that of the OECD 406 test guideline. The magnesium alloys and standard implant materials were tested for their allergenic potential in a dissolved state (dissolved by boiling in 2M hydrochloride acid and buffered with 1M sodium hydroxyde at pH 5.5) and a solid state (as solid chips) in a guinea pig animal model. A standard allergen (hydroxy-cmnamon-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. Histomorphological analyses were performed on skin biopsies taken 24 h after patch removal.

It was 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. It is concluded that no skin sensitizing potential were detected for standard materials as well as for all tested magnesium alloys by the used methods.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Justification for classification or non-classification

Based on negative results on skin sensitisation available for gluconates and organic and inorganic magnesium compounds, magnesium glucoheptonate does not meet criteria for classification and labelling as skin sensitiser according to European Regulation (EC) No. 1272/2008.