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Reaction mass of ammonium;potassium;sodium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate;magnesium, ammonium;potassium;sodium;2-[bis[2-[bis(carboxymethyl)amino]ethyl]amino]acetate;magnesium and ammonium;potassium;sodium;2-[2-[bis(carboxymethyl)amino]ethyl-(2-hydroxyethyl)amino]acetate;magnesium
EC number: 902-533-2 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
The substance is a reaction mixture of Magnesium (Mg), EDTA, DTPA and HEEDTA. None of these constituents are classified as skin sensitisers according to the ECHA dissemenation website. To support that both magnesium and the three chelating agents (EDTA, DTPA and HEEDTA) are non-sensitizers, selected studies and lines of evidence are provided.
Because none of the constituents have known skin sensitisation properties, the reaction mass of MgEDTA, MgDTPA and MgHEEDTA is also regarded as a non-sensitiser.
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- 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
- 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.
- 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. - 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 - 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
- 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
- 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).
- 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
- 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.
- Endpoint:
- skin sensitisation, other
- Type of information:
- (Q)SAR
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification
- Justification for type of information:
- 1. SOFTWARE
ToxTree 2.6.13
2. MODEL (incl. version number)
Skin sensitisation reactivity domain (Identification of mechanisms of toxic action for skin sensitisation using a SMARTS pattern based approach)
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
MgEDTA: O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
MgHEEDTA: C1(=O)CN(CC(=O)O[Na])CCN(CCO[Na])CC(=O)O[Mg]O1
MgDTPA: C(=O)(CN(CC(=O)O[Na])CCN1CC(=O)O[Mg]OC(=O)CN(CC(=O)O[Na])CC1)O[Na]
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
[Explain how the model fulfils the OECD principles for (Q)SAR model validation. Consider attaching the QMRF or providing a link]
A QMRF is not available for this substance, but see Enoch et al. 2008 for more information on used algorithm, training dataset and applicability domain.
5. APPLICABILITY DOMAIN
See attached report of the QSAR predictions.
6. ADEQUACY OF THE RESULT
The absence of skin sensitisation reactivity domains alerts supports the claim that MgEDTA, MgHEEDTA and MgDTPA are non-sensitizers. - Qualifier:
- according to guideline
- Guideline:
- other: REACH Guidance on QSARs R.6
- Principles of method if other than guideline:
- http://toxtree.sourceforge.net
- Specific details on test material used for the study:
- MgEDTA: O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
MgHEEDTA: C1(=O)CN(CC(=O)O[Na])CCN(CCO[Na])CC(=O)O[Mg]O1
MgDTPA: C(=O)(CN(CC(=O)O[Na])CCN1CC(=O)O[Mg]OC(=O)CN(CC(=O)O[Na])CC1)O[Na] - Run / experiment:
- other: MgEDTA
- Parameter:
- other: QSAR Prediction
- Remarks on result:
- other: Skin Sensitisation Reactivity Domain
- Remarks:
- No skin sensitisation reactivity domains alerts identified.
- Run / experiment:
- other: MgHEEDTA
- Parameter:
- other: QSAR prediction
- Remarks on result:
- other: Skin Sensitisation Reactivity Domain
- Remarks:
- No skin sensitisation reactivity domains alerts identified.
- Run / experiment:
- other: MgDTPA
- Parameter:
- other: QSAR Prediction
- Remarks on result:
- other: Skin Sensitisation Reactivity Domain
- Remarks:
- No skin sensitisation reactivity domains alerts identified.
- Interpretation of results:
- other:
- Conclusions:
- Based on the predictions of the ToxTree Skin Sensitisation QSAR (using SMARTS pattern based approach), no skin sensitisation reactivity domains alerts were identified for MgEDTA, MgDTPA and MgHEEDTA.
Referenceopen allclose all
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).
MgEDTA
QSNAR.SNAr-Nucleophilic Aromatic Substitution No
O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
QSB.Schiff Base Formation No
O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
QMA.Michael Acceptor No
O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
Qacyl.Acyl Transfer Agents No
O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
QSN2.SN2-Nucleophilic Aliphatic Substitution No
O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
Q6.At least one alert for skin sensitisation? No Class No
skin sensitisation reactivity domains alerts
identified.O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
MgHEEDTA
QSNAR.SNAr-Nucleophilic Aromatic
Substitution No
O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
QSB.Schiff Base Formation No
O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
QMA.Michael Acceptor No
O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
Qacyl.Acyl Transfer Agents No
O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
QSN2.SN2-Nucleophilic Aliphatic Substitution No
O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
Q6.At least one alert for skin sensitisation? No Class No
skin sensitisation reactivity domains
alerts identified.
C1(=O)CN(CC(=O)O[Na])CCN(CCO[Na])CC(=O)O[Mg]O1
MgDTPA
QSNAR.SNAr-Nucleophilic Aromatic
Substitution No
O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
QSB.Schiff Base Formation No
O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
QMA.Michael Acceptor No
O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
Qacyl.Acyl Transfer Agents No
O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
QSN2.SN2-Nucleophilic Aliphatic Substitution No
O=C1CN(CC(=O)O[Na])CCN(CC(=O)O[Na])CC(=O)O[Mg]O1
Q6.At least one alert for skin sensitisation? No Class No
skin sensitisation reactivity domains
alerts identified.
C(=O)(CN(CC(=O)O[Na])CCN1CC(=O)O[Mg]OC(=O)CN(CC(=O)O[Na])CC1)O[Na]
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not sensitising)
Justification for classification or non-classification
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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