Registration Dossier
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EC number: 239-198-0 | CAS number: 15137-09-4
- 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
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:
- key study
- Study period:
- September 2000
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- The study is well-documented by the publication and thus acceptable for assessment.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 406 (Skin Sensitisation)
- Deviations:
- yes
- Remarks:
- guinea pig sensitization test
- Principles of method if other than guideline:
- The study was conducted similar to OECD Guideline 406.
- GLP compliance:
- not specified
- Type of study:
- other: adjuvant and patch test (APT)
- Justification for non-LLNA method:
- At the time the study was performed the guinea pig sensitization test was a standard test method for the skin sensitisation potential. Thus, the study is considered to be reliable.
- Species:
- guinea pig
- Strain:
- Hartley
- Sex:
- female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Japan SLC Inc.
- Weight at study initiation: 380 to 500 g
- Housing: The animals were housed individually in a stainless-steel cage.
- Diet: ad libitum; pellet diet
- Water: ad libitum; sterilised water
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 3
- Humidity (%): 55 +/- 15
- Photoperiod: 12 hours dark/light cycle - Route:
- intradermal and epicutaneous
- Vehicle:
- water
- Concentration / amount:
- 3 %
- Route:
- epicutaneous, open
- Vehicle:
- water
- Concentration / amount:
- 0.01%, 0.03%, 0.1%, 0.3%, 1% and 3%
- No. of animals per dose:
- 5 animals for sensitizing group, 5 animals for control group
- Details on study design:
- main study:
intradermal injection of 0.1 mL emulsified FCA on day 1
The test material was applied occlusively for 24 hours
Two further occlusive applications at days 2 and 3
Occlusive applications of the test material on day 9
Exposure period from day 1 to 3
challenge exposure:
0.01 mL aliquots of various concentrations of the test material in the vehicle were applied for challenge on day 21.
duration of challenge: 1 day
Observations were conducted at day 22 and 23 - Positive control substance(s):
- not specified
- Key result
- Group:
- test chemical
- Dose level:
- 0.01 %
- No. with + reactions:
- 2
- Total no. in group:
- 5
- Remarks on result:
- other: The reactions are expressed as 40 % at a concentration of 0.01 %.
- Key result
- Group:
- test chemical
- Dose level:
- 0.03 %
- No. with + reactions:
- 5
- Total no. in group:
- 5
- Remarks on result:
- other: The reactions are expressed as 100 % at a concentration of 0.03 %.
- Interpretation of results:
- Category 1 (skin sensitising) based on GHS criteria
- Conclusions:
- Cobalt sulphate was determined to be a skin sensitizer category 1 based on the test results.
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- September 2000
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- The complex EDTA-CoNa2 consist of the organic moiety EDTA, the central atom Co2+ and the sodium ions. As the Na+ ions are known to be non-sensitizing only the EDTA-Co complex must be regarded as dangerous. In general, the complex with the chelated Co2+ ion should be less sensitizing than the free Co2+ ion. Based on that and that the complex EDTA-Co has an average stability, a worst-case assessment where the EDTA-CoNa2 complex dissociate in its components can be done and so a read-across is possible to free EDTA and other Co2+ compounds.
- Reason / purpose for cross-reference:
- read-across source
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 406 (Skin Sensitisation)
- Deviations:
- yes
- Principles of method if other than guideline:
- The study was conducted similar to OECD Guideline 406.
- GLP compliance:
- not specified
- Type of study:
- other: adjuvant and patch test (APT)
- Justification for non-LLNA method:
- At the time the study was performed the guinea pig sensitization test was a standard test method for the skin sensitisation potential. Thus, the study is considered to be reliable.
- Species:
- guinea pig
- Strain:
- Hartley
- Sex:
- female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Japan SLC Inc.
- Weight at study initiation: 380 to 500 g
- Housing: The animals were housed individually in a stainless-steel cage.
- Diet: ad libitum; pellet diet
- Water: ad libitum; sterilised water
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 3
- Humidity (%): 55 +/- 15
- Photoperiod: 12 hours dark/light cycle - Route:
- intradermal and epicutaneous
- Vehicle:
- water
- Concentration / amount:
- 3 %
- Route:
- epicutaneous, open
- Vehicle:
- water
- Concentration / amount:
- 0.01%, 0.03%, 0.1%, 0.3%, 1% and 3%
- No. of animals per dose:
- 5 animals for sensitizing group, 5 animals for control group
- Details on study design:
- main study:
intradermal injection of 0.1 mL emulsified FCA on day 1
The test material was applied occlusively for 24 hours
Two further occlusive applications at days 2 and 3
Occlusive applications of the test material on day 9
Exposure period from day 1 to 3
challenge exposure:
0.01 mL aliquots of various concentrations of the test material in the vehicle were applied for challenge on day 21.
duration of challenge: 1 day
Observations were conducted at day 22 and 23 - Positive control substance(s):
- not specified
- Key result
- Group:
- test chemical
- Dose level:
- 0.01 %
- No. with + reactions:
- 2
- Total no. in group:
- 5
- Remarks on result:
- other: The reactions are expressed as 40 % at a concentration of 0.01 %.
- Key result
- Group:
- test chemical
- Dose level:
- 0.03 %
- No. with + reactions:
- 5
- Total no. in group:
- 5
- Remarks on result:
- other: The reactions are expressed as 100 % at a concentration of 0.03 %.
- Interpretation of results:
- Category 1 (skin sensitising) based on GHS criteria
- Conclusions:
- Cobalt sulphate was determined to be a skin sensitizer category 1 based on the test results.
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- The study is well-documented by the publication and thus acceptable for assessment.
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- No guideline is mentioned in the study. However, the methods and materials are well-described and follow general scientific principles. Thus, the study is considered to be reliable.
- GLP compliance:
- not specified
- Type of study:
- guinea pig maximisation test
- Justification for non-LLNA method:
- At the time the study was performed the guinea pig sensitization test was a standard test method for the skin sensitisation potential. Thus, the study is considered to be reliable.
- Species:
- guinea pig
- Strain:
- Hartley
- Sex:
- male
- Details on test animals and environmental conditions:
- 10 male animals were obtained from Buckberg Lab Animals, Inc., New York, USA
- Route:
- other: topical treatments
- Vehicle:
- other: 9:1 solution of dipropylene glycol methyl ether and polyethylene sorbitan monooleate
- Concentration / amount:
- 10% in the solution
- Day(s)/duration:
- 4 times in 10 days
- Route:
- other: topical treatments
- Vehicle:
- other: 9:1 solution of dipropylene glycol methyl ether and polyethylene sorbitan monooleate
- Concentration / amount:
- 10% in solution
- Day(s)/duration:
- 2 weeks after the last treatment
- No. of animals per dose:
- 10 for Na3HEDTA and 10 for the positive control group
- Details on study design:
- 5 animals per cage
temperature 73 °F (ca. 23 °C)
relative humidity 45 %
light/dark cycle: 12 h/ 12 h - Positive control substance(s):
- yes
- Remarks:
- diglycidyl ether of 2,2-di(p,p-hydroxyphenyl) propane was used for the positive control group
- Positive control results:
- The positive control substance sensitized 9 of 10 animals producing a slight to marked erythema (9 of 10 animals) and a slight to moderate edema (9 of 10 animals).
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 10 %
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 10 %
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- no indication of skin sensitisation
- Group:
- positive control
- No. with + reactions:
- 9
- Total no. in group:
- 10
- Remarks on result:
- positive indication of skin sensitisation
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- The test substance was not sensitizing under the test conditions.
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of 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:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- The complex EDTA-CoNa2 consist of the organic moiety EDTA, the central atom Co2+ and the sodium ions. As the Na+ ions are known to be non-sensitizing only the EDTA-Co complex must be regarded as dangerous. In general, the complex with the chelated Co2+ ion should be less sensitizing than the free Co2+ ion. Based on that and that the complex EDTA-Co has an average stability, a worst-case assessment where the EDTA-CoNa2 complex dissociate in its components can be done and so a read-across is possible to free EDTA and other Co2+ compounds.
- Reason / purpose for cross-reference:
- read-across source
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- No guideline is mentioned in the study. However, the methods and materials are well-described and follow general scientific principles. Thus, the study is considered to be reliable.
- GLP compliance:
- not specified
- Type of study:
- guinea pig maximisation test
- Justification for non-LLNA method:
- At the time the study was performed the guinea pig sensitization test was a standard test method for the skin sensitisation potential. Thus, the study is considered to be reliable.
- Species:
- guinea pig
- Strain:
- Hartley
- Sex:
- male
- Details on test animals and environmental conditions:
- 10 male animals were obtained from Buckberg Lab Animals, Inc., New York, USA
- Route:
- other: topical treatments
- Vehicle:
- other: 9:1 solution of dipropylene glycol methyl ether and polyethylene sorbitan monooleate
- Concentration / amount:
- 10% in the solution
- Day(s)/duration:
- 4 times in 10 days
- Route:
- other: topical treatments
- Vehicle:
- other: 9:1 solution of dipropylene glycol methyl ether and polyethylene sorbitan monooleate
- Concentration / amount:
- 10% in solution
- Day(s)/duration:
- 2 weeks after the last treatment
- No. of animals per dose:
- 10 for Na3HEDTA and 10 for the positive control group
- Details on study design:
- 5 animals per cage
temperature 73 °F (ca. 23 °C)
relative humidity 45 %
light/dark cycle: 12 h/ 12 h - Positive control substance(s):
- yes
- Remarks:
- diglycidyl ether of 2,2-di(p,p-hydroxyphenyl) propane was used for the positive control group
- Positive control results:
- The positive control substance sensitized 9 of 10 animals producing a slight to marked erythema (9 of 10 animals) and a slight to moderate edema (9 of 10 animals).
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 10 %
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 10 %
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- no indication of skin sensitisation
- Group:
- positive control
- No. with + reactions:
- 9
- Total no. in group:
- 10
- Remarks on result:
- positive indication of skin sensitisation
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- The test substance was not sensitizing under the test conditions.
- Endpoint:
- skin sensitisation: in vitro
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- an in vitro skin sensitisation study does not need to be conducted because adequate data from an in vivo skin sensitisation study are available
- 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)
- Deviations:
- yes
- Remarks:
- Total amount of test material applied is not stated
- GLP compliance:
- yes
- Type of study:
- guinea pig maximisation test
- Justification for non-LLNA method:
- This study was conducted due to non-REACH regulatory requirements. With the existing data from this study not only being acceptable but of good quality (Klimisch Score 1), this study precludes the need for an additional LLNA study. In addition, a supplementary LLNA study would violate the ECHA objectives with regards to animal welfare.
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Lot/batch No.of test material: 41-9660
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
OTHER SPECIFICS
- pH (as 1% solution): 5
- Homogeneity : homogeneous by visual inspection - Species:
- guinea pig
- Strain:
- Hartley
- Sex:
- female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Charles River France, 76410 Saint-Aubin-16s-Elbeuf, France
- Age at study initiation: 3 months
- Weight at study initiation: 374 ± 22 g
- Housing: individually in polycarbonate cages with stainless steel lid
- Diet: "106 pelleted diet" ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature : 21 ± 2°C
- Relative humidity : 30 to 70%
- Light/dark cycle: 12 h/12 h
- Ventilation: approximately 12 cycles/hour of filtered, non-recycled air - Route:
- intradermal and epicutaneous
- Vehicle:
- corn oil
- Concentration / amount:
- intradermal injections: test material at the concentration of 0.5 % (w/w) in corn oil,
topical application: test material at the concentration of 30 % (w/w) in corn oil - Route:
- epicutaneous, occlusive
- Vehicle:
- corn oil
- Concentration / amount:
- intradermal injections: test material at the concentration of 0.5 % (w/w) in corn oil,
topical application: test material at the concentration of 30 % (w/w) in corn oil - No. of animals per dose:
- 5 females/control group
10 females/treated group - Details on study design:
- RANGE FINDING TESTS:
In order to determine the concentration of the test substance in the main study one range finding test were performed on two animals (1 male and 1 female).
By intradermal route (tested concentrations: 1 % and 0.1 % (w/w):
24 hours before treatment, the dorsal region of the animals was clipped, intradermal injections of the dosage form preparations (0.1 mL) were performed in the interscapular region, cutaneous reactions were evaluated approximately 24, 48 hours and 6 days after the injections.
By cutaneous route (tested concentrations: 30 % and 10 % (w/w):
24 hours before treatment, both flank regions of the animals were clipped, the filter paper of a chamber was fully-loaded with one dosage form preparation. The chamber was then applied to the clipped area of the skin (one concentration per flank) . The chamber was held in place by means of an occlusive dressing for 24 hours, cutaneous reactions were evaluated approximately 24 and 48 hours after removal of the dressings.
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: once intradermal (day 1) and additionally once cutanenously (day 8)
- Test groups: 1
- Control group: 2
INTRADERMAL EXPOSURE
- Site: six injections as pairs in the interscapular area
- Treatment: Test group: A) front row: Freund's complete adjuvant (FCA) at 50 % (v/v) in 0.9% NaCl; B) middle row: 0.1 mL test material at 0.5 % (w/w) in corn oil; C) test substance at 0.5 % (w/w) in the mixture FCA/0.9 % NaCl (50/50)
Control groups: The animals were given the same injections (A, B, C) but without test substance, only with the formulating agent.
CUTANEOUS EXPOSURE
- Site: interscapular area
- Treatment: Test group: a pad of filter paper (approximately 8 cm²) was fully-loaded with the test substance at the concentration of 30 % (w/w) and was then applied to the interscapular region of the animals. The pad was held in place for 48 hours by means of an adhesive hypoallergenic dressing and an adhesive anallergenic waterproof plaster
Control groups: received an application of the vehicle alone under the same experimental conditions.
B. CHALLENGE EXPOSURE
Challenge:
- Day of challenge: day 22 (21 days after intradermal induction)
- Exposure period: 24 h
- Site: interscapular
- Treatment: Test groups: received an application of the test substance and vehicle. The filter paper of a chamber (Finn Chambero) was fully-loaded with the test substance at the concentration of 30 % (w/w) and was then applied to a clipped area of the skin of the posterior right flank of all animals. The vehicle was applied under the same experimental conditions to the skin of the posterior left flank. The chambers were held in contact with the skin for 24 hours by means of an adhesive an allergenic waterproof plaster. On removal of the dressing, any residual test substance was removed by means of a moistened
gauze pad.
Control groups: Control group one was treated like the treatment group; control group 2 remained untreated
- Evaluation (hr after challenge): 24, 48 h
Rechallenge:
- Day of challenge: day 29
- Exposure period: 24 h
- Treatment: the animals of all groups received an application of the test substance at the concentration of 30% (w/w) to the anterior left flank and the vehicle to the anterior right flank, under the same experimental conditions as for the first challenge application.
- Evaluation (hr after challenge): 24, 48 h - Challenge controls:
- Yes, 2 groups
- Positive control substance(s):
- yes
- Remarks:
- Mercaptobenzothiazole
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 30%
- No. with + reactions:
- 3
- Total no. in group:
- 10
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 30%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- other: Negative control group 1
- Dose level:
- 0%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- other: Negative control group 1
- Dose level:
- 0%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: other: Negative control group 1. Dose level: 0%. No with. + reactions: 0.0. Total no. in groups: 10.0.
- Reading:
- rechallenge
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 30%
- No. with + reactions:
- 1
- Total no. in group:
- 10
- Reading:
- rechallenge
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 30%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- Dryness of skin in 3/10 animals
- Reading:
- rechallenge
- Hours after challenge:
- 24
- Group:
- other: Negative control group 1
- Dose level:
- 30%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Reading:
- rechallenge
- Hours after challenge:
- 48
- Group:
- other: 1egative control group 1
- Dose level:
- 30%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Clinical observations:
- Dryness of skin was observed in 1/5 animals
- Reading:
- rechallenge
- Hours after challenge:
- 24
- Group:
- other: Negative control group 2
- Dose level:
- 30%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Reading:
- rechallenge
- Hours after challenge:
- 48
- Group:
- other: negative control group 2
- Dose level:
- 30%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- positive control
- Dose level:
- 20%
- No. with + reactions:
- 7
- Total no. in group:
- 10
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- positive control
- Dose level:
- 20%
- No. with + reactions:
- 7
- Total no. in group:
- 10
- Interpretation of results:
- not sensitising
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- The complex EDTA-CoNa2 consist of the organic moiety EDTA, the central atom Co2+ and the sodium ions. As the Na+ ions are known to be non-sensitizing only the EDTA-Co complex must be regarded as dangerous. In general, the complex with the chelated Co2+ ion should be less sensitizing than the free Co2+ ion. Based on that and that the complex EDTA-Co has an average stability, a worst-case assessment where the EDTA-CoNa2 complex dissociate in its components can be done and so a read-across is possible to free EDTA and other Co2+ compounds.
- Reason / purpose for cross-reference:
- read-across source
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 406 (Skin Sensitisation)
- Deviations:
- yes
- Remarks:
- Total amount of test material applied is not stated
- GLP compliance:
- yes
- Type of study:
- guinea pig maximisation test
- Justification for non-LLNA method:
- This study was conducted due to non-REACH regulatory requirements. With the existing data from this study not only being acceptable but of good quality (Klimisch Score 1), this study precludes the need for an additional LLNA study. In addition, a supplementary LLNA study would violate the ECHA objectives with regards to animal welfare.
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Lot/batch No.of test material: 41-9660
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
OTHER SPECIFICS
- pH (as 1% solution): 5
- Homogeneity : homogeneous by visual inspection - Species:
- guinea pig
- Strain:
- Hartley
- Sex:
- female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Charles River France, 76410 Saint-Aubin-16s-Elbeuf, France
- Age at study initiation: 3 months
- Weight at study initiation: 374 ± 22 g
- Housing: individually in polycarbonate cages with stainless steel lid
- Diet: "106 pelleted diet" ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature : 21 ± 2°C
- Relative humidity : 30 to 70%
- Light/dark cycle: 12 h/12 h
- Ventilation: approximately 12 cycles/hour of filtered, non-recycled air - Route:
- intradermal and epicutaneous
- Vehicle:
- corn oil
- Concentration / amount:
- intradermal injections: test material at the concentration of 0.5 % (w/w) in corn oil,
topical application: test material at the concentration of 30 % (w/w) in corn oil - Route:
- epicutaneous, occlusive
- Vehicle:
- corn oil
- Concentration / amount:
- intradermal injections: test material at the concentration of 0.5 % (w/w) in corn oil,
topical application: test material at the concentration of 30 % (w/w) in corn oil - No. of animals per dose:
- 5 females/control group
10 females/treated group - Details on study design:
- RANGE FINDING TESTS:
In order to determine the concentration of the test substance in the main study one range finding test were performed on two animals (1 male and 1 female).
By intradermal route (tested concentrations: 1 % and 0.1 % (w/w):
24 hours before treatment, the dorsal region of the animals was clipped, intradermal injections of the dosage form preparations (0.1 mL) were performed in the interscapular region, cutaneous reactions were evaluated approximately 24, 48 hours and 6 days after the injections.
By cutaneous route (tested concentrations: 30 % and 10 % (w/w):
24 hours before treatment, both flank regions of the animals were clipped, the filter paper of a chamber was fully-loaded with one dosage form preparation. The chamber was then applied to the clipped area of the skin (one concentration per flank) . The chamber was held in place by means of an occlusive dressing for 24 hours, cutaneous reactions were evaluated approximately 24 and 48 hours after removal of the dressings.
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: once intradermal (day 1) and additionally once cutanenously (day 8)
- Test groups: 1
- Control group: 2
INTRADERMAL EXPOSURE
- Site: six injections as pairs in the interscapular area
- Treatment: Test group: A) front row: Freund's complete adjuvant (FCA) at 50 % (v/v) in 0.9% NaCl; B) middle row: 0.1 mL test material at 0.5 % (w/w) in corn oil; C) test substance at 0.5 % (w/w) in the mixture FCA/0.9 % NaCl (50/50)
Control groups: The animals were given the same injections (A, B, C) but without test substance, only with the formulating agent.
CUTANEOUS EXPOSURE
- Site: interscapular area
- Treatment: Test group: a pad of filter paper (approximately 8 cm²) was fully-loaded with the test substance at the concentration of 30 % (w/w) and was then applied to the interscapular region of the animals. The pad was held in place for 48 hours by means of an adhesive hypoallergenic dressing and an adhesive anallergenic waterproof plaster
Control groups: received an application of the vehicle alone under the same experimental conditions.
B. CHALLENGE EXPOSURE
Challenge:
- Day of challenge: day 22 (21 days after intradermal induction)
- Exposure period: 24 h
- Site: interscapular
- Treatment: Test groups: received an application of the test substance and vehicle. The filter paper of a chamber (Finn Chambero) was fully-loaded with the test substance at the concentration of 30 % (w/w) and was then applied to a clipped area of the skin of the posterior right flank of all animals. The vehicle was applied under the same experimental conditions to the skin of the posterior left flank. The chambers were held in contact with the skin for 24 hours by means of an adhesive an allergenic waterproof plaster. On removal of the dressing, any residual test substance was removed by means of a moistened
gauze pad.
Control groups: Control group one was treated like the treatment group; control group 2 remained untreated
- Evaluation (hr after challenge): 24, 48 h
Rechallenge:
- Day of challenge: day 29
- Exposure period: 24 h
- Treatment: the animals of all groups received an application of the test substance at the concentration of 30% (w/w) to the anterior left flank and the vehicle to the anterior right flank, under the same experimental conditions as for the first challenge application.
- Evaluation (hr after challenge): 24, 48 h - Challenge controls:
- Yes, 2 groups
- Positive control substance(s):
- yes
- Remarks:
- Mercaptobenzothiazole
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 30%
- No. with + reactions:
- 3
- Total no. in group:
- 10
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 30%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- other: Negative control group 1
- Dose level:
- 0%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- other: Negative control group 1
- Dose level:
- 0%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: other: Negative control group 1. Dose level: 0%. No with. + reactions: 0.0. Total no. in groups: 10.0.
- Reading:
- rechallenge
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- 30%
- No. with + reactions:
- 1
- Total no. in group:
- 10
- Reading:
- rechallenge
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- 30%
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Clinical observations:
- Dryness of skin in 3/10 animals
- Reading:
- rechallenge
- Hours after challenge:
- 24
- Group:
- other: Negative control group 1
- Dose level:
- 30%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Reading:
- rechallenge
- Hours after challenge:
- 48
- Group:
- other: 1egative control group 1
- Dose level:
- 30%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Clinical observations:
- Dryness of skin was observed in 1/5 animals
- Reading:
- rechallenge
- Hours after challenge:
- 24
- Group:
- other: Negative control group 2
- Dose level:
- 30%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Reading:
- rechallenge
- Hours after challenge:
- 48
- Group:
- other: negative control group 2
- Dose level:
- 30%
- No. with + reactions:
- 0
- Total no. in group:
- 5
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- positive control
- Dose level:
- 20%
- No. with + reactions:
- 7
- Total no. in group:
- 10
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- positive control
- Dose level:
- 20%
- No. with + reactions:
- 7
- Total no. in group:
- 10
- Interpretation of results:
- not sensitising
- Conclusions:
- Under the conditions of the test there were no evidence for skin sensitization of disodium dihydrogen ethylenediaminetetraacetate.
- Endpoint:
- skin sensitisation: in vitro
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- The chelating effect of sodium EDTA in nickel-allergic patients was investigated. It could be shown how EDTA has a blocking effect for skin irritant reaction (eczema) on humans.
- Principles of method if other than guideline:
- Study on humans in order to investigate an EDTA effect which prevent the dermatitis-provoking potential of nickel.
- GLP compliance:
- not specified
- Type of study:
- patch test
- Specific details on test material used for the study:
- aqueous nickel sulphate (prepared by the hospital pharmacist)
- Details on the study design:
- human skin model - upper back of 17 nickel-allergic female patients
The right half of the upper back was lightly rubbed with a cream containing 10% EDTA (w/w) (disodium salt of ethylenediamine tetra acetate) in cetomacrogol cream FNA. After 15 min, when the cream was no longer visible, 3 concentrations of aqueous nickel sulphate were patch tested in the pretreated area. The left upper back was pretreated in a similar way with cetomacrogol cream FNA without EDTA. The same concentrations of nickel sulphate were patch tested in this area. Patch testing was performed with the Silver Patch Testers. The reactions were graded according to the ICDRG after 48 and 72 h.
Control samples:
Yes, concurrent positive control. Cetomacrogol cream without EDTA and with 10% EDTA. The cream with 10% EDTA did not induce irritant reactions in 20 control patients (before study).
Amount/concentration applied:
0.01% (24.4 ppm), 0.1% (244 ppm), 1% (2440 ppm) - Key result
- Run / experiment:
- other: 1-6, 8-14 and 16
- Parameter:
- other: penetration time (in minutes)
- Remarks:
- After 2880 and 4320 min
- Positive controls validity:
- not specified
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- at 2440 ppm nickel sulphate
- Key result
- Run / experiment:
- other: 7, 15 and 17
- Parameter:
- other: penetration time (in minutes)
- Remarks:
- After 2880 and 4320 min
- Positive controls validity:
- not specified
- Remarks on result:
- positive indication of skin sensitisation
- Remarks:
- slight reaction was observed
- Conclusions:
- The blocking effect of the 10% EDTA cream appeared to be significant in comparison with that of the cream base only (p < 0.01). In most patients, 10% EDTA does chelate nickel sulphate in 0.01% (24.2 ppm), 0.1% (244 ppm) and 1% (2440 ppm) by reducing the dermatitis-provoking potential of nickel. A barrier cream with 10% EDTA might be of help in nickel-allergic patients with eczema of the hands.
- Executive summary:
In the area pretreated with 10% EDTA in cetomacrogol cream FNA, only 3 of 17 patients showed a + positive reaction to 1% (2440 ppm) nickel sulphate. 3 patients showed no reaction to any concentration of nickel sulphate in either area. The reactivity to nickel sulphate in the area pretreated with 10% EDTA appeared to be far less than in the control area (rank sum test p < 0.01). No skin sensitisation or irritation to the 10% EDTA cream were observed.
- Endpoint:
- skin sensitisation: in vitro
- Type of 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:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- The chelating effect of sodium EDTA in nickel-allergic patients was investigated. It could be shown how EDTA has a blocking effect for skin sensitisation/irritation (eczema) on humans.
This blocking effect results from the complexation of the irritant nickel. It is an important study which must be considered for the classification of the analogous EDTA-CoNa2 complex. - Reason / purpose for cross-reference:
- read-across source
- Principles of method if other than guideline:
- Study on humans in order to investigate an EDTA effect which prevent the dermatitis-provoking potential of nickel.
- GLP compliance:
- not specified
- Type of study:
- patch test
- Specific details on test material used for the study:
- aqueous nickel sulphate (prepared by the hospital pharmacist)
- Details on the study design:
- human skin model - upper back of 17 nickel-allergic female patients
The right half of the upper back was lightly rubbed with a cream containing 10% EDTA (w/w) (disodium salt of ethylenediamine tetra acetate) in cetomacrogol cream FNA. After 15 min, when the cream was no longer visible, 3 concentrations of aqueous nickel sulphate were patch tested in the pretreated area. The left upper back was pretreated in a similar way with cetomacrogol cream FNA without EDTA. The same concentrations of nickel sulphate were patch tested in this area. Patch testing was performed with the Silver Patch Testers. The reactions were graded according to the ICDRG after 48 and 72 h.
Control samples:
Yes, concurrent positive control. Cetomacrogol cream without EDTA and with 10% EDTA. The cream with 10% EDTA did not induce irritant reactions in 20 control patients (before study).
Amount/concentration applied:
0.01% (24.4 ppm), 0.1% (244 ppm), 1% (2440 ppm) - Key result
- Run / experiment:
- other: 1-6, 8-14 and 16
- Parameter:
- other: penetration time (in minutes)
- Remarks:
- After 2880 and 4320 min
- Positive controls validity:
- not specified
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- at 2440 ppm nickel sulphate
- Key result
- Run / experiment:
- other: 7, 15 and 17
- Parameter:
- other: penetration time (in minutes)
- Remarks:
- After 2880 and 4320 min
- Positive controls validity:
- not specified
- Remarks on result:
- positive indication of skin sensitisation
- Remarks:
- slight reaction was observed
- Conclusions:
- The blocking effect of the 10% EDTA cream appeared to be significant in comparison with that of the cream base only (p < 0.01). In most patients, 10% EDTA does chelate nickel sulphate in 0.01% (24.2 ppm), 0.1% (244 ppm) and 1% (2440 ppm) by reducing the dermatitis-provoking potential of nickel. A barrier cream with 10% EDTA might be of help in nickel-allergic patients with eczema of the hands.
By analogy the 10% EDTA cream would also be a barrier cream for cobalt as it would also form the analogous EDTA-Co complex. - Executive summary:
In the area pretreated with 10% EDTA in cetomacrogol cream FNA, only 3 of 17 patients showed a + positive reaction to 1% (2440 ppm) nickel sulphate. 3 patients showed no reaction to any concentration of nickel sulphate in either area. The reactivity to nickel sulphate in the area pretreated with 10% EDTA appeared to be far less than in the control area (rank sum test p < 0.01). No skin sensitisation or irritation to the 10% EDTA cream were observed.
Referenceopen allclose all
Sensitisation rate of CoSO4:
- 0.01% test material: 40% sensitisation
- 0.03% to 3.0% test material: 100% sensitisation
One animal of the control group 1 was found dead on day 13. Hypoactivity and dyspnea were observed prior to death. The authors stated that such spontaneous clinical signs and mortality are sometimes observed in this species.
One animal of the control group 1 was found dead on day 13. Hypoactivity and dyspnea were observed prior to death. The authors stated that such spontaneous clinical signs and mortality are sometimes observed in this species.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (sensitising)
Respiratory sensitisation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
The complex EDTA-CoNa2 consist of the organic moiety EDTA, the central atom Co2+ and the sodium ions. As the Na+ ions are known to be non-sensitizing only the EDTA-Co complex must be regarded as dangerous. In general, the complex with the chelated Co2+ ion should be less sensitizing than the free Co2+ ion. Based on that and that the complex EDTA-Co has an average stability, a worst-case assessment where the EDTA-CoNa2 complex dissociate in its components can be done and so a read-across is possible to free EDTA and other Co2+ compounds. The latter are known to be possible sensitizers. Most soluble cobalt (2 +) salts are classified as skin sensitizing.
Many cobalt(II) compounds and cobalt are known for the fact, that they may cause an allergic skin reaction.
The following substances are, inter alia, classified with H317: cobalt (Index number 027-001-00-9), cobalt dichloride (Index number 027-004-00-5), cobalt sulfate (Index number 027-005-00-0), cobalt sulfide (Index number 027-003-00-X), cobalt di(acetate) (Index number 027-006-00-6), cobalt dinitrate (Index number 027-009-00-2) and cobalt oxide (Index number 027-002-00-4).
Thus as a worst case approach the substance to be registered is classified accordingly as well.
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