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Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vitro / ex vivo
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
Specific details on test material used for the study:
aqueous nickel sulphate (prepared by the hospital pharmacist)
Test system:
human skin model
Remarks:
upper back of 17 nickel-allergic female patients
Source species:
human
Cell type:
other: human skin cells
Vehicle:
water
Details on test system:
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
other: 10% EDTA in cetomacrogol cream
Amount/concentration applied:
0.01% (24.4 ppm), 0.1% (244 ppm), 1% (2440 ppm)
Duration of treatment / exposure:
The reactions were graded after 48 and 72 h
Irritation / corrosion parameter:
penetration time (in minutes)
Remarks:
After 2880 and 4320 min
Run / experiment:
1-6, 8-14 and 16
Positive controls validity:
not specified
Remarks on result:
no indication of irritation
Remarks:
at 2440 ppm nickel sulphate
Irritation / corrosion parameter:
penetration time (in minutes)
Remarks:
After 2880 and 4320 min
Run / experiment:
7, 15 and 17
Positive controls validity:
not specified
Remarks on result:
positive indication of irritation
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 irritant reactions to the 10% EDTA cream were observed.

Endpoint:
skin irritation: in vitro / ex vivo
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 irritant reaction (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 analog irritant cobalt which can be chelated by EDTA in the same way.
Reason / purpose:
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
Specific details on test material used for the study:
aqueous nickel sulphate (prepared by the hospital pharmacist)
Test system:
human skin model
Remarks:
upper back of 17 nickel-allergic female patients
Source species:
human
Cell type:
other: human skin cells
Vehicle:
water
Details on test system:
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
other: 10% EDTA in cetomacrogol cream
Amount/concentration applied:
0.01% (24.4 ppm), 0.1% (244 ppm), 1% (2440 ppm)
Duration of treatment / exposure:
The reactions were graded after 48 and 72 h
Irritation / corrosion parameter:
penetration time (in minutes)
Remarks:
After 2880 and 4320 min
Run / experiment:
1-6, 8-14 and 16
Positive controls validity:
not specified
Remarks on result:
no indication of irritation
Remarks:
at 2440 ppm nickel sulphate
Irritation / corrosion parameter:
penetration time (in minutes)
Remarks:
After 2880 and 4320 min
Run / experiment:
7, 15 and 17
Positive controls validity:
not specified
Remarks on result:
positive indication of irritation
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 irritant reactions to the 10% EDTA cream were observed.

Endpoint:
skin irritation: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Concise International Chemical Assessment Documents (CICAD) are published by the International Programme on Chemical Safety (IPCS) — a cooperative programme of the World Health Organization (WHO), the International Labour Organization (ILO), and the United Nations Environment Programme (UNEP).
The CICAD on cobalt and inorganic cobalt compounds was prepared by Sciences International, Inc. in the United States and the Centre for Ecology and Hydrology in the United Kingdom and was based on reviews prepared by the Agency for Toxic Substances and Disease Registry (ATSDR, 2004) and the International Agency for Research on Cancer (IARC, 2005). Consequently, this CICAD includes important information about the effects on humans by cobalt and inorganic cobalt compounds.
Principles of method if other than guideline:
International Chemical Safety Cards on the relevant chemical(s) are attached at the end of the CICAD, to provide the reader with concise information on the
protection of human health and on emergency action. Information about the skin irritation and EU Classification of different Co2+ compounds can be found in the International Chemical Safety Cards.
GLP compliance:
not specified
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt (EC 231-158-0)
Remarks on result:
no indication of irritation
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt(II) chloride (EC 231-589-4)
Remarks on result:
no indication of irritation
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt(II) nitrate (EC 233-402-1)
Remarks on result:
positive indication of irritation
Remarks:
Redness.
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Dicobalt octacarbonyl (EC 233-514-0)
Remarks on result:
positive indication of irritation
Remarks:
Redness. Pain.
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt naphthenate (EC 263-064-0)
Remarks on result:
positive indication of irritation
Remarks:
Redness. Pain.
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt(II) sulfate (EC 233-334-2)
Remarks on result:
positive indication of irritation
Remarks:
Redness. Pain.
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt(II) acetate (EC 200-755-8)
Remarks on result:
positive indication of irritation
Remarks:
Redness.
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt(II) sulfide (EC 215-273-3)
Remarks on result:
no indication of irritation
Remarks:
Redness.
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt(II) oxide (EC 215-154-6)
Remarks on result:
no indication of irritation
Conclusions:
International Chemical Safety Cards of cobalt and different cobalt(II) compounds are available. These cards display the following:
Cobalt, cobalt(II) chloride and cobalt(II) oxide are not irritant to skin.
Cobalt(II) nitrate, cobalt(II) acetate and cobalt(II) sulfide caused redness of the skin.
Dicobalt octacarbonyl, cobalt naphthenate and cobalt(II) sulfate leads to redness of the skin and pain.
The Chemical Safety Cards give an indication how not chelated cobalt(II) compounds interact with skin.
Endpoint:
skin irritation: in vitro / ex vivo
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:
data from handbook or collection of data
Justification for type of information:
Concise International Chemical Assessment Documents (CICAD) are published by the International Programme on Chemical Safety (IPCS) — a cooperative programme of the World Health Organization (WHO), the International Labour Organization (ILO), and the United Nations Environment Programme (UNEP).
The CICAD on cobalt and inorganic cobalt compounds was prepared by Sciences International, Inc. in the United States and the Centre for Ecology and Hydrology in the United Kingdom and was based on reviews prepared by the Agency for Toxic Substances and Disease Registry (ATSDR, 2004) and the International Agency for Research on Cancer (IARC, 2005). Consequently, this CICAD includes important information about the effects on humans by cobalt and inorganic cobalt compounds. In turn, this is important for the skin irritation classification of the EDTA-CoNa2 complex, because as EDTA-Na2 could be identified as nonirritant only the central Co2+ moiety is of interest for the assessment.
Reason / purpose:
read-across source
Principles of method if other than guideline:
International Chemical Safety Cards on the relevant chemical(s) are attached at the end of the CICAD, to provide the reader with concise information on the
protection of human health and on emergency action. Information about the skin irritation and EU Classification of different Co2+ compounds can be found in the International Chemical Safety Cards.
GLP compliance:
not specified
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt (EC 231-158-0)
Remarks on result:
no indication of irritation
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt(II) chloride (EC 231-589-4)
Remarks on result:
no indication of irritation
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt(II) nitrate (EC 233-402-1)
Remarks on result:
positive indication of irritation
Remarks:
Redness.
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Dicobalt octacarbonyl (EC 233-514-0)
Remarks on result:
positive indication of irritation
Remarks:
Redness. Pain.
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt naphthenate (EC 263-064-0)
Remarks on result:
positive indication of irritation
Remarks:
Redness. Pain.
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt(II) sulfate (EC 233-334-2)
Remarks on result:
positive indication of irritation
Remarks:
Redness. Pain.
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt(II) acetate (EC 200-755-8)
Remarks on result:
positive indication of irritation
Remarks:
Redness.
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt(II) sulfide (EC 215-273-3)
Remarks on result:
no indication of irritation
Remarks:
Redness.
Irritation / corrosion parameter:
other: not specified
Run / experiment:
International Chemical Safety Card of Cobalt(II) oxide (EC 215-154-6)
Remarks on result:
no indication of irritation
Conclusions:
International Chemical Safety Cards of cobalt and different cobalt(II) compounds are available. These cards display the following:
cobalt, cobalt(II) chloride and cobalt(II) oxide are not irritant to skin
cobalt(II) nitrate, cobalt(II) acetate and cobalt(II) sulfide caused redness of the skin and could classified as mild irritant
dicobalt octacarbonyl, cobalt naphthenate and cobalt(II) sulfate leads to redness of the skin and pain and could classified as irritant
Endpoint:
skin irritation: in vivo
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:
guideline study with acceptable restrictions
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-irritant only the EDTA-Co complex must be regarded as dangerous. In general, the complex with the chelated Co2+ ion should be less irritant 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 dissociates in its components can be done and so a read-across is possible to free EDTA and other Co2+ compounds. For the test disodium dihydrogen ethylenediaminetetraacetate was used.
Reason / purpose:
read-across source
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
Comparable to OECD 404 (1992) with acceptable restrictions [application time: 1, 5, 15 min and 20 h (OECD: 4 h); 2 animals used (OECD: 3); observation period 7 days (OECD: 14); dose 1 g (OECD: 0.5 mL)
Principles of method if other than guideline:
BASF-TEST: Before OECD guideline 404 was established, skin irritation was tested using an internal method. White Vienna rabbits were used. Usually, 2 animals were treated for 1, 5, 15 min and 20 h using occlusive conditions. An application site of 2.5 × 2.5 cm was covered with the liquid or powdered and moistened test substance. In addition, skin tissue from the ear was tested by wrapping the ear. These results from the ear, however, would not be taken into account for evaluation as they do not represent testing of the dorsal/lateral flank of the back. After the application time, the skin was washed with water which sometimes contained a mild detergent. The animals were observed 7 days and skin changes were recorded on working days.
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2.6 and 3.1 kg
Type of coverage:
occlusive
Preparation of test site:
other: clipped
Vehicle:
water
Controls:
other: untreated skin of the same animal
Amount / concentration applied:
- Amount applied: 2 mL of 50 % test substance in water
Duration of treatment / exposure:
Dorsal skin: 1, 5, 15 min
Dorsal skin: 20 h
Ear: 20 h
Observation period:
7 days
Number of animals:
2
Details on study design:
TEST SITE
- Area of exposure: 2.5 × 2.5 cm

REMOVAL OF TEST SUBSTANCE
- Washing: once with 100 % Lutrol and additionally with 50% Lutrol in water
- Time after start of exposure: 1, 5 or 15 minutes, the areas exposed for 20 h were not washed

READING TIME POINTS
24 h, 48 h, 72 h, 6 days, 7 days after application

READING TIME POINTS USED FOR ASSESSMENT
24, 48 and 72 h.

SCORING SYSTEM:
- For the evaluation the BASF scores given in the raw data were converted to Draize scores.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 - 48 - 72 h
Score:
0.8
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 24 - 48 - 72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 24 - 48 - 72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 - 48 - 72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
- 20 h application: a very slight erythema was observable in one animal which was fully reversible within 24 h; a well defined erythema was observable in animal 2, which was fully reversible within 72 h.
- 1-15 min exposure did also cause no edema or erythema
Other effects:
- A well defined erythema was observed on the ear of both animals which was fully reversible within 48 h.
Interpretation of results:
GHS criteria not met
Conclusions:
The test substance EDTA-Na2 has not to be classified according to the regulation (EC) No 1272/2008 (CLP-regulation).
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
Comparable to OECD 404 (1992) with acceptable restrictions [application time: 1, 5, 15 min and 20 h (OECD: 4 h); 2 animals used (OECD: 3); observation period 7 days (OECD: 14); dose 1 g (OECD: 0.5 mL)
Principles of method if other than guideline:
BASF-TEST: Before OECD guideline 404 was established, skin irritation was tested using an internal method. White Vienna rabbits were used. Usually, 2 animals were treated for 1, 5, 15 min and 20 h using occlusive conditions. An application site of 2.5 × 2.5 cm was covered with the liquid or powdered and moistened test substance. In addition, skin tissue from the ear was tested by wrapping the ear. These results from the ear, however, would not be taken into account for evaluation as they do not represent testing of the dorsal/lateral flank of the back. After the application time, the skin was washed with water which sometimes contained a mild detergent. The animals were observed 7 days and skin changes were recorded on working days.
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2.6 and 3.1 kg
Type of coverage:
occlusive
Preparation of test site:
other: clipped
Vehicle:
water
Controls:
other: untreated skin of the same animal
Amount / concentration applied:
- Amount applied: 2 mL of 50 % test substance in water
Duration of treatment / exposure:
Dorsal skin: 1, 5, 15 min
Dorsal skin: 20 h
Ear: 20 h
Observation period:
7 days
Number of animals:
2
Details on study design:
TEST SITE
- Area of exposure: 2.5 × 2.5 cm

REMOVAL OF TEST SUBSTANCE
- Washing: once with 100 % Lutrol and additionally with 50% Lutrol in water
- Time after start of exposure: 1, 5 or 15 minutes, the areas exposed for 20 h were not washed

READING TIME POINTS
24 h, 48 h, 72 h, 6 days, 7 days after application

READING TIME POINTS USED FOR ASSESSMENT
24, 48 and 72 h.

SCORING SYSTEM:
- For the evaluation the BASF scores given in the raw data were converted to Draize scores.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 - 48 - 72 h
Score:
0.8
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 24 - 48 - 72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 24 - 48 - 72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 - 48 - 72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
- 20 h application: a very slight erythema was observable in one animal which was fully reversible within 24 h; a well defined erythema was observable in animal 2, which was fully reversible within 72 h.
- 1-15 min exposure did also cause no edema or erythema
Other effects:
- A well defined erythema was observed on the ear of both animals which was fully reversible within 48 h.
Interpretation of results:
GHS criteria not met
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available
Endpoint:
eye irritation: in vivo
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:
comparable to guideline study with acceptable restrictions
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-irritant only the EDTA-Co complex must be regarded as dangerous. The complex EDTA-Co has an average stability, and so 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. For the tests disodium dihydrogen ethylenediaminetetraacetate was used.
Reason / purpose:
read-across source
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
Dose not exactly specified (OECD: volume of 0.1 mL); 2 animals are used (OECD: 3); examination using fluorescein (OECD: no use of fluorescein)
Principles of method if other than guideline:
BASF-TEST: Before OECD guideline 405 was established, eye irritation was tested using an internal method. White Vienna rabbits were used. Usually approximately 50 mg of the test substance were applied to the conjunctival sac of one eye of 2 animals. In studies with solids, talcum powder was used as control. The animals were observed several times on the treatment day and up to 8 days afterwards, and findings were recorded on working days.
The eyes were not washed out after 24 h as specified in OECD Guideline 405, which could be critical for solids which thus remained on the cornea for several days, causing mechanical damage. Probably, this would have been less severe if it had been washed out after 1 day.
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 3.39; 3.15 kg
Vehicle:
unchanged (no vehicle)
Controls:
other: talcum treated eye of the same animal
Amount / concentration applied:
- Amount applied: a sharp spoon (probably approximately 50 mg)
Duration of treatment / exposure:
- substance was not washed out
Observation period (in vivo):
8 days
Number of animals or in vitro replicates:
2
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: no washing was done

READING TIME POINTS
10 min, 1 h, 3 h, 24 h, 48 h, 72 h, 6 days and 8 days after application; however the data on the 48 h, 72 h and 6 days reading of animal 2 are not reported.

READING TIME POINTS USED FOR ASSESSMENT
24, 48 and 72 h for animal 1; 24 h for animal 2

SCORING SYSTEM:
For the evaluation the BASF scores given in the raw data were converted to Draize scores

TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24 - 48 - 72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24 - 48 - 72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24 - 48 - 72 h for animal 1; 24 h for animal 2
Score:
0.5
Max. score:
3
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: 24 - 48 - 72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 h
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: 24 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 8 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24 - 48 - 72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
Both animals showed some redness of the conjunctivae (score 1), 24 h after application of the test susbtance. The same effect was observed in the talcum powder treated eye. This effect was fully reversible 48 h in animal 1 and at least within 8 days in animal 2.
Interpretation of results:
GHS criteria not met
Conclusions:
The test substance EDTA-Na2 has not to be classified according to the regulation (EC) No 1272/2008 (CLP-regulation).
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
Dose not exactly specified (OECD: volume of 0.1 mL); 2 animals are used (OECD: 3); examination using fluorescein (OECD: no use of fluorescein)
Principles of method if other than guideline:
BASF-TEST: Before OECD guideline 405 was established, eye irritation was tested using an internal method. White Vienna rabbits were used. Usually approximately 50 mg of the test substance were applied to the conjunctival sac of one eye of 2 animals. In studies with solids, talcum powder was used as control. The animals were observed several times on the treatment day and up to 8 days afterwards, and findings were recorded on working days.
The eyes were not washed out after 24 h as specified in OECD Guideline 405, which could be critical for solids which thus remained on the cornea for several days, causing mechanical damage. Probably, this would have been less severe if it had been washed out after 1 day.
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 3.39; 3.15 kg
Vehicle:
unchanged (no vehicle)
Controls:
other: talcum treated eye of the same animal
Amount / concentration applied:
- Amount applied: a sharp spoon (probably approximately 50 mg)
Duration of treatment / exposure:
- substance was not washed out
Observation period (in vivo):
8 days
Number of animals or in vitro replicates:
2
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: no washing was done

READING TIME POINTS
10 min, 1 h, 3 h, 24 h, 48 h, 72 h, 6 days and 8 days after application; however the data on the 48 h, 72 h and 6 days reading of animal 2 are not reported.

READING TIME POINTS USED FOR ASSESSMENT
24, 48 and 72 h for animal 1; 24 h for animal 2

SCORING SYSTEM:
For the evaluation the BASF scores given in the raw data were converted to Draize scores

TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24 - 48 - 72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24 - 48 - 72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24 - 48 - 72 h for animal 1; 24 h for animal 2
Score:
0.5
Max. score:
3
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: 24 - 48 - 72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 h
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: 24 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 8 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24 - 48 - 72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
Both animals showed some redness of the conjunctivae (score 1), 24 h after application of the test susbtance. The same effect was observed in the talcum powder treated eye. This effect was fully reversible 48 h in animal 1 and at least within 8 days in animal 2.
Interpretation of results:
GHS criteria not met
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

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).

In addition, the harmonized classification of the above-mentioned cobalt(II) compounds did not include the category H314 (Causes severe skin burns and eye damage) or H315 (Causes skin irritation). Also in the published dossiers on the ECHA website of the mentioned cobalt(II) compounds and cobalt bis(2-ethylhexanoate) (EC 205-250-6) no classification as skin corrosive or skin irritant was made.

Nevertheless, there are some indications that cobalt(II) compounds lead to skin irritation but this often results from strong allergic skin reactions.

Furthermore, it could be shown, that sodium EDTA does not act as skin irritant but as an useful reagent which inhibit allergic skin reaction by complexation of the irritant metal 2 + source like nickel sulfate. In an additional study it could complementary be shown that EDTA-Na2 is non-irritant and has not to be classified according to the regulation (EC) No 1272/2008 (CLP-regulation).

As in the target substance cobalt disodium ethylenediaminetetraacetate the cobalt(II) center is chelated by EDTA no classification as skin irritant will be done.

In regard to the eye-irritating properties it could be shown that EDTA-Na2 is not classified as eye irritant. But it must be considered that EDTA has a harmonised classification as substance which causes serious eye irritation (H319) according to Annex VI of the regulation (EC) No 1272/2008 (CLP Regulation). Therefore the complex EDTA-CoNa2 will also be considered as eye irritant (H319).