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The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

One OECD 406 guideline study with disodium salt of EDTA is available. In this study 3/10 animals guinea pigs showed a patch erythema after the first challenge and 1/10 after the second challenge. The reports on humans are conflicting and in case of the positive results it cannot be ruled out that the reactions reflected irritation rather than sensitisation. However, overall these results do not warrant a labelling according to EU- or GHS-criteria, which was also confirmed by the independent evaluation of the MAK Commission for the Investigation of Health Hazards of Chemical Compounds in the work area (MAK, 46. Lieferung, 2009).

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

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

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.

Interpretation of results:
not sensitising
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Justification for type of information:
READ-ACROSS CATEGORY APPROACH
The complete Read-across justification text incl. data matrix is attached in chapter 13 "Read-across Justification_2019_Tox" (two documents attached).

Read-across justification EDTA-DTPA-HEDTA aminocarboxylic acid-based metal chelants (2019). Category approach according to RAAF and the REACH Practical guide 6: How to report read-across and categories; REACH TGD, Chapter R.6: QSARs and grouping of chemicals.

Part 1: Physical Chemistry & Toxicology/Human Health
Part 2: Environmental Fate & Ecotoxicology
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across: supporting information
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:
other: Test substance: CAS 150-38-9
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:
other: Test substance: CAS 150-38-9
Endpoint:
skin sensitisation
Remarks:
in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline available
Principles of method if other than guideline:
Insult patch test:
Within 10 days animals received 4 topical treatments (0.1 mL). One group recieved Na3EDTA, a second group recieved ethylenediamine (EDA) and a third group received diglycidyl eter of 2,2-di(p,p-hydroxyphenyl). At the third time, 0.2 mL Freud`s adjuvant was additionally injected. 2-weeks after the last treatment the animals were challenged topically with the test materials. 24h and 48 h after the last application animals were graded for hyperemia and edema.
GLP compliance:
no
Type of study:
other: Insult patch test
Species:
guinea pig
Strain:
Hartley
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Buckberg Lab Animals, Inc., New York, USA
- Housing: 5 animals per cage in wire-bottom cages
- Diet: Ralston Purina, guinea pig chow
- Water: tap water ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23
- Humidity (%): 45
- Photoperiod (hrs dark / hrs light): 12
Vehicle:
other: 9:1 solution of dipropylene glycol methyl ether and polyethylene sorbitan monooleate
Concentration / amount:
10 %
Vehicle:
other: 9:1 solution of dipropylene glycol methyl ether and polyethylene sorbitan monooleate
Concentration / amount:
10 %
No. of animals per dose:
10 ( per exposure group)
Details on study design:
INDUCTION
4 topical treatments (0.1 mL) with the test substance, at the third time 0.2 mL Freud`s adjuvant was injected additionally.

CHALLENGE
2 weeks after the last treatment animals were challenged topically.
Positive control substance(s):
yes
Positive control results:
The epoxy resin sensitized 9/10 animals, producing a slight to marked erythema (9/10 animals) and a slight to moderate edema (9/10 animals).
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
10%
No. with + reactions:
0
Total no. in group:
10

- All animals treated with EDA were sensitized and displayed a slight to marked edema and erythema.

Endpoint:
skin sensitisation
Remarks:
in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Unsuitable test system
Qualifier:
no guideline followed
Principles of method if other than guideline:
A total of ten intracutaneous injections (one injection every other day) of the test substance (0.1 % in physiological saline solution) were performed with five white male guinea pigs. Two weeks after the tenth injection, a retest injection was made. Twenty-four hours later a reading of the diameter, height and color of the reaction spot was made and compared with similar reading taken after the first injection.
GLP compliance:
no
Type of study:
not specified
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source of test material: Sequestrene NA2, Alrose Chemical Co., Providence, RI, USA
Species:
guinea pig
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 400 - 450g
Route:
intradermal
Vehicle:
no data
Concentration / amount:
0.1 %
Route:
intradermal
Vehicle:
no data
Concentration / amount:
0.1 %
No. of animals per dose:
5
Details on study design:
MAIN STUDY
A. INDUCTION EXPOSURE
- 10 intracutaneous injections given on alternate days (the first of 0.1 mL, thereafter 0.2 mL)

B. CHALLENGE EXPOSURE
- 2 weeks after the tenth injection challenge injection of 0.1 ml 0.1% Na2EDTA
- Evaluation (hr after challenge): 24
Positive control substance(s):
no
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0.1%
No. with + reactions:
0
Total no. in group:
5
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

The Magnusson Klingman Test according to OECD Test Guideline 406 using Na2EDTA (purity 91 %) was chosen as key study. This test was performed under GLP by BASF (2000). 10 test animal and 5 control animals were used. A 0.5 % substance concentration in corn oil was used for intradermal induction and a 30 % test concentration for topical induction. Control animals were treated with corn oil as vehicle control. The challenge was conducted with 30 % Na2EDTA in corn oil. 3/10 test animals showed a discrete patchy erythema 24 h after patch removal, after 48 h 0/10 showed a patchy erythema. 7 days later a re-challenge was conducted using 30 % substance in corn oil. 1/10 test animals exhibited a discrete patchy erythema after 24 h, which was reversible within 48 h. Control animals did not exhibit skin reaction after challenge or re-challenge. The positive control group using 20 % mercaptobenzodiazol induced positive skin sensitisation reactions in 7/10 animals at the 24 and 48 h reading.

 

With Na3EDTA a Repeated Insult Patch Test gave a negative result (0/10 animals) (Henck et al., 1980). Within 10 days the animals received 4 topical treatments (0.1 mL) of 10 % Na3EDTA in dipropyleneglycolmethylether; at the third treatment Freud's adjuvants was injected additionally. 2 weeks after the last treatment the challenge was conducted using 10 % Na3EDTA in dipropyleneglykolmethylether. Within the same test Henck et al. also tested for cross-sensitisation between the known skin sensitizer ethylenediamine (EDA) and Na3EDTA. Animals were sensitized with EDA and challenged topically with Na3EDTA on the one flanc and EDA on the other. None of the animals reacted positive after the challenge with Na3EDTA, but all of the animals which were challenge with EDA showed a slight to marked erythema and slight edema. Therefore, it was concluded that Na3EDTA does not cross-sensitize with EDA.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

In a 5-minute inhalation challenge with 6 % Na2EDTA (as aerosol), elicited bronchoconstriction in Basenji-Greyhound dogs with hyperreactive airways but not in mongrel dogs was noted. There was an increase in pulmonary resistance (RL) (2.1 ± 0.4 cm H2O/L/s) prechallenge, 9.0 ± 1.8 postchallenge) . Exposure with 6 % CaNa2EDTA caused no changes in pulmonary resistance (Downes & Hirshman, 1983). In another study (Lindeman et al., 1993) the mechanism of chelator induced airway constriction was examined in anesthetised Basenji-Greyhound dogs after exposure of either 4% Na2EDTA or 4 % CaNa2EDTA. Collateral resistance was significantly greater after Na2EDTA than after CaNa2EDTA exposure (ca. 1.5 versus 0.5 cm H2O/L/s). Fluid volume recovered after bronchalveolar lavage (BAL), total cell counts and cell differentials did not differ significantly. However, a seven-fold increase in prostanoid concentration (PGD2) in the BAL fluid was found in Na2EDTA exposed dogs in comparison to CaNa2EDTA exposed dogs. There was a strong relationship between changes in collateral resistance and concentrations of prostanoids (PGD2) after Na2EDTA exposure but not after CaNa2EDTA exposure. It was concluded that calcium chelators such as Na2EDTA can produce airway constriction by stimulating release of bronchoconstricting prostanoids in dogs with airway hyperresponsiveness.

In letters from industry (BASF, Dow, Akzo Nobel, CEFIC) it was reported that no adverse acute or chronic respiratory health effects from exposure to EDTA or Na4EDTA have been observed in workers (BASF-Letter, 2001).


Short description of key information:
Two studies on dogs with airway hyperresponsiveness using Na2EDTA have been performed. In those dogs bronchoconstriction can be induced.
However, considering the fact that no adverse acute or chronic respiratory health effect was reported in workes exposed to Na4EDTA or edetic acid, these results do not warrant a labeling according to EU or GHS critieria.

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. The substance is not considered to be classified for skin sensitisation under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.