Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

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 rechallenge 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 rechallenge. 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 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 flank 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.

Migrated from Short description of key information:
No skin sensitisation studies on diammonium dihydrogen EDTA are available. Therefore studies using Na2EDTA and Na3EDTA have been used for read across. (For read-across justification refer to section 13). In the OECD 406 guideline study with Na2EDTA 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 can not be ruled out that the reactions reflected irritation rather than sensitisation. However, overall these results do not warrant a labeling according to EU or GHS critieria, 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).
Additionally other salt from the ammonium category show no skin sensitizing potential.

Respiratory sensitisation

Endpoint conclusion
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. There was an increase in pulmonary resistance (RL) (2.1 ± 0.4 cmH2O x l^-1 x s) prechallenge, 9 .0±1 .8 postchallenge) . Exposure with 6% CaNa2EDTA caused no changes in pulmonary resistance (Downes and 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 cmH2O x l^-1 x 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).

6/22 patients with stable asthma developed bronchoconstriction after inhaling 4 ml of a nebuliser containing EDTA (0.5 g/l) and benzalkonium bromide (0.25 g/l) as preservatives together with the bronchodilatator ipratropium bromide. When these six subjects inhaled 4 ml EDTA and benzalkonium bromide free ipratropium bromide solution all subjects showed bronchodilatation. Inhalation of EDTA and benzalkonium bromide administered separately (EDTA solutions containing 0.25-10 g/l) produced dose related bronchoconstriction which persisted for longer than 60 minutes. The cumulative geometric mean (range) of a 20% fall in FEV, (forced expiratory volume) was 2.40 g/l (1.2-12.8) for edetic acid. Although the mechanism by which edetic acid causes bronchoconstriction is uncertain, it probably relates to

its action as a chelator of calcium ions (Beasley, 1987). However in a study by the same group (Beasly, 1989) those results could not be confirmed. EDTA (0.5 g/l) did not influence the bronchodilator effect of a single dose inhaled Duovent with fenoterol (0.31 g/l) and ipratropium. bromide (0.13 g/l). However, the airway effects of repeated inhalations of EDTA were not investigated

Migrated from Short description of key information:
No studies on respiratory sensitisation of (NH4)2EDTA are available, however 2 studies on dogs with airway hyperresponsiveness using Na2EDTA have been performed. In those dogs bronchoconstriction can be induced. Additionally bronchoconstriction was induced in 6/22 asthma patients after inhaling of a nebulizer containing 0.5 g/l EDTA amongst other substances. However this effect could not be reproduced in a study by the same group. Considering the fact that no adverse acute or chronic respiratory health effect was reported in workes exposed to Na4EDTA these results do not warrant a labeling according to EU or GHS criteria.

Justification for classification or non-classification

Based on the results obtained in the toxicity studies and taking into account the provisions laid down in Council Directive 67/548/EEC and CLP, a classification has not to be done with respect to sensitisation.