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Description of key information

There are no oral repeated dose studies with the substance available. Studies on several structural analogues of the substance are available (for read-across justification refer to Section 13) which indicate no significant concerns for toxicity/carcinogenicity.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Well documented study

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
Study duration:
subchronic
Species:
rat
Quality of whole database:
Well documented study; no systemic effects observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
Study duration:
subchronic
Species:
rat
Quality of whole database:
Well documented study

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

A one month feeding study in rats of Na2EDTA, a structural analogue of the substance, revealed a NOAEL of 2.25% in the diet, corresponding to 1,125 mg/kg/day (Kawamata, 1980). In this study the substance was incorporated at levels of 1, 2.25 and 5% in the diet, corresponding to 500, 1125 and 2500 mg/kg/day). Fifteen rats/sex/dose level were exposed over a period of one month. At the high dose level body weight was decreased, some mortalities occurred and a reduction in total leucocytes and lymphocytes as well as an increase of bound urine nitrogen (BUN) and a decrease in Ca serum levels were found. Pathological investigation at this dose level revealed reduced liver, spleen and thymus weights. Histopathology revealed some parakeratosis in the oesophagus and forestomach. A 90 -day feeding study in rats with the same substance revealed a NOAEL of 500 mg/kg/day (Wynn, 1970). Groups of 10 male Holzman rats received 1, 5 and 10% (respectively 500, 2,500 and 5,000 mg/kg/day) Na2EDTA in the diet for 90 days. It should be noted that in this study detailed clinical chemistry investigations were not performed as required by OECD TG 408. Mid- and high-dose animals expressed a significant decrease in body weights and food consumption. Dose-dependent mortality was evident by 20% mortality in the 5% group and 60% mortality in the 10% group. In these groups animals exhibited diarrhoea and were emaciated. Water consumption was increased. In the high dose group there was an intermittent decrease of haematocrit and haemoglobin levels and livers appeared to be pale. Histological investigation failed to reveal any pathological alteration.

 

A two year feeding study in rats with another structural analogue (Na3EDTA x 3H2O) resulted in a NOAEL of 500 mg/kg/day (corresponding to 7,500 ppm in the diet; NTIS, 1977). In this feeding study two dose levels were investigated - 3,750 ppm and 7,500 ppm (corresponding to approximately 250 and 500 mg/kg/day). No substance related toxic effects could be observed. This substance was also investigated in a study of the same duration in mice at the same dose levels (3,750 ppm and 7,500 ppm; corresponding to approximately 469 and 938 mg/kg/day). Again there were no treatment related changes and a NOAEL of 938 mg/kg/day was assigned. Also studies with CaNa2 -EDTA showed limited toxicity.

When comparing the acute inhalation toxicity studies of HEDTA-Na3 and EDTA-Na2H2, the first one showed no lethality at the technically highest available concentration of almost 4000 mg/m3 for 4 h whereas the latter showed 30% mortality at 1000 mg/m3 for 6 h, the difference being considered to be due to the higher binding capacity of EDTA compared to HEDTA (see also read across document in section 13). For EDTA-Na2H2 a 14 -day and a 90-day inhalation toxicity study are available showing local effects in the respiratory tract mainly in the larynx. Based on the acute tests, much less local toxicity is expected for HEDTA upon repeated exposure. A study with DTPA-CaNa3 showed limited local effects at high concentrations only.

Moreover, in accordance with REACH Regulation 1907/2006 (Annex IX, 8.6.2 Column 2) testing by the inhalation route is appropriate if exposure of humans via inhalation is likely, taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size. HEDTA-Na3 consists of large particles and has a very low vapor pressure whereas HEDTA-H3 is only produced as an aqueous solution; as such there will be no exposure to dust particles, and also no exposure to the vapour because of the very low vapour pressure of HEDTA-H3.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Well documented study

Justification for classification or non-classification

According to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, classification and labelling is not indicated for repeat dose toxicity as clear functional disturbances or morphological changes were not apparent in subchronic and chronic toxicity studies with surrogate substances.