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There are no repeated dose studies with tetraammonium EDTA available. However, under physiological conditions (pH 7-9) any EDTA salt as well as edetic acid will dissociate into the cations and the respective anionic species of edetic acid depending on the dissociation equilibria of edetic acid. Under the assumption of this equivalence it is likely that all EDTA salt chelate ions in vivo. Therefore repeated dose studies with other EDTA-salts, such as Na2EDTA and Na3EDTA, have been used as read across. (For read-across justification refer to section 13).
A 90 day (Na2EDTA) as well as a 2 years (Na3EDTA) feeding study on rats provide reliable toxicological information for an overall NOAEL of about 500 mg/kg bw.
A NOAEC value of 3 mg/m³ air was established in a subchronic toxicity study with Na2H2EDTA.
It can also be ruled out that at this concentrations ammonium ions may cause any toxic effect, as ammonium ions are converted to urea in the liver or are utilized to form in amino acids and proteins. There is only a limited number on repeated dose studies with other ammonium salts available, however oral studies on rats with NH4Cl or ammonium sulfate report even higher NOAELs.

Key value for chemical safety assessment

Additional information

Oral route:

A 90 days feeding study of Na2EDTA in rats revealed a NOAEL of 500 mg/kg bw (Wynn, 1970). Groups of 10 male Holzman rats received 1, 5 and 10% (respectively 500 mg/kg bw; 2,500 mg/kg bw and 5,000 mg/kg bw) Na2EDTA in the diet for 90 days. The mid and high dose animals expressed a significant decrease of body weights and food consumption. Dose dependent mortality was evident by 20% in the 5% and 60% in the 10% group. In these groups animals exhibited diarrhea and were emaciated. Water consumption was increased. In the upper dose there was an intermittent decrease of hematocrite and hemoglobin levels, livers appeared to be pale. Histological investigation failed to reveal any pathological alteration. From this investigation, a NOAEL of 500 mg/kg/day equivalent to 1% in diet can be deduced for male rats. It should be noted that in this study no complete clinical biochemistry has been performed as required by OECD 408 guideline.

A two year feeding study with (Na3EDTA x 3H2O) to rats revealed a NOAEL of 500 mg/kg/day (corresponding to 7,500 ppm in the diet) (NTIS, 1977). In this feeding study with two dose levels 3,750 ppm and 7,500 ppm (corresponding to approximately 250 and 500 mg/kg/day) no substance related toxic effects could be observed.

The same study at the same dose levels (3,750 ppm and 7,500 ppm; corresponding to approximately 469 and 938 mg/kg/day) conducted with mice showed a NOAEL of 938 mg/kg bw/day. There were also no treatment related changes.

A one month feeding study of Na2EDTA in rats revealed a NOAEL of 1,125 mg/kg bw (this corresponds to 2.25% in the diet) (Kawamata, 1980). In this study test substance was incorporated at levels of 1, 2.25 and 5% in the diet (this corresponds to 500, 1125 and 2500 mg/kg bw). 15 rats per sex and dose level were exposed over a period of one month. At the upper dose level body weight decrease, some mortalities and a reduction of total leucocytes and lymphocytes as well as an increase of bound urine nitrogen (BUN) and a decrease Ca serum levels were found. Pathological investigation at this dose level revealed a decrease of liver, spleen and thymus weight. Some parakeratosis was detected in the oesophagus and forestomach by histopathology.

Inhalation:

In a subacute repeated dose toxicity study (BASF, 2009) 10 male Wistar rats per concentration were exposed to a respirable dust aerosol of Na2H2EDTA for 6 hours per day for 5 consecutive days at concentrations of 0, 30, 300, 1000 mg/m³ air.

Exposure in the high dose group (1000 mg/m3) was for one day only due to mortality observed. Inhalation exposure to 1000 mg/m³ disodium EDTA for 6 hours caused lethality in 6 out of 20 male rats. Histological examination of the lung of the dead rats revealed congestion, edema, multifocal hemorrhages and inflammatory cell infiltrates.

Inhalation exposure of rats to Na2H2EDTA for 6 hours per day, 5 consecutive days caused concentration-dependent lesions in the larynx and lungs that were fully reversible within 14 days. Due to histopathological changes in the low dose group a No-Observed-Adverse-Effect-Concentration could not be determined. The LOAEC was considered to be 30 mg/m³ air.

The study was planned as range finder study and conducted according to OECD Guideline 412.

In a subchronic repeated dose toxicity study (BASF, 2014) according to to OECD guideline No. 413 Wistar rats were exposed to a respirable dust aerosol of Na2H2EDTA for 6h/d on 5 consecutive d/w for 13 weeks (65 exposures in total) at concentrations of 0, 0.5, 3, 15 mg/m3 air.

Inhalation exposure of rats to Na2H2EDTA did not lead to any substance-related clinical signs of toxicity. Nor were there any effect in clinical chemistry, hematology. Histological examination revealed some effects in larynx at the highest tested concentration of 15 mg/m³. No signs of systemic toxicity were observed up to a concentration of 15 mg/m³.

Signs of local toxicity were observed only at the high concentration of 15 mg/m³. Under the current test conditions, the No Observed Adverse Effect Concentration (NOAEC) for local effect in larynx was 3 mg/m3, the NOEC for systemic effect is 15 mg/m³.

The local key effect of respirable Na2H2EDTA in the respiratory tract (larynx) is assumed to be mainly concentration-related, hence the impact of exposure time should be low at subcritical concentrations, which was confirmed by the 90d study: although the number of exposures was factor 13 higher than in the 5d dose-range-finder study, the local effects at 15 mg/m3in the subchronic inhalation study were comparably mild compared to the 5d dose-range-finder study that showed a more severe effect at 30 mg/m3.

It is justified to classify (NH4)4EDTA for repeated dose effects due to its analogue substance Na2H2EDTA that induced local effects at low concentrations and the potential human relevance of the effects. However, due to the low severity and incidence of the effects at 15 mg/m3 in the subchronic toxicity study and the reversibility of the local effects, a STOT RE Cat.2 (H373) is considered sufficiently conservative.

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 as Xn (R48/20) and STOT RE Cat 2 (H373) is justified.