Reaction mass of disodium [2,2'-(imino-κN)dibutanedioato-κ2O1,O4(4-)]magnesium(2-), sodium chloride and aspartic acid disodium salt

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics 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:

other: EU Risk Assessment Report

Data source

Reference

Reference Type:

review article or handbook

Title:

European Union Risk Assessment Report (RAR). CAS No: 60-00-4, EINECS No: 200-449-4, edetic acid (EDTA)

Author:

RAR - European Chemicals Bureau (ECB): Institute for Health and Consumer Protection

Year:

2004

Bibliographic source:

European Commission: Directorate General: Joint Research Centre: 1st Priority List Volume: 49 (http://europa.eu.int).

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

toxicokinetics

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The report summarizes the results of the animal and human studies on ADME of Ca (2Na) EDTA and sodium salts of EDTA.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Edetic acid

EC Number:

200-449-4

EC Name:

Edetic acid

Cas Number:

60-00-4

Molecular formula:

C10H16N2O8

IUPAC Name:

{[2-(Bis-carboxymethyl-amino)-ethyl]-carboxymethyl-amino}acetic acid

Constituent 2

Reference substance name:

edetic acid (EDTA)

IUPAC Name:

edetic acid (EDTA)

Constituent 3

Reference substance name:

[2-(Bis-carboxymethyl-amino)-ethyl]-carboxymethyl-amino} acetic acid

IUPAC Name:

[2-(Bis-carboxymethyl-amino)-ethyl]-carboxymethyl-amino} acetic acid

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): EDTA: [2-(Bis-carboxymethyl-amino)-ethyl]-carboxymethyl-amino} acetic acid (IUPAC Name)
- Molecular formula (if other than submission substance): C10H16N2O8 (EDTA)
- Molecular weight (if other than submission substance): 292.3 g/mol (EDTA)
- Smiles notation (if other than submission substance): OC(=O)CN(CCN(CC(O)=O)CC(O)=O)CC(O)=O (EDTA)
- InChl (if other than submission substance): InChI=1S/C10H16N2O8/c13-7(14)3-11(4-8(15)16)1-2-12(5-9(17)18)6-10(19)20/h1-6H2,(H,13,14)(H,15,16)(H,17,18)(H,19,20) (EDTA)
Key: KCXVZYZYPLLWCC-UHFFFAOYSA-N (EDTA)
- Structural formula attached as image file (if other than submission substance): see Fig.1
- Substance type: aminopolycarboxylate
- Physical state: solid (colourless crystals)
- Analytical purity: 98-100% w/w
- Impurities (identity and concentrations):
< 0.3 trisodium nitrilotriacetate
< 0.3 ethylenediaminetriacetate
< 0.3% w/w nitrilotriacetic acid
< 1% water

Radiolabelling:

yes

Remarks:

C14

Test animals

Species:

other: rats, dogs, human

Details on test animals or test system and environmental conditions:

Not applicable (the data oroginate from the review)

Administration / exposure

Route of administration:

other: oral (gavage), dermal, i.p., i.v., and s.c.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Ca(2Na)EDTA is poorly absorbed from the GI tract in animals (2 to 18 % within 24 hours) and in humans (5 %). Only 0.001 % is absorbed after dermal application (humans).

Main ADME results 2

Type:

distribution

Results:

Distribution of Ca(2Na)EDTA is limited due to its limited absorption. If absorbed, EDTA is expected to be wide distributed throughout the body. It is confirmed by rapid excretion via the urine and in respiratory CO2 in case of i.v. and i.p. administration

Main ADME results 3

Type:

metabolism

Results:

According to the dissociation equilibrium of EDTA, various anionic species of EDTA will be formed in dependence on the intestinal pH-value. In whatever salt EDTA is administered it is likely to chelate metal ions in vivo.

Main ADME results 4

Type:

excretion

Results:

After oral administration in humans: 5 % in the urine; faeces still contained the substance up until day three. Overall, 93 % was recovered.

Main ADME results 5

Type:

other: toxicokinetic

Results:

Dependent on route of exposure, retention time in the body: Oral: until three days (faeces); until 24 hours (urine); i.v.: until 24 hours; dermal and s.c.: until 24 hours.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

It can be assumed that the oral and dermal absorption of sodium salts of EDTA and of the free acid is comparable to the measured low absorption of
CaNa2EDTA.

Details on distribution in tissues:

Distribution is expected to be wide throughout the body. It is confirmed by rapid excretion in case of i.v. administration in humans: "Intravenously injected Calcium-14C-EDTA (2 mg with 2 g unlabelled CaNa2 EDTA) is excretedwithin 24 hours in the urine, 50% of it in the first hour, 90% within 7 hours".

Details on excretion:

After i.p. injection in rats, a very small amount of the radioactivity, less than 0.1% of the dose, appeared in the respiratory CO2.

Toxicokinetic parameters

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 50 min (after i.p. injection in rats, 95 to 98 % radioactivity was excreted in the urine within 6 hours)

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

The effects of CaNa2EDTA salt (280 mg/kg bw/6h for 54 hours, application s.c.) on the metabolism of Zn, Cu and Mn were investigated in dogs. The substance increased significantly the urinary excretion of Zn, Cu and Mn.

Any other information on results incl. tables

Studies in animals

Following oral administration of the calcium salt of 14C-EDTA (50 mg/kg bw) to rats the chelate was poorly absorbed from the gastrointestinal tract (2 to 18% within 24 hours). After parenteral injection of a comparable dose, 95 to 98% radioactivity was excreted in the urine within 6 hours with an elimination half-life of approximately 50 minutes. A very small amount of the radioactivity, less than 0.1% of the dose, appeared in the respiratory CO2 (Foreman et al., 1953). Ten i.p. injections of CaNa2-14C-EDTA salt (300-500 mg/kg bw/day) were applied to rats. 66 to 92% of the total activity injected was recovered in the urine. The activity of both kidneys 24 hours following the last injection was less than 0.1% of the total injected dose (Doolan et al., 1967; Miller et al., 1986). The effects of CaNa2EDTA salt (280 mg/kg bw/6h for 54 hours, application s.c.) on the metabolism of Zn, Cu and Mn were investigated in dogs. The substance increased significantly the urinary excretion of Zn, Cu and Mn (Ibim et al., 1992).

Inhalation studies are not available.

Studies in humans

Foreman and Trujillo (1954) have studied the toxicokinetics of 14C-EDTA, (CaNa2EDTA; 2 mg) using young healthy adult men. Studies were carried out after peroral and parenteral application and after application on the skin. EDTA is poorly absorbed from the gastrointestinal tract. 24 hours after oral application, a maximum of 5% of the dose was detected in the urine; faeces still contained the substance up until day three. Overall, 93% was recovered. Intravenously injected Calcium-14C-EDTA (2 mg with 2 g unlabelled CaNa2 EDTA) is excreted within 24 hours in the urine, 50% of it in the first hour, 90% within 7 hours. The dose used in skin absorption studies (2 mg calcium salt of 14C-EDTA and 1 g unlabelled CaNa2EDTA) was prepared in a water-soluble base. In one study the sodium salt of 14C-EDTA was used in the place of the calcium salt. Because of the very low activity, the urine from skin absorption studies required special treatment with the sodium salt of EDTA as carrier. The maximum of activity in the urine after application over an area of 100 cm² was 0.001%.

Inhalation studies are not available.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Free EDTA and its salts are poorly absorbed from the GI tract and dermally. Inhalation does not represent a significant hazard due to phys-chem properties of EDTA and low exposure via powdery particles or aerosols. Distribution is extensive throughout the body. It is confirmed by the fact that EDTA was excreted also in form of CO2 the expired air in treated animals. Excretion is manly via the bile (over 90%) and a negligible amount via the urine. EDTA has high binding affinity to metals and therefore will be predominantly in a chelated form in the body. No metabolites are known.

Executive summary:

There are no oral toxicokinetic studies or skin absorption studies with EDTA itself or its tetrasodium salt available. According to the dissociation equilibrium of edetic acid, administration of different sodium salts will result in dependence on the intestinal pH-value to the formation of various anionic species of EDTA. In whatever salt EDTA is administered it is likely to chelate metal ions in vivo. It can be assumed that the oral and dermal absorption of sodium salts of EDTA and of the free acid is comparable to the measured low absorption of CaNa2EDTA. Calcium salts of EDTA are poorly absorbed from the gastrointestinal tract (2 to 18% within 24 hours), a maximum of 5% was detected in the urine. Only 0.001% is absorbed after dermal application (humans). Intravenously injected EDTA is excreted within 24 hours in the urine, 50% of the substance in the first hour and 90% within 7 hours (humans).