Absorption, Distribution and Excretion
Poorly absorbed from the gastrointestinal tract. Well absorbed following intramuscular injection.
It is excreted primarily by the kidney, with about 50% excreted in one hour and over 95% within 24 hours.2 Almost none of the compound is metabolized.
Studies with (14)C-EDTA were performed in a similar manner to studies with (14)C-Diethylenetriamine Pentaacetic Acid (DTPA). (14)C-DTFA, 10 to 15mg with a (14)C activity of 15 to 20 pCi, was administered IV to 4 patients. Oral doses of (14)C-EDTA, either 3 mg with a 14C activity of 5 to 10 pCi or 50 mg (14)C-EDTA with a (14)C activity of 75 to 100 pCi, were administered to two patients. The urinary excretion pattern for (14)C-EDTA was similar to that of (14)C-DTPA. The kidneys were the major route of excretion for (14)C-DTPA after IV injection. At the end of 24 hours, 90% to 100% of the dose of (14)C-DTPA was excreted in the urine. Oral doses of (14)C-DTPA passed through the intestine and 95% to 100% of the dose was recovered in the stool within 2 to 5 days. The urinary excretion was < 8% in the seven patients who received (14)C-DTPA orally. Results for (14)C-EDTA were similar, although it was administered orally to two patients. Additionally, blood samples taken from 1 hour to 3 days after oral administration of (14)C-DTPA did not have any (14)C activity. Similar results were obtained for (14)C-EDTA.
/Investigatos/ found that increasing concentrations of EDTA increases its binding per milligram of albumin. This binding action increases as the pH values increase from 5.1 to 8.2 and the beta-globulin fraction binds more EDTA than other plasma proteins.
/Investigators/ reported that (51)Cr-EDTA moved passively across the epithelium of the gastrointestinal (GI) tract of dogs. The investigators treated muscle-stripped segments of the stomach, ileum, and colon with 0.5 mL of the chelate at a concentration of 9.0 mM. The rate of flux of the chelate was greatest in the ileum, less in the colon, and least in the stomach. No net accumulation of the probe was observed. In addition, the movement of the chelate across the ileum was not affected by neuronal blockade with tetrodotoxin. The investigators suggested that (51)Cr-EDTA moved from the gut lumen via a shunt pathway.
/Investigators/ instilled a solution containing 5 MBq (51)Cr-EDTA (in 14 mL of isotonic saline) in the nasal cavity of 6 smokers and 12 nonsmokers, and maintained the exposure for 15 minutes. Urine was collected for 24 hours after instillation. The median recovered amount of the chelate in smokers was 0.07 mL, and the median amount in nonsmokers was 0.16 mL. After instillation was repeated with the addition of 0.6% dioctylsodium sulfosuccinate to the solution, the median amount recovered for six nonsmokers increased to 1.13 mL. The investigators concluded that nasal airway absorption was not increased in smokers compared to nonsmokers. The investigators also administered 5 MBq (51)Cr-EDTA and 0.6% dioctylsodium sulfosuccinate in 2.0 mL saline to four separate subjects to determine the GI absorption of EDTA. The mean amount of the chelate recovered in the urine corresponded to 1.4% of the dose.
For more Absorption, Distribution and Excretion (Complete) data for ETHYLENEDIAMINE TETRAACETIC ACID (11 total), please visit the HSDB record page.
After intravenous administration, the chelate formed is excreted in the urine with 50% appearing in 1 hour and over 95% in 24 hours.
Disodium edentate ... /is/ poorly absorbed from the gastrointestinal tract and /is/ associated with few adverse effects when used as an excipient in pharmaceutical preparations.
Twenty male Sprague-Dawley rats were divided into four groups of five animals each. Rats in group 1 received ip injections of (14)C Disodium EDTA, group 2 received this compound on depilated skin, rats in group 3 received this compound on depilated and abraded skin (abraded every 2 or 3 cm over treated area), and group 4 was the control group. The specific activity of the (14)C Disodium EDTA was 21.6 mCi/mM and it was dissolved in saline to yield a final solution of 50 pCi/mL. Animals that received ip injections got 0.5 mL of this solution, or 25 pCi of (14)C Disodium EDTA. Animals that had the compound applied to the skin received 25 pCi of (14)C Disodium EDTA in the form of an ointment (modulan, mineral oil, petrolatum, cetyl alcohol 35:21 :25:12) spread over an area of 50 sq cm spread over a sheet of thin polyethylene. This sheet was taped to the trunk of each animal. A collar was fixed around the neck of the rats. All animals were decapitated 24 hours after treatment. The tissue distribution (per 100 mg wet organ weight) of (14)C Disodium EDTA 24 hours after ip administration was as follows: liver 577+/- 13, small intestine 631 +/- 25, large intestine 696 +/- 19, and kidney 1964 +/- 220. Twenty-four hours after application on normal skin the tissue distribution was as follows: liver 6 +/- 4, small intestine 99 +/- 22, large intestine 107 +/- 24, and kidneys 29 +/- 12. Twenty-four hours after application on abraded skin the tissue distribution was as follows: liver 139 +/- 34, small intestine 214 +/- 76, large intestine 309 +/- 115, and kidneys 222 +/- 30.
/Investigators/ reported that rats fed 0.5%, 1.0%, and 5.0% Disodium EDTA for 12 weeks excreted 82.2%, 44.5%, and 45.4%, respectively, of the ingested dose in the urine and feces. The feces contained 99.4%, 98.2%, and 97.5% of the excreted material and the urine contained 0.6%, 1.8%, and 2.5% of the material for the respective doses.
For more Absorption, Distribution and Excretion (Complete) data for Disodium EDTA (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Almost none of the compound is metabolized.
EDTA is reportedly eliminated essentially unchanged.
Almost none of the compound is metabolized.

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Biological Half-Life
The half life of edetate calcium disodium is 20 to 60 minutes.
... About 50% of EDTA admin iv is excreted within 1 hr and 90% within 7 hr. ...
After intravenous administration, the chelate formed is excreted in the urine with 50% appearing in 1 hour and over 95% in 24 hours.

Toxicity Summary
The pharmacologic effects of edetate calcium disodium are due to the formation of chelates with divalent and trivalent metals. A stable chelate will form with any metal that has the ability to displace calcium from the molecule, a feature shared by lead, zinc, cadmium, manganese, iron and mercury. The amounts of manganese and iron metabolized are not significant. Copper is not mobilized and mercury is unavailable for chelation because it is too tightly bound to body ligands or it is stored in inaccessible body compartments. The excretion of calcium by the body is not increased following intravenous administration of edetate calcium disodium, but the excretion of zinc is considerably increased.

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Toxicity Data
Inadvertent administration of 5 times the recommended dose, infused intravenously over a 24 hour period, to an asymptomatic 16 month old patient with a blood lead content of 56 mcg/dl did not cause any ill effects. Edetate calcium disodium can aggravate the symptoms of severe lead poisoning, therefore, most toxic effects (cerebral edema, renal tubular necrosis) appear to be associated with lead poisoning. Because of cerebral edema, a therapeutic dose may be lethal to an adult or a pediatric patient with lead encephalopathy. Higher dosage of edetate calcium disodium may produce a more severe zinc deficiency.

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Interactions
Total myocardial calcium content of rats treated with adriamycin was very high. Treatment with EDTA decreased calcium levels almost to normal values; however the histological adriamycin-induced cardiac alterations were not prevented.
The effect of EDTA (ethylenediaminetetraacetate) on the antimicrobial activity of 10% sodium sulfacetamide solutions was evaluated in this study by kill rate and minimum /inhibitory/ concentration (mic). EDTA improves the kill rate, but not the mic, for the pseudomonas, serratia, and candida species regardless of the preservative.
... Increased absorption of drugs ... occurs in presence of ... ethylenediaminetetraacetic acid (EDTA). When given orally ... (100-500 mg/kg in rats), the chelator increased ... /the/ rate of absorption of heparin, sulfopolyglucin, mannitol, inulin, decamethonium, sulfanilic acid ... Phenol red, all lipid-insoluble substances which ordinarily are poorly absorbed from GI tract. The wide variety of the chemical structures of these suggests that the chelating agent is acting in a nonspecific way and is not affecting the physical or chemical state of the compounds within the intestine ... /there is/ direct evidence that EDTA acts by increasing the permeability of the intestinal epithelium ... Perhaps EDTA alters permeability by increasing the size of the membrane pores or by widening the spaces between the epithelial cells through the removal of calcium ions.
The effects of EDTA on contractile responses of hamster cremaster arterioles and rat aortic strips to epinephrine (EPI) or norepinephrine (NOR) were examined. Comparable contractile responses were elicited by lower EPI or NOR concentration in presence than in absence of EDTA. Individual responses were maintained in the presence of EDTA but rapidly declined if EDTA was not present. Apparently, oxidation of EPI and NOR reduces apparent vascular reactivity and EDTA prevents or delays the reduction.
For more Interactions (Complete) data for ETHYLENEDIAMINE TETRAACETIC ACID (8 total), please visit the HSDB record page.
/Investigators/ reported that Disodium EDTA (10 mg/mL) increased the intestinal absorption of neutral, basic, and acidic compounds in the male Sprague-Dawley rat. The chelating agent increased the absorption of (14)C-mannitol and (14)C-inulin from <2% to 7%-b 1%, the absorption of (14)C-N-methyldecamethonium from 2%-3% to 11%-15%, and the absorption of sulfanilic acid from 11%-14% to 26%-32%. Plasma concentrations of the drugs were increased as much as five- or sixfold, compared to controls.
Disodium EDTA at a concentration of 1% (w/v; 24 mM) increased the in situ drug absorption of acetazolamide from the small intestine of male Charles River rats when administered with 1% (w/v) reduced glutathione. Intestinal absorption was increased by 1.5 to 2 times; however, absorption from the stomach was not affected by treatment with EDTA and glutathione. The investigators suggested that Disodium EDTA altered the aqueous permeability of the intestinal epithelium by the chelation of magnesium and calcium ions, thereby separating the epithelial cells.

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Non-Human Toxicity Values
LD50 Rat ip 512.9 mg/kg EDTA (1.38 mM/kg)
LD50 Mouse ip 250 mg/kg
LD50 Rat ip 397 mg/kg
LD50 Mouse oral 30 mg/kg
LD50 Mouse oral 400 mg/kg
LD50 Rat oral 3.7 g/kg
LD50 Rabbit iv 47 mg/kg
LD50 Rabbit oral 2300 mg/kg
For more Non-Human Toxicity Values (Complete) data for Disodium EDTA (8 total), please visit the HSDB record page.

[1]. Artifact-inducing enrichment of ethylenediaminetetraacetic acid and ethyleneglycoltetraacetic acid on anion exchange resins. Anal Biochem. 2011 May 1;412(1):34-9.

[2]. The role of ethylenediamine tetraacetic acid (EDTA) as in vitro anticoagulant for diagnostic purposes. Clin Chem Lab Med. 2007;45(5):565-76.

[3]. Chelation therapy in the treatment of cardiovascular diseases. J Clin Lipidol. 2016 Jan-Feb;10(1):58-62.

[4]. The effect of ethylenediaminetetra-acetic acid on the cell walls of some gram-negative bacteria. J Gen Microbiol. 1965 Jun;39(3):385-99.

[5]. Ethylenediaminetetraacetic acid induces antioxidant and anti-inflammatory activities in experimental liver fibrosis. Redox Rep. 2011;16(2):62-70.

[6]. Remediation of heavy metals contaminated silty clay loam soil by column extraction with ethylenediaminetetraacetic acid and nitrilo triacetic acid. Journal of Environmental Engineering, 2017, 143(8): 04017026.

[7]. Ethylenediaminetetraacetic acid (EDTA) enhances cAMP production in human TDAG8-expressing cells. Biochem Biophys Res Commun. 2022 Oct 20;626:15-20.

Therapeutic Uses
Anticoagulants; Antidotes; Chelating Agents
EDTA has been used to treat alkali, particularly lime, burns of the cornea.
(51)Cr-EDTA has been used since 1966 as a radiotracer for the assessment of glomerular filtration rate.
Chelation therapy using EDTA has been used since 1955 to treat atherosclerotic cardiovascular disease, but its efficacy has been disputed in recent years. /Former use/
For more Therapeutic Uses (Complete) data for ETHYLENEDIAMINE TETRAACETIC ACID (8 total), please visit the HSDB record page.
Anticoagulants; Chelating Agents; Food Additives
Endrate (Edetate Disodium Injection, USP) is indicated in selected patients for the emergency treatment of hypercalcemia and for the control of ventricular arrhythmias associated with digitalis toxicity. /Included in US product label/
Disodium edentate is also used therapeutically as an anticoagulant as it will chelate calcium and prevent the coagulation of blood in vitro. Concentrations of 0.1% w/v are used in small volumes for hematological testing and 0.3% w/v in transfusions.
Disodium EDTA is used occasionally to terminate the effects of injected calcium, to antagonize digitalis toxicity, or to suppress tachyarrhythmias. /Former/
For more Therapeutic Uses (Complete) data for Disodium EDTA (8 total), please visit the HSDB record page.

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Drug Warnings
... direct contact with EDTA may cause dermal sensitization (eczema) or allergic conjunctivitis.
/BOXED WARNING/ The use of this drug in any particular patient is recommended only when the severity of the clinical condition justifies the aggressive measures associated with this type of therapy.
Clinical studies of edetate disodium did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Fatal medication errors have occurred that involve confusion between edetate calcium disodium (calcium EDTA) and edetate disodium (no longer commercially available in the US). Children and adults have mistakenly received edetate disodium instead of edetate calcium disodium; at least 5 deaths have occurred as a result of inadvertent administration of edetate disodium. Although both edetate calcium disodium and edetate disodium are heavy metal antagonists, the 2 drugs were originally approved by the US Food and Drug Administration (FDA) for different uses and have different effects; edetate disodium was formerly FDA approved for use in selected patients for the emergency treatment of hypercalcemia or for the control of ventricular arrhythmias associated with cardiac glycoside toxicity. Use of edetate disodium may result in a substantial, and sometimes fatal, decrease in serum calcium concentrations. In June 2008, FDA withdrew its prior approval for edetate disodium because of safety concerns following a review of the risk-benefit profile of the drug. FDA stated that it was not considering additional action regarding edetate calcium disodium at that time; most of the fatalities following administration of an EDTA drug have involved medication errors in which edetate disodium was administered instead of edetate calcium disodium. FDA has not received reports of any fatalities resulting from the administration of edetate calcium disodium that involve a medication error.
Edetate Disodium Injection is contraindicated in anuric patients. It is not indicated for the treatment of generalized arteriosclerosis associated with advancing age.
For more Drug Warnings (Complete) data for Disodium EDTA (22 total), please visit the HSDB record page.

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Pharmacodynamics
Edetate calcium is a heavy metal chelating agent. The calcium in edetate calcium can be displaced by divalent or trivalent metals to form a stable water soluble complex that can be excreted in the urine. In theory, 1 g of edetate calcium can theoretically bind 620 mg of lead, but in reality only about 5 mg per gram is actually excreted into the urine in lead poisoned patients. In addition to chelating lead, edetate calcium also chelates and eliminates zinc from the body. Edetate calcium also binds cadmium, copper, iron and manganese, but to a much lesser extent than either lead or zinc. Edetate calcium is relatively ineffective for use in treating mercury, gold or arsenic poisoning.

C10H16N2O8

292.2426

292.09

60-00-4

Ethylenediaminetetraacetic acid trisodium salt;150-38-9;Ethylenediaminetetraacetic acid sodium hydrate;10378-23-1;Ethylenediaminetetraacetic acid disodium dihydrate;6381-92-6;Ethylenediaminetetraacetic acid tetrasodium;64-02-8;EDTA-d12;203806-08-0;Ethylenediaminetetraacetic acid-d16;203805-96-3

6049

White to off-white solid powder

1.6±0.1 g/cm3

614.2±55.0 °C at 760 mmHg

250 °C (dec.)(lit.)

325.2±31.5 °C

0.0±3.8 mmHg at 25°C

1.580

-0.43

4

10

11

20

316

0

KCXVZYZYPLLWCC-UHFFFAOYSA-N

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)

2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

0.1 M NaOH : ~6.67 mg/mL (~22.82 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)