Ethylenediamine Tetraacetic Acid (EDTA) and its salts are substituted diamines. Hydroxyethyl Ethylenediamine Triacetic Acid (HEDTA) and its salt, Trisodium HEDTA, are substituted amines. EDTA, HEDTA, and their salts function as chelating agents in cosmetics. As of January 1998, Calcium Disodium EDTA, Diammonium EDTA, TEA-EDTA, and HEDTA were not reported used. The remaining ingredients were used in a total of 4168 cosmetic formulations. Data submitted to the FDA in 1984 indicated typical use of EDTA and Tetrasodium EDTA at and lt; = 1% (with one use each at 25%) , Di- and Trisodium EDTA at and lt; = 1% and and lt; = 0.1%, respectively (with a high use up to 5%), and Trisodium HEDTA at and lt; = 1 % (with one use at 10%). Dipotassium EDTA and Tripotassium EDTA were used at unknown concentrations. Current concentration of use indicated typical use of EDTA at and lt; = 2%, Disodium EDTA and Trisodium HEDTA at and lt; = 0.5%, Tetrasodium EDTA at and lt; = 0.3% and Trisodium EDTA at and lt; = 0.2%.
Human and rat studies reported that Calcium Disodium EDTA and Disodium EDTA were poorly absorbed via oral routes of administration. A study that dosed human males both IV and IM determined that a majority of the dose of EDTA was excreted entirely through the kidneys by glomerular filtration and tubular excretion. Rats dosed IV, IM, and IP with Calcium C14 EDTA elmininated a majority of the chelate in their urine. Most of the chelate was eliminated through the feces after oral administration. A clinical study using male subjects reported almost no absorption of Calcium Disodium EDTA following dermal exposure. EDTA and the edetates can enhance penetration of some other chemicals/substances. Skin irritation and sensitization tests with guinea pigs using Di- and Trisodium EDTA at 0.2 ml and 0.1 ml of a 10% solution. respectively, did not cause any allergic reactions or sensitization.
Under specific in vitro conditions, EDTA and its edetates were cytotoxic to various cell lines. Exposure to EDTA and its edetates over time in rabbits and rats induced morphologic changes in the intestine and inhibited DNA synthesis in the rat intestine. EDTA and its edetates also demonstrated toxicity to the urothelium of the rat and dog.
In all available toxicology studies (rodent and nonrodent species), the lowest dose reported to the FDA that caused toxicological effects was 750 mg/kg/day of either Tetrasodium EDTA, Calcium Disodium EDTA, or Disodium EDTA. The acute LD5o in female rats after IP dosing for EDTA and HEDTA was 512.9 mg/kg and 645.1 mg/kg, respectively. The acute oral LD5o of Disodium EDTA was ca 3.7 mg/kg in male and female rats. Mice dosed IP with Tetrasodium EDTA, Dipotassium EDTA, Calcium EDTA, and Disodium EDTA had LD50 values of 350, 450, 500, and 400 mg/kg, respectively. In rats, the LD50 value has been reported as 7 mg/kg. Retransfusion with 4.5% isotonic Disodium EDTA at a rate of 10 ml/kg/min in dogs resulted in five of seven dogs dying as a result of increased venous pressure. In a 30-day study, the IP LD50 in female rats was 3850 mg/kg for Calcium Disodium EDTA. A single dose of 1 or 2.5 g/kg or daily IP injections of this edetate at 500 mg/kg for 21 days also resulted in mild to severe microscopic changes in the kidneys. Many studies have confirmed the nephrotoxicity of EDTA. Some studies have demonstrated toxic effects, such as increased permeability and severe congestion and hemorrhage, occurring in the intestine. A short-term toxicity study fed Trisodium EDTA Trihydrate to rats and found that male rats fed and gt; = 10,000 ppm and female rats fed and gt; = 14,700 ppm had soft stools, a sign of compound-related toxicity. No signs of organ toxicity or gross pathologic changes were observed. Rats treated for 21 days with Calcium Disodium EDTA died of nephrosis. Administration of EDTA in drinking water to mice at a concentration of 3.4 mM caused changes in the mineral content of certain tissues. Eighty rats fed 5.0% and 10.0% Disodium EDTA for 13 weeks had significantly decreased feed consumption and body weight gain compared to controls. Rats of the high-dose group also had slightly pale livers at necropsy. No other signs of toxicity were observed. Daily IP injections for 6 months of 0.8 to 1 m1 of 6% Disodium EDTA in guinea pigs resulted in animals dying of either rupture of the ventricular wall or of right ventricular failure. In several studies rabbits, rats, and dogs were fed Calcium EDTA (high dose 250 mg/kg), Disodium EDTA (high dose 5.0%), and Calcium Disodium EDTA (high doses 250 mg/kg/day and 1.0%). No gross or microscopic abnormalities were observed.
Rats dosed with Disodium EDTA on normal, abraded, and abraded and depilated skin had concentrations of this chelate present in the liver; small intestine, large intestine, and kidney. Various ocular studies have demonstrated that EDTA is both irritation and nonirritating. Other ocular studies have shown that EDTA both increased and decreased the cytoxicity of other compounds. Calcium EDTA had no effect on the wound healing or breaking strength of skin from rats in short-term studies.
Pregnant rats fed 3% Disodium EDTA at various stages of gestation demonstrated gross malformations when supplemented with 100 ppm zinc as opposed to 1000 ppm zinc. Maternal and fetal toxicity were not observed with ZnEDTA (dosed at 8 and 20 mmol/m2/day) or ZnCaEDTA (8 mmol/m2/day). EDTA administered by gavage and in feed to rats on GDs 7 to 14 at 1000 mg/kg/day and 1250 mg/kg/day, respectively, caused maternal toxicity and malformations in the offspring. In mice, however, offspring of dams treated with 1000 mg/kg/day EDTA orally on GDs 8 to 12 demonstrated no malformations. It has been suggested that the zinc deficiency produced by EDTA resulted in teratogenic effects. Treatment of rabbits with a 3% EDTA ophthalmic drop solution resulted in a significant embryocidal effect. Coadministration of Tetrasodium EDTA and Dicalcium EDTA with the teratogens norchlorcyclizine and chlorcyclizine increased the incidence of malformations present in offspring compared to the teratogen alone. Disodium EDTA (380 mg/kg) caused a significant number of resorptions in pregnant rats.
EDTA is classified as a weak mutagen in microbial systems. In a variety of studies using bacteria, mammalian cell lines, and mammals EDTA and its salts gave both positive and negative results. Irradiation of cells prior to exposure to EDTA produced both an increase and a decrease in chromosomal aberrations. In a number of studies using mammalian test systems, EDTA inhibited DNA synthesis. However, in a number of cell lines inhibition was not observed.
Trisodium EDTA Trihydrate was not carcinogenic to rats or mice fed 7500 ppm for 103 weeks. Disodium EDTA does not inhibit metabolic cooperation.
In acute clinical studies, the major route of excretion was the kidneys and intestine after IV and oral administration of EDTA. Exposure to 0.2 g of Disodium EDTA for 4 hours in a human patch test did not produce any signs of reactivity. In various studies, Calcium Disodium EDTA demonstrated either no contact sensitization or weak sensitization. Products that contained Disodium EDTA did not produce sensitization in an RIPT at concentrations of 0.02% to 0.2%. Calcium Disodium EDTA injected IV at 20 mg/kg for 6 and 10 weeks significantly increased serum concentrations of immunoglobulins.
Administration of Calcium Disodium EDTA to patients in an aerosol form produced no ill-effects during and after treatment, as the therapy was well tolerated, with no changes in the respiratory organs observed. Absorption was determined to be 10% to 30% of the dose. Stippled cell counts were somewhat irregular; however, no other changes occurred in the blood analysis as a result of Calcium Disodium EDTA inhalation. Treatment of 130 children with Calcium Disodium EDTA resulted in biochemical evidence of transient nephrotoxicity and acute oliguric renal failure.
Discussion.
The Cosmetic Ingredient Review (CIR) Expert Panel recognized that oral exposures to EDTA produced reproductive/ developmental toxicity in test animals. Dermal exposures to EDTA in cosmetic products, however, would result in very little EDTA penetrating the skin, resulting in systemic levels well below those shown to produce adverse effects in the oral dosing studies. The CIR Expert Panel was concerned, however, about EDTA in cosmetic formulations that may be inhaled and absorbed through lung tissue in sufficient amounts to produce adverse systemic effects. An exposure assessment was done assuming the maximum reported historical concentration of EDTA in any cosmetic formulation, 25%. Measurements of the amount of an aerosolized cosmetic formulation available within an individual's personal breathing space demonstrated a maximum concentration of 62 mg/m3 (Mokler1976; Elder 1983). If a 60-kg individual inhaled 0.5 1 of air with the aerosolized cosmetic formulation (assumes only one breath during use of a spray), at the maximum measured concentration that contains EDTA at the maximum concentration of 25%, then the dose of EDTA via inhalation of an aerosolized product would be 1.24 x 10-4 mg/kg. This systemic dose is below that producing reproductive/developmental toxicity. Based on this assessment, the Expert Panel is not concerned about adverse effects of EDTA and its salts in aerosolized formulations.
Very small amounts of the impurity, nitrilotriacetate, can be found in EDTA. Nitrilotriacetate is a potential oral carcinogen in rats at large doses. This is not a concern for human exposure given the low concentrations of use of EDTA and the poor dermal absorption of EDTA. Also, although nitrilotriacetate is readily absorbed from the GI tract of the rat, it is poorly absorbed in man.
The Expert Panel recognized that EDTA and its salts are penetration enhancers of certain compounds because they chelate calcium and, therefore, disrupt intercellular bridging. Formulators should be aware of this when combining EDTA and its salts with those ingredients that have been previously determined to be safe primarily because they were not significantly absorbed.
Conclusion.
On the basis of the information included in this report, the CIR Expert Panel concludes that EDTA, Calcium Disodium EDTA, Diammonium EDTA, Dipotassium EDTA, Disodium EDTA, TEA-EDTA, Tetrasodium EDTA, Tripotassium EDTA, Trisodium EDTA, HEDTA, and Trisodium HEDTA are safe as used in cosmetic formulations.