REPORT Safety Assessment of EDTA, Calcium Disodium EDTA. Diammonium EDTA, Dipotassium EDTA. 7 Disodium EDTA, TEA- EDTA, Tetrasod=um EDTA, Tripotassium EDTA, Trisodium EDTA, HEDTA and Trisodium HEDTA ABSTRACT EDTA (ethylenediamine tetraacetic acid) and its salts are substituted diamines. HEDTA (hydroxyethyl ethylenediamine triacetic acid) and its trisodium salt are substituted amines. These ingredients function as chelating agents in cosmetic formulations. The typical concentration of use of EDTA is less than 2%, with the other salts in current use at even lower concentrations. The lowest dose reported to cause a toxic effect in animals was 750 mg/kg/day. These chelating agents are cytotoxic and weakly genotoxic, but not carcinogenic. Oral exposures to EDTA produced adverse reproductive and developmental effects in animals. Clinical tests reported no absorption of an EDTA salt through the skin. These ingredients, are likely, however, to affect the passage of other chemicals into the skin because they will chelate calcium. Exposure to ED TA in most cosmetic formulations, therefore, would produce systemic exposure levels well below those seen to be toxic in oral dosing studies. Exposure to EDTA in cosmetic formulations that may be inhaled, however, was a concern. An exposure assessment done using conservative assumptions predicted that the maximum EDTA dose via inhalation of an aerosolized cosmetic formulation is below that which has been shown to produce reproductive or developmental toxicity. Because of the potential to increase the penetration of other chemicals, formulators should continue to be aware of this when combining these ingredients with ingredients that previously have been determined to be safe primarily because they were not significanUy absorbed. Based on the available data, the CIR Expert Panel found that these ingredients are safe as used in cosmetic formulations. INTRODUCTION CHEMISTRY Ethylenediamine Tetraacetic Acid (EDTA) and its salts are substituted diamines; Hydroxyethyl Definition and Structure Ethylenediamine Triacetic Acid (HEDTA) and its salt, Trisodium HEDTA, are substituted amines. EOTA, HEDTA, and their salts conform to the These ingredients function as chelating agents in formulas depicted in Figure 1 (Wenninger and cosmetic formulations by combining with McEwen, 1997). polyvalent metal cations in solution to form soluble ring structures. EDTA and its salts (known collectively as Edetates) have uses in foods, pharmaceutical products, and manufacturing, and are used to treat heavy metal poisoning and to reduce blood cholesterol. EDTA DIPOTASSIUM EDTA ~eo:~, o-~o~ EDTA (CAS No. 60-00-4) is a substituted diamine. The food- and pharmaceutical-grade compound contains not less than 98.0% and not more than 100.5% of C10H~6N208(U.S. Pharmacopeial Convention, Inc., 1995). The DISODIUM EDTA cosmetic-grade material contains 99.0-102.0% EDTA (Nikitakis and McEwen, 1990a). NaOOCCH2." /CH2COONa Other names for this ingredient include Edetic HOCCCH2?CH2CH2N , CH2COOH Acid; Edetic Acid (EDTA); Ethylene Diamine Tetra Acetic Acid; N,N'-1,2-Ethanediylbis[N- (Carboxymethyl)Glycine]; Glycine, N,N'-1,2- TEA-EDTA Ethanediylbis[N-(Carboxymethyl)- (Wenninger and McEwen, 1997); Ethylenediaminetetraacetic PI3OC~ C--kzO33H acid; Versenic Acid (Grant, 1972); Edetate (Taylor, 1988); (Ethylenedinitrio)Tetraacetic HOOOm2/E~2m2N'o.~em Acid; Edathamil (Budavari, 1989; Gennaro, 1990; U.S. Pharmacopeial Convention, Inc., 1995); Ethylenedinitrilotetraacetic Acid; TETRASODIUM EDTA Ethylenebisiminodiacetic Acid (Lewis, 1993); and 3,6-Diazooctanedioic Acid, 3,6- NaOOCCH2~ /CH2COONa bis(Carboxymethyl)- [Registry of Toxic Effects of NCH2CH2N Chemical Substances (RTECS), 1997]. NaOOCCH2/ kCH2COONa FIGURE 1 STRUCTURES OF EDTA, HEDTA, AND THEIR SALTS TRIPOTASSIUM EDTA KOCCC ~CH2COOK EDTA ~2C~N K~C__,C~/ CH2COOH TRISODIUM EDTA NaOOCCH2x , CH2COONa CALCIUM DISODIUM EDTA NaOOCCH2/ NCH2CH2N~ CH2COO H NaCOCCH2-,~ ~ ,CH2COONa HEDTA S)G I-IOC~H2\ /C~2CCC;H 0 O TRISODIUM HEDTA DIAMMONIUM EDTA NaOOCCH2., / CH2COONa ~c~c~ c~cooNa ~o::o.~/N~'~'o-~4 2 Calcium Disodium EDTA ingredient are Dipotassium Edetate Dihydrate; N,N'-1,2-Ethanediylbis[N- Calcium Disodium EDTA (CAS No. 62-33-9) is a (Carboxymethyl)Glycine], Dipotassium Salt; and substituted diamine (Wenninger and McEwen, Glycine, N,N'-1,2-Ethanediylbis[N- 1997). The food- and pharmaceutical-grade (Carboxymethyl)-, Dipotassium Salt (Wenninger chemical is a mixture of the dihydrate and and McEwen, 1997). trihydrate of Calcium Disodium EDTA (predominantly the dihydrate), and contains not less than 97.0% and not more than 100.2% of Disodium EDTA CloHI2CaN2Na208, calculated on the anhydrous basis (Gennaro, 1990; U.S. Pharmacopeial Disodium EDTA (CAS No. 139-33-3) is a Convention, Inc., 1995). substituted diamine (Wenninger and McEwen, 1997). When dried, the cosmetic-grade material Synonyms for this ingredient are Calcium contains not less than 99.0% of Disodium EDTA Disodium Ethylenediamine Tetraacetic Acid; (Yakugi Nippo Ltd., 1979); it contains 76.0- Calcium Disodium Ethylenediaminetetraacetate; 77.5% EDTA (Nikitakis and McEwen, 1990a). Edetate Calcium Disodium (Wenninger and The pharmaceutical-grade material contains not McEwen, 1997); Calciate(2-), [[N,N'-I,2- less than 99.0% and not more than 101.0% of Ethanediylbis[N-(Carboxymethyl)-Glycinato]](4- C10H14N2Na2Oa, calculated on a dried basis (U.S. )N,N',O,O',ON,oN']-, Disodium, Hydrate, (OC-6- Pharmacopeial Convention, Inc., 1995). 21)-; Disodium [Ethylenedinitrilo)Tetraacetato] Calciate(2-) Hydrate (U.S. Pharmacopeial Synonyms for Disodium EDTA include Disodium Convention, Inc., 1995); Edathamil Calcium Edetate; Disodium N,N'-l,2-Ethanediylbis[N- Disodium; CaNa2EDTA; Calcium Disodium (Carboxymethyl)Glycine]; Disodium Ethylene- (Ethylenedinitrilo)-Tetraacetate (Gosselin et al., diaminetetraacetate; Edetate Disodium; Gly-cine, 1984); EDTA Calcium; Calcium Disodium N,N'-1,2-Ethanediylbis[N-(Carboxymethyl)-, Edetate; [(Ethylenedinitrilo)Tetraacetato]- Disodium Salt (Wenninger and McEwen, 1997); Calciate(2-)Disodium; Sodium Versenate; Disodium (Ethylene Ethylenediaminetetraacetic AcJd Calcium dinitrilo) Tetraacetate Dihydrate (Gennaro, Disodium Chelate; Calcium Disodium 1990); (Ethylenedinitrilo)-Tetraacetic Acid (Ethylenedinitrilo)-Tetraacetate; Edetic Acid Disodium Salt; Ethylenediaminetetraacetic Acid Calcium Disodium Salt; Sodium Calciumedetate; Disodlum Salt; Ethylenebis(Iminodiacetic Acid) Calcitetracemate Disodium; Calcium Disodium Disodium Salt; Disodium Edathamil; EDTA Versenate (Budavari, 1989); Calcium Disodium Disodium; Terrace-mate Disodium; Disodium Edathamil; and Calcium Sodium Edetate (Taylor, Ethylenediaminetetraacetate; Endrate Diso- 1988). dium; Versene Disodium Salt; Edathamil Disodium (Budavari, 1989); and Sequestrene Diammonium EDTA (Sax, 1979). Diammonium EDTA (CAS No. 20824-56-0) is a substituted diamine that is also known as TEA-EDTA Diammonium Edetate; Diammonium N,N'-I,2- Ethanediylbis[N-(Carboxymethyl)Glycine]; TEA-EDTA (CAS No. 60544-70-9) is a Edetate Diammonium; Diammonium triethanolamine (TEA) salt of EDTA (q.v.). Ethylenediaminetetraacetate; and Glycine, N,N'- Synonyms for this ingredient are 1,2-Ethanediylbis[N-(Carboxymethyl)-, Triethanolamine EDTA and Glycine, N,N'-1,2- Diammonium Salt (Wenninger and McEwen, Ethanediylbis[N-(Carboxymethyl)- Compd. with 1997). 2,2',2"-Nitrilotris[Ethanol] (Wenninger and McEwen, 1997). Dipotassium EDTA Tetrasodium EDTA Dipotassium EDTA (CAS No. 2001-94-7) is a substituted diamine. Synonyms for this Tetrasodium EDTA (CAS No. 64-02-8) is a 3 substituted amine. The cosmetic-grade material Ethylenediaminetetraacetic Acid Trisodium Salt; contains a minimum of 99.0% Tetresodium and Edetic Acid Trisodium Salt (Budavari, 1989). EDTA as Na4EDTA ° 2H20 (Nikitakis and McEwen, 1990b; Wenninger and McEwen, HEDTA 1997). HEDTA (CAS No. 150-39-0) is a substituted Tetrasodium EDTA is also known as Edetate amine. Synonyms for this compounds are N-[2- Sodium; N,N'-1,2-Ethanediylbis[N- [Bis(Carboxymethyl) Amino]Ethyl]-N-(2- (Carboxymethyl)Glycine], Tetrasodium Salt; Hydroxyethyl)Glycine; Hydroxyethyl Glycine, N,N'-1,2-Ethanediylbis[N- Ethylenediamine Triacetic Acid; Glycine, N-[2- (Carboxymethyl)-, Tetrasodium Salt; Sodium [Bis(Carboxymethyl) Amino]Ethyl]-N-(2- Edetate; Tetrasodium Edetate; Tetrasodium Hydroxyethyl)- (Wenninger and McEwen, 1997); Edetate Dihydrate; Tetrasodium Ethylene Hydroxyethylethylenediaminetriacetic Acid Diamine Tetraacetate (Wenninger and McEwen, (Lewis, 1993); HEEDTA (Hart, 1984; HSDB, 1997); Ethylenediaminetetraacetic Acid 1998; RTECS, 1997); (N-Hydroxyethylethylene- Tetrasodium Salt; Ethylenebis(Iminodiacetatic dinitrilo)Triacetic Acid; Oxyethylethylenedia- Acid) Tetrasodium Salt; Tetrasodium minetriacetic Acid; (2-Hydroxyethyl)Ethylene- Ethylenebis(Iminodiacetate); EDTA Disodium; diaminetdacetic Acid; N-(Beta-Hydroxyethyle- Edetic Acid Tetrasodium Salt; Tetracemate thylenediamine)-N,N',N'-Triacetic Acid; N- Tetrasodium; Tetracemin; Endrate Tetrasodium (Hydroxyethyl) Ethylenediaminetriacetic Acid; (Budavari, 1989); Edathamil Tetrasodium; and and N-(2-Hydroxyethyl)Ethylenediamine-N,N',N'- Tetrasodium Ethylenediamine-N,N,N',N'- Triacetic Acid (HSDB, 1998). Tetraacetate [Hazardous Substances Data Base (HSDB), 1998]. Trisodium HEDTA Tripotassium EDTA Trisodium HEDTA (CAS No. 139-89-9) is a substituted amine that is also known as N-[2- Tripotassium EDTA (CAS No. 17572-97-3) is a Bis(Carboxymethyl)Amino]Ethyl]-N-(2- substituted diamine that is also known as Hydroxyethyl)Glycine,