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Toxicological information

Carcinogenicity

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Description of key information

In good-quality NCI studies, conducted according to a protocol similar to OECD Guideline 451, trisodium ethylenediaminetetraacetate (EDTA) showed no evidence of carcinogenic potential when fed to rats and mice in the diet for 2 years at up to 7500 ppm (about 375 and 1125 mg/kg bw/day, respectively) (NCI, 1977). Based on their structural similarity, it is expected that EDDS acid is also unlikely to induce tumorigenicity following long-term oral exposure at comparable doses.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Dose descriptor:
NOAEL
375 mg/kg bw/day

Additional information

No long-term studies assessing the carcinogenic potential of EDDS acid and its simple salts have been identified. However, EDDS acid is not classified as a mutagen (Cat. 3) and there is no evidence from repeated dose studies that the substance is able to induce hyperplasia and/or pre-neoplastic lesions, so such studies are not required under REACH at any tonnage.

 

In good-quality NCI studies, conducted according to a protocol similar to OECD Guideline 451, trisodium ethylenediaminetetraacetate (EDTA) was assessed for carcinogenic potential in 2-year dietary studies in Fischer 344 rats and B6C3F1 mice. Groups of 50 animals of each sex were fed 3750 or 7500 ppm (approximately 188 or 375 mg/kg bw/day for rats, and 563 and 1125 mg/kg bw/day for mice) for 2 years; groups of 20 control animals of each sex received the untreated diet. Animals were observed twice daily for clinical signs of toxicity and mortalities throughout the study. Body weights were recorded weekly (for the first month) and monthly thereafter. At necropsy all major organs and tissues plus any gross lesions were examined microscopically. In rats, no signs of overt toxicity were observed and body weight gain was similar in both the treated and control groups throughout the study. Survival was similar, or slightly better, in the treated animals than in the controls. In mice, no signs of overt toxicity were observed, but body weight gain was decreased in high-dose males and a small, dose-related decrease was observed in females when compared to the control groups. Survival was similar in all groups. At necropsy, there were no statistically significant differences in the incidence of tumours or non-neoplastic changes between treated animals and their matched controls (NCI, 1977). The final RAR (EU, 2004) also evaluated these studies and concluded that "that there is no concern on carcinogenic properties of EDTA".

A total of 33 Wistar rats (number and sex per group not reported) were divided into 5 groups and dosed with 0, 0.5, 1.0, or 5.0% disodium EDTA in the diet for a period of 2 years (approximately 0, 250, 500, and 2500 mg/kg bw/day, respectively). No gross lesions were observed upon histopathological examination of the internal organs and tissues (which included the heart, liver, pancreas, kidneys, urinary bladder, stomach, small and large intestines, lungs, spleen, ovaries, testes, voluntary muscle, and bone marrow smears). Based on the results of this study, the NOEL was considered to be 2500 mg/kg bw/day disodium EDTA in rats (Yang, 1952). In addition, a NOEL of 250 mg/kg bw/day (the highest tested dose) was seen in Wistar rats (25/sex/group) fed calcium disodium EDTA in the diet for 2 years (Oser et al. 1963).

[Based on its structural similarity with EDTA, and its lack of mutagenic activity, it is expected that EDDS acid is also unlikely to induce neoplasia following long-term oral exposure at comparable doses.]

References (not included elsewhere in IUCLID dossier - need to move to reference list in CSR)

BIBRA (1964). Summaries of toxicological data. Toxicology of EDTA. Food and Cosmetics Toxicology 2, 763-7.

EU (2004). European Union Risk Assessment Report (RAR); edetic acid (EDTA). Vol. 49. European Chemicals Bureau (ECB). Final report available at http://ecb.jrc.ec.europa.eu/DOCUMENTS/Existing-Chemicals/RISK_ASSESSMENT/REPORT/edtareport061.pdf.

Yang S-S (1952). Toxicological investigation of ethylenediaminetetraacetic acid in the rat. Thesis dated May 1952 (cited in BIBRA, 1964).

Justification for classification or non-classification

According to EU CLP and DSD regulations, EDDS acid would not be classified as carcinogenic based on the data described.