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Carcinogenicity

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Epidemiological studies are not available for evaluation of the carcinogenic potential of tetraammonium EDTA. There are also no carcinogenicity studies of diammonium EDTA available. Therefore the carcinogenicity studies with Na3EDTA have been used for evaluation. (For read-across justification refer to section 13). A bioassay of Na3EDTA for possible carcinogenicity was conducted by administration of test material in the diet to Fischer 344 rats and B6C3F1 mice. The studies did not report specific data on kidney toxicity in either species even though histology was performed. Although, a variety of tumors occurred among test and control animals of both species, no tumors were treatment related.
Taking together the negative results of the carcinogenicity study and of the SHE cell transformation assays as well as the general non-mutagenicity after oral doses it can be concluded that there is no concern on a carcinogenic potential of EDTA.
Additionally studies with other ammonium salts do not allow the conclusion that the ammonium ion may have carcinogenic potential (SIDS ,ammonia category).

Key value for chemical safety assessment

Additional information

A standard carcinogenicity study on mice and rats using Na3 EDTA did not demonstrate that the test substance is carcinogenic in experimental animals. 50 male and 50 female Fischer 344 rats were administered with 3,750 and 7,500 ppm (equivalent to about 248 and 495 mg/kg bw/day) daily in the diet for 103 weeks. Matched control groups were composed of 20 male and 20 female animals. The average body weights of treated males and females were comparable to those of the matched controls throughout the study. No treatment-related clinical signs were observed and no statistically significant differences in survival noted. Inflammatory and degenerative changes were observed in about the same frequency in all groups. The lesions appeared to be related to age and not to the administration of the test substance. A high incidence of tumors has been observed in the reproductive and endocrine systems and low incidences occurred in the hematopoietic, respiratory, integumentary, and digestive systems. No neoplasms were observed in the nervous, musculoskeletal, or urinary systems. No tumor appeared in a statistically significant positive trend in either dose groups or sexes. A variety of endocrine tumors were found, some types occurring only in treated animals. However, these tumors occurred in low numbers and have frequently been seen in untreated animals in other studies. Therefore, they are probably unrelated to treatment. In a similar study in mice, 50 male and 50 female B6C3Fl mice were administered with the same dose concentrations (3,750 and 7,500 ppm, equivalent to about 469 and 938 mg/kg bw/day) daily in the feed for 103 weeks. Matched control groups were composed of 20 male and 20 female animals. In male mice only the high-dose group showed a decrease in average body weight compared to the controls throughout most of the study period. In female mice average body weights of the treatment groups were depressed in a dose-related manner during the study period, although the effect was small. No treatment-related clinical signs were observed and no statistically significant differences in survival noted. Inflammatory and degenerative changes were observed in about the same frequency in all groups. The lesions appeared to be related to age and not to the administration of the test substance. A variety of neoplasms were found in both treated and control animals that were well known from historical controls of the same strain. There was a high incidence of tumors in the hematopoictic, endocrine, digestive, and respiratory systems. The incidence of neoplasms in other systems was variable. For all tumor types observed no statistical significance were seen between incidences in dose groups and control groups. With the exception of a splenic hemangioma in a control female and a 3,750 ppm-male, all of the tumors of the hematopoietic system were malignant lymphomas or leukemias. The distribution of endocrine tumors varied little between treated and control mice. For all groups, the incidences of hepatic neoplasms were considerably higher in males than in females. Liver tumors occurred in the 3,750 ppm-dose (10/44, 22%) and 7,500 ppm-dose (10/47, 21%) male groups. Percentage was approximately the same as in the male controls (3/19, 16%). Primary neoplasms of the respiratory system were observed in both treated and control groups. The highest incidence of pulmonary neoplasms was found in the 7,500 ppm-dose male mice (control : 2/18, 11% ; 3,750ppm: 8/44, 18%; 7,500ppm: 12/45, 26%). This may suggest a treatment related effect. Lung tumors were frequently seen in mice of this strain and age, and therefore, the increase of incidence in this mouse study is probably not related to treatment. In conclusion, the non-significantly increased incidence of some tumor types observed in the study provides no clear evidence of carcinogenic effects in the mice.

Justification for classification or non-classification

Based on the results obtained in the toxicity studies and taking into account the provisions laid down in Council Directive 67/548/EEC and CLP, a classification has not to be done with respect to carcinogenicity.