Disodium 2-hydroxyethyliminodi(acetate)

Carcinogenicity

Description of key information

There is no chronic/carcinogenicity study available for EDG-Na2. Based on structure similarity with NTA-Na3, the high absoprtion rate of these two substances, and the similarity of renal effects induced when comparing results of the 90-day studies it is concluded that EDG-Na2 could behave in a similar way as NTA-Na3 (see discussion).  

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

NTA related cytotoxicity plays a crucial role in the development of tumors. Cytotoxicity and tumors were seen in identical target regions of the kidneys. Cytotoxicity is an early lesion that leads to regenerative hyperplasia and hyperplasia and was often associated to tumor growth. This mode of action is in line with the criteria for a carcinogen, Carc. Cat. 2, H351, CLP. The same is expected for EDG-Na2. Because NOAELs in the repeated dose toxicity studies were in the same order of magnitude, it is proposed to use the same classification limit of 5% for both substances.

Additional information

In a series of carcinogenicity studies, NTA and Na3NTA.H20 were administered to mice and rats at dietary concentrations up to 20.000 ppm (926 mg/kg/d) (NCI, 1977). In the key studies, Fischer 344 rats were exposed to dietary concentrations of 0, 200, 2000, 20000 ppm Na3NTA.H2O (0, 9, 92, 921 mg NTA/kg/d) for 104 weeks. Primary neoplasms of the urinary tract were seen in 14/24 high dose males and 13/24 high dose females. Hydronephrosis was evident at the high dose animals. Hyperplasias and dysplasias (considered as pre-neoplasias) were present at all dose levels. At the highest does level 20/24 males and 11/24 females showed hyperplasia of tubular cells. The number of transitional cell hyperplasia in the renal pelvis, the ureter and in the urinary bladder was increased at all dose groups. Hyperplasias in the urinary bladder was reported to be most sensitive effect of chronic NTA treatment. Hyperplastic and dysplastic lesions can be considered as presumable pre-neoplastic lesion. The slight increase of these lesions at 200 ppm was not considered statistically significant, representing the (pre-neoplastic) NOAEL. The NOAEL for non-cancer effects was estimated to be 2000 ppm (92 mg/kg/d) based on increased mortality and renal hydronephrosis at the high dose level.

In a second study, Fischer 344 rats were exposed to 7500 and 15000 ppm NTA (0, 526, and 1053 mg NTA/kg bw/d ) and Na3NTA.H2O (0, 355, 724 mg NTA/kg bw/d) for 18 month followed by a 6 month recovery period (NCI, 1977). An increase in the number of tumors of the urinary system was reported at both dose levels. The effect was dose-dependent and more pronounced in females. Adenomas were found in the livers of females at both dose levels. Hepatocellular carcinomas occurred only in low dose males, and neoplastic nodules did not show statistically significance. Hyperplastic lesions of the urinary system were only seen in treated rats. Hyperplastic lesions can be considered as presumable preneoplastic. Non-neoplastic effects associated to NTA consisted of higher incidences of chronic inflammation in the kidneys, resulting in a LOAEL (noncancer) of 7500 ppm.

B6C3F1 mice were exposed to 7500 and 15000 ppm NTA (0, 752, 1504 mg NTA/kg/d) and 2500, and 5000 ppm Na3NTA.H2O (0, 169, 338 mg NTA/kg/d) for 18 month followed by a 3 month recovery period (NCI, 1977). Similar to the rat, treatment-related tumors were evident in the urinary system in a total of 32 male and female mice, pronounced as tubular cell adenocarcinomas in males. Non-neoplastic findings such as hydronephrosis were found in high and low dose males and high dose females. Tubular degeneration was evident in high dose females and one high dose male and inflammation of the kidney in high dose males only. Based on these results a LOAEL for non-neoplastic findings was 7500 ppm NTA (752 mg/kg bw/d).

Exposure to B6C3F1 mice to 2500 and 5000 ppm Na3NTA.H2O (169, 338 mg/kg/d) reduced average body weights in both sexes. No tumors of the urinary system or other treatment related tumors were observed. Hydronephrosis was the only treatment-related lesion of non-neoplastic nature occurring in high dose malesand females. The LOAEL for non-neoplastic effects was 2500 ppm Na3NTA.H2O (169 mg NTA /kg bw/d).

In summary, NTA is carcinogenic in both sexes of rats and the mice via the oral route. NTA associated development of tumors is restricted to the urinary tract. NTA induced primary tumors at several localisations in the urinary tract. Multiple tumor types were observed. Tumors in the rat kidney originated from the tubular-cell epithelium and from the pelvic transitional cell epithelium. Tumors from the transitional cell type were also found in the ureter and the urinary bladder. For the mice, tumors originated from the renal tubular epithelium and occasionally from the renal pelvis. It seems to be reasonable that NTA related cytotoxicity plays a crucial role in the development of tumors. The facts that the cytotoxicity and tumors were seen in identical target regions of the kidneys, that cytotoxicity is an early lesion that leads to regenerative hyperplasia and that hyperplasia was often associated to tumor growth provide evidence for this mode of action, which is in line with the criteria for a carcinogen, category 3. Beside the sequential cascade of morphological events – cytotoxicity, hyperplasia/dysplasia, neoplasia – other factors might contribute to disregulated cell growth and to the manifestation of neoplastic cell growth either as initial events before obvious cytotoxicity or in parallel to the cascade from cytotoxicity to tumor.

NTA does not undergo any detectable biotransformation except for cation exchange. A direct genotoxic mechanism of NTA carcinogenesis could not be demonstrated. Thus a threshold can be derived. From a 2 year feeding study in rats a lowest effective tumor dose of 92 mg Na3NTA /kg/d was established (NCI, 1977). The NOAEL was 9 mg/kg bw/d.