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In a carcinogenicity study, NTA and Na3NTA.H20 were administered to rodents in two separate laboratories (NCI, 1977). In the study conducted at the Stanford Research Institute, 24 Fischer 344 rats/sex/dose were exposed to dietary concentrations of 0, 200, 2000, 20000 ppm Na3NTA.H2O for 104 weeks. The second study was conducted at Litton Bionetics, Inc. Two groups each of 50 Fischer 344 rats and 50 B6C3F1 mice were exposed to 7500 and 15000 ppm NTA and Na3NTA.H2O, respectively. Treatment period was 18 month plus 6 month (rats) and 3 month (mice) recovery. 
In a carcinogenicity study 0.1% Na3NTA was applied in drinking water to 196 male SD rats for 2 years (Goyer, 1981).

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Dose descriptor:
9 mg/kg bw/day

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):

Fischer 344 rats (24/sex/dose) were exposed to dietary concentrations of 0, 200, 2000, 20000 ppm Na3NTA.H2O (0, 9, 92, 921 mg NTA/kg/d) for 104 weeks. Microscopic examinations were performed on 32 major tissues and organs. High dose animals gained significantly less body weight (10 - 12%). The mean survival time for males was reduced to 92 weeks compared with 104 weeks in the control group. Primary neoplasms of the urinary tract were seen in 14/24 high dose males and 13/24 high dose females. One papilloma of the bladder was present in a mid dose female. Transitional-cell carcinomas were metastatic in 5 males and 5 females of the high dose groups. Other tumor incidences were not associated to the NTA treatment. 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-neoplasitc) 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.

Fischer 344 (59/sex/dose) 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). The survival rate was similar in NTA/Na3NTA treated and control animals in both sexes. Average weight was reduced in a dose-related manner. The increase in the number of tumors of the urinary system was reported at both dose levels. The effect was dose-depended 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 (50/sex/dose) 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). The NTA treatment resulted in lower body weights of the high dose males and of females of the mid and high dose groups compared with the controls. The survival rates of all groups were comparable. 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 (50/sex/dose) to 2500 and 5000 ppm Na3NTA.H2O (169, 338 mg/kg/d) reduced average body weights in both sexes. Survival rates were not affected. 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 a carcinogenicity drinking water study, 0.1 % Na3NTA was administered to 193 male Winstar rats for 23 months (Goyer, 1981). Histological examinations were conducted on 11 organs for histological and tissues of multiple abnormal sections were analysed. Furthermore, eyes, bone, and gastrointestinal tract were examined from 10 randomly chosen animals of the control and the treated group. As a result, no significant effects were seen on body weight gain or mortality rates. Before day 550, a significant higher rate of the Na3NTA-treated animals died. 85 % of all surviving animals (>= 704 d) had some degree of nephritis and/or renal tubular hyperplasia accompanied by varying degrees of interstitial fibrosis. Most affected was the outer renal cortex, but control and experimental animals showed similar changes. The occurrence of the more severe grades of nephritis seemed to be similar for control and treated animals, but the more severe degrees of hyperplasia were found in experimental animals with a greater frequency. Glomerular changes were nonspecific and consisted of fine intra-glomerular synechia progressing to more severe stages of fibrosis and sclerosis of glomerular capillaries. There was a statistically significant increase of renal tumors in the treated group compared to the control. Renal adenomas or renal adenocarcinomas manifested in 29 from 183 rats. No other tumor types occurred with sufficient frequency to warrant statistical analysis. Considering hyperplasias as a pre-neoplastic lesions, and not toxic effects, the NOAEL for (nephro-) toxicity was 0.1 % Na3NTA (100 mg/kg/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.

Carcinogenicity: via oral route (target organ): urogenital: kidneys

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 was often associated to tumor growth. This mode of action is in line with the criteria for a carcinogen, category 3 (R40, DSD) (Carc. Cat. 2, H351, CLP).