Nitrilotriacetic acid

Carcinogenicity

Description of key information

Effect level expressed as the acid

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1977

Reliability:

2 (reliable with restrictions)

Guideline:

other: Stanford Research Institute / NCI

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: feed

Duration of treatment / exposure:

2 years

Frequency of treatment:

continuous

Post exposure period:

none

Remarks:

Doses / Concentrations:
0.02, 0.2 and 2% (15, 150 and 1500 mg/kg bw per day) as Na3NTA.H2O
Basis:
nominal in diet

No. of animals per sex per dose:

24 per sex per test group plus another 24 per sex for the control group

Control animals:

yes, concurrent no treatment

Details on results:

Hydronephrosis was pronounced at the highest dose-level. No renal and bladder tumours were observed in the controls and lower-dose groups but 1 papilloma in a female at 0.2%.

All other tumours occurred in the highest dose-level (acc. to IARC):
RCN TCC(R) TCC (U)
male (high dose) 4/24 4/24 8/24
female (high dose) 4/24 6/24 5/24

RCN = renal tubular-cell neoplasms (adenoma + carc.)
TCC = transitional-cell carcinoma, renal (R) and urinary (U)

Metastases arisen from primary tumours of the urinary tract were found in 5/24 animals each of both sexes.

A revision of histological sections from NCI study (Alden, Kanerva, 1982) substantiated recent findings from Procter & Gamble and may have resulted in a different appreciation by P&G (Anderson et al., 1982):

CONCLUSION: High doses of NTA initiate a sequential series of toxic events vi two pathways, a specific and an age-related unspecific one. Doses
of NTA that do not induce toxicity do not induce tubular tumours.
With respect to tumour formation, the adoption of a dietary chronic NOAEL of 0.2% (ca. 150 mg/kg bw*d) is justified (see also TSCATS,
OTS 0545297)

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Effect level expressed as the acid

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

chronic

Species:

rat

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

The IARC monograph on nitrilotriacetic acid (volume 73, chapter 19) from 1999, which is attached in section 13, summarizes the carcinogenic effects as follows:

Nitrilotriacetic acid was tested for carcinogenicity by oral administration in the diet to

mice and rats. It induced renal tubular tumours (adenomas and adenocarcinomas) in mice

of each sex and in male rats and transitional-cell and squamous-cell carcinomas of the

urinary bladder, hepatocellular adenomas and adrenal phaeochromocytomas in female rats.

The trisodium salt was tested for carcinogenicity in mice and rats by oral administration.

When administered in the diet as the monohydrate, it induced haematopoietic

tumours in male mice and benign and malignant tumours of the urinary system (kidney,

ureter and bladder) in rats of each sex. When administered in drinking-water to male rats,

it induced renal tubular adenomas and adenocarcinomas.

In two-stage studies of carcinogenicity in male rats treated by oral administration,

nitrilotriacetic acid and its trisodium salt increased the incidence of urinary-tract tumours

after pretreatment with various N-nitrosamines.

Nitrilotriacetic acid is absorbed in mammals, but it is not metabolized and is excreted

rapidly by filtration in the kidney.

Orally administered nitrilotriacetic acid and its trisodium salt were nephrotoxic to

rats and mice of each sex. Toxicity occurs at high doses and appears to be due to Zn++

accumulation secondary to the chelating properties of nitrilotriacetic acid; administration

of Zn++ accentuated the nephrotoxicity of the acid. Urothelial cytotoxicity and regenerative

hyperplasia were seen in male and female rats but not in mice, and only at doses

higher than those that produced nephrotoxicity. The mechanism is unclear but appears to

involve cellular Ca++ depletion secondary to the chelating effect of nitrilotriacetic acid.

Urinary microcrystals were also produced.

Nitrilotriacetic acid does not induce developmental toxicity in rats, rabbits or mice

exposed during gestation and gave negative results in short-term assays to screen for

teratogenesis in two cellular assays in Drosophila larvae and frog embryos.

No data were available on the genetic and related effects of nitrilotriacetic acid or its

salts in humans. Nitrilotriacetic acid and its disodium and trisodium salts were not genotoxic

in experimental systems in vivo, except that the acid induced aneuploidy in mouse

germ cells. Neither the acid nor its salts were genotoxic in mammalian cells in vitro and

they were not mutagenic to bacteria.

There is inadequate evidence in humans for the carcinogenicity of nitrilotriacetic acid and its salts.

There is sufficient evidence in experimental animals for the carcinogenicity of nitrilotriacetic acid and its salts.

Nitrilotriacetic acid and its salts are possibly carcinogenic to humans

Note: the effect level is expressed as the acid

Additional information

The IARC monograph on nitrilotriacetic acid (volume 73, chapter 19) from 1999, which is attached in section 13, summarizes the carcinogenic effects as follows:

Nitrilotriacetic acid was tested for carcinogenicity by oral administration in the diet

in mice and rats. It induced renal-cell adenocarcinomas in mice of each sex, renal-cell

tumours in male rats and transitional-cell and squamous-cell carcinomas of the urinary

bladder, hepatocellular adenomas and adrenal phaeochromocytomas in female rats.

Nitrilotriacetic acid, trisodium salt was tested for carcinogenicity in mice and rats by

oral administration. When administered in the diet as the monohydrate, it induced haematopoietic

tumours in male mice and benign and malignant tumours of the urinary system

(kidney, ureter and bladder) in rats of each sex. When administered in drinking-water to

male rats, it induced renal adenomas and adenocarcinomas.

In two-stage carcinogenicity studies in male rats by oral administration, nitrilotriacetic

acid and its trisodium salt increased the incidence of urinary-tract tumours after

pretreatment with various N-nitrosamines (IARC, 1990).

The nephrocarcinogenic effects of nitrilotriacetic acid in rats and mice appear to be

related to dose-dependent changes in Zn++ homeostasis. Orally administered nitrilotriacetic

acid and its trisodium salt were nephrotoxic to rats and mice of each sex. The toxicity

occurs at high doses and appears to be due to Zn++ accumulation secondary to the

chelating properties of nitrilotriacetic acid. Administration of zinc nitrilotriacetic acid or

Zn++ accentuated the nephrotoxicity of nitrilotriacetic acid.

Nitrilotriacetic acid has urothelial effects only in rats and at doses higher than those

required for nephrotoxicity and proliferative effects. Although the mechanism of induction

of the urothelial effects is not known, they are not related to Zn++ homeostasis but rather

correlate with depletion of cellular calcium and possibly the formation of nitrilotriacetic

acid-containing microcrystals.

The renal and urothelial effects of nitrilotriacetic acid are associated with cellular

toxicity and regenerative hyperplasia. Its toxic, regenerative proliferative and tumorigenic

effects occur only at high doses. No direct genotoxic effect appears to be

involved.

None of 12 renal-cell carcinomas in rats treated with ferric nitrilotriacetate acid had

mutations in codons 12, 13 or 61 of the H-, K- and N-ras genes. Only one high-grade

tumour contained a CGC→CTC transversion in codon 246 of the p53 gene (Nishiyama

et al., 1995).

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