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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
11 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Guideline:
other: no data
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Type of coverage:
open
Vehicle:
water
Duration of treatment / exposure:
28 days
Frequency of treatment:
on each working day (20 days)
Remarks:
Doses / Concentrations:
2.5% aqueous solution (50 mg/kg) as Na3NTA
Basis:
nominal per unit body weight
No. of animals per sex per dose:
6 animals in total, of which 3 treated and 3 not tretaed
Control animals:
yes, concurrent no treatment
Dose descriptor:
NOAEL
Effect level:
37 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: Effect level expressed as the acid
Critical effects observed:
not specified

No local or systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
37 mg/kg bw/day
Study duration:
subchronic
Species:
rabbit

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Guideline:
other: no data
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Type of coverage:
open
Vehicle:
water
Duration of treatment / exposure:
28 days
Frequency of treatment:
on each working day (20 days)
Remarks:
Doses / Concentrations:
2.5% aqueous solution (50 mg/kg) as Na3NTA
Basis:
nominal per unit body weight
No. of animals per sex per dose:
6 animals in total, of which 3 treated and 3 not tretaed
Control animals:
yes, concurrent no treatment
Dose descriptor:
NOAEL
Effect level:
37 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: Effect level expressed as the acid
Critical effects observed:
not specified

No local or systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

There are a number of subchronic and chronic oral dose studies available in the rat, mouse and dog. The two most reliable chronic studies (2 years in rat) have been taken up as endpoints. The other studies can be found in the attached IUCLID4 dossier in section 13.

There is one subchronic (28 days) and one chronic (91 days) dermal dose study available, both in rabbits and with the same result (no local or systemic effects). The subchronic study has been taken up as endpoint as the chronic study has a very low reliability. The other study can be found in the attached IUCLID4 dossier in secion 13.

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

Renal tubular cells show evidence of toxicity in rats and mice given high doses of

nitrilotriacetic acid or its sodium salt corresponding to the doses that produce renal-cell

tumours in these species. Regenerative proliferation ensues. The toxicity correlates with

plasma and urinary accumulation of Zn++, considered to occur secondary to the chelating

properties of nitrilotriacetic acid. Administration of zinc nitrilotriacetic acid or co-administration

of zinc salts with nitrilotriacetic acid accentuates this effect (Anderson et al.,

1985).

The urothelial effects of nitrilotriacetic acid and its sodium salt occur in rats but not

in mice, and sex differences are seen, depending on the experimental treatment. Urothelial

tumours (renal pelvis, ureters, bladder) occur in animals of each sex. In contrast

to the effect in renal tubules, the urothelial effects are not due to accumulation of zinc

but rather appear to be related to depletion of calcium. This occurs at doses higher than

those required for the nephrotoxicity produced by nitrilotriacetic acid, and the doses

correspond to those that produce urothelial toxicity and regenerative hyperplasia.

Although nitrilotriacetic acid-containing microcrystalluria occurs, this was not considered

to be a sufficient explanation for the urothelial toxic and regenerative effects

(Anderson et al., 1985).

Nitrilotriacetic acid did not mediate efficient oxidative production of single- and

double-strand breaks in DNA in vitro in supercoiled plasmid pZ189 (Toyokuni &

Sagripanti, 1993).

It increased the incidence of liver-cell nodules but not carcinomas in female rats

(IARC, 1990).


Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

At the effect levels found there is no requirement for an additional classification according to CLP for STOT RE