Nitrilotriacetic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1971

Reliability:

2 (reliable with restrictions)

Guideline:

other: Procter & Gamble (USA)

GLP compliance:

not specified

Species:

rat

Strain:

other: Charles River CD

Sex:

male/female

Route of administration:

oral: feed

Duration of treatment / exposure:

pre-mating exposure period: 8 weeks for male and female
exposure period during pregnancy: from day 6 through day 15

Frequency of treatment:

continuous

Remarks:

Doses / Concentrations:
0.1% and 0.5% (50 and 250 mg/kg bw per day as Na3NTA.H2O
Basis:
nominal in diet

No. of animals per sex per dose:

20 animals per dose per sex
20 animals per sex for control

Control animals:

yes, concurrent no treatment

F1+F2: There were no effects on conception, litter size and survival, stillborn, body weights and gain, lactation index.

F1+F2: There were no effects on number of corpora lutea, resorptions and implantations (on day 13); conception, live and dead foetuses, weight of
foetuses, gross and microscopic inspection of organs for abnormalities (day 21).

Conception varied from 86% (F2) to 97% (F1), with control 92-95%.

See for further details the in section 13 attached IUCLID4 data set.

Dose descriptor:

NOAEL

Effect level:

> 175 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Effect level expressed as the acid

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

> 175 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Effect level expressed as the acid

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

> 175 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Effect level expressed as the acid

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

175 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

The IARC monograph on nitrilotriacetic acid (volume 73, section 19) from 1999, which is atteched in section 13, summarizes the toxicity to reproduction as follows. The two most relevant studies have been taken up in the IUCLID5 dossier. All studies can be found in IUCLID4 data set which is attached in section 13.

The developmental and reproductive effects of nitrilotriacetic acid have been reviewed (Anderson et al., 1985). No significant maternal, embryonic or fetal effects were reported in rats exposed to up to 0.5% in the diet, rabbits exposed by oral gavage to up to 250 mg/kg bw per day or in mice exposed via the drinking-water at 0.2%. Addition of heavy metals such as mercury and cadmium did not change the response. Similarly, studies of reproductive toxicity did not indicate an effect on neonatal development. Nitrilotriacetic acid was used to assess the predictive value of two assays for mammalian teratogenesis in vitro: an assay for inhibition of the growth of embryonic palatal mesenchymal cells, which evaluates effects on proliferative potential, and an assay for inhibition of the attachment of mouse ascites tumour cells to concanavalin A-coated surfaces. The concentrations of nitrilotriacetic acid that inhibited growth or attachment by 50% were > 1 mmol/L in both assays, and the authors considered the results to be negative (Steele et al., 1988). Exposure of developing Drosophila larvae to nitrilotriacetic acid caused a dose-related increase in gross wing defects and extra bristles in adults, but the authors did not consider these effects predictive of developmental toxicity in mammals (Lynch et al., 1991). Nitrilotriacetic acid was evaluated for effects on amphibian embryogenesis in the frog embryo teratogenesis assay Xenopus laevis (FETAX) assay. The concentration that caused the deaths of 50% of the embryos was reported to be 540 mg/L, the concentration that induced terata in 50% of the surviving embryos was 530 mg/mL, and the teratogenic index was 1.0 mg/mL. The authors considered the effects to be due to disruption and osmoregulation and not to teratogenic potential (Dawson et al., 1989).

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.

Effect levels are expressed as the acid

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1972

Reliability:

2 (reliable with restrictions)

Guideline:

other: no data

GLP compliance:

not specified

Species:

mouse

Strain:

NMRI

Route of administration:

oral: drinking water

Duration of treatment / exposure:

from day 6 to day 18 of gestation

Frequency of treatment:

continuous

Duration of test:

18 days

Remarks:

Doses / Concentrations:
0.2% (300 mg/kg bw per day) as the acid
Basis:
nominal in water

Control animals:

yes, concurrent no treatment

Details on embryotoxic / teratogenic effects:

Details on embryotoxic / teratogenic effects:
Teratogenic investigations were combined with a series of distribution experiments to follow nitrilotriacetic acid (NTA) within dam and fetus by
means of radio labelled NTA. NTA exerted no embryotoxic effect and produced no malformations though there was appreciable placental passage of radioactivity onto the fetus.

Dose descriptor:

NOAEL

Effect level:

> 300 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

Substance is NOT a potential developmental toxicant

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

The substance showed no untoward effects and thus a classification is not required.