Registration Dossier

Toxicological information

Endpoint summary

Currently viewing:

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
450 mg/kg bw/day
Additional information

In combined reproduction/teratogenicity study Na3NTA was administered to male and female Sprague Dawley rats in dietary concentrations of 0, 0.1, and 0.5% (0, 90, and 450 mg/kg/d). There were no significant differences in food efficiency. With respect to reproductive performance there were no significant differences in the conception rate during the specific phases of the study and no significant differences in the measures of fertility and lactation in terms of average numbers of live offspring per litter, live pups on p.n. day 4, average number of weaned pups per culled litter and in the lactation index. Body weights of the offspring were not reported. Offspring weaning weights were reduced at the 0.5% level in both sexes, an effect observed in litters of the first breeding trials was statistically significant for the F1 generation only, but not consistent across successive breeding and/or across generations. No examination of effects on reproductive parameters, testes weights or morphology, epididymal sperm counts, motility, or morphology, daily sperm production, efficiency of daily sperm production, or prostate or dorsal prostate weights or histopathology was performed.

The only effect of Na3NTA on rats in this study was some growth depression in both adult and weanling animals fed the 0 .5% level continuously. This effect was probably due mostly to a reduced palatability of the feed, since no such depression was seen in the weights of fetuses removed by Caesarean-section or in the weights of 4-day-old offspring.

The study shows that Na3NTA causes no deleterious effects on reproduction in rats at dose levels that cause systemic toxicity (450 mg/kg/d).


Short description of key information:
Toxicity to reproduction was assessed in a combined Reproduction and Teratology study in rats and rabbits (Nolen, 1971). Na3NTA was administerd to 20 SD rats/sex/dose in dietary concentrations of 0, 0.1 and 0.5% (0, 90, 450 mg/kg/d). Systemic toxicity was evident in the highest dose group as a growth depression, while reproduction was not adversely effected in the F0 and F1 generation.

Effects on developmental toxicity

Description of key information
Na3NTA did not adversely affect reproductive performance and capability through two successive generations in rats at dietary levels of approximately 450 mg/kg/day, whereas some mild toxicity had been reported. In addition, any specific teratogenic potential and/or impairment of embryo/fetal development are not indicated from the same data in rats (up to 450 mg/kg/d) and rabbits (up to 250 mg/kg/d) (Nolen, 1971). These results are supported by additional non-guideline studies (Nolen, 1972; Scharpf, 1972/1073; Tjälve, 1972). Higher dose levels up to and including clearly parentally toxic doses have not been investigated. However, critical effects for Na3NTA are based on nephrotoxicity and carcinogenicity clearly occurring at lower concentrations (< 100 mg/kg/d). Hence, fertility and developmental toxicity at concentration above 450 mg/kg/d are not considered to be relevant for human risk assessment.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
450 mg/kg bw/day
Additional information

In a pre-OECD combined two-generation/teratogenicity study 20 pregnant CD rats/dose and 20 pregnant New Zealand White rabbits/dose were exposed to dietary concentrations of 0.1 and 0.5 % Na3NTA (rats) and 2.5, 25, 100, or 250 mg/kg/d (rabbits, gavage), respectively (Nolen et al., 1971). No differences were observed in the dams of the treatment groups in comparison to controls with respect to food consumption and body weight gain. Further, the treatment groups did not differ significantly from control groups with respect to average number of corpora lutea, resorptions, live or dead fetuses or in the average weight of male and female fetuses. Fetal examination included inspections for gross abnormalities, body weight changes, sexing, as well as investigations for skeletal and visceral defects. The evaluation did not reveal any skeletal defects. Soft tissue defects predominantly in the urinary system (hydroureter and/or hydronephrosis) were detected in rats; however, there was no significant difference to the F0 and F1 control groups in this study.

Na 3 NTA was further investigated by several groups for the interference with heavy metal toxicity and teratogenicity in rats (Cd, methyl-Hg). Gavage studies with the co-administration of Na3NTA (9.4 - 50.3 mg/kg/d, and 62.5 - 250 mg/kg/d, respectively) to CH3HgOH or CdCl 2 in pregnant Charles River COBS rats throughout embryogenesis did not reveal any effect, respectively enhancement of the extent or type of the teratogenicity of both metals (Scharpf et al., 1972, 1973).

In another co-administration study Na3NTA at dose levels of 0.1 or 20 mg/kg bw/day was administered with CdCl2 or CH3HgOH via drinking water to pregnant Charles River CD rats during embryogenesis. No change or increase in the incidence of Cd or Hg induced malformations was observed. However, also in the groups given only Na3NTA, there was an apparent increase in hydronephrosis and bladder defects. But, since these conditions had been observed by the authors also in other controls at significant and varying incidences (10 – 40 %) this effect was discussed not to be attributed to Na3NTA treatment (Nolen et al., 1972).

In a combined teratogenicity/toxicokinetic study, two groups of pregnant and non-pregnant NMRI or C57 Black mice were given 14 C-labelled NTA intravenously, respectively per os, and the distribution of radioactivity at different time-intervals was studied with whole-body autoradiography (Tjälve, 1972). Two additional groups of ten NMRI mice each were either given 0.2 % NTA via drinking water during embryogenesis or taken as controls. The results from autoradiography revealed a strong accumulation of NTA in the skeleton. There was also a strong accumulation in the fetal skeleton thus indicating transplacental transfer. However, external, skeletal or visceral examination of the fetuses did not reveal any teratogenic effects.

The assessment of the teratogenic potential of Na3NTA is mainly based on an older key study conducted by Nolen et al. (1971). Compared to current guideline studies, the study does not cover all possible endpoints. In addition, the maximum concentration of 450 mg/kg/d is rather low and the dose level used in the second species (250 mg/kg/d) does not cause maternal toxicity. However, administration of Na3NTA did not cause visceral or skeletal malformation in fetuses in a rodent and a non-rodent species. The available data are considered to be sufficient to prove that toxicity to reproduction does not occur at concentrations up to 450 mg/kg/d.

Justification for classification or non-classification

The NOAEL derived from a combined Reproduction and Teratology Studies is 450 mg/kg/day. Higher dose levels up to and including clearly parentally toxic doses have not been investigated. However, critical effects for Na3NTA are based on nephrotoxicity and carcinogenicity clearly occurring at lower concentrations. Hence, fertility and developmental toxicity at concentration above 450 mg/kg/d are not considered to be relevant for human risk assessment.