[ethylenebis[nitrilobis(methylene)]]tetrakisphosphonic acid, calcium sodium salt

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1982

Report date:

1982

Materials and methods

Principles of method if other than guideline:

SImilar to OECD test guidelines

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

[ethylenebis[nitrilobis(methylene)]]tetrakisphosphonic acid, sodium salt

EC Number:

244-742-5

EC Name:

[ethylenebis[nitrilobis(methylene)]]tetrakisphosphonic acid, sodium salt

Cas Number:

22036-77-7

IUPAC Name:

22036-77-7

Details on test material:

34.7% (w/w) as the free acid form of Dequest 2041 Phosphonate and 9.31% (w/w) sodium in an aqueous solution, pH 7 corresponding to Dequest 2046.
Unique identification nr - NB81635800
Molecular weight = 436 (in acid form)

Test animals

Species:

rat

Strain:

Sprague-Dawley

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

ADMINISTRATION / EXPOSURE
Doses: 0, 0.5, 1.0, 2 g/(free acid form)/ kg (bw) /day administered as an aqueous solution.
Test substance mixed with water, administered at 8 ml/kg/d.
Control group treated with 8 ml/animal 0.9% (w/v) saline.
Volume adjusted based on most recent bwt data.

Frequency of treatment:

Daily between gestation day 6 (implantation day) to gestation day 19 inclusive

Duration of test:

13 days

Doses / concentrations

Remarks:

Doses / Concentrations:
The doses used (calculated on the free acid form) were as follows 2g (free acid form)/kg (bw)/day, 1 g (free acid form)/kg (bw)/day, 0.5 g (free acid form)/kg,Control (0.9% (w/v) sodium chloride.
Basis:
other: Animals were dose by gavage on gestation days 6 through to 19 with doses for all groups corresponding to 8 ml dose volume/kg (bw)/day. The body weights used for dose calculation were the most recent body weights measured on gestation days 6, 8, 10 and 13.

No. of animals per sex per dose:

25 animals were assigned to each treatment or control group.

Control animals:

yes

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

0.5

Based on:

other: Free acid

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

> 2

Based on:

other: free acid

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

MATERNAL TOXIC EFFECTS BY DOSE LEVEL AND BY SEX
Effects with dose level: 0, 0.5, 1.0, 2 g/(free acid form)/ kg (bw) /day administered as an aqueous solution

Mortality
- no treatment related deaths during the study.
Body weight
- Significantly lower body weights for pregnant females compared to control values (ca 9% lower) in the 2g/kg dose levels beginning on gestation day 13 - day 20.
- Analysis of body weight change between day 6 – day 20 indicated significantly lower body weight gains for the 1 g/kg and 2 g/kg females compared to control values.
Clinical observations, physical signs
- The occurrence of light brown loose faeces in the high dose animals was noted. This appeared on GD 14 and generally persisted until sacrifice.
Necropsy findings
- No lesions which exhibited a pattern indicative of a treatment-related response. 
Reproductive parameters
- pregnancy rate comparable between groups, no treatment-related changes recorded.
- The increases in resorption per dam and number of dams with post implantation loss in the 1 g and 2 g/kg dose levels were not significantly significant. Similarly the lower mean corpora lutea/dam in the 1 g/kg dose level group was also not statistically significant.

FETAL DATA
The difference in the mean foetal weight of male and female foetuses was considerably lower in the high dose group compared to the controls, but it was not statistically significant.

Although a large number of foetuses had skeletal variations these were not considered to be treatment related effects.

Because there were indications of maternal toxicity at the 2 g/kg dose level any effects on post implantation loss or foetal weights could be secondary to maternal toxic effects. No significant detectable embryonic or fetotoxic effects occurred at either the 0.5 g/kg or 1 g/kg dose levels.It was also concluded that the skeletal malformations observed were secondary effects related to maternal toxicity. This was supported by comparison of the individual maternal body weight gains and skeletal malformations in the 2 g/kg dose group. Of the five females with lowest body weight gain, four females had foetuses with vertebral anomalies, indicating some correlation between individual susceptibility of the dam to treatment and induction of the vertebral effects.

Applicant's summary and conclusion

Conclusions:

Maternal toxicity NOAEL = 0.5 g/Kg (bw), foetal toxicity > 2 g/kg (bw) based on active acid.

Executive summary:

Mated female Sprague Dawley rats were dosed by gavage at levels of 0.5g, 1g and 2g/kg (bw) of Dequest 2046 (neutral sodium salt) from gestation day 6 through to day 19 inclusive. Based on indications of maternal toxicity at 1 g/kg and 2 g/kg dose levels, the NOAEL for maternal toxicity is 2 g/kg (bw). Because there were indications of maternal toxicity at the 2 g/kg dose level any effects on post implantation loss or foetal weights were viewed as being secondary to maternal toxic effects. No significant detectable embryonic or fetotoxic effects occurred at either the 0.5 g/kg or 1 g/kg dose levels. It was also concluded that the skeletal malformations observed in the high dose group were secondary effects related to maternal toxicity. On the basis of the results the NOAEL for developmental effects is > 2 g/ kg (bw).