[iminobis(ethyleneiminomethylene)]bis(phosphonic) acid, N,N-bis(phosphonomethyl) derivative, sodium salt

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The test substance in this study is the penta-phosphonate form and is one of the components in the substance to be registered. It is not considered justifiable to perform further toxicity testing on in view of the absence of adverse effects at nearly 1000 mg/kg/day over 90 days for the penta-phosphonic salt. [ref 7.5.1]

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Report date:

1998

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD 408 - 90 day oral

Principles of method if other than guideline:

90 day dietary study, dosed at up to ca. 1000 mg/kg/day equivalent

GLP compliance:

yes (incl. QA statement)

Test type:

other: Based on sub-chronic data

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

[[(phosphonomethyl)imino]bis[(ethylenenitrilo)bis(methylene)]]tetrakisphosphonic acid, sodium salt

EC Number:

244-751-4

EC Name:

[[(phosphonomethyl)imino]bis[(ethylenenitrilo)bis(methylene)]]tetrakisphosphonic acid, sodium salt

Cas Number:

22042-96-2

Molecular formula:

C9H28N3O15P5.xNa

IUPAC Name:

[[(phosphonomethyl)imino]bis[(ethylenenitrilo)bis(methylene)]]tetrakisphosphonic acid, sodium salt

Test animals

Species:

cat

Strain:

other: Alpk APfSD (Wistar derived)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Zeneca Pharmaceuticals
- Age at study initiation: 28 days
- Weight at study initiation: 159g (males); 133g (females)
- Fasting period before study: No
- Housing: Four per cage in multiple rat racks.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: One week

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: In feed

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): The experimental diets were made in 30 kg batches from premixes prepared bymixing the appropriate amount of Dequest 2066A with up to 7 lots of 1 kg batches of milled diet. The premixes were then added to the appropriate amount of diet and mixed thoroughly.
- Mixing appropriate amounts with (Type of food): Milled CTL diet (no further information)
- Storage temperature of food:

Doses:

0, 100, 1000, 10000ppm


Basis

nominal in diet




8.2, 82.5 and 841.9mg/kg (males) and 9.2, 92.3 and 902.6mg/kg (females) (expressed as salt)


Basis

other: Calculated intakes from food consumption data

No. of animals per sex per dose:

12

Control animals:

yes

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

discriminating dose

Effect level:

> 1 000 mg/kg bw

Based on:

act. ingr.

Mortality:

No mortality up to limit of dosing

Clinical signs:

other: No effects

Gross pathology:

No effects

Other findings:

HAEMATOLOGY: There was an increase in red blood cell levels in males and females at 10000 ppm. Mean cell volume and mean cell haemoglobin were also decreased at this dose. Haemoglobin and mean cell haemaglobin concentration were significantly decreased in females at top dose. Total iron binding capacity in the serum of males only were increased and the total serum iron decreased in females only. All changes described were statistically significant. Perls' staining for iron complexes showed decreases in the spleens of both sexes. Thus, the findings noted in these haematological parameters and serum iron and binding capacity are likely to result from a perturbation of iron homeostasis, which is supported by the reduction of staining in the spleen.The effects are therefore due to the iron binding characteristics of Dequest 2066A, which is a chelating agent. All of these observations are considered to be without toxicological significance.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

It is not considered justifiable to perform further toxicity testing on in view of the absence of adverse effects at nearly 1000 mg/kg/day over 90 days.

Executive summary:

From assessment of similar alkyl amine phosphonates, including the analogue substance based on penta-phosphonate,  this class of substance is noted as being acutely toxic other than for those where local corrosive effects may be the primary concern. From various data sources, it is considered unlikely that the substance will be acutely toxic with discriminating dose levels in excess of 2000 mg/kg.

 

There is evidence that these substances are absorbed by ingestion with changes in blood chemistry caused by chelating / sequestering effects’ the 90 day feeding study on the penta-phosphonate noted adaptive changes in blood chemistry and bone density.