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

Endpoint summary

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

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]

Reason / purpose for cross-reference:

reference to same study

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

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

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

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.

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. 

 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

No adverse effects at limit of dosing

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: There is no evidence of dermal toxicity in this group of substances, other than some local irritation effects It is not considered justifiable to perform dermal toxicity testing in view of the similarity with other dyes assessed.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Literature checks were made on the class of substance and there is a lot of data on alkyl amines and their salts.
Derivatives of these have been REACH registered and dossiers disseminated.

GLP compliance:

not specified

Test type:

other: Assessment of data

Species:

rat

Type of coverage:

not specified

Vehicle:

water

Details on dermal exposure:

Applied in water

Sex:

male/female

Dose descriptor:

discriminating dose

Effect level:

> 2 000 mL/kg bw

Based on:

act. ingr.

Mortality:

No indication of dose related mortality seen in any study reviewed.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Other than reports of local irritation effects, no signs of toxicity
No indication of systemic effects.

Executive summary:

From assessment of similar substances, none are noted as being acutely toxic, other than local irritation and corrosion with some amines. There is no evidence of dermal absorption, including assessment of sensitising tests. From various data sources, it is considered unlikely that the substance will be acutely toxic by the dermal route and the discriminating dose will be greater than 2000 mg/kg and the similar substances reviewed fall into this category.

 

Studies on guinea pigs and rabbits for sensitising and irritancy assessment have not revealed any evidence of adverse systemic effects. Only the maximised sensitising studies (ie injected) appear to give positive results with some azo dyes, confirming low levels of dermal absorption.

 

It is not considered justifiable to perform dermal toxicity testing in view of the similarity with other dyes assessed. It should also be noted that some other registrations have indicated waivers for this endpoint.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed