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Description of key information

No studies are provided for the endpoint 'repeated dose toxicity'. The standard testing requirement for chemicals manufactured or imported into the EU in quantities of >100 have been adapted on the basis that there is sufficient data to permit a robust conclusion on possibility of specific target organ toxicity as a result of repeated exposure.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

The justification for the adaptation from the standard testing regime for the endpoint ‘repeated dose toxicity’ is as follows:

Oral toxicity: The standard requirements for chemicals manufactured and imported into the EU in quantities of >100 tpa includes a short-term (28 day) repeated dose toxicity study (Annex VIII, Section 8.6.1, Regulation (EC) No. 1907/2006) and a sub-chronic (90 day) repeated dose toxicity study (Annex IX, Section 8.6.2, Regulation (EC) No. 1907/2006). According to the Integrated Testing Strategy (ITS) proposed in the ECHA guidance document on the information requirements and chemical safety assessment, Chapter R.7a: Endpoint specific guidance, Section 7.5.6, this study does not need to be conducted if there is sufficient information to allow:

- Characterisation of the hazard profile and the dose-response of a substance upon repeated dose exposure.

- Performance of a chemical safety assessment for repeated dose toxicity.

Tetrairon tris(pyrophosphate) is an inorganic solid substance with low water solubility (3.67 x 10-4 g/l at 20.0±0.5°C).The ionic constituents of tetrairon tris(pyrophosphate) are iron (in the ferric, Fe3+, form) and pyrophosphate (P2O74-).

Iron is an essential trace element that has important metabolic functions, such as; oxygen transport and storage (via the protein complex ferritin) and many redox reactions. Insufficient intake of iron can result in iron deficiency (anaemia), adverse outcomes in pregnancy (an increase in iron is required for many of the processes that occur during pregnancy, e.g. erythropoiesis), impaired cognitive performance and reduced immune function. As with all essential elements it is possible to overload the homeostatic mechanisms responsible for the regulation of iron. This is reported to occur at iron doses > 160 mg/day. Adverse gastro-intestinal effects noted with other iron compounds are not expected to occur with tetrairon tris(pyrophosphate) due to its low solubility and relatively low iron bioavailability.

Iron itself is poorly absorbed; a typical daily intake of iron is approximately 15 to 40 mg, but because of an intestinal mucosal block only approximately 10 % of ingested iron is absorbed. Furthermore iron can only cross cell membranes in the ferrous state (Fe2+) and as such the ferric ion (Fe3+) liberated from tetrairon tris(pyrophosphate) must first be reduced to Fe2+ before absorption can occur. It is therefore not considered likely that the industrial use and processing of tetrairon tris(pyrophosphate) will lead to significant systemic absorption, in particular as oral exposure is the least likely route of exposure.

Furthermore, in conditions such as anaemia or during pregnancy, iron (in the form of ferrous sulphate) is often administered as a therapeutic dose of up to 600 mg/day (equivalent to 195 mg Fe/day). Ferrous sulphate is considerably more soluble than tetrairon tris(pyrophosphate) and a number of investigations have been performed that suggest that the bioavailability from the similar substance iron orthophosphate (CAS # 10045-86-0) as compared to ferrous sulphate is considerably lower (values ranging from 11%-50%) and is therefore considerably less toxic. Tetrairon tris(pyrophosphate) has been found to have a lower solubility that iron orthophosphate and as such read-across approach to data generated on iron orthophosphate is considered to be appropriate. In all, a chronic iron overload as a result of the manufacture and use of tetrairon tris(pyrophosphate) in the chemical industry is practically impossible due to its relatively low bioavailability and toxicity. In the case of peak accidental exposures, tetrairon tris(pyrophosphate) is not classified as acutely toxic via the oral route and as such no risk of iron toxicity to the general population exists for the oral route.

The pyrophosphate ion is also highly regulated metabolically and should be considered as an individual moiety for the purpose of assessing its toxicological impact from the administration of tetrairon tris(pyrophosphate). Pyrophosphate is rapidly converted into orthophosphate by intestinal alkaline phosphatases and therefore the majority of diphosphate is probably absorbed as orthophosphate.

As inorganic phosphates are often used as food additives the Joint FAO/WHO Expert Committee on Food Additives (JEFCA) (which assesses and evaluates the biological data and toxicological data available for substances that are used as food additives) has published a monograph in which a number of inorganic phosphates have been evaluated for acceptable daily intake on the basis of the available toxicity data (1) An estimate of the maximum tolerable daily intake (MTDI) intake for man has been derived to be 70 mg/kg bw of phosphorus. This figure applies to the sum of phosphorus naturally present in the diet and from other sources, such as food additives. It is worth noting that this figure is derived on the basis of studies performed on inorganic phosphates that are considerably more soluble and hence the phosphate portion is more bioavailable that that in tetrairon tris(pyrophosphate).

As the uses of tetrairon tris(pyrophosphate) that fall under the scope of REACH are not considered to contribute a significant amount of phosphorus or iron to the daily intake or indeed significantly increase the systemic dose as a result of ingestion via the oral route (predominantly due to the lack of bioavailability), it is not considered to be necessary or scientifically justified to conduct further testing for repeated dose oral toxicity and as such a DNEL cannot be derived.

It is considered that the regulatory endpoint for repeated dose toxicity is fulfilled on the basis that the available information is both sufficient for characterisation of the hazard profile and the dose response of a substance upon repeated dose exposure and for the performance of a chemical safety assessment for repeated dose toxicity. It is not considered to be scientifically justified to conduct further in vivo testing for this endpoint and as such no testing is proposed. Furthermore, phosphate and iron homeostasis in animals and humans enables them to tolerate a wide range of dietary phosphate and iron intakes which may vary according to the metabolic status of the individual; it is not necessarily possible to derive a value which should not be exceeded. The effects of exposure to more bioavailable forms of iron and phosphate are well known and by comparison tetrairon tris(pyrophosphate) is considered to be relatively inert and non-hazardous.  

 

 

(1)  Evaluation of certain food additives and contaminants. Twenty-sixth report of the joint FAO/WHO expert committee of food additives. World Health Organisation. Technical Report Series 683. 1982. ISBN92 4 120683 7

 

Inhalation toxicity: According to the ECHA's Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance: For inhaled substances the processes of deposition of the substance on the surface of the respiratory tract and the actual absorption have to be differentiated. Both processes are influenced by the physico-chemical characteristics of a chemical. The following particle size distribution data is available for tetrairon tris(pyrophosphate): > 99 % of the particles are < 100 μm. This indicates that absorption via inhalation of the substance is possible as particles at the size of < 10 μm are respirable and at the size of < 4 μm are able to reach the alveoli. This was further confirmed by the acute inhalation study which found 48.3% of particles to be < 4 μm. Therefore, the risks of inhalation need to be addressed in consideration of specific target organ toxicity via repeat exposure (STOT-RE).

The absorption of iron and orthophosphate (breakdown product of pyrophosphate) through specified pore systems is possible; however, the absorption of pyrophosphate via the inhalation route is unlikely. As such, inhalation absorption is expected to be low when compared to oral absorption. Oral absorption is also low due to the low solubility and bioavailability of tetrairon tris(pyrophosphate) in comparison to other sources of iron (such as ferrous sulphate). Furthermore, transport across the lipid bilayer is negligible due to the extremely low lipophilicity of the substance.

Non-resorbed particles in the oral cavity, the thorax and the lungs will be transferred to the gastro-intestinal tract with the mucus and absorbed there. Therefore absorption from the gastrointestinal tract will contribute to the total systemic burden of the substance that is inhaled. It is anticipated that oral exposure will represent a worst-case for systemic toxicity.

The LC50 of tetrairon tris(pyrophosphate) obtained in an acute inhalation study (OECD 436) study was estimated to be greater than 5.19 mg/L air (gravimetrically determined mean aerosol concentration). This was the highest technically achievable concentration. There was no indication of relevant sex-related differences in toxicity of the test item. There were no animal mortalities during the observation period and with the exception of one instance of dark patches on the lungs, no macroscopic abnormalities were detected amongst animals at necropsy.

Taken together this evidence suggests that further in vivo testing for repeated dose toxicity; short-term, sub-chronic and chronic, is not scientifically and ethically justified and conclusions relating to repeated-dose toxicity can be drawn from the available information on the oral use of iron salts as nutritional supplements without the need for further in vivo animal studies.

 

Dermal toxicity: A dermal repeated dose toxicity study for tetrairon tris(pyrophosphate) is not considered to be necessary based on the following rationale:

The dermal route of exposure is likely for tetrairon tris(pyrophosphate) (based on patterns of use), however due to the physical nature and known toxicological properties of the substance is not anticipated to pose a hazard via the dermal route.

As tetrairon tris(pyrophosphate) is an inorganic ionic solid, with a molecular weight of >100 and is practically insoluble in water and lipids, dermal absorption can be considered to be negligible. In addition, pyrophosphate ions are, depending on the pH, highly to very highly ionised which reduces drastically the potential to penetrate the lipid rich environment of the striatum corneum.

It is therefore unlikely that a repeated-dose study conducted via the dermal route would yield any significant systemic toxic. This conclusion is further supported by the lack of evidence of systemic effects or other evidence of absorption in the skin or eye irritation studies conducted.

Based on the rationale above and taking into consideration that oral exposure represents a worst case scenario for systemic uptake. No further testing for repeated dose toxicity; short-term, sub-chronic and chronic via the dermal route is considered to be ethically or scientifically justified.

Justification for classification or non-classification

There are no data to suggest that repeated exposure to tetrairon tris(pyrophosphate) will result in specific target organ toxicity and therefore in accordance with Regulation (EC) No 1272/2008 (EU CLP) no classification for STOT-RE is proposed.