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EC number: 233-149-7 | CAS number: 10045-86-0
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
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 >1,000 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
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: inhalation
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
Reference
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
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: dermal
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Critical effects observed:
- not specified
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
The justification for the adaptation from the standard testing regime for the endpoint ‘repeated dose toxicity’ is as follows:
Oral toxicity: Iron orthophosphate is an inorganic solid substance with low water solubility (8.26 x 10-2 g/l at 20.0±0.5°C).The ionic constituents of iron orthophosphate are iron (in the ferric, Fe3+, form) and phosphate (PO43-).
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 iron orthophosphate 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 iron orthophosphate must first be reduced to Fe2+ before absorption can occur. It is therefore not considered likely that the industrial use and processing of iron orthophosphate 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 iron orthophosphate and a number of investigations have been performed that suggest that the bioavailability from iron orthophosphate as compared to ferrous sulphate is considerably lower (values ranging from 11%-50%) and is therefore considerably less toxic. In all, a chronic iron overload as a result of the manufacture and use of iron orthophosphate in the chemical industry is practically impossible due to its relatively low bioavailability and toxicity. In the case of peak accidental exposures, iron orthophosphate 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 phosphate 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 iron 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 iron orthophosphate.
As the uses of iron orthophosphate 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.
It is therefore 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 iron orthophosphate 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: 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 iron orthophosphate: > 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. 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 phosphate through specified pore systems is possible, nevertheless expected to be low as compared to oral absorption. Oral absorption is also low due to the low solubility and bioavailability of iron orthophosphate 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 iron orthophosphate obtained in an acute inhalation study (OECD 403) study was estimated to be greater than 5.05 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 there were no macroscopic abnormalities noted in the 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: The dermal route of exposure is likely for iron orthophosphate (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 iron orthophosphate 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.
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 iron orthophosphate will result in specific target organ toxicity and therefore in accordance with Regulation (EC) No 1272/2008 no classification for STOT-RE is proposed.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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