Registration Dossier
Registration Dossier
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EC number: 233-190-0 | CAS number: 10058-44-3
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
Not applicable
Effect on fertility: via oral route
- Endpoint conclusion:
- no study available
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Adaptation from the standard testing regime:
The standard requirement for chemicals manufactured or imported into the EU in quantities of >100 <1000 tpa includes a screening for reproductive toxicity and developmental toxicity (OECD 421 or OECD 422) and a two-generation reprotoxicity study (OECD 416). 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 7.6.6, if there are sufficient data to permit a robust conclusion on reproductive toxicity testing then no further testing will be required.
The justification for not conducting in vivo studies to investigate the reproductive toxicity of tetrairon tris(pyrophosphate) is as follows:
During pregnancy, accompanying physiological changes reduce the concentration of haemoglobin, leading to apparent anaemia in spite of an increase in red blood cell mass.
It is estimated that approximately >700 mg of iron is needed during pregnancy to allow for increased erythropoiesis and the transfer of iron to the placenta and foetus. This additional iron must come from iron stores and from increased absorption from dietary sources of iron and from supplements. As the absorption of iron from any source is relatively low (approximately 10% of dietary iron is absorbed) it is proposed that pregnant women require approximately 30 mg Fe/day (1).
As with cases of traditional iron-deficiency anaemia, ferrous sulphate is often given to pregnant women as a therapeutic supplement on a routine basis. Ferrous sulphate has therefore been rigorously evaluated under the relevant pharmaceutical legislation and is not considered to be a reproductive or developmental toxicant). Ferrous sulphate is considerably more soluble than tetrairon tris(pyrophosphate) and a number of investigations have been performed that suggest that the bioavailability of iron from a similar substance iron orthophosphate (CAS # 10045-86-0) as compared to ferrous sulphate is considerably lower (values ranging from 11%-50%) and can subsequently be considered to pose less of a risk to pregnant animals or humans. Read-across from information on iron orthophosphate can be justified on the following basis:
Both substances are relatively insoluble inorganic ferric (Fe3+) compounds. In conditions where the substances have limited solubility/bioavailability; ionisation to the Fe cation and the orthophosphate cation (iron orthophosphate) or pyrophosphate cation (tetrairon tris(pyrophosphate) will occur. In biological systems (i.e. in the presence of alkaline phosphatase) the pyrophosphate will be broken down into orthophosphate. It is considered that the Fe3+ cation is of most relevance when considering the genotoxic potential of the test material and as iron orthophosphate is slightly more soluble this substance is a good candidate for read-across.
Furthermore, other forms of inorganic phosphate have been assessed for reproductive and developmental toxicity and no effects have been noted with regards to maternal toxicity, reproductive functions or offspring development at dose levels well in excess of normal human exposure. This suggests that inorganic orthophosphates are not a significant risk to the reproductive process in females or males and not a significant risk to the developing foetus.
On the basis of the above discussion it does not seem scientifically or ethically justified to perform further in vivo studies to assess the risk of reproductive or developmental toxicity of iron orthophosphate as any studies performed would not be expected to indicate a risk of reproductive or developmental toxicity.
(1)Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a Request from the Commission related to the Tolerable Upper Intake Level of Iron. The EFSA Journal, 2004, 125: 1-34.
Short description of key information:
No studies are provided for the endpoint 'reproductive 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 reproductive and developmental toxicity.
Justification for selection of Effect on fertility via oral route:
Not applicable - see below for justification for the adaptation to the standard testing regime.
Justification for selection of Effect on fertility via dermal route:
Not applicable
Effects on developmental toxicity
Description of key information
No studies are provided for the endpoint 'developmental 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 reproductive and developmental toxicity.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Adaptation from the standard testing regime:
The standard requirement for chemicals manufactured or imported into the EU in quantities of >100 <1000 tpa includes a screening for reproductive toxicity and developmental toxicity (OECD 421 or OECD 422) and a pre-natal developmental toxicity study (OECD 414). 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 7.6.6, if there is sufficient data to permit a robust conclusion on reproductive and developmental toxicity testing then no further testing will be required.
The justification for not conducting in vivo studies to investigate the reproductive toxicity of tetrairon tris(pyrophosphate) is as follows:
During pregnancy, accompanying physiological changes reduce the concentration of haemoglobin, leading to apparent anaemia in spite of an increase in red blood cell mass.
It is estimated that approximately >700 mg of iron is needed during pregnancy to allow for increased erythropoiesis and the transfer of iron to the placenta and foetus. This additional iron must come from iron stores and from increased absorption from dietary sources of iron and from supplements. As the absorption of iron from any source is relatively low (approximately 10% of dietary iron is absorbed) it is proposed that pregnant women require approximately 30 mg Fe/day (1).
As with cases of traditional iron-deficiency anaemia, ferrous sulphate is often given to pregnant women as a therapeutic supplement on a routine basis. Ferrous sulphate has therefore been rigorously evaluated under the relevant pharmaceutical legislation and is not considered to be a reproductive or developmental toxicant). Ferrous sulphate is considerably more soluble than tetrairon tris(pyrophosphate) and a number of investigations have been performed that suggest that the bioavailability of iron from a similar substance iron orthophosphate (CAS # 10045-86-0) as compared to ferrous sulphate is considerably lower (values ranging from 11%-50%) and can subsequently be considered to pose less of a risk to pregnant animals or humans. Read-across from information on iron orthophosphate can be justified on the following basis:
Both substances are relatively insoluble inorganic ferric (Fe3+) compounds. In conditions where the substances have limited solubility/bioavailability; ionisation to the Fe cation and the orthophosphate cation (iron orthophosphate) or pyrophosphate cation (tetrairon tris(pyrophosphate) will occur. In biological systems (i.e. in the presence of alkaline phosphatase) the pyrophosphate will be broken down into orthophosphate. It is considered that the Fe3+ cation is of most relevance when considering the genotoxic potential of the test material and as iron orthophosphate is slightly more soluble this substance is a good candidate for read-across.
Furthermore, other forms of inorganic phosphate have been assessed for reproductive and developmental toxicity and no effects have been noted with regards to maternal toxicity, reproductive functions or offspring development at dose levels well in excess of normal human exposure. This suggests that inorganic orthophosphates are not a significant risk to the reproductive process in females or males and not a significant risk to the developing foetus.
On the basis of the above discussion it does not seem scientifically or ethically justified to perform further in vivo studies to assess the risk of reproductive or developmental toxicity of iron orthophosphate as any studies performed would not be expected to indicate a risk of reproductive or developmental toxicity.
(1)Opinion of the Scientific Panel on Dietetic Products, Nutrition and Allergies on a Request from the Commission related to the Tolerable Upper Intake Level of Iron. The EFSA Journal, 2004, 125: 1-34.
Justification for selection of Effect on developmental toxicity: via oral route:
Not applicable - see below for justification for the adaptation to the standard testing regime.
Justification for selection of Effect on developmental toxicity: via inhalation route:
Not applicable
Justification for selection of Effect on developmental toxicity: via dermal route:
Not applicable
Justification for classification or non-classification
It is not considered to be scientifically justified to further investigate the effects of tetrairon tris(pyrophosphate) on developmental or reproductive toxicity as no classification is proposed for this endpoint and no further studies are deemed necessary.
Additional information
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