Registration Dossier

Administrative data

Key value for chemical safety assessment

Additional information

In accordance with Annex XI, Section 1.5 it is considered to be adequate and reliable to fulfil the information requirements for the endpoint ‘mutagenicity’ by applying a read-across approach from data generated on the substance iron orthophosphate (CAS # 10045-86-0). 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.

Iron orthophosphate (also known as ferric phosphate) has previously been reviewed as an active substance for inclusion on Annex I of the Council Directive 91/414/EEC. Under this review, it was deemed not to be mutagenic. For the purpose of REACH the available data were reviewed and a weight of evidence approach has been used to fulfil the Annex IX requirements. 

One study to assess the genetic toxicity to bacteria was available (Brusick, 1975). The study design was comparable to OECD 471, however, the study was lacking as it only considered 3 types of S. typhimurium and did not include strain designed to detect cross-linking mutagens and is therefore only considered to be a reliability 3 (not reliable) study.

A review of the toxicity of iron salts (Iron Nutritional and physiological significance, British Nutrition Foundation. Published by Chapman & Hall, 1995) suggests that iron salts can produce strand breaks in DNA when incubated with purified DNA or isolated mitochondria and iron overloaded rats show an increased number of strand breaks in hepatic DNA. It is theorised that the mechanism of strand-breakage involves iron-catalysed production of hydroxyl radicals which can abstract hydrogen atoms from both the ribose moiety and purine/pyrimidine bases. The oxidative/catalytic mechanisms responsible for these events require the presence of iron atoms with free coordination linkages and thus cannot be mediated by transferrin-bound iron, nor by iron resident within the core of ferritin. Consequently these potentially carcinogenic reactions are only likely to occur when iron levels exceed the binding capacity of ferritin to transferrin. Saturation of transferrin occurs only in severe iron overload and therefore under normal test conditions (e.g. a chromosome aberration study) it is anticipated that no indications of genetic toxicity would be observed.

Further, a study by Dunkel et al (1999) investigated the effects of iron orthophosphate on mammalian cells; this study was comparable to the current guideline (OECD 476). The results of this study were ambiguous – a weakly positive response was detected in those cells exposed to ferric phosphate with metabolic activation and as such a study according to OECD 476 and under the conditions of GLP was performed (Brown, 2011). In this study the test item did not induce any statistically significant or dose-related increases in the mutant frequency at the TK +/- locus in L5178Y cells and is therefore considered to be non-mutagenic under the conditions of the test.

As both iron and phosphate are essential nutrients and given that humans have been exposed to iron as a nutritional supplement for many years without report of iron-induced mutagenicity it is considered unlikely that relevant mutagenic effects in humans or other mammals might result from the occupation exposure and use of tetrairon tris(pyrophosphate) and therefore no further studies are proposed

Justification for selection of genetic toxicity endpoint
No study was selected, since all data suggest that tetrairon tris(pyrophosphate) is not genotoxic.

Short description of key information:
In accordance with Annex XI, Section 1.5 it is considered to be adequate and reliable to fulfil the information requirements for the endpoint ‘mutagenicity’ by applying a read-across approach from data generated on the substance iron orthophosphate (CAS # 10045-86-0) and as such a number of studies are submitted.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Tetrairon tris(pyrophosphate) is considered to be non-mutagenic.