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Description of key information

In the absence of specific data regarding the ADME of tetrairon tris(pyrophosphate) (TTP) its physicochemical properties and relevant toxicity data (where available) were assessed for insights into likely ADME characteristics. TTP has a MW >500 and a water solubility of <1 mg/L; therefore absorption via the dermal, inhalation and oral routes is anticipated to be low. Nethertheless, the data paucity dictates a precautionary approach and thus a default value of 100% absorption could be considered appropriate for inhalation exposure, however, this is unlikely. Oral absorption is likely to be low, hence <50% is suggested. Based on MW, a default of 10% for dermal absorption is recommended. There are no substance-specific data regarding distribution and metabolism but the body is likely to handle any absorbed material in the same way that it normally deals with iron and phosphate compounds. Following ingestion, any absorbed TTP is likely to be excreted in the faeces via the bile. 

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

ABSORPTION

Oral

No data were found specifically regarding the oral absorption of tetrairon tris(pyrophosphate) (TTP). With a low aqueous solubility (0.37 mg/L) and (presumably) a low Log Pow, oral absorption is expected to be low. In addition, the molecular weight (MW) (745 Daltons) does not fall in the range considered favourable for absorption (<500) (ECHA, 2012).For a substance to be absorbed efficiently from the gastrointestinal tract it must be in solution.TTP has displayed a low aqueous solubility (Walker & O’Connor, 2010) and therefore is not expected to readily dissolve in thegastrointestinalfluids (ECHA, 2012).

Further, the mechanism of the absorption of iron salts has been extensively studied. Iron crosses cell membranes only in the ferrous state (Fe2+); ferric (Fe3+) ions are liberated in the stomach by acid digestion, reduced to the ferrous state, and absorbed. As a result of an intestinal mucosal block only approximately 10 % of ingested iron is absorbed. Absorption occurs mostly in the duodenum and upper jejunum, although the entire intestinal tract, including the colon, is able to absorb iron.

The divalent (ferrous) iron is absorbed into the gastrointestinal mucosa and converted to the trivalent (ferric) form, which attaches to ferritin in the intestinal mucosal cell wall. The ferritin-ferric storage complex then passes into the bloodstream and is attached to transferrin. Iron is then carried to the reticuloendothelial cells of the bone marrow for haemoglobin synthesis or to the liver or spleen for storage as ferritin or hemosiderin.

The amount of absorption is variable between individuals and according to the iron status of the individual at that time. It is significantly influenced by a number of factors both diet- and host-related.

Iron absorption is regulated by different mechanisms in the human or animal body. Principal factor in the regulation of iron absorption is the body iron content. The adult human body contains approximately 2.2-3.8 g of iron under iron-adequate conditions. Homeostatic mechanisms of intestinal iron absorption have evolved in such a way that intestinal absorption can be altered and iron may be preferentially supplied to functional compartments in response to deficiency or excess. 

The bioavailability of iron pyrophosphate compared to other iron sources is considered to be very poor.

 

Dermal

According to ECHA guidance, a molecule with a MW above 500 may be too large for dermal absorption (ECHA, 2012). For a compound to penetrate the stratum corneum, it must be sufficiently water soluble i.e. above 1 mg/L (ECHA, 2012). The high MW (745), low water solubility (0.37 mg/L) and (presumably) low Log Pow of TTP infer that dermal uptake is likely to be very low. Based on these factors, a value of <10% dermal absorption is proposed.

 

Inhalation

A default value of 100% inhalation absorption is usually applied. In general, very hydrophilic substances might be absorbed through aqueous pores (MW <200) or be retained in the mucous and transported out of the respiratory tract, and subsequently swallowed (ECHA, 2012). However, due to TTP’s low water solubility and high MW, the rate at which the particles dissolve into the mucous fluid will limit the amount that can be absorbed directly. In a recent study report, the mean mass median aerodynamic diameter of TTP was 4.22 µm (Griffiths, 2012). Since TTP is poorly water soluble and aerodynamic diameters are below 15 µm, the particles may reach the alveolar region of the respiratory tract (ECHA, 2012). No indication of systemic absorption was present in the acute inhalation study.

 

DISTRIBUTION and METABOLISM

No data are available regarding the distribution and metabolism for TTP. As a larger molecule, tissue distribution is expected to be limited. Since the substance is of low solubility, it will not be able to diffuse through aqueous channels and pores (ECHA, 2012). Presumably, any absorbed material will be handled in the same way as other absorbed iron and phosphate compounds.

 

Approximately two thirds of the body iron is bound to haemoglobin, less than 10 % is found in myoglobin. Excessive intracellular iron is bound to the storage protein ferritin – the serum ferritin concentration can be used as an indicator of body iron stores. The concentration of free iron in the blood is extremely low due to the high affinity binding of iron to transferrin.

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EXCRETION

Substances excreted in the urine tend to be water soluble and of low MW (ECHA, 2012), neither of which apply to TTP. Any absorbed TTP would probably be excreted in the faeces, likely via the bile, since this tends to involve substances with higher MWs (>300 in the rat) (ECHA, 2012). In general, the excretion of iron is limited as body iron is highly conserved. Renal iron excretion is reported to be as low as 0.1 mg per day and a further 0.2-0.3 mg is lost daily from the skin as a result of sloughing of mucosal enterocytes. Menstrual losses are variable

 

References

 

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. November 2012 (version 1.1).

 

Griffiths DR (2012). Tetrairon tris (pyrophosphate): Acute inhalation toxicity (nose only) study in the rat. Project number: 41201541. Harlan Laboratories Ltd, Derbyshire.

 

Walker JA & O’Conner B (2010). Tetrairon tris(pyrophosphate): Determination of melting/freezing temperature and water solubility. Project number: 2920/0050. Harlan Laboratories Ltd, Derbyshire.