Iron sulphide

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Data waiving:

other justification

Justification for data waiving:

other:

Description of key information

Extensive information is available for the iron kinetics in the body, showing that only limited amounts of iron (max. 15%) are absorbed. For iron sulfide, a basic toxicokinetics assessment was made, showing that the oral route is most appropriate for testing. Dissociation, especially in the acid gastric content, may influence the toxicokinetics and formation of ferrous and ferric ions (e.g. Fe2+, Fe3+) or iron salts (e.g. FeCl2, FeCl3, FeSO4) and sulfide (sulfur) derivatives, however iron can only be absorbed when it is in the ferrous (Fe2+) form. Therefore, a read acros proposal was made with iron or other (worst case) iron salts for the systemic toxicity evaluation of iron sulfide.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

15

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

5

Additional information

According to chapter R.7C of the endpoint specific guidance, physicochemical data may be used for a qualitative TK assessment. Next to the literature that was worked out in specific endpoint records, the data below were used for additional pharmacokinetic assessment.

 

SUMMARY BASIC TOXICOKINETICS (see detailed description attached to this section)

Absorption:

- Current physicochemical data do not indicate a high absorption of iron sulfide after oral exposure. Main arguments contra are the low water solubility (<0.87µg/L), rather high particle size (d50 = 34,5 µm) and  absence of acute oral toxicity (LD50>2000 mg/kg bw), whereas only low molecular weight (87.91 g/mol) would be in favour of absorption. Nevertheless, there might be some absorption after reaction in the gastrointestinal tract. Dissociation, especially in the acid gastric content, may influence the toxicokinetics and formation of ferrous and ferric ions (e.g. Fe²⁺, Fe³⁺) or iron salts (e.g. FeCl₂, FeCl₃, FeSO₄) and sulfide (sulfur) derivatives, however iron can only be absorbed when it is in the ferrous (Fe²⁺) form.

- Absorption by inhalation is not considered relevant based on the above mentioned properties as well as the low vapour pressure (0.000000001 Pa ). Particles could theoretically be inhaled, however they are too large to reach the alveolar region. 

- Dermal absorption of iron sulfide is also not expected based on further physicochemical properties such as rather high surface tension (72,6 mN/m) and absence of dermal irritation and toxicity (LD50>2000 mg/kg bw). QSAR for dermal absorption (Dermwin) was considered to be outside the applicability domain.  

In conclusion, the oral route is still the most appropriate application for testing, considering that iron is (partly) absorbed as (ferrous) ions. This also applies to some other iron salts, of which some are therapeutically used for iron deficiencies. For risk estimation, 15%, 5% and 5% were used as worst case absorption rates for the oral, inhalation and dermal routes, respectively.

 

For iron in general, literature on the kinetics and metabolism of iron describes that the disposition of iron is regulated by a complex mechanism to maintain homeostasis, mainly involving intake, stores, and loss. Generally, about 2-15% from ingested iron is absorbed from the gastrointestinal tract, whereas elimination of absorbed iron is only about 0.01%/day. Iron absorption is influenced by quantity and bioavailability of dietary iron, amount of storage iron, and rate of erythrocyte production. The best known enhancer is vitamin C (ascorbic acid, creating acid conditions). Absorption occurs in two steps: 1. absorption of ferrous ions (Fe²⁺) from the intestinal lumen into the mucosal cells and 2. transfer from the mucosal cell to plasma, where it is bound to transferrin for transfer to storage sites. As ferrous ion is released into plasma, it becomes oxidized by oxygen to ferric iron (Fe³⁺) in the presence of ferroxidase I, which is identical to ceruloplasmin. There are 3-5 g of iron in the body. About 2/3 is bound to hemoglobin, 10% in myoglobin andiron-containing enzymes, and the remainder is bound to the iron storage proteins ferritin and hemosiderin. Exposure to iron induces synthesis of apoferritin, which then binds ferrous ions. The major route of excretion of iron is into the gastrointestinal tract and eventually the faeces. Daily iron losses from urine, gastro-intestinal tract, and skin are ca. 0.08, 0.6 and 0.2 mg/day, respectively. Based on these data, no basic estimation of distribution, metabolism and elimination has been performed for iron sulfide, as it is believed that iron enters the body as ferrous ions and not as iron sulfide. A more detailed literature overview about distribution, metabolism and excretion of iron can be found further in the document

enclosed.

 

SUMMARY READ ACROSS (See detailed description attached to Section 13)

As iron sulfide can dissociate in Fe²⁺and S^2-, both ions should be taken into consideration for assessing appropriate read-across substances. However it can be demonstrated that the possible toxicity of iron sulfide can be mainly attributed to ferrous iron (Fe²⁺). Selection of most appropriate read-across substances was considered, taking into account physicochemical and toxicological properties and chemical reactions taking place in physiological conditions. Toxicological anchor points available were acute oral & dermal toxicity, skin & eye irritation,skin sensitization and bacterial mutagenicity. Results from these studies support and validate the further data filling strategy by a 'many to one' read-across approach. 

Based on the common constituent Fe²⁺or Fe³⁺, read-across with iron, iron oxides and iron salts was further considered first for physicochemical endpoints. Water solubility and particle size were considered the most important parameters as a starting point for read across.  Further comparative assessment for toxicology endpoints learned:

1) For the local tolerance endpoints (skin and eye irritation), iron, iron oxides and iron phosphate had a similar profile. However, as particle size was much lower (all <10 µm), it was decided that the experimental data of iron sulfide are most appropriate and read across was not applied.

2) For the systemic toxicity endpoints (acute, repeated dose, reproductive toxicity), iron sulfide will partly dissociate/dissolve inside the stomach and intestines after oral ingestion. The availability of the ions Fe²⁺ will be an important factor in assessing the toxicity of FeS. Absorption occurs in two steps: a) absorption of ferrous ions (Fe²⁺) from the intestinal lumen into the mucosal cells and b) transfer from the mucosal cell to plasma, where it is bound to transferrin for transfer to storage sites.In this case read-across with other iron salts or iron oxide(s) can be used. Based on the comparative data table, iron, iron oxides and iron phosphate are safe and may seem first choice source chemicals, however as these are fine dust products, they are not data rich for the oral application route of higher endpoints (28-day and 90-day repeated dose toxicity, reproductive and developmental toxicity). On the other hand, iron sulphate and especially iron dichloride (or iron trichloride) are most ‘data rich’ for both the lower and higher toxicity endpoints. There is however a higher toxicity profile for the acute toxicity, most likely due to higher solubility and availability of Fe²⁺, by which iron dichloride/trichloride can be considered as ‘worst case’ source chemical(s). For the threshold related endpoints (repeated dose and reproductive toxicity), a correction factor of at least 6 can be justified for NOAELs from iron dichloride based on the difference in acute oral toxicity profile (the difference in solubility is even much higher). The factor 6 is still a conservative assessment factor in favour of iron sulfide. In addition, literature shows that ferric sodium pyrophosphate (prenatal development study with absence of maternal toxicity or teratogenic effects in mice or rats) and iron (multi-generation reproduction toxicity study in Wistar rats) can be used.

3) For the genotoxicity (bacterial and mammalian mutagenicity, chromosomal aberration test), there were some equivocal findings published for iron (salts), however carcinogenicity testing with iron trichloride was negative and this overrules this issue. A further detailed description of read across argumentation is given in Section 13.