Reaction products of sodium glucoheptonate with iron sulfate and ammonium hydroxide

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

expert satement

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: An extended assessment of the toxicokinetic behaviour of iron glucoheptonate was performed, taking into account the chemical structure, the available physico-chemical-data and the available toxicity data of the structural analogues.

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

according to guideline

Guideline:

other: TGD, Part I, Annex IV, 2003; ECHA guidance R7c., 2012

Principles of method if other than guideline:

Physical chemical properties of iron glucoheptonate were integrated with the published toxicological data and data on ADME parameters of the structurally related substance iron gluconate to create a prediction of its toxicokinetic behaviour. Additionally, well investigated ADME data on iron from different sources (food, medications and other inorganic and organic compounds) have been taken into account, because the systemic toxicity of iron glucoheptonate is considered to be driven by released iron from the iron glucoheptonate complex.

Radiolabelling:

no

Type:

absorption

Results:

Due the MW of 300.8 g/mol and Log Pow -10.5, it is readily absorbed via the GI tract. Low absorption potential via dermal route and inhalation is expected due to its high water solubility (>1000 g/L) and low vapour pressure (5.13 x 10E-5 Pa).

Type:

distribution

Results:

The substance is expected to be distributed predominantly to kidneys and organs with higher expression of glucose transporters. The absorbed non-haem iron is transported via transferrin in the plasma to all body cells.

Type:

metabolism

Results:

Iron glucoheptonate is expected to be metabolised by pathways involved into intermediary carbohydrate metabolism or eliminated unchanged via the urine and to a lesser extent via the bile.

Type:

excretion

Results:

The majority of absorbed iron is lost in the feces. Glucoheptonate is mainly excreted via the kidneys

Details on absorption:

Iron glucoheptonate is expected to be moderately absorbed after oral exposure, based on its high water solubility and molecular weight suggestive for favoured absorption through gastrointestinal tract. As worst-case, 100 % oral absorption is considered appropriate. Concerning absorption after exposure via inhalation, as the chemical has a low vapour pressure, is highly hydrophilic, has a negative LogPow, and has 12 % of particles less than 100 µm, it is clear, that the substance is poorly available for inhalation and will not be absorbed significantly via lungs. However, an absorption by aspiration cannot be fully ruled out. Therefore, 100% inhalation absorption is considered. Iron glucoheptonate is not expected to be absorbed following dermal exposure into the stratum corneum and into the epidermis, due to its very high water solubility. 10 % absorption is considered.

Details on distribution in tissues:

Since iron dissociates from the glucoheptonate moiety before absorption, their distribution and accumulative potential can follow more or less independent ways.
The absorbed non-haem iron becomes available for binding onto transferrin, and is then transported via transferrin in the plasma to all body cells. Entering cells, iron may be incorporated into functional compounds, stored as ferritin or hemosiderin, or used to regulate future cellular iron metabolism. While all cells are capable of storing iron, the cells of the liver, spleen, and bone marrow are the primary iron storage sites in humans. Almost two-thirds of iron in the body is found in haemoglobin present in circulating erythrocytes. Glucoheptonate is expected to be distributed predominantly to kidneys and organs with higher expression of glucose transporters. The substance does not indicate a significant potential for accumulation.

Details on excretion:

At normal physiological conditions, only a small quantity of iron is lost each day. Body iron is therefore highly conserved and is regulated by absorption. The majority of absorbed iron is lost in the feces. Glucoheptonate is mainly excreted via the kidneys.

Details on metabolites:

Metabolism of glucoheptonate in mammalian tissues is described in several publications dealing with investigations of substrate specificity of a various number of aldonic acids and its isomeric analogues lactones. The enzyme 6-phosphogluconolactonase (catalysing the second step of pentose phosphate pathway (PPP)) was shown to possess a broad substrate specificity hydrolysing gluconolactone moieties including glucoheptonate. The enzyme is present in almost all mammalian tissues including humans. Further investigations revealed that glucoheptonate moiety undergoes a series of biochemical transformations similar to those of PPP.

Executive summary:

Iron glucoheptonate is expected to be moderately absorbed after oral exposure, based on its high water solubility and molecular weight suggestive for favoured absorption through gastrointestinal tract. As worst-case, 100 % oral absorption is considered appropriate. Concerning absorption after exposure via inhalation, as the chemical has a low vapour pressure, is highly hydrophilic, has a negative LogPow, and has 12 % of particles less than 100 µm, it is clear, that the substance is poorly available for inhalation and will not be absorbed significantly via lungs. However, an absorption by aspiration cannot be fully ruled out. Therefore, 100% inhalation absorption is considered. Iron glucoheptonate is not expected to be absorbed following dermal exposure into the stratum corneum and into the epidermis, due to its very high water solubility. 10 % absorption is considered. The substance is expected to be distributed predominantly to kidneys and organs with higher expression of glucose transporters. The substance does not indicate a significant potential for accumulation. Iron glucoheptonate is expected to be metabolised by pathways involved into intermediary carbohydrate metabolism or eliminated unchanged via the urine and to a lesser extent via the bile.

Description of key information

Toxicokinetic assessment of FeGHA (for IUCLID’s endpoint summary)

General

There are no ADME studies available for iron glucoheptonate. The toxicokinetic profile of the registered substance was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, the physical chemical properties of iron glucoheptonate were integrated with the published toxicological data and data on ADME parameters of the structurally related substance iron gluconate (here named as source substance) to create a prediction of its toxicokinetic behaviour. Additionally, well investigated ADME data on iron from different sources (food, medications and other inorganic and organic compounds) have been taken into account because the systemic toxicity of iron glucoheptonate is considered to be driven by released iron from the iron glucoheptonate complex (please refer also to read-across statement).

Toxicological profile of Iron Glucoheptonate

There are a limited number of studies available for toxicological endpoints of iron glucoheptonate. Its structurally similar substance iron gluconate is of low toxicological activity in oral acute toxicity studies in different animal species with LD50 values > 2000 mg/kg bw (Berenbaum et al., 1960; Weaver et al., 1961; Hoppe et al., 1955; Antula Healthcare, 2007; WHO, 1975). The principal findings included gastro-intestinal inflammation in treated animals. No maximum residue limit (MRL) was established for iron glucoheptonate aspharmacologically active substance in foodstuffs of animal origin. (EU Commission Regulation No. 37/2010). No dermal or inhalation studies are identified for iron gluconate.
Iron glucoheptonate was not irritating to skin and eyes in in vivo irritation studies in rabbits (Patel, 2016a,b). Iron compounds including those for treatment of iron deficiency anaemia were not sensitising in animals and humans (Hemmer et al., 1996; Ikarashi et al., 1992; Baer, 1973; EMEA, 2013). Gluconic acid and its derivatives are not skin sensitisers and used in a variety of food, cosmetic and consumer products (SIDS, 2004, CIR, 2014; Regulation (EC) No 1925/2006).

In a 12-week repeated dose toxicity study in rats, ferrous gluconate induced a depressed growth rate only in males ate the highest dose tested (100 mg Fe/kg bw). A NOAEL of 50 mg Fe/kg bw (equivalent to 427 mg/kg bw for ferrous gluconate) was established for rats (Berenbaum et al., 1960). No clinical signs or other abnormalities at necropsy were detected. In the repeated studies with gluconates, no toxicological effects have been observed up to 1000 mg/kg bw in males and up to 2000 mg/kg bw in females (SIDS, 2004). “Potential side effects were attributed to high doses of cation intake, evidenced by results from assays designed for the gluconate anion effect specifically”(SIDS, 2004). This statement clearly indicates that no toxicity can be attributed to sugar-like organic moiety while metal is responsible for toxicity effects.

In vitro and in vivo genetic toxicity studies with iron gluconate, sodium ferric gluconate complex in sucrose injection used as medicine, or gluconates were mostly negative (Fujita et al., 1994; Brusick, 1975; 1999; SIDS, 2004, CIR, 2014; Sanofi Aventis Canada, 2009). On the other hand, elemental and some salt forms of iron, including compounds being used in dietary supplements and for food fortification were reported to be mutagenic in L5178Y mouse lymphoma cells (Dunkel et al., 1999), induced chromosomal aberration, SCE and other forms of DNA damage at cytotoxicity levels (Lima et al., 2011). The authors related genotoxic potential of iron compounds to redox-activity of iron which can induce oxidative stress by cascade reactions leading to DNA damage (Lima et al., 2011).

Since iron deficiency is much more prevalent, it has been given much greater attention than iron toxicity (EPA, 1984). There are a lot of data on a great number of iron compounds available for reproductive and developmental toxicity in the scientific literature. Among reliable data, the lowest NOAEL of 200 mg Fe/kg bw was reported in a public report for ferrous sulfate heptahydrate (SIAM, 2007). This value can converted to a corresponding NOAEL for iron glucoheptonate.

Toxicokinetic analysis of Iron Glucoheptonate

Iron glucoheptonate complex with sodium is an odourless, brown solid in microgranulated form (molecular weight of 300.8 (anhydrous) or 354.8 (trihydrate) g/mol) at 20°C. The substance is completely soluble in water (1000 - 1250 g/L at 25°C) and has a negative partition coefficient (logPow = -10.5, KOWWIN v1.68 estimate). The substance has a very low vapour pressure (5.13 x 10E-5 Pa) and has a melting point of 171.4 °C under atmospheric conditions. Its boiling point could not be determined, because of decomposition of the test item at 190 - 240°C. Hydrolysis as a function of pH does not apply, as the substance forms stable complexes.

The stability of iron glucoheptonate complex is higher at alkaline conditions while the complex is expected to be not stable enough at acidic conditions as determined in numerous studies with iron gluconate and other metal –glucoheptonate complexes (please refer to read-across statement). This is because gluconate or glucoheptonate anions are fully protonated at low pH values and are not able to participate in complexation of metal cations (Alekseev et al., 1998). Moreover, lactonisation occurs at low pHs that would hinder complexation (Pallagi et al., 2010). These findings provide evidence that metals dissociate from the complexes at low pH that prevails in the stomach. It would mean that the metal cation originated from the glucoheptonate complexes is subjected to more or less an independent from the organic moiety fate of absorption into the systemic circulation. In small intestines, where pH raises, new complexes with other organic natural chelating agent i.e. from food can be formed, impacting the absorption. Therefore, the existing ADME data on several organic and inorganic iron compounds have been accounted to assess absorption behaviour and further fate of iron cations released from glucoheptonate moiety.

 

Absorption

Oral absorption

Absorption of iron glucoheptonate via gastrointestinal tract can be carried out by the intact iron-glucoheptonate complex and/or its dissociated products: iron and glucoheptonate moiety. In case of absorption of intact complex, physicochemical properties define the absorption behaviour. Oral absorption is favoured for molecules with MW below 500 g/mol. Since the molecular weight of iron glucoheptonate is 300.8 g/mol (anhydrous) or 354.8 g/mol (trihydrate), and it has high water solubility (> 1000 g/L) and the very low logP_owvalue (-10.5), it is expected to be readily absorbed via the gastrointestinal (GI) tract. The complex may be taken up also by passive diffusion through aqueous pores of the gastrointestinal epithelial by the bulk passage of water. However, absorption of very hydrophilic substances by passive diffusion may be limited by the rate at which the substance partitions out of the gastrointestinal fluid.

Since iron is expected to dissociate from the complex at acidic conditions of stomach, it will firstly join non-haem iron pool. The released iron to the physiological mucosal uptake systemis expected to underlie normal physiological pathways responsible for iron uptake and is regulated by the body needs (EPA, 1984). The released free chelator glucoheptonate anion can further sequester luminal or mucosal iron lowering the absorption. According to literature data, absorption of nutritional (especially non-haem) iron is very low. Ferric (Fe3+) food iron is precipitated from solution above pH 3.5 (Heimbach et al., 2000). This insoluble precipitate is poorly absorbed in the small intestines by humans, where non-heme iron is absorbed, unless suitable complexing agents are present (Conrad and Schade, 1968; MacPhail et al., 1981, cited in Heimbach et al., 2000).“The absorption of non-haem iron can be increased substantially by the presence of ligands, such as ascorbate, citrate and fumarate, as well as the presence of amino acids (e.g. cysteine) and oligopeptides resulting from meat digestion (Mulvihill et al, 1998). In contrast, very stable complexes, for example with phytates, phosphates and oxalates, impair non-haem iron absorption. Depending on the concentration of supportive or inhibitory ligands in the intestinal lumen the absorption of non-haem iron can vary by a factor of 10 in single-meal studies, but the effects are less pronounced in more long-term studies (Hallberg and Rossander, 1984; Rossander, 1987; Hunt and Roughead 2000”, cited in EFSA, 2006). Tea polyphenols, vegetable proteins and calcium inhibit iron absorption (IOM, 2001). The rate of iron absorption varies depending on body needs and on the presence of enhancing or inhibiting factors and lies in the range of 1-10 % for non-haem iron (EPA, 1984).

Absorption of haem iron follows another mechanism. It cannot be ruled out that iron from iron glucoheptonate interacts with the absorption mechanisms known for haem iron. Haem iron enters the mucosa via a pathway that is different for non-haem iron and involves interaction of iron with a haem receptor (EFSA, 2006) the same as iron in a porphyrin complex does. It cannot be ruled out that haem-oxygenase, the enzyme that cleaves the porphyrin and liberates iron for transfer into the body (EFSA, 2006), also interacts with the non-dissociated iron-glucoheptonate complex, releasing and taking up iron into systemic circulation. Then it can be assumed that free glucoheptonate would prevent absorption of further dietary non-haem iron in mucosa as described by Zhu et al. (2006).

Intestinal iron absorption is well investigated with EDTA compounds. After ferric sodium EDTA has been ingested, the absorption of iron is regulated through the same physiological mechanisms as other forms of iron (Zhu et al., 2006, Yeung et al., 2005). The total amount absorbed in humans was reported to be 12.0 ± 1.5 % in humans and ca 5 % in swine. Only a very small fraction of the NaFeEDTA complex (less than 1%) is absorbed intact and is rapidly and completely excreted via the kidneys in the urine. In another literature source, intestinal absorption EDTA-FeNa was estimated to be 5 % (Candela et al., 1984, EU Risk Assessment 2004a). Most of the iron absorbed after the ingestion of ferric sodium EDTA is released to the physiological mucosal uptake system before absorption. The iron is released from the complex by the intestinal cells of the duodenum and small intestine in the lumen of the gut, absorbed mainly as ferrous iron (mainly via the DMT-1 pathway) from the pylorus and upper jejunum, transferred to plasma transferrin, joining the general non haem iron pool and will finally be incorporated into the circulating hemoglobin (WHO, 2008) (as such handled systemically as any other source of iron; the safety and maximum tolerable intake of which has been reviewed and evaluated by a number of distinguished scientific committees such as JECFA, WHO, UK EVM, SCF, IOM and EFSA). The total amount of iron in the human body is ca. 4 g. In general 1 mg iron per day will be lost. These losses are replenished via the food intake. A normal diet contains ca. 10 to 15 mg Fe per day. The mucosa cells will only absorb the amount of ferric ions that is needed by the body (Candela et al., 1984, Zhu et al., 2006; WHO, 2008). Iron absorption from EDTA is about twice as high as that observed from ferrous sulfate (FeSO4 * 7H2O) (Heimbach et al., 2000). Based on this data, it can be suspected that iron uptake from other chelate compounds follow the same pathway as uptake from inorganic iron salts.

Ferric sodium EDTA is used in fortification of food to prevent iron deficiency anaemia (Heimbach et al., 2000). In this regard, absorption of ferric sodium EDTA from fortified food was studied in humans and compared to absorption of inorganic iron salts i.e ferrous sulphate or ferrous ascorbate (Layrisse, 1977; Viteri et al., 1978; McPhail et al., 1981, 1984; Ballot et al., 1989). Absorption of iron from ferric sodium EDTA was significantly higher than absorption of ferrous sulphate and was utilized efficiently for haemoglobin synthesis (Martinez et al., 1979; McPhail et al., 1981).

Gastrointestinal absorption of iron of a variety organic acids and salts is well investigated and described in the scientific literature. Oral absorption of iron gluconate, a substance structurally similar to iron glucoheptonate, is reported mostly in respect to its efficiency of iron utilisation such as daily increase in haemoglobin levels or satisfactory reticulocyte responses in anaemic patients (Reznikoff and Goebel, 1937; Khalafallah and Dennis, 2012), in animals (Lysionek et al., 2003) and in fortification studies (Villalpando et al., 2006; ). Bioavailability of iron from ferrous gluconate was 97 % and 89 % for rats and humans, respectively (Hurrel, 2002). Iron gluconate known as Fexin (iron (II) as ferrous gluconate corresponding to 80.5 mg F2+) is an oral drug to treat patients with iron deficiency anaemia states (Antula Healthcare, 2007). Iron glucoheptonate is used also as an oral drug against iron deficiency anaemia (O’Neil et al. 2006, cited in Health Canada on line).

Oral absorption is reported adequate and essentially equal from the following six ferrous salts: sulfate, fumarate, gluconate, succinate, glutamate and lactate (Goodman and Gilmann, 1975). In a study with stabilized ferrous gluconate (SFG) with glycine in rats, the iron bioavailability was calculated as the relationship between the mass of iron incorporated into haemoglobin during the treatment and the total iron intake per animal. This parameter resulted in 36.6 ± 6.2% for SFG, whereas a value of 35.4 ± 8.0% was obtained for ferrous sulfate (Lysionek et al., 2003). Absorption of iron is lower from ferrous citrate, tartrate, pyrophosphate, etc. Reducing agents such as ascorbic acid and some chelating agents such as succinic acid may increase absorption of iron from ferrous sulfates (Goodman and Gilmann, 1975; IOM, 2001).

Based on measured data, 18 percent bioavailability of iron is used to estimate the average requirements of iron for children over the age of 1 year and non-pregnant adults based on mixed diets typically consumed in the US and Canada (IOM, 2001).

Referring to absorption of glucoheptonate moiety via gastrointestinal tract, it is assumed to be similar to other well-investigated structural carbohydrates. Glucoheptonic acid is a carbohydrate and is one of the natural occurring metabolites in plants found in the potato tuber (Roessner et al., 2000), in orange trees (Liu et al., 2015), in avocado (Septon and Richmyer, 1963) and in other plants (Fraser-Reid et al., 2012). Gluconate and its isomerised product glucono-delta-lactone as the most structurally similar analogues are known to be readily absorbed in the small intestines (OECD SIDS, 2004; WHO, 1999). In a study with patients complaining about iron deficiency, iron glucoheptonate administered orally during 45 days was well absorbed and was well tolerated resulting in increased haemoglobin values (Dumont, 1965). On the other hand, other carbohydrates i.e. isomalt, lactitol, lactulose and sucralose are absorbed either only to a limited extent or not absorbed (CIR, 2014).

Based on this information, iron from iron glucoheptonate is expected to be absorbed following a pattern of non-haem iron. Absorption of glucoheptonate moiety is assumed to be similar to that of gluconate. Since toxicity effects are assumed to be driven by iron in case if iron glucoheptonate is ingested, a prediction of its absorption rate is essential for purposes of the hazard assessment of iron glucoheptonate (please refer to read-across statement). 10 % oral absorption would be theoretically appropriate for elemental iron from iron glucoheptonate, while 100 % absorption is appropriate for glucoheptonate moiety. Regarding the intact complex iron glucoheptonate, its physico-chemical characteristics are in the range suggestive of moderate absorption from the gastro-intestinal tract according to ECHA guidance. Thus, taken together, a worst-case value of 100 % will be used for the calculation of hazard values (i.e NOAELs) because no substance-specific information is available on oral absorption in mammalian species for iron glucoheptonate.

Dermal absorption

Based on physico-chemical properties of iron glucoheptonate, the substance is not likely to penetrate skin to a large extent as the substance is not sufficiently lipophilic to cross thestratum corneum(negative logP_owof -10.5 and water solubility of > 1000 g/L). The water solubility above 10,000 mg/L together with the log P value below 0 further indicates that the substance is too hydrophilic to cross the lipid rich environment of thestratum corneum. Dermal uptake of such substances will be low. There is no data on dermal absorption of the dissociation products iron and glucoheptonate ions as well as on structurally similar gluconates. The molecular weight of 300.8 g/mol (anhydrous) or 354.8 g/mol (trihydrate) of iron glucoheptonate indicates a certain potential to penetrate the skin. However, from the molecular structure (dissociating chemical to polar ions), it is suggested that it is unlikely that significant amounts of iron glucoheptonate can be resorbed through intact skin. Low absorption potential of iron ion can be deduced from an acute dermal toxicity study with iron dichloride in rats. No deaths or systemic toxicity effects were observed in animals at 2000 mg/kg bw (LD₅₀> 2000 mg/kg bw; NIER, cited in SIDS, 2004_Iron dichloride)). Moreover, an acute dermal irritation study in the rabbit (according to OECD 404) with iron glucoheptonate did not demonstrate any irritation. There were no signs of systemic adverse effect in any treated rabbits after 14 days (Patel, 2016). Thus, an enhancement of penetration due to damage of the skin can be ruled out. According to ECHA guidance R.7C (2014), 10% of dermal absorption is considered for iron glucoheptonate as a worst case value, due to negative logP_owand the very high water solubility, although realistically any dermal absorption is very unlikely. 

Inhalation absorption

Based on the low vapour pressure of -10.5 (calculated by Epiwin, Dabeer, 2017) of iron glucoheptonate, inhalation exposure via vapour is not likely. Moreover, the final product has a granulated form. The majority of the particles (87.5 %) have a size between 100 and 800 µm. 12.1 % of the particles are smaller than 100 µm but bigger than 40 µm. 0.1 % of the particles are smaller than 40 µm (Dabeer, 2011). Thus, it is very unlikely, that considerable amounts of the substance reach thoracic and alveolar regions of the lung. In cases, if the substance reaches the lung, it is taken up rapidly because of molecular weight of 300.8 g/mol (anhydrous) or 354.8 g/mol (trihydrate). The substance could be absorbed extensively through aqueous pores. Since the substance is a water soluble dust, it is also expected to diffuse/dissolve into the mucus lining the respiratory tract. The negative LogP_owpoints also to a low absorption potential across the respiratory epithelium. Based on this data, a low to moderate systemic availability after inhalation can be predicted. Since 12.1 % of particles are under 100 µm and physico-chemical characteristics of iron glucoheptonate are not in a range suggestive of significant absorption via the respiratory tract, it is very likely that the substance can be absorbed rather by aspiration. As worst-case, 100 % inhalation absorption as default guidance value is appropriate for the dust and other fractions of the microgranulated product.

Distribution and accumulative potential

Since iron dissociates from the glucoheptonate moiety before absorption, their distribution and accumulative potential can follow more or less independent ways.

The absorbed non-haem iron becomes available for binding onto transferrin, and is then transported via transferrin in the plasma to all body cells. Entering cells, iron may be incorporated into functional compounds, stored as ferritin or hemosiderin, or used to regulate future cellular iron metabolism. While all cells are capable of storing iron, the cells of the liver, spleen, and bone marrow are the primary iron storage sites in humans. Almost two-thirds of iron in the body is found in haemoglobin present in circulating erythrocytes. A readily mobilizable iron store contains another 25 percent. Most of the remaining 15 percent is in the myoglobin of muscle tissue and a variety of enzymes necessary for oxidative metabolism and many other functions in all cells (IOM, 2001). Accumulative potential is not a fully appropriate definition in case of iron. Body iron stores are highly conserved, while the body needs determine the extent of intestinal absorption. However, states of iron overload are known that are related either to genetic defects in the mechanisms involved in iron homeostasis, of which the most important is hereditary haemochromatosis, or excessive dietary intake (i.e consumption of ethanol and blood transfusion etc.).

The distribution of glucoheptonate moiety can be assessed using data on absorption of other glucoheptonate compounds, especially those used as radiotracer for imaging tumors. Tc-99m Glucoheptonate (GHA) is used as a renal imaging agent (Arnold et al., 1975; Lee and Blaufox, 1985; Wenzel et al., 1977). In a study investigating distribution of different renal imaging agents, distribution of Tc-99m glucoheptonate was into renal cortex and was similar to that of Tc-labelled gluconate (Arnold et al., 1975; Adler et al., 1976). After ip injection of [99]Tc-Sn-glucoheptonate to mice, the radiopharmaceutical was also distributed predominantly to kidney. The other organs were liver, lungs, blood, spleen and muscle (Wenzel et al., 1977). Kiewiet (1981) measured also glucoheptonate in stomach, intestines, thyroid glands and bone marrow. The renal uptake was between 14-18 % in rats (Kiewiet, 1981), 13 % in rabbits and 21 % in dogs after 1 hour injection (Arnold et al., 1975). In rats with experimental myocardial infarction, Tc-99m glucoheptonate showed significant uptake in myocardial lesions (Adler et al., 1976). Blood and urinary clearance were very fast (Arnold et al., 1975; Adler et al., 1976).Like gluconate, about 50% of the plasma activity of the GHA complex is loosely bound to plasma proteins initially, increasing to about 75% after 6 hr (Arnold et al., 1975).

Tc-99m glucoheptonate has been also used for imaging brain and lung tumors, hypoxia and ischemia (Waxman et al., 1976; Vorne et al., 1982; Vorne et al., 1987; Barai et al., 2004; Ramchandra, 2011).

According to the label on Tc99-glucoheptonate of Anazao Health corporation (2012): “When injected intravenously, Technetium Tc 99m Glucoheptonate is rapidly cleared from the blood. In patients with normal renal function, less than 15% of the initial activity remains in the blood after one hour. About 40% of the injected dose is excreted in the urine in one hour, while about 70% is excreted in 24 hours. In patients with renal disease, the blood clearance and urinary excretion of the radiopharmaceutical are delayed. Up to 15% of the injected dose is retained in the kidneys. The renal retention is greater in the cortex than in the medulla. The radiopharmaceutical may be bound to the proximal convoluted tubules, which are located primarily in the renal cortex. Technetium Tc 99m Glucoheptonate tends to accumulate in intracranial lesions that are associated with excessive neovascularity or an altered blood-brain barrier. The drug does not accumulate in the choroid plexus or salivary glands”.

According to Jaiswal et al. (2009), glucoheptonate has high degree of specificity for neoplastic tissues allowing to differentiate neoplastic lesions from non-neoplastic ones. The uptake mechanism by the cells may be linked to GLUT-1 (Glucose transporter) and GLUT-4 expression that are overexpressed in malignant tissues. Ramchandra (2011) concluded that glucoheptonates behaves as a glucose analogue, actively transported as a source of energy.

Metabolism and excretion

Metabolism of iron is associated with its main function as a component of a number of proteins participating in the transport of oxygen to tissues. It is present in biological systems in one of two oxidation states, and redox interconversions of the ferrous (Fe2+) and ferric (Fe3+) forms are central to the biological properties of this mineral. Iron is an essential constituent of oxygen carriers, such as haemoglobin and myoglobin, and the iron contained within haem is essential for the redox reactions of numerous cytochromes. Biotransformation of iron does by definition not occur: ferric ions (from whatever source in the food) can only be converted into ferrous ions, and back (IOM, 2001; EFSA, 2006).

At normal physiological conditions, only a small quantity of iron is lost each day. Body iron is therefore highly conserved and is regulated by absorption. The majority of absorbed iron is lost in the feces. Daily iron losses from urine, gastrointestinal tract, and skin are approximately 0.08, 0.6, and 0.2 to 0.3 mg/day, respectively. Depending of physiological condition (bleeding, pregnancy, iron overload or iron deficiency) iron losses may vary (IOM, 2001).

Metabolism of glucoheptonate in mammalian tissues is described in several publications dealing with investigations of substrate specificity of a various number of aldonic acids and its isomeric analogues lactones. The enzyme 6-phosphogluconolactonase (catalysing the second step of pentose phosphate pathway (PPP)) was shown to possess a broad substrate specificity hydrolysing gluconolactone moieties including glucoheptonate. The enzyme is present in almost all mammalian tissues including humans. Further investigations revealed that glucoheptonate moiety undergoes a series of biochemical transformations similar to those of PPP. Since glucoheptonic acid is a naturally occurring substance in plants (potato, orange trees, avocado etc.) and a derivative of glucoheptonic acid participates in the biosynthesis of aromatics compounds in plants as part of the shikimic acid pathway, it is involved into intermediary carbohydrate metabolism in mammals (please refer to read-across statement).

Glucoheptonate is mainly excreted via the kidneys (Kiewiet, 1981). About 12% activity remains in the renal cortex for up to 6 h, while most of the injected activity appears in the urine (Ramchandra, 2011). In a subacute toxicity study with Tc-99m glucoheptonate in rats, dogs and rabbits by iv injection, a large proportion of the dose was cleared from the plasma by glomerular filtration and was rapidly excreted (Belbeck et al., 1981). Some of glucoheptonate actively secreted in the bile and intestines (Ramchandra, 2011). Intense biliary excretion of glucoheptonate has been described in patients in the fasting state and in patients with renal insufficiency and with obstruction of the abdominal aorta. Several medications are also known to increase the biliary excretion of glucoheptonate (Siegel et al., 1992).

There are no published studies in the scientific literature on ADME behaviour of glucoheptonate after oral intake. Since Ca glucoheptonate (Ca gluceptate) is routinely used for treatment of hypocalcaemia, the substance is well investigated and therefore no classical toxicity studies were carried out with calcium glucoheptonate in laboratory animals (EMEA, 1998). Therefore, no significant bioaccumulation is expected.

Summary

Iron glucoheptonate is expected to be moderately absorbed after oral exposure, based on its high water solubility and molecular weight suggestive for favoured absorption through gastrointestinal tract. As worst-case, 100 % oral absorption is considered appropriate. Concerning absorption after exposure via inhalation, as the chemical has a low vapour pressure, is highly hydrophilic, has a negative LogPow, and has 12 % of particles less than 100 µm, it is clear, that the substance is poorly available for inhalation and will not be absorbed significantly via lungs. However, an absorption by aspiration cannot be fully ruled out. Therefore, 100% inhalation absorption is considered. Iron glucoheptonate is not expected to be absorbed following dermal exposure into the stratum corneum and into the epidermis, due to its very high water solubility. 10 % absorption is considered. The substance is expected to be distributed predominantly to kidneys and organs with higher expression of glucose transporters. The substance does not indicate a significant potential for accumulation. Iron glucoheptonate is expected to be metabolised by pathways involved into intermediary carbohydrate metabolism or eliminated unchanged via the urine and to a lesser extent via the bile.

 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100