Reaction products of sodium glucoheptonate with manganese sulfate and sodium hydroxide

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

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 MnGHA was performed, taking into account the chemical structure, the available physico-chemical-data and the available toxicity data.

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

according to guideline

Guideline:

OECD Series on Testing and Assessment No. 29 (23-Jul-2001): Guidance document on transformation/dissolution of metals and metal compounds in aqueous media

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Principles of method if other than guideline:

An assessment of toxicological behaviour of MnGHA is based on its physico-chemical properties and on the results of available toxicity data data.

GLP compliance:

no

Type:

absorption

Results:

GI absorption of 100 % and 3-5 % for the chelating agent GHA and free manganese, respectively, are considered. Dermal absorption is very low and absorption via inhalation is confined to the amount deposited in upper airways which can be swallowed.

Type:

distribution

Results:

Distribution of dissociation products absorbed from the gastrointestinal tract is expected to be extensive throughout the body. However, no wide distribution is expected in case of dermal or inhalation exposure.

Type:

excretion

Results:

The released free GHA and manganese are expected to be excreted mainly via the urine or faeces, respectively. Small amounts of manganese can be excreted via the urine. Biliary excretion was also observed for glucoheptonate.

Type:

metabolism

Results:

Glucoheptonate is involved into intermediary carbohydrate metabolism. Mn may undergo changes in oxidation state within the body: from Mn (II) to Mn (III), but the formation of complexes with biomolecules is also possible:bile salts, proteins, nucleotids.

Conclusions:

The substance will be limted absorbed following inhalation exposure due to its very low vapour pressure (12.75 x 10E-5 Pa) and microgranulated form. Dermal absorption is considered to be negligible. In case of oral route of exposure the substance will dissociate under acidic conditions releasing free GHA and manganese, which are expected be readily absorbed, wide distributed and not extensively metabolised in the body. Excretion will be primarily via the faeces and via the urine, in case of manganese and glucoheptonate, respectively.
No bioaccumulation potential is expected.

Executive summary:

Manganese 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 for the complex whereby only limited absorption (5 %) is determined for manganese. Concerning absorption after exposure via inhalation, as the chemical has a low vapour pressure, is highly hydrophilic, has a negative LogPow, and has 11.47 % 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. Manganese 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 and considering low absorption potential of manganese and glucoheptonate moieties. 10 % absorption is therefore considered for dermal route of exposure. The glucoheptonate moieties or as complex with manganese are expected to be distributed predominantly to kidneys and organs with higher expression of glucose transporters. Manganese is distributed predominantly to brain, liver, pancreas, and kidney. The substance does not indicate a significant potential for accumulation. Manganese homeostasis is regulated in mammals by gastrointestinal absorption, excretion via faeces and via the urine as well as by the release from tissues. The total body manganese is maintained constant at the physiologically required levels of manganese in the various tissues at low and high dietary manganese intakes. Manganese, if released from glucoheptonate, is distributed to all organs and tissues and will be bound with organic ligands rather than existing free in solution as a cation. Manganese is excreted mainly via the faeces. Glucoheptonate is involved into intermediary carbohydrate metabolism and eliminated unchanged primarily via the urine and to a lesser extent via the bile.

Description of key information

Manganese 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 for the complex whereby only limited absorption (5 %) is determined for manganese. Concerning absorption after exposure via inhalation, as the chemical has a low vapour pressure, is highly hydrophilic, has a negative LogPow, and has 11.47 % 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. Manganese 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 and considering low absorption potential of manganese and glucoheptonate moieties. 10 % absorption is therefore considered for dermal route of exposure. The glucoheptonate moieties or as complex with manganese are expected to be distributed predominantly to kidneys and organs with higher expression of glucose transporters. Manganese is distributed predominantly to brain, liver, pancreas, and kidney. The substance does not indicate a significant potential for accumulation. Manganese homeostasis is regulated in mammals by gastrointestinal absorption, excretion via faeces and via the urine as well as by the release from tissues. The total body manganese is maintained constant at the physiologically required levels of manganese in the various tissues at low and high dietary manganese intakes. Manganese, if released from glucoheptonate, is distributed to all organs and tissues and will be bound with organic ligands rather than existing free in solution as a cation. Manganese is excreted mainly via the faeces. Glucoheptonate is involved into intermediary carbohydrate metabolism and eliminated unchanged primarily 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

Additional information

General

There are no ADME studies available for manganese 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 manganese glucoheptonate were integrated with the published toxicological data and data on ADME parameters of the structurally related substance manganese gluconate (here named as source substance) to create a prediction of its toxicokinetic behaviour. Additionally, well investigated ADME data on manganese from different sources (food, medications and other inorganic and organic compounds) have been taken into account, because the systemic toxicity of manganese glucoheptonate is considered to be driven by released manganese from the manganese glucoheptonate complex (please refer also to read-across statement).

Toxicological profile of Manganese Glucoheptonate

 

There are a limited number of studies available for toxicological endpoints of manganese glucoheptonate. Manganese glucoheptonate was not irritating to skin and eyes in in vivo irritation studies in rabbits (Patel, 2016a,b). No other toxicological studies are available for the target substance. Its structurally similar substance Manganese gluconate is distributed as food additive and a dietary supplement. No maximum residue limit (MRL) was established for manganese glucoheptonate as pharmacologically active substance in foodstuffs of animal origin (EU Commission Regulation No. 37/2010). There are also no dermal, inhalation and oral studies identified for manganese gluconate. Since manganese glucoheptonate is expected to dissociate under acidic conditions of stomach releasing manganese and glucoheptonate anion, their absorption, distribution, metabolism and excretion in living organism is considered to follow independent ways. More attention has been paid to manganese, since the toxicity effects are considered to be mediated rather by manganese, while no or little toxicity is attributed to glucoheptonate moiety.

 

With regard to glucoheptonate moiety:

 

Glucoheptonate is considered to have low toxicological activity similarly to its structurally related gluconate. Gluconic and glucoheptonic acids can be described as sugar-like naturally occurring polyhydroxy carboxylic acids with similar molecular structure (please refer to read-across statement). Gluconic acid is a metabolite of glucose oxidation (OECD SIDS, 2004a). Glucoheptonic acid 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). It seems that gluconic and glucoheptonic moieties share partially the same metabolic pathways. They are carbohydrates involved into intermediary metabolism by pentose phosphate pathway. Gluconate, glucono-delta lactone and its sodium, potassium, magnesium and calcium salts are practically non-toxic in acute toxicity studies in animals with LD50 ranging between 5600 – 7850 mg/kg bw (SIDS, 2004; WHO, 1999). LD50 of 21,260 and 18,170 mg/kg bw were determined for magnesium glucoheptonate in white mouse and rat, respectively (US patent, 1962).

 

Gluconates are not irritating to skin and eyes, not sensitising to skin and are used in a variety of food, cosmetic and consumer products (SIDS, 2004, CIR, 2014; Regulation (EC) No 1925/2006). In the repeated studies with gluconates, no toxicological effects were 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. Magnesium glucoheptonate did not produce clinical signs and adverse effects in rats in a 30-day feeding study and in rats and no reproductive and developmental toxicity was observed in a study with pregnant rats (US patent, 1962).

 

With regard to manganese:

Regarding manganese toxicity, the most commonly reported adverse health effect in humans are neurologic effects occurring at physiologically excessive amounts of manganese (ATSDR, 2012; SCOEL, 2011). The effects appear to increase in severity as the exposure level or duration of exposure increases. Chronic exposure to manganese at very high levels results in permanent neurological damage, as is seen in former manganese miners and smelters. Chronic exposure to much lower levels of manganese (as with occupational exposures) has been linked to deficits in the ability to perform rapid hand movements and some loss of coordination and balance, along with an increase in reporting mild symptoms such as forgetfulness, anxiety, or insomnia. Results from animal studies indicate that the solubility of inorganic manganese compounds can influence the bioavailability of manganese and subsequent delivery of manganese to critical toxicity targets such as the brain; however, the influence of manganese oxidation state on manganese toxicity is not currently well understood.

In humans, inhalation of particulate manganese compounds such as manganese dioxide or manganese tetroxide can also lead to an inflammatory response in the lung. Symptoms and signs of lung irritation and injury may include cough, bronchitis, pneumonitis, and minor reductions in lung function as well as pneumonia. It is assumed that the increased susceptibility to pneumonia is mainly secondary to the lung irritation and inflammation is a consequence of inhaled particulate matter at all and not the manganese per se that causes the response. Inflammatory responses in the lungs of animals were observed in animal studies as well. Further effects described for workers exposed to manganese were cardiovascular effects such as lower mean systolic and diastolic blood pressure, abnormal electrocardiograms and sudden death mortality.

In case of oral exposure, most studies in animals indicate that manganese compounds have low acute oral toxicity when provided in feed. Nephropathy and renal failure were common effects observed in treated animals. No systemic toxic effects in humans who have ingested manganese are described. This is likely due to the strong homeostatic control the body exerts on the amount of manganese absorbed following oral exposure; this control protects the body from the toxic effects of excess manganese. Studies in humans and animals provide limited data regarding the effects of manganese ingestion on systemic target tissues.

For healthy adults, estimated acceptable or adequate dietary intakes range from 1–12.2 mg manganese/day (SCOEL, 2011). A guidance value of 0.16 mg manganese/kg/day, based on the Tolerable Upper Intake Level for 70 kg adults of 11 mg manganese/day is recommended for public health risk assessment (ATSDR, 2012). For inhalation exposure, respirable Indicative Occupational Exposure Limit Value (IOELV) of 0.05 mg/m³ and an inhalable IOELV of 0.2 mg/m³ are recommended and neither respiratory nor cardiovascular toxicity would be expected at inhalable exposures of 1 mg/m³ or less (SCOEL, 2011).

Manganese and MnCl₂were negative in the local lymph node assay (LLNA) (Basketter et al. 1999, 1992 , Ikarashi, 1992). The results of in vitro genetic toxicity studies show that at least some chemical forms of manganese have mutagenic potential. However, as the results of in vivo studies in mammals are inconsistent, no overall conclusion can be made about the possible genotoxic hazard to humans from exposure to manganese compounds. Data on carcinogenicity, mutagenicity and genotoxicity are inconclusive and inadequate to establish a definitive position on the carcinogenicity of manganese and its compounds (SCOEL, 2011). As overall conclusion of SCOEL (2011) is that reproductive toxicity profile for manganese and its compounds does not suggest that this aspect is key to an evaluation of occupational exposure standards (IEH 2004, cited in SCOEL, 2011). There is mentioned that there is little evidence for reproductive or developmental toxicity of manganese compounds.

 

Toxicokinetic analysis of Manganese Glucoheptonate

Manganese glucoheptonate complex is an odourless, brown solid in microgranulated form (molecular weight of 317.14 g/mol (monomer Mn:GHA as 1:1) or 598.28 g/mol (dimer) (most representative structure at pH 6-7) at 20°C. The substance is completely soluble in water (1000 - 1250 g/L at 20°C) and has a negative partition coefficient (logPow = -15.5, KOWWIN v1.68 estimate). The substance has a very low vapour pressure (12.75 x 10E-5 Pa) and has a melting point of 190.48 °C and a glas transition temperature is 63.55 °C under atmospheric conditions. The boiling point could not be determined because the substance turned to viscous paste and spilled out from the sample tube. Hydrolysis as a function of pH does not apply, as the substance forms stable complexes that do not hydrolyse.Therefore, chelate stability is more applicable instead.

The stability of manganese 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 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. Therefore, the absorption of the metal cation originated from the glucoheptonate complexes is more or less independent from the organic moiety. 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 manganese compounds are taken into account to assess absorption behaviour and further fate of manganese cations released from glucoheptonate moiety.

Absorption

Oral absorption

Absorption of manganese glucoheptonate via gastrointestinal tract can be carried out by the intact manganese-glucoheptonate complex and/or its dissociated products: manganese 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 manganese glucoheptonate is 598.28 (dimer) (most representative structure at pH 6-7) 317.14 (monomer) and it has high water solubility (> 1000 g/L) and the very low logP_owvalue , 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 manganese is expected to dissociate from the complex at acidic conditions of the stomach, it will follow an independent way of absorption, which is regulated by the body needs. Manganese is required by the body and is found in virtually all diets (ATSDR, 2012). Adult humans generally maintain stable tissue levels of manganese through the regulation of gastrointestinal absorption and hepatobiliary excretion. The amount of manganese absorbed across the gastrointestinal tract in humans is variable, but typically averages about 3–5 % (SCOEL, 2011). The absorption is expected to be higher for soluble forms of manganese compared with relatively insoluble forms of manganese. The absorption of manganese from the gut is dependent on several factors, including the amount ingested, iron status and other dietary components. There is very tight biological regulation of the gastro-intestinal absorption of manganese which is not the case for inhalation exposure (ATSDR, 2012).

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). Absorption of glucoheptonate moiety via gastrointestinal tract is considered to be similar to gluconate moiety. Ca gluconante was extensively absorbed in animals and in humans (WHO, 1999). 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, manganese from manganese glucoheptonate is expected to be absorbed following an independent pattern typical for soluble manganese compounds. Absorption of glucoheptonate moiety is assumed to be similar to that of gluconate. Since toxicity effects are assumed to be driven manganese in case if manganese glucoheptonate is ingested, a prediction of its absorption rate is essential for purposes of the hazard assessment of manganese glucoheptonate (please refer to read-across statement). Based on human data, 5 % oral absorption is theoretically appropriate for elemental manganese from manganese glucoheptonate, while 100 % absorption is appropriate for glucoheptonate moiety. Regarding the intact complex manganese glucoheptonate, its physico-chemical characteristics that 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 (DNELs), if required, by route-to route extrapolation, because no substance-specific data is available on oral absorption in mammalian species for manganese glucoheptonate.

Dermal absorption

Based on physico-chemical properties of manganese glucoheptonate, the substance is not likely to penetrate the skin to a large extent as the substance is not sufficiently lipophilic to cross the stratum corneum (negative logPow of -15.5 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 the stratum corneum. Dermal uptake of such substances will be low. In case, if certain amounts of manganese glucoheptonate dissociate in the moisture of skin, only negligible amounts of manganese will be available for systemic absorption. Studies regarding the absorption of manganese through the skin are very limited. No studies on acute dermal hazard are available for manganese cation (ATSDR 2012). 

There is no experimental data available on dermal absorption of the glucoheptonate ions, as well as on structurally similar gluconates. The molecular weight of 317.14 g/mol (monomer) and 598.28 g/mol (dimer) 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 manganese glucoheptonate can be resorbed through intact skin. Manganese glucoheptonate is not irritating to skin and is considered to be not sensitising to skin (Patel, 2016; Basketter et al., 1999; Ikarashi et al., 1992). 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 manganese glucoheptonate, due to negative logPow and the very high water solubility.

Absorption by inhalation

Based on the low vapour pressure (12.75 x 10E-5 Pa) of manganese glucoheptonate, inhalation exposure to vapours is not likely. There are 11.47 % of the particles smaller than 100 µm but bigger than 71 µm. There are no particles smaller than 71 µm (USP method). Thus, it is very unlikely, that big amounts of the substance reach the lung. In case of dust formation, it is expected that 100 % of the inhaled substance will be deposited in the upper respiratory tract, where the particles may be moved by mucociliary transport to the throat and where the substance is swallowed and, conclusively, enters the stomach. The particles are not expected to reach alveolar region. If the substance reaches the lung, it is not very likely that the substance is taken up rapidly (based on physical-chemical properties). The substance is expected to be predominantly in chelated form since pH of healthy lungs is between 7.38 and 7.43 (Effros and Chinard, 1969). In case of a negligible fraction of released manganese ions, the respirable manganese will be readily taken up (ATSDR, 2012). It is mainly absorbed into blood and lymph fluids, while manganese from larger particles or nano-sized particles deposited in the nasal mucosa may be directly transported to the brain via olfactory or trigeminal nerves. There is experimental evidence of olfactory uptake of manganese to the brain. The toxicological significance of this olfactory uptake to humans remains uncertain (ATSDR, 2012).

In an acute inhalation study, Mn(2Na)EDTA was absorbed by lungs of rats as confirmed by clinical signs and findings at necropsy (Jonker and van Triel, 2012). The substance was inhaled in form of aerosol (particles of 3.2 – 3.3 µm). The 4-h LC50 value exceeded 5.16 g/m³. Thus, this result indicates low systemic availability after inhalation and, if bioavailable, low toxicity effects via this route of administration. Moreover, if manganese glucoheptonate was tested in a similar acute inhalation study, no particles of ca. 3 µm is present, therefore the toxicity potential would be expected even lower.

Based on this information, the absorption by inhalation is expected to confine to the amount of manganese glucoheptonate deposited in upper airways which can be swallowed. Therefore, as worst case, 100 % absorption by inhalation (similar with oral absorption) is considered appropriate for the purposes of hazard assessment (DNEL derivation).

Distribution and accumulative potential

Since manganese can dissociate from the glucoheptonate moiety before absorption, their distribution and accumulative potential can follow more or less independent ways. When reaching the body, manganese glucoheptonate is expected to be readily available for distribution. Glucoheptonate moiety absorbed into the body, will most likely exist only in the intravascular compartment (due to its high water solubility) and will not be distributed directly into the cells, as the cell membranes require a substance to be soluble also in lipids to be taken up. This indicates a wide distribution potential and no accumulative potential. Manganese is expected to be widely distributed throughout the body.

Distribution and accumulation of glucoheptonate

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 the kidneys. 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 is also used 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 a 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.

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.

 

Distribution and accumulation of manganese

In case of dissociated fraction of manganese glucoheptonate, absorbed manganese ions will be widely distributed throughout the body (ATSDR, 2012). Manganese is a normal component of human and animal tissues and fluids. Adult humans normally maintain stable tissue levels of manganese regardless of intake; this homeostasis is maintained by regulated absorption and excretion (ATSDR, 2012). In humans, following inhalation exposure, manganese can be transported into olfactory or trigeminal presynaptic nerve endings in the nasal mucosa with subsequent delivery to the brain, across pulmonary epithelial linings into blood or lymph fluids, or across gastrointestinal epithelial linings into the blood after mucociliary elevator clearance from the respiratory tract (ATSDR, 2012). Manganese is found in the brain and all other mammalian tissues, with some tissues showing higher accumulations of manganese than others. For example, liver, pancreas, and kidney usually have higher manganese concentrations than other tissues. The lowest levels were in bone and fat. Following oral exposure, manganese preferentially accumulates in brain but to a lesser extent than after inhalation exposure (ATSDR, 2012).

Metabolism and excretion

Metabolism and excretion of manganese and glucoheptonate are considered to follow their independent pathways.

Regarding the released manganese, limited data suggest that it may undergo changes in oxidation state within the body (ATSDR, 2012). Probably, it is converted from Mn (II) to Mn (III), but the formation of complexes between Mn (II) and biomolecules is also possible (bile salts, proteins, nucleotids, etc., ATSDR, 2012). Absorbed manganese is removed from the blood by the liver where it conjugates with bile and is excreted into the intestine with following excretion predominantly via the faeces. However, some of the manganese in the intestine is reabsorbed through enterohepatic circulation. Small amounts of manganese can also be found in urine, sweat, and milk. Absorbed manganese is eliminated with a half-life of 10 to 30 days (SCOEL, 2011) whereby it is dependent on route of exposure. In humans who inhaled manganese chloride or manganese tetroxide, about 60 % of the material originally deposited in the lung was excreted in the faeces within 4 days, while humans who ingested tracer levels of radioactive manganese (usually as manganese chloride) excreted the manganese with whole-body retention half-times of 13–37 days (ATSDR, 2012). Manganese that is delivered to the brain is eliminated over time with reported half-life of 50 to 220 days (SCOEL, 2011). It is important to recognise that accumulation and clearance of manganese from the brain might have important implications for neurofunctional effects which are reported in a number of occupational studies (SCOEL, 2011).

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 is 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).