Registration Dossier

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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
other: Expert statement
Adequacy of study:
key study
Study period:
2010-04-23
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
other: Expert statement
Title:
Unnamed
Year:
2010
Report date:
2010

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Expert statement
GLP compliance:
no

Test material

Radiolabelling:
no

Test animals

Species:
other: not applicable; no animal testing
Strain:
other: not applicable; no animal testing
Sex:
not specified
Details on test animals or test system and environmental conditions:
No test animals, expert statement;

Administration / exposure

Route of administration:
other: not applicable; no animal testing
Vehicle:
other: not applicable; no animal testing
Details on exposure:
no animal testing; expert statement
Duration and frequency of treatment / exposure:
no animal testing; expert statement
Doses / concentrations
Remarks:
no animal testing; expert statement
No. of animals per sex per dose / concentration:
no animal testing; expert statement
Control animals:
other: No test animals, expert statement
Positive control reference chemical:
no animal testing; expert statement
Details on study design:
no animal testing; expert statement
Details on dosing and sampling:
no animal testing; expert statement
Statistics:
no animal testing; expert statement

Results and discussion

Preliminary studies:
No animal testing performed

Toxicokinetic / pharmacokinetic studies

Details on absorption:
When persulfate salts are dissolved in water, they dissociate and eventually form K+, Na+, NH4+, SO42- and persulfate dianion. The dissociation products K+, Na+ and SO42- are not further degraded chemically or biologically. All ions are physiologically essential to organisms. The ammonium ion, NH4+, is anticipated to either be excreted or incorporated into the nitrogen pool of organisms.
Based on the dissociation behaviour of the substances of the Persulfate Category upon contact with water, the evaluation on toxicokinetic analysis focuses on the persulfate anion and sulfate as well as respective cations, K+, Na+, and NH4+.
Details on distribution in tissues:
Based on the dissociation behaviour of the substances of the Persulfate Category upon contact with water, the evaluation on toxicokinetic analysis focuses on the persulfate anion and sulfate as well as respective cations, K+, Na+, and NH4+.
Details on excretion:
Based on the dissociation behaviour of the substances of the Persulfate Category upon contact with water, the evaluation on toxicokinetic analysis focuses on the persulfate anion and sulfate as well as respective cations, K+, Na+, and NH4+.

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
When persulfate salts are dissolved in water, they dissociate and eventually form K+, Na+, NH4+, SO42- and persulfate dianion. The dissociation products K+, Na+ and SO42- are not further degraded chemically or biologically. All ions are physiologically essential to organisms. The ammonium ion, NH4+, is anticipated to either be excreted or incorporated into the nitrogen pool of organisms.
Based on the dissociation behaviour of the substances of the Persulfate Category upon contact with water, the evaluation on toxicokinetic analysis focuses on the persulfate anion and sulfate as well as respective cations, K+, Na+, and NH4+.

Applicant's summary and conclusion

Conclusions:
Toxicokinetic Analysis of Substances of the Persulfate Category
Persulfates are inorganic salts with molecular weights of 228.20 g/mol (ammonium persulfate), 270.30 g/mol (potassium persulfate) and 238.10 g/mol (sodium persulfate). They decompose on heating without a definite melting point at temperatures above 100 °C. Boiling points were not available, as the persulfates decompose at temperatures above 100 °C. Persulfates are easily water soluble: 559 g/L at 25 °C (ammonium persulfate), 60 g/L at 25 °C (potassium persulfate) and 730 g/L at 25 °C (sodium persulfate). The vapour pressures were estimated to be in the range of <1.76E-21 Pa and <8.09E-28 Pa at 25 °C. Partition coefficients were not determined, as persulfates are inorganic compounds.
Due to their properties as inorganic salts and considering their low vapour pressures, an exposure via inhalation is not very likely. As shown in inhalation toxicity studies, no systemic effects occurred (worst-case Persulfate Category LD50 acute, inhalation value of 2950 mg/m³).
Absorption by the skin is also not very likely. Generally, salts largely do not penetrate the skin. This was confirmed in skin toxicity studies with no systemic effects detected and primary local effects revealed (worst case Persulfate Category LD50 acute, dermal value of >2000 mg/kg).
Following oral administration persulfate salts will hydrolyse in the acid environment of the stomach. Toxicity is primarily characterised by local irritation. All systemic toxicity effects observed were secondary nature. The worst case Persulfate Category LD50 acute, oral was 700 mg/kg bw.
There are no toxicokinetic, metabolism or distribution studies available to substances of the Persulfate Category.
Persulfate salts rapidly hydrolyse upon contact with water or water vapour. As a consequence thereof, persulfates will rapidly degrade and will eventually form the corresponding cations (ammonium, potassium, sodium) and persulfate anions. The persulfate anion, independent of the cation, undergoes further decomposition upon contact with water to form sulfate species. Based on these fundamental properties of persulfates, they are not likely to become bioavailable, neither by inhalation, ingestion, or contact by skin.
Toxicokinetics and dynamics will be influenced mainly by the persulfate anion. The dissociation products K+, Na+ are not further degraded. All ions are physiologically essential to organisms. The ammonium ion, NH4+, is anticipated to either be excreted or incorporated into the nitrogen pool of organisms. The persulfate anion further oxidises water to generate reactive oxygen species (hydrogen peroxide) and sulfate ion radicals. A decrease in pH would be expected from the hydrolysis of the persulfate moiety, but systemic effects would be inconsequential in the presence of physiologic buffer systems. Hydrogen peroxide, if formed, would be rapidly metabolised to oxygen and water by catalase and peroxidase enzymes. Although catalase and glutathione peroxidise enzymes are intracellular, hydrogen peroxide can readily penetrate biological membranes at a level comparable to that of water. Extracellular hydrogen peroxide is rapidly decomposed by mammalian tissues. There is practically no potential for bioaccumulation.
Based on the dissociation behaviour of persulfates upon contact with water, the toxicokinetic analysis focuses on the persulfate anion and sulfate as well as relevant cations, K+, Na+, and NH4+.
1. Potassium
The kinetic behaviour of potassium, including absorption, distribution, and excretion, is summarised in the following:
Absorption:
Following oral intake, the normal level of enteral absorption of potassium is in the range of 85 – 90 %.
Distribution:
The concentration of potassium in plasma is tightly regulated within a narrow range of about 3.5 to 5 mmol/L. The body is able to accommodate a high intake of potassium, without any substantial change in plasma concentration by synchronized alterations in both renal and extra-renal handling, with potassium either excreted in the urine or taken up into cells.
Extracellular potassium, which constitutes around 2 % of the body pool, is important for regulating the membrane potential of the cells, and thereby for nerve and muscle function, blood pressure regulation etc. Potassium also participates in the acid-base balance. The major part of the potassium in the body (98 %) is found in the cells where it is the main intracellular cation. Thus intracellular concentrations are substantially greater than extracellular concentrations. A large proportion of the body pool of potassium is found in muscle and the skeleton, and it is also present in high concentrations in the blood, central nervous system, intestine, liver, lung and skin.
Excretion:
The major excretory route of potassium is via the kidneys. Excretion in sweat and faeces is negligible.
Most of the potassium which is filtered in the glomerulus is reabsorbed in the proximal tubule and loop of Henle. Regulated excretion is determined by the rate at which potassium is secreted in the distal tubule and collecting ducts. For the normal unadapted kidney, the maximum excretion rate following an oral dose of 8 g potassium chloride (4.2 g potassium) was up to 130μmol potassium/minute (5 mg potassium/minute). If sustained this would be equivalent to excreting 7.3 g K+/day (188 mmol/day). On a normal diet a glomerular filtration rate (GFR) below 10 mL/min is rate limiting for potassium secretion if the urine output is less than 600 mL/day. However, balance can be maintained with intakes up to 5 to 10 mmol potassium/kg body weight/day (195 - 390 mg/kg body weight /day), as renal excretion through a healthy kidney which is adapted to high intakes of potassium can effectively excrete potassium at 10 to 20 times the rate of a kidney which has not been adapted to a high intake.
Evaluated on the basis of human experience, it was concluded that the risk of adverse effects from potassium intake from food sources (up to 5 - 6 g/day for adults) is considered to be low for the generally healthy population and long-term intake of doses of up to 3 g potassium per day have been shown not cause adverse effects (characterised by elevated plasma potassium or gastrointestinal symptoms) in healthy adults. Due to the polar nature and the low molecular weight, potassium is widely distributed in the organism without demonstrating a potential for bioaccumulation in view of its ionic character. In this context it should be noted that potassium is a physiologically essential nutrient involved in fluid, acid and electrolyte balance and is required for normal cellular function.
2. Sodium
Sodium ions are a normal and essential component of the human body, playing a key role in controlling and maintaining the proper osmolarity (concentration) and volume of extracellular body fluids. Both the body content of sodium and its concentration in body fluids are under homeostatic control. In addition to its role in regulating osmolarity and extracellular fluid volume, sodium is important in the regulation of acid-base balance and the membrane potential of cells. As a consequence of these vital functions, the absorption, distribution, and excretion of sodium ion has been extensively studied in both animals and humans. A brief summary of the most important aspects of sodium toxicokinetics is presented below.
Absorption:
Virtually all (99 %) of the sodium ion ingested in food and water is rapidly absorbed from the gastrointestinal tract (Stipanuk, 2000). Sodium crosses the brush border epithelial membrane of the intestine through sodium channels or by carried-mediated diffusion down an electrochemical gradient. During facilitated transport, sodium can carry chloride ion, glucose, amino acids, and other nutrients into the intestinal epithelial cells. Once sodium is in the cytosol of the brush border epithelial cell, it is actively transported into the blood by the Na+/K+-ATPase pump located in the basal and lateral membrane of the epithelial cell (Stipanuk, 2000).
Distribution:
Once absorbed, the sodium ion is rapidly distributed throughout the body. The concentration of sodium in blood and other extracellular fluids is about 145 mM (3,335 mg/L), whereas the concentration of sodium ion inside cells is about 12 mM (276 mg/L) (Stipanuk 2000). This unequal distribution of sodium between extracellular and intracellular compartments is essential to the normal functioning of all cells and tissues of the body.
Metabolism:
Sodium ion is not reactive and does not undergo any metabolic reactions in the traditional sense (i.e., it is not transformed by enzymic or non-enzymic mechanisms into any altered forms). Sodium does function as a counterion for macromolecules such as DNA, RNAs, proteins, and sulfated polysaccharides that carry a net negative change, and thus, concentrations can be enriched in the microenvironment surrounding macroion surfaces (Stipanuk, 2000).
Excretion:
Sodium is excreted mainly in the urine, although some sodium loss occurs with fecal matter and in perspiration. The kidney, nervous system, and endocrine system maintain very precise control of renal sodium excretion, with approximately 95 % to 98 % of the sodium being reabsorbed in the kidney (Stipanuk, 2000). In the proximal tubule of the kidney, sodium resorption is coupled with organic solutes and anions and protons. Entry into the proximal tubule epithelium is mediated by symporter (e.g., Na+-glucose, Na+-PO43-, Na+-lactate, and Na+-amino acid symporters) and antiporter (Na+-H+antiporter) proteins located on the apical membrane of the proximal tubule. When sodium enters the cytoplasm of the proximal tubule, it is actively transported into the blood by the Na+/K+-ATPase pump. Similar sodium resorption mechanisms occur in the loop of Henle and distal tubule.
In response to blood volume depletion (i.e., decreased blood pressure), the sympathetic nervous system stimulates sodium resorption. Hormonal control of sodium resorption is dependent on renal blood flow and nervous system stimulation. Decreased renal pressure in the renal arterioles, as well as sympathetic nervous system stimulation, results in the kidney’s production of renin. Renin cleaves circulating angiotensinogen to form angiotensin I, which is converted to angiotensin II by angiotensin-converting enzyme (ACE), an enzyme that is widely distributed in the body. Angiotensin II stimulates the adrenal gland to synthesize aldosterone, which binds to receptors in the cytoplasm of principal cells located in the collecting tubules of the kidney, and stimulates activity of the apical sodium channel and basal Na+/K+-ATPase pump. In response to increased blood and renal pressure, sympathetic nervous system stimulation and aldosterone synthesis decrease and sodium excretion increases. Of the approximately 25,200 mEq of sodium filtered through the kidneys each day, 150 mEq is excreted (Berne and Levy, 1993; Stipanuk, 2000).
3. Ammonium
Uptake:
NH4+ is anticipated to be either excreted in the urine or incorporated into the nitrogen pool of the organism.
Distribution:
In the body incorporation into polymeric nitrogen containing compounds proteins and nucleic acids occurs. Operation and mechanism of metabolic pathways is provided by proteins.
Metabolism:
Each of the monomer of these macromolecules incorporating nitrogen has an individual metabolic pathway. In addition, the monomeric nucleotides are essential for energy turnover as key intermediates in all metabolic pathways and also as second messenger molecules, often in form of cyclic nucleotides.
Amino acids contribute to carbohydrate synthesis via gluconeogenesis, to fat synthesis or energy production via acetyl-CoA, and special nitrogen compounds such as catecholamines (neurotransmitters), thyroid hormones, creatine(-phosphate), the protoporphyrin ring (heme), and contribute to nucleic acid and phospholipid synthesis as nitrogen group donor.
Excretion:
NH4+ excretion is controlled by the kidney and controls the blood plasma pH. The blood plasma pH, however, is determined by other factors as well, such as organic acids (amino acids) and carbonic acid (CO2 levels). Ammonium metabolism in kidney functions to depose H+ in urine. In a first reaction, kidney enzymes deaminate glutamine in two steps to a-ketoglutarate. The first side chain deamination is catalysed as simple hydrolysis and is not reversible.
This process is stimulated by inorganic phosphate. The free ammonia equilibrates with protons to ammonium:
NH3 + H+ = NH4+
and is trapped in the charged form inside kidney cells. The non-electrolytic ammonia is freely diffusible across cell membranes. Glutamine is the nontoxic form of NH3 and shuttles it between liver and kidney in the blood plasma. The kidney functions as H+ sink and protons are disposed in form of NH4+ while maintaining charge homeostasis using phosphate or acetoacetate.
4. Sulfate
The relevant chemical entity formed upon degradation and dissociation of persulfate dianion is the sulfate ion.
Absorption:
Following oral ingestion of a dose of magnesium sulfate (13.9 g), about one third of an orally administered dose expressed as sulfate were found to be absorbed in humans. In general, however, sulfate ion is poorly absorbed from the gastro-intestinal tract especially when administered in large doses such that the capacity of specialised transport processes for this ion in the intestines is exceeded.
Distribution:
Inorganic sulfate (SO42−) is required for the synthesis of 3′-phosphoadenosine-5′-phosphosulfate (PAPS). PAPS is required for synthesis of many important sulfur-containing compounds, such as chondroitin sulfate and cerebroside sulfate. While significant levels of sulfate are found in foods and various sources of drinking water, the major source of inorganic sulfate for humans is from biodegradation due to body protein turnover of the sulfur amino acids methionine and cysteine. Dietary sulfate in food and water, together with sulfate derived from methionine and cysteine found in dietary protein and the cysteine component of glutathione, provides sulfate for use in PAPS biosynthesis (The National Academies Press, 2004).
Excretion:
Inorganic sulfate is eliminated from the body almost entirely by renal excretion (i.e. without biotransformation) so that measurement of urinary excretion rates constitutes a direct method for determining the bioavailability of orally administered sulfate. Investigations in humans demonstrated that an average of 30.2 % of the administered dose corrected for endogenous sulfate excretions was eliminated during the subsequent 24–hour period after ingestion.
5. Persulfate dianion
The chemistry of the persulfate dianion is dependent on different pH-ranges:
1) Neutral (pH 3 to 7):
S2O82-+ H2O --> 2 HSO4- + 1/2O2;
2) Dilute acid (pH > 0.3; [H+] < 0.5 M):
S2O82-+ 2 H2O --> 2 HSO4-+ H2O2;
3) Strong acid ([H+] > 0.5 M):
S2O82-+ H2O + H+ --> HSO4- + HSO5-;
4) Alkaline (pH > 13):
S2O82- + OH- --> HSO4- + SO42- + 1/2 O2;
In the physiological range, i.e. in the pH range of 3 to 7, the reaction according to 1) was assumed as the preferred way of reaction of the persulfate dianion.
The reaction steps, as described in 2) to 4), may include formation of sulfate dianion SO4-2, hydrogen ion, H+ and molecular oxygen O2. As shown in Sect. 4, the sulfate dianion will not contribute to toxic effects of the persulfate dianion. A decrease in pH would be expected from the hydrolysis of the persulfate moiety, but systemic effects would be inconsequential in the presence of physiologic buffer systems.
Under certain circumstances, hydrolysis of the persulfate anion will yield the bisulfate anion and hydrogen peroxide.
Conclusion
The substances of the Persulfate Category rapidly hydrolyse upon contact with water. The substances degrade and will eventually form the corresponding cations (ammonium, potassium, sodium) and persulfate anions. The persulfate anion, independent of the cation, undergoes further decomposition upon contact with water to form sulfate species. Based on these fundamental properties of persulfates, they are not likely to become bioavailable, neither by inhalation, ingestion, or contact by skin. All degradation products are physiologically essential to organisms. Bioaccumulation is unlikely in view of the rapid degradation and high water solubility.
Executive summary:

Toxicokinetic Analysis of Substances of the Persulfate Category

Persulfates are inorganic salts with molecular weights of 228.20 g/mol (ammonium persulfate), 270.30 g/mol (potassium persulfate) and 238.10 g/mol (sodium persulfate). They decompose on heating without a definite melting point at temperatures above 100 °C. Boiling points were not available, as the persulfates decompose at temperatures above 100 °C. Persulfates are easily water soluble: 559 g/L at 25 °C (ammonium persulfate), 60 g/L at 25 °C (potassium persulfate) and 730 g/L at 25 °C (sodium persulfate). The vapour pressures were estimated to be in the range of <1.76E-21 Pa and <8.09E-28 Pa at 25 °C. Partition coefficients were not determined, as persulfates are inorganic compounds.

Due to their properties as inorganic salts and considering their low vapour pressures, an exposure via inhalation is not very likely. As shown in inhalation toxicity studies, no systemic effects occurred (worst-case Persulfate Category LD50 acute, inhalation value of 2950 mg/m³).

Absorption by the skin is also not very likely. Generally, salts largely do not penetrate the skin. This was confirmed in skin toxicity studies with no systemic effects detected and primary local effects revealed (worst case Persulfate Category LD50 acute, dermal value of > 2000 mg/kg).

Following oral administration persulfate salts will hydrolyse in the acid environment of the stomach. Toxicity is primarily characterised by local irritation. All systemic toxicity effects observed were secondary nature. The worst case Persulfate Category LD50 acute, oral was 700 mg/kg bw.

There are no toxicokinetic, metabolism or distribution studies available to substances of the Persulfate Category.

Persulfate salts rapidly hydrolyse upon contact with water or water vapour. As a consequence thereof, persulfates will rapidly degrade and will eventually form the corresponding cations (ammonium, potassium, sodium) and persulfate anions. The persulfate anion, independent of the cation, undergoes further decomposition upon contact with water to form sulfate species. Based on these fundamental properties of persulfates, they are not likely to become bioavailable, neither by inhalation, ingestion, or contact by skin.

Toxicokinetics and dynamics will be influenced mainly by the persulfate anion. The dissociation products K+, Na+ are not further degraded. All ions are physiologically essential to organisms. The ammonium ion, NH4+, is anticipated to either be excreted or incorporated into the nitrogen pool of organisms. The persulfate anion further oxidises water to generate reactive oxygen species (hydrogen peroxide) and sulfate ion radicals. A decrease in pH would be expected from the hydrolysis of the persulfate moiety, but systemic effects would be inconsequential in the presence of physiologic buffer systems. Hydrogen peroxide, if formed, would be rapidly metabolised to oxygen and water by catalase and peroxidase enzymes. Although catalase and glutathione peroxidise enzymes are intracellular, hydrogen peroxide can readily penetrate biological membranes at a level comparable to that of water. Extracellular hydrogen peroxide is rapidly decomposed by mammalian tissues. There is practically no potential for bioaccumulation.

Based on the dissociation behaviour of persulfates upon contact with water, the toxicokinetic analysis focuses on the persulfate anion and sulfate as well as relevant cations, K+, Na+, and NH4+.

1. Potassium

The kinetic behaviour of potassium, including absorption, distribution, and excretion, is summarised in the following:

Absorption:

Following oral intake, the normal level of enteral absorption of potassium is in the range of 85 – 90 %.

Distribution:

The concentration of potassium in plasma is tightly regulated within a narrow range of about 3.5 to 5 mmol/L. The body is able to accommodate a high intake of potassium, without any substantial change in plasma concentration by synchronized alterations in both renal and extra-renal handling, with potassium either excreted in the urine or taken up into cells.

Extracellular potassium, which constitutes around 2 % of the body pool, is important for regulating the membrane potential of the cells, and thereby for nerve and muscle function, blood pressure regulation etc. Potassium also participates in the acid-base balance. The major part of the potassium in the body (98 %) is found in the cells where it is the main intracellular cation. Thus intracellular concentrations are substantially greater than extracellular concentrations. A large proportion of the body pool of potassium is found in muscle and the skeleton, and it is also present in high concentrations in the blood, central nervous system, intestine, liver, lung and skin.

Excretion:

The major excretory route of potassium is via the kidneys. Excretion in sweat and faeces is negligible.

Most of the potassium which is filtered in the glomerulus is reabsorbed in the proximal tubule and loop of Henle. Regulated excretion is determined by the rate at which potassium is secreted in the distal tubule and collecting ducts. For the normal unadapted kidney, the maximum excretion rate following an oral dose of 8 g potassium chloride (4.2 g potassium) was up to 130μmol potassium/minute (5 mg potassium/minute). If sustained this would be equivalent to excreting 7.3 g K+/day (188 mmol/day). On a normal diet a glomerular filtration rate (GFR) below 10 mL/min is rate limiting for potassium secretion if the urine output is less than 600 mL/day. However, balance can be maintained with intakes up to 5 to 10 mmol potassium/kg body weight/day (195 - 390 mg/kg body weight /day), as renal excretion through a healthy kidney which is adapted to high intakes of potassium can effectively excrete potassium at 10 to 20 times the rate of a kidney which has not been adapted to a high intake.

Evaluated on the basis of human experience, it was concluded that the risk of adverse effects from potassium intake from food sources (up to 5 - 6 g/day for adults) is considered to be low for the generally healthy population and long-term intake of doses of up to 3 g potassium per day have been shown not cause adverse effects (characterised by elevated plasma potassium or gastrointestinal symptoms) in healthy adults. Due to the polar nature and the low molecular weight, potassium is widely distributed in the organism without demonstrating a potential for bioaccumulation in view of its ionic character. In this context it should be noted that potassium is a physiologically essential nutrient involved in fluid, acid and electrolyte balance and is required for normal cellular function.

2. Sodium

Sodium ions are a normal and essential component of the human body, playing a key role in controlling and maintaining the proper osmolarity (concentration) and volume of extracellular body fluids. Both the body content of sodium and its concentration in body fluids are under homeostatic control. In addition to its role in regulating osmolarity and extracellular fluid volume, sodium is important in the regulation of acid-base balance and the membrane potential of cells. As a consequence of these vital functions, the absorption, distribution, and excretion of sodium ion has been extensively studied in both animals and humans. A brief summary of the most important aspects of sodium toxicokinetics is presented below.

Absorption:

Virtually all (99 %) of the sodium ion ingested in food and water is rapidly absorbed from the gastrointestinal tract (Stipanuk, 2000). Sodium crosses the brush border epithelial membrane of the intestine through sodium channels or by carried-mediated diffusion down an electrochemical gradient. During facilitated transport, sodium can carry chloride ion, glucose, amino acids, and other nutrients into the intestinal epithelial cells. Once sodium is in the cytosol of the brush border epithelial cell, it is actively transported into the blood by the Na+/K+-ATPase pump located in the basal and lateral membrane of the epithelial cell (Stipanuk, 2000).

Distribution:

Once absorbed, the sodium ion is rapidly distributed throughout the body. The concentration of sodium in blood and other extracellular fluids is about 145 mM (3,335 mg/L), whereas the concentration of sodium ion inside cells is about 12 mM (276 mg/L) (Stipanuk 2000). This unequal distribution of sodium between extracellular and intracellular compartments is essential to the normal functioning of all cells and tissues of the body.

Metabolism:

Sodium ion is not reactive and does not undergo any metabolic reactions in the traditional sense (i.e., it is not transformed by enzymic or non-enzymic mechanisms into any altered forms). Sodium does function as a counterion for macromolecules such as DNA, RNAs, proteins, and sulfated polysaccharides that carry a net negative change, and thus, concentrations can be enriched in the microenvironment surrounding macroion surfaces (Stipanuk, 2000).

Excretion:

Sodium is excreted mainly in the urine, although some sodium loss occurs with faecal matter and in perspiration. The kidney, nervous system, and endocrine system maintain very precise control of renal sodium excretion, with approximately 95 % to 98 % of the sodium being reabsorbed in the kidney (Stipanuk, 2000). In the proximal tubule of the kidney, sodium resorption is coupled with organic solutes and anions and protons. Entry into the proximal tubule epithelium is mediated by symporter (e.g., Na+-glucose, Na+-PO43-, Na+-lactate, and Na+-amino acid symporters) and antiporter (Na+-H+antiporter) proteins located on the apical membrane of the proximal tubule. When sodium enters the cytoplasm of the proximal tubule, it is actively transported into the blood by the Na+/K+-ATPase pump. Similar sodium resorption mechanisms occur in the loop of Henle and distal tubule.

In response to blood volume depletion (i.e., decreased blood pressure), the sympathetic nervous system stimulates sodium resorption. Hormonal control of sodium resorption is dependent on renal blood flow and nervous system stimulation. Decreased renal pressure in the renal arterioles, as well as sympathetic nervous system stimulation, results in the kidney’s production of renin. Renin cleaves circulating angiotensinogen to form angiotensin I, which is converted to angiotensin II by angiotensin-converting enzyme (ACE), an enzyme that is widely distributed in the body. Angiotensin II stimulates the adrenal gland to synthesize aldosterone, which binds to receptors in the cytoplasm of principal cells located in the collecting tubules of the kidney, and stimulates activity of the apical sodium channel and basal Na+/K+-ATPase pump. In response to increased blood and renal pressure, sympathetic nervous system stimulation and aldosterone synthesis decrease and sodium excretion increases. Of the approximately 25,200 mEq of sodium filtered through the kidneys each day, 150 mEq is excreted (Berne and Levy, 1993; Stipanuk, 2000).

3. Ammonium

Uptake:

NH4+ is anticipated to be either excreted in the urine or incorporated into the nitrogen pool of the organism.

Distribution:

In the body incorporation into polymeric nitrogen containing compounds proteins and nucleic acids occurs. Operation and mechanism of metabolic pathways is provided by proteins.

Metabolism:

Each of the monomer of these macromolecules incorporating nitrogen has an individual metabolic pathway. In addition, the monomeric nucleotides are essential for energy turnover as key intermediates in all metabolic pathways and also as second messenger molecules, often in form of cyclic nucleotides.

Amino acids contribute to carbohydrate synthesis via gluconeogenesis, to fat synthesis or energy production via acetyl-CoA, and special nitrogen compounds such as catecholamines (neurotransmitters), thyroid hormones, creatine (-phosphate), the protoporphyrin ring (haeme), and contribute to nucleic acid and phospholipid synthesis as nitrogen group donor.

Excretion:

NH4+ excretion is controlled by the kidney and controls the blood plasma pH. The blood plasma pH, however, is determined by other factors as well, such as organic acids (amino acids) and carbonic acid (CO2 levels). Ammonium metabolism in kidney functions to depose H+ in urine. In a first reaction, kidney enzymes deaminate glutamine in two steps to a-ketoglutarate. The first side chain deamination is catalyzed as simple hydrolysis and is not reversible.

This process is stimulated by inorganic phosphate. The free ammonia equilibrates with protons to ammonium:

NH3 + H+ = NH4+

and is trapped in the charged form inside kidney cells. The non-electrolytic ammonia is freely diffusible across cell membranes. Glutamine is the nontoxic form of NH3 and shuttles it between liver and kidney in the blood plasma. The kidney functions as H+ sink and protons are disposed in form of NH4+ while maintaining charge homeostasis using phosphate or acetoacetate.

4. Sulfate

The relevant chemical entity formed upon degradation and dissociation of persulfate dianion is the sulfate ion.

Absorption:

Following oral ingestion of a dose of magnesium sulfate (13.9 g), about one third of an orally administered dose expressed as sulfate were found to be absorbed in humans. In general, however, sulfate ion is poorly absorbed from the gastro-intestinal tract especially when administered in large doses such that the capacity of specialised transport processes for this ion in the intestines is exceeded.

Distribution:

Inorganic sulfate (SO42−) is required for the synthesis of 3′-phosphoadenosine-5′-phosphosulfate (PAPS). PAPS is required for synthesis of many important sulfur-containing compounds, such as chondroitin sulfate and cerebroside sulfate. While significant levels of sulfate are found in foods and various sources of drinking water, the major source of inorganic sulfate for humans is from biodegradation due to body protein turnover of the sulfur amino acids methionine and cysteine. Dietary sulfate in food and water, together with sulfate derived from methionine and cysteine found in dietary protein and the cysteine component of glutathione, provides sulfate for use in PAPS biosynthesis (The National Academies Press, 2004).

Excretion:

Inorganic sulfate is eliminated from the body almost entirely by renal excretion (i.e. without biotransformation) so that measurement of urinary excretion rates constitutes a direct method for determining the bioavailability of orally administered sulfate. Investigations in humans demonstrated that an average of 30.2 % of the administered dose corrected for endogenous sulfate excretions was eliminated during the subsequent 24–hour period after ingestion.

5. Persulfate dianion

The chemistry of the persulfate dianion is dependent on different pH-ranges:

1) Neutral (pH 3 to 7):

S2O82-+ H2O --> 2 HSO4- + 1/2O2;

2) Dilute acid (pH > 0.3; [H+] < 0.5 M):

S2O82-+ 2 H2O --> 2 HSO4-+ H2O2;

3) Strong acid ([H+] > 0.5 M):

S2O82-+ H2O + H+ --> HSO4- + HSO5-;

4) Alkaline (pH > 13):

S2O82- + OH- --> HSO4- + SO42- + 1/2 O2;

In the physiological range, i.e. in the pH range of 3 to 7, the reaction according to 1) was assumed as the preferred way of reaction of the persulfate dianion.

The reaction steps, as described in 2) to 4), may include formation of sulfate dianion SO4-2, hydrogen ion, H+ and molecular oxygen O2. As shown in Sect. 4, the sulfate dianion will not contribute to toxic effects of the persulfate dianion. A decrease in pH would be expected from the hydrolysis of the persulfate moiety, but systemic effects would be inconsequential in the presence of physiologic buffer systems.

Under certain circumstances, hydrolysis of the persulfate anion will yield the bisulfate anion and hydrogen peroxide.

Conclusion

The substances of the Persulfate Category rapidly hydrolyse upon contact with water. The substances degrade and will eventually form the corresponding cations (ammonium, potassium, sodium) and persulfate anions. The persulfate anion, independent of the cation, undergoes further decomposition upon contact with water to form sulfate species. Based on these fundamental properties of persulfates, they are not likely to become bioavailable, neither by inhalation, ingestion, or contact by skin. All degradation products are physiologically essential to organisms. Bioaccumulation is unlikely in view of the rapid degradation and high water solubility.