Ammonium hydrogendifluoride

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
AMBI will dissociate under physiological conditions with the generation of fluoride and ammonium ions.  The basic toxicokinetics of these two ionic species are well characterised.  Ammonia is well absorbed, rapidly distributed. metabolised to urea in the liver via the urea cycle and is excreted as urea in the urine.
Short description of key information on absorption rate: 
Dermal absorption is unlikely in practice based on the physicochemical properties and corrosivity of the substamce.

Additional information

AMBI will dissociate under physiological conditions with the generation of fluoride and ammonium ions. The basic toxicokinetics of these two ionic species are well characterised and are summarised separately.

Ammonia (ammonium): basic toxicokinetics

Oral absorption

Ammonia is generated by the bacterial flora of the gastrointestinal tract (~4 g/day) and as a very small water-soluble molecule, is likely to be rapidly and extensively absorbed.

Inhalation absorption

The results of a study in the rat (Schaerdel et al, 1983) indicate that the gaseous substance is absorbed into the bloodstream following inhalation exposure; this is consistent with the water solubility and small molecular size of the substance.

Distribution

Ammonia is distributed to all tissues in the body and is capable of crossing the blood-brain barrier.

Metabolism

No studies of metabolism are available, however the physiological role of ammonia as a product of normal metabolism (protein catabolism) is very well characterised. Ammonia is rapidly detoxified in the liver by the urea cycle.

The urea cycle consists of five enzymes: carbamoylphosphate synthetase I (CPS I), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and arginase. The initial reaction of the urea cycle is the formation of carbamoyl phosphate from ammonia and bicarbonate, a reaction catalysed by CPS I, which requires N-acetylglutamate as an allosteric cofactor. Condensation of carbamoyl phosphate with ornithine yields citrulline (by OTC); this in turn condenses with aspartate to give argininosuccinate (by ASS), a reaction that requires the cleavage of two further high-energy phosphate bonds. Argininosuccinate is hydrolysed to fumarate and arginine (by argininosuccinase). Arginine is cleaved by arginase to give urea and ornithine. OTC, like CPS I, is also a major mitochondrial protein; the remaining enzymes are in the cytoplasm of hepatocytes. Urea synthesis cannot therefore be saturated at realistic substrate concentrations. The urea cycle is high capacity and the capacitty also increases short-term and long-term in reponse to increased demand (e.g. in response to dietary protein intake). It is estimated that some 7 to 25% of the ammonia delivered via the portal vein escapes periportal urea synthesis and is used for glutamine synthesis

Excretion

Ammonia is rapidly detoxified in mammals by conversion to urea by the urea cycle in liver cells and is subsequently excreted (as urea) in urine following glomerular filtration. Ammonium ions (NH4 +) are also excreted by the kidney. Hepatic excretion of urea (15 -30% of that generated) results in the generation of ammonia by the gastrointestinal flora, and subsequent reabsoprtion.

Context

The body excretes approximately 30 g urea/day; urea is synthesised by the hepatic urea cycle from ammonia generated by protein catabolism. Therefore it can be calculated that the body typically produces 16 g/day ammonia, although this figure is influenced by the amount of dietary protein. Therefore it can be concluded that exposure to ammonia at quantities in this range will be without toxicological effect. Ammonia is toxic and therefore exposures greatly exceeding the normal production may overwhelm the normal detoxification mechanisms.

The normal serum level of ammonia is 0.15 -100 ug/dL. Assuming a blood volume of 5L (55% serum), this is equivalent to approximately 0.4 -2.75 mg ammonia present in the blood of a normal adult at any point in time. However it is notable that, due to the generation of ammonia by gastrointestinal tract bacteria, the concentration of ammonia in the hepatic portal circulation is much higher than that in the rest of the systemic ciruclation.

Fluoride: basic toxicokinetics

Absorption

The absorption of inorganic fluoride across mucous membranes is passive and is independent of the fluoride source. Inhalation absorption of fluoride is likley to be extensive. Following dermal exposure to AMBI, absorption is of fluoride likely to be minimal expect in cases where the normal skin structure is compromised as a consequence of the corrosive effects of the substance. The absorption of fluoride following oral administration of AMBI has not been investigated, but is likely to be rapidly absorbed.

Distribution

Absorbed fluoride is distributed primarily in the blood, 75% in the plasma and 25% associated with erythrocytes. Half of the plasma fluoride may be bound to organic molecules. Fluoride is rapidly distributed and is sequestered in the bones and teeth, where exchange with hydroxyl groups results in incorporation into the bone and tooth structure. Levels of fluoride in bones and teeth are directly correlated with exposure levels.

Excretion

Fluoride is excreted rapidly as a consequence of glomerular filtration, with a plasma half-life of 2-9 hours. The half-life for skeletal fluoride in humans is reported to be 8-20 years.

Discussion on bioaccumulation potential result:

AMBI will dissociate under physiological conditions with the generation of fluoride and ammonium ions. The basic toxicokinetics of these two ionic species are well characterised and are summarised separately.

Ammonia (ammonium): basic toxicokinetics

Oral absorption

Ammonia is generated by the bacterial flora of the gastrointestinal tract (~4 g/day) and as a very small water-soluble molecule, is likely to be rapidly and extensively absorbed.

Inhalation absorption

The results of a study in the rat (Schaerdelet al, 1983) indicate that the gaseous substance is absorbed into the bloodstream following inhalation exposure; this is consistent with the water solubility and small molecular size of the substance.

Distribution

Ammonia is distributed to all tissues in the body and is capable of crossing the blood-brain barrier.

Metabolism

No studies of metabolism are available, however the physiological role of ammonia as a product of normal metabolism (protein catabolism) is very well characterised. Ammonia is rapidly detoxified in the liver by the urea cycle.

The urea cycle consists of five enzymes: carbamoylphosphate synthetase I (CPS I), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and arginase. The initial reaction of the urea cycle is the formation of carbamoyl phosphate from ammonia and bicarbonate, a reaction catalysed by CPS I, which requires N-acetylglutamate as an allosteric cofactor. Condensation of carbamoyl phosphate with ornithine yields citrulline (by OTC); this in turn condenses with aspartate to give argininosuccinate (by ASS), a reaction that requires the cleavage of two further high-energy phosphate bonds. Argininosuccinate is hydrolysed to fumarate and arginine (by argininosuccinase). Arginine is cleaved by arginase to give urea and ornithine. OTC, like CPS I, is also a major mitochondrial protein; the remaining enzymes are in the cytoplasm of hepatocytes. Urea synthesis cannot therefore be saturated at realistic substrate concentrations. The urea cycle is high capacity and the capacitty also increases short-term and long-term in reponse to increased demand (e.g. in response to dietary protein intake). It is estimated that some 7 to 25% of the ammonia delivered via the portal vein escapes periportal urea synthesis and is used for glutamine synthesis

Excretion

Ammonia is rapidly detoxified in mammals by conversion to urea by the urea cycle in liver cells and is subsequently excreted (as urea) in urine following glomerular filtration. Ammonium ions (NH4 +) are also excreted by the kidney. Hepatic excretion of urea (15 -30% of that generated) results in the generation of ammonia by the gastrointestinal flora, and subsequent reabsoprtion.

Context

The body excretes approximately 30 g urea/day; urea is synthesised by the hepatic urea cycle from ammonia generated by protein catabolism. Therefore it can be calculated that the body typically produces 16 g/day ammonia, although this figure is influenced by the amount of dietary protein. Therefore it can be concluded that exposure to ammonia at quantities in this range will be without toxicological effect. Ammonia is toxic and therefore exposures greatly exceeding the normal production may overwhelm the normal detoxification mechanisms.

The normal serum level of ammonia is 0.15 -100 ug/dL. Assuming a blood volume of 5L (55% serum), this is equivalent to approximately 0.4 -2.75 mg ammonia present in the blood of a normal adult at any point in time. However it is notable that, due to the generation of ammonia by gastrointestinal tract bacteria, the concentration of ammonia in the hepatic portal circulation is much higher than that in the rest of the systemic ciruclation.

Fluoride: basic toxicokinetics

Absorption

The absorption of inorganic fluoride across mucous membranes is passive and is independent of the fluoride source. Inhalation absorption of fluoride is likley to be extensive. Following dermal exposure to AMBI, absorption is of fluoride likely to be minimal expect in cases where the normal skin structure is compromised as a consequence of the corrosive effects of the substance. The absorption of fluoride following oral administration of AMBI has not been investigated, but is likely to be rapidly absorbed.

Distribution

Absorbed fluoride is distributed primarily in the blood, 75% in the plasma and 25% associated with erythrocytes. Half of the plasma fluoride may be bound to organic molecules. Fluoride is rapidly distributed and is sequestered in the bones and teeth, where exchange with hydroxyl groups results in incorporation into the bone and tooth structure. Levels of fluoride in bones and teeth are directly correlated with exposure levels.

Excretion

Fluoride is excreted rapidly as a consequence of glomerular filtration, with a plasma half-life of 2-9 hours. The half-life for skeletal fluoride in humans is reported to be 8-20 years.

Discussion on absorption rate:

Following dermal exposure to AMBI, absorption of fluoride is likely to be minimal expect in cases where the normal skin structure is compromised as a consequence of the corrosive effects of the substance. A number of human case studies with related compounds such as HF have noted elevated plasma fluoride concentrations and/or systemic fluoride poisoning in burns cases, indicating the ability of fluoride to be absorbed through damaged skin. Ammonia is a small water soluble molecule; high water solubility indicates that significant dermal absorption is unlikely under normal conditions. However the substance is corrosive, and it is possible that significant absorption may occur in situations where the integrity of the skin barrier is compromised by severe local reactions, such as in burns cases.