Ammonium fluoride

Endpoint summary

Additional information

As ammonium fluoride decomposes in an aqueous environment into ammonium and fluoride ions, basic toxicokinetics of these two ions have been studied.

Ammonium

Plodikova and Cihak published a report in 2010 assessing the toxicokinetic behaviour of ammonium chloride using data from toxicological databases and experimental data of unpublished toxicological tests.

They found that after oral application ammonium chloride enters readily the body as a result of absorption by the gastrointestinal (GI) tract. After absorption by the GI tract, the test substance is utlized in the liver to form amino acids and proteins. The main target for toxicity are the kidneys.

When ammonium ions are converted to urea, liberated hydrogen ion reacts with bicarbonate ion to form water and carbon dioxide. The chloride ion displaces the bicarbonate ion. Chloride is loaded into the kidneys. The increased chloride concentration in the extracellular fluid produces an increased load to the renal tubules.

Increased excretion of electrolytes and water causes loss of extracellular fluid and promotes the mobilisation of edema fluid.

Furthermore, the test substance induces metabolic acidosis (shown by decreased plasma- and urinary-pH) and feeding of high level of the test substance causes decreased appetite, growth retardation, increased water consumption and increased urinary volume. Several studies with rats recorded increased kidney weight, renal hypertrophy with new cell formation (increase in total DNA and total RNA) and enlargement of existing cells.

For the following parameters an increase was also recorded: urinary ammonium, urea, sodium, plasma chloride, BUN, plasma proteins, urinary calcium, phosphate excretion, total erythrocytes and haemoglobin and haematocrit concentration.

Chronic stimulation of adrenal cortex by NH₄⁺induced acidosis caused hypertrophy of adrenal zona glomerulosa.

Human incidental exposure following oral administration showed that ammonium chloride is rapidly absorbed from the gastrointestinal tract and complete absorption occurs within 3 to 6 hours. In healthy persons absorption of ammonium chloride given by mouth was practically complete. Only 1 to 3% of the dose was recovered in the faeces. Substantial first pass metabolism occurs in the liver.

Fluoride

A comparative study (Whitford et al., 1991) of fluoride pharmacokinetics in five species (dog, cat, rat, rabbit and hamster) determined that there are major quantitative differences in the metabolic handling of fluoride among the five species evaluated, and that plasma, renal and extra-renal (calcified tissue) values of the young adult dog, when factored for body weight, resemble those of a young adult human most closely. The 5-minute plasma fluoride concentrations were ordered as follows: dog > rabbit > rat > hamster > cat (concentrations were 110.8 +/- 14.3, 91.3 +/- 3.1, 78.4 +/- 5.3, 69.1 +/- 4.9 and 52.2 +/- 4.8 µmol/L respectively). In terms of body weight, the plasma clearances were highest in the hamster, rat, and cat (8.60, 7.34 and 7.24 mL/min/kg respectively), intermediate in the rabbit (5.80 mL/min/kg), and lowest in the dog (3.50 mL/min/kg). This result indicates that the hamster, rat and cat cleared fluoride from their extracellular fluids more than 2 times faster than the dog. The plasma clearance of fluoride in the rabbit was 66% faster than for the dog.

In another study (Susheela et al., 1982), rabbits were administered daily oral doses of 10 mg sodium fluoride/kg body weight by gavage for various periods of time and then levels of fluoride in serum, urine, non-calcified tissues, calcified tissues, erythrocyte membrane and hemolysate were estimated at different time intervals for the purpose of understanding how much fluoride was deposited, how much was excreted and what quantity of fluoride was in circulation. Following sodium fluoride ingestion, the circulating level of fluoride was enhanced. The increase in fluoride content was proportionate to the duration of sodium fluoride administration, at least up to 10 months. Urinary fluoride content data revealed that, due to sodium fluoride ingestion, the amount of excreted fluoride increased up to 30 days. Thereafter, for unknown reasons, fluoride excretion gradually diminished towards normal limits. Cortical and cancellous bone differed significantly in their fluoride content. Cancellous bone, upon sodium fluoride administration, showed greater affinity for fluoride uptake, possibly due to its greater surface area exposed. Fluoride content data of non-calcified tissues showed that less fluoride was taken up when compared to calcified tissue. However, in non-calcified tissues it was evident that different organ tissues varied in their affinity for fluoride and in their fluoride content. Upon sodium fluoride administration, all soft tissues investigated, including the erythrocyte membrane and hemolysate, showed enhanced fluoride content.

In an earlier study, Zipkin and Likins (1957) investigated the absorption of various fluorine compounds from the gastrointestinal tract of the rat. Sodium fluoride, as well as sodium fluorosilicate (Na₂SiF₆), sodium fluorophosphate (Na₂PO₃F) and stannous fluoride (SnF₂) were absorbed through the gastrointestinal tract of the rat to the same extent (mean 48.4 +/- 1.6%), whereas potassium hexafluorophosphate (KPF₆), tetraethylammonium hexafluorophosphate (EtNPF₆) and potassium fluoroborate (KBF₄) were absorbed to a significantly greater degree (73.6 +/- 2.0%). The results suggest that the difference in absorption rate between the two groups of fluorine compounds is related to their dissimilarity in electronic structure. In compounds with lower rates of absorption, fluorine is electrovalently bound and is present as the fluoride ion, whereas in compounds with greater rates of fluorine absorption, fluorine is covalently bound.