Dipotassium disulphate

Endpoint summary

Description of key information

The test substance will rapidly hydrolyse to sulphuric acid and sulphate anion in biological fluids and tissues. The sulphate anion is well absorbed from the lung and intestinal tract. Absorption estimates from the lung indicate a non-saturable process with an absorption half-life of 34 minutes in rats. In human studies, the data show that sulphate is essentially fully absorbed by the oral route of exposure within 2 hours. Dietary studies indicate that 97% of the ingested sulphate is found in the urine indicating essentially complete absorption and excretion. Thus these values support 100% absorption of sulphate from the oral route of exposure. The complete elimination of sulphate from balance studies indicate low potential for bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Additional information

The target substance rapidly hydrolyses in water to form sulphuric acid and potassium sulphate (K⁺₂SO₄^2-), the source substances. A hydrolysis study was undertaken where the reaction of the test substance was followed using laser Raman spectroscopy. The study demonstrated that at 1 M concentration of test substance, it took 22 minutes for the reaction to run to completion. At 0.1 M concentration of test substance it took less than 3 minutes for the reaction to go to completion. The reaction appeared to be relatively independent of starting pH. The effect of the starting test substance concentration of on the hydrolysis rate appears to be largely due to dissolution kinetics and mixing dynamics apparent at the higher test concentration. At a pH of 7.4, a biologically relevant pH given it’s the typical pH of blood/tissue, the hydrolysis products appeared to be entirely in the form of sulphate ions, SO₄^2-. The hydrolysis reaction of pyrosulphate is given by the following equation:

 

S₂O₇^2-+ H₂O -> 2HSO₄^- (1)

 

In aqueous solution, the bisulphate ion generated by this hydrolysis further transforms according to the following equilibrium equation:

 

2HSO₄^-<--> 2H⁺+ 2SO₄^2-  (2)

 

This is the functional equivalent of each mole of pyrosulphate anion producing 1 mole of sulphate and 1 mole of sulphuric acid at biologically relevant pHs.

 

S₂O₇^2-+ H₂O  -> H₂SO₄+ SO₄^2-  (3)

 

Thus potassium sulphate and sulphuric acid are considered to form a group of relevant analogues to characterise the hazard profile of the test substance.

The sulphuric acid formed from hydrolysis is not expected to be absorbed or distributed throughout the body. Instead, the acid will dissociate and the anion will enter the body’s electrolyte pool and not play a specific toxicological role. The presence of the hydronium ion will have an impact on the acute toxicity effects and, depending upon the amount, will be buffered by the various carbonate, phosphate, and protein buffer systems present in the body.

Sulphate, formed from hydrolysis of the target substance, is an important macronutrient for the normal function of cells and is the fourth most abundant anion in human plasma (300 µM). Sulphate is absorbed from the intestine by an active transport system. All cells have sulphate transporter for the influx/efflux of sulphate. Sulphate is also used for detoxification of compounds to sulphate esters, which can be excreted in the urine. Sulphate is eliminated by the kidney and levels are regulated by the kidney through a reabsorption mechanism.

Multiple absorption and kinetic studies with sulphate and sulphate ions were performed in rats and humans. In rats, absorption of inorganic sulphate after oral ingestion of 0.25 to 5 mmol was investigated. After oral administration of Na₂³⁵SO₄, radioactive³⁵S was measurable in plasma after 15 minutes, and its plasma concentration reached a peak after about 1.5-2 hours. The³⁵S-radioactivity excreted in urine during the 24 hours after ingestion of Na₂³⁵SO₄ together with varying amounts of unlabelled Na₂SO₄ (0.25--5.0 mmol Na₂SO₄ per rat) indicated an almost complete absorption of inorganic sulphate from the gastrointestinal tract. Determination of the inorganic sulphate concentration in rat serum 2 hours after oral administration of 5.0 mmol Na₂SO₄ revealed a three-fold increase in serum sulphate concentration. The data suggest a rapid and almost complete absorption of inorganic sulphate after oral administration in the rat.

To investigate the absorption of ³⁵S-sulphate ions from the rat lung in the presence of sodium ions, 0.1 ml of isotonic sucrose solution containing the salt was instilled via a tracheal cannula into anesthetized animals. After various times the lungs were removed and assayed for ³⁵S-radioactivity. Sulphate ion absorption was found to be nonsaturable and proportional to the concentration of sulphate ion, with a t_1/2 of 34.5 minutes.

Human volunteers received an i.v. dose, followed by 24-hours fluid restriction and blood and urine collection to determine radioactivity and creatinine concentration. The same volunteers received the same amount orally 2-14 days later, followed by same regimen. Plasma equilibrium was reached within 90 minutes for i.v. and 105 minutes for oral dosing. Eighty percent or greater of the ³⁵S dose was recovered in the 24-hour urine, following either i.v. or oral administration. The calculated mean extracellular fluid space was 16.8±1.1 and 15.3±1.2 respectively, or only 9%. The test substance was absorbed completely and rapidly.

In another human study, subjects received either a single dose of 18.1 g Na₂SO₄ decahydrate (800 g of the anhydrous salt) or were dosed in 4 hourly increments one week later. After dosing, urine was collected in 24-hour portions over a 72 hour period. The single dose caused severe diarrhoea, but the divided dose did not. The test substance is better absorbed from the intestine when given in a divided dose than when administered in a single large dose, indicating saturation of the transport system.

Sulphate balance studies were performed on six healthy ileostomists and three normal subjects. The subjects were fed diets which varied in sulphate content from 1.6-16.6 mmol/day. Sulphate was measured in diets, faeces (ileal effluent in ileostomists), and urine. Overall there was net absorption of dietary sulphate, with the absorptive capacity of the gastrointestinal tract plateauing at 5 mmol/day and exceeding 16 mmol/day in the normal subjects. Faecal losses of sulphate were trivial in the normal subjects at all doses. Urinary excretion of sulphate in the normal subjects correlated linearly with dietary sulphate; 97% of dietary sulphate was excreted in urine. It is concluded that diet and intestinal absorption are the principal factors affecting the amounts of sulphate reaching the colon.

Based on the multiple studies in rats and humans with sulphate, the test substance is expected to be rapidly absorbed and excreted in humans.