6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide, potassium salt

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

25

Absorption rate - inhalation (%):

100

Additional information

Acesulfame potassium has been evaluated thoroughly in a series of studies designed to establish its safety as a sweetener for food use. The database on covers chemistry, physiology, metabolism, pharmacology, pharmacokinetics and toxicology with data generated in a wide variety of in vivo and in vitro test systems including several animal species and humans.

 

Kinetics and biotransformation of Acesulfame potassium were studied in animal species and in humans. In none of the studies on biotransformation which were performed with radiolabelled material formation of metabolites was detected. Within the normal recovery rates of this type of study all activity was recovered as the unmetabolised Acesulfame and no other compounds showing activity were found.

 

The specific endpoint of the kinetic studies was the determination of maximum blood and serum levels and elimination rates but not the investigation of internal doses. Absorption and elimination were fast in rats, dogs, and man.

 

The most recent and valid study was performed in two groups of 48 male and 48 female Wistar rats each received dietary concentrations of 9000 and 15000 ppm for two weeks. The corresponding intake in mg/kg body weight was calculated on the basis of feed consumption and body weight as

9000 ppm     males:           854.68 mg/kg bw/d

females:         827.39 mg/kg bw/d

15000 ppm   males:           1367.07 mg/kg bw/d

females:         1277.22 mg/kg bw/d

No abnormalities and no intercurrent deaths occurred during the study.

The blood of one male and one female animal at each time point was collected over a period of 24 h at 0.5 h intervals by exsanguination on day 14 and 15 of the study. The levels of Acesulfame potassium in serum were thus determined over the last 24 h of the study.

 

The following AUC(24h) values were obtained:

9000 ppm      males:           848.2 µg.h/ml

females:         933.5 µg.h/ml

15000 ppm  males:           1520.6 µg.h/ml

Females:        1671.1 µg.h/ml

 

No remarkable sex differences were observed with Acesulfame potassium. The levels of Acesulfame potassium and consequently also the AUC(24h) values were about 10 % higher in females than in males_ The increase in the AUC(24h) of Acesulfame potassium was virtually proportional to the given dose. The 17 fold increase in the dose resulted in an 1.8 fold increase in the AUC(24h).

 

To compare the kinetics in dogs with the kinetics observed in rats a study using two groups of three male and three female beagle dogs each was carried out. Acesulfame potassium was administered orally in the daily diet at concentrations of 900 and 1500 mg/kg bw/d over a period of 14 days. The levels of Acesulfame potassium in serum were determined after the first and the 14th administration. Blood sampling was performed before and 0.5, 1, 1.5, 2, 3, 5, 7, 12, 20, and 24 h after administration.

 

No abnormalities were observed in the course of the study, and all dogs survived until the scheduled end of the study. While food consumption was normal in the lower dosage group, some animals of the high dosage group showed retarded food consumption.

 

The AUC(24h) ranged from 2149 to 3819 µg.h/ml in the 900 mg/kg bw/d group and from 3065 to 5722 µg.h/ml in the 1500 mg/kg bw/d group.

 

Peak concentrations of the level (Cm) of Acesulfame potassium were reached 5 to 7 h after dosing with maximum concentrations of 180 to 311 µg/ml at the 900 mg/kg bw/d dose and 273 to 491 µg/ml at 1500 mg/kg bw/d

 

The plasma half-lives (t1/2) ranged from 2.3 to 4.2 h with a median of 3.2 h.

The increase of Cmax. and AUC(24h) was virtually proportional to the dose given. The 1.7 fold increase in the dose was followed by a 1.6 to 1.9 fold increase in maximum concentrations and a 1.5 to 1.8 fold increase in AUC(24h) values.

 

No remarkable sex-specific differences were seen. Accumulation can be excluded on the basis of values obtained after the 14th administration, as the Cmax were 0.9 to 1.4 fold and the AUC(24h) 0.9 to 1.2 fold the first administration.

 

Results of the kinetic studies in rats and dogs show that the same dosage of Acesulfame potassium expressed as mg/kg body weight results in substantially higher internal doses in dogs than in rats. For 900 mg/kg the internal doses determined by AUC(24h) values are 2.3 — 4.5 fold higher in dogs than in rats and for 1500 mg/kg bw/d 1.8 — 2.7 fold higher. Even a comparison of the AUC(24h) value determined for dogs at the 900 mg/kg bw/d dosage level exceeds the AUC(24h) value for rats at the 1500 mg/kg level by a factor of 1.3 — 2.5.

 

Only steady state and not peak plasma concentration (Cmax) values, could be obtained for rats since administration was by

continuous feeding. The increases in AUC(24h) in both species and in Cmax in the dog were virtually proportional to dose

Comparative toxicokinetics of Acesulfame potassium in rats and dogs Comparative toxicokinetics of Acesulfame potassium in rats and dogs.

 

	AUC(24h) (ìg.h.ml-1)		Plasma concentration (ìg.ml-1)
Species	Rat	Dog	Rat steady state	Dog Cmax
Lower dose 1)	848-934	2149-3819	16-71	180-311
Higher dose 2)	1521-1671	3065-5722	30-119	273-491
1) Rat: 840 mg/kg bw/day via diet; dog: 900 mg/kg bw/day as bolus dose 2) Rat: 1325 mg/kg bw/day via diet; dog: 1500 mg/kg bw/day as bolus dose

  

Metabolism studies

Single oral doses of Acesulfame potassium given to dogs and rats were rapidly absorbed and excreted mainly in the urine as unchanged compound.

 

The excretion kinetics of Acesulfame potassium in the rat is biphasic with an estimated half-life in the rapid phase of approximately 4 hrs.

 

When single doses of Acesulfame potassium were given orally to dogs and pigs, maximum blood levels were reached at 1-2 hrs after dosing.

 

A single oral dose of 30 mg Acesulfame potassium given to human volunteers was rapidly and almost completely absorbed.

 

In human maximum blood concentration was reached after 1- 1.5 h and thereafter elimination occurred rapidly with a plasma half-life of 2-2.5 h. Only the parent compound could be identified in serum and urine, indicating that no significant degradation of Acesulfame potassium had occurred.