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

Endpoint summary

Description of key information

The chronic oral toxicity of Acesulfame potassium was investigated in male and female Beagle dogs. Each 4 males and 4 females received dose levels of 0, 0.3%, 1.0% and 3.0% in the diet (0, 3000, 10000, 30000 ppm, corresponding to about 0, 90, 300 and 900 mg/kg bw/day) daily during a period of two years. The no observed adverse effects level (NOAEL) for chronic (2 year) oral toxicity in male and female Beagle dogs was 30000 ppm (corresponding to about 900 mg/kg bw/day). 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

900 mg/kg bw/day

Study duration:

chronic

Species:

dog

Quality of whole database:

The quality of the whole data base is considered to be sufficient and not critical.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The subchronic oral toxicity of Acesulfame potassium was investigated in male and female Wistar rats. Each 10 males and 10 females received dose levels of 0, 1%, 3% and 10% in the diet (0, 10000, 30000 100000 ppm, corresponding to about 0, 300, 1500, 3000 mg/kg bw/day) daily during a period of 90 days. Mortality, clinical findings and behavior were examined at least once a day, while body weight, food consumption were determined at regularly intervals. At the end of the application, hematology, clinical chemistry and urinalysis were performed. After sacrifice, a complete necropsy was performed, organ weights were determined and the animals of the control and high dose groups were subjected to histopathology.

Body weight and body weight gain was slightly reduced during the first 3 - 4 weeks of treatment in the animals of both sexes. Food consumption/food efficiency of the highest dose was slightly reduced during the first two to three weeks and slightly increased thereafter. A slight increase in haemoglobin concentration was observed in males of the high dose group. Serum enzyme activities and albumin levels were comparable in all groups. Total serum protein level was slightly decreased in females of the high dose group. Urinalysis was not affected. The relative weights of the caecum were distinctly increased at the high dose group in both sexes and at the mid dose group in females only. The weights of the liver and kidneys were slightly increased in females of the high dose group. Gross pathology did not show significant findings, except for enlargement of the caecum at the high dose group in both sexes but histopatholgy revealed no substance-induced findings. Thus, the No Observed Adverse Effects Level (NOAEL) for subchronic (90 days) oral toxicity in male and female Wistar rats was 30000 ppm (corresponding to about 1500 mg/kg bw/day) under the conditions of the study.

The chronic oral toxicity of Acesulfame potassium was investigated in male and female Beagle dogs. Each 4 males and 4 females received dose levels of 0, 0.3%, 1.0% and 3.0% in the diet (0, 3000, 10000, 30000 ppm, corresponding to about 0, 90, 300 and 900 mg/kg bw/day) daily during a period of two years. Observations were made of general condition, behaviour, survival, growth, food intake, haematological and clinical chemistry parameters in blood and urine. Tests were made for liver and kidney function. At week 104 all surviving dogs were killed, examined grossly and ten different organs were weighed. Extensive microscopical examinations were carried out.

General appearance, condition, behaviour and survival were not noticeably affected by the test substance. Urolithiasis occurred in one control dog and in one dog of the low dose group. The latter dog died from this disease. Body weights and food intake were not adversely affected by the ingestion of the test substance. Haematological and biochemical blood values did not show changes that could be ascribed to the ingestion of the test compound. No indication of kidney damage was revealed by specific gravity, phenol red excretion or by any of the urine constituents examined. The BSP-retention in dogs of the control group and of the top-dose group was comparable and not indicative for any liver function impairment. Absolute and relative organ weights did not reveal any differences amongst the groups. Gross and microscopic examination failed to reveal any abnormalities that could be ascribed to treatment.

 

Finally, the no observed adverse effects level (NOAEL) for chronic (2 year) oral toxicity in male and female Beagle dogs was 30000 ppm (corresponding to about 900 mg/kg bw/day). This conclusion is in line with the assessment of theJoint FAO/WHO Expert Committee on Food Additives (1990) and re-evaluation of the European Scientific Committee on Food (SCF, 2000). In addition, both committees considered this study as relevant to establish the acceptable daily intake (ADI) of 0 - 9 mg/kg bw.

A combined chronic toxicity and carcinogenicity study with Acesulfame potassium was carried out by feeding the substance to groups of 60 male and 60 female rats at levels of 0 (control), 0.3, 1.0 or 3.0% in the diet for more than two years. The rats were descendants from parents which had been kept on the same diets since weaning age. Observations were made of general appearance, behaviour and mortality, growth, food and water intake, haematological factors and clinical constituents in blood and urine. At weeks 120-123 all surviving rats were killed by decapitation and examined grossly. Eight different organs were weighed. Tissue samples of a wide variety of organs and of all abnormal tissues were collected for histological examination

 

There were no differences in mortality rate amongst the various groups attributable to the feeding of Acesulfame potassium. Decreased body weights, not associated with decreased food intake, occurred in the high dose group in both sexes. Food efficiency, calculated over the period of rapid growth, was decreased in the high dose group in both sexes and in the mid dose group in males only. An increased water intake was noticed in the high dose group. A slight decrease in haemoglobin content, haematocrit value and red blood cell count was observed in females fed 3.0% Acesulfame potassium, only at weeks 102 and 119 of the study. Enzyme activities or levels of glucose, urea nitrogen and protein of the blood did not show any treatment-related effects. No indication of kidney damage was noticed in the volume, specific gravity, glutamic-oxalacetic transaminase activity or osmolarity of the urine. Urine composition was essentially normal. Relative organ weights did not show any treatment-related differences amongst the groups. Gross and microscopic examination did not reveal pathological changes which could be ascribed to the ingestion of the test substance.

 

Thus, it was concluded that the feeding of Acesulfame potassium at dietary levels up to 3% to male and female rats, which had been exposed in utero and then continuously throughout the major part of their life-time failed to show carcinogenic properties or other effects of obvious toxicological significance. Finally, the overall NOAEL was 3.0% (30000 ppm corresponding to about 1500 mg/kg bw/day) a dose level exceeded the current limit dose of 1000 mg/kg bw/day.

 

This conclusion is in line with the assessment of theJoint FAO/WHO Expert Committee on Food Additives (1990) and re-evaluation of the European Scientific Committee on Food (SCF, 2000). The SCF concluded in addition that “although the carcinogenicity studies are old they could still be used in the safety evaluation of Acesulfame potassium. […]. Thus there is no reason to require any additional studies of chronic toxicity/ carcinogenicity or mutagenicity”.

 

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The chronic oral toxicity of Acesulfame potassium was investigated in male and female Beagle dogs. This study is assessed as appropriate and valid since it was performed comparable to an internationally accepted testing guideline with only minor deviations. Reporting, assessment and data presentation in the study report was considered as appropriate. The no observed adverse effects level (NOAEL) for chronic (2 year) oral toxicity in male and female Beagle dogs was 30000 ppm (corresponding to about 900 mg/kg bw/day). This conclusion is in line with the assessment of the Joint FAO/WHO Expert Committee on Food Additives (1990) and re-evaluation of the European Scientific Committee on Food (SCF, 2000). In addition, both committees considered this study as relevant to establish the acceptable daily intake (ADI) of 0 - 9 mg/kg bw.

Justification for classification or non-classification

Acesulfame potassium was non-toxic after repeated oral administration up to the highest dose levels tested.

The study results triggers the following classification/labelling:

EU Directive 1999/45/EC (as amended):        none

Regulation (EC) No 1272/2008 (CLP):           none

GHS (rev. 4) 2011:                                      unclassified