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Repeated dose toxicity: oral

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chronic toxicity: oral
combined repeated dose and carcinogenicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable fpr assessment. Aluminium potassium sulfate used as read-across partner

Data source

Reference Type:
Chronic toxicity and tumorigenicty study of aluminium potassium sulfate in B6C3F1 mice
Oneda, S.
Bibliographic source:
In Vivo 8(3): 271-278

Materials and methods

Test guideline
equivalent or similar to
EU Method B.33 (Combined Chronic Toxicity / Carcinogenicity Test)
not specified
GLP compliance:
not specified
Limit test:

Test material

Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): Aluminium potassium sulfate
- Molecular formula (if other than submission substance): AlK (SO4)2 x 12H2O, APS
- Lot/batch No.: M5P2968
- Other: test chemical received from Nacalai Tesque Co., LtD., Kyoto, Japan)

Test animals

Details on test animals and environmental conditions:
- Source: Charles River Co. Japan Inc., Atsugi, Japan)
- Age at study initiation: 6 weeks
- Housing: 5 per plastic cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks

- Temperature (°C): 23 +/- 2°C
- Humidity (%): 55 +/- 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: feed
other: basal diet
Details on oral exposure:
the test chemical was mixed with the basal diet (CE-2, Nippon CLEA Co. Ltd, Tokyo, Japan) at the various concentrations mentioned below. The diets containing the test item were prepared every 2 or 3 months and kept in light-shielded boxes at room temperature. Since the test item is rather stable compound, the stability of the compound in the diet was not monitored after preparation.

Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Duration of treatment / exposure:
20 months
Frequency of treatment:
Doses / concentrations
Doses / Concentrations:
0, 1.0, 2.5, 5.0 and 10.0 (w/w)
nominal in diet
No. of animals per sex per dose:
5 groups of 60 animals of each sex and concentration
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale:
Preliminary study: 5 weeks, daily diet
Concentration: 2, 1, 0.2 and 0% (w/w)
No deaths, no abnormalities in clinical signs, food consumption, body weight or pathological evaluations at any dose
Based on the results 10.0% (w/w) was chose for the high dose level and 5.0, 2.5 and 1.0% were selected as the middle to low dose levels
Positive control:


Observations and examinations performed and frequency:
The animals were observed weekly for clinical signs of illness or death, food consumption and body weights
Sacrifice and pathology:
Spontaneously died animals were necropsied
After 20 months:
All surving animals were killed by exanguination under ether anesthesia without prior fasting. Gross findings were observed and the following organs of all mice were weighed: brain, pituitary, heart, lungs, liver, spleen, kidneys, adrenals and testes. These organs and the eye balls, harderian gland, submandibular gland, thyroid, thymus, trachea, bronchis, pancreas, stomach, small and large intestines, epididymis, prostate, ovaries, uterus, vagina, mammary glands, mesenteric lymph nodes, femoral bone marrow and skin were fixed in 10% neutraliszed formalin, embedded in paraffin, sectioned and stained with hematoxylin and eosin (HE).
Other examinations:
Data were analysed statistically by the students-t test for body weight and organ weights (absolute and relative weight) and X² test for histopathological examinations

Results and discussion

Results of examinations

Clinical signs:
no effects observed
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
The survival rates at the end of the dosing period were 73.3% (male) and 78.3% (female) in the control group, and 86.7%-95.0% (male) and 86.7-91.7% (female) in the treatment group.

Both the male and the female mice in the high dose level exhibited slight growth retardation compared with the control group after 1 month, and those in the 1.0 and 2.5 % dose groups exhibited a slight increase in body weight after 3 months. Both male and female mice receiving 5.0% test item showed growth similar to that in the control group

Food consumption did not show any variation among the groups throughout the experimental period for either males or females

A significant increase in the absolute organ weight was observed in the kidneys and heart in both sexes in the 1.0, 2.5 and 5.0% dose groups, in the pituitary in the males in the 2.5% dose group and the brain in the females in the 1.0% group compared with those in the control group. Additionally, there were significant decreases in the absolute organ weight of the liver in both sexes in the 5.0 and 10.0% dose groups, the heart and brain in both sexes in the high dose group and lungs in the males and spleen in the females in the 10% high dose group compared with those in the control group. There was a significant increase in the relative organ weight of the kidneys in the males in the 5.0% dose group and a significant decrease in the relative organ weight of the liver in both sexes in 5.0 and 10% groups and spleen in the females in the high dose group.

The incidence of myocardial eosinophilic cytoplasm showed a significant dose-dependent decrease in the male mice in the treatment groups. A comparison between the sexes revealed a significant decrease in the incidence of hepatocytic anisonucleosis, myocardial eosinophilic cytoplasm and acinar cell vacuolation of sumandibular gland in females; and lymphocyte infiltration in the renal cortex and pelvis, and vacuolation of cerebrellar white matter in the males

The incidence of the male tumour bearing mice was 40.9%, and 54.5, 36.5, 42.9 and 17.5% in the control group and 1.0, 2.5, 5.0 and 10.0% dose groups, respectively, while that of female tumour.bearing mice was 29.8, 23.6, 17.3, 11.5 and 13.5% respectively.

The incidence of all tumours and non-tumorous changes was withinh the normal range reported for spontaneous changes in B6C3F1 mice.

Effect levels

Dose descriptor:
Effect level:
100 000 ppm
Based on:
test mat.
Basis for effect level:
other: No adverse effects notified

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

In conclusion, the results of the present study indicate that long-term administration of a diet containing 10% (w/w) aluminium potassium sulfate does not exert tumorgenicity or any other toxic actions in male and female B6C3F1 mice. Thus, the NOAEL can be considered to be 100000 ppm (10 % w/w).
Executive summary:

In a chronic (20 months) combined repeated oral dose toxicity and carcinogenicity study (similar to EU method B.33) aluminium potassium sulfate dodecahydrate was administered orally via the diet to 60 male and female B6C3F1 mice at concentrations of 0, 10000, 25000, 50000 and 100000 ppm. The animals were treated with the test item 7 days per week for a period of 20 months. The treatment does not exert tumourgenicity or any other toxic action (mortality, food consumption, body weights, organ weights and histopathology) in any dose group investigated. Based on the results the chronic NOAEL for both sexes can be considered to be 100000 ppm which equals 15000 mg/kg bw/day.