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Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: well documented study according to EU Method B.33 (Combined Chronic Toxicity / Carcinogenicity Test)

Data source

Reference
Reference Type:
publication
Title:
Chronic toxicity and tumorigenicity study of aluminum potassium sulfate in B6C3F1 mice
Author:
Oneda S, Takasaki T, Kurowaki K, et al.
Year:
1994
Bibliographic source:
In Vivo 8(3):271-278

Materials and methods

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

Test material

Constituent 1
Reference substance name:
Aluminium potassium sulfate
IUPAC Name:
Aluminium potassium sulfate
Details on test material:
Aluminium potassium sulfate as dodecahydrate AlK(SO4)2*12 H2O (APS)Lot.No. M5P2968 from Nacalai Tesque Co., Ltd., Kyoto, Japan

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: basal diet
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Preliminary study: 5 weeks, daily dietConcentration: 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.Main study: 20 months, daily dietConcentrations: 10, 5, 2.5, 1 and 0 % (w/w)
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:Preliminary study: Concentration: 2, 1, 0.2 and 0% (w/w) Main study: Concentrations: 10, 5, 2.5. 1.0, 0 %Basis:nominal in diet
No. of animals per sex per dose:
5 groups of 60 animals of each sex and concentration
Details on study design:
Temperature: 23 +/- 2 °CRelative Humidity: 55 +/- 10 %12hr-light/12hr-dark cycle

Examinations

Observations and examinations performed and frequency:
Weekly control for clinical signs of illness or death, food consumption and body weight
Sacrifice and pathology:
Spontaneously died animals were necropsied.After 20 month: All surviving animals were killed by exsanguination 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, kidney adrenals and testes.These organs and the eye balls, harderian gland, submandibular gland, thyroid, thymus, trachea, bronchi, 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% neutralized formalin, embedded in paraffin, sectioned and stained with hematoxylin and cosin (HE).
Statistics:
Data were analyzed statistically by the students t-test for body weight and organ weights (absolute and relative weight), and X² testfor histopathological examinations.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
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

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
10 other: %
Based on:
test mat.
Remarks:
in diet
Sex:
male/female
Basis for effect level:
gross pathology
Dose descriptor:
NOAEL
Effect level:
15 000 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
as AlK(SO4)2*12H2O
Sex:
male/female
Basis for effect level:
other: calculated from daily basal diet of 3.5 g/d per mouse and start weight for male mouse of 22 g and 18 g for female mouse according to study
Dose descriptor:
NOAEL
Effect level:
8 160 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
AlK(SO4)2
Sex:
male/female
Basis for effect level:
other: calculated from AlK(SO4)2*12 H2O
Dose descriptor:
NOAEL
Effect level:
853 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
as Al from AlK(SO4)2
Sex:
male/female
Basis for effect level:
other: calculated from AlK(SO4)2

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The results of the present study indicate that long-term administration of a diet containing 10.0 % aluminium potassium bis sulphate (AlK(SO4)2*12H2O) does not exert tumorgenicity or any other toxic actions in B3C6F1 mice.Slight growth retardation compared with controls at 10% groups after 1 month.Slight increase of body weight at 1 and 2.5% groups after 3 month.Similar growth at 5% groups compared with controls.NOAEL-20 month B3C6F1 male/female mice oral: 10 % aluminium potassium bis sulphate *12H2O (w/w).NOAEL: 853 mg Al/kg bw/d = 8160 mg aluminium potassium bis sulphate/kg bw/d.
Executive summary:

The results of the present study indicate that long-term administration of a diet containing

10.0 % aluminium potassium bis sulphate (AlK(SO4)2*12H2O) does not exert tumorgenicity or

any other toxic actions in B3C6F1 mice.

Slight growth retardation compared with controls at 10% groups after 1 month.

Slight increase of body weight at 1 and 2.5% groups after 3 month.

Similar growth at 5% groups compared with controls.

NOAEL-20 month B3C6F1 male/female mice oral: 10 % aluminium potassium bis sulphate *12H2O (w/w).

NOAEL: 853 mg Al/kg bw/d = 8160 mg aluminium potassium bis sulphate/kg bw/d.