Aluminium nitride

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Remarks:

combined repeated dose and carcinogenicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

publication

Title:

Chronic toxicity and tumorigenicty study of aluminium potassium sulfate in B6C3F1 mice

Author:

Oneda, S.

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

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

7784-24-9

Cas Number:

7784-24-9

IUPAC Name:

7784-24-9

Constituent 2

Reference substance name:

aluminium potassium sulfate dodecahydrate

IUPAC Name:

aluminium potassium sulfate dodecahydrate

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

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- 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

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

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
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:

N.A.

Duration of treatment / exposure:

20 months

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 1.0, 2.5, 5.0 and 10.0 (w/w)
Basis:
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:

N.A.

Examinations

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:

N.A.

Statistics:

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

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:

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:

MORTALITY
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.

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

ORGAN WEIGHTS
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.

HISTOPATHOLOGY: NON-NEOPLASTIC
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

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
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.

HISTORICAL DATA
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:

NOAEL

Effect level:

100 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects notified

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

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.