Aluminium sulphate

Carcinogenicity

Description of key information

 

- Weight of evidence studies: A lifetime study in rats and mice exposed via the drinking water to 5 ppm aluminium potassium sulphate and a 20-month feeding study in mice on aluminium potassium sulphate administered via the diet at 1, 2.5, 5 and 10%.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read-across substance; details of test item, environmental conditions not reported; only one dose tested; food and water consumption, hematology not reported

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Aluminum (as the Aluminum potassium sulfate) was administered to groups of Swiss mice of the Charles River CD strain, (54/sex/dose) at the concentrations of 5 ppm in drinking water for life-term.

GLP compliance:

no

Remarks:

pre-GLP

Species:

mouse

Strain:

Swiss

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Random-bred white Swiss mice of the Charles River CD strain were born in testing laboratory from purchased pregnant females from Charles River Mouse Farms, Inc., N. Wilmington, United States.
- Housing: Animals were housed 6/sex/cage
- Diet: The diet was composed of whole untreated Balborye flour (60 %), powdered skim milk (30 %), corn oil (9 %), and iodized sodium chloride (1 %), with added vitamins and iron; ad libitum
- Water: Basal drinking water, doubly deionized and with no detectable cations, contained soluble salts as simple complexes (in ppm): zinc, 50; manganese, 10; copper, 5; chromium, 5; cobalt, 1; and molybdenum, 1., ad libitum

Route of administration:

oral: drinking water

Vehicle:

unchanged (no vehicle)

Details on exposure:

No data

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

Life-term

Frequency of treatment:

Daily

Post exposure period:

None

Dose / conc.:

5 ppm (nominal)

Remarks:

5 ppm aluminum (as the potassium sulfate);
nominal in water

No. of animals per sex per dose:

54

Control animals:

other: basal water without any of the abnormal metals

Details on study design:

No data

Positive control:

None

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: Rats were weighed at days 30, 60, 90, 120, 150, 180, 360 and 540.

FOOD CONSUMPTION: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY AND CLINICAL CHEMISTRY: No data

URINALYSIS: No data

Sacrifice and pathology:

Animals dying a natural death were weighed and dissected, gross tumors were detected, and some sections were made of heart, lung, liver, kidney, and spleen for microscopic examination.

Other examinations:

None

Statistics:

- Student's t test was used to test the difference between control and treatment groups for mortality and body weight.
- Chi-square analysis was used to test the difference between control and treatment groups for incidence of tumors.

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):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

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:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

MORTALITY:
No marked effects in longevity of the mice were observed.

BODY WEIGHT AND WEIGHT GAIN:
Aluminum did not affect growth and body weights when compared with the controls.

HISTOPATHOLOGY: NEOPLASTIC
- Leukemia lymphoma was found most frequently in the female mice treated with aluminum, however no significant difference was observed in males when compared with control group.

Dose descriptor:

NOAEL

Effect level:

5 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Aluminum had slight effects (p<0.05) in females

Remarks on result:

not determinable

Remarks:

no NOAEL identified. Effect type:carcinogenicity (migrated information)

Table 7.7/1: Body weight - results

 

Age (days)	Control	Aluminum 5 ppm
Males	Body weight (g)
30	21.7 ± 0.33	21.4 ± 1.44
60	33.0 ± 0.33	32.2 ± 1.82
90	37.7 ± 0.53	36.7 ± 1.06
120	41.5 ± 0.53	40.2 ± 1.35
150	43.0 ± 0.64	42.1 ± 1.64
180	43.5 ± 0.95	43.4 ± 1.18
360	45.2 ± 1.59	47.5 ± 1.68
540	37.7 ± 2.12	41.0 ± 2.80
Females	Body weight (g)
30	20.5 ± 0.49	18.8 ± 0.81
60	26.5 ± 0.36	25.5 ± 0.81
90	31.1 ± 0.83	30.5 ± 0.81
120	34.5 ± 0.83	34.1 ± 1.33
150	35.7 ± 1.13	36.4 ± 1.64
180	37.6 ± 1.23	38.3 ± 1.64
360	43.0 ± 3.00	44.4 ± 3.05
540	34.5 ± 2.32	35.7 ± 2.78

 

Table 7.7/2: Effects of trace metals on tumors, edema, and blanching of the incisor teeth of mice fed for life

Group	No. autopsied	Mean weight at death	No. with white teeth	Edema	Tumors
					No.	Multiple	LL	Lung	% of mice with tumors
Males
Control	38	28	3	0	11	2	3	5	28.9
Aluminum 5 ppm	41	28	11	10	15	9	9	9	36.6
Females
Control	47	26	19	3	14	4	3	9	29.8
Aluminum 5 ppm	41	33	5	4	19	12*	10**	11	46.3

*P<0.025; **significance of difference between means by chi-square p<0.05

 

Table 7.7/3: Life-spans and longevities of mice fed on aluminum

Group	No. mice	Mean	50 % dead	75 % dead	90 % dead	Last	Longevity
Males	days
Control	54	540	602	648	789	1010	920 ± 28.2
Aluminum 5 ppm	54	568	568	668	819	1086	936 ± 48.9
Females	days
Control	54	533	539	622	691	1001	823 ± 60.3
Aluminum 5 ppm	54	533	524	611	702	958	846 ± 44.0

Conclusions:

Under the test conditions, aluminum induced the gross tumors in females.

Executive summary:

In a carcinogenicity study, Aluminum (as the potassium sulphate) was administered to groups of Swiss mice of the Charles River CD strain (54/sex/dose) at the concentrations of 5 ppm in drinking water for life-term. Control animals were treated with basal water. Rats were weighed at days 30, 60, 90, 120, 150, 180, 360 and 540. Animals dying a natural death were weighed and dissected, gross tumors were detected, and some sections were made of heart, lung, liver, kidney, and spleen for microscopic examination.

No marked effects in longevity of the mice were observed. Aluminum did not affect growth and body weights when compared with the controls. Leukemia lymphoma was found most frequently in the female mice treated with aluminum, however no significant difference was observed in males when compared with control group.

Under the test conditions, aluminum induced the gross tumors in females.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

850 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Quality of whole database:

Non-GLP, possibly non-OECD study but sufficient to determine an adequate conclusion.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification for carcinogenicity according to the Regulation (EC) No. 1272/2008 (CLP).

Self classification:

Based on the available data, the substance is not classified for carcinogenicity according to the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.

Additional information

The available existing carcinogenicity studies are of low quality and are not adequate to conclude definitively on the potential carcinogenicity of aluminium sulphate. However, the available data do not indicate any concern with regard to potential carcinogenic activity in either rats or mice.

The available epidemiological studies provide limited evidence that certain exposures in the aluminium production industry are carcinogenic to humans, giving rise to cancer of the lung and bladder. However, the aluminium exposure was confounded by exposure to other agents including polycyclic aromatic hydrocarbons, aromatic amines, nitro compounds and asbestos, most of which are known carcinogens. Thus it was concluded that there is no evidence of increased cancer risk in non-occupationally exposed persons and indicates that aluminium itself is not a human carcinogen (IARC, Monograph 100F, 2012).

This view is also shared by the SCCS (2014) that stated that the available information does not support any concern regarding the potential carcinogenicity of aluminium compounds.

Both ATSDR and the WHO conclude that there are no indications for the carcinogenic potential of aluminium. From ATSDR 2008 (reported in the pesticide dossier by EFSA in 2009): The available data do not indicate that aluminium is a potential carcinogen. It has not been shown to be carcinogenic in epidemiological studies in humans, nor in animal studies using inhalation, oral and other exposure routes (Oneda et al. 1994, Schroeder & Mitchener, 1975). Although these studies have limitations ranging from use of only one species to a single dose level and limited histological examinations, the evidence strongly suggests that aluminium is not carcinogenic, indicating the additional carcinogenicity testing is not warranted.

There are some publications in the literature that suggest a weak association between the cosmetic use of aluminium and breast cancer but definitive evidence is lacking. Also, the WHO and SCCS in 2014 have reviewed these data and conclude that the reported association is spurious and of no concern, consequently these documents have not been included as either short summaries or as robust summaries in this dossier.

In terms of genotoxicity potential a GLP, Klimisch Grade 1 in vivo micronucleus study on aluminium hydroxide has been used as a read-across study in support of three key in vitro studies. The RA in vivo study provided a negative conclusion for in vivo genotoxicity, which is in agreement with the Key in vitro study results. A total of six in vitro studies and 1 in vivo study have been included as weight of evdence or disregarded studies. Some of these studies provided negative results that were in agreement with the conclusions of the Key and RA studies. However, some of the studies also provided contrary positive conclusions. But none of the studies reported as positive were GLP and were classified as Klimisch grade 3 or 4. An expert review revealed that none of these studies was considered to be sufficiently reliable to add any significant weight against the strength of the Key and RA studies.

In agreement with the general scientific concensus, the available data on carcinogenicity provides sufficient evidence that aluminium sulphate is not carcinogenic to animals or to humans.