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Toxicological information

Carcinogenicity

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Description of key information

- Key study: life time study in mice exposed via drinking water to 5 ppm aluminium potassium sulphate: negative

- Supporting studies: A lifetime study in rats 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%: negative

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:
key study
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:
reference to same study
Reason / purpose:
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 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 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. 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. Value mentioned in the SCCS Opinion on the safety of aluminium in cosmetic products (2014) was used as the NOAEL.

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The available existing carcinogenicity studies are of low quality and are not adequate to conclude definitively on the potential carcinogenicity of Aluminium chloride basic. 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 (no indication of carcinogenicity up to 850 mg Al/kg bw/day in animal's studies).

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 seven in vitro studies and 4 in vivo studies have been included as weight of evidence 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 chloride basic is not carcinogenic to animals or to humans.

Read-Across Studies

It is considered that a read-across from aluminium potassium sulfate to Aluminium chloride basic is justified and robust because the two salts have similar levels of absorption of aluminium after oral dosing (Priest., K 2010 - see toxicokinetics section)

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,Aluminium chloride basic is :

- not classified for carcinogenicity according to the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.