Dialuminium chloride pentahydroxide

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

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Read-across substance; few details of test item available, environmental conditions not reported; only one dose tested; food and water consumption not measured, hematology not reported. The types of tumours was not defined, histopathology has not been performed. Some animals died prematurely because of pneumonia, survivors treated with penicillin for 2 weeks.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Not applicable

GLP compliance:

no

Species:

rat

Strain:

Long-Evans

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Random-bred pregnant rats of the Long-Evans (BLU:LE) strain were purchased from Blue Spruce Farms, Altamount, N.Y., and their offspring were born and weaned in the testing laboratory.
- Housing: Animals were housed 4/sex/cage at weaning time, where they remained all their lives until natural death.
- Diet: The diet was made of seed rye flour (60%), dried skim milk (30%), corn oil (9%), iodized sodium chloride (1%) and assorted vitamins. To each kilogram of diet: ferrous sulfate, 100 mg: calcium pantothenate, 10 mg; niacin, 50 mg; pyridoxine hydrochloride, 1.0 mg ; and vitamin A, 5000 IU ; vitamin D, 1000 IU; ad libitum
- Water: Drinking water, ad libitum

Route of administration:

oral: drinking water

Vehicle:

unchanged (no vehicle)

Details on exposure:

None

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

Life-term

Frequency of treatment:

Daily

Post exposure period:

None

Remarks:

Doses / Concentrations:
5 ppm aluminum (as the potassium sulfate)
Basis:
nominal in water

No. of animals per sex per dose:

52

Control animals:

other: basal water without any of the abnormal metals

Positive control:

None

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: Rats were weighed at weekly intervals at first, and at monthly intervals for a year, and then at 3-month intervals.

FOOD CONSUMPTION: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

CLINICAL CHEMISTRY: Yes
- Blood samples were obtained from 12 rats of each sex and each group deprived of food for 18 hours.
- Parameters checked: Serum glucose, cholesterol and uric acid

URINALYSIS: Yes
- Parameters checked: Urine was tested semiquantitatively by sensitized paper for protein, pH and glucose.

Sacrifice and pathology:

At natural death, they were weighed, dissected, and gross pathological changes were described. Heart, lung, kidney, liver, spleen and tumors were fixed in Bouin’s solution, sectioned, stained with hematoxylin and eosin, and examined under light microscopy.

Other examinations:

None

Statistics:

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

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

males were heavier than controls after 1 year.

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:

effects observed, treatment-related

Description (incidence and severity):

Slight changes in serum glucose.

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Increase in the number of male rats with gross tumours, but malignancy rate was not increased.

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

malignancy rate was not increased in males or females.

Details on results:

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

BODY WEIGHT AND WEIGHT GAIN:
Compared with the controls, aluminum did not affect growth rates in females significantly, but males were heavier after a year of age.

CLINICAL CHEMISTRY
- No significant difference was observed between control and treatment groups for serum glucose and cholesterol in males and females, respectively. Statistically significant difference was observed between control and treatment groups for serum glucose and cholesterol in females and males, respectively. No marked difference was observed between control and treatment groups for serum uric acid.

URINALYSIS
- No significant was observed between control and treatment groups for protein, glucose and pH.

ORGAN WEIGHTS
- No significant difference was observed between control and treatment groups for organ weights.

HISTOPATHOLOGY: NEOPLASTIC
- Male rats given aluminum had more gross tumors than their controls, however no significant difference was observed in males between control and treatment groups.

Relevance of carcinogenic effects / potential:

Based on insufficient information, the effects are not considered as relevant to conclude on carcinogenic potential of aluminium sulfate.

Dose descriptor:

NOAEL

Effect level:

5 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Significantly increased incidences of gross tumors reported for male rats exposed to 0.5 ppm (estimated to 0.6 mg aluminium/kg bw/d as aluminium potassium sulfate.

Remarks on result:

not determinable

Remarks:

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

See the attached document for information on tables of results

Conclusions:

The authors of the study concluded that at the dose levels used, Aluminium potassium sulphate had little detectable effects in rats.

Executive summary:

In a carcinogenicity study, Aluminum (as the potassium sulphate) was administered to groups of Long-Evans rats (52/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 weekly intervals at first, and at monthly intervals for a year, and then at 3-month intervals. Urine was tested for protein, pH and glucose. Serum glucose, cholesterol and uric acid were analysed. Necropsy and histopathological examination performed at the end of study.

No marked effects in longevity of the rats were observed. Compared with the controls, aluminum did not affect growth rates in females significantly, but males were heavier after a year of age. No significant difference was observed between control and treatment groups for serum glucose and cholesterol in males and females, respectively. Statistically significant difference was observed between control and treatment groups for serum glucose and cholesterol in females and males, respectively. No marked difference was observed between control and treatment groups for serum uric acid. No significant difference was observed between control and treatment groups in urinalysis for protein, glucose and pH. No significant difference was observed between control and treatment groups for organ weights.

At gross necropsy, 13/25 (52%) aluminium treated male rats were found to have tumors compared to 4/26 (15.4%) controls. Six of the tumors in the aluminium-treated males were malignant compared to two malignacies in the control rats, but the percentage of the total tumours that were malignant was the same (46% in aluminium group vs 50% in the control group). In females, the % number of animals with tumours was smaller in the aluminium exposed group and the % number of malignant tumours was also smaller in the alumium group. No further deails on , for example type and site of tumors were presented. No histopathological results were reported. Also the water consumption was not provided and therefore the exact intake of aluminium is unknow, The ATSDR calculated a dose equivalent of 0.6 mg/kg bw/d based on the average water consumption of adult rat.

Under the test conditions, there was a statistically significant increase in the number of male rats with gross tumors (p<0.005) but there was no increase in the rate of malignancy. In females the number of rats with gross tumours was about the same as in controls and the rate of malignancy was slightly lower than controls. The conclusion of the author is that aluminium sulphate is non-tumourigenic.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: The publication is not available and only the abstract could has been retrieved.

Reason / purpose for cross-reference:

read-across source

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Route of administration:

oral: feed

Duration of treatment / exposure:

20 months

Conclusions:

The results of the present study indicate that long-term administration of aluminium potassium sulfate does not exert tumorigenic or any other toxic actions in B6C3F1 mice.

Executive summary:

The tumorigenic potential of aluminum potassium sulphate [A1K (SO4)2 12H2O, APS], a compound which exists widely in the environment, was investigated in B6C3F1 mice. APS was administered in the diet for 20 months at dose levels of 1.0, 2.5, 5.0 and 10.0% (w/w). One group receiving the basal diet served as the control. Body weight gain in both sexes was decreased in the 10.0% APS treated group, and increased in the 1.0 and 2.5% APS treated groups. 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 APS treated groups. The survival rate showed a tendency to increase in both sexes in all the APS treated groups. In the tumor pathology, the incidence of hepatocellular carcinoma was significantly decreased in the males in the 10% APS treated group. The incidence of hepatocellular carcinoma was significantly decreased in females in all groups including the control group. As regards the nontumorous pathology, the incidence of myocardial eosinophilic cytoplasm showed a significant dose-dependent decrease in males in the APS treated groups. A comparison between the sexes revealed a significant decrease in the incidence of hepatocytic anisonucleosis, myocardial eosinophilic cytoplasm and acinar cell vacuolation of the submandibular gland in the females; and lymphocyte infiltration in renal cortex and pelvis, and vacuolation of cerebellar white matter were noted in the males.

The results of the present study indicate that long-term administration of APS does not exert tumorigenic or any other toxic actions in B6C3F1 mice.

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 chloride hydroxide 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 chloride hydroxide sulphate is not carcinogenic to animals or to humans.