Aluminium potassium bis(sulphate)

Endpoint summary

Description of key information

NOAEL-20 month chronic oral systemic toxicity mouse: 8160 mg/kg bw/d Aluminium potassium bis sulphate 
NOAEC-86 weeks chronic inhalative systemic toxicity rat: 6.2 mg/m³ Aluminium potassium bis sulphate (calculated)
NOAEL-43 days subchronic dermal systemic toxicity human: 8.52 mg /kg bw/d Aluminium potassium bis sulphate (calculated)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

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)

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.33 (Combined Chronic Toxicity / Carcinogenicity Test)

Deviations:

not specified

GLP compliance:

not specified

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

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

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

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.

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

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

Critical effects observed:

not specified

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

8 160 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Quality of whole database:

well documented chronic long-term study.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: peer-reviewed report and publication, basic data given

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

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: No data- Age at study initiation: No data- Weight at study initiation: No data- Fasting period before study: No data- Housing: No data- Diet: ad libitum- Water: ad libitum- Acclimation period: No dataENVIRONMENTAL CONDITIONS- Temperature (°C): 25 °C- Humidity (%): 50% ± 10%- Air changes (per hr): No data- Photoperiod (hrs dark / hrs light): No data

Route of administration:

inhalation: dust

Type of inhalation exposure:

not specified

Vehicle:

not specified

Details on inhalation exposure:

The rats were exposed in 1.4 m³ inhalation chambers that could house a total of 40 adult rats or, short-term, 50 young rats. Dust clouds were generated using dispensers (Timbrell, Hyett and Skidmore , Ann. Occup. Hyg., 1968, 11: 273) with modifications after 2 months of exposure (Beckett, Ann. Occup. Hyg., 1975, 18:187) that resulted in an improvement in concentration stability.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Respirable dust concentrations were measured with size-selective gravimetric dust samplers (Casella Type 113A; Dunmore, Hamilton and Smith, 1964). The collected samples were weighed at the end of each day’s exposure and, if necessary, modifications to air flow were made to correct variations. Total atmospheric samples were taken from the exposure chambers for 1-hour periods during the exposure. These samples, together with the readings from the Casella dust samplers, were used to estimate the respirable fraction.

Duration of treatment / exposure:

86 weeks for the test fibres; 77 weeks for the positive control;86 weeks, followed by 42-week observation period

Frequency of treatment:

6 hours a day (frequently extended by 2-3 hours) 5 days a week,6h/d, 5d/week, 86 weeks, 42-week observation period

Remarks:

Doses / Concentrations:Saffil – 2.18 mg/m³; “Aged” Saffil – 2.45 mg/m³; UICC chrysotile asbestos – 4.57 mg/m³ - 2.18 or 2.45 mg Al-oxide/m³Basis:nominal conc.

No. of animals per sex per dose:

50 animals per group (25 of each sex)

Details on study design:

Interim killings were performed at 14 weeks (2 animals of each sex per group) and 27 weeks (2 animals of each sex per group) and at 53 weeks (one animal of each sex per group) of the experiment. The other animals were allowed to live until they died, appeared distressed, or until 85% mortality (averaged over all groups) was reached.

Positive control:

Yes. Exposed to a standard reference sample of UICC chrysotile A (Rhodesian) asbestos obtained from the Medical Research Council Pneumoconiosis Research Unit, Llandough Hospital, Penarth, Glamorgan.

Observations and examinations performed and frequency:

Frequency of the observations and examinations:No information on frequency of health monitoring is provided. Pathology examination was performed at 14, 27, 53 weeks of the experiment, after animals’ natural death, killing because of distressed condition or at the termination of the experiment when 85% mortality was reached. Sacrifice and Pathology (methods):The animals were killed by overexposure to halothane BP The lungs were removed and inflated with formol saline; the nasal cavity was irrigated with formol saline also. Grossly abnormal tissues and samples of the major organs were fixed in formol sublimate and embedded in paraffin; 5 µm sections were cut and stained with haematoxylin and eosin. A median sections from each lung lobe were also stained and examined.

Sacrifice and pathology:

Gross Pathology: Yes Histopathology: Yes

Other examinations:

The other lung sections were stained with van Gieson’s stain for collagen and by Gordon and Sweet’s method for reticulin.

Statistics:

Statistical analysis was not conducted; the results are presented qualitatively.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

not specified

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 specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

Non-neoplastic lesionsHistopathological examination at interim killing At 14, 27 and 53 weeks lesions characteristic of a low grade pneumonitis were seen in both treated and control animals. The lesions were attributed to respiratory infection.Generally there was a minimal reaction to both types of alumina fibres; Saffil fibres were seen in alveolar macrophages and in the superficial mediastinal lymph node of one animal killed at 27 weeks; in one animal Saffil fibres were seen in an area of alveolar epithelialization. Other lesions were described as typical of the Alderley Park rat colony and not due to treatment. Focal necrosis and regeneration of olfactory epithelium was seen nasal cavity tissue of 2 animals exposed to Saffil fibres and in one animal exposed to asbestos. Histopathological examination at animals’ death or terminal killing Saffil fibres were seen in the lungs of most rats exposed to Saffil. The observed effect was limited to pigmented alveolar macrophages.A minimal alveolar epithelialization was observed in some control animals and in one female exposed to Saffil as manufactured. The number of animals with alveolar epithelialization was slightly higher in rats exposed to aged Saffil; this lesion was minimal in most animals, was more prevalent in females than in males, and was no longer evident after 106 weeks. In the authors’ opinion, this lesion might be at least partly attributable to intercurrent infection. There was no fibrosis in the lungs of the Saffil-treated animals.In some animals, small numbers of Saffil fibres were seen in nasal passages with evidence of slight irritation of the nasal mucosa with minimal focal necrosis. Degeneration of olfactory epithelium with replacement by respiratory epithelium seen in all groups was attributed to spontaneous age-related change. Positive control In animals exposed to asbestos, a minimal asbestosis was detected at week 14, which progressed to slight asbestosis by week 53 and became more marked as the experiment continued. All animals exposed to asbestos showed asbestosis of some degree. NeoplasmsNo pulmonary tumors (either benign or malignant) were found in the negative control (16 males and 18 females examined), in rats treated with Saffil fibres as manufactured (13 males and 19 females examined) or treated with aged Saffil (19 males and 19 females examined). In the positive control, 2 tumors (1 adenoma and one squamous cell carcinoma) were found among 19 examined male rats, and 7 tumors (4 adenomas, 1 adenocarcinoma and 2 squamous cell carcinomas) among 19 examined female rats. The tumors in the positive control were observed late in the experiment (the first benign tumor at 109 weeks and malignant tumors – at weeks 128 and 129). Examination for extrapulmonary tumors did not include interim kills. There were no significant group differences in the frequency of extrapulmonary tumors (see table 1).

Dose descriptor:

NOAEC

Effect level:

2.45 mg/m³ air

Based on:

test mat.

Sex:

not specified

Basis for effect level:

histopathology: neoplastic

histopathology: non-neoplastic

Critical effects observed:

not specified

Table 1:

	Number examined		Benign tumors		Malignant tumors
	male	female	Male	female	male	female
Negative control	19	19	9	21	2	8
Positive control	19	20	10	23	5	6
Saffil as manufactured	13	19	8	20	4	8
“Aged” Saffil	19	20	9	26	3	5

Conclusions:

Exposure to both types of alumina fibres produced minimal pulmonary reaction and no fibrosis. There were no lung tumors in the Saffil treated groups, and no significant group difference in the frequency of extrapulmonary tumors was observed. The authors concluded that the pulmonary reaction to Saffil fibres observed in this study is consistent with their classification as biologically inert materials.Pigott et al. did not find evidence of lung fibrosis in rats exposed to 2.18 or 2.45 mg/m3manufactured or aged Saffil alumina fibres; Saffil alumina fibre is a refractory material containingaluminium oxide (insoluble) and about 4% silica. The animals were exposed for 86 weeks followedby a 42-week observation period.NOAEL = 2.45 mg Al2O3/m³ airCalculated for Aluminium potassium bis sulphate:NOAEC = 6.20 mg Aluminium potassium bis sulphate/m³ air.

Executive summary:

Pigott et al. (1981) reported no evidence of fibrosis in a repeated dose inhalation study that administered alumina fibres (Saffil) at levels between 2 and 3 mg/m³ for 86 weeks. The respirable fraction of the particulates was 30 - 40% and the median diameter ca. 3.0 μm). The only pulmonary response observed was the occurrence of pigmented alveolar macrophages. The authors reported qualitatively that a minimal alveolar epithelialization was seen in control animals but that the numbers were slightly higher in rats dosed with aged Saffil. There were no lung tumors in the Saffil treated animals, and no significant group difference in the frequency of extrapulmonary tumors.

Pigott et al. did not find evidence of lung fibrosis in rats exposed to 2.18 or 2.45 mg/m3 manufactured or aged Saffil alumina fibres; Saffil alumina fibre is a refractory material containing aluminium oxide (insoluble) and about 4% silica. The animals were exposed for 86 weeks followed by a 42-week observation period. NOAEC = 2.45 mg Al2O3/m³ air

Calculated for Aluminium potassium bis sulphate:

NOAEC = 6.20 mg Aluminium potassium bis sulphate/m³ air.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

6.2 mg/m³

Study duration:

chronic

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: dermal

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: peer-reviewed report

Qualifier:

no guideline available

Deviations:

not specified

Principles of method if other than guideline:

In the study of Flarend et al. (2001), 26-Al-chlorohydrate (aluminum complex inantiperspirant) was applied to a single underarm of one man and one woman.:Aluminium chlorohydrate (ACH), the active ingredient in many antiperspirants, was labelled with the radioisotope 26Al. The labelled ACH was then fractionated into about 100 samples using gel filtration chromatography. Each fraction was analyzed for 26Al and total aluminium content. Aluminium-26 was only detected in the fractions that also contained aluminium, which verified that the ACH was uniformly labelled. 84 mg of the labelled ACH was then applied to a single underarm of two adult subjects with blood and urine samples being collected over 7 weeks. Tape-stripping and mild washings of the skin were also collected for the first 6 days.5 - 7.5 % Al concentration, daily exposure 50 - 75 mg Al.

GLP compliance:

not specified

Species:

other: human

Sex:

male/female

Type of coverage:

other: single underarm

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

5 - 7.5 % Al concentration, daily exposure 50 - 75 mg Al

Duration of treatment / exposure:

43 days

Remarks:

Doses / Concentrations:5 - 7.5 % Al concentration, daily exposure 50 - 75 mg Al Basis:other: 5 - 7.5 % Al concentration, daily exposure 50 - 75 mg Al

Observations and examinations performed and frequency:

cumulative urinary excretion

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

15% of the total absorbed dose of 6 - 9 µg Al/day = 0.9 - 1.35 µg Al/day or for a 70 kg worker 0.013 - 0.019 µg Al/kg bw/day.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

85% of the total absorbed dose of 6 - 9 µg Al/day are excreted via urine: 5.1 - 7.65 µg Al/day or for 70 kg worker 0.07 - 0.11 µg Al/kg bw/day.

Details on results:

No adverse effects were reported.

Dose descriptor:

NOAEL

Effect level:

>= 0.71 - <= 1.07 mg/kg bw/day (nominal)

Based on:

other: as Aluminium

Sex:

male/female

Basis for effect level:

other: Calculated from experimental results from daily exposure of 50 until 75 mg/day and a 70 kg worker.

Critical effects observed:

not specified

Conclusions:

The cumulative urinary excretion after 43 days following the application accounted for 0.0082% (male) andfor 0.016% (female) of the applied dose. Presumed dose level: 50-75 mg/day.Estimated percentage absorbed Al: up to 0.012 % Al or 6 - 9 µg Al/day. Excretion via urine: 85% of total absorbed Al or 5.1 - 7.7 µg Al/day. Resulting absorbed Al: 0.9 - 1.3 µg Al/day or for 70 kg worker 0.013 - 0.019 µg Al/kg bw/day.After correcting this fraction for the aluminum notexcreted in urine (15% of the absorbed dose), this application was estimated to result in adermal bioavailability of about 0.012%. On the basis of these data, the authors estimated thatthe amount of aluminum absorbed from regular use would be 0.25 μg/d.Therefore, a one-time use of ACH applied to the skin is not a significant contribution to the body burden of aluminiumand there is no relevant dermal repeated dose toxicity to be expected.NOAEL: 0.71 - 1.07 mg Al/ kg bw/day. Mean value: 0.89 mg Al /kg bw/day.Calculated for Aluminium potassium bis sulphate:NOAEL: 6.79 - 10.24 mg Aluminium potassium bis sulphate/ kg bw/day.Mean value NOAEL: 8.52 mg Aluminium potassium bis sulphate/kg bw/day.

Executive summary:

The cumulative urinary excretion after 43 days following the application

accounted for 0.0082% (male) and for 0.016% (female) of the applied dose.

Presumed dose level: 50-75 mg/day. Estimated percentage absorbed Al: up to 0.012 % Al or

6 - 9 µg Al/day. Excretion via urine: 85% of total absorbed Al or 5.1 - 7.7 µg Al/day.

Resulting absorbed Al: 0.9 - 1.3 µg Al/day or for 70 kg worker 0.013 - 0.019 µg Al/kg bw/day.

After correcting this fraction for the aluminum not excreted in urine (15% of the absorbed dose),

this application was estimated to result in a dermal bioavailability of about 0.012%.

On the basis of these data, the authors estimated that the amount of aluminum

absorbed from regular use would be 0.25 μg/d.

Therefore, a one-time use of ACH applied to the skin is not a significant contribution to the body burden of aluminium

and there is no relevant dermal repeated dose toxicity to be expected.

NOAEL: 0.71 - 1.07 mg Al/ kg bw/day. Mean value: 0.89 mg Al /kg bw/day.

Calculated for Aluminium potassium bis sulphate:

NOAEL: 6.79 - 10.24 mg Aluminium potassium bis sulphate/ kg bw/day.

Mean value NOAEL: 8.52 mg Aluminium potassium bis sulphate/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

8.52 mg/kg bw/day

Study duration:

subchronic

Species:

other: human

Additional information

Repeated dose toxicity: oral

Based on the Key study from Oneda et al. and the other supporting studies the NOAEL-20 month chronic oral systemic mouse

is NOAEL-20 month mouse = 8160 mg/kg bw/day Aluminium potassium bis sulphate.

Repeated dose toxicity: inhalation

Based on the peer-reviewed report (key study) from Gezondheidsraad Health Council of the Netherlands (2010) and the supporting study

from Finelli et al. the calculated NOAEC-86 weeks chronic inhalative systemic toxicity rat is 6.2 mg/m³ Aluminium potassium bis sulphate.

Repeated dose toxicity: dermal

Based on the peer-reviewed report from Environment Canada Health Canada (2010) and the publication from

Flarend et al (2001) the calculated NOAEL-43 days of the subchronic dermal study human is 8.52 mg/kg bw/day

Aluminium potassium bis sulphate.

Based on the results of the long-term Repeated Dose oral, inhalative and dermal toxicity studies:

no classification on repeated dose toxicity of the substance aluminium potassium bis(sulphate)

according EU regulation EU 1272/2008 and EU regulation 286/2011 (2. ATP).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Well documented chronic Key study.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Well documented Key study of Read-across substance aluminium oxide.
pH value in human and animal alveolar system is in the range of pH 7.4. At this pH value range
the adsorbed Al of AlK(SO4)2 should exist as Al(OH)3. This Al compound is not water soluble
and for this property comparable with the studied aluminium oxide.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Well documented study.

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: bone marrow; cardiovascular / hematological: heart; cardiovascular / hematological: lymph nodes; cardiovascular / hematological: spleen; cardiovascular / hematological: thymus; digestive: liver; digestive: pancreas; digestive: stomach; glandular: adrenal gland; glandular: mammary gland; glandular: thyroids; neurologic: brain (multiple sections); neurologic: eyes (retina, optic nerve); neurologic: pituitary; respiratory: lung; respiratory: trachea; urogenital: epididymides; urogenital: kidneys; urogenital: ovaries; urogenital: prostate; urogenital: testes; urogenital: uterus; urogenital: vagina; other: skin

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: lung

Repeated dose toxicity: dermal - systemic effects (target organ) urogenital: urinary bladder

Justification for classification or non-classification

Based on the results of the long-term Repeated Dose oral, inhalative and dermal toxicity studies:

no classification on repeated dose toxicity of the substance aluminium potassium bis(sulphate)

according EU regulation EU 1272/2008 and EU regulation 286/2011 (2. ATP).