Aluminium potassium bis(sulphate)

Repeated dose toxicity: inhalation

Administrative data

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

Data source

Reference

Reference 1

Reference Type:

secondary source

Title:

Aluminium and aluminium compounds

Author:

Gezondheidsraad Health Council of the Netherlands

Year:

2010

Bibliographic source:

Health Council of the Netherlands

Reference 2

Reference Type:

publication

Title:

Effects of long term inhalation of alumina fibres in rats

Author:

Pigott GH, Gaskell BA, & Ishmael Jer FL, & Haseman JK

Year:

1981

Bibliographic source:

Br J Exp Pathol, 62: 323-331

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:

Aluminium oxide

IUPAC Name:

Aluminium oxide

Details on test material:

The test materials were Saffil alumina fibres as manufactured and after thermal “aging”, supplied by I.C.I. Ltd, Mond Division, The Health, Runcorn, Cheshire. Saffil fibres were supplied in 2 major batches; the third batch derived from the second by ball milling was used during the last 8 weeks of exposure.“Aged” fibres were supplied in three batches. During the last 6 weeks of exposure, samples prepared from batch 3 by ball milling were used but were not additionally characterized. Chemical analyses of the fibre samples are not reported. It is stated in the introduction that Saffil alumina fibre contains about 4% silica

Test animals

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

Administration / exposure

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

Doses / concentrations

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.

Examinations

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.

Results and discussion

Results of examinations

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).

Effect levels

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

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.