Aluminum chloride, basic, reaction products with silica

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

chronic toxicity: inhalation

Remarks:

other: See deficiencies

Type of information:

experimental study

Adequacy of study:

key study

Study period:

June 1976 - Nov 1978

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study was completed before OECD guidlines were established, nevertheless it fulfills the essential requirements for determination of chronic toxicity by inhalation. Clinical chemistry and haematology were less vigorous, there was no urinanalysis or opthalmoscopy. Group sizes wre half those used in modern assays for carcinogenicity but sufficient for extended chronic toxicity but is only supplementary for carcinogenicity.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1980

Report date:

1980

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Study was carried out before guidelines were established, whole body inhalation study was used to examine chronic toxicity and detect carcinogenicity.

GLP compliance:

no

Remarks:

Study carried out before GLP established

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

oxo[(oxoalumanyl)oxy]alumane

EC Number:

614-074-2

Cas Number:

675106-31-7

Molecular formula:

UVCB

IUPAC Name:

oxo[(oxoalumanyl)oxy]alumane

Details on test material:

Saffil alumina fibre, Median diameters circa 3 microns and length circa 50 microns. Material is indefinitely stable at room temperature.

Test animals

Species:

rat

Strain:

other: Alpk/AP (Wistar derived)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Bred at ICI CTL
- Age at study initiation: Seven weeks old at delivery to lab
- Weight at study initiation: 143 g for Males +/- 20% , Females: 148 g +/- 20%
- Housing: 12 or 13 cages constructed in stainless steel mesh. in purpose built exposure chambers.
- Diet : Cubed powder 'O' ad libitum
- Water : Municipal supply ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): nominal 22 degrees C
- Humidity (%): neither controlled or recorded
- Air changes (per hr): During exposure minimum flow rate of 100 litres per minute was maintained
- Photoperiod (hrs dark / hrs light): 12 hours light/ dark cycle.

IN-LIFE DATES: From: June 1976 To: November 1978

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: Not measured, respirable dust selected using a Mines Research respirable sampler (MRE600).

Details on inhalation exposure:

Exposure in whole body chambers to target concentration of 12mg / m3 of respirable dust as measured using MRE600 portable dust monitor placed on top of the cages. Dusts were generated using a Timbrell dust generator.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Dust measured using MRE600 portable dust monitor.

Duration of treatment / exposure:

Interim sacrifices after 14 and 27 weeks, one rat per sex per group after 56 weeks exposure. Surviving rats in Saffil groups exposed for 86 weeks, and in asbestos group for 77 weeks.

Frequency of treatment:

7 hours per day, 5 days per week

Doses / concentrations

Remarks:

Doses / Concentrations:
For both saffil groups overall cumulative dose of 7000 mg/m3 hours respirable dust was used.
Basis:
analytical conc.

No. of animals per sex per dose:

Groups of fifty rats, 25 of each sex were used for each dust and for air control.

Control animals:

yes, concurrent vehicle

Details on study design:

Study was designed to compare aluminosilicate fibre as manufactured with the same material after artificial aging to mimic after use fibres and with the known pathogenic chrysotile asbestos.

Positive control:

UICC Chrysotile A

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
Animals examined before and after each exposure period and at least once a day when not exposed

DETAILED CLINICAL OBSERVATIONS: Yes
Thorough clinical examination including palpation for tumours at least fortnightly.

BODY WEIGHT: Yes
At study start, at removeal from chamber and subsequently every 2 weeks until termination

HAEMATOLOGY / Blood chemistry
- Time schedule for collection of blood: heart blood at sacrifice. Blood was also taken from the tail vein of 8 male and 8 female rats per group before exposure and at 14 and 27 weeks. Where possible the same rats were sampled at each time point.

- Parameters checked : Glucose, urea and alanine and aspartate transaminases were measured in plasma.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Full necropsy as soon as possible after death. Special attention to thoracic cavity and parietal pleura All macroscopic abnormalities and full tissue list sampled, Respiratory and digestive tracts, liver kidney, spleen adrenals heart, representative lymph nodes and gross abnormalities processed.

HISTOPATHOLOGY: Yes
Abnormalities were examined microscopically ( H and E with special stains at pathologist discretion) Other tissues were stored.
Samples of lung tissue from control rats and those inhaling chrysotile asbestos from both and 27 week sacrifice, were examined in the electron microscope for evidence of asbestos fibres in tissue.

Statistics:

Bodyweights: Student’s t test
Tumour incidence: Fishers exact test

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

There were no biologically significant intergroup differences in mortality. Although control rats tended to die earlier.

Mortality:

no mortality observed

Description (incidence):

There were no biologically significant intergroup differences in mortality. Although control rats tended to die earlier.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight - there were no statistically differences in males, though females that had inhaled heated saffil tended to lower body weight which reached statistical difference on some occasions. Pre exposure weights were lower for these rats so these minor

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

Urea, glucose, alanine and aspartate transaminase were measured in plasma

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Fibrosis in asbestos control, not in Saffil. Saffil fibres in lungs of exposed rats. 1 male sacrificed at 14 weeks had focal necrosis of olfactory epithelium with proliferation of Bowman's glands. Focal necrosis of olfactory epithelium was seen in all rat

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Excess tumors in asbestos control only generally seen late in the experiment. Tumors were of epithelial origin, adenomas and adinocarcinomas or squamous cell carcinomas. An adenoma of the nasal septum was seen in one male rat. One male rat in the asbestos

Effect levels

Dose descriptor:

NOAEL

Effect level:

> 12 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Mean body weights male rats(g) at selected intervals during the study

Weeks on test		control	Aged SAFFIL	UICC chrysotile	SAFFIL
0	Mean S D	144.9 7.1	142.5 13.2	142.9 9.8	142.5 7.0
88	Mean S D	571.2 40.0	575.6 51.8	568.7 36.8	575.1 44.8
100	Mean S D	543.5 54.8	542.4 56.7	511.5 47.5	554.2 50.9
120	Mean S D	448.2 47.0	455.2 43.7	461.0 42.6	462.7 31.6
128 term)	Mean S D	436.3 30.6	418.0 47.9	425.0 46.0	393.3 43.2

 

 

  

Mean body weights female rats(g) at selected intervals

 

Weeks on test		control	UICC chrysotile	SAffil	Aged SAFFIL
0	Mean S D	149.7 12.8	144.8 13.2	144.1 11.1	150.0 17.9
88	Mean S D	380.9 58.3	328.6* 50.2	340.3* 40.4	374.1 64.6
100	Mean S D	380.9 55.0	345.1 45.5	.335.2* 19.7	.369.8 .336.1
120	Mean S D	354.6 77.7	350.0 55.2	311.3 22.3	351.6 39.4
128 (term)32	Mean S D	318.0 45.3	388.0	281.8 11.1	338.8 43.2

Incidence of neoplastic findings and selected tumour types

	Control	Aged SAFFIL	UICC Asbestos	SAFFIL
Males
Number Examined*	19	19	19	13
Total number of neoplasms	11	12	17	12
Rats with benign tumours	6	7	6	4
Rats with malignant tumours	2	3	5	4
Pulmonary tumours
Adenoma	0	0	0	0
Adenocarcinoma	0	0	0	0
Carcinoma	0	0	1	0
Females
Number Examined*	19	20	20	19
Total number of neoplasms	29	31	36	28
Rats with benign tumours	11	13	9	9
Rats with malignant tumours	5	5	8	7
Pulmonary tumours
Adenoma	0	0	4	0
Adenocarcinoma	0	0	1	0
Carcinoma	0	0	2	0
Nasal sinus adenoma	0	0	1	0

Applicant's summary and conclusion

Conclusions:

Inhalation of polycrystalline fibres in either as manufactured or thermally aged forms at the maximally achievable aerosol concentrations did not result in fibrosis or other progressive lung disease in rats, no tumours of the respiratory tract or pleura were seen after Saffil inhalation. the positive control UICC chrysotile A asbestos produced the expected results.

Executive summary:

This study raises no concerns over the inhalation of the test material. However testing is difficult with a material one of whose essential properties is large diameter fibres which preclude more aggressive testing.