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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
It was not possible to grind the test substance to a fine powder able to generate an appropriate inhalation atmosphere for testing as shown in the feasibility report presented in 7.2.2. According to ECHA guidance document R7.A for inhalation route, no testing is required if it is not technically possible to generate a testing atmosphere Provided that testing is not possible, read-across to individual constituents is ventured for C&L purposes Studies on chronic inhalation of aluminium oxide forms also support the characterization of aluminium oxide as an inert dust of limited toxicological profile

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1981

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Study performed before EU/OECD protocol establishment
GLP compliance:
no
Remarks:
Study performed before EU/OECD protocol establishment

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Saffil fibres (Aluminium oxide with 4% silica) before and after thermal ageing particle size by count: Saffil:98-99% < 5 μm, 87-89% < 4μm, 40-50%< 3 μm, 6-11%< 2 μm,
Aged Saffil: 97-98%< 5 μm, 86%< 4 μm, 29-48%< 3 μm, 1-6%< 2 μm, 0-0.2%< 1 μm,
mean diameter: Saffil : 3-3.2μm, Aged Saffil: 3.05-3.3 μm
Length distribution: Saffil:10.5-35 μm, Aged Saffil: 56-67 μm

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
40 rats in 8 cages. The chambers were housed within a Portkabin and filtered conditioned air was blown through the chambers continuously. A sensor in the common extract duct allowed feedback control of incoming air to maintain the chamber temperature at a nominal 25+/1 degrees C and the relative humidity nominally at 50% +/- 10%.

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
Animals were exposed to 2.18 mg Saffil/m3, 2.45 mg respirable aged Saffil/m3 or asbestos or control group for 21.5 months for a nominal 6h/day, and 5d/wk.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Respirable dust concentrations were measured using size-selective gravimetric dust samplers (Cassella type 113A; Dunmore, Hamilton and Smith, 1964) and the collected samples were weighed at the end of each day's exposure.
Duration of treatment / exposure:
88 weeks for Saffill fibres
77 weeks for asbestos
Each rat was allowed to live until it died or appeared distressed, until 85% mortality was reached
Frequency of treatment:
A nominal 6 h/day for 5 days/week. Occasionally the exposure times were extended by 2-3 hours.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
2.18mg/m3 Saffil fibres
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
2.45mg/m3 respirable aged Saffil
Basis:
nominal conc.
Details on study design:
40 rats in 8 cages exposed to 2.18 mg Saffil/m3, 2.45 mg respirable aged Saffil/m3 or asbestos or control group for 21.5 months (6h/day, 5d/wk). experiment terminated (all animals killed) when mortalities up to 85% in each group was reached.
Average respirable concentration by size-selective gravimetric dust samplers
Lungs and nasal cavity removed and inflated with formol as well as major organs. Lungs subsequently stained. Asbestosis grading (explained in text)

Examinations

Observations and examinations performed and frequency:
Lungs and nasal cavity removed and inflated with formol as well as major organs. Lungs subsequently stained. Asbestosis grading (explained in text).
Interim killings were performed at 14, 27 and 53 weeks.
Sacrifice and pathology:
Animals for interim killings, those in a distressed condition and survivors at termination were killed by overexposure to halothane BP and subject to immediate postmortem examination. Animals found dead were examined in a postmortem examination. The lungs were removed and inflated with formol saline and the nasal cavity was irrigated with this fixative. Samples of all grossly abnormal tissues and of the major organs were also taken for histopathology. The tissues were fixed in formol sublimate, embedded in paraffin wax and 5μm sections were cut and stained. After fixation, the lung lobes were separated and embedded whole in 3 blocks of paraffin wax. Each was trimmed down and a median section of each lobe was stained for histopathological examination.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Experiment was carried until 85% mortality
Mortality:
mortality observed, treatment-related
Description (incidence):
Experiment was carried until 85% mortality
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:
no effects observed
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:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
No asbestosis symptoms in Saffil groups. Saffil fibres found in alveolar macrophages. Reaction was generally minimal and confined to the presence of pigmented alveolar macrophages which contained the fibres. Minimally higher alveolar epithelialisation in
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
No asbestosis symptoms in Saffil groups. Saffil fibres found in alveolar macrophages. Reaction was generally minimal and confined to the presence of pigmented alveolar macrophages which contained the fibres. Minimally higher alveolar epithelialisation in
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Pulmonary neoplasms were seen only in the asbestos group. Incidence of other neoplasms was comparable in all groups and is age related
Details on results:
No asbestosis symptoms in Saffil groups. Saffil fibres found in alveolar macrophages. Reaction was generally minimal and confined to the presence of pigmented alveolar macrophages which contained the fibres. Minimally higher alveolar epithelialisation in Saffil groups than in controls which ceased after week 106. in a few animals of Saffil group slight irritation with focal necrosis of nasal cavity was seen. degeneration of olfactory epithelium was seen in all groups and was age related. Pulmonary neoplasms were seen only in the asbestos group. Incidence of other neoplasms was comparable in all groups and is age related

Effect levels

Dose descriptor:
NOAEC
Remarks on result:
not determinable
Remarks:
no NOAEC identified

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion