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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
chronic toxicity: inhalation
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From: 24th May 1988 To: 14th November 1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
There was little attempt to justify the use of the doses particularly the MTD. The gravimetric estimate of 30 mg/m3 was used for all types of fibre in two species with no further range finding efforts. Otherwise the study was a very high quality but the test substance used was heavily contaminated by non fibrous particulate not produced during the normal handling and use of this product. These particles were not completely enumerated during the study and their significance not realised.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1995
Report date:
1995
Reference Type:
publication
Title:
The Importance of fibre biopersistence and lung Dose in Determining the chronic Inhalation -Effects of X607,RCF1 and Chryotile Asbestos in rats
Author:
Hesterberg TW et al.
Year:
1998
Bibliographic source:
Toxicology and Applied Phamacology 153, 68-82

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
to make it suitable for use with fibres
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Reference substance name:
dioxosilane;oxo(oxoalumanyloxy)alumane - Amorphous glass fibre produced from silica dioxide and aluminium oxide and a range of oxides such as zirconia, ferric oxide, titanium oxide, magnesiumoxide, calcium oxide, other alkaline earth oxides including sodium oxide, potassium oxide,,barium oxides
Cas Number:
142844-00-6
Molecular formula:
amorphous glass Si(n)O(3n+1) polymeric anions bonded to Zr and Al(3+)
IUPAC Name:
dioxosilane;oxo(oxoalumanyloxy)alumane - Amorphous glass fibre produced from silica dioxide and aluminium oxide and a range of oxides such as zirconia, ferric oxide, titanium oxide, magnesiumoxide, calcium oxide, other alkaline earth oxides including sodium oxide, potassium oxide,,barium oxides
Details on test material:
- Name of test material (as cited in study report): RCF 1
- Substance type: mineral fibre
- Physical state: solid
- Analytical purity: assumed>99%
- Stability under test conditions:indefinite
- Batch number : 7309
- Storage condition of test material:room temperature , protected from the light

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Kingston, Stone Ridge, N.Y., USA
- Age at study initiation: 8 weeks
- Weight at study initiation: 130-150g
- Housing: during exposure and beginning of recovered, stainless steel wire cages, during major part of recovery period Macrolon Cages Type IV with standard softwood bedding
- Diet (e.g. ad libitum): pelleted standard Kliba 343, rat/mouse maintenance diet
- Water: ad libitum
- Acclimation period: 18 days from day of delivery

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12hrs

IN-LIFE DATES: From: 24th May 1988 To: 14th November 1990

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
nose only
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: Fibre sizes are not reported as MMAD. Fibre respirability is determined by fibre diameters with mass playing a secondary role. The aerosol:WHO fibres had a mean length of 16+- 3 and a diameter of 0.8+- 0.2.
Details on inhalation exposure:
Exposure was for 104 weeks. The aerosol was generated by a brush disperser, fed with test material. Static was neutralised using a 63 nickel radiation source. The airflow to each animal was 1 litre/min calculated to be laminar. The animals were restrained in Battelle tubes.

-GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: flow -past nose-only design
- Method of holding animals in test chamber: makrolon tubes, batelle?
- System of generating particulates/aerosols: fibres were aerosolised using a stepping motor and stainless steel brush to bring them into the tangential air stream, following aerosolisation the fibres passed through a Nickel63 charge neutraliser to reduce electrostatic charge
- Temperature, humidity, pressure in air chamber: 22degC, 30-70%
- Air flow rate: 0.9 litre/ airport/min?
- Method of particle size determination: fibre size measurements carried out by SEM

TEST ATMOSPHERE
- Brief description of analytical method used: mass concentration (gravimetric), fibre number concentration, fibre size measurements and impactor sampling.
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Fibres were collected on membrane filters and quanitified by weighing and microscopy. Fibre lengths were measured using light microscopy and diameters using SEM.
Duration of treatment / exposure:
104 weeks followed by 23 weeks recovery (until survival less than 20%)
Frequency of treatment:
6 hours/day/5days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
RCF1 - 162 WHO f/ml +/- 37
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
RCF1 - 91 WHO f/ml +/- 34
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
RCF1 - 36 WHO f/ml +/-17
Basis:
analytical conc.
No. of animals per sex per dose:
140 males
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:as fractions of the dose used in the study report number 092507 (30mg) section 7.7.2
- Rationale for animal assignment (if not random):random

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily prior and following exposure and once daily on non- exposure days

BODY WEIGHT: Yes
- Time schedule for examinations:each during acclimation period , weekly dueing the first 13 weeks and at least monthly thereafter

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
Samples of neoplastic tissue were taken and sent frozen in liquid nitrogen to CIIT North Carolina. Lungs were examined under a dissection microscope for detection and identification of small macroscopic lesions. Lungs were inflated with formaldehyde photographed and sections taken for histopathology after sacrifices at 13, 26, 39 and 52 weeks lungs were instilled with Karnowski's fixative and sampled as detailed in full study report.
Statistics:
Body weight and organ weight were analysed using Dunnetts' test ,age specific survival rates were calculated . Statistical evaluations for the neoplastic lesions was performed according to Peto et al 1980.

Results and discussion

Results of 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):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Other effects:
not specified
Details on results:
The exposures and tumour and fibrosis data are shown in table 1

Effect levels

Key result
Dose descriptor:
LOAEC
Remarks:
Fibrosis
Effect level:
ca. 9 - < 16 mg/m³ air
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Remarks on result:
other:
Remarks:
Fibrosis at 16 and 9 mg/m3 just reached significant levels but not at the 3 mg/m3. None of the tumour incidences were higher than the the historical control values for this strain of animals

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1 Exposure conditions and results for the 3 exposure levels of RCF and control (air).

Number of animals at risk

Aerosol conc. f/ml (SD)

Mg/m3 (SD)

Concentration of Non-fibrous particles <3µm diameter

(mean no. of particles/ml)

 

Aerosol fibre dimensions

 

Geometric mean (GSD

Fibrosis

 

(Wagner Grade)

Tumour Incidence

%

 

diameter

length

Lung

Mesothelial

132

na

na

na

na

1

0.8

0

 

126

162 (37)

16.5 (1.1)

156

0.82 (1.99)

13.8 (2.4)

4.2

1.6

0

128

91 (34)

 8.8 (0.7)

141

0.80 (2.03)

13.9 (2.5)

4.0

3.9

0.8

125

36 (17)

3.0 (0.4)

51

0.80 (2.06)

13.5(2.6)

3.2

1.6

0

Applicant's summary and conclusion

Conclusions:
The particle contaminated RCF1 was still capable of causing overload at these low concentrations used but not until late in life consequently there was not a significant increase in tumour burden.
Executive summary:

The deficencies in the 30mg/m3 study (section 7.5.3.5) were repeated in this lower dose study. Only one of the four samples of RCF was tested at these concentrations