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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
15th August 1997 To:14th December 1997
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Only one sex was used and indeed is required by the related test protocol. All the exposures produced lung burdens that inhibited macrophage clearance of tracer particles, such exposures produce effects regardless of the materials causing this inhibition. Only one exposure concentration was used and this does not enable the complete comparison of does and effect for different materials,
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report date:
2001

Materials and methods

Objective of study:
other: The purpose of this study was to compare various fibres at identical concentrations during the development of substitute fibres for the present classified material therefore it is not possible to use this study to identify no effect levels etc as no dose
Test guideline
Qualifier:
according to guideline
Guideline:
other: ECB/TM/16/97
Deviations:
yes
Remarks:
high doses conc
GLP compliance:
yes (incl. QA statement)

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:
Exposure was to a test article prepared from commercial high purity RCF wool (sample designated d in tables) prepared by milling, grinding and size separation -as the activity of fibres is determined to a large part by their size, the sizes of the fibres in the test materials are detailed in table 1 in additional material section
Radiolabelling:
other: integrity of macrophage clearance from the lung was estimated by thoracic radioactivity measurements after a brief inhalation of tracer particles

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland
- Age at study initiation: 9-10 weeks
- Weight at study initiation: 110-120g at start of exposure
- Housing: polypropylene cage 2 rats /cage
- Diet (e.g. ad libitum):ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: 2weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C):22+-2C
- Humidity (%):55+- 15%
- Photoperiod (hrs dark / hrs light): 12 hours day/night cycle

IN-LIFE DATES: From: 15th August 1997 To:14th December 1997

Administration / exposure

Route of administration:
inhalation
Vehicle:
unchanged (no vehicle)
Remarks:
air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The aerosol was generated by a pneumatic disperser, static was neutralised using a 63 nickel radiation source. - nose only flow past system as described in doses and concentrations
- Method of holding animals in test chamber: Battelle tube
- Air flow rate: 1litre/min per rat
- Method of particle size determination: Samples of aerosol were collected membrane filters, these were weighed for gravimetric and fibres counted by SEM except for the amosite positive control where TEM was used
- Samples taken from breathing zone: yes

Duration and frequency of treatment / exposure:
6 hours/day 5 days /week -89days, to a target concentration of 150 fibres longer than 20 microns/ml
Doses / concentrations
Remarks:
Doses / Concentrations:
515+-139 WHO f/ml, 137+- 30 fibres longer than 20 micron/ml mass conc 58.6+-10.4 mg.m3
No. of animals per sex per dose / concentration:
57 males
Control animals:
yes, concurrent no treatment
Positive control reference chemical:
Amosite asbestos long fibered 146 f/ml
756+-133 WHO f/ml
146+-20 fibres longer than 20 micron/ml
mass conc 65+0.3 mg.m3
Details on study design:
The study was carried out at the same time on less biopersistent fibres
The controls were: Non fibrous particulate with the same composition as this fibre, a long fibre amosite asbestos and an unexposed group(air).
The state of macrophage mediated lung clearance was monitored by studying a group of rats exposed for 10 min to a radioactive aerosol. Retained
particulate estimated in live animals by counting the thoracic content of isotope

- Dose selection rationale: To ensure consistent dosing of long fibres with positive control
- Rationale for animal assignment (if not random):Randomly assigned by body weight using datatox systems so that mean weight of group was within 1% of overall mean

The EU guideline ECB/TM/16(97) rev. 1 was largely followed except that some animals were allowed to survive for one year after exposure for 90 days to enable any pathology to resolve or develop. Cell proliferation in the terminal bronchioles and in the lung parenchyma was measured by the BrDU method. The dose of fibres in the lung was estimated by counting the fibres in the ashed tissue. RCF fibres were counted by SEM and amosite by TEM Non fibrous aluminosilicate glass content was measured using chemical analysis for the aluminium content of the ash. The dust content of the lung associated lymph nodes was also measured. The integrity of macrophage clearance from the lungs was estimated by thoracic radioactivity measurements after a brief inhalation of tracer particles
Details on dosing and sampling:
Inhalation as described in doses above, fibres samples taken from breathing zone of animals for analysis by SEM and optical microscopy , biverate distribution and gravimeteric analysis.
Statistics:
Difference between groups were considered statistically significant at p<0.05. Data were analysed using analysis of variance. If the group means differed significantly by analysis of variance the means of the treated groups were compared with the means of the control groups based on the Dunnetts' test

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
None
Details on distribution in tissues:
NA
Details on excretion:
Half life clearance from lung see table 5

Metabolite characterisation studies

Metabolites identified:
not specified
Details on metabolites:
Material is not metabolised.

Any other information on results incl. tables

Table 3 Terminal Body weights (SD) male rats(g)

Control

Amosite asbestos

RCF

Non fibrous aluminosilicate

259.0 (17.4)

235.1 (11.8)

259.1 (22.6)

250.0

(8.7)

 

Table 4 Terminal lung weights

Control

Amosite asbestos

RCF

Non fibrous aluminosilicate

1.049 (0.080)

1.214

 (0.031)

1.188 (0.087)

1.425

(0.096)

Table 5 Clearance of test substance from the lung Mean (90%CL) days

Material

HALF TIME IN DAYS

Number of fibres

Number of WHO fibres

Number of fibres >20 microns long

Mass

RCF

338(286-389)

328(269-388)

145(120-170)

145(120-170)

Amosite

402(270-536)

502(298-706)

561(174-948)

444(295-594)

Non fibrous alumina silicate glass

 

 

 

91(79-102

Half times calculated according to ECB/TM/26 counts less than 5% of initial burden discounted.

Table 6 Clearance of Tracer particles from alveolar region of lung

Materials

Half time of alveolar tracer clearance (95 CL) days

 

5 days post exposure

6 months post exposure

Control

 

56

(54-58)

66

(60-73)

RCF

 

435

(243-594)

467

 (314-908)

AES

88

(79-98)

86

(79-95)

 

Nonfibrous aluminosilicate

1202

(778-2641)

infinite

Amosite asbestos

 

125

 (112-140)

81(

75-89)

All clearance times significantly slower than control at p<0.001

RCF, amosite and AES and the non-fibrous aluminosilicate glass deposited in the lung at concentrations that overloaded lung clearance. But the effect of the non-fibrous materials is much more extreme.

 

Applicant's summary and conclusion

Conclusions:
All the exposures produced lung burdens that inhibited macrophage clearance of tracer particles, such exposures produce effects regardless of the materials causing this inhibition
Executive summary:

Following this study a standard protocol for the 90 day study was adapted by the ECB. The EU guideline ECB/TM/16(97) rev. 1 was largely followed except that some animals were allowed to survive for one year after exposure for 90 days to enable any pathology to resolve or develop. Cell proliferation in the terminal bronchioles and in the lung parenchyma was measured by the BrDU method.. The dose of fibres in the lung was estimated by counting the fibres in the ashed tissue. RCF fibres were counted by SEM and amosite by TEM Non fibrous aluminosilicate glass content was measured using chemical analysis for the aluminium content of the ash, The dust content of the lung associated lymph nodes was also measured. The integrity of macrophage clearance from the lungs was estimated by thoracic radioactivity measurements after a brief inhaltion of tracer particles