Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Remarks:
performed under GLP

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993
Reference Type:
publication
Title:
Investigation of the biodurabililty of wollastonite and xonotlite
Author:
Bellman, N., Muhle, H.
Year:
1994
Bibliographic source:
Environmental Health Perspectives, Volume 102, Suppl. 5, p191-195

Materials and methods

Objective of study:
other: elimination kinetics
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Wistar rats were exposed to the test substance via intratracheal instillation into the lungs. The distribution of the test substance in the lung was analysed by scanning electron microscopy after 2 and 14 days, 1, 3, and 6 months to determine elimination kinetics.
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): crystalline Silicic acid, calcium salt (xonotlite)
- Substance type: synthetic calcium silicate hydrate
- Physical state: solid (single crystals with acicular morphology)
- Analytical purity: confidential information
- Lot/batch No.: confidential information
- Expiration date of the lot/batch: confidential information
- Stability under test conditions: stable in study conditions
- Storage condition of test material: stable at normal room conditions
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, FRG
- Age at study initiation: about 10 weeks
- Weight at study initiation: about 200 g
- Housing: Individually in polycarbonate (MakrolonTM) type III cages
- Diet: Commercail chow in pellet form (Altromin 1324 N), fresh diet offered every week
- Water: Fresh, filtered tap water, offered fresh weekly or more often if necessary
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
No data

IN-LIFE DATES:
No data

Administration / exposure

Route of administration:
intratracheal
Vehicle:
other: 0.9% NaCl solution
Details on exposure:
TYPE OF INHALATION EXPOSURE: other: intratracheal instillation

TEST ATMOSPHERE:
Two fractions of the stock test materials were prepared using a dry sizing technique:
1) thoraric particulate mass, median aerodynamic diameter of 10 µm±1.0 µm, with a geometric standard deviation of 1.5 (±0.1)
2) respirable particulate mass, median aerodynamic diameter of 3.5 µm±0.3 µm, with a geometric standard deviation of 1.5 (±0.1)
Duration and frequency of treatment / exposure:
Single exposure
Doses / concentrations
Dose / conc.:
2 other: mg fibres in 0.3 mL of 0.9% NaCl solution
No. of animals per sex per dose:
30 animals/fraction or negative control
10 animals/positive control
Control animals:
yes
Positive control:
UICC crocidolite (substance with demonstrated high biopersistence)
Details on study design:
- Rationale for animal assignment (if not random): animals were allocated on a body weight bases to assure all animals had body weights within the mean weight ±20%
Details on dosing and sampling:
The following parameters were investigated:
- Distribution in the lungs, with Scanned Electron Microscopy (SEM)
- Body weight
- Lung weight
- Clinical signs
- Histopathology of the lung
Statistics:
Dunnets procedure - body weight and lung weight multiple comparison of means
Comparison of regression coefficients (Sachs, 1992) - clearance kinetics of different test materials
Fishers exact test - homogeneity of contingency tables for histopathological data

Results and discussion

Preliminary studies:
Not relevant

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Not relevant
Details on distribution in tissues:
Not relevant
Details on excretion:
Not relevant

Metabolite characterisation studies

Details on metabolites:
Not relevant

Any other information on results incl. tables

A fraction of 0.5% of xonotlite crystals was found to be longer than 5 µm. No effects were observed on survival, body weight and wet lung weights. Furthermore, the histopathological examination of the lungs did not reveal changes which could be related to the test material.

2 days after intratracheal instillation, SEM analysis showed minimal presence of xonotlite fibres or aggregations of such fibres in the lung. The estimated mass of single fibers was <10 µg per lung, in the thoraric fraction 0.4% of the mass fraction of single fibers present in the injected test material was detectable in the lungs, whereas only 0.08% of the alveolar fraction was detected. Furthermore, about 85 -89% of the agglomerates were eliminated. After 3 months, no fibers or agglomerates were detected. Based on the very rapid 2 -day clearance, it was not possible to calculate a half-time (half-time < 2 days).

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: crystalline calcium silicate hydrate is eliminated from the lung very fast
Under the conditions of the study, elimination of crystalline calcium silicate hydrate from the lungs after intratracheal instillation was very fast. No half time could be calculated as 2 days after exposure, minimal presence of crystalline calcium silicate hydrate was observed in the lung.
Executive summary:

Wistar rats were exposed to xonotlite via intratracheal instillation into the lungs. The distribution of the test substance in the lung was analysed by scanning electron microscopy after 2 and 14 days, 1, 3, and 6 months to determine elimination kinetics.

A fraction of 0.5% of xonotlite crystals was found to be longer than 5 µm. No effects were observed on survival, body weight and wet lung weights. Furthermore, the histopathological examination of the lungs did not reveal changes which could be related to the test material.

The elimination kinetics of xonotlite from the lung was very fast, 2 days after intratracheal installation, minimal presence of xonotlite fibers or aggregations of such fibers in the lung was observed. Therefore, no half-time could be calculated (half-time<2). The fast elimination may be due to fast dissolution of xonotlite crystals as a result of the small diameter and large surface. The absence of lesions in the lung may also be explained by dissolution of xonotlite.