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Link to relevant study record(s)

Reference
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
Objective of study:
other: elimination kinetics
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. QA statement)
Radiolabelling:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system 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
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
Dose / conc.:
2 other: mg fibres in 0.3 mL of 0.9% NaCl solution
No. of animals per sex per dose / concentration:
30 animals/fraction or negative control
10 animals/positive control
Control animals:
yes
Positive control reference chemical:
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
Preliminary studies:
Not relevant
Details on absorption:
Not relevant
Details on distribution in tissues:
Not relevant
Details on excretion:
Not relevant
Details on metabolites:
Not relevant

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).

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.

Description of key information

Background

A key study is available in which the elimination of xonotlite/tobermorite from the lung was tested. Also the physicochemical properties are available to assess the toxicokinetics behaviour.

 

Physical and chemical properties

The physical/chemical properties that are of importance to assess the toxicokinetics behaviour of xonotlite/tobermorite are:

  • Molecular weight – xonotlite: 741.99g/mol, tobermorite 702.36 g/mol
  • Water solubility – decomposes in water: 37 mg/L based on silicium analysis
  • Particle size distribution – D (0.5) is between 35.7 um and 61.3 um.

    No particles were found under 0.417 µm and above 316.228 µm

  • Log Kow – not applicable (inorganic)
  • Vapour pressure – not applicable (inorganic)

 

Absorption

The calcium silicate hydrate is xonotlite/tobermorite, which are inorganic substances. Therefore a log Kow and vapour pressure is not applicable. The water solubility is moderate; the crystalline structure decomposes in water and the elements are present as ions in solution. Based on the water solubility study, a hydrolysis rate of <6 days was estimated.

 

Exposure through inhalation of xonotlite/tobermorite particles is the main route of possible exposure. The elimination kinetics (biodurability) of xonotlite/tobermorite was investigated by Bellman (1994), in a study in which the substance was administered by intratracheal instillation in rats. Elimination from the lungs was studied by scanning electron microscopy after 2 and 14 days, 1, 3, and 6 months.

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 days). The fast elimination may be due to fast dissolution of xonotlite crystals as a result of the small diameter and large surface, and the absence of lesions in the lung by dissolution of xonotlite fibers. (Bellman, 1994)

 

Based on the molecular weight and the water solubility, absorption via the oral and dermal route is expected to be limited. This is supported by the absence of effects observed in the skin irritation and skin sensitization study.

 

 

Conclusion

Xonotlite/tobermorite can be absorbed after respiratory exposure, but the amount of absorption will be limited, due to the fast clearance of particles from the lungs, for which the half-time is <2 days. Based on the physical/chemical properties, oral absorption and dermal absorption are expected to be limited.

Key value for chemical safety assessment

Additional information