Man-made vitreous (silicate) fibres with random orientation with alkaline and alkali earth oxides (Na2O+K2O+CaO+ MgO+BaO) content greater than 18% by weight and fulfilling one of the CLP Regulation Annex VI Note Q conditions

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Toxicokinetics Assessment report based on available literature

Adequacy of study:

key study

Study period:

January 2010-May 2010

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline studies are used for the assessment report along with the acceptable well documented publications which meets basic scientific principles used for the Toxicokinetic Assessment Report.

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Toxicokinetics assessment report based on available literature.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Man-made vitreous (silicate) fibres with random orientation with alkaline and alkali earth oxides (Na2O+K2O+CaO+MgO+BaO) content greater than 18% by weight and fulfilling one of the Nota Q conditions

EC Number:

926-099-9

Molecular formula:

Not applicable as UVCB

IUPAC Name:

Man-made vitreous (silicate) fibres with random orientation with alkaline and alkali earth oxides (Na2O+K2O+CaO+MgO+BaO) content greater than 18% by weight and fulfilling one of the Nota Q conditions

Radiolabelling:

no

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

No data have been identified on dermal or oral absorption. In chronic inhalation studies, the liver, spleen, kidneys and heart were routinely examined histopathologically with no exposure related lesions observed, indicative of no systemic effects.

Main ADME results 2

Type:

distribution

Results:

No data have been identified on distribution.

Main ADME results 3

Type:

metabolism

Results:

MMVF note Q fibres dissolve rapidly in vitro at pH 4.5 or 7.5. Fibres dissolution by lung fluid at neutral pH or acidic pH by macrophages is making them brittle and the longer fibres are then broken in shorter fibres.

Main ADME results 4

Type:

excretion

Results:

The shorter broken fibres are removed from the lung either by the lymphatic system or via the mucociliary escalator and either expelled from the body by coughing or swallowed.

Metabolite characterisation studies

Metabolites identified:

no

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
The most likely exposure routes for MMVF note Q fibres are evaluated to be by inhalation and skin contact. Fibres may be swallowed after clearance from the respiratory tract; whereas ingestion is considered very unlikely. There is no information on absorption of MMVF note Q fibres through the skin or the gastrointestinal tract. But because MMVF note Q fibres are inorganic with low potential to penetrate biological membranes absorption through the skin and the gastrointestinal tract is assessed to be negligible. MMVF note Q fibres that are exposed to an acidic environment have been shown to disintegrate rapidly. Thus, systemic exposure to MMVF note Q fibres leading to toxic reactions is evaluated to be very unlikely.

Executive summary:

Introduction:The potential health effects of airborne fibres are associated with the length and diameter of the fibre which determine their airway deposition and with durability (bio-persistence).

The clearance of fibres deposited in the respiratory tract results from a combination of physiological clearance processes (mechanical translocation/removal; macrophage mediated clearance) and physico-chemical processes (chemical dissolution and leaching, mechanical breaking). Long and short fibres differ in the way in which their elimination from the respiratory tract is affected by each of these mechanisms. Short fibres are taken up by macrophages and subjected to chemical dissolution/leaching within an acidic milieu while at the same time they are actively removed by these phagocytic cells primarily by the tracheal bronchial tree and the lymphatic system. In contrast, long fibres (longer than approximately 20 µm) which can only be incompletely phagocytised by macrophages, cannot be efficiently removed from the lung parenchyma by physical translocation but may be subjected to chemical dissolution/leaching at acidic pH where macrophages attach to the long fibres, and at neutral pH when in contact with the lung surfactant.

Fibres which deposit in the bronchial tree are removed from the lung via the mucociliary escalator and either expelled from the body by coughing or swallowed. If swallowed, the MMVF note Q fibres will disintegrate rapidly at acidic gastric pH.

 

Absorption:

                     Skin: No data have been identified on dermal absorption. MMVF note Q fibres are inorganic and it is evaluated that MMVF nota Q fibres have low potential for crossing biological membranes and that systemic exposure through dermal exposure is negligible.

                     Oral: No data have been identified on oral absorption. However, MMVF note Q fibres degrade at acidic pH (see below) resulting in dissolution and breakage into to smaller fibres (length less than 20 μm). Also, as they are inorganic it is evaluated that MMVF note Q fibres have low potential for crossing biological membranes and that systemic exposure through oral exposure is negligible.

                     Inhalation: No data have been identified on absorption following inhalation. However, in the chronic inhalation studies of MMVF (e.g. McConnell, 1994), the liver, spleen, kidneys and heart were routinely examined histopathologically with no exposure related lesions observed in these organs in any of the studies of MMVF thus indicative of no systemic effects. MMVF note Q fibres are inorganic and it is evaluated that MMVF note Q fibres have low potential for crossing biological membranes and that systemic exposure following inhalation is negligible. Regarding the further fate in the lung see metabolism below.

 

Distribution: No data have been identified on distribution.

 

Metabolism: The fate of fibres deposited on surfaces within the respiratory system depends on two different but simultaneously occurring processes: dissolution and disintegration (T. Hesterberg et al., 1996; T. W. Hesterberg et al., 1998b; Muhle et al., 1997; Zoitos et al., 1997).

Dissolution: MMVF note Q fibres exhibit a high degree of leaching (incongruent dissolution), in which certain components dissolve more rapidly than others (T. W. Hesterberg et al., 2001). Hence, following in vivo inhalation it has been demonstrated that the composition of MMVF note Q fibres changes with time in the lungs, with a depletion in Na₂O, CaO and MgO and a corresponding relative enrichment in SiO₂and Al₂O₃(Lehuede et al., 1997). Furthermore, MMVF note Q fibres have been shown to develop severe surface etching and deterioration starting as early as 1 week post exposure to the rat lung environment in vivo (T. W. Hesterberg et al., 1998a).

Studies show that MMVF note Q fibres dissolve rapidlyin vitroat pH = 4.5 (Guldberg et al., 2002; Kamstrup et al., 1998; Knudsen et al., 1996). For this fibre type the dissolution rate k_dis is 517-620 ng x cm^-2x hour^-1. For non-note Q synthetic mineral fibres the dissolution rate is approximately 10 times slower. Consequently, the elimination half-life (WT_½) for MMVF note Q fibres is approx. 10 times lower than that of non-note Q fibres (Guldberg, et al., 2002). Additionally, for certain glass wool types (MMVF note Q fibres) k_dis at pH = 7.4 has been determined to be 100 ng x cm^-2x hour^-1(Eastes et al., 1995).

Furthermore, rats exposed to MMVF note Q fibres(30 mg/m³; 6 hour/day, 5 days/week for 2 years) showed lung concentrations for fibres with lengths >20 μm of 8, 11, 10, and 11 x10³fibres per mg dry lung at sampling times of 3, 6, 12, and 18 months, respectively (Kamstrup, et al., 1998). These findings are consistent with early attainment of a balance between continued exposure and fast dissolution (i.e., low biopersistence) of this fibre type. The concentrations in rats exposed to the moderately bio-persistent, non-note Q fibres were higher and showed evidence of accumulation with time at the same sampling times: 18, 23, 55, and 62 x10³fibres per mg lung.

                     Disintegration: It has been demonstrated that after two days, the fraction of inhaled fibres < 15 μm increased from 5% to 50% (Eastes et al., 2007). Since the MMVF note Q fibres dissolve rapidly at acidic pH but slowly at near neutral pH (e.g. in the extracellular lung fluid), it is likely that acid attack by phagocytic cells (macrophages) is causing the longer fibres to dissolve and break into shorter fibres (Eastes, et al., 2007). The shorter fibres will be removed from the lung either by the lymphatic system or via the mucociliary escalator and either expelled from the body by coughing or swallowed. If swallowed, the MMVF note Q fibres will dissolve rapidly at acidic gastric pH (Bernstein, 2007).

 

Excretion: Clearance of fibres from the lung occurs through physiological clearance by alveolar macrophages, in vivo dissolution of fibres in the extracellular fluid and the breakage of long fibres into short segments (T. W. Hesterberg, et al., 2001; Yu et al., 1998). The shorter broken fibres are removed from the lung either by the lymphatic system or via the mucociliary escalator and either expelled from the body by coughing or swallowed. If swallowed, the MMVF note Q fibres will disintegrate rapidly at acidic gastric pH.

 

Conclusion: The most likely exposure routes for MMVF note Q fibres are evaluated to be by inhalation and skin contact, and possibly by ingestion/swallowing following the inhalation for workers. Fibres which are exposed to an acidic environment have been shown to disintegrate rapidly. Thus systemic exposure to MMVF note Q fibres leading to toxic reactions is evaluated to be very unlikely.