Man-made vitreous (silicate) fibres with random orientation with alkaline oxide and alkali earth oxide (Na2O+K2O+CaO+MgO+BaO) content greater than 18 % by weight

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Available litterature

Adequacy of study:

key study

Study period:

september 2010

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The toxicolkinetic assessment is based on the available litterature

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Man-made vitreous (silicate) fibres with random orientation with alkaline oxide and alkali earth oxide (Na2O+K2O+CaO+MgO+BaO) content greater than 18% by weight

IUPAC Name:

Man-made vitreous (silicate) fibres with random orientation with alkaline oxide and alkali earth oxide (Na2O+K2O+CaO+MgO+BaO) content greater than 18% by weight

Constituent 2

Reference substance name:

MMVF 21

IUPAC Name:

MMVF 21

Constituent 3

Reference substance name:

MMVF 33

IUPAC Name:

MMVF 33

Constituent 4

Reference substance name:

FMMVF

IUPAC Name:

FMMVF

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

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

Main ADME results 2

Type:

absorption

Results:

Oral: No data have been identified on oral absorption.

Main ADME results 3

Type:

absorption

Results:

No data have been identified on absorption following inhalation.

Main ADME results 4

Type:

distribution

Results:

No data have been found on distribution

Main ADME results 5

Type:

metabolism

Results:

Dissolution: FMMVF fibres exhibit a small degree of leaching (incongruent dissolution), in which certain components dissolve more rapidly than others

Main ADME results 6

Type:

metabolism

Results:

biopersistence was inversely correlated with fibre length, fibres longer than 20 µm, and shorter than 5 µm, showed half-lifetimes of 56 and 174 days, respectively.

Main ADME results 7

Type:

metabolism

Results:

Disintegration: Since FMMVF fibres dissolve slowly at neutral pH (eg. In the extracellular lung fluid) it is likely that acid attack from alveolar macrophages are causing the longer fibres to dissolve and break into smaller fibres

Main ADME results 8

Type:

excretion

Results:

When deposited in the lungs, the fibers will clear via the mucociliary escalator and will be expelled via coughing, or swalloved.

Main ADME results 9

Type:

excretion

Results:

Excretion: It is expected that FMMVF fibres when swallowed, will be mixed with the gut content and be expelled via the gastric system, due to the low solubility.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Skin: No data have been identified on dermal absorption. FMMVF fibres are inorganic and it is evaluated that FMMVF fibres have low potential for crossing biological membranes and that systemic exposure through dermal exposure is negligible.
Oral: Oral: No data have been identified on oral absorption. However, FMMVF 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 FMMVF fibres have low potential for crossing biological membranes and that systemic exposure through oral exposure is negligible.However, FMMVF 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 FMMVF 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 et al., 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.
FMMVF fibres are inorganic and it is evaluated that FMMVF fibres have low potential for crossing biological membranes and that systemic exposure following inhalation is negligible.

Details on distribution in tissues:

Distribution: No data have been identified on distribution.

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

No metabolites will be formed. FMMVF fibres exhibit a small degree of leaching (incongruent dissolution), in which certain components dissolve more rapidly than others (Cullen et al., 2000). Hence, following inhalation by rats, it has been demonstrated that the composition of FMMVF fibres changes with time in the lungs, with a depletion in Na2O, CaO and MgO and a corresponding relative enrichment in SiO2 and Al2O3 (Cullen et al., 2000). Furthermore, FMMVF fibres (475) 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 (Hesterberg et al., 1998a).

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results At the concentrations used experimentally small amounts of fibres persist one year after cease of exposure, at the exposure levels in industrial settings no accumulation is expected due to the relative low concentration, the clearance capacity of humans
The most likely routes of exposure for FMMVF fibres is evaluated to be by inhalation. Fibres have been shown to disintegrate slowly in acidic environment. Inhaled fibres are subjected to breakage, leading to shorter fibre length. Due to the inert nature of the substance, and the fact that the substance does not cross biological barriers, systemic exposure leading to toxic reactions is evaluated to be very unlikely.

Executive summary:

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 via 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 FMMVFfibreswill incongruently leach alkali earth metals at acidic gastric pH, thereby creating a silicate enriched brittle crust, and the fibre will tend to break perpendicular to the length, into smaller pieces.

No data has been identified on absorption following exposure via the dermal or oral route, or via inhalation. FMMVF fibres have low potential for crossing biological membranes and it is therfore evaluated that systemic exposure is negligible.

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((Hesterberg et al., 1996);(Hesterberg et al., 1998b);(Muhle and Bellmann, 1997);(Zoitos et al., 1997)).

Dissolution:FMMVFfibres exhibit a small degree of leaching (incongruent dissolution), in which certain components dissolve more rapidly than others(Cullen et al., 2000). Hence, following inhalation by rats, it has been demonstrated that the composition of FMMVFfibres changes with time in the lungs, with a depletion in Na₂O, CaO and MgO and a corresponding relative enrichment in SiO₂and Al₂O₃(Cullen et al., 2000). Furthermore, FMMVF fibres (475) 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(Hesterberg et al., 1998a).

Studies show that FMMVFfibresdissolve significantly slower than MMVF note Q fibresin vitroat pH = 4.5(Kamstrup et al., 1998;Guldberg et al., 2002). For this fibre type the dissolution rate k_disis 620 ng x cm^-2x hour^-1, which is approximately 10 times higher than dissolution rates, 55 ng x cm^-2x hour^-1, obtained from FMMVF fibres (MMVF 21) in the same study. Consequently, the elimination half-lifetime (WT_½) for MMVFnote Q fibresis approx. 10 times lower than that of non-note Q fibres.

Biopersistence of MMVF 21 and MMVF 33 (475) fibres were reported by Hesterberg, et. al., 1998a, following 5 days inhalation exposure on rats. The fibre concentration was 58 and 51 mg/m³, corresponding to 466 and 371 WHO fibres per cm³, for MMVF 21 and MMVF 33, respectively. At 365 days post-exposure, 7% and 8% of the deposited fibres still remained in the lungs. The weighted half-lifetime for fibres longer than 20 µm was calculated as 67 and 49 days, for MMVF 21 and MMVF 33, respectively. In another study by Hesterberg et al. (1996) it was demonstrated that biopersistence was inversely correlated with fibre length, fibres longer than 20 µm, and shorter than 5 µm, showed half-lifetimes of 56 and 174 days, respectively.

 

Disintegration:Since FMMVF fibres dissolve slowly at neutral pH (eg. In the extracellular lung fluid) it is likely that acid attack from alveolar macrophages are causing the longer fibres to dissolve and break into smaller 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 FMMVF fibreswill dissolve slowly at acidic gastric pH(Bernstein, 2007).

Excretion:It is expected that FMMVF fibres when swallowed, will be mixed with the gut content and be expelled via the gastric system, due to the low solubility.

 

Conclusion:The most likely routes of exposure for FMMVF fibres is evaluated to be by inhalation. Fibres have been shown to disintegrate slowly in acidic environment. Inhaled fibres are subjected to breakage, leading to shorter fibre length. Due to the inert nature of the substance, and the fact that the substance does not cross biological barriers, systemic exposure leading to toxic reactions is evaluated to be very unlikely.