Glass, oxide, chemicals

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Toxicokinetics Assessment report based on expert evaluation of relevant available literature

Adequacy of study:

weight of evidence

Study period:

September 2010-October 2010

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Studies comparable to guideline are used for the Toxicokinetic Assessment Report together with the acceptable, well documented publications, which meets basic scientific principles.

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Toxicokinetic Assessment Report based on available literature and expert evaluation.

Test material

Test material information

Constituent 1

Reference substance name:

E-glass microfibre

IUPAC Name:

E-glass microfibre

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.

Main ADME results 2

Type:

absorption

Results:

It is evaluated that systemic exposure following long-term inhalation is negligible.

Main ADME results 3

Type:

distribution

Results:

No data have been identified on distribution, i.e no histopathological information on liver, spleen, kidneys or heart could be found from long-term inhalation studies.

Main ADME results 4

Type:

metabolism

Results:

E-glass microfibre dissolves relatively slowly in vitro at pH 7.4 and in lung fluid. Fibre dissolution by lung fluid at acidic pH by macrophages is making them brittle and the longer fibres are then broken in shorter fibres.

Main ADME results 5

Type:

excretion

Results:

The shorter broken fibres are removed from the lungs either by migration or by ingestion by macrophages that “travel” to the lymphatic system and further degraded. If swallowed, the fibres will dissolve at acidic gastric pH and be excreted.

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 route for E-glass microfibre is by inhalation. In long-term inhalation toxicity studies E-glass microfibre was observed to undergo congruent dissolution. E-glass microfibre has been shown to have low solubility at neutral pH and to disintegrate in acidic environment. Inhaled E-glass microfibre dissolves in the rat lung through the acidic attack of macrophages and will subsequently break into shorter pieces. Removal of fibres deposited on surfaces within the respiratory system involves dissolution and disintegration of the longer fibres, and dissolution and phagocytosis by alveolar macrophages for shorter fibres.

E-glass microfibre has been shown to induce lung tumours (carcinoma and adenoma) at high concentrations in long-term inhalation studies, probably due to the higher biopersistence of fibers longer than 20 µm. The mechanism of which E-glass microfibre induces lung tumours is not fully elucidated but overload of cellular clearance mechanisms have been suggested (Searl et al., 1999).

Finally, due to the inert nature and the low possibility of crossing biological barriers, systemic exposure to E-glass microfibre 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, diameter and biosolubility of the fibre, which determine their airway deposition, clearance and durability (biopersistence).

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 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 in an acidic milieu within the macrophages, 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.

 

Mesothelioma was found in carc-studies, and this means that the fibres translocated through the lung tissue into the pleurae where carcinoma developed. So translocation is also a possibility to remove fibres from the lung/alveolar lumen. 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, E-glass microfibre dissolves at acidic gastric pH and/or is excreted. Overall, short fibres are largely cleared by cellular processes which includes engulfment by macrophages whereas long fibres are cleared by the combined processes of dissolution and disintegration (Searl et al., 1999; Zoitos et al., 1997).

 

Absorption:

Skin: No data have been identified on dermal absorption during the literature search. E-glass microfibre is inorganic and it is evaluated that E-glass microfibre has low potential for crossing biological membranes and that systemic exposure through dermal exposure is negligible.

Oral:No data have been identified on oral absorption during the literature search. However, if swallowed, E-glass microfibre dissolves at acidic gastric pH. Also, as E-glass microfibre is inorganic it is evaluated that E-glass microfibre has low potential for crossing biological membranes and that systemic exposure through oral exposure is negligible.

Inhalation:No data have been identified on systemic absorption following inhalation during the literature search. In the long-term inhalation toxicity studies of E-glass microfibre (Cullen et al., 2000; Searl et al., 1999), no information could be retrieved on histopathological examinations of the liver, spleen, kidneys and heart. It is evaluated that systemic effects from E-glass microfibre absorption following inhalation are highly unlikely to happen. In support, the possible systemic effect from absorption following long-term inhalation of other synthetic vitreous fibres was studied, showing no exposure related lesions in liver, spleen, kidneys and heart (McConnell, 1994). E-glass microfibre is inorganic and it may cross biological membranes, but systemic exposure following inhalation is negligible. Regarding the further fate in the lung, see metabolism below.

 

Distribution:

No data have been identified on distribution during the literature search.

 

Metabolism:

The fate of fibres deposited on surfaces within the respiratory system depends on different processes. Short fibres are largely cleared by cellular processes which includes engulfment by macrophages subsequent clearance via the lymphatic system, whereas long fibres are cleared depending upon biosolubility by the combined processes of dissolution and disintegration (Searl et al., 1999; Zoitos et al., 1997).

 

Dissolution: E-glass microfibre appears to undergo congruent dissolution once deposited in the lung with no indication of preferential leaching of one component over another. Following long-term inhalation, with a target dose of 1000 WHO fibre, it has been demonstrated that the overall composition of E-glass microfibre did not change in the lungs for up to 24 months (12 months of exposure and 12 months of recovery) (Cullen et al., 2000; Searl et al., 1999). When pre-treated with acid (1.4 M HCl, 20^oC, 24 h), E-glass microfibre, with a diameter between 0.1-0.2µm and longer than 5µm were shown to undergo incongruent dissolution in a 2-year study using intratracheal installation with Mg, Al and Ca leached to a higher degree than silicon (Bellmann et al., 1987).

Studies show that E-glass microfibre dissolvesin vitroat pH = 7.4, with a dissolution rate constant (k_dis) of 9-10 ng x cm^-2x hour^-1and a corresponding half-life time of fibres longer than 20 µm in an inhalation biopersistence study of 62-79 days (Hesterberg et al., 1998; Searl et al., 1999). In another study using a simulated lung fluid, k_diswas evaluated to be 2.3 ng x cm^-2x hour^-1(Fayerweather et al., 1997). A correlation between biosolubility and chemical components of fibres has been established showing that higher content of Al correlates with lower solubility. Hence, E-glass microfibre has a lower k_discompared to other fibre types due to the higher content of Al (Bernstein, 2007a).

 

The biopersistence of E-glass microfibre in the lung following 5 days inhalation exposure in rats was reported by Hesterberg et al. (1998). The fibre concentration was 51 mg/m³corresponding to 316 WHO fibres per cm³. The weighted half-life time of fibres longer than 20 µm was calculated to 79 days. Furthermore, in a long-term inhalation toxicity study in rat, with a target dose of 1000 WHO fibres, the mean lung concentration of fibres remaining in the lung <5 µm was much higher than the number of fibres >5 µm with the lowest concentration of fibres > 20µm after 12 months of exposure. After a 12-month recovery period, the retained lung burden (fibre of all lengths) was approximately 30% of that at the end of the 12 month exposure period. The highest persistence ratio (%) was seen for fibres in the length category 5-10 µm (58%) and 10-15 µm (57%). These findings are consistent with early attainment of a balance between continued exposures, low dissolution and higher biopersistence of E-glass microfibre involved in the induction of lung tumours (carcinoma and adenoma) in this study (Cullen et al., 2000).

 

In a 2-year rat study using intratracheal installation, E-glass microfibre (at a dose of 2 mg), with a diameter of 0.1-0.2 µm and longer than 5 µm, was shown to have a half-life time of 55 days for fibres longer than 5 µm and a half-life time of 40 days for fibres shorter than 5 µm . A proposed mechanism is phagocytosis of the shorter fibres by alveolar macrophages, followed by transport to the ciliated airways and then to the gastrointestinal tract (Bellmann et al., 1987). In another rat study, using intratracheal instillation of E-glass microfibre (at a dose of 2 mg) analysis of fibres in the lungs after up to 18 months following treatment was performed (Bellmann and Muhle, 1997). A mean half-life time for the elimination of fibres with length of >20 µm was calculated to be 226 days. It is difficult to compare results following intratracheal installation with those from inhalation exposure studies as at an intratracheal installation dose of 2 mg, agglomeration of fibres in the airways is frequently observed which results in prolonged clearance half-life time.

 

The biopersistence was also investigated in a 3 month inhalation study using rats (Bellmann et al., 2003). The rats were exposed to a mean fibre aerosol concentration of approximately 197, 623 and 1886 WHO fibres/ml within which there were 14, 43 and 120 fibres longer than 20 µm per ml, respectively. After 3 months of exposure, mean lung retention of fibres longer than 20 µm was 17x10⁶for the high dose group. This amount had decreased to approximately 40% after a 3 month recovery period. The mean estimated half-life time for clearance was 62 days for the high dose group of fibres longer than 20 µm and 155 days for fibres of all length. Other biological effects measured, which included inflammation, proliferation and histopathological lesions, showed dose-dependent effects of E-glass microfibre in biochemical parameters, in polymorphonuclear leukocytes in the bronchoalveolar lavage fluid, in proliferation of terminal bronchiolar epithelium, and in interstitial fibrosis. However, these measured parameters could not be related to fibre concentrations and fibre length.

 

Disintegration:  Since the E-glass microfibre dissolves 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 disintegrate and break into smaller fibres (Eastes et al., 2007). The shorter fibres will be removed from the lung either via the lymphatic system or via the mucociliary escalator and subsequently either expelled from the body by coughing or swallowed. If swallowed, the E-glass microfibre will dissolve at acidic gastric pH and be excreted subsequently via the gastric system (Bernstein, 2007b).

 

Excretion:

Clearance of fibres from the lung occurs through physiological clearance by alveolar macrophages, in vivo dissolution of fibres in the extracellular fluid and within the acidic milieu of the macrophage and through breakage of long fibres into shorter segments. The shorter broken fibres are removed from the lung either via the lymphatic system or via the mucociliary escalator and either expelled from the body by coughing or swallowed. If swallowed, the E-glass microfibre will dissolve at acidic gastric pH and be excreted subsequently via the gastric system (Bernstein, 2007b).

 

Conclusions:

The most likely exposure route for E-glass microfibre is assessed to be inhalation. In long-term inhalation studies E-glass microfibre was observed to undergo congruent dissolution. E-glass microfibre has been shown to have low solubility at neutral pH and to disintegrate in acidic environment. Inhaled E-glass microfibre dissolves in the rat lung and is subjected to breakage through the acidic attack of macrophages. Removal of fibres deposited on surfaces within the respiratory system involves dissolution and disintegration and phagocytosis by alveolar macrophages for shorter fibres.

 

E-glass microfibre has been shown to induce lung tumours (carcinoma and adenoma) at high concentrations in long-term inhalation studies, probably due to the higher biopersistence of fibers longer than 20 µm. The mechanism of which E-glass microfibre induces lung tumours is not fully elucidated but overload of cellular clearance mechanisms have been suggested (Searl et al., 1999). Finally, due to the inert nature and the low possibility of crossing biological barriers, systemic exposure to E-glass microfibre leading to toxic reactions is evaluated to be very unlikely.