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Table 3 Tiered Testing Strategy to support the HARN IATA. Recommended methods and models to address each IATA decision node are set-out according to the appropriate tier of testing.

From: Grouping MWCNTs based on their similar potential to cause pulmonary hazard after inhalation: a case-study

Can HARN deposit in the distal lung? Does the HARN dissolve very slowly in lung lining fluid (pH7.4)? Does the HARN dissolve very slowly in lysosomal fluid (pH4.5)? Is HARN length > 5 µm? Is HARN rigid and maintain a needle-like morphology? Does HARN cause frustrated phagocytosis?
Tier 1
Review existing data sets
Estimation of aerodynamic diameter from diameter and density of HARN Batch dissolution test or dissolution in continuous flow system in lung lining fluid Batch dissolution test or dissolution in continuous flow system in lysosomal fluid Length distribution profile from TEM/SEM images Mean diameter of HARN from TEM/SEM. Include supporting images Inflammasome activation in macrophage exposed to HARN: IL-1β release
Tier 2
Review existing data sets
Measurement of mass median aerodynamic diameter (MMAD) from airborne dispersion of material   Durability in cellular systems HARN length measurement from airborne dispersion of material from TEM/SEM images HARN size measurement from airborne dispersion of material from TEM/SEM images. Include supporting images In vitro granuloma formation
Tier 3
Review existing data sets
Quantification of lung deposition during in vivo inhalation studies Quantification of lung burden and clearance kinetics during in vivo inhalation studies    Fibre rigidity of HARN demonstrated by morphological assessment and/or size measurements after incubation with macrophages in vitro or in vivo Evidence of frustrated phagocytosis and granuloma formation from in vivo exposure (OECD GD 39)