Table 1.

Common routes of administration/exposure: important considerations relating nanomaterials characteristics and the various routes of exposure (Agrawal et al., 2014; Blanco et al., 2015; Date et al., 2016; Palmer and DeLouise, 2016; Boyes et al., 2017).

Route of exposure	Considerations on the exposure route	Nanomaterials characteristics and its relation with the exposure route
Respiratory	- The most common route of exposure in the workplace - Nanomaterials inhaled for drug delivery must overcome bronchial mucociliary clearance - Inhaled nanomaterials may translocate to various regions of the brain, without crossing the blood–brain barrier - Inhaled nanomaterials can cross the alveoli–blood barrier, reaching the systemic-circulation portion of the cardiovascular system, without gastric passage or a first-pass metabolism	Size	Particles of about 20 nm have the highest proportional deposition rate in the alveolar region Particles smaller than 55 nm will penetrate the alveoli more efficiently than particles of 200 nm or greater
		Charge	Positively charged nanomaterials will exhibit greater interaction with the mucus' negative charge, thus avoiding fast mucociliary clearance
		Others	Inhalation flow-rate influences which region of the respiratory tract nanomaterials will reach The mucoadhesive properties of nanomaterials may increase their residence time in nasal mucosa, increasing drug absorption
Oral	- The first choice, non-invasive route - Inhaled nanomaterials cleared by the mucociliary system may be ingested - Ingested nanomaterials can reach and interact with different organs of the GI tract, such as the esophagus, stomach, small and large intestine and colon - Ingested nanoparticles can translocate into the systemic-circulation portion of the cardiovascular system, but to do so they must resist a wide range of pH environments and enzymatic degradation until they reach the small intestine - The absorption of ingested nanomaterials can be hindered by the poor permeability of the intestinal epithelium - Before reaching systemic circulation, ingested nanomaterials and cargo drugs will undergo a first-pass metabolism in the liver	Size	Particles with a diameter of <50 nm are known to cross epithelial barriers via paracellular passage, whereas larger particles are endocytosed by intestinal enterocytes (<500 nm) or taken up by M cells in Peyer's patches (<5 mm)
		Charge	Positively charged nanomaterials may exhibit greater interaction with intestinal mucus, therefore improving nanoparticle retention, but also decreasing nanoparticle absorption Neutrally charged nanomaterials diffuse more efficiently through the mucus layers
		Others	Surface coating nanomaterials with enteric polymers improves their resistance in the gastrointestinal (GI) tract Hydrophilicity and poor chemical or enzymatic stability in the GI tract diminish intestinal absorption
Injectable	- Most commonly used routes for injectables include intravenous, intramuscular, subcutaneous and intradermal administration - Injectables are the first choice for active pharmaceutical ingredients with narrow therapeutic indices, poor bioavailability or administration to unconscious patients - Intravenously injected nanoparticles are distributed throughout the circulatory system, reaching different organs - Intradermal injection leads to uptake by the lymphatic system - Intramuscularly injected particles are taken up via the neuronal and lymphatic systems - Intravenously injected nanoparticles are rapidly cleared by the kidneys and liver, or via the reticuloendothelial system (res)	Size	Smaller nanomaterials are mostly absorbed into capillaries, whereas larger nanomaterials are drained by the lymphatic system
		Charge	Nanomaterials with positively charged surfaces exhibit greater interactions with blood components and are therefore more rapidly cleared by the mononuclear phagocyte system Nanomaterials with neutral and negatively charged surfaces have longer circulation half-lives
		Others	Nanomaterial surface hydrophobicity increases interaction with blood components and therefore increases nanomaterial clearance via the mononuclear phagocyte system Nanomaterial surfaces coated with hydrophilic polymers or surfactants exhibit decreased clearance by opsonisation
Dermal	- Mostly used for the topical delivery of molecules intended to act locally (sunscreens, antifungals, anti-inflammatory or keratolytic agents, etc.) - Accumulation in hair follicles can increase the penetration of nanomaterials and cargo drugs - Damaged skin is more permeable to larger nanomaterials - Small, lipophilic molecules can penetrate easily into the skin and eventually reach the bloodstream or the lymphatic system	Size	Nanomaterials <20 nm may penetrate or permeate intact skin Nanomaterials <45 nm may penetrate damaged skin Nanomaterials >45 nm may translocate or be stored in skin appendages (i.e., air follicles)
		Charge	Cationic nanoparticles have an affinity for the negatively charged skin pores (which can limit their subsequent diffusion)
		Others	Physicochemical methods, such as the application of low-frequency ultrasound or surfactants (i.e., sodium lauryl sulfate), are used to disturb the skin barrier and promote nanomaterial absorption