Carbon nanotubes (CNT) are of great commercial interest. Theoretically, during processing and handling of CNT and in abrasion processes on composites containing CNT, inhalable CNT particles might be set free. For hazard assessment, we performed a 90-day inhalation toxicity study with a multiwall CNT (MWCNT) material (Nanocyl NC 7000) according to Organisation for Economic Co-operation and Development test guideline 413. Wistar rats were head-nose exposed for 6 h/day, 5 days/week, 13 weeks, total 65 exposures, to MWCNT concentrations of 0 (control), 0.1, 0.5, or 2.5 mg/m(3). Highly respirable dust aerosols were produced with a proprietary brush generator which neither damaged the tube structure nor increased reactive oxygen species on the surface. Inhalation exposure to MWCNT produced no systemic toxicity. However, increased lung weights, pronounced multifocal granulomatous inflammation, diffuse histiocytic and neutrophilic inflammation, and intra-alveolar lipoproteinosis were observed in lung and lung-associated lymph nodes at 0.5 and 2.5 mg/m(3). These effects were accompanied by slight blood neutrophilia at 2.5 mg/m(3). Incidence and severity of the effects were concentration related. At 0.1 mg/m(3), there was still minimal granulomatous inflammation in the lung and in lung-associated lymph nodes; a no observed effect concentration was therefore not established in this study. The test substance has low dust-forming potential, as demonstrated by dustiness measurements, but nonetheless strict industrial hygiene measures must be taken during handling and processing. Toxicity and dustiness data such as these can be used to compare different MWCNT materials and to select the material with the lowest risk potential for a given application.

The tissue distribution and toxicity of intravenously administered nanoparticles of titanium dioxide (TiO2) (>10 wt.% at <100 nm size) were investigated because of the fundamental importance to obtain information on the kinetics of this widely used nanoparticle in a situation of 100% bioavailability. Male Wistar rats were treated with single intravenous injections of a suspension of TiO2 in serum (5 mg/kg body weight), and the tissue content of TiO2 was determined 1, 14, and 28 days later. Biochemical parameters and antigens in serum were also assessed to determine potential pathological changes. The health and behavior of the animals were normal throughout the study. There were no detectable levels of TiO2 in blood cells, plasma, brain, or lymph nodes. The TiO2 levels were highest in the liver, followed in decreasing order by the levels in the spleen, lung, and kidney, and highest on day 1 in all organs. TiO2 levels were retained in the liver for 28 days, there was a slight decrease in TiO2 levels from day 1 to days 14 and 28 in the spleen, and a return to control levels by day 14 in the lung and kidney. There were no changes in the cytokines and enzymes measured in blood samples, indicating that there was no detectable inflammatory response or organ toxicity. Overall, rats exposed to TiO2 nanoparticles by a route that allows immediate systemic availability showed expected tissue distribution, no obvious toxic health effects, no immune response, and no change in organ function. Therefore, even with 100% bioavailability of the 5 mg/kg TiO2 dose afforded by the intravenous route of administration, there were no remarkable toxic effects evident in the experimental animals. These results indicate that TiO2 nanoparticles could be used safely in low doses.

Nanomaterials can display distinct biological effects compared with bulk materials of the same chemical composition. The physico-chemical characterization of nanomaterials and their interaction with biological media are essential for reliable studies and are reviewed here with a focus on widely used metal oxide and carbon nanomaterials. Available rat inhalation and cell culture studies compared to original results suggest that hazard potential is not determined by a single physico-chemical property but instead depends on a combination of material properties. Reactive oxygen species generation, fiber shape, size, solubility and crystalline phase are known indicators of nanomaterials biological impact. According to these properties the summarized hazard potential decreases in the order multi-walled carbon nanotubes >> CeO(2), ZnO > TiO(2) > functionalized SiO(2) > SiO(2), ZrO(2), carbon black. Enhanced understanding of biophysical properties and cellular effects results in improved testing strategies and enables the selection and production of safe materials.

The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) 'Nano Task Force' proposes a Decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping) that consists of 3 tiers to assign nanomaterials to 4 main groups, to perform sub-grouping within the main groups and to determine and refine specific information needs. The DF4nanoGrouping covers all relevant aspects of a nanomaterial's life cycle and biological pathways, i.e. intrinsic material and system-dependent properties, biopersistence, uptake and biodistribution, cellular and apical toxic effects. Use (including manufacture), release and route of exposure are applied as 'qualifiers' within the DF4nanoGrouping to determine if, e.g. nanomaterials cannot be released from a product matrix, which may justify the waiving of testing. The four main groups encompass (1) soluble nanomaterials, (2) biopersistent high aspect ratio nanomaterials, (3) passive nanomaterials, and (4) active nanomaterials. The DF4nanoGrouping aims to group nanomaterials by their specific mode-of-action that results in an apical toxic effect. This is eventually directed by a nanomaterial's intrinsic properties. However, since the exact correlation of intrinsic material properties and apical toxic effect is not yet established, the DF4nanoGrouping uses the 'functionality' of nanomaterials for grouping rather than relying on intrinsic material properties alone. Such functionalities include system-dependent material properties (such as dissolution rate in biologically relevant media), bio-physical interactions, in vitro effects and release and exposure. The DF4nanoGrouping is a hazard and risk assessment tool that applies modern toxicology and contributes to the sustainable development of nanotechnological products. It ensures that no studies are performed that do not provide crucial data and therefore saves animals and resources.

Sunscreens containing titanium dioxide (TiO(2)) and zinc oxide (ZnO) nanoparticles (NP) are effective barriers against ultraviolet B (UVB) damage to skin, although little is known about their disposition in UVB-damaged skin. Pigs were exposed to UVB that resulted in moderate sunburn. For in vitro studies, skin in flow-through diffusion cells were treated 24 h with four sunscreen formulations as follows: 10% coated TiO(2) in oil/water (o/w), 10% coated TiO(2) in water/oil (w/o), 5% coated ZnO in o/w, and 5% uncoated ZnO in o/w. TiO(2) (rutile, crystallite) primary particle size was 10 × 50 nm with mean agglomerates of 200 nm (range ca. 90 nm--460 nm); mean for ZnO was 140 nm (range ca. 60--200 nm). Skin was processed for light microscopy, scanning (SEM) and transmission electron microscopy (TEM), and time-of-flight secondary ion mass spectrometry (TOF-SIMS). UVB-exposed skin had typical sunburn histology. TEM showed TiO(2) NP 17 layers into stratum corneum (SC), whereas ZnO remained on the surface. TOF-SIMS showed TiO(2) and ZnO epidermal penetration in both treatments. Perfusate analyzed by TEM/energy dispersive x-ray spectroscopy or inductively coupled plasma mass spectrometry detected no Ti or Zn, indicating minimal transdermal absorption. In vivo, skin was dosed at 24 h occluded with formulations and at 48 h. TiO(2) NP in o/w formulation penetrated 13 layers into UVB-damaged SC, whereas only 7 layers in normal skin; TiO(2) in w/o penetrated deeper in UVB-damaged SC. Coated and uncoated Zn NP in o/w were localized to the upper one to two SC layers in all skin. By SEM, NP were localized as agglomerates in formulation on the skin surface and base of hair. TOF-SIMS showed Ti within epidermis and superficial dermis, whereas Zn was limited to SC and upper epidermis in both treatments. In summary, UVB-damaged skin slightly enhanced TiO(2) NP or ZnO NP penetration in sunscreen formulations but no transdermal absorption was detected.

Nanocomposites are the dominating class of nanomaterials to come into consumer contact, and were in general assumed to pose low risk. The first data is now emerging on the exposure from nanocomposites, but little is yet known about their hypothetical nanospecific physiological effects, giving ample room for speculation. For the first time, this comprehensive study addresses these aspects in a systematic series of thermoplastic and cementitious nanocomposite materials. Earlier reports that 'chalking', the release of pigments from weathered paints, also occurs for nanocomposites, are confirmed. In contrast, mechanical forces by normal consumer use or do-it-yourself sanding do not disrupt nanofillers (nanoparticles or nanofibers) from the matrix. Detailed evidence is provided for the nature of the degradation products: no free nanofillers are detected up to the detection threshold of 100 ppm. Sanding powders measuring 1 to 80 μm in diameter are identified with the original material, still containing the nanofillers. The potential hazard from aerosols generated by sanding nanocomposites up to the nuisance dust limit is also investigated. In-vivo instillation in rats is used to quantify physiological effects on degradation products from abraded nanocomposites, in comparison to the abraded matrix without nanofiller and to the pure nanofiller. In this pioneering and preliminary evaluation, the hazards cannot be distinguished with or without nanofiller.

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BackgroundA standard short-term inhalation study (STIS) was applied for hazard assessment of 13 metal oxide nanomaterials and micron-scale zinc oxide.MethodsRats were exposed to test material aerosols (ranging from 0.5 to 50 mg/m3) for five consecutive days with 14- or 21-day post-exposure observation. Bronchoalveolar lavage fluid (BALF) and histopathological sections of the entire respiratory tract were examined. Pulmonary deposition and clearance and test material translocation into extra-pulmonary organs were assessed.ResultsInhaled nanomaterials were found in the lung, in alveolar macrophages, and in the draining lymph nodes. Polyacrylate-coated silica was also found in the spleen, and both zinc oxides elicited olfactory epithelium necrosis. None of the other nanomaterials was recorded in extra-pulmonary organs. Eight nanomaterials did not elicit pulmonary effects, and their no observed adverse effect concentrations (NOAECs) were at least 10 mg/m3. Five materials (coated nano-TiO2, both ZnO, both CeO2) evoked concentration-dependent transient pulmonary inflammation. Most effects were at least partially reversible during the post-exposure period.Based on the NOAECs that were derived from quantitative parameters, with BALF polymorphonuclear (PMN) neutrophil counts and total protein concentration being most sensitive, or from the severity of histopathological findings, the materials were ranked by increasing toxic potency into 3 grades: lower toxic potency: BaSO4; SiO2.acrylate (by local NOAEC); SiO2.PEG; SiO2.phosphate; SiO2.amino; nano-ZrO2; ZrO2.TODA; ZrO2.acrylate; medium toxic potency: SiO2.naked; higher toxic potency: coated nano-TiO2; nano-CeO2; Al-doped nano-CeO2; micron-scale ZnO; coated nano-ZnO (and SiO2.acrylate by systemic no observed effect concentration (NOEC)).ConclusionThe STIS revealed the type of effects of 13 nanomaterials, and micron-scale ZnO, information on their toxic potency, and the location and reversibility of effects. Assessment of lung burden and material translocation provided preliminary biokinetic information. Based upon the study results, the STIS protocol was re-assessed and preliminary suggestions regarding the grouping of nanomaterials for safety assessment were spelled out.