COMMISSION STAFF WORKING PAPER

Types and uses of nanomaterials, including safety aspects

Accompanying the

Communication from the Commission to the European Parliament, the Council and the European Economic and Social Committee

on the Second Regulatory Review on Nanomaterials

1. Introduction

The European Parliament in its resolution of 24 April 2009 on Regulatory Aspects of Nanomaterials[1] called on the Commission to compile an inventory of nanomaterial types and uses. In particular, it stated:

“H. whereas there is no clear information about the actual use of nanomaterials in consumer products, for instance:

- while inventories by renowned institutions list more than 800 manufacturer-identified nanotechnology-based consumer products currently on the market, trade associations of the same manufacturers question these figures, on the basis that they are overestimations, without providing any concrete figures themselves,

- while companies happily use “nano-claims”, as the term “nano” seems to have a positive marketing effect, they are strictly opposed to objective labelling requirements,

J. whereas presentations about the potential benefits of nanotechnologies predict an almost infinite diversity of future applications of nanomaterials, but fail to provide reliable information about current uses,

16. Calls on the Commission to compile before June 2011 an inventory of the different types and uses of nanomaterials on the European market, while respecting justified commercial secrets such as recipes, and to make this inventory publicly available; furthermore calls on the Commission to report on the safety of these nanomaterials at the same time”

In its response[2] of 14 July 2009 the Commission stated in relation to paragraph 16 of the above resolution that “the Commission intends to present information on types and uses of nanomaterials, including safety aspects, in 2011.” This formulation was chosen because at the time of the resolution the implications of an “inventory” were unclear and required further analysis, including an analysis of registration dossiers under the first registration deadline of the REACH Regulation[3] and of notification dossiers under the CLP Regulation[4].

In its conclusions on “improving environmental policy instruments” of 20 December 2010[5], the Council invited the Commission to “evaluate the need for the development of specific measures for nanomaterials relating to risk assessment and management, information and monitoring, including the further development of a harmonized database for nanomaterials, while considering potential impacts”.

This Staff Working Paper intends to present available information on types and uses of nanomaterials, including safety aspects and to discuss options for a harmonised database for nanomaterials, considering potential impacts.

In principle, the Staff Working Paper covers nanomaterials within the scope of Commission Recommendation 2011/696/EU on the definition of nanomaterial.[6] Nevertheless, as the request by the European Parliament is related to nanomaterials on the market, this document focuses on manufactured nanomaterials, and does not cover naturally occurring nanomaterials (e.g. dust, volcanic ash etc.) and incidental nanomaterials (e.g. particulate matter from combustion installations).

The current EU definition of nanomaterial focuses on nanomaterials with a majority of particles in the nanoscale (1 nm to 100 nm). It is noted that particular varieties of many of the particulate materials discussed in this Staff Working Paper may or may not fall under the definition in Recommendation 2011/696/EU, depending on their specific particle size distribution. For reasons of readability, the Staff Working Paper follows the common practice in using terms for nanomaterials, i.e. when referring to nano-titanium dioxide[7], the prefix “nano” is not always used, whereas it is used in other cases such as “nanosilver”. However, any numbers such as production tonnages or market values always refer to the total of all nanoforms on the market, unless indicated otherwise.

In chapters 2 to 5, the Staff Working Paper intends to give further explanations on the EU definition of nanomaterial, give an overview of the main types and uses of nanomaterials on the EU market, as well as information on their safety, according to current knowledge available to the Commission, and an overview of issues and activities relating to risk assessment of nanomaterials. In principle, such information can be presented from the perspective of substances at nanoscale, i.e. chemical substances as defined under REACH which are nanomaterials or have forms which are nanomaterials[8], enumerating their main uses through the supply chain and in final products, or from the perspective of finished products or product areas. In this document, the former approach has been chosen because the number of substances at nanoscale is much more limited than the number of products containing nanomaterials and it is therefore easier to present the information in a structured manner. Information on uses in products can be found under each substance heading.

This document can, however, not give a complete or exhaustive picture on all nanomaterial forms or variations of substances. Nanomaterials are often tailored in a very specific way to achieve desired properties. This may alter their behaviour as well as their toxicological and ecotoxicological properties, throughout their life-cycles. In considering the safety of individual forms or variations, care should therefore be taken to properly take into account such variations in combination with specific uses of a particular form, where resulting in different exposure scenarios.

In chapter 6, the Staff Working Paper analyses existing databases on nanomaterials and gives information on a planned European Commission web platform on nanomaterials types and uses, including safety aspects.

2. Definition and types of nanomaterials

The Commission adopted on 18 October 2011 Commission Recommendation 2011/696/EU on the definition of Nanomaterial.[9] The Recommendation responds to the increasing use of specific legislative provisions addressing nanomaterials and the need to ensure harmonised terminology across different pieces of legislation, as well as to a request by the European Parliament.[10]

The Recommendation is based on the ISO term “nanomaterial”[11], a Reference Report of the European Commission’s Joint Research Centre (JRC)[12], an opinion of the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR)[13], on the 195 contributions received during public consultation[14] in October – November 2010, as well as on a number of other sources. The advice is presented in more detail below in chapters 2.2 and 2.3.

The core elements of the definition are laid down in articles 2 to 4:

“2. "Nanomaterial" means a natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for 50 % or more of the particles in the number size distribution, one or more external dimensions is in the size range 1 nm - 100 nm.

In specific cases and where warranted by concerns for the environment, health, safety or competitiveness the number size distribution threshold of 50 % may be replaced by a threshold between 1 and 50 %.

3. By derogation from point 2, fullerenes, graphene flakes and single wall carbon nanotubes with one or more external dimensions below 1 nm should be considered as nanomaterials.

4. For the purposes of point (2), "particle", "agglomerate" and "aggregate" are defined as follows:

(a) "Particle" means a minute piece of matter with defined physical boundaries;

(b) "Agglomerate" means a collection of weakly bound particles or aggregates where the resulting external surface area is similar to the sum of the surface areas of the individual components;

(c) "Aggregate" means a particle comprising of strongly bound or fused particles.”

The purpose of the Recommendation is to ensure consistency across legislative areas as well as across guidance and other technical documents by the European Commission. In addition, the Commission invites Member States, the Union agencies and economic operators to use this definition, for example, in the adoption and implementation of legislation and policy and research programmes concerning products of nanotechnologies

2.1. Application in legislation

The definition will primarily be used in future legislation or in updates of existing legislation to identify materials for which special provisions (concerning for example risk assessment or ingredient labelling) might apply. Those special provisions are not part of the definition but of specific legislation in which the definition will be used. The Recommendation offers a common understanding of the term “nanomaterial” to avoid confusion on terminology and inconsistency between different pieces of legislation. This does not mean that specific legislation needs to apply to all nanomaterials, or that there could not be legislation covering similar materials outside the definition. Since the definition is broad in its coverage, further sector specific qualifiers may be needed in order to identify more precisely those materials that should potentially be subject to specific legislative requirements or policy attention.

For example it is likely that in many cases only materials that are a designed product of a deliberate manufacturing process will be of interest (commonly referred to as "engineered" or "manufactured" nanomaterials). Thus further qualifiers may be added on a case-by-case basis, in order to target the specific materials that qualify for special attention within each regulatory sector.

Another consideration is that in certain specific sectors, like pharmaceuticals, it is established practice to refer to nanoscale being broader than 1 nm – 100 nm. The Recommendation clearly specifies that in such a situation other "nano"-terms may be needed to describe those products.

2.2. Reference Report of the Joint Research Centre

In June 2010 the Joint Research Centre of the European Commission released its Reference Report 'Considerations on a Definition of Nanomaterial for Regulatory Purposes'.[15] The aim of this report was to review and discuss issues and challenges related to a definition of ‘nanomaterial’, and to provide practical guidance for a definition for regulatory purposes. The report suggests that a definition for regulatory purposes should:

· only concern particulate nanomaterials,

· be broadly applicable in EU legislation, and in line with other approaches worldwide,

· use size as the only defining property.

2.3. The SCENIHR opinion

The Commission also invited the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) to provide scientific input on elements to consider when developing a definition of the term "nanomaterial" for regulatory purposes. The opinion "Scientific basis for the definition of the term 'Nanomaterial" was adopted on 8 December 2010.[16] SCENIHR concluded that:

· "Whereas physical and chemical properties of materials may change with size, there is no scientific justification for a single upper and lower size limit associated with these changes that can be applied to adequately define all nanomaterials.

· There is scientific evidence that no single methodology (or group of tests) can be applied to all nanomaterials.

· Size is universally applicable to define all nanomaterials and is the most suitable measurand. Moreover, an understanding of the size distribution of a nanomaterial is essential and the number size distribution is the most relevant consideration.

In order to define an enforceable definition of “nanomaterial” for regulatory use it is proposed to set an upper limit for nanomaterial size and to add to the proposed limit additional guidance (requirements) specific for the intended regulation. Crucial in the guidance that needs to be provided is the extended description of relevant criteria to characterise the nanoscale. Merely defining single upper and lower cut-off limits is not sufficient in view of the size distributions occurring in manufactured nanomaterials.

Alternatively, a tiered approach may be required depending on the amount of information known for any specifically manufactured nanomaterial and its proposed use.

The scientific opinion recognises however that specific circumstances regarding risk assessment for regulatory purposes for certain areas and applications may require the adaptation of any overarching definition.

It should be stressed that 'nanomaterial' is a categorization of a material by the size of its constituent parts. It neither implies a specific risk, nor does it necessarily mean that this material actually has new hazard properties compared to its constituent parts or larger sized counterparts."

2.4. The international context

Several countries, both inside and outside the EU have developed and use working definitions. All these have been carefully scrutinised. There is variability between the different working definitions but most of them are not as precise as the Commission Recommendation. Most non-EU countries generally use their definitions in a different regulatory context mainly to identify individual materials and/or uses, which then may be subject to specific data provision or risk assessment obligations. In the EU, provisions in individual pieces of legislation (e.g. ingredient labelling, prior notification and authorisation etc.) apply directly to all producers of products containing nanomaterials. Therefore, much more precision is required to provide legal clarity.

Several international organisations have developed their definition of the term nanomaterial. Among these, the definition released by ISO in 2010 (in ISO/TS 80004-1) was developed with the broadest stakeholder base. The approved definition ('material with any external dimension in the nanoscale (2.1) or having internal structure or surface structure in the nanoscale') is fundamentally based on the term 'nanoscale' which was previously defined by ISO (in 2008 in ISO/TS 27687) as 'the size range from approximately 1 nm to 100 nm'.

The ISO definition is used as a working definition for example by the OECD Working Party on Manufactured Nanomaterials (OECD-WPMN). Whilst this broad working definition has proved useful for progressing research and development in this field, it could not be directly used for legal texts, for example due to the approximate nature of the term nanoscale.

2.5. Essential elements of the definition

2.5.1. The size range 1 nm – 100 nm

There is no clear scientific justification for setting the thresholds at 1 nm and 100 nm, as specific effects may also occur at a lower and higher size range. On the other hand, particles within the size range of 1 nm to 100 nm may also not show a specific behaviour different from the behaviour of larger particles of the same material. Nevertheless, many of the described specific properties of nanomaterials are actually generated by physics and chemistry within that range.[17] Therefore, in the absence of better arguments for other thresholds, the Commission decided to follow the approach most commonly applied to date, i.e. a size range between 1 nm and 100 nm. This is in line with the advice from SCENIHR and other scientific bodies, as well as with the size range used in the ISO term “nanomaterial”. To make the definition useful for regulatory purposes, it was chosen not to retain the term 'approximately', which qualifies the 1 nm to 100 nm range in the ISO definition.

2.5.2. Aggregates and agglomerates

To some extent, agglomerated or aggregated particles may exhibit the same properties as unbound particles and are therefore covered by the definition. Moreover, there can be cases during the life-cycle of a nanomaterial where the particles are released from weakly bound agglomerates or under certain conditions even from more strongly bound aggregates. The definition in the Recommendation therefore includes particles in agglomerates or aggregates whenever the constituent particles are in the size range 1 nm - 100 nm.

2.5.3. Based on number of particles, not mass

The amount of nanoparticles in a material can be determined based on their mass fraction (weight of nanoparticles relative to total weight of material) or based on the particle number fractions (number of nanoparticles to total number of particles, "number size distribution"). Most measurement methods produce an intensity-weighted size distribution (expressing the fractions of particles of a particular size as their relative contribution to the total measured signal intensity). There is a relation between these different size distributions, for every material, but these relations are not usually known and the different size distributions are therefore not directly convertible.

SCENIHR argued in its opinion that "a low mass concentration of nanoparticles in a product may still represent a high number of particles and a mass based distribution can be skewed by the presence of relatively few large and thus heavy particles". As the smallest particles have a proportionally higher specific surface area, which may be relevant for toxicity properties, SCENIHR considered number size distribution as a more relevant metric for possible effects of nanoparticles.

The Commission followed this choice of metrics. Further work is certainly needed on the metrological and standardisation aspects. Previous efforts, for example in the field of fine dust (PM10, PM2.5, etc.), are naturally extending now into the nanoscale. The Commission has already started work to provide practical guidance on particle size measurement methods[18],[19] and quality assurance tools such as interlaboratory studies,[20],[21] nanoparticle reference materials[22],[23],[24] for particle size analysis (see also Appendix 9 for further detail), and characterization of complex mixtures of nanoparticles.[25]

2.5.4. A threshold in the number size distribution

There is no unequivocal scientific basis to suggest a specific threshold in the size distribution below which materials containing particles in the size range 1 nm – 100 nm are not expected to exhibit properties specific to nanomaterials. Because of the proportionally higher specific surface area which may be relevant for toxicity properties exhibited by the smallest particles, and following a classic scientific approach to consider three standard deviations, the SCENIHR's advice was to use a threshold value of 0.15 %.

The Commission decided to deviate from this threshold value based on several considerations. Nanoparticles are present in low quantities in most solid materials. The percentage may be significant, in particular in certain powders. Therefore, a threshold of 0.15 % could include too broad a range of materials within the definition, and would have made it difficult to tailor regulatory provisions appropriately.

Nevertheless, in accordance with SCENIHR's advice, even a small number of particles in the range between 1 nm – 100 nm may in certain cases justify a targeted assessment. For such cases, the Recommendation clearly specifies that where warranted by specific concerns for the environment, health, safety or competitiveness a threshold between 1 % and 50 % may be set. These threshold values will be subject to further review by 2014.

2.5.5. The Volume specific surface area

It is possible to measure a specific surface area by mass for dry solid materials or powders with the gas adsorption method (“BET-method”). If the particle density is also known, then the 'volume-specific surface area' can be calculated and used as a proxy to identify a potential nanomaterial. For some materials, there can be a discrepancy between the measurement of the specific surface area and the number size distribution. The measurement of the specific surface area is also sensitive to the measurement method used. It is therefore specified that the results for number size distribution should prevail and it should not be possible to use the specific surface area to demonstrate that a material is not a nanomaterial.

2.5.6. Practical use of the definition

Guidance and standardised measurement methods as well as knowledge about typical concentrations of nanoparticles in representative sets of materials should be developed where feasible and reliable to facilitate the application of the definition in a specific legislative context. The Commission will address these aspects as a matter of priority. However, the use of the definition should not await the outcome of this work and a pragmatic case-by-case approach needs to be applied for the time being. In fact, this should be an iterative process where practical experience will form an important aspect of the further development of measurement methods and standards.

2.5.7. Review of the definition

Some methodological issues and questions of scope could not be fully answered in the preparatory work for the definition. Moreover the nanotechnology sector is rapidly developing and it is therefore expected that the market developments will require the Commission Recommendation to be reviewed at certain intervals. The Recommendation will be reviewed by December 2014.

In view of this review, the Commission services continue to follow up wider work on terms related to nanotechnology and nanomaterials, for example by the International Organization for Standardization (ISO). Details about this work and its relation with the current EU definition are presented in Appendix 1. More information about standardisation work in relation to nanomaterials is given in Appendix 9.

3. Overview of nanomaterials, their markets, uses and benefits

Nanomaterials cover a heterogeneous range of materials. In terms of market volume the main categories on the market include inorganic non-metallic nanomaterials (e.g. synthetic amorphous silica, aluminium oxide, titanium dioxide), carbon based nanomaterials (e.g. carbon black, carbon nanotubes), metal nanoparticles (e.g. nanosilver) and organic, macromolecular or polymeric particulate materials (e.g. dendrimers). Nanomaterials often exist in a variety of forms and may be tailored for individual properties or uses. It was not possible to give market information at such a level of detail, as this information is, if at all, not readily available.

In terms of industrial impact and public exposure the above-mentioned nanomaterials are of immediate regulatory relevance. However, there are also new types of nanomaterials in development, which are often referred to as “second generation” (targeted drug delivery systems, adaptive structures and actuators), “third generation” (novel robotic devices, three-dimensional networks and guided assemblies), and “fourth generation” (molecule-by-molecule design and self-assembly capabilities) nanomaterials.[26],[27],[28] However, those are either at research or development stage or at an early stage of market development. Due to the limited available information on those materials, they are not further considered in this Staff Working Paper.

Any estimates of the market size need to be taken with a certain degree of caution, although the general patterns of the estimates (i.e. order of magnitude of tonnage and market value, and relative size of market between the various materials) seem to be rather reliable. According to market data from SRI consulting the global quantity of nanomaterials marketed annually is around 11.5 million tonnes, with a market value of roughly 20 bn €.[29] The market is dominated by two very widespread commodity materials, i.e. carbon black (9.6 million t), and synthethic amorphous silica (1.5 million t). Other nanomaterials with significant amounts on the market include aluminium oxide (200 000 t), barium titanate (15 000 t), titanium dioxide (10 000 t [30]), cerium oxide (10 000 t), and zinc oxide (8 000 t). Carbon nanotubes and carbon nanofibres are currently marketed at annual quantities of several hundreds of tonnes (other estimates go up to a few thousands of tonnes). Nanosilver is estimated to be marketed in annual quantities of around 20 tonnes. In addition, there is a wide variety of nanomaterials which are either still at the research and development stage, or which are marketed only in small quantities, mostly for technical and biomedical applications.

The uses of nanomaterials vary substantially, from commodity applications in everyday goods to highly specialised low-volume technical applications, e.g. in electronics or biomedicine. By far the biggest use is as a reinforcing agent for rubber in tyres and other rubber goods (global market around 15 bn €, mainly carbon black), followed by functional fillers in polymers (around 1.5 bn €, mainly synthetic amorphous silica, in lower quantities also other metal oxides and silver), various uses in electronics (1 bn €), in cosmetics (100 m €) and biomedical applications (60 m €). In electronics, the biggest use are CMP[31] slurries, i.e. fine abrasives (mainly colloidal synthetic amorphous silica) used in the preparation of electronic components, followed by multi-layered ceramic capacitors (MLCC, mainly barium titanate). In cosmetics, the main nanomaterials are synthetic amorphous silica, titanium dioxide and zinc oxide. Among biomedical applications, gold nanoparticles in medical diagnostics and silver nanoparticles (e.g. in hospital textiles) seem to be the biggest applications in terms of market value. In addition to those applications, there is use of a wide range of nanomaterials in paints and coatings, catalysts, solar and fuel cells, etc.

The economic sectors with the highest use of nanomaterials[32] are aerospace (e.g. lightweight materials, resistant paints and coatings for aerodynamic surfaces); automotive industry and transport (e.g. scratch-resistant paints and coatings, plastics, lubricants, fluids, tyres); agrifood (e.g. sensors to optimise food production); construction (e.g. insulation, stronger building materials, self-cleaning windows); energy generation (e.g. photovoltaics) and storage (e.g. fuel cells and batteries); environment (e.g. soil and groundwater remediation); cosmetics (e.g. sunscreens, tooth paste, face creams); health, medicine and nanobiotechnology (e.g. targeted drug delivery); information and communication technologies, electronics and photonics (e.g. semiconductor chips, new storage devices and displays); security (e.g. sensors to detect biological threats); and textiles (e.g. protective clothing, stronger, self-cleaning or fire resistant fibres).

The benefits of nanomaterials are as diverse as the nanomaterials and their uses. They range from saving lives (e.g. targeted cancer drug delivery) to major technological breakthroughs enabling new applications or reducing the environmental impact of our society (e.g. photovoltaic cells and batteries, light-weight high-strength materials), to improving the function of everyday commodity products (e.g. carbon black in tyres, synthetic amorphous silica in polymers, or as food or cosmetics additive) and to improvements which are mainly of convenience nature (e.g. anti-odour socks).

Nanotechnology has been identified as a key enabling technology (KET) by the High Level Expert Group (HLG) on Key Enabling Technologies.[33] It is highly innovative and provides the basis for further innovation and new products in a wide range of industries, as mentioned above.[34] Products underpinned by nanotechnology are forecast to grow from a volume of 200 bn € in 2009 to 2 trn € by 2015.[35] These applications will be essential for the competitiveness of a wide area of EU products in the global market. There are also many newly founded SMEs and spin-off companies in this high technology area. Currently, the direct employment in nanotechnology is estimated at around 300000 to 400000 jobs in the EU.[36]

In many areas, nanomaterials can significantly contribute to mastering the challenges of the future and the objectives of the EU 2020 Strategy, such as smart growth, developing an economy based on knowledge and innovation, and sustainable growth, promoting a low-carbon, resource-efficient and competitive economy. They can provide essential contributions to green technologies and environmental protection (e.g. sensors for smart electricity grids, filters for drinking water). They can also contribute to inclusive growth by providing new employment and keeping jobs in the EU.

It is difficult to find reliable information on the relative strength of the EU in nanotechnology compared to other regions of the world. The work on this document, in particular Appendix 2, shows that manufacturers and users of nanomaterials are spread all over the industrialised world. Among them are major companies that are located in the EU. The KET HLG report mentions that the EU accounts for 27% of world wide public funding on nanomaterials, 17% of patents[37], and 15% of nano-based products.[38] To an extent, this may be influenced by the ongoing debate in the EU on regulating nanomaterials. According to a recent survey[39], half of the manufacturers and importers of nanomaterials in Europe replying to the survey considered the regulatory uncertainties the most important challenge in bringing nanomaterials on the market. The emerging economies such as the BRIC[40] countries are still behind the industrialised countries in terms of production and uptake of nanomaterials but are quickly progressing.

4. Health and safety aspects

Health and safety aspects include possible intrinsic hazard patterns of the nanomaterials, exposure to workers, consumers and at the waste stage, as well as applicable risk management measures. Hazards are determined by the properties of the material itself.[41] However, these hazards will only lead to health or environmental risks[42]if parts of the human body or the environment are exposed to doses of the nanomaterial which can create harmful effects. Correspondingly, risks are determined by a combination of hazards and the probability of exposure.

4.1. Hazard patterns

The hazard patterns vary largely between different nanomaterials. In its opinion of 19 January 2009[43], the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) concluded: “The health and environmental hazards were demonstrated for a variety of manufactured nanomaterials. The identified hazards indicate potential toxic effects of nanomaterials for man and environment. However, it should be noted that not all nanomaterials induce toxic effects. Arguably, some manufactured nanomaterials have been in use for a long time (carbon black, TiO2) and show low toxicity. The hypothesis that smaller means more reactive and thus more toxic cannot be substantiated by the published data. In this respect nanomaterials are similar to normal substances in that some may be toxic and some may not. As there is not yet a generally applicable paradigm for nanomaterial hazard identification, a case by case approach for the risk assessment of nanomaterials is recommended.”

In their recent joint report "Impact of Engineered Nanomaterials on Health: Considerations for Benefit-Risk Assessment" EASAC[44] and the European Commission's Joint Research Centre conclude that "there is only a limited amount of scientific evidence to suggest that nanomaterials present a risk for human health".[45]

Nanomaterials may have a wide range of potential toxic effects, depending on their chemical nature, particle size distribution, particle shape, surface state (e.g. surface area, surface functionalisation, surface treatment), state of aggregation/agglomeration etc. Some of the main known effects from experimental studies are described below and in Appendix 2, under the relevant substance heading. Under experimental conditions, the most common effects observed are a potential to cause oxidative stress and, for some, inflammatory responses or even genotoxic effects.

Like for all chemicals, the potential harmful effects of nanomaterials depend on the doses to which human beings or the environment are exposed to. Typically, experimental data are generated with high doses, identifying effects, and subsequently determining no-effect levels. At low doses, most nanomaterials show little effects in these experiments. Views on whether nanomaterials are hazardous or pose risks diverge, as they depend crucially on whether the experimental data are considered representative for real life conditions.[46] Some consider that high dose experiments are a normal way of identifying hazards and their results should be an indication of potential risks, whereas others consider that experiments with such high doses are unrealistic and that similar effects could be found at those doses even with very common, non-hazardous substances. Moreover, the route and the conditions under which test animals are exposed to nanomaterials is also critical and subject to substantial methological discussions.[47] There is however, a consensus on the principle that hazards and risks differ significantly between nanomaterials and that some are hazardous and others are not.

For example, the joint EASAC-JRC report considers that “Overload conditions especially in the lung (macrophages) have been described for 20 years. It is now well known that overloading the lung with dust particles will severely influence (reduce) the clearance process, thereby prolonging dramatically the biological lifetime of particles within the lung. Eventually, this leads to persistent inflammatory effects with all the characteristics of lung diseases which often end in tumour formation. Therefore, it is recommended that overload conditions should be avoided both in animal studies and for in vitro experiments otherwise excessive doses will generate false-positive results.

This sense of realism is equally warranted for intended applications where engineered nanomaterials are targeted to the individual in relatively precise amounts. Moreover, testing genotoxicity with overloading concentrations (often cytotoxic concentrations) is also unrealistic as dying cells (apoptosis as well as necrosis) cleave their own DNA, resulting again in false-positive effects[48]. If non-overload conditions are chosen, no carcinogenic effects for such dust particles are found[49]."[50]

There are little epidemiological data, directly evaluating effects of nanomaterials under real life conditions. The few available studies, e.g. on carbon black, are considered as inconclusive because of inconsistent epidemiological evidence.[51] Some other nanomaterials such as synthetic amorphous silica have been on the market for a considerable time, including in high exposure conditions, with little, if any, known adverse health or environmental effects. However, there is also an ever growing variety of new uses and modified forms, for which such experience does not exist. Until understanding is available on the impacts of different forms and modifications of nanomaterials on the hazard patterns, particular care should be taken to avoid undue generalisation of data from one form to another.

In its 2006[52], 2007[53] and 2009[54] opinions, the SCENIHR acknowledged the possibility that translocation of nanoparticles away from the portal of entry may occur in humans and other species, and that the passage of nanoparticles across membranes could give rise to adverse effects, for example within the cardiovascular system or following passage across the blood – brain barrier.

A number of in-vivo studies in rats have demonstrated that certain nanomaterials can penetrate into the body and reach certain organs and tissues (for example in the lung, liver, kidneys, heart, reproductive organs, foetus, brain, spleen, skeleton and soft tissues) via several routes (following inhalation, crossing the pulmonary epithelium and entering the blood stream; or reaching the brain via the olfactory nerve; or crossing the intestinal epithelium after ingestion).[55],[56],[57],[58],[59],[60],[61],[62],[63],[64] Moreover, there are open questions on bioaccumulation of nanomaterials and elimination mechanisms from cells and organs.

In animal studies, a whole series of effects have been observed under experimental conditions with high doses (for methodological discussions around such tests, see above). The most important effects have been found in the lungs: there is evidence of inflammation, tissue damage, oxidative stress, chronic toxicity, cytotoxicity, fibrosis, tumours.[65] Tumour formation was found in rat lungs following intraperitoneal introduction of certain nanomaterials. Furthermore, in long-term studies with intratracheal instillation with nanostructured carbon black, aluminium oxide, aluminium silicate, titanium dioxide (hydrophilic and hydrophobic) and amorphous silicon dioxide, tumours were induced by all of them[66],[67],[68],[69],[70]. Effects like inflammation, fibrosis and tumours were induced by several granular nanomaterials in the lungs after respiratory exposure. Some nanomaterials, including carbon black and titanium dioxide, were on the basis of experimental animal studies classified as “possibly carcinogen to humans” (group 2B) by IARC.[71]

In particular, carbon nanotubes (CNTs) of length, diameter and rigidity ratios comparable to those of toxic forms of asbestos were shown to have a potential under experimental conditions to induce effects similar to those of asbestos.[72] There is no clear evidence of acute effects in other organs than lungs but chronic exposure may lead to elevated accumulation of translocated nanomaterials eventually leading to adverse health effects.[73],[74],[75],[76],[77] In particular, in case of respiratory exposure to nanomaterials special attention is to be given to the cardio-vascular system as natural ambient particles and incidental ultrafine particles (e.g. welding fumes and combustion products) show some similarities (poor solubility, persistence in the lungs) that might indicate some common properties. [78],[79],[80],[81],[82],[83]

Extensive data[84] on adverse effects of particles of different sizes in ambient and indoor air can also contribute to the understanding of the safety aspects of nanomaterials in certain circumstances, in particular epidemiological and toxicological studies addressing ultrafine particles.[85],[86],[87] Ultrafine particles are present in our everyday lives and at various conventional workplaces, generated by the applied work processes (i.e. work processes generating ultrafine dust, aerosols or fumes, such as spraying, dry-cutting, polishing, material processing with laser applications, combustion processes, welding processes generating metal-welding fumes, etc.).[88],[89],[90] Diesel exhaust exposure and PM10 concentrations have been related to higher mortality in the general population at higher pollution rates, and to aggravation of asthma and lung cancer in workers.[91] Fine particulate matter exposures have also been linked to cardiovascular effects.[92],[93] Metal oxide fumes, for example by welding, casting and abrasive treatment, may lead to metal fume fever and more severe irreversible respiratory illness.[94] There are continuous gaps in knowledge in relation to health effects of individual components of particulate matter.[95] There is major ongoing research on the health impact of particulate matter, including in particular transport-related particles, on human health.[96] A significant body of EU environmental regulation including emission standards[97] and workplace codes of practice or regulations have been designed to limit exposure to particulate matter.[98]

Catalytic effects and the risk of fire or explosion should be taken into account in the risk assessment of handling powders consisting of nanomaterials (nanopowders), in particular metal nanopowders.[99]

There is a number of experimental studies on ecotoxicity of nanomaterials which show varying results and a variety of ecotoxic effects. For example Zhu et al[100] report reduced length and body weights of fish as a result of exposure to fullerene aggregates. Silver and copper nanoparticles are known to be strongly ecotoxic. There are indications that this is primarily related to ion release (which is relatively high compared to bigger particles due to the larger specific surface) rather than to the particles themselves. There are also many studies on titanium dioxide and zinc oxide, showing diverging results, depending on the forms of nanoparticles studied.[101] Unfortunately, those forms were often inadequately characterized to enable the results from these studies to be extrapolated to other circumstances. Overall, the level of ecotoxicological knowledge is significantly lower than the level of toxicological knowledge. There are many uncertainties relating to simulation of environmental conditions in experiments (usually much higher concentration and more short-term exposure than realistic environmental conditions, interferences through solvents, strong dependence on forms of nanoparticles, surface treatment etc.). There are also open questions on bioaccumulation and long term exposure, even though this does not seem to be a general issue for all nanomaterials, as shown by the long presence of certain nanomaterials on the market, and the absence of observed effects for these nanomaterials.

Although it is not always possible to identify which information in REACH registration dossiers relates to or covers the nanoform(s), it should be noted that most of the substances registered under REACH which have nanoforms have not been classified by the registrants for any hazard endpoint.[102]

In conclusion, toxicological knowledge about nanomaterials is improving continuously. Despite the open questions described above, available toxicological knowledge on nanomaterials suggests that many nanomaterials are non-hazardous at moderate doses while others are hazardous. There is a need for a more focused risk assessment of nanomaterials, on a case-by-case basis. This should allow indentifying risks related to specific nanomaterials and their uses, and taking appropriate risk management measures. In the absence of more detailed knowledge, there is a need to apply precautionary considerations to reduce exposure, in particular at the workplace. Workplace exposure should be reduced to the minimum applying the hierarchy of control measures according to the workplace legislation such as Directive 98/24/EC and specific guidance from the OECD (see 4.2). and, where these would not be possible because of insufficient scientific information for the necessary hazard and/or risk characterisation, applying the ALARA[103] principle on the workplace exposure to ensure the safe use of nanomaterials in other ways.

Moreover, this also does not preclude that additional precautionary action such as substance or use restrictions for individual substances (including on particular forms or modifications of nanomaterials) may become necessary if new information becomes available indicating serious potential risks. Scientific work to inform the risk assessments process should continue, especially regarding nanomaterials for which initial information suggests possible serious hazards, and for developing a better understanding of the role of different forms and modifications of nanomaterials in generating specific hazard patterns.

4.2. Exposure patterns

There are very few measured data on exposure to nanomaterials and available exposure models. Therefore, exposure aspects can be mainly addressed through general considerations and assumptions in exposure scenarios. One known important factor to characterise exposure is whether nanoparticles occur as free particles, whether they occur in aggregates or agglomerates, whether they are bound in a matrix or enclosed in equipment, or whether they are transformed during the production process in a way that they do not occur as nanoparticles in the finished product.

Exposure is likely to be most serious if particles occur in free form, although this seems to be relatively rare. Often, nanoparticles aggregate or agglomerate under normal environmental conditions, thereby changing (but not necessarily losing) their nanospecific properties. Studies are investigating whether, once inhaled and in lung fluid, such aggregates/agglomerates could de-aggregate/de-agglomerate and nanoparticles could be released.[104],[105] There can be cases during the life-cycle of a nanomaterial where the particles are released from weakly bound agglomerates or under certain, perhaps rather unlikely, conditions even from more strongly bound aggregates. Exposure is less likely if nanomaterials are bound in a matrix or enclosed in equipment. It may still occur in the long term, through environmental degradation or at the waste stage, or during specific operations such as abrasion or machining of the matrix. This may also have impacts on the environment and indirectly on humans (e.g. through drinking water or air), though the evidence is still very limited and controversial.[106],[107]Generally, the highest risk of exposure to nanomaterials is to workers at the production stage, although this is also where exposure is generally best controlled with the use of closed systems.[108] Nevertheless, risks of exposure during maintenance and cleaning of such closed systems, as well as in the case of leakage have to be considered. Measurements of airborne nanomaterials have shown higher levels where processes such as extrusion and cutting of bags containing nanomaterials, or dry-sawing of nanomaterial-containing composites took place.[109] The risk of chronic exposure of workers to situations where such nanomaterials-containing products are processed (e.g. polishing) requires further investigation.

Although there are very little measured data, it seems quite obvious that exposure at the use stage varies strongly, depending on the type of application. In technical applications where the nanomaterials are bound in a matrix (e.g. paints or construction materials) or embedded in equipment parts (e.g. in electronics), exposure during use is estimated to be relatively low. Exceptions might be when such matrices are for example abraded or machined (e.g. dry-sawed).[110] In general, little or no information is currently available in the Safety Data Sheets (SDS)[111],[112],[113],[114], making it often difficult for employers and workers at the use stage to assess specific exposure to nanomaterials and to implement adequate prevention measures. Relevant changes in REACH Annex II, which is the legal framework for Safety Data Sheets, have been made recently[115], and the recent guidance from ECHA on the Safety Data Sheets gives further advice on how to address characteristics of nanomaterials.[116] There are ongoing discussions whether leaching (e.g. of outdoor paints or release at the end-of-life) could lead to the release of significant amounts of nanoparticles. In other applications such as in food and cosmetics, exposure is estimated to be high due to ingestion or direct contact with the skin. In between there are applications such as tyres, where a certain degree of wear and thus environmental exposure occurs.

Exposure to nanomaterials may also occur at the waste stage. Although still controversial and subject to debate, there are results from studies on grinding of materials consisting of nanomaterials bound in a common matrix[117] which do not confirm that those nanoparticles are released from the matrix during grinding (like in any fine grinding process, there can be release of nanoparticles but these are also formed in a similar way from the matrix in which the bound nanoparticles are embedded or from matrices which do not contain any nanomaterials at all). However, fine airborne particles containing manufactured nanoparticles could be inhaled and thus could possibly serve as a “vehicle” transporting nanomaterials into the body. Studies are investigating whether, once in the body, such bound nanomaterials could be released (for example in lung fluid) or would influence the toxicity of the fine particles.[118],[119]

There are few studies on the environmental fate and behaviour of nanomaterials. This is mainly due to a lack of methods to detect nanoparticles in the environment. A particular problem is the distinction between manufactured nanoparticles and incidental or natural nanoparticles. Even under workplace conditions, the background level in airborne nanoparticles (e.g. through diesel exhaust nanoparticles) may dominate over additions through emissions from the manufacturing process. Apart from clear indications that nanoparticles interact with natural organic matter, there is also little information about the fate of nanoparticles in the aquatic environment.

In addition, there may also be exposure to nanomaterials as a result of their presence in recycled materials. While there is no information available on any identified adverse effects to date, the issue is starting to be considered.[120],[121],[122]

In conclusion, much more work on developing exposure data and detection methods for nanomaterials in the environment is needed.

4.3. Risk characterisation

Mainly as a result of the lack of exposure data[123], risk characterisation and combining hazard and exposure data necessarily remains at a very preliminary and qualitative level. As long as the considered nanomaterials are non-hazardous and do not bio-accumulate, this is a limited problem, as exposure to such materials is unlikely to cause toxic and ecotoxic effects, at least at moderate doses. Where exposure is unlikely to occur, either because nanomaterials are strictly contained or embedded in a matrix, or as a result of risk management measures, this will also be a limited problem. Therefore, the focus of attention of the regulators should be those nanomaterials for which initial information suggests possible hazards or bioaccumulation and the applications of these nanomaterials where significant exposure of workers, consumers or the environment may occur.

According to current knowledge, examples of such nanomaterials are the different forms of nano-titanium dioxide and nano-zinc oxide (due to high potential exposure, in particular in their applications as UV-filters), carbon nanotubes (for the possible carcinogenicity of certain forms) and nano-silver (for possible ecotoxicity).

However, priorities will need to be reviewed depending on the outcome of this work and on new scientific and market developments. In particular in emerging uses, hazard patterns of nanomaterials may be different from studied forms, including through modification by downstream users of nanomaterials. Exposure patterns of nanomaterials may change with their uptake in specific new applications. Therefore, care must be taken that those trends are adequately reflected in risk assessments, including exposure scenarios.

4.4. Risk management

There is a variety of possible risk management measures to avoid exposure, in particular at the workplace. Prevention of occupational risks is an employer’s responsibility according to Directive 89/391/EEC on the introduction of measures to encourage improvements in the safety and health of workers at work.[124] In situations where elimination of the risk or substitution by a substance less hazardous are not possible, the hierarchy of control measures as provided for by Directive 98/24/EC on the protection of the health and safety of workers from the risks related to chemical agents at work[125] gives priority to reduction of the risk at source. Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens or mutagens at work[126] introduces more stringent provisions in the case of carcinogen or mutagen substances, for example regarding substitution. These risk management measures include, as also for traditional chemicals, process control (e.g. various degrees of containment, applying work processes where nanomaterials are in a fluid matrix instead of in the powder form), local ventilation and discharge control measures (e.g. filtration), organisational measures (reducing the number of workers exposed, reducing the exposure time, etc.) and, as last resort, personal protective equipment. The risks of exposure due to technical problems (damage, poor tightness) of the containment systems as well during maintenance and cleaning operations have to be considered. An overview of relevant literature on workplace exposure to nanoparticles, on risk communication on nanomaterials in the workplace, as well as company Good Practice examples on the risk management of nanomaterials[127] has been compiled by the European Agency for Safety and Health at Work (EU-OSHA). An updated list of major information sources with regard to occupational safety and health (OSH) and nanomaterials, including examples of risk assessment tools and guidance developed in EU Member States is included in Appendix 6. By end 2012, EU-OSHA will make a web portal dedicated to OSH and nanomaterials containing information material for workplaces available on its website.[128]

A tiered pragmatic approach to exposure measurements and assessment of nanoscale aerosols for workplace operations was recently developed in Germany in a dialogue between a number of institutions.[129] The approach combines established risk management concepts with elements of exposure assessment according to the current technology, and it is based on the experience of the participating practitioners.

In order to better understand and improve the knowledge base on protection of workers from possible risks arising from exposure to and use of nanomaterials and/or nanotechnology in the workplace, the Commission has launched a study[130] aiming to: (i) check the extent to which the current EU OSH legal framework covers sufficiently and effectively nano-related risks in the workplace; (ii) delineate a series of possible scenarios that should help shed light on which options may be better suited to tackling nano-related workplace risks without undue demands on businesses; and (iii) the drafting of a practical guidance document that may help tackle the mentioned workplace risks in waiting for a developed regulatory framework to be put in place. To achieve this, the study will include an in-depth characterisation of likely exposures of workers to nanomaterials, relevant risk assessment issues, types and effectiveness of risk management measures and relevant regulatory issues. The study is scheduled to be finalised by early 2013. The Commission will also give consideration to requesting a more robust involvement of the EU-OSHA with a view to raise awareness and/or disseminate information, as appropriate, in relation to any possible risks posed by nanomaterials and/or nanotechnology in EU workplaces.

Awaiting the outcome of this study, new approaches aiming to control workers exposure have recently been presented. An example is the so-called Nano Reference Values (NRVs) system[131] proposed as provisional alternatives for HBR-OELs[132] or DNELs[133] or US-NIOSH’s approach in recommending an OEL for TiO2 nanoparticles.[134] This system is based on a precautionary, thus not on a risk-based approach. While not guaranteeing that exposures below the NRV-level are safe, NRVs define a maximum generic level for the concentration of nanoparticles in the workplace atmosphere, corrected for the background particle concentration. NRVs are intended to be a warning level to urge for risk management of nanoparticles at the workplace. According to this approach, when exceeding this level of exposure, reducing measures should be taken. In any event such measures should also be considered for exposures below the NRVs.

Exposure to consumers and the environment at the use stage, and to an extent also at the waste stage is more difficult and often impossible to control through risk management measures at the place of exposure. There are in principle many tools to manage risks for consumers and the environment at the place of exposure such as proper use instructions, disposal or recycling of products.[135] Nevertheless, as they are not always effective, the most realistic and promising approach to control exposure to consumers and the environment, where needed, remains the reduction of emissions at source.

In conclusion, where risks are identified, appropriate risk management measures need to be taken. This includes a range of possible measures to control exposure at the workplace or minimize exposure to consumers and the environment through risk management measures at source, and to the extent possible through measures such as proper use instructions, disposal or recycling of products. Where the application of current regulatory obligations such as from REACH registration or the Chemical Agents Directive may not be sufficiently effective, further regulatory action, including possible restrictions of use of certain nanomaterials may become necessary.

5. Risk assessment

5.1. The opinions of the EU risk assessment bodies

In light of the benefits derived from applications of the nanotechnologies and resulting, expected growth of their presence on the EU market, following an initial mapping of the potential risks of nanotechnologies in March 2004[136], the European Commission asked, respectively, the three non-food Scientific Committees (Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR), Scientific Committee on Consumer Safety (SCCS), Scientific Committee on Health and Environmental Risks (SCHER))[137], the European Food Safety Authority (EFSA)[138], the European Medicines Agency (EMA)[139], and the European Chemicals Agency (ECHA)[140] to address the safety of nanomaterials.

SCENIHR concluded that “while risk assessment methodologies for the evaluation of potential risks of substances and conventional materials to man and the environment are widely used and are generally applicable to nanomaterials, specific aspects related to nanomaterials still require further development. This will remain so until there is sufficient scientific information available to characterise the harmful effects of nanomaterials on humans and the environment.”[141]

The guidance provided by EFSA (2011)[142] offers a strategy for risk assessment in food and feed. It concerns (i) characterisation requirements of engineered nanomaterials used in food and feed and (ii) testing approaches to identify and characterise hazards to human health during use. The guidance lowers information requirements in the absence of exposure, i.e., no migration from a food contact material, or of absorption of engineered nanomaterials as such because of complete degradation/dissolution. The guidance also flags uncertainties.

In the food area, EFSA assessed the safety of silver hydrosol[143] and titanium nitride[144] for use as food contact materials. Titanium nitride, silicon dioxide (synthetic amorphous silica) and carbon black are authorised with specifications as food contact materials.[145]

In the medicinal products area, EMA has been examining applications of nanotechnologies to medicinal products since 2006.[146] To date, recommendations from the EMA Committee for Medicinal Products for Human Use (CHMP) has led to the approval of about twenty medicines based on nanotechnology. They include medicines containing liposomes (microscopic fatty structures) containing active substances, such as doxorubicin[147]; mifamurtide[148] and doxorubicin[149] and nanoscale particles of active substances, such as paclitaxel[150], aprepitant[151] and sirolimus[152].[153]

Marketed medical devices using nanotechnologies concern a broad range of medical applications, ranging from traditional medical equipment to sophisticated electronic biomimetic devices via orthopaedic, dental or cardiovascular implants and novel treatments against cancer. A report published by the French Health Products Agency (AFSSAPS) on 18 August 2011 lists 17 products in the EU alone.[154] Some national authorities in the EU Member States have developed specific guidance. The European Commission envisages addressing the issue of nanomaterials in the context of the revision of the medical device legislation planned for 2012.

In the cosmetics area, the European Commission mandated the SCCS to develop guidance on nanomaterial risk assessment, including criteria for their categorisation[155] and assess four nanomaterials used as UV-filters (titanium dioxide, zinc oxide, ETH-50, HAA299).[156] On 11 November 2011, SCCS concluded that the use of 10% ETH-50 is safe for dermal application but that sprays containing ETH-50 cannot be recommended until additional information is provided. The evaluation of the other three materials is ongoing.

Absence of product recalls

The EU has two rapid alert systems, one for products (Rapid Alert System for Non-Food Dangerous Products, RAPEX[157]) and one for food and feed (Rapid Alert System for Food and Feed, RASFF[158]). No nanomaterial has so far been recalled under RAPEX or RASFF.

5.2. REACH registration dossiers

In close collaboration with ECHA, the Commission has assessed how nanomaterials have been addressed in REACH registration and CLP notification dossiers. At the end of February 2012, 7 registrations and 18 notifications had ticked the voluntary field "nanomaterial" as the form of the substance[159]. The further assessment identified three groups of registration dossiers, where a) the registrants recognized nanomaterials (8 dossiers /5 substances); b) substances exist only as nanomaterial (12/9), and c) the assessors identified nanomaterials on the basis of the particle size distribution (5/5). It is possible that additional substances with nanoform(s) may have been registered or notified but were not retrieved from the REACH and CLP database when the search-term "nano" was not used in any text field in the dossier or when the other search criteria used were not fulfilled.

In the assessed dossiers, different ways were used to present identification of substances that include or in one case exclude, nanoforms, and to organize nanoform(s) relevant information. Within groups a) and b) data could generally be linked to nanomaterial but, in particular for the a) group, its data quality was often in question due to the lack of justification or adequate characterisation of the addressed nanoform(s) or the testing material. For the group c) it was not possible to distinguish which data are for nanomaterial. These findings can partly be explained by the absence of detailed guidance to registrants on registration for nanomaterials, the absence of a definition of nanomaterial and the general wording of the REACH annexes.

5.3. The conclusions from RIPoNs on the applicability of the testing strategies to nanomaterials

The Commission’s Joint Research Centre carried out a number of REACH Implementation Projects on Nanomaterials (RIP-oNs) to evaluate the applicability of the existing REACH guidance to nanomaterials, and if needed, to develop specific advice on how the guidance could be updated to better address nanomaterials. Three reports are available:

RIP-oN 1 relates to "Substance identification of nanomaterials". Under REACH, substance identification determines whether substances must be registered separately or data on the same substance must be shared between the registrants. The objective of the project was to evaluate the applicability of existing guidance and, if needed, to develop specific advice on how to establish the substance identity of nanomaterials. The opinions of the participating experts from Member State Competent Authorities, industry, NGOs and ECHA diverged on several key issues, including whether size or surface treatment/functionalisation should affect substance identification or characterization of physicochemical properties. It was not possible to reconcile these opinions. Therefore, the report[160] mainly describes options/approaches rather than providing explicit recommendations. ECHA has been asked to develop such recommendations as it starts gaining practical experience through the evaluation of relevant registration dossiers.

The objectives of the RIP-oN 2 report on "Specific Advice on Fulfilling Information Requirements for Nanomaterials under REACH”[161] were to provide advice how REACH information requirements on intrinsic properties of nanomaterials can be fulfilled, including the appropriateness of the relevant test methods (and dosimetry) for nanomaterials, and outline, when relevant, possible specific testing strategies. It was also set to provide advice on the information that is needed for safety evaluation and risk management of nanomaterials. The objective of the RIP-oN 3 project "Specific Advice on Exposure Assessment and Hazard/Risk Characterisation for Nanomaterials under REACH" was to develop advice on how to do exposure assessment for nanomaterials within the REACH context and how to conduct hazard and risk characterisation for nanomaterials.

Neither RIP-oN 2 or RIP-oN 3 specifically addressed presentation of information on multiple nanoforms within dossiers (RIP-on 1 task) or the practical implications of multiple nanoforms of the same substance for chemical safety assessment. The reports however recognize the possibility, when scientifically justified, to apply the same data for different forms and substances (read across, grouping) and to use non-testing approaches (e.g. (Q)SAR, in silico). They also recommend further research on non-testing approaches as a high priority to be addressed within the short term.

RIPoN 2 concludes that the existing guidance and the information requirements on (eco)toxicological data (based on the OECD Test Guidelines and ISO/CEN standards) are considered applicable for the assessment of nanomaterials. Attention needs to be given to measuring, dosing, delivery and tracking of nanomaterials in the test system. Representative sample preparation and thorough and accurate physico-chemical characterisation using multiple techniques are an essential component of assessing the potential (eco)toxicity of nanomaterials. The report proposes the introduction of additional physico-chemical property information requirements and of an advisory note on sample preparation.

The guidance on physico-chemical properties was considered to be generally applicable to nanomaterials. However, the limited relevance and applicability of the property and methods for surface tension, flash point and viscosity was recognized, and the further evaluation of suitability of existing methods for water solubility, partition coefficient, adsorption/desorption was recommended.

The guidance on toxicological Information Requirements is considered applicable, although it was highlighted that attention needs to be given to measuring, dosing, delivery and tracking of nanomaterials in the test system. In general, the basic ecotoxicological properties and endpoints described in the OECD Test Guidelines for the determination of potential effects of test substances in relevant environmental compartments (aquatic, terrestrial, sediment) after acute or chronic exposure were considered adequate and relevant for nanomaterials. However, the report acknowledges the fact that OECD Test Guidelines were not specifically designed for the testing of nanomaterials, and the guidance provided on important measurement aspects such as the sample preparation, the delivery of test substances to test system or the exposure quantifications/metrics, in all of these test guidelines is considered to be insufficient for testing of nanomaterials. These issues have been preliminarily addressed in the OECD specific Preliminary Guidance Notes on Sample Preparation and Dosimetry.[162]

The identified potential additional relevant specific intrinsic properties include:

(a) Physico-chemical properties (Particle shape, Surface area, Surface energy, Surface chemistry, Surface charge, Redox potential, Cell-free ROS/RNS production capacity, State of dispersion, State of agglomeration). Additional guidance chapters were recommended only for shape and surface area;

(b) Toxicological endpoints (Cell uptake, Cell viability, Oxidative stress, Inflammation, Fibrosis, Immunotoxicity/sensitisation, Cardiovascular toxicity); no additional guidance chapter for them was recommended;

(c) Ecotoxicological endpoints, Ventilation rate, Gill pathologies, Mucus secretion, Brain pathology, Animal behaviour, Oxidative stress biomarkers[163]; no additional guidance chapter for them was recommended.

On certain endpoints[164] there was limited or no body of evidence available to inform the provision of specific practical advice. The published scientific evidence demonstrated that representative sample preparation and thorough and accurate physico-chemical characterisation using multiple techniques is an essential component of assessing the potential (eco)toxicity of nanomaterials. Factors such as the exposure method, dose selection, species used, cell type under investigation, as well as coating/functionalisation of the surface and particle impurities, release of free metal ions and particle aggregation all have the potential to impact on the assessed (eco)toxicity of nanoparticles. The full extent of influence of these factors on (eco)toxicological impact of nanomaterials is however still emerging.

While, in general, it was reported that only minor updates are necessary to some of the existing Integrated Testing Strategies (ITS) for the intrinsic properties/endpoints considered, a substantive update to the ITS for particle size analysis (or granulometry) was recommended, together with the expressed need to justify scientifically the use of QSAR and/or read-across. Advice was provided on the scientific basis for the categorisation of nanomaterials and application of in silico methods, read-across and category approaches for deriving hazard information for nanomaterials from the information on bulk substances or from comparison between nanomaterials. Whilst the lack of data across a wide range of structural and compositionally different nanomaterials precludes a fully prescribed category-based approach being developed, the suggested approaches for possible development indicate where such groupings may be applied.

RIPoN 3 concludes that there is still very limited evidence to draw any generalized conclusions or recommendations for the chemical safety assessment of nanomaterials under REACH. Known exposure assessment methods are generally applicable but may still experience methodological challenges, such as how to distinguish manufactured nanoparticles from background level of natural and incidental nanoparticles. No new nano-specific risk management measures need to be developed, but it is important to include specific information on nanomaterials in the safety data sheets (SDS) and assess the effectiveness of measures in place to ensure adequate protection. Due to lack of evidence, no recommendation is provided regarding risk management measures relating to the environment or the consumer.

The exposure scenarios (ES) case studies performed under RIPoN-3 highlighted general difficulties with the application of current guidance to nanomaterials. The ‘hierarchy of control’ concept which underpins much of the Operational Conditions (OC) and Risk Management Measures (RMM) REACH guidance in this area was considered to be equally valid for nanomaterials as for other substances. There is evidence that already known control and risk management methodologies can provide levels of protection for workers from exposure to engineered nanomaterials. It was not considered necessary to recommend the development of new nano-specific RMMs. However, the specific protection provided against specific nanomaterials needs to be evaluated. The project found that current exposure estimation models are not validated for nanomaterials and should not be used for nanomaterials without accompanying measurement data or scientific justification.

Emissions to the workplace may be substantially reduced if a process involving engineered nanomaterials is performed in a properly designed enclosure/containment, especially when adequately addressing what happens when the containment is opened. Worker exposure can be significantly reduced or prevented through the use of correctly designed and implemented extraction ventilation and filtration. Filtration theory indicates that filtration will be effective for particles in the nanometre size range. This also applies to personal protective equipment, where several studies clearly demonstrate the potential of respirator filters to capture nanoparticles. As for chemicals in general, further work is required to evaluate human factors such as leakage around face-piece filter and test protective suits and gloves.

The RIP-oN 3 report states that at current stage, Control Banding (CB) cannot be used to demonstrate that the risks are adequately controlled, but might support users in initial selection of control measures. No guidance can be given at this time as regards preliminary medical surveillance activities, though they are likely to be beneficial in the long term. Similarly, no recommendations for risk management measures in REACH guidance relating to the environment or consumer exposure can be made at this time, due to lack of evidence.

For safety data sheets (SDS), it is important that information provided for a nanomaterial is representative, valid and provides the protection needed for the forms addressed by the SDS.

Some of the key issues in exposure estimation are the discrimination from background nanoparticles and the adequate consideration of high spatial and temporal variability. The full particle size distribution curve as well as presence of ‘bundles’ or ‘clumps’ of high aspect ratio nanomaterials should be reported when measuring, and model estimates should not be relied on alone without scientific justification and further confirmation of their validity in individual cases. Adequate particle characterisation within test systems as well as the exposure environment is important as e.g. aggregation/agglomeration of nanoparticles may affect standard toxicity tests and affect parameters such as deposition zone in the lung or uptake by organisms.

For the most part, the current guidance in relation to deriving exposure limits provides sufficient flexibility to address areas of uncertainty, data gaps and, if justified, deviations from the default approach and the current assessment factors derived from classical (soluble substance) toxicity. Regarding hazard and risk characterisation, an alternative approach for extrapolating from experimental animals to humans for inhalation exposure was suggested for consideration and development.

RIP-oNs 2 and 3 work identified the critical items on exposure/dose descriptors and outlined needs for adequate exposure assessment metrics/parameters compatible with those used for hazard assessment. The metrics currently used in risk assessment across exposure, toxicology and risk, are based on mass or number. Based on toxicological evidence on inflammation, the most prominent emerging alternative or additional metric is surface area. With no definitive conclusions on the best dose metric, there was consensus that there should be sufficient characterisation of the forms of a substance tested to allow the dose response to be expressed in the different metrics discussed - number, surface area and mass. There are other parameters as well which can act as modifiers of the toxicity, including particle size, size distribution, density, surface modification, aggregation/agglomeration state and shape, but these parameters would not generally be considered as scalable dose quantities and do not therefore appear to conform to the current use of the term “metric” under REACH.

A comprehensive synthesis of findings, implications, issues and advice was developed and integrated through the Task Reports and the Final Project Report of the RIP-oN2 and RIP-oN3. Where considered relevant, feasible and justified, specific advice for updating REACH guidance was provided. For issues which were not currently technically/scientifically mature for developing detailed guidance, the need for further research and development was indicated. It must be noted in any case that the update of REACH guidance and thus inclusion of any of the advice from the reports into the ECHA guidance is exclusively the responsibility of ECHA.

5.4. JRC Nanohub

The European Commission’s Joint Research Centre’s (JRC) NANOhub is a comprehensive, non-public IT platform designed for addressing and hosting information on nanomaterials. It is based on IUCLID, which provides an accepted basis for regulatory use of data on chemicals in the EU. With its web-based functionality it is intended to boost interconnections and to facilitate synergies for collaboration within research projects.

It has been developed on behalf of the JRC as a tool to address nano-safety and measurements of nanomaterials, supported by an international stakeholder network from academia, industry, Member States, ISO, CEN, OECD, and NGOs. The JRC NANOhub hosts, among others, data and studies from the OECD Working Party on Manufactured Nanomaterials (WPMN) sponsorship programme on the safety testing of a representative set of nanomaterials, as well as test and measurement results on materials from the JRC Repository of Representative Nanomaterials (see also Appendix 9).

The data structure builds on IUCLID chapters and on the OECD Harmonised Templates. These chapters have been expanded to add additional templates for nanomaterial-specific endpoints listed by the OECD WPMN in the Guidance Manual of the sponsorship programme.[165] Once these new templates have been tested and finalised, they will be submitted to the OECD for harmonisation and possible implementation in IUCLID.

JRC NANOhub provides features to address data quality, to create reports and dossiers, and to exchange data, and it provides collaborating parties with a facilitated frame for hosting and sharing data. In this way it facilitates cooperation between international parties and research projects using the World Wide Web. JRC NANOhub consists of independent, consortium-specific installations hosted by the JRC with options to protect confidentiality but also to share results between different consortia. A listing of hosted projects can be found on www.nanohub.eu.

5.5. Organisation for Economic Co-operation and Development: Working Party on Manufactured Nanomaterials

In 2006 the OECD Working Party on Manufactured Nanomaterials (WPMN) was established, bringing together relevant Ministries and Agencies responsible for human and environmental safety, as well as representatives from other stakeholder groups.

A formal four-year programme of work was endorsed by the OECD Chemicals Committee to cover the period 2009 to 2012 which aimed at the development of a globally harmonised approach to the management of nanomaterials.

The WPMN published a booklet[166] in February 2011 summarising the first five years of the programme, noting in that report its work on:

· Testing specific nanomaterials for their human health and safety evaluation, while ensuring appropriate testing methods (in vivo & in vitro), in addition to promoting the development of alternative test methods to nano-toxicity testing;

· Promoting co-operation on voluntary schemes and regulatory programmes;

· Facilitating international co-operation on risk assessment strategies;

· Developing guidance on exposure measurement and exposure mitigation at the workplace, for consumers and for the environment; and;

· Promoting the environmentally sustainable use of nanotechnology through enhancing the knowledge base about life cycle aspects of manufactured nanomaterials. This should be done at their different stages of development and applications.

This work has already started to generate guidance literature for those working in this field such as 'Preliminary Guidance Notes on Sample Preparation and Dosimetry'[167] and a 'Guidance Manual for the Testing of Manufactured Nanomaterials (First Revision)'.[168] A full list of relevant OECD publications can be found on the dedicated WPMN website.[169]

The ninth meeting of the WPMN took place in December 2011 to examine progress made on the current work plan. The tenth meeting of the WPMN is scheduled for June 2012.

5.6. Strategic Approach to International Chemicals Management (SAICM)

In 2006 the International Conference on Chemicals Management (ICCM) adopted the Strategic Approach to International Chemicals Management (SAICM).[170] This provides a UNEP level policy framework to promote chemical safety around the world.

In May 2009 ICCM2 adopted Resolution II/4 on emerging policy issues which covered the specific issue of nanotechnologies and manufactured nanomaterials, recognising their potential benefits and potential risks to human health and the environment.

Since then work has been taken forward to build a fuller understanding of this issue. The above Resolution prompted a number of Regional workshops on the issue led by UNITAR and the OECD and also the drafting of a Report[171] on nanomaterials within the context of SAICM which was presented to the SAICM Open Ended Working Group in November 2011. Also during this meeting work was undertaken to develop actions that could be added to the Global Plan of Action (which acts as a guidance document and working tool to support implementation) in due course. This issue will be revisited during ICCM3 which is due to take place in September 2012.

5.7. Research on nanomaterial safety

The European Commission has started funding projects specifically addressing nanosafety since the 5th EU Framework Programme for Research and Technological Development (FP5, 1998-2002), with a regular budget increase. So far, 46 nanosafety projects have been funded. They represented a total EU investment of 130 M€ (corresponding to a total projects costs of 185 M€). The framework programme calls are conceived to cover all aspects necessary for the risk assessment and risk management of nanomaterials: physico-chemical characterisations of nanomaterials, fate and behaviour in biological and environmental media, bio-nano interactions, nano-toxicity and nano-ecotoxicity, life cycle analysis of nanomaterial-embedded products (including recycling and final treatment), measurement devices, exposure, worker protection, risk assessment tools and risk management strategies.

The EU projects are requested to join forces through the NanoSafety Cluster to maximise synergies, to facilitate the formation of a consensus on nanotoxicology in Europe; to improve the coherence of nanotoxicology studies and harmonize methods; and to provide a single voice for discussions with external bodies and to provide industrial stakeholders and the general public with appropriate knowledge on the risks of nanoparticles and nanomaterials for human health and the environment.

6. Information and databases on the use of nanotechnology and nanomaterials

The European Parliament has called on the Commission to compile “an inventory of the different types and uses of nanomaterials on the European market, while respecting justified commercial secrets such as recipes, and to make this inventory publicly available”. [172] The Council invited the Commission to “evaluate the need for […] the further development of a harmonized database for nanomaterials, while considering potential impacts.” [173]

While the European Parliament does not specify the meaning of the term “inventory”, in particular on whether this inventory should be presented in the form of a document or database, the Council invites the Commission to evaluate the need for the further development of a harmonized database. The Commission therefore has, in addition to the information on types and uses of nanomaterials in section 3 and Appendix 2 of this document, compiled information on existing databases in section 6.1 and Appendix 8. Section 6.2 gives information on plans to set up a European Commission web platform on nanomaterial types and uses, including safety aspects.

6.1. Existing databases on, or with relevance to, nanomaterials on the market

Databases on nanomaterials on the market can in principle be structured either from the perspective of nanomaterials (and possibly cover their uses in products in more or less concrete terms) or from the perspective of products on the market containing nanomaterials. Both approaches have been used in different existing databases. There are also databases which have elements of both. In addition, the nature of databases differs largely. An overview of existing databases is contained in Appendix 8.[174]

A database with a clear substance-structure is REACH-IT.[175] REACH registrations for substances are stored in the REACH-IT database. REACH is specific for substances and it is possible to indicate that the registered substance is a nanomaterial or includes nanoforms in REACH registrations (for example, there is a voluntary tick-box to identify the substance or form of a substance as a nanomaterial). There is also ECHA advice on how to enter relevant data in IUCLID. This information is retrievable from the registration database. It is however not always easy to identify which information relates to the nanoform(s) and which information to the bulk form(s) of the substances. Also, the description of uses in REACH dossiers is rather generic, and therefore it is not possible to identify concrete applications from the REACH dossiers. A screening of the REACH registration dossiers and CLP notifications was performed to identify information about substances in the nanoform. Methodology and outcome of this work is reported in Appendix 3.

An example of a mixed database is ObservatoryNano.[176] Although the main aim of the database is not an exhaustive inventory of nanomaterials and their uses on the market, it contains a number of factsheets, briefings and reports which give an overview of nanomaterials, as well as product areas in which those substances are used. The database has a relatively strong focus on new developments in terms of research and innovation, and therefore does not always distinguish between widespread commercial use of nanomaterials and applications at the pre-market stage.

Moreover, there is a series of databases focusing on products on the market containing nanomaterials. Examples for such databases include the Woodrow Wilson database (“The Project on Emerging Nanotechnologies”)[177], the ANEC-BEUC 2010 inventory of consumer products containing nanomaterials (ANEC-BEUC 2010)[178], the online database of the German Environmental NGO ‘BUND’ (Friends of the Earth Germany)[179], and the nanotechnology products database of Nanowerk.[180] Those databases are all attempts to collect as much information as possible on products containing nanomaterials at the level of individual products and brands. However, they are neither based on systematic data collection over a wide range of products, nor is it certain that the products mentioned indeed contain nanomaterials. This is because the databases are at least partly based on claims by manufacturers which may, or may not be correct. Given the multitude of applications identified in the course of the analysis of nanomaterials on the market (see Appendix 2) and the limited number of products identified (e.g. around 1300 products worldwide for the Woodrow Wilson database), it seems however likely that those databases only cover a very small fragment of products containing nanomaterials on the market.

There are also a number of voluntary one-off reporting schemes in EU Member States such as the United Kingdom, France, Denmark, Germany and Ireland, as well as in several non-EU countries.[181] However, those schemes only received very little feedback and generally do not give a satisfactory overview of nanomaterials on the market. France has recently introduced regulatory measures for a mandatory registry for substances at nanoscale, mixtures from which nanomaterials can be released, and articles with an intended release of nanomaterials.

In addition to the product databases listed above, an overview is presented in Appendix 8 on databases not predominantly considering products, but containing information related to the potential toxicity or hazard of nanomaterials. Two of those databases provide information on experimental data and the projects and/or organisations in which these data are obtained. Two other databases specifically focus on industry needs.

(2) The OECD Database on Research into Safety of Manufactured Nanomaterials

(3) JRC NanoHub

(4) nanotech-data.com

(5) nanoproducts.de

6.2. Plans for a European Commission web platform on types and uses of nanomaterials, including safety aspects

The interest in an inventory/harmonised database expressed by the European Parliament and the Council reflects a widely perceived lack of information on nanomaterials on the market. Existing databases are either not clear enough on the types of uses of nanomaterials, or are rather sketchy and incomplete in terms of products containing nanomaterials. In some cases, there is little quality control of the information, and therefore there are doubts on the factual correctness of at least part of the contained information. The Commission therefore has gathered available information in Appendix 2 to this Staff Working Paper.

However, the Commission understands that there is an interest in keeping this information updated and completed by new information on nanomaterials and products containing nanomaterials. The Commission is ready to host an inventory in the form of a web platform on nanomaterials and their uses. Preparatory work to set up such a web platform, led by the Commission’s Joint Research Centre, has already started. Discussions among the responsible Commission services on capturing specific requirements have been initiated in order to support the European Commission's policies such as environment, consumers, health, business, employment and innovation.

The web platform should enable the user to retrieve comprehensive information on nanomaterials, presenting that information in an easily searchable way and linking to the main information sources and databases. This web platform will both present general summary information on nanomaterials and their uses, including safety aspects, building on the present Staff Working Paper, and link up to and build upon various existing or planned activities (e.g., JRC NANOhub, OECD WPMN, French Grenelle 2 bill, and others). Depending on the intended users of such a web platform (consumers, downstream/workplace users, regulators, researchers) it is necessary to consider what kind of information should be available to these different groups, and certain filtering mechanisms should be considered. A web platform design would be advantageous which would be able to incorporate existing information and be at the same time capable of being adaptable to future options.

Strengths and weaknesses of existing databases on nanomaterials and/or products containing nanomaterials are being analyzed. Publicly available databases/inventories of nanomaterials and their use often lack clear criteria for inclusion, quality assurance of the data content and being up to date. These shortcomings should be addressed, and for the part of information handled under the responsibility of the Commission, appropriate quality assurance, sustaining and periodic updating of the information should be guaranteed.

Work towards a harmonized European web platform will benefit from the recently concluded project on “Development of an inventory for consumer products containing nanomaterials” carried out by RIVM on behalf of the Commission.[182] A data model was already developed in that project to record a multitude of nanomaterial relevant information related to a product in a structured manner. Furthermore, a methodology was developed to identify consumer products on the EU market containing nanomaterials, and it was subsequently used to populate a pilot version of a searchable database containing such products.

When setting up such a harmonised Commission database it will also be necessary to take into account the situation in Member States where regulatory measures (France) or discussions were already initiated in parallel to activities within the Commission.

Appendix 1 Types of nanomaterials

1. Introduction

This Staff Working Paper is focused on the materials that meet the EU definition of nanomaterial (see Chapter 2). The EU has defined this single term while being well aware of the heterogeneous range of materials it covers, as shown in Chapter 3. This appendix provides an overview of the most important and common types or subcategories of nanomaterials, based on the EU definition of nanomaterial, but using also the more extensive nanomaterial terminology developed by ISO.[183] The appendix thereby also intends to clarify the relation between the EU and ISO nanomaterial definitions.

Section 1 explains and defines a number of basic terms which are used to describe and categorize nanomaterials. Section 2 lists the types of nanomaterials which are covered by the current EU definition of the term "nanomaterial". Section 3 discusses materials which do not comply with the current EU definition, but which fall under the scope of the broader ISO definition of nanomaterial, and which may have to be considered in the review of the current EU definition, scheduled before end 2014.

1.1. Basic terms and definitions

Nanoscale

The key term in most of the definitions of terms used in nanotechnology and nanosciences is the term nanoscale. Unless otherwise specified, and in accordance with ISO and EU practice, this term has in this document been used as short for the range from 1 nm to 100 nm.[184]

Nano-objects

ISO/TC 229 (the ISO Technical Committee on Nanotechnologies) invented the word nano-object and defined it (first in ISO/TS 27687:2008, later confirmed in ISO/TS 80004-1:2010) to describe particles which have at least one of their 3 (orthogonal) external dimensions in the nanoscale.[185] Several subclasses of nano-objects are distinguished, such as nanoparticles (nano-objects with all 3 external dimensions in the nanoscale), nanofibres (grouping nanorods and nanotubes), and nanoplates.[186] All particulate materials consisting for more than 50 % of nano-objects fall under the EU definition of nanomaterial.

Aggregates and agglomerates, primary and secondary particles

Nano-objects, like other particles, have a natural tendency to agglomerate: they form groups which are held together by weak forces (e.g., van der Waals forces) or by simple physical entanglement. The tendency to form agglomerates generally increases with decreasing particle size due to the higher surface energy and because inertial forces, which can 'deconstruct' agglomerates for example during sonication, become relatively less important with decreasing volume/surface area ratio.

Often, nano-objects are encountered in the form of aggregates. Aggregates are groups of particles which, unlike agglomerates, are held together by strong forces (for example covalent chemical bonds) or by complex physical entanglement. Aggregates are most often created during the processing of the nano-objects, e.g., when they are formed in a hot gaseous phase and collide with each other at a temperature above or near to their melting temperature.

Both aggregates and agglomerates are also called secondary particles, as they consist of groups of smaller, so-called primary particles. It is difficult and often impossible to turn aggregates back into individual primary particles other than by high-energy processes such as mechanical milling or abrasion. On the other hand, the number of primary particles in an agglomerate can change easily, e.g., under the influence of changing environmental conditions. Correspondingly, the methods to distinguish between agglomerates and aggregates are based on the detection of the change in size of the secondary particles upon sonication or upon the change of pH or other environmental conditions.

Both agglomerates and aggregates of nano-objects are covered by the EU definition of nanomaterial.

Nanostructure

The current ISO definition for nanostructure is 'a composition of inter-related constituent parts, in which one or more of those parts is a nanoscale region, where a region is defined by a boundary representing a discontinuity in properties'[187] Examples of a nanoscale region are nanophases or nanopores.

Dispersion

A dispersion is a material that consists of a dispersing medium (a continuous, matrix phase) and a dispersed phase (a collection of particles or small phases of the same kind, which are separated from each other by the dispersing medium). Both the dispersing medium and the dispersed phase can be solid, liquid or gaseous, leading to a number of possible combinations:

|| Dispersed phase

Continuous phase || solid || liquid || gas

solid || (kind of) composite material || porous material filled with liquid || porous material filled with gas

liquid || suspension || emulsion || foam

gas || aerosol || aerosol || (does not apply)

1.2. Nanomaterials – general definitions

The EU definition of nanomaterial

The EU definition of nanomaterial has been shown in Chapter 2 of this Staff Working Paper, which explains how the definition was developed and on which materials it is focused. In the Recommendation on the nanomaterial definition, the Commission commits to review its current definition by December 2014, in the light of experience and of scientific and technological developments. In particular, the review should assess whether the number size distribution threshold of 50 % should be increased or decreased and whether to include materials with internal structure or surface structure in the nanoscale such as nanoporous and nano-composite materials. For this reason, it is useful to look also at the current ISO definition, which is broader and inter alia includes nanostructured materials other than aggregates and agglomerates.

The International Organization for Standardization (ISO) definition of nanomaterial

Section 1.1 lists a number of terms and concepts used to describe features of materials that are called nanomaterials. ISO has used these terms in its definition of the term nanomaterial in its Technical Specification 80004-1[188]:

“A nanomaterial is a material with any external dimension in the nanoscale or having internal structure or surface structure in the nanoscale

Note 1: This generic term is inclusive of nano-object and nanostructured material.

Note 2: See also engineered nanomaterial, manufactured nanomaterial and incidental nanomaterial."

As is the case for all ISO Technical Specifications, this definition will have to be confirmed in a full ISO standard, or be revised.[189] Some of the questions to be solved are:

– is one single nano-object a nanomaterial?

– since all materials have a structure at the nanoscale, is everything a nanomaterial?

The first question is implicitly answered in the EU definition, which considers nanomaterials to be particulate materials with a p