Definitions and regulatory information

The state of the art of regulatory information, in relation to the definitions of Nanomaterials, is presented in RiskGONE deliverable D3.1, and an extract is presented below. An overview of relevant regulatory documents for Europe and globally is available at the Nanorisk Governance Portal regulation page.

Definition of Nanomaterials: State of the art

ENMs, due to their exciting and unique properties at the nano size range, are widely used in several industrial and innovative technological applications (Vance et al. 2015; Lövestam et al. 2010). Extensive production and use of ENMs raised alarms among different stakeholders concerning their use and potential impact on human and environmental health. In general, ENM can be defined as a material with at least one dimension measured in the size range of 1-100 nm (although the microplastics community, which looks mostly at secondary (weathered from larger pieces) plastic debris has determined that nanoplastics span the range up to 1000 nm as per Hartmann et al, 2019). However, definition of NMs in general has been an active debate in terms of policy making. However, definition of NMs in general has been an active debate in terms of policy making.

Intentionally manufactured nanomaterials, or ENMs, are produced with variable properties and therefore the size alone based definition may not be enough to define ENMs. Moreover, a standard and internationally accepted definition of ENMs is mandatory to identify them, and to implement specific risk assessment and management measures (Bleeker et al. 2013; Lövestam et al. 2010). A standard definition accepted at the global level is yet to be available. As a result, national and international standardisation bodies, organisations, and authorities have proposed several definitions ENM (Potočnik 2011). The EC recommended definition of NM (EC NM definition) states,

“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 %.

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

The Joint Research Centre (JRC), in its recent report published in 2019, stated that this is still a recommendation and not legally binding to any legislation (Rauscher et al. 2019). The EC’s NM definition was developed to provide a common basis across different areas and therefore, pieces of this definition was integrated into different legislations such as chemicals, medical devices and biocides except for novel foods and cosmetic products (see Table 2 for various NMs definitions). Moreover, the definition in general is in line with other NM definitions (Boverhof et al. 2015), but was proposed to be more specific and quantitative, which enables its implementation in a regulatory framework. Other member states such as Belgium, France, Denmark, Norway, Sweden) are already using the EC NM definition, either in whole or core parts of it, as their basis of their national ENMs registries (Rauscher et al. 2019).

Definitions of NM proposed by Europe based legislations

European Commission, Biocides legislation (European Commission 2012) and Medical devices (European Commission 2017)	Nanomaterial means a natural or manufactured active substance or non-active substance 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 1-100 nm. Fullerenes, graphene flakes and single-wall carbon nanotubes with one or more external dimensions below 1 nm shall be considered as nanomaterials
European Commission, Chemicals- REACH legislation (European Commission 2018)	A nanoform is a form of a natural or manufactured substance 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, including also by derogation fullerenes, graphene flakes and single wall carbon nanotubes with one or more external dimensions below 1 nm
European Commission, Cosmetic products legislation (European Commission 2009)	Nanomaterial means an insoluble or biopersistant and intentionally manufactured material with one or more external dimensions, or an internal structure, on the scale from 1 to 100 nm
European Commission, novel food products (European Commission 2015)	Engineered nanomaterial means any intentionally produced material that has one or more dimensions of the order of 100 nm or less or that is composed of discrete functional parts, either internally or at the surface, many of which have one or more dimensions of the order of 100 nm or less, including structures, agglomerates or aggregates, which may have a size above the order of 100 nm but retain properties that are characteristic of the nanoscale.
Norway, Denmark (Potočnik 2011)	Adopted EC definition of NMs as it is
Belgium (FPS Health 2014)	A substance containing bound particles or forming an aggregate or agglomerate with a proportion of at least 50 % in the distribution of sizes by number, having one or more external dimensions ranging between 1 nm and 100 nm, excluding natural substances which have not been chemically modified and substances where the fraction between 1 nm and 100 nm is a by-product of a human activity. Fullerenes, graphene flakes and single wall carbon nanotubes with one or several external dimensions less than 1 nm will be considered as manufactured nanoparticle substances.
France (ANSES 2012)	Substance at nanoscale is defined as intentionally produced substance at nanometric scale, containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for a minimum proportion of 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, this minimum proportion may be reduced. This minimum proportion is specified in a joint order issued by the Ministers of environment, agriculture, health, labour and industry. By derogation from this definition, fullerenes, graphene flakes and single-wall carbon nanotubes with one or more external dimensions below 1 nm should be considered as substances at nanoscale.
Switzerland (Höck et al. 2011)	Manufactured materials are considered to be nano-relevant if they contain particles in the un-bound state as an aggregate7 or agglomerate and in which at least 50% of the particles in the number size distribution have one or more external dimensions in the 1 to 100 nm range. In case of precaution, manufactured materials are considered to be nano-relevant if they contain particles in the unbound state as an aggregate or agglomerate and in which one or more external dimensions are between 1 and 500 nm

United States of America

The Food and Drug Administration (FDA) is responsible for protecting the public health by assuring the safety, efficacy, and security of drugs, biological and medical products, food, cosmetics, and products that emit radiation and, provides accurate, science-based health information to the public. The FDA has not established any working regulatory definitions but if a product involves the application of nanotechnology, FDA requires information on whether a material or end product is engineered to have at least one external dimension, or an internal or surface structure, in the nanoscale range (approximately 1 nm to 100 nm). In addition, FDA also asks for information on whether a material or end product is engineered to exhibit properties or phenomena, including physical or chemical properties or biological effects, that are attributable to its dimension(s), even if these dimensions fall outside the nanoscale range, up to one micrometer (1,000 nm) (FDA, 2014).

The United States Environmental Protection Agency (EPA) also plays a pivotal role in the regulation chemicals, pesticides, food, cosmetics and drugs (EPA). Like the FDA, the US EPA has no formal regulatory definition but proposed guidelines to differentiate nanoscale materials from chemicals. Under the rule of Working Guidance on EPA’s Section 8(a): materials defined as a solid at 25 °C and standard atmospheric pressure, that is intentionally manufactured or processed in a form where any particles, including aggregates and agglomerates, are in the size range of 1–100 nm in at least one dimension, and exhibit unique and novel properties because of its size. In addition, the rule excludes substances with 1% by weight of any particles, including aggregates and agglomerates, in the size range of 1-100 nm (EPA, 2017).

Canada

Health Canada plays a crucial role in regulating substances and consumer products, and protect and promote health by using existing legislative and regulatory frameworks (Health Canada). Health Canada’s policy statement on working definition of Nanomaterial considers any manufactured substance or product and any component material, ingredient, device, or structure to be nanomaterial if a) it is at or within the nanoscale in at least one external dimension, or has internal or surface structure at the nanoscale, or b) it is smaller or larger than the nanoscale in all dimensions and exhibits one or more nanoscale properties/phenomena (Health Canada, 2011).

Australia

The Australian Government Department of Health National Industrial Chemicals Notification and Assessment Scheme (NICNAS), now called as Australian Industrial Chemicals Introduction Scheme (AICIS), regulates the industrial chemicals and developed a working definition for industrial NMs. It states that “industrial materials intentionally produced, manufactured or engineered to have unique properties or specific composition at the nanoscale, that is a size range typically between 1 [nanometer (nm)] and 100 nm, and is either a nano-object (i.e., that is confined in one, two, or three dimensions at the nanoscale) or is nanostructured (i.e., having an internal or surface structure at the nanoscale)”(Ferraris et al. 2021).

South Korea

Guidance to safe handling of manufactured nanomaterials in workplace/industry (KS A 6202, 2009 and KS A 27687 (2010)), include definitions of a nanomaterial, aligned with the definition ISO TS 27687 (2009), and ISO TS 80004-1 (2010) of nano-objects and nanomaterials. Plus, more extensive definitions of nanomaterials are also still being considered by the ISO TC 229 Working group. Thus, there is diversity in the approaches taken across regulatory regimes, and the terms themselves are evolving, to include also nanoforms, nanoobjects and more recently advanced materials. The next table provides a comparison of the elements in the NMs definitions used by different regulatory organisations.

Comparison of elements in NM definition proposed by different organizations

Organization	Size range	Agglomerates and aggregates	Distribution threshold	Novel properties
EC	1-100 nm	Included	50 % by number	Not included
EC biocides legislation	1-100 nm	Included	50 % by number	Not included
EC medical devices legislation	1-100 nm	Included	50 % by number	Not included
EC chemicals legislation	1-100 nm	Included	50 % by number	Not included
EC Cosmetic products legislation	1-100 nm	Not included	Not included	Not included
EC novel food products legislation	Less than 100 nm and larger	Included	Not included	Included
Belgium registry of nanomaterials	1-100 nm	Included	50 % by number	Not included
France registry of nanomaterials	1-100 nm	Included	Not included	Not included
Switzerland registry of nanomaterials	1-100 nm and larger	Included	50 % by number	Not included
FDA	1-100 nm and larger	Not included	Not included	Included
EPA	1-100 nm	Included	Not included	Not included
Canada	1-100 nm and larger	Not included	Not included	Included
Australia	1-100 nm	Not included	Not included	Included

Size was used as the primary defining element across all ENM definitions but the upper size limits differ in some definitions. In most definitions, the size 100 nm was used as the upper size limit for ENMs without any strong scientific consensus indicating that the nanoscale properties abruptly change beyond this size threshold. The defined lower limit 1 nm is also controversial as properties of the materials are predominantly defined by chemical nature of the molecule (Boverhof et al. 2015). Organizations from Europe (EC novel food products legislation), Canada (Health Canada), USA (FDA) and Switzerland (Swiss Federal Office of Public Health and Federal Office for the Environment) included size larger than nanoscale (1-100 nm) in their definitions. However, there is no scientific consensus to verify the toxicological/biological appropriateness of these size ranges.

The term Agglomerates and aggregates (AA) was the second most used element in ENM definitions. Although agglomerates and aggregates are often erroneously considered similar and interchangeably used, they are, however, two different secondary structures of particulate materials. In agglomerates, the particles bind together by weak forces, which are reversible, while, in aggregates, particles fuse irreversibly together (Walter 2013). AA are included in ENM definition mainly due to their tendency of ENMs to form AA and their potential to release/break down into primary ENMs in any part of their life cycle; particularly from agglomeration (Bruinink et al. 2015). The terms AA attracted in recent years attention among the policy makers, consumers, ENM producers and regulatory authorities regarding their potential influence on human health effects (Bruinink et al. 2015; Boverhof et al. 2015). However, no sound scientific data justify that AA may or may not be relevant from a chemical and/or toxicological perspective.

Recent studies observed that unbound NPs and their AA with size greater than 100 nm were not necessarily biologically less active than their nanosized counterparts (size less than 100 nm) (Murugadoss et al. 2020a; Murugadoss et al. 2020b; Murugadoss et al. 2021). This indicate that the upper size threshold (100 nm) in ENM definition may not be appropriate. It is also important to notice from Table 2 that several organizations adopted unbound or AA of size larger than nanoscale (1- 100 nm) in their definitions. In a recent review of the EC recommendation for the definition of nanomaterial, EU reported that that they received suggestions to extend the upper size limit and agreed that it can be done only if it strengthens the conceptual link either to nanoscale phenomena or to possible nanospecific hazards (Rauscher et al. 2015). Therefore, it appears that EC is open to modifications, and more research such as ours is required to provide scientific consensus for the reconsideration of upper size limit in the definition. Altogether, this study can intrigue larger community such as EC to realize toxicological relevance of AA and focus more on these aspects in the future.

Particle size-based Number distribution was the most considered distribution threshold to define a substance as ENM but exposure and hazard assessment of ENMs mostly employed mass-based metrics (Boverhof et al. 2015). Novel properties and/or nanoscale phenomena are mentioned in some definitions. While size dependent properties such as surface reactivity and solubility are known to be toxicologically relevant (Luyts et al. 2013), there was limited guidance provided for the consideration of nanoscale properties that are relevant for hazard assessment.

The current state of the art suggests that the size alone cannot be a useful metric to define ENM when taking into account their safety assessment. Moreover, there are inconsistencies in definitions proposed by different organizations, leading to confusion in defining whether a given substance is a nanomaterial or not. Consistency is essential to warrant stakeholder confidence in the current regulatory frameworks, and continuous sustainability of nanotechnology. In the future, core elements for the development of ENM should be more focussed on properties that are not only relevant for the identification of ENM but also for the hazard assessment. Hazard assessment of NMs should also be performed addressing the core elements such as size and agglomeration/aggregation to validate and incorporate existing ENM definitions into the existing risk assessment framework.