The New EU Nanotechnology Regulation
On December 3, 2018, the European Commission (EC) adopted Regulation 2018/1881, amending the existing , amending the existing Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation, to directly address nanoparticles. The nanotechnology regulation applies to any substance that might be, or might contain, a nanomaterial (e.g., powder), whether or not it has been manufactured as a nanotechnology. Crucially the revised nanoparticle regulation applies to both new and registered substances and all dossiers will need to be updated with the necessary data.
Timeline for Nanomaterial Registration
The deadline for implementation of the new requirements is January 1, 2020.
What is a Nanomaterial?
Terminology around nanotechnology varies, with terms like nanoparticle and nanomaterial used interchangeably. In general, nanomaterials are defined as chemical substances or materials with particle sizes between 1 and 100 nm in at least one dimension.
The EC first defined nanomaterials in 2011 (2011/696), with the new REACH regulation (2018/1881) including a definition of a nanoform that is specific to REACH (Figure 1). There are some differences between these definitions that relate to the concept of particles, agglomerates and aggregates (Table 1).
Figure 1: Definitions of a nanomaterial and nanoform
Proteins, polymers and macromolecules are excluded from the nanoparticle definition, as they are viewed as single molecules. However, they can be considered particles if they are assembled into stable, solid objects with clearly defined external boundaries and external dimensions that can be measured.
Figure 2: Terminology related to particles
What’s in the New Regulation?
The key changes in Regulation 2018/1881 were:
- Definition of a nanoform
- Provision for grouping nanoforms with similar characteristics into ‘sets of similar nanoforms’
- Amendments to specific Annexes (Table 1)
Sets of Similar Nanoforms
- Using sets of similar nanoforms makes the regulation workable and reduces unnecessary hazard and risk testing. Grouping must define set boundaries and justify why variation within the boundaries does not affect the hazard, exposure or risk assessment of individual nanoforms within a set. Nanoforms can only belong to one set of similar nanoforms.
- Groupings must have a clear scientific justification. This can be achieved using read-across methodologies to compare nanoforms, or even nanoforms and conventional substances, if scientifically justified.
Annex amendments are listed in Table 2. Guidance and tests for nanomaterial assessment are evolving. Detailed information on current status is available in an Organization for Economic Co-operation and Development (OECD) publication (Rasmussen 2019), and guidance related to the EU is planned for publication by the Joint Research Center (JRC) at the end of 2019.
Table 1: Annex changes with Regulation 2018/1881
What New Analytical Tests are Required?
The biggest challenge with the new regulation is nanoform characterization as this will require the use of new methodologies. In addition, physiochemical, toxicological, environmental fate and behavior endpoints may demand the use of a different analytical focus.
Nanoform Characterization and Grouping
Nanomaterial production methods can produce multiple nanoforms, varying in size distribution, shape and surface chemistry. These characteristics may impact the behavior and reactivity of each nanoform. Nanoform behavior is influenced by factors such as solubility, hydrophobicity or the ease of dispersal – all of which can affect where the nanoform ultimately ends up in biological systems. Reactivity determines what the nanoforms do and their subsequent toxicologic or ecotoxicologic impact.
Under REACH nanoparticle regulation, three features are assessed in submissions (Table 2):
- Particle size/number size distribution
- Particle shape
- Surface chemistry
Table 2: Nanoform characterization required under REACH regulation
ECHA has published a best-practice guide for nanomaterial characterization under REACH.
Grouping nanoforms into similar sets of nanoforms is crucial if the substance has many nanoforms. The ECHA guidance document on quantitative structure–activity relationships (QSAR) and grouping explains how best to tackle this. Optimizing the grouping enables the use of read-across methodologies to address the endpoints required for hazard assessment, and could obviously reduce the need for costly additional studies.
Physiochemical Endpoints Overview
The partition coefficient (Kow) is inappropriate for nanomaterials as their small size means they easily cross biological membranes, regardless of their water solubility. Alternative characteristics to assess are:
- Dispersion stability in octanol and water (where determination of the octanol/water partition coefficient is not possible)
- Rate of dissolution in water and relevant aqueous environments e.g., bodily fluids.
Toxicokinetic assessment should be conducted on the nanoform and the bulk substance, unless the nanoform dissolves quickly on entering the organism.
For substances registered at a volume above 10 tons per annum, specific relevant physicochemical properties may provide useful information on a case-by-case basis (e.g., agglomeration/aggregation state, surface morphology/topography, and crystallinity).
Toxicological Endpoints Overview
The Ames test for mutagenicity (Annex VII) is a standard endpoint for conventional substances. This test is not applicable to nanoforms, which are too large to cross bacterial cell walls. Alternative mammalian cell studies are therefore required. For substances registered at a volume of 1–10 tons per annum, consider one or more in vitro mutagenicity studies, in addition to the standard data requirement for bacterial mutagenicity.
Inhalation studies are especially relevant for nanomaterials, as the main route of exposure is likely to be through inhalation. Sub-chronic repeated-dose tests carried out via inhalation exposure should include histopathological determination of brain and lung tissues, as well as examination of bronchoalveolar lavage fluid, kinetics and an appropriate recovery period.
Environmental Fate and Behavior Endpoints Overview
The dispersal stability and dissolution rate will largely determine the tests needed for environmental fate studies. However, it’s important to consider how the environment may alter nanoforms and the subsequent implications for environmental fate and behavior.
The waivers available for conventional substances with low water solubility do not apply to nanoforms.
What Do You Need to Do Next?
If you have a substance that is registered under REACH and you suspect it may contain nanoforms, you will need to confirm this. A useful approach is to ask the following questions:
- Is the substance a solid or a liquid?
- Does the substance consist of particles or aggregates/agglomerates of particles that have an external dimension between 1 nm and 100 nm?
- Does the particle size distribution data indicate the possibility of nanoparticles (>50% having a diameter below 100 nm)?
- What is the particle shape (e.g., sphere, cube, tube, wire or plate)?
If the substance is confirmed to be a nanomaterial, you will need to fully identify and characterize it and update your dossier in line with the new regulatory requirements.
Finally, Regulation 2018/1881 requires manufacturers and importers to assess, and where relevant generate, the necessary information. Manufacturers and importers also need to document in the chemical safety report that the risks, arising from the identified uses of substances with the nanoforms that they manufacture or import, are adequately controlled.
The EU nanotechnology regulation 2018/1881 means that all existing substance dossiers must be updated to include nanoparticle endpoints by January 1, 2020. Regardless of whether a substance is or isn’t a nanomaterial, all registrants must provide enough evidence to support their classification. For registrants with nanomaterials, regulatory success depends on having a strategic analytic approach driven by in depth understanding of the science and regulatory context.
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