Regulatory Cooperation Council (RCC) Nanotechnology Initiative FINAL REPORT

Transcription

1 Regulatory Cooperation Council (RCC) Nanotechnology Initiative FINAL REPORT Work Element 2, Priority Setting: Development of a Joint Nanomaterials Classification Scheme 1

2 Table of Contents 1.0 Context Existing Classification Schemes for Nanomaterials Classification of Nanomaterials by Chemical Composition... 5 Figure 1: Nanomaterial classification scheme suggested by Stone et al. (2010) Classification for Regulatory Purposes Proposed Chemical Classification Scheme... 8 Figure 2: Proposed classification scheme based on similarities in chemical composition Carbon Nanotubes Inorganic Carbon Metal Oxides and Metalloid Oxides Metal, Metal Salts, and Metalloid Nanoparticles Semiconductor Quantum Dots Organics Other Moving Forward Next Steps Towards Common Terminology and Definitions Towards Nanomaterials of Potential Concern/No-Concern Conclusion Appendix I: Examples of Classification Schemes in Literature

3 1.0 Context The Regulatory Cooperation Council (RCC) Nanotechnology Initiative was established to increase alignment in regulatory approaches for nanomaterials between Canada and the United States (US) 1 in order to reduce risks to human health and the environment while also fostering innovation. The Work Plan that was developed to achieve greater regulatory alignment consists of five Work Elements, each designed to realize specific final deliverables: Principles, Priority-Setting, Risk Assessment/Management, Commercial Information, and Regulatory Cooperation in Areas of Emerging Technologies. The RCC Nanotechnology Initiative primarily focuses on those industrial nanomaterials that would be considered new substances (referred to herein as nanomaterials), regulated in Canada under the Canadian Environmental Protection Act (CEPA) and in the US under the Toxic Substances Control Act (TSCA). The overarching action item of Work Element 2, Priority-Setting, is to establish criteria for identifying key characteristics of nanomaterials and subsequently determining which nanomaterials are sufficiently different from their non-nano counterparts to warrant a closer examination for environmental, human health, and safety endpoints (those of concern); and which nanomaterials are sufficiently similar to their non-nano counterparts to be considered as traditional chemicals for regulatory purposes (those of no-concern). Work Element 2 Deliverables: By November, 2013: Develop draft criteria for identifying characteristics of nanomaterials that are of potential concern/no-concern. Beyond November, 2013: Draft technical language providing common descriptions and criteria of classes of nanomaterials, and incorporate into summary report. Beyond November, 2013: Draft document on a common Canada/US approach to definition, characteristics and test methods for assessing nanomaterials. The first deliverable for this Work Element is to develop draft criteria for identifying characteristics of nanomaterials of potential concern/no-concern. As part of this Work Element, the Canadian New Substance Program and the US New Chemicals Program (Canada/US Programs) developed a classification scheme which identifies which nanomaterials are likely to typically behave differently on the nanometer scale when compared to their bulk or molecular counterparts, and, those that are unlikely to behave differently than their bulk or molecular counterparts. Currently, this list is used only for sorting those nanomaterials which need additional nano-specific consideration (concern) and those 1 While this document focuses on industrial nanomaterials, some of the uses of these materials may fall under the jurisdictions of other regulatory agencies in the U.S. and Canada. This document is not intended to address the materials/products or their intended uses that are appropriately regulated by the other agencies. 3

4 that can be considered as traditional chemicals (no-concern). Exceptions will continue to be considered on a case-by-case basis. To further develop this approach, scientific information is still needed on what unique properties nanomaterials have and how these properties affect organisms. This information will be incorporated as it becomes available. Since there is no regulatory definition for nanomaterials, the Canada/US Programs both identify nanomaterials based on: (1) a size range of 1-100nm; and/or (2) particles which exhibit nanomaterial properties outside the 1-100nm size range. These nanomaterial identification criteria, identified by stakeholders at the November 28, 2012 RCC webinar, will evolve with the science. In the absence of specific criteria to determine nanomaterials of potential concern/no-concern for hazard assessment (more scientific information must be generated to determine criteria), the Canada/US Programs, in consultation with stakeholders, have developed a classification scheme for nanomaterials based on similarities in chemical composition that will support the use of analogue/read across information. (That is, identification of a chemical analogue to the nanomaterial in question and allocation of known characteristics from that analogue to the new nanomaterial.) The Canada/US Programs believe this is an appropriate first step in fostering discussion on the utilization of read-across information for similar nanomaterials. The RCC classification scheme provides the Canada/US Programs with a framework to: (1) identify which classes of nanomaterials typically require nano-specific considerations in risk assessments; and, (2) support the selection of appropriate analogue/read-across information to be used in substance-specific risk assessments for nanomaterials. In addition, the classification scheme will also highlight the type of information needed for characterization of the nanomaterials within each class, providing consistency within classes in the information required by the Canada/US Programs for regulatory purposes. This shared approach is expected to result in increased transparency, consistency, predictability and alignment between the Canadian New Substances Program and the US New Chemicals Program in the assessment and management of nanomaterials. This classification scheme is intended to be continually refined by Canada and the US as more scientific knowledge becomes available. The Canada/US Programs will also look to the global research community to help to validate and refine this approach. In this document, the term classification scheme will refer to the organization of nanomaterials for regulatory purposes. The word classification is not intended to be similar to its use in other regulatory/policy documents in Canada, the US or internationally. 4

5 2.0 Existing Classification Schemes for Nanomaterials There are many different ways to classify nanomaterials including chemical composition, similarities in shapes, location within the final end-use product and risk-based analysis. Classification schemes that are based on similarities in chemical composition are discussed further in this section. For clarity, this document does not reference all existing classification schemes for nanomaterials 2, Classification of Nanomaterials by Chemical Composition A nanomaterial classification scheme based on similarities in chemical composition could work well for regulatory programs which are based on traditional chemical frameworks. International bodies such as the Organization for Economic Cooperation and Development (OECD), as well as leading scientists in the nanomaterial field, are currently working on chemical-based classification of nanomaterials in order to utilize analogue/read-across information to determine potential safety implications. The OECD s Working Party on Manufactured Nanomaterials (WPMN) was formed in 2006 to spearhead international co-operation in understanding the health-related and environmental safety-related aspects of manufactured nanomaterials among member countries 4. One of the organization s key projects is the testing of a representative set of 13 nanomaterials for human health and environmental safety. Nanomaterials which are already in use or will be soon, including fullerenes (also known as "bucky balls"), single-wall (SWCNTs) and multi-wall (MWCNTs) carbon nanotubes are being tested for their physiochemical parameters, environmental degradation and accumulation, environmental toxicology, and mammalian toxicology. Within each 'class' of the 13 nanomaterials, different forms of chemically similar nanomaterials have been identified for testing; for example, different sizes and surface coatings of the same core nanomaterial - such as titanium dioxide - will be included in the research. One of the intents of this testing is to be able to utilize read-across information on these chemically similar nanomaterials. To build on this theme, the OECD WPMN is also organizing an expert workshop in 2014 to establish categories of nanomaterials with the expected goal of feeding into testing, read across/structure-activity relationships, risk assessment and risk management. Stone et al. (2010) have developed a classification scheme for nanomaterials based on similarities in chemical composition from an environmental perspective 5. In their work, the proposed classes are carbon, metals or metal oxides, and organic (see Figure 1 below). 2 Nel, A.; Xia, T.; Mädler, L.; Li, N.Science, 2006, 311, Olson, M.; Gurian, P. J. Nanopar. Res., 2012, 14, Available online at: 5 Stone, V.; Nowack, B.; Baun, A.; Brink, N.; Kammer, F.; Dusinska, M.; Handy, R.; Hankin, S.; Hassellov, M.; Joner, E.; Fernandes, T. Sci. Total Env., 2010, 408,

6 Figure 1: Nanomaterial classification scheme suggested by Stone et al. (2010) 2.2 Classification for Regulatory Purposes Several suggestions for nanomaterial classification schemes for RCC regulatory purposes emerged during discussions with stakeholders and other experts at the March 20, 2013 RCC Nanotechnology Initiative Workshop 6 in addition to the examples discussed above and in Appendix I. There was consensus that many of the proposed classification schemes do not meet Canada/US regulatory requirements, while others still require extensive research in order to be considered. Stakeholders suggested that nanomaterial classifications schemes could be based on the following, (if/when sufficient science is available): Exposures (powdery/aerosolized, liquid exposure, life cycle analysis, and consumer exposure); Use profiles (industrial use only, consumer, commercial); Toxicological mode of action of nanomaterials (e.g., structure activity relationships); and, Physicochemical properties (e.g., surface activity, catalytic activity, electronic activity). 6 Regulatory Cooperation Council Nanotechnology Initiative Multi-Stakeholder Workshop Report March 20, A copy can be obtained by contacting Rccnanoccr@ec.gc.ca 6

7 One of the goals of the classification scheme developed through the RCC Nanotechnology Initiative is to use it as a framework to support the selection of appropriate analogue/read-across information to be used in substance-specific risk assessments for nanomaterials when possible. At present, there are no nanomaterial-specific regulatory frameworks in either Canada or the US. The Canada/US Programs acknowledge that sufficient comprehensive scientific knowledge does not yet exist to develop a validated classification scheme for nanomaterials, as was done when classification schemes were created for traditional chemicals. However, a classification scheme for nanomaterials based on similarities in chemical composition which allows analogue/read-across information to be utilized will provide the Canada/US Programs with a good starting point for nanomaterial classification, and is considered suitable given the existing regulatory frameworks. This proposed nanomaterial classification scheme will be refined as scientific knowledge of nanomaterials continues to increase, eventually focusing on specific characteristics such as mode of action. The following section introduces the nanomaterial classification scheme developed as part of the RCC Nanotechnology Initiative. It also highlights certain physicochemical parameters that may be important in identifying whether two nanomaterials share sufficient similarities to utilize analogue/read-across information. 7

8 3.0 Proposed Chemical Classification Scheme In 2009, prior to the establishment of the RCC Nanotechnology Initiative, the US EPA worked independently on the development of a nanomaterial classification scheme based on similarities in chemical composition, drawing primarily on scientific literature and submissions to their program. This classification scheme was further developed in concert with their Canadian counterparts at Environment Canada and Health Canada under the RCC Nanotechnology Initiative s Work Element 2, and resulted in the chemical classification scheme proposed in this document. This classification scheme will be used: (1) to focus on nanomaterials which are expected to typically behave differently on the nanometer scale; and, (2) to select appropriate analogue/read-across information within a class of nanomaterials. As the science develops, approaches for selecting analogue/read-across information across different classes will be considered. Experts and stakeholders were asked to provide input into the proposed classification scheme during the March 20, 2013 RCC Nanotechnology Initiative Workshop. The refined classification scheme, reflecting that input, is presented below in Figure 2. Stakeholders and experts at the workshop agreed that this proposed classification scheme is an appropriate starting point 7. By identifying these classes of nanomaterials, the Canada/US Programs are indicating which nanomaterials they believe behave differently from their non-nanoscale forms. For example, gold nanoparticles display different properties as compared to bulk gold. Substances such as organic polymers and pigments, however, have not typically been found to exhibit unique nanoscale properties/phenomena. (Those substances have been on the nanometer scale due to their synthetic route, and, as such, have undergone traditional chemical risk assessments.) The classes in Figure 2 are not exhaustive and will be modified as new nanomaterials are notified to the Canada/US Programs, and as the scientific knowledge increases. Hybrid nanomaterials (for example, a carbon nanotube with a metal oxide surface modification which displays unique behaviour) are not part of the proposed classification scheme as they fall into multiple chemical composition classes. For that reason, all hybrid nanomaterials will continue to be assessed on a case-by-case basis without the inclusion of analogue/read-across information. The class for organics (section 3.6) was added to the classification scheme based on stakeholder feedback received at the March 20, 2013 RCC Nanotechnology Initiative Workshop ; it represents an emerging area of nanotechnology, one which the Canada/US Programs know relatively little about at this point. That is expected to change as scientific knowledge increases, especially with the emergence of nano-cellulosic materials into the marketplace. 8

9 Figure 2: Proposed classification scheme based on similarities in chemical composition. The blue boxes in Figure 2 represent the classes the Canada/US Programs and their stakeholders believe that nanomaterials can fall into, based on similarities in chemical composition. The physiochemical parameters listed (in the white boxes) represent the intrinsic physicochemical parameters which must be similar between two nanomaterials for them to be considered for analogue/read-across information (e.g., if two nanomaterials within a class have the same physiochemical parameters, it is likely that they will have similar properties and behavior in, for instance, wastewater treatment plants). In this document, the terms solubility, degradation of the nanomaterial surface, and dissolution are used interchangeably and are meant to broadly encompass the release of ions from the nanoparticle in solvent media over time. It is important to note that measuring solubility is still complex (e.g., measuring dispersions vs. solubility vs. dissolution). Size refers to primary particle size or mean size in the absence of primary particle size information. Surface modification refers to chemical changes to the surface of the nanoparticle (including surface oxidation, chemical functionalization, etc.). Surface chemistry refers to the properties of the surface (e.g., surface charge). Both surface chemistry and surface modification are integrally linked and inter-dependent. In addition to supporting analogue/read-across information, many of these physiochemical parameters are important markers for understanding nanomaterial fate and behavior during risk assessments. As such, it is likely that the Canada/US Programs will request all relevant information (in the case of the identification of analogues/read-across, all physiochemical parameters listed are required) during the 9

10 regulatory process. Other information, including extrinsic parameters - such as aggregation, agglomeration, and de-agglomeration - which are used in the risk assessment process but are not part of this classification scheme may, nonetheless, be requested during the regulatory process to help assess hazard, fate, and effects. The classification scheme presented in this document should not be used to infer toxicological modes of action for nanomaterials as the science for this is still emerging (e.g., Nel et al. (2012) 7 ). The work by Nel and others on toxicological modes of action still needs to be evaluated for reproducibility both within the proposed classes and across different classes to determine their applicability in classification processes. However, available information on two nanomaterials which have been found to have similar chemical composition and parameters, as outlined in Figure 2, could be used to increase the weight-ofevidence to support toxicology assessments. (For example, if two submissions for multi-walled carbon nanotubes (MWCNTs) had sufficiently similar * physiochemical parameters (as listed in Figure 2), data from one could potentially be used as read-across for the other to increase the weight-of-evidence in the assessment). In addition, while still very early, it may also be of benefit to consider extrapolations between nanoparticles of different compositions if their physicochemical parameters are sufficiently similar * within a class. (For example, if titanium dioxide and silicon dioxide display the same physicochemical parameters, could they also potentially display the same environmental fate?) Sections contain information on each of the nanomaterial classes listed in Figure 2, including how differences in their physiochemical parameters can lead to differences in fate and effects. 3.1 Carbon Nanotubes Carbon nanotubes (CNTs) are typically described as seamlessly rolled sheets of graphite 8. These rolls can be of single sheets (single-walled carbon nanotubes, or SWCNTs), or multiple sheets (double and MWCNTs). Both the Canadian New Substance Program and US New Chemicals Program consider CNTs as new substances that do not have any non-nano counterparts (this includes graphite and graphene) and, as such, have assessed and will continue to assess each CNT (SWCNT and MWCNT) individually. There exists scientific information showing links between the physicochemical parameters outlined in Figure 2 for CNTs and their fate and effects. Length 9 and diameter 10 (aspect ratio) have been demonstrated to be physical features of CNTs that are considered determinants for their pulmonary toxicity. Bussy et al. (2012) 11 showed 7 Nel, A.; Xia, T.; Meng, H.; Wang, X.; Lin, S.; Ji, Z.; Zhang, H. Acc. Chem. Res., 2013, 46, * The term sufficiently similar is undefined and will be discussed and agreed to once this classification scheme is implemented in the regulatory process. The authors welcome any ideas on what constitutes two parameters to be similar e.g., differences of 10 %? Or similarity based on a minimum number of identified parameters? 8 Baughman, R.; Zakhidov, A.; de Heer, W. Science, 2002, 297, Poland, C.A.; Duffin R.; Kinloch I.; Maynard A.; Wallace WA.; Seaton A.; Stone, V.; Brown, S.; MacNee, W.; and Donaldson, K. Nature Nanotechnol., 2008, 3, Fenoglio, I.; Aldieri, E.; Gazzano, E.; Cesano, F.; Colonna, M.; Scarano, D.; Mazzucco, G.; Attanasio, A.; Yakoub, Y.; Lison, D.; and Fubini, B. Chem. Res. Toxicol., 2012, 25,

11 linkages between the changes in surface modifications and surface chemistry as a result of changing aspect ratios of CNTs, and corresponding CNT-induced inflammation. Surface modification and surface chemistry 12 : Pasquini et al. (2012) have demonstrated the differences in cell viability (invitro toxicological endpoint) as a function of surface modification and surface chemistry on SWCNTs, suggesting that surface chemistry and surface modifications may be an important parameter in understanding CNTs behavior. Liu et al. (2013) 13 have reviewed the physicochemical parameters important in understanding the toxicity of CNTs. The number of walls and reactivity, driven in part by the CNT end-caps (capped/uncapped) and chirality 14, were found to be important factors in understanding effects. The Canada/US Programs have concluded that the physicochemical parameters listed in Figure 2 are important to distinguish CNTs within the same class. The examples cited clearly demonstrate that differences in these parameters can lead to differences in behaviors. If these parameters are the same, or sufficiently similar (see footnote), it is expected that analogue/read-across information can be used. This approach was recently used on a CNT assessment in Canada. Through the selection of an appropriate analogue using the criteria above, differences in CNT environmental behavior and effects due to the dispersability in environmental media were identified. 3.2 Inorganic Carbon The Canada/US Programs have limited datasets on the inorganic carbon class; past evidence indicates that this class includes graphenes (2D sp 2 bonded carbon sheets 15 ), fullerenes (soccer ball-shaped carbon macrostructures 16 ), and nano-carbon black (carbon-based filler 17 ). Although inorganic carbons are similar to CNTs, CNTs were excluded from this category because there is sufficient information indicating that their behavior is dictated by physical attributes unique to CNTs tubular structures. There is a significant amount of literature suggesting that inorganic carbons exhibit differences in their behavior and effects based on the physiochemical parameters identified in Figure 2. Many uncertainties remain for this class, however, including which other materials could fall into the inorganic carbon class, and whether information from one type of material can be used to increase the weight-of-evidence for another type of material within the class. 11 Bussy, C.; Pinault, M.; Cambedouzou, J.; Landry, M.; Jegou, P.; Mayne-L hermite, M.; Launois, P.; Boczkowski, J.; Lanone, S. Particle and Fibre Tox., 2012, 9, Pasquini, L.; Hashmi, S.; Sommer, T.; Elimelech, M.; Zimmerman, J. ES&T, 2012, 46, Liu, Y.; Zhao, Y.; Sun, B.; Chen, C. Acc. Chem. Res., 2013, 46, Skandani, A.; Zeineldin, R.; Al-Haik. Langmuir, 2012, 28, Steurer, P.; Wissert, R.; Thomann, R.; Mulhaupt, R. Macro. Rapid Comm., 2009, 30, Tegos, G.; Demidova, T.; Arcila-Lopez, D.; Lee, H.; Wharton, T.; Gali, H.; Hamblin, M. Chem & Bio., 2005, 12, Praveen, S.; Chattopadhyay, P.; Albert, P.; Dalvi, V.; Chakraborty, B.; Chattopadhyay, S. Comp. App Sci. & Manuf., 2009, 40,

12 Jachak et al. (2012) 18 found that the biological effects of graphenes are driven by the number of layers, surface area, size and shape (lateral dimensions), stiffness, surface modifications, and surface chemistry. Similar findings were found for fullerenes in a review by Sergio et al. (2012) 19. They note that size, chemical modifications (such as the introduction of zinc inside the fullerenes) and surface chemistry, among other properties, affect reactivity. This class of inorganic carbon is also consistent with the work done by Stone et al. (2010) on the development of classes (see Section 2.1). 3.3 Metal Oxides and Metalloid Oxides According to a global marketplace report 20, metal oxide and metalloid oxide nanoparticles represent one of the largest classes of nanomaterials in terms of volumes, uses, and applications. This class does not represent a specific chemical composition, but rather generic compositional information: MO x, M a M b O x, in which M is a metal/metalloid and O is oxygen. There is a wealth of information on the fate and effects of metal oxides and metalloid oxides being driven by size, shape, composition, crystal structure (e.g., titanium dioxide), surface chemistry and surface modifications. Horie and Fujita (2011) 21, for example, demonstrated the importance of those physiochemical parameters on the effects of metal oxide and metalloid oxide nanoparticles. In addition to those parameters, where the metal oxides or metalloid oxides are soluble (see previous discussion on solubility/dissolution), the solubility will also need to be measured before analogue/readacross information can be shared between two substances. The concept of dissolution/solubility of nanomaterials is currently being discussed internationally within the OECD WPMN, as well as within certain European projects, in order to increase knowledge on how the dissolution of a nanomaterial into its ionic forms would impact its consideration from a risk-assessment perspective. With this and the following class (3.4 Metal, Metal Salts, and Metalloid Nanoparticles), only nanoparticles of the same chemical composition will be considered for use of analogue/read-across information; for example, two nanoparticles of titanium dioxide with similar physiochemical parameters can be considered for analogue/read-across information. As scientific knowledge increases, considerations will be given to using analogue/read-across information for compounds of varying compositions when their physiochemical parameters are sufficiently similar*. 3.4 Metal, Metal Salts, and Metalloid Nanoparticles Metals, metal salts, and metalloids (M 0+ ) behave similarly to the metal oxides and metalloid oxides (section 3.3) in terms of key physicochemical parameters (see common physicochemical parameters in Figure 2). In addition, solubility is of particular importance for this class, a fact reflected by the inclusion 18 Jachak, A.; Creighton, M.; Qiu, Y.; Kane, A.; Hurt, R. MRS Bull., 2012, 37, Sergio, M.;Behzadi, H.; Otto, A.; Spoel, D. Env. Chem. Let., 2012, DOI: /s x. 20 The Global Nanotechnology and Nanomaterials Industry Technology Report No. 68 by Future Markets, Inc. 21 Horie, M., and Fujita, K. (2011) Toxicity of metal oxide nanoparticles, p: , in Advances in Molecular Toxicology, volume 5. Oxford, United Kingdom, 251 p. 12

13 of both solubility and oxidation states in its physiochemical parameters (Figure 2). The role of solubility on fate and effects of metal, metal salts, and metalloid nanoparticles is well documented in literature (See Casals et.al [2012] for the fate and effects of solubility on nanoparticles) 22. In biological or environmental systems, nanoparticles will likely be driven to higher or even complete dissolution. As such, metal, metal salts and metalloid nanoparticles may possess associated toxicity and environmental risks because they will act as a source of potentially toxic cations (e.g., silver nanoparticles have a bactericidal effect that has been correlated with the number of released Ag + ions). In addition, consideration should also be given to the creation of nanoparticles different from the parent particle due to the dissolution of surface ions (e.g., different sizes, shapes, surface chemistry, etc.). 3.5 Semiconductor Quantum Dots Quantum dots are semiconductor nanoparticles with composition and size-dependent electronic properties 23. In addition to the importance of the physiochemical parameters outlined in the preceding classes (size, shape, composition, crystal structure, surface chemistry, and surface modifications), liberation of the ions through degradation and core-shell composition are key parameters in understanding the fate (such as releases) and effect of quantum dots. The comprehensive review by Hardman (2006) 24 and the study by Liu et. al. (2012) 25 investigating releases of quantum dots from nanocomposite lighting demonstrate the importance of the physicochemical parameters identified for this class within the proposed classification scheme. 3.6 Organics The Canada/US Programs acknowledge that many organic chemical substances may be on the nanoscale, but are not engineered on this size scale to exploit any nano-specific property. These typically include organic dyes, polymers, and organic pigments. However, there are situations where an organic substance, such as nanocrystalline cellulose (NCC), takes advantage of a nanoscale property 26. NCC has unique nanoscale properties including high specific strength and modulus, optical properties, and high surface area 27. It is these types of substances that are considered part of this class. Further discussion is required to understand what specific nanoscale properties or behaviors of engineered organic substances in this class would be of interest for regulatory oversight. 3.7 Other This category includes emerging nanomaterials and/or nanomaterials with which the Canada/US Programs have had very limited experience, or for which there is insufficient science to classify based on similarities in chemical composition. To date, these have included metal alloys (e.g., tungsten carbide 28 ), 22 Casals, E.; Gonzalez, E.; Puntes, V.F. J. Phys. D.: Appl Phys., 2012, 45, Michalet, X.; Pinaud, F.; Bentolila, L.; Tsay, J.; Doose, S.; Li, J.; Sundaresan, G.; Wu, A.; Gambhir, S.; Weiss, S. Science, 2005, 307, Hardman, R. Env. Health. Persp. 2006, 114, Liu, J.; Katahara, J.; Li, G.; Coe-Sullivan, S.; Hurt, R. ES&T, 2012, 46, Cranston, E.; Gray, D. BioMacromolecules, 2006, 7, Peng, B.L., Dhar, N., Liu, H.L., and Tam, K.C. (2011) Can. J. Chem Eng. 9999: Kühnel, D.; Bush, W.; Meissner, T.; Springer, A.; Potthoff, A.; Richter, V.; Gelinsky, M.; Scholz, S.; Schirmer, K. Aq. Tox., 2009, 93,

14 nanoclays 29, and tubular structures of metals/metal salts/metalloids 30. It is believed that for tubular structures of different metals/metal salts/metalloids, the requirements to consider two nanomaterials similar are likely similar to those of carbon nanotubes. Bionanomaterials, or substances which combine biotechnology and nanotechnology to produce advanced functional materials 31, were identified by stakeholders at the March 20, 2013 RCC Nanotechnology Initiative Workshop as an emerging area that should be considered for regulatory purposes because of their potential commercial impact. Bionanomaterials - in this context - does not refer to nanomaterials interacting with an organism. At this point, the Canada/US Programs have not received any notifications for bionanomaterials. The ISO (the International Organization for Standardization) is carrying out work regarding the vocabulary around the interface between nanomaterials and biology: It is up to the discretion of the Canada/US Programs to make classes and use analogue/read-across information where appropriate for the nanomaterials which fall into the other category. Further discussions on this category will be required between Canada and the US to ensure their New Substance/Chemicals Programs remain aligned. 29 Lordan, S.; Kennedy, J.; Higginbotham, C. Jo. App. Tox., 2011, 31, Kar, A.; Smith, Y.; Subramanian, V. ES&T, 2009, 43, Whitesides, G. Nature Biotechnology, 2003, 21,

15 4.0 Moving Forward 4.1 Next Steps The Canada/US Programs intend to use the classification scheme outlined in this document as a starting point to increase the utilization of analogue/read-across information in the assessment of new substances regulated under CEPA and TSCA. The Canada/US Programs will determine whether the proposed use of analogue/read-across information by notifiers is appropriate and valid. It is expected that as scientific knowledge increases, additional layers or tiers will be added to the proposed classification scheme, likely targeting more specific endpoints (e.g., tiers based on toxicological modes of action). As has been the practice under the RCC Nanotechnology Initiative, additions or changes to the nanomaterial classification scheme will be done in collaboration with stakeholders. The Canada/US Programs intend to increase their understanding of hybrid nanomaterials (also called second and third generation nanomaterials) and of bionanomaterials which are increasingly being seen in the marketplace; although there have been notifications for hybrid nanomaterials, no notifications for bionanomaterials have yet emerged as noted in section 3.7. It is expected that within 3-5 years scientific knowledge will advance enough to support identification of the physiochemical parameters necessary to develop a class for these substances, as well as the potential usage of analogue/ readacross information within those classes. Until that time, the Canada/US Programs will continue to evaluate hybrid nanomaterials on a case-bycase basis; additional discussions are needed between the Canada and US New Substances/Chemicals groups to further develop strategies to address hybrid nanomaterials. The Canada/US Programs acknowledge that there is some uncertainty with the scientific foundation of this proposed classification scheme and the information necessary to validate this approach. However, it is expected that the proposed classification scheme, based on known science and endorsed and validated by stakeholders, will foster research on these nanomaterial classes to help to validate and further refine the physicochemical parameters and the boundaries proposed for them. The research community is invited to help better the regulatory decision making of nanomaterials by generating data on this classification scheme so it can continue to be refined. 4.2 Towards Common Terminology and Definitions Under the RCC Nanotechnology Work Plan deliverables, the Canada/US Programs were asked to consider approaches to develop common terminology and definitions for nanomaterials. It has been agreed that any terminology and nomenclature should not be developed in isolation within Canada and the US. After discussions with stakeholders at the March 20, 2013 RCC Nanotechnology Initiative Workshop 7 it was concluded that the RCC should collaborate with the International Organization for Standardization (ISO) Technical Committee 229 Nanotechnologies which is developing international standards for various nanomaterial-specific functions including test methodologies, specifications for 15

16 reference materials and terminology and nomenclature 32. The ISO has already developed and published several documents on terminology for nanomaterials 33, and both the Canadian and US Programs have actively participated in the ISO committee since its inception. Because of the formation of the RCC, additional mechanisms will be considered to ensure that Canada/US needs for terminology and definitions are provided to ISO. For nomenclature, the Canada/US Programs are also actively working within ISO as part of the ISO and International Union of Pure and Applied Chemistry (IUPAC) joint project on developing nomenclature for classes of nanomaterials 34. The two countries will consider how best to implement the outputs of these international standard committees into their respective regulatory frameworks. 4.3 Towards Nanomaterials of Potential Concern/No-Concern As part of the RCC Work Element 2 deliverables, the Canada/US Programs were asked to determine whether they could move towards the development of classes of nanomaterials of potential concern/no-concern, as has been done for many traditional chemicals. By developing a classification scheme under the RCC, the Canada/US Programs have taken a first step towards identifying which nanomaterials they consider to be sufficiently different than their non-nano counterparts to be of concern, and which therefore may need a closer examination for environmental, human health, and safety endpoints; and, those nanomaterials which can be considered as traditional chemicals for regulatory purposes, or those of no-concern. Currently, this list is used only for sorting which nanomaterials need additional nano-specific consideration and which can be considered as traditional chemicals. There are, it should be noted, exceptions to this list which will continue to be considered on a case-by-case basis. To further inform the list, hazard classification must be taken into account, as is done when concern/no-concern lists are generated for traditional chemicals. The Canada/US Programs believe it is still early to develop a hazard-specific list of nanomaterials of concern/no-concern because of the lack of appropriate scientific information; the approach will continue to evolve as relevant scientific information is generated. The Canada/US Programs intend to foster research and regulatory capacity in Canada and the US to help to move toward understanding which nano-properties are relevant to hazard and exposure, and how those properties affect organisms. Dialogue and harmonization activities between the Canadian and US Programs will continue post-rcc (beyond 2014) to support further refinement of the approach outlined in this paper. 4.4 Conclusion The Canadian New Substances Program and the US New Chemicals Program, using input from stakeholder consultations, are proposing a classification scheme for nanomaterials based on similarities in chemical composition to support the use of analogue/read-across information in regulatory risk assessments. This is the first time regulatory programs have considered the use of a classification Preliminary work done by ISO TC/229 under ISO/DTR

17 scheme for nanomaterials in regulatory decision-making to increase the utilization of analogue/readacross information. The Canada/US Programs are currently exploring activities to determine how this classification scheme can be incorporated into their regulatory processes. Using a classification scheme supports the utilization of an analogue/read-across approach among similar nanomaterials and will provide increased transparency, consistency and alignment between the US and Canada regulatory approaches for stakeholders. 17

18 Appendix I: Examples of Classification Schemes in Literature Classification of nanomaterials by their containing matrix The US Army is developing a classification scheme to take into account the behaviour of the nanomaterial in products. They have suggested the following classes: freely dispersed particles, particles in viscous media, particles in diffuse coatings, durable coatings and composites, and nanostructured products. This classification scheme is meant to provide data to regulators on army-specific products along with providing improved criteria to determine potential EHS risks associated with nanomaterials. The reader is invited to contact Jeffery Steevens (Jeffery.A.Steevens@usace.army.mil) for more information on this project. The US National Institute of Occupation Safety and Handling (NIOSH) has suggested grouping of nanomaterials by physical state to improve safe handling and reduce worker exposure 35. The suggested classes are: (a) bound of fixed nanostructures (polymer matrix); (b) liquid suspension, liquid dispersion; (c) dry dispersible nanomaterials and agglomerates; and (d) nanoaerosols and gas phase synthesis (on substrate). Similar to the NIOSH approach, Hallock and colleagues 36 have suggested classifying nanomaterials by product matrix: pure nanomaterials, items contaminated with nanomaterials, liquid suspensions, and solid matrices to ensure safe disposal. In the work by Foss Hansen and colleagues 37, the team suggests a classification approach based on the location of the nanomaterial on the product, i.e., as part of a bulk substance (e.g., nanoelectronics), on the surface (e.g., films), or as particles (e.g., liquid suspensions) thereby allowing one to distinguish which nanoparticles are expected to cause exposure, which may cause exposure, and are not expected to cause exposure to the consumer. 35 US NIOSH General Safe Practices for Working with Engineered Nanomaterials in Research Laboratories DHHS (NIOSH) Publication No Available at 36 Hallock, M.; Greenley, M.; DiBerardinis.; Kalin, D. Jo. Chem. Health & Safety, 2009, 16, Hansen, S. F.; Michelson, E.; Kamper, A.; Borling, P.; Stuer-Lauridsen, F.; Baun, A. Ecotoxicology, 2008, 17,