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Risk Assessment/Management

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The Regulatory Cooperation Council (RCC) Nanotechnology Initiative was established to increase alignment of regulatory approaches for industrial nanomaterials (herein referred to as “nanomaterials”) between Health Canada/Environment Canada and the United States (US) Environmental Protection Agency. This report presents findings from Work Element 3: Risk Assessment/Risk Management; the overarching action item for this work element was the sharing of best practices for assessing and managing the risks of nanomaterials.   

In order to provide regulatory context to the analysis of risk assessment and risk management methods used by the New Substances Program in Canada and the New Chemicals Program in the US (Canada/US Programs), and to develop an understanding of the regulatory requirements, policies and options in Canada and the US, a comparative analysis of regulatory frameworks under the Canadian Environmental Protection Act, 1999 (CEPA 1999) and the Toxic Substances Control Act (TSCA 1976) was undertaken through a review and analysis of the respective legislations, regulations, policies and material definitions.  Though no specific regulations for nanomaterials have been developed, both jurisdictions believe that existing regulatory tools for industrial chemicals are applicable to nanomaterials. Nanomaterials are not specifically named in any of the regulations, although the definitions of a ‘chemical’ or a ‘substance’ under these legislative tools are considered broad enough to include nanomaterials.  This finding is consistent with the international consensus that current regulatory frameworks are appropriate for nanomaterials, albeit with some modifications (i.e., Draft OECD Council Recommendation on the Safety Testing and Assessment of Manufactured Nanomaterials).

Though some regulatory differences were identified between the Canada/US Programs within their respective pre-market notification requirements, information packages, assessment timelines, and target populations of interest, the overarching principles for the assessment and management of the risks of nanomaterials are consistent between the two.  

In order to develop an understanding of the methodologies and tools used by the Canada/US Programs to support regulatory decisions, a comparative analysis of current risk assessment and risk management approaches to nanomaterials in Canada and in the US was conducted using a case study approach.  This analysis demonstrated that the Canada/US Programs share many more commonalities in their approaches to the risk assessment and risk management of nanomaterials than they do differences: risk assessments of nanomaterials in the Canada/US Programs employ a conservative approach and are assessed on a case-by-case basis. Furthermore, management efforts are designed to reduce exposures and allow further assessment of potential scenarios of increased environmental release and/or direct human exposure when appropriate. 

After the comparative analysis of regulatory frameworks and approaches was complete, a common framework for systematically focusing human health concerns and additional testing requirementsfor nanomaterials based on physical-chemical characteristics, and a common outlook on the environmental fate and ecological effects of nanomaterials were developed. The development of these common approaches reflects an effort to increase consistency, transparency, and predictability between the jurisdictions.

Further areas of possible collaboration and harmonization were also discussed.  It was recognised that ongoing collaboration would be constrained by the current inability to readily exchange notification information because of Confidential Business Information (CBI) requirements. 

Future areas that were identified for collaborative activities include:

  • Further development of common approaches/standard operating procedures (SOPs) for the assessment of human health hazard, exposure, environmental fate and ecotoxicity of nanomaterials to be used by both jurisdictions.
  • Development/adoption of new approaches to screening and prioritizing toxicological testing (e.g., the use of in vitro/high throughput methodologies), data generation, and risk assessment of nanomaterials as nanotechnology and nanoscience evolves.

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, 1999 (CEPA 1999) and in the US under the Toxic Substances Control Act (TSCA 1976).

The overarching action item identified for Work Element 3, Risk Assessment/Risk Management, in the RCC Nanotechnology Work Plan is to share best practices for assessing and managing the risks of nanomaterials.  In order to share best practices and develop mechanisms of cooperation on risk assessment and risk management between Canada and the US, the work plan included the following objectives:

  • development of an understanding of the regulatory requirements, policies, and regulatory options available to each jurisdiction;
  • development of an understanding of the methodologies and tools used by the Canadian New Substances Program and US New Chemicals Program (Canada/US Programs); 
  • identification of mechanisms for sharing information and tools (including Confidential Business Information [CBI], subject to appropriate protections); and,
  • development of mechanisms for stakeholder outreach and engagement.

(Because CBI sharing and stakeholder outreach are issues that affect each of the RCC Joint Action Plan Work Elements, these are not specifically addressed within this report.) 

In order to meet the proposed objectives, the following tasks were undertaken:

  • A comparative analysis of regulatory frameworks was conducted in order to identify commonalities, differences and gaps.
  • A comparative analysis of current assessment approaches for nanomaterials in the Canada/US Programs was conducted through case studies/peer reviews of each other’s assessments.
  • A best practices document for the assessment and management of nanomaterials was prepared, taking into consideration current data/knowledge gaps.
  • Barriers to and opportunities for ongoing collaborations and regulatory alignment were identified.

After the comparative analysis of regulatory frameworks was complete, a common framework for systematically focusing on human health concerns and additional testing requirements for nanomaterials based on physical-chemical characteristics, and a common outlook on the environmental fate and ecological effects of nanomaterials were developed. The development of these common approaches reflects an effort to increase consistency, transparency, and predictability between the jurisdictions.

Further areas of possible collaboration and harmonization were also discussed.  Future areas that were identified for collaborative activities include:

  • further development of common approaches/standard operating procedures (SOPs) for the assessment of human health hazard, exposure, environmental fate and ecotoxicity of nanomaterials to be used by both jurisdictions; and,
  • development/adoption of new approaches to screening and prioritizing toxicological testing (e.g., the use of in vitro/high throughput methodologies), data generating, and risk assessment of nanomaterials as nanotechnology and nanoscience evolves.

This report is a summary of the work conducted under Work Element 3 over from November 2012 to April 2014  . Supporting information and a more detailed description of the tasks described above can be found in the Appendices.



[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.

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Comparative Analysis of Regulatory Frameworks for Risk Management of Nanomaterials

Existing domestic statutes have provided a firm foundation for the regulation and oversight of a wide range of industrial chemicals/substances, and jurisdictions around the world have concluded that for the most part, existing regulatory authorities for industrial chemicals are applicable to nanomaterials.[1]  Even though nanomaterials are not specifically named in any of the current regulations, the definitions of a ‘chemical’ or a ‘substance’ under these legislative tools are considered broad enough to include them.  Recently however, specific advisory notes or notification procedures have been issued by agencies within Canada, the US, the European Commission (EC) and several other countries to make it clearer how, when, and which nanomaterials should be notified/registered. 

Although neither the Canadian New Substances Program nor the US New Chemicals Program have developed regulations specific to nanomaterials, reviewing the regulatory frameworks for pre-market assessment of chemicals in both jurisdictions does provide the RCC with an analysis of the current regulatory environment overseeing nanomaterials.  

A comparative analysis of regulatory frameworks under CEPA 1999 and TSCA was completed by reviewing and analyzing the two countries’ respective legislations and regulations, policies and material definitions. This provided regulatory context to the analysis of risk assessment and risk management approaches used by the Canada/US Programs, as well as an understanding of the regulatory requirements, policies and regulatory options available in Canada and the US.  In addition, a scan of regulatory tools, policies and definitions for nanomaterials in other jurisdictions (including Australia, members of the European Union and Japan) was completed.  A copy of the entire report can be found in Appendix A.

Although there are statutory differences surrounding pre-market notification requirements, information packages, assessment timelines, and target populations of interest between the Canadian and US Programs, it was found that the overarching principles for the risk assessment/risk management of nanomaterials are consistent[2],[3]

The following conclusions/observations were noted with respect to the pre-market notification of industrial chemicals and nanomaterials in the Canada/US Programs:

  • Canada and the US share more commonalities in their approaches to the management of ‘new’ chemicals and nanomaterials than they do differences.  Both countries have the capacity to issue reporting requirements, request additional information/testing, impose conditions of use or prohibitions if a ‘new’ substance is deemed to pose an unacceptable risk to health or the environment. 
  • Both Canada and the US provide notification exemptions and/or exclusions which are carefully defined and described in legislation and regulations, and are further explained in guidance documents.
  • While both countries require industry to notify their substances/nanomaterials prior to import or manufacture within their jurisdictions, the regulations under CEPA 1999 have volume triggers ranging from ≥ 100 kg/calendar year to ≥ 50,000 kg/calendar year, while TSCA has no such triggers.
  • In both countries, notifiers and evaluators are bound by timelines for new substance notifications, although those timelines are different.  Assessment periods in Canada for chemicals can be very short, ranging from 5 to 75 days.  In the US, all assessment periods are 90 days unless the assessment is for a chemical for which an exemption is requested (assessment periods are then either 30 days or 45 days). Assessment periods can be extended under both CEPA 1999 and TSCA if additional time/information is needed based on a concern to humans or the environment.  
  • The required information packages for new substances differ significantly between Canada and the US. In Canada, the identification of the substance and test data needed to evaluate hazard for the human health and the environment are prescribed in a tier-like fashion by quantity of chemical intended to be imported or manufactured. In the US, under TSCA, there are pre-market notification requirements to provide all known information; however, more detailed information is requested by the EPA only after an initial screening if it considers that there is cause for concern for human health, including specific concerns related to worker health, or for the environment.  Both Canada and the US have indicated to their industry partners a desire to receive early notification of nanomaterials and as much information as possible on the characterization and properties of these substances.
  • Both programs apply conservative assumptions about dispersal, persistence, and bioaccumulation of nanomaterials in their evaluations when there is little suitable test data available for exposure, hazard and/or risk assessment.
  • Both programs apply significant new use type provisions for notified substances about which they have concern for impacts on health and the environment (that is, permit the current use but require additional information and assessment if the use were to change).
  • International cooperation and harmonization, to the extent to which legislation permits, is also seen by both countries as a necessary and desirable objective.  



[1] OECD. 2011. Regulated Nanomaterials: 2006-2009. ENV/JM/MONO(2011)52

[2] “Policy Statement on Health Canada's Working Definition for Nanomaterial”, located at http://www.hc-sc.gc.ca/sr-sr/pubs/nano/pol-eng.php (accessed on December 9, 2013).

[3] ‟Policy Principles for the U.S. Decision-Making Concerning Regulation and Oversight of Applications of Nanotechnology and Nanomaterials", http://www.whitehouse.gov/sites/default/files/omb/inforeg/for-agencies/nanotechnology-regulation-and-oversight-principles.pdf (accessed on December 9, 2013).

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Comparative Analysis of Current Risk Assessment Approaches for Nanomaterials

In order to develop an understanding of the methodologies and tools used by the Canada/US Programs to support regulatory decisions, a comparative analysis of current risk assessment and risk management approaches to nanomaterials in Canada (under CEPA 1999) and in the US (under TSCA) was conducted using a case-study approach. Industry stakeholders were asked to nominate potential nanomaterials for the case-study; nominated nanomaterials were subsequently ranked against relevant criteria such as commercialization and market availability. After a thorough analysis, Multiwalled Carbon Nanotubes (MWCNTs) were selected.  To facilitate the case-study, guidance for the conduct of the comparative analysis was drafted (Appendix D), and information exchanged between the Canada/US Programs.

From that comparative analysis, it was concluded that the Canada/US Programs have similar conservative approaches to the risk assessment and risk management of nanomaterials.  Additionally, identified risks, including areas of uncertainty, are mitigated through processes specifically designed to reduce exposures and allow further assessment for potential scenarios of direct human exposure and/or increased environmental release.  The Canada/US Programs agree that sufficient scientific knowledge does not yet exist on the behaviour, toxicity, mode of action and environmental fate of nanomaterials to allow for the development of a risk assessment methodology that would benefit from the use of analogue/read-across information.  As scientific knowledge evolves, understanding of these relationships will allow risk assessment to evolve from a case-by-case to a more generalized paradigm. 

Material Selection

The process for selecting a nanomaterial for the case study included a request for nominations from stakeholders.  A letter was sent to stakeholders in both Canada and the US on October 9, 2012, inviting nomination of candidate substances that could be considered for the case study (Appendix B). Four nanomaterials were nominated: Multiwalled Carbon Nanotubes (MWCNTs), Nano Crystalline Cellulose (NCC), Nano Silver (nAg) and Nano Titanium Dioxide (nTiO2).

The following criteria (See Appendix C for detailed criteria) were considered in the selection of an appropriate nanomaterial for the purposes of conducting a comparative analysis of current risk assessment methods and risk management approaches[1]:

  • commercialization and market availability;
  • substance composition/ production;
  • information availability; and,
  • relevance to RCC.

Based on the responses/information that was provided from stakeholders, MWCNTs were selected for the first nanomaterial case study.  Table 1 briefly summarizes the information received from stakeholders and the rationale for selecting MWCNTs.

Table 1: Summary ranking of nanomaterials nominations

NanomaterialMWCNTNCCnAgnTiO2
Commercial ApplicationsResins, coatings and compositesPaints, coatings, composites, oil drillingTextilesNone provided
Regulatory status in Canada and USNotified in BOTH countriesNotified in Canada onlyNOT notified to either ProgramNOT notified to either Program
Type of available informationPhysical-chemical, volumes, toxicity, leachability, etc.Physical-chemical, volumes, toxicity, industrial releasePhysical-chemicalNone provided
Relevance Rank to RCC1234

NOTE: Future work may include conducting additional case studies from the other nominated nanomaterials with packages of greater or lesser information.

Comparison of Risk Assessment Methods

Though statutory differences surrounding pre-market notification requirements, information/data packages, assessment timelines and target populations of interest do exist, the overarching principles for the assessment and management of nanomaterials are consistent between the Canada/US Programs.  Because very few nanomaterial-specific evaluation methodologies, tools or models exist in Canada or the US, existing methodologies for the assessment of chemical substances are being used in both countries, where appropriate.  Numerous similarities in the Canadian and US chemical assessment protocols were revealed during the comparative analysis exercise. (Detailed comparison available in Appendix E.) The following key observations, risk assessment approaches and methods were noted during the discussions.

Identity/Physical-chemical Properties

Identity and chemical structure of traditional chemicals are usually confirmed through spectroscopic (e.g., infrared), resonance (e.g., nuclear magnetic resonance) and/or mass spectrometric (e.g., ionization mass spectrometry) techniques.  Additional particle-based techniques such as microscopic (e.g., scanning electron microscopy or transmission electron microscopy), light scattering (e.g., dynamic light scattering), and electronic are needed in order to adequately identify and characterize a nanomaterial.   However, there are currently very few standardized methodologies for these techniques, and conducting these measurements in complex environments presents many challenges.

The physical-chemical properties relevant to risk assessments of traditional chemicals -  including end-points such as melting-point, boiling point, vapour pressure, and water solubility -  are of limited value for nanomaterials.   End-points such as particle size distribution, surface charge, aggregation state, and specific surface area are more relevant in determining the toxicity, environmental fate, and behaviour of nanomaterials.  

Based on the lack of appropriate standardized methodologies needed to properly identify nanomaterials, the Canada/US Programs compared what kind of information they request from notifiers to identify similarities and differences in the two countries’ approaches.  Key findings are as follows:

  • Standard physical-chemical properties provided with new substances submissions do not usually contain adequate information for nanomaterial characterization or relevant physical-chemical properties such as particle size distribution, shape, and degree of agglomeration/aggregation.  Both countries feel this information is crucial to understanding the behaviour and toxicity of the nanomaterial.
  • Both jurisdictions request similar data sets to better characterize the substance (e.g., length, diameter, size, SSA, agglomeration/aggregation, purity, etc.).
  • For the most part, the OECD Test Guidelines for Chemicals are considered to be adequate for the testing of nanomaterials by both jurisdictions with some modifications.  However, some standard physical-chemical test guidelines for chemicals are not considered appropriate for assessing nanomaterials (e.g., OECD water solubility test guideline 105).
  • Both jurisdictions agree that no models are available to validate or predict physical-chemical data on nanomaterials. Appropriateness/relevance of data provided is assessed by professional judgment.

Environmental Fate and Release

Quantifying the releases from industrial activities of nanomaterials is not currently possible. In traditional chemical risk assessments, the releases of a substance can be appropriately quantified using mass balance models and traditional physical-chemical end-points. Emission scenario documents[2] from the OECD provide a solid basis for calculating the release from many different chemical uses; as well, models based on physical-chemical parameters, such as vapour pressure and degradation, can be used to predict behaviour in, for example, sewage treatment facilities to help calculate predicted environmental concentrations and the environmental fate of a substance.

There are no emission scenario documents specific to releases of nanomaterials. Release scenario documents relevant to particles do exist; however their applicability to nanomaterials is still uncertain. As can be seen in the high-level findings below, the Canada/US Programs rely on these particle-based release documents, or use conservative release scenarios, to calculate predicted environmental concentrations.

Most of the endpoints used for traditional chemicals cannot be used for nanomaterials, and no suitable models exist to adequately quantify or predict their environmental fate; additional properties such as aggregation state, surface charge, and surface area are needed to determine their environmental fate from a qualitative perspective. For example, carbon nanotubes may undergo settling through hetero- and homo- aggregation in rivers, embedding in sediments; they may stay in the water column through stabilization with natural organic matter; and they may be mobile or immobile in the soil, depending on their surface charge.

Key findings on environmental fate and release are as follows:

  • Due to the uncertainties associated with predicting the partitioning behaviour of nanomaterials, the Canada/US Programs assume that nanomaterials will likely be present in all compartments: water, soil, sediment, and air.
  • Both jurisdictions believe that the potential for long-range transport of nanomaterials is low; however, the potential for vectorization (i.e., nanoparticles binding to other particulates and undergoing transport) is uncertain and considered possible. 
  • Both jurisdictions believe that octanol-water partitioning coefficient (Log KOW) is not a useful predictor for bioconcentration/bioaccumulation for nanomaterials since their behaviour at the octanol-water interface is governed by different mechanisms than traditional chemicals (Hou et al., 2013)[3].
  • Overall, Canadian and US assumptions and approaches to environmental fate and release are similar: both countries consider industrial releases to waters through wastewater treatment processes to be a major route of release (similar to traditional chemicals)[4], releases to air are considered where appropriate, and land-spray applications are considered in cases where the substance partitions to biosolids. However, in the absence of experimental or predictive data, conservative values may be used for estimating exposures (e.g., 0% removal at a sewage treatment plant).
  • Environmental releases consider two worst-case scenarios: 100% release to the aquatic compartment from wastewater treatment (i.e., no removal from treatment) and 100% release to biosolids (i.e., 100% removal from treatment). These two extremes allow the Canada/US Programs to develop conservative scenarios to calculate predicted environmental concentrations.

Exposure Assessment

In a traditional pre-market chemical risk assessment, exposure is estimated following accepted paradigms and exposure scenarios based on known applications and the use-patterns identified. However, in the case of nanomaterials, it is currently not possible to accurately quantify exposure because nanomaterials can undergo various transformations during their lifecycle, including aggregation/agglomeration, changes in shape, and being surface-coated by different substances. In the absence of relevant information, the traditional chemical risk assessment framework is used to inform potential exposure scenarios, and conservative qualitative estimates of exposures are developed.  Exposure assessments of nanomaterials are generally conservative, assuming worst-case scenarios.  It is expected that as more models emerge and understanding increases, better identification and quantification of relevant exposures for nanomaterials will be developed.

  • Both Canada and the US agree it is impossible to quantify exposure with much certainty due to the novel nature of nanomaterials, uncertainty in release/fate (see 4.2), and the uncertainty of applying existing models.
  • The applicability of some data to ‘real world’ exposure is considered questionable; for example,  how does the surface of a nanomaterial change when it is released from an end-use coating, and is the information on the pure nanomaterial sufficient to address that exposure?

Hazard Assessment

Traditional chemical hazard assessments in the Canada/US Programs rely on test data for the notified substance, analogue/read-across data and in-silico modelling (e.g., QSAR). Hazard assessments of nanomaterials generally lack substance-specific test data, have limited access to adequate analogue data and no access to reliable in-silico models.  Key findings pertaining to the hazard assessment of nanomaterials are as follows:

  • For the most part, the EPA and OECD Test Guidelines for Chemicals are considered to be adequate for the testing of nanomaterials by both jurisdictions, albeit with some modifications and additional physical-chemical characterisation data.  However, some standard toxicity test guidelines for chemicals are not appropriate for assessing nanomaterials (e.g., bacterial reverse mutation test for genotoxicity).
  • Physical-chemical characterization of the test material is critical for adequately interpreting study results, assessing the toxicity of nanomaterials, and for comparison to other nanomaterials.
  • Data on the bulk-sized substances and similar nano-scale materials are used as qualitative indicators in hazard identification but not in point-of-departure quantification of hazard.
  • The suitability of analogs for read-across is determined based on degree of similarity between relevant physical-chemical properties of the new substance and those of the proposed analogs (e.g., size, shape, number of walls, and surface chemistry).
  • There is agreement in the interpretation of toxicity test results and critical endpoints by regulators in both jurisdictions.
  • No software models are used in Canada or the US for prediction of human health hazard or ecotoxicity.

Overarching Similarities and Differences in Risk Assessment Approaches

Overarching similarities in Canada/US approaches to nanomaterial risk assessment are as follows:

  • Both jurisdictions apply conservative assumptions about human health hazard and ecotoxicity potential when there is little test data available suitable for hazard or risk assessment of nanomaterials.
  • The Canada/US Programs rely heavily on published peer-reviewed scientific literature to fill data gaps.
  • Better characterization of nanomaterials  is considered essential by both Programs for assessing the applicability/reliability of any supplied test data for conducting quantitative risk assessments, and for applying methods of comparison (such as analogue/read-across) when possible.
  • Risk management recommendations reflect both the degree of risk and the level of uncertainty (e.g., the applicability of the available data and the lack of substance-specific information).

Differences in assessment approaches and in methods used were most often the result of differences in regulatory mandates or data availability.  The following identifies differences in observations, risk assessment approaches and methods between the Programs:

  • In general, Canada receives more test data than the US at the time of notification, due to the test data requirements prescribed under the New Substances Notification regulations (NSNR) in Canada; no similar requirements are prescribed in the US under TSCA.
  • The occupational workplace is a focus of attention in US risk assessments, while in Canada, general population exposure and lifecycle considerations are the focus in risk assessments of nanomaterials under CEPA 1999.
  • Consequently, Pre-Manufacture Notices (PMNs) in the US usually contain detailed information on manufacturing processes and industrial releases not usually received with submissions to Canada.
  • Canadian exposure assessments usually include consideration of potential use scenarios in addition to those identified in the submission, while in the US assessments generally only consider applications reported/mentioned in the submission.
  • The US receives a greater number of nanomaterial submissions and consequently has greater access to information on potential analogs to support the use of analogue/read-across information in quantitative risk assessment and decisions-making. As a result, the EPA uses analog data for conducting quantitative risk assessment of some PMN nanomaterials
  • Most of these differences are due to differences in regulations, rather than how information is reviewed and/or evaluated in the two countries. 

Comparison of Risk Management Approaches Used

Canada and the US have similar approaches for the management of nanomaterials. Both countries try to manage exposure in order to manage risk. This can be done through the application of significant new use type provisions for those notified substances of concern, or, those that may impact on health or the environment. Both countries also work closely with industry in order to best mitigate potential risks to the environment or human health.

Identified risks or areas of uncertainty are mitigated through an approach designed to reduce exposures and allow further assessment of potential scenarios of increased environmental release and/or direct human exposure. 

Key Conclusions

The US and Canada have similar approaches to risk assessment and risk management of nanomaterials based on case-by-case assessments and utilizing a conservative screening approach.  Identified risks or areas of uncertainty are mitigated by methodologies designed to reduce exposures and to allow further assessment for potential scenarios of increased environmental release and/or direct human exposure. 

Both jurisdictions agree that sufficiently comprehensive scientific knowledge on the behaviour, toxicity, mode of action and environmental fate of nanomaterials does not yet exist to allow for routinely conducting quantitative risk assessment, but as scientific knowledge evolves, understanding of these relationships will allow increasingly more data to be incorporated into assessments. 

Differences in exposure assessment scope were discussed during the comparative analysis exercise.  These include a focus on occupational exposure in US assessments as compared to a focus on general population exposure in Canadian assessments, differences in the initial data sets submitted to both jurisdictions and differences in the extent to which assessments would cover potential uses and life cycle considerations.  These differences stem from the respective regulatory frameworks rather than differences in approaches as to how data is evaluated. 

Based on the analysis and discussions that occurred during the case study/comparative analysis exercises, it became clear that the development of common approaches for the systematic assessment of physical-chemical properties, environmental fate, exposure and hazard of nanomaterials would contribute to increase consistency, transparency and predictability between the Canada/US Programs.



[1] Note: Nomination/identification of a nanomaterial for the purposes of this comparative analysis does not constitute a finding that the nanomaterial presents a risk to human health or the environment

[3] Hou, W.; Westerhoff, P.; Posner, J.Env. Sci. Processes & Impacts, 2013, 15, 103-122

[4] Gottschalk, F.; Sonderer, T.; Scholz, R.; Nowack, B. ES&T, 2009, 43, 9216-9222.

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Development of Common Approaches to the Risk Assessment of Nanomaterials

Nanoparticle Human Health Screening Assessment Framework

Following the analysis and discussions that occurred during the case study/comparative analysis exercises, a common approach for assessing and identifying additional testing requirements for nanoparticles was developed by the two countries, based on current knowledge of particle toxicology. This common framework is summarized here, and represents an effort to systematically focus human health concerns and additional testing requirements for nanoparticles based on physical-chemical characteristics (e.g., particle shape, aspect ratio, particle/fibre size, solubility, composition and surface chemistry).  (Refer to Appendix F for a more detailed discussion.)

The manipulation of matter at the nano-scale is creating many novel substances with characteristics which are not always easily predicted from current knowledge. For example, a substance with a fixed composition can be engineered into many different forms (e.g., spheres, fibres, or sheets) with varying physical characteristics (e.g., size, shape, and surface properties).  Though these different forms possess identical composition, the effects of changing the physical-chemical parameters may alter the substance’s behaviour in environmental and biological media. The near-limitless diversity of substances that can be engineered from one particular composition can also have a near-limitless spectrum of toxicity: some particles may confer health benefits, others may be harmless, some become toxic, and some may retain the toxicity profile of the original bulk counterpart. 

Nanoparticles come in all sorts of sizes, shapes, and composition. Currently, nanoparticles are identified by name and by their Chemical Abstract Services Registry Number (CASRN), which are nomenclature methods primarily based on composition. One name and/or CASRN may represent a wide array of substances with the same composition. For example, a material of one composition will have a size distribution that can vary depending on manufacture and processing methods, and, can exhibit varied crystal structure, shape, surface chemistry, aggregation/agglomeration and other characteristics.

Particle toxicology is different from molecular toxicology in that the physical characteristics of the particles are most often the primary drivers of toxicity rather than their composition alone. Consequently, different paradigms are required in nanoparticle risk assessment than in molecular risk assessment.

Traditionally, classification of particles has been conducted on the basis of size based on the principle that as particle size decreases, the greater the potential impact on human health because the particles can be more easily inhaled[1]. Additionally, numerous reports exist in published literature showing that the toxicity of particles (on a mass basis) generally increases as their size decreases. The terms nanoparticles (NPs) and ultrafine particles (UFP) describe particles in the same size range (less than 100 nm), but nanoparticles usually refer to manufactured/engineered materials while ultrafine particles are defined as naturally occurring or those arising in ambient air (Donaldson et al. 2013)[2].

 

Figure 1: Important characteristics affecting particle toxicology (from Hristozov et al. 2012)

Characteristics affecting particle toxicology.

It has been demonstrated in literature that changes in a particle’s physical characteristics (e.g., size, shape, aspect ratio, surface area, surface coatings, chemical composition, impurities and crystalline structure) will influence the particle’s environmental fate (Klaine et al. 2008)[3] and toxicological properties (Figure 1; ENMs- Engineered Nanomaterials)[4]. The surface chemistry parameters of a nanomaterial (e.g., composition, coatings, charge, placement of ligands and wettability) affect cellular fate, uptake, and interactions with ions and various biomolecules (Zhu et al. 2013)[5]. The relationship between a particle’s physical characteristics and toxicity has been further emphasized in a mini-review by Warheit (2013)[6] that describes measuring hazard/risks following exposures to nanoscale or pigment-grade titanium dioxide particles:

It is important to note that particle-types of different TiO2 compositions may have variable toxicity potencies, depending upon crystal structure, particle size, particle surface characteristics and surface coatings.

The magnitude and specificity of this influence on the toxicokinetics and environmental fate of a manufactured nanoparticle are currently impossible to predict in the absence of particle-specific test data - a viewpoint that is highlighted in a paper by Ma-Hock et al. (2013)[7] which investigates the comparative inhalation toxicity of multi-wall carbon nanotubes, graphene, graphite nanoplatelets and low surface carbon black. Nevertheless, currently existing particle toxicology paradigms are being applied in an effort to focus human health hazard concerns for nanoparticles (Donaldson & Poland 2012)[8].

This document summarizes a proposed approach to systematically focus human health concerns and additional testing requirements for nanoparticles based on their physical characteristics, including size, particle shape, aspect ratio, composition and surface chemistry.  

The schematic presented in Figure 2 assumes that the nanoparticle is novel and that this approach will be applied prior to conducting or requesting toxicity testing.

As scientific knowledge evolves and mechanisms of action are better understood, existing toxicity information could be used to further identify concerns and/or additional relevant nanoparticle-specific toxicity testing. For example, available information on nanoparticles with similar physical characteristics and composition could be used as analogue/read-across information.  Depending on the nanoparticle in question, various physical and chemical characteristics will need to be considered in order to make direct or indirect correlations between relevant data sets, especially for nanoparticles where significant uncertainty exists in regards to the degree of influence slight changes in physical and chemical characteristics may exert in determining toxicity.

For example, following the framework described in Figure 2, the testing strategies for “Insoluble Biopersistent” nanoparticles should also consider their surface characteristics/reactivity/composition, so that different testing would be required for those nanoparticles that, based on available information, are expected to display “low reactivity/toxicity” and those that are expected to display some inherent toxicity.

Using the approach outlined herein should lead to more focused toxicological testing and a more tailored risk assessment of new nanomaterials.

Figure 2: Schematic for focusing concerns and additional testing requirement for novel nanoparticles

Diagram showing testing requirements for novel nanoparticles

 

Common Outlook on the Environmental Fate and Ecological Effects of Nanomaterials

In general, an ecological risk assessment takes into account the fate and effects of a substance in air, water, soil, and sediment compartments. As well, the behaviour of the substance in wastewater treatment plants is also considered as this has an impact on environmental fate. This approach is depicted in Figure 3 below.

Figure 3: A general framework for ecological risk assessment[1]

A general framework for ecological risk assessment

There remain many uncertainties in accurately determining the environmental fate and ecological effects of nanomaterials.  Traditionally, chemicals (typically organics) undergo partitioning between water, sediment, soil and air depending on their physical-chemical parameters (See section 3.2). Nanomaterials are, however, more complex than traditional chemicals. As seen in Figure 3, nanomaterials can undergo a variety of transformations once in the environment including (bio)degradation, dissolution, hetero- and homo-aggregation, and speciation. It is currently not always possible to predict these processes and to then properly quantify the environmental fate and effects, however, which makes risk evaluation challenging.

During discussions within the RCC context, these uncertainties were primarily attributed to the fact that this is an emerging science, and that the application of chemically-based regulatory regimes to nanomaterials is challenged by the fact that nanomaterials have modifying factors such as size, shape, and reactivity.     

As was highlighted from the joint case-study analysis on MWCNTs, in the face of uncertainty the Canada/US Programs use similar approaches and safety factors to assess the environmental fate and ecological effects of nanomaterials. 

While the outcomes in Section 3.2 summarize the major findings arising from the case-study and the current thinking of the Canada/US Programs, some common assumptions in dealing with environmental fate and ecological effects are presented below; these will be refined as better scientific information becomes available. Common approaches to physical-chemical endpoints and characterization techniques for environmental fate and effects are not proposed since these depend on the type of material being tested, the media, and measurement needs, and are captured under the nano-specific OECD Guidance on Sample Preparation and Dosimetry.

Environmental Fate:

  • Due to the uncertainties associated with predicting partitioning behaviour of nanomaterials, the Canada/US Programs will continue to assume that they may end up in all compartments: water, soil, sediment, and air.
  • The potential for long-range transport of is expected to be low; however, vectorization (i.e., nanoparticles binding to other particulates and undergoing transport) is still considered possible. 
  • The Log octanol-water partitioning (Log Kow) coefficient is not a useful predictor for bioconcentration/ bioaccumulation.
  • While agreeing that the concentration of nanomaterials in the environment is important, the Canada/US Programs will be considering the bioavailable fractions of these substances in the environment. These take into account interactions with environmental media, such as humic/fulvic acids.
  • Environmental exposure will consider two worst-case scenarios:  100% release to the aquatic compartment from wastewater treatment (i.e., no removal from treatment) and 100% release to biosolids (i.e., 100% removal from treatment). These two extremes will allow for the development of conservative scenarios to calculate predicted environmental concentrations.

Ecological toxicity:

  • Physical-chemical characterization is critical for adequately assessing the ecotoxicity of nanomaterials. The Canada/US Programs will continue to require this information, including separation of the ionic and particulate species.[2]
  • The OECD Test Guidelines will continue to be considered adequate for nanomaterials; the OECD is currently considering appropriate modifications to address specific properties of nanomaterials.[3]
  • Due to the lack of predictability for bioconcentration (log octanol-water (Log Kow)), the OECD test guideline on bioconcentration (TG 305) may apply to nanomaterials, but only when conducted through the dietary route.
  • In addition to traditional safety/uncertainty factors when extrapolating from acute to chronic environmental effects, additional factors will be used when appropriate to take into account the interaction with organic matter.
  • Both Programs will use the OECD nano-specific Guidance on Sample Preparation and Dosimetry[4] to help identify appropriate methods and measurement techniques for the testing of nanomaterials.



[1] Batley, G.E., Kirby, J.K., McLaughlin, M.J., Acc. Chem. Res, 2013, 46 (3), 854-862

[2] Meesters, J. A.J., Veltman, K., Hendriks, A.J., van de Meent, D. Integr Environ Assess Manag, 2013, 9, e15-e26

[4] ENV/JM/MONO(2012)40. Guidance on Sample Preparation and Dosimetry for the Safety Testing of Manufactured Nanomaterials. Series on the Safety of Manufactured Nanomaterials No. 36.



[1] http://www.epa.gov/airscience/air-particulatematter.htm

[2] Donaldson K, Duffin R, Langrish JP, Miller MR, Mills NL, Poland CA, Raftis J, Shah A, Shaw CA, Newby DE. 2013. Nanoparticles and the cardiovascular system: a critical review. Nanomedicine 8(3): 403-423

[3] Klaine SJ, Alvarez PJJ, Batley GE, Fernandes TF, Handy RD, Lyon DY, Mahendra S, McLaughlin MJ, Lead JR. 2008. Nanomaterials in the environment: behavior, fate, bioavailability, and effects. Environ Toxicol Chem  27(9):1825-1851

[4] Hristozov DR, Gottardo S, Critto A, Marcomini A. 2012. Risk assessment of engineered nanomaterials: a review of available data and approaches from a regulatory perspective. Nanotoxicology 6(8):880-898

[5]  Zhu M, Nie G, Meng H, Xia T, Nel A, Zhao Y. 2013. Physicochemical properties determine nanomaterial cellular uptake, transport, and fate.  Accounts of Chemical Research 46 (3):622-631

[6] Warheit DB. 2013. How to measure hazards/risks following exposures to nanoscale or pigment-grade titanium dioxide particles.  Toxicol Lett  220(2):193-204

[7] Ma-Hock L, Strauss V, Treumann S, Küttler K, Wohlleben W, Hofmann T, Gröters S, Wiench K, van Ravenzwaay B, Landsiedel R. 2013. Comparative inhalation toxicity of multi-wall carbon nanotubes, graphene, graphite nanoplatelets and low surface carbon black. Part Fibre Toxicol 10(1):23

[8] Donaldson K, Poland CA. 2012. Inhaled nanoparticles and lung cancer - what we can learn from conventional particle toxicology. Swiss Med Wkly 142: 13547

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Future Harmonization Considerations

Areas of further collaboration and harmonization for risk assessment and risk management of nanomaterials between Canada and the US were discussed as part of the work undertaken by this task group[1].  Areas of future collaboration include:

  • Development of common approaches/SOPs for the assessment of human health hazard, exposure, environmental fate and ecotoxicity of nanomaterials to be used by both jurisdictions.
  • Development/adoption of new approaches to screening nanomaterials for toxicity and prioritising toxicological testing (e.g., use of in vitro/high throughput methodologies), data generating and risk assessment as nanotechnology and nanoscience evolves.

Harmonization Timelines

The following could be harmonized in the short- to mid-term:

  • Sharing/development of standard operational procedures and guidelines to be used by both jurisdictions, including:
  1. use of similar criteria to choose analogues/surrogates;
  2. use of similar criteria to identify structures/characteristics of concern;
  3. creation of a list of structures/characteristics of concern to be used by both jurisdictions (possible); and,
  4. use of similar exposure control measures by controlling the allowed uses of the new substance.
  • Importance/weight given to a particular type of study for the assessment of toxicity (related to the notified use(s) and relevant route of exposure).
  • Criteria for evaluating the quality and relative weight of data from published scientific articles

The following could also be harmonized, although a longer timeline is likely:

  • Requirement of the same data/studies for the same uncertainties/concerns.
  • Coordinating the development of new approaches to developing data and assessing risk.

Areas That Cannot be Harmonized

  • Harmonization of assessment triggers, assessment timelines and data requirements, which are all prescribed in the regulations of each jurisdiction, would not be possible without amendments to regulatory statutes or regulations.



[1] It was recognised, however, that detailed discussions would be constrained by the inability to readily exchange information subject to CBI claims.

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Appendices

APPENDIX A- Comparative Analysis of Regulatory Frameworks in Canada and the United States for the Risk Management of Nanomaterials (2013)

[AVAILABLE UPON REQUEST]

APPENDIX B- Stakeholder Call for Nominations

http://content.govdelivery.com/attachments/USAEPA/2012/10/10/file_attachments/166590/RCC%2BNano%2BWebinar%2BInvitation%2B10%2B2012.pdf

 

APPENDIX C- Material Selection Criteria

Definitions of Criteria used in the Nomination of Candidate Nanomaterials

Nanomaterials have been widely developed and are commercially available. They are used in a variety of products and applications such as medicine, energy, electronics, cosmetics, packaging, environmental decontamination, and many other fields. Both the U.S. and Canada are in the process of developing approaches to inform government oversight and strengthen regulatory decision making activities. Conducting a comparative analysis of current risk assessment and management approaches to nanomaterials in Canada (e.g., under Canadian Environmental Protection Act, 1999) and in the U.S. (e.g., under Toxic Substances Control Act) through case studies will aid and assist the relevant regulatory bodies with identifying common approaches/practices and helping to develop a joint framework to ensure consistency for evaluating potential risks to consumers and industries within and between both countries.

The following criteria have been developed to assist in the selection of an appropriate nanomaterial for the purposes of conducting a comparative analysis of current risk assessment approaches. These criteria have been broadly classified into the following five categories:

NOTE: Nomination/identification of a nanomaterial for the purposes of this comparative analysis does not itself constitute a finding that the nanomaterial presents a risk to human health or the environment.

Commercialization and market availability

Nanomaterials that are already in the stream of commerce will be given the highest priority, especially high production volume compounds.  Product capacity will reflect the market size in the near future and will aid with selecting nanomaterials.  With increasing quantity/volume/mass of nanomaterial(s) used, the prices will be expected to decrease and will aid with identifying specific, market-accessible HPV nanomaterials.

Substance composition/ production

Well-characterized and consistently-produced nanomaterials will ensure the least uncertainty with regard to composition and potential toxicity, based on available data, for new substances undergoing risk assessments.

Information availability- Exposure

The risk assessments of nanomaterials will be greatly aided by more complete databases on potential exposure pathways, which include those that occur during manufacture, transport and use, and ultimately end of life.  The availability of this information will aid regulators in Canada and the US in determining the quality, reliability, relevancy of these data for use in robust risk assessments and subsequent peer reviews.

Information availability- Hazard

Information on hazard will be evaluated in conjunction with available exposure information.  As with exposure information, these types of data will be assessed with regard to quality, reliability, and relevancy for use in risk assessments and subsequent peer reviews.

Relevance to the Canadian and US Regulatory Cooperation Council (RCC)

Evaluating materials that have already gone through the regulatory processes in Canada and the US will allow the RCC to identify the similarities and differences by which Canada and US assess risk(s) for nanomaterials, and ultimately aid with harmonizing and streamlining future new nanomaterial submissions in these jurisdictions.

Proposed Material: Short tangled multi-wall carbon nanotubes obtained by catalytical chemical vapour deposition

Market/Commercialization availabilityY or N
Is the material manufactured in Canada and/or the U.S.?N
Is the material capable of being used across many product types (wide application)?Y
Are high volumes of the material being/anticipated to be imported or manufactured?Y
Is there an industry demand for the product now or in the near future?Y
Substance features/production 
Is the material well defined and characterized (e.g. size, shape, surface area, surface chemistry, surface charge, agglomeration/aggregation)?Y
Is the material being manufactured on a commercial scale?Y
Is the production of the material under QA/QC control?Y
Can the material be produced in a consistent manner (e.g. batch to batch consistency)??
Information availability- ExposureY/N
Have the physical/chemical properties and environmental fate of the substance been studied?Y
Is there potential for consumer exposure?Y
Is there anticipated to be environmental release?Y
Are there models available to predict environmental fate and exposure?N
Information availability- Hazard 
Has the standard suite* of toxicity test for industrial substances been conducted?Y
Were the tests conducted according to GLP and acceptable protocols (e.g. OECD, and/or OPPTS Harmonized Test Guidelines)?Y
Have bulk version(s) of the material been tested for, or have any known, toxicity?N
Has characterization of the material 'as dosed' been conducted?Y
Have different sizes/morphology of analogous materials been tested for toxicity?Y
Relevance to Canada/U.S. regulatory co-operation 
Has the material been notified under CEPA (1999)?Y
Has the material been notified under TSCA?Y
Have risk management measures been proposed by the Government of Canada?Y
Have risk management measures been proposed by the US EPA??
Is the material listed on the TSCA inventory?N
Is the material listed on the Canadian DSL?N
Will the notifier allow sharing of CBI across the respective organizations?Y
Total17

Yes = 1; No = 0
* standard suite of toxicity tests includes- Acute toxicity, irritation, sensitization, repeated dose toxicity, in-vitro gene mutation, in-vitro chromosomal aberration, and in-vivo genotoxicity

 

APPENDIX D- Peer Review Guidance Document

Checklist for Internal Peer Review of Nanomaterial Risk Assessment Reports

Peer Reviewer: _____________________________________________________________

Organization: _______________________________________________________________

Date: ___________________

Substance Identity Comments
Was the particle size/distribution data accurate (were the proper methods used)?

Yes

No

N/A

 
Is the name an accurate reflection of the material?

Yes

No

N/A

 
Are there any impurities?

Yes

No

N/A

 
Was the manufacturing technique of the material described?

Yes

No

N/A

 
Was the shape of the particle described?

Yes

No

N/A

 
Was the agglomeration/aggregation potential of the substance described?

Yes

No

N/A

 
Physical/Chemical Properties Comments
Was the solubility/dispersability of the material addressed?

Yes

No

N/A

 
Was the agglomeration/aggregation potential of the substance described?

Yes

No

N/A

 
Was zeta potential, surface charge or surface density measured?

Yes

No

N/A

 
Were changes in phys/chem parameters considered for the test media?

Yes

No

N/A

 
Were models or measured data used to predict any phys/chem parameter?

Yes

No

N/A

 
Lifecycle Comments
Were current and anticipated production/import quantities considered?

Yes

No

N/A

 
Were all steps in the lifecycle described from material manufacture to material disposal (‘cradle to grave’)?

Yes

No

N/A

 
Were current and potential uses considered?

Yes

No

N/A

 
Environmental Fate and Bioaccumulation Comments
Hydrolysis as a function of pH?

Yes

No

N/A

 
Ready/ultimate biodegradation?

Yes

No

N/A

 
Were persistence and bioaccumulation addressed?

Yes

No

N/A

 
Were all compartments addressed?

Yes

No

N/A

 
Was the stability in each compartment addressed?

Yes

No

N/A

 
Were ‘conservative’ assumption made in absence of compartment specific information?

Yes

No

N/A

 
Environmental Release and Exposure Comments
Was an exposure scenario used? What kind of scenario (provide comment)

Yes

No

N/A

 
Was STP removal considered? If so what percentage and on what basis (literature report etc.)

Yes

No

N/A

 
Was a PEC calculated? If so what assumptions were made (provide comment)

Yes

No

N/A

 
Direct human exposure Comments
Was information on end-use products available/described?

Yes

No

N/A

 

Will the product be used in consumer goods?

Was leaching from the consumer good considered?

Yes

No

N/A

 
Was the physical form of the material in the end-use product considered?

Yes

No

N/A

 
Was 100% bioavailability assumed?  If not, are data available that support an alternate bioavailability assumption?

Yes

No

N/A

 
Indirect Human Exposure Comments
Were releases from all sources identified in the lifecycle analysis addressed?

Yes

No

N/A

 
Were releases from the end-use product considered?

Yes

No

N/A

 
 

Yes

No

N/A

 
Environmental Hazard Assessment (Ecotoxicity) Comments
Were ecotoxicity tests provided (e.g OECD tests methods 211,212, 204, 202, and 201 following GLP guidelines)?

Yes

No

N/A

 
Were analogues identified, if so on what criteria?

Yes

No

N/A

 
Were the concentrations measured in each test? How were they monitored (e.g. UV-Vis)

Yes

No

N/A

 
Were impurities present? How were they measured?

Yes

No

N/A

 
If impurities were present was their effect addressed?

Yes

No

N/A

 
Was the substance or any impurities soluble?

Yes

No

N/A

 
Was the material characterized (e.g. purity, size, shape, manufacture technique, aggregation/agglomeration potential, surface area etc.)?

Yes

No

N/A

 
Was there sufficient information regarding the testing and methodology?

Yes

No

N/A

 
Were safety factors considered? If so which ones?

Yes

No

N/A

 
Was a PNEC calculated? What was the assessment factor used?

Yes

No

N/A

 
Was an endpoint reported for each test? If not was suitable justification provided?

Yes

No

N/A

 
Human Health Hazard Assessment (mammalian toxicity testing) GENERAL Comments
Acute oral toxicity
Was the material characterized (e.g. purity, size, shape, manufacture technique, aggregation/agglomeration potential, etc…)?

Yes

No

N/A

 
Were the effects of the dosing method on the phys/chem properties of the material investigated?

Yes

No

N/A

 
Was there sufficient information in the summary regarding dose preparation, animals, methodology, etc…?

Yes

No

N/A

 
Acute dermal toxicity
Was the material characterized (e.g. purity, size, shape, manufacture technique, aggregation/agglomeration potential, etc…)?

Yes

No

N/A

 
Were the effects of the dosing method on the phys/chem properties of the material investigated?

Yes

No

N/A

 
Was there sufficient information in the summary regarding dose preparation, animals, methodology, etc…?

Yes

No

N/A

 
Acute inhalation toxicity  
Was the material characterized (e.g. purity, size, shape, manufacture technique, aggregation/agglomeration potential, etc…)?

Yes

No

N/A

 
Were the effects of the dosing method on the phys/chem properties of the material investigated?

Yes

No

N/A

 
Was there sufficient information in the summary regarding dose preparation, animals, methodology, etc…?

Yes

No

N/A

 
Skin irritation
Was the material characterized (e.g. purity, size, shape, manufacture technique, aggregation/agglomeration potential, etc…)?

Yes

No

N/A

 
Were the effects of the dosing method on the phys/chem properties of the material investigated?

Yes

No

N/A

 
Was there sufficient information in the summary regarding dose preparation, animals, methodology, etc…?

Yes

No

N/A

 
Eye irritation
Was the material characterized (e.g. purity, size, shape, manufacture technique, aggregation/agglomeration potential, etc…)?

Yes

No

N/A

 
Were the effects of the dosing method on the phys/chem properties of the material investigated?

Yes

No

N/A

 
Was there sufficient information in the summary regarding dose preparation, animals, methodology, etc…?

Yes

No

N/A

 
Skin Sensitization
Was the material characterized (e.g. purity, size, shape, manufacture technique, aggregation/agglomeration potential, etc…)?

Yes

No

N/A

 
 Were the effects of the dosing method on the phys/chem properties of the material investigated?

Yes

No

N/A

 
Was there sufficient information in the summary regarding dose preparation, animals, methodology, etc…?

Yes

No

N/A

 
Repeated dose toxicity
Was the material characterized (e.g. purity, size, shape, manufacture technique, aggregation/agglomeration potential, etc…)?

Yes

No

N/A

 
Were the effects of the dosing method on the phys/chem properties of the material investigated?

Yes

No

N/A

 
Was there sufficient information in the summary regarding dose preparation, animals, methodology, etc…?

Yes

No

N/A

 
In-vitro genotoxicity (mutation)
Was the material characterized (e.g. purity, size, shape, manufacture technique, aggregation/agglomeration potential, etc…)?

Yes

No

N/A

 
Were the effects of the dosing method on the phys/chem properties of the material investigated?

Yes

No

N/A

 
Was there sufficient information in the summary regarding dose preparation, animals, methodology, etc…?

Yes

No

N/A

 
In-vitro genotoxicity (chromosomal aberration)
Was the material characterized (e.g. purity, size, shape, manufacture technique, aggregation/agglomeration potential, etc…)?

Yes

No

N/A

 
Were the effects of the dosing method on the phys/chem properties of the material investigated?

Yes

No

N/A

 
Was there sufficient information in the summary regarding dose preparation, animals, methodology, etc…?

Yes

No

N/A

 
In-vivo genotoxicity
Was the material characterized (e.g. purity, size, shape, manufacture technique, aggregation/agglomeration potential, etc…)?

Yes

No

N/A

 
Were the effects of the dosing method on the phys/chem properties of the material investigated?

Yes

No

N/A

 
Was there sufficient information in the summary regarding dose preparation, animals, methodology, etc…?

Yes

No

N/A

 
Other
Was the material characterized (e.g. purity, size, shape, manufacture technique,    aggregation/agglomeration potential, etc…)?

Yes

No

N/A

 
Were the effects of the dosing method on the phys/chem properties of the material investigated?

Yes

No

N/A

 
Was there sufficient information in the summary regarding dose preparation, animals, methodology, etc…?

Yes

No

N/A

 
General
Was all available information considered?

Yes

No

N/A

 
Were analog substances considered? How appropriate were the analogs?

Yes

No

N/A

 
Was information on a bulk counterpart considered?

Yes

No

N/A

 
Were the effects of changing phys/chem parameters (e.g. size, shape, surface chemistry,           agglomeration/aggregation potential, etc…) discussed?

Yes

No

N/A

 
Was a key study identified?

Yes

No

N/A

 
Environmental Risk Assessment Comments
Was a PEC/PNEC ratio calculated?

Yes

No

N/A

 
Were all environmental concerns summarized?

Yes

No

N/A

 
 

Yes

No

N/A

 
Human Health Risk Assessment Comments

Was a quantitative risk assessment conducted?

If yes what safety factors were used?

Yes

No

N/A

 
Were potential uses addressed?

Yes

No

N/A

 
Does the toxicity data match the exposure data (e.g. oral exposure vs oral effect)?

Yes

No

N/A

 
Have all target populations been considered?

Yes

No

N/A

 
Were the uncertainties/gaps/ variability in the risk assessment addressed?

Yes

No

N/A

 

 

APPENDIX E- RCC Task Group Case Study

Availability of this document is being discussed with the sponsor as it contains proprietary information that will require sponsor’s consent for wider distribution.

[AVAILABLE UPON REQUEST]

 

APPENDIX F- Particle Screening Framework

[AVAILABLE UPON REQUEST]


APPENDIX G- List of Participants of TG3

Myriam HILL (Co-Chair)

Nanotechnology Section

New Substances Assessment and Control Bureau

Health Canada

Myriam.Hill@hc-sc.gc.ca

Todd STEDEFORD (Co-Chair)

Risk Assessment Division

Office of Pollution Prevention and Toxics

US Environmental Protection Agency

Stedeford.Todd@epa.gov

Abdul AFGHAN

Nanotechnology Section

New Substances Assessment and Control Bureau

Health Canada

Abdul.Afghan@hc-sc.gc.ca

Jim ALWOOD

Chemical Control Division

Office of Pollution Prevention and Toxics

US Environmental Protection Agency

Alwood.Jim@epamail.epa.gov

Fred ARNOLD

Office of Pollution Prevention and Toxics

US Environmental Protection Agency

Arnold.Fred@epamail.epa.gov

Stéphane BERNATCHEZ

Nanotechnology Section

New Substances Assessment and Control Bureau

Health Canada

Stephane.Bernatchez@hc-sc.gc.ca

Lie CHEN

Nanotechnology Section

New Substances Assessment and Control Bureau

Health Canada

Lie.Chen@hc-sc.gc.ca

Richard FEHIR

Office of Pollution Prevention and Toxics

US Environmental Protection Agency

Fehir.Richard@epamail.epa.gov

Cathy FEHRENBACHER

Exposure Assessment Branch

Office of Pollution Prevention and Toxics

US Environmental Protection Agency

Fehrenbacher.Cathy@epamail.epa.gov

Tariq FRANCIS

Nanotechnology Section

Emerging Priorities Division

Environment Canada

Tariq.Francis@ec.gc.ca

Doug GREEN

New Substances Assessment and Control Bureau

Health Canada

Doug.Green@hc-sc.gc.ca

David LAI

Risk Assessment Division

Office of Pollution Prevention and Toxics

US Environmental Protection Agency

Lai.David@epamail.epa.gov

Kristan MARKEY

Chemical Control Division

Office of Pollution Prevention and Toxics

US Environmental Protection Agency

Markey.Kristan@epamail.epa.gov

Justin ROBERTS

Office of Pollution Prevention and Toxics

US Environmental Protection Agency

Roberts.Justin@epamail.epa.gov


Phil SAYRE

Associate Director, Risk Assessment Division

Office of Pollution Prevention and Toxics

US Environmental Protection Agency

Sayre.Phil@epamail.epa.gov

Yasir SULTAN

Nanotechnology Section

Emerging Priorities Division

Environment Canada

Yasir.Sultan@ec.gc.ca

Eva M. WONG

Exposure Assessment Branch

Office of Pollution Prevention and Toxics

US Environmental Protection Agency

Wong.Eva@epamail.epa.gov

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