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Nanomaterials: Hazards and risks to health and the environment.

A supplementary guide for the UK Voluntary Reporting Scheme

This supplementary guide on hazards and risks from nanoscale materials has been prepared to complement existing guidance for the Voluntary Reporting Scheme (VRS). Chapter 2 establishes the rationale and benefits of the VRS. Chapter 3 provides a specific list of the relevant physical, chemical, toxicological and ecotoxicological data to include when reporting to the scheme and the relevant hazard, exposure and risk context for the information requested. Chapter 4 sets out a context and summary for nanomaterial hazard and risk to human health and the environment. The purpose of the Voluntary Reporting Scheme is to develop a better understanding of the properties and characteristics of different engineered nanoscale materials, so enabling potential hazard, exposure and risk to be considered. Building an evidence-base in this way will allow for a more informed debate about the nature of appropriate controls. This supplementary guide has been prepared for the Defra by SM Hankin, RJ Aitken and CL Tran of the Institute of Occupational Medicine. This publication (excluding the royal arms and departmental logos) may be reused free of charge in any format or medium provided that it is reused accurately and not used in a misleading context. The material must be acknowledged as crown copyright and the title of the publication specified.

Department for Environment, Food and Rural Affairs Nobel House 17 Smith Square London SW1P 3JR Telephone 020 7238 6000 Website: http://www.defra.gov.uk Crown copyright 2008 Copyright in the typographical arrangement and design rests with the Crown. This publication (excluding the royal arms and departmental logos) may be re-used free of charge in any format or medium provided that it is re-used accurately and not used in a misleading context. The material must be acknowledged as crown copyright and the title of the publication specified. Information about this publication and further copies are available from: Chemicals and Nanotechnologies Division Defra Area 2A Nobel House 17 Smith Square London SW1P 3JR Tel: 020 7238 1577 Fax: 020 7238 1602 E-mail: nano.technology@defra.gsi.gov.uk This document is also available on the Defra website. Published by the Department for Environment, Food and Rural Affairs

Contents

Introduction
1.1 How to use this supplementary guide

2 3 4 6

2 3

Context and Rationale for the Voluntary Reporting Scheme Data Requirements in the Voluntary Reporting Scheme 3.1 How to complete the VRS Reporting Form 3.2 Identity of the engineered nanoscale material (Part 2 of the VRS Form) 3.3 Information on the engineered nanoscale material (Part 3) 3.4 Physico-chemical properties of the engineered nanoscale material (Part 4) 3.5 Toxicological data (Part 5) 3.6 Ecotoxicological data (Part 6) 3.7 Risk management practices (Part 7)

6 10 10 11 12 13 14
15 18

4 5

Hazard, Exposure and Risk References

Introduction

1.

Assessing the risk posed by a potentially hazardous material involves the integration of information on potential sources, hazard characteristics, pathways and likelihood of exposure, and the human and environmental receptors. The systematic identification and characterisation of nanoscale materials is an important first step in an assessment of their risk. Detailed datasets of information on the physico-chemical properties and toxicity of different engineered nanoscale materials are needed to enable the potential hazards, exposures and risks to be considered along with the need and nature of appropriate controls. Information on the sources and manufacturing processes is important as many types of nanoscale materials (NM) can be produced using different processes that yield several derivatives of the same material. For example, single-walled carbon nanotubes can be produced by different processes that can generate products with different physico-chemical characteristics (e.g., size, shape, composition, contaminants) and potentially different ecological and toxicological properties. In addition, information on a substances manufacture and formulation is important in understanding purity, product variability, performance, and use. The potential hazard of a material is characterised by consideration of the physical properties that may impart a safety hazard (e.g. flammability, explosive potential), and the toxicological and ecotoxicological properties that may impart a human health and/or environmental hazard. A materials physico-chemical properties also influence the materials behaviour in the physical and biological environments, which in turn influences both the exposure and the consequences of exposure. Characterising the exposure and its likelihood from intended (and anticipated unintended) use of nanoscale materials, ideally with measurements of concentration and duration of contact, is the critical link to establishing whether a hazard presents a risk. This information, when combined with the conditions of manufacture/use and the measures required to control exposure during its life cycle, becomes an exposure scenario. Consideration of the likelihood, magnitude and consequences of the risk will inform the risk management practices and control measures that should be adopted to minimise the risk to the relevant human and environmental receptors. The purpose of the Voluntary Reporting Scheme (VRS) is to develop a better understanding of the properties and characteristics of different engineered nanoscale materials, so enabling potential hazard, exposure and risk to be considered. Building an evidence base in this way will allow for a more informed debate about the nature of appropriate controls.

2.

3.

4.

5.

6.

1.1 How to use this supplementary guide

7. This supplementary guide on hazards and risks from nanoscale materials has been prepared to complement existing guidance for the VRS and help reporters understand the important role of information on the properties and characteristics of engineered nanoscale materials when considering the potential hazards, exposures and risks. Chapter 2 establishes the rationale and benefits of the VRS. Chapter 3 provides a specific list of the relevant physical, chemical, toxicological and ecotoxicological data to include when reporting to the scheme and the relevant hazard, exposure and risk context for the information requested. Chapter 4 sets out a context and summary for nanomaterial hazard and risk to human health and the environment. When contributing to the VRS, it is recommended that a nomenclature convention is adopted to eliminate ambiguity when communicating differences between NM and bulk materials and when reporting data. The British Standards Institutes PAS71 Vocabulary for Nanoparticles, and forthcoming Good Practice Guides for Specifying Nanomaterials and the Safe Handling and Disposal of Engineered Nanoparticles are recommended.

8.

9.

Context and rationale for the Voluntary Reporting Scheme

10. Nanotechnology is an emerging field and as more products containing nanoscale materials (NM) are developed, there is greater potential for occupational, consumer and environmental exposures. Whilst there is an important distinction between applications that use fixed and free NM, concerns have been expressed that the novel properties of engineered NM might have adverse health and environmental impacts in circumstances where release and exposure can occur. 11. The natural environment is composed of many complex ecosystems comprising atmospheric, terrestrial, fresh water and marine compartments. The number of species potentially at risk from engineered NM is extremely large. Exposure to hazards associated with NM could potentially impact on the structure and function of the ecosystem as a whole. Moreover, the nanoscale form of a material may be subject to novel changes that affect both exposure (including environmental fate and persistence, uptake, metabolism, clearance and bioaccumulation) and the nature and magnitude of any adverse effect(s). 12. Assessing the risks and benefits of NM is complex and multi-factorial, and is potentially influenced by a variety of physicochemical properties such as size and shape, and surface properties such as charge, area, and reactivity. To develop our understanding and overcome the challenges of assessing the risks posed by NM, it is prudent to have knowledge of each product and process that involves NM, in the context of: Safety during the manufacture, use, importation, research, or management of wastes of engineered NM; Safety of consumers using products that contain NM; Safety of local populations in the event of chronic or acute release of NM from manufacturing and/or processing facilities; The impact on the various environmental compartments (e.g. air, soil, water) and their ecosystems, resulting from production, formulation and use, and on the potential for human re-exposure through the environment; The environmental and human health risks involved in the disposal or recycling of NM-containing products. 13. The potential risks following exposure to a substance are generally associated with the magnitude and duration of the exposure, the persistence of the material, the inherent toxicity of the material, and the susceptibility of the receptor. Comprehensive assessment of the risks associated with exposure to NM requires an understanding of the physical, chemical, and toxicological properties associated with these materials and the levels of exposure which are likely to occur. 14. Results of existing studies in animals or humans on exposure and response to ultrafine or other respirable particles provide a basis for preliminary estimates of the possible adverse health effects from exposures to similar engineered materials on a nanoscale. Experimental studies in rodents and cell cultures have shown that the toxicity of ultrafine or nanoparticles is greater than that of the same mass of larger particles of similar chemical composition.

15. Toxicity information about a material (at the bulk scale) can help provide a baseline for anticipating the possible adverse health effects that may occur from exposure to that same material on a nanoscale. However, the large surface area, crystalline structure, reactivity and exotic properties of some NM, coupled with what appears to be an imminent shift away from laboratory based development to industrial manufacture, strongly indicates a need for a clearer understanding of the risks associated, perhaps uniquely with NM, and the need to relate toxicity information to relevant exposure scenarios. 16. The EUs Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) emphasise the importance of specifying clearly the product specification and the amount that is expected to be produced along with the anticipated uses and proposed routes for disposal/recycling of the product(s) at the end of its useful life. It is probable that different manufacturers will produce NM of rather similar chemical composition that are not identical in all their properties. It is therefore vital that the specification of the NM form is thorough and comprehensive. SCENIHRs recommended information description, largely adopted by the UK Voluntary Reporting Scheme and other stewardship frameworks for responsible development (e.g. USEPA and the Environmental Defense DuPont Nano Partnership), includes: The chemical composition of the NM including formulation components and impurities, surface chemistry, acidity/basicity, redox potential, reactivity (redox, photoreactivity etc.) and the nature of any surface coating or adsorbed species; The particle size range (and distribution) to which humans and/or the environment will be exposed, along with information on other physical characteristics, e.g. purity, phase, shape, density, surface area and charge, solubility, porosity, roughness morphology, crystallinity and magnetic properties. Note that the nature of the NM to which organisms or individuals are exposed may differ, for example between workers, consumers and the environment, and might also differ from the particle size distribution in the product itself; Intended use along with the identification of each of the likely exposure scenarios (including potential for accidental exposure); Both normal and high level use situations need to be identified in order to assess emission routes, levels and duration of human exposure and the release and distribution in the various environmental compartments. This may need to include possible misuses and accidents that could result in substantial human and/or environmental exposure; Their chemical and physical stability under relevant environmental conditions including potential for coalescence and/or degradation (along with the identification of the degradation products); The extent to which the released NM are soluble in aqueous media, and/or biodegradable. This is likely to be a major factor in limiting their accumulation and persistence in man and the environment; Potential methods of disposal of the product at the end of its use and the exposure consequences for the environment should be considered.

Data Requirements in the Voluntary Reporting Scheme

3.1 How to complete the VRS Reporting Form

17. The information requested in the VRS pertains to NM actually produced or used by the reporter. The scheme provides a means to develop a profile of the NMs composition, properties, inherent hazards, uses and probable exposures throughout the materials life cycle. The properties profile identifies and characterises a NMs physical and chemical properties. The hazard profile identifies and characterises the NMs potential safety, health, and environmental hazards, and the exposure profile identifies and characterises the opportunities for human or environmental exposure to the NM, principally through intended use. 18. The information requested in the scheme includes: General information about the reporter Identifying information about the NM and its composition Production, importation, and use information Exposure information Physico-chemical properties Toxicity data Ecotoxicity data Risk management practices 19. The requested information is regarded as the minimum required to compile an evidence-base to inform the consideration of appropriate controls. Information gained from the scheme will provide a basis for developing reasonable and responsible approaches for managing the risks from NM. 20. The scheme is not meant to provide a comprehensive assessment or full toxicological profile of a given NM. However, it is designed to provide a reasonable balance between an adequate characterisation of properties, hazards, and exposure to inform a practical strategy for the consideration and development of risk management and regulatory measures for NM. 21. The scheme is not meant to be overly prescriptive, as it may not be necessary to determine certain data for all material types. For example, where it is possible to exclude a particular pathway of exposure, it is sufficient to limit the characterisation and assessment to the appropriate pathways. Equally, there is provision to report more information than is requested specifically, where such information is available. The requested information represents a standard set of information considered important to making informed risk decisions. 22. This information should profile, as fully as possible, the materials properties and its hazard and exposure potential at various life cycle stages, including manufacture, use, and disposal. 23. A description of the measurement technique(s) used to gather specific data is very important to assist with comparability of data often gathered using a variety of methods. The information provided should include a description of the relevant experimental conditions used.

24. The scheme is designed to gather detailed information from manufacturers, importers, users and researchers and identify gaps in what is known about the specific nanoscale material being reported. This could include, for example, data from investigations carried out by the reporter or published in a Material Safety Datasheet provided with the material. Generic properties or data sourced from the published literature are not relevant to this scheme and should not be reported. Data solely on materials in the bulk form is also not relevant. 25. As the scheme is inclusive of manufacturers, users, importers, researchers and those managing wastes from engineered nanomaterials, it is anticipated that not all of the requested information may be available or relevant for all reporters. Where a request for information is not relevant to the nature of the reporters activities, please disregard the question but make reference to your status declared in 1.7-1.12 of Part 1 of the reporting form. 26. Table 1 and the following section describes the technical information components requested in parts 2-7 of the Voluntary Reporting Schemes form and provides context for the specific information requested.

Table 1: Data requirements for the VRS

Information/Data requested 2 Identity of the engineered nanoscale material

CAS number and name (if available) and any other names, including trade names or synonyms Composition and structural formula Degree of purity (%) Nature of impurities, including isomers and by-products Percentage of main impurities Presence of a stabilising agent, inhibitor or other additive Spectral data (e.g. IR, UV, NMR, mass spectrum) Chromatographic data (e.g. HPLC, GC) Analytical methods of detection and determination Additional information (e.g. anticipated changes in properties that would impact on the identity of the material; analytical quality assurance procedures)

Where to report in the VRS Form

Paragraph in this guide for further information

2.1 2.2.1 2.2.2 2.2.3 2.2.4 2.2.5 2.2.6 2.2.7 2.2.8 2.2.9

27 28

29

30

Information/Data requested 3 Information on the engineered nanoscale material

Physical dimensions and shape, including the measurement technique employed Manufacturing process Source of the material (to be completed by those not manufacturing the reported nanoscale material) Intended use Potential human and environmental exposure pathways and likelihood of exposure Benefits of the uses of the material Agglomeration and aggregation properties

Where to report in the VRS Form

Paragraph in this guide for further information

3.1 3.2

31

32 3.3 3.4 3.5 3.6 3.7 33 34 35 36

4 Physico-chemical properties of the engineered nanoscale material

Physical form at 20C and 101.3kPa Melting point Boiling point Relative density Vapour pressure Surface tension Water solubility Partition coefficient (octanol-water) Flash point Flammability Explosive properties Self-ignition temperature Oxidising properties Particle size distribution 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 4.10 4.11 4.12 4.13 4.14 37, 41 37, 40 37, 39 37, 38

Information/Data requested 5 Toxicological Data

Acute toxicity (following oral administration) Acute toxicity (following inhalation) Acute toxicity (following skin application) Skin irritation Eye irritation Skin sensitisation Repeated dose toxicity (28 days) Mutagenicity Reproductive toxicity Toxicokinetic behaviour Non-animal toxicity test results

Where to report in the VRS Form

Paragraph in this guide for further information

5.1.1 5.1.2 5.1.3 5.1.4 5.1.5 5.1.6 5.2.1 5.3.1 47 5.3.2 5.3.3 5.3.4 48 49 46 45 42, 43, 44

6 Ecotoxicological Data
Acute toxicity for fish Acute toxicity for daphnia Growth inhibition of algae Bacteriological inhibition Biotic degradation Abiotic degradation Absorption/desorption Bioaccumulation Distribution among environmental media 6.1.1 6.1.2 50, 51 6.1.3 6.1.4 6.2.1 6.2.2 6.3 6.4 6.5 52

7 Risk management practices

Recycling Neutralisation of unfavourable effects Destruction Other means of managing risk 7.1 7.2 53, 54, 55 7.3 7.4

3.2 Identity of the engineered nanoscale material (Part 2 of the VRS Form)
27. The basic identity information (2.1) should include the name of the material and any identifiers that are used to distinguish it from similar materials or those in bulk form. Chemical Abstracts Service (CAS) registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences, mixtures and alloys. The Chemical Abstracts Service, a division of the American Chemical Society, assigns these identifiers to every chemical that has been described in the literature. The CAS numbers are used routinely in many databases including the European chemical Substances Information System (ESIS). 28. The composition and structure of the substance (2.2.1) should describe how it is packaged and/or used (for example as a loose powder, contained in a liquid dispersion, agglomerated into larger-size particles) as the state of the material will have implications for potential routes of human or environmental exposure. Information on the phase, molecular structure and physical form can lead to better understanding of potential structure-property relationships and how easily they might disperse when entering various media or the environment. 29. Information on the chemical composition of a NM should also include any accompanying substances arising from its preparation, incorporation into products, or use etc. Surface treatments and lattice doping are often used in NM and should be reported, as they may affect toxicity and exposure. Information on the purity of the material should characterise the main composition of the NM (2.2.2). Impurities in the material, and the extent of contamination, should be identified (2.2.3-2.2.4), and any additives stated (2.2.5). Information on the spectroscopic and microscopy technique(s) used to determine the composition (2.2.6-2.2.7) should be stated along with the methods suitable to detect the substance and any transformation products after discharge into the environment (2.2.8). 30. Any additional information on the identity of the engineered NM should be provided (2.2.9), including any anticipated changes in relevant physical and chemical properties during the life cycle of the material, and information on the quality assurance procedures for each method of determining data, including calibration, use of reference materials, and statistical measures employed (e.g. number of samples analysed, confidence intervals, etc).

3.3 Information on the engineered nanoscale material (Part 3)

31. Information on the key physical characteristics of the NM should include the size, shape, structure, solubility, and surface area, along with details of the measurement technique used (3.1). The mean particle size and surface area (including the distributions around the means) are important because the surface-area-to-mass ratio is important to understanding many aspects of the toxicity and reactivity of NM. Shape influences how materials interact with other particles and with biological systems, and how easily they disperse when entering various media or the environment. 32. A brief description of the manufacturing process of the substance (3.2) should be provided to help characterise the potential sources of release to the workplace and environment. The description of the technique (e.g. chemical vapour deposition, arc discharge, molecular beam epitaxy, etc) should also include information on the production volume, any waste products, and control measures used to limit releases and personal exposure. Where the notifier is not manufacturing the reported NM, information should be provided on the source (3.3) of the material (i.e. name and contact details of the supplier or importer).

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33. A basic description covering the materials intended uses (3.4), at all stages in its life cycle, should be provided that indicates how the material is used within your organisation (i.e. the processes to which the material is subjected) and intended or reasonably forseeable uses by downstream users (e.g. industrial processes, product manufacturers, consumers, etc). Detailed information should be provided on who is using the material, where it is being used, how it is being used (i.e. purpose, frequency and duration of use), and the exposure controls required. This information will help to understand more about potential sources of post-manufacture exposure and releases to the environment. 34. Details of the pathways of exposure (e.g. inhalation, dermal contact, ingestion), the receptor (e.g. human, environmental compartment, etc.) and any available exposure measurement data should be provided with an estimation of the likelihood of exposure (e.g. high or low) in the form of exposure scenarios across the life cycle of the material, in (3.5). Such exposure scenarios should include the appropriate risk management measures (e.g. PPE) and operational conditions that, when properly implemented, ensure that the risks from the uses of the material are adequately controlled. 35. A balanced approach to the risk assessment of a material includes appropriate consideration of the benefits from the materials use. Please provide a statement regarding the benefits of the uses of the material (3.6) with reference to any available supporting evidence. 36. The particle agglomeration properties of the material give a further indication of the dustiness of a nanomaterial when handled in its powder form and provide information on the likely size distribution of inhalable particles as well as on their relative ease of dispersion. An agglomerate is defined, in BSIs PAS71, as a group of strongly associated particles that cannot easily be re-dispersed by mechanical means; an aggregate is a weakly associated group of particles that can be re-dispersed by mechanical means. The likelihood and conditions under which reversible and/or irreversible agglomeration or aggregation take place should be described (3.7).

3.4 Physico-chemical properties of the engineered nanoscale material (Part 4)

37. The fundamental physico-chemical properties of the engineered nanoscale material requested in Part 4 are required to help those working with the material, and those assessing the risks, to better understand its behaviour, potential safety issues, and possible effects following release. 38. The physical form of the material at room temperature and pressure influences how materials interact with other particles and with biological systems, and how easily they may disperse when entering various media or the environment. The physical form of material should be described in terms of whether it is crystalline or amorphous, the constituent particles shape spherical, fibre-like, or plate-like, and the homogeneity of the material with regard to these factors (4.1). 39. Data on additional physical properties including melting point (4.2), boiling point (4.3), relative density (4.4), vapour pressure (4.5), surface tension (4.6), water solubility (4.7), and the octanol-water partition coefficient (4.8) should be provided to allow determination of how easily the material can be dispersed into air and water and how it subsequently behaves in the atmosphere and aquatic environments.

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40. Information should be provided on the key safety properties important in assessing the hazards of NM, including the flash point (4.9) and flammability the ability of a material to readily ignite and burn (4.10); explosivity the ability of a material to rapidly release gas and heat when subjected to high temperature, pressure or shock (4.11); self-ignition temperature (4.12); and oxidising properties leading to a hazardous reaction when in contact with an incompatible material (4.13). 41. Information should be provided on the particle size distribution of the NM as it will be marketed (4.14). The mean particle size and distribution around the mean is important to characterise as it is vital in interpreting many aspects of their toxicity and reactivity.

3.5 Toxicological data (Part 5)

42. Data from toxicological testing of the engineered NM is useful and should be fully reported, if available, to characterise any toxic effects a substance can produce and inform the assessment of risks to health and the environment. Acute toxicity studies evaluate the health effects from short-duration exposures. It is conventional to conduct studies by two relevant routes of exposure, one of which should be by the materials intended route of use. Recommended protocols, for example those published by the OECD, should be followed. The specific data requested in Part 5 should be accompanied by detailed information on the techniques employed, experimental conditions, doses, methods of administration and other information contingent with the principles of Good Laboratory Practice (GLP). GLP helps assure regulatory authorities that the data submitted are a true reflection of the results obtained during the study and can therefore be relied upon when making risk/safety assessments. Where possible, toxicity and ecotoxicity data should be related to the relevant exposure scenarios described in (3.5). 43. If ingestion is a known or potential route of exposure, data from oral administration should be provided (5.1.1). If inhalation is a known or potential significant route, or if no dominant exposure route is known or expected, data from inhalation administration should be provided (5.1.2). If both inhalation and ingestion are known or expected to be significant routes of exposure, data from oral toxicity and either an inhalation study or instillation study should be reported. If there is a reasonable likelihood of substantial exposure to the material by skin contact, data from cutaneous administration should be provided (5.1.3). 44. Data reported should include available information on the concentration-response relationship; LD50 or data from an Up-and-Down Procedure (UDP); the incidence and severity of effects (behavioural and clinical) and their reversibility; body weight changes; and any other toxic effects. 45. Any existing data from skin irritation (5.1.4), eye irritation (5.1.5), and skin sensitisation (5.1.6) should be provided, however alternatives to in vivo skin and eye irritation studies are now recommended (e.g. ICCVAM & ECVAM, OECD). If these alternative tests fail to show skin corrosivity, additional data on skin sensitisation should be obtained. 46. Subacute (repeated dose) toxicity provides information on the toxicity of a substance after repeated administration and assists in establishing doses for any required longer-term testing. Data reported (5.2.1) should include available information from haematology, clinical chemistry and histopathology correlated with any toxic effects observed, post-testing pathology results, and, where determined, the no observed adverse effect level.

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47. Information on other effects should include data on mutagenicity (5.3.1) to determine whether the substance has potential to cause genetic damage and induce a mutation in cells; and reproductive related toxicity (5.3.2), examining the effect of the substance on male and female reproductive processes and the development of the embryo and foetus. Recommended protocols have been published for such testing. 48. An assessment of the materials toxicokinetic behaviour (5.3.3) (i.e. absorption, distribution, biotransformation, and excretion) derived from the aforementioned data (e.g. haematology and blood chemistry measurements) would be useful. This might include the volume of distribution, percent of dose eliminated, and half-life of the substance administered. 49. Information on any toxicity assessments derived from non-animal test methods or models that include in vitro tests methods, quantitative structure-activity relationships (QSAR), and perhaps epidemiological data (5.3.4) would be useful.

3.6 Ecotoxicological data (Part 6)

50. Ecotoxicology can be defined as the study of the fate and effects of toxic substances on an ecosystem and is based on scientific research employing both field and laboratory methods. Inclusion of aquatic toxicity data in the scheme is intended to provide information to determine whether NM are toxic to aquatic organisms. Measurements of ecotoxicological impact (e.g. biochemical, physiological and behavioural) are obtained using species-specific response to toxicants through to the impacts on populations within the ecosystem under study. These data, combined with measurements of distribution, transformation, and uptake, are critical in developing an ecological risk assessment. The requested information should include data from acute toxicity tests in three different classes of aquatic organisms (fish, daphnia and algae) which may well exhibit independent mechanisms and extents of toxicity. These three toxicity tests should be performed as standard procedure, unless release to the aquatic environment at any point in the NMs life cycle can be definitively ruled out. Recommended protocols, including those published by organisations such as the OECD, should be followed. 51. Information on the acute toxicity of the NM to fish (6.1.1) and daphnia (6.1.2) and the growth inhibition of algae (6.1.3) and bacteriological inhibition (6.1.4) from laboratory studies is important for the determination of any pathological effects of the substance. These data provide concentration-response data when assessing the potential consequences of likely exposures in following release to the environment. Acute toxicity tests are limited in that they typically measure only lethality as an adverse effect; they are not capable of detecting sublethal effects, which may arise through entirely different mechanisms of action. Data reported should include available information on the concentration-response relationship; LC50; the incidence and severity of effects (behavioural and physiological) and their reversibility; body weight changes; and any other toxic effects. 52. To inform the understanding of how NM behave in the environment, available information should be provided on biotic and abiotic degradation (6.2.1 and 6.2.2), adsorption/ desorption coefficients (6.3) in soil (if land-applied or deposited to soil) or sludge (if discharged from wastewater treatment), the bioaccumulation factor (6.4), and the partition coefficients for distribution (6.5) between relevant media (e.g. vegetation/atmosphere, soil/atmosphere, atmosphere/water, sediment/water and biota/water).

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3.7 Risk management practices (Part 7)

53. Information on the management of post-production risks to the environment and consumer are expected to be derived from consideration of the physico-chemical and toxicological data provided in the preceding parts. 54. The risk management practices covering the materials life cycle are of particular value. 55. Available information should be provided on whether it is possible to recycle the NM, including free and bound in products (7.1); whether and how unfavourable effects may be neutralised (7.2); the conditions under which the material may be destroyed (7.3); and any other information on management practices that reduce or remove the risks associated with the material. Information should be provided on the recycling and disposal procedures to be employed.

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Hazard, Exposure and Risk

56. Risk assessment involves the consideration of potential sources, pathways of exposure, and receptors along with information that characterises the hazard and likelihood of exposure to a material. Determining the physico-chemical properties of a material is an essential step in characterising the hazards posed by that material, which can then be used in conjunction with likely exposure pathways (illustrated in Figure 1) to estimate risk and implement appropriate control measures.

Figure 1. Some possible exposure routes for nanoscale materials based on current and potential future applications (reproduced with permission from the Royal Society). 57. For a hazardous material to cause harm to human health, it must be involved in processes by which the material contacts or enters the body and interacts with cells locally or systemically, leading to tissue-damaging reactions. 58. Studies have demonstrated that NM toxicity is extremely complex and multifactorial, potentially being influenced by a variety of physico-chemical properties including size, shape, surface area, solubility, and composition, including surface charge and adsorbed species. Surface modification, aggregation and dissolution or degradation are also significant factors.

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59. These intrinsic properties of a NM may be used to assess its potential to damage health or the environment (or human health through the environment). They are used in the assessment of a materials toxicity (as discussed above), its potential to translocate, persist, bioaccumulate, or dissolve, and ultimately the magnitude, duration and likelihood of exposure. 60. Translocation across cell and tissue boundaries potentially subjects other parts of the body (e.g. brain, circulatory system) to the toxicological effects that some NM may exert. 61. Persistence will depend on whether the material decomposes, for example by oxidation, and on whether the particles are modified in the environment, for example by agglomerating or adhering to other materials so that they lose the particular properties that could make them hazardous as NM. Bioaccumulation will depend on the surface properties of NM, which will determine whether they are likely to be taken up by the fatty tissues, bone or proteins in the body. 62. Nanoscale materials that are readily soluble in the physiological environment lose their particle specific effects, but remain of concern if they dissolve to yield harmful molecules. For particles that are essentially insoluble, there is the possibility of biopersistence, resulting in longer term exposure and NM-specific effects. For insoluble particles or an insoluble core of a complex particle, only the surface interacts with the biological system, therefore, the total surface area in contact with the biological system represents the dose. For soluble particles or those with soluble species on the particles surface, there is potential for an extra toxic effect due to the soluble material e.g. metals, organics etc. 63. There is good data to support the contention that NM toxicity is dependent on particle size or more specifically on the surface area. For example, for low toxicity, low solubility particles such as the titanium dioxide, carbon black and polystyrene latex, there is clear enhancement of the NMs ability to cause inflammation compared to fine particles of the same material (Brown et al. 2001, Donaldson et al. 2000, Donaldson et al. 1999). There was no relationship with the mass instilled but when the data was re-expressed as the surface area instilled there was a clear linear relationship between extent of inflammation and surface area of particulate in the lungs (Duffin et al. 2002). Small size alone is not the critical factor in the toxicity of nanoparticles; the overall number and thus the total surface area are also important. NM are known to have various shapes and structures such as spheres, needles, tubes, plates, etc. For fibre-like materials, long implies a length greater than 15000 nm (15 m) and short implies a length less than 5000 nm (5 m) since these are the critical dimensions for harmfulness in the fibre paradigm (Mossman et al. 2007). The relationship between shape and toxicity of NM is not yet fully known and is being investigated and is an important feature to characterise. 64. Molecular weight and effective cross-sectional diameter are important factors in uptake of materials across the gill membranes of aquatic organisms or the GI tract of both aquatic and terrestrial organisms. A particles charge is also an important characteristic that can influence uptake and distribution. 65. Surfaces, organics and transition metals all generate oxidative stress that drives the pro-inflammatory response to NM in the lungs. The combination of small particle size, large surface area, and ability to generate reactive oxygen species have been suggested as key factors in induction of lung injury following exposure to some NM (Nel et al. 2006).

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66. Very little is known about the safety risks (e.g. fire and explosion) that engineered NM might pose, beyond some data indicating that they possess certain properties associated with safety hazards in traditional materials. From currently available information, the potential safety concerns most likely would involve catalytic effects or fire and explosion hazards if NM are found to behave similarly to traditional materials in key respects. Any dry, fine and combustible powder poses an explosion or fire risk, either through spontaneous combustion or ignition. The increased surface area of NM might mean that they would be more likely to become self-charged, and be more easily ignited. In addition, because of their small size, NM may persist for longer in the air, may be harder to detect and may be invisible to the naked eye, making crude detection difficult. 67. During the formulation of the NM into products (e.g. coatings and composite materials), workplace releases and exposures may be most likely to occur during the transfer/unloading of NM from shipping containers and during cleaning of process equipment and vessels. During the use of some of these products in workplace settings, releases of and exposures to NM are highly dependent upon the application. 68. In addition to inhalation by air-breathing organisms, exposure to NM could occur from surface contact or from ingestion. Other organisms such as bacteria and protozoa may take in NM through their cell membranes, and thus allow the particles to enter a biological food chain. 69. The general population may be exposed as a result of environmental releases from the production and use of NM and from direct use of products containing NM. During the production of NM, there are several potential sources for environmental releases including the evacuation of production vessels, filter residues, losses during spray drying, emissions from filter or scrub break-through, and wastes from equipment cleaning and product handling. The most likely pathway for general population exposure from releases from industrial processes is direct inhalation of materials released into the air during manufacturing (Royal Society, 2004). 70. The estimation of possible risks depends on a consideration of the life cycle of the material being produced, which involves understanding the processes and materials used in manufacture, the likely interactions between the product and individuals or the environment during its manufacture and useful life, and the methods used in its eventual disposal. Risk is controlled by limiting release of the material to air or water, and/or by interrupting the pathways by which the substance reaches the receptor where it could cause harm (for example an organ in the body), hence an understanding of exposure pathways and likely quantities is essential to risk management. 71. The assessment of risk should be made using the best available information, so that appropriate control strategies can be developed and implemented. However, the scientific communitys understanding of how these factors are influenced by the novel properties of engineered NM is still developing. Information collated by the UK Voluntary Reporting Scheme will make a valuable contribution to bridging the gaps in knowledge about material characteristics and the factors that influence risk such as pathways of exposure, likelihood of translocation, interaction and fate of materials once they enter the body or the environment.

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References

British Standards Institutes PAS71 Vocabulary for Nanoparticles: http://www.bsi-global.com/en/Standards-and-Publications/IndustrySectors/Nanotechnologies/PAS-71/ Brown D.M., Wilson M.R., MacNee W., Stone V., and Donaldson K. (2001). Size-dependent proinflammatory effects of ultrafine polystyrene particles: a role for surface area and oxidative stress in the enhanced activity of ultrafines. Toxicol.Appl.Pharmacol. 175, 191-199. Donaldson, K., Stone, V., Gilmour, P. S., Brown, D. M., and MacNee, W. (2000). Ultrafine particles: mechanisms of lung injury. Phil. Trans. R. Soc. Lond. A 358, 2741-2749. Donaldson K., Stone V., and MacNee W. (1999). The toxicology of ultrafine particles. In Particulate matter: properties and effects upon health. Eds Maynard R.L. and Howards C.V., Bios, Oxford 115-127. Duffin R., Clouter A., Brown D.M., Tran, C.L., MacNee W., Stone V., and Donaldson K. (2002). The importance of surface area and specific reactivity in the acute pulmonary inflammatory response to particles. Ann Occup.Hyg 46 Suppl 1, 242-245. European Centre for the Validation of Alternative Methods (ECVAM) http://ecvam.jrc.it/index.htm Environmental Defense Du Pont Nano Partnership http://www.environmentaldefense.org/documents/6496_Nano%20Risk%20Framework.pdf Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) http://iccvam.niehs.nih.gov/ Mossman BT, Borm PJ, Castranova V, Costa DL, Donaldson K, Kleeberger SR. 2007. Mechanisms of action of inhaled fibers, particles and nanoparticles in lung and cardiovascular diseases. Particle and Fibre Toxicology doi:10.1186/1743-8977-4-4. http://www.particleandfibretoxicology.com/content/4/1/4 Nel A., Xia T., Mdler L., Li N. (2006). Toxic potential of materials and the nanolevel. Science 311, 622-7. OECD Guidelines for the Testing of Chemicals http://www.oecd.org/document/22/0,2340,en_2649_34377_1916054_1_1_1_1,00.html The Royal Society and The Royal Academy of Engineering. (2004) Nanoscience and nanotechnologies: Opportunities and uncertainties. London, UK. http://www.nanotec.org.uk/finalReport.htm SCENIHR Opinions on nanotechnology http://ec.europa.eu/health/ph_risk/nanotechnology/nanotechnology_en.htm USEPA Nanotechnology Materials Stewardship Program http://www.epa.gov/oppt/nano/

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PB12952. February 2008 Published by the Department for Environment, Food and Rural Affairs. Crown Copyright 2008. Printed on material that contains a minimum of 100% recycled fibre for uncoated paper and 75% recycled for coated fibre. www.defra.gov.uk