nanoreg safe-by-design (sbd) concept · safe-by-design (sbd) concept combined with a regulatory...

(c) RIVM and TEMAS AG 2015 NANoREG /32

NANoREG

Safe-by-Design (SbD)

Concept To be used for the first ProSafe Call und EU US CoR

Author(s) and company: Sips Adrienne, RIVM1; Cornell Noorlander2, RIVM, Hans Christian Lehmann3, TEMAS, Karl Höhener4, TEMAS AG

Work package/task: WP6, T6.3, WP7 T7.2 and T7.3

Document status: draft / final

Confidentiality: confidential / restricted / public (Working document)

Key words: Safety, Safe by Design, nano materials, human health, environment, precautionary principles, regulation

DOCUMENT HISTORY

Version Date Reason of change 1 2014/11/16 First working document

2 2015/05/17 New working document based on 20150504 by hoe

3 2015/05/26 Changes by AS conform discussion 20150521 by hoe and AS/Extract for EU-US document

4 2015/05/30 Consolidated version after Lisbon Meeting 20.5.2015

1 [email protected], 2 [email protected] 3 [email protected] 4 [email protected]

mailto:[email protected]





Summary Within NANoREG I a Safe-by-Design (SbD) concept is worked out. Within NANoREG II, the SbD concept will be combined with a Regulatory Preparedness (RP) concept and both concepts will be embedded into a Safe Innovation (SI) approach.

The Safe Innovation Approach aims at:

1. Reduced uncertainty and managed risks of innovative materials, products and processes at the time of market introduction. This should be accomplished with the help of the SbD concept.

2. Earlier, increased and improved interaction between innovators and regulatory authorities in trusted environments (so-called SAFE HOUSES): from sharing expertise and knowledge with innovators to identify uncertainties and potential risks towards guidance registration or market approval. This should be accomplished with the help of the RP concept.

Both concepts and thus the approach will especially consider the characteristics and peculiarities of manufactured nanomaterials (MNMs) or products containing MNMs and related processes. MNMs are an example of new materials fraught with a lot of uncertainties and perceived risks for both the innovators and the regulatory authorities.

The conceptual basis for both concepts and thus the approach are the already industrially used stage gate innovation and standard risk management processes.

Figure 1: The Safe Innovation Approach

However, the design of an innovation and risk management process alone cannot completely eliminate uncertainties or risks; it can only help to reduce them. Indeed, most companies would only amend but not completely change the design of their currently used innovation and risk management processes, if they were to implement the SbD concept at all.

In addition to process design, uncertainties or risks can be reduced by


- altering the way the processes are run for an individual innovation project (i.e. flexible adaption and fit size of processes to extent of risks),

- the right tools for the problem at hand, - enough reliable data, - being aware of case specific uncertainties and risks (e.g. the similarities and differences

between macro- and nano-scalar materials).

For these reasons, the SI approach as well as the SbD and RP concepts - will be supplemented by a toolbox containing standard, adapted and specific tools, - will be supported by nano-related data being collected from various sources in (EU

projects, academia etc.), - will be run in case studies. demonstrators and dedicated projects providing process and

implementation know how

These concepts are designed to be used by industry with their current innovation and risk management processes.


Table of Contents

I. INTRODUCTION ................................................................................................................... 6

1. PREFACE ......................................................................................................................... 6

2. OBJECTIVE, SCOPE AND ALIGNMENT WITH THE RESEARCH PROGRAMS ................................ 7

3. R&D IN NON-PROFIT ORGANISATIONS................................................................................ 7

4. DEFINITIONS, UNDERSTANDINGS AND CAVEATS .................................................................. 8 Risk versus uncertainty ................................................................................. 8 Risk of an innovation project versus risk of a product .............................. 8 Acceptable risks and societal consensus ................................................... 9 The impossibility of proving safety (Caveat about Safety) ........................ 9 Nano-related risk and regulations vs. other risks and regulations ........... 9

II. STATE OF THE ART: CURRENT INDUSTRIAL INNOVATION PROCESSES ................ 10

1. INDUSTRIAL PROCESSES, ENTERPRISE VALUE CHAINS AND PRODUCT LIFE CYCLES ............. 10 Value chains and product life cycles .......................................................... 10 Industrial processes relevant for SbD ........................................................ 10

2. THE STAGE GATE INNOVATION MODEL ............................................................................. 12 Stages and Gates .......................................................................................... 12 IT-tools used for stage gate processes ...................................................... 12

3. CURRENT RISK MANAGEMENT PROCESSES ...................................................................... 13 Risk identification and formulation............................................................. 13 Risk exposure, exposure scenarios and exposure targets ...................... 13

3.2.1. Human exposure .............................................................................. 13 3.2.2. Environmental exposure (imissions into the environment) .............. 15

Risk quantification ........................................................................................ 15 Costs in the risk analysis ............................................................................. 15 General risk treatment options: what to do with assessed risks? .......... 16 Risk assessment options and pre-defined safety levels .......................... 16 Problems with the current risk analysis to be solved with better data ... 16

4. RISK MANAGEMENT IN THE STAGE GATE MODEL ............................................................... 18 Risk assessment in the stages.................................................................... 18 Risk treatment in the gates .......................................................................... 19

III. THE SAFE-BY-DESIGN (SBD) CONCEPT ........................................................................ 20

1. SBD CONCEPT VS. MNM-RELATED SCIENTIFIC DATA ....................................................... 20

2. THE SAFE-BY-DESIGN (SBD) CONCEPT ........................................................................... 21

3. COSTS IN THE SBD CONCEPT ......................................................................................... 22

4. RISK DECOMPOSITION WITHIN THE SBD-CONCEPT: EXPOSURE AND EFFECT ...................... 23 Risk exposure: MNM specific exposure scenarios to be considered ............. 23 Risk effects: specific risk potentials to be considered for MNMs along

stages ............................................................................................................. 24

5. THE TOOLBOX: TOOLS TO SUPPORT THE NANOREG SBD CONCEPT ................................ 28

The precautionary matrix for synthetic nanomaterials .................................... 28 Life cycle analysis and life cycle mapping ...................................................... 29


Tools under development and evaluation ....................................................... 30

1. DATA USED BY THE SBD CONCEPT .................................................................................. 31

Data formats ................................................................................................... 31

2. IMPLEMENTATION OF THE SBD CONCEPT AND OUTLOOK ................................................... 32

SbD for already existing products and processes .......................................... 32 Training, education and workshops ................................................................ 32 Outlook ............................................................................................................ 32


I. Introduction 1. Preface Innovation is seen as an important tool to boost economic growth, sustainable development, and as one of the most important drivers of societal prosperity. Likewise, material and product innovations are one of the most important drivers of an industrial enterprise’s prosperity.

Therefore, emerging technologies such as nanotechnology and new materials such as graphene can rely on huge public and private funding to stimulate their development into commercial utilization.

However, if and when innovative products near commercialisation, discussions about human and environmental safety seem to threaten the investments because industry and regulatory authorities have a different opinion and the regulation takes place with a significant time lag.

Industry is of the opinion that “there is no risk or no reason to assume a risk” and thus there is no need to change approaches or to do extra safety testing as long as they are not required by present regulations. Industry thus seems not to see or not want to see the open issues about the safety of its innovations. Industry also argues that they already address safety in all kind of ways. That is true of course, but often it just does not know what regulatory authorities think and hence has to make guesses and assumptions.

Regulatory authorities state that risks cannot be excluded on the basis of the present information, but also do not clearly state what they want and need. Regulatory authorities thus act in a too reactive way. It seems as if there is a lack of regulatory preparedness concerning safety requirements to absorb innovations. Regulation can provide a context of confidence for the safety of innovations. It also provides guidance for industry on what information should be present to assess regulatory safety. Of course, regulations must be based on the current scientific state of the art.

Overall, the discussions are more about uncertainties rather than not knowing how to deal with identified risks. This leads to endless circular discussions frustrating all stakeholders. Even worse, these discussions prevent industry from achieving safe innovations in an efficient and feasible way.

Hence, to improve the present situation, it is inevitable that there must be a closer collaboration between industry and regulatory authorities within a generally accepted overall framework containing to common standards.

Such a framework would be the Safe Innovation (SI) approach: It is envisioned to contain a Safe-by-Design (SbD) concept combined with a Regulatory Preparedness (RP) concept. Through this combined approach safe innovation can become a common activity of industry and regulatory authorities.

Unfortunately, there is no generally accepted definition what constitutes a SbD concept. The understanding about safety, uncertainty and risk is diffuse and sometimes misleading: e.g. similar terms such as “safe by design” and “safety by design” have different meanings, backgrounds and impact depending on one’s background.

In this document, Safe-by-Design (SbD is used.


2. Objective, scope and alignment with the research programs This paper covers the SbD concept developed in NANoREG I that will be complemented in NANoREG II. The Safe Innovation Approach and the Regulatory Preparedness (RP/RP) concept will be worked out in detail in NANoREG II.

Starting from a common understanding of safety, uncertainty and risk a harmonized SbD concept is conceptualised. It will be used within the NANoREG I, NANoREG II and PROSAFE projects.

The SbD concept should form an exemplary platform for the early stage application of the precautionary principle in R&D projects in industrial innovation processes. This platform includes precautionary measures and tools for the timely identification of uncertainties and potential risks as well as timely actions to reduce or eliminate these uncertainties and if possible the respective risks at the earliest possible and/or feasible stage of development.

To facilitate the industrial implantation of the SbD concept, it is not intended as a substitute but as an add-on for current industrial innovation processes. Because of this, the SbD concept is designed so that it can be seamlessly integrated into the innovation processes of enterprises along the entire value chain. In this context, the current industrial innovation processes are used as template for innovation processes. However, the problems arising from a lack of information cannot be solved by the process design, but only with more and better data and information.

Both concepts (SbD and RP) and thus the SI approach will especially consider the characteristics and peculiarities of Manufactured Nano Materials (MNMs) and products containing MNMs because new manufactured nanomaterials and products containing MNMs are often fraught with a lot of uncertainties and perceived risks for both the innovators and the regulatory authorities.5

In addition, it is foreseen that SbD will specifically treat branch specific value chains.

Nevertheless, being an expansion developed with the aim of improving the shortcomings of current processes, the SbD concept can and should also be implemented in innovation processes not or not exclusively dealing with MNMs by companies from various industrial branches.

What constitutes a nanomaterial is a matter of definition and common practice both of which vary with time and place and respective regulatory system.

3. R&D in non-profit organisations Research and development conducted in non-profit organizations (universities, research institutions etc.) is usually unrelated to large scale industrial processes and thus any risks associated with these processes. But, they still must have to install occupational hazard management systems to protect their personnel, and have to deal with the environmental issues of their waste.

Nonetheless, their research is of utmost importance because the data they generate (e.g. physico-chemical properties, structure, toxicology etc.) is used by the SbD concept.

5 Throughout the document, only MNM or MNMs will be used as an abbreviation.


4. Definitions, understandings and caveats For general definitions we refer to the Consolidated Framework for EHS of Manufactured Nanomaterials. This framework has been developed under the ERANET project "Safe Implementation of Innovative Nanoscience and Nanotechnology (SIINN)".6

Risk versus uncertainty Within NANoREG we use the ISO standard specification family ISO 31000:20097 for risk management: - ISO 31000:2009 contains risk management implementation principles and guidelines - ISO/IEC 31010:2009 contains risk management and assessment techniques - SO Guide 73:2009 contains the vocabulary of risk management ISO also designed its ISO 21500 Guidance on Project Management standard to align with ISO 31000:2009. This is an important remark, because proper project management is a prerequisite and necessity for a successful innovation project.

According to these ISO standards, a risk is the “negative or positive or deviation from the expected effect of uncertainty on objectives”. Hence, risks are the consequences of uncertainties and uncertainties are the cause of risks.

Risk is often described by an event, a change in circumstances or a consequence.

In addition, a risk can be decomposed into the probability of risk occurrence (e.g. exposure) and the risk effect (e.g. costs, toxicity, hazard) once it occurs. Thus, there can be: - Uncertainty about the risk occurrence expressed as a range of risk probabilities (if a single

probability was stated without a safety/error margin and without a caveat or assumption, then the uncertainty must be 0%!).

- Uncertainty about the risk effect once it occurs. Because ambiguous or missing or faulty information/data causes uncertainties, they also cause risks. Hence, to reduce uncertainties and risks, more or more reliable/objective information/data is needed.

Risk of an innovation project versus risk of a product There are two objects which can have a risk: - An innovation project is subjected to project management risks (missing due dates, failure

to achieve the goals of a project etc.) - The outcome of an innovation project, i.e. a material, product or process, can have risk

relating to its properties (e.g. toxicity) or use (e.g. financial return, exposure, etc). One problem here is that the risk of an outcome could be the risk of the innovation project itself: e.g. too high toxicity of a potential product can kill the complete project.

Another problem is that industry and regulatory authorities have different interests and decision criteria: - Industry in the end is only concerned with the innovation project and its monetary outcome;

of course, industry needs scientific data as a decision basis for, but all scientific data is somehow monetised to allow non-experts to make a decision about a project and its outcome. I.e. industry balances risk versus benefit mainly on a monetary basis.

6 http://www.siinn.eu/bin/D2.6_Consolidated_Framework_for_EHS_FinalVersion.pdf 7 2009 refers to the publication date November 13th 2009 and is the newest version of ISO 31000.


- The regulatory authorities are primarily interested in the scientific data of the project outcome (and mainly EHS data not product properties relating to the intended use). I.e. the regulatory authorities usually only consider the risk but not the benefits (except for registered products such as pharmaceuticals) based on scientific data.

E.g. If a given material has a certain toxicity reducing its applicability for different customers, then industry is mainly interested in the lower market potential and it weighs the costs of toxicity reduction vs. the potential market size (i.e. there is a negative correlation between market potential and toxicity). The regulatory authorities are mainly interested in the level of toxicity and in the potential exposure.

Acceptable risks and societal consensus Acceptable risks are a matter of societal consensus and not a matter of science and technology as can be seen in the ongoing public debates about nuclear power, anthropogenic climate change, nanotechnology etc. This is very important with regard to risks which are scientifically safe, but still not accepted by society.

A societal consensus is transferred to regulatory authorities (part of the executive branch i.e. government or administration) via the legislative branch of a territorial entity’s (supranational e.g. EU, national, subnational, regional, municipal etc.) political system: I.e. a territorial entity’s society elects its legislators (organised in political parties/factions and in a parliament) according to the society’s consensus about an acceptable risk (e.g. the political parties differ in their acceptance of nuclear power generation); a majority of legislators in the legislative branch can turn the societal consensus into a law (e.g. the phasing out of nuclear power) which in turn must be executed by the territorial entity’s government or administration. During the legislative and executive process the societal consensus is refined step by step into ever more detailed regulation (in the form of laws, order, issues, provisions etc. containing e.g. forms, safety levels, threshold values, scenarios to be taken into account etc.), partially with the help of scientific data.

The impossibility of proving safety (Caveat about Safety) It should be noted that it is difficult if not impossible in most cases to prove safety. Also, a common misconception in the public discussion is that absolute safety can be achieved: risks can only be reduced and weighed against each other (because avoiding one risk often leads to exposure to another risk) as well as costs associated with risk reduction can be compared to the costs of the risk itself / the risk effect.

Thus, the aim of an implemented SbD concept cannot be to prove safety. Instead, an implemented SbD concept should help to reduce uncertainties and risks or even help to exclude risks. In addition, the concept should help to discuss/draft/show risk management options together with their associated costs, help to determine the costs of a risk and its effect, and help to detect knowledge gaps / to determine missing information.

Nano-related risk and regulations vs. other risks and regulations It must be understood that even if no MNM-related risks are present or if all nano-specific regulations are fulfilled, then other risks may be present and other regulations (REACH, Pharma, Food, EHS, environmental laws etc.) may still have to be fulfilled.

Thus, other risks and uncertainties must also be considered and possibly reduced as well as other regulations fulfilled!


II. State of the art: Current industrial innovation processes The SbD concept has to be compatible with and also has to improve the existing industrial innovation processes to have a chance for industrial implementation with respect to nano-safety. Thus, the SbD concept will conceptually be built on the state of the art. Hence, relevant existing industrial processes are described and problems with them are identified in this part II.

1. Industrial processes, enterprise value chains and product life cycles This chapter gives a general overview on industrial processes and identifies the processes relevant for the SbD concept.

Value chains and product life cycles The different processes and activities of a given business unit, company, industry etc. constitute their respective value chains containing the different value chain steps:

Figure 1: An exemplary value chain with standard value chain step types

Although there is a myriad of different activities and processes, they belong to only a small number of standard value chain step types corresponding to the typical product life cycle stages: a product goes through every value chain step during its life cycle.8 Thus, value chains focus on the activities of an enterprise whereas products are the focus of a product life cycle.

The position of a value chains step in a value chain is given relative to one production or formulation9 step associated with one company: Upstream refers to any activity in a value chain step supplying the precursors of a company’s products, i.e. the activities of its suppliers and their suppliers up to and including the extraction of natural resources as the first step of any material value chain: e.g. raw material extraction, precursor production.

Downstream refers to any activity in a value chain step using a company’s products, i.e. the activities of its customers and their customers down to and including the consumers: e.g. product application, use, fate of a product/material.

Recycling closes the loop by converting used consumer goods back into raw materials; i.e. the recycling value chains run antiparallel to the normal value chains.

Industrial processes relevant for SbD There are two types of MNM-related und thus relevant firm activities and processes.

8 The physical product life cycle must not be confused with marketing product life cycle describing the life of a product from its inception to its phase out by the last customer. 9 Formulation is the process of “mixing” ingredients together to obtain a new product (e.g. drug or paint or plastic). Often, the formulation is separated from the production of the ingredients and formulators may form an own (sub-) branch (e.g. pharmaceutical industry formulates drugs, plastic processing industry, adhesives, paints and coatings etc.) separate from the chemical industry proper producing “only pure ingredients”. However, for exposure and safety considerations, formulation can be regarded as part of the production.


1. Large scale industrial activities and processes convert raw materials to products (production of goods) or vice versa (recycling): standard value chain step types/life cycle stages extraction of natural resources, in-bound logistics, production incl. formulation, packaging, out-bound logistics, transportation, trade, application or end use, and waste-handling (collection, storage, distribution).

2. Industrial innovation activities and processes create the knowledge and knowhow of the large scale industrial activities and processes: standard value chain step types/ life cycle stages applied R&D, product and process development etc. Any risks for the R&D personnel have to be mitigated by the existing occupational hazard management systems as well as any prudent GLP (Good Laboratory Practice).

In the past, the industrial innovation and large scale activities and processes were closely linked within one company; nowadays, with the ever more collaborative value chains (e.g. CRO or CMO, i.e. contract research or manufacturing organisations), knowledge sharing becomes ever more important to avoid unnecessary risks.

Even though the large scale industrial activities and processes pose the real risks, they must be considered during the innovation activities and processes: Once the development is completed, only risk management options remain.

Hence, the large scale processes are neglected for the SbD concept, and current industrial innovation processes are used as the basis for the development and implementation of the SbD concept.


2. The stage gate innovation model In industry, no matter the name, some sort of stage gate10 or phase gate process is the de facto standard for all kinds of innovation processes and R&D projects (products, processes, technologies etc.). Consequently, the stage gate model is the conceptual framework for SbD.

Stages and Gates During the stages the proper work is carried out: ideation, development, tests, up-scaling etc.

In each gate so-called gatekeepers decide on the fate of an innovation project: proceed, alter (proceed through gate but minor alterations in the next phase), recycle (repeat the stage with major alterations), on-hold (wait for other projects, technologies, licenses, regulations etc.), and terminate. The decision is always based on balancing costs and benefits.

Figure 2: The stage gate innovation model

Whether, how and to which extent a stage gate process is run depends on the scope of an innovation project: - For smaller projects stages 1 and 2 and/or stages 3 and 4 can be merged; with only 1 idea

for a smaller project gate 1 may be merged with gates 2 and 3. - The stage gate process can be run in two or more sequences and these also in parallel: E.g.

During the first stage gate process /innovation project a technology is developed, during a second a product platform using this technology (there might be other platforms and products developed in yet other stage gate processes) and in the third every geographical business unit develops a product for its market’s requirements (i.e. several daughter projects run parallel).

- The stage gate process can even contain built in loops within a stage e.g. if certain criteria are failed.

IT-tools used for stage gate processes Today it is state of the art to support the stage gate process with (adapted) proprietary (such as Gensight®) or completely home made IT-tools, esp. in bigger companies. Nonetheless, also the smaller companies use some IT support e.g. gantt charts or Excel® lists.

Thus, the Safe-by-Design concept will be compatible with the currently used IT-tools; also with respect to data formats etc. See chapter 1 SbD data for more information on this topic.

10 Dr. Robert G. Cooper: http://www.bobcooper.ca/about-dr-cooper


3. Current risk management processes The risk management process used also follows ISO 31000 as does the risk definition (part I chapter 4.1 risk definition): It is split into risk assessment (incl. risk identification and formulation, analysis, evaluation) and risk treatment.

As stated in the risk definition (part I chapter 4.1 risk definition), a risk can be expressed as product of exposure and effect. In the course of a risk assessment, once the risk has been identified and the risk situation formulated, exposure and effect are investigated independently (indeed, there are experts for both areas). For the risk treatment, however, both have to be taken into account simultaneously.

Risk identification and formulation Before any risk can be analysed and evaluated in the risk assessment, they have to be identified. To identify risks, typical situations and scenarios in the life cycle of a product have to be created. These scenarios should contain the most relevant (“bad”) situations of the product whilst it is produced, formulated, applied, used and recycled. Often, the problem lies in the risk identification. Thus, a tool like scenario technique can be very helpful.

Risk exposure, exposure scenarios and exposure targets Exposure is usually investigated with the help of exposure scenarios. They are the same or very similar scenarios like the ones used for risk identification. For a specific risk analysis, relevant exposure scenarios with potentially high exposures have to be formulated.

Each exposure scenario contains human and an environmental exposure targets. From a liability and thus from a prevention perspective, the responsibility for the exposure of the different exposure targets depends on the exposure target and the type of use.

3.2.1. Human exposure Human exposure can be divided into occupational (worker and professional) exposure, consumer exposure or patient exposure. For each type of exposure different exposure scenarios should be regarded. Moreover, risk-benefit is weighed differently in the risk assessment of a substance. In case of patient exposure some side effects are accepted whereas this is not the case for consumer applications. Moreover, the potential control of exposure varies between these three groups. In a workers environment exposure is reduced if required, whereas for patients exposure is precisely defined by means of prescribed dose regiment. Exposure in the population of consumers is most variable. There is a huge variety in ages, lifestyle, health conditions, etc. that all may affect the extent of exposure.

Main routes of exposure into the human body are: ingestion, inhalation or dermal uptake via the three carrier media air, liquids and solids.

The hazard of a substance in the body then must be regarded of most likely exposure scenarios. In case a substance is metabolised or transformed, this process must be taken into account in the risk assessment of a substance. This implies the presence of metabolising/transformation capacity in a test system is pivotal for risk assessment.


3.2.1.1. Occupational exposure Occupational exposure can occur during commercial use. The responsibility for occupational exposure lies with the legal entity owning the commercial process used:

On the one hand, there is internal or in-house use (logistics, production and formulation, packaging) falling under the organisation’s own responsibility. Within this setting exposure scenarios regarding R&D or full production circumstances need to be regarded.

On the other hand, there is external commercial use (industrial use incl. contract manufacturing and professional end use, but also transportation and trade)11 by another legal entity falling under the legal entity’s responsibility. With an external commercial user, a proper handling can be assumed, and any improper and/or non-intended use is the fault of the commercial user, and not of the producer: If a cosmetic company purchases a nanopowder containing industrial lubricant for an cosmetic formulation via an intermediary without telling neither the producer nor the intermediary the intended use, the producer cannot be sued by the cosmetic company.

3.2.1.2. Consumer exposure to MNM Consumer exposure containing MNM is due to high uncertainties about safety. It is unclear to which extent and which products contain MNM, thereby implying high uncertainty about exposure. Exposure is further complicated as MNM will undergo changes during the process of production. The impact of such changes for hazard of the MNM in that form is unknown at this moment. Beside exposure also hazard of the applied MNM in products is insufficiently known, thus increasing uncertainties about safety even more.

MNM are applied in a wide variety of consumer products e.g. personal care products, cosmetics and textiles. Nanoclaims on product labels or websites are difficult to interpret as they do not always reflect the actual presence of nanomaterials. To obtain a better insight into the use of nanomaterials in consumer products approaches such as measurements, verified product labeling or validated inventories on nanomaterials are essential. The current uncertainty about the use of nanomaterials hampers the process of risk assessment for consumer products. The recent obligatory labelling for nanomaterials in cosmetic products and biocides in the EU is an important step forward and may serve as a test case for nanomaterial related product information in consumer products.

Various measurement and analysis methods are available for the characterization of nanomaterials, dependent on the nanomaterial and the matrix in which the nanomaterials is present (solid, cream/ emulsion, gas, surface). Generally speaking the available analysis methods are expensive and need further development and validation. In addition, measurements in consumer products don’t distinguish between engineered nanomaterials and natural nanomaterials.

Consumers can come into contact with MNM in consumer products via all known exposure routes. The greatest concern at the moment is about the effects following inhalation exposure to nanoparticles, such as from increasing use of spray products and powders. Less concern exists in the case of dermal application because of the apparent lack of penetration of nanoparticles through the skin. To assess the exposure, it is important to distinguish between

11 Industrial use is the industrial processing of goods; professional use is the small scale application of final goods (e.g. painter applying coatings).


the presence of MNM in consumer products and the release of MNM from these products. Realistic user scenarios are key tools in this context.12

3.2.2. Environmental exposure (imissions into the environment) Environmental exposure can occur in/during any value chain step /life cycle stage and thus the responsibility lies mostly with the actor of the value chain step esp. in the case of improper use. In the case of proper use the producer has some shared responsibility with the user for environmental exposure.

Environmental exposure of the environmental or earth spheres hydrosphere, atmosphere, pedosphere, and from there into all living organisms (bio- and anthroposphere) occurs via the three carrier media air, liquids, and solids.

It is important to note that all environmental systems can be exposed by all carrier media: e.g. nanomaterial dissolved in some solvent mixture can leak into the soil where one solvent evaporates into the atmosphere, the nanomaterials sticks in the soil and the second solvent ends up in the ground water.

Risk quantification There are two main ways of quantifying risks: a) toxicological approach and b) probability approach. Both ways are used when it comes to safe-by-design.

The toxicological approach considers a risk as a combination of expected exposure and hazard of the compound. 13

For the purpose of a risk evaluation, values for probability for a negative effect and impact – e.g. on a scale from 1-9 – are derived in a risk analysis and the risk itself then is mathematically expressed as the product of probability of risk event and impact of risk event: R=P*E. Uncertainty (U) can be included in this formula as additional weighing factor either overall (U*P*E) or for both probability (P) and effect (E) (UP*P*UE*E) or summand (P*E+U). These formulas are also used in the precautionary matrix for synthetic nanomaterials (see chapter 5.1 in part III).

Costs in the risk analysis Costs of measures to reduce a risk have a direct impact on the remaining risk: the higher the costs, the lower the remaining risk. However, the costs of risk reduction have to be balanced with the costs of the remaining risk to find the most efficient solutions (e.g. a reduction of a risk to zero is usually inefficient because of exponentially increasing costs).

Also, if somebody further down the value chain obtains windfall benefits of upstream risk reduction, the price setting or market power (i.e. the power of accessing the windfall benefits) has to be taken into consideration. A similar situation arises if somebody downstream demands a higher than necessary risk reduction with which higher benefits are possible (e.g. If a toxic

12 Assessing health and environmental risks of nanoparticles current state of affairs in policy, science and areas of application. RIVM Report

123456789/2015

13 In FP7 EU-projects like MARINA, GUIDEnano and SUN descriptions of risk, uncertainty and probability are developed. We will tune

the description in this document to outcomes of these projects.


substance has a NOEL and regulatory limit for a concentration of 1 ppm but the customer demands 1 ppb).

Risk reduction

investment Benefit of investment Remaining risk Remark

Early small large Small Small investments have large benefits

in time medium medium Medium Late large small Large Large investments

have small benefits Figure 3: Cost of uncertainty and risk reduction

As can be seen from Table 1, the earlier a potential risk is addressed, the smaller the necessary costs for a given risk-reduction or the smaller the costs for a given remaining risk potential.

General risk treatment options: what to do with assessed risks? In a risk assessment, once risks have been identified, analysed and evaluated, all techniques for the risk treatment fall into one or more of these four major categories from best to worst option (or biggest to smallest risks):

Typical risk type High impact and High probability

Low impact and High probability

High impact and Low probability

Low impact and Low probability

Risk treatment option

Risk Avoidance Risk Reduction Risk Sharing Risk Retention

What to do with the risk?

eliminate withdraw from avoid involvement

optimise mitigate (impact) reduce probability

transfer outsource insure and budget

accept and budget

Figure 4: Risk types and their treatment options

Risk assessment options and pre-defined safety levels A Safety Level (SL) can be defined as a specific target level of risk. These safety levels can be predefined by the regulatory authorities, by an industry or an enterprise and thus can vary; they also vary with time reflecting changing knowledge.

As is current practice e.g. in the chemical industries, risks can be compared to safety levels: - Some risks have to be reduced below a pre-defined safety level for all exposures in all

conditions. It then has to be convincingly demonstrated that the technology has the capacity to bring the risk level as low as requested.

- Some risks can be above pre-defined safety levels for some exposures and under some conditions; these have to be monitored and controlled.

In the case of regulatory risks (no registration or market approval), a close and as soon as possible dialogue between the respective regulatory authority and the company must be maintained. A dialogue can also help if there are doubts about the safety of a product.

Problems with the current risk analysis to be solved with better data There are certain problems with the currently used industrial risk analyses which cannot be solved by the design of the SbD concept, but only with more and better information/data.

Often, uncertainties hinder the identification and proper assessment of potential risks:


- Repeatedly, the problem is not the risk analysis, but the exhaustive, systematic and methodical identification of potential risks or risk areas. Evidently, before any risk can be theoretically or experimentally assessed, it has to be identified!

- With the current knowledge about nanotechnology there is also a problem with the theoretical and the experimental assessment of risks due to a lack of information/data. If a risk cannot be properly assessed, then the worst case is assumed, which in turn may terminate a complete project.

So for nanotechnology uncertainties and risks are due to: - general lack of knowledge on what information is pivotal to guarantee human health and

environmental safety. - lack of valid methods to determine safety with tests that are already agreed on for their

usefulness to prove safety - lack of relevant and robust data Thus, the research being part of the NANoREG projects’ should help with these problems: - E.g. an exhaustive, systematic and methodical list of potential risks or risk areas for specific

classes of products, industries and applications would be very valuable in the industrial praxis.

- E.g. a sharing and systemisation of all the existing knowledge as well as a transformation of tacit knowledge (knowhow) into explicit knowledge would improve the theoretical assessment of risks in stage 2 and thus avoid unnecessary experimental work in stage 3.

- E.g. a definition of proper test and analysis methods – i.e. the elaboration of SOPs – would reduce unnecessary experimental work as well as facilitate data sharing and comparison

- .


4. Risk management in the stage gate model In some companies, a risk management process (environmental, health and safety {EHS}, economic, technical and other risks) is already implemented in the stage gate processes.

Obviously, a full-fledged risk management process like a full-fledged stage gate process is only carried out for major projects, not for minor alterations. Hence, the process design must make sure that small but risky alterations (such as label changes) are subjected to an appropriate risk management process. On the other hand, there must not be too much red tape esp. for smaller and riskless projects.

Risk assessment in the stages The risk assessment and the drafting of risk treatment options is carried in the stages:

Figure 5: Current industrial innovation and risk management processes

No risk identification must be carried prior to gate 1: in it, mainly external (e.g. economic potential) and internal (e.g. capabilities, strategic fit) factors of an idea should be considered.

The risk assessment then starts after gate 1 in stage1. It is a living, iterative process incorporating ever more specific data from stage to stage:

- During stage 1 potential risk situations and scenarios are formulated as well as risks identified and listed for gate 2.

- During stage 2 a theoretical (i.e. only using subjective and existing objective data) risk assessment is carried out and risk treatment options are prepared for gate 3.

- During stage 3 the risk assessment and risk treatment options are updated with the development results for gate 4.

- During stage 4 the risk assessment and risk treatment options are updated with the results of market testing and upscaling for gate 5.

- During stage 5 the risk assessment and risk treatment options are updated with the feedback from the market introduction for gate 6, the post launch review (PLR).


Risk treatment in the gates For gate 1, the gate keepers do not have to consider any risks.

For gate 2, the gate keepers only have a list of potential risks and formulated risk situations. Their main task is to check the formulated situations and scenarios and esp. the assumptions made therein. Certain risks such as regulatory risks may warrant special attention in the form of additional approval, additional processes or simple (temporary) stop signal.

In each gate from gate 3 on, the gate keepers have to decide on the risk treatment options (balancing of risk reduction costs with costs of remaining risk) for each risk of the innovation project and weigh the costs of the risk against the (monetary or monetised) benefits resulting from the innovation project. Of course, a gate keeper also can and should check the risk assessment and esp. the assumptions made therein.

In a gate, of course, one or several specific risks or the whole risk assessment can be the reason why a project is terminated, put on hold, altered or recycled.


III. The Safe-by-Design (SbD) concept In this part the SbD concept based on the stage gate model and the scientific MNM-related data the SbD concept integrates will be described in detail.

1. SbD Concept vs. MNM-related scientific data There must be a strict differentiation between the Safe-by-Design concept and the MNM-related data the concept is using even though both are part of the NANoREG projects.

The concept can be conceptualised rather quickly – independently from any scientific data – from current industrial practice and from management science knowledge; it remains relatively unchanged over time and always uses the best currently available scientific data no matter the source. The concept will be used only by industry and to a certain extent also by regulation authorities.

Figure 6: The SbD concept versus the data it is using

MNM-related scientific data is continuously generated in industrial R&D and academia to be used for many different purposes one of which would be the Safe-by-Design concept; in addition, a lot of specific MNM-related data has yet to be generated. Scientific data is used by industry, academia and regulatory authorities alike.

Whereas the concept can be applied for many different products, companies and industries, the data is case specific, i.e. for every product a new data set is needed.


2. The Safe-by-Design (SbD) concept The SbD concept can be seen as MNM-related add-on for existing industrial innovations processes encompassing different activities.

SbD supplements the risk analysis part starting in stage 1 and continues into the risk management in stage 5. Thus, every activity carried out during a “normal” risk analysis is also carried out within a SbD process:

Figure 7: Current industrial innovation processes and risk management (white background), additional SbD activities (grey background) and nano related risk assessment and regulatory

requirements (orange background)

Figure 5 structures different enterprise activities along an exemplary stage gate process:

- On white background, activities in the current industrial innovation and risk management processes are shown; see part II, State of the art: Current industrial innovation processes.

- On grey background, the additional SbD activities are listed; see part III, The Safe-by-Design (SbD).

- On orange background, and nano related risk assessment and regulatory requirements.


3. Costs in the SbD concept Costs in the SbD concept are treated analogously to a normal risk analysis (see chapter 3.4, in part II, State of the art: Current industrial innovation processes):

Figure 6 shows that:

- The costs of uncertainty reduction and the risk potential of each stage need to be treated individually.

- There are costs attached to achieving some pre-defined safety level.

- Every risk management option has some investment cost attached to it and that there always will be a residual risk remaining which itself can be monetised.

In addition, every assessment is based on current knowledge which later on can be superseded by newer knowledge.

Figure 8: Cost and the SbD processes

The funnel graph (Figure 7) visualises in a nutshell for each scenario and risk the associated - uncertainty (opening width of funnel), - risks levels and - costs for risk reduction (both on y-axis)

along the innovation/stage-gate-process or against time/amount of knowledge (x-axis).

Pre-determined safety levels can be plotted as well.

Figure 9: funnel like development of costs and risks per stage


4. Risk decomposition within the SbD-concept: exposure and effect As stated in parts I (Chapter 4.1, Risk versus uncertainty) and II (Chapter 3.3, Risk quantification), a risk can be expressed as product of exposure and effect. Both have to and can be (approximately) investigated independently. Indeed, there are experts for both areas.

Risk exposure: MNM specific exposure scenarios to be considered There are no really specific nano-related exposure scenarios because the situations leading to exposure are not nano-specific (worker spilling material, consumer brushing/swiping cosmetic into the eye, product disintegrating during recycling etc.).

The amount of exposure, however, may vary in the same circumstances due to the specific properties of MNMs: spilling material may lead to a higher exposure for nanomaterials because of their smaller particle mass and thus their higher flowability/ dispersibility.

Several MNM specific control banding tools have been generated to investigate exposure:

- The control banding nanotool (Zalk, Paik, & Swuste, 2009) - The Groso method (Groso, Petri-Fink, Magrez, Riediker, & Meyer, 2010), - The Stoffenmanager nano (Van Duuren-Stuurman et al., 2012), - The Precautionary matrix (FOPH/FOEN, 2008).

These tools are based on a series of exposure determinants that are relevant in environmental, occupational and consumer settings, respectively. Not all settings can be investigated with every tool.

Figure 10: Life cycle stages and potential exposure of workers (orange lines),

consumers/patients (violet line) and the environment (green lines)14

14 NANoREG I Project: Deliverable D 3.1 :Gap analysis report, identifying the critical exposure scenarios within the key value chains


Risk effects: specific risk potentials to be considered for MNMs along stages Different approaches and strategies for the risk assessment of nanomaterials are being developed in projects such as MARINA, GUIDEnano, ITS NANO and NANoREG. Although the approaches have different aims and expected users, there is overlap between the different approaches. Using these overlapping elements, six risk potentials have been identified as most suitable in a first screening or prioritization step within the risk assessment of nanomaterials.

Figure 11: Specific MNM-related risk potentials to considered in a stage gate process15

Within NANoREG project, the applicability of risk potentials in early phases of innovation is explored.

However, at the same time the risk potentials can be regarded as a first attempt to help prioritizing already marketed nanomaterials that need improved attention for human and environmental health issues. The aim of this first screening strategy is to give direction to further steps within the risk assessment process. It needs to be stressed that this is a screening strategy that does not dismiss a producer from meeting the regulatory requirements for marketing!

15 NANoREG I Project: Deliverable D 6.4: Inventory of (existing regulatory accepted) toxicity tests applicable for safety screening of MNMs


What is the argumentation for the selection of the risk potentials? The argumentation behind the selection of each of the six risk potentials is closely connected to the description of what is covered by the risk potential. Below we describe each of the potentials more into detail. Solubility/dissolution rate: If a MNM dissolves into its molecular form, no nano-specific risk assessment is needed and one can refer to the risk assessment of the molecular form. It is highly relevant to describe the time frame in which the MNM dissolves but also the medium should be described in detail.

Stability of the particle coating: The stability of the particle coating is very important for the behavior and effects in humans and the environment. This risk potential should answer the question if the surface coating or modification of a nanomaterial will maintain or will be removed from the nanomaterials in its different life cycle stages. This will give direction to further risk assessment. Should there be a focus on the surface coating or modification, the core, or both?

Accumulation: The ability of nanomaterials to accumulate in the human body or environment may cause effects after long-term exposure even when the single exposures are low (sub-acute but chronic exposure). This is most important, because most likely and reasonable exposures do not involve doses leading to acute adverse effects (because most “killer substances” are anyway banned large scale emissions are pretty rare and usually involve (freak) accidents or black swans).

Genotoxicity: Fibrous Nanoparticles that look like asbestos (e.g. some carbon nanotubes), may cause genotoxic or carcinogenic effects cancer, but also other types of nanomaterials may be able such effects via other mechanistic pathways. Such effects are regarded as irreversible and unwanted.

Inflammation/immunotoxicity: Capability of MNMs to trigger an immune response causing for example inflammation is regarded as a unifying mechanism for several health effects such as lung cancer, cardiovascular disease, neurological diseases, etc. This risk potential may include reactivity and the ability to cause oxidative stress.

Ecotoxicity: Also for environmental health effects some first screening is necessary. Screening tests addressing fate and potential for toxicity in various species should be regarded.


Suggestions for parameters to be tested per potential Parameters describing each risk potential

1. MNM 2. Stablility of coating

3. Solubility/ dissolution

4. Accumu-lation

5. Geno-toxicity

6. Immuno-toxicity

7. Eco-toxicity

Composition Composition Composition Composition Composition Composition Composition

Size (distribution)

Size (distribution)

Size (distribution)

Size (distribution)

Size (distribution)

Size (distribution)

Size (distribution)

Shape Shape Shape Shape Shape Shape Shape

Surface area Surface area Surface area Surface area Surface area Surface area Surface area

Agglomeration/aggregation







Surface treatment

Surface treatment

Surface treatment

Surface treatment

Surface treatment

Surface treatment

Surface treatment

Solubility/dissolution






Solubility/ dissolution

Number of particles

Surface charge

Surface charge

Surface charge

Surface charge

Surface charge

Surface charge

Coating material

Stability Hydrophobicity

Stability Hydrophobicity

Bio-degradation

Degree of coating

Hydrophobicity

Exposure route

Cellular uptake

Stability Crystalline structure

Hydrolytic stability

Cellular uptake

Cytotoxicity ROS generation

Impurities

Acid dissociation

Protein binding

ROS generation

Cytokine induction

Reactivity

Half life Photo-reactivity

Figure 12: Parameters to be tested per potential

The grey cells demonstrate a broad range of potentials can already be screened by a small set of basic parameters. This implies that valid test methods for these parameters are of significant importance.

Also the potentials are open to a stepwise approach. The scheme in Table 3 demonstrates the pivotal role of information on solubility/dissolution rate.


Figure 13: Decision tree for assessing possible safety concerns for MNMs.


5. The toolbox: Tools to support the NANoREG SbD concept

The precautionary matrix for synthetic nanomaterials The precautionary matrix (PCM) for synthetic nanomaterials was developed and implemented by TEMAS on behalf of the Swiss authorities (FOPH, FOEN and SECO)16 in 2008.

Figure 14: PCM processing stages as part of the entire life cycle

With the PCM, uncertainties and potentials risk of NMNs can be identified, and precautionary measures can be initiated to reduce the identified uncertainties and risks. It allows a structured, preliminary risk assessment based on the current state of knowledge and indicates where further clarification is needed.

Figure 15: The concept for estimating precautionary need

The PCM helps ensure safety in connection with the development of new products. The PCM is designed to help industry and trade comply with their due diligence and their duty to exercise self-control opposite employees, consumers and the environment.

16 SECO is the Swiss State Secretariat for Economic Affairs, FOEN the Swiss Federal Office for the Environment and FOPH the Swiss Federal Office of Public Health.


Potential human exposure, potential input into the environment, potential effect, and available information are each evaluated using a parameter selected for the class, and related together to determine the precautionary need. To this end, tables of relationships and corresponding parameter-dependent functions are both used.

Figure 16: Parameters for estimating the precautionary need

The PCM is regularly revised by an expert panel in close cooperation with industry, science and trade as well as consumer and environmental organisations based on experiences and new scientific knowledge. The current version 3.0 was released in November 2013.

Life cycle analysis and life cycle mapping The cradle-to-grave-thinking is not inherent in the current innovation processes because every company is primarily concerned with its processes and activities and thus its value chain. Hence, the complete value chain is not necessarily investigated in a life-cycle-analysis (LCA) of an innovation project by every company:

The downstream value chain is always the focus because the producer can be made liable for its products.

The upstream value chain is usually totally ignored because the product is obviously usually not yet existent (provided a chemical transformation or formulation). In addition, a consideration of raw materials and precursors is often very difficult to impossible for various reasons: costs, company sizes, geography, language, contracts, intermediary dealers, collaboration with the suppliers etc.

Still, no matter the extent, a life cycle analysis and esp. a life cycle map may help in detecting potential risks esp. for environmental exposures:

http://www.bag.admin.ch/nanotechnologie/12171/12174/index.html?lang=en


Figure 17: Life cycle map for Ag nanoparticles used in textiles.17

Tools under development and evaluation The projects NANoREG I, ProSafe and Nanoreg II are ongoing resp. starting. A set of tools are still under development. For specific needs please contact the authors.

- Reengineering of MNMs

- Exposure (Human and environment) of MNMs

- Hazard of MNMs

17 NANoREG I Project: Deliverable D 3.1 Gap analysis report, identifying the critical exposure scenarios within the key value chains


1. Data used by the SbD concept No data will ever be exact i.e. 100% objective: there is a continuous evolution process from more subjective to less subjective or from less to more objective data.

More subjective data sources More objective data sources Personal assumptions References from databases (usually material specific) Laboratory work; esp. under standardised conditions

(SOPs) in validated processes, with validated methods and with qualified instruments

Simulations (source of subjectivity are not the calculations but the underlying personal assumptions and the quality of the data input {“shit in, shit out”}) Comparisons or similarities (e.g. grouping)

Inter- and Extrapolations: Interpolations are usually more objective than Extrapolations and using reference data is more objective than using (own) laboratory work

Figure 18: List of data sources according to subjectivity or objectivity of data.

To efficiently work with the information/data used and needed by the SbD concept as well as the data/information generated by the NANoREG projects, certain prerequisites have to be fulfilled. These are described in the next 4 sub-chapters.

Data formats A prerequisite for comparing data within a database are harmonized data formats (such as ISO-TAB-nano) or computer infrastructure (such as developed by the project eNanoMapper).


2. Implementation of the SbD concept and outlook SbD might not be applicable for basic research conducted in industry - e.g. exploratory scoping or high-through-put screening (HTS) if no formal innovation process is used.

SbD for already existing products and processes Obviously, by definition, stage gate processes are only used for de novo designs or alterations of existing products, processes and technologies, not for unaltered ones.

Of course, the SbD process can also be carried out in existing unaltered material value chains. However, it is unlikely that industry will touch existing value chains without having a problem or being forced to do it.

Likewise, using existing and already registered materials in new formulations or for new applications may not require a new regulatory approval. Thus, the regulatory part may be omitted in the stage gate process of such an innovation project. But, this does not mean that no risk analysis is carried out; whether a risk analysis is carried out depends on industry, company, and the project itself.

Finally, this point depends on jurisdiction and regulated area (“normal” chemicals, pharmaceuticals, food, cosmetics, medicinal products etc.). And, of course, regulations may change...

Training, education and workshops Training and education of all involved personnel with an appropriate knowledge about SbD is paramount to its successful implementation in industry. Even today, a proper innovation process execution and risk analysis/management is often hampered by a lack of training. The following training modules are under preparation:

- Workshop on Safe-by-Design as general information for interested persons

- Training for the implementation of Safe-by-Design in industrial innovation processes

Outlook Nanoreg II (task 3.6) will investigate whether and how the stage-gate approach in terms of safety issues can be applied for post marketing situations.

nanoreg safe-by-design (sbd) concept · safe-by-design (sbd) concept combined with a regulatory...

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