Guiding the development of sustainable nano-enabled products for the conservation of works of art: proposal for a framework implementing the Safe by Design concept

Abstract

Nanotechnology provides innovative and promising solutions for the conservation of cultural heritage, but the development and application of new nano-enabled products pose concerns regarding their human health and environmental risks. To address these issues, we propose a sustainability framework implementing the Safe by Design concept to support product developers in the early steps of product development, with the aim to provide safer nano-formulations for conservation, while retaining their functionality. In addition, this framework can support the assessment of sustainability of new products and their comparison to their conventional chemical counterparts if any. The goal is to promote the selection and use of safer and more sustainable nano-based products in different conservation contexts. The application of the proposed framework is illustrated through a hypothetical case which provides a realistic example of the methodological steps to be followed, tailored and iterated along the decision-making process.

Full text

RESEARCH ARTICLE
Guiding the development of sustainable nano-enabled
products for the conservation of works of art: proposal
for a framework implementing the Safe by Design concept
Elena Semenzin
1
&Elisa Giubilato
1
&Elena Badetti
1
&Marco Picone
1
&Annamaria Volpi Ghirardini
1
&
Danail Hristozov
1
&Andrea Brunelli
1
&Antonio Marcomini
1
Received: 7 February 2019 /Accepted: 24 June 2019 /Published online: 6 July 2019
Abstract
Nanotechnology provides innovative and promising solutions for the conservation of cultural heritage, but the development and
application of new nano-enabled products pose concerns regarding their human health and environmental risks. To address these
issues, we propose a sustainability framework implementing the Safe by Design concept to support product developers in the
early steps of product development, with the aim to provide safer nano-formulations for conservation, while retaining their
functionality. In addition, this framework can support the assessment of sustainability of new products and their comparison to
their conventional chemical counterparts if any. The goal is to promote the selection and use of safer and more sustainable nano-
based products in different conservation contexts. The application of the proposed framework is illustrated through a hypothetical
case which provides a realistic example of the methodological steps to be followed, tailored and iterated along the decision-
making process.
Keywords Sustainability .Safe by Design .Conservation science .Nanomaterials .Chemical safety .Safe innovation .Decision
support
Introduction
Nanotechnology provides innovative and promising solutions
to contrast degradation processes of artistic materials and
achieve long-term conservation of cultural heritage (Baglioni
and Chelazzi 2013). This is particularly beneficial in the case
of the complex and often unstable materials used by contem-
porary artists. Some issues of conventional techniques for re-
medial conservation and restoration can be overcome by
nano-based formulations specifically developed for the con-
trolled cleaning of surfaces, such as nanofluids composed of
micelles or microemulsions (Chelazzi et al. 2018)applied,for
example, to frescos (Baglioni et al. 2014) or to graffiti (Giorgi
et al. 2017). Nanoscience also provided valuable solutions for
polymer film dewetting by water/surfactant/good-solvent
mixtures (Baglioni et al. 2018) and for the consolidation and
stabilisation of different artistic surfaces like cellulose
(calcium hydroxide nanoparticles in Poggi et al. 2014), paint-
ing canvases (combined nanocellulose/nanosilica in Kolman
et al. 2018) or bronze (layered double hydroxide nanoparticles
filled with corrosion inhibitors in Salzano De Luna et al.
2016), while innovative nano-based solutions are still under
development for plastic surfaces (Shashoua 2016).
However, the development and application of new
nanomaterials and technologies for the conservation of cultur-
al heritage (where, with the term conservation, we refer to
remedial conservation and restoration as defined by the
International Council of Museums—committee for conserva-
tion (ICCOM-CC 2008), thus excluding preventive conserva-
tion) pose several concerns regarding their human health and
environmental risks (Eason et al. 2011). Therefore, there has
been growing research into the health and environmental im-
plications of these nano-enabled formulations. Some
Responsible editor: Michel Sablier
*Elena Semenzin
semenzin@unive.it
1
Department of Environmental Sciences, Informatics and Statistics,
Ca’Foscari University of Venice, Via Torino 155,
30172 Venice, Italy
Environmental Science and Pollution Research (2019) 26:26146–26158
https://doi.org/10.1007/s11356-019-05819-2
#The Author(s) 2019
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

examples of recent European research projects focusing on
these aspects are NANOforART, HEROMAT,
NANOMATCH, NanoCathedral, NANORESTART and
InnovaConcrete.
Even without specifically considering the inclusion of
nanomaterials in conservation products, the use of chemical
substances and mixtures, the fact that restorers are often oper-
ating in indoor environments and the high variability of both
magnitude and duration of exposure (due to a high variability
in the performed activities) can result into serious chemical
health risks, ranging from mildly irritative changes in the up-
per airways induced by nuisance dust to the carcinogenic ef-
fects of certain paints and pigments (Varnai et al. 2011;
D’Angelo and Accardo 2012). Moreover, the disposal of
chemical waste and the limited application of emissions con-
trol could represent a threat to the natural environment
(D’Angelo and Accardo 2012). However, despite an increas-
ing attention in recent years to “green restoration”of cultural
heritage through developing safer and “greener”technologies
(Balliana et al. 2016), very few works performed actual as-
sessment of health and environmental risks by means of ex-
perimental or modelling techniques (Tedesco et al. 2015;
Ferrarietal.2015;Turketal.2017;Pinedaetal.2017;
Franzoni et al. 2018;MaukoPranjićet al. 2018), mainly fo-
cusing on life cycle assessment (LCA) of consolidants for the
conservation of immovable cultural heritage (e.g. historical
buildings), and an overarching framework for assessing the
sustainability of the nano-enabled products used in the con-
servation of cultural heritage is currently lacking.
Such a framework should explicitly incorporate the Safe by
Design (SbD) concept, which offers a sound strategy for en-
suring the safety of new products in the early design stage,
while retaining their performance and functionality in com-
mercially viable ranges (Gottardo et al. 2016;Noorlanderetal.
2016; Kraegeloh et al. 2018). The implementation of this con-
cept in the domain of conservation of cultural heritage is es-
sential as this field has been traditionally driven by technical
requirements (e.g. compatibility with artistic materials, con-
trollability and selectivity of the treatment) (Baglioni and
Chelazzi 2013), while the safety and sustainability aspects
have been neglected. Moreover, the application of a SbD con-
cept can limit the need to find better alternatives in the future,
once the products are ready to enter or are already in the
market (e.g. Giubilato et al. 2016; Aschberger et al. 2017).
The SbD concept will be further presented and discussed in
“Background: the Safe by Design concept”.
In the scientific literature, the safety of products is
pinpointed as a key element in the overall sustainability of
nanotechnology (Dhingra et al. 2010; Mulvihill et al. 2011;
Schulteetal.2013;Hjorthetal.2017), where the concept of
“sustainable nanotechnologies”,althoughincreasinglyusedto
guide decisions on technological development, has not been
clearly defined (Subramanian et al. 2014). There is a general
consensus on considering material price, carbon footprint, re-
source scarcity, ecotoxicity or human health effects among
sustainability concerns (Babbit and Moore 2018; Linkov
et al. 2009), but a clear operationalization of a strategy for
sustainable nanotechnology innovation has just started to
emerge as a result of a nascent dialogue among stakeholders
from industry, academia and regulation (Falinski et al. 2018;
Babbit and Moore 2018; Cinelli et al. 2016; Subramanian
et al. 2016; van Harmelen et al. 2016; Subramanian et al.
2015;Linkovetal.2015; Falkner and Jaspers 2012).
From a regulatory point of view, in Europe, the REACH
(European Commission 2006) and the CLP regulations
(European Commission 2008) represent the references for
the safety assessment and management of nanomaterials for
conservation when they occur as substances or in mixtures.
These pieces of legislation provide the boundaries for the
chemical safety assessment of new formulations along their
life cycle and set the ground for a more comprehensive ap-
proach to cope with the several issues related to the sustain-
ability of the new products, where information on environ-
mental, economic and social dimensions are integrated ac-
cording to the so-called triple bottom line (TBL) approach
(Elkington 1999).
To address this gap, we propose a framework to inform the
design of sustainable nano-based products for conservation of
art, taking into account the current EU legislative context as
well as the specific features of the innovation process in the
cultural heritage conservation field, which demands a high
interaction between the product developers and the restorers
(Ormsby et al. 2016; Baglioni et al. 2015). This framework
was developed in the frame of the NANORESTART
(NANOmaterials for the REStoration of works of ART) EU
project with the aim of assisting formulators in the early steps
of development and refinement of these new products. In ad-
dition, to support efficient innovation pathways, the frame-
work is expected to facilitate communication with conserva-
tors for selection and use of safer and more sustainable nano-
based products in different conservation contexts.
Background: the Safe by Design concept
The development of a sound approach to tackle sustainability
of nanomaterials, including Environmental Health and Safety
(EHS), for artworks conservation cannot overlook the SbD
concept, which gained an increasing attention in recent years
in European FP7 and H2020 research projects focused on
engineered nanomaterials (Hjorth et al. 2017). The basic idea
to implement the “safety by design”consists of anticipating
potential human or environmental impacts of a new material
or product, with the objective of modifying its design to avoid
undesired properties while keeping the required functionali-
ties. Since it was developed in a regulatory context, regulatory
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requirements, such as those included in REACH, Biocidal
Products Regulation or Occupational Safety information re-
quirements, are at the core of SbD (Kraegeloh et al. 2018).
The most comprehensive definition of the SbD concept for
nanomaterials has been so far developed within the
NANoREG and NanoReg2 EU projects, where SbD has been
presented as an approach to transfer the precautionary princi-
ple into practical use, by considering the functionality of a
nanomaterial and its toxicity/safety in an integrated way
(Gottardo et al. 2016; Noorlander et al. 2016; Kraegeloh
et al. 2018).
The Cooper Stage-Gate innovation model (Cooper 1990,
Cooper and Robert 2011) was chosen as the backbone for the
SbD concept, with the aim of incorporating SbD in already-
used structured innovation management processes. Stage-
Gate is an industrially standard systematic approach that di-
vides the innovation process into a predefined set of stages
(usually five), moving from new product ideas to launch to
market and beyond. Each stage includes specific activities
(e.g. preliminary market assessment, detailed financial analy-
sis and laboratory work), and the advancement from one stage
to the following one is regulated by a gate, where the innova-
tion project is judged according to a set of criteria. The output
of each gate is a Go/Kill/Hold/Recycle decision about the
project and an action plan for the next stage.
The gate decisions, in the SbD concept, depend also on
safety considerations and risk potentials associated with the
development, manufacturing, use and disposal of the new
nanomaterials. For this reason, currently used management
processes for innovation risks, EHS, regulatory requirements
and safety data handling have been integrated in the SbD
concept (Noorlander et al. 2016). The innovation risk man-
agement process deals with all risks considered “conse-
quences of uncertainties”according to ISO 31000 standard
(ISO 2009) and includes risk assessment and risk treatment
phases. EHS management process focuses on the screening
and management of occupational health hazards and possible
environmental impacts related to the innovation project,
adopting a product life cycle perspective which can foresee
also the application of typical LCA tools. Regulatory manage-
ment requires the identification of applicable regulations and
their implementation using appropriate data, including the re-
lationship with regulatory authorities. Finally, safety data
management process specifically refers to the collection and/
or generation of data necessary to implement the aforemen-
tioned processes.
The SbD concept was also combined with the Regulatory
Preparedness (RP) concept, which is based on promoting ear-
ly interactions between innovators and regulatory authorities
with the goal of sharing expertise for an early identification of
uncertainties and potential risks and for acquiring the neces-
sary knowledge to meet all regulatory requirements in due
time. Both concepts (SbD and RP) were finally embedded in
the Safe Innovation Approach (SIA) which is expected to be
implemented through an intense interaction and collaboration
between industry and regulators since the very beginning
steps of the innovation process (Kraegeloh et al. 2018).
Even if weaknesses and criticalities in the version of the
NANoREG/NanoReg2 SbD concept have been identified
(Hjorth et al. 2017), nonetheless this concept and its incorpo-
ration into the SIA currently represent the most comprehen-
sive approach to the safer development of new nanomaterials
and should therefore constitute a fundamental reference also
in the development of new nano-based products for
conservation.
Methods
The proposed stepwise sustainability assessment framework
is depicted in Fig. 1, against the Stage-Gate innovation pro-
cess briefly described in “Background: the Safe by Design
concept”. Itcovers the first part of the value chain, from “basic
research”to “materials R&D and processing”up to “applied
R&D”(as described by Noorlander et al. 2016), thus not in-
cluding industrial manufacturing, transport, use and end of
life, although use scenarios are roughly identified. It allows
the comparative assessment of new nano-based products
against conventional products (if they exist) and focuses on
application and post-application stages, since the manufactur-
ing stage cannot be considered until the industrial upscale of
the new products has been completed. Each step of the sus-
tainability assessment framework isdescribed in the following
paragraphs.
Step 0: State-of-the-art assessment Before starting any inno-
vation process, a detailed assessment of the state-of-the-art in
a specific field must be performed in order to discover oppor-
tunities and to generate new product ideas (the so-called stage
0 of the Stage-Gate innovation process). Specifically, product
developers should at least know (i) which are the stake-
holders’needs in terms of functionalities (e.g. cleaning of
paints, coating of metal substrates for indoor/outdoor condi-
tions), (ii) if there are products already on the market covering
a specific functionality, as well as if there is any environmen-
tal, economic or social issue associated with them and (iii)
whether there is any promising ingredient in the nanoform
they would like to use. For this latter, the application of the
adapted Ashby’s framework for sustainable engineered
nanomaterials (ENMs; Falinski et al. 2018;Babbitand
Moore 2018) could be considered to support the selection of
appropriate ENMs to be incorporated into the innovative
formulations.
In this step, technical (e.g. compatibility with artistic mate-
rials), environmental (e.g. toxicity of ingredients), social (e.g.
ethical criteria such as reversibility of treatment) and
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economic (e.g. cost of the final product) criteria are broadly
considered by product developers in order to generate a first
idea of the innovative product.
Step 1: Initial formulation According to the results of the pre-
vious step, product developers propose a set of innovative
formulations for a specific functionality, taking into account
the final goal of developing safe (green) products (stage 1).
This means that, in this step, mainly technical and environ-
mental criteria are considered, although some social and eco-
nomic aspects could be already in the background.
Step 2: Screening hazard assessment (EU CLP) In this step, the
environmental performance of innovative formulations pro-
posed in step 1 is checked by a screening hazard assessment.
For this purpose, the EU CLP self-classification approach for
mixtures is applied (European Chemicals Agency 2017)in
order to derive the health (H) and environmental (ENV) haz-
ards potentially associated with the innovative products in a
quick and inexpensive manner (stage 2). At this level, usually
“test data on the mixture itself are not available for a mixture,
therefore bridging principles and weight of evidence determi-
nation using expert judgement for all the necessary H and
ENV hazard assessments may not be applied. In these cases,
classification must be based on calculation or on concentration
thresholds referring to the classified substances present in the
mixture”(European Chemical Agency (ECHA) 2017).
According to ECHA (2017), concentration thresholds are “ge-
neric cut-off values i.e. the minimum concentrations for a
substance to be taken into account for classification purposes,
and generic concentration limits (GCL) i.e. the minimum con-
centrations for a substance which trigger the classification of a
mixture if exceeded by the individualconcentration or the sum
of concentrations of relevant substances (where the individual
substance concentrations can be ‘added’to each other in a
straight forward way)”.Asanexample,“the generic cut-off
value for a skin irritant substance which is present in a mixture
is 1 %. A GCL of the skin irritant substance above or equal to
Fig. 1 Sustainability assessment framework implementing the SbD concept mapped against the Stage-Gate innovation process
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the concentration limit of 10% triggers classification of the
mixture for skin irritation. However, at ≥1%andbelow10
%, the substance may still contribute to the classification of
the mixture as skin irritant. This because the concentration
would be taken into account if other skin corrosive/irritant
substances are present in the mixture below the relevant ge-
neric concentration limits”(ECHA 2017).
To apply such self-classification approach, the following
data should be collected: (i) the list of ingredients included
in each formulation, (ii) their safety data sheets (SDS) includ-
ing the classification for H and ENV hazards according to the
EU CLP regulation and (iii) the percentage (w/was single
value or range of values) of each ingredient in the formulation.
In some cases, the SDS of a specific ingredient could not be
available because, for example, it was newly synthetized by
the product developer or it is in a specific nanoform while the
SDS is available for the bulk counterpart only. In these cases,
one can decide to indicate that H and ENV hazards are un-
known for a specific percentage of the formulation (i.e. the
%w/wof the specific ingredient) or to use the SDS of the
ingredient bulk form. The results of the screening hazard as-
sessment are communicated to the product developers along
with an explanation of the thresholds applied for each hazard
and the indication of how specific hazards could be avoided
(e.g. reducing the %w/wof a specific ingredient or substituting
it with a safer alternative).
Step 2bis: Adjustment or elimination According to the results
of the previous step, product developers can adjust the initial
formulation to reduce its hazard or decide to discard it in case
an adjustment to the composition would negatively impact its
technical performance and functionality. Step 2 can be iterated
several times (i.e. subsequent adjustment and self-
classification of the formulations) according to the needs of
the product developers. The result is a reduced number of
formulations for which a good environmental performance
(where “environmental”refers to the “environmental pillar”
of sustainability although hazards for both human health and
the environment are checked) is demonstrated through a the-
oretical approach (i.e. self-classification for H and ENV haz-
ards according to CLP regulation) (stage 2).
Step 3: Advanced hazard assessment: integrated testing strat-
egy The environmental performance of the selected formula-
tions is further checked in this step through an advanced haz-
ard assessment in which computational (e.g. in silico models)
as well as experimental (e.g. in vitro and in vivo (eco) toxico-
logical tests) approaches could be adopted, according to an
integrated testing strategy (stage 3).
An integrated (or intelligent) testing strategy (ITS) is a
hierarchical, resource-effective testing scheme consisting of
a set of decision nodes, allowing for taking different routes
for information gathering and inference for decision-making
about a chemical’shazardorrisk(Hengstleretal.2006;Van
Leeuwen et al. 2007). ITSs emerged in the mid-nineties from
several research initiatives examining how to combine differ-
ent testing and non-testing methods (including in silico,
in vitro, in vivo and omics methods) in order to reduce, refine
and replace animal testing of chemicals (3Rs principle)
(Blaauboer et al. 1999; Hakkinen and Green 2002; Salem
and Katz 2003; Vermeire et al. 2007) and had a considerable
expansion after the introduction of the REACH regulation in
2006 (Jaworska et al. 2010). As reported by the NanoSafety
Cluster Working Group (WG) 10 (Oomen et al. 2014), inte-
grated approaches to testing and assessment (IATA), in the
literature also referred to as ITS, are required for an adequate
assessment of the impact of nanomaterials (NM) on human
health and environment. They should (1) stand in line with
current EU guidance on NM safety testing, (2) consider real-
life exposure situations in order to assess toxicity of relevant
form(s) along the NM life cycle and (3) include possibilities
for the grouping of NM (i.e. by waiving tests based on
categorisation of NM or by providing test results relevant for
grouping). A comprehensive IATA is currently being devel-
oped by the NanoSafety Cluster WG 10 and should be ready
by 2020 (Oomen et al. 2014). Meanwhile, Oomen et al.
(2014) presented a first proposal of integrated approaches
for NM toxicity and ecotoxicity testing and assessment in
which a tiered structured is adopted to move from basic or
general testing (e.g. in vitro tests for short-term toxicity;
standardised short-/long-term test systems with laboratory or-
ganisms for ecotoxicity and additional endpoints such as en-
zymatic effects and functional genomics to predict NM
ecotoxicity) to specific testing (e.g. in vivo tests for establish-
ing general concepts for NM toxicity, environmental simula-
tion studies for ecotoxicity). In this process, relevant support is
provided by (1) the possibility of grouping NM (and therefore
to waive some tests) and (2) the identification of main expo-
sure paths (thus avoiding unnecessary testing).
Since these considerations are valid also for ITS not
targeted to NM (Jaworska et al. 2010), they can be extended
to the case of assessing mixtures containing NM, where the
type and percentage of a specific NM in the final composition
could affect its behaviour (e.g. whether particles are released
along the life cycle) and overall toxicity. In this context, the
applicability of computational approaches (e.g. read-across)
as well as the clear identification of relevant exposure paths
should be verified on a case-by-case basis.
Regarding the latter, information about relevant exposure
scenarios for both human health (i.e. occupational and public
health) and the environment (i.e. technical compartments such
as waste systems and environmental compartments such as
soil and water systems) along the life cycle of the innovative
products should be collected or generated. Specifically, in ad-
dition to exposure measurements in occupational settings
(Gherardi et al. 2007), data/information on product
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degradation and/or release throughout their life cycle should
be collected, to evaluate medium- and long-term behaviour of
nano-based products (Zuin et al. 2014).
Step 4: Safety assessment The results of exposure and
hazard assessments performed in steps 2 and 3 are here
combined to derive conclusions on the safety of the
formulations in each life cycle stage and identify any
hotspot (Gottardo et al. 2017). Risks to human health
(for workers) or environmental compartments can be
estimated through qualitative or semi-quantitative (e.g.
control banding tools for occupational exposure scenar-
ios), or quantitative methodologies, depending on the
typologies of hazard and exposure information and data
available from previous steps (Hristozov et al. 2016).
Sources of uncertainties in the risk assessment process
must be identified and, when possible, uncertainties
should be quantified (Hristozov et al. 2018;Pang
et al. 2017). In addition, in this step, suitable risk man-
agement measures (RMMs) for the relevant scenarios
are selected from those showing efficacy in controlling
nanomaterials (e.g. gloves, filtering masks and suitable
ventilation as reported in Oksel et al. 2016)andare
communicated to product developers and restorers for
a safe manufacturing and application of the selected
products (stage 3).
Step 5: Sustainability assessment In addition to the results
from the advanced hazard and safety assessments (steps
3 and 4), to reach stage 4 of the Cooper innovation
process, one should provide validation also of the cus-
tomer acceptance, the economics and the social implica-
tions of the product. Therefore, in this step, sustainabil-
ity is assessed by integrating information related to en-
vironmental, economic, social and technical aspects,
through multi-criteria decision analysis (MCDA)
methods (Giove et al. 2009). Results allow to rank in-
novative formulations as well as to compare them to
relevant conventional products, if any, and therefore de-
cide whether to proceed later with a pilot industrial
upscale. Since the framework is aimed at guiding the
design of formulations early in their development at
laboratory scale, advanced tools such as LCA (ISO
2006a,2006b) are not included in the sustainability as-
sessment step under the environmental pillar or under
the economic and social pillars as life cycle costing
(Swarr et al. 2011)orsocialLCA(Pettietal.2016),
respectively. However, as more detailed information be-
come available in moving from laboratory scale to in-
dustrial production, the framework can be iterated, and
tools like the life cycle–based two-tiered SUNDS
(Subramanian et al. 2016) can be adopted to support
both steps 4 and 5.
Hypothetical case study
In this paragraph, an example of application of the sustainabil-
ity assessment framework implementing the SbD concept is
provided by considering the design of a hypothetical innova-
tive nano-based consolidation system for contemporary works
of art (step 0). The new system should be able to tackle the
peculiar instability and variability of complex materials used
by contemporary artists and must be environmentally friendly
and sustainable in all its life cycle stages (with special atten-
tion to application and post-application stages). Moreover, the
product developer is considering feasibility, long-term impact
on conservation, material costs and potential for industrial
scalability.
The composition of the initial formulation (IF) is provided
as concentration of each ingredient in terms of ranges of
values (%w/w), as depicted in Fig. 2(step 1). In addition,
SDS are provided for the two ingredients (only ingredient 1
being in nano-form), thus allowing the self-classification of
the mixture according to CLP guidance (European Chemical
Agency 2017). Obtained results (reported in the rightmost
column in Fig. 2) are communicated to the product developer
along with the thresholds leading to that classification (step 2),
with the aim to provide a guidance for subsequent adjustment
of formulation’s composition. Specifically, in this case, the
suggestion is to reduce the concentration of ingredient 2 (the
one leading to the classification of the IF for acute oral toxic-
ity, eye irritation, skin sensitisation and chronic aquatic haz-
ard) below 25%, thus avoiding the aquatic toxicity, or 10%,
additionally avoiding eye irritation, or even 1% (which will
result in no hazards).
According to the provided information, the product devel-
oper further works on IF and succeeds in the development of
two adjusted formulations: AF1 and AF2, by including only
0.70% (w/w) and 0.01% (w/w)ofingredient2,respectively,
and by adding the new, not hazardous, ingredient 3 in AF2.
The self-classification of both formulations is reported in
Fig. 3(step 2bis).
At this point, AF1 and AF2 represent the most promising
innovative nano-based consolidants to be further checked ac-
cording to a tiered integrated testing strategy (ITS) in the ad-
vanced hazard assessment (step 3). Although both AFs con-
tain a low percentage of nanomaterials (NM), exposure to
nanoparticles along the life cycle cannot be completely ex-
cluded a priori. In fact, freshwater could receive released
(nano) materials leached from treated artefacts, and wastewa-
ter could receive end-of-life residues of the products, thus
affecting both ecological and human targets. For these rea-
sons, the water compartment is identified as one of the main
concerns for the assessment of potential environmental im-
pacts of such innovative products.
Accordingly, the first ITS tier (tier 1) is focused on the
assessment of the acute aquatic toxicity, by applying a set of
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three bioassays aiming at the identification of the possible
short-term effects generated by the release of the formulation
into the aquatic environment (i.e. OECD standard method 202
with the crustacean Daphnia magna (OECD 2004), OECD
201 with the algae Pseudokirchneriella subcapitata (OECD
2011) and ISO 11348:2007 (ISO 2007) with the bacteria
Aliivibrio fischeri). According to CLP regulation, only formu-
lations with EC
50
< 1 mg l
−1
for at least one species are clas-
sified as acutely toxic (acute I). If this criterion is not met for
any species, the toxicological testing should move to tier 2.
The second tier of the ITS focuses on the long-term
(chronic) effects through the D. magna reproduction test, the
standard OECD method 211 (OECD 1998). According to
CLP regulation, formulations with NOEC in the range 0.1–
1mgl
−1
are classified as “Chronic 3”, formulations with
NOEC in the range 0.01–0.1 mg l
−1
are classified as
“Chronic 2”, and formulations with NOEC ≤0.01 are classi-
fied as “Chronic 1”, the more hazardous class concerning the
long-term effects. If these criteria are not met, the toxicologi-
cal testing should move to tier 3.
Finally, the third and last ITS tier is aimed at the exploration
of possible effects that cannot be detected by applying acute
and chronic toxicity test, such as cytotoxicity, DNA damage
and mutagenicity. To this end, the set of bioassays has been
expanded with the addition of the umu- and SOS Chromotest
systems ISO 13829:2000 (ISO 2000), two short-term test sys-
tems based on the detection of chemically induced DNA le-
sions that could lead to DNA mutations or SOS response
(bacterial error prone repair system) to bacterial strains that
have been genetically engineered and providing screening in-
formation also on the genotoxic potential for human and eco-
logical hazard assessment (OSPAR Commission 2002).
Both AF1 and AF2 are therefore tested according to the
described tiered ITS and the results show that (Fig. 4), while
AF1 is classified as acute 1, due to an estimated EC50 <
1mgl
−1
for the algae Pseudokirchneriella subcapitata,AF2
is not acutely toxic (i.e. EC50 > 1 mg l
−1
for all the three tested
species); however, it shows a moderate chronic toxicity (i.e.
0.01 mg l
−1
<NOEC≤0.1 mg l
−1
) to the aquatic invertebrate
Daphnia magna.
Accordingly, only AF2 is selected as the most promising
innovative nano-based consolidant to be checked according to
subsequent steps (safety and sustainability assessment).
However, before moving to step 4 for safety assessment,
ADJUSTED
FORMULATION 2 /
CLP h azard s
Wate r
93.25%
Ingr edient 1
(nano)
6.00%
Ingr edient 2
0.01%
Ingr edient 3
0.74%
Self-
classificaon of the
mixture (ECHA, 2017)
Acute toxicity - - cat 4 - H302 - Not classified
Serious eye
damag e/i rrita on
-- cat 2-H319- Not classified
Skin se nsis aon - - ca t 1 - H317 - Not classified
Hazardous to aqua c
environment
-- cat 2 -H411- Not classified
ADJUSTED
FORMULATION 1 /
CLP h azard s
Wate r
92.30%
Ingr edient 1
(nano)
7.00%
Ingr edient 2
0.70%
Self-classificaon of th e mixture
(ECHA, 2017)
Acute toxic ity - - cat 4 - H3 02 Not classified
Serious eye
damag e/i rrita on
-- cat 2-H319Not classified
Skin se nsis aon - - ca t 1 - H317 Not classified
Hazardous to aqua c
environment
-- cat 2 -H411Not classified
Fig. 3 Results of step 2bis:
screening hazard assessment of
adjusted formulations (AF1 and
AF2)
INITIAL
FORMULATIO N /
CLP h azard s
Wate r
50-95%
Ingr edient 1
(nano)
2.5-25%
Ingr edient 2
2.5-25%
Self-classificaon of the
mixture
(ECHA, 2017)
Acute toxi city - - cat 4 - H302 cat 4 - H302
(cut-off v alue 1%)
Serious eye
damage/ irritaon
-- cat 2-H319cat 2 - H319
(when concentraon ≥ 10%)
Skin s ensisaon - - cat 1 - H317 cat 1 - H317
(threshold > 1%)
Hazardous to aqua c
environment
-- cat 2 -H411cat 2 - H411
(when concentraon = 25%)
Fig. 2 Results of steps 1 and 2:
screening hazard assessment of
the initial formulation (IF)
26152 Environ Sci Pollut Res (2019) 26:26146–26158
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

exposure assessment must be carried out for both application
ad post-application phases. As far as application phase is con-
cerned, since usually nanomaterials represent only a very
small percentage in the composition of innovative systems
for conservation of works of art and therefore exposure in
occupational settings (i.e. conservation studios and laborato-
ries) is mainly driven by volatile compounds (e.g. solvents), it
was decided to define four exposure classes according to the
concentration (%w/w) of hazardous volatile components in the
formulation. Specifically, exposure is classified as follows:
negligible when the concentration of hazardous volatile com-
ponents is lower than 1% (i.e. the cut-off value suggested also
in CLP regulation) or when all recommended risk manage-
ment measures (RMMs; e.g. gloves, goggles and suitable ven-
tilation) are applied; low when the concentration of hazardous
volatile components is between 1% and 10% and recommend-
ed RMMs are not applied; medium when the concentration is
between 11% and 50% (with no RMMs); and finally, high
when the concentration is higher than 50% (with no
RMMs). Accordingly, since AF2 is composed by over 99%
of water and the nano-ingredient 1, restorer’sexposuretoit
can be classified as negligible both with and without the ap-
plication of suitable (and recommended) RMMs.
As far as the post-application phase is concerned, releases
of formulations’components (including nanomaterials) can be
considered negligible or not significant because it is assumed
that after application the consolidation system is bounded to
the substrate and cannot be distinguished from it. For this
reason, toxicity testing on released materials cannot be
performed and safety assessment is carried out for the appli-
cation phase only.
To this end (step 4), hazard and exposure data and
information collected or generated in the previous steps
are integrated according to the semi-quantitative control
banding approach depicted in Fig. 5, where the results
of hazard and exposure assessments are expressed ac-
cording to five and four classes, respectively. The five
hazard classes correspond to the number of human (H)
and environmental (ENV) hazards assigned to a specific
formulation according to the CLP self-classification ap-
proach. When formulation’s toxicity and ecotoxicity are
also experimentally tested (as in step 3 of the sustain-
ability assessment framework), these results can be used
to adjust hazard classification in the matrix (e.g. by
counting “hazard to the aquatic environment”if such
environmental hazard is indicated by experimental tests
performed on the formulation, although not assigned by
CLP self-classification). The four exposure classes are
those explained above (i.e. negligible, low, medium
and high). By combining each of them in the control
banding matrix, safety is assessed by using a simple
colour code, from the greenest top left corner (i.e. ex-
cellent level of safety, which corresponds to a mixture
with a concentration of hazardous volatile components
up to 10% and classified for up to two health (H) and
ENV hazards) to the reddest bottom right corner (i.e.
bad level of safety, which corresponds to a mixture with
a concentration of hazardous volatile components higher
Fig. 4 Results of step 3: advanced hazard assessment of adjusted formulations (AF1 and AF2)
Environ Sci Pollut Res (2019) 26:26146–26158 26153
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

than 50% and classified for more than six H and ENV
hazards).
Considering AF2, since exposure is negligible and the only
assigned hazard is the chronic toxicity for aquatic environ-
ment, it is falling in the top safety class (i.e. excellent; see
Fig. 5).
Finally, the sustainability of AF2 is evaluated and com-
pared with the one of conventional products (i.e. at least one
benchmark consolidant already on the market, if existing),
through a methodology based on MCDA, suitable to support
the integration of heterogeneous data from different domains
(step 5). Although such methodology is still under develop-
ment, we can anticipate that it will integrate information from
the three sustainability pillars (i.e. environment, economy and
society), as well as information on technical features of the
new products, described through semi-quantitative indicators
(e.g. market size, regulatory barriers and compatibility).
Under each pillar, indicators are scored according to five clas-
ses representing the level of satisfaction, from “excellent”to
“bad”, of a specific product solution, i.e. 5 is assigned to
“excellent”,4to“good”,3to“moderate”,2to“poor”and 1
to “bad”, and then mathematically aggregated to calculate an
overall sustainability score. As an example of its application,
Fig. 6reports the sustainability scores obtained for AF2 and a
conventional product (CP), showing that the overall sustain-
ability of the innovative system is indeed very high and better
than the CP’sone.
More specifically, according to the results of safety assess-
ment, the environmental pillar reaches the highest score (i.e.
5) for AF2 while CP, composed by more hazardous ingredi-
ents and thus classified for a higher number of H and ENV
hazards, lags behind; the same score is obtained by technolog-
ical pillar, thus reflecting the highly satisfying performance of
such an innovative consolidation system (AF2) compared
with CP, the latter being characterised by worse efficiency
and compatibility. Economic and social/ethical/legal pillars
obtain slightly lower scores (i.e. between 4 and 5) for AF2
than the other two pillars, due to the need to further invest on
its industrial upscale and on addressing easy to be solved
regulatory barriers (i.e. formalising compliance to relevant
legislation), respectively. However, by comparing them with
those obtained by CP, while economic scores are equal (the
reason is that although CP is already industrially upscaled, it
has a higher market price), AF2 performs better than CP ac-
cording to the social/ethical/legal pillar, thanks to the fact that
it allows a complete re-treatability of the artworks and an
excellent long-term action.
1.0
2.0
3.0
4.0
5.0
Technological
Econ omic
Environmental
Social/Ethical/
Legal
Sustainability scores
AF2 Convenonal product
Fig. 6 Results of step 5: sustainability assessment of AF2 and CP
LEGEND
0 1-2 3-4 5-6 >6
negligible AF2
low
medium
high
scarse
poor
bad
very good
excellent
good
moderate
Consolidaon
systems
HAZARD
ERUSOPXE
Fig. 5 Results of step 4: safety
assessment in the application
phaseofAF2
26154 Environ Sci Pollut Res (2019) 26:26146–26158
Discussion
The proposed sustainability framework implementing the
Safe by Design (SbD) concept allows to guide step by step
product developers in the early design of sustainable innova-
tive solutions for the conservation of works of art by suggest-
ing a way to proceed towards sustainability along the Stage-
Gate innovation process.
To this end, the triple bottom line (TBL) approach is
adopted, although at a screening level, in the first two steps
of the framework, and it is later expanded and fully cov-
ered by the fifth and last steps, where a MCDA-based
methodology is applied to integrate environmental, eco-
nomic, social/ethical/legal and technical aspects related to
innovative products and to allow their comparison with
conventional ones, if existing.
In between (steps 3 and 4), large space is devoted to inves-
tigating the environmental pillar of sustainability through the
inclusion and implementation of the SbD concept. This is
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

done by adopting a tiered approach, which includes both
screening and advanced hazard assessments. While screening
hazard assessment that is based on the use of information
available in SDS and on the application of the CLP self-
classification approach can always be applied, advanced haz-
ard assessment requires a further investment on computational
and/or experimental activities, which is more difficult to get at
industrial level (particularly by small and medium enterprises
because of resource constraints). However, it must be noted
that, when dealing with mixtures containing nanoparticles,
adequate physicochemical and (eco) toxicological informa-
tion about these ingredients are not always available through
SDS. Moreover, their behaviour can vary significantly accord-
ing to the media in which they are embedded. For this reason,
it is recommended to experimentally investigate how ingredi-
ents in the nanoform behave in the specific mixture and how
this can drive exposure and (eco) toxicity to different targets.
This would allow to reduce the uncertainty associated to the
results of the screening assessment and therefore to obtain a
more robust safety classification.
In the framework, human health and environmental safety
is checked in the fourth step through semi-quantitative or
quantitative approaches, according to data availability.
Specifically, while for safety in the application phase, a con-
trol banding approach is proposed, which allows for the inclu-
sion of appropriate RMMs, for safety in the post-application
phase, a deterministic estimation is preferred, which allows to
mathematically combine the previously derived predicted en-
vironmental concentration (PEC) and predicted no-effect con-
centration (PNEC).
Such flexibility of the framework allows its applicability in
different contexts, by iterating and tailoring each step accord-
ingtospecificusers’(i.e. mainly product developers but also
restorers) needs, thus facilitating the high interaction
demanded in the field of conservation science. As far as avail-
able tools and information which can be used for applying the
framework, the user can refer to the NanoReg2 SIA Toolbox
(https://www.siatoolbox.com/) and to the two databases now
accessible through the European Union Observatory for
Nanomaterials (EUON): NanoData (https://nanodata.echa.
europa.eu/) and eNanoMapper (https://euon.echa.europa.eu/
enanomapper).
However, the proposed framework should not be consid-
ered restricted to cultural heritage science and to nano-based
formulations only but can be extended to the development of
innovative chemical products across various application do-
mains, regardless of whether they occur as individual sub-
stances or in mixtures. The adjustment of the integrated testing
strategy (ITS) used in safety assessment as well as of some
specific criteria for sustainability assessment (e.g. criteria for
the social/ethical/legal or technological pillars) will be the
only requirement needed for using the sustainability assess-
ment framework in other application contexts.
Conclusions and future developments
The potential impacts on environment and human health of
innovative nano-based products for conservation of works of
art should be addressed already starting from the first stages of
the innovation process, according to a SbD approach. The
assessment of their safety should also be included in a more
comprehensive assessment of their sustainability, suitable to
evaluate and weight the environmental, economic and social
implications of the new products as required under the autho-
risation and restriction provisions of the REACH regulation.
In this work, taking into account state-of-the-art ap-
proaches for safety and sustainability assessment of
nanomaterials, a sustainability assessment framework
implementing the SbD concept has been proposed with
the aim of supporting product developers in the devel-
opment of innovative and sustainable nano-based prod-
ucts for cultural heritage conservation. Its goal is to
guide them in investing additional efforts in the design
phase in order to limit the need to find better alterna-
tives in the future, once the products are ready to enter
or are already in the market. This could imply addition-
al costs in the design phase (negligible for the screening
hazard assessment while more relevant in case-specific
ecotoxicological tests are performed within the advanced
hazard assessment), which however would be lower
than the personnel and economic resources to be spent
for the identification of safer alternatives at later stages
of the innovation process.
The example of application on a hypothetical (although
realistic) case study allowed us to illustrate how the proposed
framework can be applied inpractice through structured meth-
odological steps, which can be further tailored and iterated as
long as it is needed in the decision-making process.
Application to real case studies is currently being
finalised and will be presented in other papers
(Semenzin et al. in preparation; Giubilato et al. in
preparation). A set of nano-based products for cleaning,
strengthening and protection has been developed, and
their screening (i.e. CLP self-classification) and ad-
vanced (i.e. according to ITS) hazard assessments as
well as human health and environmental safety assess-
ment were completed. The development of the MCDA-
based methodology for sustainability assessment is be-
ing completed, and its application will allow the evalu-
ation of innovative products in terms of environmental,
economic, social and technical performance as well as
their comparison with conventional products if any.
Funding information This work has received fundingfrom the European
Union’s Horizon 2020 Research and Innovation Programme under Grant
Agreement No. 646063 (NANORESTART - NANOmaterials for the
REStoration of works of ART).
Environ Sci Pollut Res (2019) 26:26146–26158 26155
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Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give appro-
priate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
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