Supporting safety assessments of chemical substances and nanomaterials
Supporting safety assessments of chemical substances and nanomaterials: commonalities and differences CEFIC LRI AMBIT Tool Supporting Read-across Dr. Nina Jeliazkova Ideaconsult Ltd. Sofia, Bulgaria www. ideaconsult. net 1
Content Ø REACH regulation ØNon-testing (Alternative methods) ØNanoforms Ø CEFIC LRI AMBIT Tool Supporting Read-across ØChemical substances and nanoforms ØECHA dissemination data ØRead across workflow 2
3 REACH: The Registration, Evaluation, Authorization and Restriction of Chemicals • Enacted in 2006, amended 33 times since coming into force on 1 June 2007 • Managed by ECHA (European Chemicals Agency) • Aim: “ensure a high level of protection of human health and the environment as well as the free movement of substances, on their own, in preparations and in articles, while enhancing competitiveness and innovation. This Regulation should also promote the development of alternative methods for assessments of hazards of substances” • Main activities: the registration of substances with the general rule being “no data, no market” meaning that “substances on their own, in M 3 mixtures or in articles shall not be manufactured in the Community or placed on the market unless they have been registered. ” 3
4 REACH: chemical substances registration • Introduced gradually • November 2010 - general deadline for registering substances manufactured in the EU or imported if <1000 tonnes or more a year; • May 2013 – deadline for registering substances between 100 and 1000 tonnes a year; • The number of pre-registered substances between 1 June and 1 December 2008 reached 145 299. • Currently: 14 137 unique substance in 54466 dossiers. • May 2018 – deadline for registering substances between 1 and 100 tonnes a year. Expected to greatly affect the scope of the regulation. 4
5 REACH Annex XI: Alternative methods (“where testing does not appear scientifically necessary”) Read across and category formation (grouping): • Substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. • Application of the group concept requires that physicochemical properties, human health effects and environmental effects or environmental fate may be predicted from data for reference substance(s) within the group by interpolation to other substances in the group (read-across approach). This avoids the need to test every substance for every endpoint. • 1) a common functional group; 2) the common precursors and/or the likelihood of common breakdown products via physical and biological processes, which result in structurally similar chemicals; 3) a constant pattern in the changing of the potency of the properties across the category. 5
6 Read-across and Category formation Ø Non-testing methods which are regularly applied to assess the safety of Chemicals § Report on the Operation of REACH and CLP 2016, European Chemicals Agency, May 2016 www. echa. europa. eu/documents/10162/13634/operation_reach_clp_2016_en. pdf § Used on average in 20% of the Endpoint Study Records, while QSAR is used in < 1% § “the read across approach was used to fulfill at least one endpoint in 75% of the dossiers assessed” Ø Accepted by most Regulatory Bodies if the approach taken is sufficiently justified and documented Ø Supported by in-silico tools (see ECETOC, 2012, TR 116) § Using various methodologies like QSARs, rule-based predictions , similarity tools, etc. 6
REACH: “Chemical substance, a material with a definite chemical composition” http: //echa. europa. eu/documents/10162/13643/nutshell_guidance_substance_en. pdf The REACH definition of a substance encompasses all forms of substances and materials on the market, including nanomaterials; and may have complex composition. – Mono-constituent: A substance with one main constituent. – Multi-constituent: A substance with two or more main constituents. - Main constituent: A constituent, not being an additive or impurity, in a substance that makes up a significant part of that substance. Contributes to the naming of the and substance. Most in-silico tools chemical Concentration of the main constituent(s) = purity of the substance. structure databases do not support – Additive: A substance that has been intentionally added to substance compositions relate stabilise the substance. Contributes to the substance and composition. one structure to a substance ! – Impurity: An unintended constituent present in a substance, as produced. Does not contribute to the naming of the substance non-confidential REACH data supplied by ECHA http: //ambitlri. ideaconsult. net 7
LRI AMBIT Chemoinformatics System Ø Online at https: //ambitlri. ideaconsult. net/ Ø Developed within a CEFIC Long-Range Initiative (LRI) Project in 2005; part of the LRI Toolbox CEFIC : European Chemical Industry Council http: //cefic-lri. org/ Ø AMBIT was continuously developed further ; A state of the art Java web application running on all Operating Systems supporting Java Ø Goal of the CEFIC LRI EEM 9. 3 -IC project was enhancing the predictive power of AMBIT ; Using large datasets of quality Substance data: ECHA & company DB & other sources Ø Implementing workflows for Assessments supporting the assessor in setting up a read across/category approach and in establishing a valid justification for the approach Ø Minimizing overall animal testing and resource costs by using available studies for other substances as well if appropriate 8
LRI AMBIT Chemoinformatics System Ø An Open Source Application with the following functions ØSearch for structure(s) [exact, similar, substructure] and meta data ØAssigning structures to constituents, impurities … ØAssessment tools (read across/category formation) ØPrediction tools e. g. Toxtree (including Cramer rules , Protein binding, etc. ), descriptor calculation, p. Ka etc; ØData analysis tools e. g. regression, classification, clustering etc; ØData management : flexible import/export of data ØData exchange tools: manual or automated via REST Web services API; Ø Source code and application download http: //ambit. sourceforge. net 9
1 0 Substance and Composition http: //iuclid. eu Ø Every Substance in IUCLID is characterized by at least one composition. Ø A Composition consists of Ø CONSTITUENTS n>= 1 Ø IMPURITIES n>=0 Ø ADDITIVES n>=0 Ø A IUCLID substance itself has no chemical structure. Only constituents, impurities and additives have a structure. Ø As a IUCLID composition has at least of 1 constituent, at least one structure is assigned. Most IUCLID substances are related to more than 1 structure. http: //ambit. sf. net Ø Chemical structures and properties only (till 2013) Ø Updated AMBIT data model ØSubstance composition ØMeasured properties assigned to substances ØCalculated properties assigned to structures ØWhen the IUCLID composition is transferred, AMBIT assigns automatically searchable structures to constituents, impurities and additives 10
AMBIT Search for Structures & Endpoint data 1) Find Structure(s) 2) Find Substance(s) 3) Display data 11
IUCLID Substance Data in AMBIT Ø Composition Data in AMBIT allow a straightforward overview on constituents, impurities & additives as well as the concentrations associated 12
1 3 What about nanomaterials? SUBSTANCE (FORMALDEHYDE) GOLD NANOPARTICLE Additive Constituents Coating Main constituent Core Impurity 9/29/2 020
IUCLID substances in AMBIT 14
Regulations related to nanomaterials – Nanomaterials are in the scope of the REACH regulation – EC Second Regulatory Review on Nanomaterials (2012) “overall the Commission remains convinced that REACH sets the best possible framework for the risk management of nanomaterials when they occur as substances or mixtures but more specific requirements for nanomaterials within the framework have proven necessary. The Commission envisages modifications in some of the REACH Annexes” – Nevertheless, REACH does not currently explicitly contain any information regarding any specific regulatory approach towards nanomaterials. – Definition (recommendation, not legally binding) : “‘Nanomaterial’ means a natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for 50 % or more of the particles in the number size distribution, one or more external dimensions is in the size range 1 nm-100 nm” 15
Regulations related to nanomaterials – EC Third Regulatory Review on Nanomaterials (expected late 2016) – Regulation of nanoforms is high on the current legislative agenda. – ECHA Report on the Operation of REACH and CLP 2016: - “does not see the urgent need to Revise the REACH Regulation” - “the coverage of nano forms of substances in registration dossiers must improve” - “amendments of the REACH annexes for information requirements are urgently needed to ensure that sufficient clarity is given to registrants for their registrations of substances with nanoforms and so that their safety can be better assessed. ” 16
ECHA report (March 2016) : nanoforms Ø “Usage of (eco)toxicological data for bridging data gaps between and grouping of nanoforms of the same substance” Ø Aim: “to consolidate existing information and develop approaches that a registrant can use to scientifically justify that certain (eco)toxicological studies undertaken on one nanoform of a substance (or the non-nanoform) can be used to predict the hazard properties of (an)other form(s) of the same substance” Ø Nanoforms and non-nanoforms 1. a nanoform has a corresponding non-nanoform 2. a nanoform has no corresponding non-nanoform Ø Multiple different nanoforms can exist depending on variations of physicochemical parameters 17
ECHA report (March 2016) : nanoforms Ø “The information currently required under REACH in Annex VI may in some cases not be sufficient to identify and characterise nanoforms […] thus additional information on particle characteristics is essential to enable proper hazard assessment of nanoforms. […] “ Ø “There is general agreement that, in addition to the standard data requirements for physicochemical properties, some further properties to be routinely considered for studies of nanoforms include: Øspecific surface area, particle size and particle size distribution, surface chemistry, agglomeration and aggregation, crystalline phase, shape and aspect ratio, photo-catalytic properties, porosity and pour density, dustiness, dispersibility, zeta potential and reactivity (redox potential, radical formation)” 18
1 9 IUCLID Substance Data in AMBIT IUCLID 5. 5 XML schema Ø Endpoint study records : 126 OECD Harmonized templates (OHT) Øphysicochemical, environmental Øhealth hazard Øtoxicity endpoints Ø 79 templates, defining Endpoint summaries. Ø Large and complex data model: thousands of data fields Ø different documents linked by UUIDs Ødifferent data types Ødeeply nested data structures. Data for >43 Endpoints from IUCLID The specific templates and fields imported are based on recommendations by the Clariant Comp. Tox team 19
Data Import filter for AMBIT Ø The filter allow to select which data of an IUCLID substance should be imported into AMBIT and work for manual data import from. i 5 z files and automatic import from IUCLID 5 web services 20
2 1 The LRI AMBIT tool is loaded with nonconfidential REACH data supplied by ECHA to CEFIC-LRI under a specific agreement CEFIC LRI would like to thank ECHA for providing the nonconfidential IUCLID data which are accessible on the ECHA Website Datasets on 14570 Substances have been provided on January 12, 2016 by ECHA in Computer readable format allowing the import into AMBIT 21
IUCLID Substance Data in AMBIT non-confidential REACH data supplied by ECHA http: //ambitlri. ideaconsult. net 22
IUCLID Substance Data in AMBIT Ø IUCLID Data in AMBIT are organized in tab sections allowing easy access by clicking on the tab of interest 23
IUCLID Substance Data in AMBIT Ø TOX section 24
Communications with other systems Transfer via Web service or *. i 5 z files Company IUCLID DB & ECHA IUCLID DB as Major Data Sources Data transfer Other Databases Data transfer LRI AMBIT Supporting Read across & Category formation Transfer of 14570 Dossiers Data transfer Other Tools 25
Combining information from other data sources and prediction results The vertical sidebar allows collating data and model information with the search results.
Toxtree predictions integrated in AMBIT Standalone Toxtree at http: //toxtree. sf. net 27
Create Assessment and define the target T Workflow on Read across & Category formation – “Assessment workflow” Refine if necessary Search for Source structures S or Category members CM Select relevant structures Select data for T, S / CM Select relevant Endpoints Establish Data Matrix Fill data gaps for T / CM Evaluate Gap filling Save Assessment & Create Report 28
Assessment Workflow in AMBIT Using a Tab Structure 29
New Assessment & Identifier (Tab 1) 30
Collect structures for Assessment (Tab 2) T = Target, S = Source, CM = Category member Ø Based on the SMILES code of the Target Diglyme a substructure search was carried out limited to those having substance data Ø Clicking T, S or CM allows to assign the structure for intended purpose 31
List collected structures for Assessment T = Target, S = Source, CM = Category member Ø Based on the SMILES of the Target Diglyme a substructure search was carried out limited to those having substance data 32
Search Substances associated to the Structures Ø When clicking the Tab “Endpoint data used” the associated substances are displayed and can be selected for further use (Subtab “Search substance(s)”) 33
Search Substances (Tab 3) Ø When clicking the Tab “Endpoint data used” and subsequently the sub-tab “Selection of endpoints”, a list of IUCLID Endpoints are displayed for selection by check marking 34
Working matrix (Tab 4) Composition section 35
Working matrix (Endpoint section) 36
The working matrix is editable (Tab 4) 37
Modified working matrix (Tab 4) 38
Model predictions in the working matrix (Tab 4) Automatic merge with predicted values (e. g. Toxtree, log. P) 39
EXCEL Export of the Working Matrix (Tab 4) Ø AMBIT has several reporting functions, one is the export of the Working matrix into EXCEL for easier handling and printing 40
Assessment report (Tab 5) Ø AMBIT has several reporting functions, one is creating an assessment report in Word 41
Assessment report with final matrix (section 5 & 6) Ø The report describes the read across workflow in 6 sections and 5 annexes 42
Read-across and grouping of nanoforms Ø ECHA report (March 2016) “Usage of (eco)toxicological data for bridging data gaps between and grouping of nanoforms of the same substance” Ø ECHA has put a particular emphasis on read-across in the report, stating in that regard: “[…]the main challenge is to devise an approach that enables an acceptable level of confidence that test data generated on one or more nanoform(s) (or on non-nanoforms) apply to other nanoform(s) without compromising the hazard assessment. ” Ø“grouping of nanoforms based on similarity and read-across between nanoforms within a registration dossier may be a useful tool for demonstrating safe use for all nanoforms of a registered substance. ” Ø An open problem: a number of recent publications and ongoing activities on grouping of nanomaterials 43
can be downloaded or consulted online: Ø Publicly available https: //ambitlrli. ideaconsult. net - Clients only need a web browser Ø More information and download links - http: //cefic-lri. org/news/cefic-launches-ambit-chemical-safety-prediction-software/ Ø Installation options Ø LOCAL on a LAPTOP/DESKTOP - Local database, local webserver Ø SERVER (on company INTRANET) - Shared database and web server. Clients only need a web browser. Ø Requirements - Java 7, My. SQL 5. 7, Web server (servlet container, e. g. Apache Tomcat 7. x) Ø TECHNICAL SUPPORT contact Ideaconsult Ltd, Sofia www. ideaconsult. net , email: support@ideaconsult. net 44
4 5 AMBIT publications and contributing projects Peer reviewed publications (excerpt) 1. 2. 3. 4. Ø CEFIC LRI EEM 9. 3 N. Jeliazkova and V. Jeliazkov, “AMBIT § P&G (J. Jaworska), Nina Jeliazkova RESTful web services: an implementation of the Open. Tox application programming Ø CEFIC LRI EEM 9. 3 -IC (2013 -2015) interface, ” J. Cheminform. , vol. 3, no. 1, p. § Idea. Consult Ltd. , Clariant, UM 18, Jan. 2011. Ø Projects contributed to the N. Jeliazkova and N. Kochev, “AMBITdevelopment SMARTS: Efficient searching of chemical § EC FP 7 Open. Tox (2008 -2011) structures and fragments, ” Mol. Inform. , vol. 30, no. 8, pp. 707– 720, 2011. § EC FP 7 Tox. Bank (2011 -2015) N. Kochev, V. Paskaleva, and N. § EC FP 7 e. Nano. Mapper (2014 -2017) Jeliazkova, “AMBIT-Tautomer: An open § EC H 2020 Ex. CAPE (2015 -2018) source tool for tautomer generation, ” Mol. Inform. , vol. 32, pp. 1– 24, 2013. § (and more) N. Jeliazkova, et al, “The e. Nano. Mapper Ø Open source libraries database for nanomaterial safety § The Chemistry Development Kit information, ” Beilstein J. Nanotechnol. , vol. 6, pp. 1609– 1634, Jul. 2015. § (and many more) 45
Acknowledgements Ø CEFIC LRI EEM 9. 3 -IC o Ø Bruno Hubesch Project idea for LRI EEM 9. 3 -IC o Volker Koch, Clariant Ø Project input : Ø Clariant Comp. Tox Team o Udo Jensch (Toxicologist) o Volker Koch (Ecotoxicologist) o Qiang Li (Toxicologist) o Joachim Schneider-Reigl (Ecotoxicologist) Ø Project implementation Ø Ideaconsult Ltd. www. ideaconsult. net 46
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