CEFIC LRI Project EEM9.3

Transcription

1 REACH INFORMATION & EXPERIENCE EXCHANGE FORUM IV 19 JUNE 2015 CEFIC LRI Project EEM9.3 Linking LRI AMBIT Chemoinformatic System with the IUCLID Substance Database to Support Read across of Substance Endpoint data & Category Formation Dr. Volker Koch, Clariant CEFIC RIEF IV CEFIC LRI Project EEM Public

2 2 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Introduction Public Dr. Volker Koch, Clariant CEFIC RIEF IV CEFIC LRI Project EEM

3 3 Confidential, Outline CLN CompTox Project Computational Toxicology (1) Non-testing approaches are used to fill gaps in Human and Environmental Safety Assessment (ECETOC, 2012 TR116) : To avoid animal testing Reduce resource costs Bridge the gap of laboratory capacity availability Methods used for read-across and Category formation Read-across - Uses endpoint information for one chemical to predict the same endpoint for another chemical (also used in Category formation) Category formation of Chemicals - A Weight of Evidence approach using experimental and estimated data from different category members involving expert knowledge Read-across and Category formation is supported by in-silico tools (see ECETOC, 2012, TR 116) using various methodologies like QSARs, Expert systems allowing rule-based predictions, Similarity tools etc.

4 4 Confidential, Outline CLN CompTox Project Computational Toxicology (2) MAJOR GOALS OF THE CEFIC LRI PROJECT Enhancing the predictive power of in-silico tools like LRI AMBIT Use of Substance data which are already available in a company IUCLID Database. In addition CEFIC LRI is checking how to receive the data from the ECHA Dissemination site for ca substances. But other reliable data will be integrated as well Support read across and category formation workflows Avoiding animal tests and enhance the justification for read across and category formation as requested by authorities. Minimize overall testing and resource costs Using available studies for other substances as well

5 5 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Project overview Company IUCLID DB ECHA IUCLID DB As Major Data Source Search for data possible but not for structures Data transfer CEFIC LRI AMBIT Chemoinformatics System Supporting Read across & Category formation AMBIT FUNCTIONS Assigning structures -to constituents, impurities Search structures & Data - exact, similar, substructure - combined with data search Read across/category formation -Workflows supporting the user Prediction tools -Cramer rules, Protein binding etc Data analysis tools -Regressions, clustering etc. Data management -flexible import/export of data Data exchange - manual or automated e.g. webservices

6 6 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID IUCLID Data handling, Retrieval & Export Public Dr. Volker Koch, Clariant CEFIC RIEF IV CEFIC LRI Project EEM

7 7 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID IUCLID Database Name: o-anisidine CAS No IUCLID Version 4 IUCLID Version 5 Many page scrolls IUCLID 4 had ca. 850 Database fields IUCLID 5 has > 8500 Database fields

8 8 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID IUCLID Substance ID & Composition IUCLID Substance ID & Composition Every Substance in IUCLID is characterized by at least one composition A Composition consists of CONSTITUENTS n>= 1 IMPURITIES n>=0 ADDITIVES n>=0 A IUCLID substance itself has no chemical structure. Only constituents, impurities and additives have a structure 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 When the IUCLID composition is transferred, AMBIT assigns automatically searchable structures to constituents, impurities and additives (if they are available in the AMBIT structure pool of > structures)

9 9 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Data retrieval in IUCLID 5 (1) Manually Query Subst. ID Select Substance Select Endpoint Select EP record Scroll to data point of interest Using the IUCLID Query Tool Example: Searching a Substance and a specific endpoint e.g. Biodegradation Filing of Query blocks required (see next slide)

10 10 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Data retrieval in IUCLID 5 (2) The IUCLID Query Tool The Query tool supports searching for specific data using large and very detailed input screens (due to the large number of database fields). Less experienced users may get lost when they try to define a query Query block for Substance ID Query block for Biodegradation

11 11 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Data retrieval in IUCLID 5 (3) Data types to be retrieved with the IUCLID Query Tool Substance identity data e.g. Name, CAS No., substance type Composition data e.g. constituents, impurities, additives, purity of substance Structural information (not always available) Smiles notation, InChI, Structure as Image of reference substances of constituents, impurities and additives (please note: only exact search with Smiles code, NO SUBSTRUCTURE, NO SIMILARITY SEARCH Endpoint data Physico-chemical data, Environmental fate, Ecotoxicity, Toxicology

12 12 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Limitations of the IUCLID Query If the Smiles code is available in IUCLID, exact structure search is possible IUCLID cannot perform structure searches related to substructures or topological similarity which is indispensable for read across or category formation For substructure and similarity searches a Chemoinformatic system is required allowing to retrieve relevant endpoint AND structure and perform all kind of searches

13 13 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Transferring IUCLID Data into a Chemoinformatics System IUCLID has a so called Bulk Export Assistant (manual interaction required) IUCLID can exchange data via Webservice ((semi)automatically), automatic update of data as well

14 14 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID AMBIT Data import Public Dr. Volker Koch, Clariant CEFIC RIEF IV CEFIC LRI Project EEM

15 15 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Import filter for AMBIT These filter allow to select which data from an IUCLID substance should be imported into AMBIT

16 16 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID AMBIT Chemoinformatics System Data & Structure handling Functions Communication Public Dr. Volker Koch, Clariant CEFIC RIEF IV CEFIC LRI Project EEM

17 17 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID LRI AMBIT Chemoinformatic System AMBIT Chemoinformatics System was developed within a CEFIC LRI Project in 2005 and is part of the LRI Toolbox ( AMBIT was continuously developed further and is now a state of the art Java application running on all Operating Systems supporting Java AMBIT is an OpenSource Application with the following functions Search for structure(s) [exact, similar, substructure] and meta data Assessment tools (read across/category formation) currently developed Has Prediction tools e.g. Cramer rules, Protein binding, pka etc Has Data analysis tools e.g. regression, classification, clustering etc Data exchange tools: manual or automated via Opentox API, Webservices etc

18 18 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID AMBIT Search for Structures

19 19 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID AMBIT Search for Structures & Endpoint data 1) Find Structure(s) 2) Find Substance(s) 3) Display data

20 20 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Structures of Constituents, Impurities, Additives

21 21 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID IUCLID Substance Data in AMBIT

22 22 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID IUCLID Substance Data in AMBIT

23 23 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID IUCLID Substance Data in AMBIT Data for 44 Endpoints from IUCLID

24 24 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID IUCLID Substance Data in AMBIT

25 25 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID IUCLID Substance Data in AMBIT

26 26 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID IUCLID Substance Data in AMBIT

27 27 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID IUCLID Substance Data in AMBIT

28 28 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID AMBIT Communication Other Databases & Tools

29 29 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Workflow Read across & Category formation Public Dr. Volker Koch, Clariant CEFIC RIEF IV CEFIC LRI Project EEM

30 Maybe iterative process 30 AMBIT Workflows on Read across & Category formation Creating Assessment and defining initial target Searching for other targets and allied structures Selecting relevant structures Selecting data sources Selecting endpoints Data gathering Gap filling Evaluation Report generation using predefined templates Doc link Assessment Storage Finalizing Assessment dataset

31 31 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID New Assessment & Identifier

32 32 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Collected structures for Assessment T = Target, S = Source

33 33 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID List of Substances related to the structures Substance(s) related to structure 1 Substance(s) related to structure 2

34 34 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Substance composition matrix

35 35 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Assessment data matrix Substance No Tag CM CM CM CM Substance name Monoglyme Diglyme Triglyme Tetraglyme CAS No Pow / Log Pow Biodeg. In Water: Screening Bioaccumulation: aquatic /sedment Short-term tox. To fish Short-term tox. To aq. Invert. not readily biodegradable not readily biodegradable not inherently biodegradable Read-across: not readily biodegradable Read-across: not readily biodegradable Waiving Waiving Waiving Waiving Read-across: LC50(96h):100mg/l LC50(96h):>5000mg/l LC50(96h):>5000mg/l Read-across: LC50(96h):>5000mg/l EC50(48h): 4000mg/l EC50(48h): 943mg/l EC50(48h): 5000mg/l EC50(48h): 5000mg/l Toxicity to algae Long-term tox. To aq. Invert Toxicity to microorganisms Acute toxicity: oral Skin sensitisation Repeat. dose tox. :oral Genetic toxicity in vitro Genetic toxicity in vivo Develop. Tox. / teratogenicity ErC50(72h): 9120mg/l ErC10(72h): 3793mg/l Read-across:NOEC(21d):>100mg/l NOEC(3h): 200mg/l ErC50(72h): >10000mg/l ErC10(72h): 8318mg/l NOEC(21d): 230mg/l NOEC(3h): 1067mg/l ErC50(72h): >6000mg/l ErC10(72h): 3000mg/l Read-across:NOEC(21d):>100mg/l NOEC(3h): >5000mg/l ErC50(72h): 8996mg/l ErC10(72h): 2871mg/l Read-across:NOEC(21d):>100mg/l Read-across:NOEC(3h):>100mg/l LD50: 5370 mg/kg LD50: 4760 mg/kg LD50: 5390 mg/kg LD50: 3850 mg/kg bw Read-across:Not sensitizing Read-across:'Not sensitizing Read-across:'Not sensitizing Not sensitizing Read-across: NOEL: 62.5 mg/kg (rat; 28day) bacterial reverse mutation assay (e.g. Ames test): Negative mammalian cell gene mutation assay: Negative in vitro mammalian chromosome aberration test: Negative in vitro mammalian chromosome aberration test: Negative in vitro mammalian chromosome aberration test: Negative in vitro mammalian chromosome aberration test: Negative micronucleus assay: Negative chromosome aberration assay: Negative NOEC(developmental, inhalation): 0.06 mg/l air ( OECD 414) NOEC(maternal, inhalation): mg/l air (OECD 414) NOEC(developmental, inhalation): mg/l air (OECD 414) NOEC(maternal, inhalation): mg/l air (OECD 414) Read-across:NOEL(developmental, oral): 25 mg/kg bw (OECD 414) Read-across:NOEL(maternal, oral) 50 mg/kg bw (OECD 414) Read-across: NOEL: 62.5 mg/kg (rat; 28day) bacterial reverse mutation assay (e.g. Ames test): Negative bacterial reverse mutation assay (e.g. Ames test): Negative mammalian cell gene mutation assay: Negative (read-across) in vitro mammalian chromosome aberration test: Negative micronucleus assay: Negative Read-across:chromosome aberration assay: Negative NOEL(developmental, oral): 25 mg/kg bw (OECD 414) NOEL(maternal, oral) 50 mg/kg bw (OECD 414) NOEL(developmental, oral): 62.5 mg/kg bw (OECD 414) NOEL (maternal, oral): 500 mg/kg bw (OECD 414) Read-across:NOEC(developmental, inhalation): mg/l air (OECD 414) Read-across:NOEC(maternal, inhalation): mg/l air (OECD 414) NOEL: 62.5 mg/kg (rat; 28day) Read-across:bacterial reverse mutation assay (e.g. Ames test): Negative mammalian cell gene mutation assay: Negative Read-across:in vitro mammalian chromosome aberration test: Negative Read-across:micronucleus assay: Negative Read-across:chromosome aberration assay: Negative NOEL(developmental, oral): 75 mg/kg bw (OECD 414) NOEL(maternal, oral): 125 mg/kg bw (OECD 414) Read-across:NOEC(developmental, inhalation): mg/l air (OECD 414) Read-across:NOEC(maternal, inhalation): mg/l air (OECD 414) NOEL: 250 mg/kg (rat; 28day) Read-across:bacterial reverse mutation assay (e.g. Ames test): Negative Read-across:in vitro mammalian chromosome aberration test: Negative Read-across:mammalian cell gene mutation assay: Negative Read-across:micronucleus assay: Negative Read-across:chromosome aberration assay: Negative Read-across:NOEL(developmental, oral): 25 mg/kg bw (OECD 414) Read-across:NOEL(maternal, oral) 50 mg/kg bw (OECD 414) Read-across:NOEC(developmental, inhalation): mg/l air (OECD 414) Read-across:NOEC(maternal, inhalation): mg/l air (OECD 414)

36 36 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Project status Public Dr. Volker Koch, Clariant CEFIC RIEF IV CEFIC LRI Project EEM

37 37 Functions Data transfer from IUCLID 5.6 to AMBIT is fully working Assessment workflow for read across & category formation in Beta testing Formatted Export of Data matrices of read across & category formation into EXCEL is currently implemented Report for Justification of Read across / Category formation Definition of the format is done, implementation running Automated data filling from estimation tools or other databases not implemented yet

38 38 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Project information Project idea Volker Koch, Clariant LRI Manager Bruno Hubesch Contractors Nina Jeliazkova, Ideaconsult Ltd Egon Willighagen, University of Mastricht Clariant Team for System design Udo Jensch, Toxicologist Volker Koch, Ecotoxicologist Qiang Li, Toxicologist Joachim Schneider-Reigl, Ecotoxicologist Project end September 2015

39 39 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Beta Testing Public Dr. Volker Koch, Clariant CEFIC RIEF IV CEFIC LRI Project EEM

40 40 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID Beta Tester We are looking for Beta tester Willing to test the functionality available so far Sending us feedback and report bugs Beta tester Will get access to a public AMBIT Webserver having a number of IUCLID substances with full data sets Will receive a detailed step by step guidance how to use the system If interested send an to me

41 41 Public, LRI PROJECT EEM9.3LINKING AMBIT WITH IUCLID CEFIC LRI Workshop on Project EEM9.3 Linking AMBIT with IUCLID Date September 23, 2015 Location CEFIC Premises Brussels Public Registration starting July 24, 2015 see LRI Website Registration form first come, first served Dr. Volker Koch, Clariant CEFIC RIEF IV CEFIC LRI Project EEM