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Predictive Toxicology for Greener Chemicals
Craig Rowlands, PhD, DABTSenior Scientist for InnovationUnderwriters Laboratories
UL | Empowering Trust in a Complex World
Global Chemical Market
>130x106
Chemical structures synthesized
140,000Industrial chemicals used in global commerce
10,500chemicals used in personal care products
4,500Food Additives chemicals currently in use
Important data gaps may exist regarding chemical use and human & environmental health impact!
Chemical Compliance Pressures are Increasing
Dramatic increases in safety testing due to European REACH Registrations
- 2010 & 2013 → testing proposals- May 2018 → full submissions- ≥ 30,000 chemicals
New or changing regulations- Korea-REACH, Taiwan-REACH, China-REACH- Lautenberg Chemical Safety Act (new TSCA)
Other assessment/testing needs- Endocrine disruptors- Mixtures- Nanomaterials….
3
Chemical Sustainability Compliance Pressures are Increasing
• chemicals alternatives assessment (CAA) to substitute for the use of hazardous chemicals in products.
• >100 tools for comparing hazard characteristics of different chemicals.
• selection of alternatives for:• banned or restricted chemicals or
materials;• chemicals that are perceived as
hazardous by the public;• developing environmentally preferred
products.
The new regulator
CHEMICAL SUPPLY CHAINS ARE COMPLEX
sustainable productscompliant products
product safety (SDS)
innovate products
better ingredients
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Need for Hazard ata
Can conventional toxicology approaches keep pace with the demands for chemical hazard data?
picture© ChemSec
$$$$$$$$$$$$$$$$$$$$$$
R&D Regulatory toxicology(e.g. REACH, EPA …)
Follow-up MoA(e.g. human relevance)
Example - Two-generation reproductive toxicity study:LAnimal-intensive (>3,000 animals)LExpensive (>$500,000) LSlow (15 months)
Minimal involvement of Toxicologist inproduct designor selection
Conventional Toxicology
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New Safety Assessment Paradigm
$$$$$$$$$$$$$
R&D Toxicity testing,risk assessment
Early safety prediction
Moleculardesign
Selection
Read-acrossOptimize
formulations
Exposure assessment
Informtesting
Defense of commercialized or legacy molecules
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Predictive Toxicology Integrated Technology Platforms
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In Vitro Biological Profiling
Cheminformatics Exposure modeling
Cell cultures Zebrafish Genomics
PREDICT SAFETY
In Vitro Assays for Bioprofiling
Ex: Assays for Skin Sensitization*
Wong et al Front Pharmacol 6: 1-13, 2015
Class Test methodsCorrosion In vitro Skin Corrosion: Transcutaneous Electrical Resistance Test Method (TER): TG430
In vitro Skin Corrosion: Reconstructed Human Epidermis (RHE) test method: TG431
CORROSITEX Skin Corrosivity Test: TG435
Skin irritation In vitro Reconstructed Human Epidermis (RhE) Test methods, EpiDerm, EPISKIN, SkinEthic,LabCyte EPI-Model: TG439
Phototoxicity 3T3 NRU Phototoxicity Test: TG432
Eye irritation Bovine Corneal Opacity and Permeability Test Method for Identifying i) Chemicals InducingSerious Eye Damage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage: TG437Isolated Chicken Eye Test Method for Identifying i) Chemicals Inducing Serious Eye Damage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage: TG438
Fluorescein Leakage Test Method for Identifying Ocular Corrosives and Severe Irritants: TG460Short Time Exposure In Vitro Test Method for Identifying i) Chemicals Inducing Serious EyeDamage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious EyeDamage: TG491Reconstructed human Cornea-like Epithelium (RhCE) test method for identifying chemicalsnot requiring classification and labelling for eye irritation or serious eye damage: TG492
Skin sensitization In Chemico Skin Sensitization, Direct Peptide Reactivity Assay (DPRA): TG442CIn Vitro Skin Sensitization, ARE-Nrf2 Luciferase Test Method: TG442D
Endocrine activity screening
Performance-Based Test Guideline for Stably Transfected Transactivation In Vitro Assays toDetect Estrogen Receptor Agonists and Antagonists: TG455
H295R Steroidogenesis Assay :TG456BG1Luc Estrogen Receptor Transactivation Test Method for Identifying Estrogen ReceptorAgonists and Antagonists: TG457Performance-Based Test Guideline for Human Recombinant Estrogen Receptor (hrER) In VitroAssays to Detect Chemicals with ER Binding Affinity: TG493
Genotoxicity Bacterial Reverse Mutation Test : TG471In vitro Mammalian Chromosome Aberration Test: TG473In Vitro Mammalian Cell Gene Mutation Tests using the Hprt and xprt genes: TG476In vitro Micronucleus Test: TG487In Vitro Mammalian Cell Gene Mutation Tests Using the Thymidine Kinase Gene: TG490
Skin absorption Skin Absorption: In vitro Method: TG428
OECD Test Guidelines for in vitro Test Methods
Cheminformatics QSAR methodologies have been developed
• Cheminformatics is the integration of all relevant information on a compound and its structural or substructural analogs in order to make a preliminary assessment of potential toxicity
• Statistical – Predictions are made using a multilinear regression models fit to the training set using an algorithm-based approach.
• Mechanistic- Predictions are made using a multilinear regression model for toxicity modes of action associated with specific chemical features.
• Nearest neighbor method – The predicted toxicity is estimated by taking an average of a predefined number of chemicals in the training set that are most similar to the test chemical.
• Consensus method – The predicted toxicity is estimated by taking an average of the predicted toxicities from each of the above QSAR methodologies.
Cheminformatics
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Public domain data
ACToRToxNETNTP PubmedIUCLIDOECD Tool Box
Mining tool
Expert
Tox studiesPhys-chempropertiesExposure
Business data
Mining tool
SAR ToolsOASIS DEREKEPA TEST EpiWinEpiSuite ToxTreeOECD Toolbox TopKatECOSAR REACHAcross
Assessment
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Validated ApproachesValidated Approaches
Tier 2:Bioprofiling
QSAR, e.g., REACHAcross:
Acute mammalian toxicity
EPI Suite:Ecotox &
EnvFate (PBT)
in vitro:Acute mammalian
toxicity & Endocrine activity
BioprofilingDose-response (POD)
Mode of Actionin vitro
Transcriptomics: Chronic, DART, Neuro
BioprofilingDose-response (POD)
Exposure
Calculation of Human equivalent POD
exposure
Screening Level Risk Assessment: Biological Activity Based Margin of ExposureScreening Level Risk Assessment: Biological Activity Based Margin of Exposure
IVIVE: in vitro to in vivo extrapolation
Tier 1: Cheminformatics
Research ApproachesResearch Approaches
Integrated Non-animal Testing Strategy: New and Existing ChemicalsIntegrated Non-animal Testing Strategy: New and Existing Chemicals
Confirm &
Dose-response
Confirm & Dose-response
THE OPPORTUNITY OF BIG DATA & CHEMINFORMATICS
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Big Data – Rapid Increase in Availability of Chemical and Toxicology Data
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ECHA Animal & in vitro toxicity dataOver 20,000 compoundsEPA Over 2,000 compoundsEFSA Close to 10,000 compounds
Animal & in vitro toxicity dataAnimal & in vitro toxicity data
Vector (binary descriptor)2D Conformational Substructure Fingerprints
Comparing Chemicals to Establish Structural Similarities
16
Hazard Predicted by Nearest Neighbor
A B90%
17
33383 Unlabeled Chemicals
Similarity Map to300 Labeled Chemicals
Similarity Map to600 Labeled Chemicals
Similarity Map to1387 Labeled Chemicals
Increasing “Similars” with adding new Chemicals
Network Connections → Increasing Information
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REACH SkinSensitization
REACH allchemicals
Chemical Similarity
19
UL REACHAcross™ Internal Validation
EndpointAcute Toxicity-OralAcute Toxicity-DermalAcute Toxicity-InhalationSkin SensitizationSkin IrritationEye IrritationMutagenicityAcute Aquatic ToxicityChronic Aquatic Toxicity
Total Pos Neg12157 10225 1932
6314 4334 19806184 4812 13724751 2865 1886
15106 13758 134815722 14778 944
3395 600 27952043 1122 9212805 2554 251
Se%777774796983757678
BAC%777674717070737572
BAC%9278
84768475
Sp%777575637156717466
Nine endpoints:REACH 2018 <10 tons/a
Internal validation for unprecedented
number of chemicals
Correctly Identified True
PositivesTrue
Negatives
AverageSe + Sp
AnimalStudies
Accuracy similarto animal test
Cheminformatics (e.g., QSAR) for Green ChemistryCriteria for a useful toxicology tool:
• Assess human health AND environmental end points
• Rapid • Relatively inexpensive • No test material required• User friendly
Resources:USEPA: Toxicity Estimation Software Tool (TEST) https://www.epa.gov/chemical-research/toxicity-estimation-software-tool-testECHA JRC Computational Tools: https://eurl-ecvam.jrc.ec.europa.eu/laboratories-research/predictive_toxicology/qsar_toolsUL REACHAcross: https://www.ulreachacross.com/
The Crossroads of Chemistry and Toxicology: Advancing Greener, Safer Ingredients and Products
Pamela J. Spencer, Ph.D., D.A.B.T.Senior Director of Regulatory Affairs & Product StewardshipANGUS Chemical Company
Toxicology
Chemistry
Overview
§ Our Products
§ Market Challenges
§ New Product Introduction
§ Early safety screening strategies
§ Next steps
§ Q&A
2
OUR PRODUCTS
3
ChemistryANGUS is the only manufacturer in the world that uses propane nitration technology to create a unique set of products.
4
Propane
Nitroalkanes(Nitromethane, Nitroethane)
Nitroalcohols
Aminoalcohols(AMP, TRIS AMINO)
Aminoalcohol Derivatives(Zoldine MS-Plus, ALKATERGE)
Nitration of propane yields our Nitroalkane products
Nitroalcohols are formed via the reaction of nitroalkanes and aldehydes
Aminoalcohols are formed via the reduction of nitroalcohols
Aminoalcohols are converted to derivatives via reactions withaldehydes or carboxylic acids
Technology innovator with over 70 years of nitration expertise
Performance Attributes• Improves the quality and performance of a variety of formulations
• Extremely versatile and can be tailored to solve multiple challenges
• Multifunctional attributes may include several of the following:
• Neutralization • Alkaline pH development
• Corrosion Control • Emulsification (oil/water; water/oil)
• Surfactancy • Moisture Displacement
• pH buffering • Dispersancy
• Moisture Scavenging • Chemical scavenging
• Oxygen Scavenging • Free-radical scavenging
• Many of our products are known for their mildness and are suitable for sensitive applications such as personal care, pharmaceuticals and other life science utilities
5
Revenue Split by Industry
Market Overview
Revenue Split by Geography
Global specialty platform serving a diversified set of industries
North America
EMEA
Asia-Pacific
Latin America
Strong, balanced portfolio:• Product• End Market• Geography
Life Science
Paints
Personal Care
MWF
Rubber
BiocidesOthers*
Others*:• Gas Treating• Mineral Slurries• Leather• Adhesives • Industrial Water
Revenue Split by Geography
MARKET CHALLENGES
7
Ingredient Safety – Ingredient Bans
NEW PRODUCT INTRODUCTION
9
Commercial
R & D
Toxicologists work with R& D chemists & the rest of the project management team from the idea generation stage
Iterative Nature of Early R&D
11
Molecular Design
and Synthesis
Performance /Efficacy
MammalianToxicity
andEcotox
EnvironmentalFate
R&D Teams
Integration of New Tools into NPI
Screen
Lit /database
search
Physical /
chemical
properties
in silico
profiling
Flag issues
for early
testing
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Can
dida
tes
Disc.Stage
1
Disc.Stage
2
Disc.Stage
3
Dev.Stage
1
Dev.Stage
2
Dev.Stage
3
Dev.Stage
4
Dev.Stage
5
Test Flagsin vivo acute
-Tox- Ecotox
in vitro screen
Env. Fate probe
AcuteStudiesFinish Acute
-Tox- Ecotox
Env. Fate
SelectionRisk review
Select chemical
Development decision
Sub-chronic studies
Chronic studies
Registration
Manufacturing startup
Front End Loading in Research can pay huge dividends in Development:
Greener products, more cost effective, less waste
Early Screens: Toxicology “Red Flags”
• CMRs• Carcinogen• Mutagen• Reproductive/Developmental Toxicant
• PBTs• Persistent• Bioaccumulative• Toxic to the Environment
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Confirm Relevant QSAR Models for Target Chemistry
QSAR Validation Project
• A number of QSAR models and assessed their applicability for the ANGUS nitroparaffin and derivative chemicals with reference to sensitization, mutagenicity, and ready biodegradability
• TopKat QSAR model not recommended for future use for Angus molecules
• In silico models were improved by acquiring additional data to enhance the training sets
• For mutagenicity the QSAR tools appear to have some degree of reliability
• In the case of skin sensitization, it is evident that providing a predictive set of in vitro and QSAR models is complex and needs further research
• conflicting results from in vitro assays compared with in vivo assay may be the result of the potential for in vivo skin metabolism, corrosive properties of these compounds
• different vehicles used in performing the tests
• For biodegradability when multiple models were used some reliability was also found.
14
Flow Chart of Screening Level Assessment & Green Chemical Evaluation Process
15
ExistingData
CandidateChemical
AssessData
Screening Level Assessment (SLA)
Report
Yes
No
Data Gaps
Relevant Data
PredictEffects
O
CH3
CH3
CH3CH3
O
CH3
CH3 CH3
CH3
Comparison Table
Outcome
ExpertJudgment
CompTox
Literature Reports•Name•Synonyms•CAS Number•Structure•Sub-structure•Chemical analogs
read across
Mammalian Toxicity • Oasis™ -Toolbox/Times• EPA Chemistry Dashboard™
EcoToxicity& Env. Fate • Oasis™ -Times/Catabol• EpiWin™
ExpertJudgment
Expert Judgment
EARLY SAFETY SCREENING STRATEGIES IN PRACTICE
16
It all starts with a structure!
Which one is safer?17
Step 1. Read Across to a Chemically Similar Analog*
Endpoint Analog
Acute Oral LD50 688 mg/kg Rats
Acute Dermal LD50 ~2000 mg/kg Rats
Skin Irritation/Corrosion Corrosive
Eye Irritation/Corrosion Corrosive
Skin Sensitization Sensitizer LLNA
Repeated Dose Mild Liver effects at 1000 mg/kg
Reproduction NOAEL 1000 mg/kg
Genotox Negative in all in vitro and in vivo studies
Biodegradation 57% degradation in 56 days in OECD 301F
Acute Aquatic Toxicity EC/LC50 >10-100
*The chemical structures and following data are meant to serve as an illustrative example and do not represent an actual data for the structures.
New chemical candidate Read across analog
Step 2. OECD Toolbox Modeling for Candidate Chemical
Endpoint Model(s) Result
Acute Oral Cramer Original/Extension
Low Toxicity
Skin Irritation/Corrosion Inclusion/Exclusion rules by BfR
Inclusion Rules Not Met
Eye Irritation/Corrosion Inclusion/Exclusion rules by BfR
Inclusion Rules Not Met
Skin Sensitization OASIS v.1.4 No Alerts
Genotox alerts by ISS No Alerts
Repeated Dose HESS Not Categorized
Developmental/Reproduction DART Scheme v.1.0. No Alerts
Primary Biodegradation Biowin 4 Degradation in weeks to months
Ecotoxicity Verharr (Modified) Determination Not Possible
Report Out Weight of Evidence Safety Assessment
• No significant alerts resulted from read across or modeling
• OECD ToolboxØModeling results were supported by the testing for chemical
analog, except for skin sensitization
ØThree endpoints (skin/eye irritation/corrosion and ecotoxicity) where the target molecule was out of scope for the models utilized
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Recommendations/Next Steps
• Advanced candidate chemical to Step 3: in vitro testing to better characterize endpoints out of scope of modeling tools and/or did not align with chemical analog data
• Invitro Test Results:ØSkin/eye irritation – non irritating
ØSkin sensitization – not a skin sensitizer
• Biodegradation/ecotoxicity screen may also be necessary• Continue engagement with Project Management Team for NPI
to plan for key studies need to ultimately register new product in target global regions
21
Future Work
• Collaborative project underway with UL to validate REACHAcross ™ Tool for use with ANGUS Chemistry
• Project will be modeled will utilize data set from previous QSAR validation work
• Goal – determine if REACHAcross™ tool has improved domain coverage over other QSAR tools currently utilized
22
Summary• Concerns over product safety can determine success or failure
of product
• Companies can now apply quick and inexpensive tools for estimating EH&S issues early in product development (ID Red Flags)
• When a concern is highlighted via these tools a thoughtful approach to resolving the concern with toxicology data can be prepared in advance to avoid adverse findings in screening analysis
• Increases the ability to launch sustainable new products more cost effectively
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Thank You