1. Health-Related Components of DSL Categorization under CEPA 1999 Exposure and Hazard Tools Presented by: Jesse Ng Existing Substances Division Health Canada Oct 20, 2005 Health-Related Components of DSL Categorization under CEPA 1999 Exposure and Hazard Tools Presented by: Jesse Ng Existing Substances Division Health Canada Oct 20, 2005

2. 2 Outline The Canadian Environmental Protection Act Health Canada’s mandate Categorization –Principles and objectives Maximal List Exposure Tools Hazard Tools Input from stakeholders Screening Assessments Key messages

3. 3 Existing Substances under the Canadian Environmental Protection Act (CEPA) CEPA is administered jointly by Environment Canada and Health Canada CEPA 1999 – extended our mandate from Priority Substances to Categorization of the approximately 23,000 existing substances on the Domestic Substances List (DSL) by September 2006 The DSL was created for the purpose of defining a “new substance” under CEPA Includes substances “grandfathered” under the legislation Substances in use between January 1, 1984 and December 31, 1986 Organics (50%), organic metal salts, organometallics, inorganics, polymers and substances of unknown or variable composition, complex reaction products & biological materials (UVCBs)

4. 4 Health Canada’s Mandate on Existing Substances Address both exposure and effects to set priorities for risk assessment and management under CEPA Source characterizations to inform risk management –Information Gathering/Industrial Surveys Publicly accountable – transparent process and content, peer input, consultation and review, documented outcome

5. 5 Categorization – human health Need to consider: “Greatest potential for exposure” (GPE) – all DSL substances “Inherently Toxic to humans” (IT human ) – subset of substances [Those that are P or B [but not inherently toxic to environmental organisms (IT eco )] Challenges: Categorization must be completed by September 2006 Consistency with Priority Substances outcomes for high hazard

6. 6 CATEGORIZATION of the Domestic Substances List (DSL) (First Phase) (n=23,000) Decisions of Other Jurisdictions Public Nominations No further action under this program CEPA-Toxic No further action under this program CEPA-Toxic IN-DEPTH ASSESSMENT Priority Substances List (Third Phase) Risk Management Greatest Potential for Human Exposure Substances that are Persistent or Bioaccumulative “Inherently Toxic” to Humans “Inherently Toxic” to non-Human Organisms SCREENING ASSESSMENT (Second Phase) STAGE 1 STAGE 2 STAGE N-1 STAGE N STAGE 3 CEPA Existing Substances Program

7. 7 Categorization Objectives Set priorities for data generation and health assessment for all Existing Substances Health protective approach, conservative in the absence of information Complex program architecture requires multiple stages of increasing complexity which address all groups of compounds concomitantly –First stages: simple/pragmatic to address all substances, based on limited information for each or many Simple tools –Subsequent stages must be discriminating to set true priorities for further work Complex tools Avoid continuing bias to focus on data-rich Existing Substances

8. 8 Identifying Highest Priorities for Human Health Approach Initial application of simple, discriminating tool on exposure to address all 23,000 substances to prioritize “Greatest Potential for Exposure” (GPE), “Intermediate Potential for Exposure” (IPE) & “Lowest Potential for Exposure” (LPE) –Draws on information submitted in compilation of the Domestic Substances List Application of simple, discriminating tool to address hazard for all 23,000 substances –Draws on work completed internationally Priority-based application of more complex tools to additionally refine & prioritize

9. DOMESTIC SUBSTANCES LIST Substances that are Persistent and/or Bioaccumulative According to the Regulations Organic Substances that are Persistent and/or Bioaccumulative and Not “Inherently Toxic” to Non-human Organisms Substances that are Persistent and/or Bioaccumulative and “Inherently Toxic” to Non-human Organisms ENVIRONMENT CANADA No Further Action (Not 64c “toxic”) INTEGRATED FRAMEWORK Highest Lowest HEALTH CANADA DSL Substances Identified as Hazardous to Human Health DSL Substances Ranked According to Potential For Exposure HC Maximal List EC Substances Identified for Screening Assessment Substances Prioritized & Identified For Full Screening Health Assessment Application of Complex Tools Application of Simple Tools

10. 10 The Maximal List High 576 Moderate 989 Low 331 301 LPE, High Hazard 275 GPE or IPE & High Hazard 121 IPE, P or B 480 GPE 388 IPE, P or B unknown 183 Low Hazard 148 “other”

11. 11 What Do the Groups on the Maximal List Mean? High likelihood of remaining for further work beyond 2006 –Subset of 301 for risk management (LPE & high hazard) Moderate likelihood of remaining as health priorities beyond 2006 –Information will help here UVCBs, polymers, wide range use substances delineated as priorities Low likelihood of remaining for further work beyond 2006 –Low hazard –Substances already addressed CEPA

12. 12 DSL TOOLS - HEALTH Exposure SimET (Relative ranking of all DSL substances based on submitters (S),quantity (Q) and expert ranked use (ERU) ComET (Quantitative plausible maximum age-specific estimates of environmental and consumer exposure for individuals based on use scenario (sentinel products), phys/chem properties & bioavailability) Hazard Quantification (Previously Exposure-Response) HazQ (measures of exposure-response developed (where possible) on the basis of measured or predicted carcinogenic potency, reference values or effect levels Hazard [High (H) or Low (L)] SimHaz (identification of high or low hazard compounds by various agencies based on weight of evidence) ComHaz (Hierarchical approach for multiple endpoints & data sources (e.g., QSAR) including weight of evidence

13. 13 Simple Exposure Tool - SimET SimET is a relative ranking tool by which we have “binned” all substances on the DSL –Considers potential for environmental and consumer exposure Based on three different lines of evidence, derived from the limited information provided for all substances on the DSL: –quantity (estimated annual quantity of use, Q), –number of submitters, S –use (sum of normalized expert ranked use codes, U), reflecting two workshops Industrial sector and functional use codes

14. 14 Criteria for Greatest, Intermediate and Lowest Potential for Exposure (GPE, IPE & LPE) Quantity (kg/year) Number of Submitters Sum of the Expert Ranked Use Code Indices GPE> 100 000Top 10% IPE> 10 000n.a.Top 30% LPEAll

15. 15 Provides quantitative plausible maximum estimates of exposure of individuals in the general population by age group for consumer (near-field) & multimedia environmental (far-field) exposure Far-field exposure –Based on concentrations in environmental media estimated from fugacity modelling Near-field exposure –Frequency and duration of product use –Based on “Sentinel” product scenarios Exposure for all age groups to be addressed The Complex Exposure Tool (ComET)

16. 16 Chemical Identity Physical/ Chemical Properties Substance Profile Production Quantity Measures of Dose- Response for Critical Effects Priority for Assessment Production Quantity Bin + Release Factor Emissions Near-fieldFar-field Human Exposure Sentinel Products SP 1 SP 2 SP 3 SP n Far Field Age Specific Variables Overview of ComET

17. 17 Principles in Developing ComET Transparency in the approach and assumptions –Uncertainties and data gaps identified Defensibility, Consistency and Inclusiveness –Drawing maximally on the documented work of others by building on existing scenarios Data call in to stakeholders Peer input, consultation and review Outreach to other jurisdictions Fit for purpose –Conservative and protective assumptions for priority setting, but adaptable to enable incorporation of more refined models Readily useable and applicable to all chemicals irrespective of data available –Drawing maximally on generic information

18. 18 ComET – Far-field Exposure from DSL substances in the environment Extension of existing fugacity models (e.g., ChemCAN) to estimate concentrations of substances in environmental media (Mackay model) –Physical/Chemical properties –Emissions/Releases –Distribution of substances into relevant media, e.g., air, water, soil, sediment –Fate, e.g., drinking water, foodweb Generic unit world model that can be scaled and modified for further refinement Applied to substances for which little or no empirical property data are available and emission rates are known only approximately

19. 19 Substance Calculate Unit Emissions Ambient Concentrations Integrate with Near-field Component The Far-field Model Scale unit concentrations using actual emissions, production quantities and use information Phys-Chem properties and use information (Substance Profile) Transformation and fate Migration into media for uptake

20. Route of exposure Estimated intake (μg/kg-bw per day) of (name of substance from DSL) by various age groups 0–6 months 0.5–4 years 5–11 years 12–19 years 20–59 years 60+ years formula fed not formula fed Ambient air Indoor air Drinking water Food and beverages Soil Total intake Far-field - Output

21. 21 ComET – Near-field Exposure from DSL substances in consumer products Selection of “sentinel” products –Identification of use of a substance for a specific function in a product (e.g., surfactant in paint, solvent in paint, pigment in paint) –Physical/Chemical properties –Bioavailability Sentinel Product Scenario –Contains elements of exposure, i.e., exposure factors Maximum proportion generically used for a specific function in a product (e.g., % of surfactant in paint, etc.) Frequency and duration of product use Amount transferred during use Age-specific personal factors Designed to provide a reasonable worst-case estimate of exposure

22. 22 “Sentinel” Product (SP) A sentinel product is a specific type of consumer product with a defined composition and use that yields the highest exposure to an individual for one of its component substances as compared to other consumer products containing that substance Sentinel products are selected from broader classes, e.g. personal care products A specific substance is then matched to one or more sentinel product(s) based on generic information about its use pattern e.g. for acetone, possible SPs are: nail preparations acrylic paints There may be more than one SP for a given substance

23. 23 Product categories generally accepted to represent high exposure potentials: –Household cleaning products –Soaps and detergents –Cosmetics and personal care products –Food additives –Fabric treatments –Paints and coatings –Adhesives and sealants –Hobby and craft products –Automotive care and maintenance products –Lubricants –Fuels and solvents –Lawn and garden care products Considerations for selection of Sentinel Products

24. 24 Scenarios for Sentinel Products Routes of exposure (oral, dermal, inhalation) determine how scenarios are developed Information gathering: –In-house contracts, surveys, e.g., CEPA sect. 71 –MSDS, e.g., CCOHS, NIOSH –Public sources, e.g., Scorecard, Household Product Database, etc. –Industry input, e.g., Soap and Detergent Association (SDA) Appropriate algorithms are selected from an exposure matrix including ComET and other publicly available models (e.g., ConsExpo, ECETOC TRA, CEM, etc.) Appropriate conservative exposure factors are used to populate the algorithms (e.g., Versar, SDA, etc.) ComET contains ~146 different Sentinel Products scenarios, each of which contains one or more exposure route(s)

25. 25 Scenario Algorithm - Example Inhalation ED = WF x A x ET x IR x EF BW x RV x AT where ED = estimated dose per event (mg/kg-bw perday) WF = weight fraction of substance in product A = amount of product used per event (mg) ET = exposure time (i.e., duration of exposure) (h) EF = Exposure frequency (unitless) IR = inhalation rate (m 3 /h) BW = body weight (kg-bw) RV = room volume (m 3 ) AT = Averaging time (day) Age-specific variables }

26. 26 ComET output – Near-field exposure When a substance occurs in more than one product or is described by more than one use code, ComET will provide an estimate of either: –Sum of doses or highest dose Estimate values for any of the different types of exposure: –Acute, sub chronic, or chronic; –Any of the six age groups; –Any of the three route specific exposures or the total dose

27. 27 ComET – Next Steps Completion of taxonomy of sentinel products and algorithms for sentinel products Solicit input/information/comment on the architecture, and data to populate for decision making –Availability of habit and use surveys –Example: SDA Document exposure and risk screening methods for consumer product ingredients Peer review of taxonomy, algorithms and default values –Need for adequate documentation as a basis for default parameters in the algorithms and selection of sentinel products –Public availability of habit and use survey information –Consistency with well documented sources –Process – peer input, consultation, review

28. 28 Exposure Tools Phase Categorization Screening Assessments In-depth Assessments - Priority Substances Tool Simple Exposure Tool Complex Exposure Tool Consumer exposure scenarios/algorithms Consumer Exposure Models (wall paint exposure model) –WPEM (wall paint exposure model), –CEM (consumer exposure module, E-Fast), –ConsExpo

29. 29 DSL TOOLS - HEALTH Exposure SimET (Relative ranking of all DSL substances based on submitters (S),quantity (Q) and expert ranked use (ERU) ComET (Quantitative plausible maximum age-specific estimates of environmental and consumer exposure for individuals based on use scenario (sentinel products), phys/chem properties & bioavailability) Hazard Quantification (Previously Exposure-Response) HazQ (measures of exposure-response developed (where possible) on the basis of measured or predicted carcinogenic potency, reference values or effect levels Hazard [High (H) or Low (L)] SimHaz (identification of high or low hazard compounds by various agencies based on weight of evidence) ComHaz (Hierarchical approach for multiple endpoints & data sources (e.g., QSAR) including weight of evidence

30. 30 SimHaz Tool Applied to entire DSL Defines high or low hazard from classifications/assessments of other agencies based on weight of evidence Appropriate assessments selected based on comprehensiveness of review, peer review process, etc.

31. 31 SimHaz Tool Endpoints chosen based on general population concerns High Hazard Lists/Endpoints –Cancer (IARC, EU, HC, US EPA etc.) –Genotoxicity (EU) –Developmental Toxicity (EU) –Reproductive Toxicity (EU) Low Hazard Lists –PMRA 4a/US EPA –OECD Low Concern Respiratory sensitization endpoint – dropped from SimHaz as more relevant to occupational exposure

32. 32 SimHaz Tool Strengths and Limitations Strengths –Efficient Takes advantage of critical review of others –Consistency Assessments/classifications internationally Limitations –Bias towards data-rich substances

33. 33 ComHaz Tool Hierarchical approach for multiple endpoints & data sources, including limited weight of evidence, for identifying compounds for further consideration. - Qualitative and/or quantitative criteria developed for various endpoints. - Conservative so that confidence is high that substances that are not considered priorities for further consideration based on any of the criteria are non hazardous. - For qualitative endpoints, weight of evidence is assessed, where possible. Currently, confidence in predictive tools only for cancer/genotoxicity

34. 34 Complex Hazard (ComHaz) Tool

35. 35 ComHaz Tool Sources of Information –Comprehensive literature searching (electronic & hardcopy resources) –Reviews or secondary accounts of toxicological or epidemiological studies –Original Toxicological and Epidemiological Studies –[(Quantitative) Structure Activity Relationship (QSAR)]Models (TOPKAT, CASETOX) –Chemical structures of concern, Structure Activity Relationship (SAR) models (DEREK), surrogate/analogue approaches (Leadscope)

36. 36 ComHaz Tool Qualitative criteria –Cancer –Genotoxicity –Developmental toxicity Quantitative criteria –Regulatory/reference values –Developmental toxicity –Reproductive toxicity –Long term toxicity –Shorter term toxicity –Acute toxicity

37. 37 ComHaz Tool – Criteria EndpointInformation SourceCriteria CancerData or (Q)SARWeight of evidence GenotoxicityData or (Q)SARWeight of evidence Regulatory/Reference Value International & National Assessments Ref Value ≤ 0.1 mg/kg bw/day ≤ 0.4 mg/m³ Developmental ToxicityDataNO(A)EL ≤ 90 mg/kg bw/day NO(A)EC ≤ 270 mg/m³ (Q)SARPositive Prediction Reproductive ToxicityDataNO(A)EL ≤ 10 mg/kg bw/day NO(A)EC ≤ 30 mg/m³ Longer Term ToxicityData or (Q)SAR (where appropriate) NO(A)EL ≤ 10 mg/kg bw/day NO(A)EC ≤ 30 mg/m³ Short Term ToxicityDataNO(A)EL ≤ 30 mg/kg bw/day NO(A)EC ≤ 90 mg/m³ Acute ToxicityData or (Q)SAR (where appropriate) LD 50 ≤ 500 mg/kg bw LC 50 ≤ 1500 mg/m³

38. 38 ComHaz Tool Preliminary Weight of Evidence (WoE) Framework Why Cancer/Genotoxicity? ComHaz endpoints for which capture rate is highest –Qualitative ComHaz criteria are very conservative (i.e., first hit) –Need to increase discrimination to identify priorities for further consideration Confidence in (Q)SAR greatest for these endpoints –Larger more diverse training sets (e.g., simple screening assays such as Ames test) –Potential for combining relevant endpoints –Relevance to specific modes of action Genotoxic carcinogenicity is critical endpoint for more in- depth assessments (i.e., screening/PSL)

39. 39 Preliminary WoE Framework Development Process Draft approach developed Acquired operational experience through consideration of individual compounds Continued to revise approach based on this experience as well as internal and external consultation –Internal consultation with genotox specialists –External peer consultation (www.tera.org)

40. 40 Preliminary WoE Framework Principles/Approach Separate consideration of endpoints: Carcinogenicity; Genotoxicity Separate consideration of lines of evidence: –Empirical data, QSAR, SAR For (Q)SAR models, output is weighted based on predictive power of both the assays and validation results for similar compounds. Equivocal data/inconclusive predictions noted, but not weighted “Call” for a line of evidence based on consideration of ratio of positives/negatives and degree of confidence Degree of confidence based on consistency between data and predictions

41. 41 Preliminary WoE Framework (Q)SAR Models

42. 42 Preliminary WoE Framework Outcomes CHEMICAL X From Moderate Group of Maximal List Positive carcinogenicity study or QSAR prediction Positive genotoxicity study or QSAR prediction ? Meets criteria for remaining quantitative endpoints in Hierarchical Approach? WoE Cancer/Genetox High Potential for Genotoxic Carcinogenicity? Next Step: Hazard Quantification Tool (Exposure-Response Characterization) SET ASIDE NO YES

43. 43 ComHaz Tool Process – Development/Testing Considerable internal operational experience External testing for consistency of output based on search strategy/approach External peer review of internal/external consistency of critical aspects of approach Internal QA/QC Expert consultation –e.g., genotoxicity, WoE

44. 44 ComHaz Tool Strengths and Limitations Strengths –Health protective –Comprehensive –High confidence in “set asides” –No bias towards data rich substances –Designed for high throughput –Takes advantage of critical reviews of others –Significant contribution of QSAR component to international priority setting –External input, consultation, peer review Limitations –Resource intensive

45. 45 Hazard Quantification Tool (Previously called Exposure-Response Tool) Developed from a Toxicity Profile –For compounds that are ComHaz IN –All toxicological endpoints considered (i.e., carcinogenicity, developmental, reproductive, acute, etc.) –For each endpoint, the Quantified Hazard (carcinogenic potential, NOEL/LOEL, etc) is determined for various durations of exposure –Available data on pharmacokinetics, mode of action and species specificity are also considered –Informs as to what type of Screening Model will be proposed for compound (ie. Various screening assessment models are being drafted; in some cases, input from Exposure Tools will be required). –Toxicity Profile and Tool still in development

46. 46 Hazard Tools Phase Categorization Screening Assessments In-depth Assessments - Priority Substances Tool Simple Hazard Tool (SimHaz) high and low hazard Complex Hazard Tool first stage QSAR/SAR WoE (if needed) Exposure-Response (Hazard Quantification)Tool

47. 47 Input from Stakeholders 60-day comment period on the Proposed Integrated Framework for the Health-Related Components of DSL categorization ended August 30, 2005. Data requested on DSL compounds, especially those on the Maximal List, Deadline for submission was Sept. 16, 2005. Responses received from Industry –e.g., ACC, ATOFINA, BASF, CPMA, Degussa, Nova Chemicals Input from Environmental Non-Governmental Organizations

48. 48 Screening Assessments Need to assess more compounds more quickly No legislated deadlines, however high expectations Draw on international/assessments to extent possible and considerable collective experience in HC and limited external peer review Consistent with principles of in-depth PSL assessments

49. 49 Full Focused Screening Assessments Decisions based on consideration of: –Nature of critical effect –Margin between critical effect level and upper bounding estimate of exposure –Adequacy of margin to account for uncertainties in database Possible outcomes: –Not “toxic” under CEPA 1999 –Further in-depth assessment required –“Toxic” under CEPA 1999

50. 50 Screening Assessments - Status Public comments received on:PBDEs & PFOS Screening Health Assessments to be released on our Listserv: Quinoline MBMBPMBOCA 1,2-Dibromoethane 1,1-Dichloroethene BiphenylEthylbenzene DNOCHexachloroethane

51. 51 IN-DEPTH ASSESSMENT-Priority Substances List FOCUSED SCREENING ASSESSMENT Use and Emission Profiling; Current Control Measures Toxicity Profiling of Effects and other Related Data + Substance Profile and Issues Flagged Not a priority for further consideration Prioritized for further consideration Issue Identification CEPA-Toxic No further action under this program Substances Prioritized for further consideration from Categorization Phase I Phase II Phase III

52. 52 Framework developed to identify true priorities from a human health perspective. –takes into account both exposure and hazard. Series of simple and complex “tools” developed. –exposure assessment and hazard identification. Tools applied in identification and prioritization of substances for assessment. –also as part of the health risk assessment process itself. Innovative and ensures efficient assessment to meet CEPA 1999 mandate. Key Messages

53. 53 More Information? Health Canada Existing Substances Division Website – http://www.hc-sc.gc.ca/ewh- semt/contaminants/existsub/index_e.html Health Canada Maximal List and Integrated Proposal Framework – http://www.hc-sc.gc.ca/ewh- semt/contaminants/existsub/framework-cadre_e.html Health Canada Existing Substances Mailing List – http://www.hc-sc.gc.ca/ewh- semt/contaminants/existsub/mail-avis_e.html CEPA Registry – http://www.ec.gc.ca/CEPARegistry/default.cfm