Outline

1. Health-Related Components of DSL Categorization under CEPA 1999Exposure and Hazard ToolsPresented by: Jesse NgExisting Substances DivisionHealth CanadaOct 20, 2005

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

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

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

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

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. 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) DSL TOOLS - HEALTH 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 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

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. Criteria for Greatest, Intermediate and Lowest Potential for Exposure (GPE, IPE & LPE)

15. The Complex Exposure Tool (ComET) • 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

16. Chemical Identity Measures of Dose-Response for Critical Effects Physical/ Chemical Properties Substance Profile Production Quantity Production Quantity Bin + Release Factor Near-field Far-field Emissions Age Specific Variables Human Exposure Far Field Sentinel Products Priority for Assessment SP1 SP2 SP3 SPn Overview of ComET

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

20. Far-field - Output

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. “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. Considerations for selection of Sentinel Products • 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

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. 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 (m3/h) BW = body weight (kg-bw) RV = room volume (m3) AT = Averaging time (day) } Age-specific variables

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

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 [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 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

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

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. Complex Hazard (ComHaz) Tool

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. 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. ComHaz Tool – Criteria

38. ComHaz ToolPreliminary 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. Preliminary WoE FrameworkDevelopment 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. Preliminary WoE FrameworkPrinciples/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. Preliminary WoE Framework (Q)SAR Models

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

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

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. 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. 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. Screening Assessments - Status • Public comments received on: PBDEs & PFOS • Screening Health Assessments to be released on our Listserv: Quinoline MBMBP MBOCA 1,2-Dibromoethane 1,1-Dichloroethene Biphenyl Ethylbenzene DNOC Hexachloroethane