DecisionToolforAssessingPolymersandPolymericSubstancesDecisionToolforAssessingPolymersandPolymericSubstanceswithPotentialHazardstoHumanHealthwithPotentialHazardstoHumanHealth

1BernardGadagbui,1AndrewMaier,1PatriciaNance,2MichaelJayjock,2ClaireFranklin;1ToxicologyExcellenceforRiskAssessment,2TheLifeLineGroup

OverviewofthePolymerHazardCharacterizationDecisionFrameworkOverviewofthePolymerHazardCharacterizationDecisionFramework

*See Detailed Hazard Characterizaon Decision Tree for Polymers

AbstractAbstract Polymers display a wide variety characteriscs e.g., presence of nonbound residual monomers, polymerizaon chemicals, degradaon products, and addives that can generate a potenal health hazard. There is a paucity of direct tesng data on many polymers to adequately evaluate their toxicity, but several regulatory agencies have provided guidance for assessing polymer safety. We evaluated each of these approaches and idenfied the strengths and weaknesses of each. No single published model appears to cover all characteriscs of interest and this suggests the need to develop a comprehensive decision tool to idenfy polymeric substances that may pose potenal toxicological hazards to human health. We developed a decision tool that incorporates a weight of evidence approach integrang informaon for many individual hazard flags. Hazard flags were placed into four broad categories: (1) empirical hazard informaon on the polymer or residual monomer; (2) evidence of toxicity based on structural properes (i.e., based on polymer class, monomer components, or reacve funconal groups); (3) potenal for significant ssue dose (i.e., based on molecular weight distribuon or systemic bioavailability); and (4) hazard based on foreseeable special use consideraons. Some of these hazard flags have not been considered previously by the regulatory agencies. We tested this approach for a number of polymers to demonstrate how the tool integrates all available regulatory approaches and provides a comprehensive decision framework for evaluang polymer safety. IntroductionIntroduction Why is this framework needed? Several regulatory agencies have guidance on assessing polymer safety No single published model covers all characteriscs of interest Suggests the need to develop a comprehensive decision tool

ApproachApproach Intended to cover the assessment of polymers based on their innate propensity to cause toxic eects

Also taking into consideraon the impacts of polymer uses and exposure scenario informaon that directly impacts the characterizaon of hazard potenal Designed with several guiding principles Provision for incorporang weight of evidence principles in reaching the ulmate conclusion regarding hazard potenal Need to reflect the preference for direct hazard data over surrogate or indirect evidence of hazards, without providing too rigid a hierarchy Breadth of applicability to polymers with wide ranging characteriscs and data sets. for most applicaons, the assessments will be done with a paucity of direct hazard informaon a robust set of criteria to capture a range of physical or chemical characteriscs in the weight of evidence decision is

provided. Recognion that hazard potenal reflects innate properes, many of which reflect the ability to achieve an adequate s

sue dose Properes related to toxicokinecs (e.g., bioavailability or release of toxic molecules) as well as toxicodynamics (presence of biologically acve reacve funconal groups) are included in the assessment Hazard potenal may also reflect directly special use condions or exposure scenarios and such consideraons are included in the process

HazardEvaluationFormHazardEvaluationForm Documents the presence or absence of important hazard flags relevant to the polymer under review Lists flags under one of four queson categories Presence of a hazard flag is based on the specific criteria for each parameter Presence of any one flag triggers a check for the overall hazard flag within a queson category A check in any one queson is translated to a yes answer in the Final Hazard Characterizaon Decision

Flow Chart for that queson All yes quesons then must be evaluated, using professional judgment, to determine whether the var

ious flags constute a moderate or high concern based on the science If no hazard flags are checked, this result is translated as a no answer in the Final Hazard Characteriza

on Decision Flow Chart for that quesonFourQuestionCategoriesFourQuestionCategories

Q.1. Is there sucient empirical evidence of toxicity? Q.2. Is there sucient evidence of toxicity based on structural properes (i.e., based on polymer class, monomer components, or reacve funconal groups)? Q.3. Is there potenal for significant ssue dose (i.e., based on molecular weight distribuon, reacve funconal groups, charge density, or systemic bioavailability)? Q.4. Is there addional hazard based on foreseeable special use consideraons?

WeightofEvidenceDecisionFlowChartWeightofEvidenceDecisionFlowChart

DetailedHazardCharacterizationDecisionTreeforPolymersDetailedHazardCharacterizationDecisionTreeforPolymers

ChemicalClass

EmpiricalHazardInformation

MonomerComponents

MolecularWeightDistribution

RelativeFunctionalGroup/SideChain

ConclusionConclusionWe have developed a framework for assessing polymers and polymeric substances with potenal for hazards to human health

Final determinaon of hazard potenal reflects a weight of evidence decision that integrates informaon for many individual hazard flags

Order of data to flag a polymer: relevant and reliable empirical toxicity data > toxicity based on structural properes > potenal for significant ssue dose > foreseeable use consideraons

Reevaluate polymer if new data becomes available.

FundingforthisprojectwasprovidedbyHealthCanadaunderthestandingoffercontract#4600000343.

GuidanceDocumentsReviewedGuidanceDocumentsReviewed United States Europe Canada Australia Japan Korea China A complete list of references available on request. A literature search was conducted to supplement above list of agency documents.