Mammalian Toxicology Data Requirements For Antimicrobial .

Mammalian Toxicology DataRequirements forAntimicrobial Pesticides158W40 CFR §158.2200Slide 1

Outline Toxicology Data Requirements under 158W Determining Toxicology Data requirements based on use patterns forAntimicrobial Pesticides Important points about toxicology data requirements Toxicology data requirements examples -direct, indirect, and nonfood uses Attributes of test notes Alternative approaches to fulfilling data requirements2

Toxicology Data Requirements under 158W Toxicology data requirements for antimicrobial pesticides arepresented in §158.2230 of the final rule for part 158, subpart W(See 40 CFR §158.2200). EPA is required to meet the statutory standard of section408(b)(2)(ii) of the Federal Food, Drug, and Cosmetic Act(FFDCA): “ that there is a reasonable certainty that no harm willresult from aggregate exposure to the pesticide chemical residue,including all anticipated dietary exposures and all otherexposures for which there is reliable information.” Thus, toxicology data requirements are based on both thepotential exposures occurring from the use(s) of the pesticideincluding exposure duration and exposure route, as well as theneed for determining the hazard of the antimicrobial pesticide.Slide 3

Toxicology Studies –OCSPP Series 870Guidelines To assist registrants in conducting studies to fulfilltoxicology data requirements, the Office of ChemicalSafety and Pollution Prevention (OCSPP) of EPA haspublished the 870 series Health Effects Test Guidelines.Studies conducted using these guidelines are intendedto satisfy the data requirements for determining humanhealth impacts of pesticide chemicals under the FIFRAstatute. The final 870 test guidelines can be found at: elinesSlide 4

1 2 Major Use Patterns for Antimicrobial Pesticides 1.Agricultural Premises and Equipment Food Handling/Storage Establishments, Premises and EquipmentCommercial, Institutional and Industrial Premises and EquipmentResidential and Public Access PremisesMedical Premises and EquipmentHuman Drinking Water SystemsMaterials PreservativesIndustrial Processes and Water SystemsAntifouling Coatings and Ballast Water TreatmentsWood PreservativesSwimming Pools and SpasAquatic Areas2.3.4.5.6.7.8.9.10.11.12.*Use patterns highlighted in RED denote where potential for food contact may be expected.Slide 5

Use Sites for Antimicrobial Pesticides Specific use sties are listed within each of the 12major antimicrobial use patterns. Toxicology data requirements for specific use site(s)will be consistent with the requirements under themajor use pattern that contains the specific usesites. A use site index has been published to assist indetermining data requirements and can beconsulted to help determine the toxicology datarequired. The index is available atwww.regulations.gov under docket ID: EPA-HQ-OPP2015-0302-00016

Determining Toxicology Data Requirements For purposes of determining toxicology datarequirements, the use patterns in the table areorganized according to: whether there is the expectation that the pesticide maycome into contact with food and/or be present in waterfrom antimicrobial uses or whether there is no expectation that the antimicrobial willcome into contact with food and/or be present in waterfrom antimicrobial uses Food use designations, direct food, indirect food, andnonfood appear in the column headers in the toxicologydata tables and are key considerations whendetermining toxicology data requirements.7

Determining Toxicology Data Requirements Food uses for which there is the expectation that thepesticide may come into contact with food are dividedinto direct food and indirect food uses Non-food uses, those for which there is noexpectation that the pesticide may come into contactwith food, are divided into specified non-food usesites and all other non-food uses Direct food use: Pesticide is intended to be applieddirectly to food or to material/article for the purposeof treating food Indirect food use: Application of antimicrobial in/onmaterial/article that comes into contact with food butuse is not intended for pesticidal treatment of food8

Dietary Assessment Dietary assessment contains two parts: food and drinkingwater Although drinking water assessment is part of a dietaryassessment, it is not part of a food assessment Drinking water exposure can occur from anything that maygo down-the-drain, from drinking water treatment, or fromindustrial discharges Potential concerns for human exposure to antimicrobialsfrom ingestion of drinking water could trigger toxicologydata requirements9

Toxicology Data Requirements Decision TreeSlide 10

Determining Toxicology Data Requirements First determine the major use pattern from the USI. Second, determine the specific use site(s) for the antimicrobial pesticide. Third, determine whether there is potential for exposure to theantimicrobial from direct food use, indirect food use or non-food use. Next, consult the appropriate column of the toxicology datarequirements table to applicable data requirements. Generally, direct food uses, indirect food uses where total dietaryresidue from the use is 200ppb, and certain specific uses (swimmingpools, wood preservatives, metalworking fluids, aquatic areas) requirethe most toxicology data than indirect food uses where total dailydietary residue is less than or equal to 200 ppb and “all other nonfooduses”.11

Important Points on Toxicology Data Requirements Note that for any antimicrobial use pattern, there arecore toxicology data that are always required: Acute toxicity battery (6-pack)*Mutagenicity testing battery90-Day toxicity - rodentDevelopmental Toxicity – two species (rat and rabbitpreferred) Reproduction and fertility effects Immunotoxicity*The agency has published guidance for when these studies can be waived. T his guidance isavailable ing-or-waiving-data-requirements12

Important Points on Toxicology Data Requirements Required studies are listed in the table as (R).Required studies will always include the core dataand, depending on the use site(s), additionaltoxicology data would potentially be required. Forexample, as noted in the toxicology datarequirements table, swimming pool, woodpreservative, metalworking fluid, and aquatic areasuses require toxicology data in addition to the coretoxicology data. Again, the use pattern and specific use site(s)should be examined to determine the datarequired.13

Conditional Toxicology Data Requirements Toxicology studies in addition to the core studies and any otherrequired studies may also be conditionally required, designatedas CR in the data requirements table. The test notes in thetoxicology data requirements table explain conditions underwhich these data are or are not required. For example, a study may be CR based on findings from arequired study. If evidence of neurotoxicity is observed in arequired study (such as the subchronic oral toxicity test), aspecific neurotoxicity study is triggered. A study may be designated as CR based on the potential toreduce animal usage (such as conduct of a combined chronictoxicity and carcinogenicity study, or addition of measurementssuch as Immunotoxicity to a required study to eliminate the needfor two separate studies).Slide 14

Important Points on Toxicology Data Requirements158W contains two new toxicology datarequirements: Developmental neurotoxicity test (870.6300)- aconditionally required study Immunotoxicity test (870.7800) - a requiredstudy for all uses.Slide 15

Toxicology DataRequirements- Examples16

E xample #1: Direct Food Use (fruit and vegetablewash) Direct food use: A use is considered to be a direct food use if anantimicrobial pesticide is used to directly treat food and/or foodsources and as a result, finite residues in or on food are expected orreasonably likely to result. A fruit and vegetable wash will be expectedto have finite residues of the pesticide. The data requirements for a direct food use are similar to those neededfor agricultural pesticides. This is because a direct food use isinterpreted the same, whether the pesticide is an agricultural orantimicrobial pesticide. In both cases, finite residues in or on food areexpected or reasonably likely to result. The column header “Direct food uses” would be used in this example todetermine the required and conditionally required data.Slide 17

Toxicology Data Requirements: 158.2230GuidelineNumberData RequirementDirectFoodUsesFood UsesIndirectIndirectFood Uses Food Uses( 200( 200ppb)ppb)Nonfood UsesTest SubstanceSwimming Pools,All Other to SupportAquatic Areas,Nonfood MPEPWood Preservatives, UsesMetal WorkingFluidsAcute Testing870.1100Acute oral toxicity – ratRRRRR870.1200Acute dermal toxicityRRRRR870.1300RRRRRRRR870.2500Acute inhalation toxicity - RratPrimary eye irritation RrabbitPrimary dermal irritation RRRRR870.2600Dermal sensitizationRRRRR870.6200Acute neurotoxicity - ratSubchronic Testing870.310090-Day oral toxicity rodent870.315090-Day oral toxicity nonrodent870.320021/28-Day dermal toxicityRRCRRCRMP andTGAIMP andTGAIMP andTGAIMP andTGAIMP andTGAIMP TGAI870.325090-Day dermal toxicityCRCRCRCRCRTGAI870.346590-Day inhalation toxicity - ratCRCRCRCRCRTGAIEP andTGAIEP andTGAITGAI870.2400EP andTGAIEP andTGAIEP andTGAIEP andTGAIEP andTGAIEP andTGAITGAITest NoteNo.1, 21, 2, 32, 41, 2, 31, 2, 31, 2, 3, 56, 118, 9, 15,3810, 1512, 137, 13, 14,157, 15, 16,17Slide 18

Toxicology Data Requirements: 158.2230Chronic Testing870.4100Chronic oral toxicity Rrodent870.4200Carcinogenicity – twoRrodent species – rat andmouse preferredDe velopmental Toxicity and Reproduction870.3700Prenatal developmentalRtoxicity - rat and rabbitpreferred870.3800Reproduction and fertility Reffects870.6300DevelopmentalCRneurotoxicityMutag enicity870.5100Reverse mutation assayRRCRRCRTGAITGAI18, 19, 20RCRRCRTGAITGAI19, 21, 22RRRRTGAITGAI23, 24, 25,26RRRRTGAITGAICRCRCRCRTGAITGAI26, 27, 28,2928, 29, 30RRRRTGAITGAI31, 32870.5300In vitro mammalian gene870.5375mutation870.5385In vivo cytogenetics870.5395Special Testing870.7485Metabolism andpharmacokinetics870.7200Companion animal safety870.7600Dermal penetrationRRRRRTGAITGAI31, 33RRRRRTGAITGAI31, 34RRCRRCRCRCRCRCRCRCRCRCRPAI orPAIRAChoiceChoice35, 39CRCRPAI y363, 37Slide 19

E xample #2: Indirect Food Use (kitchen countertopuse) A use is considered to be an indirect food use if food may come intocontact with an antimicrobial pesticide, but the pesticide is notintended to be applied directly to food. As a result of contact with asurface and/or material that has been treated and/or impregnated withan antimicrobial pesticide, there is a potential for finite residues in or onfood.In this example, a kitchen countertop may contain an antimicrobialapesticide that is incorporated into the countertop material. Food mayacome into contact with the pesticide when it is placed on the countertopaand some pesticide may migrate from the countertop into the food. Indirect food use data requirements are based on the estimated ormeasured residue of the antimicrobial pesticide in the total daily dietaryintake from the use (i.e. is the total daily dietary residue or 200ppb?).Slide 20

Example #2: Indirect Food Use (kitchen countertopuse) Similar to the example for direct food use, the toxicologydata requirements table is consulted to determine the datarequirements under the ‘indirect food uses ( 200ppb)’column or the ‘indirect food uses ( 200ppb)’ column, asappropriate. Toxicology data where dietary residue 200ppb will be thesame as required for a direct food use. In the majority ofcases for an indirect food use, total daily dietary residue is 200ppb and less data would be expected to be required.21