Page 1 of 26 **UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, D.C. 20460 OFFICE OF**  **CHEMICAL SAFETY AND POLLUTION PREVENTION**  **MEMORANDUM Date:**  28 - JAN - 2015 **Subject: Pyrimetha**  **n il**  . Human Health Risk Assessment for Proposed Post - Harvest Use

on Pomegranates . **PC Code:** 288201 **DP Barcode**  **:** D 417167 **Decision No.:** 484376 **Registration No. :**  43813 - 32 **Petition No.:** 3F8213 **Regulatory Action:**  Section 3 **Risk Assessment Type:** Single Chemical/Aggregate Assessment **Case No.:** 7059 **T XR No.:**  None **CAS No.:** 53112 - 28 - 0 **MRID No.:** None **40 CFR** §180.518 **From:** Jennifer R. Tyler, Chemist

Jacly n P yn e, Biologist Anwar Y. Dunbar, Ph.D., Pharmacologist Risk Assessment Branch 1 (RAB1)/Health Effects Division (HED; 7509P) **Through:** Charles W. Smith III , Branch Chief

George F. Kramer, Ph.D., Senior Chemist RAB1/HED (7509P) **To:** Hope Johnson/ Cy nthia Giles - Parker , RM 21 Registration Division (RD; 7505P) The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from proposed and currentl y registered uses of the active ingredient (ai) py rimethanil (4,6 - dimethyl -N - phenyl - 2 - py rimidinamine ) . Baye r CropScience has submitted a petition for the post - harvest use of py rimethanil on pomegranates . The risk assessment and occupational/residential exposure assessment w ere provided by Jennifer Tyler (RAB1); the residue chemistry review and dietary exposure assessment by

Jacl yn P yn e (RAB1); the hazard characterization by Anwar Dunbar (RAB1); and the drinking water assessment by James Wolf of the Environmental Fate and Effects Division (EFED). **NOTE:** A human health risk assessment was comple ted on 22 - MAY - 2013 by HED ( Memo, J. Tyler et al. , D389923) . In th e present memo, dietary , occupational, and aggregate risks were re evaluated based on the addition of pomegranates to the py rimethanil use pattern.P yrimethanil Human Health Risk Assessment DP# 417167

Page 2 of 26 **Table of Contents** 1.0 Executive Summary 3 2.0 HED Recommendations 5 2.1 Data Deficiencies/Conditions of Registration 5 2.2 Tolerance Considerations 6 3.0 Introduction 6 3.1 Chemical Identity 7 3.2 Physical/Chemical Characteristics 7 3.3 Pesticide Use Pattern 7 3.4 Anticipated Exposure Pathways 8 3.5 Consideration of Environmental Justice 8 4.0 Hazard Characterization and Dose Response Assessment 9 4.1 Summary of Toxicological Effects 9 4.2 Safety factor for Infants and Children (FQPA Safety Factor) 10 4.3 Toxicity Endpoint and POD Selections 11 5.0 Dietary Exposure and Risk Assessment 14 5.1 Residues of Concern Summary and Rationale 14 5.2 Food Residue Profile 14 5.3 Water Residue Profile 15 5.4 Dietary Risk Assessment 16 6.0 Residential (Non - Occupational) Exposure/Risk Characterization 17 7.0 Aggregate Exposure/Risk Characterization 17 7.1 Acute Aggregate Risk 17 7.2 Short - and Intermediate - Term Aggregate Risk 17 7.3 Chronic Aggregate Risk 18 7.4 Cancer Risk 18 8.0 Cumulative Risk Characterization/Assessment 18 9.0 Occupational Exposure/Risk Pathway 18 9.1 Handler Exposure and Risk Estimates 18 9.2 Post - application Exposure and Risk Estimates 20 10.0 References 21 Appendix A: Toxicity Profile Tables. 22 Appendix B: Metabolism Assessment. 26P yrimethanil Human Health Risk Assessment DP# 417167

Page 3 of 26 **1.0 Executive Summary**  Baye r CropScience has submitted a petition for the post - harvest use of Penbotec ® 400 Soluble Concentrate (SC) (EPA Reg. No. 43813 - 32), a SC formulation containing 3.27 pounds (lb) ai/gallon (gal) [400 grams (g) ai/liter (L)] on pomegranates . The petitioner reques ts the establishment of a 5.0 - ppm tolerance for resid ues of py rimethanil in/on pomegranate. Py rimethanil is an amino acid sy nthesis inhibitor that inhibits the secretion of enzy mes necessary for fungal infection. Py

rimethanil is currentl y registered in the U.S. for use on several raw agricultural commodities (RACs) . Permanent tolerances have been established for residues of py rimethanil per se in/on plant commodities at levels ranging from 0.05 ppm in/on vegetable, tuberous and corm, subgroup 1C to 150 ppm in/on citrus oil [40 CFR §180.518(a)(1)]. Tolerances have also been established for p yrimethanil residues and its metabolite 4 - [4,6 - dimethyl - 2 - py

rimidinyl)amino]phenol in fat (0.01 ppm), kidney (2.5 ppm) and by

products (except kidney) (0.01 ppm) of cattle, goats, horses and sheep and in milk (0.05 ppm) [40 CFR §180.518(a)( 2)]. There are no registered or proposed residential uses. Proposed Use : The proposed use to the subject crops is as a single post - harvest application at 0.82 lb ai/100 gal via in - line dip/drench wash tanks. Applications can be made to the fruit on the same day as sold or consumed . Toxicity Profile : Py

rimethanil is of low acute lethality by the oral, dermal, and inhalation routes. It is a slight eye irritant, is not irritating to the skin, and it is not a dermal sensitizer. A single oral dose of 1000 mg/kg produced a number of acute signs of neurotoxicity , including ataxia, dilated pupils, and decreases in motor activity , hind limb grip strength, and body temperature. However, there was no evidence of neurotoxicity with repeated dosing in a subchroni c neurotoxicity

study in rats. The major target organs of repeated oral exposure were the liver and the thy roid. These effects were accompanied by decreased body weight. Reproductive toxicity was not observed, and developmental effects (e.g., decreased fetal weight, retarded ossification, extra ribs) were observed only at maternall y toxic doses. Special short - term exposure studies demonstrated increased liver uridine diphosphate glucuronosyl transferase (UDPGT) activity leading to decreases in thy roid h ormones (T3, T4) and compensatory increases in thy

roid stimulating hormone (TSH) in adult rats. Thyroid adenomas were seen in rats following long term exposure, and it was concluded that they were mediated via disruption of the thy roid/pituitary

axis. There were no concerns for mutagenicity . Dose - response and Food Quality Protection Act ( FQPA ) Assessment : The py

rimethanil risk assessment team has evaluated the hazard and exposure data; and, based on these data, recommended that the FQPA Safety Factor (SF) be reduced to 1X . The toxicological is complete and there is no evidence of increased offspring susceptibility . The exposure databases are sufficient to determine the nature/magnitude of the residue in food and dietary anal ys es are unlikely to under estimate risk of exposure from p yrimethanil. Although there is evidence of neurotoxicity

in the acute neurotoxicity study , concern is low since effects were onl y seen at the limit dose, effects are well - characterized with clearly established no - observed adverse effect level/lowest observed adverse effect level (NOAEL/LOAEL) values, and the selected endpoints are protective for the observed effects .P yrimethanil Human Health Risk Assessment DP# 417167

Page 4 of 26 Residue Chemistry : The qualitative nature of the py rimethanil residue in plant commodities is adequatel y understood based on acceptable metabolism studies in lettuce, grapes, and tomatoes. The HED Metabolism Assessment Review Committee ( MARC ) has determined that for risk assessment and tolerance expression, parent only is the residue of concern. The data - collection method used to generate pomegranate residue data in conjunction with magnitude of the residue study associated with this petition was a gas chromatography method with mass - selective detection (GC/MSD). There are also adequate methods available to enforce tolerances for residues of p yrimethanil in/on pomegranate. The submitted field trial residue data for pomegranate are adequate. The field trial data reflect the proposed use pattern, an adequate number of trials were conducted, and samples were anal yz ed for the residue of concern using validated data - collection methods. Using the Organization for Economic Co - operation and Development (OECD) tolerance calculation procedures for the residue data set indicates that the requested tolerance of 5.0 ppm for residues of p yr imethanil in/on pomegranates is appropriate. For plant commodities, the U.S., Canadian, and Codex residue definitions are harmonized. There are currently

no established Codex or Canadian MRL s for residues of py rimethanil in/on pome granates; therefore, harmonization is not an issue for this petition. Drinking W

ater Exposure and Risk : Based on the information provided, EFED considers the proposed post - harvest dip use of p yrimethanil as an indoor use that would pose minimal exposure to the environment, provided that release of the chemical and contaminated water are controlled. Therefore, EFED concluded that an updated drinking water assessment is not needed for the proposed use. HED used estimated drinking water concentrations ( EDWCs ) provided by EFED in conjunction with the most - recent human health risk assessment . Surface and ground EDWCs were generated by EFED using the Pesticide Root Zone Modeling/Exposure Anal ys is Modeling S ys tem (PRZM/EXAMS) and the Screening Concentration in Ground Water Model (SCI - GROW) models, respectively . The EDWCs for the combined total residues (py rimethanil + 2 - amino - 4,6 - dimethylpy rimidine) in groun d water are not expected to exceed 4.8 μg/L based on the registered seasonal application rate of 2.1 lb ai/A on strawberry in Florida. The EDWCs for combined residues of py rimethanil (parent + 2 - amino - 4,6 - dimethylpy rimidine) in raw surface source water are not expected to exceed 86.5 μg/Lfor the peak 1 - in - 10 - ye ar concentration; and 29.4 μg/L for the 1 - i n - 10 - ye ar annual mean concentration. Dietary Exposure and Risk : Acute and chronic dietary exposure assessments were conducted using the using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (D EEM - FCID) Version 3.16 . The acute and chronic dietary anal ys e s assumed default processing factors (as necessary), empirical processing factors for orange and apple juice, tolerance - level residues, 100% crop treated ( CT ) for all commodities and EDWCs ( acute 86.5 ppb , chronic 29 .4 ppb ) for direct and indirect water sources. The resulting acute dietary risk estimates (f

ood and drinking water) were ≤38 % of the a cute population - adjusted dose (aPAD) and are not of concern to HED (<100% aPAD; children 1 - 2 years old were the most high ly exposed population subgroup). The resulting chronic dietary risk estimates (f

ood and drinking water) were ≤76 % of the chronic population - adjusted dose ( cPAD ) and are not of concern to HED (< 100% cPAD; children 1 - 2 years old were the most highly exposed population subgroup). Residential Exposure : Currentl y, there are no registered/proposed uses of pyrimethanil that result in residential exposures. Therefore, a residential exposure assessm ent was not performed. Aggregate Risk : The Agency conducts aggregate exposure assessments by summing dietary (food and water) and residential exposures (residential or other non - occupational exposures).P yrimethanil Human Health Risk Assessment DP# 417167

Page 5 of 26 Since there are no registered/proposed uses of py rimethanil that result in residential exposures, the acute and chronic aggregate risk assessment s are equal to the acute dietary and chronic dietary estimate s (food and water onl y) , respectively . The acute and chronic aggregate exposure s to the general U.S . population and all other subpopulations from the uses of p yrimethanil do not exceed HED ’s level of concern (LOC) . Occupational Exposure/Risk : Based on the anticipated use patterns and current labeling, dermal and inhalation exposure occupational pesticide handlers are expected to be mixer/loaders using open - pour loading of liquids for automated s ys tems. Occupational handler dermal and inhalation risk estimates were calculated. An MOE ≥100 is adequate to protect occupational pesticid e handlers from dermal and inhalation exposures. Dermal and inhalation risks for occupational handlers are above the LOC (100) with label - required personal - protective equipment (PPE) (i.e., long - sleeved shirt, long pants, shoes plus socks and chemical - res istant gloves ) ; and, therefore, are not of concern. Based on the proposed use pattern, HED expects post - application dermal and inhalation exposure for workers while sorting and packing treated pomegranates, as well as indirect inhalation exposure for workers present in the warehouse, but not directly involved in the treatment process. The short - and intermediate - term risk estimates are not of concern (i.e., MOEs ≥100) at baseline (i.e., t - shirt and no gloves and no respirator) for all post - application exp osure activities. Environmental Justice Considerations : Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," http://www.epa.gov/compliance/environmentaljustice/resources/policy /exec_order_12898.pdf

. Review of Human Research : This exposure/risk assessment relies in part on data from studies in which adult human subjects were intentionall y exposed to a pesticide or other chemical. These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Outdoor Residential Exposure Task Force (ORETF) database; the Agricultural Re - entry Task Force (ARTF) database, are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies , that review may

have included review b y the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler- exposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.html . **2.0 HED**  **Re commen**  **dations** HED concludes that the toxicological, residue chemistry and occupational/residential databases support a Section 3 registration and establishment of the tol erances listed in Section 2.2.2 . HED is not recommending for any additional data or label modifications in conjunction with this petition. **2.1 Data Deficiencies/Conditions of Registration**  No additional data are required to support the proposed use.P yrimethanil Human Health Risk Assessment DP# 417167

Page 6 of 26 **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  A residue anal ytical m ethod entitled “Anal ytical Method for the Determination of Residues of ZK 100309 in Vines, Strawberries, and Apples by HPL C” was submitted in conjunction with an earlier p yrimethanil petition, PP#4E4384, for the establishment of a tolerance on imported wine grapes. The method has been subjected to a successful petition method validation (PMV) by Analy tical Chemistry

Branch (ACB)/Biological and Economics Anal ys is Division (BEAD) (DP# 288256, E. Kolbe, 7/7/04). In addition, the QuEChERS method has been shown to adequatel y quantify residues of py

rimethanil (http://www.crl pesticides.eu/library

/docs/fv/CRLFV_Multiresidue_methods.pdf ). **2.2 .2**  **Recommended Tolerances Table 2.2.2**  **. Tolerance Summary for Pyrim ethanil.**  Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition **40 CFR §180.518 (a)(1)** Pomegranate 5.0 5.0 **2.2.3 Revisions to Petitioned**  **- For Tolerances**  HED is not recommending for any changes to the proposed tolerance. **2.2. 4**  **International Harmonization** For plant commodities, the U.S., Canadian, and Codex residue definitions are harmonized. There are currently

no established Codex or Canadian MRL s for residues of py rimethanil in/on pomegranates; therefore, harmonization is not an issue for this petition. **2.3 Label Recommendations**  HED is not recommending for any changes to Penbotoc ® 400 SC (EPA Reg. No. 43813 - 32) label. **3 .0**  **I ntroduction**  Py rimethanil is an anilinopy rimidine fungicide that inhibits the secretion of fungal enz ym es that are required during the infection process. Py rimethanil blocks the ability of the fungus to degrade and digest the plant tissues, thus stopping penetration and development of the disease. The precise mechanism of inhibition of enzy me secretion has not been fully esta blished. Protein sy nthesis is not inhibited, and evidence suggests that extracellular enz ym es accumulate inside the fungus, their release being blocked in the presence of the fungicide. P yrimethanil penetrates rapidly into the plant tissues, where it sto ps the development of the disease, providing a significant curative action. In vitro , germ tube extension and mycelial growth are inhibited.P yrimethanil Human Health Risk Assessment DP# 417167

Page 7 of 26 Py rimethanil does not exhibit cross - resistance to sterol - inhibitors, dicarboximides, benzimidazoles, quinone outs ide inhibitors, or phenylamides, but may exhibit cross - resistance in certain plant pathogenic fungi including anilinopy ridine (AP) compounds such as cy prodinil and mepanipy rim. **3.1 Chemical Identity**  **Table 3.**  **1 . Test Com** **pound Nom enclature.**  Chemical struc ture

N N C H 3 N

C H 3 H

Common name Py rimethanil IUPAC name N - (4,6 - dimethylpyrimidin - 2yl)aniline CAS name 4,6 - dimethyl -N -phenyl - 2 -py

rimidinamine CAS # 53112 - 28 - 0 End - use product/(EP) Penbotoc ® 400 SC (EPA Reg. No. 43813 - 32 ) **3.2 Physical/Chemical**  **Characteristics Table**  **3. 2. Physicochem** **ical Properties of the Technical Grade Test Compound.** Parameter Value References Melting point 96 o C The Pest Manual. British Crop Protection Council. T we lfth Edition, Editor: C.D.S. Tomlin. pH (water solution at 25 o C) 6.1 Specific gravity at 20 o C 1.15 Water solubility (g/l at 25 o C) 0.121 Solvent solubility (g/l at 20 o C) acetone

– 389, ethyl acetate

– 617, methanol

– 176, methylene chloride

– 1000, n - hexane

– 23.7, toluene

– 412 Vapor pressure at 25 o C 2.2 mPa Octanol/water partition coefficient log (KOW) 2.84 UV/visible absorption spectrum No UV absorption above 290 nm Pest Management Regulatory Agency Health, Canada, 2006. **3.3 Pesticide Use Pattern**  Table 3. 3 provides a summary of the proposed use patterns. Penbotec ® 400SC is formulated as a SC, and is proposed at a maximum application rate of 32 fl oz formulation/100 gal water, water wax, or wax - oil emulsion (0.82 lb ai/100 gal) via in - line dip/drench wash t anks to harvested pomegranates . A single post - harvest application is permitted. There is no post - treatment interval prior to human consumption. The product label requires applicators and other handlers to wear PPE which consists of long - sleeved shirt, l ong pants, shoes plus socks and chemical resistant gloves.P yrimethanil Human Health Risk Assessment DP# 417167

Page 8 of 26 **Table 3.3. Summ ary of Proposed Directions for Use of Pyrim**  **ethanil. 1**  **Comm odity**  **Trade Name**

**(EPA Reg. No.) Application** 

**Timing, Type, Equipment**  **Application**

**Rate (lb ai/100 gal)**  **Maximum**

**Seasonal Application**  **Rate (lb ai/100 gal)**  **PHI**

**(days) RTI** 

**(days) Min.** 

**GPA** Pomegranate Penbotec ® 400

SC (43813 - 32) In - line

dip/drench 0.82 0.82 NA NA NA 1. PHI = preharvest interval; RTI = retreatment interval; GPA = gallons of water per acre; NA = not applicable. HED Conclusions : The submitted label is adequate to allow evaluation of the residue data relative to the proposed post - harvest us e on pomegranates. **3.4 Anticipated Exposure Pathways**  RD has requested an assessment of human health risk to support the proposed new post - harvest use of py rimethanil on pomegranates . Humans may be exposed to py

rimethanil in food and drinking water since py

rimethanil may

be applied directly

to growing crops, and applications may result in py

rimethanil reaching surface and ground water sources of drinking water . There are no r egistered residential uses of py rimethanil ; therefore, human exposure in residential or non - occupational settings are expected . In an occupational setting, workers may be exposed while handling the pesticide p rior to application as well as when performing sorting and packing tasks. Additionally , there is a potential for indirect inhalation exposure for workers in the warehouse or packaging facility not directly

inv olved in the automated treatment process. A human health risk assessment was completed on 22 - MAY - 2013 by HED ( Memo, J. Tyler et al. , D389923) . This risk assessment considers all of the aforementioned exposure pathway s based on the proposed new use of py rimethanil , but also considers the existing uses as well, particularl y for the dietary exposure assessments. **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http: //www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy, HED estimates risks to population sub groups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled b y the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additionally , OPP is able to assess dietary

exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures base d on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committe d resources andP yrimethanil Human Health Risk Assessment DP# 417167

Page 9 of 26 expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. **4 .0**  **Hazard Characterization and Dose Resp onse**  **Assessment** Since the last risk assessment, the conclusions and study classification for the subchronic neurotoxicity

study have been revised so that no LOAEL was observed, and so that it is now an acceptable/guideline study (Memo, A. Dunbar, 14 - AUG - 2 014; TXR# 0057032). The toxicology database for p yrimethanil is therefore now complete. The HED HASPOC looked at all existing hazard and exposure data, and current use patterns for p yrimethanil; and, using a weight - ofevidence (WOE) approach, concluded that subchronic inhalation and dermal toxicity studies are not required for p yrimethanil at this time (Memo, J. Van Alstine, 8 - FEB - 2013; TXR# 0056470). **4.1 Summary of Toxicological Effects**  Py rimethanil is of low acute lethality by the oral, dermal, and inhalation routes. It is a slight eye irritant, is not irritating to the skin, and it is not a dermal sensitizer. Through the oral route, py rimethanil was well absorbed from the gastrointe stinal tract. Following a single oral dose of 10 mg/kg, p yrimethanil was eliminated within 24 hours, and the major route of elimination was via the urine (  72%). Approximately 17 - 18% of the dose was eliminated via the feces. Detectable levels of p yri methanil were found in the adrenals, blood, kidney , liver, spleen, and thy roid less than 24 hours post dosing. The chemical was detected only in the liver, kidney , thy

roid, and blood at 24 hours post dose. Four day s post - dose, detectable levels of the chemi cal were found onl y in the liver, kidney , and thy roid. Regarding the total detectable levels per tissue, the highest levels of the chemical were detected in the liver in both sexes. There were no significant sex differences in metabolites generated. Py rimethanil was well absorbed through the dermal route. In a dermal penetration study , the compound was applied to the shaved dorsal skin of male Sprague Dawley rats. Total absorbed dose (based on the sum of urine, feces, cage wash, blood, carcass, and no n - treated skin) for the low, intermediate, and high doses at 10 hours post - treatment were 37.22, 35.77, and 20.39%, respectivel y. The “potentially absorbable” dose (combined tape stripping excluding first two tape strips and treated skin after tape stripp ing) for low, intermediate, and high dose at 10 hours post - treatment was 13.95, 5.55, and 4.80%, respectively . Absorption increased with greater exposure time, and the percent of dose absorbed increased with lower doses. The value ultimately

used for ris k assessment was calculated by combining the absorbed dose (37.22%) with the potentially

absorbable dose (13.95%) from the study , which would be equal to 51.2%. Use of the 51% dermal absorption value for dermal exposure assessment for human risk is consid ered conservative and protective. By the oral route of exposure, the rat was the most sensitive species to py rimethanil toxicity followed b y the dog and then the mouse. The major target organs of repeated oral exposure were the liver, kidney , and the thy roid, and effects observed were manifested as some clinical signs (vomiting, diarrhea, and salivation in the dog for example), changes in clinical chemical parameters (liver enzy

mes), changes in organ weights (mostly relative), and finally

macroscopic and microscopic organ changes. There were also decreased body weights throughout the database. No reproductive toxicity was observed, and developmental effects (e.g., decreasedP yrimethanil Human Health Risk Assessment DP# 417167

Page 10 of 26 fetal weight, retarded ossification, extra ribs) were observed onl y at maternally toxic doses. There was no evidence of neurotoxicity in either of the acute or subchronic studies. There were no indicators of targeted effects on the immune system in the guideline Immunotoxicity study . . Special short - term exposure studies demonstrated increased liver UDPGT activity leading to decreases in thyroid hormones (T3, T4) and compensatory increases in TSH in adult rats. Thy roid adenomas were seen in rats following long - term exposure, and it was concluded that they were mediated vi a disruption of the thy roid/pituitary

axis. In the newly

submitted mouse carcinogenicity

study , there was no evidence of thy roid tumors up to the highest dose tested. There are no concerns for mutagenicity . The thy roid has been shown to be one of the target organs in adult animals for py rimethanil induced toxicity

thus raising a potential concern for thy roid toxicity

in the young. However, HIARC previously concluded that there is no concern for thy roid toxicity

in the young based on the following weight of evidence considerations the effects seen on the thy roid and the liver in the database, while treatment - related, are not severe in nature; and in each of the studies that show an effect on thyroid hormone levels, as well as in all studies chosen for poi nts of departure ( PODs ) selection, there is a wide dose spread (~10 - fold difference between NOAELs and LOAELs) which provides a measure of protection for any potential effects linked to decreased thy roid hormone levels in offspring. **4.2 Safety factor for**  **Infants and Children (FQPA Safety Factor)** The py rimethanil risk assessment team has evaluated the hazard and exposure data; and, based on these data, recommend ed that the FQPA SF be reduced to 1X . The toxicological is complete and there is no evidence of increased offspring susceptibility . The exposure databases are sufficient to determine the nature/magnitude of the residue in food and dietary anal ys es are unlikely to underestimate risk of exposure from p yrimethanil. Although there is evidence of neuro toxicity

in the acute neurotoxicity study , concern is low since effects were onl y seen at the limit dose, effects are well - characterized with clearly established NOAEL/LOAEL values, and the selected endpoints are protective for the observed effects . **4.2 .1**  **Completeness of the Toxicology Database** The toxicology

database for py

rimethanil is adequate for FQPA consideration. The following studies are available: Developmental toxicity studies in rats and rabbits, a two - generation reproduction toxicity

study , and both acute and subchronic neurotoxicity studies. **4.2 .2**  **Evidence of Neurotoxicity** Clinical signs of neurotoxicity (ataxia, decreased motor activity , decreased body temperature, decreased hind limb grip strength in males, and dilated pupils) were observed in females in the acute neurotoxicity

study in rats at the highest dose tested only (1000 mg/kg). Although the limit dose was not tested in the subchronic neurotoxicity study, no clinical signs, behavioral changes or neuropathology

were seen at 1/2 l imit dose (up to 430 mg/kg/day) . In addition, no neurotoxic signs were seen in the rest of the database and the target organ for toxicity for py rimethanil is the thy roid . The concern for neurotoxicity therefore is low .P yrimethanil Human Health Risk Assessment DP# 417167

Page 11 of 26 **4.2.3 Evidence of Sensitivity/S**  **usceptibility in the Developing or Young Animal** There is no evidence of qualitative or quantitative increased susceptibility following pre - /post natal exposure to py

rimethanil in the developmental toxicity studies in rats and rabbits or in the two - generation reproduction study in rats. **4.2.4 Residual Uncertainty in the Exposure Database**  There are no residual uncertainties with respect to exposure data. The dietary food exposure assessment utilizes tolerance - level residues (established or recommended) and 100% CT for all proposed/established commodities. By using these assumptions, the acute and chronic exposures/risks will not be underestimated. The dietary drinking water assessment utilizes water concentration values generated b y models and associat ed modeling parameters that are designed to provide conservative, health - protective, high - end estimates of water concentrations that will not likely be exceeded. There are no residential uses. **4.3 Toxicity Endpoint and P**  **O D**  **Selections** The selected toxicity

endpoints are s ummarized in Tables 4.3.1 and 4.3.2 . Acute Dietary Endpoint (Females Age 13 - 49) : The endpoint used for establishing the aPAD for females 13 - 49 years of age was selected from the prenatal developmental toxicity study in rabbits. An aPAD of 0.45 mg/kg/day was derived from a developmental NOAEL of 45 mg/kg/day

and a 100 - fold factor that included 10X for inter- species extrapolations, 10X for intra - species variations, and 1X FQPA SF. The endpoint of concern is a developmental effect c haracterized as increases in fetuses with 13 thoracic vertebrae and 13 pairs of ribs observed at 300 mg/kg (LOAEL). These developmental anomalies are presumed to be the result of a single oral dose following in utero exposure; and, therefore, are relevant to pregnant females. Acute Dietary Endpoint (General U.S. Population) : The endpoint used for establishing the aPAD for the general population including infants and children was selected from the acute neurotoxicity

study in rats. An aPAD of 1.0 mg/kg/d ay was derived from a NOAEL of 100 mg/kg/day

and a 100 - fold factor that included 10X for inter- species extrapolations, 10X for intra - species variations, and a 1X FQPA SF. Effects at the LOAEL of 1000 mg/kg (highest dose tested) included decreased motor activity , ataxia, decreased body temperature, hind limb grip strength, and dilated pupils. The effects were seen after a single oral dose and thus appropriate for this exposure scenario and the population of concern. Chronic Dietary Endpoint (All Popula tions) : The endpoint used for deriving the cPAD was selected from a chronic toxicity study with rats. The cPAD was derived from a NOAEL of 17 mg/kg/day

and a 100 - fold factor that included 10X for inter- species extrapolations, 10X for intra - species variations, and 1X FQPA SF. The LOAEL of 221 mg /kg/day is based on increased serum cholesterol and gamma glutanyltransferase (GGT), increased relative liver/body- weight ratios, necrops y, and histopathological findings in the liver and thyroid. The endpoint o f concern was seen following repeated oral exposure in the most sensitive species; and, thus, is appropriate for assessing potential risk via chronic dietary exposure to py

rimethanil. Incidental Oral [short (1 - 30 days) - and intermediate (1 - 6 months) - term ] : There are no residential uses for p yrimethanil. Therefore, an incidental oral endpoint was not chosen.P yrimethanil Human Health Risk Assessment DP# 417167

Page 12 of 26 Dermal [short (1 - 30 days) - and intermediate (1 - 6 months) - term ] : The py

rimethanil database does not contain a dermal toxicity study . Therefore, the Agency has selected an oral NOAEL of 23 mg/kg/day

for short and intermediate term dermal risk assessments. The endpoint of concern is based on decreasedbody weight observed in the rat two - generation reproduction toxicity study at the LOAEL of 294 mg/kg/day . Since an oral dose was selected a dermal absorption factor of 51% should be used for route - to - route extrapolation which yields a dermal equivalent dose of 45 mg/kg/day

(23 mg/kg/day

÷ 0.51 DAF = 45 mg/kg/day). The LOC for occupational dermal expo sures is 100 (10X for inter - species extrapolation and 10X for intra - species extrapolation). Inhalation [short (1 - 30 days) - and intermediate (1 - 6 months) - term ] : An inhalation toxicity study was not submitted. The short - and intermediate - term inhalation endpoints are based upon the parental effect of decreased body weights observed in the two - generation reproduction toxicity study . The NOAELis 23.1 mg/kg/day . This endpoint is appropriate for the duration of exposure and the populations of concern. Inh alation exposure is assumed to be equivalent to oral exposure. The LOC for occupational inhalation exposures is 100 (10X for inter- species extrapolation and 10X for intra - species extrapolation). **Table 4. 3.1**  **. Summary of Toxicological Doses and Endpoints for Pyrim**  **ethanil for Use in Dietary and Non**   ** Occupational** **Hum an Health**  **Risk Assessments. Exposure/**  **Scenario POD**  **UFs/ FQPA SF**  **RfD, PAD,**

**LOC Study and Toxicological Effects**  Ac ute Dietary (Females 13 - 49 years of age) NOAEL

= 45 mg/kg/da y UF A = 10X

UF H = 10X FQPA SF = 1X Ac ute RfD =

0.45 mg/kg/day aPAD = 0.45 mg/kg/day Developmental Toxicity - Rabbit:

LOAEL = 300 mg/kg/day based on increases in fetuses with 13 thoracic vertebrae and 13 pairs of ribs. Ac ute Dietary (General Population, including Infants and Children) NOAEL

= 100 mg/kg/da y UF A = 10X

UF H = 10X FQPA SF = 1X Ac ute RfD = 1

mg/kg/day Ac ute Neurotoxicity - Rat: LOAEL =

1000 mg/kg/day based on decreased mo tor activity, ataxia, decreased body tem perature, hind limb grip strength, and dilated pupils. Chronic Dietary (All Populations) NOAEL

= 17 mg/kg/da y UF A = 10X

UF H = 10X FQPA SF = 1X Chronic RfD =

0.17 mg/kg/day cPAD = 0.17 mg/kg/day Chronic Toxicity - Rat:

LOAEL = 221 mg/kg/day based on decreased body - weight gains; increased serum cholesterol and GGT, increased relative liver/body weight ratios, necropsy and histopathological findings in the liver and thyroid. Cancer (oral, dermal, inhalation) CARC Classification: “Not Likely To Be Carcinogenic To Humans At Doses That Do Not

Alter Rat Thyroid Hormone Homeostasis” **Table 4.3.2 . Summary of Toxicological Doses and Endpoints for Pyrim**  **ethani l for Use in Occupational**  **Hum an**  **Health Risk Assessments .** 

**Exposure Scenario**  **POD LOC for Risk**  **Assessment Study and Toxicological Effects**  Short (1 - 30 days) and Intermediate (1 - 6 months) Term Dermal Oral NOAEL = 23.1 mg/kg/day (dermal absorption a = 51 %) Occupational LOC

for MOE = 100 Reproductive Toxicity - Rat

LOAEL = 294 mg/kg/day based on decreased mean body weights and body- weight gains. Short (1 - 30 days) and Intermediate (1 - 6 months) Oral NOAEL = 23.1 mg/kg/day Occupational LOC

for MOE = 100 Reproductive Toxicity - Rat

LOAEL = 294 mg/kg/day based onP yrimethanil Human Health Risk Assessment DP# 417167

Page 13 of 26 **Table 4.3.2 . Summary of Toxicological Doses and Endpoints for Pyrim**  **ethani l for Use in Occupational**  **Hum an**  **Health Risk Assessments .** 

**Exposure Scenario**  **POD LOC for Risk**  **Assessment Study and Toxicological Effects**  Term Inhalation (inhalation absorption

b = 100 %) decreased mean body weights and body- weight gains. Cancer (oral, dermal, inhalation) CARC Classification: “Not Likely To Be Carcinogenic To Humans At Doses That Do Not Alter Rat Thyroid Hormone Homeostasis” Point of departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no - observed adverse - effect level. LOAEL = lowest - observed adverse - effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (intraspecies). UF H = potential variation in sensitivity among members of the human population (interspecies). FQPA SF = FQPA Safety Factor. PAD = population - adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. a= dermal - absorption factor, from MRID 46630101. b= Inhalation - absorption factor assumed. **4.3.1 Recommendation for Combining Routes of Exposures for Risk Assessment**  HED notes that the same oral toxicity study w as selected for assessment of short - /intermediate term dermal and inhalation exposures and thus the dermal and inhalatio n routes of exposure should be combined. **4.3.2 Cancer Classification and Risk Assessment Recommendation**  In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March 2005), the Cancer Assessment Review Committee (CARC) classified p y rimethanil as “ **Not Likely To Be Carcinogenic To Humans At Doses That Do Not Alter Rat Thyroid Hormone**  **Homeostasis”** (TXR#0056151, J. Rowland, 23 - DEC - 2011). This decision was based on the following: i) Treatment - related increases in thy roid follicular cell tumors in male and female Sprague Dawley rats at doses which were considered adequate to assess carcinogenicity ; ii) No treatment - related tumors were seen in male or female CD - 1 mice at doses which were considered adequate to assess carcinogenicity ; iii) There is no mutagenicity concern and there is no evidence for thy roid carcinogenesis mediated through a mutagenic mode of action; iv) The non - neoplastic toxicological evidence (i.e., thy roid growth, thy

roid hormonal changes) indicated that p yrimethanil was inducing a disruption in the thy roid - pituitary

hormonal status. The overall weight - of - evidence was considered sufficient to indicate that Py rimethanil induced thyroid follicular tumors through an antithy roid mode of action; and v) Rats are substantially more sensitive than humans are to the development of thy roid follicular cell tumors in response to thy roid hormone imbalance. **Quantification of Carcinogenic Risk** : Quantification of carcinogenic risk is not required. The CARC determined that the thy roid tumors arise through a non - linear mode of action and the NOAEL (17 mg/kg/day) established for deriving the c PAD is not expected to alter thy roid hormone homeostasis nor result in thy roid tumor formation.P yrimethanil Human Health Risk Assessment DP# 417167

Page 14 of 26 **5.0 Dietary Exposure and**  **Risk Assessment**  The residue chemistry

data submitted in support of proposed uses were evaluated by HED on 12 - AUG - 2014 (Memo, J. Py ne ; D 416841 ). The drinking water assessment was completed by EFED on 26 - SEP - 2011 (Memo, J. Wolf; DP389925). The dietary exposure assessment was completed i n a HED memorandum dated 12 - AUG - 2014 (Memo, J. Py ne ; D417165 ). **5.1 Residues of Concern Summary and Rationale**  The residues which are regulated in plant commodities are p yrimethanil, per se (40 CFR §180.518). For risk assessment purposes, the residues of concern are: 1) pyrimethanil for plant commodities; 2) in livestock, py rimethanil + metabolite AEC614276 for ruminant muscle, fat and by products; and 3) py

rimethanil + metabolite AEC614277 for milk. In drinking water, residues of concern are py rimethanil + Degradate 1 (2 - amino - 4,6 - dimethylpy rimidine). **Table 5.1 . Summ**  **ary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression.**  **Matrix Residues**  **included in Risk Assessment**  **Residues included in Tolerance Expression**  Plants Primary Crop Py rimethanil, per se Py rimethanil, per se Rotational Crop Py rimethanil, per se Py rimethanil, per se Livestock Ruminant Py rimethanil + AEC614276 for muscle, fat, and byproducts. For milk, pyrimethanil + AEC614277. Py rimethanil + AEC614276 for muscle, fat, and byproducts. Py rimethanil + AEC614277 for milk. Poultry Not Applicable Not Applicable Drinking Water Parent (Pyrimethanil) + Degradate 1 (2 - amino - 4,6 - dimethylpyrimidine) Not Applicable **5.2 Food**  **Residue Profile**  The data - collection method used to generate pomegranate residue data in conjunction with magnitude of the residue study associated with this petition was a GC/MSD method . The procedure derived from “Fruit and Vegetables: Analy tical Method for the Determination of Residues (Improved Version), Py rimethanil, Active Substance,” M.H. Peatman, 15/FEB/1999, and Morse Labs’ modifications to the analy tical method dated 6/FEB/2012 and 10/FEB/2012. The lowest level of method validation (LLMV) was 0.05 ppm. This method was adequate for data collection. There are also adequate methods available to enforce tolerances for residues of py rimethanil in/on pomegranate. The pomegranate samples analyzed in this study were held in frozen storage for a maximum of 92 day s for the whole fruits and 93 day s for flesh prior to anal ys is of py rimethanil residues. Acceptable storage stability data are available demonstrating that residues of py ri methanil are stable under frozen storage conditions in: carrot, lettuce, and tomato for up to 12 months; in apples for up to 676 day s (22.2 months); and peaches for up to 651 - 658 day s (21.4 - 21.6 months) (refer to DP#s 284001 and 284870, J. Morales and G. Kramer, 1/12/04). The available storage stability data are adequate to support the storage conditions and durations for samples of pomegranate (whole fruit and flesh) from the submitted crop field trial study .P yrimethanil Human Health Risk Assessment DP# 417167

Page 15 of 26 The submitted field trial residue data for pomegranate are adequate. The field trial data reflect the proposed use pattern, an adequate number of trials were conducted, and samples were anal yz ed for the residue of concern using validated data - collection methods. Two pomegranate field trials were submitted. Each field trial had four samples that were treated post - harvest with an SC formulation of py

rimethanil (Penbotec ® 400SC), with two samples treated at a 1X rate (1,000 ppm) and two samples treated at a 2X rate (2,000 ppm). Per- trial - average - re sidues of py rimethanil in/on pomegranate, whole fruit ranged 1.51 - 1.66 ppm from the 1X trial and from 2.50 to 3.01 ppm in the 2X trial . Residues were below the limit of quantitation (L OQ; <0.05 ppm) in/on pomegranate flesh treated at a 1X rate. The OECD tolerance - calculation procedures were used to determine the tolerance for residues of py rimethanil in/on pomegranate. Per - trial - average - residues from the 1,000 - and 2,000 - ppm trials were used to calculate the tolerance. Since the label proposes applicati ons of 1,000 ppm, proportionality

was used for the 2,000 - ppm trial residues. The OECD tolerance - calculation procedures for the residue data set indicates that the requested tolerance of 5.0 ppm for residues of py rimethanil from a treatment solution of 1,0 00 ppm in/on pomegranate is appropriate. There are no livestock food/feed items of regulatory concern the pomegranate; therefore, a discussion of livestock residues is not germane to this petition. **5.3 Water Residue Profile**  Based on the information provided, EFED considers the proposed post - harvest dip use of py rimethanil as an indoor use that would pose minimal exposure to the environment, provided that release of the chemical and contaminated water are controlled. Therefore, an updated drinking w ater assessment is not needed for this new use (Memo, J. Wolfe, 30 - JUN - 2014; D416873). HED used EDWCs provided by EFED in conjunction with the most - recent human health risk assessment (Memos, J. Wolfe, 22 - OCT - 2003, D283999 and D290313; 08 - JAN - 2009, D35318 0). Tier I SCI - GROW screening concentration of combined total residues (py rimethanil + 2 - amino - 4,6 - dimethylpy rimidine) in ground water for uses on small berries (caneberries and bushberries) are not expected to exceed 4.8 μg/Lfor previousl y estimated use s based on the registered seasonal application rate of 2.1 lb ai/A on strawberry in Florida Tier II PRZM - EXAMS screening drinking water concentrations for combined residues of py rimethanil (parent + 2 - amino - 4,6 - dimethylpy rimidine) in raw surface source water are not expected to exceed 86.5 μg/Lfor the peak 1 - in - 10 - ye ar concentration; 29.4 μg/Lfor the 1 - in - 10 - ye ar annual mean concentration; and, 17.9 μg/L for the 30 - ye ar annual average concentration. These EDWCs correspond to the FL/strawberries (acute) and NY/grapes (chronic) scenarios. **Table 5.3**  **. Estim ated Drinking Water Concentrations**  **for Com bined Total Residues, Parent**  **(Pyrim ethanil) Plus Major Degradate (2**  **- amino**  **- 4,6**  **- dimethylpyrimidine).**  **Chemical Acute (peak)** 

**Surface Water Concentration**  **(ppb) Annua**  **l Average**

**Surface Water Concentration**  **1 -**  **in -**  **10 -** **yr (ppb) Average of Annual** 

**Average Surface Water Concentration**  **(ppb) Ground Water** 

**Concentration (ppb)**  Py rimethanil plus 2 - amino - 4,6 - dimethylpyrimidine. 86.5 29.4 17.9 4.8P yrimethanil Human Health Risk Assessment DP# 417167

Page 16 of 26 In this assessment, the annual average surface water concentration (29.4 ppb) and the acute peak surface water concentrations (86.5 ppb) were used for chronic and acute dietary exposure assessments, respectively. **5.4 Dietary Risk Assessment**  Unrefined acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using DEEM - FCID Version 3.16. This software uses 2003 - 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA) . **5. 4.1**  **Description of Residue and Percent Crop Treated Data Used in Dietary Assessment**  The acute and chronic dietary exposure assessment was unrefined, using tolerance - level residues and assuming 100% CT for all registered and proposed commodities. DEEM Version 7.81 default processing factors were used to estimate residues in processed commodities, as available, and empirical processing factors were used for orange and apple juice. Drinking water was incorporate d directl y into the dietary assessment using the EDWCs generated by the PRZM/EXAMS surface water model. Based on the proposed use pattern for a postharvest dip treatment, a revised drinking water assessment was not required. **5.4.2 Acute Dietary Risk Asses**  **sm ent**  Using the DEEM - FCID software, dietary risk is estimated at 9.8% of the aPAD for the general U.S. population and 38% of the aPAD for children 1 - 2 years old, the population subgroup with the highest estimated acute dietary exposure. Therefore, the acute dietary risk assessment shows that for all included commodities plus drinking water, the acute dietary risk estimates are below HED’s LOC for the general U.S. population and all population subgroups (i.e., <100% aPAD). **5.4.4 Chronic Dietary Risk Asses**  **sment** Using the DEEM - FCID software, dietary risk is estimated at 14% of the cPAD for the general U.S. population and 76 % of the cPAD for children 1 to 2 years old, the population subgroup with the highest estimated chronic dietary exposure to py

rimethanil . The chronic dietary risk assessment shows that for all included commodities plus drinking water, the chronic dietary risk estimates are below HED ’s LOC for the general U.S. population and all population subgroups (i.e., <100% cPAD). **5.4.5 Cancer**  **Dietary Risk Assessment** A cancer dietary

assessment was not conducted because py rimethanil is classified as “Not Likel y To Be Carcinogenic To Humans At Doses That Do Not Alter Rat Thyroid Hormone Homeostasis.”P yrimethanil Human Health Risk Assessment DP# 417167

Page 17 of 26 **5.4.6 Summary Table**  **Table 5.4.6. Summa**  **ry of Dietary (Food and Drinking Water)**  **Exposure and Risk for Pyrim ethanil.**  **Population Subgroup Acute Dietary**  **(95 th**  **Percentile) Chronic Dietary**  **Cancer Dietary**  **Exposure (m** **g/k g/day)**  **% aPAD 1**  **Dietary Exposure**  **(m g/k** **g/day) % cPAD**  **Dietary Exposure**  **(m g/k** **g/day) Risk**  General U.S. Population 0.97834 9.8 0.023739 14

N/A N/A All Infants (<1 year old) 0.344534 34 0.085185 50 **Children 1 -**  **2 years old 0.380589**  **38 0.128860**  **76** Children 3 - 5 years old 0.241219 24 0.078291 46 Children 6 - 12 years old 0.131512 13 0.036225 21 Youth 13 - 19 years old 0.059804 6.0 0.015366 9.0 Adults 20 - 49 years old 0.056534 5.6 0.013819 8.1 Adults 50 - 99 years old 0.058642 5.9 0.016149 9.5 Females 13 - 49 years old 0.058418 13 0.014775 8.7 1. Population subgroup with the highest exposure and risk is in **bold type.** The aPAD for Females 13 - 49 years of a ge is 0.45 mg/kg/day; aPAD for g eneral U.S. p opulation is 1 mg/kg/day . **6 .0**  **Residential (Non -**  **Occupational) Exposure/Risk Characterization** Currently , there are no registered/proposed uses of py rimethanil that result in residential exposures. Therefore, a residential exposure assessment was not performed. **7.0 Aggregate Exposure/Risk Characterization**  In accordance with the FQPA, HED must con sider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard ( e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. In the case of p yrimethanil , aggregate risk assessments were performed for acute aggregate exposure (food + drinking water) and chronic aggregate exposure (food + drinking water). A cancer aggregate risk assessment was not performed because imidacloprid is not carcinogenic. All potential exposure pathway s were assessed in the aggregate risk assessment. **7 .1**  **Acute Aggregate Risk** No acute residential/recreational exposures are expected. In the case of p yrimethanil, the acute aggregate risk is composed of exposures to py rimethanil residues in food and drinking water and is equi valent to the acute dietary risk discussed in S ection 5.4.1 . As shown in Table 5. 4 .6 , the acute risk es timates do not exceed the HED ’s LO C for the general U.S. population and all population subgroups. **7 .2**  **Short -**  **and Intermediate -**  **Term Aggregate Risk** Py ri methanil is not registered for residential uses. Therefore, short - and intermediate term residential exposure s are not expected.P yrimethanil Human Health Risk Assessment DP# 417167

Page 18 of 26 **7 .**  **3 Chronic**  **Aggregate Risk** A long - term aggregate risk assessment was not performed, because long - term residential exposure to py

rimethanil (i.e., >6 months) is unlikely to occur based upon the use patterns. Specificall y, i n the case of py rimethanil , the chronic aggregate risk is composed of exposures to py rimethanil residues in food and drinking water and is equivalent to th e chronic die tary risk discussed in Section 5. 4.2. As shown in Table 5. 4 .6 , the chronic risk es timates do not exceed the HED ’s LOC for the general U.S. population and all population subgroups. **7 .4**  **Cancer Risk** Py rimethanil is classified as “Not Likel y To Be Carcinogenic To Humans At Doses That Do Not Alter Rat Thy

roid Hormone Homeostasis.” Therefore, a cancer aggregate risk assessment was not conducted. **8 .0**  **Cumulative Risk Characterization/Assessment** Unlike other pesticides for which EP A has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for py rimethanil and any

other substances, and py rimethanil does not appear to produce a toxic metabolite produced b y other substanc es. For the purposes of this action, therefore, EPA has assumed that py

rimethanil does not have a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mech anism on EPA’s website at http://www.epa.gov/pesticides/cumulative/ . **9 .0**  **Occupational Exposure/Risk Pathway** Based on the proposed application scenario and toxicological considerations, non - cancer occupational handler (dermal and inhalation) and occupational post - ap plication (dermal and inhalation) risk assessments were conducted. The proposed new uses were evaluated in the cited memorandum and the resulting occupational exposure/risks were reviewe d by the HED Science Advisory Council for Exposure (ExpoSAC; Memo, J. Tyler, 20 - AUG - 20 14 , D417166 ). **9 .1**  **Handler Exposure and**  **Risk Estimates**  Based on the anticipated use patterns and current labeling, typ es of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is based on the mixing/loading liquids for automated s ys tem exposure scenario. A separate applicator assessment was not conducted as the application of py rimethanil is mechanically automated for the in - line dip/drench wash tanks. A mixer/loader assessment was performed and is considered to result in a conservative estimate of handler risk. HED classifies exposures from 1 to 30 day s as short - term and exposures 30 day s to six months as intermediate - term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the culturalP yrimethanil Human Health Risk Assessment DP# 417167

Page 19 of 26 practices surrounding that use site. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one - month time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region). For p yrimethanil, based on the proposed use pattern, short - and intermediate - term exposures are expected. In addition, the short - and intermediate - term PODs are the same; therefore, estimates for short - term durations are protective of longer - term exposure durations. The average adult body weight of 80 kg was used for estimating dermal and inhalation doses. No chemical - specific handler exposure data were submitted in support of this Section 3 registration. It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as sur rogate data in the absence of chemical - specific data, include PHED 1.1, the Agricultural Handler Exposure Task Force (AHE TF) database , or other registrant - submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) . The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures , ” are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler- exposure - table.pdf), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler- exposure data.html . Estimates of dermal and inhalation exposure were calculated for various levels of PPE. Results are presented for “baseline,” defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc). The py rimethanil product labels direct mixers, loaders, applicators and other handlers to wear long - sleeved shirt, long pants, shoes plus socks and chemical - resistant gloves. Table 9.1 provides a summary of the estimated exposures and risks to occupational pesticide handlers. An MOE ≥ 100 is adequate to protect occupational pesticide handlers from dermal and inhalation exposure. Dermal and inhalation risks for occupational handlers are above the LOC (100) with label - required PPE (i.e., wear long - sleeved shirt, long pants, shoes plus socks and chemical - resistant gloves ) .P yrimethanil Human Health Risk Assessment DP# 417167

Page 20 of 26 **Table 9.1 . Occupational Handler Non**  **- Cancer Exposure and Risk Estimates for Post**  **- harvest Use on Pom**  **egranates** . **Exposure Scenario**  **Crop LOC**  **Dermal Unit**  **Exposure (μg/lb ai)**  **1 Inhalation** 

**Unit Exposure**  **(μg/lb ai) 1**  **Ma x.** 

**App. Rate**  **(lb ai/gal solution)**  **2 Am**  **ount**

**Handled Daily**  **(gal/day) 3**  **Dermal Inhalation**  **Total Mitigation**  **Level Mitigation** 

**Level Dose**  **(m g/k** **g/day) 4**  **MOE 5**  **Dose (m** **g/k g/day)**  **6 MOE**  **7 MOE**  **8** Mixer/Loader Open Mixing/ Loading Liquids for Automated System Pomegranates 100 Baseline: 220 PPE - G: 37.6 Baseline:

0.219 0.0082 25,000 Baseline: 0.289 PPE - G : 0.0494 Baseline:

80 PPE - G : 470 Baseline: 0.000565 Baseline :

41,000 Baseline:

80 PPE - G : 460 1 . Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (May 2013 ); Level of mitigation: Baseline = Long sleeved shirt, long pants, shoes plus socks and no gloves (dermal); no respirator (inhalation). PPE - G = Long - sleeved shirt, long pants, shoes plus socks and chemical - resistant gloves. 2 . Based on registered or proposed label (Reg. No. 43813 - 32). 3 . HED ExpoSAC Policy/Guidance “Assessment of Occupational Exposure for Post - Harvest Commodity Pesticide Treatments.” 4 . Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/gal) × Amount Handled (gal/day) × DAF ( 51 %) ÷ BW (80 kg). 5 . Dermal MOE = Dermal NOAEL ( 23.1 mg/kg/day) ÷ Dermal Dose (mg/kg/day). 6 . Inhalation Dose = I

nhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/g al) × Amount Handled (gal/day) ÷ BW (80 kg). 7 . Inhalation MOE = I

nhalation NOAEL ( 23.1 mg/kg/day) ÷ I nhalation Dose (mg/kg/day). 8 Total MOE = NOAEL ( 23.1 mg/kg/day) ÷ Dermal Dose + I nhalation Dose. **9 .2**  **Post -**  **application Exposure and**  **Risk Estimates**  Durin g automated treatments, dermal and inhalation exposure is anticipated for workers performing sorting and packing tasks. Since the workers experience exposure following the treatment, this is technically “post - application” exposure; however, unlike other p ost - application activities (e.g., harvesting, scouting, etc.), this treatment is not governed by the Worker Protection Standard (WPS) and potential re stricted - entry intervals (REI s). Additionally , for workers in the warehouse or packaging facility not directly

involved in the automated treatment process, there is potential for indirect inhalation exposure. Exposures for these various scenarios are assessed using HED ExpoSAC Policy /Guidance “Assessment of Occupational Exposure for Post - Harvest Commodity Pe sticide Treatments” (M. Crowley , 23 - MAR - 2012). HED classifies exposures from 1 to 30 day s as short - term and exposures 30 day s to six months as intermediate - term. For py rimethanil, based on the proposed use pattern, short - and intermediate - term exposures are expected. In addition, the short - and intermediate - term PODs are the same; therefore, estimates for short - term durations are protective of longer - term exposure durations. The short - and intermediate - term risk estimates are not of concern (i.e., MOEs ≥100) at baseline (i.e., t - shirt and no gloves and no respirator) for all post - application exposure activities.P yrimethanil Human Health Risk Assessment DP# 417167

Page 21 of 26 **Table 9.2.1. Occupational Post**  **- application Non**  **- Cancer Exposure and Risk Estimates for Pyrim**  **ethanil. Crop/Site**  **Activities Ma** **x App. Rate**  **(% ai**  **in solution)**  **Dermal Inhalation**  **Combined**

**Unit Exposure**  **(μg/% ai)**  **1 Dose** 

**(m g/k** **g/day) 2**  **MOE 3**  **Unit Exposure**  **(μg/% ai)**  **1 Dose** 

**(m g/k** **g/day) 4**  **MOE 5**  **MOE 6**  **Mitigation Level**  **Mitigation Level**  Pomegranates Sorter 0.1 T - shirt/NG: 21,600 T - shirt/NG:

0.0139 1,700 NR 6,720 NR 0.0085 NR 2,700 T - shirt/NG and NR 1,000 Packer T - shirt/NG:

15,300 T - shirt/NG:

0.0098 2,400 NR 6,760 NR 0.0085 NR 2.700 T - shirt/NG and NR 1,300 1. Based on Table 2 in ExpoSAC Policy/Guidance “Assessment of Occupational Exposure for Post - Harvest Commodity Pesticide Treatments” (M. Crowley, 23 - MAR - 2012); Level of mitigation: T - shirt/NG = t - shirt and no gloves; NR = no respirator. 2. Dermal Dose = [Unit Exposure (μg/% ai) * Application Rate (% ai in solution) * Adjustment Factor (0.001 μg/mg)] ÷ Body W eight (80 kg). 3. Dermal MOE = Dermal POD (23.1 mg/kg/day)/Dermal Dose. 4. I nhalation Dose = [Unit E xposure (μg/% ai) * A pplication Rate (% ai in solution) * Adjustment F actor (0.001 μg/mg)] ÷ B ody W eight (80 kg). 5. I nhalation MOE = Inhalation POD (23.1 mg/kg/day)/I nhalation Dose. 6. Total MOE = NOAEL (23.1 mg/kg/day) ÷ (Dermal Dose + I nhalation Dose). **Table 9 .2.2. Occupational Post**  **- application Non**  **- Cancer Indirect Inhalation Exposure and Risk Estimates for**  **Pyrim ethanil.** 

**Crop/Site Ma** **x App. Rate (%**  **ai in solution) Inhalation** 

**Unit Exposure (μg/% ai)**  **1 Inhalation Dose**  **(m g/k** **g/day) 2**  **MOE 3**  **Mitigation Level** Pomegranates 0.1 NR 307 NR 0.0004 NR 60,000 1. Based on Table 4 in ExpoSAC Policy/Guidance “Assessment of Occupational Exposure for Post - Harvest Commodity Pesticide Treatments” (M. Crowley, 23 - MAR - 2012); Level of mitigation: NR = no respirator. 2 . Inhalation Dose = [Unit E xposure (μg/% ai) * A pplication Rate (% ai in solution) * Adjustment Factor (0.001 μg/mg)] ÷ Body Wei ght (80 kg)]. 3 . Inhalation MOE = I

nhalation POD (23.1 mg/kg/day)/I nhalation Dose. **10 .0**  **References**

 Toxicity

Profile Tables.  Metabolism Assessment.

RDI: G. Kramer ( 21 - JUL - 2014 ); RAB1 (23 - JUL - 2014 ) ; C. Smith (23 - JUL - 2014) J. Tyler:S10943:PY1:(703) - 851 - 5825(7509P)P yrimethanil Human Health Risk Assessment DP# 417167

Page 22 of 26 **Appendix A: Toxicity Profile Tables .**  **A.1 Toxicology Data Requirements**  The requirements (40 CFR 158.340) for food and non - food uses for p yrimethanil are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. **Table A.1 .**  **Toxicological Dat a Requirements for Pyrim**  **ethanil .**  Study Technical Required Satisfied 870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Primary Eye Irritation ................................ .................... 870.2500 Primary Dermal Irritation ................................ .............. 870.2600 Dermal Sensitization ................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ................................ ............... 870.3150 Oral Subchronic (nonrodent) ................................ ......... 870.3200 21 - Day

Dermal ................................ .............................. 870.3250 90 - Day

Dermal ................................ .............................. 870.3465 90 - Day

Inhalation ................................ .......................... yes yes no no no yes

yes no no no 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700b Developmental Toxicity (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ . yes yes yes yes

yes yes 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200b Oncogenicity (mouse) ................................ .................... 870.4300 Chronic/Oncogenicity (rat) ................................ ............ yes yes yes yes

yes yes 870.5100 Mutagenicity

—Gene Mutation - bacterial ..................... 870.5100 Mutagenicity

—Gene Reverse Mutation - bacterial ....... 870.5300 Mutagenicity

—Gene Mutation - mammalian ................ 870. 5395 Mutagenicity

—Micronucleaus Assay in Bone Marrow 870. 5550 Mutagenicity

—Unscheduled DNA Synthesis .............. yes yes yes yes yes yes

yes yes yes yes 870.6100a Acute Delayed Neurotoxicity (hen) ............................... 870.6100b 90 - Day

Neurotoxicity (hen) ................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat) ................. 870.6200b 90 - Day

Neurotoxicity Screening Battery (rat) ............... 870.6300 Develop. Neurotoxicity ................................ ................. no no yes yes no no

no yes yes

- 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes yes yes yes

yes yes **Table A. 2**  **. Acut e Toxicity Profile**  **– Pyrim**  **ethanil .**  **Guideline No./Study Type MRID No.**  **Results Toxicity**  **Category** 870.1100/Acute oral toxicity 43345002 LD 50 = 4149 mg/kg, M 5971 mg/kg, F III 870.1200/Acute dermal toxicity 43345003 LD 50 >5000 mg/kg IV 870.1300/Acute inhalation toxicity 43301604 LC 50 >1.98 mg/L III 870.2400/Primary eye irritation 43345004 slight eye irritant IV 870.2500/Primary dermal irritation 43345005 non irritant IV 870.2600/Dermal sensitization 43301605 not a sensitizer **Table A.3. Toxicity Profile for Pyrim**  **ethanil.**P yrimethanil Human Health Risk Assessment DP# 417167

Page 23 of 26 **Guideline No./Study Type MRID, (year)/**  **Classification/Doses Results**  870.3100(a) 90 - Day Oral Toxicity (rat) 43345006 43301608 (1990, 1992)/ acceptable/guideline 0, 80, 800, 8000 ppm 0/0, 5.4/6.8, 54.5/66.7, 529.1/625.9 mg/kg/day [M/F] NOAEL = 54.5 mg/kg/day [M], 66.7 mg/kg/day [F] . LOAEL = 529.1 mg/kg/day [M], 625.9 mg/kg/day [F] based on  body weights (20%), body- weight gain(30%), food consumption, brown urine,  urinary protein;  abs. heart, adrenal, spleen, thymus weights ;  rel. liver, kidney, gonad weights , liver, thyroid hypertrophy. 870.3100(b) 90 - Day Oral Toxicity (mouse) 43301606 (1991) acceptable/guideline 0, 80, 900, 10,000 ppm 0/0, 12/18, 139/203, 1864/2545 mg/kg/day [M/F] NOAEL = 139 [M] mg/kg/day, 203 [F] mg/kg/day . LOAEL = 1864 [M] and 2545 [F] mg/kg/day based on  bodyweight gain (7 - 12%),  cholesterol, bilirubin [F/M], dark thyroids,  rel. liver weights, kidney, thyroid, bladder histopathology. 870.3150 90 - Day Oral Toxicity (dog) 43301610 (1991) acceptable/guideline 0, 6, 80, 1000/800 mg/kg/day [M/F] NOAEL = 80 mg/kg/day . LOAEL = 1000/800 mg/kg/day based on  water consumption, vomiting, diarrhea, salivation, hypoactivity. 870.3700(a) Developmental Toxicity (rat) 43301617 43345018 43301619 (1991) acceptable/guideline 0, 7, 85,1000 mg/kg/day NOAEL = Maternal: 85 mg/kg/day . Developmental: 85 mg/kg/day . LOAEL = Maternal: 1000 mg/kg/day based on  body weight, and body- weight gain. Developmental: LOAEL = 1000 mg/kg/day based on  in mean litter weight and mean fetal weight. 870.3700(b) Developmental Toxicity (rabbit) 43301620 43301621 43301622 (1991) acceptable/guideline 0, 7, 45, 300 mg/kg/day NOAEL = Maternal: 45 mg/kg/day . Developmental NOAEL = 45 mg/kg/day . LOAEL = Maternal: 300 mg/kg/day based on deaths,  body wt, body- weight gain, food consumption, production, and size of fecal pellets. Developmental: 300 mg/kg/day based on deaths,  body weight , body- weight gain, food consumption, production and size of fecal pellets  fetal weight,  fetal runts, retarded ossification, 13 thoracic vertebrae and pai rs of ribs. 870.3800 Two - Generation Reproduction and Fertility Effects (rat) 43301623 (1993) acceptable/guideline 0, 32, 400, or 5000 ppm 0/0,1.9/2.2,23.1/27.4, 294/343 mg/kg/day [M/F] NOAEL = Systemic: 23.1 [M] mg/kg/day, 27.4 mg/kg/day [F] . Repro: 294/343 mg/kg/day . Offspring: 23.1 mg/kg/day [M], 27.4 mg/kg/day [F] . LOAEL = Systemic: 294 mg/kg/day [M], 343 mg/kg/day [F] based on  body weight (11 - 13%), and body- weight gain (11 - 17%) . Repro: >294/343 mg/kg/day . Offspring: 294 mg/kg/day based on  pup body weights on PND 21. 870.4100b Chronic Toxicity (dog) 43345007 43301614 (1992) acceptable/guideline 0, 2, 30, 400/250 mg/kg/day NOAEL = 30 mg/kg/day . LOAEL = 250 mg/kg/day based on  body weight, food & water consumption, food efficiency,  neutrophils,  clotting time. 870.4200b Carcinogenicity (mouse) 43301615 (1992) unacceptable/guideline 0, 16, 160, 1600 ppm 0/0, 2/2.5, 20/24.9, 210.9/253 mg/kg/day [M/F] NOAEL = 210.9 mg/kg/day [M], 253.8 mg/kg/day [F] . No toxicologically significant effects were found.

870.4200b Carcinogenicity (mouse) 48046301 (2010) acceptable/guideline 0 (2 groups), 3,500, or 7,000 ppm (equivalent to 0, 0, 477/594, 984/1217 mg/kg bw/day [M/F]) NOAEL = 477/594 mg/kg/day [M/F]. LOAEL = 984/ 1217 mg/kg/day based on increased livers weights (both absolute and relative) in both males and females and increased thyroid colloidal alteration mainly in males at the high dose. There were no compound related carcinogenic effects seen in this study. 870.4300 Combined Chronic/Carcinogenicity (rat) 43301612 - 3 (1993)/ acceptable/guideline 0, 32, 400, 5000 ppm 0/0, 1.3/1.8, 17/22, 221/291 mg/kg/day [M/F] NOAEL = 17 mg/kg/day [M], 22 mg/kg/day [F] . LOAEL = 221 mg/kg/day [M], 291 mg/kg/day [F] based on  body- weight gain (5 - 15% [M]; 15 - 45% [F]) [10 - 15%@ 6 mo nth s],  serum cholesterol, GGT, rel. liver weights; liver, thyroid histopathology [  thyroid adenomas].

870.5100 Gene Mutation 43301624 (1990); 0, 15, 50, 150, 500 , or 1500 μg/plate in the presence and absence of mammalian metabolic activation (S9 - mix) Acceptable/Guideline There was no evidence of induced mutant colonies over background.

870.5300 Gene Mutation 43301625 (1991); 0, 15, 50, 150, 500 , or 1500 There was no clear evidence of biologically significant induction of mutant colonies over background.P yrimethanil Human Health Risk Assessment DP# 417167

Page 24 of 26 **Table A.3. Toxicity Profile for Pyrim**  **ethanil. Guideline No./Study Type**  **MRID, (year)/ Classification/Doses**  **Results** μg/plate in the presence and absence of mammalian metabolic activation (S9 - mix) Acceptable/Guideline 870.5375 Chromosome aberration 43301627 (1990); 0, 7.8, 31.3 , or 62.5 μg/mL without metabolic activation (S9 - mix) and to concentrations of 0, 31.3, 125 , or 250, μg/mL with S9 - mix. Acceptable/Guideline There was no evidence of chromosome aberrations induced over background.

870.5395 Mammalian erythrocyte micronucleus test in mice 43301626 (1991); 0, 225, 450 , or 900 mg/kg body weight Acceptable/Guideline There was no statistically significant increase in the frequency of micronucleated polychromatic erythrocytes in mouse bone marrow at any dose or harves t time. 870.5550 Unscheduled DNA synthesis in mammalian culture 43301628 (1991) 0, 100, 300 , or 1000 mg/kg body weight Acceptable/Guideline Negative in inducing unscheduled DNA synthesis in rat hepatocytes as a result of in vivo gastric intubation.

870.6200a Acute -Neurotoxicity Screening Battery (rat) 45657221 45657220 (2001) acceptable/guideline 0, 30, 100, 1000 mg/kg/day NOAEL = 100 mg/kg/day [M], 100 mg/kg/day [F] . LOAEL = 1000 mg/kg/day [M], 1000 mg/kg/day [F] based on  motor activity, ataxia, and body temperature in both sexes,  hindlimb grip strength in males, and  dilated pupils in females on Day 1.

870.6200b Subchronic -Neurotoxicity Screening Battery (rat) 45657222 (1998) Acceptable/Guideline 0, 60, 600, 6000 ppm 0/0, 4/4.6, 38.7/44.3, 391.9/429.9 mg/kg/day [M/F] The systemic NOAEL = 6000 ppm (391.9/429.9 mg/kg/day [M/F]) A LOAEL for systemic toxicity was not observed. The neurotoxicity NOAEL is 6000 ppm (391.9/429.9 mg/kg/day [M/F]). A LOAEL for neurotoxicity was not observed.

870.7465 Metabolism and Pharmacokinetics 43301629 (1991), 10 mg/kg (28 days consecutive days) [M] acceptable/guideline 43345009 (1993), 11.8 mg/kg or 800 mg/kg (single dose), 10 mg/kg/day (14 days repeated dosing) [M/F] acceptable/guideline 43750101 (1995) 10 mg/kg [M/F] (single dose) Acceptable/guideline At a dose level of 10 mg/kg, pyrimethanil was eliminated within 24 hours, and the major route of elimination was via the urine [  72%]. Approximately 17 - 18% of the dose was eliminated via the feces. Radiolabel was detected only in the liver, kidney, and blood at study termination [24 hours post dose]. Th e highest residue was displayed in the liver in both sexes. There was no significant sex difference . The overall recovery of radiolabel was  91% . Detectable levels of radiolabel were found in the adrenals, blood, kidney, liver, spleen, and thyroid following exposure. Only the blood and liver displayed detectable levels of radiolabel after a single dose [24 -hour sample]. Four days after the last dose, detectable levels of radiolabel were found only in the liver, kidney, and thyroids. It appears that the levels in the blood, kidney, and thyroid would continue to increase with increased exposure time, whi le the level in the adrenal appears to have reached a plateau, and that in the liver appears to be declining. Th e main pathways of metabolism involved oxidation to phenols in either or both aromatic rings, and the minor pathways involved oxidation of the methyl group to the corresponding alcohol. Minor differences were observed between the high- and low- dose exposures, the single low- and repeat low- dose exposures, and between the sexes, but none appear to be of any toxicological significance. 870.7600 D ermal Penetration 46630101 (2005) Ac ceptable/guideline 0.6, 6.0, and 60 μg ai/cm2 The dermal - absorption value at 10 hours is 51.2%. This value is very similar to 60% absorption (57.20% absorbed dose plus 2.77% potentially absorbable dose) for which the skin site was washed after 10 hours, and which were sacrificed after 120 hrs. Therefore, using the 51% dermal absorption value for dermal exposure assessment for human risk is conservative and considered protective. 870.7800 Immunotoxicity 48263901 (2010 ) 0, 80, 800, or 8000 ppm (0, 6.9, 69.5, or 652 mg/kg bw/day, respectively [F]) Immunotoxicity NOAEL = 8000 ppm (652 mg/kg/day) . Immunotoxicity LOAEL is not established .P yrimethanil Human Health Risk Assessment DP# 417167

Page 25 of 26 **Table A.3. Toxicity Profile for Pyrim**  **ethanil. Guideline No./Study Type**  **MRID, (year)/ Classification/Doses**  **Results** Acceptable/GuidelineP yrimethanil Human Health Risk Assessment DP# 417167

Page 26 of 26 **Appendix B: Metabolism Assessment .**  **Table B .**  **1. Pyrim ethanil**  **Me tabolites of Concern.**  Common name/ ID No. Chemical name Chemical structure AE C614276 4 - [4,6 - dimethyl - 2 - pyrimidinyl)amino]phenol

AE C614277 4,6 - dimethyl - 2 - (phenylamino) - 5 - pyrimidinol Degradate 1 2 - amino - 4,6 - dimethylpyrimidine. N H N N C H 3

C H 3 O H N

H N N C H 3

C H 3 O H N H 2 N N C H 3

CH 3