Page 1 of 36 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF**  **CHEMICA L SA**  **FETY AND**  **POLLUTION PREVENTION**

**MEMORANDUM Date**  **:** 31 - JUL - 2013 **SUBJECT:** Prometry

n: Human - Health Risk Assessment for the Proposed Uses on Snap Bean and Dill. **PC Code:** 080805 **DP Barcode:** D403975 **Decision No.:** 467531 **Registration No. :**  100 - 620 **Petition No .:**  2E8052 **Regulatory Action:**  Section 3 Registration **Risk A**  **ss essment Typ**  **e :**  Single C hemical/Aggregate **Case No.:** 467 **T XR No.:**  NA **CAS No.:** 7287 - 19 - 6 **MRID No.:** NA **40 CFR:** §180.222 **FROM:** Kelly

M. Lowe, Environmental Scientist Anwar Y. Dunbar, Ph.D., Pharmacologist Sarah J. L ev y, Chemist Lata Venkateshwara , Environmental Scientist Risk Assessment Branch 1 (RAB1) Health Effects Division (HED, 7509P) **THROUGH:** Dana M. Vogel, Associate Director

George F. Kramer, Ph.D., Senior Chemist RAB1/HED (7509P) **TO:** Laura Nollen

Barbara Madden 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 Interregional Research Project No. 4 (IR - 4) has requested registration of the active ingredient (ai) prometry n for use on snap bean and dill. The RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occu pational, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the proposed /registered uses of prometry n. A summary

of the findings and an assessment of human - health risk resulting from the proposed and registered uses of prometry n are provided in this document. The risk assessment was provided b y Kell y Lowe (RAB1); the residue chemistry and dietary

assessments by

Sarah Lev y (RAB1); the hazard characterization and endpoint selection by Anwar Dunbar (RAB1); the occupational and residential exposure assessment by Lata Venkateshwara (RAB1); and thePrometryn Human - Health Risk Assessment D403975

Page 2 of 36 drinking water exposure assessment by Mohammed Ruhman of the Environmental Fate and Effects Division (EFED).Prometryn Human - Health Risk Assessment D403975

Page 3 of 36 **Table of Contents 1.0**  **Executive Summary ................................**  **................................ ................................**  **........... 5**  **2.0 HED Recommendations**  **................................ ................................**  **................................ ....**  **8 2.1**  **Data Deficiencies ................................**  **................................ ................................**  **............ 8**  **2.2 Tolerance Considerations**  **................................ ................................**  **.............................. 8**  **2.2.1 Enforcement Analytical Method**  **................................ ................................**  **........... 8**  **2.2.2 Recommended Tolerances**  **................................ ................................**  **...................... 9**  **2.2.3 Revisions to Petitioned**  **- For Tolerances**  **................................ ..............................**  **10 2.2.4**  **International Harmonization ................................**  **................................ ...............**  **10 2.3**  **Label Recommendations ................................**  **................................ ..............................**  **10 2.3.1**  **Recommendations from Residue Reviews ................................**  **.......................... 10**  **2.3.2 Recommendations from Occupational Assessment**  **................................ ...........**  **1 0**  **3.0 Introduction**  **................................ ................................**  **................................ ......................**  **11 3.1**  **Chemical Identity ................................**  **................................ ................................**  **......... 11**  **3.2 Ph**  **ysical/Chemical Characteristics ................................**  **................................ .............**  **12 3.3**  **Pesticide Use Pattern ................................**  **................................ ................................**  **.... 12**  **3.4 Anticipated Exposure Pathways**  **................................ ................................**  **................. 13**  **3.5 Consideration of Environmental Justice**  **................................ ................................**  **.... 13**  **4.0 Hazard Characterization and Dose**  **- Response Assessment**  **................................ ..........**  **14 4.1**  **Toxicology Studies Available for Analysis ................................**  **................................ .**  **14 4.2**  **Absorption, Distribution, Metabolism, & Elimination (ADME) .............................**  **14 4.2.1**  **Dermal Absorption ................................**  **................................ ...............................**  **15 4.3**  **Toxicological Effects ................................**  **................................ ................................**  **.... 15**  **4.4 Safety Factor for Infants and Children (FQPA SF)**  **................................ ..................**  **16 4.4.1**  **Completeness of the Toxicology Database ................................**  **.......................... 16**  **4.4.2 Evidence of Neurotoxicity**  **................................ ................................**  **.................... 16**  **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Anim**  **al ....**  **16 4.4.4**  **Residual Uncertainty in the Exposure Database ................................**  **................ 16**  **4.5 Toxicity Endpoint and Point of Departure Selections**  **................................ ..............**  **16 4.5.1**  **Dose -**  **Response Assessment ................................**  **................................ ..................**  **16 4.5.2**  **Recommendation for Combining Routes of Exposures for Risk Assessment**  **. 18**  **4.5.3 Cancer Classification and Risk Assessment Recommendation**  **........................ 18**  **4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk**  **Assessment ................................**  **................................ ................................**  **........................... 18**  **5.0 Dietary Exposure and Risk Assessment**  **................................ ................................**  **......... 19**  **5.1 Metabolite/Degradate Residue Profile**  **................................ ................................**  **....... 19**  **5.1.1 Summary of Plant and Livestock Metabolism Studies**  **................................ ......**  **19 5.1.2**  **Summary of Environmental Degradation ................................**  **.......................... 20**  **5.1.3 Comparison of Metabolic Pathways**  **................................ ................................**  **.... 20**  **5.1.4 Residues of Concern Summary and Rationale**  **................................ ...................**  **20 5.2**  **Food Residue Profile ................................**  **................................ ................................**  **.... 21**  **5.3 Water Residue Profile**  **................................ ................................**  **................................ ..**  **22 5.**  **4 Dietary Risk Assessment**  **................................ ................................**  **.............................. 23**  **5.4.1 Description of Residue Data Used in Dietary Assessment**  **................................ 23**  **5.4.2 Percent Crop Treated Used in Dietary Assessment**  **................................ ...........**  **23 5.4.3**  **Acute Dietary Risk Assessment ................................**  **................................ ...........**  **23 5.4.4**  **Chronic Dietary Risk Assessment ................................**  **................................ .......**  **23 5.4.5**  **Cancer Dietary Risk Assessment ................................**  **................................ .........**  **23 5.4.6**  **Summary Table ................................**  **................................ ................................**  **..... 23**  **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  **............................. 24** Prometryn Human - Health Risk Assessment D403975

Page 4 of 36 **6.1 Residential Bystander Post**  **- application Inhalation Exposure**  **................................ .**  **24 6.2**  **Spray Drift ................................**  **................................ ................................**  **.................... 24**  **7.0 Aggregate Exposure/Risk Characterization**  **................................ ................................**  **.. 25**  **7.1 Acute Aggregate Risk**  **................................ ................................**  **................................ ...**  **25 7.2**  **Chronic Aggregate Risk ................................**  **................................ ..............................**  **25 8.0**  **Cumulative Exposure/Risk Characterization ................................**  **............................... 25**  **9.0 Occupational Exposure/Risk Characterization**  **................................ ............................**  **26 9.1**  **Short -** **/Intermediate -**  **Term Handler Risk ................................**  **................................ ...**  **26 9.2**  **Short -** **/Intermediate -**  **Term Post -**  **Application Risk ................................**  **.................... 27**  **9.2.1 Dermal Post**  **- application Risk**  **................................ ................................**  **.............. 27**  **9.2.2 Inhalation Post**  **- application Risk**  **................................ ................................**  **......... 28**  **10.0 References**  **................................ ................................**  **................................ .........................**  **29 Appendix A.**  **Toxicology Profile and Executive Summaries ................................**  **.................. 31**  **A.1 Toxicology Data Requirements**  **................................ ................................**  **................... 31**  **A.2 Toxicity Profiles**  **................................ ................................**  **................................ ............**  **32 Append**  **ix B. Physical/Chemical Properties ................................**  **................................ .............**  **35 Appendix C. Review of Human Research**  **................................ ................................**  **................ 36** Prometryn Human - Health Risk Assessment D403975

Page 5 of 36 **1.0 Executive Summary**  **Background:** Prometry

n [2,4 - bis(isopropylamino) - 6 - methylthio - s - triazine] is a substituted thiomethyl triazine herbicide (Group 5) registered in the U.S. for the control of weeds in a number of agricultural crops, such as celery , cotton, dill, pigeon peas, carrot, celeriac, cilantro, okra, parsley , and leaf petioles (crop subgroup 4B). Permanent tolerances for the residues of prometry n are currentl y established i n/on a variety of crops (40 CFR §180.222). There are no residential uses registered for prometry n. IR - 4 and the registrant, Sy ngenta, have submitted a petition proposing a tolerance for prometry n use on snap bean and dill. Proposed end - use product labels were not submitted with this petition due to indemnification concerns . Indemnification allows registrants to place a waiver of liability statement on their product lab el. It is currentl y only available through the Section 24(c) process, and is int ended mainly

for minor - use crops. According to the petition, Sy ngenta does intend to allow this use via a Section 24(c) in the future. Section B of the petition provides indemnified label language for the IR - 4 submission of the end use product Caparol ® 4L(EPA Reg. #100 - 620) . The language indicate s that the user i s to follow all applicable directions, restrictions, Worker Protection Standard (WPS) requirements, and precautions on the EPA - registered end - use product label. Caparol ® 4Lis a selective her bicide that may be applied either before or after weeds emerge for control of most annual broadleaf weeds and grasses. The proposed use directions allow for one application per year on snap beans and dill at rates ranging up to 1.6 pounds (lbs) ai per acre (A) using ground equipment. Preharvest intervals (PHIs) of 52 and 30 day s are proposed for snap bean and dill, respectivel y . In conjunction with this petition, IR - 4 has requested the establishment of permanent tolerances for the residues of prometry n i n or on the commo dities summarized in Table 2.2. 2.1 . **Hazard Assessment:** Prometryn was categorized as having minimal acute toxicity via the oral, dermal, and inhalation routes (Category III or IV). It was mildly irritating to the eyes and slightly irritating to the skin, but not a sensitizer of the skin. Prometry n is distributed primarily to the blood, spleen, and lungs. It is extensively metabolized in rats, with <2% of recovered material representing the parent compound, and is excreted predomin antl y i n the urine and feces. No evidence of local or systemic toxicity was observed in a 21 - day dermal toxicity

study in rabbits. The only

subchronic oral feeding study available for prometry

n is a 28 - day

feeding study in mice, in which prometry n caused decreased body

weight and/or mortality

at doses that exceeded the limit dose. In chronic oral toxicity studies, effects primaril y occurred onl y at the highest doses tested for dogs (degenerative hepatic changes, renal tubule degeneration, and bone marrow atrophy) , rats (decreased body weight , decreased body- weight gains , and renal toxicity) , and mice (decreased body - weight gain) , with the dog considered to be the most sensitive species. In developmental studies with prometry n, effects were observed pri marily at the highest doses tested. Furthermore, fetal effects (decreased fetal body weight , incomplete ossification of sternebrae and metacarpals in rats, and a decreased number of viable litters and live fetuses in rabbits) were observed at the same dos es as maternal toxicity (decreased body weight, decreased food consumption, and clinical signs of toxicity in rats, and decreased food consumption and an increased incidence of resorptions, abortions, and post - implantation loss in rabbits) . In the two gen eration rat reproductive study , no evidence of toxicity to the reproductive organs was observed and the effects that were observed in the offspring (decreased body weights) occurredPrometryn Human - Health Risk Assessment D403975

Page 6 of 36 at the same dose as those observed in parental animals (decreased food con sumption, body weight, and body- weight gain). Preliminary

review of the rat acute and subchronic neurotoxicity studies reveals lower mean total and/or ambulatory

locomotor activity

counts noted for both sexes on the first day of treatment in the acute study , and no signs of neurotoxicity in the subchronic study . In the immunotoxicity study , there was a decreased humoral response in the sheep red blood cell assay , though this effect is not expected to impact the risk assessment. There was no evidence o f carcinogenicity in either mice or rats, and prometry n was non - mutagenic. Since the last risk assessment, HED’s Hazard and Science Policy Council (HASPOC) evaluated all existing hazard and exposure data, and current use patterns for prometryn, and used a weight of - evidence approach to require a subchronic inhalation toxicity study . In the absence of a route specific inhalation study, the HASPOC recommends that a 10X database uncertainty factor be applied when assessing risks for inhalation exposure scenarios. **Dose -**  **Response and Food Quality Protection Act (FQPA) Assessments:** The prometryn risk assessment team has recommended that the FQPA Safety Factor (SF) be reduced to 1X for the following reasons: (1) there is an adequate toxicity database for prometry

n ; (2) p reliminary review of the neurotoxicity studies show some indication of neurotoxicity in the acute study; however, the level of concern (LOC) is low since the point of departure ( POD ) chosen for risk assess ment is lower and considered protective of these effects ; (3) there is no evidence of susceptibility , and no residual uncertainties concerning pre - or post - natal toxicity ; and (4) there are no residential uses for prometry n, and the dietary

assessments wil l not underestimate exposure. A no - observed adverse - effect level (NOAEL) of 12 mg/kg/day from the developmental toxicity study in rabbits was chosen for the acute reference dose (aRfD) for females 13 - 49 years of age. A NOAEL of 3.75 mg/kg/day from the chronic toxicity study in the dog was chosen for the chronic reference dose (cRfD) . Since the FQPA SF has been reduc ed to 1X, both the acute population - adjusted dose (aPAD) and the chronic population - adjusted dose (cPAD) are equal to the aRfD and the cRfD, respectivel y. The short - and intermediate - term dermal and inhalation PODs are based on the NOAEL of 12 mg/kg/day from the oral developmental toxicity study in the rabbit. The LOC is for margins of exposure (MOEs) < 100 for dermal (10X interspecies factor and 10X intraspecies factor) and < 1000 for inhalation (10X interspecies factor, 10X intraspecies factor, and 10X database uncertainty factor). **Metabolism and Food Residue Profile :**  Acceptable plant and livestock metabolism studies have been submitted, with the exception of a root crop metabolism study . The studies already submitted and reviewed indicate that the metabolic pathway involves N

- dealkylation and hydrol ys is of prometry

n. HED determined that the resid ue of concern in plants and livestock is the parent, prometry

n per se , which is the currently regulated residue. The submitted residue anal yt ical methods data are adequate to satisfy data requirements for the proposed uses. Acceptable enforcement methodo logy is available for tolerance enforcement purposes for the proposed uses, and adequate data - collection methods were used in the submitted field trial and processing studies. **Dietary Exposure and Risk Assessment:** Acute and chronic risk assessments we re conducted for dietary

exposure based on the existing and proposed uses. The acute and chronic assessments directly incorporated drinking water estimates. Assumptions for the acute and chronicPrometryn Human - Health Risk Assessment D403975

Page 7 of 36 assessment s included tolerance - level residues for all foods , Dietary Exposure Evaluation Model (DEEM) 7.81 default processing factors (where provided), and 100% crop - treated (CT). All exposure and risk estimates were not of concern. The resulting acute dietary (food + drinking water) risk estimates utilized 17 % of the aPAD for the females 13 - 49 years old population subgroup, the onl y acute population subgroup of concern for this assessment. The resulting chronic dietary

(food + drinking water) risk estimates utilized 8.6 % of the cPAD for the general U.S. populat ion and 23 % of the cPAD for all infants (<1 year old) , the most highl y exposed population subgroup . A cancer dietary assessment was not conducted because prometry n is classified as “Group E: Evidence of non - carcinogenicity for humans.” **Residential (Non -**  **O ccupational) Exposure/Risk Assessment:**  There are no registered or proposed residential uses for prometry n ; therefore, a residential exposure assessment was not conducted. **Aggregate Exposure/Risk Assessment:** Since there are no residential uses, only acut e and chronic aggregate risk assessment s were conducted, and are made up onl y of dietary sources (food and drinking water) . T he dietary exposure analy ses represent acute and chronic aggregate exposure, respectivel y. Prometry n is classified as “Group E: E vidence of non - carcinogenicity for humans” ; therefore, cancer aggregate risk assessments were not performed. **Occupational Exposure/Risk Assessment:** Based on the proposed use pattern s, there is potential for short - and intermediate - term occupational exposure to prometry n during mixing, loading, applying, and other handling tasks for groundboom and chemigation applications ; and during post - application activities. Additionally , since the same endpoint and POD were selected for short - and intermediate - term durations, short - term exposure and risk estimates are considered to be protective of potential longer - term exposure and risk. Chronic exposure is not expected for the proposed agricul tural uses. For the proposed uses, all occupational handler scenarios, except mixing/loading liquids for chemigation applications, result in MOEs greater than the LOC (i.e., MOEs ≥100 for dermal and ≥1,000 for inhalation) at baseline (i.e., single layer o f clothing, no gloves, no respirator) and the combined dermal and inhalation risk estimates, expressed as an aggregated - risk index (ARI), are greater than 1 with baseline attire . HED has determined that gloves are required to reach acceptable MOEs and ARI s for the mixing/loading liquids for chemigation applications scenario . The registered label for Caparol ® 4L(EPA Reg. #100 - 620) already requires the use of chemical - resistant gloves as personal - protective equipment (PPE) for applicators and other handler s ; therefore, there is no risk of concern for this scenario with the current label PPE. HED has determined that short - and intermediate - term risk estimates are not of concern (i.e., MOEs ≥100) on the day

of treatment (i.e., day 0) for most post - application exposure activities. However, there were risk estimates of concern related to one post - application activity for snap beans and dill: hand - set irrigation (MOE s of 81 and 86 on Day 0 for snap bean and dill, respectivel y) . It should be noted that the transfer coefficient used to represent the hand - set irrigation activity

is based on a study

in which wet foliage was contacted by volunteers , and in addition, the volunteers performing the activities in the study (potato irrigation) did not wear waterproof boots, which would normally be worn. Therefore, the use of this transfer coefficient to represent activity

associated with hand - set irrigation is considered a conservative assumption. This is particularly

true for the proposed u ses being assessed here, snap bean and dill, where the applications are to be made earl y s eason (pre - emergence or soon after emergence), while the applications in the transfer coefficient study were made late season when the crop (potato) was fairl y tall .Prometryn Human - Health Risk Assessment D403975

Page 8 of 36 This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. Please refer to Appendix C for a discussion of the human study data used in this risk assessment. **2.0 H**  **ED Recommendations**  HED can recommend for a registration and tolerance for the use of prometry n on snap bean and dill. Additional data are needed as outlined in S ection 2.1 below. The specific tolerance recommendations are discussed in Section 2.2, and l abel modif ications are discussed in S ection 2.3. **2.1 Data Deficiencies**  The following data gaps have been identified:

 Nature of the Residue Study in a root crop ( OCSPP 860.1300 ): This is an outstanding data request from the 2009 risk assessment (W. W assell et al. , 05 - AUG - 2009; D367830 ) . The registrant submitted a metabolism study in rice with rationale as to why this study was submitted instead of the requested study in a root crop . HED reviewed this study and while it is adequate, it presents a qualitativel y different metabolic profile than the other submitted studies on celery and cotton; therefore, HED is still requesting the root crop metabolism study

in this current risk assessment. D epending on results of the root crop metabolism study , additional field trial data could be required .  90 - Day

Inhalation Toxicity

Study (OCSPP 870.3465): This is a new requirement based on an evaluation b y HED’s HASPOC.  Dislodgeable Foliar Residue (DFR) Study (OCSPP 875.2100): This is a new requirement based on HED’s Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies (Memo, J. Housenger, 12 - DEC - 20 12). In addition, there are risk estimates of concern for post - application activities for the proposed uses using our default assumptions at the 12 - hour restricted entry interval (REI) currentl y on the label . The REIon the label will need to be changed to 48 hours based on the current assessment. **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Meth**  **od** Adequate enforcement methodology is available to enforce the proposed tolerances. Prometry n is completely

recovered (>80% recovery) using the Food and Drug Administration’s (FDA’s) Multiresidue Section 302 and partiall y recovered (22 - 87% recovery) usi ng Sections 303 and 304, with the recovery

varying depending upon the choice of Florisil sy stem used. In addition, an acceptable gas chromatograph y (GC) method with flame - photometric detection in the sulfur mode (FPD/S) , Ciba - Geigy Method AG - 559, is avail able for use as a single - analy te confirmatory

method. Method AG - 559 has undergone a successful independent laboratory validation (ILV ; Memo, E. Zager, 24 - MAY - 1991; D160100 ) . This method was radiovalidated using samples from the celery metabolism study ; however, these samples contained no detectable residues of prometry n. HED previously

concluded that Method AG - 559 is acceptable for enforcement purposes, pending completion of a successful Agency method validatio n trial.Prometryn Human - Health Risk Assessment D403975

Page 9 of 36 The Residue Chemistry

Chapter of the Prometry

n RED also required radiovalidation of the method using samples from the cotton metabolism study . In response to the radiovalidation data requirements, Sy ngenta submitted a method description and vali dation data for a GC/nitrogen phosphorous detector (NPD ) method, Method AG - 673, for the determination of prometry n residues in/on cotton matrices. The method adequatel y determines residues of prometry n , and its metabolites GS - 11354 and GS - 26831 , in cotton seed and gin b yp roducts. Method AG - 673 specifies that anal yt e residues may be confirmed b y equipping the GC s ys tem with a flame - photometric detector (FPD), as described for Method AG 559. The extraction procedures of Method AG - 673 are similar to those of AG - 559. No ILV data were submitted for Method AG - 673; however, since adequate ILV data have been submitt ed for Method AG - 559, HED will not require additional ILV data for Method AG - 673. Method AG 673 and Method AG - 559 are both considered adequate for en forcement purposes. **2.2. 2**  **Recommended Tolerances** Pending submission of a revised Section F (see requirement in Section 2.2.3) , HED recommends granting a registration and tolerance for the use of prometry n on the requested crops. The proposed uses and the submi tted data support the tolerances identified in Table 2.2.2.1 for residues of the herbicide prometry n in or on the commodities. Compliance with the tolerance levels specified below is to be determined b y measuring onl y prometryn [2,4 - bis(isopropyl amino) - 6 - methylthio - s - triazine] . **Table 2.2.2.1**  **. Tolerance Summary for**  **Prom etryn**  **Comm odity**  **Established/Proposed**

**Tolerance (ppm) HED**  **** **Recommended Tolerance (ppm)**  **Comments**

**Correct Commodity Definition** Bean, snap, succulent 0.05 0.05 Bean, forage 0.09 0.09 A tolerance is not necessary for this commodity. Dill, leaves 0.3 0.30 Concurrent with granting a national registration, the removal of the regional restrictions on dill should be

removed. Dillweed, fresh leaves Dill, dried leaves 1.1 1.1 Dill, oil 1.3 -- A tolerance is not necessary for this commodity . In accordance with the most recent guidance concerning tolerance expressions, HED recommends that the tolerance expression for 40 CFR §180.222 be changed as indicated below. “(a) General. Tol erances are established for residues of the herbicide prometry n, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only

prometry n ([ 2,4 - bis(isopropylamino) - 6 - methylthio - s - triazine] in or on the following raw agricultural commodities: and (d) Indirect or inadvertent residues. Tolerances are established for indirect or inadvertent residues of the herbicide prometry n, including its met abolites and degradates, in or on thePrometryn Human - Health Risk Assessment D403975

Page 10 of 36 commodities in the table below. Compliance with the tolerance levels specified below is to be determined b y measuring only prometryn ([2,4 - bis(isopropylamino) - 6 - methylthio - s - triazine] in or on the following raw agricu ltural commodities:” **Note to PM:** Concurrent with the establishment of the HED - recommended tolerances for residues in/on dillweed, fresh leaves and dill, dried leaves, the established tolerance of 0.3 ppm in/on dill with regional restriction should be rem oved in 40 CFR §180.222(c). **2.2. 3**  **Revisions to Petitioned -**  **For Tolerances** In accordance with Agency guidance on tolerance expressions, the tolerance expressions for prometry n we re revised by

clarifying that the tolerances cover “residues of prometry n , including its metabolites and degradates.” There were no additional revisions needed to the petitioned - for tolerances for bean, snap, succulent or dill, dried leaves. T here is currentl y a prometry n tolerance established in/on dill, leaves at 0.3 ppm with a regional restriction. This tolerance level is adequate and HED agrees with the petitioner to remove the regional restriction for this crop. However, the commodity definition should be changed from dill, leaves to dillweed, fresh leaves. The petitioner also propos ed tolerance s for residues of prometry n in/on bean, forage and dill, oil; however, tolerance s are not necessary as bean, forage is an insignificant livestock feed item and dil l, oil is not a regulated commodity . **2.2.4 International Harmonization**  There are currently

no established Codex maximum residue limits (MRL s) for prometry n; therefore, harmonization is not an issue. **2.3 Label Recommendations**  **2.3.1 Recommendations fro**  **m Residue Reviews**  There are no label recommendations based on the residue chemistry reviews. **2.3.2 Recommendations**  **from Occupational Assessment** HED recommends that RD ensure the appropriate REIfor prometry n be included on the product label based on the results of the occupational post - application exposure assessment. MOEs are not of concern for the hand - set irrigation activity for the proposed crops 2 day s (48 hours) after application. Chemical - specific DFR data are not available for prom etry n, and could be used to refine the assessment.Prometryn Human - Health Risk Assessment D403975

Page 11 of 36 N N N OH

N N CH H CH 3 CH 3 CH H H 3 C CH 3 **3.0 In**  **troduction 3.1**  **Chemical Identity Table 3.1.1. Prom**  **etryn Nomenclature.** Chemical structure

Common name Prometryn Com pany experimental name G - 34161 IUPAC name N,N'- diisopropyl - 6 - (methylthio) - 1,3,5 - triazine - 2,4 - diamine CAS name N,N'- bis(1 - methylethyl) - 6 - (methylthio) - 1,3,5 - triazine - 2,4 - diamine CAS registry number 7287 - 19 - 6 End - use product (EP) Caparol ® 4L (4 lb/gal FlC; EPA Reg. No. 100 - 620) GS - 11354

2 - amino - 4 - iospropylamino - 6 - methylthio -s - triazine GS - 26831 N N N NH 2

NH 2 S C H 3 2,4 - bis - amino - 6 - methylthio - s - triazine GS - 11526

4,6 - bis - isopropylamino - [1,3,5]triazine - 2 - ol N N N S CH 3

N N CH H CH 3 CH 3 CH H H 3 C CH 3

N N N S CH 3

N CH

H CH 3 CH 3 N H HPrometryn Human - Health Risk Assessment D403975

Page 12 of 36 **Table 3.1.1. Prom etryn Nomenclature.**  GS - 16141

4,6 - bis - isopropylamino - 2 - methanesulfinyl - [1,3,5] triazine GS - 17794

4 arnino - 6 - isopropylarnino - (1,3,5jtriazine - 2 - ol) **3.2 Physical/Chemical Characteristics**  Prometry n is a substituted thiomethy l triazine herbicide. It s vapor pressure is 8.54 x 10 - 7 mm Hg at 25oC . Prometry

n and its degradates are mobile to very mobile in soil. Potential transport mechanisms include runoff to surface water, leaching to ground water, spray drift, and secondary drift of volatilized or soil - bound residues leading to deposition onto nearby or more distan t ecos ys tems. According to the submitted physical - chemical and environmental fate data, the degradation of prometry

n is driven by

microbial (biotic) activity and not b y abiotic processes; however, biotransformation is slow . The major biotransformation pr oduct is GS - 11526. The low Freundlich adsorption coefficient of prometryn suggests that the chemical has the potential to run off and/or leach to ground water. Prometryn is stable to hy drol ys is and direct photolysis in aqueous media. A table of the phys icochemical properties can be found in Appendix B. **3.3 Pesticide Use Pattern**  The petitioner has submitted a petition proposing a tolerance for prometry n use on snap bean and dill. Proposed end - use product labels were not submitted with this petition d ue to indemnification concerns (i.e., waivers of liability statements on the product label). The intent of the company is to allow this use via a Section 24(c) in the future. Se ction B of the petition provides indemnified Caparol ® 4L label language for the IR - 4 subm ission . The language indicates that the user i s to follow all applicable directions, restrictions, WPS requirements, and precautions on the EPA - registered end - use product label (EPA Reg. #100 - 620) . The i nformation pertain ing to the proposed uses is listed in Table 3.3 . 1. A summary

of the recommended label changes can be found in Section 2.3. It should be noted that prometry n is already registered for use on dill; however, the current registration is limited to a region al tolerance . The petitioner has submitted additional data to expand the regional tolerance to a national tolerance. N N N S CH 3

N N CH H CH 3 CH 3 CH H H 3 C CH 3 OPrometryn Human - Health Risk Assessment D403975

Page 13 of 36 Permanent tolerances for the residues of prometryn are currentl y established in/on a wide variety of crops and crop groups in 40 CFR §180 . 222 (a), ranging from 0. 05 ppm for okra and celeriac roots to 9 ppm for the dried leaves of coriander . A tolerance with a regional exemption is established in 40 CFR §180. 222 ( c ) for dill at 0.3 ppm . Additionally , indirect tolerances are established in 4 0 CFR §180. 222 ( d) for a variety of food commodities including barley , oat, rye, triticale, and wheat, ranging from 0.3 to 1.0 ppm . **Table 3.3. 1.**  **Summary of Directions for Use of Prom etryn**  **Applic. Timing, Type,**  **and Equip. Form**  **ulation**

**[EPA Reg. No.]**  **Max .** 

**Applic. Rate (lb**  **ai/A) Max. No.** 

**Applic. per Season**  **Max.**

**Seasonal Applic. Rate**  **(lb ai/A) PHI** 

**(days) Use Directions and** 

**Limitations Snap Bean**  Groundboom Chemigation Caparol ® 4L,

44% prometryn (ai), 4 lb ai/gal liquid formulation [100 - 620] 1.5 1 1.5 per crop cycle 52 Can be applied

preemergence (post planting). Do not use on sand or loamy sand soil. **Dill** Groundboom Chemigation Caparol ® 4L,

44% prometryn (ai), 4 lb ai/gal liquid formulation [100 - 620] 1.6 1 1.6 per crop cycle 30 Can be applied either pre emergence (post planting) or post - emergence. Do not use on sand or loamy sand soil. **3.4 Anticipated Exposure Pathways**  RD has requested an assessment of human health risk to support the proposed new use of prometry n on snap bean and dill. Humans may be exposed to prometry

n in food and drinking water, since prometry

n may be applied directl y to growing crops and application m ay result in prometry n reaching surface and ground water sources of drinking water. There are no residential uses of prometry

n, so exposure is not likely in residential or non - occupational settings. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is a potential for post - application exposure for workers re - entering treated fields. Risk assessments have been previousl y prepared for the existing uses of prometry n. This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of prometry

n, but also considers the existing uses as well for the dietary exposure assessment. **3.5 Consideration of Environmental Just**  **ice** 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 Populat ions and L ow - Income Populations . " 1 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

1 http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdfPrometryn Human - Health Risk Assessment D403975

Page 14 of 36 population subgroups from pesticide e xposures 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 by the United States Dep artment of Agriculture (USDA) under the National Health and Nutrition Examination Survey , What We Eat in America (NHANES/WWEIA; 2003 - 2008), and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized b y subgroups based on age, season of the year, 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 based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post - application are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to b ys tanders and farm workers as well as lifestyl e and traditional dietary patterns amon g specific subgroups. **4.0 Hazard Characterization and Dose**  **- Response Assessment**  **4.1 Toxicology Studies Available for Analysis**  The toxicology

database for prometry

n is adequate for characterization of its hazard, toxicity endpoint selection, and FQPA cons ideration. In the last Section 3 risk assessment (W. Wassell et al. , 05 - AUG - 2009; D367830 ), immunotoxicity and neurotoxicity

screening battery

test studies were reported as data gaps. These studies have since been submitted and are pending formal review . Preliminary

review suggests that they will not affect the endpoints selected for assessing dietary and occupational risks of concern. Since the last risk assessment, HED’s HASPOC evaluated all existing hazard and exposure data, and current use pattern s for prometry n, and used a weight - of

- evidence approach to require a subchronic inhalation toxicity study (Memo, J. Van Alstine, 21 - FEB - 2013; TXR#005625). In the absence of a route - specific inhalation study , the HASPOC recommends that a 10X database uncertainty factor be applied when assessing risks for inhalation exposure scenarios. **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  In the rat metabolism study , animals received a single dose of prometry n at 0.46 mg/kg (low dose) and 467 mg/k g (high dose). Animals were also repeatedl y dosed at 0.46 mg/kg for 14 day s. Absorption from the gastrointestinal (GI) tract was not experimentally measured; however, estimates were made based upon the urinary excretion profile; 47.06 - 53.3% of the 0.46 m g/kg single oral dose was estimated to have been absorbed. A bile duct ligation experiment was not performed, so it is unclear whether there was a greater amount of absorption from the GI tract than the fraction detected in the urine. Prometry n is distributed primarily

to the blood, spleen, and lungs. There was a dose - related increase in tissue levels. Prometry n is extensively metabolized in rats, with <2% of recovered material representing the parent compound. Prometry n is excreted predominantly in th e urine (47.06 - 53.3%) and feces (33.13 - 45.48%) out to 7 day s post - dosing. These values were similar following 14 day s of repeated low dosing, and for the high - dose group at 7 day s. Greater than 90% of the radiolabel was excreted by both sexes in the low - dose groups b y 24 hours. Urinary and fecal excretion was greater than 90% complete for the high - dose animals at 72 hours post dosing.Prometryn Human - Health Risk Assessment D403975

Page 15 of 36 **4.2.1 Dermal Absorption**  A dermal absorption study is not available for evaluation. An absorption factor of 15% was e stimated based on comparison of data from the developmental and dermal studies in rabbits ( Memo, J. Rowland, 24 - OCT - 1997; TXR#0012371) . In the oral developmental toxicity study in rabbits, the lowest - observed adverse - effect level (LOAEL) was 72 mg/kg/day based on decreased food consumption, increased resorptions, abortions , and post implantation loss as well as a decreased number of viable litters and fetuses. In the dermal toxicity study in non - pregnant adult rabbits, no dermal or sy stemic toxicity was observed at the limit - dose of 1000 mg/kg/day . Due to the uncertainties in extrapolating from the oral to dermal route from the available data, a conservative dermal - absorption factor of 15% was se lected (72 mg/kg/day ÷ 1000 mg/kg/day

* 2), in the absence of definitive dermal - absorption data. **4.3 Toxicological Effects**  Prometry n was categorized as having minimal acute toxicity via the oral, dermal, and inhalation routes (Category

I II or IV). It wa s mildly irritating to the eyes and slightly irritating to the skin, but not a sensitizer of the skin. The only subchronic oral feeding study available for prometry

n is a 28 - day

feeding study

in mice. In this study , prometry n caused decreased body

weight and/or mortality

at doses that exceeded the limit dose (1000 mg/kg/day). In chronic oral toxicity

studies, effects primaril y occurred onl y at the highest doses tested for dogs, rats, and mice, though the dog is considered the most sensitive species. Effects in the dog included degenerative hepatic changes, renal tubule degeneration, and bone marrow atrophy . In a combined chronic toxicity /carcinogenicity study in rats, effects included decreased body weight and body- weight gains and renal toxicity (mineralized concretions). In a carcinogenicity study in mice, the onl y effect was decreased body- weight gain. In developmental studies with prometry n, effects were observed primarily at the highest doses tested. Furthermore, fetal effects were observed at the same doses as maternal toxicity . In rats, decreased body weight and food consumption, and clinical signs of toxicity were observed in dams. Decreased fetal body weight and incomplete ossification of sternebrae and metacarpals were observed at the same dose in offspring. In rabbits, decreased food consumption and an increased incidence of resorptions, abortions, and post - implantation loss were observed in maternal animals and corresponded with a decreased number of viable litters and live fetuses. In the two - generation rat reproductive study, decreased food consumption, body weight, and body- weight g ain were observed in parental animals, and decreased body weights were observed in offspring at the same dose. There was no evidence of toxicity to the reproductive organs. Preliminary

review of the rat acute and subchronic neurotoxicity studies reveals lower mean total and/or ambulatory

locomotor activity

counts noted for both sexes on the first day of treatment in the acute study and no signs of neurotoxicity in the subchronic study . In the immunotoxicity study , there was a decreased humoral response i n the sheep red blood cell assay , though this effect is not expected to impact the risk assessment. No evidence of local or systemic toxicity was observed in a 21 - day dermal toxicity

study in rabbits.Prometryn Human - Health Risk Assessment D403975

Page 16 of 36 **4.4 Safety F**  **actor for Infants and Children (FQPA SF**  **)** The prometry

n risk assessment team has recommended that the FQPA SF be reduced to 1X for the following reasons: (1) there is an adequate toxicity database for prometry

n; (2) preliminary review of the neurotoxicity studies show some indication of neurotoxicity in the acute study; however, the LOC is low since the POD chosen for risk assessment is lower and considered protective of these effects; (3) there is no evidence of susceptibility , and no residual uncertainties concerning pre - or post - natal toxicity ; and (4) there are no residential uses fo r prometry n, and the dietary assessments will not underestimate exposure. **4.4 .1**  **Completeness of the Toxicology Database** The toxicology

database is adequate for characterizing prometry n toxicity and quantification of hazard for dietary

exposures. Develop mental toxicity studies in rats and rabbits, and a two generation reproduction study in rats are available to assess potential fetal/offspring sensitivity . **4.4.2 Evidence of Neurotoxicity**  Preliminary

review s of the rat acute and subchronic neurotoxicity studies show some indication of neurotoxicity in the acute study and no signs in the subchronic study . The LOC is low for the effects identified in the preliminary review of the acute study because the endpoint chosen for the acute dietary

exposure scenario for females 13 - 49 occurs at a lower dose and is considered protective. The effects observed in the acute neurotoxicity study occur at higher doses than those being used for risk assessment . **4.4.3 Evidence of Sensitivity/Susceptibility in the Developin**  **g or Young Animal** There is no evidence of increased quantitative prenatal susceptibility for prometry

n. In both rats and rabbits, there are fetal and offspring effects which occur at maternal/parental doses. The LOC for all of these effects is low becau se: (1) the effects are well characterized, (2) clear NOAELs were established, and (3) the developmental rabbit study is being used in endpoint selection. **4.4.4 Residual Uncertainty in the Exposure Database**  There are no currently

registered residential uses for prometry n. The acute and chronic dietary (food + water) exposure assessments utilize tolerance - level residues, DEEM 7.81 default processing factors (where provided), 100% CT information for all commodities , and screening level drinking water esti mates . By using these screening - level assessments, actual exposures/risks will not be underestimated. **4.5 Toxicity Endpoint and Point of Departure Selections**  **4.5.1 Dose**  **- Response Assessment**  Tables 4.5.4.1 and 4.5.4.2 summarize the toxicological doses and endpoints selected for human health risk assessment . Acute Dietary Endpoint (Females 13 - 49 years of age): The aRfD for females 13 - 49 years of age was established based on the NOAEL of 12 mg/kg/day from the developmental toxicity study inPrometryn Human - Health Risk Assessment D403975

Page 17 of 36 rabbits. The LOAEL of 72 mg/kg/day is based on an increased incidence of resorptions, abortions, and post - implantation loss leading to a decreased number of viable litters and live fetuses . The endpoints in this study are the most appropriate for single - dose effec ts for this population of concern. For reasons outlined in Section 4.4, the FQPA SF has been reduced to 1X for this exposure scenario ; therefore, the aPAD is the same as the aRfD . Acute Dietary Endpoint (General Population): There were no effects observ ed in oral toxicity studies that could be attributable to a single dose (exposure) for the general population . Therefore, a dose and an endpoint were not selected for this exposure scenario. Chronic Dietary Endpoint (General Population): The cRfD was es tablished based on the NOAEL (3.75 mg/kg/day) from the chronic toxicity study in the dog. The L OAEL of 37.5 mg/kg/day

is based on degenerative hepatic changes, renal tubule degeneration, and bone marrow atroph y. The NOAEL of 3.75 mg/kg/day was chosen bec ause it is the lowest in the database and because the study duration is appropriate for the duration of exposure. This study also protects for similar renal effects in the rat. For reasons outlined in Section 4.4, the FQPA SF has been reduced to 1X for this exposure scenario ; therefore, the cPAD is the same as the cRfD . Short- and Intermediate - Term Incidental Oral Exposure: There are no proposed or registered r esidential uses for prometry n. Therefore, an endpoint for incidental oral exposure was not chosen. Short- and Intermediate - Term Dermal Endpoints: The oral developmental toxicity study in the rabbit was chosen for the short - and intermediate - term derma l occupational exposure scenarios. Even though there is a route - specific study available in which no effects were observed, the NOAEL and endpoint from the oral developmental toxicity study in rabbits was selected for the dermal route since developmental parameters were not evaluated in the dermal toxicity study . Effects observed in the oral developmental toxicity study included an increased incidence of resorptions, abortions, and post - implantation loss in maternal animals leading to a decreased number o f viable litters and live fetuses occurring at the maternal LOAEL of 72 mg/kg/day (NOAEL = 12 mg/kg/day) . Since an oral dose was selected, a dermal - absorption factor of 15% should be used for dermal risk assessment. T he effects in this study are conside red to be due to a “single dose ” ; however, the excretion data show that the compound is mostly cleared within 24 hours at lower doses, and thus this study is protective of daily

exposures. This study also protects for the parental/offspring decreased body we ights in the two - generation reproduction study that were seen at similar doses. The two - generation reproduction study was considered for these scenarios as well, but not chosen because the low NOAELs in that study are believed to be an artifact of the dos e spacing. Based upon the standard 10X interspecies and the 10X intraspecies uncertainty factors, the LOC for the dermal exposure scenarios is for MOEs < 100. This study

is protective of pregnant females in occupational settings. Short- and Intermediate - Term Inhalation Endpoints: Similar to the dermal scenarios, the developmental rabbit study was chosen for the short - and intermediate - term inhalation occupational scenarios and the POD for the maternal effects is being used. Because an oral study is be ing used for inhalation exposure scenarios, and an inhalation study is required, a 10X database uncertainty

factor will be combined with the 10X interspecies and 10X intraspecies uncertainty factors for a LOC for MOEs of < 1000. For inhalation exposures scenarios, 100% absorption of the oral dose should be assumed.Prometryn Human - Health Risk Assessment D403975

Page 18 of 36 **4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment**  For occupational exposure, dermal and inhalation exposures should be combined sinc e the toxicological effects of concern are the same and were identified from the same study . Currently , there are no registered residential uses of prometry n. **4.5.3 Cancer Classification and Risk Assessment Recommendation**  Prometry n was classified by

the HED Peer Review/Cancer Committee (July 26, 1994 Report) as a Group E chemical (“Evidence of non - carcinogenicity for humans”), based on the lack of oncogenic effects at an y dose in both rats and mice. Prometry n was determine d to be non mutagenic and non - clastogenic in in vitro and in vivo genotoxicity assay s. **4. 5**  **. 4**  **Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment**  **Table 4.5.4.1. Summ ary of Toxicological Doses and Endpoints for Prom**  **etryn fo**  **r Use in Dietary Hum**  **an**   ** Health Risk Assessments.** **Exposure Scenario POD**  **Uncertainty/ FQPA**  **SF s**  **RfD, PAD, LOC**

**for Risk Assessment**  **Study and Toxicological Effects**  Ac ute Dietary (Females 13+) NOAEL = 12

mg/kg/day UF A = 10X

UF H = 10X UF FQPA = 1X aRfD = aPAD =

0.12 mg/kg/day Developmental toxicity

(rabbit) LOAEL = 72 mg/kg/day based on increased incidence of resorptions, abortions, and post - im plantation loss leading to decreased number of viable litters and live fetuses. Chronic Dietary (All populations) NOAEL =

3.75 mg/kg/day UF A = 10X

UF H = 10X UF FQPA = 1X cRfD = cPAD =

0.04 mg/kg/day Chronic toxicity (dog; dietary)

LOAEL = 37.5 mg/kg/day based on degenerative hepatic changes, renal tubule degeneration, and bone marrow atrophy. Cancer (oral, dermal, inhalation) Classification: “Group E: Evidence of non - carcinogenicity for humans . ” 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 - eff ect level. LOAEL = lowest - observed adverse - effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Sa fety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose (a = acute, c = chronic) . **Table 4.5.4.2.**  **Summ ary of Toxicological Doses and Endpoints for Prom**  **etryn for Use in Occupational**  **Hum an**  **- Health Risk Assessments.**  **Exp osure**  **Scenario POD**  **Uncertainty Factors**  **L O**  **C for Risk**

**Assessment Study and Toxicological**  **Effects** Dermal Short - and Intermediate Term (1 - 30 days and 1 - 6 mo nths) NOAEL = 12

mg/kg/day Dermal absorption factor = 15% UF A = 10X

UF H = 10X Occupational LOC for

MOE <100 **Developm ental toxicity**  **(rabbit)** LOAEL = 72 mg/kg/day based on increased incidence of resorptions, abortions, and post im plantation loss leading to decreased number of viable litters and live fetuses.Prometryn Human - Health Risk Assessment D403975

Page 19 of 36 **Table 4.5.4.2.**  **Summ ary of Toxicological Doses and Endpoints for Prom**  **etryn for Use in Occupational**  **Hum an**  **- Health Risk Assessments.**  **Exp osure**  **Scenario POD**  **Uncertainty Factors**  **L O**  **C for Risk**

**Assessment Study and Toxicological**  **Effects** Inhalation Short - and Intermediate Term (1 - 30 days and 1 - 6 mo nths) NOAEL = 12

mg/kg/day 100% inhalation assumed UF A = 10X

UF H = 10X UF DB = 10X Occupational LOC for

MOE <100 0 **Developm ental toxicity**  **(rabbit)** LOAEL = 72 mg/kg/day based on increased incidence of resorptions, abortions, and post im plantation loss leading to decreased number of viable litters and live fetuses. Cancer (oral, dermal, inhalation) Classification: “Group E: Evidence of non - carcinogenicity for humans . ” 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 - ob served adverse - effect level. LOAEL = lowest - observed adverse - effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = database uncertainty factor. MOE = margin of exposure. LOC = level of concern. **5.0 Dietary Exposure and Risk Assessment**  **5.1 Metabolite/Degradate Residue Profile**  **5.1.1 Summary of Plant and**  **Livestock Metabolism Studies**  Memo, S. Levy, 31 - JUL - 2 013 ; D408525 Acceptable cotton and celery metabolism studies were previousl y reviewed (Residue Chemistry Chapter of the Prometry

n RED, C. Swartz 08 - DEC - 1994; D207139; Memo, W. Wassell, 22 - DEC - 2010; D382622 ). The results of the metabolism studies showed metabolic pathway s involving N

- dealkyl ation and hydrolysis of prometry n. HED determined that the residue of concern in cotton and cel e ry consists of the parent, prometry n per se , which is the currentl y regulate d residue. The petitioner recentl y s ubmitted a metabolism study in rice, which has been reviewed (Memo, S. L ev y, 13 - MAR - 2013; D 398563). Although the rice metabolism study was deemed adequate, it presents a qualitativel y different metabolic profile than the celery and cotton profiles (Memo, C. Swartz, 05 - DEC - 1994; D208880 and 09 - DEC - 1995; D207139, respectively). In the celery and cotton metabolism studies, parent is the major residue and in the rice metabolism study metabolite GS - 17794 is the major residu e. The available cotton, celery , and rice metabolism data are adequate to support the proposed uses; however, no data are available reflecting metabolism in a root crop to support the existing uses on carrot and celeriac. OCSPP 860.1300 specifies that a metabolism study should be submitted for each type of plant for which use is proposed, or metabolism studies on three dissimilar crops must be provided which indicate a similar metabolic route. Note that IR - 4 and Sy ngenta submitted a letter stating that they were working together to plan and conduct a nature of the residue study of prometryn on carrots or another root crop and asked for additional time to conduct this study

(with a deadline of January 5, 2012). HED responded that this request was reasona ble, considering the length of the study ( Memo, W. Wassell, 22 - DEC - 2010; D382622) . HED has not received this root crop metabolism study and , therefore , this deficiency remains outstanding. Depending on the results of the root crop metabolism study , addit ional field trial data could be required.Prometryn Human - Health Risk Assessment D403975

Page 20 of 36 The nature of the residue in livestock is adequately understood based on acceptable poultry and ruminant metabolism studies. The residue of concern (and that which should be regulated) in livestock is the parent, prometry n per se . As in plants, the metabolism of prometry n in livestock involves N

- dealkylation along with hydrol ys is and/or amino acid conjugation. **5.1.2 Summary of Environmental Degradation**  According to the submitted phy sical - chemical and environmental fate data, the degradation of prometry n is driven b y m icrobial (biotic) activity and not by

abiotic processes; however, biotransformation is slow. The major biotransformation product is GS - 115 26. The low Freundlich adsorption coefficient of prometry n suggests that the chemical has the potential to run off and/or leach to ground water. Prometry n is stable to hydrol ys is and direct photoly sis in aqueous media. Prometry n and its degradates are m obile to very mobile in soil. Potential transport mechanisms include runoff to surface water, leaching to ground water, spray drift, and secondary

drift of volatilized or soil - bound residues leading to deposition onto nearby or more distant ecosystems. The US Geological Survey (USGS) has reported data on the presence of pesticides in rain and wet deposition in four US agricultural watersheds. Among other pesticides, prometry n was detected in rain and wet deposition in California. **5.1.3 Comparison of Me**  **tabolic Pathways** The primary

routes of metabolism in livestock and plants and degradation in the environment were basicall y the same and involves dealkylation along with hydrol ys is and/or amino acid conjugation. The metabolism of prometry n in rotational crops is similar to that of the primary crops and involves N

- dealkylation, oxidation, hydroxylation, deamination, and conjug ation. In the environment, prometryn is stable to abiotic hydrolysis, soil photoly sis, direct h ydrol ys is aerobic soil metabolism, and anaerobic soil metabolism. **5.1.4 Residues of Concern Summary and Rationale**  In the previous risk assessment for prometry n (Memo, W. Wassell et al. , D367830 , 05 - AUG 2009), the residues of concern in drinking water were liste d as parent plus all degradates, while the residues of concern identified in the EFED drinking water memo were parent onl y (Memo, S. Termes, 06/19/2009 ; D357096) . In the recent scoping document for prometryn (Memo, K. Lowe et al., D407422, 28 - FEB - 2013), HED determined that the residues of concern for prometry n drinking water estimates should be parent plus the degradate, h ydrox ypropazine (GS - 11526). Th is decision was based on information on the degradates of prometry n provided by

EFED (Memo, M. Ruhman and N. Mastrota, 08 - JAN - 2013, D408043), which showed that the onl y major degradate of prometry n identified in the submitted environmental fate studies was hydrox yp ropazine (GS - 11526). This transformation product accounted for 27% of the maximum percent applied radioactivity in the aerobic soil study . It also accounted for 16 - 18% in the aerobic aquatic study and 15 - 31% in the terrestrial field dissipation study . All other transformation products identified in these studies were ≤ 7 % of the applied radioactivity . T here is limited information regarding the toxicity of hydroxy

propazine; therefore, in the scoping document, HED proposed to include both parent p lus hydrox ypropazine (GS - 11526) in the drinking water estimates .Prometryn Human - Health Risk Assessment D403975

Page 21 of 36 In the drinking water memo supporting the proposed uses (Memo, M. Ruhman, D403977, 13 - MAR - 2013), EFED proposed that the previous drinking water estimates be used even though th o se drinking water estimates represent parent only . HED has determined that this will be adequate for risk assessment purposes . H aving limited information regarding the toxicity of the degradate, HED would make the assumption of equivalent toxicity for the parent and major degradate . Drinking water estimates based on parent only should then be similar to estimates based on a combination of parent and degradate ( totaling 100%) . Therefore, for the current risk assessment, the residue of concern in drinking water is prometry n per se . **Table 5.1.4 .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 Proposed/registered

Primary Crop s Prometryn Prometryn Rotational Crop Livestock Ruminant Prometryn Prometryn Poultry Drinking Water Prometryn Not Applicable **5 .2**  **Food Residue**  **Profile** Memo, S. Levy, 31 - JUL - 2013 ; D408525 Crop Field Trials : Crop field trials were conducted for both dill and snap bean in support of the proposed uses. These studies were deemed adequate for risk assessment and tolerance assessment. Two dill field trials were conducted with applications made at approximately the same rate as that being proposed when plants were at the vegetative growth stage. Fresh dill leaves with stems were harvested at commercial maturity (pre - bloom) at PHI s of 27 or 29 day s, and dill seed was harvested at seed maturity at PHIs of 62 or 6 8 day s. At one trial, additional fresh dill leaves with stems were harvested and dried to generate dried dill leaves with stems. Residue decline was not evaluated. Prometry n residues were <0.05 - 0.10 ppm in/on fresh dill leaves/stems, 0.26 - 0.29 ppm in/on dried dill leaves/stems, and below the LOQ ( <0.05 ppm) in/on dill seed . Seven snap bean field trials were conducted with applications made to the soil at either the same or slightl y less rate than that being proposed. Snap beans (pods with seed) and sna p bean plants (foliage with pods and seed) were harvested at commercial maturity at PHIs of 52 - 68 day s. Residue decline was not evaluated. Prometry n residues were below the L OQ (<0.05 ppm) in/on all samples of snap beans, and ranged from <0.05 - 0.077 ppm in/on snap bean plants. Processing Studies : The IR - 4 submitted a processing study for prometry

n on dill, which showed that following the processing of the raw agricultural commodity samples (i.e., dill fresh leaves/stems), which did not have quantifiable residues (i.e., all residues <LOQ) , total residues of prometry n concentrated in dill oil ( >6.6 X) . The petitioner recommended a tolerance for residues of prometry

n in/on dill, oil; however, a tolerance is not necessary since dill oil is not a regulated co mmodity . Storage Stability : Storage stability data are available for fortified samples of celery , cottonseed , fresh and dried parsley , pigeon peas, and sesame seed. In addition, concurrent storage stability data were generated with snap beans, snap b ean plants, fresh and dried dill and seed matrices, as well as dill oil. These data are adequate to support the storage conditions and durations of samples from the magnitude of the residue and processing studies on snap beans and dill. ThesePrometryn Human - Health Risk Assessment D403975

Page 22 of 36 data show that corrections for storage degradation of residues are not required for the submitted studies. Meat, Milk, Poultry , and Eggs : The 1994 Residue Chemistry Chapter concluded that residues of prometry n per se in meat and milk can be classified under Categ ory 3 of 40 CFR §180.6(a): “That it is not possible to establish with certainty whether finite residues will be incurred, but there is no reasonable expectation of finite residues . ” No tolerances were required, and therefore, livestock feeding studies we re not needed. In the current petition, there are no significant livestock feed items; therefore, a newl y constructed dietary burden was not warranted for this petition. Pending submission of an additional plant metabolism study , HED tentativel y conclude s that the Category 3 situation remains valid for this registration request. Rotational Crops : The nature of the residue in rotational crops is adequately understood. The metabolism of prometry

n in rotational crops is similar to that of celery and cotton and involves dealkyl ation, oxidation, hydroxylation, deamination, and conjugation. Based on the results of a confined rotational crop study submitted previously , where residues from all plant back intervals (PBIs) were greater than 0.01 ppm, the regis trant also submitted limited field rotational crop studies. Based on the results of these studies, HED previously determined that the minimum plant back restrictions for crops not listed on prometry n labels should be as follows: 1) Following maximum applic ation to any primary crop at up to 3.2 lb ai/A: a 5 - month PBI for leafy vegetables, an 8 - month PBI for root crops, and a 9 - month PBI for small grains and all other crops. 2) Following application at rates higher than 3.2 lb ai/A and up to 6.0 lb ai/A: an 8 - month PBI for root crops; rotation to all other crops is prohibited. The PBI restrictions listed on the EPA - registered Caparol ® 4LL abel remain appropriate for the proposed crops. **5.3 Water Residue Profile**  Memo, M. Ruhman, 13 - MAR - 2013; D403977 In the drinking water assessment prepared for the proposed uses of prometry n on snap bean and dill (Memo, M. Ruhman, 13 - MAR - 2013, D403977) , EFED indicated that the currently established estimated drinking water concentrations (EDWCs) for prometry n based on th e last assessment (Memo, S. Termes, 19 - Jun - 2009, D357096) can be used for the new use . In the previous assessment, EDWCs were established for uses on carrots, okra, parsley , cilantro, celeriac, and leafy

petioles using the Tier I FIRST ( F QPA Index R eservo ir S creening T ool; Version 1.1.1) model for surface water and the Tier I SCI - GROW ( S creening C oncentration In Gro und W ater; Version 2.3) regression model for groundwater . The driver for both surface and groundwater was the use on carrots (three ground ap plications at 2 lbs ai/A, 30 day s apart). EDWCs for okra and cilantro were also estimated , and were much lower than EDWCs from the carrot use. T he proposed application rate for snap beans is the same as that for previously modeled okra (one ground applic ation at 1.5 lbs a.i/A) and gives the same Tier I EDWCs. Inaddition, the proposed application rate for dill is the same as that for previously

modeled cilantro (one ground application at 1.6 lbs a.i/A) and gives the same Tier I EDWCs. Therefore, it was concluded that the previous drinking water assessment would be protective for the proposed uses. Water residues were incorporated directly into the DEEM FCID into the food categories “water, direct, all sources” and “water, indirect, all sources.”Prometryn Human - Health Risk Assessment D403975

Page 23 of 36 **Table 5.3**  **.1. Summary of Estim**  **ated Surface Water and Groundwater Concentrations for Prom**  **etryn .** 

**Scenario Surface Water Conc., ppb**  **1 Groundwater Conc., ppb**  **2** Ac ute 377.4 23.2 Chronic (non - cancer) 157.9 1 From the Tier I

FIRST model. I

nput parameters are based on three ground applications to carrots @ 2 lb ai/acre, 30 days apart. 2 From the SCI - GROW model. **5.4 Dietary Risk Assessment**  **5.4.1 Description of Residue Data Used in Dietary Assessment**  Acute and chronic dietary- exposure (food plus water) and risk assessments were conducted using DEEM - FCID, Version 3.16, which uses food consumption data from the USDA’s NHANES/WWEIA survey from 2003 through 2008. The assessments were performed for the gen eral U.S. population and all population subgroups. Assumptions for the acute and chronic assessment s include tolerance - level residues for all foods, DEEM 7.81 default processing factors (where provided), and 100% CT. Drinking water estimates were provide d by EFED. The EDWC values were generated using the registered carrot use pattern and the Tier I FIRST model. The resulting acute EDWC estimate of 377.4 ppb was used for the acute assessment, and the chronic EDWC estimate of 157.9 ppb was used for the chronic assessment . **5.4.2 Percent Crop Treated Used in Dietary Assessment**  The acute and chronic dietary analy ses assumed 100% CT for all commodities. **5.4.3 Acute Dietary Risk Assessment**  Acute dietary

risk estimates (food and drinking water) are not of concern at the 95 th percentile of the exposure for females 13 to 49 years old, the only acute population subgroup of concern for this assessment . The resulting acute risk estimate is 17% of the aPAD of the exposure distribution. A summary table of dietary exposure and risk for prometry n can be found in Section 5.4.6. **5.4.4 Chronic Dietary Risk Assessment**  Chronic dietary

risk estimates (food and drinking water) are not of concern for the general population or any

other population subgroup. The most highly exposed population was all infants (<1 ye ar old) , utilizing 23% of the cPAD. The chronic exposure estimate for the general U.S. population utilized 8.6 % of the cPAD. A summary table o f dietary

exposure and risk for prometry n can be found in Section 5.4.6. **5.4.5 Cancer Dietary Risk Assessment**  A cancer dietary

assessment was not performed because prometry n was classified as “Group E: Evidence of non - carcinogenicity for humans.” **5.4. 6**  **Summary Table** The acute and chronic analy ses assumed tolerance - level residues, 100% CT, and DEEM (ver. 7.81) default processing factors. These anal ys es are considered very conservative and could bePrometryn Human - Health Risk Assessment D403975

Page 24 of 36 refined using anticipated - residue estimates (ARs), percent market share data, and/or empirical processing factors. However, at this time , refinement is not necessary . **Table 5.4.6.1. Summ ary of Dietary**  **(Food + Drinking Water) Exposure and Risk for Prom**  **etryn. Population Subgroup**  **1 Acute Dietary**  **2 (95th**  **Percentile) Chronic Dietary**  **Cancer Dietary**  **Exposure (m**  **g/kg/day) % aPAD**  **Dietary Exposure**  **(m g/kg/day)**  **% cPAD Dietary**  **Exposure (m**  **g/kg/day) Risk**  General U.S. Population N/A N/A 0.003426 8.6

N/A N/A All Infants (<1 year old) **0.009081 23**  Children 1 - 2 years old 0.005136 13 Children 3 - 5 years old 0.004274 11 Children 6 - 12 years old 0.003041 7.6 Youth 13 - 19 years old 0.002484 6.2 Adults 20 - 49 years old 0.003390 8.5 Adults 50 - 99 years old 0.003366 8.4 Females 13 - 49 years old **0.020659 17**  0.003377 8.4 1 The values for the highest exposed population for each type of risk assessment is bolded. 2 An acute dietary endpoint (aPAD = 0.12 mg/kg/day) was only determined for females 13 - 49 years old (see Table 2). **6.0 Residential**  **(Non -**  **Occupational) Exposure/Risk Characterization** The proposed uses are not expected to result in residential exposure, and there are no currently registered residential uses of prometry n; therefore, a quantitative residential exposure assessment was not conducted. **6.1 Residential Bystander**  **Post -**  **application Inhalation Exposure**  Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for prometry n at this time primarily

because of the low acute inhalation toxicity

(Toxicity Category IV) and low vapor pressure ( 8.54 x 10 - 7 mm Hg at 25oC) . However, volatilization of pesticides may be a source of post - application inhalation exposure to individuals nearb y pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 2 . The Agency is in the process of evaluating the SAP report and may , as appropriat e, develop policies and procedures to identify the need for and, subsequently , the way to incorporate post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post application inhalation exposure assessment for prometry n. **6.2 Spray Drift**  Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for prometry n. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State Lead Agencies for pesticide regulation and other parties to develop the best spray- drift -

2 Available: http://www.epa.gov/scipoly/SAP/meetin gs/2009/120109meeting.htmlPrometryn Human - Health Risk Assessment D403975

Page 25 of 36 management practices (see the Agency ’s Spray Drift website for more information 3 ) . The Agency has completed its evaluation of the new database submitted by the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriatel y apply

the data and the AgDRIFT ® computer model to its risk assessments for pesticides applied b y air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency

may impose further refinements in spray- drift - management practices to reduce off - target drift with specific products with significant risk estimates associated with drift. **7.0 Aggregate Exposure/Risk Characterization**  In accordance with the FQPA, HE D must consider 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. For prometry

n, aggregate exposure risk assessments were performed for the following scenarios: acute aggregate exposure (food and drinking water), and chronic aggregate exposure (food and drinking water). Short - and intermediate - term aggregate assessments, which are used to evaluate aggregate dietary

and residential e xposures, were not performed because there are no registered or proposed residential non - food uses. Prometry n is classified as “Not Likely to be Carcinogenic to Humans”; therefore, cancer aggregate risk assessments were not performed. **7.1 Acute Aggregate**  **Risk** The acute aggregate risk assessment takes into account exposure estimates from dietary consumption of prometryn (food and drinking water). The acute dietary exposure estimates are not of concern to HED (<100% aPAD) at the 95 th exposure percentile for females 13 - 49 years old (see Table 5.4.6). The dietary exposure assessment utilized tolerance - level residues, 100% CT information for all proposed agricultural uses, DEEM 7.81 default processing factors (where provided), and Tier 1 acute surface water EDWCs . **7.2 Chronic Aggregate Risk**  The chronic aggregate risk assessment takes into account average exposure estimates from dietary consumption of prometry n (food and drinking water). The chronic dietary exposure estimates are not of concern to HED (<100% cPAD) for the general U.S. population and all population subgroups (see Table 5.4.6). The dietary exposure assessment utilized tolerance - level residues, 100% CT information for all proposed agricultural uses, DEEM 7.81 default processing factors (where provided), and Tier 1 chronic surface water EDWCs. **8.0 Cumulative Exposure/Risk Characterization**  Prometry n is a triazine, and certain triazine pesticides were identified as a common mechanism group (CMG) b y the Agency in a 2002 paper entitled, “ The Grouping of a Series of Triazine Pesticides Based on a Common Mechanism of Toxicity . 4 ” However, prometry n was excluded

3 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 4 http://www.epa.gov/oppsrrd1/REDs/triazine_cumulative_risk.pdfPrometryn Human - Health Risk Assessment D403975

Page 26 of 36 from the triazine CMG because it does not share the toxicity profile of the CMG triazines. Therefore, for the pur

poses of this action, EPA is assuming that prometry n does not have a common mechanism of toxicity with other substances. **9.0 Occupational Exposure/Risk Characterization**  **9.1 Short**  **- /Intermediate**  **- Term Handler Risk**  Occupational handler exposure is expected from the proposed uses, b ased on the anticipated use patterns , proposed labeling, types of equipment , and techniques that can potentially be used. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios: (1) m ixing/ l oading liquids for ground a pplication, (2) m ixing/ l oading liquids for c hemigation application, and (3) a ppl yi ng b y ground a

pplication. Short - and intermediate - term exposures are anticipated for the following reasons: (1) the product can be applied once per season , (2) the product can be applied to multiple application sites , and (3) there may be a large agribusiness and/or commercial applicators who may appl y a product over a period of weeks. The short - and intermediate - term dermal and inhalation endpoints are the same for prometry

n; therefore, the short - term assessment is protective of longer durations of exposure. Application rates used in the occupational handler assessment are identified in Table 3.3.1 (Summary

of Use Directions). Generic handler data were used as surrogate data in the absence of chemical - specific data, and were based on the Pesticide Handlers Exposure Database ( PHED ) 1.1, the Agricultural Handlers Exposure Task Force (AHETF ) database, the Outdoor Residential Exposure Task Force (ORETF) 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 FIFRA. Results are presented for “baseline,” defined as a single lay er of clothing consisting of a long - sleeved shirt, long pants, shoes plus socks, no prot ective gloves, and no respirator , as well as baseline plus gloves for certain scenarios . Summary of Occupational Handler Non - Cancer Exposure and Risk Estimates : Table 9.1.1 provides a summary

of the estimated exposures and risks to occupational pesticid e handlers. All occupational handler scenarios, except mixing/loading liquids for chemigation applications, result in MOEs greater than the LOC (i.e., MOEs ≥100 for dermal and ≥1,000 for inhalation) , and the combined dermal and inhalation risk estimates, expressed as an ARI, are greater than 1 with baseline attire (i.e., single layer of clothing, no gloves, no respirator). HED has determined that risks are of concern for short - and intermediate - term exposures (i.e., MOEs <100 for dermal) for mixing/loadi ng liquids for chemigation applications at baseline, and require gloves to reach acceptable MOEs and ARIs . The registered label for Caparol ® 4L(EPA Reg. #100 - 620) already

requires the use of chemical - resistant gloves as PPE for applicators and other handlers ; therefore, there is no risk of concern for this scenario with the current label PPE .Prometryn Human - Health Risk Assessment D403975

Page 27 of 36 **Table 9 .1.1**  **. Short**  **- and Interm**  **ediate -**  **Term Occupational Exposure and Risk Estimates for Prom etryn**  **. Exposure**  **Scenario Crop** 

**or Target**  **Unit Exposure**

**(ug/lb ai) 1**  **Ma xim**  **um**

**Application Rate (lb**  **ai/A) 2**  **Area**

**Treated (acres)**  **3 Dermal**  **Inhalation ARI**  **8 Dermal**  **Inhalation Dose**  **(m g/k** **g/day) 4**  **MOE 5** 

**LOC = 100 Dose** 

**(m g/k** **g/day) 6**  **MOE 7** 

**LOC = 1000 Mi** **xer/Loader** Liquid - Chemigation Dill Baseline: 220 Baseline:

0.219 1.6 350 0.267 **45** 0.00178 6700 **0.42** SL Gloves: 37.6 0.0459 260 1.9 Snap Bean Baseline:

220 Baseline:

0.219 1.5 350 0.252 **48** 0.00167 7200 **0.45** SL Gloves: 37.6 0.0428 280 2.0 Liquids

– Groundboom Applications Dill Baseline: 220 Baseline:

0.219 1.6 80 0.0613 200 0.000406 30,000 1.9 Snap Bean Baseline:

220 Baseline:

0.219 1.5 80 0.0574 210 0.000381 31,000 2

**Applicator** Groundboom Applications Dill Baseline: 78.6 Baseline:

0.34 1.6 80 0.022 550 0.00063 19,000 4.3 Snap Bean Baseline:

78.6 Baseline:

0.34 1.5 80 0.0205 590 0.000591 20,000 4.6 **Bolded values indicate risk estimates are less than the LOC.**  1 Unit Exposures are taken from “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table,” September 2012 . Baseline = single layer of clothing, no gloves, no respirator. SL Gloves = single layer of clothing, gloves, no respirator. 2 Based on proposed label (Reg. No. #100 - 620). 3 Units Treated are taken from “Standard Values for Daily Acres Treated in Agriculture”; ExpoSAC SOP No. 9.1, revised 25 September 2001. 4 Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre) x Area Treate d (A /day) x DAF ( 15 %)/BW (69 kg). 5 Dermal MOE = Dermal NOAEL ( 12 mg/kg/day)/Dermal Dose (mg/kg/day). 6 Inhalation Dose = I

nhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre) x Are a Treated (A/day)/BW (69 kg). 7 Inhalation MOE = I

nhalation NOAEL ( 12 mg/kg/day)/I nhalation D ose (mg/kg/day). 8 Combined risks were calculated using the ARI I ndex method. ARI

total = 1/[(1/ARIdermal ) + (1/ARIinhal )] , where ARI dermal = MOE dermal/100 and AR Iinhal = MOE inhal/1000. ARI s greater than 1 are not of concern. **9.2 Short**  **- /Intermediate**  **- Ter**  **m Post**  **- Application Risk**  **9.2.1 Dermal**  **Post -**  **application Risk**  Based on the anticipated use patterns and proposed labeling, occupational post - application exposure is expected from the proposed uses . P ost - application exposure is expected to be short and intermediate - term based on information provided on proposed labels ; however, since both the short - and intermediate - term PODs are the same, the short - term assessment is protective of longer exposure durations. Application rates used in the occupational po st - application assessment are identified in Table 3.3.1 (Summary of Use Directions). Generic post - application exposure data were used as surrogate data in the absence of chemical - specific data, and are derived from the Agricultural Reentry Task Force (ART F ) exposure monitoring studies and, as proprietary

data, are subject to the data protection provisions of FIFRA. Chemical - specific dislodgeable foliar residue data have not been submitted for prometry n. Therefore, this assessment uses HED’s default assumption that 25% of the application rate is available for transfer on day

0 following the application , and that the residues dissipate at a rate of 10% each following day .Prometryn Human - Health Risk Assessment D403975

Page 28 of 36 Occupational Post - application Non - Cancer Dermal Risk Estimates : HED has determined that short - and intermediate - term risk estimates are not of concern (i.e., MOEs ≥100) on the day of treatment (i.e., day 0) for most post - application exposure activities. However, there were risk estimates of concern related to one post - application activity for snap beans and dill : hand - set irrigation. Itshould be noted that the transfer coefficient used to represent the hand - set irrigation activity is based on a study in which wet foliage was contacted b y volunteers and , in addition, the volunteers perf

orming the act ivities in the study (potato irrigation) did not wear waterproof boots, which would normally be worn . Therefore, the use of this transfer coefficient to represent activity associated with hand - set irrigation is considered a conservative assumption. This is particularl y true for the proposed uses being assessed here, snap bean and dill , where the applications are to be made earl y s eason (pre - emergence or soon after emergence), while the applications in the transfer coefficient study were made late season when the crop (potato) was fairl y tall. Table 9.2.2.1 presents a summary of occupational post - application risk estimates associated with use of prometry n. **Table 9.2.2.1**  **. Summ**  **ary of Short -**  **and Intermediate -**  **term Occupational Post -**  **application Risk Esti**  **ma tes for**  **Prom etryn**  **. Crop/Site**  **Activities Transfer Coefficient**  **(cm 2**  **/hr) DFR** 

**(μg/cm 2**  **) 1**  **Day Dermal Dose**  **(m g/k** **g/day) 2**  **MOE 3**  Bean, snap (Crop Grouping 6A) Irrigation (hand set) 1,900 4.21 0 0.139 **86** 3.79 1 0.125 **96** 3.41 2 0.113 110 Hand harvesting 1,100 4.21 0 0.0805 150 Scouting 210 4.21 0 0.0154 780 Weeding, hand 70 4.21 0 0.00513 2300 Dill (Crop Group 19A) Irrigation (hand set) 1,900 4.49 0 0.148 **81** 4.04 1 0.133 **90** 3.63 2 0.12 100 Scouting 1,100 4.49 0 0.0859 140 Weeding, hand 70 4.49 0 0.00547 2200 1 DFR (dislodgeable - foliar residue) = Application Rate × F × (1 - D) t × 4.54E8 μg/lb × 2.47E - 8 acre/cm2 ; where F = 0.25 and D = 0.10 per day. 2 Daily Dermal Dose = [DFR (μg/cm2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)] /BW (69 kg). 3 MOE = POD (mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR/TTR (μg/cm 2 ) × TC × 0.001 mg/μg × 8 hrs/day × dermal absorption factor (%)] /BW (69 kg). REI : Prometry

n is classified as Toxicity Category IV via the dermal route and Toxicity Category IV for skin irritation potential . Itis not a skin sensitizer. Short - and intermediate - term post - application risk estimates were not a concern on day 0 (12 hours following application) for most activities. However, there were risk estimates of concern related to one post - application activity for snap beans and dill: hand set irrigation. As stated above , the transfer coefficient for the hand - set irrigation is considered a conservative estimate for the hand - s et irrigation activity . The WPS minimum REIis 12 hours based on acute toxicity of the active ingredient; however , HED is noting that there are risk estimates of concern for some post - application scenarios based on default assumptions . There are no chemi cal - specific DFR data available to refine the post application assessment. MOEs are not of concern for the hand - set irrigation activity 2 day s (48 hours) after application. **9.2.2 Inhalation**  **Post -**  **application Risk**  Based on the Agency ’s current practices , a quantitative post - application inhalation exposure assessment was not performed for prometry n at this time primarily

because of the low acute inhalation toxicity

(Toxicity Category IV) and low vapor pressure ( 8.54 x 10 - 7 mm Hg at 25oC) . However, there are multiple potential sources of post - application inhalation exposure toPrometryn Human - Health Risk Assessment D403975

Page 29 of 36 individuals performing post - application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP’s final report on March 2, 2010 5

. The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated by the ARTF and may , as appropriate, develop policies and procedures, to identify the need for and, subsequentl y, the way to incorporate occupational post - applicat ion inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for prometry n . Although a quanti tative occupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to re sult in higher exposure than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios. **10.0 References**  Previous Risk Assessment: W. Wassell et al. , 05 - AUG - 2009; D367830 Scoping Document: Memo, K. L owe et al. , 28 - FEB - 2013 , D407422 EFED Document Supporting Residues of Concern Decision: Memo, M. Ruhman and N. Mastrota, 08 - JAN - 2013 , D408043 HASPOC Memo: J. Van Alstine ; 21 - FEB - 201 3 ; TXR # 0056525 Chemistry Memo: S. Levy ; 31 - JUL - 2013 ; D408525 Previous Chemistry Memos: Memo, E. Zager, 24 - MAY - 1991; D160100 Residue Chemistry

Chapter of the Prometry

n RED, C. Swartz 08 - DEC - 1994; D207139 Memo, W. Wassell, 22 - DEC - 2010; D382622 Memo, S. L ev y, 13 - MAR - 2013; D398563 Memo, C. S wartz, 05 - DEC - 1994; D208880 Memo, C. Swartz, 09 - DEC - 1995; D207139 Drinking W

ater Memo: M. Ruhman ; 1 3 - MAR - 2013 ; D 403977 Previous Drinking Water Memo: Memo, S. Termes, 19 - JUN - 2009; D357096 Dietary Memo: S. Lev y; 31 - JUL - 2013 ; D408528 Occupational Exposure Memo: L. Venkateshwara; 31 - JUL - 2013 ; D408529

5 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlPrometryn Human - Health Risk Assessment D403975

Page 30 of 36 cc: S. Levy, A. Dunbar, L. Venkateshwara RDI: RAB1 ( 08 - MAY - 2013) K. Lowe : S - 10 947 : Potomac Yard 1 (PY1): (703) 347 - 8989 : 7509P: RAB1Prometryn Human - Health Risk Assessment D403975

Page 31 of 36 **A ppendix**  **A .**  **Toxicology Profile and Executive Summaries A.1**  **Toxicology Data Requirements** The requirements (40 CFR 158.340) for a food use for prometryn are in Table 1 . Use of the new guideline numbers does not imply that the ne w (1998) guideline protocols were used. **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 yes no yes 1 yes

no yes

-- n o 1 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700b Developmental Toxicity (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ . yes yes yes yes

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

yes yes yes yes 870.5100 Mutagenicity

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

—Gene Mutation - mammalian ................ 870. 5400 Mutagenicity

— Structural Chromosomal Aberrations ... 870. 5500 Mutagenicity

—Other Genotoxic Effects ....................... yes yes yes no 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 no no -

- yes yes

- 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes no yes yes

- yes Special Studies for Ocular Effects

Ac ute Oral (rat) ................................ ........................... Subchronic Oral (rat) ................................ .................. Six - mo nth Oral (dog) ................................ .................. no no no -

-

- 1. The HASPOC met on 21 - FEB - 2013 (TXR# 005625) and concluded that a repeated exposure inhalation toxicity study is required for prometryn at this time.Prometryn Human - Health Risk Assessment D403975

Page 32 of 36 **A.2 Toxicity Profile**  **s Table A.2.1. Acute Toxicity Profile**  **– Prom**  **etryn .**  **Guideline No.**  **Study Type MRID(s)**  **Results Toxicity**  **Category** 870.1100 Ac ute oral (rat) 00060314 LD 50 = 1802 (1265 - 2568)/ 2076 (1654 - 2607) mg/kg (M/F) III 870.1200 Ac ute dermal (rat) 00060647 LD 50 > 3170 mg/kg III 870.1300 Ac ute inhalation (rat) 42325503 LC 50 = 4.96 mg/L IV 870.2400 Primary eye irritation (rabbit) 40776601 Mild Irritation III 870.2500 Primary dermal irritation (rabbit) 00060317 Slight Irritation IV 870.2600 Dermal sensitization (Guinea pig) 00256682 Not a sensitizer N/A **Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile**  **– Prom**  **etryn .**  **Guideline No.**  **Study Type MRID No./**  **Classification /Doses Results**  870.3100 28 - Day

oral toxicity (mouse) 40457 515 (1977)

Acceptable/non - guideline 0, 30, 100, 300, 600, 1,000, 3,000, 10,000 or 30,000 ppm NOAEL = 3000 ppm (~450 mg/kg/day) . LOAEL = 10000 ppm (~1500 mg/kg/day) based on decreased body weight. 870.3200 21 - Day

dermal toxicity (rabbit) 40573702 (1988)

Acceptable/guideline 0, 10, 100, or 1000 mg/kg bw /day (limit dose) NOAEL = 1000 mg/kg/day .

LOAEL not established. 870.3700a Prenatal

developmental (rat) 404574517 (1987)

Acceptable/guideline 0, 10, 50, or 250 mg/kg bw /day Maternal NOAEL = 50 mg/kg/day . LOAEL = 250 mg/kg/day based on salivation and decreases in body - weight and food consumption. Developmental NOAEL = 50 mg/kg/day . LOAEL = 250 mg/kg/day based on decreased fetal body - we ight and incomplete ossification of sternebrae & metacarpals. 870.3700b Prenatal

developmental (rabbit) 00157995 (1985)

Acceptable/guideline 0, 2, 12, or 72 mg/kg bw /day Maternal NOAEL = 12 mg/kg/day . LOAEL = 72 mg/kg/day based on decreased food consumption and increased incidence of resorptions, abortions, and post - implantation loss leading to decreased number of viable litters and live fetuse s. Developmental NOAEL = 12 mg/kg/day . LOAEL = 72 mg/kg/day based on increased incidence of resorptions, abortions, and post im plantation loss leading to decreased number of viable litters and live fetuses. 870.3800 2 - gen. reproduction

and fertility effe cts (rat) 41445101 (1990)

Acceptable/guideline 0, 10, 750, or 1500 ppm (0/0, 0.6/0.7, 47.8/53.6, or 96.7/105.6 mg/kg bw/day [M/F]) Parental NOAEL = 10 ppm (0.6/0.7 mg/kg/day [M/F]) . LOAEL = 750 ppm (47.8/53.6 mg/kg/day [M/F]) based on decreased food consumption, body weight & body - we ight gain. Reproductive NOAEL = 750 ppm (47.8/53.6 mg/kg/day [M/F]) . LOAEL not observed. Offspring NOAEL = 10 ppm (0.6/0.7 mg/kg/day [M/F]) . LOAEL = 750 ppm (47.8/53.6 mg/kg/day [M/F]) based on decreased pup weight.Prometryn Human - Health Risk Assessment D403975

Page 33 of 36 **Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile**  **– Prom**  **etryn .**  **Guideline No.**  **Study Type MRID No./**  **Classification /Doses Results**  870.4 100 Chronic toxicity (2 -

year; dog) 00042794 (1965)

Acceptable/guideline 0, 15, 150, or 1500 ppm (0.0, 0.375, 3.75, or 37.50 mg/kg/d) NOAEL = 150 ppm (3.75 mg/kg/day) . LOAEL = 1500 ppm (37.5 mg/kg/day) based on degenerative hepatic changes, renal tubule degeneration, and bone marrow atrophy. 870.4300 Com

bined Chronic Toxicity/ Carcinogenicity (rat) 41901201 (1991)

Acceptable/guideline 0, 10, 100, 750 or 1500 ppm (males: 0, 0.38, 3.90, 29.45, or 60.88 mg/kg/d; females: 0, 0.49, 4.91, 37.25, or 80.62 mg/kg/d) NOAEL = 750 ppm (29.45/37.25 mg/kg/day [M/F]) . LOAEL = 1500 ppm (60.88/80.62 mg/kg/day [M/F]) based on decreased body - weight and b ody - weight gains (both sexes) and renal lesions (mineralized concretions) (M). No evidence of oncogenicity 870.4200 Carcinogenicity

(mouse) 40466201 (1981)

Acceptable/guideline 0, 10, 1000, or 3000 ppm (0, 1, 100, or 300 mg/kg/d) NOAEL = 1000 ppm (100 mg/kg/day) . LOAEL = 3000 ppm (300 mg/kg/day) based on decreased body - weight gain (F). No evidence of oncogenicity. 870.5100 Bacterial Gene

Mutation 40457518 (1987)

Acceptable/guideline Up to 1000 - 2000 ug/plate Negative 870.5100 Bacterial Gene

Mutation 40457519 (1979)

Acceptable/guideline Up to 1000 ug/plate Negative 870.5385 In vivo bone

marrow chromosomal aberration assay (Chinese hamster) 40457520 (1986)

Acceptable/guideline Up to 5000 mg/kg bw Negative

870.5550 In vitro UDS assay

(rat hepatocytes) 40457522 (1984)

Acceptable/guideline Up to 156.25 ug/ml Negative 870.6200a Ac ute neurotoxicity

screening battery (rat) 49021204 (2012)

Classification: Pending 0, 150, 500, 1500 mg/kg [M/F] Preliminary Systemic NOAEL = 500 mg/kg . Preliminary Systemic LOAEL = 1500 mg/kg based upon decreased defecation, mean body weight losses with corresponding reductions in food consumption, and lower mean absolute body weights. Neurotoxic NOAEL = 150 mg/kg/day. Neurotoxic LOAEL = 500 mg/kg/day was based upon lower mean total and/or ambulatory locomotor activity counts noted for males and females in the 500 and 1500 mg/kg groups during the 0 - 10 minute interval t the time of peak effect on study day 0. 870.6200b Subchronic

neurotoxicity screening battery (rat) 48306973 (2012)

Classification: Pending 0, 250, 500, 1000, 2000 ppm (0, 19, 33/40, 67/79, and 135 mg/kg/day [M/F]) Sy stemic NOAEL = 33/79 mg/kg/day). Sy stemic LOAEL = 67/135 ([M/F]) mg/kg/day based upon decreased absolute body weights. Neurotoxic NOAEL = 135 mg/kg/day. Neurotoxic LOAEL was not observed.Prometryn Human - Health Risk Assessment D403975

Page 34 of 36 **Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile**  **– Prom**  **etryn .**  **Guideline No.**  **Study Type MRID No./**  **Classification /Doses Results**  870.7485 Metabolism and

pharmacokinetics (rat) 41255901 (1989)

Acceptable/guideline 0.46 or 467 mg/kg bw (single) 0.46 mg/kg bw

(repeat) Prometryn is distributed in blood > spleen >

lungs (the three highest tissues measured) . Distribution is not dosage - dependent . It is extensively metabolized with <2% of recovered 14 C radioactivity representing the parent compound . Twenty - eight metabolites were identified in the urine, and 28 in the feces . T en metabolites were identified in both urine and feces . Prometryn is excreted predominantly in the urine and feces, with slightly higher concentrations in the urine . The 7 - day recovery of 14 C radioactivity averaged 95% for all dosing groups. 870.7485 Immunotoxicity

(mouse) 48936501 (2012)

Classification: Pending 0, 500, 2000, 5000 ppm (0, 105.8, 413.1, 1044.5 mg/kg/day) Preliminary NOAEL = 413.1 mg/kg/day . Preliminary LOAEL = 1044.5 mg/kg/day based upon a reduced humoral immune response using the sheep red blood cell assay.Prometryn Human - Health Risk Assessment D403975

Page 35 of 36 **Appendix B**  **. Physical/Chemical Properties**  **Table C.1. Physico -**  **Chemical Properties of Prom etryn.**  **Param eter**  **Value Reference**  Melting range 118 - 120  C DP# 207139, 12/8/94, C. Swartz pH 6.7 at 20oC (saturated solution) RCB # 2907, 12/4/87, G. Makhijani Density 1.16 g/mL at 20oC Water solubility 33 ppm at 20oC DP# 207139, 12/8/94, C. Swartz Solvent solubility 10 - 30 g/100 mL in acetone, dichloromethane, methanol, octanol, and toluene at 20oC Vapor pressure 8.54 x 10 - 7 mm Hg at 25oC DP#s 196116 & 196123, 4/25/94, K. Dockter Dissociation constant, pKa 4.09 at 20oC RCB# 2907, 12/4/87, G. Makhijani Octanol/water partition coefficient KOW = 2140 at 25oC DP#s 196116 & 196123, 4/25/94, K. Dockter UV/visible absorption spectrum Not availablePrometryn Human - Health Risk Assessment D403975

Page 36 of 36 **Appendix C**  **. Review of Human Research**  This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These data, which include studies from the PHED 1.1, the AHETF database, and the ARTF database are (1) subj ect to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics 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 the Agency website 6

.

6 http://www.epa.gov/pesticides/science/handler - exposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.html