Page **1** of **54 UNITED ST**  **AT ES ENVIRONMENT**  **AL PROTECTION A** **GENCY**

**WA SHINGTON, D.C. 20460**  **OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION MEMORANDUM**  July 1 , 201 5 SUBJECT: **Cyprodinil.** Human Health Risk Assessment for the Expansion of Existing Crop

Group/Representative Commodity Uses to Stone Fruit Group 12 - 12, and Adding New Uses on the Artichoke, Guava, Pomegranate, Passionfruit, Feijoa, Jaboticaba, Wax Jambu, Starf r uit, and Acerola and Amended Uses on Greenhouse Cucumbers and Small Tomatoes. **PC Code:** 288202 **DP Barcode:** D42 5998 **Decision No.:** 490951 **Registration Nos. :**  100 - 811, 100 - 828, 100 - 953, and 100 - 1317 **Petition No.:** 4E8273 **Regulatory Action:** Section 3 **Risk Assessment Type:**  NA **Case No.:** 7025 **T XR No.:**  NA **CAS No.:** 121552 - 61 - 2 **MRID No.:** 4 934690 1

– 05 **40 CFR:** 180.532 **FROM:** Thurston Morton, Risk Assessor

Abdallah Khasawinah, PhD., Toxicologist Iv an Nieves, Chemist Risk Assessment Branch IV Health Effects Division (7509P) **THROUGH:** Charles Smith , Acting Branch Chief

Risk Assessment Branch 4 Health Effects Division (7509P) **TO:** Laura Nollen/Barbara Madden, RM20

Risk Integration, Minor Use & Emergency Response Branch Registration Division (RD) (7505P) This document provides the Health Effects Division’s (HED’s) risk assessment of the proposed use of cy prodinil on globe artichoke, guava, p assionfruit, f eijoa, j aboticaba, w ax j ambu, s tarfruit , a cerola , post - harvest use on p omegranate , and amended u ses on greenhouse c ucumbers and s mall t omatoes .Page **2** of **54**

**1.0 EXECUTIVE SUMMARY**  **................................ ................................**  **................................ 5**  **2.0 HED RECOMMENDATIONS**  **................................ ................................**  **.......................... 9**  **2.1 Da**  **ta Deficiencies/Conditions of Registration ................................**  **................................ 9**  **2.2 Tolerance Considerations**  **................................ ................................**  **............................. 10**  **2.2.1 Enforcement Analytical Method**  **................................ ................................**  **........... 10**  **2.2.2 International Harmonization**  **................................ ................................**  **................. 10**  **2.2.3 Recommended Tolerances**  **................................ ................................**  **...................... 10**  **2.2.4 Revisions to Petitioned**  **- For Tolerances**  **................................ ................................**  **11 2.3**  **Label Recommendations ................................**  **................................ ...............................**  **11 3.**  **0 INGREDIENT PROFILE**  **................................ ................................**  **................................ 11**  **3.1 Chemical Identity**  **................................ ................................**  **................................ ..........**  **11 3.2**  **Physical/Chemical Characteristics ................................**  **................................ ...............**  **11 3.3**  **Pesticide Use Pattern ................................**  **................................ ................................**  **..... 12**  **3. 4**  **Anticipated Exposure Pathways ................................**  **................................ ...................**  **14 3.5**  **Considerations of Environmental Justice ................................**  **................................ ....**  **14 4.0**  **HAZARD CHARACTERIZATION/ASSESSMENT ................................**  **................... 15**  **4.1 Toxicology Studies Available for Analysis**  **................................ ................................**  **.. 15**  **4.2 Absorption, Distribution, Metabolism and Excretion**  **................................ ................**  **15 4.3**  **Toxicological Effects ................................**  **................................ ................................**  **...... 16**  **4.4 Safety Factor for Infants and Children (FQPA Safety Factor)**  **................................ .**  **17 4.4.1**  **Completeness of the Toxicology Database ................................**  **............................ 17**  **4.4.2 Evidence of Neurotoxicity**  **................................ ................................**  **...................... 17**  **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  **...... 18**  **4.4.4 Residual Uncertainty in the Exposure Database**  **................................ ..................**  **18 4.5**  **Toxicity Endpoint and Point of Departure ................................**  **................................ ..**  **18 4.5.1**  **Dose -**  **Response Assessment ................................**  **................................ ....................**  **18 4.5.2**  **Recommendations for Combining Exposure Routes ................................**  **........... 19**  **4.5.3 Classification of Carcinogenic Potential**  **................................ ...............................**  **19 4.5.4**  **Summary of Points of Departure Used in Risk**  **Assessment ...............................**  **19 5.0**  **DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT ....**  **21 5.1**  **Metabolite/Degradate Residue Profile ................................**  **................................ .........**  **21 5.1.1**  **Summary of Plant and Livestock Metabolism Studies ................................**  **........ 21**  **5.1.2 Comparison of Metabolic Pathways**  **................................ ................................**  **...... 21**  **5.1.3 Environmental Fate and Transport**  **................................ ................................**  **...... 21** Page **3** of **54**

**5.1.4 Residues of Concern**  **Summary and Rationale ................................**  **..................... 22**  **5.2 Food Residue Profile**  **................................ ................................**  **................................ .....**  **22 5.2.1**  **Residues in Crops ................................**  **................................ ................................**  **.... 22**  **5.3 Water Residue Profile**  **................................ ................................**  **................................ ...**  **23 5.3.1**  **Estimated Drinking Water Concentrations ................................**  **.......................... 23**  **5.4 Dietary and Drinking Water Exposure and Risk**  **................................ .......................**  **24 5.4.1**  **Acute Dietary and Drinking Water Analysis ................................**  **....................... 24**  **5.4.2 Chronic Dietary and Drinking Water Analysis**  **................................ ...................**  **25 6.0**  **RESIDENTIAL EXPOSURE AND RISK ASSESSMENT ................................**  **.......... 25**  **6.1 Residential Bystander Postapplication Inhalation Exposure**  **................................ ....**  **26 6.2**  **Spray Drift ................................**  **................................ ................................**  **...................... 26**  **7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT**  **................................ ............**  **27 7.1**  **Acute & Chronic Aggregate Risk ................................**  **................................ .................**  **27 7.2**  **Short -**  **and Intermediate -**  **Term Aggregate Risk ................................**  **......................... 27**  **7.3 Intermediate**  **- Term Aggregate Risk**  **................................ ................................**  **............. 27**  **8.0 CUMULATIVE RISK**  **................................ ................................**  **................................ ......**  **28 9.0**  **OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION ..............................**  **28 9.1**  **Exposure Scenarios ................................**  **................................ ................................**  **....... 28**  **9.2 Handler Exposure**  **................................ ................................**  **................................ ..........**  **29 9.2.1**  **Handler Exposure Scenarios ................................**  **................................ ..................**  **29 9.2.2**  **Handler Exposure Data ................................**  **................................ ..........................**  **29 9.2.3**  **Handler Exposure Assumptions ................................**  **................................ ............**  **29 9.2.4**  **Handler Exposure and Risk Estimates ................................**  **................................ .**  **30 9.3**  **Post Application Exposure ................................**  **................................ ............................**  **30 9.3.1**  **Post Application Exposure Scenarios ................................**  **................................ ...**  **32 9.3.2**  **Post Application Exposure Assumptions ................................**  **.............................. 33**  **9.3.3 Post**  **- Application Exposure and Risk Estimates**  **................................ ...................**  **33 9.3.4**  **Restricted Entry Interval ................................**  **................................ .......................**  **35 10.**  **REFERENCES ................................**  **................................ ................................**  **.................. 35**  **A TOXICOLOGY DATA SUMMARY**  **................................ ................................**  **.............. 36**  **A.1 Guideline Data Requirements**  **................................ ................................**  **................ 36**  **A.3 Toxicological Endpoints**  **................................ ................................**  **............................. 36**  **APPENDIX B. Chemical Names And Structures Of Metabolites ................................**  **......... 51**  **B.1 Chemical Names And Structures**  **................................ ................................**  **................. 52** Page **4** of **54**

**APPENDIX C. Physical/Chemical Properties ................................**  **................................ ..........**  **53 APPENDIX D. Studies Reviewed for Ethical Conduct**  **................................ ..........................**  **53**Page **5** of **54**

**1.0 EXECUTIVE SUMMARY**  This assessment provides information to support a Section 3 registration for the use of cy prodinil on globe artichoke, guava, p assionfruit, f eijoa, j aboticaba, w ax j ambu, s tarfruit , a cerola , and post - harvest use on p omegranate , along with expansion of the fruit, stone, group 12 to fruit, stone, group 12 - 12 . This document addresses the dietary , drinking water, residential and occupational exposure and risk associated with currently registered uses and proposed new uses of cy prodinil. It provides a reassessment of tolerances (pesticide residue limits in foo d) to ensure that they meet the safety

standard established b y the Food Quality Protection Act (FQPA) of 1996. **Use Profile** Cy prodinil (4 - cyclopropyl - 6 - methyl -N - phenyl - 2 - py

rimidinamine) is a s ys temic anilino py rimidine fungicide. Permanent tolerances are established at 40 CFR §180.532 for residues of cy prodinil per se in/on a variety of crop commodities, at levels ranging from 0.02 ppm in/on almonds to 340 ppm in citrus oil. Cy prodinil is a sy stemic fungicide and is active through inhibition of methi onine biosy nthesis. Cy

prodinil is applied to food crops with aircraft and ground application equipment. Cy prodinil is used on ornamental landscapes on golf courses and around residential, institutional, public, commercial and industrial buildings, parks, recreational areas and athletic fields. It is applied to non - food areas with ground - boom and handheld spray equipment. Since the label does not limit use to “professional” or certified applicators, there is potential for residential “handlers” to obtain and to apply the product. Residential exposures are limited to residential applicators; however, since cyprodinil is only used on ornamentals and there is no dermal POD, only inhalation exposure was assessed. Proposed New/Amended Uses In conjunction with PP#1E7854, IR - 4 is requesting a Section 3 registration for VanguardTM WG (EPA Reg. No. 100 - 828), a 75% water dispersible granule (WDG) formulation for use on globe artichoke, acerola, feijoa, guava, jaboticaba, passionfruit, starfruit, and wax jambu; Switch ® 62.5 WG Fungicide (EPA Reg. No. 100 - 953), a 37.5% water dispersible granule (WDG) formulation of cy prodinil for use on guava, passionfruit, starfruit, and pomegranate (post - harvest); and Inspire Super TM Fungicide (EPA Reg. No. 100 - 1317), a 2.09 lb ai/gallon emulsion oil in water (EW) formulation to artichoke. In support of these new uses, IR - 4 has submitted new magnitude of the residue data for cyprodinil using the WDG formulation of cy prodinil at the proposed use rate.Page **6** of **54**

In addition, IR - 4 is reque sting amendments for the Section 3 registrations for VanguardTM WG (EPA Reg. No. 100 - 828) and Inspire Super TM Fungicide (EPA Reg. No. 100 - 1317) to expand currentl y registered foliar uses for stone fruit group 12 to include the additional commodities specified under the following new crop group: Fruit, stone, group 12 - 12 No amendments to the use patterns (i.e., maximum use rates, retreatment intervals, preharvest intervals, use of adjuvants, etc.) on the subject crops have been proposed. No new residue chemistry data were submitted to support these uses. Instead the petitioner wishes to rel y on previously submi tted residue chemistry

data to support the currently registered uses of cy

prodinil. In addition, IR - 4 is proposing to remove the restriction against using VanguardTM WG (EPA Reg. No. 100 - 828) and Switch® 62.5 WG Fungicide (EPA Reg. No. 100 - 953) on small tomatoes along with removing the restriction against using Inspire Super TM Fungicide (EPA Reg. No. 100 - 1317) on greenhouse cucumbers. **Hazard Identification** T he toxicology

database for cy

prodinil is adequate for evaluating and characterizing toxicity and selecting endpoints for purposes of this risk assessment. The major target organs of cy prodinil are the liver in both rats and mice and the kidney in rats. Liver effects observed consistently in subchronic and chronic studies in rats and mice include increased liver weights, increases in serum clinical chemistry parameters associated with adverse effects on liver function, hepatocy te h yp ertroph y, and hepatocellular necrosis. Adverse kidney effects include tubu lar lesions and inflammation following subchronic exposure of male rats. The hematopoietic s ys tem also appeared to be a target of cy prodinil, causing mild anemia in rats exposed subchronically . Chronic effects in dogs were limited to decreased body- weight gain, decreased food consumption and decreased food efficiency . There was no evidence of increased susceptibility

in the developmental rat or rabbit study following in utero exposure or in the two generation reproduction study following pre - or post - nat al exposure. There was no evidence of neuropathological or other neurological effects in the available acute or subchronic neurotoxicity study . The submitted 28 - day immunotoxicity

study concluded no apparent suppression of the humoral component of the immune sy stem. No dermal or s ys temic toxicity was seen following repeated dermal application at the highest dose in a 21 day dermal toxicity

study in rabbits. There was no evidence of carcinogenic potential in either the rat chronic toxicity /carcinogenicity or mouse carcinogenicity studies. Cy prodinil has low acute toxicity via the oral, dermal, and inhalation routes (Toxicity Category III). Cy prodinil is mildly

irritating to the eyes (Toxicity Category I II) and negligibl y irritating to the skin (Toxic ity

Category IV). It is a dermal sensitizer. **Dose Response Assessment** Toxicological points of departure (PODs) were selected for dietary , occupational, and residential exposure scenarios. A POD (NOAEL = 200 mg/kg/day) for acute dietary exposure was selected for the general population and all population subgroups from an acute neurotoxicity study in rats based on clinical signs (hunched posture, pilorection, and reduced responsiveness to sensoryPage **7** of **54**

stimuli, reduced motor ac tivity and hy pothermia) . The POD (NOAEL = 2.7 mg/kg/day) for chronic dietary

exposure was selected from a chronic/carcinogen icity feeding study

in rats based on degenerative liver lesions (spongiosis hepatitis) in males. A dermal exposure endpoint was no t selected as no s ys temic toxicity was seen at the highest dose test in a 21 day dermal toxicity study in rabbits. A short - and intermediate term inhalation exposure POD of 62 mg/kg/day (No Observable Adverse Effect Level; NOAEL) was selected from a 28 - day feeding study in rats based on decreased body - weight gain, increased cholesterol and phospholipid levels, microcy tosis, and hepatocy

te hy pertroph y s een at the L owest Observed Adverse Effect Level (LOAEL) of 299 mg/kg/day . Th e POD of 62 mg/kg/day is appro priate and protective for the longer - term intermediate exposure scenario since there is no progression of toxicity observed in the 90 - day

SCN study

where the NOAEL is 54 mg/kg/day based on decreased body weight gain, hepatocy te h yp ertroph y, kidney tubular casts, th yr oid follicular cell h ypertrophy at the LOAEL of 600 mg/kg/day . An uncertainty factor of 100x was applied to PODs for both acute and chronic dietary

exposure (10x for interspecies extrapolation, 10x for intraspecies variation). A recent HASPOC d ecision (TXR 0054812), based on a weight of evidence approach is requiring a 90 - day inhalation toxicity

study to reduce uncertainty

associated with the use of an oral POD for assessing risk via the inhalation route. Therefore, in the absence of a route - sp ecific inhalation study , a 10X database uncertainty factor for occupational workers and a 10x FQPA SF factor for residential scenarios should be applied specifically to the inhalation assessment. **Exposure/Risk Assessment and Risk Characterization** Risk assessments were conducted for dietary (food and water) and occupational exposure based on registered uses and requests for new or expanded use of cy prodinil on a number of commodities. The proposed uses will not result in residential exposure; however, there is a currentl y registered ornamental use that has been previously evaluated to reflect updates to HED’s 2012 Residential Standard Operating Procedures (SOPs) ( D398361, I . Nieves, 5/3/12) . No residential risks of concern were identified. Conservative acute and moderatel y refined chronic dietary

and drinking water risk assessments for cy prodinil conclude that dietary and drinking water exposure estimates are below HED’s level of concern for the general population and all population subgroups. Dermal risks to agricultural workers following treatments were not assessed since no short - or intermediate - term dermal endpoint of concern was identified. The majority

of the proposed uses have been previously assessed in association with evaluation for similar use patterns (D398361, I. Nieves, 5/3/12), and no risk estimates of concern were identified. The proposed use on cucumbers grown in greenhouses was re - assessed based on a change in formulation (previously assessed as a dry

flowable; proposed as a liquid) ( D362494, I. Nieves, 8/4/09) and recent updates to unit exposures and body weight assumptions. Occupational handler risk estimates resulted above HED’s LOC of 1,000 and therefore not of concern. At baseline, the occupational handler inhalation MOEs range from 1,300 to 1,100,000, depending on the scenario. The proposed use on post - harvest pomegranates resulted in i nhalation exposure risk estimates above HED’s LOC of 1,000 at baseline. MOEs resulted in 4,900 and 11,000. E xposure and risk estimates from post - application inhalation exposure for sorter and packers for the proposed use on pomegranates results in n o risk estimates of concern. MOEs resulted in 15,000 for direct inhalation exposure, and 320,000 for indirect inhalation exposure.Page **8** of **54**

**Use of Human Studies**  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 studies, listed in Appendix D have been determined to require a review of their ethical conduct. Some of these studies are also subject to review b y the Human Studies Review Board. All of the studies used have received the appropriate review. Environmental Justice Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ). As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy , HED estimat es risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. 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 currently in development, a s OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. Tolerance Recommendat ion Pending submission of a minor revision to Section F (see requirements under Section 2.2.3 Recommended Tolerances), there are no residue chemistry issues that would preclude granting the proposed use or establishment of the following tolerance for resi dues of cy prodinil . Artichoke, globe..... ................................ ................................ . 4.0 ppm Guava ................................ ................................ ........................ 1.5 ppm Passionfruit.............................................................1.5 ppm Feijoa....................................................................1.5 ppm Jaboticaba...............................................................1.5 ppm Wax Jambu.............................................................1.5 ppm Starfruit ................................ ................................ .................... 1.5 ppm Acerola ................................ ................................ ...................... 1.5 ppm Pomegranate ................................ ................................ ............... .1 0 ppm Fruit, stone, group 12 - 12.................. ................................ ... 2.0 ppmPage **9** of **54**

**Table 1**  **. Tolerance Summary for Cyprodinil**  Commodity Established/Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition **Tolerances Proposed Under PP#1E7854**  Artichoke 4.0 4.0 Artichoke, globe Guava 1.5 1.5 --- Passionfruit 1.5 1.5 --- Feijoa 1.5 1.5 --- Jaboticaba 1.5 1.5 --- Wax Jambu 1.5 1.5 --- Starfruit 1.5 1.5 --- Acerola 1.5 1.5 --- Pomegranate 7.0 10 --- Fruit, stone, group 12 - 12 2.0 2.0 --- No Codex MRL s are established in/on globe artichoke, acerola, feijoa, guava, jaboticaba, passionfruit, starfruit, wax jambu, and pomegranate . A Mexican MRLhas not been established for the requested crops. The Agency with be harmonized with Codex on the fruit, stone, group 12 - 12 MRL of 2.0 ppm . **2.0 HED RECOMMENDATIONS**  **2.1 Data Deficiencies/Conditions of Registration**  There are no deficiencies in the residue chemistry or exposure data requirements for the proposed actions. Tolerances should be revised, as specified in Table 1 Section 2.2.3. Revised Sections B and F are required for the IR - 4 Petition PP# 4E8273 . The HASPOC concluded (TXR 0054812), based on a weight of evidence (WOE) approach, that a 90 - day inhalation toxic ity study is required at this time to reduce uncertainty associated with the use of an oral POD for assessing risk via the inhalation route. This determination considered all of the available hazard and exposure information for cy prodinil, including: (1) the use of an oral POD results in MOEs as low as 150 for risk via the inhalation route for intermediate - term exposure from occupational uses; and (2) the toxicological profile of cy prodinil indicates that toxicity increases with increased exposure from sho rt - term to intermediate durations. Therefore, in the absence of a route - specific inhalation study , a 10X database uncertainty factor for occupational workers and a 10x FQPA SF factor for residential scenarios should be applied specifically to the inhalati on assessment. **Note to PM:** Revised Section s B & F required.Page **10** of **54**

**2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  Adequate HPLC/UV methods (AG - 631 and AG - 631B) are available for enforcing tolerances of cy prodinil on plant commodities. The limits of quantitation (L OQ) for the plant methods range from 0.005 to 0.065 ppm depending on the commodity . An adequate LC/MS me thod (GRM010.01A) is also available for enforcing tolerances of cy prodinil residues in livestock commodities. The method L OQ for this method is 0.02 ppm for the combined residues of cy prodinil and its metabolite CGA - 304075 (free and conjugated), expressed as parent. **2.2.2 International Harmonization**  No Codex MRL s are established in/on globe artichoke, acerola, feijoa, guava, jaboticaba, passionfruit, starfruit, wax jambu, and pomegranate . A Mexican MRLhas not been established for the requested crops. The Agency with be harmonized with Codex on the fruit, stone, group 12 - 12 MRLof 2.0 ppm. There are no tolerances established in Mexico. **2.2.3 Recommended Tolerances**  HED has examined the residue chemistry database for cy

prodinil and recommends in favor of the es tablishment of a tolerance for residues of cy prodinil in/on the following: Artichoke, globe..... ................................ ................................ . 4.0 ppm Guava ................................ ................................ ........................ 1.5 ppm Passionfruit.............................................................1.5 ppm Feijoa....................................................................1.5 ppm Jaboticaba...............................................................1.5 ppm Wax Jambu.............................................................1.5 ppm Starfruit ................................ ................................ .................... 1.5 ppm Acerola ................................ ................................ ...................... 1.5 ppm Pomegranate ................................ ................................ ........... 10 ppm Fruit, stone, group 12 - 12.................. ................................ ... 2.0 ppmPage **11** of **54**

**Table 2.2.3**  **. Tolerance Summary**  **for Cyprodinil** Commodity Established/Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition **40 CFR §180. 532**  Artichoke 4.0 4.0 Artichoke, globe Guava 1.5 1.5 --- Passionfruit 1.5 1.5 --- Feijoa 1.5 1.5 --- Jaboticaba 1.5 1.5 --- Wax Jambu 1.5 1.5 --- Starfruit 1.5 1.5 --- Acerola 1.5 1.5 --- Pomegranate 7.0 10 --- Fruit, stone, group 12 - 12 2.0 2.0 --- Adequate crop field trial data reflecting the proposed use patterns were submitted in support of the proposed use and tolerance. The Organization for Economic Cooperation and Development tolerance calculation procedures were utilized in determining the appropriate tolerance level for the proposed use. The proposed and recommended tolerance for residues of cy prodinil as a result of the subject action are presented in Table 2.2.3 . **2.2.4 Revisions to Petitioned**  **- For Tolerances**  No significant changes to the petitioned - for tolerance are required. However, the proposed Artichoke tolerance must be corrected to artichoke, globe . Inaddition, the pomegranate tolerance level should be revised to 10 ppm. This is because different fie ld trial use patterns should not be mixed in the OECD MRLcalculator. **2.3 Label Recommendations**  The label instructions for Artichoke should be revised to specify Globe Artichoke . The proposed use directions are adequate. Directions on the proposed supplemental label to InspireTM Fungicide (EPA Reg. No. 100 - 1262) coupled with the spray volume and confined rotational crop restrictions on the current Inspire R Fungicide Label (EPA Reg. No. 100 - 1262 are adequate. **3 .0**  **INGREDIENT PROFILE 3.1**  **Chemical Ide ntity**  Structure and nomenclature are reported in Table 3.1 . **Table 3.1**  **. Cyprodinil Nomenclature.** Page **12** of **54**

**Table 3.1**  **. Cyprodinil Nomenclature.**  Chemical structure

Common name Cy prodinil Company experimental name CGA219417 IUPAC name (4 - cyclopropyl - 6 - methyl - pyrimidin - 2 - yl) - phenyl - amine CAS name 2 - pyrimidinamine, 4 - cyclopropyl - 6 - methyl -N - phenyl CAS registry number 121552 - 61 - 2 Molecular weight 225.29 End -use product s (EP ) 75% water - dispersible granule (WDG) formulation (VangardTM Fungicide; EPA Reg. No. 100 - 828); a multiple active ingredient (MAI) end - use product (Inspire Super TM Fungicide; EPA Reg. No. 100 - 1317) formulated as an emulsion [oil] in water (EW), containing 8.4% difenoconazole and 24.1% cyprodinil **3.2 Physical/Chemical Characteristics**  The phy sicochemical properties of cy prodinil are reported in Appendix C. **3.3 Pesticide Use Pattern**  Proposed cy

prodinil use patterns taken from submitted supplemental labels ( Table 3.3 ). N N

C H 3 N HPage **13** of **54**

**Table 3.3**  **. Summ ary of Proposed Directions for**  **Use of Cyprodinil Applic. Timing, Type, and**  **Equip. Form**  **ulation [EPA Reg.**  **No.] Applic. Rate** 

**(lb ai/A) Max.** 

**No. Applic.**  **Per Season**  **Max. Seasonal**

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

**(days) Use Directions**  **and Limitations Artichoke**  **1** Broadcast foliar Ground/Aerial/Chemigation Vangard WG 75% WDG [100 - 828] 0.33 4 im plied 1.3 3 A minimum retreatment interval (RTI) of 14 days is proposed. Broadcast foliar Ground Only Inspire Super

2.09 lb/gal EW [100 - 1317] 0.33 4 im plied 1.3 3 A minimum retreatment interval (RTI) of 7 - 10 days is proposed. **Acerola, feijoa, guava, jaboticaba, passionfruit, starfruit, wax jambu** Broadcast foliar Ground/Aerial/Chemigation Vangard WG 75% WDG [100 - 828] 0.33 2 by aerial 4 im plied 1.3 0 A minimum retreatment interval (RTI) of 7 - 10 days is proposed. Broadcast foliar Ground Only Switch 62.5WG 37.5% WDG [100 - 953] 0.33 1 by aerial 4 im plied 1.3 0 A minimum retreatment interval (RTI) of 7 - 10 days is proposed. Aerial application in California only. **Stone fruits Crop Group 12 -**  **12**

Broadcast foliar Ground/Aerial Vangard WG

75% WDG [100 - 828] 0.47 2 by aerial 4 im plied 1.4 2 Apply maximum of 2 applications during the pre harvest period through 2 days prior to harvest needed. California only Inspire Super 2.09 lb/gal EW [100 - 1317] 0.33 2 by aerial 4 im plied 1.4 A minimum retreatment interval (RTI) of 7 is proposed. **Cucumber Grown in Greenhouses** Broadcast foliar Ground Only Inspire Super

2.09 lb/gal EW [100 - 1317] 0.0075 lb

ai/1000 ft2 NS NS 7 A minimum retreatment interval (RTI) of 7 - 10 days is proposed.Page **14** of **54**

**Table 3.3**  **. Summ ary of Proposed Directions for**  **Use of Cyprodinil Applic. Timing, Type, and**  **Equip. Form**  **ulation [EPA Reg.**  **No.] Applic. Rate** 

**(lb ai/A) Max.** 

**No. Applic.**  **Per Season**  **Max. Seasonal**

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

**(days) Use Directions**  **and Limitations Pom**  **egranate (Post -**  **harvest dip /drench**  **)**

In - Line Dip/Drench Switch 62.5WG 37.5% WDG [100 - 953] 0.45 lb ai/100

gal of water, wa x/emulsion, or aqueous dilution of wa x/oil em ulsion 2 0.45 - 0.90 lb

ai/100 gal of water, wa x/emulsion, or aqueous dilution of wa x/oil em ulsion 0 For maximum

decay control, treat fruit once before storage and once after storage, prior to marketing. 1 Although not specified in the use direction, the use of artichoke is intended to be for globe artichoke consist ent with the supporting data. **3.4 Anticipated Exposure Pathways**  The Registration Division has requested an assessment of human health risk to support the proposed new uses of cy

prodinil on globe artichoke, guava (along with other tropical fruits) and post - harvest use on pomegranate . For domestic uses, humans may be exposed to cy

prodinil in food and drinking water, since cy prodinil may

be applied directl y to growing crops and application may

result in cy

prodinil reaching surface and ground water source s of drinking water. There are also residential uses of cy prodinil , so there is exposure in residential or non occupational settings. Inan 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 cy prodinil . This risk assessment considers all of the aforementioned exposure pathway s based on the proposed use of cy prodinil , but also considers the existing uses as well, particularl y for the dietary exposure assessment. **3.5 Considerations of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP p olicy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey /What We Eat in America, (NHANES/WWEIA), are used in pesticide risk assessments for all registered food usesPage **15** of **54**

of a pe sticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additionally , OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are p erformed 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 pos t - application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. **4.0 HAZARD CHARACTERIZATION/ASSESSMENT**  **4.1 Toxicology Studies Available for Analysis**  T he toxicology

database for cy

prodinil is adequate for evaluating and characterizing cy prodinil toxicity and selecting endpoints for purposes of this risk assessment. Acute neurotoxicity (MRID 48304202) and immunotoxicity studies (MRIDs 48304203, 4829350) required under revised 40 CFR Part 158 Toxicology Data Requirements have been submitted and determined to be acceptable. Based on a weight of evidence ( WOE) approach a 90 - day inhalation toxicity study is required at this time to reduce uncertainty associated with the use of an oral POD for assessing risk via the inhalation route (HASPOC, TXR 0054812). **4.2 Absorption, Distribution, Metabolism and Excretion**  Absorption, distribution, metabolism, and excretion of cy prodinil were studied in rats. In an initial study , single oral doses (0.5 or 100 mg/kg bw) of phenylor p yrimidyl - radiolabelled cy prodinil were administered with one low - dose group receiving unlabeled cy prodinil for 2 weeks prior to treatment with radiolabelled compound. Absorption wa s very rapid (peak concentration at 0.3 hours) with rapid clearance (half - life of < 2 hrs). A minimum of 75% of the administered dose was absorbed. Excretion was rapid and almost complete, with urine as the principle route of excretion (48 - 68%), and >90% of the administered dose detected in the urine and feces within 48 hours. Tissue residues declined rapidl y, with the highest concentrations ( < 1.8 ppm) found in kidneys, liver, lungs, spleen, th yroid, whole blood, and carcass. The urine, fecal, and bile metabolite patterns were complex, with 8, 8 and 9 defined metabolite fractions, respectivel y. Unchanged parent compound was detected in feces extract only. Excretion, distribution and metabolite profiles were independent of dose level, pretreatment, and ty pe of label, although there were some quantitative differences sex - dependent qualitative differences in two urinary

metabolite fractions. In a follow - up study , e xcreta and bile from radiolabelled rats from the previous study were used to characterize, isolate and identify the metabolites detected in that study . Eleven metabolites were isolated from urine, feces and bile, and the metabolic pathway s in the rat were proposed. All urinary

and biliary

metabolites but one were conjugated with glucuronic ac id or sulfonated, and excreted. C yprodinil was almost completely metabolized by hydrox yl ation of the phen yl ring or p yr imidine ring, followed by conjugation. An alternative pathway involved oxidation of the phen ylring followed by glucuronic acid conjug ation. The major metabolic pathway s ofPage **16** of **54**

cy prodinil were not significantly influenced by

the dose, treatment regimen, or sex of the animal. **4.3 Toxicological Effects**  The major target organs of cy prodinil are the liver and the kidney . Liver effects were consistent among male and female rats and mice in both subchronic and chronic studies and ty pically included increased liver weights along with increases in serum clinical chemistry parameters associated with adverse effects on liver function ( i.e. , increa sed cholesterol and phospholipid levels). Microscopic lesions in rats and mice included hepatocy te hy pertrophy and hepatocellular necrosis. In the kidney s, adverse effects were seen as chronic tubular lesions and chronic kidney

inflammation following sub chronic exposure of male rats. Chronically , cy prodinil caused increased kidney weights and progressive nephropath y in male rats. Chronic effects in dogs were limited to decreased body- weight gain, decreased food consumption and decreased food efficiency; liver toxicity was not seen in the dog. The hematopoietic sy stem also appeared to be a target of cy prodinil as mild anemia was seen in rats exposed subchronicall y (reductions in hematocrit and hemoglobin and microcy tosis). Although increases in thy roid weight and/or h ypertrophy of th yroid follicular cells were observed at higher doses in the rat 28 - day oral - toxicity

studies (both feeding and oral gavage) and in the 90 - day oral - toxicity

study in rats, treatment related changes in thy roid weights or gross/microscopic observations were not observed in the chronic rat study or in other studies (thy

roid hormones were not evaluated in any study). A 28 - day

dietary immunotoxicity

study in mice resulted in no apparent suppression of the humoral component of the i mmune sy stem. The only effect attributed to cy

prodinil treatment was higher mean absolute, relative (to body weight), and adjusted liver weights for the 5000 ppm group. There were no treatment - related effects on absolute, adjusted, or relative spleen or thy mus weights; no effects on specific activity or total activity of splenic Ig M antibody- forming cells to the T cell - dependent antigens RBC. No dermal or s ys temic toxicity was seen following repeated dermal application at the highest dose in a 21 day der mal toxicity

study in rabbits. An acute neurotoxicity

study indicated sy stemic toxicity with signs of induced hunched posture, pilorection, and reduced responsiveness to sensory stimuli and reduced motor activity . Females were slightly

more affected than males per dail y clinical observations, which disappeared b y day 3 to 4. A dose - related reduction in body temperature was seen in all treated animals, thus hy pothermia is considered a compound - related effect in the HDT and was found to be statistically

si gnificant, whereas the lower dosed animals was not or only marginally

significant and was full y reversible in all groups. Clinical signs, hy pothermia, and changes in motor activity were found to all be reversible by day 8 and 15 investigations. There were no histopathological findings to support evidence of damage to the central nervous s ys tem, eyes, optic nerves, or skeletal muscles. A subchronic neurotoxicity study showed no treatment related effects on mortality , clinical signs, or gross or histologica l neuropathology . FOB and motor activity testing revealed no treatment related effects up to the highest dose tested. No clinical signs suggestive of neurobehavioral alterations or evidence of neuropathological effects were observed in the available oral - toxicity

studies. There was also no evidence of a neurodevelopmental effect in the rat or rabbit developmental - toxicity studies or in the rat two generation reproductive - toxicity study . There was no evidence of increased susceptibility in the developm ental rat or rabbit studyPage **17** of **54**

following in utero exposure or in the two - generation reproduction study following pre - and post natal exposure. Fetal toxicity , manifested as significantly lower fetal weights and an increased incidence of delayed ossification in the rat and a slight increase in litters showing extra ribs (13 th ) in the rabbit, was reported in developmental toxicity studies. In a rat two generation reproduction study, significantly lower pup weights for F 1 and F 2 offspring were observed. However, each of these fetal/neonatal effects occurred at the same dose levels at which maternal toxicity (decreased body weight gain) was observed and were considered to be secondary to maternal toxicity . Cy prodinil has low acute toxicity via the oral, dermal, and inhalation routes (Toxicity Category III). C yprodinil is mildly irritating to the eyes (Toxicity Category I II) and negligibl y irritating to the skin (Toxicity

Category IV). It is a dermal sensitizer. The complete toxicity

profile for cy

prodinil is provided in Appendix A. **4.4 Safety Factor for Infants and Children (FQPA Safety Factor)**  For non - inhalation routes of exposure, the FQPA factor for potential susceptibility to infants and children is reduced to 1x based on the following considerations. Further discussion may be found in the following sections.

- The toxicology

data base for cy

prodinil is complete and adequate for assessing susceptibility

under FQPA.

- Th ere is no indication of susceptibility of rats or rabbit fetuses to in utero and/or postnatal exposure in the developmental and reproductive toxicity data.

- There are no residual uncertainties in the exposure database.

- The dietary

and residential exposure and risk assessments are conservative and will not underestimate exposure to cy prodinil. For inhalation exposure scenarios for all population groups, EPA is retaining a 10X FQPA safety factor for the lack of a route specific inhalation study . **4.4.1 Completeness of the Toxicology Database**  The toxicity

database for cy

prodinil is sufficient for a full hazard evaluation and is considered adequate to evaluate risks to infants and children. Acceptable studies have been submitted for developmental toxicity, reproductive toxicity , acute and subchronic neurotoxicity and immunotoxicity . However, in the absence of a route - specific inhalation study , a 10X database uncertainty factor for occupational workers and a 10x FQPA SF factor for residential scenarios sh ould be applied specifically to the inhalation assessment. **4.4.2 Evidence of Neurotoxicity**  In a subchronic neurotoxicity study in rats, there were no treatment related effects on mortality , clinical signs, or gross or histological neuropathology . Functional Observational Battery (FOB) and motor activity

testing revealed no treatment related eff ects up to the highest dose tested. InPage **18** of **54**

an acute neurotoxicity

study in mice, clinical signs, hy pothermia, and changes in motor activity were all found to be reversible and no longer seen at day 8 and 15 investigations. There were no treatment related ef

fects on mortality , gross or histological neuropathology. Reduced motor activity , induced hunched posture, pilorection and reduced responsiveness to sensory stimuli were observed and disappeared in all animals by day 3 to 4. **4.4.3 Evidence of Sensitivit** **y/Susceptibility in the Developing or Young Animal** The available acceptable guideline studies indicated no increased susceptibility of rats or rabbits to in utero and/or from postnatal exposure to cy prodinil. In the prenatal developmental toxicity studie s in rats and rabbits and the two - generation reproduction study in rats, toxicity

to the fetuses/offspring, when observed, occurred at the same doses at which effects were observed in maternal/parental animals. In a rat developmental toxicity study , the re were significantl y lower mean fetal weights in the high - dose group compared to controls as well as a significant increase in skeletal anomalies in the high - dose group due to abnormal ossification. The skeletal anomalies/variations were considered to be a transient developmental delay that occurs secondary

to the maternal toxicity noted in the high - dose group. In the rabbit study , the only treatment related developmental effect was indication of an increased incidence of a 13th rib at maternall y toxic do ses. Signs of fetal effects in the reproductive toxicity study included significantl y lower F1 and F2 pup weights in the high - dose group during lactation, which continued to be lower than controls post - weaning and after the pre - mating period (examination in F1 generation onl y). Reproductive effects were seen only at doses that also caused parental toxicity . **4.4.4 Residual Uncertainty in the Exposure Database**  There are no residual uncertainties in the exposure database. The residue data base is adequate. The dietary

risk assessment is conservative and will not underestimate dietary exposure to cy prodinil. The residential exposure estimates included in the ag gregate risk assessment are conservative based on maximum use rates and will not underestimate non - dietary risks to homeowners. **4.5 Toxicity Endpoint and Point of Departure**  **4.5.1 Dose**  **- Response Assessment**  An acute POD of 200 mg/kg was selected from an acute neurotoxicity study in rats based on LOAEL of 600 mg/kg showing clinical signs (hunched posture, pilorection, and reduced responsiveness to sensory stimuli, reduced motor activity and h ypothermia). An uncertainty factor (UF) of 100x (10x to account for interspecies extrapolation and 10x for intraspecies variation) was applied to the NOAEL to obtain an acute reference dose (aRfD) of 2.0 mg/kg/day . Since the FQPA factor has been reduced to 1X, the acute p opulation adjusted dose (aPAD) is equivalent to the aRfD. The selected e ndpoint is considered appropriate for acute dietary exposure because effects were seen after a single dose.Page **19** of **54**

A chronic POD of 2.7 mg/kg/day (NOAEL) was selected from a chronic/carc inogenicity oral study in rats based on the histopathological alterations in the liver (spongiosis hepatis) in males at 35.6 mg/kg/day

(LOAEL). The selected NOAEL is the lowest NOAEL observed in the most sensitive species following long - term exposure. A UF 100x (10x to account for interspecies extrapolation and 10x for intraspecies variation) was applied to the dose to obtain a chronic reference dose (cRfD/cPAD) of 0.027 mg/kg/day . A POD for dermal exposure was not selected because no dermal or s ys temic toxicity was seen following repeated dermal application at the highest dose tested in a 21 day dermal toxicity study in rabbits. A short - and intermediate term inhalation exposure POD of 62 mg/kg/day (No Observable Adverse Effect Level; NOAEL) was select ed from a 28 - day feeding study in rats based on decreased body- weight gain, increased cholesterol and phospholipid levels, microcy tosis, and hepatocy te h yp ertroph y s een at the Lowest Observed Adverse Effect Level (LOAEL) of 299 mg/kg/day . This POD of 62 mg/kg/day is appropriate and protective for the longer - term intermediate exposure scenario since there is no progression of toxicity observed in the 90 - day SCN study

where the NOAELis 54 mg/kg/day based on decreased body weight gain, hepatocy

te hy pertrophy , kidney

tubular casts, thy

roid follicular cell hy

pertroph y at the LOAEL of 600 mg/kg/day . The toxicological profile of cy prodinil indicates that toxicity increases with increased durations, specifically between short - term (28 - day) and long - term exposures (2 - ye ar). Therefore, based on the weight of evidence regarding cy prodinil, a 90 - day inhalation toxicity study is required to reduce uncertainties associated with the use of an oral POD for assessing risk via the inhalation route. **4.5.2 Recommendations**  **for Combining Exposure Routes** When there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. T here are no residential incidental oral (i .e., hand to mouth) exposures to cy prodinil, therefore, aggregate exposure from food and incidental oral exposures is not required. However, an aggregate risk assessment of combined short - term inhalation and background dietary exposure is required for res idential handlers because PODs selected for these exposure routes are based on common toxicological effects (i.e., liver effects). **4.5.3 Classification of Carcinogenic Potential**  Based on the lack of evidence of carcinogenicity i n mice and rats at doses that were judged to be adequate to assess the carcinogenic potential, cy prodinil was classified by the HED Hazard Id entification Assessment Review Committee (HIARC) (TXR number 0051 401 ) as “not likel y to be carcinogenic to humans.” **4.5.4 Summary of**  **Points of Departure Used in Risk Assessment**  Toxicological doses/endpoints selected for the cyprodinil risk assessment are provided in Table 4.5.4.1 and 4.5.4.2.Page **20** of **54 Table**  **4.5.4.1 .**  **Summary of Toxicological Doses and Endpoints for Cyprodinil for Use in Dietary Hum an Health Risk**  **Assessments Exposure/Scenario**  **Point of Departure**  **Uncertainty/F**

**QPA Safety Factors**  **RfD, PAD, LOC**

**for Risk Assessment**  **Study and Toxicological Effects** Ac ute Dietary (All Populations) NOAEL = 200 mg/kg UF A= 10x

UF H =10x FQPA SF= 1x Ac ute RfD = 2.0

mg/kg aPAD = 2.0 mg/kg/day Ac ute Neurotoxicity - Rat

LOAEL = 600 mg/kg based on clinical signs of toxicity (hunched posture, pilorection, and reduced responsiveness to sensory stimuli, reduced motor activity and hypothermia) Chronic Dietary (All Populations) NOAEL= 2.7 mg/kg/day UF A= 10x

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

0.027 mg/kg/day cPAD = 0.027mg/kg/day 2 - Year Chronic Toxicity/ Carcinogenicity - rat

LOAEL = 35.6 mg/kg/day based on degenerative liver lesions (spongiosis hepatitis) in males. Cancer (all routes) Classification: “Not likely to be carcinogenic to humans” (TXR 0051401 ) 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 o bserved 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). SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose.
**Table 4.5.4.2**  **. Summ ary of Toxicological Doses**  **and Endpoints for Cyprodinil for Use in Non -**  **Dietary Hum an Health Risk**  **Assessments Exposure/Scenario**  **Point of Departure**  **Uncertainty**

**Factors Level of Concern** 

**for Risk Assessment**  **Study and Toxicological Effects** Dermal Short - Term (1 - 30 days) No dermal or systemic toxicity was seen following repeated dermal application at the highest dose tested for 21 days to rabbits. Therefore a POD for dermal exposure was not selected. Inhalation Short - / Intermediate Term (1 - 30 days) Oral NOAEL= 62 mg/kg/day (inhalation absorption rate = 100%) Residential:

UF A = 10x UF H = 10x FQPA SF = 10X* Occupational: UF A = 10x UF H = 10x UF DB = 10X Residential LOC

for MOE = 1,000 Occupational LOC for MOE = 1,000 28 - Day Feeding/Range - Finding - Rat LOAEL = 299 mg/kg/day based on decreased body - weight gain, increased cholesterol and phospholipid levels, microcytosis, and hepatocyte hypertrophy. The POD of 62 mg/kg/day is appropriate and protective for the longer - term intermediate exposure scenario since there is no progr ession of toxicity observed in the 90 - day SCN study where the NOAEL is 54 mg/kg/day based on decreased body weight gain, hepatocyte hypertrophy, kidney tubular casts, thyroid follicular cell hypertrophy at the LOAEL of 600 mg/kg/day. Cancer (all routes) Not likely human carcinogen Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = lack of inhalation study. SF = FQPA Safety Factor MOE = margin of exposure. LOC = level of concern . * FQPA SF is composed of the 10X factor for the inhalation study data gap.Page **21** of **54**

**5.0 DIETARY AND DRINKING WATER EXPOSURE**  **AND RISK ASSESSMENT**  **5.1 Metabolite/Degradate Residue Profile**  **5.1.1 Summary of Plant**  **and Livestock Metabolism Studies**  The nature of the residue in plants is adequatel y understood based on acceptable metabolism studies on apple, peach, potato, tomato, and wheat. The nature of the residue in ruminants is adequatel y understood based on acceptable lactating goat metabolism studies. A poultry metabolism study

is not available but is not required for this action sinc e there are no poultry feed stuffs associated with the proposed new use of cy prodinil on leafy

petiole group 4B. The nature of the residue in confined rotational crops is understood. **5.1.2 Comparison of Metabolic Pathways**  Based on acceptable metabolism studies on apple, peach, potato, tomato, and wheat, cy prodinil is metabolized primarily

by hydrox yl ation followed by sugar conjugation. Cleavage of the amino bridge, opening of the p yrimidine ring, opening of the cycloprop ylring and formation of thiolactic acid conjugates are minor pathway s. The metabolism of cy prodinil in ruminant proceeds predominantl y via hydrox yl ation followed by conjugation with sulfuric and glucuronic acid. Breakdown of the py rimidinyl ring was seen only in the liver an d resulted in Metabolite L1. Cleavage of the amino bridge between the phenyl and the py rimidinyl rings was only

a minor reaction as indicated by the small amounts of CGA 249287 found in the liver and kidney s of goats dosed with [ 14 C - py rimidinyl] cy

prodinil. Free and conjugated CGA - 304075 was a major residue in muscle, liver, kidney , and milk based on acceptable lactating goat metabolism studies using [ 14 C - phenyl] and [ 14 C - py rimidinyl] cy

prodinil. In metabolism studies in rats, cy prodinil was alm ost completely metabolized by

hydrox yl ation of the phen ylring or py

rimidine ring, followed b y conjugation. An alternative pathway involved oxidation of the phenyl ring followed by glucuronic acid conjugation. In the rat study , eleven metabolites were is olated from urine, feces and bile, and the metabolic pathway s in the rat were proposed. All urinary

and biliary

metabolites but one were conjugated with glucuronic acid or sulfonated, and excreted. CGA 304075 was not separately identified as an isolated metabolite in the rat study . **5.1.3 Environmental Fate and Transport**  The environmental fate data base for cy prodinil is substantially

complete. Cy

prodinil has a relativel y low solubility

in water. Based on its octanol/water partition coefficient, it is likely to partition with organic tissues and other organic media. It is alkaline in water. It is not likely to volatilize substantially

based on its low vapor pressure and Henry ’s Law constant. Cy prodinil appears to bind strongl y t o particulate an d sediment, showing relatively low soil mobility . It appears to be a persistent compound under most conditions, except aerobic soil metabolism, as demonstrated in laboratory studies. Its potential for groundwater contamination appears to be low. Howeve r, due to its high persistence under aquatic conditions, aquifers that lie below areas that have low organic content and coarse textured soils or shallow leaky aquifers could be pronePage **22** of **54**

to contamination. Even though buffer zones can ameliorate moderately th e level of spray

drift, the potential for runoff still exists for long periods of time. Cy prodinil has a high affinity to sorb to soil and particulate suggests the potential for runoff in eroded particles. This stability and binding to particulate and organic matter (aerobic and anaerobic conditions) suggests that cy prodinil residues in sediments could contribute to a possible resuspension of the compound through mixing and mass balance for an extended period. Degradates of cyprodinil include 4 - cycloprop yl - 6 - methyl - 2 - amine - py rimidine, CGA - 275535 (slightly mobile), CGA - 321915 (mobile to moderatel y mobile), and CGA - 249287 (moderatel y mobile) (degradate identified of concern in this assessment; 11.7% at 28 day s in the aerobic soil metabolism study , and 14.2% in the aerobic aquatic metabolism study ). The water residues of concern are the parent and CGA 249287 (4 - cyclopropyl - 6 - methylpy rimidin - 2 - amine) (D292557, 6/8/03). **5.1.4 Residues of Concern**  **Summary and Rationale** Residues of concern for dietary and drinking water risk assessment and tolerance expression for cy prodinil are provided in Table 5.1.4 . HED has concluded that the residues of concern for livestock for both risk assessment and the tolerance definition shou ld include the combined residues of cy

prodinil and free and conjugated CGA - 304075 (4 - [(4 - cyclopropyl - 6 - methylpy rimidin - 2 - yl )amino] - phenol, expressed in parent equivalents (D345970 and D345182, G. Kramer, 6/4/08). The water residues of concern are the parent and CGA 249287 (4 - cyclopropyl - 6 - methylpy

rimidin - 2 - amine) (D292557, 6/8/03). **Table 5.1.4. Summary of Metabolites and Degradates to be included in the Risk Assessment and**  **Tolerance Expression for**  **Cyprodinil Matrix**  **Risk Assessment Tolerance**  **Expression** Plants cy

prodinil cy prodinil Livestock cy

prodinil and CGA - 304075 cy prodinil and CGA - 304075 Water cy

prodinil and CGA 249287 NA **5.2 Food Residue Profile**  **5.2.1 Residues in Crops**  Following four applications of a 2.09 lb ai/gal EW formulation at a total application rate of 1.30

– 1.33 lbs ai/A, individual sample (and per - trial average) residues of cy prodinil were 0.08

–0.62 ppm (0.11

–0.58 ppm) in/on cucumber fruit collected at a PHI of 0 day s. There were no significant differences between the residues in the large variety cucumbers vs. the small variety cucumbers. Following four or five applications of a 2.09 lb ai/gal EW formulation at a total application rate of 1.300

– 1.655 lbs ai/A, individual sample (and per - trial average) residues of cy prodinil were 0.825

– 1.52 ppm (0.932

– 1.33 ppm) in/on mature globe artichoke flower buds collected at a PHI of 3 day s. There were no significant differences between the residues in the perennial gl obe artichokes vs. the annual globe artichokes.Page **23** of **54**

Following four applications of Switch ® 62.5WG at a total application rate of 1.31

– 1.43 lbs ai/A, individual sample (and per - trial average) residues of cy prodinil were 0.345

–0.626 ppm (0.353

– 0.522 ppm) in/on guava fruit collected at a PHI of 0 day s. Data reflect three different post - harvest treatment scenarios/techniques of 1 or 2 applications using a water dispersible granule (WDG) formulation of cy prodinil (Switch ® 62.5WG. Each of these post - harvest scenarios/techniques are considered separate/discrete datasets for tolerance determination. Following one application as a dip with wax at 0.45 lb ai/100 gal, individual sample (and per - trial average) residues of cy prodinil were 0.24 - 1.60 ppm (0.93 - 1.52 p pm) in/on pomegranate collected on the day of treatment. Following a total of two applications, one application as a dip with wax at 0.45 lb ai/100 gal and a second application as a dip with no wax at 0.45 - 0.46 lb ai/100 gal, individual sample (and per - trial average) residues of cy prodinil were 2.22 - 3.60 ppm (2.56 - 3.42 ppm) in/on pomegranate treated and collected on the same day . Following a total of two applications, one application as a dip with wax at 0.45 - 0.46 lb ai/100 gal and then a drench applicati on with no wax at 0.45 - 0.46 lb ai/100 gal, individual sample (and per trial average) residues of cy prodinil were 0.38 - 2.69 ppm (0.53 - 2.25 ppm) in/on pomegranate treated and collected on the same day . Side - by- side field trial data on lettuce, mustard gre ens and tomatoes comparing residues of cy prodinil resulting from multiple late season uses of the EW formulation with a WDG formulation of cy

prodinil are available ( DP# 354013, 3/20/09, B. Cropp - Kohlligian). C yprodinil residues were similar for the EW and WDG formulations on all three crops. The previousl y submitted stone fruit field trial data and processing data are adequate to support the proposed expansion of those uses to stone fruit group 12 - 12 . No additional data are required. The recommended t olerance for residues of cy prodinil in/on fruit, stone, group 12 - 12 (2. 0 ppm) is the same as the petitioned - for tolerance. **5.3 Water Residue Profile**  **5.3. 1**  **Estimated Drinking Water Concentrations** Drinking water residues were incorporated directly into the acute and chronic dietary analy ses as “water, direct, all sources” and “water, indirect, all sources” and were provided by the Environmental Fate and Effects Division (EFED) (D421158, J Melendez 1 /12/15). The tier 2 aquatic models PRZM (Pesticide Root Zone Model) - EXAMS (Exposure Analy sis Modeling Sy stem), and the models Screening Concentration in Ground Water ( SCI - GROW ) and Pesticide Root Zone Model for Groundwater ( PRZM - GW ) w ere used to obtain es timated drinking water concentrations ( EDWCs ) in surface water and groundwater, respectivel y. The acute EDWC in surface water is 34.8 μg/Lfor the total residues of cy prodinil plus CGA - 249287. The chronic EDWC in surface waters is 24.7 μg/Lfor the total residues of cy prodinil and CGA - 249287. The cancer/chronic EDWC in surface waters is 16.4 μg/Lfor the total residues of cy prodinil and CGA - 249287. All surface waters EDWCs were obtained using the New York grapes PRZM scenario. The PRZM - GW generated EDW C for the use on grapes, using the FL citrus surrogate scenario were 2.05 μg/Lfor the total residues of cy prodinil and CGA - 249287 (acute) and 1.80Page **24** of **54**

μg/Lfor the total residues (chronic). For details on methods, characterization of results, uncertainties, etc., please, refer to the previous DWAs. Table 5.3.1 provides a summary of the Tier 2 modeled drinking water concentrations. **Table 5.3.1**  **. M**  **axim um** **E stimated**  **Drinking Water**  **Concentrations for**  **the Use**  **of Cyprodinil**  **(expressed as**  **total residues of cyprodinil plus its degradate CGA**  **- 249287)**  **DRINKING WATER SOURCE (MODEL USED)**  **USE (rate modeled per year**  **) MAXIMUM ESTIMATED DRINKING WATER**  **CONCENTRATION (EDWC) ( ppb**  **)** Groundwater ( PRZM - GW ) FL citrus 1 (1.4 lb a.i.) Ac ute 2.05 Chronic 1.80 Surface water (PRZM/EXAMS) NY grapes (1.4 lb a.i.) Ac ute **34.8** Chronic **24.7** Cancer/Chronic 16.4 1 Scenario wa s used as a surrogate and run with the maximum application rate for grapes. **5 .**  **4 Dietary and Drinking Water Exposure and Risk**  Screening level acute and refined chronic dietary and drinking water exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity

Intake Database DEEM - FCIDTM, Version 3.16, which incorporates cons umption data from USDA’s National Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008. Dietary risk assessment incorporates both exposure and toxicity of a given pesticide. For acute and chronic dietary

assessments, the risk is expressed as a percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result in no unreasonable adverse health effects). This dose is referred to as the population adjus ted dose (PAD). The PAD is equivalent to the reference dose (RfD) divided b y the additional Safety Factor, if applied. For acute and non - cancer chronic exposures, HED is concerned when estimated dietary risk exceeds 100% of the PAD. **5 .**  **4 .1**  **Acute Dietar y and Drinking Water Analysis**  A new dietary

assessment was conducted for the proposed new use s . The proposed use s results dietary risk estimates below HED’s level of concern; see Table 5.4.1 .1 . The highest is children 1 - 2 ye ars resulting in 8.6 % of the aPAD.

**Table 5.4.1 .1**  **. Summ ary of Acute Dietary (Food plus Water) Exposure and Risk for**  **Cyprodinil at the 95**  **th Percentile.** Page **25** of **54**

**Population Subgroup aPAD (m**  **g/kg) Exposure (mg/kg)**  **%aPAD** General U.S. Population

2.0 0.095198 4.8 All Infants (< 1 year old) 0.101588 5.1 **Children 1 -**  **2 years old 0.**  **172629 8.6**  Children 3 - 5 years old 0.158663 7.9 Children 6 - 12 years old 0.083374 4.2 Youth 13 - 19 years old 0.071553 3.6 Adults 20 - 49 years old 0.091866 4.6 Adults 50 - 99 years old 0.091595 4.6 Females 13 - 49 years old 0.096706 4.8 The bolded %aPAD is the highest. **5 .**  **4 .2**  **Chronic Dietary and Drinking Water Analysis** A new dietary

assessment was conducted for the proposed new use s of cy prodinil and results in dietary risk estimates below HED’s level of concern; see Table 5.4.2 . **Table 5.4.2. Summary of Chronic Dietary (Food plus Water) Exposure and Risk for cyprodinil**  **. Population Subgroup**  **cPAD (m g/kg/day)**  **Exposure (mg/kg/day) %cPAD**  General U.S. Population

0.027 0.007794 29 All Infants (< 1 year old) 0.013042 48 **Children 1 -**  **2 years old 0.023**  **045 85**  Children 3 - 5 years old 0.016592 62 Children 6 - 12 years old 0.008522 32 Youth 13 - 19 years old 0.004665 17 Adults 20 - 49 years old 0.006327 23 Adults 50 - 99 years old 0.007772 29 Females 13 - 49 years old 0.006706 25 The bolded %cPAD is the highest. **6 .0**  **RESIDENTIAL EXPOSURE AND RISK ASSESSMENT** The proposed uses will not result in residential exposure; however, there is a currently registered ornamental use that has been previousl y evaluated to reflect updates to HED’s 2012 Residential Standard Operating Procedures (SOPs) ( D398361, I . Nieves, 5/3/12) . No risk estimates of concern were identified. The updated results for the residential use impacting the aggregate are presented below i n table 6 .0 for reference purposes. Post - application exposure was not quantified since no dermal endpoint was identified for cy prodinil.

**Table 6**  **.0. Residential Handler Inhalation Exposure and Risk Estimates for Cyprodinil.** Page **26** of **54**

**Application Site**  **Application**

**Equipment Max** 

**Application Rate**  **a Am**  **ount**

**AI Handled**  **b Unit** 

**Exposures c**  **(m g/lb ai)**  **Absorbed**

**Daily Dose d**  **(m g/kg**  **- day)**  **MOE e** 

**LOC=100 0**  **( lb ai/gallon**  **solution) (gallons** 

**solution)** Ornamentals Manually pressurized Handwand 0.00141 5 1.1 0.000098 640,000 Hose - end Sprayer 11 0.0014 0.00000027 230,000,000 Backpack 5 1.1 0.000098 640,000 a. Application Rate based on proposed use on label for PalladiumTM Fungicide (EPA Reg. No. 100 - 1328). b. Based on 2012 Residential SOPs. c. Unit Exposures based on 2012 Residential SOPs. d. Inhalation Dose (mg/kg/day) = daily unit exposure (mg/ lb ai) * application rate (lb ai/gallon) * amount handled (gallons) / body weight (80 kg); e. Inhalation MOE = PoD (NOAEL of 62 mg/kg/day) / Daily inhalation dose (mg/kg/day). Level of concern = 1000. **6.1 Residential Bystander Postapplication Inhalation Exposure**  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 Scientific Advisory

Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipol y/ SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screenin g Tool and a subsequent Volatilization Screening Analy sis (http://www.regulations.gov/#!docketDetail;D=EPA - HQ - OPP - 2014 - 0219 ). During Registration Review, the agency wil l utilize this analy sis to determine if data (i.e., flux studies, route - specific inhalation toxicological studies) or further analy sis is required for cy prodinil. **6.2 Spray Drift**  Spray drift is a potential source of exposure to those nearby pesticide app lications. This is particularl y the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) emplo yed for cyprodinil. The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call - In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency ’s Spray Drift website for more information). The agency has also developed a policy on how to appropriatel y consider spray

drift as a potential source of exposure in risk assessments for pesticides . The potential for spray

drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently . The approach is outlined in the revised (2012) Stan dard Operating Procedures For Residential Risk Assessment (SOPs)
- Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non - occupational exposure to drift.Page **27** of **54**

**7 .0**  **AGGREGATE EXPOSURE AND RISK ASSESSMENT** In accordance with the FQPA, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major routes: oral, dermal, and inhalation. There are three sources for these types of exposures: food, drinking water, and residential uses. In an aggregate assessment, exposures from relevant sources are risks themselves and can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. Since there are no resid ential incidental oral (i.e., hand to mouth) exposures to cy prodinil based on existing registered products and use patterns, aggregate exposure from food and incidental oral exposures is not required. Short - term residential handler exposures are expected based on current use patterns. Intermediate - term residential exposures are not anticipated. An aggregate risk assessment of combined short - term inhalation and oral (dietary and drinking water) exposure is required for residential handlers because PODs se lected for these exposure routes are based on common toxicological effects (i.e., liver effects). T he acute and chronic exposure estimates from the dietary exposure analy ses represent aggregate risk for acute and chronic exposures and are not of concern. **7.1 Acute & Chronic Aggregate Risk**  Acute and chronic aggregate exposures include food plus drinking water exposures. As demonstrated under Section 5. 4, acute and chronic aggregate risks are not of concern. **7.2 Short**  **- Term Aggregate Risk**  Short term aggregate exposure takes into account residential exposure plus average exposure levels to food and water (considered to be a background exposure level). The short term aggregate risk for residential handlers is the estimated risk associated w ith combined risks from average food and drinking water exposures and inhalation exposures to adult applicators. Short term aggregate risk estimates for residential handlers are provided in Table 7.2 . Aggregate margins of exposure (MOEs) are not of concern. **Table 7.2**  **. Short -**  **Term Aggregate Risk Assessment for Cyprodinil**  **Residential Handler Exposure Scenario**  **Food + Water Exposure (m**  **g/kg/day) 1**  **Short -**  **Term Residential**

**Exposure, (mg/kg/day) 2**  **MOE Food + Water + Residential**  **3 Mixing/Loading/Applying WDG** 
**– Ornamentals**  Manually - pressurized Handwand 0.007 8 0.000098 79 00 Hose - end Sprayer 0.00000027 Backpack 0.000098 **1** Chronic Dietary/Drinking Water Exposure (mkd) (Adults 50+ years old) **2** Residential Exposure = I nhalation Daily Dose (mkd) **3** Aggregate Food/Water/Residential MOE = I nhalation Short - term endpoint (NOAEL 62 mkd)/ Food & Water Exposure (mkd) + Residential Exposure (mkd)
**7. 3**  **Intermediate -**  **Term Aggregate Risk**Page **28** of **54**

There are no residential use scenario s that will result in potential intermediate term exposure to cy prodinil . Therefore, an intermediate - term aggregate was not performed. **8.0 CUMULATIVE RISK**  Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify , or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide's residues and “other substances that have a common mechanism of toxicity .” EPA does not have, at this time, available data to dete rmine whether cy prodinil has a common mechanism of toxicity

with other substances. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity , EPA has not made a common mechanism of toxicity findi ng as to cy

prodinil and any

other substances and, cy prodinil does not appear to produce a toxic metabolite produced by other substances which have tolerances in the U. S. For the purposes of this tolerance reassessment action, therefore, EPA has not assum ed that cy prodinil has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/fedrgstr/EPA_PEST/2002/January /Day _16/ . **9 .0**  **OCCUPATIONAL EXPOSURE /** **RISK CHARACTERIZATION**  **9 .1**  **Exposure Scenarios**  Occupational exposure scenarios on artichoke, guava, passionfruit, feijoa, jaboticaba, wax jambu, starfruit, acerola, tomato (small), and stone fruit, group 12 - 12 have been previousl y evaluated at the same rate (i.e., 0.33 lb ai/A) for the same registered end - use products than currentl y proposed ( D398361, I . Nieves, 5/3/12) . No estimated risks of concern were identified at label required PPE (i.e., filtering piece respirator). MOEs were above the Agency ’s LOC (MOEs >LOC=1000) and ranged from 1,500 to 990,000 for short - and intermediate - term durations. Occupational exposure risk potential scenarios for uses on cucumber grown in greenhouses have also been assessed on a previous memo ( D362494, I . Nieves, 8/4/09), at the same application rate (i.e., 0.33 lb ai/A) but to account for a difference in formulation (i.e., liquid instead of the dry flowable previously

assessed) an d recent updates to unit exposures and body weight assumptions, an updated quantification of risks for the proposed use is presented below. The post - harvest use on pomegranates have never been assessed before therefore an occupational assessment for this use was performed and presented below.Page **29** of **54**

**9 .**  **2 Handler**  **Exposure** The term “handler” applies to individuals who mix, load, and apply the pesticide product. There is a potential for exposure to cy prodinil during mixing, loading, and application activities through the inhalation route. Cy prodinil products are applied using groundboom and chemigation equipment. **9.2.1 Handler Exposure Scenarios**  HED uses the term handlers to describe those individuals wh o are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each app lication), the kinds of equipment used, the target being treated, and the level of protection used b y a handler can cause exposure levels to differ in a manner specific to each application event. Based on the anticipated use patterns and current labeling, typ es of equipment and techniques that can potentially

be used, occupational handler exposure is expected from the proposed uses on cucumber grown in greenhouses and post - harvest use on pomegranates. For the proposed post - harvest use on pomegranates, the quantitative exposure/risk assessment developed for occupational handlers is based on the mixing/loading water dispersable granules (WDG) or a dry flowable formulation (DF) for automated s ys tem exposure scenario and a mechanically pressured handgun. A separate applicator assessment was not conducted as the application of cy prodinil is mechanically

automated for the in - line dip/drench wash tanks. A mixer/loader assessment was performed and is considered to result in a conservative estimate of handler ri sk. **9.2.2 Handler**  **Exposure Data** A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments. Each assumption and factor is detailed below on an individual basis. **9.2. 3**  **Handler Exposure Assumptions**  A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments. Each assumption and factor is detailed below on an individual basis. Application Rate : The application rate is the maximum rate identified on the proposed Inspire Super® and Switch ® 62.5WG labels (See Section 4.0) for cucumbers grown in greenhouses and post - harvest pomegranates, accordingly . Unit Exposures: It is the policy of HED to use the best available data to ass ess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical - specific data, include PHED 1.1, the AHETF database, the ExpoSAC “Assessment of Occupational Exposure for Post - Harvest Commodity Pesticide Treatments” (M. Crowley , 3/23/2012), 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. The standard values recommended forPage **30** of **54**

use in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 1 ”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 2

. Amount Handled: Information on amount handled per day was taken from HED ExpoSAC Policy /Guidance “Assessment of Occupational Exposure for Post - Harvest Commodity Pesticide T reatments” (M. Crowley , 3/23/2012). Since the label specifies the application rate as a % solution and does not provide information on the amount of commodity to be treated, a default estimate of 25,000 gallons was used. Exposure Duration: HED classifi es exposures from 1 to 30 day s as short - term and exposures 30 day s to six months as intermediate - term. Exposure duration is determined by man y things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one - month time frame; however, there may be a large agribusi ness and/or commercial applicators who may appl y a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region). For cy prodinil, based on the proposed use pattern, short - and intermediate - term exposures are expected. Mitigation/Personal Protective Equipment: Estimates of dermal and inhalation exposure were calculated for various levels of PPE. Results are presented for “baseline,” defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator. Occupational Handler Non - Cancer Exposure and Risk Estimate Equations The algorithms used to estimate non - cancer exposure and dose for occupational handlers can be found in Appendix A. **9.2. 4**  **Handler Exposure and Risk**  **Estimates** Summary of Occupational Handler Non - Cancer Exposure and Risk Estimates Table 9.2.4.1 provides a summary of the estimated exposures and risks to occupational pesticide handlers for the proposed use on cucumbers grown in greenhouses. An MOE ≥ 1000 was selec ted to protect occupational pesticide handlers from inhalation exposure (TXR# 0054812, K. Rury , 3/29/12) . Occupational handler risk estimates resulted above HED’s LOC of 1,000 and therefore not of concern. At baseline, the occupational handler inhalation MOEs range from 1,300 to 1,100,000, depending on the scenario. **Table 9.2.4**  **. 1.**  **Occupational Exposure Risk Estimates for Cyprodinil Use on Cucumbers Grown in Greenhouses.** 

1 Available: http://www.epa.gov/opp00001/science/handler - exposure - table.pdf 2 Available: http://www.epa.gov/pesticides/science/handler - exposure - data.htmlPage **31** of **54**

**Application Equipment**  **Max**

**Application Rate**  **1 Area** 

**Treated 2**  **Inhalation Unit**

**Exposure 3**  **(ug/lb ai) Short**  **- & Intermediate**  **- Term**  **Inhalation Mitigation Level**  **Dose 4** 

**(m g/kg**  **- day)**  **MOE 5** 

**LOC=1,000 Mixer/Loader**  Chemigation/ Groundboom 0.33

lb ai/acre 60

acres 0.219 0.000054 1,100,000 **Applicator** Groundboom 0.33

lb ai/acre 60

acres 0.34 0.000084 740,000 **Mixer/Loader/Applicator** Backpack 0.033

lb ai/gallon 40

gallons 140 0.0023 27,000 Manually - pressurized Handwand 30 0.000495 130,000 Mechanically pressurized Handgun 1000 gallons 120 0.0495 1,300 1 Based on registered or proposed label (Reg. No.100 - 1317). 2 Exposure Science Advisory Council Policy #9.1. 3 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (May 2013 ); Level of mitigation: Baseline = Long - sleeved shirt, long pants, shoes plus socks and no resp irator. PF10 R = filtering facepiece respirator 4 Inhalation Dose = I

nhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/gal) × Amount Handled (gal/day) ÷ BW (80 kg). 5 ST& IT I

nhalation MOE = I

nhalation NOAEL (6 2 mg/kg/day) ÷ I nhalation Dose (mg/kg/day). Table 9.2.4 .2 provides a summary of the estimated exposures and risks to occupational pesticide handlers for the proposed use on post - harvest pomegranates. An MOE ≥ 1000 is considered protective to occupational pesticide handlers from inhalation exposure (TXR# 0054812, K. Rury , 3/29/12) . Inhalation exposure risk estimates scenarios for this proposed use resulted above HED’s LOC of 1,000 at baseline. MOEs resulted in 4,900 and 11,000.

**Table 9.2.4.2**  **. Occupational Handler Non -**  **Cancer Exposure and Risk Esti mates**  **for Post -**  **harvest Use on Pomegranates** .

**Exposure Scenario**  **Inhalation Unit Exposure**  **(μg/lb ai) 1**  **Ma x.**  **App. Rate**

**(lb ai/gal solution)**  **2 Am**  **ount Handled**

**Daily (gal/day)**  **3 Short**  **- &** 

**Intermediate -**  **Term Inhalation**  **Mitigation Level: Baseline**  **Dose (m**  **g/k g/day)**  **4 MOE**  **5**

**LOC=1000 Mi** **xer/Loader**Page **32** of **54**

**Table 9.2.4.2**  **. Occupational Handler Non -**  **Cancer Exposure and Risk Esti mates**  **for Post -**  **harvest Use on Pomegranates** .

**Exposure Scenario**  **Inhalation Unit Exposure**  **(μg/lb ai) 1**  **Ma x.**  **App. Rate**

**(lb ai/gal solution)**  **2 Am**  **ount Handled**

**Daily (gal/day)**  **3 Short**  **- &** 

**Intermediate -**  **Term Inhalation**  **Mitigation Level: Baseline**  **Dose (m**  **g/k g/day)**  **4 MOE**  **5**

**LOC=1000** WDG for Automated System 8.96 0.0045 25,000 0.013 4,900 **Mi xer/Loader/Applicator**  WDG for Mechanical Pressure

Handgun 3.9 0.0045 25,000 0.0055 11,000 1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( May 2013 ); Level of mitigation: Baseline = Long sleeved shirt, long pants, shoes plus socks and no respirator. PF10 R = Long - sleeved shirt, long pants, shoes plus socks and a filtering facepiece respirator 2 Based on registered or propo sed label (Reg. No.100 - 953). 3 HED ExpoSAC Policy/Guidance “Assessment of Occupational Exposure for Post - Harvest Commodity Pesticide Treatments.” 4 Inhalation Dose = I

nhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate ( lb ai/gal) × Amount Handled (gal/day) ÷ BW (80 kg). 5 ST & IT I

nhalation MOE = I

nhalation NOAEL (62 mg/kg/day) ÷ I nhalation Dose (mg/kg/day). **9 .3**  **Post Application Exposure**  HED uses the term post - application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities relate d to crop production, such as scouting for pests or harvesting ; or in the case of post - harvest applications, sorting and packing fruit after it has been treated . Post - application exposure levels vary over time and depend on such things as the ty pe of acti vity , the nature of the crop or target that was treated, the ty pe of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatl y reduce the potential for post - application exposure. **9.3.1 Post Application Exposure Scenarios**  For the proposed use on cucumbers grown in greenhouses, although a quantitative 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 result in higher exposure than post - application exposure. Therefore, it is expected that these handler inhalati on exposure estimates would be protective of most occupational post - application inhalation exposure scenarios. The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and aft er greenhouse applications through the use of ventilation requirements.[40 CFR 170.110, (3) (Restrictions associated with pesticide applications)] During automated treatments, for the proposed use on post - harvest pomegranates, inhalation exposure is antic ipated for workers performing sorting and packing tasks. Since the workers experience exposure following the treatment, this is technically “post - application” exposure; however, unlike other post - application activities (e.g., harvesting, scouting, etc.), this treatmentPage **33** of **54**

is not governed b y the Worker Protection Standard (WPS) and potential re - entry intervals (REI s). Additionally , for workers in the warehouse or packaging facility not directly

involved in the automated treatment process, there is potential f or indirect inhalation exposure. Exposures for these various scenarios are assessed using HED ExpoSAC Policy /Guidance “Assessment of Occupational Exposure for Post - Harvest Commodity Pesticide Treatments” (M. Crowley , 23 - MAR - 2012). **9.3.2 Post Applicatio**  **n Exposure Assumptions** A series of assumptions and exposure factors served as the basis for completing the occupational post - application risk assessments. Each assumption and factor is detailed below on an individual basis. Exposure Duration: HED classifies exposures from 1 to 30 day s as short - term and exposures 30 day s to six months as intermediate - term. For cy prodinil, based on the proposed use pattern, short - and intermediate - term exposures are expected. Application Rate: The application rate is the maximum rate identified on the proposed Switch ® 62.5WG label (See Section 4.0). Exposure Time: The average occupational workday is assumed to be 8 hours. **9.3.3 Post**  **- Application Exposure and Risk Estimates**  Occupational Post - ap plication Non - Cancer Risk Estimates: Table 9.3.3 .1 summarizes exposure and risk estimates from post - application inhalation exposure for sorter and packers. Table 9.3.3 .2 provides a summary for post - application indirect inhalation exposure risk estimates. No risk estimates of concern (MOEs > LOC of 1,000) were identified at baseline for short - and intermediate - term durations for all scenarios. MOEs resulted in 15,000 for direct inhalation exposure, and 320,000 for indirect inhalation exposure. **Table 9.3.3**  **. 1. Occupational Post**  **- application Inhalation Exposure and Risk Estimates for Cyprodinil on Pomegranates.**  **Activity Ma** **x App. Rate**  **1 (%**  **ai in solution)**  **Unit Exposure**  **2 (ug/% ai)**  **Short -**  **& Intermediate**  **- term**  **Inhalation Mitigation Level**  **Dose (m**  **g/kg -**  **day) 3**  **MOE 4** 

**LOC=1,000** Sorter 0.05 6720 0.0042 15,000 Packer 6760 0.0042 15,000 1. Percent cyprodinil in solution: (19.2 oz/100 gal) x (1 lb/16oz) x (37.5% cyprodinil formulation) x (H2 O density: 8.329 lb/gal) x 100 = 0.05% 2. Based on Table 2 in ExpoSAC Policy/Guidance “Assessment of Occupational Exposure for Post - Harvest Commodity Pesticide Treatments” (M. Crowley, 3/23/2012); Level of mitigation: T - shirt and NR = no respirator; PF10 Respirator = filtering facepiece respirator. 3. I nhalation Dose = [Uni t Exposure (μg/% ai) * Application Rate (% ai in solution) * Adjustment Factor (0.001 μg/mg)] ÷ Body Weight (80 kg). 4. I nhalation MOE = I

nhalation POD (62 mg/kg/day)/I nhalation Dose. **Table 9.3.3**  **.2. Occupational Post -**  **application Indirect Inhalation Expos ure and Risk Estimates for**  **Cyprodinil. Crop/Site**  **Max App. Rate**

**(% ai in solution) Short**  **- &**  **Intermediate -**  **Ter m**  **Inhalation**Page **34** of **54 Unit Exposure**  **(μg/% ai) 1**  **Dose**

**(m g/kg/day)**  **2 MOE**  **3 Mitigation Level**  Pomegranates 0.05 307 0.0002 320,000 1. Based on Table 2 in ExpoSAC Policy/Guidance “Assessment of Occupational Exposure for Post - Harvest Commodity Pesticide Treatments” (M. Crowley, 3/23/2012); Level of mitigation: T - shirt and NR = no respirator. 2. I nhalation Dose = [Unit Exposure (μg/% ai) * Application Rate (% ai in solution) * Adjustment Factor (0.001 μg/mg)] ÷ Body Weight (80 kg). 3. I nhalation MOE = I

nhalation POD (62 mg/kg/day)/I nhalation Dose. No dermal or s ys temic toxicity was seen following repeated de rmal application at the highest dose tested for 21 day s to rabbits. Therefore, a POD for dermal exposure was not selected and a dermal assessment was not quantified.Page 35 of 54

**9.3. 4**  **Restricted Entry Interval** Cy prodinil is classified as Toxicity Category I II for acute dermal and eye irritation, and Toxicity Category IV for skin irritation potential. Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye irrit ation and primary skin irritation are assigned a 12 - hour REI. Therefore, the REI of 12 hours required in the registered labels is adequate to protect agricultural workers from post - application exposures to cy prodinil . **10. REFERENCES**  Cy prodinil. Expansions of Existing Crop Group/Representative Commodity Uses to Stone Fruit Group 12 - 12, and Adding New Uses on the Artichoke, Guava, Pomegranate, Passionfruit, Feijoa, Jaboticaba, Wax Jambu, Starf ruit, and Acerola. Summary of Analytical Chemistry and Resi due Data. , T. Morton , D 4 21157 , 04 /23 /201 5 Cy prodinil

– Acute and Chronic Dietary and Drinking Water Exposure and Risk Assessment. T. Morton , D4 25997 , 07 / 01 /20 15 Cy prodinil. Occupational and Residential Exposure Assessment for a Proposed Uses on Cucumber (greenhouse), Artichoke, Guava, Passion fruit, Feijoa, Jaboticaba, Wax Jambu, Starfruit, Acerola, Pomegranate (post - harvest), Tomato (small), and Stone Fruit, Gro up 12 - 12. I. Nieves, D 425999 , 0 5 / 05 /2015 Estimated Drinking Water Concentrations for Cyprodinil and its Metabolite CGA - 249287 for the New Uses of the Chemical on Certain Stone Fruits (Crop Group 12 - 12), Certain Tropical Fruits, Artichoke, Cucumber (Greenhouse Use), and Pomegranate (Postharvest Dip) J. Melende z , D421158 , 1 / 1 2 /1 5Page 36 of 54

APPENDI CES **A TOXICOLOGY DATA SUMMARY**  **A .1**  **Guideline Data Requirements** 

**Guideline No.**  **Study Type Technical**  **MRID No. Require**  **d Submitte** 

**d** 870.3100 870.3150 870.3200 870.3250 870.3465 Subchronic (Oral) Toxicity - Rodent ................................ ...............................

Subchronic (Oral) Toxicity - Non - Rodent ................................ ....................... 21/28 - Day Dermal Toxicity ................................ ................................ 90 - Day Dermal Toxicity 90 - Day Inhalation Toxicity ................................ ................................ Y Y N N Y **1** Y

N Y N N 43709027

43709026 43709028 43709029 47526801
870.3700a 870.3700b 870.3800 Prenatal Developmental Toxicity - Rodent ................................

Prenatal Developmental Toxicity - Non - Rodent ................................ Reproduction and Fertility Effects ................................ ................................ Y Y Y Y

Y Y 43709033

43709032 43709034 870.4100a 870.4100b 870.4200a 870.4200b 870.4300 Chronic (Oral) Toxicity - Rodent ................................ ................................

Chronic (Oral) Toxicity - Non - Rodent (Dog) ................................ Carcinogenicity - Rat.................. ................................ ............................... Carcinogenicity - Mouse Com bined Chronic Toxicity /Carcinogenicity Y Y Y Y Y Y

Y Y Y Y 43737602

43709030 43737602 42710006 43737602 870.6100a 870.6100b 870.6200a 870.6200b 870.6300 870.7800 Neurotoxicity - Ac ute Delayed Neurotox. - Hen ................................

Neurotoxicity - Subchronic - Hen ................................ ................................ Neurotoxicity - Ac ute - Rat ................................ ................................ Neurotoxicity - Subchronic - Rat ................................ ................................ Developmental Neurotoxicity.................. Immunotoxicity............................. ................................ ......................... N N Y Y N Y N

N Y Y N Y ---

--- 48304202 45906101

--- 48304203 48293501 1 Based on WOE by HASPOC (TXR 0054812) A .2 Toxicity

Profiles **Table 1 Acute Toxicity of Cyprodinil. Guideline No.**  **Study Type MRIDs #**  **Results Toxicity**  **Category** 870.1100 Ac ute Oral 43709014 LD 50 = 2796 mg/kg III 870.1200 Ac ute Dermal 43709016 LD 50 > 2000 mg/kg III 870.1300 Ac ute Inhalation 43709018 LC 50 = 1.2 mg/L III 870.2400 Primary Eye Irritation 43709021 mild/mod irritant III 870.2500 Primary Skin Irritation 43709022 very slight irritant IV 870.2600 Dermal Sensitization 43709024 44392102 positive NA **Table 2. Toxicity Profile of Cyprodinil Technical.**Page 37 of 54

**Guideline No./ Study Type**  **MRID No. (year)/**

**Classification /Doses Results**  870.3100 90 - Day oral toxicity (mouse) 43709027 (1991)

Acceptable/guideline 0, 500, 2000, 6000 ppm M: 0, 73.3, 257, 849 mg/kg/day F: 0, 103, 349, 1121 mg/kg/day NOAEL = 73.3/103 mg/kg/day, M/F LOAEL = 257/349 mg/kg/day, M/F, based on histopathological changes in the liver

870.3100 90 - Day oral toxicity (rat) 43709026 (1991)

Acceptable/guideline 0, 50, 300, 2000, 12,000 ppm M: 0, 3.14, 19, 134, 810 mg/kg/day F: 0, 3.24, 19.3, 137, 803 mg/kg/day NOAEL =3.14 mg/kg/day LOAEL = 19 mg/kg/day based on increased tubular kidney lesions in males

Non - guideline 28 - Day Feeding/ Range Finding (rat) 43866301 (1989)

Acceptable/Non guideline 0, 100, 600, 3000, 15000 ppm M: 10.3, 64.8, 316, 1460 mg/kg/day F: 0, 10.1, 62.2, 299, 1390 mg/kg/day NOAEL = 64.8/62.2 mg/kg/day, M/F LOAEL = 316/299 mg/kg/day, M/F, based on lower body weight gains, microcytosis, increase cholesterol and phospholipid levels, and hepatocyte hypertrophy

Non - guideline 28 - Day Gavage/ Range Finding (rat) 43737601 (1991)

Acceptable/Non guideline 0, 10, 100 1000 mg/kg/day NOAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day based on increased liver weights and abnormalities in liver morphology
870.3150 90 - Day oral toxicity (dog) 43709028 (1991)

Acceptable/Guideline 0, 200, 1500, 7000, 20000 ppm M: 0, 6.07, 45.85, 210.33, 559.66 mg/kg/day F: 0, 6.79, 52.75, 231.93, 580.95 mg/kg/day NOAEL =210/232 mg/kg/day, M/F LOAEL = 560/581 mg/kg/day, M/F, based on lower body weight gains and decreased food consumption in both sexes

870.3200 21/28 - Day dermal toxicity (rat) 47526801 ( 008 )

A cceptable/ Guideline 0, 5, 25, 125, 1000 mg/kg/day NOAEL = 1000 mg/kg/day LOAEL = Not established

870.3700a Prenatal developmental (rat) 43709033 (1991)

Acceptable/Guideline 0, 20, 200, 1000 mg/kg/day **Maternal** NOAEL = 200 mg/kg/day LOAEL = 1000 mg/kg/day based on lower body weight/body - weight gain and reduced food consumption **Developm ental**  NOAEL = 200 mg/kg/dayPage 38 of 54

**Table 2. Toxicity Profile of Cyprodinil Technical. Guideline No./**  **Study Type MRID No. (year)/** 

**Classification /Doses Results**  LOAEL = 1000 mg/kg/day based on lower mean fetal weights and increased incidence of delayed ossification 870.3700b Prenatal developmental (rabbit) 43709032 (1991)

Acceptable/Guideline 0, 5, 30, 150, 400 mg/kg/day **Maternal** NOAEL = 150 mg/kg/day LOAEL = 400 mg/kg/day based on decreased body - weight gain **Developm ental**  NOAEL = 150 mg/kg/day LOAEL = 400 mg/kg/day based on slight increase of litters showing extra (13 th) ribs 870.3800 Reproduction and fertility effects (rat) 43709034 (1993)

Acceptable/Guideline 0, 10, 100, 1000, 4000 ppm M: 0, 0.7, 6.7, 68, 273 mg/kg/day F: 0, 0.8, 8.2, 81, 326 mg/kg/day **Maternal/System ic**  NOAEL = 81 mg/kg/day LOAEL = 326 mg/kg/day based on decreased body weight gain in the F0 females during the pre - mating period. **Reproductive/Developmental** NOAEL = 81 mg/kg/day LOAEL = 326 mg/kg/day based on decreased pup weights (F1 and F2)
870.4300 Chronic toxicity/ Carcinogenicity (feeding) (rat) 43737602 (1994)

Acceptable/Guideline 0, 5, 75, 1000, 2000 ppm M: 0, 0.177, 2.7, 35.6, 73.6 mg/kg/day F: 0, 0.204, 3.22, 41.2, 87.1 mg/kg/day NOAEL = 2.7 mg/kg/day LOAEL = 35.6 mg/kg/day based on degenerative liver lesions (spongiosis hepatis) in males **No evidence of carcinogenicity** 870.4100b Chronic toxicity (dog) 43709030 (1991)

0, 25, 250, 2500, 15000 M: 0, 0.72, 6.87, 65.35, 449.25 mg/kg/day F: 0, 0.76, 6.80, 67.99, 446.37 mg/kg/day NOAEL = 65.63/67.99 mg/kg/day, M/F LOAEL = 449.25/446.3, M/F, mg/kg/day based on lower body - weight gains and decreased food consumption and food efficiency
870.4200 Carcinogenicity - (mouse) 43709031, 44417902

Acceptable/Guideline 0, 10, 150, 2000, 5000 ppm M: 0, 1.15, 16.1, 212.4, 630 mg/kg/day F: 0, 1.08, 14.7, 196.3, 558.1 mg/kg/day NOAEL = 16.1 mg/kg/day LOAEL = 212.4 mg/kg/day based on a dose - related increase in the incidence of focal and multifocal hyperplasia of the exocrine pancreas in males **No evidence of carcinogenicity** 870.7800 Immunotoxicity (mouse) 48304203

Acceptable /Guideline 0, 500, 2000, 5000 ppm 0, 103.8, 468.3, 1245.3 mg/kg/day NOAEL > 1245.3 mg/kg/day LOAEL > 1245.3 mg/kg/day There were no cyprodinil - related effects on absolute, adjusted, or relative spleen or thymus weights; no effects on specific activity or total activity of splenic IgM antibodyforming cells to the T cell - dependent antigen sRBC. Cy prodinil attributed effects was higher mean absolute, relative (to body weight), and adjusted liver weights at HDT.Page 39 of 54

**Table 2. Toxicity Profile of Cyprodinil Technical. Guideline No./**  **Study Type MRID No. (year)/** 

**Classification /Doses Results**  8 70.6200a Ac ute Neurotoxicity 48304202

Acceptable/Guideline 0, 200, 600, 2000 mg/kg / day NOAEL = 200 mg/kg/day LOAEL = 600 mg/kg/day Based on clinical signs of toxicity and low motor activity and reversible hypothermia, no neuropathic changes were noted at any dose level. 870.6200b Subchronic Neurotoxicity 45906101

Acceptable/Guideline 0,80, 800, 8000 ppm M: 0, 5.8, 54.5, 601 F: 0, 6.3, 58.7, 631 mg/kg/day Neurotoxicity NOAEL > 601 mg/kg/day M; 631 mg/kg/day F Neurotoxicity LOAEL > 601 mg/kg/day M; 631 mg/kg/day F Sy stemic toxicity NOAEL = 54.5 mg/kg/day M; 58.7 mg/kg/day F Sy stemic LOAEL = 601 mg/kg/day M; 631 mg/kg/day F based on decreased body weight gain and microscopic les ions in the liver (hepatocellular hypertrophy), kidney (tubular casts) and thyroid gland (follicular cell hypertrophy) 870.5100 Gene Mutation - Bacteria 43709037 (1990)

Acceptable/Guideline In a reverse gene mutation assay with Salmonella typhimurium/Escherichia coli , cyprodinil was negative up to concentrations ( 1 2 5 0 μg/plate +/ - S9) that produced reproducible cytotoxicity for the majority of strains. Com pound insolubility was reported at 3 1 3 μg/plate. 870.5300 Gene Mutation - In vitro mammalian cell 43709036 (1990)

Acceptable/Guideline In a Chinese hamster V79 cell HGPRT forward gene mutation assay, cyprodinil was negative up to cytotoxic concentrations ( 9 6 . 0 μg/mL with S9) ( 2 4 μg/mL without S9). 870.5375 Cy togenetics/ In vitro Chromosomal Aberration 43709038 (1991)

Acceptable/Guideline In an in vitro assay for chromosome aberrations in Chinese hamster ovary (CHO) cells, cyprodinil gave negative results up to cytotoxic concentrations ( 5 0 μg/mL without S9, 18 - or 42 - hour cell harvest or 2 5 μg/mL with S9, 18 - hour cell harvest) or to the highest sub - cy totoxic concentration (50 μg/mL with S9, 42 - hour cell harvest). 870.5395 Cy togenetics/ In vivo bone marrow micronucleus 43709039 (1990)

Acceptable/Guideline In an in vivo bone marrow micronucleus assay, cyprodinil wa s negative when administered orally (gavage) at 5000 mg/kg (HDT) to both sexes of Tif:MAGF mice. No signs of overt toxicity or clear evidence of cytotoxicity for the target organ were noted at any dose or sacrifice time. 870.5550 UDS 43709035 (1991)

Acceptable/Guideline In an UDS assay in primary rat hepatocytes, cyprodinil was negative up to a cytotoxic concentration (80 μg/mL) 870.7485 Metabolism and pharmacokinetics 43709040 (1992)

Acceptable/Guideline Single oral doses (0.5 or 100 mg/kg bw) of phenyl or pyrimidyl - radiolabelled CGA 219417 (purity 9 8 % ) we r e administered to Tif:RAIf(SPF) rats, with one low - dose group receiving unlabeled CGA 219417 (purity 9 9 % ) f o r 2 weeks prior to treatment with radiolabelled compound. Absorption was very rapid (t cmax= 0.3 hours) with rapid clearance (t cmax/2 =1.2 hours). A minimum of 75% of the administered dose was absorbed. Excretion was rapid and almost complete, with urine as the principle route ofPage 40 of 54

**Table 2. Toxicity Profile of Cyprodinil Technical. Guideline No./**  **Study Type MRID No. (year)/** 

**Classification /Doses Results**  excretion (48 - 68%), and >90% of the administered dose detected in the urine and feces within 48 hours. Excretion, distribution and metabolite profiles were essentially independent of dose level, pretr eatment, and type of label, although there were some quantitative differences sex dependent qualitative differences in two urinary metabolite fractions. 870.7485 Metabolism and pharmacokinetics 43709041 (1992)

Acceptable/guideline Must be considered with MRID 43709040. Excreta (Group D1 and D2) and bile (Group G1) from radiolabelled CGA 219417 - treated Tif:RAIf(SPF) rats of a previous ADME study (MRID 43709040) were used to characterize, isolate and identify CGA 219417 metabolites (MRID 43709041). El even metabolites were isolated from urine, feces and bile, and the metabolic pathways in the rat were proposed. All urinary and biliary metabolites (with the exception of 7U) were conjugated with glucuronic acid or sulfonated, and excreted. CGA 219417 wa s almost completely metabolized by hydroxylation of the phenyl ring (position 4) or pyrimidine ring (position 5), followed by conjugation. An alternative pathway involved oxidation of the phenyl ring followed by glucuronic acid conjugation. A quantitativ e sex difference was observed with respect to sulfonation of the major metabolite that formed 6U. The mo nosulfate metabolite (1U) was predominant in females, whereas equal amounts of mono - and disulfate (6U) conjugates were noted in males. Most of the si gnificant metabolites in feces were exocons of biliary metabolites (2U, 3U, 1G). These were assumed to be deconjugated in the intestines, partially reabsorbed into the general circulation, conjugated again, and eliminated renally. The major metabolic pathways of CGA 219417 were not significantly influenced by the dose, treatment regimen, or sex of the animal. 870.7600 Dermal Absorption (rat) 45906102 (1999)

In review 6 μg/cm

2 or 870 μg/cm2 In a dermal absorption study with CGA 219417 formulated

as SWITCH 62.5 WG in the rat, the maximum systemic absorption was 21.71% (at 24 hours). An additional 12% of the applied dose (that is potentially available for absorption) remained on the treated skin at 24 hours.

**A.3 Toxicological Endpoints** Page 41 of 54

**A.3.1 Acute Reference Dose (aRfD)** 
**– All Populations**  **Selected Study** : Acute Neurotoxicity Rat; MRID 48304202 Dose and Endpoint for Establishing a POD : NOAEL= 200 mg/kg from an acute neurotoxicity study based on LOAEL of 600 mg/kg showing clinical signs (hunche d posture, pilorection, and reduced responsiveness to sensory stimuli, reduced motor activity and h yp othermia). Uncertainty Factor (UF) : 1000x (10x for interspecies and 10x for intraspecies variation; and 10X for lack of 90 - day

inhalation study) **Acute RfD**  = 200 mg/kg (NOAEL) = 0.20 mg/kg 1000 (UF) [Note: The acute RfD has been revised from previous risk assessments based on receipt and review of an acute neurotoxicity study and subsequent reevaluation of available data.] A. **3.2 Chronic Reference Dose (cRfD)**  **- All Populations**  **Selected Study** : Combined Chronic Toxicity /Carcinogenicity- Rat; MRIDs 43737602, 44429401 and 44417902 Dose and Endpoint for Establishing a POD : 2.7 mg/kg/day (NOAEL) based on the histopathological alterations in the liver (spongiosis hepatis) in males at 35.6 mg/kg/day (LOAEL). Uncertainty Factor (UF) : 100x (10x for interspecies and 10x for intraspecies variation, and 10X for lack of 90 - day

inhal ation study) Comments about Study

/Endpoint : The selected NOAEL is the lowest NOAELobserved in the most sensitive species following long - term exposure.

**Chronic RfD** = 2.7 mg/kg (NOAEL) = 0.0027 mg/kg 1000 (UF) **A.3.3 Inhalation Exposure (Short to Intermediate Term**  **)** A No Observable Adverse Effect Level (NOAEL) of 62 mg/kg/day was identified for short to intermediate - term inhalation risk assessments. The N OAEL is based on decreased body weight gains, microcy

tosis, increased cholesterol and phospholipid levels, and hepatocy te hy pertrophy seen at the Lowest Observable Adverse Effect Level (LOAEL) of 299 mg/kg/day from a 28 - Day Feeding/Range - finding study on r ats with cy

prodinil. **A.4 EXECUTIVE SUMMARIES FOR SUPPORTING TOXICITY STUDIES**  **A.4.1 Subchronic Toxicity** Page 42 of 54

**870.3100 90**  **- Day Oral Toxicity** 
**– Rat MRID 43709026**  In a subchronic toxicity

study (MRID 43709026), CGA 219417 (cy prodinil; 99.5% ai; L ot No. P 912004) was administered in the diet to 20 rats/sex/dose at dose levels of 0 or 12000 ppm (0 or 810 mg/kg/day , respectively , for males; 0 or 803 mg/kg/day , respectivel y, for females), and to 10 rats/sex/dose at dose levels of 50, 300, or 2000 ppm (3.14, 19 .0, or 134 mg/kg/day , respectivel y, for males; 3.24, 19.3, or 137 mg/kg/day for females) for 90 day s. All animals were sacrificed at 90 day s except for 10 control and 10 2000 ppm rats/sex which were sacrificed after a 4 weekrecovery

period. At 50 ppm and above there were - increased cholesterol and phospholipid levels in females (18% for both) which increased with increasing dose [cholesterol - 300 ppm (20%), and male and female 2000(37 - 48%) and 12000 (85 - 105%) ppm groups; phospholipid - 300 ppm (23%) grou p, and male and female 2000 (36%) and 12000(71 - 90%) ppm groups.] At 300 ppm and above there was - increased alkaline phosphatase in the male with females affected at 12000 ppm. Liver abnormalities at 300 ppm included hepatocyte hy pertrophy and hepatocy te necrosis observed in male rats, with females affected at 2000 and 12000 ppm. Kidney abnormalities included a low incidence (0, 0, 10, 10, 20% for males onl y, control to high dose) vacuolization of the epithelium of the proximal convoluted tubules, and chronic tubular lesions (0, 0, 30, 50, 80% for males and 20, 20, 0, 50, 80% for females, control to high dose), in male and/or female rats at 300 ppm. The tubular lesions were more frequent at 2000 and 12000 ppm. Enlarged (h yp ertrophic) pituitary cells in the adenohy

pophy sis were observed in males in the 300 ppm group, and males and females in the 2000 and 12000 ppm groups. “Minimal” to “moderate” hy pertrophy of the follicular epithelia of the thyro id was noted in males in the 300, 2000, and 12000 ppm groups. At 2000 ppm and above there were additional hepatic lesions consisting of “sharpl y demarcated membranous structures containing a vacuolated eosinophilic material” (“cy toplasmic inclusion bodies”) and renal chronic tubular lesions in 50 % of the males and females. There was an increase in protein and globulin levels in the males. Relative liver weights were higher for male and female rats in the 2000 and 12000 ppm groups. Relative thy roid weights were higher for male rats in the 2000 ppm group, and male an d female rats in the 12000 ppm groups. At 12000 ppm there was - a decrease in body weight gains of female and male rats (20 - 26% lower than controls at the termination of the study). Hemoglobin and hematocrit values were lower, albumin levels higher and glucose levels lower in the males. Leukocy te counts and gamma glutam yltranspeptidase activity levels were higher in the male and female groups. Additional renal lesions included nephrocalcinosos (0, 0, 10, 0, 50%, control to high dose in males only). Relati ve kidney weights were also higher for high dose males. The relative weights of the adrenals in males were greater than the controls, with “minimal” increases in the amount of fat vesicles in the adrenal cortex noted in a majority of these animals. Foll owing a 4 - week post treatment recovery period (using 0 and 12000 ppm rats only), all hematological and blood chemistry differences lost significance, with the exception ofPage 43 of 54

cholesterol and phospholipid concentrations in females. The relative weights of the liver and thy roid glands of males in the 12000 ppm groups remained greater than those of the control group, but with the exception of chronic tubular kidney lesions, the prevalence of all microscopic abnormalities was reduced. Most changes at 50 were not adequate to establish an LOAEL therefore the LOAEL is 300 ppm (19 mg/kg body weight/day) for rats, based on increased chronic tubular kidney lesions in males. The NOAEL is 50 ppm (3.14 mg/kg/day). This subchronic toxicity

study is classified acceptable ( guideline), and satisfies the guideline requirement for a subchronic oral study (82 - 1) for rodents. **870.3100 90**  **- Day Oral Toxicity** 
**– Mouse MRID 43709027**  A 3 - month study

(MRID 43709027) was carried out in Tif:MAGf(SPF) albino mice where animals (10 mice/s ex/dose) were fed diets containing 0, 500,2000 or 6000 ppm (actual concentrations: males - 0, 73.3, 257 or 849 mg/kg/day ; females - 0, 103, 349 or 1121 mg/kg/day) of CGA 219417 technical (99.5% a.i., Batch No - P 912004). There was no effect on mortality , or hematology

parameters, and no clinical sighs of toxicity . Treatment - related effects included increased absolute and relative liver weights (112 - 118 %) in 6000 ppm males, and hepatic changes in mid - and high dose males and females that consisted of multi focal hepatocy te necrosis in 2000 and 6000 ppm males (30 % as compared to 0 in the control and low dose groups) and gl yco gen depletion in 2000 and 6000 ppm females (10, 10, 70 and 100% from controls to high dose). The LOAEL is 2000 ppm based on histopathol ogical changes in the liver. The NOAEL is 500 ppm (malts - 73.3; females - 103 mg/kg/day). This study is acceptable (guideline) even though it is listed as a range - finding study. It satisfies the guideline requirement for a subchronic study in the rodent (82 - 1(a)). **870.3100 90**  **- Day Oral Toxicity** 
**– Dog MRID 43709028**  A 3 - month study

was carried out in Beagle dogs where animals (4/sex/dose) were fed diets containing 0, 200, 1500, 7000 or 20000 ppm (actual concentrations: males - 0, 6.07, 45.87, 210.33 or 55 9.66 mg/kg/day ; females - 0, 6.79, 52.75, 231.93 or 580.95 mg/kg/day) CGA 219417. There was no effect on mortality, or clinical chemistry parameters. Vomiting was observed in all high - dose females during the first week of treatment, and an increase in mean platelet count was noted in high - dose females at weeks 7 and 13. Lower body weight gains (64 - 76%) and decreased food consumption were apparent in high - dose males and females throughout the study period. There was a transient decrease in body weight gain and food consumption in 7000 ppm females, which was noted after the first week of treatment onl y, and this was considered non - adverse. The LOAEL is 20,000 ppm (males - 560, females - 581 mg/kg/day) based on lower bodyw eight gains and decreased food consumption in both sexes. The NOAEL is 7000 ppm (males - 210, females - 232 mg/kg/day). **870.3200 28 Day Dermal Toxicity**
**– Rat MRID 47526801**  In a 28 - day

dermal toxicity

study (MRID 47526801), Cy

prodinil (99%, P012011) was applied toPage 44 of 54

the shaved skin of 50 HanRCC Wist ar Rats/sex/dose at dose levels of 0 (vehicle control), 5 , 25 , 125 and 1000 mg/kg bw/day , 6 hours/day for 5 day s/week during a 28 - day period, for a total treatment of 20 day s. The following parameters were measured: general clinical observations, detailed behavioral observations. Body weight and food consumption, functional observational battery including grip strength and locomotor activity . Ophthalmoscopic examination, hematology and clinical chemistry . Organ weights, macroscopic and histopathological ex amination of selected organs. No treatment related effects were seen at any concentration when measuring body weight gain, food consumption, hematological parameters, clinical chemical parameters, organ weights, gross or histopathology . Skin lesions characterized by fissures, scabs, ery

thema, hair loss, sores, were common in all experimental groups and the control group, probably resulting from shaving the skin to apply the test article or vehicle. The NOAEL is 1000 mg/kg/day . The LOAEL is not esta blished. This 28 - day

dermal toxicity

study in the HanRCC Wistar rats is acceptable guideline and satisfies the guideline requirement for a 28 - day dermal toxicity

study (OPPTS 870.3200; OECD 410) in rats . **A.4.2 Prenatal Developmental Toxicity**  **- Rat**  **870 .3700a Prenatal Developmental Toxicity Study** 
**– Rat MRID 43709033**  In a developmental toxicity study (MRID No. 43709033), CGA 219417 technical (99.5% a.i., Batch No. P912004) was administered in 3% aqueous corn starch suspension by oral gavage to 20 - 23 Tif: RAIf(SPF) females albino rats per dose of 0, 20, 200 or 1000 mg/kg/day or gestation day s 6 - 15. Treatment related findings included reduced locomotor activity (one high dose female), significantly

lower mean body weight (16%), body weight gain (65%), gravi d uterine weight (18%), and mean carcass weight (10%), and significantl y decreased food consumption (32 - 42%) in high - dose females. The LOAEL for maternal toxicity is 1000 mg/kg/day

based on lower body weight/body weight gain and reduced food consumption. The NOAEL was 200 mg/kg/day . There were significantl y lower mean fetal weights (11%) in the high - dose group compared to controls as well as a significant increase in skeletal anomalies in the high - dose group relative to the control, which was due to abnorm al ossification (4/20 litters in the high dose group compared to 0 in any other group), primarily

as absent or reduced metacarpal 5 ossification. The skeletal anomalies/variations were considered to represent a transient developmental delay

that occurs sec ondary

to the maternal toxicity

noted in the high - dose group. The LOAEL for developmental toxicity is 1000 mg/kg/day

based on lower mean fetal weights and an increased incidence of delayed ossification. The NOAEL for developmental toxicity is 200 mg/kg/day . This study is classified acceptable (guideline) and satisfies the guideline requirement for a developmental study in the rat [(OPPTS 870.3700 (83 - 3a)]. **870.3700b Prenatal Developmental Toxicity Study**
**– Rabbit MRID 43709032** Page 45 of 54

In a developmental toxicity (MRID No. 43709032), CGA 219417 technical (99 5%a.i., Lot# P9t2004) was administered in 3% aqueous corn starch suspension to 19 inseminated female rabbits (Russian Chbb:HM, SPF)/dose by gavage at dose levels of 0,5; 30; 150, or 400 mg/kg/day

from days 7 through 19 of gestation. Mean maternal body weight gain (p <0.01) and food consumption (not significant) decreased, mainly during the first week of treatment in the 400 mg/kg/day

group. Mean body

weight gain was 622% less than controls (p <0.01) in this gro up between day s 7 and 13 of gestation. The maternal LOAEL is 400 mg/kg/day , based on decreased body weight gain. The maternal NOAEL is 150 mg/kg/day. Fetuses at the 400 mg/kg/day

dose exhibited indications of an increased incidence of a 13th rib (not signi ficant). Although there were indications of developmental delays in fetal skeletons, such as poor or absent ossification of the sternebrae and metacarpals at all dose levels, only the extra rib is likely to be compound related. Uni - or bilateral h yp erflexi on of the carpal joint at the 400 and 150 mg/kg/day

doses (not significant) was not associated with the skeletal changes. The fetal developmental LOAEL is 400 mg/kg/day based on a slight increase of litters showing extra (13th) ribs. The fetal developmental NOAEL is 150 mg/kg/day . The developmental toxicity study in the rabbit is classified acceptable (guideline) and satisfies the guideline requirement for a developmental toxicity

study (OPPTS 870.3700; §83 - 3 (b)) in rabbit. **A.4.3 Reproductive Toxicity**  **870.3800 Reproduction and Fertility Effects**
**– Rat**  **MRID 43709034**  In a two - generation reproduction study (MRID No. 43709034), Tif:RAIf rats (30 rats/sex/dose), with one litter per generation received CGA219417 (99.5 % a.i., Batch No. P912004) in the diet at doses of 0, 10, 100, 1000 or 4000 ppm (actual intake, males: 0, 0.7, 6.7, 68 or 273; females: 0, 0.8, 8.2, 81 or 326 mg/kg/day) for a 10 week pre - mating period. Signs of toxicity at 4000 ppm consisted of lower body weights (12.5%) in the F0 females after the pre - mating period. Increased liver weight in 1000 (marginal) and 4000 ppm males and females was not supported b y histopathological findings. Although these were considered treatment related, they were considered to be non - adverse. The LOAEL for matern al s ys temic toxicity is 4000 ppm (about 326 mg/kg/day) based on lower body weights in the F0 females during the pre - mating period. The NOAEL for maternal sy stemic toxicity was 1000 ppm (about 81 mg/kg/day). HIARC determined that premating body weight gain (not absolute body weight) should be used as the basis of the NOAEL. Signs of reproductive toxicity included significantl y lower F1 and F2 pup weights in the high - dose group during lactation, which continued to be lower than controls post weaning and afte r the pre - mating period (examination in F1 generation only). The LOAEL for reproductive/developmental toxicity is 4000 ppm (about 326 mg/kg/day) based on decreased pup weights (F1 and F2). The NOAEL for reproductive toxicity is 1000 ppm (about 81 mg/kg/day). The two - generation reproduction study in the rat is classified acceptable (guideline) and satisfies the guideline requirement for a two - generation reproduction study (OPPTS 870.3800; §83 - 4) in rat. **A.4.4 Chronic Toxicity**  **870.4100a (870.4300) Combined Chronic Toxicity/Carcinogenicity** 
**– Rat MRIDs** Page 46 of 54

**43737602, 44429401, 44417902**  In a 24 - month chronic toxicity /oncogenicity

study (MRID No: 43737602, 44429401,44417902), Tif:RAI f rats (50 rats/sex/dose - carcinogenicity portion, plus 20/sex/dose laboratory inve stigations) were fed diets containing 0, 5, 75, 1000 or 2000 ppm (actual concentrations: males 0, 0.177, 2.7, 35.6 or 73.6 mg/kg/day ; females 0, 0.204, 3.22, 41.2 or 87.1 mg/kg/day) CGA 219417(99.2 - 99.6% a.i. Batch No. P 912006). An additional 10/sex/dose were fed test diets for 12 months (interim sacrifice). Survival was slightl y lower in males at 2000 ppm relative to control and other dose groups (54, 50, 50, 49, and 44%, from controls to high dose). Toxicologically

significant findings included increase d liver weights in high - dose males (10.7%) and a dose - related increase in the incidence of spongiosis hepatis in the liver of 1000 and 2000 ppm males (5, 5, 3, 17 and 23 %, controls to high dose). For chronic toxicity , the NOAEL was 75 ppm (2.7 mg/kg/day) and the LOAEL was 1000 ppm (35.6 mg/kg/day) based on degenerative liver lesions (spongiosis hepatis) in males. This chronic carcinogenicity study in the rat is acceptable (guideline). **870.4100b Chronic Toxicity -**  **Dog MRID 43709030**  A 1 - year study (MRID 4 3709030) was carried out in Beagle dogs where animals (4/sex/dose) were fed diets containing 0,25,250,2500 or 15,000 ppm (actual concentrations: males - 0, 0.72, 6.87, 65.63 or 449.25; females - 0, 0.76, 6.80, 67.99 or 446.37 mg/kg/day) CGA 219417 (99.6% a.i ., Batch No. P 912006). There was no effect on mortality , hematological, or clinical chemistry parameters, and no clinical signs of s ys temic toxicity . Throughout the first half of the study , lower body weight gains (31 - 38% less) (attributable primarily to 2/4 of each sex) and decreased food consumption were apparent in high - dose males and females; with reduced food efficiency in high dose males and females in the latter part of the study . The LOEL is 15,000 ppm (males - 449.25, females 446.37 mg/kg/day) bas ed on lower bodywei ght gains and decreased food consumption and food efficiency . The NOAEL is 2500 ppm (males - 65.63, females - 67.99 mg/kg/day). This study is classified as acceptable (guideline) and satisfied the guideline requirement for a chronic oral dog study (870.4100b). **A.4.5 Carcinogenicity**  **870.4200a Carcinogenicity/Chronic Study**
**– Mice MRID 43709031**  An 18 - month oncogenicity study was carried out in Tif:MAGf(SPF) albino mice where animals (50 mice/sex/dose - carcinogenicity portion, plus 10/sex/dose - hematology) were fed diets containing 0, 10, 150, 2000 or 5000 ppm (actual concentrations: males - 0, 1.15, 16.1, 212.4 or 630; females - 0, 1.08, 14.7, 196.3 or 558.1 mg/kg/day) of CGA 219417 (99.0 - 99.5% a.i., Batch No. P912006). There was n o effect on mortality , or hematology parameters, and no clinical signs of toxicity . Treatment - related effects included lower body weight and bodyweight gain (males - 10%, females - 27%) at 5000 ppm, reduced food efficiency and increased relative liver weights (16%) in high - dose males and females, and a dose - related, increase in minimal to marked pancreatic acinar cell hyperplasia in 2000 and 5000 ppm males (8, 8, 10, 16, 28% incidence,Page 47 of 54

from control to high dose). The LOAEL is 2000 ppm (males - 212.4 mg/kg/day) based on a dose - related increase in the incidence of focal, and multifocal hy perplasia of the exocrine pancreas in. males. The NOAEL was 150 ppm (males - 16.1 mg/kg/day). This study was tested to adequate levels based on signs of toxicity in males at 20 00 ppm and female at 5000 ppm. This chronic carcinogenicity

study in the mouse is acceptable/guideline. **A.4.6 Mutagenicity**  **Gene Mutation** Guideline # 870.5100 Bacterial assay MRID 43709037 Acceptable/Guideline Guideline #870.5300, In vitro mammalian cell gene mutation test MRID 43709036 Acceptable Guideline Not mutagenic Not mutagenic in the presence or absence of S9 - activation up to cytotoxic concentrations ( 9 6 . 0 μg/mL with S9) ( 2 4 μg/mL without S9). **Cytogenetics** Guideline # 870.5375, Cy togenetics/

In vitro Chromosomal Aberration MRID 43709038 Acceptable Guideline Guideline #870.5395 Cy togenetics/

In vivo bone marrow micronucleus MRID 43709039 Acceptable Guideline cy prodinil gave negative results up to cytotoxic concentrations
negative

**A.4.7 Neurotoxicity**  **870.6100 Delayed Neurotoxicity Study**
**– Hen**  **- NA**  **870.6200a Acute Neurotoxicity Screening Battery** MRID 48304202 In an acute neurotoxicity

study in mice **(**MRID 48304202 **)** CGA 219417 technical (batch #: P.012011 a light beige powder with a purity of 99.2%) was administered to rats to assess the potential acute neurotoxicity and to estimate the NOAEL of exposure of the test compound, a fungicide, when administered b y gavage. The test article was administered by gavage as single oral dose of 0, 200, 600, and 2000 mg/kg to a total of 80 Sprague - Dawley- derived rats (10 males, and 10 females, per dose group). Mortality , clinical signs, body weight, and food consumption were monitored throughout the study . A 'Functional Observ ational Battery' (FOB) was performed pretest, at the time of peak effect (2 hours post - dose, and on test day s 8 and 15. At necropsy , animals were sacrificed by in situ perfusion. The brain, spinal cord, peripheral nerves and eyes were collected, prepared f or histological evaluation and 5 animals per sex each of the control and top - dose group (experimental group I) examined microscopicall y. Two animals of group 3 died spontaneously . The male, found dead on test day 2, was most likelyPage 48 of 54

miss - intubated. For the female, which was found dead on test day 18, the cause of death could not be identified. Body weight gain and food consumption were not affected by treatment. Observations and functional tests conducted as part of the FOB showed relevant changes at the ti me of peak effect only . In females of group 3 and 4 reduced activity , hunched posture, piloerection, and increased responsiveness to sensory stimuli were observed with hunched posture seen also in few group 2 females. In females of group 3 and 4, signs las ted up to test day 4 and were considered to indicate toxicity . A dose related decrease in body temperature was observed, being minimal in animals of group 2. Changes in motor activity parameters were limited to the time of peak effect. In group 4 males an d in females of group 3 and 4 horizontal and vertical activity

parameters were reduced. Macroscopic and microscopic examination of the multiple areas of the central and peripheral nervous sy stem, the eyes, optic nerves, and skeletal muscle of the male and female, control and high - dose animals of experimental group I didn’t reveal an y treatment - related neuropathic changes. Based on these data it was concluded that CGA 219417 tech., when administered to rats at a single oral dose of 200, 600 or 2000 mg/kg, induced a dose - related hy pothermia. Due to its full reversibility in all dose groups, the slightly reduced body t emperature in low - dose animals was not considered as adverse. A dose of 200 mg/kg thus represented the NOAEL for this study. The LOAEL was dee med to be 600 mg/kg and greater induced signs of toxicity at the time of peak effect which disappeared within a few day s as well. In the absence of any permanent or delayed functional changes and of neuropathic changes in the central and peripheral nervou s s ys tem, CGA 219417 tech was considered not to be neurotoxic up to the near lethal dose of 2000 mg/kg. **870.6200b Subchronic Neurotoxicity Screening Battery** MRID 45906101 In a subchronic neurotoxicity study (MRID 45906101) CGA 219417 technical (99.2% a.i., batch #: P. 012011) was administered to 10 Tif: RAIf Sprague - Dawley derived albino rats/sex/group at dose levels of 0, 80, 800, or 8000 ppm (equivalent to 0, 5.8, 54.5, and 601 mg/kg bw/day in males and 0, 6.3, 58.7, and 631 mg/kg bw/day in females) for 90 consecutive day s. Neurobehavioral assessment (functional observational battery and motor activity

testing) was performed in 10 animals/sex/group pre - exposure and at wee ks 4, 8, and 13. At study termination, 10 animals/sex/group were euthanized and perfused in situ for neuropathological examination. Of the perfused animals, 5/sex/group of the control and high - dose groups were subjected to histopathological evaluation of brain and peripheral nervous s ys tem tissues. In addition, the liver, kidney s, thy

roid gland, and pituitary

were collected from all animals and examined microscopicall y.Page 49 of 54

There were no treatment related eff ects on mortality , clinical signs, or gross or histological neuropathology . FOB and motor activity testing revealed no treatment related effects up to the highest dose tested (8000 ppm). In high - dose animals, absolute body weight was significantly or sli ghtly less than the controls throughout the study due to reduced weight gain by the treated animals. Cumulative weight gain b y the high - dose groups was significantl y less than that of the control groups during weeks 1 - 6 and 8 for males and weeks 1, 4, and 11 - 13 for females. The most pronounced effect on weight gain was during the first week of the study when high - dose males and females gained 59% and 38%, respectively , of the control levels. Overall weight gain by the high - dose males and females was 87% and 79%, respectively , of the controls. Food consumption by

the high - dose animals was reduced only at week 1 to 89% and 77% of controls for males and females, respectively . In the high - dose group, absolute and relative liver weights were increased in both sexes (126 - 138% and 121 - 125% of controls for males and females, respectivel y). Absolute and relative kidney weights were elevated in high - dose females (112 - 118% of controls). Microscopic examination revealed an increase in the incidence, but not in sev erity, at the high dose of lesions in the liver, kidney , and thy roid. Hepatocellular h yp ertrophy in the liver was observed in 5/10 high - dose males compared with 1/10 controls and in 5/10 high - dose females compared with 0/10 controls; this is an adaptive response. Tubular lesions or tubular casts were seen in the kidney s of 4/10 high - dose males and 5 - 7/10 high - dose females vs 0 - 2/10 animals in the control groups. Hy

pertrophy of the follicular epithelial cells in the thy roid gland occurred in 5/10 high - dos e males and 4/10 high - dose females compared with onl y 1/10 control males. Based on the results of this 90 - day subchronic oral neurotoxicity study , the neurotoxicity LOAEL for CGA 219417 technical in male and female rats was not identified, while the NOAEL is  8000 ppm (601 mg/kg bw/d in males; 631 mg/kg bw/d in females). The sy stemic toxicity

L OAELfor CGA 219417 technical in male and female rats is 8000 ppm (601 mg/kg bw/d in males and 631 mg/kg bw/d in females) based on decreased body weight gain, tubular casts in the kidney s, and thy roid follicular cell hy

pertrophy . The NOAE L is 800 ppm (54.5 mg/kg bw/d in males and 58.7 mg/kg bw/d in females). The study is classified as **Acceptable/Guideline** and satisfies the guideline requirement for a subchronic neurotoxicity

study in rats (870.6200b).

**A.4.8 Metabolism** Page 50 of 54

**870.7485 Metabolism** 
**– Rat**  **Study 1** In a metabolism study

(M RID 43709040), single oral doses (0.5 or 100 mg/kg bw) of phen ylor py rimidyl - radiolabelled CGA - 219417 (purity  98%) were administered to Tif:RAI f(SPF) rats, with one low - dose group receiving unlabeled CGA 219417 (purity  99%) for 2 weeks prior to treatment with radiolabelled compound. Absorption was very rapid (t cmax= 0.3 hours) with rapid clearance (t cmax/2 =1.2 hours). Am inimum of 75% of the administered dose was absorbed. A biphasic firs t order kinetics was observed for radioactivity d epletion, with a duration of 0.3 - 1.2 hours for the first phase, and 27 - 65 hours for the second phase. E xcretion was rapid and almost complete, with urine as the principle route of excretion (48 - 68%), and >9 0% of the administered dose detected in the urine and feces within 48 hours. T issue residues declined rapidly , with the highest concentrations (  1.8 ppm) found in kidney s, liver, lungs, spleen, thy roid, whole blood, and carcass. The urine, fecal, and bi le metabolite patterns were complex, with 8, 8 and 9 defined metabolite fractions, respectivel y. Unchanged parent compound was detected in feces extract only . E xcretion, distribution and metabolite profiles were essentially i ndependent of dose level, pre treatment, and ty

pe of label, although there were some quantitative differences sex - dependent qualitative differences in two urinary metabolite fractions. This study

i s classified as acceptable (guideline) and when taken together with study ( MRID 43709041 ) satisfies the guideline requirement for a metabolism study in rats (85 - 1). **Study 2** Excreta (Group D1 and D2) and bile (Group G1) from radiolabelled CGA 219417 - treated Tif:RAI f(SPF) rats of a previous ACME s tudy ( MRID 43709040) were used to characterize, isolate and identify

C GA 219417 metabolites (MRID 43709041). E leven metabolites were isolated from urine, feces and bile, and the metabolic pathway s in the rat were proposed. A ll urinary and biliary

m etabolites (with the exception of 7U) we re conjugated with glucuronic acid or sulfonated, and excreted. C GA 219417 was almost completely me tabolized by

hydroxylation of the phen ylring (position 4) or py rimidine ring (position 5), followed by c onjugation. An alternative pathway

i nvolved oxidat ion of the phenyl ring followed by g lucuronic acid conjugation. Aquantitative sex difference was observed with respect to sulfonation of the major metabolite that formed 6U. T he monosulfate metabolite (1U) was predominant in females, whereas equal amounts of mono - and disulfate (6U) conjugates were noted in males. Most of the significant metabolites in feces were exocons of biliary m etabolites (2U, 3U, 1G). T hese were assumed to be deconjugated in the intestines, partially reabsorbed into the general c irculation, conjugated again, and eliminated renall y. T he major metabolic pathway s of CGA 219417 were not significantl y influenced by the dose, treatment regimen, or sex of the animal. This study

i s classified as acceptable (guideline) and when taken tog ether with study ( MRID 43709040) satisfies the guideline requirement for a metabolism study in rats (85 - 1).Page 51 of 54

**A.4.9 Immunotoxicity**  **870.7800 Immunotoxicity** 
**– Mice MRID 48304203**  In an immunotoxicity

study (MRID 48304203), the test substance cy prodinil was offered ad libitum in the diet of Crl:DC1 (I CR) female mice, for 28 consecutive day s to three groups (Groups 2 - 4) at dietary

concentrations of 500, 2000, and 5000 ppm, respectively . Mice in Group 5 were administered the positive control substance, cyclop hosphamide (CPS), via IP (50 mg/kg/day) for four consecutive day s (study day s 24 - 27). The vehicle and positive control groups (Groups 1 and 5, respectivel y) were offered a basal diet on a comparable regimen as the cy prodinil - treated groups. In addition, all mice were immunized with sheep red blood cells (sRBC) on study

day 24. All animals were euthanized on day 28. Mortality

and morbidity

were observed twice dail y in all animals, while clinical exams were performed once a day. More detailed ph ys ical ex ams were performed once a week and the day of necropsy . Single animal body weights were recorded two times a week and food consumption was recorded weekl y. Complete necropsies were conducted on all animals. Organs (liver, spleen, and thy mus) were collec ted and weighed at scheduled necrops y. Spleens were anal yz ed b y ImmunoTox®,Inc . for IgM antibody

forming cells directed towards the sRBC determination. Test substances were 0, 103.8, 468.3, and 1245.3mg/kg/day or 0, 500, 2000, and 5000ppm, respectively , for the entire 4 - week study. All animals survived to necrops y. There were no test substance - related clinical observations, no effects on body- weight, food consumption, no macroscopic findings. There were no cy

prodinil - related effects on absolute, adjus ted, or relative spleen or thy mus weights; no effects on specific activity or total activity of splenic IgM antibody- forming cells to the T cell dependent antigen sRBC. Effects did include higher mean absolute, relative to body weight, and adjusted liver weights noted in the 5000ppm cy prodinil - treated group were consistent with previous studies assessing cy prodinil at similar exposure levels. Noted for the positive control (CPS) were lower mean absolute and adjusted spleen and th ymus weights when compared to vehicle control group. All effects seen with the CPS were consistent with the known immunosuppressant effects and also validated the appropriateness of the AFC assay. No mention of a NK cell activity assay was performed. It is unclear why this test was not performed and no justification was noted in the study write - up. Based on the study , treatment of female Crl:CD - 1(I CR) mice with cy prodinil given on a continued basis in the diet for 28 sequential day s resulted in no apparent suppression of the humoral component of the immune sy stem. The NOEL for the suppression of the immune response in female CD - 1 mice given cy prodinil was 5000ppm (1245.3mg/kg/day). The onl y effect attributed to cy

prodinil treatment was higher mean absolute, relative to body weight, and adjusted liver weights also for the 5000ppm group.
**APPENDIX B. Chemical Names And Structures Of Metabolites** Page 52 of 54

**B.1 Chemical Names**  **a nd Structures**  **Table B.1 Cyprodinil and Metabolites Nam es and Structures**  Chemical Name/Code Chemical Structure **Cyprodinil** (CGA - 219417)
4 - cyclopropyl - 6 - me thyl -N - phenyl - 2 - py rimidinamine N N

C H 3 N H

**CGA -**  **232449** 6 - cyclopropyl - 2 - (phenylamino) - 4 - py rimidinemethanol N N

O H N H

**CGA -**  **304075** 4 - [(4 - cyclopropyl - 6 - me thyl - 2 - 2 - py rimidinyl)amino] - phenol N N

C H 3 N H

O H

**CGA -**  **304076** N N N H

C H 3 O H

**NOA -**  **413167**
N N N H O H

C H 3Page 53 of 54

**Table B.1 Cyprodinil and Metabolites Nam es and Structures**  Chemical Name/Code Chemical Structure **CGA -**  **249287** 4 - cyclopropyl - 6 - me thyl - 2 - py rimidinamine N N

C H 3 N H 2

**NOA -**  **422054** 4 - cyclopropyl - 6 - hydroxymethyl - 2 - py rimidinamine N N

O H N H2

**CGA -**  **263208** phenylguanidine N H NH NH2

**APPENDIX C. Physical/Chemical Properties Table C.1 Physicochemical Properties of Technical Grade of Cyprodinil.**  Parameter Value Reference Melting point/range 75.9 0 C DP# 345970, W. Cutchin, 6/4/08 pH 9.5 at 25 0 C (1% aqueous dispersion) Density 1.21 g/cm3 at 20 0 C Water solubility (mg/L at 25 C) 16 at pH 7.6, 20 at pH 5, 13 at pH 7, 5 at pH 9 Solvent solubility (g/L at 25 C) ethanol - 160, acetone - 610, toluene - 460, n - octanol - 160, n - hexane - 30Page 54 of 54

Vapor pressure 3.8 x 10 - 6 mm Hg at 25 0 C Dissociation constant, pKa 4.44 at 20 0 C Octanol/water partition coefficient, Log(KOW) at 25 C 3.9 at pH 5, 4.0 at pH 7, 4.0 at pH 9 UV/visible absorption spectrum (molar absorption coefficients for the absorbance ma ximum) 29,200 L/mol ∙cm at 270.8 nm (neutral) 29,200 L/mol ∙cm

at 251.6 nm (acidic) 29,200 L/mol ∙cm

at 316.8 nm (acidic) 28,400 L/mol ∙cm

at 270.8 nm (basic) **APPENDIX D. Studies Reviewed for Ethical Conduct** The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency , and the National Agricultural Chemicals Association, released February , 1995. Agricultural Re - entry

Task Force (ARTF) data base (SOP #3.1)