Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 1 of 21 **UNITED STA**

**TES ENVIRONMENTA L PROTECTION A** **GENCY WA** **SHINGTON, D.C. 20460 OFFICE OF**  **CHEMICAL SAFETY AND**  **POLLUTION PREVENTION MEMORANDUM**  **Date :**  July

1 

### , 201 5 **SUBJECT: Cyprodinil**  **.** Expansions of Existing Crop Group/Representative Commodity

Uses to Stone Fruit Group 12 - 12 , and Adding New Use s on the Artichoke, Guava, Pomegranate, Passionfruit, Feijoa,Jaboticaba, Wax Jambu, Starfuit, and Acerola and Amended Uses on Greenhouse Cucumbers and Small Tomatoes. **Summary of Analytical Chem**  **istry and Residue Data. PC Code:**  288202 **DP Barcode:** D421157 **Decision No.:** 490951 **Registration No s**  **. :**  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. 5 32 **FROM:** Thurston G. Morton , Chemist

Risk Assessment Branch 4 Health Effects Division (7509 P ) **THROUGH:** Charles Smith, Acting Branch Chief

Risk Assessment Branch 4 Health Effects Division (7509 P ) And Sheila Piper, Senior Chemist RAB 6 /HED, 7509P , Chemistry Science Advisory

Council (ChemSAC ) Sumitra Bose Biswas, Chemist RAB 6 /HED, 7509P , ChemSAC **TO:** Laura Nollen/Barbara Madden , RM20

Minor Use & Emergency Res ponse Branch Registration Division (7505P)Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 2 of 21 **Executive Summary** Cy prodinil is an anilino - py

rimidine fungicide used to control various plant diseases on a wide variety of fruit, nut, vegetable and herb crops. Under PP# 4E8273 , Interregional Research Project No. 4 (hereafter referred to as IR - 4), on behalf of the Agricultural Experiment Stations, is requesting the establishment of tolerances for residues of cy prodinil [ 4 - cyclopropyl - 6 - methyl -Nphenyl - 2 - py

rimidi namin ] in/on the following raw agricultural commodities: Artichoke ..... ................................ ................................ ............ 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 ................................ ................................ .............. 7.0 ppm Fruit, stone, group 12 - 12 .................. ................................ .... 2.0 ppm Inaddition, IR - 4 is requesting the removal of the currently established tolerance for residues of cy prodinil in/on Fruit, stone, group 12 ( 2.0 ppm) once the fruit, stone, group 12 - 12 is established. Inconjunction with PP# 4E8273 , 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 artichoke, acerola, feijoa, guav a, 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 In spire 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 th ese new use s , IR - 4 has submitted new magnitude of the residue data for cy

prodinil using the WDG formulation of cy prodinil at the proposed use rate. Inaddition, IR - 4 is requesting amendments for the Section 3 registrations for VanguardTM WG (EPA Reg. No. 100 - 828) and In spire Super TM Fungicide (EPA Reg. No. 100 - 1317) to expand currently 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 th e subject crops have been proposed. No new residue chemistry data were submitted to support these uses. Instead the petitioner wishes to rely on previously

submitted residue chemistry

data which support the currently registered uses of cy

prodinil . Inaddition, 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 In spire Super TM Fungicide (EPA Re g. No. 100 - 1317) on greenhouse cucumbers. IR - 4 has submitted new greenhouse grown cucumber magnitude of the residue data to demonstrate that the existing tolerance for residues of cy prodinil in/on vegetable, cucurbit, group 9 (0.70 ppm) is adequate for th e proposed use. IR - 4 has also submitted new small tomato magnitude of the residue data to demonstrate the existing toleranceCyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 3 of 21 for residues of cy

prodinil in/on vegetable, fruiting, group 8 - 10 (1.5 ppm) is adequate for the proposed use. **One of the products**  **(EPA Reg. No. 100 -**  **1317) addressed herein contain**  **s a second active**  **ingredient ( difenoconazole**  **) and another product (EPA Reg. No. 100**  **- 953)**  **also contains**  **a second active (**  **fludioxonil )**  **. D**  **ifenoconazole and fludioxonil are addressed under separate reviews. The**  **subject review addresses the proposed uses and supporting data for cyprodinil**  **only.** The nature of cy

prodinil residues in plants is understood based on adequate metabolism studies on apple, peach, potato, tomato, and wheat. O nly residues of parent cy

prodinil need to be included in the tolerance expression and considered for risk assessment for plant commodities. The nature of cy

prodinil residues in ruminants is also understood based on an adequate goat metabolism study . The residues of concern in ruminants are cy prodinil and its hydroxylated metabolite CGA - 304075 (free and conjugated). No poultry metabolism study

is available , but HED has conclude d that none is required . There are no new livestock feed stuffs associated with the proposed new use s of cy prodinil . Adequate HPLC/UV methods (Methods AG - 631 and AG - 631B) are available for enforcing tolerances of cy

prodinil in/ on plant commodities . The limits of quantitation ( LOQ ) for the plant methods range from 0.01 to 0.0 6 5 ppm depending on the commodity . An adequate LC/MS method (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. Inthe submitted field trial study, residues of cy prodinil were determined with a method using high performance liquid chromatography with a tandem mass spectrometer (L C/MS/MS), which is a modified version of the HPL C/UV Sy ngenta Method AG - 631B, “Analy tical Method for the Determination of Residues of CGA - 219417 in Crops by High Performance Liquid Chromatography

with Column Switching.” Sy ngenta Methods AG - 631 and AG - 631B are the current tolerance enforcement methods for determining cy prodinil in plant commodities. Cucumber, globe artichoke, guava, pomegranate, and tomato samples were stored frozen ( - 20°C ± 10°C) for up to 1 2 , 2 , 22, 11, and 1 0 months before analysis, respectively . The stability of cy prodinil has been demonstrated in a variety of other crops, including mustard greens for 20 months and grape, wine, apple, wheat (ear and stalk), strawberry, and potato for up to 2 years. Therefore , the submitted field trial data are supported by acceptable storage stabili ty data. Data are adequate to support the proposed uses of cy prodinil. The HAFT residue level of cy prodinil in greenhouse cucumber , globe artichoke , guava, and small greenhouse tomato resulting from four applications for a seasonal rate of 1.3 lb cy pro dinil a.i. /A was 0.58 , 1.33, 0.522 , and 1.12 ppm , respectively . Maximum residue levels of cy prodinil were 0.62 ppm in greenhouse cucumber , 1.52 ppm in globe artichoke, 0.626 ppm in guava , and 1.28 ppm in small greenhouse tomato . The HAFT residue level and maximum residue level of cy prodinil resulting from post - harvest treatment of pomegranate were 3.42 and 3.60 ppm, respectively . There are an adequate number of field trial s from representative geographical locations.Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 4 of 21 The Organization for Economic Cooperation and Development ( OECD ) tolerance calculation procedures were used to determine appropriate tolerance level s . A tolerance level of 1 0 ppm for pomegranate, 4.0 ppm for globe artichoke, and 1. 5 ppm for guava is appropriate. The 1.5 ppm tolerance fo r guava was translated to acerola, feijoa, j aboticaba, passionfruit, starfruit , and wax jambu , in accordance with “Reviewer’s Guide and Summary of HED ChemSAC Approvals for Amending Crop Group/Subgroups [40 CFR 180.41] and Commodity Definitions [40 CFR 180 .1(h)]” ( B. Schneider, 6/14/06 ) . **Note that the recommended**  **tolerance level for**  **pomegranate is different than th**  **at p**  **etitioned -**  **for by the registrant**  **due to the decision that each of the post**  **- harvest**  **scenarios/ techniques represented by the data constitutes s**  **eparate datasets for tolerance determination with the**  **OECD tolerance calculation procedures**  **.** No Codex MRL s are established in/on globe artichoke, acerola, feijoa, guava, jaboticaba, passionfruit, starfruit, wax jambu, and pomegranate . Canadian and Mexican MRL s has not been established for the requested crops. The Agency will be harmonized with Codex on the fruit, stone, group 12 - 12 MRL of 2.0 ppm . **Regulatory Recommendations and Residue Chemistry Deficiencies** HED has examined the residue chemistry database for cy

prodinil . With regards to cy prodinil for PP# 4E 8273 , pending submission of a revised Section B (see requirements under Directions for Use) and a revised Section F (see requirements under Proposed Tolerances), there are no residue chemistry issues that would preclude granting amended registrations for VanguardTM WG (EPA Reg. No. 100 - 828), Switch® 62.5 WG Fungicide (EPA Reg. No. 100 - 953), and In spire Super TM Fungicide (EPA Reg. No. 100 - 1317) to expand currently registered fol iar uses for globe artichoke, acerola, feijoa, guava, jaboticaba, passionfruit, starfruit, wax jambu, and pomegranate; along with the expansion of fruit, stone, group 12 - 12 or es tablishment of tolerances for residues of cy prodinil only

in/on the following commodities: 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 pp m Pomegranate............................................................10 ppm Fruit, stone, group 12 - 12 .................. ................................ .... 2.0 ppm Inaddition, the restriction on use of Switch® 62.5 WG Fungicide (EPA Reg. No. 100 - 953) and VanguardTM WG (EPA Reg. No. 100 - 828) on small size tomato may be removed. The restriction on use of In spire Super TM Fungicide (EPA Reg. No. 100 - 1317) on greenhouse cucurbits may also be removed. The approved amended registrations for VanguardTM WG (EPA Reg. No. 100 - 828), Switch® 62.5 WG Fungicide (EPA Reg. No. 100 - 953), and In spire S uper TM Fungicide (EPA Reg. No.Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 5 of 21 100 - 1317) are limited to expansions to add the commodities specified under the new crop groups/subgroups and do not include substantive changes to currently registered use patterns (i.e., maximum use rates, retreatment interv als, preharvest intervals, use of adjuvants, etc.). A human health risk assessment is forthcoming. 860 .1200 Directions for Use

– Pertains to Cy prodinil Only Section B of petition 4E8273 pertaining to uses on artichoke should be revised to specify globe artichoke only . [Note: IR - 4 submitted draft supplemental labels which are substantially similar to Section B of the petition and should be amended as well.] 860.1550 Proposed Tolerances Section F of petition 4E8273 must be revised as follows. The re commended tolerance for residues of cy

prodin i l in/on pomegranate (10 ppm) is not the same as the petitioned - for tolerance (7.0 ppm) due to the decision that data reflecting each of the three post - harvest scenarios/techniques constitute separate datasets fo r tolerance determination with the OECD tolerance calculation procedures. Inaddition the commodity definition should be for Artichoke, globe. **Background** Cy prodinil is an anilino - py

rimidine fungicide used to control various plant diseases on a wide variety of fruit, nut, vegetable and herb crops. Tolerances for residues of cy prodinil have been established in/on a variety of crop commodities at levels ranging from 0.02 - 17 0 ppm [40 CFR §180.532] . Tolerances have also been established at 0.02 ppm for cy p rodinil residues in meat by products of cattle, goats, horses, and sheep. No tolerance is established for poultry by products. The chemical structure, nomenclature, and physicochemical properties of the technical grade of cy prodinil are presented in Tabl es 1 and 2. **Table 1. Cyprodinil Nom**  **enclature.** Compound

N N

C H3 N H

Common name Cyprodinil 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 reg istry number 121552 - 61 - 2 End - use product (EP) 75% water - dispersible granule formulation (Vangard® WG 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 e mulsion [oil] in water (EW), containing 8.4% difenoconazole and 24.1% cyprodinilCyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 6 of 21 **Table 2. Physicochem** **ical Properties of Technical Grade of Cyprodinil.** Parameter Value Reference Melting point/range 75.9 0 C DP#s 345970 and 345182, 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) pH 7.6 16 pH 5 20 pH 7 13 pH 9 15 Solvent solubility (g/L at 25 C) ethanol 160 acetone 610 toluene 460 n - octanol 160 n - hex ane 30 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 th e absorbance maximum) 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)Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 7 of 21 **860.1200 Directions for Use Table**  **3. Summary of**  **Proposed Direc**  **tions for Use of Cyprodinil**  Applic. Timing, Ty pe, and Equip. Formulation

[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% W DG [100 - 828] 0. 33 4 implied 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. 3 3 4 implied 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% W DG [100 - 828] 0.33 2 by aerial 4 implied 1.3 0 A minimum retreatment interval (RTI) of 7 - 10 days is proposed. Broadcast foliar Ground Only Switch

62.5WG 37.5% W DG [100 - 953] 0.33 1 by aerial 4 implied 1.3 0 A minimum retreatment interval (RTI) of 7 - 10 days is proposed. Aerial application in California only. Pomegranate (Post - harvest dip /drench)

In - Line Dip/Drench Switch

62.5WG 37.5% W DG [100 - 953] 0.45 lb

ai/100 gal of water, wax/emul sion, or aqueous dilution of wax/oil emulsion 1 - 2 0.45 - 0.90 lb ai/100 gal of water, wax/emulsion, or aqueous dilution of wax/oil emulsion 0 For maximum decay

control, treat fruit once before storage and once after storage, prior to marketing.

Green House Grow

n Cucumbers 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. 1 Although not specified in the use directions, the use on artichoke is intended to be for globe artichoke consistent with the supporting data. Conclusions . The proposed use directions are sufficient to allow for evaluatio n of the available residue data.Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 8 of 21 **860.1300 Nature of the Residue -**  **Plants** DP# 2 19794 , G. Kramer, 2/ 13 /9 6 DP# 233182, G. Kramer, 2/20/98 MARC Decision Memo, DP# 243198, G. Kramer, 3/11/98 The nature of the residue in plants is adequately understood based on acceptable metabolism studies on apple, peach, potato, tomato, and wheat. These studies indicated that cy prodinil is metabolized primarily

by hydroxylation followed by sugar conjugation. Cleavage of the amino bridge, opening of the py rimidine ring, opening of the cyclopropyl ring and formation of thiolactic acid conjugates are minor pathways. Incorporation into starch was observed in potato tubers and wheat grain. The MARC reviewed these studies and determined that the residue of concern, for purposes o f tolerance enforcement and risk assessment, is cy prodinil . **860.1300 Nature of the Residue -**  **Livestock** DP# 233182, G. Kramer, 2/20/98 MARC Decision Memo, DP# 243198, G. Kramer, 3/11/98 DP# 345970 and 345182, G. Kramer, 6/4/08 DP# 362486, J. Stokes, 9/1 5/09 The nature of the residue in ruminants is adequately understood based on acceptable lactating goat metabolism studies using [ 14 C - phenyl] and [ 14 C - py rimidinyl ] cy

prodinil . The metabolism of cy prodinil in ruminants proceed predominantly via hydroxylation followed by conjugation with sulfuric and glucuronic acid. Breakdown of the py rimidinyl ring was seen only in the liver and resulted in Metabolite L 1. 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 kidneys of goats dosed with [ 14 C - py rimidinyl]cy

prodinil. HED originally concluded th ere were no cy prodinil metabolites of toxicological or regulatory concern in ruminant milk and tiss ues based on the dietary burden associated with the registered cy prodinil uses at that time (362486, J. Stokes, 09/15/09; 378920, B. Cropp - Kohlligian, 10/27/10). However, HED noted that if future uses significantly increase the potential livestock dietary burden, then a new cy prodinil feeding study

would be required in which residues of cy prodinil and CGA 304075 (both free and conjugated) are determined. ARIA subsequently has concluded that the residues of concern for both risk assessment and the toleranc e definition should include the combined residues of cy prodinil and metabolite CGA - 304075 ( free and conjugated) , expressed in parent equivalents. A poultry metabolism for cy

prodinil has not been submitted and none has been requested since the potential di etary

exposure of poultry

to cy prodinil residues is extremely low ( estimated at 0.005 ppm based on canola meal consumption) . There is no reasonable expectation of finite residues in poultry and egg . However, if future crop s are added that substantially i ncrease the poultry dietary burden , then HED may

require a study .Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 9 of 21 **Summary of Metabolites and Degradates to be included in the Risk Assessm ent and Tolerance Expression**  **for Cyprodinil**  **Matrix Risk Assessment**  **Tolerance Expression** Plants cyprodinil cy prodinil Livestock cyprodinil and CGA - 304075 cyprodinil and CGA - 304075 Water cyprodinil and CGA 249287 NA **860.1340 Residue Analytical Methods** Enforcement m ethods. Adequate HPLC/UV methods with column switching (Sy ngenta Methods AG - 631 and AG - 631B ) are available for enforcing tolerances of cy prodinil on plant commodities. The LOQs for these methods range from 0.01 to 0.0 6 5 ppm depending on the plant commodities . Method AG - 631B also contains proced ure s for confirmatory

analysis by GC/NPD . An adequate HPL C/MS method (GRM010.01A) is also available for enforcing tolerances in livestock commodities. This method determine s residues of both parent and the metabolite CGA - 304075 ( free and conjugated), expressed as parent. The L OQ is 0.01 ppm for each analyt e for a combined LOQ of 0.02 ppm. Data collection methods. Inthe submitted field trial studies , residues of cy prodinil were determined with a method using high performance liquid chromatography with a tandem mass spectrometer (LC/MS/MS), which is a m odified version of the HPL C/UV Sy ngenta Method AG 631B, “Analy

tical Method for the Determination of Residues of CGA - 219417 in Crops by High Performance Liquid Chromatography with Column Switching .” Sy ngenta Methods AG - 631 and AG - 631B are the current tolerance enforcement method s for determining cy prodinil in plant commodities For method AG - 631B , residues of cy prodinil were extracted with methanol:water (8:2, v/v), filtered, and acidified with dilute HCl. Residues were then cleaned - up by elution through a SPE column with ammoniated methanol. Residues were concentrated, reconstituted with 0.1% ammonium acetate , and analy zed by L C/MS/MS using a Phenomenex Sy nergi 4 micron PolarRP 80A column (75 x 2.00 mm) and a multi - component mobile phase (Component A was 0.1% ammonium acetate in water and Component B was 90/10 acetonitrile:water plus 0.1% ammonium acetate) with gradient elution. The m/z 226.1 →93.1 ion transition was used for detection and quantitation of cy prodinil . Residues were quantified using extern al standards. The validated L OQ was 0.0 1 ppm ; the L OD was not reported . The method was validated in conjunction with the analysis of field trial samples. Control samples of were fortified with cy prodinil at 0.01 - 2.1 ppm. Recoveries ranged from 70 - 109 % . Control samples were fortified with cy prodinil at 0.02 - 10 ppm. Recoveries ranged from 68 - 112 % . Conclusions . Adequate HPLC/UV methods are available for enforcing the proposed new uses . All resi d ues of cy prodinil were determined using an adequate HP LC /UV or LC /MS/MS m ethod .Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 10 of 21 **860.1360 Multiresidue Methods** G. Kramer, 11/28/1995 Data are available depicting the recovery of cy prodinil and its metabolite CGA - 232449 through FDA Multiresidue method testing protocols (C through E). Acceptable recoveries were obtained for cy prodinil in apple fortified at 0.50 ppm using Protocol D. These data were forwarded to FDA . **860.1380 Storage Stability** D233182, G. Kramer, 02/20/98 D288706, T. Bloem ,7/24/03 Cucumber, globe artichoke, guava, pomegranate , and tomato samples were stored frozen ( - 20°C ± 10°C) for up to 1 2 , 2 , 22 , 1 0 , and 11 months before analysis , respectively . The stability of cy prodinil has been demonstrated in a variety of other crops, including mustard greens for 20 months and grape, wine, apple, wheat (ear and stalk), strawberry, and potato for up to 2 years. Therefore , the submitted field trial data are supported by acceptable storage stability data. **860.1400 Water, Fish, and Irrigated Crops** The proposed use s are not relevant to this guidelin e . **860.1460 Food Handling** The proposed use s are not relevant to this guideline. **860.1480 Meat, Milk, Poultry, and Eggs** DP# s 345970 and 345182, W. Cutchin, 6/4/08 DP# 362484, J. Stokes, 9/15/09 DP# 378920, B. Cropp - Kohillig i an , 10/27/10 Adequate cattle feeding studies are available for cy prodinil , and tolerances for cy prodinil residues in livestock commodities were assessed in conjunction with petitions for tolerances on various plant commodities . Using the Agency ’s most recent guidance on constructing reasonably balanced livestock diets the maximum reasonably dietary burdens (M RDB s ) of livestock for c yp rodinil residues were calculated to be 0.8 8 ppm for beef cattle, 1.2 ppm for dairy c attle , and 0.0 05 ppm for poultry

and swine . Based on these MDBs, to lerances for residues of cy prodinil and free and conjugated CGA - 304075, expressed in parent equivalents, were required on meat by products of cattle, goats, horses, and sheep at 0.02 ppm (LOQ). Previously, HED recalculated the dietary burden using almond hull in place of wet apple pomace. The dietary

contribution from the almond hulls alone did not increase the total dietary burden . However, this proposed amended use on almonds was withdrawn and the increased tolerance for almond hulls did not occur. C onclusions. The proposed new uses do not contain any livestock feed stuffs , therefore, HED has determined that the currently established 0.0 2 ppm tolerance level s for meat by products of cattle, goats, horses, and sheep are adequate .Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 11 of 21 **860.1500 Crop Field Trials**  MRID # s 493469 01, 493469 02, 493469 03, 49346904, & 49346905 DP# 354013, 3/20/09, B. Cropp - Kohlligian The results from the field trials are summarized below . Cucumber (Greenhouse) Small and L arge Varieties Following four applications of a 2.09 lb ai/gal E W 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 o f 0 days . There were no significant differences between the residues in the large variety cucumbers vs. the small variety cucumbers. **Table 4.**  **Summary of Residues from Cucum** **ber (Greenhouse) Field Trials with E W**  **Form ulation of**  **C yprodinil**  **.** Crop Matrix Total

Application Rate (lb ai/A) PHI

(days) n 1 Residues (ppm)

Min. 2 Max. 2 LAFT 3 HAFT 3 Median 3 Mean 3 SD 3 **C yprodinil**  Cucumber (Large and Small), fruit 1.3030

– 1.3276 0 5 0.08 0.62 0.11 0.58 0.34 0.32 0.20 1 n = number of field trials. 2 Values based on total number of samples. 3 Values based on per - trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ are a ssumed to be at the LOQ . The LOQ was 0.01 5 ppm for cyprodinil in all matrices . Artichoke, globe Following four or five applications of a 2.09 lb ai/gal E W formulation at a total application rate of 1 . 300

– 1.655 lbs ai/A, individual sample (and per- trial average) residues of c yp rodinil were 0 . 825

– 1 . 52 ppm (0.932

– 1.33 ppm) in/ on mature globe artichoke flower buds collected at a PHI of 3 days . There were no significant differences between the residues in the perennial globe artichokes vs. the annual globe artichokes. **Table 5.**  **Summary of Residues from Globe Artichoke Field Trials with E**  **W Form** **ulation of Cyprodinil**  **.** Crop Matrix Total

Application Rate (lb ai/A) 4 PHI

(days) n 1 Residues (ppm)

Min. 2 Max. 2 LAFT 3 HAFT 3 Median 3 Mean 3 SD 3 **Cyprodinil** Globe artichoke, mature flower buds 1.300

– 1.655 3 4 0.825 1.52 0.932 1.33 1.22 1.17 0.18 1 n = number of field trials. 2 Values based on total number of samples. 3 Values based on per - trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ are a ssumed to be at the LOQ . The LOQ was 0.01 ppm for cyprodinil in all matrices . 4 Calculated by the reviewer . S ide - by- side fi eld trial data on lettuce, mustard greens 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 yp rodini l residues were similar for the EW and WDG f ormulations on all three crops.Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 12 of 21 Guava 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 c yp rodinil were 0 . 345

–0.626 ppm (0.353

– 0.522 ppm) in/ on guava fruit collected at a PHI of 0 days . **Table 6.**  **Summary of Residues from Guava Field Trials with WDG Form** **ulation of Cyprodinil .**  Crop Matrix Total

Application Rate (lb ai/A) 4 PHI

(days) n 1 Residues (ppm)

Min. 2 Max. 2 LAFT 3 HAFT 3 Median 3 Mean 3 SD 3 **Cyprodinil** Guava fruit 1.31

– 1.43 0 4 0.345 0.626 0.360 0.522 0.487 0.464 0.07 1 n = number of independent field trials. 2 Values based on total number of samples. 3 Values based on per - trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ are a ssumed to be at the LOQ . The LOQ was 0.01 ppm for cyprodinil in all matrices . 4 Calculated by the reviewer . Pomegranate (Post - Harvest) 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 62.5WGTM). Each of these po st - 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 ppm) 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 drenc h application with no wax at 0.45 - 0.46 lb ai/100 gal, individual sample (and pertrial 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 . **Table 7.**  **Sum mary of Residues from**  **Pom egr**  **anate Post -**  **Harvest Trials with WDG Form ulation of Cyprodinil.**  Crop Matrix Total Application

Rate ( oz ai/ 100gal ) 1 / [lb ai/100 gal] 1 PHI

(days) n 2 Residues (ppm)

Min. 3 Max. 3 LAFT 4 HAFT 4 Median4 Mean4 SD 4 **Cyprodinil** Pomegranate 7.2 / [0.45] 5 0 4 0.24 1.60 0.93 1.52 1.155 1.02 0.576 Pomegranate 14.4 - 14.6 / [0.9] 6 0 4 2.22 3.60 2.56 3.42 3.260 3.13 0.384 Pomegranate 14.4 - 14.6 / [0.9] 7 0 4 0.38 2.69 0.53 2.25 1.845 1.55 0.893 1 Calculated by the reviewer . 2 n = number of independent trials. 3 Values based on total number of samples. 4 Values based on per - trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ are a ssumed to be at the LOQ . The LOQ was 0.01 ppm for cyprodinil in all matrices . 5 O ne application as a dip with wax . 6 Total of two applications. O ne application as a dip with wax (0.45 - 0.46 lb ai/100 gal) and a second application as a dip with no wax (0.45 - 0.46 lb ai/100 gal). Applications were allowed to dry before the second application was applied. Samples were treated and collected on the same day. 7 Total of two applications. O ne application as a dip with wax (0.45 - 0.46 lb ai/100 gal) and then a drench application with no wax (0.45 - 0.46 lb ai/100 gal). Applications were allowed to dry before the second application was applied. Samples were treated and collected on the same day.Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 13 of 21 Tomato (Greenhouse) Small Varieties Following four appli cations of a 37.5% water dispersible granule (WDG) formulation at a total application rate of 1.31 - 1.33 lb ai/A , individual sample (and per- trial average) residues of cy prodinil were 0. 278

– 1.28 ppm (0. 317

– 1.12 ppm) in/on tomato fruit collected at a PHI of 0 days. **Table 8.**  **Summary of Residues from Tom**  **ato (Greenhouse) Sm all Variety**  **Field Trials with WDG**

**Form ulation of Cyprodinil**  **.** Crop Matrix Total

Application Rate ( lb ai/A) 4 PHI

(days) n 1 Residues (ppm)

Min. 2 Max. 2 LAFT 3 HAFT 3 Median 3 Mean 3 SD 3 **Cypr odinil**  Tomato fruit 1.31 - 1.33 0 3 0.278 1.28 0.317 1.12 0.365 0.600 0.45 1 n = number of independent field trials. 2 Values based on total number of samples. 3 Values based on per - trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ are a ssumed to be at the LOQ . The LOQ was 0.01 ppm for cyprodinil in all matrices . 4 Calculated by the reviewer . Conclusion: The data adequately support the requested tolerance s and proposed use patterns. **860.1520 Processed Food and Feed** None of the new uses have processed commodities that require a processing study . **860.15 5**  **0 Harmonization with Codex**  No Codex MRL s are esta blished in/on globe artichoke, acerola, feijoa, guava, jaboticaba, passionfruit, starfruit, wax jambu, and pomegranate . Canadian and Mexican MRL s have not been established for the requested crops. The Agency with be harmonized with Codex on the fruit, st one, group 12 - 12 MRL of 2.0 ppm . **860.1650 Submittal of Analytical Reference Standards** Analy tical standard s for cy

prodinil ( expiration date 7 /30/201 8 ) and CGA - 304075 (expiration date 8/31/201 6 ) are currently available in the EPA National Pesticide Standards Repository ( email communication with T. Cole , ACB, 0 4 / 08 /20 15 ). **860.1850/1900 Confined and Field Accumulation in Rotational Crops** DP# D257898, S. Levy, 2/8/2000 DP# D326346, W. Wassell, 10/18/2006 Adequate confined and limit ed field rotational crop studies are available and were conducted at 2.2x and 1.5x the current maximum use rate for rotated crops (1.3 lb ai/A). On the basis of these studies, the HED requested a field rotational crop study which also monitored for residu es of CGA - 232449, NOA - 422054, CGA - 249287, and CGA - 263208. Inthe subsequent field accumulation study, cy prodinil (WDG) was applied to mustard greens at four test sites in CA (2 tests) and NY (2 tests) as four broadcast foliar applications at 0.328 lb ai/A/application at 7 - day retreatment intervals for a total of 1.31 lb ai/A (1x rate). The primaryCyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 14 of 21 mustard greens crop was destroyed and removed 7 days after the final application, and rotational crops of wheat, lettuce and garden beets were planted at PBI s of 27 to 32 days. Samples of lettuce, garden beet roots and tops, and wheat forage, hay, straw and grain were collected from each test at the appropriate stage of maturity . All samples were analy zed for residues of parent and each metabolite ( CGA - 232449 , NOA - 422054, CGA - 249287, and CGA - 263208 ) using an adequate HPLC/MS method (Method 2213 - 01), which has a validated L OQ of 0.05 ppm for parent and each metabolite. As residues of parent and each metabolite were <LOQ in/on all lettuce, garden beet and whe at RAC samples, HED concluded that rotational crop tolerances are not currently required. **860.1550 Proposed Tolerances** The Agency

has determined that the residue of concern in plant commodities for the tolerance expression is only cy

prodinil . Tolerance s have been established for residues of cy prodinil in/on a variety of crop commodities, at levels ranging from 0.02 ppm in/on almond to 340 ppm in citrus oil [40 CFR §180.532(a)]. Tolerances have also been established at 0.02 ppm for cy prodinil and its me tabolite CGA - 304075 residues in meat by products of cattle, goats, horses and sheep. **Table 8**  **. Tolerance Sum**  **ma ry for**  **Cyprodinil** Commodity Established/Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition **Tolerance s Proposed Under PP#**  **4E8273** 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 --- **References** DP Numbers: 378920 Subject: Cyprodinil. Cyprodinil. Amended Use and Amended Tolerance Petition for Pome Fruit.

Summary of Analytical Chemistry and Residue Data. From: B. Cropp - Kohlligian To: L. Jones Dated: 10/27/10 MRID(s): 47644301Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 15 of 21 DP Numbers: 362486 Subject: Cyprodinil. Petition for Tolerance on Canola Seed Imported from Canada. Summary of

Analytical Chemistry and Residue Data. From: J. Stokes To: L. Jones Dated: 0 9/15/09 MRID(s): 47644301 DP Num bers: 345970 and 345182 Subject: Cyprodinil. Section 3 Requests for Uses on Tomato, Avocado, Herbs, Root Vegetables, Leaves of

Root and Tuber Vegetables, Lemon, Lime, Cucurbits, Kiwifruit, Green and Dry Bulb Onions, and Straw berries. Registrant’s Respon se to Conditional Registration on Carrots and Brassica Vegetables and Livestock Feeding Study. Summary of Analytical Chemistry and Residue Data. From: W. Cutchin To: W. Cutchin/B. Madden Dated: 0 6/ 0 4/08 MRID(s): 47161101 - 47161107 and 47169305 - 4716931 1 DP Number: 326346 Subject: Registration: 100 - 953; PP#8E05012; Cyprodinil on Onions. Review of Revised Label, Field Accumulation in Rotational Crops, Storage Stability, and Analytical Methods Data Requested as Conditions of Registration. From: W. Wass ell To: L. Jones/M. Waller Dated: 10/18/06 MRID(s): 46078901, 46078903, 46165901 DP Number: 288706, 288708, 288710, and 288773 Subject: Cyprodinil (PC Code 288202). Section 3 Registration for Application of Cyprodinil to Lychee,

Longan, Spanish Lime, Ramb utan, and Pulasan (ID# - 2E06447); Brassica Leafy Greens Crop Subgroup, Head and Stem Brassica Crop Subgroup, and Turnip Greens (ID# - 2E06485); Carrot (ID# - 2E06461); and Herb Crop Subgroup (ID# - 3E06529). Summary of Residue Chemistry Data. From: T . Bloem To: R. Forrest Dated: 0 7/24/03 MRID(s): 45682401, 45721502, 45726101, 45726102, 45795301, 45795302, and 45839801 DP Number: 257898 Subject: PP# 8E05012. Cy prodinil in/on Straw

berries and Bulb Vegetables (Crop Group 3). Evaluation of Residue Data and Analytical Methods. From: S. Levy To: R. Forrest/S. Brothers Dated: 0 2/ 0 8/00 MRID(s): 44615602, 44615601, 44867312, 44867314 DP Numbers: 243198 Subject: Cyprodinil. HED Metabolism Assessment Review Committee Meeting of 0 2/10/98. From: G. Kramer T o: HED MARC Members Dated: 0 3/11/98 MRID(s): NoneCyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 16 of 21 DP Numbers: 233561, 233562, 233928, 233182, 239674, and 236086 Subject: PP# 6F04656. New Chemical - Cyprodinil (i.e., Vangard®) in/on Stone Fruit, Pome Fruit, Almonds and Grapes. Evaluation of Residue Data and Analytical Methods. From: G. Kramer To: M. Waller/T. Ellwanger Dated: 0 2/20/98 MRID(s): 44186401, 44186404 and 44186410 thru 44186420; 43908402, 43908403 and 43908438 thru

43908445; 44382601; and 44275401 and 44275402 DP Number: 219794 Subject: PP#s 5G04553. New Chemical

– Cyprodinil and Propiconazole in or on Stone Fruit. Evaluation of Residue Data and Analytical Methods. From: G. Kramer To: C. Welch/ K. Whitby Dated: 0 2/13/96 MRID(s): 43709001 through 43709004, 43709048 through 43709055, and 4373 7603 DP Number: None Subject: Multiresidue Method Testing Data for Cyprodinil and CGA - 232449 From: G. Kramer To: B. McMahon, FDA Dated: 11/28/95 MRID(s): 43709050 Attachments: Appendix I - International Tolerances Appendix II

– To lerance Assessment Calculations **F. DOCUMENT TRACKING**  RDI: C. Smith 0 7 / 01 /1 5 Petition Number: 4E8273 DP#: 421157 PC Code: 288202 Template Version September 2005Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 17 of 21 **Appendix I. International Tolerances**  **Cyprodinil** (PC Code 288202; 03/12/15) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 40 CFR 180.532: Plant: C yp rodinil ( 4 - cyclopropyl - 6 - methyl N -phenyl - 2 -py

rimidinamine ) . 4 - cyclopropyl - 6 - methyl -N -phenyl - 2 - py rimidinamine Cy prodinil The residue is fat soluble. Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex Artichoke , globe 4.0 Guava 1.5 Passionfruit 1.5 Feijoa 1.5 Jaboticaba 1.5 Wax Jambu 1.5 Starfruit 1.5 Acerola 1 .5 Pomegranate 10 Fruit, stone, group 12 - 12 2.0 2 Completed: M. Negussie; 03/19/15 1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the appl icant. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 18 of 21 **Appendix II**  **. Tolerance Assessment Calculations.** For each of the crops listed below, the OECD MRL Calculator User Guide (SOP), along with the tolerance spreadsh eet, was used for calculating recommended tolerances. As specified in the SOP, the tolerance calculation is in the region of the 95 th percentile of the underlying residue distribution, and is more likely to overestimate rather than underestimate the 95 th percentile. The rounding procedures specified in the SOP were also used. The OECD tolerance spreadsheet does not require the use of maximum - likelihood estimation (MLE) procedures for values <LOQ. Using the OECD MRLCalculator , the recommended tolerances are 1.5 ppm for guava , 10 ppm for pomegranate, and 4.0 ppm for globe artichoke .Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 19 of 21 **Cyprodinil Guava**  **US 1.31**  **- 1.43 lb ai/A**  **Total number of data (n)** 4 **Percentage of censored data** 0% **Number of non -**  **censored data** 4 **Lowest res idue**  0.360 **Highest residue** 0.522 **Median residue** 0.487 **Mean** 0.464 **Standard deviation (SD)** 0.071 **Correction factor for censoring (CF)** 1.000 **Proposed MRL estimate**

**- Highest residue**  0.522

**- Mean + 4 SD**  0.749

**- CF x 3 Mean**  1.392 **Unrounded MRL**  1.392 **Rounded MRL 1.5**  High uncertainty of MRL estimate. [Small dataset] **Residues (mg/kg) n**  0.36 1 0.483 1 0.491 1 0.522 1Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 20 of 21 **Cyprodinil Pomegranate**  **US 0.9 lb ai**  **/100 gal 1**  **Total number of data (n)** 4 **Perc entage of censored data**  0% **Number of non -**  **censored data** 4 **Lowest residue** 2.560 **Highest residue** 3.420 **Median residue** 3.260 **Mean** 3.125 **Standard deviation (SD)** 0.384 **Correction factor for censoring (CF)** 1.000 **Proposed MRL estimate**

**- Highes**  **t residue** 3.420

**- Mean + 4 SD**  4.662

**- CF x 3 Mean**  9.375 **Unrounded MRL** 9.375 **Rounded MRL 10**  High uncertainty of MRL estimate. [Small dataset] **Residues (mg/kg) n**  2.56 1 3.26 2 3.42 1

1 Total of two applications. O ne application as a dip with wax (0.45 - 0.46 lb ai/100 gal) and a second application as a dip with no wax (0.45 - 0.46 lb ai/100 gal). Applications were allowed to dry before the second application was applied. Samples were treated and collected on the same day.Cyprodinil Summary of Analytical Chemistry and Residue Data DP#: 421157

Page 21 of 21 **Cyprodinil Artichoke**  **, globe**

**US 1.300**  **– 1.655 lbs ai/A**  **Total number of data (n)** 4 **Percentage of censored data** 0% **Number of non -**  **censored data** 4 **Lowest residue** 0.932 **Highest residue** 1.330 **Median residue** 1.215 **Mean** 1.173 **Standard deviation (SD)** 0.180 **Correction factor for censoring (CF)** 1.000 **Proposed MRL estimate**

**- Highest residue**  1.330

**- Mean + 4 SD**  1.894

**- CF x 3 Mean**  3.519 **Unrounded MRL** 3.519 **Rounded MRL 4**  High uncertainty of MRL estimate . [Small dataset] **Residues (mg/kg) n**  0.932 1 1.14 1 1.29 1 1.33 1