UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON D

. C ., 20460 

## MAY 

## 01 2015

MEMORANDUM OFFICE OF CHEMICAL SAFETY AND PO L LUTION PREVENT I ON

SUBJECT: Review of Benefi t s for the Proposed Registration of a New Fung icide Active Ingredient lsofetamid (D P 425463) 

### FROM: Leonard Youm1an , Plant Pathologist Biologica l Analys i s Branch T HRU : Arnet Jones, Ch ief Biological Analysis Branch Biological**a~d** Economic Ana ly · TO: Heather Garvie, C hem ical Rev iew Manager Fung i cide Branch Registration Division (7504P)
Product Re v iew Panel: March 18, 2015


### SUMMARY OPP is rev i ewing the application for registration of isofetam id as a new fungicide act ive ingredient with proposed uses in cl udin g a lmond , gr ape, small berries , lettuce, oil seed crops , and turf. I sofetamid is a succ in ate dehydrogenase inhibitor (S DHI ) fungicide

. Resistance to some registered SDH I fungicides has limited their efficacy in some use sites. Fung i c ide sensiti vity tests of various pathogens indicated that isofetamid is not cross- r esistant to some current ly registered SDH I fungicides ." Therefore , i sofetam id can offer a benefit to growers as an effect ive SD HI component in an integrated fungicide program where S DHI resistant populations have reduced the efficacy of some c urrently registered SDHI fungicides. Under conditions where SDH l -resistance has been ide nti fied in the field there i s the potential for increases in crop yield , quality , and revenue with the use of isofetamid as an a lternat ive to manage pathogens resistant to some other SDH l fungic ides. Benefits might also be r ecog ni zed for isofetamid treatments o n registered crops with minor pesti c ide uses (e.g. , strawberries or other small be rri es)

. It i s not a nti cipated that isofetamid wou ld enhance yi e ld , quality, or revenue increases compared to cur rent ly registered fungicides in situations w here S DHI- res i stance has not developed.

### There may be a further benefit of isofetamjd field applications , which may provide postharvest resid ual activity on strawberry fruit th at could reduce the incidence of gray mold 

### (Botrytis cinerea). Growers and co n sumer s may benefit from imp roved control of gray mold on ripe strawberry fruit.


### BACKGROUND Isofetamid i s be in g reviewed by OPP as a new fungicide active ingredient. OP P considers both the potenti a l risks and benefits of a pesticide in its decision on the requested registration. Here , B EAD prov ides information regarding the potential benefits of i sofetamid use. T sofetam id i s classified as a succinate dehydrogenase inhibi to r (SDHT) of funga l pathogens (FRAC, 2015). The Fung icide R esis tance Ac ti on Comm ittee ass i gns SDHI chem icals as Group 7 fungicides. Group 7 includes fungicides with different chem ica l compositions that general ly act to inhibit e lectron transport in the funga l mitochondria , thereby affectin g respiration. Group 7 fungicides include isofetamid (pheny l- oxo-ethyl thiophene am ide) , boscalid (pyridine-carboxamide) , fluopyram (pyridin y l- ethy l-benzam ide) , penthiopyrad and fluxapyroxad (pyrazole

- 4

- carboxamide) , flutolanil (pheny l-benzamide), a nd car b oxin and oxycarboxin (oxathiincarboxamides)

. S DHI fungicides occupy an important place in disease management due to their activ ity against a broad spectrum of pathogens, especially for important target pathogen s that include 

### Afonilinia spp . (al mond), 

### Bollytis cinerea (g rapes , berries) , and 

### Sclerot inia spp. (lettuce , canola, turf).


### BIOLOGICAL B ENEFITS Effectiveness Against Some SOHi-res ista nt Pathogens There co uld be a benefit to the use of isofetamid to enhance both resistance a nd disease management where SDHI-resistant populations have reduced the efficacy of some cu rre ntl y registered SO Hi fungicides

. Field resistance to some SDHJ fu ng ic ides by imp ortant pathogens such as 

### Botryt is cinerea and 

### Alternaria solan i was observed not long after the fi r st field use (e.g., Fernandez-Ortuno et al. , 2012 ; Miles et al. , 20 1 3; Gudm estad et al., 2013; Yi n et al. , 201 1 ). For examp le , the reported loss of efficacy of a mixed S DHl/ Qol (quinone out side inh ibitor) fungicide against gray mold in No rth Caro lin a strawberries led to the discovery th at 61.5% of sampled**isol~tes** 

### of 

### B. cinerea were resistant to the SDHI fung ic ide (Fernandez-O rtuno et al. , 20 12). Reports of cross - resistance by 

### A. solani to both bosca lid and penthiopyrad (M il es et a l. , 2013) or bosca lid a nd carboxin (A venot and Mic ha il ides, 2010) indicate the potentia l for cross-resis tance and a reduction of the effectiveness of at least some of the SDHTfungicides. In studies su bmitted by the registrant , isofeta mid was shown to be effect ive even at low rates when tested against vario u s S OHi- resistan t isolates

. Th ese res ult s are consistent with published reports that indicate that not a ll SD HI fungicides exhib it c r oss -resistance (Gudmestad et al. , 2013; Avenot and Michailides , 2010). However , the effect on sensitivity ofpathogens to isofetamid after commercial field u se is not known. In 

### spite of differences in chemistry and sensiti v iti es by pathogens to the various SDH I fungicides , FRAC guidelines indicate that a pat hogen population



### 2resistant to one SDHI chemistry may be p r eselected to eventuall y form resistance to another (Sierotzki and Scalliet , 2013).



### Posth arvest Resi du a l Activ ity-Strawber ry Because of common and significant losses from gray mo ld fruit rot 

### (B. cinerea) a reduction in gray mold rots would be a benefit to growers and consumers (Turechek, 2013 ). 

### B. cinerea initially infects flowers and remains l atent until fruit is ripe. In storage (typically only 5-7 days for strawbeD"ies) B. 

### cinerea becomes active and infected fruit can " nest " as adjacent fru it become infected. The registrant submitted results of field trials conducted in 2011-2012 on Florida strawbeD"ies. At harvest the incidence of 

### B. cinerea was low (Table 9 , p 3 3-Leggett, 2015). Yet after seven days in storage gray mold incidence on fruit from untreated and boscalid/pyraclostrobin-treated plants was 70% and 80% , respectively (Tab l e 12 , p 36

- Leggett , 2015)

. Results i ndicated that isofetamid-treated strawberries had significantly reduced incidence of gray mo ld (rang ing from 7-17% depending on rate) seven days postharvest. Fieldapplied treatments of cyprod inil/fludioxonil resulted in 47% incidence of gray mold on fru it after seven days in storage (Table 12 , p 36-Leggett, 2015). Similar results were found in tria l s conducted in Florida in 2012-2013 (Table 12 , p 161

- Leggett , 2015). lsofetamid (used alone or with another fungicide) field-treated strawberry pl ants provided statistically reduced incidence of 

### B. cinerea on harvested strawberr i es (ranging from 7

- l 0%) stored for seven days compared to boscalid / pyraclostrobin treatments (48% incidence) and untreated (43%)

. Cyprodinil/fludioxoni l and penthiopyrad field treated plants provided statistically similar incidence of 

### B

. cinerea compared to isofetamid of 16% and 15%, respectively. A 2012-2013 trial with field-app li ed fungicides on A lbion strawbeny in California (Table 3 , p 259

- Leggett , 2015) indicated that isofetamid (35-79% control) , penthiopyrad (27%), fluopyranv trifloxystrobin (12%) , and cyprodinil/fludioxonil (84%) provided statistically s imilar control of gray mold on fru it stored after 5-7 days. All provided s i gnificantly greater control than the untreated or boscalid/pyrac lostrob i n-treated pl ants , which had comparable control (0%). However , yietd and economic return were not different for any treatment. Studies on the effect of field-treated p lants on postharvest gray mold contro l were conducted in North Carolina (Table 2 , p 325-

. Leggett, 2015)

. Field treatments w ith isofetamid or cyprodini l/fludioxonil provided s ign ificantly greater control of 

### B. cinerea than standard fungicide treatments. There was no s ignificant difference in marketab le yield among fungicide treatments. A ll treatments provided statistically greater marketable yield than the untreated control. Overall, marketable yields of harvested strawberry plants treated with isofetamid were statistically comparable to plants treated with current standards

.

3

### C omp a r ati ve E ffi c a cy The registrant submitted res ults of field tria ls with treatments of i sofetamid and several standard fungicides unde r conditions w here resistant pathogen popu l ati ons we r e not identified. T rials were conducted on almond , canola, grape, lettuc e, strawberry, and turf (Grove, 2013; Leggett , 2015)

. Comparative e fficac y r es ults were reported for major disea se targets of the crops that were tested (Tabl e I). Compariso ns were conducted gene rally with s ingl e active ingredients or sometimes two-a.i. products. I sofetamid provided at least comparable disease control (measured as disease incidenc e and severit y) when compared to standard treatments. Typ icall y, in an integrated fungicide spray program a few to several fungicides with different modes of action are rotated depending on the disease and relevant s pray timing. Treatments included current fungicides tebucona zo le/trifloxystrobin , captan , p e nthiopyrad , difenocona zo le/ cyprodinil, fluopy rarn/tebuconazo le , metconazole, cyprod ini l , fenhexam i d , fludioxon il/cy prodi ni l, boscalid/pyraclostrobin , fluazinam , and ziram. 

### Tab le 1. Field trials were conducted to compare the efficacy of isofetamid and standard fungicides against selected target diseases.

Crop Tan!et Di seases (numb er o f tri a l s I Almond Brown rot blossom blight (Monili11ia spp.) [ 11] Shot hole (Wilsonomyces carp op hilus) [9] Gray mold (8011y1is cinerea) [2] Anthracnose (Colletotrich11111 lri fo lii) [ 21 Ca no la White mold (Sclerotinia sclero tio rw11) Grape Bunch rot (B. c inerea) (8) Powdery mildew (£1ysiphe 11eca1 o r) [3] Rioe rot (Colletotrichum soo.) [21 Lettuce Sclerotinia drop (S. mino r. S. sclero 1io ru111) f61 Strawberry Gray mold (8. ci n e rea) [8] Powder y mildew (Sphaerotheca ma cularis ) [2] Anthracnose (Colletotrich11111 ac 111a111111) [2] Turf Dollar s oot (S. homeocarpa) [ 15]


### EC O NOMI C B E NEF ITS Under conditions where S OHi-resistance has been id e ntifi ed in the field th ere i s the potential for increases in crop yie ld. quality , and re ven ue w ith the use of isofetamid as an a lternati ve to manage pathogens resistant to some other SDI II fungic ides. Therefore, there could be a benefit for growers with th e u se of isofetamid in an integrated fungicide spray rotation program where it could replace a SDHI fungicide that has shown red uced efficacy due to pathogen resistance. It is not ant icipated that isof e tamid would enha nce y ield. qua li ty, or revenue in si tuations where SOHi-resistance has not developed

. There could be an additional economic benefit if 

### B. ciner ea damage is reduced after fruit harvest as it appears from the experimental s tudie s that isofetamid has some postharves t residual effect on reducin g gray mold in storage. In genera l , the purpose of an economic analysis i s to quantify , to the extent possible, the benefits that arise from the use of a new pesticide. Conceptually , a new pesticide represents a change in technology used to produce an agricultural commodity or some other commodity or service. 

### If the new pesticide represe nts an improvement over existing technology (e.g., increased efficacy 4or improvement in resistance management) , then users of the pesticide may benefit because production of their com m od ity or service is e nh anced

. There are genera ll y three ways in which production may be improved with the use of a new pesticide

. F irst, u se of a pesticide avoids pest dan1age and allows a g reater quantity to be produc e d. Second, the avo ided damage may result in a hi g her qua li ty of product as measured by grade o r type of market (e.g

.. fresh vs processed), thus returning a higher price. Third , the new pesticide is more cost-effective , resulting in lower production costs. Any o r all of these improvements might occur in a given situation. Further , beyond the direct benefits to producers who use the pesticide , consumers of the co mmodi ty o r service may benefit if it becomes less expensive and more abundant.


### C ONCLUSION The use of isofetamid co uld offer benefits as an al t ernative SDHT fungicide where SDHIresistant pathogen populations have resulted in disease co ntrol failures. Benefits might also be recognized for i sofetamid treatments on registered crops with minor pesticide uses (e.g., strawberries or other sma ll berries). Isofetamid could act as an alternative SDHI component in an integrated fungicide program since some known SDHI

- resistant pathogens appear to be sensitive to it. Resistance tests indicated high sensitivity to isofetamid among isolates that had strong resistanc e to boscalid. It is not known , however , if°the sensitivity trait exhib ited by isofetan1id prior to it s com me rcial use will pers ist long-term with us e in field applications. Benefits might includ e g rea ter crop yie ld a nd quality compared to a situation where a SOH i fungicide has fai led to control disease due to substan tial resistant popu lati ons. However , because SDHI fungicides are often used as part of a rotation program, season long benefits regarding yield or enhanced revenue may be difficult to assess. Where SDHI-resistance has not been a concern isof etamid appears to offer similar efficacy to registered S OHi fung ic ide s suc h as boscalid, fluopyram. and penthiopyrad. It would likely have a similar use patt ern to some other registered SDHI fungicides. Another potentia l benefit may be isofetamid 's appa rent residual activity o n harve ste d strawberry fruit in s hort-term s to ra ge. 

### Botrytis cinerea is an important postharve st pathogen and can cause extensive losses. Sma ll experimental trials indicated that isofetarnid-treated plants provided significant ly reduced incidence and greater cont r ol of 

### B. cinerea o n fruit after 5-7 d in storage compared to untreated or boscalid/pyraclostrobin treatments. Generally. cyprodinil/fludioxonil field treatments provided sim ilar postharvest control of 

### B. cinerea as isofetamid on fru it. H o-vvever, cyprodinil/fludioxonil may be applied only twice per season and isofetamid could be beneficial as a rotat ion partner.



### 5

### REFERENCES Avenot. H.F. and Michailides , T. J. 2010. Progress in un ders tanding molecular mechanisms and evolution of resistance to succinate dehydrogenase inhibiting ( SOHi) fungicides in phytopathogenic fungi. Crop Protect ion 29 :64 3-65 1. http ://ac.clscdn

. com/ S0261219410000554/l

- s2

. 0

- S026121941000055-t-main.pdf? tid = b40868c6

-d 144

- 1 1c3-9152-00000aacb362&acdnat= 1398958056 ca9bdalJ2ab85c80ae08caa29d08c644 Fernandez-Ortuno. 

### D., Chen , 

### F. , and Schnabel, G. 2012. Resistance to pyraclostrobin and boscalid in Botrytis cinerea isolates from strawberry fields in th e Carolinas. Plant D isease 96:1198-1203. http ://www.apsnct.om / pub li catio n s/ p lan td iseasc/ 2012/ August / Pagcs/ 96 8 1 198.aspx FRA C. 20 15

. F ungicide Resistance Action Committee Code Li st: Fungicides Sorted by Mode of Action. http: //www . frac. i nfo/ docs/ default

- source/ pub! ications / frac-code-1 ist / frac-code

- 1ist

- 2015

- tinalC2AD7AA36764 .pd f?sfvrsn = 4 Grove. M. 

### D. 2013

. Summary of comparative perfonnance (efficacy) data for isof etami d 400SC (crop and turf labels) fungicide. Submitted by I SK Biosciences Corporation , IB-2013-MDG-OO 1- 00 1 , Apri l 12 , 2013. Gudmestad. N. C

.. Arabiat , S. , Miller , J. S., and Pa sche, 

### J. S. 2013. P revale nc e and impact of SO Hi fungicide resistance in 

### Alternaria solani

. Plant Disease 97:952-960. http: //www.ndsu.edu/fi leadm in / potatopathologv / Papcrs / A 1 tcrnaria sol an i. pd f L eggett , 

### M. F. 20 15. Comparative performance of isofetamid 400SC fungicide on select fungal pathogens. S ubmitted by ISK Biosciences Corporation , IB-2015-ML-001-0 

### I, Apri l 

### 2, 2015, 329 pp. Mil es , 

### T. D. , Fairc hi ld , K. L. , Merlington , A., Kirk , W. W. , Ros e n zwe ig , N. , and Wharton , P. S. 2013. First repo rt of boscalid and penthiopyrad-resi s tant isolates of Alternaria so lani causing early blight of potato in Michigan. Plant Disea se 97: 1655. http: //apsjourna ls . apsnct
. o rg/do i / abs/l 0.1094/ P DIS

- 03-13-0279-PD Sierotzki. H. and Scalliet, G. 20 13. A review of current knowledge of resistance aspects for the next-generation succinate dehydrogenase inhibitor fungicides. Phytopathology 103 :880-887. http: //apsjournals.apsnct.org/doi/ pdf/l 0 .10 9-t / PI IYT0-01-13-0009

- RVW Tu rechek. B. 20 1 3. Managing gray mold of strawberry. Dept. P lant Pathology , Cornell Univers it y. http: //\\\\'w.fruit.comell.edu/berrv/ ipm/ ipmpdfs / strnravmoldcontrol .pdf Yin , Y. N

.. Kim , Y. K. , and Xiao, C. L. 2011. Molecular c har acterizat ion of boscalid resistanc e in field isolates of Botrytis cinerea from apple. Phytopathology I 0 I :986-995.



### 6