UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON D.C., 20460 

MAY 01 2015 

MEMORANDUM 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Review of Benefits for the Proposed Registration of a New Fungicide Active 

Ingredient lsofetamid (DP 425463) 

FROM: Leonard Y oum1an, Plant Pathologist 

Biological Analysis Branch 

THRU: Arnet Jones, Chief 

Biological Analysis Branch 

Biological a~d Economic Analy · 

TO: Heather Garvie, Chemical Review Manager 

Fungicide Branch 

Registration Division (7504P) 

Product Review Panel: March 18, 2015 

SUMMARY 

OPP is reviewing the application for registration of isofetamid as a new fungicide active 

ingredient with proposed uses including almond, grape, small berries, lettuce, oil seed crops, and 

turf. Isofetamid is a succinate dehydrogenase inhibitor (SDHI) fungicide. Resistance to some 

registered SDHI fungicides has limited their efficacy in some use sites. Fungicide sensitivity 

tests of various pathogens indicated that isofetamid is not cross-resistant to some currently 

registered SDHI fungicides." Therefore, isofetamid can offer a benefit to growers as an effective 

SDHI component in an integrated fungicide program where SDHI resistant populations have 

reduced the efficacy of some currently registered SDHI fungicides. Under conditions where 

SDHl-resistance has been identified in the field there is the potential for increases in crop yield, 

quality, and revenue with the use of isofetamid as an alternative to manage pathogens resistant to 

some other SDHl fungicides. Benefits might also be recognized for isofetamid treatments on 

registered crops with minor pesticide uses (e.g., strawberries or other small berries). It is not 

anticipated that isofetamid would enhance yield, quality, or revenue increases compared to 

currently registered fungicides in situations where SDHI-resistance has not developed. 
There may be a further benefit of isofetamjd field applications, which may provide postharvest 

residual activity on strawberry fruit that could reduce the incidence of gray mold (Botrytis 

cinerea). Growers and consumers may benefit from improved control of gray mold on ripe 

strawberry fruit. 

BACKGROUND 

Isofetamid is being reviewed by OPP as a new fungicide active ingredient. OPP considers both 

the potential risks and benefits of a pesticide in its decision on the requested registration. Here, 

BEAD provides information regarding the potential benefits of isofetamid use. Tsofetamid is 

classified as a succinate dehydrogenase inhibitor (SDHT) of fungal pathogens (FRAC, 2015). 

The Fungicide Resistance Action Committee assigns SDHI chemicals as Group 7 fungicides. 

Group 7 includes fungicides with different chemical compositions that generally act to inhibit 

electron transport in the fungal mitochondria, thereby affecting respiration. Group 7 fungicides 

include isofetamid (phenyl-oxo-ethyl thiophene amide), boscalid (pyridine-carboxamide), 

fluopyram (pyridinyl-ethyl-benzamide), penthiopyrad and fluxapyroxad (pyrazole-4-

carboxamide), flutolanil (phenyl-benzamide), and carboxin and oxycarboxin (oxathiincarboxamides). SDHI fungicides occupy an important place in disease management due to their 

activity against a broad spectrum of pathogens, especially for important target pathogens that 

include Afonilinia spp. (almond), Bollytis cinerea (grapes, berries), and Sclerotinia spp. (lettuce, 

canola, turf). 

BIOLOGICAL BENEFITS 

Effectiveness Against Some SOHi-resistant Pathogens 

There could be a benefit to the use of isofetamid to enhance both resistance and disease 

management where SD HI-resistant populations have reduced the efficacy of some currently 

registered SOHi fungicides. Field resistance to some SDHJ fungicides by important pathogens 

such as Botrytis cinerea and Alternaria solani was observed not long after the first field use (e.g., 

Fernandez-Ortuno et al., 2012; Miles et al., 2013; Gudmestad et al., 2013; Yin et al., 201 1). For 

example, the reported loss of efficacy of a mixed SDHl/Qol ( quinone outside inhibitor) fungicide 

against gray mold in North Carolina strawberries led to the discovery that 61.5% of sampled 

isol~tes of B. cinerea were resistant to the SDHI fungicide (Fernandez-Ortuno et al., 2012). 

Reports of cross-resistance by A. solani to both boscalid and penthiopyrad (Miles et al., 2013) or 

boscalid and carboxin (A venot and Michail ides, 2010) indicate the potential for cross-resistance 

and a reduction of the effectiveness of at least some of the SDHT fungicides. In studies 

submitted by the registrant, isofetamid was shown to be effective even at low rates when tested 

against various SOHi-resistant isolates. These results are consistent with published reports that 

indicate that not all SDHI fungicides exhibit cross-resistance (Gudmestad et al., 2013; Avenot 

and Michailides, 2010). However, the effect on sensitivity of pathogens to isofetamid after 

commercial field use is not known. In spite of differences in chemistry and sensitivities by 

pathogens to the various SDHI fungicides, FRAC guidelines indicate that a pathogen population 

2 
resistant to one SDHI chemistry may be preselected to eventually form resistance to another 

(Sierotzki and Scalliet, 2013). 

Postharvest Residual Activity-Strawberry 

Because of common and significant losses from gray mold 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 latent 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 fruit 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 (Table 12, p 36- Leggett, 

2015). Results indicated that isofetamid-treated strawberries had significantly reduced 

incidence of gray mold (ranging from 7-17% depending on rate) seven days postharvest. Fieldapplied treatments of cyprodinil/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 trials 

conducted in Florida in 2012-2013 (Table 12, p 161- Leggett, 2015). lsofetamid (used alone or 

with another fungicide) field-treated strawberry plants provided statistically reduced incidence of 

B. cinerea on harvested strawberries (ranging from 7- l 0%) stored for seven days compared to 

boscalid/pyraclostrobin treatments (48% incidence) and untreated (43%). Cyprodinil/fludioxonil 

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-applied fungicides on Albion 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 similar 

control of gray mold on fruit stored after 5-7 days. All provided significantly greater control 

than the untreated or boscalid/pyraclostrobin-treated plants, which had comparable control (0%). 

However, yietd and economic return were not different for any treatment. 

Studies on the effect of field-treated plants on postharvest gray mold control were conducted in 

North Carolina (Table 2, p 325-. Leggett, 2015). Field treatments with isofetamid or 

cyprodinil/fludioxonil provided significantly greater control of B. cinerea than standard 

fungicide treatments. There was no significant difference in marketable yield among fungicide 

treatments. All 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 
Comparative Efficacy 

The registrant submitted results of field trials with treatments of isofetamid and several standard 

fungicides under conditions where resistant pathogen populations were not identified. Trials 

were conducted on almond, canola, grape, lettuce, strawberry, and turf (Grove, 2013; Leggett, 

2015). Comparative efficacy results were reported for major disease targets of the crops that 

were tested (Table I). Comparisons were conducted generally with single active ingredients or 

sometimes two-a.i. products. Isofetamid provided at least comparable disease control (measured 

as disease incidence and severity) when compared to standard treatments. Typically, in an 

integrated fungicide spray program a few to several fungicides with different modes of action are 

rotated depending on the disease and relevant spray timing. Treatments included current 

fungicides tebuconazole/trifloxystrobin, captan, penthiopyrad, difenoconazole/cyprodinil, 

fluopyrarn/tebuconazole, metconazole, cyprodinil, fenhexamid, fludioxon il/cyprodinil, 

boscalid/pyraclostrobin, fluazinam, and ziram. 

Table 1. Field trials were conducted to compare the efficacy of isofetamid and standard 

fungicides against selected target diseases. 

Crop Tan!et Diseases (number of trials I 

Almond Brown rot blossom blight (Monili11ia spp.) [ 11] 

Shot hole (Wilsonomyces carpophilus) [9] 

Gray mold (8011y1is cinerea) [2] 

Anthracnose (Colletotrich11111 lrifolii) [21 

Cano la White mold (Sclerotinia sclerotiorw11) 

Grape Bunch rot (B. cinerea) (8) 

Powdery mildew (£1ysiphe 11eca1or) [3] 

Rioe rot (Colletotrichum soo.) [21 

Lettuce Sclerotinia drop (S. minor. S. sclero1ioru111) f 61 

Strawberry Gray mold (8. cinerea) [8] 

Powdery mildew (Sphaerotheca macularis) [2] 

Anthracnose (Colletotrich11111 ac111a111111) [2] 

Turf Dollar soot (S. homeocarpa) [ 15] 

ECONOMIC BENEFITS 

Under conditions where SOHi-resistance has been identified in the field there is the potential for 

increases in crop yield. quality, and revenue with the use of isofetamid as an alternative to 

manage pathogens resistant to some other SDI II fungicides. Therefore, there could be a benefit 

for growers with the use of isofetamid in an integrated fungicide spray rotation program where it 

could replace a SDHI fungicide that has shown reduced efficacy due to pathogen resistance. It is 

not anticipated that isofetamid would enhance yield. quali ty, or revenue in situations where 

SOHi-resistance has not developed. There could be an additional economic benefit if B. cinerea 

damage is reduced after fruit harvest as it appears from the experimental studies that isofetamid 

has some postharvest residual effect on reducing gray mold in storage. 

In general, the purpose of an economic analysis is 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 represents an improvement over existing technology (e.g., increased efficacy 

4 
or improvement in resistance management), then users of the pesticide may benefit because 

production of their commodity or service is enhanced. There are generall y three ways in which 

production may be improved with the use of a new pesticide. First, use of a pesticide avoids pest 

dan1age and allows a greater quantity to be produced. Second, the avoided damage may result in 

a higher qua li ty of product as measured by grade or 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 or all of these improvements might occur in a given situation. Further, 

beyond the direct benefits to producers who use the pesticide, consumers of the commodity or 

service may benefit if it becomes less expensive and more abundant. 

CONCLUSION 

The use of isofetamid could offer benefits as an alternative SDHT fungicide where SDHIresistant pathogen populations have resulted in disease control failures. Benefits might also be 

recognized for isofetamid treatments on registered crops with minor pesticide uses (e.g., 

strawberries or other small 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 resistance to boscalid. It is not known, however, if°the sensitivity trait exhibited by 

isofetan1id prior to its commercial use will persist long-term with use in field applications. 

Benefits might include greater crop yield and quality compared to a situation where a SOHi 

fungicide has fai led to control disease due to substantial resistant populations. 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 isofetamid appears to offer similar efficacy to registered SOHi fungicides such as 

boscalid, fluopyram. and penthiopyrad. It would likely have a similar use pattern to some other 

registered SDHI fungicides. 

Another potential benefit may be isofetamid's apparent residual activity on harvested strawberry 

fruit in short-term storage. Botrytis cinerea is an important postharvest pathogen and can cause 

extensive losses. Small experimental trials indicated that isofetarnid-treated plants provided 

significantly reduced incidence and greater control of B. cinerea on fruit after 5-7 d in storage 

compared to untreated or boscalid/pyraclostrobin treatments. Generally. cyprodinil/fludioxonil 

field treatments provided similar postharvest control of B. cinerea as isofetamid on fruit. 

Ho-vvever, cyprodinil/fludioxonil may be applied only twice per season and isofetamid could be 

beneficial as a rotation partner. 

5 
REFERENCES 

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evolution of resistance to succinate dehydrogenase inhibiting (SOHi) fungicides in 

phytopathogenic fungi. Crop Protection 29:643-65 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 the Carolinas. Plant Disease 

96:1198-1203. 

http://www.apsnct.om/publi cations/plantdiseasc/2012/ August/Pagcs/96 8 1198.aspx 

FRAC. 20 15. Fungicide Resistance Action Committee Code List: Fungicides Sorted by Mode of 

Action. http://www. frac. info/docs/default-source/pub! ications/frac-code-1 ist/frac-code-1ist-2015-

tinalC2AD7 AA36764.pd f?sfvrsn=4 

Grove. M. D. 2013. Summary of comparative perfonnance (efficacy) data for isofetamid 400SC 

(crop and turf labels) fungicide. Submitted by ISK Biosciences Corporation, IB-2013-MDG-OO 1-

00 1, April 12, 2013. 

Gudmestad. N. C .. Arabiat, S., Miller, J. S., and Pasche, J. S. 2013. Prevalence and impact of 

SOHi 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 

Leggett, M. F. 20 15. Comparative performance of isofetamid 400SC fungicide on select fungal 

pathogens. Submitted by ISK Biosciences Corporation, IB-2015-ML-001-0 I, April 2, 2015, 329 

pp. 

Miles, T. D., Fairchild, K. L., Merlington, A., Kirk, W. W., Rosenzweig, N., and Wharton, P. S. 

2013. First report of boscalid and penthiopyrad-resistant isolates of Alternaria solani causing 

early blight of potato in Michigan. Plant Disease 97: 1655. 

http://apsjournals.apsnct.org/doi/abs/l 0.1094/PDIS-03-13-0279-PD 

Sierotzki. H. and Scalliet, G. 20 13. A review of current knowledge of resistance aspects for the 

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http://apsjournals.apsnct.org/doi/pdf/l 0.109-t/PI IYT0-01-13-0009-RVW 

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University. http://\\\\'w.fruit.comell.edu/berrv/ipm/ipmpdfs/strnravmoldcontrol.pdf 

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