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UNITED STATES ENVIRONMENT AL PROTECTION AGENCY WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION
MEMORANDUM 

## JAM 2 8 

## 2021

SUBJECT: Review ofthe Registrant's response to the data deficiencies found by the Agency in its review ofproduct chemistry, manufacturing process oftwo products: NoFly Technical and NoFly WP containing the new AI 

### Paeci/omyces.fumosoroseus strain FE 9901. FROM: 

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### S. Barsoum, Ph.D., Microbiologist,**~~. ~o--**  Microbial Pesticides Branch,
THROUGH: Biopesticides and Pollution Prevention Division**~** John L. Kough, Ph.D., Senior Scientist

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TO: Microbial Pesticides Branch, Biopesticides and Pollution Prevention · · on A Anna Gross, Regulatory Action Leader Microbial Pesticides Branch, Biopesticides and Pollution Prevention Division (7511C)
ACTION REQUESTED: To review the Registrant's response (letter dated 11/9/2010) to the deficiencies found by the Agency (letter dated 11/5/20l0) in its review ofproduct chemistry, manufacturing process oftwo products: NoFly Technical and NoFly WP containing the new AI 

### Paeci/omyces.fumosoroseus strain FE 9901.
CONCLUSION: SUPPLEMENTAL The registrant has successfully responded to one ofthe deficiencies concerning the nature ofthe test material used in acute toxicity/pathogenicity studies but has not shown definitive evidence that toxic metabolites are not produced by NoFly Technical and NoFly WP.
CONTAINS FIFRA CONFIDENTIAL BUSINESS INFORMATION

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DATA REVIEW RECORD Active Ingredient: Product Name: Company Name: Reg. No: Chemical Number: Decision Number: DP Barcode: MRIDNo: BACKGROUND: 

### Paecilomycesfumosoroseus strain FE 9901 NoFly Technical, and NoFly Wettable Powder Natural Industries Inc., Houston, TX 

### 73314-A, 733314-T 115003 416481 384372 482912-01 

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Paecilomyces.fumosoroseus is a naturally-occurring fungus in most countries ofthe world and occurs in various soil types at very low densities. Its target organisms are the whiteflies. In its natural environment, 

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. fumosoroseus strain FE 990l is dispersed as conidia orblastospores, either by air or water movement or by other insects and/or mites. The mode ofinfection proceeds as such: conidial attachment, germination, penetration ofthe insect cuticle, vegetative growth, and conidiogenesis. The infection cycle of

### P.fumosoroseus strainFE 9901 is particularly rapid under optimal conditions. The Agency has reviewed a submission for registration ofNoFly Technical and NoFly WP containing

### Paecilomyces.fumosoroseus strain FE 9901by Natural Industries Inc. and found deficiencies intheir application (letter dated 11/5/20l0). The registrant has responded to the deficiencies in a letter dated 11/9/2010 and a new study on secondary metabolites and cytotoxicity in still and bioreactor cultures of

### Paecilomyces.fumosoroseus strain FE 9901. Registrant's Response to the Deficiencies found by the Agency in its review ofproduct chemistry, manufacturing process, and acute toxicity studies ofNoFly Technical and NoFly WP containingthe new Al Paecilomvcesfumosoroseus strain FE 9901 Deficiency 1: Nature ofthe Test Material. Indicate from where in the integrated process ofthe manufacturing procedure the test material used for the acute toxicity/pathogenicity studies was obtained. Response: The registrant has confirmed that all acute toxicity/pathogenicity studies, and mutagenicity study (Ames test) were carried out with freeze dried TGAI which contained blastopores and mycelium of

### Paecilomyces fumosoroseus strain FE 9901; residual fermentation solids; and as cryoprotectant materials. The test material used is at the end stage ofthe manufacturing process as shown inthe schematic diagram. Reviewen' conclusion; Acceptable
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Deficiency 2: Discussion offormation ofunintentional ingredients. The Agency is concerned that

### Paecilomyces fumosoroseus strain FE 9901is capable ofproducing toxic metabolites in fermented cultures used inthe manufacture ofNoFly Technical and consequently cannotissue an exemption from the requirement ofa tolerance for residues of 

### Paecilomycesfumosoroseus strain FE 9901for food use. Response: The registrant affirms that it is highly unlikely that beauverolides or any other metabolites could be produced by

### Paecilomyces fumosoroseus strain FE 9901underthe conditions ofcommercial manufacture ofNoFly Technical. The registrant has submitted a supplemental study on the active ingredient

### Paecilomycesfumosoroseus strain FE 9901 to demonstrate that fermentation in stirred tank reactors would notresult intheproduction ofmetabolites ofconcern. In this study {MRID No. 482912-01), extracts ofbiomass and culture filtrate derived from still culture and stirredtank reactor (STR) fermentations of

### Paecilomyces fumosoroseus strain FE 9901were analyzed to detect the presence ofsecondary metabolites and to evaluate their cytotoxicity onhuman Jung cancer (Hep-2) and Madin Darby canine kidney {MDCK) cell lines. The analysis by HPLC combined withESI-MS chromatography revealed the presence of beauverolides M and I in the extracts from still cultures with no significant levels ofthese compounds detected inthe STR extracts. The growth inhibition assay on cell lines revealed a dose dependent cytotoxicity in the extracts from still culture that is 6 - IOX higher thanin stirred cultures, and no antiproliferative activity was detected in any ofthe extracts. The authors ofthe study conclude that these results suggestthat fermentation of

### Paecilomyces fumosoroseus strain FE 9901 in stirred tank reactors does notproduce unintentional compound oftoxic concern. Reviewers' conclusion: 1- Cytotoxicity bas been shown in both still and stirred cultures, even though toxicity is 6 - 1

OX higher in still vs. stirred cultures. 2- The diagrams shown in HPLC andESI-MS chromatograms for secondary metabolites in still vs. 

### stirred cultures are illegible and no conclusion canbe made based on these diagrams. 3- There is concern that there is a potential for the presence oftoxic metabolites in the technical product and, as such, the Agency cannot support use on food crops. 4- Five batches analysis should be done on the technical product from the actual production site to demonstrate that there are no toxic metabolites produced.

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