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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 of the Registrant's response to the data deficiencies found by the 

Agency in its review of product chemistry, manufacturing process of two 

products: NoFly Technical and NoFly WP containing the new AI 

Paeci/omyces .fumosoroseus strain FE 9901. 

FROM: 'Hf IJ .. II. fl __ # J-.N-1/ Ibrahim S. Barsoum, Ph.D., Microbiologist, ~~. ~o--

Microbial Pesticides Branch, 

THROUGH: 

Biopesticides and Pollution Prevention Division ~ 

John L. Kough, Ph.D., Senior Scientist ct:~ t 

TO: 

Microbial Pesticides Branch, 

Biopesticides and Pollution Prevention · · on A 

Anna Gross, Regulatory Action Leader 

Microbial Pesticides Branch, Biopesticides and 

Pollution Prevention Division (7511 C) 

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 of product chemistry, manufacturing 

process of two 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 of the deficiencies concerning the nature of the 

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: 

Paecilomyces fumosoroseus 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 of the world and 

occurs in various soil types at very low densities. Its target organisms are the whiteflies. In its 

natural environment, P. fumosoroseus strain FE 990 l is dispersed as conidia or blastospores, 

either by air or water movement or by other insects and/or mites. The mode of infection proceeds 

as such: conidial attachment, germination, penetration of the insect cuticle, vegetative growth, 

and conidiogenesis. The infection cycle of P. fumosoroseus strain FE 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 9901 by Natural 

Industries Inc. and found deficiencies in their application (letter dated 11/5/20 l 0). 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 of product 

chemistry, manufacturing process, and acute toxicity studies ofNoFly Technical and NoFly 

WP containing the new Al Paecilomvces fumosoroseus strain FE 9901 

Deficiency 1: Nature of the Test Material. 

Indicate from where in the integrated process of the 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 

of the manufacturing process as shown in the schematic diagram. 

Reviewen' conclusion; Acceptable 

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*Manufacturing process information may be entitled to confidential treatment*
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Deficiency 2: Discussion of formation of unintentional ingredients. 

The Agency is concerned that Paecilomyces fumosoroseus strain FE 9901 is capable of producing 

toxic metabolites in fermented cultures used in the manufacture ofNoFly Technical and 

consequently cannot issue an exemption from the requirement of a 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 9901 under the conditions of commercial 

manufacture ofNoFly Technical. The registrant has submitted a supplemental study on the active 

ingredient Paecilomyces fumosoroseus strain FE 9901 to demonstrate that fermentation in stirred 

tank reactors would not result in the production of metabolites of concern. 

In this study {MRID No. 482912-01), extracts of biomass and culture filtrate derived from still 

culture and stirred tank reactor (STR) fermentations of Paecilomyces fumosoroseus strain FE 

9901were analyzed to detect the presence of secondary metabolites and to evaluate their 

cytotoxicity on human Jung cancer (Hep-2) and Madin Darby canine kidney {MDCK) cell lines. 

The analysis by HPLC combined with ESI-MS chromatography revealed the presence of 

beauverolides M and I in the extracts from still cultures with no significant levels of these 

compounds detected in the STR extracts. The growth inhibition assay on cell lines revealed a 

dose dependent cytotoxicity in the extracts from still culture that is 6 - I OX higher than in stirred 

cultures, and no antiproliferative activity was detected in any of the extracts. The authors of the 

study conclude that these results suggest that fermentation of Paecilomyces fumosoroseus strain 

FE 9901 in stirred tank reactors does not produce unintentional compound of toxic 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 and ESI-MS chromatograms for secondary metabolites in 

still vs. stirred cultures are illegible and no conclusion can be made based on these 

diagrams. 

3- There is concern that there is a potential for the presence of toxic 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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