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**EPA BIOPESTICIDES AND POLLUTION PREVENTION DIVISION COMPANY**  **NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE**  **FEDERAL REGISTER EPA**  **Biopesticides and Pollution Prevention Division contact:**  **[insert name and telephone number with area code]**  **INSTRUCTIONS: Please utilize this outline in preparing**  **the pesticide petition. In**  **cases where the outline element does not apply ,**  **please insert “NA -**  **Remove” and maintain the outline. Please do not chang**  **e the margins, font, or format in your**  **pesticide petition . Simply replace the instructions that appear in**  **green , i.e., “**  **[ insert**  **company name ]**  **,” with the information specific to your ac tion.**  **SUBMISSION: E**  **- mail the completed template to:**  **hollis .**  **linda @epa.gov.**  **TEMPLATE: DSM Food Specialties, B.V.**  **[Insert petition number]** EPA has received a pesticide petition **( [insert**  **petition number] )**  from **DSM Food Specialties, B.V.**  **, PO Box 1, 2600 MA Delft, The Netherlands**  proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180. **( Options (pick one)**  1. by establishing a tolerance for residues of NA
- Remove 2. to establish an exemption from the requirement of a tolerance for NA
- Remove 3. to establish an amendment/exp ansion of an existing tolerance exemption for the **(Options (pick one)** 1. microbial pesticide NA
- Remove 2. biochemical pesticide Natamycin 3. plant

- pesticide NA
- Remove in or on NA
- Remove2

Pursuant to section 408(d)(2)(A)(i) of FFDCA, as amended, **DSM Food Specialties, B.V.**  has submitted the following summary of information, data, and arguments in support of their pesticide petition. This summary was prepared b y **DSM Food Specialties, B.V.**  and EPA has not fully evaluated the merits of the pesticide petition. The summary may have been edited by

EPA if the terminology

used was unclear, the summary contained extraneous material, or the summary unintentionall y m ade the reader conclude that the findings reflected EPA’s position and not the position of the petitioner. **I. DSM Food Specialties, B.V.**  **Petition Summary [Insert petition number]**  A. Product Name and Proposed Use Practices Natamycin is already approved for use as a fungistat to prevent and control mold and ye ast spores in the growth media of mushrooms produced in enclosed mushroom facilities (EPA Reg. No. 87485
- 2) and for use on pineapple as a post harvest treatment (EPA Reg. No. 874 85
- 3)

. Additional uses are being proposed t o control several postharvest dis eases in or on c itrus, pome, stone fruit crop groups, avocado, kiwi, mango and pomegranates by d ip, drench, flood or spray in packinghouse facilities. B. Product Identity/Chemistry 1. Identity of the pesticide and corresponding residues

. Natamycin L contains 10.34% (b y wt) Natamyc in anhydrous

. 2. Magnitude of residues at the time of harvest and method used to determine the residue

. Not applicable

. 3. A statement of why an analytical method of detecting and measuring the levels of the pesticide residue are not needed. An analy tical method for detecting and measuring the levels of pesticide residue for Natamycin is not applicable. Iti s expected that, when used as proposed Natamycin would not result in residues that are of toxicological concern. C. Mammalian Toxicological Profile The toxicology

d ata in dicate that the active ingredient, Natamycin is of low acute toxicity and is not a develop m ental toxicant, a m utagen, or toxic via repeat oral exposure. Acute Toxicity : Acute toxicity studies on Natamycin TGAI (98.17% and 98.27% pure), confirm a low toxicity pro f ile. The acute toxicity data show nontoxicity for al l routes of exposure. It can be concluded that any dietary ri sks associated with Natamycin would be negligible. 1. The acute oral LD 50 in rats was greater than 2,000 milligram s per kilogram ( m g/kg)3

body weight. There were no ob s erved toxicological effects on the test subjects in the acute o ral study sub mitted (MRID No. 48105505). Natamycin is cla s sified as Toxicity Category III f

o r acute oral toxicity

. 2. The acute der

mal LD 50 i n rats was greater than 5,050 m g/kg body w eight (MRID 48105506). Natamycin is classified as Toxicity Category IV for acute der m al toxicity

. 3. The acute inhalation LC 50 was greater than 2.39 milligram s per lit er ( mg/L) in rats an d showed no signi f

i cant inhalation t o xicity (MRID 48105507). Natamycin is classified as Toxicity Category IV for acute inhalation toxicity

. 4. Ap ri mary eye irritation study on rabbits indicat e d that Natamycin is severel y irritating to the eye but with no effects observed at 24 hours after treatm ent (MRID 48015508). Natamycin is clas s i fied as Toxicity Category IV for pri mary eye irritation. 5. A skin irritation study on rabbits indicates that Natamycin is slightl y irritating (MRID 48105509). Natamycin is classified as Toxicity Category IV for pri mary skin irritation. 6. Data indicate that Natamycin is not a der mal sensitizer (MRID 48105510). Mutagenicity : Two m

utagenicity studies, using Natamycin TGAI w ere performed. These studies c o nfirm that there are no e xpected dietary or non - occupational risks of mutageni c ity with regard to food use of Natamycin

. 1. A Bacterial Reverse Gene Mutation Test ( M RID No. 48105513) investigating doses of test substance up to those that were cy totoxic, both with and without m etabolic S9 activation, found no incidences of a 2
- fold or greater in crea s e in th e num ber of revertants c o mpared to th e corresponding solvent control in two independently repeated experi m ents. Natam

ycin is consi d ered to be non - mutagenic under the co n ditions of th is assay . 2. An in vit

ro Mammalian Cell Chromoso me Aberration Test (MRID No. 48105514) tested Natamycin genotoxicity on culture d peripheral human ly m phocy tes in the presence an d absence of m etabolic S9 activ ati o n. Natamycin did not in d uce a statistically significant or biologically relev ant in crease in the num ber of cells with c hro moso m e aberrations in th e absence an d in the presence of S9
- mix, in two independentl y repeated experiments. Inaddition, all of the negative, solvent, and positi v e co ntrols g ave a ppropriate responses. Natamyc in is considered to be non m utagenic and does not cause chro moso m e aberrations. Subchronic Toxicity : In a sub c hronic oral toxicity study u s ing Natamycin TGAI, doses of 125 and 500 mg/kg/day showed no treatm ent related findings. The highest concentration l level, 2,000 mg/kg/day , showed reduced weight f or both male and f

e m ale rats (MRID 48105511). The Agency did not consider the tem porary decrease in body

w eight or food intake observed in the 2, 0 00 mg/kg bw/day test group to be an adverse effect, as this is likely d u e to the p alatab i lity of th e food containing th is high dose of test substance. T he Agency established the NOAE L (No Observed Adverse Effect Level) for this study as4

2,000 mg/kg bw/day

. A LOAEL ( L owest Observed Adverse Effect Level) was not identified, suggesting that the test ani mals could have tolerated a higher dose. Develop m ental Toxicity : A develop m ental toxicity study using Natamycin TGAI (MRID 48105512) showed no discernable effects on growth, reproduction, teratological or m utagenic respo n ses, or on gross and mi croscopic pathology , at concentration levels 0, 5, 15 and 50 mg/kg bw/day

. D

. Aggregate Exposure 1. Dietary exposure. Dietary e xposure from the additional uses of Natamycin L being proposed for the control of postharvest fungal diseases on citrus, po me, stone fruit crop groups, avocado, kiwi, mango and pomegranates b y dip, drench or spray in packinghouse facilities is expected to be minimal. i. Food. Natamycin has a long history o f use. Natamycin has been used as a food p reservative worldwide for over 5 0 ye ars and is approved as a food additive/preservative by the European Union, the World Health Organization and individual countries for use as a fungistat to suppress mold on cheese, meats and sausage. In the United States, Natamycin is approved by

The F ood and Drug Administration (FDA) as a direct food additive/preservative for the inhibition of mold and ye ast on the surface of cheeses (21 CFR § 172.155) and as an additive to the feed and drinking water of broiler chickens to retard the growth of specifi c molds (21 CFR § 573.685). Natamycin is also FDA approved for use as a treatment to suppress fungal eye infections such as blepharitis, conjunctivitis, and keratitis. Natamycin is already approved for use as a fungistat to prevent and control mold and yea st spores in the growth media of mushrooms produced in enclosed mushroom facilities (EPA Reg. No. 87485
- 2) and to control fungal growth postharvest on pineapples indoors (EPA Reg. No. 87485
- 3)

. The results of toxicity

t esting indicate there is little if any risk to human health from exposure to Natamycin

. The absence of toxicity in laboratory animals demonstrates the lack of toxicological concern for any increase in dietary e xposure from the use Natamycin L. In a review of toxicological literature by

the European Food Safety A genc y (EFSA, 2009), Natamyci n was shown to be poorl y absorbed by g astrointestinal sy stems of mammals and rapidly

e xcreted in the feces (Blankwater and Hespe, 1979; Hespe and Meier, 1980; both reviewed and cited in EFSA, 2009). Inaddition, Natamycin is rapidly

degraded by

stomach acids, with a 1

- hour half

- life in simulated gastric juice (Morgenstern and Muskens, 1976; reviewed and cited in EFSA, 2009). Inaddition, Daamen and van den Berg (1985) and Kiermeier and Zierer (1975) demonstrated that Natamycin remained on the surface of cheese and only slight amounts penetrated into the cheese. It is expected the same thing would occur, when fruit is treated w ith Natamycin postharvest, that Natamycin will remain on the surface of the5 fruit and very

l ittle would penetrate into the fruit and add to the dietary intake. All inert ingredients used in the end

- use product, Natamycin L, are approved for food use under 40 CFR 180.950 and 40 CFR 180.960; and are considered to be Generall y Recognized As Safe (GRAS) b y FDA. ii. Drinking water. There are no concerns for exposure of humans to Natamycin in drinking water. Based on the additional proposed postharvest uses in treatment facilities on citrus fruit, pome fruit, stone fruit and cherries it is highly unlikel y that residues of Natamycin will enter any s ources of drinking water. In addition, due to its low solubility in water its concentration in surface water s would never exceed 50 ppm. Natamycin is also extremely s ensitive to UV light and is completel y degraded by

UV within 24 hours of exposure in aqueous solution (Koontz et. al., 2003). 2. Non

- dietary exposure . The potential for non - dietary e xposure to the general population, including infants and children is not expected because Natamycin is not approved for residential uses and the use sites are for enclosed mushroom production facilities or postharvest treatment facilities. E. Cumulative Effects The Fo od Quality Protection Act of 1996 requires the EPA to consider the cumulative effects of chemicals with a common mechanism of toxicity in its tolerance assessment decisions. There is no indication that Natamycin has a common mechanism of action with other compounds to result in any cumulative effects. F . Safety Determination 1. U.S. population. Toxicity studies have shown that Natamycin is non - toxic to mammals following acute exposures. These results indicate the product is not of toxicological concern for the general population when used as proposed on the label. Based on the data available, there is a reasonable certainty of no harm to the general US population from exposure to Natamycin from the proposed additional uses

. 2. Infants and children

. As mentioned above, it is expected that, when used as proposed, Natamycin would not result in residues that are of concern for potential toxicity

. Based on the data provided, there is a reasonable certainty of no harm for infants and children from exposure to Natamycin from the proposed additional uses. G. Effects on the Immune and Endocrine Systems6 To date there is no evidence to suggest that Natamycin functions in a manner similar to any

known hormone, or that it acts as an endocrine disrupter. H. Existing Tolerances Natamycin is exem

pt from the requirem ent of a t olerance as stated at 40 C FR § 180.1315: 4 0 CF R § 18 0
. 1 31 5 Natamyc in; e x emption from the requirement of a toleranc e **.** An exemption from the requirement of a tolerance is established for residues of natamycin in or on mushrooms when applied as a fungistat to prevent the germination of fungal spores on mushrooms produced in enclosed mushroom production facilities, and in or on pineapples when applied as a fungistat in accordance with label directions and good agricultural practices. I . International Tolerances There are no current tolerances or tolerance exemptions in place for Natamycin.

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