Document ID: EPA-HQ-OPP-2015-0811-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-04-25T04:00Z

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 change 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 action.

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/expansion of an existing tolerance exemption for the

(Options (pick one)
   
 microbial pesticide  NA-Remove
         
 biochemical pesticide Natamycin

 plant-pesticide NA-Remove in or on NA-Remove
         
	
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 by 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 unintentionally made 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 yeast 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. 87485-3). Additional uses are being proposed to control several postharvest diseases in or on citrus, pome, stone fruit crop groups, avocado, kiwi, mango and pomegranates by dip, drench, flood or spray in packinghouse facilities. 

B. Product Identity/Chemistry

      1. Identity of the pesticide and corresponding residues. Natamycin L contains 10.34% (by wt) Natamycin 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 analytical method for detecting and measuring the levels of pesticide residue for Natamycin is not applicable. It is expected that, when used as proposed Natamycin would not result in residues that are of toxicological concern. 

C. Mammalian Toxicological Profile

	The toxicology data indicate that the active ingredient, Natamycin is of low acute toxicity and is not a developmental toxicant, a mutagen, or toxic via repeat oral exposure.

Acute Toxicity: Acute toxicity studies on Natamycin TGAI (98.17% and 98.27% pure), confirm a low toxicity profile. The acute toxicity data show nontoxicity for all routes of exposure. It can be concluded that any dietary risks associated with Natamycin would be negligible. 

1. The acute oral LD50 in rats was greater than 2,000 milligrams per kilogram (mg/kg) bodyweight. There were no observed toxicological effects on the test subjects in the acute oral study submitted (MRID No. 48105505). Natamycin is classified as Toxicity Category III for acute oral toxicity.

2.   The acute dermal LD50 in rats was greater than 5,050 mg/kg body weight (MRID 48105506). Natamycin is classified as Toxicity Category IV for acute dermal toxicity.

3.   The acute inhalation LC50 was greater than 2.39 milligrams per liter (mg/L) in rats and showed no significant inhalation toxicity (MRID 48105507). Natamycin is classified as Toxicity Category IV for acute inhalation toxicity.

4.   A primary eye irritation study on rabbits indicated that Natamycin is severely irritating to the eye but with no effects observed at 24 hours after treatment (MRID 48015508). Natamycin is classified as Toxicity Category IV for primary eye irritation.

5. A skin irritation study on rabbits indicates that Natamycin is slightly irritating (MRID 48105509). Natamycin is classified as Toxicity Category IV for primary skin irritation.

6.   Data indicate that Natamycin is not a dermal sensitizer (MRID 48105510).

Mutagenicity: Two mutagenicity studies, using Natamycin TGAI were performed. These studies confirm that there are no expected dietary or non-occupational risks of mutagenicity with regard to food use of Natamycin.

1. A Bacterial Reverse Gene Mutation Test (MRID No. 48105513) investigating doses of test substance up to those that were cytotoxic, both with and without metabolic S9 activation, found no incidences of a 2-fold or greater increase in the number of revertants compared to the corresponding solvent control in two independently repeated experiments. Natamycin is considered to be non-mutagenic under the conditions of this assay.

2. An in vitro Mammalian Cell Chromosome Aberration Test (MRID No. 48105514) tested Natamycin genotoxicity on cultured peripheral human lymphocytes in the presence and absence of metabolic S9 activation. Natamycin did not induce a statistically significant or biologically relevant increase in the number of cells with chromosome aberrations in the absence and in the presence of S9-mix, in two independently repeated experiments. In addition, all of the negative, solvent, and positive controls gave appropriate responses. Natamycin is considered to be non-mutagenic and does not cause chromosome aberrations.

Subchronic Toxicity: In a subchronic oral toxicity study using Natamycin TGAI, doses of 125 and 500 mg/kg/day showed no treatment related findings. The highest concentration l level, 2,000 mg/kg/day, showed reduced weight for both male and female rats (MRID 48105511). The Agency did not consider the temporary decrease in body weight or food intake observed in the 2,000 mg/kg bw/day test group to be an adverse effect, as this is likely due to the palatability of the food containing this high dose of test substance. The Agency established the NOAEL (No Observed Adverse Effect Level) for this study as 2,000 mg/kg bw/day. A LOAEL (Lowest Observed Adverse Effect Level) was not identified, suggesting that the test animals could have tolerated a higher dose.

Developmental Toxicity: A developmental toxicity study using Natamycin TGAI (MRID 48105512) showed no discernable effects on growth, reproduction, teratological or mutagenic responses, or on gross and microscopic pathology, at concentration levels 0, 5, 15 and 50 mg/kg bw/day.

D. Aggregate Exposure

      1. Dietary exposure. Dietary exposure from the additional uses of Natamycin L being proposed for the control of postharvest fungal diseases on citrus, pome, stone fruit crop groups, avocado, kiwi, mango and pomegranates by dip, drench or spray in packinghouse facilities is expected to be minimal. 

            i. Food. Natamycin has a long history of use. Natamycin has been used as a food preservative worldwide for over 50 years 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 Food and Drug Administration (FDA) as a direct food additive/preservative for the inhibition of mold and yeast 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 specific 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 yeast 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 testing 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 exposure from the use Natamycin L. In a review of toxicological literature by the European Food Safety Agency (EFSA, 2009), Natamycin was shown to be poorly absorbed by gastrointestinal systems of mammals and rapidly excreted in the feces (Blankwater and Hespe, 1979; Hespe and Meier, 1980; both reviewed and cited in EFSA, 2009). In addition, 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). In addition, 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 with Natamycin postharvest, that Natamycin will remain on the surface of the fruit and very little 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 Generally Recognized As Safe (GRAS) by 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 unlikely that residues of Natamycin will enter any sources of drinking water. In addition, due to its low solubility in water its concentration in surface waters would never exceed 50 ppm. Natamycin is also extremely sensitive to UV light and is completely degraded by UV within 24 hours of exposure in aqueous solution (Koontz et. al., 2003). 

      2. Non-dietary exposure. The potential for non-dietary exposure 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 Food 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 Systems

      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 exempt from the requirement of a tolerance as stated at 40 CFR § 180.1315:

40 CFR § 180.1315 Natamycin; exemption from the requirement of a tolerance.

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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