BIOPESTICIDES REGISTRATION ACTION DOCUMENT



## Natamycin

PC Code: 051102

U.S. Environmental Protection Agency Office of Pesticide Programs Biopesticides and Pollution Prevention Division

(last updated November 7, 2014)Natamycin

PC Code 051102 Biopesticides Registration Action Document

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### Table of Contents

I. EXECUTIVE SUMMARY .................................................................................................. 5

II. ACTIVE INGREDIENT OVERVIEW .............................................................................. 7

III. REGULATORY BACKGROUND...................................................................................... 7

A. Application for Pesticide Registration ............................................................................... 7

B. Food Clearances/Tolerances ............................................................................................... 8

IV. RISK ASSESSMENT ........................................................................................................... 8

A. Product Analysis Assessment (40 CFR § 158.2030) .......................................................... 8

B. Human Health Assessment.................................................................................................. 9

1. Tier I Toxi cology ............................................................................................................. .............................. 9

2. Tier II and Tier III T oxicity Studies ......................................................................................... ................. 10

3. Effects on the E ndocrine System ............................................................................................... ................. 10

4. Dose Response Assessment ...................................................................................................... ................... 11

5. Drinking Water Exposure a nd Risk Characterization ............................................................................ 11

6. Occupational, Residential, School and Day Care Exposure and Risk Characterization ...................... 11

a. Occupational Exposure and Risk Characterization ............................................................................... .. 11

b. Residential, School and Day Care Expo sure and Risk Characterization ............................................... 11

7. Aggregate Exposure from Multiple Routes Including Dermal, Oral, and Inhalation ........................... 11

a. Food Exposure ................................................................................................................. ............................ 12

b. Drinking Wat er Exposure ....................................................................................................... ................... 12

c. Other Non-occupational Exposure ............................................................................................... ............. 12

8. Cumulative Effects from Substances with a Common Mechanism of Toxicity ..................................... 12

9. Determination of Safety for United Stat es Population, Infa nts and Children ....................................... 12

10. Risk Characterization ......................................................................................................... ........................ 13

C. Environmental Assessment ............................................................................................... 13

1. Ecological Hazards ............................................................................................................ .......................... 13

2. Environmental Fate and Ground Water Data ...................................................................................... .... 13

3. Ecological Exposure and Risk Characterization ................................................................................. ..... 13

4. Endangered Species Assessment ................................................................................................. ............... 14

D. Product Performance Data ............................................................................................... 14

V. RISK MANAGEMENT DECISION ................................................................................. 14

A. Determination of Eligibility for Registration .................................................................. 14

B. Regulatory Decision ........................................................................................................... 14Natamycin

PC Code 051102 Biopesticides Registration Action Document

3 C. Environmental Justice ....................................................................................................... 1 5

VI. ACTIONS REQUIRED BY REGISTRANTS.................................................................. 15

A. Reporting of Adverse Effects ............................................................................................ 15

B. Reporting of Hypersensitivity Incidents .......................................................................... 15

VII. APPENDIX A: DATA TABLES ....................................................................................... 16

VIII. APPENDIX B: REFERENCES ....................................................................................... 18

IX. GLOSSARY OF ACRONYMS AND ABBREVIATIONS ............................................. 23Natamycin

PC Code 051102 Biopesticides Registration Action Document

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### BIOPESTICIDES REGISTRATION AC TION DOCUMENT (BRAD) TEAM

Office of Pesticide Programs Biopesticides and Pollution Prevention Division

Biochemical Pesticides Branch

Linda A. Hollis, M.S., Branch Chief Russell Jones, Ph.D., Senior Scientist Miachel Rexrode, Ph.D., Senior Scientist Cheryl Greene, Regulator Action Leader Gina Burnett, M.S., Regulatory Action LeaderNatamycin

PC Code 051102 Biopesticides Registration Action Document

5 I. EXECUTIVE SUMMARY

Natamycin is a biochemical pesticide active ingredie nt intended for use as a fungistat to control the germination of mold and yeast spores in the growth media of mushrooms produced in enclosed mushroom production facilities and on pineapples. Natamycin is a naturally-occurring antimycotic compound derived from the common soil microorganisms Streptomyces natalensis, Streptomyces lydicus, and Streptomyces chattanoogensis. It is commercially produced by a submerged oxygen-based fermentation of Streptomyces natalensis cells, which are then lysed by increasing the temperature in the fermentation vessel thereby causing the release of natamycin

from the cell solids. Natamycin was originally discovered in Streptomyces natalensis in South Africa in the early 1950s, and was subsequently discovered to also occur naturally in North

America in Streptomyces lydicus and Streptomyces chattanoogensis. Natamycin has a non-toxic mode of action and functions as a fungistat, pr eventing the germination of fungal spores. It has no effects on fungal mycelia. Development of antib iotic resistance to Na tamycin has not been reported during its entire history of use.

Natamycin has been used as a food preservative worldwide for over 40 y ears 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 su ppress mold on cheese, meats and sausage. In the United States, natamycin is approve d 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 drin king water of broiler chickens to retard the growth of specific molds (21 CFR § 573.685). Nata mycin is also FDA approved for use as a treatment to suppress fungal eye infections such as blepharitis, conjuncti vitis, and keratitis. On August 17, 2007, the EPA’s Biochemical Classifica tion Committee classified Natamycin as a

Biochemical Pesticide active. Streptomyces lydicus (the source of natamycin) is currently registered by the Agency under Registration Nos. 73314-1, -2, and -4 as a microbial pesticide for greenhouse, nursery, turfgrass, ag ricultural, and seed treatment uses. Natamycin is currently registered by the Agency under Registration Nos. 87485-1 and -2 for use in enclosed mushroom production facilities. The pending product registration for natamycin is EPA File Symbol 87485- G; this product is intended for use post-harvest, indoors, on pineapples.

The Agency has concluded that adequate product chemistry and mammalian toxicology data are available to support natamycin (U.S. EPA, 2010; U.S. EPA, 2011a; U.S. EPA, 2011b; U.S. EPA 2011c; U.S. EPA, 2014). Acute toxicity stud ies on natamycin (98.17% and 98.27% pure), confirm a low toxicity profile. The acute toxicity data show virtual nontoxic ity for all routes of exposure (Toxicity Category III for acute oral to xicity and primary eye irritation; Toxicity Category IV for acute dermal toxicity, acute inha lation toxicity, and primary dermal irritation; not a dermal sensitizer). A 90-Day Oral study on natamycin indicated no adverse effects up to the highest dose tested, which was 2,000 milligrams (mg) per kilogram (kg) body weight (bw) per day. No 90-Day Dermal or 90-Day Inhalatio n studies were submitted and none are required since products containing natamycin will be used indoors only by applicators wearing appropriate Personal Protective Equipment (PPE), as stated on the product labels. A prenatal developmental toxicity study showed no effect s up to the highest dose tested, which was 50 mg/kg bw/day. Submitted studies indicate that natamycin is non-mutagenic. Therefore, the Agency concludes that this active ingredient is not likely to result in adverse human healthNatamycin

PC Code 051102 Biopesticides Registration Action Document

6 effects, based upon available reports and information.

Tier I studies were not submitted for non-target organisms and environmental fate data requirements for natamycin and such studies are not required. Based on its use pattern and use instructions as a fungistat in tended solely for use indoors (in enclosed mushroom production facilities or in packaging facili ties on pineapples), natamycin expos ure to non-target organisms is not expected. Further, EPA has determined that natamycin will have " No Effect " on any currently listed threatened or e ndangered species or any designat ed critical habitat based on its

use pattern.

On October 1, 2009, the U.S. Environmental Prot ection Agency (EPA or the Agency) announced a policy to provide a more meaningful opportuni ty for the public to participate in major registration decisions before they occur. A ccording to this polic y, EPA provides a public comment period prior to making a registration decision for the follo wing types of applications: new active ingredients; first food uses; first outd oor uses; first resident ial uses; or any other registration actions for which EPA believes there may be significan t public interest.

Consistent with the policy of making registration decisions more transparent, the public is provided 15 days in which to submit comments to the Agency regarding its pending decision to register a product containing natamycin for us e on pineapples post-harvest, indoors. Thefollowing documents are available for comment in the docket, identification number EPA-HQOPP-2014-0352: a draft of this Bi opesticides Registration Acti on Document (BRAD) and the draft product label for Zivion P (EPA File Symbol 87485-G).

Altogether, the Agency believes that, based on the existing information in the Agency’s database on natamycin and the recent information submitted in support of the registration of a pesticide product containing natamycin for use on pineapples , post-harvest, indoors , it is in the best interest of the public to issu e the registration for Zivion P (EPA File Symbol 87485-G). The

basis for this decision can be found in the science review memo randums for these products (U.S. EPA, 2010; U.S. EPA, 2011a; U.S. EPA, 2011b; U.S. EPA 2011c; U.S. EPA, 2014) and the existing information in the Agency’s database on natamycin, all of whic h are characterized in

this BRAD.

For definitions of scientific terms, please refer to http://www.epa.gov/pesticides/glossary/

.

=Natamycin

PC Code 051102 Biopesticides Registration Action Document

7 II. ACTIVE INGREDIENT OVERVIEW

Common Name: Natamycin

Chemical Names: IUPAC Chemical Name: (1 R ,3 S ,5 R ,7 R ,8 E ,12 R ,14 E ,16 E ,18 E ,20 E ,22 R ,24 S ,25 R ,26 S )- 22-[(3-amino-3,6-dideoxy- β -D-mannopyranosyl)oxy]- 1,3,26-trihydroxy-12-methyl-10-oxo-6,11,28- trioxatricyclo[22.3.1.05,7]octacosa-8,14,16,18,20- pentaene-25-carboxylic acid

Trade & Other Names: Natamycin L

Pimaricin

Tennectin

Delvocid

CAS Registry Number: 7681-93-8

OPP Chemical Code: 051102

Type of Pesticide: Biochemical Pesticide – Fungistat

Biochemical Classification

On August 17, 2007, EPA’s Biochemical Classifica tion Committee classified natamycin as a

Biochemical Pesticid e active ingredient.

III. REGULATORY BACKGROUND

A. Application for Pesticide Registration

On May 20, 2010, EPA received an application filed by Keller and Heckman, 1001 G Street, N.W., Suite 500 West, Washington, D.C.20001 on behalf of DSM Food Specialties B.V. (hereafter referred to as “DSM” or “applic ant”), Alexander Fleminglaan 1, Delft, The Netherlands 2613AX to register the products Natamycin TGAI (EPA Reg. No. 87485-1), and Natamycin L (EPA Reg. No. 87485-2) containi ng the new biochemical active ingredient natamycin. The application was submitted to both EPA and The Health Canada Pest Management Regulatory Agency (PMRA) along with a request for a North American Free Trade Agreement (NAFTA) Joint Review of the applica tions. Concurrent with these applications, DSM filed a petition for a tolerance exemption for re sidues of natamycin on mushrooms when used as a fungistat in enclosed mushroom producing fa cilities. No comments were received following publication of the notice. On November 24, 2010, EPA published in the Federal Register (76 FR 22067) a Notice of Receipt (NOR) announcing recei pt of the applications, and on April 20, 2011 EPA published in the Federal Register (76 FR 22067) a Notice of Filing (NOF) announcing receipt of the petition.Natamycin

PC Code 051102 Biopesticides Registration Action Document

8 On January 6, 2014, Becker Underwood, on behalf of DSM, submitted an application to register a biochemical pesticide product, Zivion P (EPA File Symbol 87485-G), containing natamycin as its active ingredient. Zivion P is intended for use as a fungistat applied to pineapples post-harvest in indoor packages facilities. In the Federa l Register of August 1, 2014 (79 FR 44729), a NOF announced the pesticide toleran ce petition (PP 4F8233) by DSM. The petition requested that 40 CFR part 180 be amended by establishing an exemp tion from the requirement of a tolerance for residues of natamycin post-harvest, indoors, on pi neapples. There were no comments received in response to this NOF.

B. Food Clearances/Tolerances

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

40 CFR § 180.1315 Natamycin; exemption from th e 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.

The proposed end-use product, Zivion P (EPA File Symbol 87485-G), will be used post-harvest on pineapples inside packaging f acilities (indoor use only). With th e registration of this product, the Agency will also amend the tolerance ex emption at 40 CFR § 180.1315 to read as follows:

40 CFR § 180.1315 Natamycin; exemption from th e 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, an d in or on pineapples when applied as a fungistat

in accordance with label directions and good agricultural practices

IV. RISK ASSESSMENT

A. Product Analysis Assessment ( 40 CFR § 158.2030 )

Biochemical pesticide product analysis data requirements include product chemistry and composition, analysis and certified limits, and phys ical and chemical characteristics. Product chemistry and composition data include informati on about the identity of the active ingredient, the manufacturing process, and discussion of the potential for formation of unintentional ingredients. Analysis and certifi ed limits data include information on analysis of samples and certification of limits. Physical and chemical charact eristics data describe basic characteristics of the registered pesticide products, including color, physical state, odor, stability, miscibility, pH, corrosion characteristics, viscosity and density.

All product chemistry data requirements have been satisfied for the active ingredient (natamycin) and the proposed product, Zivion P (E PA File Symbol 87485-G). Refer to Appendix A for a summary of natamycin product chemistry data.Natamycin

PC Code 051102 Biopesticides Registration Action Document

9 B. Human Health Assessment

1. Tier I Toxicology

All applicable mammalian toxicology data require ments an exemption from the requirement of a tolerance for residues of natamycin when used on mushrooms in enclosed production facilities and on pineapples, indoors, post-harvest have been fulfilled with data submitted by the petitioner. These data indicate that the active ingr edient is of low acute toxicity and is not a developmental toxicant, a mutagen, or toxic via repeat oral exposure.

The following is a summary of EPA’s review of the toxicity profile of this biochemical:

Acute Toxicity: Acute toxicity studies on natamycin (98.17% and 98.27% pure), confirm a low toxicity profile. The acute toxicity data show virtual nontoxicity for al l routes of exposure. Therefore, it can be concluded that any dietary ri sks associated with this biochemical would be negligible.

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

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

3. The acute inhalation median lethal c oncentration (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 indicate s 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 Ca tegory III 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 no t a dermal sensitizer (MRID 48105510).

Mutagenicity: Two mutagenicity studies, using natamycin (98.17% and 98.27% pure) as the test substance, were performed. These studies are su fficient to confirm that there are no expected dietary or non-occupational risks of mutagenic 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 cytotoxic, both with and wit hout metabolic S9 activation, found no incidences of a 2-fold or gr eater increase in the number of revertants compared to the corresponding solvent control in two independently repeated experiments. Therefore, natamycinNatamycin

PC Code 051102 Biopesticides Registration Action Document

10 is considered to be non-mutagenic under the conditions of this assay.

2. An in vitro Mammalian Cell Chromosome Aberra tion Test (MRID No. 48105514) tested natamycin genotoxicity on culture d peripheral human lymphocytes in the presence and absence

of metabolic S9 activation. Nata mycin did not induce a statistica lly significant or biologically

relevant increase in the number of cells with ch romosome 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 re sponses. Therefore, under the conditions of this assay, natamycin is considered to be non-mutagenic and does not cause chromosome aberrations.

Subchronic Toxicity: In a subc hronic oral toxicity study us ing natamycin (98.17% and 98.27% pure) as the test substance, doses of 125 and 500 mg/kg/day showed no treatment related findings. The highest concentration level, 2,000 mg/kg/day, showed reduced weight for both male and female rats (MRID 48105511). The Agency does not consider the temporary decrease in body weight or food intake observed in the 2,0 00 mg/kg bw/day test group to be an adverse effect, as this is likely due to the palatabi lity of the food containing this high dose of test substance. Therefore, the Agency establishes the NOAEL (No Observed Adverse Effect Level) for this study as 2,000 mg/kg bw/day. A LOAEL (L owest Observed Adverse Effect Level) was not identified, suggesting that the test animals could have tolerated a higher dose.

Developmental Toxicity: A developmental t oxicity study using natamycin (98.17% and 98.27% pure) as the test substance (MRID 48105512) showed no discernable effects on growth, reproduction, teratological or mutagenic respon ses, or on gross and microscopic pathology, at concentration levels 0, 5, 15 and 50 mg/kg bw/day.

2. Tier II and Tier III Toxicity Studies

The biochemical pesticide Human Health Assessment data require ments for Tier II and Tier III were not required due to the low toxicity of th e active ingredient and the low levels of exposure expected from its intended uses in EP products.

3. Effects on the Endocrine System

As required under FFDCA section 408(p), EP A has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (inc luding pesticide active and other ingredients) may have an effect in humans or wildlife si milar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two-tiered ap proach to making the statutorily required

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.Natamycin

PC Code 051102 Biopesticides Registration Action Document

11 Between October 2009 and February 2010, EPA issued test orders and data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and nine inert ingredients.

This list of chemicals was selected based on th e potential for human exposure through pathways such as food and water, residen tial activity, and certain post-applic ation agricultural scenarios.

This list should not be construed as a lis t of known or likely e ndocrine disruptors.

Natamycin is not among the group of 58 pesticide active ingredients on the initial list to be

screened under the EDSP. Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuing fu ture EDSP test orders and data call-ins for all pesticide active ingredients.

For further information on the status of the ED SP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, pleas e visit our website: http://www.epa.gov/endo/

.

4. Dose Response Assessment

No toxicological endpoints have been identified for natamyci n; therefore, a dose-response assessment was not required.

5. Drinking Water Exposure and Risk Characterization

Exposure of humans to natamycin in drinking water is not expected because natamycin is approved for application indoors only (enclose d mushroom houses or pineapple packing facilities).

6. Occupational, Residential, School and Day Care Exposure and Risk

Characterization

a. Occupational Exposure and Risk Characterization

Occupational exposure to register ed pesticide products containing natamycin is not expected due to mitigation through precautionary language an d personal protective equipment (PPE) on the

label.

b. Residential, School and Day Care Ex posure and Risk Characterization

Natamycin is intended for use only in enclos ed mushroom houses and in indoor packaging facilities on pineapples. No indoor residential, school, or day care uses are currently approved for products containing natamycin.

7. Aggregate Exposure from Multiple Routes Including Dermal, Oral, and Inhalation

There is reasonable certainty of no harm to U. S. populations, including infants and children, from aggregate exposures to residues of natamy cin when used as proposed. This includes all anticipated dietary exposures and all other expos ures for which there is reliable information.Natamycin

PC Code 051102 Biopesticides Registration Action Document

12 Moreover, potential non-occupational inhalation a nd dermal exposure is not likely to pose any adverse effects to exposed populations via aggregate and cumulative exposure.

a. Food Exposure

Dietary exposure to residues of na tamycin is expected to be insi gnificant, even in the event of exposure. The lowest NOEL (No observed effect level) for natamycin is 50 mg/kg/day. The application of natamycin on pineapples produces resi dues in the edible portions (meat and juice) in the range < 0.01 – 0.07 ppm . A human adult exposure thre shold was calculated at 30 mg/day (NOEL/uncertainty factor x 60kg; 50 mg/kg/da y/100 x 60 kg = 30 mg/day). Oral exposure to children (1-2 years old, 11.2 kg) was found at 5.6 mg/day (50 mg/kg/day/100 x 11.2 kg = 5.6 mg/day). Therefore, expected re sidue levels on natamycin on pin eapple meat and juice are about three orders of magnitude below the adu lt and children exposure threshold (EPA, 2014). Furthermore, the active ingredient is of low acute toxicity and is not a developmental toxicant, a mutagen, or toxic via repeat oral exposure

b. Drinking Water Exposure

Exposure of humans to natamycin in drinking water is not expected because natamycin is approved for application indoors only (enclose d mushroom houses or pineapple packing facilities).

c. Other Non-occupational Exposure

Non-occupational exposure is not expected because natamyci n is not approved for residential uses. The active ingredient is applied directly to commodities and degrades rapidly.

8. Cumulative Effects from Substances wi th a Common Mechanism of Toxicity

The EPA has not found natamycin to share a co mmon mechanism of toxi city with any other substances, and natamycin does not appear to produce a toxic metabolite produced by other substances. For the purposes of this toleran ce action, therefore, the EPA has assumed that natamycin does not have a common mechanism of toxicity with other substances. Following from this, the EPA concludes that there are no cu mulative effects associated with natamycin that need to be considered. For information regarding the EPA’s efforts to determine chemicals that have a common mechanism of toxicity and to eval uate the cumulative effects of such chemicals,

see the EPA’s website at http://www.epa.gov/pesticides/cumulative

.

9. Determination of Safety for United States Population, Infants and Children

FFDCA section 408(b)(2)(C) provides that, in considering the esta blishment of a tolerance or tolerance exemption for a pesticide chemical residue, the EPA shall assess the available information about consumption patterns among in fants and children, special susceptibility of infants and children to pesticide chemical resi dues, and the cumulative effects on infants and

children of the residues and othe r substances with a common mech anism of toxicity. In addition,Natamycin

PC Code 051102 Biopesticides Registration Action Document

13 FFDCA section 408(b)(2)(C) provides that the EPA shall appl y an additional tenfold (10X) margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of th e database on toxicity and exposure, unless the EPA determines that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referr ed to as the Food Quality Protection Act Safety Factor. In applying this provisi on, the EPA either retains the de fault value of 10X, or uses a different additional or no safety factor when reliable data are available to support a different additional or no safety factor.

Because there are no threshold effects associated w ith this biochemical, an additional margin of safety for infants and chil dren is not necessary.

EPA has determined that there are no foreseeab le dietary risks to th e U.S. population, including infants and children, from the use of natamyci n as a pesticide (fungi cide) on mushrooms in

enclosed mushroom facilities a nd post-harvest, indoors, on pineapples when label instructions and good agricultural practices are followed. The avai lable data and information indicate that the chemical is of low toxicity a nd not a developmental toxicant. Therefore, EPA concludes that there is a reasonable certainty that no harm w ill result to the U.S. population, including infants and children, from aggregate exposure to the resi dues of natamycin when it is used as labeled and in accordance with good agricultural pract ices. Such exposure includes all anticipated dietary exposures and all other exposures for which there is reliable information. EPA has

arrived at this conclusion because the data and information available on natamycin do not demonstrate significant toxic potential to mammals, including infants and children.

10. Risk Characterization

The Agency considered human exposure to natamyci n in light of the releva nt safety factors in FQPA and FIFRA. A determination has been made that no unreasonable a dverse effects to the U.S. population in general, and to infants and chil dren in particular, will result from the use of products containing natamcyin when label instructions are followed.

C. Environmental Assessment

1. Ecological Hazards

Tier I studies were not submitted but are not requ ired. However, based on its use pattern and use instructions as a fungistat intende d solely for use in indoors, expos ure to non-target organisms is not expected.

2. Environmental Fate and Ground Water Data

Environmental fate and groundwater data are not required at this time because the results of the nontarget organism toxicity assessment (Tier I da ta requirements) did not trigger these Tier II data requirements.

3. Ecological Exposure and Ri sk CharacterizationNatamycin

PC Code 051102 Biopesticides Registration Action Document

14 Exposure and risk from the registered and propo sed uses of natamycin are expected to be minimal for nontarget organisms becau se all uses are indoors only.

4. Endangered Species Assessment

Based on its use pattern and use instructions, EP A has determined that natamycin will have " No

Effect " on any currently listed threat ened or endangered species or any designated critical

habitat.

D. Product Performance Data

Product performance (efficacy) data must be devel oped for all pesticides to ensure that the products will perform as intended and that unn ecessary pesticide exposure to the environment

will not occur as a result of the use of ineffec tive products. The Agency reserves the right to require, on a case-by- case basis, the submissi on of efficacy data for any pesticide product registered or proposed for registration, but applic ations to register pes ticide products intended to control a pest of significance publ ic health importance, as defi ned in FIFRA section 28(d) and section 2(nn), must include such data. For further guidance on the product performance data requirement, refer to Pesticide Registration Noti ce (PR) Notices 96-7, 2002-1 and Explanation of Statutory Framework for Risk-Benefit Bala ncing for Public Health Pesticides (http://www.epa.gov/PR _Noti ces/pr1996-7.pdf) (http://www. ea.gov/PR_Notices/pr2002-1.pdf)

and ( http://www.epa.gov/pesticides /health/risk-be nefit.htm).

Natamycin is not intended to be formulated in to products to control public health pests as defined in FIFRA section 28(d) and section 2(nn ), and product performance (efficacy) was not evaluated by the Agency.

V. RISK MANAGEMENT DECISION

A. Determination of Eligibility for Registration

Section 3(c)(5) of FIFRA provides for pesticide product registration if it is determined that: (A) its composition warrants proposed claims; (B) its labeling and other materials comply with the requirements of FIFRA; (C) it will perform its intended function without unreasonable adverse effects on the environment; and (D) when used in accordance with widespread and commonly recognized practice, it will not ge nerally cause unreasonable adverse effects on the environment.

The four eligibility criteria have been satisfi ed for the proposed pestic ide product containing the active ingredient natamycin (a nd for all previous registered pesticide products containing natamycin).

B. Regulatory Decision

The data submitted fulfill the requirements for the unconditional registration of Zivion P (EPA File Symbol 87485-G) as an EP for use on pineappl es, post-harvest, indoors, and EPA believes it

is in the best interest of th e public to grant this registrati on. For product-specific labels andNatamycin

PC Code 051102 Biopesticides Registration Action Document

15 information on other product containing natamycin, please refer to http://www.epa.gov/pesticides/pestlabels

.

C. Environmental Justice

EPA seeks to achieve environmen tal justice—the fair treatment and meaningful involvement of all people regardless of race, color, national or igin, or income—with respect to the development, implementation, and enforcement of environmental laws, regulations, and po licies. At this time, EPA does not believe that products containing th e active ingredient natamycin, or the use of natamycin on pineapples post-harvest, indoors, will cause harm or a disproportionate impact on

at-risk communities. For additional information re garding environmental justice issues, please

visit EPA’s website at http://www.epa.gov/compliance/en vironmentaljustice/index.html

.

VI. ACTIONS REQUIRED BY REGISTRANTS

EPA evaluated all data submitted in connecti on with the registrati on of natamycin and

determined that these data are sufficient to sa tisfy current registrati on data requirements for Zivion P (EPA File Symbol 87485-G). At this ti me, no additional data must be submitted to EPA. For new uses and/or changes to existing uses, EPA may require additional data.

Notwithstanding the information stated in the pr evious paragraph, it should be clearly understood that certain specific data are requi red to be reported to EPA as a requirement for maintaining the federal registration for a pesticide product. A br ief summary of these t ypes of data are listed

below.

A. Reporting of Adverse Effects

Pursuant to FIFRA section 6(a)(2), reports of al l incidents of adverse effects to the environment

must be submitted to EPA.

B. Reporting of Hypersensitivity Incidents

Under the provisions of 40 CFR Part 158.2050(d), all incidents of hypersensitivity (including both suspected and confirmed incidents) must be reported to the Agency.Natamycin

PC Code 051102 Biopesticides Registration Action Document

16 VII. Appendix A: Product Chemistry Data Tables

TABLE 1. Product Chemistry Da ta Requirements for Natamycin Technical (40 CFR § 158.2030)

OSCPP Guideline

No. Study Results MRID No.

880.1100

880.1200

880.1400 Product identity; Manufacturing process;

Discussion of formation of impurities Submitted data satisfy the requirements for product identity, manufacturing process, and discussion of formation of impurities. 48105401

48105501

47206713

47760931

830.1700 Analysis of samples Submitted data satisfy the requirements fo r analysis of samples. 48105502

830.1750 Certification of limits Limits listed in the

confidential statement of formula are acceptable 48105402

830.1800 Analytical me thod Acceptabl e 48105403

TABLE 2. Physical and Chemical Properties of Natamycin Technical (40 CFR § 158.2030)

OCSPP

Guideline No. Property Description of Results MRID

830.6302 Color Colourless 48105503 830.6303 Physical State Viscous liquid 48105503

830.6304 Odor Odorless 48105503

830.6313

Stability to Normal and Elevated Temperatures,

Metals and Metal Ions Natamycin was found stable at 54°C for 14 days. Storage stability studies supporting pharmaceutical uses found acceptable stability in tests of 2 to 5 years in duration. Natamycin is degraded by contact

with most metals and metal ions. However, the product is never packaged in metal containers. 48105504

830.6315 Flammability Does not contain any flammable components. Consists of ~ 80%

water. 48105503

830.6317 Storage Stability The product is stable when stored

for 12 and 18 months in HDPE plastic bottles at 25 o C. 8105405

48439301

48544501 830.6320 Corrosion Characteristics The product is not corrosive. 48105405

48439301

48544501 830.7000 pH 6.5 (1% aqueous solution) 6.5 (1% aqueous solution). May vary between 5 to 7.5 48105503?

830.7100 Viscosity ~2200 mPa.s, Brookfield Test

Method: RPM-20, Axe=3, T=20°C. 48105503

830.7220 Boiling Point/Range N/A The product is a solid. 48105503 830.7300 Density Loose bulk density 0.3 g/mL Tapped bulk density 0.59 g/mLNatamycin

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17 TABLE 2. Physical and Chemical Properties of Natamycin Technical (40 CFR § 158.2030)

OCSPP

Guideline No. Property Description of Results MRID

830.7560

830.7570 Octanol/water partition coefficient (K

ow ) Log K
ow = – 3.67 48105503

830.7840 Water Solubility 30-50 ppm @ 20-25°C and pH 5- 7.5; very soluble at pH ≥ 10 or pH ≤ 2 but rapidly degrades. 8105503

830.7950 Vapor Pressure NA The product is a solid 48105503

Formulation Type Suspension (SU) 48105501

Container Material and Description HDPE plastic bucket, jerry can, drum or jumbo container (5 to 1000 Litres) 48105501

830.7000 pH 6.5 (1% aqueous solution) 6.5 (1% aqueous solution). May vary between 5 to 7.5 48105503

830.6314 Oxidizing or Reducing Action Not applicable. Does not contain oxidizing or reducing chemicals. 48105503

830.6316 Explodability Not applicable. Does not contain any substance capable of exploding. 48105503

830.6319 Miscibility Not formulated to be mixed with petroleum solvents. 48105503

830.6321 Dielectric Breakdown Voltage Not applicable. Not intended to be used around electrical equipment. 48105503

1 A = Acceptable; N = Unacceptable (see Deficiency); N/A = Not applicable.

2 For example, “brown” for 830.6302; “1.021” for 830.7300.

3. There was a slight shift in the retention time (close to a minute) for the active ingredient based on the chromatograms provided for the 18-month storage stability study. The applicant provided a rationale indicating that there was a change in the column packing mate rial (new batch). The applicant provided additional chromatograms for the controls (standard sample) for th e 6- and 18-month to confirm the slight shift in the

retention times for the active. The rationale is accepted.Natamycin

PC Code 051102 Biopesticides Registration Action Document

18 VIII. Appendix B. References

EPA Science Review Memos

U.S. EPA, 2010. Jones, Russell, Ph.D. Scien ce Review in Support of Natamycin Technical, Containing 91.02% Natamycin as Its Active Ingredie nt. United States Environmental Protection Agency (U.S. EPA) Memorandum dated 10/15/2010.

U.S. EPA, 2011a. Jones, Russell, Ph.D. Scien ce Review in Support of Natamycin Technical, Containing 91.02% Natamycin as Its Active Ingredie nt. United States Environmental Protection Agency (U.S. EPA) Memorandum dated 04/04/2011.

U.S. EPA, 2011b. Jones, Russell, Ph.D. Scien ce Review in Support of Natamycin Technical, Containing 91.02% Natamycin as Its Active Ingredie nt. United States Environmental Protection Agency (U.S. EPA) Memorandum dated 07/11/2011.

U.S. EPA, 2011c. Jones, Russell, Ph.D. Scien ce Review in Support of Natamycin Technical, Containing 91.02% Natamycin as Its Active Ingredie nt. United States Environmental Protection Agency (U.S. EPA) Memorandum dated 12/13/2011.

U.S EPA, 2014. Rexrode, Miachel, Ph.D., Request for new food use (post-harvest treatment of pineapples) to the active ingred ient, Natamycin. United States E nvironmental Protection Agency (U.S. EPA) Memorandum dated 10/01/2014.

Data Volumes Submitted to the Agency on Natamycin

MRID Citation Reference

59399 American Cyanamid Company (1959) Antibiotic A-5283, Myprozine: Acute Toxicity to Rats; Subacute Toxicity to Rats and Dogs: Re- port No. 59-4. (Unpublished study received on unknown date un- der unknown admin. no.; CDL:223651-A)

59400 American Cyanamid Company (1963) Pimaricin (Myprozine^(R)I): Report on Two-Year Toxicity Studies. Summ ary of studies 223651-C through 223651-H. (Unpublished study received on unknown date under unknown admin. no.; CDL:223651-B)

59401 American Cyanamid Company (1963) Pi maricin: Two-Year Feeding to Dogs: Report No. 63-6. (Unpublished study r eceived on unknown date under unknown admin. no.; CDL:223651-C)

59402 American Cyanamid Company (1963) Pi maricin: Two-Year Feeding to Rats: Report No. 63-7. (Unpublished study, incl uding report no. 63-8, received on unknown date under unknown admin. no.; CDL: 223651-D)

59403 Levinskas, G.J.; Bushey, C.; Kunde, M.L. ; et al. (1963) Pima ricin: Successive Generation Studies: Report No. 63-9. (Unpublished study received on unknownNatamycin

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19 date under unknown admin. no.; submit- ted by American Cyanamid Co., Princeton, N.J.; CDL:223651-E)

59404 Shirk, R.J.; Lovesky, R.L. (1963) A Gross Examination of the Fecal Flora of Rats

Sustained for Two Years on Diets Contai ning from 0 to 1000 ppm. Pimaricin: Report FS 3. Progress rept., Jun 21, 1962 to Aug 1, 1962. (Unpublished study received on unknown date under unknown admin. no.; submitted by American Cyanamid Co., Princeton, N.J.; CDL:223651-F)

59405 Shirk, R.J. (1963) The Fecal Excretion and Non-absorption of Pima- ricin in Animals: Report FS 3. Progress rept. (U npublished study received on unknown date under unknown admin. no.; submit- ted by American Cyanamid Co., Princeton, N.J.; CDL:223651-G)

48105400 DSM Food Specialties B.V. (2010) Subm ission of Product Chemistry, Residue, Toxicity, and Exposure and Risk Data in Support of the Application for Registration of Natamycin L and the Petit ion for Tolerance of Netamycin for Use

on Mushrooms. Transmittal of 11 Studies.

48105401 van der Lee, J.; Jovanovich, A. (2010) Natamycin L: Product Identity, Composition, and Formulation. Unpublished study prep ared by Keller and Heckman LLP. 48 p.

48105402 van der Lee, J.; Jovanovich, A. (2010) Na tamycin L: Certified Limits. Unpublished study prepared by Keller and Heckman LLP. 9 p.

48105403 van Hilten, P. (2010) Natamycin L: En forcement Analytical Method. Unpublished study prepared by Keller and Heckman LLP. 18 p.

48105404 van der Lee, J.; Jovanovich, A. (2010) Natamycin L: Summary of Physical/Chemical Properties and Self-C ertification. Unpublished study prepared by Keller and Heckman LLP. 32 p.

48105405 van der Lee, J.; Jovanovich, A. (2011 )(Sic) Natamycin L: Interim Report for Storage Stability and Corrosion Characteristics. Project Number: STAB/SLD/09/008. Unpublished study prepar ed by DSM Food Specialties B.V. 24

p.

48105406 Jovanovich, A. (2010) Residue Data: Chemi cal Identity and Directions for Use for Natamycin L. Unpublished study prepared by Keller and Heckman LLP. 9 p.

48105407 Marin, J. (2010) Development and Validat ion of an Analytical Method for the Determination of Natamycin in Mushr ooms and Mushroom Compost, Casing and Casing plus Innoculum. Project Numb er: 1869W. Unpublished study prepared by PTRL West, Inc. 73 p.

48105408 Marin, J. (2009) Magnitude of the Residue of Natamycin in Mushrooms. Project Number: 1915W. Unpublished study pr epared by PTRL West, Inc. 165 p.

48105409 Wilms, L.; Jovanovich, A. (2010) Natamy cin L: Request for Waiver of 5 Acute Toxicity Tests. Unpublished study prep ared by Keller and Heckman LLP. 16 p.Natamycin

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20 48105410 Kuhn, J. (2009) Natamycin Liquid Formul ation: Acute Eye Irritation Study in Rabbits: Final Report. Project Number: 12753/09. Unpublished study prepared by Stillmeadow, Inc. 20 p.

48105411 Wach, M. (2010) Natamycin L: Descripti ons of Human Activity for Natamycin L. Unpublished study prepared by Keller and Heckman LLP. 10 p.

48105500 DSM Food Specialties B. V. (2010) Submi ssion of Product Chemistry and Toxicity Data in Support of the A pplication for Registration of Natamycin TGAI and the Petition for Tolerance of Natamycin for Use on Mushroom. Transmittal of 14

Studies.

48105501 Zuur, P.; Hee, P.; Roghoenath, D.; et al. (2010) Natamycin TGAI: Product Identity, Composition, and Production. Unpublished st udy prepared by Keller and Heckman LLP. 252 p.

48105502 Zeeman, M.; Boogers, I.; Van der Lee, J.; et al. (2010) Natamycin TGAI: Preliminary Analysis and Certified Lim its. Unpublished study prepared by Keller and Heckman LLP. 140 p.

48105503 Van der Lee, J.; Jovanovich, A. (2010) Natamycin TGAI: Physical and Chemical Properties. Unpublished study prepared by Keller and Heckman LLP. 9 p.

48105504 Van der Lee, J.; Jovanovich, A. (2010) Stability to Normal and Elevated Temperatures, Metals, and Metals Ions . Unpublished study prepared by Keller and Heckman LLP. 27 p.

48105505 Kuhn, J. (2008) Natamycin TGAI: Acute Or al Toxicity Study (UDP) in Rats: Final Report. Project Number: 11403/07. Unpublis hed study prepared by Stillmeadow, Inc. 12 p.

48105506 Kuhn, J. (2008) Natamycin TGAI: Acute Dermal Toxicity Study in Rat: Final Report. Project Number: 11404/07. Unpublis hed study prepared by Stillmeadow, Inc. 13 p.

48105507 Crutchfield, V. (2008) Nata mycin TGAI: Acute Inhalation Toxicity Study in Rats: Final Report. Project Number: 11405 /07. Unpublished study prepared by Stillmeadow, Inc. 19 p.

48105508 Kuhn, J. (2008) Natamycin TGAI: Acute Eye Irritation Study in Rabbits: Final Report. Project Number: 11406/07. Unpublis hed study prepared by Stillmeadow, Inc. 18 p.

48105509 Kuhn, J. (2008) Natamycin TGAI: Acute Dermal Irritation Study in Rabbits: Final Report. Project Number: 11407/07. Unpublis hed study prepared by Stillmeadow, Inc. 13 p.

48105510 Kuhn, J. (2008) Natamycin TGAI: Skin Sens itization: Local Lymph Node Assay in Mice: Final Report. Project Number : 11408/07. Unpublished study prepared by Stillmeadow, Inc. 13 p.Natamycin

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21 48105511 Otterdijk, F. (2003) Natamycin TGAI: 90 Day Oral Toxicity Study with Natamycin in the Rat. Project Number: NOTOX/PROJECT/339323, 002019. Unpublished study prepared by Notox B.V. 220 p.

48105512 Knickerbocker, M. (1979) Natamycin TGAI : Teratologic Evaluation of Pimaricin in Dutch-Belted Rabbits. Project Number: 5906. Unpublished study prepared by Food & Drug Research Laboratories, Inc. 290 p.

48105513 Verspeek, C. (2002) Natamycin TGAI: Ev aluation of the Mutagenic Activity of Natamycin in the Salmonella typhimuri um Reverse Mutation Assay and the Escherichia coli Reverse Mutation Assay (w ith Independent Rat) . Project Number: NOTOX/PROJECT/339345. Unpublished st udy prepared by Notox B.V. 29 p.

48105514 Meerts, I. (2002) Natamycin TGAI: Evaluation of the Ability of Natamycin to

Induce Chromosome Aberra tions in Cultured Peripheral Human Lymphocytes. Project Number: NOTOX/PROJECT/ 339356. Unpublished study prepared by Notox B.V. 28 p.

48439300 DSM Food Specialties (2011) Submission of Product Chem istry Data in Support of the Application for Registration of Natamycin L. Transmittal of 1 Study.

48439301 van der Lee, J.; Jovanovich, A. (2011) 12-Month Interim Report for Storage Stability and Corrosion Characteristi cs: Natamycin L. Project Number: STAB/SLD/09/008. Unpublished study prepar ed by DSM Food Specialties B.V. 38

p.

48544501 van der Lee, J.; Jovanovich, A. (2011) 18- Month Final Report for Storage Stability and Corrosion Characteristics: Natamyci n L. Project Number: STAB/SLD/09/008. Unpublished study prepared by DSM Food Specialties B.V. 41p.

48593400 DSM Food Specialties B.V. (2011) Submission of Toxicity Data in Support of the Application for Registration of Na tamycin L. Transmittal of 1 Study.

48593401 Cox, G.; Bailey, D. (1973) Natamycin TGAI Rat Development Toxicity Study. Project Number: 1052. Unpublished study prepared by Food & Drug Research Laboratories, Inc. 495p.

48613501 Thate, C.; Jovanovich, A. (2011) Nata mycin TGAI: Request for Waiver of Teratology Study Data Requirement. U npublished study prepared by Keller and Heckman LLP and DSM Food Specialities. 177p.

48966100 DSM Food Specialties (2012) S ubmission of Exposure/Risk Data in Support of the Amended Registration of Zivion M. Transmittal of 1 Study.

48966101 Novak, M. (2012) Scientific Justifica tion for Shortening the Restricted Entry Interval (REI) From 12 Hour s to 4 Hours: Zivion M. Unpublished study prepared by Keller and Heckman LLP. 14p.

49188300 DSM Food Specialties (2013) Submission of Residue Data in Support of the Amended Registration of Natamycin L. Transmittal of 1 Study.Natamycin

PC Code 051102 Biopesticides Registration Action Document

22 49188301 Cassidy, P. (2013) Natamycin Residue An alysis in Mushrooms, Compost and Casing: Amended Report. Project Nu mber: 029035/1/1, 029035. Unpublished study prepared by Ricerca Biosciences, LLC. 101p.

49254800 DSM Food Specialties B.V. (2013) Subm ission of Product Chemistry Data in Support of the Amended Registration of Zivion M. Transmittal of 1 Study.

49254801 Graham, D. (2013) Measurements Vi scosity, Density and pH: (Zivion M). Unpublished study prepared by DSM Food Specialties B.V. 30p.

49292400 DSM Food Specialties B.V. (2014) Submi ssion of Product Chemistry, Toxicity and Residue Data in Support of the Applica tion for Registration of Zivion P, the Amended Registration of Natamycin TGAI and the Petition for Tolerance of Natamycin for Use on Pineapple. Transmittal of 5 Studies.

49292401 Ramdjielal, J.; Graham, D. (2013) Produc t Identity, Compostion, and Formulation: Zivion P. Unpublished study prepared by DSM Food Specialties B.V. 32p.

49292402 Ramdjielal, J.; Graham, D. (2013) Summ ary of Physical/Chemical Properties and Self-Certification: Zivion P. Unpublis hed study prepared by DSM Food Specialties B.V. 6p.

49292403 Devine, J.; Maryann C. (2013) Magnitude of Residues of Natamycin in PostHarvest Treated Pineapples (Declin e, Processing). Project Number: 197SRUS12R/1, 029653/1, 029653. Unpublished study prepared by SynTech Research. 204p.

49292405 Ramdjielal, J. (2013) Descriptions of Human Activity for Zivion P. Unpublished study prepared by DSM Food Specialties B.V. 5p.Natamycin

PC Code 051102 Biopesticides Registration Action Document

23 IX. GLOSSARY OF ACRONYM S AND ABBREVIATIONS

a.i. active ingredient BPPD Biopesticides and Pollu tion Prevention Division BRAD Biopesticide Registration Action Document bw body weight

CBI Confidential Business Information CFR Code of Federal Regulations

cm 3 cubic centimeter

CSF Confidential Statement of Formula °C degrees Celsius

EC 50 median effective concentra tion. A statistically derive d single concentration in environmental medium that can be expected to cause an effect in 50% of the test animals when administrated by the route in dicated (inhalation). It is expressed

as a concentration in ai r or water (e.g. mg/L). EDSP Endocrine Disrupt or Screening Program EDSTAC Endocrine Disruptor Screeni ng and Testing Advisory Committee EP end-use product EPA Environmental Protection Agency (the “Agency”) FDA Food and Drug Administration FFDCA Federal Food, Drug, and Cosmetic Act FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FQPA Food Quality Protection Act FR Federal Register

g gram ha hectare kg kilogram Kow octanol-water partition coefficient

L liter

LC 50 median lethal concentration. A statistically derived singl e concentration in air or water that can be expected to cause d eath in 50% of the test animals when administrated by the route indicated (inhalation and environment). It is expressed as a concentration in air or water (e.g. mg/L).

LD 50 median lethal dose. A statistically de rived single dose that can be expected

to cause death in 50% of the test an imals when administered by the route indicated (oral and dermal). It is expressed as a weight of substance per unit weight of animal (e.g., mg/kg).

MRID No. Master Record Identification Number mg milligram mPa millipascal

mL milliliter MP manufacturing-use product N/A not applicable

NE “No Effect” NIOSH National Institute for Occupational Safety and HealthNatamycin

PC Code 051102 Biopesticides Registration Action Document

24 nm nanometer
NOEL no-observed-effect-level NOF notice of filing NOR notice of receipt OPP Office of Pesticide Programs

OCSPP Office of Chemical Safe ty and Pollution Prevention pa pascal PPE personal protective equipment PR Notice Pesticide Registration Notice

TGAI technical grade of the active ingredient ug microgram

USDA United Stat es Department of Agriculture

UV ultra-violet