**BIOPESTICIDE S**  **REGISTRATION ACTION DOCUMENT**

**Natamycin**

**PC Code: 051102** 

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

**May 14, 2012 Natam** **ycin** Page 2

Biopesticides Registration Action Document **TABLE OF CONTENTS I.**  **EXECUTIVE SUMMARY ................................**  **................................ ................................**  **.... 4**  **II. ACTIVE INGREDIENT OVERVIEW**  **................................ ................................**  **................. 7**  **III. REGULATORY BACKGROUND**  **................................ ................................**  **........................ 7**  **A. C**  **lassification**

................................ ................................ ................................ .................... 7 B **. Food Clearances/Tolerances.........................................................** 

.... 8 **IV. RISK ASSESSMENT**  **................................ ................................**  **................................ .............**  **8 A. Acti**  **ve Ingredient Characterization Error! Bookmark not defined.**  **Error! Bookmark not defined. B.**  **Human Health Assessment**

................................ ................................ ............................ 8 **C. Environmental Assessment Error! Bookmark not defined.**  **Error! Bookmark not defined. V. ENVIRONMENTAL JUSTICE**  **.** Error! Bookmark not defined. Error! Bookmark not defined. **VI. RISK MANAGEMENT AND REGISTRATION DECISI ONS**  **................................ .......**  **14 A. Determination of Eligibility** 

................................ ................................ .......................... 14 **B. Regulatory**  **Decision**

................................ ................................ ................................ ...... 15 **C. Labeling** 

................................ ................................ ................................ .......................... 15 **VII. ACTIONS REQUIRED OF THE REGISTRANT ................................**  **........................... 16**  **A. R eporting of Adverse Effects and Hypersensitivity Incidents** 

................................ .. 16 **VIII. GLOSSARY OF ACRONYMS AND ABBREVIATIONS** Error! Bookmark not defined. Error! Bookmark not defined. **IX. BIBLIOGRAPHY STUDIES SUBMITTED IN SUPPORT OF THESE**  **REGISTRATIONS ................................**  **................................ ................................**  **............... 24**  **A. Studies Submitted in Support of Natamycin ................................**  **................................ ..**  **B. EPA Risk Assessment Memoranda** 

................................ ................................ .............. 27 **C. References**

................................ ................................ ................................ ...................... 27**Natam ycin**  Page 3

Biopesticides Registration Action Document

**BIOPESTICIDES REGISTRATION ACTION DOCUMENT TEAM**

**Office of Pesticide Programs Biopesticides and Pollution Prevention Division**  **Biochemical Pesticides Branch (BPB)**
Ch eryl Greene Regulatory Action Leader Russell Jones, Ph.D. Lead Science Reviewer/Senior Biologist Linda Hollis Branch Chief

**HEALTH CANADA PEST M ANAGEMENT REGULATORY**  **AGENCY** Bing Dang Science Coordination Officer PMRA, Health Canada 2720 Riverside Drive Ottawa, ON K1A 0K9**Natam ycin**  Page 4

Biopesticides Registration Action Document **I. EXECUTIVE SUMMARY** Natam ycin is a new biochemical pesticide active ingredient intended for use as a fungistat to control the germination of mold and y east spores in the growth media of mushrooms produced in enclosed mushroom production facilities. Natam ycin is a naturall y - occurring antim ycotic compound derived from the common soil microorganisms, Streptomyces natalensis, Streptomyces lydicu s , and Streptomyces chattanoogensis. It is commercially p roduced b y 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.

. Natamy cin was originall y disco vered in Streptomyces natalensis in South Africa in the earl y 1950s , and was subsequent ly discovered to also occur naturally in North America in Streptomyces lydicu s , and Streptomyces chattanoogensis. Natamy cin has a non

- toxic mode of action and functions as a fungistat, preventing the germination of fungal spores. It has no effects on fungal m yc elia. Development of antibiotic resistance to Natamy cin has not been reported during its entire history of u se. Natam ycin has been used as a food preservative worldwide for over 40 ye ars (WHO TRS 430) and is approved as a food additive/preservative b y the European Union, the World Health Organization and i ndividual countries for use as a fungistat to suppress mold on cheese, meats and sausage. In the United States, Natamy cin is approved b y The Food and Drug Administration (FDA) as a direct food additive/ preservative for the inhibition of mold and y east on the surface of cheeses ( 21CFR172 .155 ) and as an additive to the feed and drinking water of broiler chickens to retard the growth of specific molds ( 21CFR573.685 ). Natam ycin is also FDA approved for use as a treatment to suppress fungal ey e infections such as blepharitis, conjunctivitis and keratitis

. On August 17, 2007, the EPA’s Biochemical Classification Committee classified Natam ycin as a Biochemical Pesticide active ingredient, and

- 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, agricultural, and seed treatment uses. The Biopesticides and Pollution Prevention Division (BPPD) determined that the data/information submitted for product chemistry and Tier I acute toxicity

for Natam ycin satisfy the current guideline requirements. Acceptable s tudies were submitted for the subchronic 90

- day oral (OCSPP 870.3100) and 90

- d ay inhalation (OCSPP 870.3465) data requirements. Th ose data showed no biologically

significant changes in the hematology or clinical chemistry

profiles of the test animals. No 90

- Day Dermal (OCSPP 870.3250) o r 90

- Day I nhalation (OCSPP 870.3465 ) studies were submitted and none are required since p roducts containing Natamy cin will only be applied in irrigation water to mushrooms growing in enclosed facilities. Based on this application method, the Agency does not anticipate an y repeated dermal exposure to Natam ycin

. In lieu of a Guideline study the applicant developed a science based rationale in support of Prenatal Developmental Toxicity ((OCSPP 870.3700) for Natam ycin. The rationale was supported w ith information and data obtained from the open technical literature. The rationale relies primaril y on a comprehensive review of Natamycin b y the European Food Safet y Authority (EFSA, 2009) and its associated citations. By way of the EFSA review of Natam ycin (aka Pimaricin), the rationale demonstrated that Natamy cin is poorly absorbed by

mammals and**Natam ycin**  Page 5

Biopesticides Registration Action Document that it does not pose any

dietary concerns based on current usage. The Agency concurs with this conclusion b ased on per capita consumption of all mushroom commodities in the United States (USDA/ERS, 2010), dietary intake from treated, unwashed mushrooms is conservativel y estimated to be no more than 0.00030 mg a.i./kg bw/person/day . This value is well below any known acute oral, subchronic and chronic dietary , reproductive, and developmental endpoints for Natam ycin b y man y orders of magnitude. In addition, the estimated dietary intake from unwashed, treated mushrooms also is well below the Acceptable Dietary I ntake (ADI) of 0.3 established by

Joint FAO/WHO Expert Committee on Food Additives (JECFA, 2001& 2006) and an ADI of 0.1 established European Food Safety Authority

(EFSA, 2009). The information submitted by

the registrant, along with open technical literature also support the Tolerance Exemption Petition submitted for Natam ycin. Tier I studies were not submitted for non

- target organisms and environmental fate data requirements (OCSPP 850.1010 to 850.4450) for Natam ycin and such studies are not required. Based on its use pattern and use instructions as a fungistat intended solel y for use in indoor, enclosed mushroom production facilities, Natam ycin exposure to non
- target organisms is not expected. Further, EPA has determi ned that Natamy cin will have " **No Effect** " on an y currently listed threatened or endangered species or an y designated critical habitat b ased on its use pattern and use instructions and the fact that Natam ycin is intended solely for indoor use in enclosed mus hroom production facilities. Based on the acute toxicity data for Natam ycin , the active ingredient is toxicity category I II. EPA has not identified any toxic endpoints for nontarget mammals, birds, plants, aquatic, or soil organisms. EPA has no concerns for any nontarget organisms exposed to Natamy cin when used in accordance with approved label directions. Given that Natam ycin has very low toxicity

and presents little, if an y , risk to nontarget organisms, EPA has concluded that it is in the best interest s of the public to issue the registration for the Natam ycin TGAI ( EPA File Sy mbol No. 8 7485

- 1 ) and the end

- use product Natam ycin L ( EPA File Sy mbol No. 8 7485

- 2 ), which contain this new active ingredient, Natamy cin. The Agency has reviewed the data/information in support of the requirements for granting registration under Section 3(c)(5) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) and determined that the data/information submitted adequatel y satisfy current guideline requi rements ( see 40 CFR Subpart U § 158.2000). On October 1, 2009, EPA announced a new policy to provide a more meaningful opportunit y for the public to participate on major registration decisions before they occur. According to this policy , EPA provides a p ublic comment period prior to making a registration decision for the following t ypes of applications: new active ingredients, first food use, first outdoor use, first residential use; and an y registration decisions for which the Agency believes there may

b e substantial public interest. Consistent with the policy of making registration actions more transparent, Natam ycin was subject to a 30 day

comment period as a “new active ingredient”. The notice for this comment period include d the draft Biopesticide s Registration Action Document (BRAD) and draft product labels for the technical grade active ingredient, Natamy cin TGAI and the EP, Natamy cin L.**Natam ycin**  Page 6

Biopesticides Registration Action Document which contain this new active ingredient, Natamycin. The docket identification (ID) number is EPA

- HQ

- OPP

- 2010

- 0685 . The Agency believes that based on the risk assessment and information submitted in support of the registration of the EP containing Natamy cin , it is in the best interests of the public to issue the registration for Natam ycin L . The basis for this de cision can be found in the risk assessment for Natam ycin , which is characterized in this BRAD.**Natam ycin**  Page 7

Biopesticides Registration Action Document **II. ACTIVE INGREDIENT OVERVIEW**  **Common Name:** Natamy cin **Chemical Name:** IUPAC Chemical Name:

( 1 R ,3 S,5 R ,7 R ,8 E ,12 R ,14 E ,16 E ,18 E ,20E ,22 R ,24 S,25 R ,26 S )

- 22

- [(3

- amino

- 3,6

- dideox y - β

- D

- mannopy ranos yl )ox y]

- 1,3,26

- trihy droxy

12

- methyl

- 10

- oxo - 6,11,28

- trioxatricy clo[22.3.1.0 5,7 ]octacosa

8,14,16,18,20

- pentaene
- 25

- carbox yl ic acid **Trade & Other Names:** Natam ycin L Pimaricin Tennectin Delvocid **CAS Registry Number:**  76 8 1

- 93

- 8

**OPP Chemical Code: 051102**  **Type of Pesticide:** Fungistat

**III. REGULATORY BACKGROUND** O n May 20, 2010 , E PA 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., Alexander Fleminglaan 1, Delft, The Netherlands 2613AX to register the products Natam ycin TGAI (EPA File Sy

mbol No. 87485

- 1 ) , and Natamy cin L ( EPA File S ymbol No. 87485

- 2 ) containing the new biochemical active ingredient Natam ycin. The application was submitted to both the U.S. Environmental Protection Agency (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 applications 1 . Concurrent with these applications , DSM filed a petition for a tolerance exemption for residues of Natam ycin on mushrooms whe n used as a fungistat in enclosed mushroom producing facilities. 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 receipt 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.

**A. C**  **lassification**

1 See http://www.epa.gov/oppfead1/international/naftatwg/guidance/jointreview

- biope.pdf

.**Natam ycin**  Page 8

Biopesticides Registration Action Document Natam ycin was classified as a Biochemical Pesticide by the Agen cy ’s Classification Committee on August 17, 2007 . The Classification C ommittee confirmed its nontoxic mode of action, its natural occurrence in the environment, and its history of exposure to humans and the environment without known toxicity

. B **. Food Clearance/Tolerances** Natam ycin is intended for use as a fungistat only on mushrooms grown in enclosed mushroom growing facilities. The Agency considers this use to be a food use. On April 20, 2011 the Agency issued a notice in the federal register (76 FR 22067) of the filing of a petition by DSM for the exemption of residues of on mushrooms. **IV . RISK**  **ASSESSMENT A. Active Ingredient Characterization**  Natam ycin is a biochemical active ingredient intended for use as a fungistat to be in enclosed mushroom production facilities for the control of fungi and mold on mushrooms. It is derived from the common soil microorganism, Streptomyces natalensis and is commerciall y produced b y submerged aerobic fermentation by Streptomyces natalensis , Streptomyces lydicu s , and Streptomyces chattanoogensis. Fermentation is conducted for several day s, and the antibiotic is isolated either b y broth extraction or by extraction of the myc elium. Dried Natam ycin recovered from the fermentation broth is white to cream

- colored and has little or no odor or taste; in the cr ys talline form it is very stable. During the extraction procedure the N atamy cin is dissolved and filtered through a membrane

. The membrane is not permeable to the organism and the concentration of the extraction is high enough to kill the organism. None of the microorganism that is used to produce Natamy cin is viable at the end of this process. All product chemistry and composition data requirements for Natam ycin have been satisfied

. The information submitted to support the product chemistry and composition data requirements for Natam ycin are summarized in Table s 1 and 2 in Appendix A. **B. H**  **uman Health Assess ment**  **1. Toxicology**  For acute toxicity

data requirements, toxicity categories are assigned based on the hazard(s) identified from studies and/or information on file with the Agency . The active ingredient is classified into Toxicity

Category I , II, III or IV where Toxicity Cat egory Iindicates the highest toxicity and Toxicity

Category I V indicates the lowest toxicity

. Adequate mammalian toxicology data/information is available to support registration o Natam ycin. All toxicology data requirements for Natam ycin have been **satisfied. Natam** **ycin** Page 9

Biopesticides Registration Action Document

**a. Acute Toxicity**  Acute toxicity

testing is required to 1) determine sy stemic toxicity from acute exposure via the dermal, inhalation and oral routes, 2) determine irritant effects from exposure to the ey es, and 3) determine the potential for s kin sensitization (allergic contact dermatitis). Tier I acute toxicity

studies submitted and reviewed showed that Natam ycin is Toxicity Category III for acute oral toxicity

and Toxicity

Category IV for acute dermal toxicity , acute inhalation toxicity , p rimary

ey e irritation, and primary dermal irritation. Natamy cin is not a sensitizer. Natam ycin is not a mutagen and is not cy totoxic. For more information regarding acute toxicity data requirements, refer to Table 3 in Appendix A. **b. Subchronic**  **Toxicity** Subchronic data are required to determine a no

- observed

- effect

- level (NOEL) and an y toxic effects associated with repeated or continuous exposure to a test substance for a period of ninet y day s
. Subchronic (90

- day) dermal toxicity and Subchronic inhalation studies were not submitted, but are not required based on a lack of repeated exposure to workers and applicators via these two routes of exposure. A 90

- day oral (OCSPP 870.3100) and 90

- day inhalation (OCSPP 870.3465) study was submitted and is acceptable based on the data demonstrating that no biologically significant changes in the hematology or clinical chemistry profiles were observed. The Agency concurs with the findings. For more information regarding the subchronic data requirements, refer to Table 3 in Appendix A.

**c. Developmental Toxicity and Mutagenicity**  In lieu of a Guideline study the applicant developed a science based rationale in support of Developmental Toxicity

((OCSPP 870.3700) for Natam ycin. The rationale was supported with information and data obtained from the open technical literature. The rationale relies primarily on a comprehensive review of Natamy cin by the European Food Safety Authority

(EFSA, 2009) and its associated citations. By way of the EFSA review of Natam ycin (aka Pimaricin), the rationale demonstrated that Natam ycin is poorl y absorbed b y mammals and that it does not pose any dietary concerns based on current usage. The Agency concurs with this concl usion b ased on per capita consumption of all mushroom commodities in the United States (USDA/ERS, 2010), dietary intake from treated, unwashed mushrooms is conservativel y estimated to be no more than 0.00030 mg a.i./kg bw/person/day . This value is well bel ow an y known acute oral, subchronic and chronic dietary , reproductive, and developmental endpoints for Natamy cin by man y orders of magnitude. In addition, the estimated dietary intake from unwashed, treated mushrooms also is well below the Acceptable Dietary I ntake (ADI) of 0.3 established b y J oint FAO/WHO Expert**Natam ycin**  Page 10

Biopesticides Registration Action Document Committee on Food Additives (JECFA, 2001& 2006) and an ADI of 0.1 established European Food Safet y Authorit y (EFSA, 2009). The information submitted by the registrant, along with open technical li terature also support the Tolerance Exemption Petition submitted for Natam ycin

. For more information regarding developmental toxicity and Mutagenicity data requirements, refer to Table 3 in Appendix A.

**d. Tier II and Tier III (40 CFR**  **§ 158.2050)**  No Tier II and Tier III studies were required , based on a lack of acute toxicity in the Tier I studies and a lack of exposure relative to Natam ycin’s use pattern as a fungistat to control mold on mushrooms in enclosed mushroom producing facilities.

**c. Effects on the Endocrine System** As required under Federal Food, Drug, and Cosmetic Act ( FFDCA ) section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced b y a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employ s a two
- tiered approach to making the statutoril y required determinations. Tier 1 consists of a battery of 11 screening assays to identify

the pot ential of a chemical substance to interact with the estrogen, androgen, or thy roid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal sy stems will proceed to th e next stage of the EDSP where EPA will determine which, if any , of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify an y adverse endocrine

- related effects caused b y the substance, and establish a quantitati ve relationship between the dose and the E, A, or T effect. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This lis t of chemicals was selected based on the potential for human exposure through pathway s such as food and water, residential activity , and certain post

- application agricultural scenarios. This list should not be construed as a list of known or likely endocri ne disruptors. Natam ycin 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), EPA must screen all pesticide chemicals. Accordingl y, EPA anticipates issuing future EDSP orders/data call

- ins for all pe sticide active ingredients. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery , please visit our website: htt

p://www.epa.gov/endo/

.**Natam ycin**  Page 11

Biopesticides Registration Action Document **2. Dose Response Assessment** No definitive toxicological endpoints were identified for Natam ycin and no effects were observed at maximum hazard doses. **3. Dietary Exposure and Risk Characterization** Dietary exposure to Natamy cin is expected to be minimal. Natamy cin is a fungistat that has a long history

of use in food for the prevention of spoilage. The active ingredient was demonstrated to be minimally toxic in OCSPP Guideline studies using the TGA I (see Appendix A, Table 4 ). In a review of toxicological literature by the European Food Safet y Agency (EFSA, 2009), Natam ycin was shown to be poorl y absorbed by gastrointestinal s ys tems 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, Natam ycin is rapidl y degraded b y stomach acids, with a 1

- hour half

- life in simulated gastric juice (Morgenstern and Muskens, 1976; reviewed and cited in EFSA, 2009). All inert ingredients used in the end

- use product, Natam ycin 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. **Acute and Chronic Dietary Exposure and Risks for Sensitive Subpopulations, Particularly**  **Infants and Children** Based on the minimal toxicity of Natam ycin demonstrated in laboratory testing of the TGAI (see Table 4 ), the anticipated minimal dietary exposure, and the mode of action of Natam ycin as a fungis tat, acute and chronic dietary risks for sensitive subpopulations are not anticipated.

**4. Drinking Water Exposure Risk Characterization**  Based on the intended use sites (enclosed mushroom production facilities) and use directions (steam sterilization of compost and casing prior to disposal outside of the mushroom growth facility), it is highly

unlikely that residues of Natamy cin will enter any sources of drinking water. However, in the unlikely

event that Natam ycin residues escape from its indoor ap plication site (completel y enclosed mushroom houses), its concentration in surface waters would never exceed 30

- 50 ppm due to its low solubility in water; up to 50 ppm @ 20

- 25°C and pH 5

- 7.5; and at t <pH2 or >pH 10 it completely degrades (USEPA, 2011). Natam ycin is extremel y sensitive to UV light and is completely degraded b y UV within 24 hours of exposure in aqueous solution (Koontz et. al., 2003). Even assuming that no environmental degradation takes place, should Natam ycin be ingested via drinking water, gastric juices ty pically found in the human stomach will completely

degrade Natam ycin within 24 hrs (JECFA, 2006). Finall y, the non

- definitive endpoints for acute oral toxicity (>1820 ppm) and subchronic oral toxicity (>500 ppm in the diet) (USEPA, 2011) are approximately 36X and 10X greater than the highest measured solubility of Natam ycin in water. For these reasons, the Agency believes that there are no concerns for exposure of humans to Natamy cin in drinking water.**Natam ycin**  Page 12

Biopesticides Registration Action Document **5 .**  **Occupational, Residentia l, School and Day Care Exposure and Risk**  **Characterization** Based on use sites (enclosed mushroom production facilities) and use directions (steam sterilization of compost and casing prior to disposal outside of the mushroom growth facility), no Residenti al, School, or Day

- Care exposure is expected.

**a. Occupational Exposure and Risk Characterization**  Occupational exposure to mixer/loader/applicators is expected to be minimal, but can be mitigated with appropriate Personal Protective Equipment (PPE). **See Discussion of Human Activities below.**  **b. Residential, School and Day Care Exposure and Risk Characterization**  A residential, school and day care exposure assessment was not conducted for Natam ycin. However, based on use sites of products containing Natam ycin (enclosed mushroom production facilities) and use directions (steam sterilization of compost and casing prior to disposal outside of the mushroom growth facility), no Residential, School, or Day

- Care exposure is expected. **6 .**  **Aggregate Exposure from Multiple Routes Including Dermal, Oral, and Inhalation**  Based on the mode of action of the active ingredient as a fungistat, no aggregate exposure is anticipated. **7 .**  **Cumulative Effects** Based on the mode of action of the active ingredient as a fungistat, minimal dietary exposure (see Dietary

Exposure and Risk Characterization above) and rapid degradation and excretion from animal sy stems (EFSA, 2009), no cumulative exposure is anticipated

. Pursuant to FFDCA section 408(b)(2)(D)(v), EPA has considered available information concerning the cumulative effects of Natam ycin residues and other substances that have a common mechanism of toxicity . These considerations include the potential for c umulative effects on infants and children of Natamy cin residues and other substances with a common mechanism of toxicity . Because Natam ycin has a long history of dietary

consumption without incident, and because the available data show a lack of acute toxi city in the Tier I studies as well as a lack of exposure relative to Natamy cin’s use pattern as a fungistat to control mold on mushrooms in enclosed mushroom producing facilities, the Agency concludes that Natam ycin does not share a common mechanism of tox icity and that there are no potential cumulative effects arising from incidental exposures to Natamy cin residues in or on food commodities.**Natam ycin**  Page 13

Biopesticides Registration Action Document **8 .**  **Risk Characterization** The Agency

considered human exposure to Natamy cin in light of the standard for registration in the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the relevant safet y factors in FFDCA. A determination has been made that no unreasonable adverse effects to the U.S. population in general, and to infants and children in particular, will result from the use of Natam ycin when label instructions are followed. **C. ENVIRONMENTAL ASSESSMENT**  **1. Ecological Hazards** Tier I studies were not submitted but are not required. However, b ased on its use pattern and use instructions as a fungistat intended solely for use in indoor, enclosed mushroom production facilities, exposure to non

- target organisms is not expected. Additionally , based on its use pattern and use instructions, EPA has determined that Natam ycin will have " **No Effect** " on an y currentl y listed threatened or endangered species or an y designated critical habitat. For more information regarding nontarget organism toxicity data re quirements, please refer to Table 4 in Appendix A. **2. E**  **nvironmental 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 data requirements) did not trigger these Tier II data requirements. **3 . Endangered Species Assessment**  The Agency

has not conducted a risk assessment that supports a complete endangered species determination. The ecological risk assessment planned during registration review will allow the Agency to determine whether Natamy cin use has “no effect” or “may eff ect” federall y listed threatened or endangered species (listed species) or their designated critical habitats. When an assessment concludes that a pesticide’s use “may affect” a listed species or its designated critical habitat, the Agency

will consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries Services (the Services) as appropriate. **D. EFFICACY DATA**  Product performance data must be developed for all pesticides to ensure that pesticide products will perform as intended an d that unnecessary pesticide exposure to the environment will not occur as a result of the use of ineffective products. The Agency reserves the right to require on a case - by

- case basis, submission of efficacy data for any

pesticide product registered or p roposed for registration that are intended to be used to control a pest of significance public health importance and a public health pest as defined in FIFRA section 28(d) and section 2(nn). For further guidance on product performance requirement, refer to Pesticide Registration Notice (PR)**Natam ycin**  Page 14

Biopesticides Registration Action Document Notices 96

- 7, 2002

- 1 and Explanation of Statutory Framework for Risk

- Benefit Balancing for Public Health Pesticides ( http://www.epa.gov/PR _Notices/pr1996

- 7.pdf ) ( http://www.ea.gov/PR_Notices/pr2002

- 1.pdf ) and ( http://www.epa.gov/pesticides/health/risk

benefit.htm ). The EPs submitted with this new active ingredient did not list pests of significance public health importance or a public health pest as defined in FIFRA section 28(d) and section 2(nn). Therefore, the Agency

does not require product performance for Natamy cin under the proposed uses. However, these data are required b y C anada/PMRA and was submitted and reviewed b y Canada/PMRA as part of the joint review of the active ingredient. We are reporting the r esults of that review below. **Canada/PMRA Review** Natam ycin has proven to be an extremel y effective in food preservation because its mode of action is to stop the growth of molds and y easts before damage begins. Curative fungicidal treatments cannot alway s negate the harmful effects that a growing m yc elium leaves behind. In addition, fungi can produce dangerous m ycotoxins, some of which are even carcinogenic, that can cause health problems. Removing the fungi has no effect on my cotoxins once they are embed ded. Natam ycin is able to protect food products against mold growth for long periods of time due to its stability

and cry stalline form. It has a low level of solubility in water (~50 ppm) and in organic materials. Specificall y, Natam ycin can reduce the dev elopment of Verticillium disease

- a use for which this active ingredient is being registered

- of the commercial mushroom. As a fungistat to control Verticillium disease, the best control was noted when 2 mL(form) per sq m were applied. There appears to be little difference between 2 applications (pinning and casing) or 4 applications (pinning, casing, between 1 st and 2 nd breaks and between 2 nd and 3 rd breaks). All product performance data required b y Canada/PMRA for registration of Natam ycin have been **s atisfied** 

. **V . Environmental Justice**  EPA seeks to achieve environmental justice, the fair treatment and meaningful involvement of all people, regardless of race, color, national origin, or income, in the development, implementation, and enforcement of environmental laws, regulations, and policies. To help address potential environmental justice issues, the Agency seeks information on any groups or segments of the population who, as a result of their location, cultural practices, or other factors, may have aty pical, unusually

high exposure to Natamy cin, compared to the general population. Please comment if y ou are aware of any sub

- populations that may have at ypical, unusually high exposure compared to the general population. **V I**  **. R** **isk Management and Regist ration Decision**  **A. Determination of Eligibility**  Section 3(c)(5) of FIFRA provides for the registration of new active ingredients if it is determined that (A) its composition is such as to warrant the proposed claims for it; (B) its labeling and other materials required to be submitted comply with the re quirements of FIFRA;**Natam ycin**  Page 15

Biopesticides Registration Action Document (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 generally cause unreasonable adverse effec ts on the environment. The four criteria of the Eligibility Determination for Pesticidal Active Ingredients are satisfied b y the science assessments supporting products containing Natam ycin

. Such products are not expected to cau se unreasonable adverse ef fects and are likel y to provide protection as claimed when used according to label instructions. Therefore, EPA concludes that Natam ycin is eligible for registration for the labeled uses. **B. Regulatory**  **Decision** On October 1, 2009, the EPA announced a new policy to provide a more meaningful opportunity for the public to participate in major registration decisions before they occur. According to this policy , EPA intends to provide a public comment period prior to m aking a registration decision for, at minimum, the following t ypes of applications: new active ingredients; first food uses; first outdoor uses; first residential uses; or any other registration actions for which EPA believes there may be significant publi c interest. A ccordingl y, this pesticide was subject ed to a 30

- day comment period as a new active ingredient with outdoor uses. The Agency believes that the data submitted fulfill the requirements of registration for products containing Natam ycin for use as a fungistat for use on mushrooms in enclosed mushroom production facilities. Acute toxicity data for Natamy cin demonstrate that it is toxicity category III and IV for all routes of exposure. (No toxicological endpoints were established.) Data confirm that Natam ycin does not demonstrate subchronic or developmental toxicity , and it is not mutagenic or genotoxic. EPA has no concerns for any nontarget organisms exposed to Natam ycin in accordance with its approved uses. EPA has not identif ied any toxic endpoints for nontarget mammals, birds, plants, aquatic, or soil organisms. Nor are there any anticipated concerns for an y threatened and endangered species. Given the nontoxic character of Natam ycin and because all applicable data requirements have been fulfilled , EPA supports its registration under FI FRA section 3(c)(5)

. **C. Labeling** Before releasing pesticide products containing Natamy cin for shipment, the applicant is required to provide appropriate labels. Such labeling for the technical grade ac tive ingredient (TGAI) must include personal protection equipment (PPE) requirements as follows : “Mixer/loader/applicators are required to wear the following Personal Protection Equipment (PPE):

 **eye protection**
 **l ong pants** 
 **long -**  **sleeved shirt**
 **closed shoes**
 **gloves Natam** **ycin** Page 16

Biopesticides Registration Action Document **VII. AC TI**  **ONS REQUI RED**  **OF THE REGISTRANT**  The Agency

evaluated the data submitted in connection with the initial registration of Natam ycin and determined that these data fulfill current registration guideline requirements. No additional data are required to be submitted to the Agency at this time. Additional data may be required for new uses and/or changes to existing uses. Notwithstanding the information stated in the previous paragraph, it should be clearly understood that certa in, specific data are required to be reported to the Agency as a requirement for maintaining the Federal registration for a pesticide product. A brief summary of these t ypes of data are listed below. **A. R eporting of Adverse Effects and Hypersensitivity Incidents**  Reports of all incidents of adverse effects to the environment must be submitted to the Agency under the provisions stated in FIFRA s ection 6(a)(2). Additionally , all incidents of hy persensitivity

(including both suspected and confirmed incidents) must be reported to the Agency under the provisions of 40 CFR § 158.2050(e)

.**Natam ycin**  Page 17

Biopesticides Registration Action Document **VIII. GLOSSARY OF ACRONYMS AND ABBREVIATIONS** ADI average dail y intake BPB Biochemical Pesticides Branch BRAD Biopesticides Registration Action Document CA chromosomal aberrations CAS Chemical Abstracts Service CFR Code of Federal Regulations EDSP Endocrine Disruptor Screening Program EP End

- use Product EPA United States Environm ental Protection Agency (Agency) FDA United States Food and Drug Administration FFDCA Federal Food, Drug, and Cosmetic Act FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FR Federal Register g gram g/mL gram per milliliter Hg mercury HSDB Hazar dous Substances Data Bank LC 50 median lethal concentration. A statistically derived concentration of a substance that can be expected to cause death in 50% of test animals. It is usually expressed as the weight of substance per weight or volume of water, air or feed (e.g., mg/L, mg/kg, or ppm). LD 50 median lethal dose. A statistically derived single dose that can be expected to cause death in 50% of the test animals when admin istered by the route indicated (oral, dermal, or inhalation). It is expressed as a weight of substance per unit weight of animal (e.g., mg/kg). LOC level of concern LOEL lowest observed effect level μg microgram μm micrometer MRI D No. Master Record Ide ntification Number mg/kg milligram per kilogram mg/L milligram per liter mg/ml milligram per milliliter ml milliliter mm millimeter MP Manufacturing

- use Product nm nanometer NOAEL no observed adverse effect level NOEC no observed effect concentration NOEL no observed effect level OCSPP Office of Chemical Safety and Pollution Prevention OPP Office of Pesticide Programs Pa pascal PC Code Pesticide Chemical Code**Natam ycin**  Page 18

Biopesticides Registration Action Document ppb parts per billion PPE personal protective equipment ppm parts per million RQ risk quotient SCE sister chromatid exchange**Natam ycin**  Page 19

Biopesticides Registration Action Document **IX . Appendix A. Data Requirements (40 CFR Part 158** 
**- Subpart U)**  *NOTE: Master Record Identification (MRID) numbers listed in the following tables are representative of supporting data/information for the original registration of the product containing this active ingredient. Subsequent to this registration, there may be additional MRI Ds that support registration of other products containing this active ingredient.
**TABLE 1. Product Chemistry Data 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 Analy sis of samples Submitted data satisfy the requirements for anal ys is of samples. 48105502

830.1750 Certification of limits Limits listed in the confidential statement of formula are acceptable 48105402

830.1800 Analy

tical method Acceptable 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 Phy sical State Viscous liquid 48105503 830.6304 Odor Odorless 48105503 830.6313 Stability

to Normal and Elevated Temperatures, Metals and Metal Ions Natam ycin was found stable at

54°C for 14 day s. Storage stability studies supporting pharmaceutical uses found acceptable stability

in tests of 2 to 5 y ears in duration. Natam ycin is degraded by contact with most metals and metal ions. However, the product is never packaged in metal 48105504**Natam ycin**  Page 20

Biopesticides Registration Action Document **TABLE 2. Physical and Chemical Properties of Natamycin Technical**  **(40 CFR § 158.2030) OCSPP**  **Guideline No.**  **Property Description of Results**  **MRID** containers. 830.6315 Flammability Does not contain an y 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 densit y 0.59 g/mL 830.7560 830.7570 Octanol/water

partition coefficient (K ow) Lo g 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 Ty

pe Suspension (SU) 48105501 Container Material and Description HDPE plastic bucket, jerry can, drum or jumbo container (5 to 1000 L itres) 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 48105503**Natam ycin**  Page 21

Biopesticides Registration Action Document **TABLE 2. Physical and Chemical Properties of Natamycin Technical**  **(40 CFR § 158.2030) OCSPP**  **Guideline No.**  **Property Description of Results**  **MRID** exploding. 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 material (new batch). The applicant provided additional chromatograms for the controls (standard sample) for the 6

- and 18

- month to confirm the slight shift in the retention times for the a ctive. The rationale is accepted.

;

**Table 4. Acute**  **Toxicity Data**  **for the**  **Technical Grade**  **Active Ingredient**  **Product, Natamycin** 

**TGAI (91.02% a.i.); EPA File Symbol No. 87485** 
**- R**  **Study Type/OCSPP Guideline LD**  **50 /LC**  **50 /Results**  **Toxicity Category**  **MRID** Acute Oral Toxicity

/OCSPP 870.1100 >2000 mg/kg

(>1820 mg a.i./kg) **ACCEPTABLE** III 48105505 Acute Dermal Toxicity

/OCSPP 870.1200 >5050 mg/kg (>4696.5 mg a.i./kg) **ACCEPTABLE** IV 48105506
Acute Inhalation Toxicity/OCSPP 870.1300 >2.39 mg/L (2.18 mg a.i./L ) IV 48105507**Natam ycin**  Page 22

Biopesticides Registration Action Document **Table 4. Acute**  **Toxicity Data**  **for the**  **Technical Grade**  **Active Ingredient**  **Product, Natamycin** 

**TGAI (91.02% a.i.); EPA File Symbol No. 87485** 
**- R**  **Study Type/OCSPP Guideline LD**  **50 /LC**  **50 /Results**  **Toxicity Category**  **MRID ACCEPTABLE**  Primary Ey e I rritation/OCSPP 870.2400 No corneal or positive irritation effects at 24

- hr post instillation **ACCEPTABLE** IV 48105508

Primary Dermal Irritation/OCSPP 870.2500 PI I = 0.1 **ACCEPTABLE** IV 48105509 Skin Sensitization

- LLNA/OCSPP 870.2600 LLNA SI <3 **ACCEPTABLE 1**  Not a sensitizer 48105510

**TABLE 3a. Natamycin residues in mushrooms from the first break (** MRI D 48105408) **Treatment Treatment date**  **Sampling date**  **Tray no. Residue (mg/kg)**  Delvocid 2 mL/m 2 At casing, January 26 At pinning, February

2 February

11 29 0.0590

29 0.0890 30 0.0267 30 0.0285 31 0.0287 31 0.0178 32 0.0180 32 0.0192 1 0.0230 1 0.0221 2 0.0369 2 <0.01 3 0.0271 3 0.0344 4 0.0340 4 0.0274 Untreated control NA February 11 9 <0.01

9 <0.01 10 <0.01 10 <0.01**Natam ycin**  Page 23

Biopesticides Registration Action Document **TABLE 3b. Natamycin residues in washed and unwashed mushrooms from the second and third breaks (treated three or four times, respectively)**  MRID 48105408 **Treatment Treatment date**  **Sampling date**  **Tray**

**no. Residue** 

**(mg/kg)** Delvocid 2 mL/m 2 , **unwashed** At casing, January 26 At pinning, February

2 Between breaks 1 & 2, February 13 February 17 1 0.2370

1 0.1420 At casing, January

26 At pinning, February

2 Between breaks 1 & 2, February 13 Between breaks 2 & 3, February 20 February 25 1 0.0407

1 0.1452

Delvocid 2 mL/m 2 , **washed** At casing, January 26 At pinning, February

2 Between breaks 1 & 2, February 13 February 17 1 <0.01

1 0.0755 At casing, January

26 At pinning, February

2 Between breaks 1 & 2, February 13 Between breaks 2 & 3, February 20 February 25 1 0.0123

1 0.0220

Untreated control NA February 17 10 <0.01 February 25 10 <0.01**Natam ycin**  Page 24

Biopesticides Registration Action Document **X. BIBLIOGRAPHY** 
**MRID Citation Reference**  59399 American C yan amid Company (1959) Antibiotic A

- 5283, My prozine: 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 C yan amid Co mpany (1963) Pimaricin (My

prozine^(R)I): Report on Two

Year Toxicity

Studies. Summary

of studies 223651

- C through 223651

- H. (Unpublished study

received on unknown date under unknown admin. no.; CDL :223651

- B) 59401 American C yan amid Company (1963) Pimaricin: Two

- Year Feeding to Dogs: Report No. 63

- 6. (Unpublished study received on unknown date under unknown admin. no.; CDL :223651

- C) 59402 American C yan amid Company (1963) Pimaricin: Two

- Year Feeding to Rats: Report No. 63

- 7. (Unpublished study , including 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) Pimaricin: Successive

Generation Studies: Report No. 63

- 9. (Unpublish ed study received on unknown date under unknown admin. no.; submit

- ted by American Cy anamid Co., Princeton, N.J.; CDL :223651

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

Sustained for Two Years on Diets Conta ining 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 C yanamid Co., Princeton, N.J.; CDL :223651

- F) 59405 Shirk, R.J. (196 3) The Fecal Excr etion and Non

- absorption of Pimaricin in Animals:

Report FS 3. Progress rept. (Unpublished study received on unknown date under unknown admin. no.; submit

- ted by American C yanamid Co., Princeton, N.J.; CDL :223651

- G) 48105400 DSM Food Sp ecialties B.V. (2010) Submission of Product Chemistry , Residue,

Toxicity , and Exposure and Risk Data in Support of the Application for Registration of Natam ycin L and the Petition for Tolerance of Natam ycin for Use on Mushrooms. Transmittal of 11 Studies. 48105401 van der Lee, J.; Jovanovich, A. (2010) Natam ycin L: Product Identity, Composition,

and Formulation. Unpublished study prepared by

Keller and Heckman LLP. 48 p. 48105402 van der Lee, J.; Jovanovich, A. (2010) Natam ycin L: Certified Limits. Unpublished

study prepared by

Keller and Heckman LL P. 9 p. 48105403 van Hilten, P. (2010) Natamy cin L: Enforcement Analy tical Method. Unpublished**Natam ycin**  Page 2 5

Biopesticides Registration Action Document **MRID Citation Reference** 

study prepared by

Keller and Heckman LL P. 18 p. 48105404 van der Lee, J.; Jovanovich, A. (2010) Natam ycin L: Summary of Phy sical/Chemical Properties and Self

- Certification. 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 Characteristi cs. Project Number: STAB/SLD/09/008. Unpublished study

prepared by

DSM Food Specialties B.V. 24 p. 48105406 Jovanovich, A. (2010) Residue Data: Chemical Identity and Directions for Use for Natam ycin L. Unpublished study prepared b y Keller and Heckman LLP. 9 p. 48105407 Marin, J. (2010) Development and Validation of an Analy tical Method for the Determination of Natamy cin in Mushrooms and Mushroom Compost, Casing and Casing plus Innoculum. Project Number: 1869W. Unpublished study prepared by PTRLWest, Inc. 73 p. 48105408 Marin, J. (2009) Magnitude of the Residue of Natamy cin in Mushrooms. Project

Number: 1915W. Unpublished study prepared b y PTRLWest, Inc. 165 p. 48105409 Wilms, L .; Jovanovich, A. (2010) Natamy cin L : Request for Waiver of 5 Acute

Toxicity Tests. Unpublished study prepared by

Keller and Heckman LLP. 16 p. 48105410 Kuhn, J. (2009) Natamy cin L iquid Formulation: Acute Ey e Irritation Study in Rabbits: Final Report. Project Number: 12753/09. Unpublished study prepared by Stillmeadow, Inc. 20 p. 48105411 Wach, M. (2010) Natamycin L: Descriptions of Human Activity for Natamy cin L. Unpublished study

prepared by

Keller and Heckman LL P. 10 p. 48105500 DSM Food Specialties B. V. (2010) Submission of Product Chemistry and Toxicity Data in Support of the Application for Registration of Natam ycin TGAI and the Petition for Tolerance of Natam ycin for Use on Mushroom. Transmittal of 14 Studies. 48105501 Zuur, P.; Hee, P.; Roghoenath, D.; et al. (2010) Natamy cin TGAI: Product Identity ,

Composition, and Pro duction. Unpublished study prepared by

Keller and Heckman LLP. 252 p. 48105502 Zeeman, M.; Boogers, I.; Van der Lee, J.; et al. (2010) Natam ycin TGAI: Preliminary

Analy sis and Certified Limits. Unpublished study prepared by

Keller and Heckman LLP. 140 p. 48105503 Van der Lee, J.; Jovanovich, A. (2010) Natam ycin TGAI: Physical and Chemical

Properties. Unpublished study prepared by

Keller and Heckman LL P. 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.**Natam ycin**  Page 26

Biopesticides Registration Action Document **MRID Citation Reference**  48105505 Kuhn, J. (2008) Natamy cin TGAI : Acute Oral Toxicity Study (UDP) in Rats: Final Report. Project Number: 11403/07. Unpublished study prepared by

Stillmeadow, Inc. 12 p. 48105506 Kuhn, J. (2008) Natamy cin TGAI : Acute Dermal Toxicity Study in Rat: Final Report. Project Number: 11404/07. Unpublished study prepared by

Stillmeadow, Inc. 13 p. 48105507 Crutchfield, V. (2008) Natamy cin TGAI: Acute Inhalation Toxicity Stu dy in Rats: Final Report. Project Number: 11405/07. Unpublished study prepared by Stillmeadow, Inc. 19 p. 48105508 Kuhn, J. (2008) Natamy cin TGAI : Acute Ey e I rritation Study in Rabbits: Final Report. Project Number: 11406/07. Unpublished study prepared by Stillmeadow, Inc. 18 p. 48105509 Kuhn, J. (2008) Natamy cin TGAI : Acute Dermal Irritation Study in Rabbits: Final Report. Project Number: 11407/07. Unpublished study prepared by

Stillmeadow, Inc. 13 p. 48105510 Kuhn, J. (2008) Natamy cin TGAI : Skin Sensit ization: L ocal Ly mph Node Assay

in Mice: Final Report. Project Number: 11408/07. Unpublished study prepared by Stillmeadow, Inc. 13 p. 48105511 Otterdijk, F. (2003) Natamy cin TGAI: 90 Day Oral Toxicity

Study with Natamy cin in the Rat. Project Number: NOTOX/PROJECT/339323, 002019. Unpublished study prepared b y Notox B.V. 220 p. 48105512 Knickerbocker, M. (1979) Natam ycin TGAI: Teratologic Evaluation of Pimaricin in

Dutch

- Belted Rabbits. Project Number: 5906. Unpublished study prepared by

Food & Drug Re search Laboratories, Inc. 290 p. 48105513 Verspeek, C. (2002) Natamy cin TGAI: Evaluation of the Mutagenic Activity of Natam ycin in the Salmonella typhimurium Reverse Mutation Assay and the Escherichia coli Reverse Mutation Assay (with Independent Rat). Pr oject Number: NOTOX/PROJECT/339345. Unpublished study prepared by

Notox B.V. 29 p. 48105514 Meerts, I. (2002) Natam ycin TGAI: Evaluation of the Ability of Natamy cin to Induce Chromosome Aberrations in Cultured Peripheral Human Ly mphocy tes. Project Number: NOTOX/PROJECT/339356. Unpublished study prepared by

Notox B.V. 28 p. 48439300 DSM Food Specialties (2011) Submission of Product Chemistry Data in Support of the Application for Registration of Natam ycin L. Transmittal of 1 Study. 48439301 van der Lee, J .; Jovanovich, A. (2011) 12

- Month Interim Report for Storage Stability

and Corrosion Characteristics: Natamy cin L. Project Number: STAB/SLD/09/008. Unpublished study

prepared by

DSM Food Specialties B.V. 38 p.**Natam ycin**  Page 27

Biopesticides Registration Action Document **MRID Citation Reference**  48544501 van der Lee, J.; Jovanovich, A. (201 1) 18

- Month Final Report for Storage Stability

and Corrosion Characteristics: Natamy cin L. Project Number: STAB/SLD/09/008. Unpublished study

prepared by

DSM Food Specialties B.V. 41p. 48593401 Cox, G.; Bailey , D. (1973) Natam ycin TGAI Rat Development Toxicity Study

. Project Number: 1052. Unpublished study prepared by

Food & Drug Research Laboratories, Inc. 495p. 48613501 Thate, C.; Jovanovich, A. (2011) Natam ycin TGAI: Request for Waiver of

Teratology

Study Data Requirement. Unpublished study prepared by

Keller and Heckman LLP and DSM Food Specialities. 177p.

**B. EPA Risk Assessment Memoranda**  U.S. EPA. 2010

- Jones, Russell , Science Review in Support of Natamy cin Technical, Containing 91.02% Natam ycin as It s Active Ingredient. Memorandum dated 10/1 5 /2010 2011a. Jones, Russell , Science Review in Support of Natam ycin Technical, Containing 91.02% Natam ycin as Its Active Ingredient. Memorandum dated 04/04/2011 U.S. EPA. 2011b. Jones, Russell, Science Revi ew in Support of Natamy cin Technical, Containing 91.02% Natamy cin as It s Active Ingredient. Memorandum dated 07/11/2011

. U.S. EPA. 2011c. Jones, Russell, Science Review in Support of Natamy cin Technical, Containing 91.02% Natamy cin as It s Active Ingredie nt. Memorandum dated 12/13/2011 06/16/2011.

**C. References** Joint FAO/WHO Expert Committee on Food Additives (JECFA). 2001. Safet y Evaluation of Certain Food Additives and Contaminants. Natamycin (Pimaricin). WHO Food Additives Series: 48 http://www.inchem.org/documents/jecfa/jecmono/v48je06.htm Joint FAO/WHO Expert Committee on Food Additives (JECFA). 2006. Summary and Conclusions. Sixty

- Seventh Meeting. Rome, 20

- 29 June 2006. ftp://ftp.fao.org/ag/agn/jecfa/jecfa67_final.pdf (Acc essed 04/04/2011) European Food Safety

Authority

(EFSA). 2009. Scientific opinion on the use of Natam ycin (E 235) as a food additive. EFSA Panel of Food Additives and Nutrient Sources added to Food (ANS). EFSA Journal 7(12):1412, 25 p. http://www.efsa.europa.eu/en/efsajournal/doc/1412.pdf (Accessed 04/04/2011)**Natam ycin**  Page 28

Biopesticides Registration Action Document USDA/ERS. 2010. Mushrooms: Supply and Utilization and Per Capita Consumption. February 2010 Update. www.ers.usda.gov/data/food **consumption** /spreadsheets/ **mushroom** .xls (Accessed 04/04/2011). World Health Organization (WHO). 2009. The WHO Recommended Classification of Pesticides by

Hazard and Guidelines to Classification. Joint FAO/WHO Expert Committee on Food Additives (JECFA). 1968, 1976, 2002, 2006, and 2007. See EFSA 2009 for specific reference citations. European Food Safety

Authority

(EFSA). 2009. Scientific opinion on the use of Natam ycin (E 235) as a food additive. EFSA Panel of Food Additives and Nutrient Sources added to Food (ANS). EFSA Journal 7(12):1412, 25 p. http://www.efsa.europa.eu/en/efsajournal/doc/1412.pdf (Accessed 04/04/2011) USDA/ERS. 2010. Mushrooms: Supply and Utilization and Per Capita Consumption. February 2010 Update. www.ers.usda.gov/data/food **consumption** /spreadsheets/ **mushroom** .xls (Accessed 04/04/2011). **REFERENCES CITED BY EFSA (2009).** Blankwater, Y. J. and W. Hespe. 1979. Autoradiographic and bioautographic study of the distribution of oral Natamy cin in the rat. Unpublished report No. 20.502, dated 8 May 1979 from Gist

- Brocdades NV, Delft. Cox, G. E., D. E. Bailey , and K. Morgareidge. 1973. Multigeneration studies in rats with Delvocid brand of Pimaricin . Unpublished report No. 1

- 1052 submitted to W HO by Food and Drug Research Laboratories, Inc. Hespe, W. and A. M. Meier. 1980. Studies involving in regard to the resorption of radioactivit y following the oral administration of 14C

- pimaricin, applied on cheese, in comparison to other oral forms of administration. Unpublished report No. 20.532, dated 4 February 1980, submitted to WHO by

Gist

- Brocades NV, Haarlem. Hutchinson, E. B., W. E. Ribelin, and G. J. L evinskas. 1966. Report on acid

- degraded Pimaricin : Ninety

- eight day repeated feeding to rats. Unpublished report submitted to WHO by Ame rican C yan amid Co., Central Medical Department. Levinskas, G. J., C. B. Shaffer, C. Bushey , M. L. Kunde, D. W. Stackhouse, L . B. Vidone, B. Javier, and E. Monell. 1963. Two y ear feeding study in rats. Unpublished report from the Central Medical depar

tment. Submitted to WHO by American C yan amid Co. Levinskas, G. J., W. E. Ribelin, and C. B. Shaffer. 1966. Acute and chronic toxicity of Pimaricin . Toxicology

and Applied Pharmacology 8: 97

- 109. Morgenstern, A. P. and G. J. A. M. Muskens. 1976. Further data on the toxicity of the decomposition products of Pimaricin . Unpublished report Gist

- Brocades NV, Delft, 4 pages.**Natam ycin**  Page 29

Biopesticides Registration Action Document Pacifici, G. M. and R. Nottoli. 1995. Placental transfer of drugs admini stered to the mother. Clinical Pharmacokinetics 28(3): 235

- 269. Van Ecken, C. J., R. D. R. Birtwhistle, and M. J. e. Aboulwafa

- wan Velthoven. 1984. Three months study

in dogs of the toxicity

of Natam ycin by

addition to the food. Unpublished report 12.401, 24 October 1984. Submitted to WHO by Gist

- Brocades Research and Development. 