1

**Federal Food, Drug, and Cosmetic Act (FFDCA) Considerations fo**  **r Natamycin** 

**Docket ID Number: EPA**  **- HQ**  **- OPP**  **- 20**  **14 -**  **0352**

**Date: November 7**  **, 2014** Section 408(c)(2)(A)(i) of FFDCA allows the U.S. Environmental Protection Agency ( EPA or the Agency) to establish an exemption from the requirement for a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if the EPA determines that the exemption is “safe.” Section 408(c)(2)(A)(ii) of FFDCA defines “safe” to mean that “there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information.” This includes exposure through drinking water and in residential settings but does not include occupational exposure. Pursuant to FFDCA section 408( c )(2)(B) , in establishing or maintaining in effect an exemption from the requirement of a tolerance, the EPA must take into account the factors set forth in FFDCA section 408(b)(2)(C), which require the EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance exemption , and to “ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue....” Additionally , FFDCA section 408(b)(2)(D) requires that the EPA consider “available information concerning the cumulative effects of [a particular pesticide's] . . . residues and other substances that have a common mechanism of toxicity .” The EPA performs a number of analy ses to determine the risks from aggregate exposure to pesticide residues. First, the EPA de termines the toxicity of pesticides. Second, the EPA examines exposure to the pesticide through food, drinking water, and through other exposures that occur as a result of pesticide use in residential settings. **I. Summary of Petitioned -**  **for Tolerance Exemp tion**  In the Federal Register of August 1, 2014 (79 FR 44729) (FRL

- 9911

- 67), EPA issued a notice pursuant to FFDCA section 408(d)(3), 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide tolerance petition (PP 4F8233) b y DSM Food Specialties B.V. (the Petitioner), Alexander Fleminglaan 1, 2613 AX Delft, The Netherlands. The petition requested that 40 CFR part 180 be amended b y establishing an exemption from the requirement of a tolerance for residues of natamycin for post

- harvest indoor use on pineappl es. The notice referenced a summary of the petition prepared by the Petitioner, which is available in D ocket ID Number EPA

- HQ

- OPP

- 2014

- 0352 via http://www.regulations.gov

. **II .**  **Toxicological Profile** Consistent with section 408(b)(2)(D) of FFDCA, the EPA reviewed the available scientific data and other relevant information on natamycin , and considered its validity , completeness, and reliability , as well as the relationship of this information to human risk. The EPA a lso considered available information concerning the variability

of the sensitivities of major identifiable subgroups of consumers, including infants and children. **A. Overview of Natamycin**  Nat am ycin is a naturally occurring compound derived from the common soil micro organisms Streptomyces natalensis, Streptomyces lydicus, and Streptomyces chattanoogensis. Natamycin was originally discovered in Streptomyces natalensis in South Africa in the earl y 1950s, and was subsequently d iscovered to also occur naturall y in North America in Streptomyces lydicus and Streptomyces chattanoogensis. Itis commerciall y produced by a submerged ox ygen - based fermentation of Streptomyces natalensis,2 Streptomyces lydicus, or Streptomyces chattanoogen sis. Natam ycin has been used as a food preservative worldwide for over 40 ye ars (Ref.1) and is approved as a food additive/preservative b y the European Union, the World Health Organization, and individual countries including New Zealand and Australia for u se as a fungistat to suppress mold on cheese, meats and sausage. In the United States, natamycin is approved b y the Food and Drug Administration (FDA) as a direct food additive/preservative for the inhibition of mold and yeast on the surface of cheeses (21 CFR 172.155) and as an additive to the feed and drinking water of broiler chickens to retard the growth of specific molds (21CFR 573.685). Natam yci n is also FDA approved for use as a treatment to suppress fungal ey e infections such as blepharitis, conjunct ivitis, and keratitis. As a biochemical pesticide active ingredient, natamycin is intended for use as a fungistat to prevent and control the germination of mold and y east spores in the growth media of mushrooms produced in enclosed mushroom production fac ilities (77 FR 29543), and to control fungal growth post

- harvest on pineapples treated indoors. Natam yc in has a non

- toxic mode of action, has no effects on fungal mycelia, and development of antibiotic resistance to natam ycin has not been reported during i ts entire history of use (77 FR 29543)

. Based on the data submitt ed in support of this petition ( s ummarized in Unit II. B., below) and the comprehensive risk assessment conducted b y the Agency (Ref. 2, below ) , EPA concludes that there is a reasonable certainty

of no harm from aggregate exposures to natamycin , including the consumption of food treated with this active ingredient in accordance with label directions and good agricultural practices. EPA has made this determination because available toxicology data indicate that the active ingredient is of low acute toxicity

and is not a developmental toxicant , a mutagen, or toxic via repeat oral exposure

. **B. Biochemical**  **Pesticide Toxicology Data Requirements** All applicable mammalian toxicology data requirements supporting the request for an amendment to the existing exemption from the requirement of a tolerance for residues of natamycin when used post

- harvest, indoors, on pineapples, have been fulfilled with data submitted by the petitioner. The following is a summary of EPA’s review of the toxicity profile of th is biochemical: Acute Toxicity : Acute toxicity studies on natam yc in (98.17% and 98.27% pure), confirm a low toxicity profile. The acute toxicity data show virtual nontoxicity for all routes of exposure . Therefore, it can be concluded that an y dietary risks 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) bod yw eight. There were no observed toxicological effects on the test subjects in the acute oral study submitted (MRID No. 48105505 ). Natam yc in is classified as Toxicity Category I II for acute oral toxicity

. 2. The acute dermal LD50 in rats was greater than 5,05 0 mg/kg body weight (MRID 48105506 )

. Natam ycin is classified as Toxicity Category IV for acute dermal toxicity

. 3. The acute inhalation median lethal concentration (LC50) was gr eater than 2.39 milligrams per liter (mg/L) in rats and showed no significant inhalation toxicity (MRID 48105507 )

. Natam ycin is classified as Toxicity

Category IV for acute inhalation toxicity

. 4. A primary

eye irritation study

on rabbits indicates that natamycin is severely irri tating to the eye but with no effects observed at 24 hours after treatment (MRID 48015508 )

. Natamycin is classified as3

Toxicity Category I II for primary

eye irritation. 5. A skin irritation study on rabbits indicates that natamycin is slightly irritating (MRID 48105509 )

. Natam ycin is classified as Toxicity Category IV for primary

skin irritation. 6. Data indicate that natamycin is not a dermal sensitizer (MRID 48105510 ). Mutagenicity : Two mutagenicity studies, using natamycin (98.17% and 98.27% pure) as the test substance, were performed. These studies are sufficient to confirm that there are no expected dietary or non occupational risks of mutagenicit y with regard to food use of natam ycin. 1. A Bacterial Reverse Gene Mutation Test (MRID No. 48105513 ) investigating doses of test substance up to those that were cy

totoxic, both with and without metabolic S9 activation, found no incidences of a 2

- fold or greater increase in the number of revertants compared to the corresponding solvent control in two independentl y repeated experiments . Therefore, natamycin is considered to be non

- mutagenic under the conditions of this assay

. 2. An in vitro Mammalian Cell Chromosome Aberration Test (MRID No. 48105514 ) tested natam ycin genotoxicity

on cultured peripheral human ly mphocy tes in the prese nce and absence of metabolic S9 activation. Natam ycin did not induce a statistically significant or biologically relevant increase in the number of cells with chromosome a berrations in the absence and in the presence of S9

- mix, in two independentl y repeated experiments

. Inaddition, a ll of the negative, solvent, and positive controls gave appropriate responses. Therefore, under the conditions of this assay , natamycin is con sidered to be non

mutagenic and does not cause chromosome aberrations. Subchronic Toxicity : In a subchronic oral toxicity study using natam ycin (98.17% and 98.27% pure) as the test substance , dose s 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 2,000 mg/kg bw/day test group to be an adverse effect, as this is likely due to the palatability of the food containing this high dose of test substance. Therefore, the Agency establishes the NOAEL (No Observed Adverse Effect L evel) for this study as 2,000 mg/kg bw/day . A LOAEL (Lowes t Observed Adverse Effect Level) was not identified, suggesting that the test animals could have tolerated a higher dose. Developmental Toxicity : A developmental toxicity study using natam ycin (98.17% and 98.27% pure) as the test subs tance (MRID 48105512 ) showed no discernable effects on growth, reproduction, teratological or mutagenic responses , or on gross and microscopic pathology , at concentration levels 0, 5, 15 and 50 mg/kg bw/day

. **III. Aggregate Exposure**  In examining aggregate exposure, FFDCA section 408 directs the EPA to consider available information concerning exposures from the pesticide residue in food and all other non

- occupational exposures, including drinking water from ground water or surface water and exposure through pesticide use in gardens, lawns, or buildings (residential and other indoor uses). Food Exposure : Die tary

exposure to residues of natamycin via pesticidal use is expected to be insignificant, even in the event of exposure. Some dietary exposure to natam ycin might occur through other nonpesticidal4 sources as a result of its use as a food additive/preservative. Should exposure occur, however, minimal to no risk is expected for the general population, including infants and children, due to the low toxicity of natamycin. T he active ingredient is of low acute toxicity and is not a developmental toxicant, a mutagen, or toxic via repeat oral exposure

. Drinking W

ater Exposure : Exposure of humans to natamycin in drinking water is not expected because natamycin is approved for application indoors only (enclosed mushroom houses or pineapple packing facilities). Other Non

- occupational Exposure : Non

- occupational expo sure is not expected because natamycin is not approved for residential uses. The active ingredient is applied directly to commodities and degrades rapidly

. **IV .**  **Cumulative Effects from Substances with a Common Mechanism of Toxicity** Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify , or revoke a tolerance, the EPA consider “available information concerning the cumulative effects of [a particular pesticide’s] . . . residues and other substances that have a common mechanism of toxicity .” The EPA has not found natamycin to share a common mechanism of toxicity with an y other substances, and natam ycin does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance 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 cumulative effects associated with natam ycin that need to be considered. For information regarding the EPA’s efforts to determine chemicals that have a common mechanism of toxicity and to e valuate the cumulative effects of such chemicals, see the EPA’s website at http://www.epa.gov/pesticides/cumulative

. **V. Determination of Safety for the United States Population, Infants and**  **Children** FFDCA section 408(b)(2)(C) provides that, in considering the establishment of a tolerance or tolerance exemption for a pesticide chemical residue, the EPA shall assess the available information about consumption patterns among infants and children, special susceptibility of infants and children to pesticide chemical residues, and the cumulative effects on infants and children of the residues and other substances with a common mechanism of toxicity . In addition, FFDCA section 408(b)(2)(C) provides that the EPA shall apply

an additional tenfold (10X) margin of safet y for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure, unless the EPA determines that a different margin of safet y will be safe for infants and children. This additional margin of safet y is commonly referred to as the Food Quality Protection Act Safet y Factor. In applying this provision, the EPA either retains the defaul t value of 10X, or uses a different additional or no safet y factor when reliable data are available to support a different additional or no safety factor. Because there are no threshold effects associated with this biochemical, an additional margin of sa fety for infants and children is not necessary

. EPA has determined that there are no foreseeable dietary risks to the U.S. population, including infants and children, from the use of natamycin as a pesticide ( fungicide ) on mushrooms in enclosed mushroom facilities and on pineapples when label instructions and good agricultural practices are followed. The available data and information indicate that the chemical is of low toxicity and not a developmental toxicant

. Therefore, EPA concludes that there is a reasonable certainty that no harm will result to the U.S.5 population, including infants and children, from aggregate exposure to the residues of natamycin when it is used as labeled and in accordance with good agricultural practices. 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 natam ycin do not demonstrate significant toxic potential to mammals, includ ing infants and children. **VI .**  **Conclusions** EPA concludes that there is a reasonable certainty that no harm will result to the U.S. population, including infants and children, from aggregate exposure to residues of natamycin

. Therefore, an exemption is es tablished for residues of the biochemical pesticide natam ycin when used on mushrooms in enclosed mushroom production facilities and when used on pineapples in accordance with label directions and good agricultural practices. **VII . References**  1. Joint FAO/WHO Expert Committee on Food Additives (JECFA). 1968, 1969, 1976, 2002, 2006, and 2007. See EFSA 2009 for specific reference citations. 2. E PA (2014 ) Environmental Protection Agency (EPA) Risk Assessment: Request for new food use (post

- harvest treatment of pineapples) to the active ingredient, Natam ycin. October 1, 2014

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