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~ ` UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 OFFICE OF CHEMICAI, SAFETY ANll POLLU'I'ION PRE:IVENTION

DECISION MEMORANDUM

SUBJECT: Registration of the New Active Ingredient Kasugamycin

TO: Jack E. Housenger., Director

Office of Pesticide Programs

FROM: Lois Rossi, Director

Registration Division, Office of Pesticide Programs

This memorandum recommends that you concur on the first registration of the new active ingredient kasugamycin, an agricultural antibiotic for use on pome fruit (crop group 11-10). r1 summary of the human health, ecological and resistance risks and the final regulatory decision are in the attached Final Decision Document. The Science Divisions have reviewed all available data and the Registration Division has concluded that the criteria for registration under FIFRA section 3(c)(5) have been met.

RECOMMENDATIONS: I recommend for the registration of kasugamycin under FI RA section 3( 5). 1.

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~ I I Concur

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c . House , irect r ffice of Pestic de Programs



### Nonconcur Jack E. Housenger, Director

Office of Pesticide Programs

Attachment: Final Decision Document

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### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

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# Final Unconditional, Time-limited Registration Decision for Kasugamycin on 1'orxie Fruit.

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# Final LJnconditional, Time-limited Registration Decision for Kasugamycin on Pome Fruit.

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Lois Rossi, Director Registration Division, Office of Pesticide Programs

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### REGULATORY DECISION

The U.S. Environmental Protection Agency referred to thereafter as EPA or the Agency, is granting an unconditional, time-limited registration of four years for the use of the active ingredient (a.i.) kasugamycin for use on pome fruit (crop group 11-10). The registrations will include one technical (Kasugamycin Technical) and one end use pesticide product (Kasumin 2L).

Kasugamycin is produced from 

### Streptomyces karu,,aen.ris and belongs to the aminoglycoside class of compounds, a group of antibiotics that inhibit microbial protein synthesis. This class also includes streptomycin, apramycin, kanamycin, paromomycin, and-neomycin, some of which have human and/or veterinary medicinal uses. Kasugamycin has a different mode of action from other antibiotics registered for agricultural use (i.e. streptomycin and oxytetracycline). Specifically, the protein target inhibition site differs for kasugamycin from that shared by streptomycin and oxytetracycline. Kasugamycin is not used for human or veterinary purposes in the United States but has been used clinically in Japan to treat urinary tract infections due to 

### Pseudomona.r aeruginosa'. Kasugamycin has never been approved as a human drug in the United States.
Tolerances are currently established for kasugamycin in/on imported tomatoes and peppers at 0.04 ppm and a Section 18 tolerance of 0.05 ppm is established for kasugamycin use on apples. Canada recently established maximum residue limits (MRLs) for pome fruits at 0.2 ppm, fruiting vegetables at 0.1 ppm and walnuts at 0.04 ppm. There are no established or proposed Codex MRLs.

II. HUMAN HEALTH RISK A suznmary of the human health risk as assessed in the Agency document titled "Kasugamycin. 1-iuman Health Risk rlssessment for the Proposed Use of the Fungicide on Fruiting Vegetables, Pome Fruits, and Walnuts" Ouly 13, 2012) is provided below. The following summary information identifies the risk resulting from exposure to the active ingredient, kasugamycin. The toxicology database for kasugamycin is considered complete. A subchronic inhalation study in the rat is not required based on the toxicity profile, low use rate and high margins of exposure (MOEs) achieved for handler inhalation exposure using an endpoint from an oral study. The level of concern for all exposure scenarios is for 

### MOEs below 100.

A. Toxicological End Points 1. Aeute Dietary: There were no toxic effects associated with a single dose of kasugamycin;

I Schu

~ virth, B.S., J.M. Day, C.W. Hau, G.R. Janssen, A.E. Dahlberg, J.H. Doudna Cate, and r1.Vila-Sanjurjo, 2006. Structural analysis of kasugamycin inhibition of translation. Nat Stuct Viol Biol. 12(10):879-886 4therefore, an acute dietary endpoint and dose were not selected for the general US population, or any

population subgroup.



### 2. Chronic Dietary: For chronic dietary exposure, the rat combined chronic toxicity/carcinogenicity study was selected: The no-observed-adverse-effect level (NOAEL) of 11.3 mg/kg/day was based on testicular softening and atrophy at the lowest- observed-adverse-effect level (LOr'1EL) of 116 mg/kg/day. Testicular atrophy was also observed in the rat two-generation reproduction study at 425.3 mg/kg/day (NOr1EL = 70.3 mg/kg/day), and in the mouse subchronic study above the limit dose.



### 3. Short- and Intermediate-Term Dermal: For dermal exposure, a dose and endpoint were not selected because no systemic toxicity was observed in the rat 21-day dermal study, which tested up to doses causing local dermal irritation. Endpoints of concern identified in oral studies (body weight, renal and testicular toxicity, gastrointestinal and oral cavity effects) were evaluated in the dermal study.



### 4. Short- and Intermediate-Term Inhalation: For inhalation exposure, the subchronic dog and the rabbit developmental toxicity studies were selected as co-critical. The endpoint of concern was irritation, since kasugamycin appears to be irritating to the oral cavity and gastrointestinal tract mucosa following oral exposures. In the subchronic study with dogs, the NOAEL was 11 mg/kg/day (selected as the point of departure), and the LOAEL was 106 mg/kg/day, based on irritation of the oral cavity, characterized as tongue lesions, swollen mouth, excessive salivation, and thickening of the skin at the commissures of the mouth. The irritation potential of kasugamycin is further demonstrated with the presence of anal lesions, and perianal/perigenital staining seen in the subchronic mouse study; red/swollen skin around the anal opening, and inflammation/ulceration of the rectum in the offspring of both sexes in the two-generation reproduction study; and distention of the large intestine in the developmental rat study.
The developmental rabbit study (supported by its range-finding study) was selected as the cocritical study since the maternal NOAEL (10 mg/kg/day, highest dose tested) was comparable to the NOAEL in the subchronic dog study. In the range-finding study, maternal toxicity manifested as abortions and weight loss at 30 mg/kg/day (LOAEL). The incidence and severity of the maternal toxicity was increased at the high dose (100 mg/kg/day) where one doe died, abortions were seen in 3 of 4 litters, and the weight loss was more pronounced.
Given kasugamycin's apparent poor oral absorption (< 5% in the rat metabolism study), and the consistent evidence of irritation effects to mucous membranes seen across numerous species, it is

5reasonable to surmise that the bolus (gavage) dosing causes irritation to the gastrointestinal tract,

resulting in maternal toxicity. rllthough a subchronic inhalation toxicity study is not available and is not required, the oral study is considered protective because use of the oral N0AEL results in margins of exposure (MOEs) ranging from 58,000 to 2,500,000 for risk from occupational exposure via the inhalation route and is therefore protective of potential inhalation effects.



### 5. Caneer: The Agency has classified kasugamycin as "Not Likely to be Carcinogenic to Humans" based on lack of evidence of carcinogenicity in mice and rats, and the lack of evidence for mutagenicity in both 

### in vivo and 

### in vitro assays.

B. FQPA Safety Factor Based on review of the available hazard and exposure data, the rlgency determined that the FQPA SF can be reduced to 1X. There are low concerns and no residual uncertainties with regard to pre- and/or post-natal toxicity, and there is no concern for neurotoxicity. Furthermore, the dietary risk assessment is highly conservative and is not expected to underestimate exposure and risk. This recommendation is based on the following:

1. The toxicology database is complete, including developmental studies in two species, a rat twogeneration reproductive study, rat acute and subchronic neurotoxicity screening studies, and a mouse immunotoxicity study.

2. Based on the lack of observed neurotoxicity, a DNT study is not required.

3. There is no evidence of increased quantitative or qualitative pre- and/or postnatal susceptibility observed in developmental toxicity studies in the rat and rabbit, or in a two- generation reproduction study in the rat.

4. The exposure assessment for food and drinking water will not underestimate potential dietary exposure to kasugamycin, and there are no proposed or existing residential uses for kasugamycin.

C. Cumulative Effects Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, the Agency has not made a common mechanism of toxicity finding as to kasugamycin and any other substances, and kasugamycin does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that kasugamycin has a common mechanism of toxicity with other substances. For information regarding EPt1's efforts to determine which chemicals have a common mechanism of 6toxicity, and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA's OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.



### D. Residential Risk There are no proposed residential uses for kasugamycin associated with the subject petition, nor are there any currently registered residential uses. Kasugamycin is not intended for use in public or residential settings. Therefore, residential exposure is not expected, and residential risks are not of

concern. 

### E. Aggregate (Food + Drinking Water) Risk In accordance with the FQPA, the Agency must consider and aggregate pesticide exposures and risk estimates from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from dietary and residential sources are added together. Since there are no residential sources of exposure for kasugamycin, the only aggregate risk scenario is chronic dietary (food and water), which is not of concem.



### F. Occupational Risk Based on the proposed use patterns, both short- and intermediate-term exposure and risk assessments were conducted for occupational handlers, or those who mix, load and apply pesticides. In addition, the Agency considered the potential for post-application exposure for those re-entering treated sites. Since there is no dermal hazard, occupational risk for handlers was only assessed for the
inhalation route.



### 1. Short- and Intermediate-Term Handler Exposure and Risk: Occupational handler exposures to kasugamycin were estimated assuniing the maximum application rate, baseline personal protective equipment (PPE) [long-sleeved shirt, long pants, shoes and socks], application equipment and methods as specified on the proposed label, and standard assumptions with respect to the area treated. In the . absence of chemical-specific data to assess handlers' exposure and risk, the Agency relied on surrogate unit exposure data to estimate exposure and risk. The resulting handler risk estimates, or MOEs, were all above 100, and are thus below the Agency's level of concern (LOC). Depending on the scenario, MOEs ranged from 58,000 to 2,500,000.



### 2. Short- and Intermediate-Term Post-Application Exposure and Risk: Dermal post application exposure was not assessed due to the lack of toxicity via the dermal route. There is no

7dermal risk associated with post-application activities following application of kasugamycin on the

proposed crops. The Restricted Entry Interval (RET) is based on the acute toxicity of kasugamycin technical material, which is classified in acute Toxicity Categories III and IV. rlcute Category III or IV chemicals require a 12-hour REI. Thus, the 12-hour REI that appears on the proposed label is adequate.
A quantitative post-application inhalation exposure assessment was not performed for kasugamycin, primarily because it has a low vapor pressure (vapor pressure <0.013 mPa at 25°C), and it is applied at low application rates. However, volatilization of pesticides may be a potential source of post-application inhalation exposure to individuals nearby pesticide applications. Although a quantitative occupational post- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational handlers. This assessment resulted in risk estimates that did not exceed the Agency's LOC at baseline inhalation PPE. Handler exposureresulting from application of pesticides outdoors is likely to result in higher exposure than postapplication exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.



### III. ENVIRONMENTAL RISK A summary of the ecological effects and risks of kasugamycin and the proposed end-use product, Kasumin 2L, as assessed in the Agency document titled "Environmental Fate and Ecological Risk Assessment for the Registration of the New Chemical Kasugamycin" (February 19, 2013), is provided below.



### A. Environmental Fate
1. Persistence and Transformation: Kasugamycin is applied as kasugamycin hydrochloride, an acid, and dissociates into its salt immediately after application. Kasugamycin is mostly present in solution at pH values < 3.23, while its two primary degradates, kasugamycinic acid and kasuganobiosamine, are mostly present in pH solutions of 3.23 to 7.73, and 7.73 to 11, respectively. Kasugamycin is also a zwitterion, contains a carboxylic acid fragment and an amino group. This means that in more acidic pHs, kasugamycin will act more like a cation. As a result, kasugamycin is more likely to sorb to soil (especially clay) in lower pH environments. As the pH increases, the zwitterion will act more like an anion, and will be less likely to sorb to soil. The major routes of degradation for kasugamycin are aqueous photolysis, aerobic biodegradation, and hydrolysis.
Abiotic routes of degradation include photolysis and hydrolysis. In the aqueous photolysis 8study, the half-life in natural lake water was 17.4 days as opposed to the phototransformation half-life

in sterile water of 630 days. The hydrolysis study showed that kasugamycin tends to degrade much faster in neutral to alkaline environments. T'he hydrolysis half-life at pH 4, 5, 7, and 9 was 462, 630, 79.7, and 11.4 days, respectively.
Biotic routes of degradation include soil and aquatic metabolism under both aerobic andanaerobic conditions. The aerobic aquatic metabolism half-life was approximately 45 days in lake waterloamy sand sediment and river water-clay loam sediment. In soil, the half-life was 73 days in an aerobic clay-loam soil, and 147 days in an aerobic/anaerobic soil metabolism study performed under paddy conditions. The anaerobic aquatic metabolism study total system half-life was 105 days.
Biodegradation studies of kasugamycin parent produced kasugamycinic acid under aerobic and anaerobic conditions and kasuganobiosamine under anaerobic conditions. In these studies, thekasuganomycinic acid was present at 3.1% at 180 days (the termination of the paddy study) in nonsterile soil and 12% in the sterile soil. Kasugamyeinic acid was seen at a maximum of 31% after 14 days in the aerobic aquatic metabolism study, but was only present at 0.6% by the termination of the study (100 days). In the anaerobic metabolism study, kasugamycinic acid was present at 29% at termination of the study (368 days) and a maximum of 36% at 185 days into the study. Kasuganobiosamine was a major degradate in the anaerobic aquatic metabolism study with 45% present in the total system at study termination (368 days) and a maximum of 48% present in the total system after 277 days. Kasuganobiosamine was also detected in the aerobic aquatic metabolism, but was not quantified.

2. 

### Transport, Mobility and Bioaccumulation: Kasugamycin is classified as mobile to moderately mobile. The mobility of kasugamycin acid and kasuganobiosamine is expected to be similar to or greater than the parent compound. Both of these degradates have the potential to be found in drinking water and ground water. Kasugamycin is highly soluble in water (228 g/L at 25°C and pH 7). With a vapor pressure of 1.3 x 10 -2 mPa at 25 ° C, the compound does not appear to volatilize. The compound is not expected to bioaccumulate with an octanol-water partition coefficient (K ou ,) of 0.0196 at 23°C and pH 5.


### B. Ecological Risk Ecological risk characterization integrates the results of the exposure and ecotoxicity data to evaluate the likelihood of adverse ecological effects. The means of integrating the results of exposure and ecotoxicity data is called the quotient method. For this method, risk quotients (RQs) are calculated

9by dividing exposure estimates by ecotoxicity values, both acute and chronic (RQ =

Exposure/Toxicity). RQs are then compared to the Agency's LOCs. The LOCs are criteria used by the Agency to indicate potential risk to nontarget organisms. The criteria indicate whether a pesticide, when used as directed, has the potential to cause adverse effects to nontarget organisms.
AQ,uatic Animals and Plants


### 1. Aquatic Animals. Kasugamycin is classified as `practically nontoxic' to fish and aquatic invertebrates on an acute exposure basis. Since there are no definitive acute endpoints available for aquatic animals 

### (i.e:, all of the available LC50/EC50 values are `greater than' values and there were no effects noted at the highest concentrations tested), acute RQs are not calculated.
The only chronic endpoint available for aquatic animals and kasugamycin is for freshwater fish. In the chronic freshwater fish study there were no effects noted at the highest concentration tested, resulting in a NOAEC of 9.5 mg a.i./L. The highest 60-day estimated environmental concentration (EEC) from the aquatic modeling is 4.53 μg a.i./L. Therefore, the highest calculated chronic exposure RQ for freshwater fish is <0.001 (4.53 μg a.i./L/9,500 μg). This is below the Agency's LOC (RQ = 1) for chronic risk to aquatic animals. There are currently no chronic data available for freshwater or estuarine/marine aquatic invertebrates. Aquatic invertebrates would need to be significantly more sensitive on a chronic exposure basis than an acute exposure basis for a chronic risk LOC to be exceeded 

### (i.e., >11,885 times more sensitive). Since this is unlikely given the toxicity profile for this chemical, risk to aquatic invertebrates from chronic exposure to kasugamycin is not expected.



### 2. Aquatic Plants. The highest peak EEC from the aquatic modeling is 6.53 μg a.i./L. Comparing this EEC with the EC50 (86,000 μg a.i./L and 650 μg a.i./L) and NOAEC/ECO5 values (26,000 μg a.i./L and 200 μg a.i./L) from the most sensitive aquatic vascular (duckweed) and non-vascular plants (cyanobacteria), respectively, results in RQs C 0.03. 'I11ese RQs are all below the Agency's LOC (RQ < 1) for risk to listed and non-listed aquatic plants.

Terrestrial Animals. Invertebrates and Plants


### 1. Birds. Based on the LD50 values for the northern bobwhite 

### quail (Colinus virginianus), mallard duck 

### (Anas platyrhynchos), and Zebra finch 

### (Taeniopygiaguttata) of >2,000 mg a.i./kg-bw, kasugamycin is characterized as "practically nontoxic" to avian species on an acute oral-exposure basis. Kasugamycin is no more than "slightly toxic" to avian species on a sub-acute dietary-exposure basis, with LC50 values of > 4,858 mg/kg-diet reported for northern bobwhite quail and mallard ducks. A subacute dietary 10LC50 value of >4,858 mg a.i./kg-diet and an acute oral LD50 of >2,000 mg a.i./kg body weight were

used to assess the risk of kasugamycin to birds. None of the avian RQs calculated for chronic exposure exceed the Agency's LOC for risk to listed and non-listed species. Therefore, risks to birds from the proposed kasugamycin uses are not expected.



### 2. Mammals. Based on the LD50 value for the Norway rat 

### (Kattus norvegicus) of >5,000 mg a.i./kgbw, kasugamycin is characterized as "practically nontoxic" to mammalian species on an acute oralexposure basis. For the proposed pome fruit use, the dose-based chronic RQs for mammals that eat short grass (all size classes); 15-g mammals that eat tall grass and/or broadleaf plants/small insects; and 35-g mammals that eat broadleaf plants/small insects, exceeded the Agency's chronic risk LOC. However, a maximum single application rate of 0.0841bs a.i./A (64 fl. oz product/A) would result in a chronic RQ of 0.64 for the most sensitive mammals, 

### i.e., 15-g mammals feeding on short grass, and would fall below the chronic risk LOC. Additionally, inherent hazard to mammals of kasugamycin is lower in comparison to most registered alternatives (Prohexidione, Streptomycin and Copper) for pome
fruit diseases 2 (Table 1).

Table 1. Comparison of Mammalian Chronic NOAECs and NOAELs for Kasugamycin to other treatment alternatives (conventional pesticides). Chemical PC Code NOAEL
m -bw NOAEC

m -diet MRID
Prohexidione 112600 1.75* 35 44457764

Stre tom cin 006306 10 200* As reported in most recent risk assessment' Co er 2 008101+ 3 11.7 -° Sam le et al., 1996 5 Kasu am cin 230001 13.7 274* 45910023 Oxytetracycline 006304 <60* <1200 

## 1 001323-91 ' Section 18: USEPA Emergency Exemption Use of Streptomycin Sulfate (Streptomycin) on Grapefruit in Florida. Environmental Fate and Effects Division. Office of Pesticide Programs. United States Environmental Protection Agency. Washington, D.C. July 3, 2012. z Copper refers to copper-containing compounds
3 Includes the following PC codes 008141, 008001, 022501, 022702, 022703, 022901, 023104, 023401, 023501, 023503, 024401, 024403, 024405, 024407, 024409, 023306, 025601, 039105, and 042401 ' NOAEL based on mink and not rats; therefore, endpoint was not converted from NOAEL to NOAEC
5 Sample, BE, Opresko, DM, and Suter II, GW. 1996. Toxicological Benchmarks for Wildlife, 1996 Revision, June 1996. Report ES/ER/TM-86/R3, prepared by the Risk Assessment Program, Health Sciences Research Division, Oak Ridge National Laboratory. * Calculated based on T-REX model (Version 1.5.2)

2 Chronic Mammalian Toxicity Endpoint Comparison for Kasugamycin and Its Alternatives. DP Barcode: 420419. U.S. EPA. May 29, 2014.
11

### 3. Terrestrial Invertebrates. Kasugamycin is classified as `practically nontoxic' to non- target

terrestrial invertebrates on an acute oral and contact exposure basis. In an acute contact study with honey bees, the NOAEL was 100 μg a.i./bee (the highest concentration tested) and mortality in the study ranged from 0 to 16.7% in the different treatment groups. In the acute oral bee study a defuutive NOAEC could not be determined due to ? 23% mortality in all treatment groups. Although a NOAEC could not be determined, a definitive acute oral LD50 of 30.3 μg a.i./bee was determined based on availa.ble data. Toxicity information for beneficial insects is used to develop precautionary label language where necessary 

### (eg., when the acute toxicity endpoint is less than 11 ug a.i./bee). Based on the available data, precautionary label language for bees is not necessary 

### (i.e., the LC50 value is greater than 11 ug a.i./bee). There were no mortalities or sublethal effects noted in the earthworm study; therefore the NOAEC is 1,000 mg a.i./kg-dw substrate (the highest concentration tested).



### 4. Terrestrial Plants. The LOC for non-listed terrestrial plants was not exceeded for monocots or dicots. However, there is some uncertainty regarding this result for monocots since onion and wheat had inhibitions in dry weight of 26 and 37%, respectively, in the seedling emergence study. If effects to monocots were linear (which is an assumption since there is no dose-response information from the Tier I plant study), the effects in non-target plants found adjacent to the site of application would be below the 20% effect level. Under these assumptions, risks to non-listed monocots would not be expected. For listed terrestrial plants, none of the RQs for dicots exceed the LOC. For listed monocots, because a definitive NOAEC value was not established for monocots in the Tier I seedling emergence study 

### (i.e., there were effects noted at the concentration tested), risk to listed monocots from potential exposure via runoff and spray drift cannot be precluded at this time. Because definitive no-effect values were not established for monocots in the seedling emergence study, risk to listed monocots from the proposed use of kasugamycin is an uncertainty. These findings are based solely on EPA's screening level assessment and do not constitute "may effect" findings under the Endangered Species Act. Additionally, with the limited use of kasugamycin (pome commodities only), low application rates (0.083 lb active ingredient (A.I.) per acre (A); maximum seasonal use of 0.3331b A.I. /A) and ground based application methods, risks to listed monocots should be reduced.

12

### IV. CONCERNS FOR DEVELOPMENT OF RESISTANCE

As with all antibiotics, concerns exist regarding the potential for development of resistance, or cross-resistance with other aminoglycoside antibiotics, that could result from pesticidal applications. To address these concerns, EPA consulted with public health officials from the Food and Drug Administration (FDA) and the Center for Disease Control (CDC). As with the previous assessments for kasugamycin (Section 18 requests), EPA requested that Arysta provide information relative to the resistance potential of the proposed kasugamycin uses per FDA's Guidance for Industry (GFI) #152. This document focuses on the concern that the use of new antimicrobials in food-production will result in the emergence and selection of antibiotic resistant food-borne bacteria, which impact human health adversely.
FDA's 152 is a qualitative risk assessment consisting of release, exposure, and consequence assessments. Risk estimation for the release and exposure (ranked low, medium or high) and consequence (ranked important, highly important or critically important) findings are used to determine the overall estimate of risk (ranked low, medium or high) associated with the proposed antibiotic use.
A summary of the resistance risk of kasugamycin as assessed in the Agency document titled "Review of Arysta Life Science's Analysis of Kasugamycin's Safety with Regard to Its Microbiological Effect on Bacteria of Human Healtli Concern (FDA/CVM Guidance to Industry #152)" (8/29/12), is provided below.



### A. Release Assessment. The release assessment estimates the probability that the proposed use of an antimicrobial drug (e.g. antimicrobial pesticide) in or on food crops will result in the emergence or selection of resistant bacteria. Primary expression of resistance would be a failure of the antibiotic to control the target plant pathogen. An additional adverse outcome could be the appearance of resistance to non-target bacteria in the soil or on the plant surface. Either scenario could indicate an
increase in the likelihood of antibiotic resistance transfer to microbes of human health concern and would require a closer examination of the resistance trait to determine its mobility among bacterial populations. The human health concern comes mostly from contamination of food crops with
bacteria of human health concern and the transfer of resistance traits to these microbes of human health concern, not from strains with resistance traits found in the environment. The boundaries of the release assessment relate to the proposed use patterns and estimated percent-crop-treated. The release assessment rating for pome commodities is "low" considering the long pre-harvest interval (90 days) and application of kasugamycin prior to fruit development. In 13addition, no adverse effects were noted with the Section 18 use in Michigan relative to resistance

detection (within the target or non-target pests).



### B. Exposure Assessment. The exposure assessment considers the probability that humans would ingest or be

. exposed to potentially resistant bacteria from the treated food commodity. The incidence of foodborne illness associated with consumption of the crop would provide the background for the exposure scenarios. Increasing exposure to resistant bacteria of human health concern through the use of improperly treated animal manures is also a consideration.
In general, the level of food commodity contamination for pome crops is low but variable. The incidence of apple consumption being implicated in food poisoning incidents has increased in recent
years 3 . Currently, in the U.S., kasugamycin has only been used as an emergency option under Section 18 in Michigan. The use has been limited by both time and location for only a single crop, apples. Since the proposed Section 3 registration request expands use of kasugamycin both geographically and by crop (although only including other pome fruits), the exposure, and consequently, the selection pressure for resistance, will expand. Additionally, expanded use of kasugamycin potentially increases the amount of the treated food commodity being consumed. Expanded use of kasugamycin and low commodity contamvnation (considering applications prior to fruit development, and low but variable incident of contamination for commodity pome fruit) would yield a rating of "medium" for the exposure assessment.
The plant agricultural use of antibiotics has a much greater environmental exposure (compared to animal agricultural use) due to the application by air blast or other spray technologies. The plant agricultural use exposes a broader set of bacteria to selection for antibiotic resistance. But exposure to a broader set of bacteria may have little direct impact on bacteria of human health concern since bacteria of human health concern are a relatively minor component of the general environment (unless improperly handled animal manures are used in treated fields, which EPA proposed to address through the labeling).



### C. Consequence Assessment. The consequence assessment considers the probability that the

3 Painter JA, Hoekstra RM, Ayers T, Tauxe RV, Braden CR, ringulo FJ, et al. Attribution of foodbome illnesses, hospitalizations, and deaths to food commodities by using outbreak data, United States,1998-2008. Emerg Infect Dis [Internet] . 2013 IVIar.

14exposure to resistant bacteria could result in an adverse health consequence. Any change in the

incidence of foodborne disease found with consumption of the treated crop or an increased failure to treat human disease related to ingesting the crop would be cogent for the consequence assessment. The consequence assessment is ranked as "important," the lowest ranking for a consequence assessment, based on the monitoring data resulting from use in Michigan showing no change in resistance frequency to other aminoglycosides in the presence of kasugamycin resistance in tested bacteria. There are currendy no clinical uses for kasugamycin. It is unlikely that kasugamycin will be approved for human or veterinary use. This assessment may change to "highly important" or "critical" if it is found that kasugamycin resistance can provide cross resistance to clinically important aminoglycosides.


### D. Overall Qualitative Risk Estimate. The overall risk estimate represents the potential for human health to be adversely impacted by the selection or emergence of antimicrobial resistant bacteria associated with the use of the kasugamycin. The overall qualitative risk estimate integrates the three previous assessments. With a"low" release, "medium" exposure and "important" consequence ratings, the overall qualitative risk estimation for kasugamycin use on pome commodities per GFI #152 is "low", for the registration period being proposed here.
Although the overall risk estimation for antibiotic resistance for the proposed registration use is classified as "low," there are a number of uncertainties relative to the proposed use patterns for kasugamycin and the ranking. Primarily,
1. The 152 assessment was based on monitoring data resulting from Section 18 use of kasugamycin. rls the Section 3 registration request would expand the use of kasugamycin, the exposure, selection pressure for resistance and consumption of treated commodities could also increase. With knowledge that the available field monitoring data resulting from use in Michigan has not shown a change in resistance frequency to other aminoglycosides in the presence of kasugamycin resistance in tested bacteria, the Agency feels it is acceptable to permit use of kasugamycin on pome commodities provided that a stewardship program inclusive of resistance management is initiated and
maintained.

2. The use of antibiotics on crops, although minor relative to total antibiotic use, can result in situations that impact the buildup of resistant bacteria. Antibiotics used as agricultural pesticides can be applied over large areas of land to densely vegetated fields and orchards. This can lead to the proliferation and rapid spread of resistant genes in the bacterial population. Provided a stewardship program inclusive of resistance management is maintained by the registrant, the Agency feels it is

15acceptable to permit use of kasugamycin on pome commodities.

3. Kasugamycin may be most active against plant pathogens, but there is evidence from studies on other antibiotics to suggest that established resistance in bacteria can be spread to other strains or species of bacteria (via plasmids). There is also evidence to suggest that resistance established through plasmids can carry more than one antibiotic resistance factor leading to resistance against multiple antibiotics. Although the probability is low, there is a potential for bacterial resistance to cross between plant bacteria and human bacteria.

4. Bacteria serve an essential role in cycling nutrients and energy in the environment (e

~ ., through decomposition of organic materials and nitrogen-fixation). The effects of the potential reduction or alteration of the microorganism community from the proposed kasugamycin uses are unknown. Given that kasugamycin represents a new active ingredient, the Agency does not believe that this is a concern for the time period for which this registration is being proposed.

V. FINAL REGULATORY DECISION The Agency is granting an unconditional, time-limited registration of four years for the active ingredient, kasugamycin for use on pome fruits (crop group 11-10) under FIFRA Section 3(c)(5), as
amended. As required by FIFRA, the Agency published a notice of receipt for the applications to register Kasugamycin technical and Kasumin 2L. The notices of receipt were published in the Federal Register on May 19, 2010 (Volume 75, No. 96, page No. 28011). No comments were received in response to the notices of receipt. As required by FFDCA, the Agency published a notice of filing for the establishment of tolerance for residues of kasugamycin. The notice of filing was published in the Federal Register on May 5, 2010 (75 FR pages 24694-24695). There were no comments received in response to the notice of filing. As part of the public participation process, the Proposed Decision Document was published on March 18, 2014 and the 30 day public comment period was open until April 17, 2014. Seventeen comments were received during the comment period. All of the comments received can be found in the docket (EPA-HQ-OPP-2010-0297). In general, comments were in support of a kasugamycin registration. A summary of the substantive comments from the Center for Biological Diversity and Arysta LifeScience will be discussed within this document.



### Comments to the Agency's Proposed Regulatorv Decision


### 16

### Center for Biological Diversity (CBD) comment # EPA-HQ-OPP-2010-0297-0028

Given the results, the stated uncertainties and data gaps, from the ecological risk assessment for kasugamycin, the EPA must begin the informal consultation process with the Services and work towards the preparation of a nationwide biological assessment of kasugamycin. The ecological risk assessment has concluded that there is the "potential for direct adverse effects to listed and non-listed mammals from chronic exposure. Additionally risks to listed terrestrial plants (monocots) from any of the proposed uses cannot be precluded based on available data. This indicates a potential risk for direct adverse effects to federally-listed monocots, and mammals and indirect adverse effects to any listed species that rely on these taxa as resources critical to their life cycle."
Section 7(d) of the ESA provides that once a federal agency initiates consultation on an action under the ESA, the agency "shall not make any irreversible or irretrievable commitment of resources with respect to the agency action which has the effect of foreclosing the formulation or implementation of any reasonable and prudent alternative measures which would not violate subsection (a)(2) of this section. The purpose of Section 7(d) is to maintain the environmental status quo pending the completion of consultation. Section 7(d) prohibitions remain in effect throughout the consultation period and until the EPA has satisfied its obligations under Section 7(a)(2) that the action will not result in jeopardy to the species or adverse modification of its critical habitat. An active ingredient cannot be registered for use prior to the completion of the consultation process. The registration of an active ingredient prior to the completion of consultations would represent an irreversible and irretrievable commitment of resources, and would violate the basic requirement of the ESA that each agency of the federal government insure that their actions do not jeopardize listed species or adversely modify critical habitat.
CBD also commented that the ecological risk assessment for kasugamycin is underprotective of listed species and should be revisited in light of the findings of the National Academy of Sciences Report and Interim Approaches Document.


### EPA response: The Nr1S report, available at http://www.nap.edu/catalogphp?record id=18344, outlines recommendations on specific scientific and technical issues related to the development of pesticide risk assessments that are compliant with the Endangered Species Act and the Federal Insecticide, Fungicide, and Rodenticide Act. In November, the EPA, along with the U.S. Fish & Wildlife Service (USFWS), the National Marine Fisheries Service (NMFS) (collectively, the Services), and the US. Departrnent of Agriculture (USDA), released a summary of their joint Interim 17Approaches for assessing risks to listed species from pesticides. The Interim Approaches were

developed jointly by the Agencies in response to the NAS' recommendations and reflect a common approach to risk assessment shared by the Agencies as a way of addressing scientific differences between EPA and the Services. The joint Interim Approaches were released prior to the stakeholder workshop held on November 15, 2013. EPA presented the joint Interim Approaches at the December 2013 PPDC and SFIREG meetings, allowing additional opportunities for stakeholders to comment on the Interim Approaches. As discussed at the November 2013 workshop, and consistent with the March 2013 stakeholder engagement process for FIFRA-ESA consultations, the Agencies have invited comment on the Interim Approaches as preparations are made to apply these new approaches in the context of upcoming registration review decisions. The Agencies intend to jointly implement these approaches as part of a phased iterative process that takes account of the input received and the lessons learned from the initial efforts to work with the Interim Approaches.
Itis important to understand that the development of the Interim Approaches does not by its terms suggest that existing or recently developed risk assessments using the criteria articulated in OPP's 2004 Overview document are necessarily "under-protective." The Interim Approaches are intended to identify interim thresholds for interagency review as the Agencies jointly work to implement the recommendations of the NAS on certain specific registration review actions. The Agencies have made no determination that these thresholds are necessary to prevent take and preclude likely jeopardy and, in any case, the Interim Approaches do not establish legally binding thresholds for consultation under the Services implementing regulations. As EPA and the Services work through the.initial actions that are being reviewed under the Interim Approaches, the Agencies will determine whether these thresholds should be modified before they are extended more broadly to additional regulatory actions. The details of the joint Interim Approaches are contained in the white paper "Interim Approaches for National-Level Pesticide Endangered Species Act Assessments Based on the Recommendations of the National Academy of Sciences Apri12013 Report," dated November 1, 2013, available at http://www.epa.gov/espp/2013/nas.htrril.
As the Agency has emphasized in multiple forums, EPA is focusing most of its resources for assessing impacts to listed species on its registration review program for currently registered pesticides. EPA believes that as a general matter currently registered pesticides present a greater degree of risk to listed species than most new chemistries coming to market, including 18kasugamycin, and that it is therefore environmentally preferable in most circumstances for EPA to

assess the impacts of existing pesticides sooner in the process than newer pesticides that are designed to compete with more risky alternatives. As a result, EPA does not believe the environment or the public would be best served by delaying the registration of kasugamycin to complete consultation. Focusing EPA's, FWS', and NMFS' limited resources on completing a consultation on the effects of kasugamycin would by necessity come at the expense of putting more resources into evaluating —and consequently regulating, where appropriate —what EPA believes to be more toxic compounds that, among other things, pose greater risk to endangered species than does kasugamycin. With respect to the evaluation of kasugamycin specifically, it is important to understand that under any internal or interagency review, the ecological risk evaluation will continue to rely on the body of information used in the current EPA ecological assessment. As explained in this document, those data indicate that the ecological risks presented by uses of kasugamycin are generally low, especially given the application rate (single and seasonal maximum) and application rnethod.
While EPA is not consulting with the Services on the issuance of the kasugamycin registration, EPA is currently working to prioritize its consultation activities with Services and will evaluate the appropriate timing and scope of consultation on kasugamycin in connection with those efforts. In addition, to the extent EPA receives new information indicating that kasugamycin may pose a greater risk to listed species than indicated by the existing scientific database for this pesticide, EPA will re-evaluate the terms of registration and determine whether additional use restrictions to protect listed species are necessary.


### Arysta LifeScience North America (Arysta) comment # EPA-HQ-OPP-2010-0297-0032 Arysta requests the approval include items 1-3 as detailed below:
1. Removal of use restriction: "Do not apply kasugamycin as the first spray of the season."
2. The term "Bactericide" should be used instead of "Agricultural Antibiotic"
3. Establishment of additional tolerances for harmonization with existing MRLs in Canada, so as to
avoid a trade irritant situation



### EPA response: The Agency is in agreement that the requirement to utilize a registered alternative as the first application during the use season may place an undue burden on growers for Section 3 use. The restriction was initially proposed as a carryover from the Section 18, where mitigating an existing 19emergency pest management situation was critical. As such, the requirement to use a registered

alternative as the first application during the use season will be removed.
While products may have the term "Bactericide" in their brand names, the Agency has referred to the active ingredients Streptomycin 4 and Oxytetracycline s as agricultural antibiotics. Consistent with the drug classification among CDC and FDA, the Agency will continue to utilize the term "antibiotic" (specifically agricultural antibiotic) when referencing oxytetracycline, streptomycin and kasugamycin."Bactericide" represents a broader classification of chemicals which can include antibiotics and nonantibiotics, such as some copper based compounds which are effective against bacteria.
With regard to the additional tolerance requests, the Agency will establish a tolerance for pome fruits only. Data specific to field monitoring and/or laboratory cross resistance screenings, were not available to support the overall safety finding for fruiting vegetables and walnuts. Until the Agency receives and reviews additional information relative to resistance risks, additional tolerances for these crops will not be granted. Additionally tolerance requests for fruiting vegetables and walnuts under the current petition were withdrawn. The existing tolerance for imported fruiting vegetables will remain unchanged.

Regulatory Decision Consistent with Section 3(c)(5) of FIFRA, the Agency believes that: kasugamycin is formulated to warrant the proposed claims, that the labeling and other material required to be submitted comply with the requirements of FIFRA, and that the end-use product (Kasumin 2L) will perform its intended function. Under the time-limited registration (four years), the Agency believes that kasugamycin will be used without unreasonable adverse effects on the environment and when used in accordance with widespread and commonly recognized practice, kasugamycin will not generally cause urireasonable adverse effects on the environment. Therefore, the Agency will register kasugamycin for use on or in pome fruits (crop group 11-10).

A. Data Requirements: There are no outstanding data requirements for kasugamycin
B. Labeling Requirements: The following statements have be added to the end use product label prior to approval.

' Reregistration Eligibility Document (RED) Streptomycin and Streptomycin Sulfate, U.S. EPA. September 30, 1992. ' Reregistration Eligibility Document (RED) Hydroxptetracyline Monohydrochloride and Oxytetracycline Calcium, U.S. EPr1. March 30, 1993. 20o Do not apply Kasumin 2L within 90 days of harvest.

o Do not apply kasugamycin in orchards in which the soil has been fertilized with animal
waste/rnanure. o Animal grazing in treated areas is prohibited. The public must be notified by posting restriction signs along the perimeter of the treatment area. o Use only the specified and full strength application rates. o Do not apply more than two consecutive applications. o Resistance Management: Kasumin 2L (kasugamycin) is a Group 24 fungicide. The mode of action for Kasumin 2L is the inhibition of protein synthesis. This product should be used to treat or prevent infections that are proven or strongly suspected to be caused by the indicated target bacteria. To reduce the likelihood of bacteria developing resistance to kasugamycin, follow the crop specific resistance management and use direction information present on this labeling. Use of this product should conform to resistance management practices/strategies established for the crop and use area, (for example the use of IPM, disease forecasting models, resistant crop varieties, etc.). Consult your local extension/crop consultant or State agricultural authority if reduced efficacy is suspected.

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