# Proposed Registration Decision for Kasugamycin on Pome Fruits.

March 12, 2014

U.S. Environmental Protection Agency Office of Pesticide Programs Registration Division3 REGULATORY PROPOSAL The Agency is proposing an unconditional, time-limited registration of four years for the use of the active ingred ient (a.i.) kasugamycin for use on pome fruit (crop group 11-10) under the Federal Insecticide, Fungicide and Rodentic ide Act (FIFRA), as amended. Separately, the Agency is also proposing to establish tolerances for residues of kasugamycin in or on these crops under the Federal Food, Drug and Cosmetic Act (FFDCA). Kasugamycin is produced from Streptomyces kasugaensis and belongs to the aminoglycoside class of compounds, a group of antibiotics that inhibit microbial protein synthesis. This class also includes strept omycin, apramycin, kanamycin, paromomycin, and neomycin, some of which have human and/or ve terinary medicinal uses. Kasugamycin has a
different mode of action from other antibiotics re gistered for agricultural use (i.e. streptomycin and oxytetracycline). Specifi cally, the protein target inhibition site differs for kasugamycin from that shared by streptomycin and oxytetracyclin e Kasugamycin is not used for human or veterinary purposes in the United States but has been used clini cally in Japan to treat urinary
tract infections due to Pseudomonas aeruginosa 1

. 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. There are no established or proposed Codex maximum residue limits (MRLs).

I. HUMAN HEALTH RISK A summary of the human health risk as assessed in the Agency document titled “Kasugamycin. Human Health Risk Assessment for the Proposed Use of the Fungicide on Fruiting Vegetables, Pome Fru its, and Walnuts” (July 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 ra t is not required based on the toxicity profile, low use rate and high margins of exposure (MOEs) achieve d for handler inhalation exposure using an endpoint from an oral study.

1 Schuwirth, B. S., J. M. Day, C. W. Hau, G. R. Janssen, A. E. Dahlberg, J. H. Doudna Cate, and A. Vila-Sanjurjo. 2006. Structural analysis of kasugamycin inhibition of translation. Nat Struct Mol Biol. 12(10): 879-886.4 A. Toxicological End Points
1. Acute Dietary: There were no toxic effects asso ciated with a single dose of kasugamycin; therefore, an acute dietary endpoint and dose were not selected for the general US population, or any population subgroup.
2. Chronic Dietary: For chronic dietary exposur e, the rat combined chronic toxicity/carcinogenicity study was selected. The no-obser ved-adverse-effect level (NOAEL) of 11.3 mg/kg/day was ba sed on testicular softening and atrophy at the lowestobserved-adverse-effect leve l (LOAEL) of 116 mg/kg/day. Testicular atrophy was also observed in the rat two-generation repr oduction study at 425.3 mg/kg/day (NOAEL = 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 toxic ity 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 ev aluated in the dermal study.
4. Short- and Intermediate-Term Inhalation: For inhalation exposure, the subchronic dog and the rabbit developmental toxicity stud ies were selected as co-critical. The endpoint of concern was irritati on, since kasugamycin appears to be irritating to the oral cavity and gastrointestinal tract mucosa fo llowing oral exposures. In the subchronic study with dogs, the NOAEL was 11 mg/kg/day (s elected as the point of departure), and the LOAEL was 106 mg/kg/day, ba sed 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 irritati on potential of kasugamycin is further demonstrated with the presence of anal lesi ons, and perianal/perigen ital staining seen in the subchronic mouse study; red/swollen skin around the anal opening, and
inflammation/ulceration of the r ectum in the offspring of bot h sexes in the two-generation reproduction study; and distention of the large in testine in the devel opmental rat study. The developmental rabbit study (suppor ted by its range-finding study) was selected as the co-critical study since the maternal NOAEL (10 mg/kg/day, highest dose tested) was comparable to the NOAEL in th e subchronic dog study. In the range-finding study, maternal toxicity manifested as a bortions and weight loss at 30 mg/kg/day5 (LOAEL). The incidence and seve rity of the maternal toxicity was increased at the high dose (100 mg/kg/day) where one doe died, aborti ons 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 irritati on effects to mucous membranes seen across numerous species, it is reasonable to surm ise that the bolus (gavage) dosing causes irritation to the gastrointes tinal tract, resul ting in maternal toxicity. Although a subchronic inhalation toxicity st udy is not available and is not required, the oral study is considered protective because use of the oral NOAEL results in margins of exposure (MOEs) ranging from 58,000 to 2,500,000 for ri sk from occupational exposure via the
inhalation route and is ther efore protective of potentia l inhalation effects.
5. Cancer: The Agency has classified kasugamycin as “Not Likely to be Carcinogenic to Humans” based on lack of evidence of carcinoge nicity in mice and ra ts, 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 ex posure data, the Agency 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 hi ghly conservative and is not exp ected to underestimate exposure and risk. This recommendation is based on the following: 1. The toxicology database is complete, includi ng developmental studi es in two species, a rat two-generation reproductive study, ra t acute and subchronic neurotoxicity screening studies, and a m ouse immunotoxicity study.
2. Based on the lack of observed neurotoxi city, a DNT study is not required. 3. There is no evidence of increased quantita tive or qualitative pr e- and/or postnatal susceptibility observed in developmental toxicity studies in the rat a nd rabbit, or in a twogeneration reproduction st udy in the rat. 4. The exposure assessment for food and dr inking water will not underestimate potential dietary exposure to kasugamycin, and there ar e no proposed or exis ting residential uses for kasugamycin.6 C. Cumulative Effects Unlike other pesticides for which EPA has fo llowed a cumulative risk approach based on
a common mechanism of toxicit y, the Agency has not made a common mechanism of toxicity finding as to kasugamycin and any other substa nces, and kasugamycin does not appear to produce a toxic metabolite produced by other substa nces. For the purposes of this tolerance action, therefore, EPA has not assumed that ka sugamycin has a common mechanism of toxicity
with other substances. For in formation regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity, and to eval uate the cumulative effects of such chemicals, see the policy statements released by EPA’s OPP concerning common mechanism determinations and procedures for cumulating e ffects 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 fo r kasugamycin associated with the subject petition, nor are there any currently registered residential uses . Kasugamycin is not intended for use in public or residential se ttings. 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 wa ter, 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 concern.

F. Occupational Risk
Based on the proposed use patter ns, both short- and intermed iate-term exposure and risk assessments were conducted for occupational ha ndlers, 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.7 1. Short- and Intermediate-Term Handler Exposure and Risk: Occupational handler exposures to kasugamycin were estimate d assuming the maximum application rate, baseline personal protective equipment (PPE) [long-sleeved shirt, l ong 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 ris k, the Agency relied on surrogate unit exposure data to estimate exposure and risk. The resu lting handler risk estim ates, 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 Pos t-Application Exposure and Risk: Dermal postapplication exposure was not asse ssed due to the lack of toxic ity via the dermal route. There is no dermal risk associated with pos t-application activities following application of kasugamycin on the proposed crops. The Re stricted Entry Interv al (REI) is based on the acute toxicity of kasugamycin technical mate rial, which is classified in acute Toxicity Categories III and IV. Acute 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 25oC), and it is applied at low app lication rates. Howe ver, volatilization of pesticides may be a potential source of post-application inhalation exposure to individuals nearby pesticide applications. Although a quantitative occupational postapplication inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational hand lers. This assessment resulted in risk estimates that did not exceed the Agency’s LOC at baseline inhalation PPE. Handler exposure resulting from application of pestic ides outdoors is likely to result in higher exposure than post-application exposure. Ther efore, it is expected that these handler inhalation exposure estimates would be protec tive of most occupatio nal post-application inhalation exposure scenarios.8 II. ENVIRONMENTAL RISK A summary of the ecological effects and ri sks 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 kasuga nobiosamine, are mostly present in pH solutions of 3.23 to 7.73, and 7.73 to 11, respectiv ely. 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 ka sugamycin are aqueous photolysis , aerobic biodegradation , and hydrolysis. Abiotic routes of degrada tion include photolysis and hydr olysis. In the aqueous photolysis study, the half-life in natural lake water was 17.4 days as opposed to the phototransformation half-life in sterile wate r of 630 days. The hydrolysis study showed that kasugamycin tends to degr ade much faster in neutral to alkaline environments. The 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 and anaerobic conditions. The aerob ic aquatic metabolism half-life was approximately 45 days in lake water-loamy 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 tota l system half-life was 105 days. Biodegradation studies of kasugamycin parent produced kasugamycinic acid
under aerobic and anaerobi c conditions and kasuganobiosamine under anaerobic9 conditions. In these studies, the kasuganomycinic acid was present at 3.1% at 180 days (the termination of the paddy study) in non-st erile soil and 12% in the sterile soil. Kasugamycinic 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 maxi mum 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 syst em after 277 days. Kasuganobiosamine was also detected in the aerobic aquatic metabolis m, 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 compoun d. Both of these degradates have the potential to be found in drinki ng water and ground water. Kasugamycin is highly soluble in water (228 g/L at 25oC 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 ow ) of 0.0196 at 23°C and pH 5.

B. Ecological Risk Ecological risk characterizati on integrates the results of th e exposure and ecotoxicity data to evaluate the likelihood of adverse ecological e ffects. The means of in tegrating the results of exposure and ecotoxicity data is called the quo tient method. For this method, risk quotients (RQs) are calculated by dividing exposure es timates 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 potenti al risk to nontarget or ganisms. The criteria indicate whether a pesticide, when used as direct ed, has the potential to cause adverse effects to nontarget organisms. Aquatic Animals and Plants
1. Aquatic Animals. Kasugamycin is classified as ‘practic ally nontoxic’ to fish and aquatic invertebrates on an acute exposure basis. Since there are no definitive acute endpoints10 available for aquatic animals ( i.e ., all of the available LC 50 /EC 50 values are ‘greater than’
values and there were no effects noted at th e highest concentrations tested), acute RQs
are not calculated. The only chronic endpoint available for a quatic animals and kasugamycin is for
freshwater fish. In the chronic freshwater fish study there were no effects noted at the highest concentration tested, re sulting in a NOAEC of 9.5 mg a.i./L. The highest 60-day
estimated environmental con centration (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 be low the Agency’s LOC (RQ = 1) for chronic risk to aquatic animals. There are currently no chronic data availabl e 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 ch emical, 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 EC 50 (86,000 μg a.i./L and 650 μg a.i./L) and
NOAEC/EC 05 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 ≤ 0.03. These 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 LD 50 values for the northern bobwhite quail ( Colinus virginianus ), mallard duck ( Anas platyrhynchos ), and Zebra finch ( Taeniopygia guttata ) of >2,000 mg a.i./kg-bw, kasugamycin is characterized as “p ractically nontoxic" to avian species on an acute oral-exposure basis. Kasugamycin is no mo re than “slightly toxic” to avian species on a sub-acute dietary-exposure basis, with LC 50 values of > 4,858 mg /kg-diet reported for northern bobwhite quail and mall ard ducks. A subacute dietary LC 50 value of >4,858 mg a.i./kg-diet and an acute oral LD 50 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 chronic11 exposure exceed the Agency’s LOC for risk to listed and non-listed species. Therefore, risks to birds from the proposed ka sugamycin uses are not expected.

2. Mammals. Based on the LD 50 value for the Norway rat ( Rattus norvegicus ) of >5,000 mg a.i./kg-bw, kasugamycin is characterized as “practically nontoxic" to mammalian species on an acute oral-exposure basis. For the proposed pome fruit use, the dos e-based chronic RQs for mammals that eat short grass (all size classes); 15-g ma mmals 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 single application of 0.084 lbs a.i./A (64 fl. oz product/A) rate would result in a chroni c 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. This rate reflects the maximum application rate for pome commodities.

3. Terrestrial Invertebrates. Kasugamycin is classified as ‘practically non toxic’ to nontarget terrestrial invertebrate s on an acute oral and contact exposure basis. In an acute contact study with honey bees, the NOAE L was 100 μg a.i./bee (the highest concentration tested) and mort ality in the study ranged from 0 to 16.7% in the different treatment groups. In the acute oral bee study a definitive NOAEC could not be
determined due to ≥ 23% mortality in all treatment groups. Alt hough a NOAEC could not be determined, a definitive acute oral LD 50 of 30.3 μg a.i./bee was determined based on available data. Toxicity information fo r beneficial insects is used to develop precautionary label language where necessary ( e.g ., when the acute toxicity endpoint is less than 11 ug a.i./bee). Based on the avai lable data, precautionary label language for bees is not necessary ( i.e ., the LC 50 value is greater than 11 ug a.i./bee). There were no
mortalities or sublethal eff ects noted in the earthworm study; therefore the NOAEC is 1,000 mg a.i./kg-dw substrate (the hi ghest concentration tested).

4. Terrestrial Plants. The LOC for non-listed terrestrial plants was not exceeded for monocots or dicots. However, there is so me uncertainty regard ing this result for
monocots since onion and wheat had inhibi tions in dry weight of 26 and 37%, respectively, in the seedling emergence study. If effects to monocots were linear (which12 is an assumption since there is no dose-response information fr om 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 assump tions, risks to non-listed monocots would not be expected. For listed terrestrial plants, none of the RQ s 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 not ed at the concentration tested), risk to listed monocots from potenti al 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 lim ited use of kasugamycin (pome commodities only), low application rates ( 0.083 lb active ingredient (A.I .) per acre (A); maximum seasonal use of 0.333 lb A.I. /A) and ground ba sed application met hods, risks to listed
monocots should be reduced.

III. CONCERNS FOR DEVELOPMENT OF RESISTANCE As with all antibiotics, concerns exist re garding the potential for development of resistance, or cross-resistance with other ami noglycoside antibiotics, that could result from pesticidal applications. To address these conc erns, 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 potentia l 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 antimicrobial resistant food-borne bacteria, which impact huma n health adversely. The sc ope is the effect of
the transmission of bacteria of human health c oncern through the consumption of food products. Antimicrobial drug residues present in or on food may cause a dverse effects on the ecology of the intestinal microflo ra of consumers. In consideration of the use pattern for13 kasugamycin (application occurring prior to fruit development) a nd low residue levels detected in field trials, the Agency does not believe this is a concern. FDA's 152 is a qualitative risk assessment consisting of release, exposure, and consequence assessments. Risk estimation for th e release and exposure (ranked low, medium or high) and consequence (ranked im portant, highly important or critically impor tant) findings are used to determine the overall estimate of risk (r anked low, medium or high); associated with the proposed antibiotic use. A summary of the resistance ri sk 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 Health 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 cr ops will result in the emer gence or selection of resistant bacteria. Primary expression of resistan ce 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 pl ant surface. Either scen ario 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 hum an health concern comes mostly from contamination of food crops with bacteria of human health concern a nd 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 re late to the proposed use patterns and estimated percent-crop-treated. The release a ssessment rating for pome commodities is “low” considering the long pre-harvest interval (90 days ) and application of kas ugamycin prior to fruit development. In addition, no adverse effects we re noted with the Section 18 use in Michigan
relative to resistan ce detection (within the target or non-target pests).

B. Exposure Assessment The exposure assessment considers the proba bility that humans would ingest or be14 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 resi stant 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 appl e being implicated in food pois oning incidents ha s increased in recent years 2 . Currently, in the U.S., kasugamycin ha s only been used as an emergency option
under Section 18 in the Mi chigan. The use has been limited by both time and location for only a single crop, apples. Since the proposed Sec tion 3 registration reque st expands use of kasugamycin both geographically and by crop (a lthough only including other pome fruits), the exposure, and consequently, the selection pre ssure for resistance, will expand. Additionally, expanded use of kasugamycin increases the am ount of the treated food commodity being consumed. Expanded use of kasugamycin a nd low commodity contam ination (considering applications prior to fruit development, and lo w but variable incident of contamination for commodity pome fruit) would yield a rating of “medium” fo r the exposure assessment. The plant agricultural use of antibiotics has a much gr eater environmental exposure (compared to animal agricultural use) due to the application by air blast or other spray technologies. The plant agricultural use exposes more different types of bacteria to selection for
antibiotic resistance. Bu t exposure to a broader set of bacter ia may have little direct impact on
bacteria of human health concern since bacteria of human health concer n are a relatively minor component of the general environment (unless imp roperly handled animal manures are used in treated fields, which EPA proposed to address through the labeling).

C. Consequence Assessment The consequence assessment considers the pr obability that the e xposure to resistant
bacteria could result in an adverse health co nsequence. Any change in the incidence of
foodborne disease found with consum ption of the treated crop or an increased failure to treat human disease related to ingesti ng the crop would be cogent for the consequence assessment. The consequence assessment is ranked as “impor tant,” the lowest ranking for a consequence

2 Painter JA, Hoekstra RM, Ayers T, Tauxe RV, Braden CR , Angulo FJ, et al. Attribution of foodborne illnesses, hospitalizations, and deaths to food commodities by usin g outbreak data, United States, 1998–2008. Emerg Infect Dis [Internet]. 2013 Mar.15 assessment, based on the monitoring data resultin g from use in Michigan showing no change in resistance frequency to other aminoglycosides in the presence of kasugamycin resistance in
tested bacteria. There ar e currently no clinical uses for kasugamycin. It is not expected 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 resist ance can provide cross resistance to clinically im portant aminoglycosides.

D. Overall Qualitative Risk Estimate The overall risk estimate represents the pot ential for human health to be adversely impacted by the selection or emergence of antimicro bial resistant bacteria associated with the use of the kasugamycin. The overall qualitative ri sk estimate integrates the three previous assessments. With a “low” release, “medium” exposure and “important” consequence ratings, the overall qualitative risk estimation for ka sugamycin use on pome commodities per GFI #152 is “low”, for the registrati on period being proposed here. Although the overall risk estimation for antibioti c resistance for the pr oposed registration use is classified as “low,” th ere are a number of uncertainti es relative to the proposed use patterns for kasugamycin and the ranking. Primarily,
1. The 152 assessment was based on monitoring da ta resulting from Section 18 use of kasugamycin. As the Section 3 regist ration request would expand the use of kasugamycin; the exposure, selection pressure for resistance and consumption of treated
commodities would also increase. With know ledge 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 kas ugamycin resistance in tested bacteria, the Agency feels it is acceptable to permit use of kasugamycin on pome commodities provided that a stewardship progr am inclusive of resistance management is initiated and
maintained.
2. The use of antibiotics on crops, although minor relative to tota l antibiotic use, can result in situations that impact the buildup of resistant bacteria. An tibiotics used as agricultural pesticides can be applied over large areas of land to densely vegetated fields and orchards. This can lead to the proliferati on and rapid spread of resistant genes in the bacterial population. Provided a stewards hip program inclusive of resistance16 management is maintained by the registrant, the Agency feels it is acceptable to permit use of kasugamycin on pome commodities.
3. Kasugamycin may be most active against pl ant pathogens, but there is evidence from studies on other antibiotics to suggest that esta blished resistance in ba cteria can be spread to other strains or species of bacteria (via pl asmids). There is also evidence to suggest that resistance established through plasmids can carry more than one antibiotic resistance factor leading to resistance against multiple an tibiotics. Although the probability is low, there is a potential for bact erial resistance to cross betw een plant bacteria and human
bacteria.
4. Bacteria serve an essential role in cycling nutrients and energy in the environment ( e.g ., through decomposition of organic materials and nitrogen-fixa tion). The effects of the potential reduction or alte ration 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.

IV. PROPOSED REGULATORY DECISION In February 2010, Arysta LifeScience re quested the registration of two products containing kasugamycin - one technical and one end-use formulation for use on pome fruit, walnuts and fruiting vegetables. 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 no tices of receipt. As require d by FFDCA, the Agency published a notice of filing for the establishment of tolera nce for residues of kasugamycin. The notice of filing was published in the Federal Regist er on May 5, 2010 (75 FR pages 24694-24695). There were no comments received in response to the notice of filing. The tolerance requests for walnuts and fruiting vegetable were later withdrawn. As such, the Agency is proposing to issue a 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.17 In lieu of multiple field monitoring tria ls for kasugamycin resistance bacteria, a laboratory assay was suggested by CDC during a secondary cons ultation. The purpose of the laboratory screening will be to determine whet her there is cross-resistance between specific resistance mechanisms for aminoglycosides used in humans. To date, no cross-resistance has been identified between kasugamycin resistance mechanisms and resistance to aminoglycosides used in humans (amikacin, gentamicin, tobramyci n, netilmycin). However, there are no data indicating whether there is cross resistance between human bacterial pathogens carrying aminoglycoside resistance mechanisms and kasu gamycin. The Agency has determined that the screening assay will be critical to future kasugamycin use requests.

A. Proposed Terms of Registration:
EPA proposes to require the registrant to submit a qualitative summary addressing release, exposure, consequence assessments and an overall risk estimation w ith regard to adverse public health effects resulting from the approved pome fruit registration. The summary must be provided on a yearly basis by Dec 31 st and be reflective of use on appl es and pears (as labeled) in all states where kasugamycin is registered a nd used for the growing season prior to Dec 31 st

. Registration for kasugamycin will be time-limited to four years. Given the time needed to establish registration at the state level, the Agen cy expects that a minimum of three years of use information would be available for the qualita tive assessments. This would provide some similarity to the Section 18 use period in Mich igan. The Agency feels that a minimum of three use seasons across varying geographically region s for pome commodities is critical to the
confirmation of current risk determinations and future extended use of kasugamycin. The registration is contingent on the yearly submission of an updated qualitative summary. In the event that adverse effects are detected, the Ag ency may cancel the registration or deny requests to extend the registration. Additionally, as requ ired under FIFRA Section 6(a)(2), the registrant is required to report information concerning unreasonable adverse e ffects, which includes information regarding re sistance detection and mi suse information.

EPA proposes to require the following labeling changes: 1. In review of the submitted residue data, th e PHI must be revised to reflect 90 days for

pome crops.18 2. The following risk mitigations to reduce resistance development, consistent with the Section 18 approvals, must be adde d to the end-use product label:

o Do not apply kasugamycin as the first spra y of the season. Do not apply more than two consecutive applications.

o Do not apply kasugamycin in orchards in which the soil has been fertilized with
animal feces.

o Animal grazing in treated areas is pr ohibited. 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. 3. Resistance management statements on th e end-use product label would be revised to reflect the following information:

o Resistance Management: Kasumin 2L (k asugamycin) 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 preven t infections that ar e proven or strongly suspected to be caused by the indicated ta rget bacteria. To reduce the likelihood of bacteria developing resistance to kasuga mycin, follow the crop specific resistance management and use direction informati on present on this labeling. Use of this product should conform to resistance mana gement practices/strategies established for the crop and use area, (for example th e use of IPM, resistant crop varieties, etc.). Consult your local extension/crop consultant or State agricultural authority if reduced efficacy is suspected.

B. FIFRA Section 3(c)(5) Finding Section 3(c)(5) of FIFRA authorizes the Agency to issu e a registration for a pesticide product containing a new active ingredient if th e Agency determines the following: 1) its composition is such as to warrant the proposed cl aims for it; 2) its labeling and other material required to be submitted comply with the requirem ents of FIFRA; 3) it will perform its intended
function without unreasonable adverse effects on the environment; and 4) when used in accordance with widespread and commonly rec ognized practice it will not generally cause
unreasonable adverse effects on the environment.19 All studies required in accordance with 40 CFR Part 158 data requirements have been submitted and reviewed in support of the new ac tive ingredient kasugamycin. Kasugamycin is expected to play an integral role in the dis ease management programs for fire blight, and the proposed product labeling will comply w ith the requirements of FIFRA.

C. Agency's Proposed Decision The Agency believes, in accordance with FI FRA § 3(c)(5), 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 proposed end-use product will perform its intended function. Under the time-limited registra tion (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 unreasonable adverse effect s on the environment. Therefore, the Agency proposes to register kasugamycin for use on or in pome fruits (c rop group 11-10).