Proposed Registration Decision for Kasugamycin on 

Pome Fruits. 

March 12, 2014 

U.S. Environmental Protection Agency 

Office of Pesticide Programs 

Registration Division 

 

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REGULATORY PROPOSAL

The Agency is proposing 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) under 

the Federal Insecticide, Fungicide and Rodenticide 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 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 Pseudomonas aeruginosa1

. 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 Fruits, 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 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. 

 

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 associated 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 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 lowestobserved-adverse-effect level (LOAEL) of 116 mg/kg/day. Testicular atrophy was also 

observed in the rat two-generation reproduction 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 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 co-critical 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 
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(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 reasonable to surmise that the bolus (gavage) dosing causes 

irritation to the gastrointestinal tract, resulting in maternal toxicity. Although a 

subchronic inhalation toxicity study 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 risk from occupational exposure via the 

inhalation route and is therefore protective of potential inhalation effects. 

5. Cancer: 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 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 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 two-generation 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 twogeneration 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. 
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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 EPA’s efforts to determine which chemicals 

have a common mechanism of toxicity, 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 concern. 

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. 
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1. Short- and Intermediate-Term Handler Exposure and Risk: Occupational handler 

exposures to kasugamycin were estimated assuming 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 postapplication exposure was not assessed due to the lack of toxicity via the dermal route. 

There is no dermal risk associated with post-application activities following application 

of kasugamycin on the proposed crops. The Restricted Entry Interval (REI) is based on 

the acute toxicity of kasugamycin technical material, 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 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 postapplication 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 

exposure resulting from application of pesticides outdoors is likely to result in higher 

exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios. 

 
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II. 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 study, 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. 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 aerobic 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 total system half-life was 105 days. 

Biodegradation studies of kasugamycin parent produced kasugamycinic acid 

under aerobic and anaerobic conditions and kasuganobiosamine under anaerobic 
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conditions. In these studies, the kasuganomycinic acid was present at 3.1% at 180 days 

(the termination of the paddy study) in non-sterile 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 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 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 (Kow) 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 by 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. 

Aquatic 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 
10

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/EC05 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 LD50 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 “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 LC50 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 
11

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 (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 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 single application of 0.084 lbs a.i./A (64 fl. 

oz product/A) rate 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. 

This rate reflects the maximum application rate for pome commodities. 

3. Terrestrial Invertebrates. Kasugamycin is classified as ‘practically nontoxic’ to nontarget 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 definitive 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 available data. Toxicity information for 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 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 
12

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 0.333 lb A.I. /A) and ground based application methods, risks to listed 

monocots should be reduced. 

III. 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 antimicrobial 

resistant food-borne bacteria, which impact human health adversely. The scope is the effect of 

the transmission of bacteria of human health concern through the consumption of food products. 

Antimicrobial drug residues present in or on food may cause adverse effects on the 

ecology of the intestinal microflora of consumers. In consideration of the use pattern for 
13

kasugamycin (application occurring prior to fruit development) and 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 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 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 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 addition, 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 
14

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 being implicated in food poisoning incidents has increased in 

recent years2

. Currently, in the U.S., kasugamycin has only been used as an emergency option 

under Section 18 in the 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 increases the amount of the treated food commodity being 

consumed. Expanded use of kasugamycin and low commodity contamination (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 more different types 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 exposure 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 

 

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 using outbreak data, United States, 1998–2008. Emerg Infect 

Dis [Internet]. 2013 Mar. 
15

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 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 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. As the Section 3 registration request would expand the use of 

kasugamycin; the exposure, selection pressure for resistance and consumption of treated 

commodities would 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 
16

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 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.g., 

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. 

IV. PROPOSED REGULATORY DECISION

 In February 2010, Arysta LifeScience requested 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 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. 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 trials for kasugamycin resistance bacteria, a 

laboratory assay was suggested by CDC during a secondary consultation. The purpose of the 

laboratory screening will be to determine whether 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, tobramycin, netilmycin). However, there are no data 

indicating whether there is cross resistance between human bacterial pathogens carrying 

aminoglycoside resistance mechanisms and kasugamycin. 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 with regard to adverse 

public health effects resulting from the approved pome fruit registration. The summary must be 

provided on a yearly basis by Dec 31st and be reflective of use on apples and pears (as labeled) in 

all states where kasugamycin is registered and used for the growing season prior to Dec 31st

. 

Registration for kasugamycin will be time-limited to four years. Given the time needed to 

establish registration at the state level, the Agency expects that a minimum of three years of use 

information would be available for the qualitative assessments. This would provide some 

similarity to the Section 18 use period in Michigan. The Agency feels that a minimum of three 

use seasons across varying geographically regions 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 Agency may cancel the registration or deny requests 

to extend the registration. Additionally, as required under FIFRA Section 6(a)(2), the registrant 

is required to report information concerning unreasonable adverse effects, which includes 

information regarding resistance detection and misuse information. 

EPA proposes to require the following labeling changes: 

1. In review of the submitted residue data, the PHI must be revised to reflect 90 days for 

pome crops. 
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2. The following risk mitigations to reduce resistance development, consistent with the 

Section 18 approvals, must be added to the end-use product label: 

o Do not apply kasugamycin as the first spray 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 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. 

3. Resistance management statements on the end-use product label would be revised to 

reflect the following information: 

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, 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 issue a registration for a pesticide 

product containing a new active ingredient if the Agency determines the following: 1) its 

composition is such as to warrant the proposed claims for it; 2) its labeling and other material 

required to be submitted comply with the requirements 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 recognized practice it will not generally cause 

unreasonable adverse effects on the environment. 
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All studies required in accordance with 40 CFR Part 158 data requirements have been 

submitted and reviewed in support of the new active ingredient kasugamycin. Kasugamycin is 

expected to play an integral role in the disease management programs for fire blight, and the 

proposed product labeling will comply with the requirements of FIFRA. 

C. Agency's Proposed Decision 

The Agency believes, in accordance with FIFRA § 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 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 unreasonable adverse effects on the environment. Therefore, the Agency 

proposes to register kasugamycin for use on or in pome fruits (crop group 11-10).