Kasugamycin Human Health Risk Assessment DP Barcode D433630

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, DC 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

MEMORANDUM

DATE: 27 Septem her 2017

SUBJECT: Kasugamycin. Human Health Risk Assessment forthe Proposed Section 3 Registration of New Uses of the Antibiotic Fungicide on Cherry Subgroup 12-12A and Walnuts.

DP Barcode: PC Code: 230001 D433630 Registration Number: Decision Number: 513997 66330-404 Regulatory Action: Petition Number: 6E8450 Section 3 Registration (Tolerance Petition) Risk Assessment Type: Single Chemical Aggregate Case Number: 7045 TXR Number: NA CAS Number: 6980-18-3 (19408-46-9, HCI salt) MRID Number: NA 40CF�{\1,_80.6�4 � FROM: Linnea J. Hansen, Biologis��sor cJvv" William T. Drew, Chemist � � Gerad Thornton, Environmental Protection Specialist��--­ Registration Action Branch II Health Effects Division (HED), 7509P

THROUGH: Christina Swartz, Chief Risk Assessment Branch II Health EffectsDivision (HED), 7509P

To: Hope Johnson and Fatima Sow, PM Team 21 Fungicide Branch (FB) Registration Division (RD), 7505P and Tamica Cain Minor Use and Emergency Response Branch (MUERB)/RD, 7505P

Page 1 of 45 Kasugamycin Human Health Risk Assessment DP Barcode D433630

Table of Contents 1.0 Executive Summary ...... 4 2.0 HED Recommendations...... 6 2.1 Data Deficiencies ...... 6 2.2 Tolerance Considerations ...... 6 2.2.1 Enforcement Analytical Method ...... 6 2.2.2 International Harmonization ...... 7 2.2.3 Recommended Tolerances ...... 7 2.2.4 Revisions to Petitioned-for Tolerances ...... 8 2.3 Label Recommendations ...... 8 2.3.1 Recommendations from Residue Reviews ...... 8 2.3.2 Recommendations from Non-Dietary Exposure Reviews ...... 8 3.1 Chemical Identity ...... 8 3.2 Physical/Chemical Properties ...... 9 3.3 Pesticide Use Pattern ...... 9 3.4 Anticipated Exposure Pathways ...... 10 3.5 Consideration of Environmental Justice ...... 10 4.0 Hazard Characterization and Dose-Response Assessment ...... 11 4.1 Toxicology Studies Available for Analysis ...... 11 4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ...... 11 4.2.1 Dermal Absorption...... 12 4.3 Toxicological Effects ...... 12 4.4 Safety Factor for Infants and Children (FQPA Safety Factor)...... 14 4.4.1 Completeness of the Toxicology Database ...... 14 4.4.2 Evidence of Neurotoxicity ...... 14 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ...... 14 4.4.4 Residual Uncertainty in the Exposure Database ...... 14 4.5 Toxicity Endpoint and Point of Departure Selections ...... 15 4.5.1 Dose-Response Assessment ...... 15 4.5.2 ...... Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment ...... 15 5.0 Dietary Exposure/Risk Characterization ...... 16 5.1 Metabolite/Degradate Residue Profile ...... 16 5.1.1 Residues of Concern: Summary of Residue Data and Rationale ...... 16 5.2 Food Residue Profile ...... 18 5.3 Water Residue Profile ...... 19 5.4 Dietary Risk Assessment ...... 20 5.4.1 Description of Residue Data and Percent Crop Treated Used in Dietary Assessment ……………………………………………………………………………………..20 5.4.2 Chronic Dietary Risk Assessment ...... 20 6.0 Residential (Non-Occupational) Exposure/Risk Characterization ...... 21 6.1 Spray Drift ...... 21 7.0 Aggregate Exposure/Risk Characterization ...... 22

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8.0 Cumulative Exposure/Risk Characterization ...... 22 9.0 Occupational Exposure/Risk Characterization ...... 22 9.1 Short- and Intermediate-Term Handler Exposure and Risk ...... 23 9.2.1 Dermal Post-Application Risk ...... 25 9.2.2 Inhalation Post-Application Risk ...... 25 10.0 References ...... 27 Appendix A. Toxicology Requirements and Profile...... 29 A.1 Toxicology Data Requirements ...... 29 A.2 Toxicity Profiles for Kasugamycin ...... 31 Appendix B. Metabolism Summary Tables ...... 41 Appendix C. Physical/Chemical Properties Table ...... 43 Appendix D. International Maximum Residue Limit Status for Kasugamycin...... 44 Appendix E. Review of Human Research ...... 45

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1.0 Executive Summary

The Interregional Research Project Number 4 (IR-4) has submitted a petition for the registration and establishment of permanent Section 3 tolerances for residues of the aminoglycoside fungicide kasugamycin (3-O-[2-amino-4-[(carboxyimino-methyl)amino]-2,3,4,6-tetradeoxy-α-D- arabino -hexopyranosyl]-D-chiro -inositol; CAS #6980-18-3) in or on cherry subgroup 12-12A and walnuts. The Registrant, Arysta LifeScience North America LLC, is proposing to use the currently registered product Kasumin 2L (EPA Registration No. 66330-404), a 2% a.i. liquid formulation. The proposed application rate is 0.084 lb a.i./acre (maximum annual application rate 0.336 lb a.i./acre/year) using ground or aerial application methods.

Kasugamycin is a low-use-rate, wide-spectrum aminoglycoside antibiotic fungicide produced from Streptomyces kasugaensis . Kasugamycin formulations are applied as foliar sprays in agriculture and horticulture. Kasugamycin has preventative, curative and systemic activity at low application rates and controls a range of phytopathogenic organisms in the proposed crops. In the United States, kasugamycin is currently registered for use on pome fruits group 11-10.

The aminoglycoside antibiotic group which also includes streptomycin and gentamicin, inhibits bacterial protein synthesis by binding to the 30S subunit of the bacterial ribosome. Their penetration through the cell membrane of the bacterium depends partly on oxygen-dependent active transport by a polyamine carrier system that seems to be absent in mammalian systems. This risk assessment document does not address the potential impact of the pesticidal use of kasugamycin on antibiotic resistance. Tolerance levels as recommended within this document are presented excluding antibiotic resistance impacts/concerns.

The toxicology database for kasugamycin is complete and adequate to support human health risk assessment. HED’s Hazard and Science Policy Council (HASPOC) determined that a rat subchronic inhalation study is not needed, based on low volatility, lack of residential uses and low inhalation exposure. Metabolism data in the rat indicate low oral absorption. The major effects observed in the toxicity studies were decreased body weights and body weight gains, testicular atrophy, kidney toxicity and irritation to the oral cavity or the anorectal area. There was no evidence of neurotoxicity or immunotoxicity. Kasugamycin exhibits low acute toxicity. Kasugamycin is classified as "not likely to be carcinogenic to humans.”

Kasugamycin shows no evidence of increased qualitative or quantitative susceptibility in the offspring, or in the developing fetus. Based on the hazard and exposure data, HED has recommended that the required Food Quality Protection Act (FQPA) 10X safety factor be reduced to 1X. Therefore, uncertainty factors used in the assessment consist of a 10X factor for interspecies extrapolation, and a 10X factor for intraspecies variability.

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Kasugamycin Human Health Risk Assessment DP Barcode D433630

There were no toxic effects associated with a single dose of kasugamycin; therefore, an acute dietary endpoint was not selected for the general US population, or for any population subgroup. The endpoint for chronic dietary exposure and risk assessment was selected from the rat combined chronic toxicity/carcinogenicity study. The no adverse effect level (NOAEL) of 11.3 mg/kg/day was based on testicular softening and atrophy at the LOAEL of 116 mg/kg/day.

A dermal endpoint was not selected due to lack of an endpoint in the dermal study (i.e., there was no systemic toxicity associated with dermal exposure). For inhalation exposure (short- and intermediate-term), dog subchronic and rabbit developmental toxicity studies were selected as co-critical. In the dog subchronic study, evidence of irritation to the oral cavity was observed at the LOAEL = 106 mg/kg/day (NOAEL = 11 mg/kg/day). The rabbit developmental study was selected as co-critical since the maternal NOAEL (10 mg/kg/day) was comparable and the maternal toxicity may have resulted from irritation.

The residue chemistry database is complete with respect to the existing and proposed uses. The nature of kasugamycin residues in plants and livestock (ruminants) is adequately understood. The residue of concern for tolerance enforcement and risk assessment is the parent compound. No tolerances are needed in livestock commodities based on the proposed uses. The parent kasugamycin and two degradates with similar mobility were recommended for inclusion in the drinking water modeling. Adequate residue data were submitted to support the proposed uses on cherries subgroup 12-12A and walnuts. HED has used conservative assumptions to assess the risk from chronic dietary exposure to kasugamycin through food and drinking water, including the use of recommended tolerance-level residues, modeled drinking water estimates and the assumption that all requested commodities are treated, or 100% crop treated (CT). Tolerance levels are proposed for residues of kasugamycin in cherry subgroup 12-12A at 0.6 ppm, and in walnuts at 0.04 ppm.

Chronic dietary risk estimates for kasugamycin are below HED’s level of concern (LOC) of 100% of the chronic population adjusted dose (cPAD) for all population subgroups. The most highly exposed population subgroup, children 1-2 years old, had a risk estimate of 4.2% cPAD.

There are no existing or proposed residential uses of kasugamycin. Therefore, the only aggregate scenario assessed was chronic aggregate risk, equivalent to chronic dietary risk, which is not of concern.

Occupational handler exposures to kasugamycin were estimated assuming the maximum application rate, and label-recommended equipment and methods, and standard assumptions with respect to the area treated. In the absence of chemical-specific data to assess handlers’ exposure and risk, HED relied on surrogate unit exposure data to estimate exposure and risk. HED assumed a single layer of clothing (baseline), without additional personal protective equipment (PPE). The resulting handler risk estimates, or margins of exposures (MOEs), are all above 100,

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Kasugamycin Human Health Risk Assessment DP Barcode D433630

and are thus below HED’s LOC. Depending on the scenario, MOEs ranged from 58,000 to 6,400,000.

A quantitative occupational post-application inhalation exposure assessment was not performed. However, handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure. The handler assessment for kasugamycin resulted in risk estimates that did not exceed HED’s LOC at baseline inhalation PPE. Therefore, it is expected that handler inhalation exposure estimates would be protective of occupational post-application inhalation exposure scenarios.

Review of human research: This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies (listed in Appendix E) have been determined to require a review of their ethical conduct, have received that review, and have been determined to be ethically conducted.

2.0 HED Recommendations

2.1 Data Deficiencies

None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate analytical methods are available for the purpose of tolerance enforcement.

Plant Methods: An approved tolerance enforcement method for crops is available for kasugamycin using a reverse-phase, ion pairing HPLC/UV method (Morse Laboratories Method #Meth-146, Revision #4) for collecting data and enforcing tolerances for kasugamycin in plant commodities.

Briefly, following a methanol:water (7:3 v:v) extraction of macerated or ground frozen samples, extracts are filtered, combined and concentrated, then filtered through diatomaceous earth to remove precipitates. The filtered concentrate is diluted with water, and purified by two separate ion-exchange columns. The resulting purified extract is concentrated before analysis. The validated limit of quantitation (LOQ) is 0.040 ppm, determined as the lowest level of method validation (LLMV), and the calculated limit of detection (LOD) is 0.013 ppm. Radio-validation is not available, but not required since the proposed enforcement method’s extraction procedure is very similar to that utilized on samples during the metabolism study.

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Kasugamycin Human Health Risk Assessment DP Barcode D433630

Conclusions: The residue analytical method is adequate for tolerance enforcement of kasugamycin residues in plant commodities.

Livestock Methods: There is no expectation of kasugamycin residues in meat, milk, poultry or eggs arising from the proposed or existing uses. Therefore, no livestock commodity methods have been submitted, and none are required for the purposes of this petition.

Conclusions: Based on no expectation of residues, testing of livestock commodities is not required.

Multiresidue Methods

Kasugamycin was analyzed according to the FDA Multi-Residue Method Test guidelines in PAM Volume I (dated January 1994). Kasugamycin was evaluated through Protocol B, and tested through Protocol C. In Protocol C testing, neither the test compound nor its methylation product produced a response on any of the appropriate DG modules; therefore, kasugamycin was not further tested through Protocols B or D through F. Kasugamycin is not an N-methyl carbamate or a substituted urea; therefore, testing under Protocols A and G was not required.

Based on the results of the testing, the multiresidue methods are not appropriate for determining kasugamycin.

2.2.2 International Harmonization

Codex has not established any maximum residue limits (MRLs) for kasugamycin in any commodities. Canada’s Pest Management Regulatory Agency (PMRA) has established MRLs in capulins and cherries (black, Nanking, sweet and tart) at 0.6 mg/kg, and in walnuts (black and English) at 0.04 mg/kg. HED’s recommended tolerances of 0.60 ppm in stone fruit subgroup 12- 12A, and 0.04 ppm in walnuts, are harmonized with PMRA’s MRLs. An International Maximum Residue Limit Status sheet for kasugamycin is appended as Appendix D.

2.2.3 Recommended Tolerances

HED recommends in favor of registration and establishment of tolerances for the use of kasugamycin on cherry subgroup 12-12A and walnuts, as described below.

TABLE 2.2.3 Tolerance Summary for Kasugamycin (40CFR §180.614[a]). Commodity Proposed Recommended Comments; Correct Commodity Tolerance (ppm) Tolerance (ppm) Definition Fruit, stone, subgroup 12-12A 0.6 0.60 Based on submitted cherry field trial data. Walnut 0.04 0.04 Based on submitted walnut field trial data.

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Kasugamycin Human Health Risk Assessment DP Barcode D433630

2.2.4 Revisions to Petitioned-for Tolerances

In cherry subgroup 12-12A, the recommended tolerance level includes an additional significant figure (0.60 ppm rather than the proposed 0.6 ppm). This is in order to avoid the situation where rounding of an observed residue to the level of precision of the tolerance expression would be considered non-violative (such as 0.64 ppm being rounded to 0.6 ppm).

Because HED is recommending a different tolerance for residues in cherry subgroup 12-12A than that proposed by the petitioner, the petitioner should submit a revised Section F of the petition to reflect the tolerance as recommended by HED.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

None

2.3.2 Recommendations from Non-Dietary Exposure Reviews

The general use directions for the product label for Kasumin 2L (EPA File Symbol 66330-UNU) should be amended as stipulated below:

- The label should clarify whether cherries are the only crop for which application via chemigation is not allowed, or whether chemigation is also not allowed for use on other crops. - The label should also clarify whether application via aerial equipment is allowed only for walnuts, or may be used for other crops.

3.0 Introduction 3.1 Chemical Identity

The chemical structure and nomenclature of kasugamycin are presented in Table 3.1 (below).

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Kasugamycin Human Health Risk Assessment DP Barcode D433630

TABLE 3.1 Kasugamycin Nomenclature. NH Chemical Structure NH 2 H3C HO O N H O OH O OH

HO

OH OH [∙HCl ∙H2O]

Empirical Formula C14 H25 N3O9 [C 14 H25 N3O9•HCl•H 2O] Common Name Kasugamycin [Kasugamycin hydrochloride hydrate] Company Experimental Name TM-416 IUPAC Name (Kasugamycin) 1L-1,3,4/2,5,6-1-deoxy-2,3,4,5,6-pentahydroxycyclohexyl-2-amino-2,3,4,6- tetradeoxy-4-(α-iminoglycino)-α-D-arabino-hexopyranoside or [5-amino-2-methyl-6-(2,3,4,5,6-pentahydroxycyclohexyloxy)tetrahydropyran-3- yl]amino-α-iminoacetic acid CAS Name (Kasugamycin) 3-O-[2-amino-4-[(carboxyiminomethyl)amino]-2,3,4,6-tetradeoxy-α-D-arabino- hexopyranosyl]-D-chiro-inositol CAS Registry Number 6980-18-3 [19408-46-9] End-Use Product Kasumin 2L; 0.168 lb ai/gal liquid formulation (EPA Registration #66330-404) Chemical Class Aminoglycoside antibiotic fungicide Known Impurities of Concern None

3.2 Physical/Chemical Properties

Kasugamycin is an aminoglycoside antibiotic that has high stability and water solubility. It has a low vapor pressure (0.013 mPa). Its major routes of degradation in the environment are aqueous photolysis , aerobic biodegradation , and hydrolysis. Kasugamycin and its’ degradates are likely to be mobile in soils, but are not persistent. Based on the available information, there is no indication that kasugamcyin is likely to bioaccumulate. A detailed description of the physicochemical properties of kasugamycin is provided in Table C (see Appendix C). 3.3 Pesticide Use Pattern

A liquid (L) formulation end-use product (EP) containing 2% kasugamycin (by weight) is being petitioned by IR-4 for use as a foliar broadcast spray on cherries subgroup 12-12A and walnuts. The product will be marketed under the trade name Kasumin 2L, and is formulated with kasugamycin hydrochloride hydrate at 2.3% (by weight), which is equivalent to 2% kasugamycin

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Kasugamycin Human Health Risk Assessment DP Barcode D433630

(0.1667 lb ai/gal), the free base. Table 3.3 (below) summarizes the proposed use patterns. It is noted that use on walnuts was previously proposed in 2012 (D376608), but this use was not registered at the time because it was withdrawn by the Registrant.

The personal protective equipment (PPE) requirements require that applicators and other handlers must wear chemical resistant gloves in addition to baseline attire (i.e., long pants, long- sleeved shirt, shoes and socks). For the proposed applications, the end-use product may be applied using handheld (i.e., mechanically-pressurized handgun), aerial, airblast, and chemigation (walnut only) equipment.

Table 3.3. Summary of Directions for Kasugamycin. Formulation Max Max Seasonal Max Number Application Rep. Use Use Directions and [EPA Reg. Application Application of Applications PHI Equipment Site Limitations No.] Rate Rate per Season Walnut and Cherry (crop subgroup 12-12A) Apply in at least Aerial, 0.08 lb 100 gallons of water Airblast, 30 ai/acre for ground Chemigation 1, Liquid Orchard/ (cherry) 0.34 lb ai/acre 4 applications. Apply Mechanically- [66330-404] Vineyard 100 0.0008 lb in at least 20 Pressurized (walnut) ai/gallon gallons for aerial Hangun applications. 1 1. Chemigation is prohibited on cherries. 3.4 Anticipated Exposure Pathways

RD has requested that HED perform an assessment of human health risk to support the IR-4 petition for kasugamycin uses on cherry subgroup 12-12A and walnuts. Humans may be exposed to kasugamycin through consumption of food and drinking water containing kasugamycin residues. In addition, occupational handlers may be exposed via the dermal and inhalation routes when they mix/load and apply the pesticide to growing crops. Bystanders may be exposed unintentionally due to spray drift during application to crops. Finally, workers re- entering treated areas to conduct crop-related activities may be exposed via the dermal route. The current risk assessment considers these potential exposure pathways, in conjunction with the hazard database, and the endpoints and doses selected for risk assessment.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered for this human health risk assessment, in accordance with US Executive Order 12898, Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations (https://www.archives.gov/files/federal-register/executive-orders/pdf/12898.pdf ).

As a part of every pesticide risk assessment, the Office of Pesticide Programs (OPP) considers a large variety of consumer subgroups according to well-established procedures. In line with OPP

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Kasugamycin Human Health Risk Assessment DP Barcode D433630 policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by USDA under the Continuing Survey of Food Intakes by Individuals (CSFII), and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups, and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products, and the associated risk estimates for adult applicators, and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated. Further considerations are currently in development, as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers, as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

There are no further updates to the hazard characterization for kasugamycin since the previous assessment (D376608, 2012). The toxicology database is considered complete at this time.

4.1 Toxicology Studies Available for Analysis

Studies considered for this assessment include acute lethality (oral, dermal and inhalation), eye and dermal irritation, dermal sensitization, subchronic oral toxicity (rat, mouse, dog), rat 21-day dermal toxicity, dog chronic toxicity, rat combined chronic toxicity/carcinogenicity, mouse carcinogenicity, developmental toxicity (rat, rabbit), rat two-generation reproductive toxicity, genotoxicity, rat metabolism, rat acute and subchronic neurotoxicity, and mouse immunotoxicity. The HED HASPOC previously determined that a rat 28-day inhalation study was not needed to assess risk from inhalation exposure to kasugamycin (TXR #0052461).

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Kasugamycin was poorly absorbed and metabolized (<5% of the administered radioactive dose, or AD) in the rat following oral exposure to 100 or 1000 mg/kg/day. The maximum plasma concentration occurred about one hour after the administration of a single low or high dose, with a t 1/2 of 1.17-1.55 hours. Bioavailability, as indicated by the area under the curve (AUC) was proportional to the dose. At 168 hours post-dosing, the majority of the AD was excreted in feces (81.9 to 93.9% AD), with only small amounts in urine (1.26-3.07% AD). Most of the excreted radioactivity was recovered within 48 hours. Biliary excretion was not observed; fecal radioactivity therefore represented unabsorbed kasugamycin. Most of the excreted radioactivity in urine and feces was the un-metabolized parent compound, and metabolism was not affected by dose, duration of dose, or sex. Minor amounts (<1%AD) of the metabolite kasuganobiosamine

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Kasugamycin Human Health Risk Assessment DP Barcode D433630 were identified in the urine, liver, kidney and plasma, but none was detected in the feces.

4.2.1 Dermal Absorption

A dermal absorption study is not available for kasugamycin. However, no systemic effects were observed in the rat 21-day dermal toxicity study at doses causing dermal irritation at the application site.

4.3 Toxicological Effects

Kasugamycin is an aminoglycoside antibiotic pesticide with limited activity against some plant bacterial and fungal pathogens. There are no human or veterinary therapeutic applications due to low efficacy, but at one time was used clinically in Japan to treat Pseudomonas kidney infections in humans (Shuwirth et al (2006) Nat. Struct. Mol. Biol. 13(10):879-886). The mode of action is distinct from other aminoglycosides such as streptomycin, which also has pesticidal uses. Kasugamycin inhibits formation of the 30S ribosomal subunit at initiation of protein synthesis by perturbing the mRNA-tRNA codon/anticodon interaction. Other aminoglycoside antibiotics bind to the 30S ribosomal subunit, but disrupt translation of mRNA at later stages of initiation.

The primary target organs identified for kasugamycin were the testes and kidney. These effects were seen at higher dose levels, generally at the highest dose tested (HDT). In the rat combined chronic toxicity/carcinogenicity study, an increased incidence and severity of testicular tubular atrophy was observed at histopathological evaluations at 6, 12 and 24 months. Testicular degeneration and atrophy were also observed in adult F1 males in the rat reproductive toxicity study at the highest dose. Testicular tubular dilatation and degeneration were observed in the subchronic mouse study at a dose that exceeded the limit dose, but not in the mouse carcinogenicity study, which tested at much lower doses. In the dog chronic toxicity study, testicular inflammation was reported at the high dose, but was not accompanied by atrophic or degenerative changes, and was not considered a treatment-related adverse effect.

Kidney toxicity is often associated with exposure to aminoglycoside antibiotics. In the rat reproductive toxicity study, kidney dilatation and increased incidence of chronic progressive nephropathy were observed in F1 males. In the subchronic rat study, increased incidence of eosinophilic bodies (slight severity) in the renal proximal tubular cells was reported in males at several dose levels. These effects were considered treatment-related but not adverse due to the low severity and lack of associated findings. However, in female rats, increased epithelial cells in the urinary sediment, along with decreased urine pH (also seen in males), was considered evidence of possible kidney toxicity. Slight lipofuscin deposition in the rat combined chronic toxicity/carcinogenicity study was not considered adverse due to the lack of other related findings (this study tested up to the NOAEL of the subchronic study). The rat metabolism study indicated higher levels of radioactivity in the kidneys than other tissues. In the subchronic

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Kasugamycin Human Health Risk Assessment DP Barcode D433630 mouse study, minimal to severe basophilia/hyperplasia in the renal pars recta in females was observed. No renal effects were seen in the mouse carcinogenicity study or in the dog. Kasugamycin caused decreased body weight and/or weight gain in subchronic studies in the rat, mouse and dog. The chronic studies, which tested at lower doses, did not show body weight effects. Decreased body weight was also observed in developmental and reproductive studies in the rat and the range-finding study for the rabbit developmental study. Body weight effects in the mouse immunotoxicity study were observed only at a dose exceeding the limit dose.

Kasugamycin appears to be irritating to the oral and gastrointestinal tract mucosa. Anal lesions and perianal/perigenital staining were observed in the subchronic mouse study. Red and swollen skin around the anal opening, and inflammation and ulceration of the rectum, were noted in male and female rats of both generations in the two-generation reproduction study. In the rat developmental toxicity study, distention of the large intestine with stool in the cecum, and an increased incidence of loose stool, were reported. Similar findings were seen in the rabbit developmental range-finding study among females that died or were sacrificed in extremis. These effects may be related to the acidity (or other irritant property) of the active ingredient, which is primarily excreted unabsorbed and un-metabolized in the feces. In the dog, tongue and mouth lesions were reported at the highest dose tested in the subchronic toxicity study (but not the chronic study, which tested at a lower dose). Systemic effects were not observed in the rat 21-day dermal study at doses up to the limit dose, but local dermal irritation was observed.

The available studies, including rat acute and subchronic neurobehavioral screening studies, did not show evidence of neurotoxicity. A 28-day mouse immunotoxicity study did not show evidence of immune system effects.

There was no evidence of increased quantitative or qualitative susceptibility in rat or rabbit developmental toxicity studies, or in the rat reproductive study. No developmental effects were seen in the rat developmental study up to doses causing maternal toxicity (decreased body weight gain, food consumption, and feed efficiency). No maternal or developmental toxicity was observed in the main rabbit developmental toxicity study, in the dose range-finding study, but maternal weight loss, reduced food consumption during dosing and abortions (GD 18 or later) were observed at higher doses. Fetal weight was decreased at the maternally toxic dose, but could not be evaluated at higher doses due to maternal death and abortions. In the rat reproductive toxicity study, parental toxicity included decreased body weight/weight gain. No offspring toxicity was observed. Reproductive toxicity at the highest dose tested (above the parental LOAEL) included testicular atrophy, decreased fertility and fecundity in the F1 parents for both litters, and an increased pre-coital interval during the F2b litter mating period.

Kasugamycin is classified as “not likely to be carcinogenic to humans,” based on lack of evidence of carcinogenicity in rat and mouse carcinogenicity studies. There was no evidence of genotoxicity.

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Kasugamycin Human Health Risk Assessment DP Barcode D433630

The acute toxicity of kasugamycin is low by all routes (Category III-IV). It is a mild dermal and ocular irritant (Category III), and does not show potential for dermal sensitization.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

HED recommends that the 10X FQPA safety factor for infants and children be reduced to 1X for kasugamycin, based completeness of the database, lack of evidence of increased pre- and/or post-natal susceptibility, lack of evidence of neurotoxicity, a dietary exposure estimate that will not underestimate potential dietary exposure, and lack of residential uses.

4.4.1 Completeness of the Toxicology Database

The database is considered adequate to assess the susceptibility of infants and children to the effects of kasugamycin. Acceptable rat and rabbit developmental toxicity studies, a rat multigeneration reproductive toxicity study, rat acute and subchronic neurotoxicity studies, and a mouse immunotoxicity study are available.

4.4.2 Evidence of Neurotoxicity

Kasugamycin did not show evidence of neurotoxicity in the available studies, including rat acute and subchronic neurotoxicity studies. A developmental neurotoxicity (DNT) study is not required.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There was no evidence of increased quantitative or qualitative pre- and/or postnatal susceptibility in developmental toxicity studies in two species, or the rat two-generation reproductive toxicity study. Abortions and a reduction in fetal body weight in the rabbit developmental toxicity range- finding study were considered secondary to maternal toxicity (weight loss, and decreased food consumption). No toxicity to offspring was observed in the rat reproductive toxicity study.

4.4.4 Residual Uncertainty in the Exposure Database

There is low concern, and no residual uncertainty, for susceptibility for the reasons discussed above. Underestimation of exposure is not anticipated because conservative assumptions (tolerance-level crop residues, and modeled drinking water estimates) were used to estimate risk from dietary exposure, and there are no existing or proposed residential uses.

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4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

There have been no changes to the dose-response assessment, cancer classification or recommendations for combining routes of exposure from the previous assessment (refer to the 2012 assessment). Toxicity endpoints and points of departure (PODs) and cancer classification for human health risk assessment are summarized in Tables 4.5.2.1 and 4.5.2.2.

4.5.2 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

TABLE 4.5.2.1 Summary of Kasugamycin Toxicological Doses and Endpoints for Use in Dietary Human Health Risk Assessments. Exposure Scenario Point of Uncertainty RfD, PAD, LOC Study and Toxicological Effects Departure and FQPA for Risk Safety Factors Assessment Acute dietary (all An appropriate dose and endpoint for this risk assessment scenario was not identified, based populations) on a lack of single-dose effects in the database. Chronic dietary NOAEL = 11 UF A = 10X Chronic RfD = Combined chronic (all populations mg/kg/day UF H = 10X 0.11 mg/kg/day toxicity/carcinogenicity study in the including infants FQPA SF = 1X rat and children, and cPAD = 0.11 females age 13 to mg/kg/day LOAEL = 116 mg/kg/day, based on 49) testicular atrophy and softening. Cancer (oral, Classification: “Not likely to be carcinogenic to humans.” dermal, inhalation) Point of Departure (POD) = a data point or estimated point derived from observed dose-response data, which is used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. HDT = Highest Dose Tested. UF = Uncertainty Factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. NOAEL = No Observed Adverse Effect Level. LOAEL = Lowest Observed Adverse Effect Level. PAD = Population Adjusted Dose (c = chronic). RfD = Reference Dose. LOC = Level of Concern.

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TABLE 4.5.2.2 Summary of Kasugamycin Toxicological Doses and Endpoints for Use in Occupational Human Health Risk Assessments. Exposure Point of Uncertainty RfD, PAD, Study and Toxicological Effects Scenario Departure Factors LOC for Risk Assessment Dermal, short- An appropriate dose and endpoint for these scenarios was not identified. No toxicity was term (1 to 30 observed in the rat 21-day dermal toxicity study, which tested up to doses causing local dermal days) and irritation. intermediate- term (1 to 6 months) Dermal, long- Long-term dermal exposure is not anticipated from the proposed or existing uses. term (>6 months) Inhalation, Oral NOAEL = 11 UF A=10X Occupational Co-critical studies: short-term (1 mg/kg/day* UF H=10X LOC for MOE to 30 days) and ≤100 1. Subchronic oral toxicity in the dog; intermediate- LOAEL = 106 mg/kg/day term (1 to 6 months) 2. Developmental toxicity study in rabbits. Maternal LOAEL = 30 mg/kg/day

Endpoint of concern is irritation (see Section 4.5.1 for details). Inhalation long- Long-term inhalation exposure is not anticipated from the proposed or existing uses. term (>6 months) Cancer (oral, Classification: “Not likely to be carcinogenic to humans.” dermal, inhalation) Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data, which is used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. UF = Uncertainty Factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). NOAEL = No Observed Adverse Effect Level. LOAEL = Lowest Observed Adverse Effect Level. MOE = Margin of Exposure. LOC = Level of Concern. * Toxicity via the inhalation route is assumed to be equivalent to toxicity via the oral route.

5.0 Dietary Exposure/Risk Characterization 5.1 Metabolite/Degradate Residue Profile

5.1.1 Residues of Concern: Summary of Residue Data and Rationale

An updated summary of residue and analytical chemistry has been prepared for kasugamycin (W. Drew, D437251, 22 February 2017). The residue of concern for the proposed and existing uses (for both tolerance setting and risk assessment purposes) is the parent compound,

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Kasugamycin Human Health Risk Assessment DP Barcode D433630 kasugamycin (ROCKS memo, D387527). The residues of concern for dietary risk assessment and the tolerance expression are summarized in Table 5.1.1.1. However, for any future requested uses on leafy, root or grain crops (or other crops dissimilar to tree nuts, fruiting vegetables, or pome fruit), metabolism studies would be required in order to determine the residues of concern in those commodities. The comparative metabolism and environmental degradation of kasugamycin were previously addressed and the nature of residues is understood. Methodology for analysis of residues is adequate. Further information may be found in the 2012 assessment (D376608).

TABLE 5.1.1.1. Summary of Metabolites and Degradates to be Included in Risk Assessments and the Tolerance Expression. Matrix Residues Included in Risk Residues Included in the Assessments Tolerance Expression Plants Primary crop Parent kasugamycin only Parent kasugamycin only Rotational crop Parent kasugamycin only Parent kasugamycin only Livestock Ruminant Parent kasugamycin only Parent kasugamycin only Poultry NA* NA Drinking Water Kasugamycin, kasugamycinic acid, NA and kasuganobiosamine * NA = Not Applicable.

IR-4 has submitted storage stability and crop field trial data for kasugamycin on walnuts and on cherries. For both crops, the maximum label application and seasonal application rates using foliar treatment were applied. The submitted concurrent storage stability data for kasugamycin in walnuts and cherries are adequate to support the submitted crop field trial studies. The data indicate that there are no storage stability issues, and no corrections for decline during storage are needed.

Walnuts: Three field trials on walnuts were conducted in the US, in North American Free Trade Agreement (NAFTA) Growing Zone 1 (CA) during the 2007 growing season. The pre-harvest interval (PHI) arranged from 98 to 110 days. Residue data are summarized below in Table 5.1.1.2:

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TABLE 5.1.1.2 Summary of Residue Data from Walnut Field Trials with Kasugamycin. Crop, Matrix Total Use Rate PHI Residue Levels (ppm) (lb ai/A) (Days) n Min. 1 Max. 1 LAFT 2 HAFT 2 Median 2 Mean 2 SD 2 Walnut, nutmeat 0.335-0.340 98-110 3 <0.040 0.040 <0.040 <0.040 0.040 0.040 0 n = number of independent field trials; LAFT = Lowest Average Field Trial; HAFT = Highest Average Field Trial; SD = Standard Deviation. For computation of the median, mean and standard deviation, values

Cherries: IR-4 and Agriculture and Agri-Food Canada (AAFC) have submitted crop field trial data for kasugamycin on cherries. Thirteen field trials (combined) were conducted in the US and Canada during the 2008-2009 growing seasons in NAFTA Growing Zones 1 (NY; 1 trial, tart), 4 (MI; 4 trials, 2 tart and 2 sweet), 5 (ON; 3 trials, 1 sweet and 2 tart), 9 (CO; 1 trial, tart), 10 (CA; 2 trials, sweet) and 11 (BC; 2 trials, sweet). The PHI ranged from 27 to 33 days, with some trials having additional PHIs of up to 30-40 days to assess residue decline. Residue decline data showed that residues of kasugamycin decrease with increasing PHIs. Table 5.1.1.3 summarizes the residue data from the cherry field trials that were conducted.

TABLE 5.1.1.3 Summary of Residue Data from Cherry Trials with Kasugamycin. Crop, Matrix Total Use PHI Residue Levels (ppm) Rate (lb ai/A) (Days) n Min. 1 Max. 1 LAFT 2 HAFT 2 Median 2 Mean 2 SD 2 Cherry, fruit 0.33-0.35 27-33 13 0.043 0.358 0.043 0.330 0.082 0.128 0.095 n = number of independent field trials; LAFT = Lowest Average Field Trial; HAFT = Highest Average Field Trial; SD = Standard Deviation. For computation of the median, mean and standard deviation, values

Based on the submitted studies, the field trials are adequate and support the use of kasugamycin formulated as an L on walnuts and cherries per the foliar directed use pattern studied.

5.2 Food Residue Profile

The submitted field trial studies (see Section 5.1.1) are adequate for supporting regulatory conclusions, establishing appropriate tolerance levels for enforcement, and for purposes of risk assessment. Analysis of residues can be accomplished through standard analytical techniques, and residues do not show any trends for dissipation during frozen storage. The field trial study results are supported by adequate storage stability data, and the studies were conducted using a method based on the validated analytical enforcement method. For a summary of residue data from crop field trials with kasugamycin on crops evaluated in the previous assessments, refer to the 2012 risk assessment (Table 5.2 in D376608).

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Following foliar applications, if made in accordance with label directions, kasugamycin is rapidly taken up into plant tissue and translocated. In general, kasugamycin residues do not tend to concentrate in processed fractions.

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED) in the drinking water assessment (DWA) memorandum, Drinking Water Assessment for IR-4 Petition for Use of Kasugamycin [EPA Reg. No. 66330-404] on Cherry Subgroup 12-12 and Walnuts (D433631; J. Hetrick; 7 December 2016). The residue values from this assessment were incorporated directly into the dietary exposure assessment.

The Residues of Concern Knowledgebase Subcommittee (ROCKS) determined that parent kasugamycin and two major degradation products, kasuganobiosamine and kasugamycinic acid, are the residues of concern in drinking water (D387527; I. Negrón-Encarnación; 4 May 2011). It was assumed that the toxicity of these two degradates is equivalent to the parent compound, and a Total Toxic Residue (TTR) approach is therefore appropriate. The estimated drinking water concentrations (EDWCs) provided in the memo represented the total toxic residues of kasugamycin plus its major degradation products, kasuganobiosamine and kasugamycinic acid. These EDWCs were incorporated into the DEEM-FCID model in the food categories “water, direct, all sources” and “water, indirect, all sources.”

The proposed new uses of kasugamycin on walnuts and cherries were evaluated using the Pesticide Root Zone Model for ground water (PRZM-GW). This model and its description are available at the EPA internet site at https://archive.epa.gov/oppefed1/web/pdf/wqtt_przm_gw_guidance.pdf . No surface or groundwater monitoring data were available for kasugamycin.

Based on the results of the PRZM-GW modelling, EFED recommended that the long-term average (chronic) concentration of 0.04171 ppm be used to represent kasugamycin TTR concentrations in the chronic dietary risk assessment. The peak concentration was not used for assessment of drinking water exposure because an acute dietary endpoint was not identified. Tier 1 drinking water concentrations are presented below in Table 5.3:

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Table 5.3. PRZM-GW Tier I drinking water concentrations (EDWCs) for the proposed kasugamycin uses. Crop Maximum Total Minimum 1st Application or Application (season Application Scenario Application Method Concentration Crop Rate or Interval date (State crop) (µg/L) Group crop) (mn-day) 1 lb Scenario Breakthrough lb a.i./acre (days) a.i./acre Peak Concentration DelmarvaMD Ground 33.30 28.78 Cherry FLpotato Ground 2.79 2.00 0.084 0.336 7 4-15 Walnut FLcitrus Ground 34.78 29.65 GApeanuts Ground 9.72 8.83 WIcorn Ground 49.97 41.71

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data and Percent Crop Treated Used in Dietary Assessment

An updated unrefined chronic aggregate dietary (food and drinking water) exposure and risk assessment was conducted for kasugamycin (D437252; W.T. Drew; 22 February 2017) using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID™), Version 2.03. This model uses food consumption data from the US Department of Agriculture’s (USDA’s) Continuing Surveys of Food Intakes by Individuals (CSFII), collected from 1994 to 1996, and 1998.

The residue inputs into the dietary model were the recommended tolerance level residues; default processing factors were used, with the exception of the apple juice processing factor, for which the 1.5X data-derived factor was used. The dietary exposure assessment is based on the assumption of 100% CT for all crops with proposed uses on the kasugamycin label.

5.4.2 Chronic Dietary Risk Assessment

Based on these highly conservative assumptions, chronic dietary risk estimates are less than or equal to 4.2% of the cPAD for all population subgroups. Children 1-2 years of age are the most highly exposed population subgroup, with a risk estimate of 4.2% of the cPAD, while the general US population had a risk estimate of 1.3% of the cPAD. Generally, HED is concerned when risk estimates exceed 100% of the PAD; therefore, all chronic dietary risk estimates are not of concern (see Table 5.4.2).

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TABLE 5.4.2. Summary of Chronic Dietary Exposure and Risk Estimates for Kasugamycin. Population Subgroup* cPAD (mg/kg/day) Dietary Exposure Estimate % cPAD [Years of Age] (mg/kg/day) General US Population 0.1 1 0.001389 1.3 All Infants [< 1] 0.11 0.004105 3.7 Children [1-2] 0.11 0.004665 4.2 Children [3-5] 0.11 0.003088 2.8 Children [6-12] 0.11 0.001611 1.5 Youth [13-19] 0.11 0.000994 <1.0 Adults [20-49] 0.11 0.001149 1.0 Adults [50-99] 0.11 0.001115 1.0 Females [13-49] 0.11 0.001153 1.0 * Values for the population subgroup with the highest risk are in bold type.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed residential uses for kasugamycin associated with the subject petition, nor any currently registered residential uses; it is not intended for use in public or residential settings. Therefore, residential exposure is not expected and residential risks are not of concern. 6.1 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., aerial and airblast) employed for kasugamycin . The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency’s Spray Drift website for more information). 1 The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the registration review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non- occupational exposure to drift.

1 Available: http://www2.epa.gov/reducing-pesticide-drift

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7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED 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 (see Table 5.4.3).

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA 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 https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/pesticide- cumulative-risk-assessment-framework.

9.0 Occupational Exposure/Risk Characterization

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. An occupational exposure assessment for kasugamycin (S. Wang, 6/26/12, D376591) was previously conducted for the 2012 human health risk assessment for proposed new uses on fruiting vegetables, pome fruits and walnuts (D376608). The 2012 risk assessment included uses on pome fruits and walnuts using ground equipment at the same application rate as proposed in the current action, with no risks of concern identified. Furthermore, walnut and pome fruit (crop group 11-10) are protective for any similar uses on other orchard/vineyard crops (i.e., cherry crop subgroup 12-12A). Therefore, an updated comprehensive occupational handler assessment for these applications is not required for the proposed new uses in this action. An updated occupational exposure and risk assessment has been conducted for kasugamycin (G. Thornton, D437237 dated February 22, 2017) to provide additional exposure and risk estimate scenarios, based on the IR-4 proposed uses of kasugamycin on walnut and cherry that were not applicable at the time of the previous exposure assessment (i.e., aerial, chemigation and mechanically-pressurized handgun application).

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9.1 Short- and Intermediate-Term Handler Exposure and 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, HED considered the potential for post-application exposure for those re- entering treated sites.

Previous exposure assessment: In the previous risk assessment of kasugamycin, the following handler scenarios, expected to result in the highest exposure for the proposed application scenarios, were assessed:

• Mixing/loading liquids for aerial, air-blast application; • Applying sprays using air-blast equipment, • Mixing/loading/applying sprays using a manually pressurized handwand.

For ground application methods, no risks of concern were identified for any exposure scenario, with MOEs ranging from 58,000 to 1,300,000 (see Table 9.1, D376608).

Updated exposure assessment: The updated quantitative exposure/risk assessment developed for occupational handlers is based on the following additional scenarios:

• Mixing/loading liquids for aerial and chemigation application on orchard/vineyards; • Applying sprays via aerial application on orchard/vineyards; • Flagging for aerial application on orchard/vineyards; and • Mixing/loading/applying liquids via mechanically-pressurized handgun to orchard/vineyards.

Occupational Handler Data and Assumptions: Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include PHED 1.1 and the AHETF database. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 2”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 3.

Based on the anticipated use patterns and current labeling, types of equipment and techniques

2 Available: http://www2.epa.gov/sites/production/files/2015-09/documents/handler-exposure-table-2015.pdf 3 Available: http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handler- exposure-data

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Kasugamycin Human Health Risk Assessment DP Barcode D433630 that can potentially be used, occupational handler exposure is expected from the proposed uses. No data on the number of exposure days per year was provided. For this risk assessment, HED assumed that most handlers would be exposed for less than 6 months (short-term and intermediate-term exposure). However, since the short- and intermediate-term toxicological endpoints are the same, only short-term exposure was quantitatively assessed, and the risk estimate is considered protective of potential intermediate-term exposure.

Based on HED’s Exposure Science Advisory Council (ExpoSAC) Policy #9.1, the following assumptions were used for acres treated per day:

1. 40 acres/day for air blast applications, 2. 350 acres for airblast applications on orchard/vineyards 3. 1000 gallons for mechanically-pressurized handgun application on orchard/vineyards.

The handler exposure estimates in this assessment are based on a central tendency estimate of unit exposure, and an upper-percentile assumption for the application rate. The uncertainties associated with this assessment stem from the use of surrogate exposure data (such as differences in use scenario, and data confidence), and assumptions regarding the amount of chemical handled. The estimated exposures are believed to be reasonable high-end estimates, based on observations from field studies, and professional judgment.

In the updated exposure assessment, all MOEs for handlers using aerial or mechanically pressurized handgun applications are greater than 100 (ranging from 89,000 to 6,400,000), and are not of concern. The exposure and risk estimates for occupational handlers using kasugamycin are presented in Table 9.1.

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Table 9.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Kasugamycin. Maximum Inhalation Application Application Area Unit Inhalation Formulation Representative Use Site Equipment Rate 1 Treated 2 Exposure (lb ai/A) (μg/lb ai) 3 MOE 4 Mixer/Loader Aerial 140,000 Liquid Orchard/Vineyard 0.08 350 acres 0.219 [No R] Chemigation 140,000 Applicator Spray Aerial Orchard/Vineyard 0.08 350 acres 0.0049 [EC] 6,400,000 Flagger Spray Aerial Orchard/Vineyard 0.08 350 acres 0.35 [No R] 89,000 Mixer/Loader/Applicator Mechanically- 0.008 lb 1000 Liquid pressurized Orchard/Vineyard 8.68 [No R] 130,000 ai/gallon gallons Handgun 1 Based on proposed label (Reg. No. 66330-404). 2 Exposure Science Advisory Council Policy #9.1. 3 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September 2015); Level of mitigation: No respirator (No R) and Eng. Controls (EC). 4 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Inhalation Dose = Inhalation Unit Exposure ( μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/acre) × Area Treated (A) ÷ BW (80 kg).

9.2 Short- and Intermediate-Term Post-Application Exposure and Risk

9.2.1 Dermal Post-Application Risk

Dermal post-application 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 kasugamcyin on the proposed crops.

Restricted Entry Interval (REI): Kasugamycin is classified as Toxicity Category III for acute dermal toxicity, as well acute eye and acute dermal irritation. It is not a skin sensitizer. Under 40 CFR 156.208 (c) (2), a.i.’s classified as Acute III for acute dermal, eye irritation, or primary skin irritation are assigned a 12-hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post- application exposures to kasugamycin. An REI of 12 hours is listed on the end-use product label, and is adequate to protect against post-application exposure.

9.2.2 Inhalation Post-Application Risk

There are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on 2 March 2010

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(http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0687-0037 ).

In addition, the Agency is continuing to evaluate the available post-application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency’s risk assessments.

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 HED’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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10.0 References

Risk Assessment Memorandum

Kasugamycin. Human Health Risk Assessment for the Proposed Use of the Fungicide on Fruiting Vegetables, Pome Fruits, and Walnuts; D376608; W.T. Drew; 13 July 2012.

Kasugamycin. Human Health Risk Assessment for Proposed Food Uses of the Fungicide Kasugamycin on Imported Fruiting Vegetables (Group 8) ; D301735; W.T. Drew; 17 August 2005.

Residue Chemistry Summary Document Memorandum

Kasugamycin. Petition Proposing the Establishment of Permanent Tolerances and Section 3 Registration for New Uses of the Antibiotic Fungicide on Cherry Subgroup 12-12A and Walnuts. Summary of Analytical Chemistry and Residue Data; D437251; W.T. Drew; 22 February 2017.

Kasugamycin. Petition to Establish Permanent Tolerances for Residues of the Fungicide Resulting from Food Use on Fruiting Vegetables, Pome Fruit, and Walnuts (PP#0F7689). Summary of Analytical Chemistry and Residue Data ; D376563; W.T. Drew; 13 July 2012.

Occupational and Residential Exposure Assessment Memorandum

Kasugamycin. Occupational and Residential Exposure Assessment for IR-4 Proposed New Uses on Walnut and Cherry (crop subgroup 12-12A). D437237; G. Thornton; 22 February 2017.

Kasugamycin: Occupational and Residential Exposure/Risk Assessment for Section 3 Registration on Pome Fruit, Walnuts, and on Fruiting Vegetables ; D376591; S.C. Wang; 26 June 2012.

Dietary Exposure Memorandum

Kasugamycin. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration of New Uses of the Antibiotic Fungicide on Cherry Subgroup 12-12A and Walnuts ; D437252; W.T. Drew; 22 February 2017.

Kasugamycin. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action Associated with Food/Feed Use of the Fungicide on Fruiting Vegetables, Pome Fruit, and Walnuts (PP#0F7689).; D390458; W.T. Drew; 13 July 2012.

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Drinking Water Assessment Memorandum

Drinking Water Assessment for IR-4 Petition for Use of Kasugamycin [EPA Reg. No. 66330- 404] on Cherry Subgroup 12-12A and Walnuts; D433631; J. Hetrick; 7 December 2016.

Drinking Water Assessment for Tolerance Petition for New Chemical Kasugamycin [EPA Est No. 075703-JPN-001] ; D376600; T. Dowen, J. Hetrick, Dana Spatz; 28 April 2011.

ROCKS Decision Memorandum

Kasugamycin. Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS) ; D387527; I. Negrón-Encarnación; 4 May 2011.

HASPOC Decision Memo

Kasugamycin: Summary of Hazard and Science Policy Council (HASPOC) Meeting of March 15, 2012: Recommendation on the need for a 28-day inhalation study ; J. Van Alstine; June 14, 2012; TXR #0052461.

ToxSAC Decision Memo

Kasugamycin – Summary of Toxicology Science Advisory Council (ToxSAC) Meeting of May 10, 2012. J. Kidwell; 7 June 2012.

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Appendix A. Toxicology Requirements and Profile

A.1 Toxicology Data Requirements

The requirements (40CFR §158.340) for food use of kasugamycin are shown in Table A.1, below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

TABLE A.1 Toxicology Data Requirements for Kasugamycin, Technical. Test Required Satisfied 870.1100 Acute Oral Toxicity ...... yes yes 1 870.1200 Acute Dermal Toxicity ...... yes yes 1 870.1300 Acute Inhalation Toxicity ...... yes yes 870.2400 Primary Eye Irritation ...... yes yes 870.2500 Primary Dermal Irritation ...... yes yes 870.2600 Dermal Sensitization ...... yes yes 870.3100 Oral Subchronic (rodent) ...... yes yes 870.3150 Oral Subchronic (nonrodent) ...... yes yes 870.3200 21-Day Dermal ...... yes yes 870.3250 90-Day Dermal ...... no -- 870.3465 28-Day Inhalation ...... no 2 -- 870.3700a Developmental Toxicity (rodent) ...... yes yes 870.3700b Developmental Toxicity (nonrodent) ...... yes yes 870.3800 Reproduction ...... yes yes 870.4100a Chronic Toxicity (rodent) ...... yes yes 3 870.4100b Chronic Toxicity (nonrodent) ...... yes yes 3 870.4200a Oncogenicity (rat) ...... yes yes 870.4200b Oncogenicity (mouse) ...... yes yes 870.4300 Chronic/Oncogenicity ...... yes yes 870.5100 Mutagenicity—Gene Mutation - bacterial ...... yes yes 870.5300 Mutagenicity—Gene Mutation - mammalian ...... yes yes 870.5375 Mutagenicity—Structural Chromosomal Aberrations . yes yes 870.5550 Mutagenicity—Other Genotoxic Effects ...... yes yes 870.6100a Acute Delayed Neurotoxicity (hen) ...... no -- 870.6100b 90-Day Neurotoxicity (hen) ...... no -- 870.6200a Acute Neurotoxicity Screening Battery (rat) ...... yes yes 870.6200b 90-Day Neurotoxicity Screening Battery (rat) ...... yes yes 870.6300 Develop. Neurotoxicity ...... no --

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TABLE A.1 Toxicology Data Requirements for Kasugamycin, Technical. Test Required Satisfied 870.7485 General Metabolism ...... yes yes 870.7600 Dermal Penetration ...... no no 870.7800 Immunotoxicity Series...... yes yes Special Studies for Ocular Effects Acute Oral (rat) ...... no -- Subchronic Oral (rat) ...... no -- Six-month Oral (dog) ...... no -- 1. Test material purity for the material used in these studies not provided in report, but was reported in a different study. 2. Study waived by HED, based on low acute toxicity, exposure potential, and high MOEs (HASPOC memo, TXR #0052461). 3. Satisfied by OCSPP Toxicity Test Guideline 870.4300.

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Kasugamycin Human Health Risk Assessment DP Barcode No. D433630

A.2 Toxicity Profiles for Kasugamycin

TABLE A.2.1 Acute Toxicity Profile for Kasugamycin Technical Product. Test Material 1 Guideline Study Type MRID Results Toxicity [% ai] Number Number Category Technical 870.1100 Acute oral - rat 45910012 LD50 ( ♂+♀) > 5000 mg/kg IV 2 product [81] Technical 870.1200 Acute dermal-rat 47945757 LD50 ( ♂+♀) > 2000 mg/kg III 2 product [81] Technical 870.1300 Acute inhalation - rat 47945758 LC50 ( ♂+♀) > 4.892 mg/L IV product [84.8] Technical 870.2400 Acute eye irritation - 47945759 Mild eye irritant (iritis at 1 III product [84.8] rabbit hour, resolving by 24 hours; conjunctivitis at 1 hour, resolving by 24 hours). Technical 870.2500 Acute dermal 47945760 Not irritating to the skin. III product [84.8] irritation - rabbit Technical 870.2600 Skin sensitization - 47945761 Not a sensitizer under the Not product [84.8] guinea pig conditions of this study. applicable. 1. Technical product Lot #KP-913 contains 81%, and Lot #KP-459 contains 84.8% kasugamycin hydrochloride hydrate. Not adjusted for the free acid. 2. Studies considered “supplementary/upgradable” due to lack of information on purity and characterization of test material. However, a stated purity of 81% for kasugamycin technical product Lot #KP-913 was located in other studies.

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Kasugamycin Human Health Risk Assessment DP Barcode No. D433630

TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Kasugamycin. Guideline Study Type/ MRID Doses Results Number Classification Number 870.3100 90-Day oral toxicity 45910020 0, 300, 1000, 3000, 6000 NOAEL = 176.7/201.0 mg/kg/day rodents - rat ppm (M/F) LOAEL = 354.8/395.5 mg/kg/day Acceptable/guideline M: 0, 17.5, 58.2, 176.7, (M/F) based on decreased body 354.8 mg/kg/day weights and body weight gains and F: 0, 20.3, 69.2, 201.0, kidney effects in females (increased 395.5 mg/kg/day urinary pH and epithelial cells in urine). Slight lipofuscin deposition in the proximal tubule cells were observed at ≥1000 ppm in males but were not considered adverse). 870.3100 90-Day oral toxicity 45910019 0, 300, 1000, 3000, 10000 NOAEL = 135.4/170.9 mg/kg/day rodents - mouse ppm (M/F) LOAEL = 408.5/565.6 mg/kg/day Acceptable/guideline M: 0, 41.2, 135.4, 408.5, (M/F) based on increased mortality 1559 mg/kg/day and anal lesions (M&F), and kidney F: 0, 58.0, 170.9, 565.6, lesions (F). 1834 mg/kg/day At 1559/1834 mg/kg/day (M/F), decreased body weights and body weight gains (M&F), testicular tubular dilatation and degeneration, perianal/perigenital staining (F), and extramedullary hematopoiesis of the spleen (M) were seen. 870.3150 90-Day oral toxicity 46030302 0, 300, 3000, NOAEL = 10.6/11.4 mg/kg/day in nonrodents - dog 6000/0/4500* ppm (M/F) LOAEL = 106.0/107.9 mg/kg/day Acceptable/guideline M: 0, 10.6, 106.0, 182 (M/F) based on tongue lesions, few mg/kg/day feces, swollen mouth, excessive F: 0, 11.4, 107.9, 179 salivation, and thickened skin at the mg/kg/day commissure of the mouth.

* The high-dose group At 182/170 mg/kg/day (M/F), was exposed to 6000 ppm decreased body weights, body on weeks 1-5, control diet weight gains, and food consumption on weeks 6-8, and 4500 were seen. ppm on weeks 8-13.

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Kasugamycin Human Health Risk Assessment DP Barcode No. D433630

TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Kasugamycin. Guideline Study Type/ MRID Doses Results Number Classification Number 870.3200 21-Day dermal 47945762 M: 0, 50, 250 or 500 Systemic toxicity – rat mg/kg/day NOAEL ≥ 500 mg/kg/day (M), ≥ F: 0, 50, 250/100 or 500/200 mg/kg/day (F). Acceptable/guideline 500/200 mg/kg/day, LOAEL - not determined. No applied to the shaved effects observed at the highest dose skin; highest two dose tested. levels were decreased beginning on Day 8. Dermal NOAEL = 250 mg/kg/day (M), 250/100 mg/kg/day (F). LOAEL = 500 mg/kg/day (M), 500/200 mg/kg/day (F), based on erythema, edema, eschar, ulceration, scabbing; microscopic findings of acanthosis, inflammation, and ulceration. 870.3250 90-Day dermal Not required. toxicity 870.3465 90-Day inhalation Not required. toxicity 870.3700 Pre-natal 45910022 0, 40, 200, 1000 Maternal developmental in mg/kg/day NOAEL = 200 mg/kg/day rodents - rat LOAEL = 1000 mg/kg/day based on decreased body weights, Acceptable/guideline body weight gains, and food consumption; increased incidence of loose stool; distention of the large intestine with stool in the cecum.

Developmental NOAEL = 1000 mg/kg/day LOAEL = >1000 mg/kg/day

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Kasugamycin Human Health Risk Assessment DP Barcode No. D433630

TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Kasugamycin. Guideline Study Type/ MRID Doses Results Number Classification Number 870.3700 Pre-natal 46030303 0, 1, 3, 10 mg/kg/day Maternal developmental in (main (Main study) NOAEL = 10 mg/kg/day nonrodents - rabbit study) LOAEL = 30 mg/kg/day, based on 46428701 Range finding study: the range-finding study results of Acceptable/guideline (range- maternal weight loss and decreased finding 0, 10, 30, 100 mg/kg/day food consumption during treatment , study) abortion (1/4) on GD 22. Initial range finding study 0, 250, 500, 1000 – all At 100 mg/kg/day – weight loss, doses of kasugamycin abortions in 3 of 4 females, GD 18- resulted in severe 27. maternal toxicity and Developmental euthanasia. NOAEL = 10 mg/kg/day LOAEL = 30 mg/kg/day (range- finding study) based on decreased mean fetal body weight

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Kasugamycin Human Health Risk Assessment DP Barcode No. D433630

TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Kasugamycin. Guideline Study Type/ MRID Doses Results Number Classification Number 870.3800 Reproduction and 45910023 0, 200, 1000, 6000 ppm Parental/Systemic fertility effects - rat NOAEL = 70.3/82.9 mg/kg/day M: 0, 13.7, 70.3, 425.3 (M/F) Acceptable/guideline mg/kg/day LOAEL = 425.3/503.4 mg/kg/day F: 0, 16.2, 82.9, 503.4 (M/F), based on decreased body mg/kg/day weights and body weight gains in P males, and red and swollen skin around the anal opening (M&F) (P and F1 animals).

Reproductive NOAEL = 70.3/82.9 mg/kg/day (M/F) LOAEL = 425.3/503.4 mg/kg/day (M/F) based on testicular atrophy/degeneration in F1 males, decreased fertility and fecundity in the F1 parents for both litters and increased pre-coital interval during the mating period for the F2 litter.

Offspring NOAEL = 425.3/503.4 mg/kg/day (M/F) LOAEL = >425.3/503.4 mg/kg/day (M/F) 870.4100 Chronic toxicity - See 870.4300. This study includes rodents requirements of both 870.4100 and 870.4200. 870.4100 Chronic toxicity - 46185901 0, 300, 1000, 3000 ppm NOAEL = 99.6/103.6 mg/kg/day dog (M/F) M: 0, 10.5, 30.5, 99.6 LOAEL = >99.6/103.6 mg/kg/day Acceptable/guideline mg/kg/day (M/F) F: 0, 9.4, 33.4, 103.6 mg/kg/day 870.4200 Carcinogenicity - rat See 870.4300. This study includes requirements of both 870.4100 and 870.4200.

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Kasugamycin Human Health Risk Assessment DP Barcode No. D433630

TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Kasugamycin. Guideline Study Type/ MRID Doses Results Number Classification Number 870.4200 Carcinogenicity - 46030304 0, 50, 300, 1500 ppm NOAEL = 186.3/215.2 mg/kg/day mouse (M/F) M: 0, 5.93, 34.94, 186.3 LOAEL = >186.3/215.2 mg/kg/day Acceptable/guideline mg/kg/day (M/F) F: 0, 7.25, 42.29, 215.2 mg/kg/day No evidence of carcinogenicity 870.4300 Combined chronic 45910024 0, 30, 300, 3000 ppm NOAEL = 11.3/140 mg/kg/day toxicity/ (M/F) carcinogenicity - rat M: 0, 1.1, 11.3, 116 LOAEL = 116/>140 mg/kg/day mg/kg/day (M/F) based on increased testicular Acceptable/guideline F: 0, 1.4, 13.4, 140 softening and atrophy in males. mg/kg/day No evidence of carcinogenicity 870.5100 Gene mutation - 45910028 0, 5, 10, 50, 100, 500 No mutagenic activity in bacteria bacterial reverse µg/plate, with or without (Salmonella typhimurium and mutation assay S9 activation for Escherichia coli ) under conditions of Salmonella typhimurium this assay. Unacceptable/ strain G46 (his -). upgradable Not tested up to the limit dose, no 0, 5, 10, 50, 100, 200 indication of cytotoxicity, and no µg/plate, with or without defined limit of solubility. S9 activation for all other strains tested. 870.5100 Gene mutation - 47945764 0, 1.5, 5.0, 15, 50, 150, No mutagenic activity in bacteria bacterial reverse 500, 1500 or 5000 (Salmonella typhimurium and mutation assay µg/plate, in the presence Escherichia coli ) under conditions of or absence of S9 this assay. Acceptable/guideline activation for Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537, and for Escherichia coli strain WP2 uvrA. 870.5300 Cytogenetics - in 45910026 0, 0.5, 1, 2, 4, 6, 8, 10 No increase in mutant frequency at vitro mammalian cell mg/ml the HGPRT locus, in the presence or gene mutation test absence of S9 activation. (CHO Cells)

Acceptable/guideline

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Kasugamycin Human Health Risk Assessment DP Barcode No. D433630

TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Kasugamycin. Guideline Study Type/ MRID Doses Results Number Classification Number 870.5375 Cytogenetics - in 45910025 0, 1, 2, 3, 4, 5 mg/ml No increase in mutant frequency, in vitro mammalian cell the presence or absence of S9 chromosome activation. aberration test (CHO Cells) The time from treatment to cell harvest was insufficient. Unacceptable/not upgradable 870.5375 Cytogenetics - in 47945765 0, 1085, 2170 or 4340 No increase in mutant frequency, in vitro mammalian cell µg/ml, with or without S9 the presence or absence of S9 chromosome activation. activation. aberration test (CHO cells)

Acceptable/guideline 870.5395 Cytogenetics - 46030305 0, 200, 1000, 5000 No evidence of induced mammalian mg/kg, with or without S9 chromosomal damage or other erythrocyte activation. damage leading to micronucleus micronucleus test, formation. mice

Acceptable/guideline 870.5550 Other effects - 45910027 First assay: 0-2.5 mg/ml No evidence that unscheduled DNA unscheduled DNA Second assay: 0-10 synthesis was induced. synthesis in cultured mg/ml mammalian cells, Third assay: 0-10 mg/ml, HeLa S3 cells both assays with or without S9 activation. Acceptable/guideline 870.6200a Acute neurotoxicity 47945766 0, 500, 1000 or 2000 NOAEL = 2000 mg/kg screening battery - mg/kg by gavage LOAEL not determined. No rat systemic or neurotoxic effects were (dose range-finding observed at the highest dose tested. study)

Acceptable /nonguideline (range- finding study)

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Kasugamycin Human Health Risk Assessment DP Barcode No. D433630

TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Kasugamycin. Guideline Study Type/ MRID Doses Results Number Classification Number 870.6200a Acute neurotoxicity 47945767 0, 500, 1000 or 2000 NOAEL = 2000 mg/kg screening battery - mg/kg by gavage LOAEL not determined. No rat systemic or neurotoxic effects were observed at the highest dose tested. Acceptable/guideline 870.6200b 90-day neurotoxicity 47945768 0, 300, 3000 or 6000 ppm Systemic screening battery - in the diet NOAEL = 210/238 mg/kg/day rat (M/F) M: 0, 21, 210 or 439 LOAEL = 439/486 mg/kg/day Acceptable/guideline mg/kg/day, males; (M/F), based on decreased body F: 0, 23, 238 or 486 weight and body weight gain. mg/kg/day, females Neurotoxicity NOAEL ≥ 439/486 mg/kg/day. LOAEL not determined. No neurotoxic effects were observed at the highest dose tested.

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Kasugamycin Human Health Risk Assessment DP Barcode No. D433630

TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Kasugamycin. Guideline Study Type/ MRID Doses Results Number Classification Number 870.7485 Metabolism and 46030306 (1) 100 mg/kg The mean radioactivity recovery 168 pharmacokinetics - radiolabeled, single dose hours after exposure ranged between rat by oral gavage. 90.6-96.7%, with the majority of the dose recovered within 48 hours in Acceptable/guideline (2) 100 mg/kg unlabeled, the feces (81.9-93.9%) and urine 14 days in the diet, PLUS (1.26-3.07%). The maximum 100 mg/kg radiolabeled, concentration found in the plasma of single dose by oral both males and females occurred gavage. approximately one hour after the administration of a single low or (3) 1000 mg/kg high dose. Between one and six radiolabeled, single dose hours after a single low or high dose, by oral gavage. more kasugamycin accumulated in the kidneys, urinary bladder, and (4) 1000 mg/kg lymph nodes than in the blood, but unlabeled, 14 days in the after 168 hours, little or no diet, PLUS 1000 mg/kg kasugamycin was found in these radiolabeled, single dose tissues. The absorption and by oral gavage. metabolism of kasugamycin in rats was limited (<5% dose) and was not affected by sex, dose level, or duration of dosing. Parent compound was the major component identified in the urine, feces, liver, kidney, and plasma. Minor amounts (<1% dose) of the metabolite kasuganobiosamine were identified in urine, liver, kidney, and plasma, but none was detected in the feces. Elimination occurred primarily in the feces (87.7-94.5%); however, kasugamycin was not excreted in the bile (enterohepatic circulation did not occur).

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Kasugamycin Human Health Risk Assessment DP Barcode No. D433630

TABLE A.2.2 Subchronic, Chronic and Other Toxicity Profile for Kasugamycin. Guideline Study Type/ MRID Doses Results Number Classification Number 870.7800 Immunotoxicity - 48132601 0, 300, 3000 or Systemic female mice 10,000/7000 ppm in the NOAEL = 755/691 mg/kg/day (AFC diet for 28 days group/NK group) Acceptable/guideline LOAEL = 2468/2531 mg/kg/day AFC group: 0, 70, 755 (AFC group/NK group), based on or 2468 mg/kg/day; clinical observations, decreased NK group: 0, 68, 691 or mean body weights and decreased 2531 mg/kg/day (high hematological parameters. dose reduced to 7000 ppm on Day 16) Immunotoxicity NOAEL ≥ 2468/2531 mg/kg/day (AFC group/NK group) LOAEL not determined. A significant decrease (p ≤0.05) in Total Spleen Activity (AFC/spleen) was only observed at a dose causing excessive toxicity (HDT) and that exceeded the limit dose.

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Kasugamycin Human Health Risk Assessment DP Barcode No. D433630

Appendix B. Metabolism Summary Tables

TABLE B.1 Chemical Names and Structures of Compounds Detected in the Rat and Tomato Metabolism Studies. Common Name [Code] Chemical Name Chemical Structure % Total Radioactive Residues NH Kasugamycin, 3-O-[2-amino-4- NH H C 2 [(carboxyimino- 3 Parent Compound [TM-416] HO O methyl)amino]-2,3,4,6- N Rat tetradeoxy-α-D-arabino - H O Essentially 100% TRR hexopyranosyl]-D-chiro - OH Tomato (Fruit) inositol O OH 90-94% TRR (2-hour, 1-day) 69% TRR (7-day) HO 55-60% TRR (14-, 21-, 28-day) OH Tomato (Foliage) OH 75-84% TRR (2-hour, 1-day) 70% TRR (7-day) 52-57% TRR (14-, 21-, 28-day)

O Kasugamycinic acid N-[5-amino-2-methyl-6- NH 2 H3C [KA-2] (2,3,4,5,6-pentahydroxy- HO O cyclohexyloxy)-tetrahydro- N Tomato (Fruit) pyran-3-yl]-oxalamic acid H O 10% TRR (21-day) OH 12% TRR (28-day) O OH Tomato (Foliage) 2-7% TRR (all PHIs) HO OH OH Kasuganobiosamine 6-(3,5-diamino-6-methyl- NH H C 2 •2HCl [KB-2] tetrahydro-pyran-2-yloxy)- 3 O

cyclohexane-1,2,3,4,5-pentol H2N . 2 HCl Tomato (Foliage) hydrochlorate 1% TRR (1- to 28-day) OH O OH

HO

OH OH

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Kasugamycin Human Health Risk Assessment DP Barcode No. D433630

TABLE B.1 Chemical Names and Structures of Compounds Detected in the Rat and Tomato Metabolism Studies. Common Name [Code] Chemical Name Chemical Structure % Total Radioactive Residues NHCOCH 2-N-acetyl-kasugamycin [KN-2] [5-acetylamino-2-methyl-6- NH 3 (2,3,4,5,6-pentahydroxy- H C HO 3 O Tomato (Foliage) cyclohexyloxy)-tetrahydro- N 1-2% TRR (14-, 21-, 28-day) pyran-3-ylamino]-imino- H O acetic acid OH O OH

HO

OH OH Tomato metabolism: MRID #45910006. Single, foliar broadcast application of [ 14 C]-kasugamycin to tomato plants at 0.17 lb ai/A (roughly 3X the proposed maximum seasonal rate); fruit and foliage harvested at PHIs of 2 hours, 1, 7, 14, 21, and 28 days. Rat metabolism: MRID #46030306. Oral gavage dosing of [ 14 C]-kasugamycin at a single low dose (100 mg/kg bw); a single radiolabeled high dose (1000 mg/kg bw); repeated unlabeled low doses (100 mg/kg bw) for 14 days in the diet, plus 100 mg/kg bw radiolabeled single dose; or repeated unlabeled high doses (1000 mg/kg bw) for 14 days in the diet, plus 1000 mg/kg bw radiolabeled single dose.

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Kasugamycin Human Health Risk Assessment DP Barcode No. D433630

Appendix C. Physical/Chemical Properties Table

TABLE C Physicochemical Properties of the Technical Grade Test Compound (Kasugamycin Hydrochloride Hydrate). Parameter Value Reference Molecular Weight 433.8 PP#3E6579 administrative materials Melting Point/Range 202-230ºC (decomposing) (MRIDs #45910004 and -05) pH 4.35 at 24.5ºC (1% wt/vol solution) Density 0.43 g/mL at 24.5 ºC Water Solubility g/100 mL pH 5 20.7 pH 7 22.8 pH 9 43.8 Solvent Solubility g/100 mL Methanol 0.744 Hexane <1 x 10 -5 Acetonitrile <1 x 10 -5 Methylene chloride <1 x 10 -5 Vapor Pressure <0.013 mPa at 25ºC

Dissociation Constant (pK a) pK a1 = 3.23 pK a2 = 7.73 pK a3 = 11.0 Octanol/Water Partition Coefficient <1.96 at 23ºC and pH 5 (Log [K OW ]) UV/Visible Absorption Spectrum Not available

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Kasugamycin Human Health Risk Assessment DP Barcode No. D433630

Appendix D. International Maximum Residue Limit Status for Kasugamycin.

Kasugamycin (PC Code 230001) Summary of US Tolerances, and International Maximum Residue Limits. Residue Definitions US Canada Mexico 1 Codex 40CFR §180.614[a] All commodities: Kasugamycin (3- No MRLs are O-[2-amino-4- established for Plants: Kasugamycin (3-O-[2-amino-4- [(carboxyiminomethyl)amino]- kasugamycin. [(carboxyiminomethyl)amino]-2,3,4,6- 2,3,4,6-tetradeoxy-α-D-arabino - tetradeoxy-α-D-arabino -hexopyranosyl]-D- hexopyranosyl]-D-chiro -inositol). chiro -inositol). Commodity 2 Tolerance Maximum Residue Limit (mg/kg) (ppm) 3 US Canada Mexico 1 Codex Fruit, stone, subgroup 12-12A 0.60 Capulin, black cherry, Nanking cherry, sweet cherry, tart cherry 0.6 Walnut 0.04 English walnut, black walnut 0.04

Completed: W.T. Drew; 11 January 2017. 1. Mexico adopts US tolerances, and/or Codex MRLs, for its export purposes. 2. Includes only commodities of interest for this action. 3. Tolerance values are those recommended by HED, not necessarily those proposed by the petitioner.

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Kasugamycin Human Health Risk Assessment DP Barcode No. D433630

Appendix E. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, and the Agricultural Re-entry Task Force (ARTF) database are subject to ethics review pursuant to 40CFR §26, have received that review, and are compliant with applicable ethics requirements. For certain studies, that review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at: http://www.epa.gov/pesticides/science/handler-exposure- data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html .

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