Kasugamycin Human Health Risk Assessment DP Barcode D41 5977 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, DC 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 

Subject: 

20 November 2013 

Kasugamycin. ADDENDUM to the Human Health Risk Assessment for the 

Proposed Use ofthe Fungicide on Fruiting Vegetables, Pome Fruits, and Walnuts. 

PC Code: 230001 DP Barcode: 0415977 

Decision Number: 427886 Registration Number: 66330-404 

Petition Number: OF7689 Regulatory Action: Section 3 Registration 

Risk Assessment Type: Single Chemical Aggregate Case Number: 7045 

TXR Number: NA CAS Number: 6980-18-3 

MRID Numbers: NA 40CFR: §1 80.614 

From: 

R

William 

egistratio

T. 

n 

Dr

Action 

ew, Ch

Branch 

emist/Ri

II 

sk 

(RAB2) 

Assessor ~ 

Through: 

To: 

Health Effects Division (HED), 7509P 

Christina Swartz, Chief 

RAB2/HED, 7509P ~~ 

Shaunta Hill and Hope Johnson, RM Team 21 

Fungicide Branch (FB) 

Registration Division (RD), 7505P 

Back!!round: Canada's Pest Management Regulatory Agency (PMRA) has recently established 

maximum residue limits (MRLs) for kasugamycin in fruiting vegetables, pome fruits, and 

walnuts that differ from the US tolerances previously recommended by HED in its latest risk 

assessment (0 376608; W.T. Drew; 13 July 2012). In order to harmonize with the MRLs 

established by Canada, HED has revised its recommended tolerances in fruiting vegetables 

(group 8-1 0), pome fruits (group 11-1 0), and walnuts. Pursuant to that decision, this addendum 

addresses HED's revised tolerance and label recommendations, and the resulting changes to the 

dietary exposure and risk assessment. All other aspects of the human health risk assessment 

remain unchanged since the 2012 assessment, and are not re-iterated herein. 

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Kasugamycin Human Health Risk Assessment DP Barcode 0415977 

1.0 Executive Summary 

Arysta LifeScience North America LLC, as an agent for Hokko Chemical Industry Company 

Limited (Japan), has proposed the establishment of permanent tolerances for residues ofthe 

amino glycoside fungicide kasugamycin (3-0-[2-amino-4-[( carboxyimino-methyl)amino ]-

2,3,4,6-tetradeoxy-a-D-arabino-hexopyranosyl]-D-chiro-inositol, CAS #6980-18-3) in or on 

fruiting vegetables group 8-10, pome fruits group 11-10, and walnuts. The proposal is associated 

with the first US registration for this active ingredient (ai). 

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. The compound controls a range of phytopathogenic organisms in the 

proposed crops. Kasugamycin is currently used in over 20 countries on different crops including 

tomato, paprika, eggplant, rice and potato. HED previously recommended in favor of a tolerance 

for residues ofkasugamycin in imported fruiting vegetables and a time-limited tolerance for 

residues in apples. 

Kasugamycin is a member of the aminoglycoside family of antibiotics, which also includes 

streptomycin and gentamicin. These agents inhibit 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 ofkasugamycin on antibiotic resistance. Tolerance 

levels as recommended within this document are presented excluding antibiotic resistance 

impacts/ concerns. 

Toxicology: The toxicology database is complete for kasugamycin, and the available guideline 

toxicity data are considered adequate for risk assessment purposes. Kasugamycin exhibits low 

acute toxicity. The major effects observed across species in multiple-dose studies were 

decreased body weights and body weight gains. Testicular atrophy was also observed in the rat 

reproductive and mouse subchronic toxicity studies, but only at doses significantly higher than 

the lowest-observed-adverse-effect level (LOAEL) in the rat study, or above the limit dose in the 

mouse. There was no evidence that exposure to kasugamycin results in neurotoxicity, and a 

developmental neurotoxicity (DNT) study is not required. A 28-day rat inhalation toxicity study 

has not been submitted. However, HED's Hazard and Science Policy Council (HASPOC) has 

determined that a repeated exposure inhalation study is not required, based on the available 

hazard and exposure information, including the following considerations: selection of irritation 

as the endpoint of concern for inhalation exposure, based on irritation seen following oral 

exposures in multiple studies; the use of an oral no-observed-adverse-effect level (NOAEL) 

which results in occupational handler margins of exposure (MOEs) ranging from 58,000 to 

2,500,000 for risk via the inhalation route; the physicochemical properties, and low volatility, of 

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kasugamycin; the low acute inhalation toxicity (Toxicity Category IV); and the low potential for 

inhalation exposure, based on the proposed use pattern (TXR #0052461). 

Because of kasugamycin’s toxicological profile, low application rates, low vapor pressure, lack 

of residential uses, lack of persistence in the environment, and inhalation MOEs all ≥58,000, a 

10X UFDB is not required for the lack of the inhalation study. 

The database is complete with respect to pre- and post-natal toxicity, and 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. There was no evidence of carcinogenicity in male and female mice, nor 

in male and female rats at doses that were adequate to assess the carcinogenic potential of 

kasugamycin. There was no evidence of mutagenicity. Based on the overall weight of the 

evidence, kasugamycin is classified as "not likely to be carcinogenic to humans”. 

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. The dose and endpoint from the rat combined chronic toxicity/carcinogenicity study 

were selected for chronic dietary exposure and risk assessment. The NOAEL of 11.3 mg/kg/day 

was based on testicular softening and atrophy at the LOAEL of 116 mg/kg/day. Testicular 

atrophy is consistent with findings of other studies. 

There was no systemic toxicity associated with dermal exposure in an acceptable dermal toxicity 

study in the rat, and therefore a dermal endpoint and dose were not selected. For inhalation 

exposure (short- and intermediate-term), the dog subchronic and rabbit developmental toxicity 

studies were selected as co-critical studies. The endpoint of concern is irritation since 

kasugamycin appears to be irritating to the oral and gastrointestinal tract mucosa following oral 

exposures. In the subchronic study with dogs, irritation of the oral cavity was characterized as 

tongue lesions, swollen mouth, excessive salivation, and thickening of the skin at the 

commissures of the mouth. The NOAEL was 11 mg/kg/day, and the LOAEL was 106 

mg/kg/day. The developmental rabbit study was selected as the co-critical study since the 

maternal NOAEL (10 mg/kg/day) was comparable to the NOAEL in the dog study, and the 

maternal toxicity may have manifested due to the irritation potential of the compound. The use of 

the oral NOAEL results in MOEs ranging from 58,000 to 2,500,000 for risk from occupational 

exposure via the inhalation route. 

Residue Chemistry: 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, although no tolerances are needed in livestock commodities based on the 

proposed uses. The parent kasugamycin and 2 degradates with similar mobility were 

recommended for inclusion in the drinking water modeling. Adequate residue data were 
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submitted to support the proposed uses on fruiting vegetables group 8-10, pome fruits group 11-

10, and walnuts. HED has used conservative assumptions to assess the risk from chronic dietary 

exposure to kasugamycin through food and drinking water. These include 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). 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 3.1% cPAD. 

Residential/Aggregate Exposure and Risk: 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 Exposure and Risk: 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 chemicalspecific 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 MOEs, 

are all above 100, and are thus below HED’s LOC. Depending on the scenario, MOEs ranged 

from 58,000 to 2,500,000. 

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 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 D) 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

HED recommends in favor of establishing tolerances for the use of kasugamycin on fruiting 

vegetables (crop group 8-10), pome fruits (crop group 11-10), and walnuts, as described below.

2.1 Data Deficiencies

None.
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2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

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

level of method validation (LLMV) was 0.040 ppm in each matrix tested. 

2.2.2 International Harmonization

There are no established or proposed Codex MRLs for kasugamycin in any food or feed crops. 

Tolerances were established in 40CFR §180.614 at 0.04 ppm to cover residues in/on imported 

tomatoes and peppers from Mexico. There are no issues regarding compatibility of the proposed 

tolerances because Mexico adopts US tolerances, and/or Codex MRLs, for its export purposes. 

The proposed uses have been reviewed by Canada’s PMRA; EPA and PMRA have agreed to 

harmonize the recommended tolerances/MRLs, based on use of the OECD tolerance calculation 

procedure. 

2.2.3 Recommended Tolerances

Note to RD: The tolerance expression should be revised to reflect specific coverage and 

compliance statements for the tolerances to be properly enforced in accordance with the Federal 

Food, Drug and Cosmetic Act (FFDCA). Therefore, the tolerance expression for kasugamycin 

cited in 40CFR §180.614[a] should be revised to state: 

Tolerances are established for residues of kasugamycin, including its 

metabolites and degradates, in or on the commodities listed in the table 

below. Compliance with the tolerance levels specified below is to be 

determined by measuring only kasugamycin (3-O-[2-amino-4-

[(carboxyimino-methyl)amino]-2,3,4,6-tetradeoxy-α-D-arabinohexopyranosyl]-D-chiro-inositol) in or on the commodity. 

HED is now recommending the removal of the established tolerance in imported fruiting 

vegetables at 0.04 ppm, concomitant with the establishment of a domestic crop group tolerance 

in fruiting vegetables, group 8-10, at 0.10 ppm. 

HED has reviewed the available toxicological and residue chemistry studies for kasugamycin, 

and is recommending that permanent tolerances be established in/on the commodities in Table 

2.3.3, at the specified levels. 
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TABLE 2.3.3 Tolerance Summary for Kasugamycin.*

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Correct Commodity Definition

Comments

Vegetable, fruiting, 

Group 8

0.15 0.10 Vegetable, fruiting, group 8-10

Pome Fruit, Group 

11

0.25 0.20 Fruit, pome, group 11-10

(Provided that the label is amended to 

specify a 90-day PHI for pome fruits.) 

Walnut 0.04 0.04

* Tolerance levels as recommended within this document exclude any consideration of antibiotic resistance impacts

and/or concerns. 

2.2.4 Revisions to Petitioned-for Tolerances

Although a pome fruit crop group tolerance (fruit, pome, group 11-10) was requested, HED 

previously recommended for the establishment of individual tolerances in each commodity

included in the crop group, since the residue data for apple, one of the representative 

commodities of crop group 11-10, reflected a different use pattern than for pear, the other 

representative commodity. Specifically, the pre-harvest interval (PHI) used in the apple field 

trials was significantly greater than the proposed label PHI (90 days instead of the proposed 30), 

which was used in the pear field trials. 

In order to harmonize HED’s recommended US tolerances with PMRA’s recently established 

MRLs in the various commodities, the rationales described below were used. 

Fruiting vegetables (group 8-10): When using the OECD tolerance calculation procedure for 

non-bell peppers, 3 of the 4 residue values entered into the OECD calculator were censored. 

Therefore, due to the small dataset, the calculator indicated that there was a high level of 

uncertainty associated with the recommended tolerance in non-bell peppers. Additionally, the 

maximum residue reported in non-bell peppers was 0.107 ppm (HAFT = 0.084 ppm), the 

calculated tolerance in tomatoes was 0.09 ppm, and the calculated tolerance in bell peppers was 

0.08 ppm. Therefore, HED has determined that a tolerance of 0.10 ppm is appropriate in the 

entire crop group. 

Pome fruits (group 11-10): The calculated tolerance in apples, at a PHI of 90 days, was 0.08

ppm. The calculated tolerance in pears, at a PHI of 30 days (with a maximum residue of 0.172 

ppm, HAFT = 0.166 ppm) was 0.30 ppm. Provided that the label is amended to specify a 90-day 

PHI for pome fruits, HED has determined that a tolerance of 0.20 ppm is appropriate in the entire 

crop group. 

Walnuts: The calculated tolerance in walnuts was 0.07 ppm. However, 2 of the 3 residue values 

entered into the OECD calculator were censored. Therefore, due to the small dataset, the 

calculator indicated that there was a high level of uncertainty associated with the recommended 

tolerance in walnuts. Given that 5 of 6 individual samples had residues less than 0.040 ppm, and 
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that the sixth was reported at 0.0400 ppm, HED has determined that a tolerance of 0.04 ppm is

appropriate in walnuts. 

2.3 Label Recommendations

2.3.1 Recommendations from Residue Chemistry Reviews

The product label for Kasumin 2L (EPA File Symbol 66330-UNU) should be amended as 

stipulated below and revised petition Sections B and F should be submitted. 

General use directions: In its most recent risk assessment (D376608; W.T. Drew; 13 July 2012),

HED stated that the label should specify that adjuvants may not be added to spray mixtures for 

crops other than pome fruits and walnuts, as adjuvants had not been used in the fruiting 

vegetables field trials. Based on recent decisions by the Chemistry Science Advisory Council 

(ChemSAC), that label revision is unnecessary; adjuvants may be used in spray mixtures applied 

to fruiting vegetables. 

Rotational crop statement: No rotational crop restrictions are specified on the proposed label. 

The label should be revised to specify a 30-day plant-back interval (PBI) for all crops except 

those which are on the label as directly treated crops (which may be planted at any time). 

PHI: For use on pome fruits, the product label should be amended to specify a minimum PHI of 

90 days. 

5.4 Dietary Risk Assessment

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

An unrefined chronic aggregate dietary (food and drinking water) exposure and risk assessment 

was conducted for kasugamycin (D415989; W.T. Drew; 8 November 2013) using the Dietary 

Exposure Evaluation Model software with the Food Commodity Intake Database (DEEMFCID), Version 3.16. This software uses 2003-2008 food consumption data from the US 

Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, 

What We Eat in America, (NHANES/WWEIA). 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 3.1% of the cPAD for all population subgroups. Children 1-2 years of age are the most 
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highly-exposed subgroup, with a risk estimate of 3.1% of the cPAD, while the general US 

population had a risk estimate of <1.0% of the cPAD. Generally, HED is concerned when risk 

estimates exceed 100% of the PAD; therefore, all chronic dietary risk estimates are below HED’s 

level of concern (see Table 5.4.3).

5.4.3 Summary Table 

TABLE 5.43 Summary of Chronic Dietary Exposure and Risk Estimates for Kasugamycin.

Population Subgroup*

[Years of Age]

cPAD (mg/kg/day) Dietary Exposure Estimate 

(mg/kg/day)

% cPAD

General US Population 0.11 0.000526 <1.0

All Infants [< 1] 0.11 0.001899 1.7

Children [1-2] 0.11 0.003385 3.1

Children [3-5] 0.11 0.002015 1.8

Children [6-12] 0.11 0.000840 <1.0

Youth [13-19] 0.11 0.000367 <1.0

Adults [20-49] 0.11 0.000295 <1.0

Adults [50-99] 0.11 0.000264 <1.0

Females [13-49] 0.11 0.000299 <1.0

* Values for the population subgroup with the highest risk are in bold type.