Kasugamycin Summary of Analytical Chemistry and Residue Data DP Barcode D415991

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, DC 20460

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: 5 December 2013

Subject: Kasugamycin. ADDENDUM to Summary of Analytical Chemistry and 

Residue Data for the Proposed Use of the Fungicide on Fruiting Vegetables, 

Pome Fruits, and Walnuts.

PC Code: 230001 DP Barcode: D415991

Decision Number: 427886 Registration Number: 66330-404

Petition Number: 0F7689 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: §180.614

From: William T. Drew, Chemist

Registration Action Branch II (RAB2)

Health Effects Division (HED), 7509P

Through: Christina Swartz, Chief

RAB2/HED, 7509P

To: Shaunta Hill and Hope Johnson, RM Team 21

Fungicide Branch (FB)

Registration Division (RD), 7505P

Background: 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 residue 

chemistry summary document (D376563; W.T. Drew; 13 July 2012). In order to harmonize with 

the MRLs established by Canada, HED has revised its recommended tolerances. Pursuant to that 

decision, this addendum addresses HED’s revised tolerance and label recommendations. All 

other aspects of the previous residue chemistry summary document remain unchanged, and are 

not re-iterated herein. 
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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 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 

fruiting vegetables, pome fruits, and walnuts, at the levels listed below. The proposal is 

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

Vegetable, fruiting, Group 8 ....................................0.15 ppm

Pome Fruit, Group 11 ..............................................0.25 ppm

Walnut......................................................................0.04 ppm

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 including, 

but not limited to, fire blight in pome fruit (Erwinia amylovara), walnut blight (Xanthom onas 

campestris pv juglandis), bacterial speck in fruiting vegetables (Psuedomonas syringae pv. 

tomato), and bacterial spot in fruiting vegetables (Xanthomonas campestris pv vesicatoria). 

Kasugamycin is currently used in over 20 countries on different crops including tomato, paprika, 

eggplant, rice and potato. HED has previously recommended in favor of a tolerance for residues 

of kasugamycin 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. Because it acts at a different point in protein 

syntheses than that affected by other aminoglycoside antibiotics, cross-resistance between 

kasugamycin and similar antibiotic fungicides is expected to be unlikely. 

In a previous petition (PP#3E6579; D308573; W.T. Drew; 17 August 2005), Arvesta 

Corporation, as an agent for Hokko, proposed tolerances for kasugamycin’s use on imported

fruiting vegetables grown in Mexico. Tolerances for residues of kasugamycin have been 

established under 40CFR §180.614, and are expressed in terms of the pesticide kasugamycin (3-

O-[2-amino-4-[(carboxyimino-methyl)amino]-2,3,4,6-tetradeoxy-α-D-arabino-hexopyranosyl]-

D-chiro-inositol). A permanent tolerance has been established under 40CFR §180.614[a] for 

residues of kasugamycin in/on imported fruiting vegetables (group 8) at 0.04 ppm. A timelimited tolerance for residues of kasugamycin has also been established (in connection with 

Section 18 emergency exemptions) in/on apples at 0.05 ppm under 40CFR §180.614[b]; this 

tolerance expires on 31 December 2015. 
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In the current petition (PP#0F7689), Arysta LifeScience North America LLC is now seeking a 

US registration of a liquid (L) formulation containing 2% ai by weight (0.1667 lb ai/gal), 

Kasumin 2L, for use on fruiting vegetables, pome fruit, and walnuts. The petitioner is proposing 

application of kasugamycin as a foliar broadcast spray. 

The nature of kasugamycin residues in fruiting vegetable commodities is understood, based on 

the available tomato metabolism study. The residue of concern (ROC) in fruiting vegetables for 

tolerance expression and risk assessment purposes is parent kasugamycin only (Kasugamycin 

RAD Team decision; D301735; meeting of 23 February 2005). The ROC for tolerance 

expression and risk assessment in pome fruit (due to the similarity to fruiting vegetables) and 

walnuts is also kasugamycin only (ROCKS decision memo, meeting of 17 March 2011; 

D387527; I. Negrón-Encarnación; 4 May 2011). A metabolism study is not required for walnuts, 

since the maximum field trial residues were at the limit of quantitation (LOQ), 0.040 ppm, and 

are therefore unlikely to be present in quantities sufficient to allow characterization. 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 ROCs in those commodities. 

The confined rotational crop study (MRID #47945756) submitted with the current petition cited 

two plant metabolism studies (with lettuce and rice) in delineating the metabolic pathway. The 

study reviewer checked these references with the kasugamycin bibliography to obtain MRID 

citations. No citations were found for the lettuce or rice metabolism studies; it appears that these 

studies have not been submitted for review. 

Acceptable metabolism studies were conducted in goat and rotational crops (lettuce, radish, and 

wheat). These studies were conducted using test substances radiolabeled in the D-glucosamineU ring of kasugamycin. Based on the results of the goat metabolism study, kasugamycin 

residues orally ingested by a lactating goat were poorly absorbed from the gastro-intestinal (GI) 

tract of the goat, and the small fraction of the dose that was absorbed was rapidly excreted 

unchanged in the urine. Kasugamycin did not accumulate in the milk or edible tissues of the 

goat. In the confined rotational crop study no ROCs were found in following crops planted after 

application of kasugamycin to soil, with the possible exception of an unknown metabolite in the 

30-day wheat straw. For the purposes of tolerance enforcement and risk assessment, HED has 

determined that the ROC in livestock and rotational crops is parent only (ROCKS decision 

memo, meeting of 17 March 2011; D387527; I. Negrón-Encarnación; 4 May 2011). 

In conjunction with the previous petition (PP#3E6579), the petitioner proposed a reverse phase, 

ion pairing method utilizing high-performance liquid chromatography with ultraviolet detection 

(HPLC/UV) for the enforcement of tolerances for residues of kasugamycin in plant commodities. 

The method is entitled Determination of Kasugamycin in Tomatoes, Potatoes, and Peppers 

(Morse Laboratories Method #Meth-146). The enforcement method for kasugamycin residues, 

as originally proposed, was forwarded to the Biological and Economic Analysis Division’s 
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(BEAD’s) Analytical Chemistry Branch (ACB) for a petition method validation (PMV) trial 

(PMV Request Memo; D313672, W.T. Drew; 1 March 2005), which it failed (PMV Results 

Memo; D313673; P. Schermerhorn; 13 July 2005). The method was subsequently modified as 

recommended by ACB, and was then deemed acceptable as an enforcement method. 

The HPLC/UV enforcement method (Meth-146, Revision #4) was used to determine residues of 

kasugamycin in tomato, pepper and walnut samples from the crop field trial and tomato 

processing studies associated with this petition. Samples from the submitted apple and pear field 

trials, and the apple processing study were analyzed for residues of kasugamycin using 

laboratory working methods (FEQL Project #0407 for apple commodities, and FEQL Project 

#0706 for pears) which were adapted from Method #Meth-146, Revision #4, and included minor 

modifications to improve the performance of the methods. The methods were adequately 

validated both prior to, and in conjunction with, the analysis of the field trial and processing 

study samples. The lowest level of method validation (LLMV) was 0.040 ppm in each matrix 

tested. 

Adequate multiresidue method data for kasugamycin were previously submitted. Based on the 

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

ROCs. The multiresidue test data will be forwarded to FDA for further evaluation. 

To support the sample storage durations in the submitted crop field trials and processing studies, 

concurrent and extended storage stability studies were conducted using control samples of each 

matrix fortified with kasugamycin at a target level of 0.40 ppm. These data support the storage 

conditions and durations for apple, pear, walnut, tomato and pepper raw agricultural commodity 

(RAC) samples, apple processed commodities (juice and wet pomace), and tomato processed 

commodities (puree and paste). 

The only dairy cattle feedstuff associated with the proposed uses of kasugamycin is wet apple 

pomace. The petitioner did not submit a livestock feeding study. Because of low transfer factors 

from the goat metabolism study, and the low predicted residues in cow milk and tissues, HED is 

waiving the requirement for a cow feeding study and, ergo, tolerances in livestock commodities. 

The waiver applies to this petition only, and if additional uses are proposed in the future, then the

requirement for a feeding study will need to be re-evaluated. There are no poultry feedstuffs 

associated with the subject petition, therefore data requirements pertaining to poultry and eggs 

are not relevant to this petition. 

There are adequate magnitude of the residue data for the representative commodities of pepper 

(bell and non-bell) and tomato to support the establishment of a domestic crop group tolerance in 

the fruiting vegetables group (crop group 8-10). 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. 
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There are adequate magnitude of the residue data to support the establishment of a tolerance in 

walnuts at 0.04 ppm. 

There are adequate magnitude of the residue data for the representative commodities of apple 

and pear to support the establishment of a domestic crop group tolerance in the pome fruits group

(crop group 11-10). HED is now recommending the removal of the established time-limited 

tolerance in apples at 0.05 ppm, concomitant with the establishment of a domestic crop group 

tolerance in pome fruits, group 11-10, at 0.20 ppm, provided the label is amended to specify a 

90-day pre-harvest interval (PHI) for all pome fruit crops. 

Processing studies were conducted with apples and tomatoes. The results of the submitted apple 

and tomato processing studies show that residues of kasugamycin were below the LLMV 

(<0.040 ppm) in the respective RACs following application at approximately 1X. The Agency 

would have preferred the use of exaggerated rates in the conduct of the processing study to yield 

a RAC with quantifiable residues. Following processing of apple fruit (RAC) bearing residues at 

the LOQ (0.033 ppm), the residues concentrated slightly in apple juice (1.5X). No processing 

factor could be calculated for wet pomace because residues were below the LOQ in pomace. 

The maximum expected residues of kasugamycin in apple juice resulting from the proposed use 

are 0.10 ppm. This value was calculated by multiplying the concentration factor of 1.5X by the 

HAFT residue of 0.068 ppm. A tolerance in apple juice is not needed because the maximum 

expected residues of 0.10 ppm will be covered by the assessed tolerance of 0.20 ppm in apples

(the RAC). Additionally, a tolerance is not required in wet pomace since residues were below 

the LOQ. 

The submitted processing data for tomatoes are considered to be adequate. Following processing 

of tomato fruit (RAC) bearing non-quantifiable residues from a field trial conducted at 

approximately 1X the maximum seasonal application rate, no measurable processing factors can 

be calculated because the processed commodities of tomatoes also bore residues below the 

LLMV (<0.040 ppm). In conjunction with the previous petition (PP#3E6579; D308573; W.T. 

Drew; 17 August 2005), the petitioner provided supporting information, and was granted a 

waiver from the requirement for a tomato processing study. Since the currently proposed use is 

nearly identical to the previous use directions for fruiting vegetables, for the purpose of this 

petition only, HED recommends in favor of a waiver from the requirement for a new tomato 

processing study at exaggerated rates. 

An adequate confined rotational crop study has been submitted. 

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

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

tomatoes and peppers from Mexico. Ergo, with respect to Mexico and Codex, there are no issues 

regarding compatibility of the proposed tolerances because Mexico adopts US tolerances, and/or 

Codex MRLs, for its export purposes. 
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The proposed uses have been reviewed by Canada’s PMRA, and PMRA has recently established 

MRLs for kasugamycin in fruiting vegetables, pome fruits, and walnuts that differ from the US 

tolerances previously recommended by HED (D376563; W.T. Drew; 13 July 2012). EPA and 

PMRA have agreed to harmonize the recommended tolerances/MRLs, based on use of the 

Organization for Economic Cooperation and Development (OECD) tolerance calculation 

procedure. In order to harmonize with the MRLs established by Canada, HED has revised its 

recommended tolerances in fruiting vegetables (group 8-10), pome fruits (group 11-10), and 

walnuts. 

Regulatory Recommendations

HED recommends in favor of the establishment of permanent tolerances for residues of 

kasugamycin on fruiting vegetables (crop group 8-10), pome fruits (crop group 11-10), and 

walnuts, as described below.

Residue Chemistry Data Deficiencies

None.

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 recommends the removal of the established tolerance in imported fruiting vegetables at 

0.04 ppm (under 40CFR §180.614[a]), concomitant with the establishment of a domestic crop 

group tolerance in fruiting vegetables, group 8-10, at 0.10 ppm (under 40CFR §180.614[a]). 

HED also recommends the removal of the established time-limited tolerance in apples at 0.05 

ppm (under 40CFR §180.614[b]), concomitant with the establishment of a domestic crop group 

tolerance in pome fruits, group 11-10, at 0.20 ppm (under 40CFR §180.614[a]). 
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HED has reviewed the available residue chemistry studies for kasugamycin, and is 

recommending that permanent tolerances be established in/on the commodities in Table 1

(below), at the specified levels. 

The petitioner should submit a revised petition Section F to reflect the recommended tolerances 

and corrected commodity definitions presented in Table 1. 

TABLE 1 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. 

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

that the sixth was reported at 0.0400 ppm, HED has determined that a tolerance of 0.04 ppm is

appropriate in walnuts. 

Label Recommendations from Residue Chemistry Reviews

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

stipulated below, and a revised petition Section B should be submitted. 

General use directions: In its most recent residue chemistry summary document (D376563; 

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.