Kasugamycin Summary of Analytical Chemistry and Residue Data DP Barcode D 4 159 91

Page 1 of 8 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, DC 20460

OFFICE OF CHEMICAL S AFETY 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: D4 159 91
Decision Number: 4 27886 Registration Number : 66330

- 404 Petition Number: 0F7689 Regulatory Action: Section 3 Registration Risk Assessment Type: Single Chemical Aggregate Case N umber : 7045
T XR Number: NA CAS Number: 6980

- 18

- 3
MRID N umbers : 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 recommend ations. All other aspects of the previous residue chemi stry summary document remain unchanged, and are

not re

- iterated herein.Kasugamycin Summary of Analytical Chemistry and Residue Data DP Barcode D 4 159 91

Page 2 of 8 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 f ruits , 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

- rat e, 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 applic ation 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 recom mended 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 ge ntamicin . 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 sy stem 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 u nlikely.

In a previous petition (PP#3E6579; D 308573; W. T. Drew ; 17 August 2005), Arvesta Corporation, as an agent for Hokko , proposed tolerances for kasugamycin’s use on import ed fruiting vegetables grown in Mexico. Tolerances for residues of kasugamycin have been established under 40CFR §180.614, and are expressed in terms of the pesticid e kasugamycin ( 3

- O

- [2

- amino

- 4

- [(carboxyimino

- methyl)amino]

- 2,3,4,6

- tetradeoxy

- α

- D

- arabino

- hexopyranosyl]

- D

- chiro

- inositol ). A p erm anent 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 time

limited tolerance for residues of kasugamycin has also been established (in connection with
Section 1 8 emergency exemptions) in/on apples at 0.05 ppm under 40CFR §180.614[b]; this tolerance expires on 31 December 201 5

.Kasugamycin Summary of Analytical Chemistry and Residue Data DP Barcode D 4 159 91

Page 3 of 8 In the current petition (PP#0F7689), A rysta LifeScience North America LLC is now seeking a US registra tion 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 veget able commodities is understood

, based on the available tomato metabolism study. The residue of concern (ROC) in fruiting vegetables for
tolerance e xpression and risk assessment purposes is parent kasugamycin only (Kasugamycin RAD Team decision; D301735; m eeting 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

- Encarnac ión; 4 May 2011 ). A metabolism study is not required for walnuts,

s ince 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 r otational 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 obt ain 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
wh eat). These studies were conducted using test substances radiolabeled in the D

- glucosamine

U 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 ga stro

- 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 R OCs 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 pro posed 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, an d Peppers (Morse Laboratories Method #Meth

- 146)

. The enforcement method for kasugamycin residues, as originally proposed, was forwarded to the Biological and Economic Analysis Division’sKasugamycin Summary of Analytical Chemistry and Residue Data DP Barcode D 4 159 91

Page 4 of 8 (BEAD’s) Analytical Chemistry Branch (ACB) for a petition method val idation (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 enforcem ent method.

The HPLC/UV enforcement method (Meth

- 146, Revision #4) was used to determine residues of kasugamycin in tomato, pepper and walnut samples fr om the crop field trial and tomato processing studies associated with this petition. Samples from th e 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 pear s ) 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 lev el 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 kasugamyc in
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 usi ng control samples of each matrix fortified with kasugamycin at a target level of 0.4 0 ppm. These data support the storage conditions and durations for apple, pear, walnut, tomato and pepper raw agricultural commodity (RAC) samples, apple processed commod ities (juice and wet pomace), and tomato processed commodities (puree and paste).

The only dairy cattle feedstuff associated with the proposed use s 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 futu re, 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 vegetable s group (crop group 8

- 10). HED is now recommending the re moval 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.Kasugamycin Summary of Analytical Chemistry and Residue Data DP Barcode D 4 159 91

Page 5 of 8 Ther e 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 dome stic crop group tolerance in the pome fruit s group (crop group 11

- 10 ) . HED is now recommending the removal of the established time

- limited
tolerance in app les at 0.0 5 ppm, concomitant with the establishment of a domestic crop group tolerance in pome fruits, group 11

- 10, at 0. 2 0 ppm , provided the label is amended to specify a
90

- day pre

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

Processing studies were conducte d 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 prefer red 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 L OQ 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 th e concentration factor of 1.5 X by the HAFT residue of 0.068 ppm. A tolerance in apple juice is not needed because the maximum expected residues of 0. 1 0 ppm will be covered by the assessed tolerance of 0. 2 0 ppm in apple s (the RAC)

. Additionally, a toleran ce 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

a pproximately 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). I n conjunction with the previous petition (PP#3E6579 ; D 308573 ; 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 fr om the requirement f or a new tomato processing stud y a t 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 a re established in 40CFR §180.614 at 0.04 ppm to cover residues in/on imported tomatoes and peppers from Mex ico. Ergo, with respect to Mexico and Codex, t here are no issues regarding compatibility of the proposed tolerances because Mexico adopts US tolerances, and/or Codex MRLs, for its export purposes.Kasugamycin Summary of Analytical Chemistry and Residue Data DP Barcode D 4 159 91

Page 6 of 8 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 recommen ded 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 vegeta bles (group 8

- 10), pome fruits (group 11

- 10), and
walnuts.

Regulatory Recommendations

HED recommend s in f av or o f the establishment of permanent tolerance s 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 i ts 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

- arabino

hexopyranosyl]

- D

- chiro

- inositol) in or on the commodity.

HED recommends the re moval 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 0.1 0 ppm (under 40CFR §180.614[a])

.

HED al so recommend s 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 domes tic crop group
tolerance in pome fruit s, group 11

- 10 , at 0.2 0 ppm (under 40CFR §180.614[a])

.Kasugamycin Summary of Analytical Chemistry and Residue Data DP Barcode D 4 159 91

Page 7 of 8 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 s ho u l d submit a revised petition Section F to reflect the re commend ed tolerances
and corrected commodity definitions presented in Table 1.

T ABLE 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

- f or 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 g roup 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 describ ed 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 indica ted 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 w as 0.1 07 ppm (HAFT = 0.084 ppm)

, the
calculated tolerance in tomatoes was 0.09 pp m, and the calculated tolerance in bell peppers was
0.0 8 ppm . Therefore, HED has determined that a tolerance of 0.1 0 ppm is appropriate in the entire crop group.

Pome fruits (group 11

- 10): T he calculated tolerance in appl es , at a PHI of 90 days, was 0. 08

ppm

. T he calculated tolerance in pe a rs , at a PHI of 3 0 days (with a maximum residue of 0.172

ppm, HAFT = 0. 166 ppm) was 0. 3 0 ppm. Provided that the label is amended to specify a 90

- dayKasugamycin Summary of Analytical Chemistry and Residue Data DP Barcode D 4 159 91

Page 8 of 8 PHI for pome fruits , HED has determined that a tolerance of 0.2 0 ppm is appropriate in the entire

crop group.

Walnuts: The calculated tolerance in walnut s was 0.0 7 ppm. However, 2 of the 3 residue values entered into the OECD calculator were censored. Therefore, due to the small dataset, the
calculator indicated t hat 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. 0 4 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 t he label should s pecify 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

.

Rotat ional crop statement : No rotational crop restrictions a re specified on the proposed label.
T he 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.