Document ID: EPA-HQ-OPP-2008-0805-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-08-13T04:00Z

SEQ CHAPTER \h \r 1 

	UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		27-May-2009

Subject:	Spinetoram.  Application of Spinetoram to Date, Pomegranate,
Pineapple, Spice (subgroup 19B; except black pepper), Hop, Tree Nuts
(crop group 14), and Pistachio.  Summary of Analytical Chemistry and
Residue Data.  

PC Code:  110008	DP Barcodes:  D358160

Decision No.:  401004	Registration No.:  62719-541 and 62719-545

Petition No.:  8E7450	Regulatory Action:  Section 3 Registration and
Label Amendment

Risk Assessment Type:  not applicable	Case No.:  not applicable

TXR No.:  not applicable	CAS No.:  187166-40-1 and 187166-15-0

MRID No:  none	40 CFR:  180.635

From:		Tom Bloem, Chemist

			Health Effects Division/Risk Assessment Branch 1 (HED/RAB1; 7509P)

Through:	George F. Kramer, Ph.D., Senior Chemist

			HED/RAB1 (7509P)

	

To:			Daniel Rosenblatt (RM 05)

			Registration Division (7505P) 

The Interregional Research Project Number 4 (IR-4) requested a Section 3
registration for application of spinetoram to date, pomegranate,
pineapple, spice (subgroup 19B; except black pepper), and hop and a
label amendment for pistachio and tree nuts (crop group 14).  The
petitioner is also proposing the establishment of the following
tolerances for the combined residues of XDE-175-J, XDE-175-L, ND-J, NF-J
(see attachment 1 for structures and names):  almond, hulls - 9.0 ppm;
nut, tree, group 14 - 0.08 ppm; pistachio - 0.08 ppm; date - 0.1 ppm;
pomegranate - 0.3 ppm; pineapple - 0.02 ppm; pineapple, processed waste
- 0.08 ppm; spice, subgroup 19B, except black pepper - 1.7 ppm; and hop,
dried cones - 22 ppm.  

Executive Summary

Background:  Spinetoram (XDE-175) is a multicomponent tetracyclic
macrolide developed for the control of lepidopterous larvae, leafminers,
and thrips on a variety of crops.  It consists of two closely related
active ingredients, XDE-175-J and XDE-175-L, present in an approximate
3:1 ratio (J:L; see attachment 1 for structures).  Spinetoram is a
fermentation product of Saccharopolyspora spinosa and is an analogue of
the insecticide spinosad (PC code 110003); its mode of action is
disruption of nicotinic/gamma amino butyric acid (GABA)-gated chloride
channels.  The petitioner is requesting a Section 3 registration for
application of spinetoram to date, pomegranate, pineapple, spice
(subgroup 19B; except black pepper), and hop and a label amendment for
tree nuts (crop group 14) and pistachio.

 

Application Scenarios:  The petitioner submitted supplemental labeling
for Delegate WG™ (water dispersible granule; 25% ai; EPA Reg. No.
62719-541) and Radiant™ SC (soluble concentrate; 1 lb ai/gal; EPA Reg.
No. 62719-545).  Table 3 is a summary of the proposed application
scenarios.  The petitioner should submit a revised Section B specifying
a 7-day retreatment (RTI) for dates (Delegate WG™ (25% ai; EPA Reg.
No. 62719-541)) and 30-day plant-back interval (PBI) for all non-labeled
crops following application to spices (subgroup 19B, except black
pepper; Radiant™ SC (1 lb ai/gal; EPA Reg. No. 62719-545)).  

Nature of the Residue - Plants:  The petitioner submitted turnip, apple,
and lettuce metabolism studies conducted with spinetoram (XDE-175-J and
XDE-175-L) uniformly labeled throughout the macrolide ring.  Based on
these data, it appears that three metabolic pathways are responsible for
the breakdown of spinetoram in plants.  One pathway involves changes to
the N-demethyl moiety on the forosamine sugar to give the N-demethyl
(<1-20% total radioactive residue (TRR)) and N-formyl (<1-17% TRR)
metabolites (see attachment 2 for structures).  Due to the presence of
these metabolites in the 0-day preharvest interval (PHI) samples, it is
thought that these changes may be the result primarily of photolysis. 
The second pathway involves cleavage of the macrolide ring system at one
or more positions, ultimately resulting in a complex residue mixture
consisting of numerous components (≤89% TRR).  The third pathway
involves changes to the rhamnose sugar of XDE-175-J only, producing the
3-O-deethyl (≤4% TRR) and C9-pseudoaglycone metabolites (apple fruit
only; ≤4% TRR) or cleavage of the forosamine sugar to yield
C17-pseudoaglycone-175-J (turnip tops only; <1% TRR).  All of the
forosamine-altered metabolites and rhamnose-altered metabolites were
subject to breakdown via the second pathway, which is the reason that
the second pathway ultimately predominated in the residue profile for
both test materials.  It is presumed that XDE-175-L also underwent
degradation by the third pathway, but was degraded too quickly via the
second pathway to enable detection of any metabolites.  

Based on the turnip, apple, and lettuce metabolism studies, HED
concluded that the residues of concern in plants are as summarized in
Table 4.  For further information concerning these conclusions, see the
HED human-health risk assessment D331741 (PV Shah et al., 10-Sep-2007).

Nature of the Residue - Livestock:  The petitioner submitted goat and
hen metabolism studies conducted with spinetoram (XDE-175-J and
XDE-175-L) uniformly labeled throughout the macrolide ring.  No
significant metabolism of spinetoram (XDE-175-J and XDE-175-L) was
observed in ruminants, as the unchanged parent molecule was the primary
residue component identified in milk and all tissue samples (26-84%
TRR).  Ruminant liver and muscle contained one unidentified metabolite
(XDE-175-J - <10% TRR; XDE-175-L - <27% TRR); ruminant liver also
contained a minor amount of ND-J and ND-L (≤2% TRR).  Parent was also
the primary residue component in all hen matrices (45-80% TRR) excluding
liver (12-13% TRR).  In hen liver, the O-deethyl (≤18% TRR) and
O-demethyl (≤20% TRR) metabolites were also observed indicating that
the metabolic pathway in hens is primarily through dealkylation of the
rhamnose sugar.

Based on the goat and hen metabolism studies, HED concluded that the
residues of concern in livestock are as summarized in Table 4.  For
further information concerning these conclusions, see the HED
human-health risk assessment D331741 (PV Shah et al., 10-Sep-2007).

toram plant metabolism studies resulted in the incorporation of
radioactivity into numerous peaks with each representing ≤3% TRR (PHI
= 0-30 days); (3) the proposed spinetoram application rates were less
than or equal to the application rates used in the spinosad field trial
studies; and (4) the spinosad and spinetoram side-by-side residue data
indicated that, in general, residues of spinetoram (combined XDE-175-J,
XDE-175-L, ND-J, NF-J) were comparable to residues of spinosad (combined
spinosyn A and D) provided the application scenarios were similar.  HED
also concluded that translation of the spinosad processing factors to
spinetoram was acceptable (D357703, T. Bloem, 28-Apr-2009). Based on
these conclusions, and since the proposed spinetoram application
scenarios are similar to that of spinosad (spinetoram application rates
≤ to spinosad; similar RTIs and PHIs), HED concludes that translation
of the spinosad residue data to spinetoram is acceptable and the
tolerances listed in Table 7 for the combined residues of XDE-175-J,
XDE-175-L, ND-J, and NF-J are appropriate.  

Magnitude of the Residue - Livestock:  Based on the revised Table 1
feedstuffs (OPPTS 860.1000), the only feed item associated with the
current petition is almond hulls which are fed to only dairy cattle
(roughage; 10% of the diet; 90% dry matter).  The previously calculated
dairy cattle maximum reasonable dietary burden (MRDB) was 7.64 ppm
(D325387, T. Bloem, 12-Sep-2007) with the roughage component consisting
of wheat forage (3.50 ppm; 25% dry matter; 25% of the diet), soybean
forage (2.29 ppm; 35% dry matter; 10% of the diet), and leaves of root
and tuber vegetable (1.33 ppm; 30% dry matter; 10% of the diet). 
Therefore, inclusion of almond hulls in the dietary burden calculation
instead of leaves of root and tuber vegetables results in and increase
in the dietary burden to 8.42 ppm.  

HED previously reviewed a ruminant feeding study (47030801.der.wpd). 
The study employed dosing with spinetoram (XDE-175-J:XDE-175-L; 3:1) at
a dietary burden of 37.85 ppm or a mixture of
XDE-175-J:XDE-175-L:ND-J:NF-J (1:0.25:1.1:1.2) at dietary burdens of
1.18 ppm, 3.69 ppm, 11.46 ppm, and 38.59 ppm.  Since the nature of the
residue in ruminants following dosing with ND-J and NF-J has not been
demonstrated, HED concludes that the results from the feeding study
which employed dosing with only parent will be used for determination of
the magnitude of the residue in ruminants.  Using these data, the
estimate residues in ruminants at the current MRDB are less than the
currently-established tolerances; therefore, the currently-established
tolerances remain appropriate.  

Analytical Enforcement Method:    SEQ CHAPTER \h \r 1 Method GRM 05.03
was developed for the determination of residues of XDE-175-J, XDE-175-L,
ND-J, and NF-J in plant matrices using high-performance liquid
chromatography with positive-ion electrospray (ESI) tandem mass
spectrometry (HPLC-MS/MS).  The petitioner submitted adequate validation
data, independent laboratory validation (ILV), and radiovalidation for
method GRM 05.03; HED forwarded this method to the Biological & Economic
Analysis Division (BEAD) Analytical Chemistry Laboratory (ACL) for
petition method validation (PMV D335231, T. Bloem, 18-Jan-2007).  The
ACL determined that method GRM 05.03 is an adequate enforcement method
and HED forwarded this method to the Food and Drug Administration (FDA;
D343662, T. Bloem, 12-Sep-2007).  The limit of quantitation (LOQ) for
all analytes/matrices is 0.01 ppm.  HED concludes that this method is
acceptable for enforcement of the tolerances associated with the current
petition.  

on rates (≤0.46 lb ai/acre), HED previously concluded that a 30-day
plant-back interval for all non-labeled crops was appropriate (D325387,
T. Bloem, 12-Sep-2007; D353933, T. Bloem, 28-August-2008).  Since the
proposed spice rate is 0.305 lb ai/acre, HED concludes that the spice
label should indicate that a 30-day PBI for all nonlabeled crops.  A
revised Section B is requested.

Recommendations:  Provided the petitioner submits revised Sections B and
F, HED concludes that the residue chemistry database supports an
unconditional registration and establishment of the tolerances listed in
Table 7 for the combined residues of XDE-175-J, XDE-175-L, ND-J, and
NF-J.  

Summary of Residue Chemistry Deficiencies:

(Revised Section B.

(Revised Section F.

Detailed Considerations 

Background

Spinetoram (XDE-175) is a multicomponent, tetracyclic macrolide
developed for use as an insect control agent on a variety of crops that
are subject to attack by lepidopterous and sucking insects.  It consists
of two closely related active ingredients, XDE-175-J and XDE-175-L,
present in an approximate 3:1 ratio (J:L).  Spinetoram is a fermentation
product of Saccharopolyspora spinosa and is an analogue of the
insecticide spinosad; its mode of action is disruption of
nicotinic/GABA-gated chloride channels.  The subject petition represents
the first food/feed use for spinetoram.  Tables 1 and 2 are summaries of
the test compound nomenclature and physical chemical properties,
respectively.  

 

                               XDE-175-J                                
                        XDE-175-L

Common name	Spinetoram (mixture of XDE-175-J and XDE-175-L)

Company experimental name	XDE-175-J (TSN104472; 3’-O-ethyl 5,6-dihydro
spinosyn J; 175-J)

XDE-175-L (TSN104480; 3’-O-ethyl spinosyn L; 175-L)

IUPAC name	XDE-175-J  SEQ CHAPTER \h \r 1 : 	

(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-13-{[(2R,5S,6R)-5-(dimethylamino)-
6-methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-14-methyl-7,15-dioxo-2,3,3
a,4,5,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-octadecahydro-1H-as-indaceno
[3,2-d]oxacyclododecin-2-yl
6-deoxy-3-O-ethyl-2,4-di-O-methyl-alpha-L-mannopyranoside

XDE-175-L:

(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-13-{[(2R,5S,6R)-5-(dimethylamino)-
6-methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-4,14-dimethyl-7,15-dioxo-2
,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexadecahydro-1H-as-indaceno
[3,2-d]oxacyclododecin-2-yl
6-deoxy-3-O-ethyl-2,4-di-O-methyl-alpha-L-mannopyranoside

CAS name	  SEQ CHAPTER \h \r 1 XDE-175-J:

1H-as-indaceno[3,2-d]oxacyclododecin-7,15-dione,
2-[(6-deoxy-3-O-ethyl-2,4-di-O-methyl-a-L-mannopyranosyl)oxy]-13-[[(2R,5
S,6R)-5-(dimethylamino)tetrahydro-6-methyl
2H-pyran-2-yl]oxy]-9-ethyl-2,3,3a,4,5,5a,5b,6,9,10,11,12,13,14,16a,16b-h
exadecahydro 14-methyl- (2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)

XDE-175-L:

1H-as-indaceno[3,2-d]oxacyclododecin-7,15-dione,2-[(6-deoxy-3-O-ethyl-2,
4-di-O-methyl-a-L-mannopyranosyl)oxy]-13-[[(2R,5S,6R)-5-(dimethylamino)t
etrahydro-6-methyl-2H-pyran-2-yl]oxy]-9-ethyl-2,3,3a,5a,5b,6,9,10,11,12,
13,14,16a,16b-tetradecahydro-4,14-dimethyl-
(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)	

CAS #	XDE-175-J: 187166-40-1 

XDE-175-L: 187166-15-0

End-use product/EP	GF-1587 SC Naturalyte Insect Control Product

GF-1640 WG Naturalyte Insect Control Product



Table 2:  Physicochemical Properties of Spinetoram.

Melting points	XDE-175-J: 143.4°C

XDE-175-L: 70.8°C

pH	6.46 at 23.1°C for 1% w/w aqueous solution

Density	1.1485 g/cm3 at 20°C

Water solubility (20°C)	  SEQ CHAPTER \h \r 1 XDE-175-J

10.0 mg/L in purified water

423 mg/L in pH 5 buffer

11.3 mg/L in pH 7 buffer

approx. 8 mg/L in pH 9 buffer

6.27 mg/L in pH 10 buffer

XDE-175-L

31.9 mg/L in purified water

1630 mg/L in pH 5 buffer

46.7 mg/L in pH 7 buffer

1.98 mg/L in pH 9 buffer

0.706 mg/L in pH 10 buffer

Solvent solubility (20°C)	  SEQ CHAPTER \h \r 1 Solvent                
          Solubility (g/L)

Methanol                          >250

Acetone                            >250

n-Octanol                           132

Ethyl Acetate                   >250

1,2-dichloromethane        >250

Xylene                              >250

Heptane                              61.0

Vapor pressure 	XDE-175-J:   SEQ CHAPTER \h \r 1 5.3 x10-5 Pa  at 20°C,
    SEQ CHAPTER \h \r 1 6.0 x10-5 Pa  at 25°C

XDE-175-L: 2.1 x10-5 Pa at 20°C,     SEQ CHAPTER \h \r 1 4.2 x10-5 Pa 
at 25°C

Dissociation constant (pKa)	XDE-175-J : pKa = 7.86

XDE-175-L : pKa = 7.59

Octanol/water partition coefficient (20°C)	  SEQ CHAPTER \h \r 1
XDE-175-J:              pH              Log Kow

                                   5                   2.44

                                   7                   4.09

                                   9                   4.22 

XDE-175-L:              pH              Log Kow

                                   5                   2.94

                                   7                   4.49

                                   9                   4.82

UV/visible absorption spectrum	XDE-175-J:

		         Wavelength       Extinction coefficient

Solution		         (max, nm	       (, L/(mol*cm)

Neutral	   245	            	12200

Basic (pH 12.6)	   246	  	    	11700	

Acidic (pH 1.04)         	247	             	12400

XDE-175-L:

		     Wavelength		Extinction coefficient

Solution		      (max, nm	(, L/(mol*cm)

Neutral 	243	          	11100

Basic (pH 12.6)  	244	  	11200	

Acidic (pH 1.04)    	202	            	9800

	245	          	11400

OPPTS GLN 860.1200 Directions for Use

Delegate WG™ (25% ai; EPA Reg. No. 62719-541) and Radiant™ SC (1 lb
ai/gal; EPA Reg. No. 62719-545).  Table 3 is a summary of the proposed
application scenarios.  The petitioner should submit a revised Section B
specifying a 30-day PBI for all non-labeled crops following application
to spices (subgroup 19B, except black pepper; Radiant™ SC (1 lb
ai/gal; EPA Reg. No. 62719-545)).  

Table 3:  Proposed Application Scenarios.

Formulation	Rate

(lb ai/acre)	No. Apps.	Max. Sea. Rate (lb ai/acre)	PHI (days)	Comments

tree nuts and pistachio

Delegate WG™ (25% ai; EPA Reg. No. 62719-541)	0.023-0.109	4	0.438	1
-7-day RTI

-crop oils may be added to the spray solution

pomegranate

Delegate WG™ (25% ai; EPA Reg. No. 62719-541)	0.062-0.109	3	0.219	1
-4-7-day RTI

date

Delegate WG™ (25% ai; EPA Reg. No. 62719-541)	0.109	4	0.305	7	-7-day
RTI

hop

Delegate WG™ (25% ai; EPA Reg. No. 62719-541)	0.039-0.063	5	0.305	1
-4-day RTI

spices (subgroup 19B; except black pepper)

Radiant™ SC (1 lb ai/gal; EPA Reg. No. 62719-545)	0.039-0.062	5	0.305
14	-10-day RTI

pineapple

Radiant™ SC (1 lb ai/gal; EPA Reg. No. 62719-545)	0.031-0.062	6	0.305
7	-7-day RTI

1  PHI = preharvest interval; RTI = retreatment interval.  

860.1300 Nature of the Residue - Plants and Livestock

≤89% TRR).  The third pathway involves changes to the rhamnose sugar
of XDE-175-J only, producing the 3-O-deethyl (≤4% TRR) and
C9-pseudoaglycone metabolites (apple fruit only; ≤4% TRR) or cleavage
of the forosamine sugar to yield C17-pseudoaglycone-175-J (turnip tops
only; <1% TRR).  All of the forosamine-altered metabolites and
rhamnose-altered metabolites were subject to breakdown via the second
pathway, which is the reason that the second pathway ultimately
predominated in the residue profile for both test materials.  It is
presumed that XDE-175-L also underwent degradation by the third pathway,
but was degraded too quickly via the second pathway to enable detection
of any metabolites.  

Based on the turnip, apple, and lettuce metabolism studies, HED
concluded that the residues of concern in plants are as summarized in
Table 4.  For further information concerning these conclusions, see the
HED human-health risk assessment D331741 (PV Shah et al., 10-Sep-2007).

 (≤2% TRR).  Parent was also the primary residue component in all hen
matrices (45-80% TRR) excluding liver (12-13% TRR).  In hen liver, the
O-deethyl (≤18% TRR) and O-demethyl (≤20% TRR) metabolites were also
observed indicating that the metabolic pathway in hens is primarily
through dealkylation of the rhamnose sugar.

Based on the goat and hen metabolism studies, HED concluded that the
residues of concern in livestock are as summarized in Table 4.  For
further information concerning these conclusions, see the HED
human-health risk assessment D331741 (PV Shah et al., 10-Sep-2007).

Table 4:  Residues for Tolerance Expression and Risk Assessment.

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants	XDE-175-J, XDE-175-L, ND-J, and NF-J	XDE-175-J, XDE-175-L, ND-J,
and NF-J

Ruminants1	XDE-175-J, XDE-175-L, ND-J, and NF-J	XDE-175-J, XDE-175-L,
ND-J, and NF-J

Hen1	XDE-175-J, XDE-175-L, ND-J, NF-J, 3'-O-deethyl-175-J,

3'-O-deethyl-175-L, and O-demethyl-175-L2	XDE-175-J, XDE-175-L, ND-J,
and NF-J

1  ND-J and NF-J were included as residues of concern in livestock due
to their presence in/on feed commodities.

2  O-demethyl-175-L is either 2’-O-demethyl-175-L or
4’-O-demethyl-175-L or a mixture of both.

OPPTS GLN 860.1340 Residue Analytical Methods

47554001.der.doc

Method GRM 05.03 was developed for the determination of residues of
XDE-175-J, XDE-175-L, ND-J, and NF-J in plant matrices using HPLC-MS/MS
(ESI).  The petitioner submitted adequate validation data, ILV, and
radiovalidation for method GRM 05.03; HED forwarded this method to BEAD
for PMV (D335231, T. Bloem, 18-Jan-2007).  The ACL determined that
method GRM 05.03 is an adequate enforcement method and HED forwarded
this method to the FDA (D343662, T. Bloem, 12-Sep-2007).  The LOQ for
all analytes/matrices is 0.01 ppm.  HED concludes that this method is
acceptable for enforcement of the tolerances associated with the current
petition.  

OPPTS GLN 860.1360 Multiresidue Methods (MRMs)

XDE-175-J, XDE-175-L, ND-J, NF-J, ND-L, and NF-L were screened through
the Food and Drug Administration (FDA) Pesticide Analytical Manual (PAM)
I MRMs.  None of the test substances were found to be fluorescent using
procedures outlined in Protocol A.  All test substances were subjected
to Protocol C, modules DG1, DG5, DG13, DG17 and DG18.  Test substances
were determined to be non-chromatographable by the chosen gas
chromatography modules described in Protocol C.  Due to the poor
sensitivity of the test substances to detection by methods described in
Protocol C, no further analyses were performed by Protocols D, E or F. 
Since the test substances are not acids, phenols, or substituted ureas,
analyses were not performed using Protocols B or G.  The test substances
were not detectable through FDA PAM I Protocols A and C; therefore,
these methods are unsuitable for enforcement.  The MRM results were
forwarded to the FDA (D335229, T. Bloem, 18-Jan-2007).  

OPPTS GLN 860.1480 Meat, Milk, Poultry, and Eggs

Based on the revised Table 1 feedstuffs (OPPTS 860.1000), the only feed
item associated with the current petition is almond hulls which are fed
to only dairy cattle (roughage; 10% of the diet; 90% dry matter).  The
previously calculated diary cattle MRDB was 7.64 ppm (D325387, T. Bloem,
12-Sep-2007) with the roughage component consisting of wheat forage
(3.50 ppm; 25% dry matter; 25% of the diet), soybean forage (2.29 ppm;
35% dry matter; 10% of the diet), and leaves of root and tuber vegetable
(1.33 ppm; 30% dry matter; 10% of the diet).  Therefore, inclusion of
almond hulls in the dietary burden calculation instead of leaves of root
and tuber vegetables results in and increase in the dietary burden to
8.42 ppm.  Table 5 is a summary of these calculations.  

HED previously reviewed a ruminant feeding study (47030801.der.wpd). 
The study employed dosing with spinetoram (XDE-175-J:XDE-175-L; 3:1) at
a dietary burden of 37.85 ppm or a mixture of
XDE-175-J:XDE-175-L:ND-J:NF-J (1:0.25:1.1:1.2) at dietary burdens of
1.18 ppm, 3.69 ppm, 11.46 ppm, and 38.59 ppm.  Since the nature of the
residue in ruminants following dosing with ND-J and NF-J has not been
demonstrated, HED concludes that the results from the feeding study
which employed dosing with only parent will be used for determination of
the magnitude of the residue in ruminants.  Table 6 is a summary of the
magnitude of the residue in ruminants following dosing with parent at a
dietary burden of 37.85 ppm, the estimated residues at the current dairy
cattle dietary burden 8.42 ppm (0.22x the feeding study), and the
currently established ruminant tolerances.  Since the estimated residues
at the current MRDB are less than the currently-established tolerances,
HED concludes that current tolerances remain appropriate.  

Table 5:  Calculation of MRDB.

Feed

Commodity	% Dry

Matter1	% Diet1	Recommended Tolerance (ppm)	Dietary

Contribution (ppm)2

Dairy Cattle

wheat forage (R)	25	25	3.5	3.50

soybean foliage (R)	35	10	8.0	2.29

almond hulls (R)	90	10	19	2.11

sorghum grain (CC)	86	40	1.0	0.47

sugar beet molasses (CC)	75	5	0.75	0.05

cottonseed (PC)	88	10	0.04	0.004

dietary burden	--	100	--	8.42

1  OPPTS 860.1000 Table 1 (August 1996).

2  dietary contribution = tolerance ( % dry matter x % diet. 

3  R = roughage; CC = carbohydrate concentrate; PC = protein
concentrate.



Table 6:  Residue Data from Ruminant Feeding Study with Spinetoram
(XDE-175-J:XDE-175-L; 3:1; dietary burden of 37.85 ppm).

Matrices	Residues (ppm)1	Residue Normalized to the Dairy Cattle MRDB
(ppm)	Current Tolerance (ppm)

	XDE-175-J	XDE-175-L	ND-J	NF-J	Average Total

kidney	1.133, 0.502, 0.6330	0.612, 0.306, 0.377	0.045, 0.022, 0.060	ND,
ND, ND	1.24	0.273	0.60

liver	0.704, 0.353, 1.590	0.582, 0.264, 0.803	0.077, 0.034, 0.171	ND,
ND, (0.008)	1.54	0.339	0.85

muscle	0.343, 0.304, 0.264	0.191, 0.186, 0.151	(0.009), (0.006), 0.017
ND, ND, ND	0.50	0.110	0.20

mesenterial fat	7.411, 5.497, 6.2650	3.820, 2.871, 2.958	0.052, 0.029,
0.069	ND, ND, ND	9.67	2.127	5.5

perirenal fat	10.961, 7.255, 9.652	5.563, 3.783, 5.119	0.076, 0.034,
0.058	(0.006), ND, ND	14.18	3.120	5.5

subcutaneous fat	5.763, 3.047, 1.533	2.932, 1.645, 0.793	0.048, 0.017,
0.021	(0.004), ND, ND	5.28	1.159	5.5

composite fat	10.100, 6.359, 5.875	5.187, 3.36, 2.976	0.059, 0.034,
0.055	(0.005), ND, ND	11.35	2.497	5.5

milk (day 14)	0.492, 0.498, 0.410	0.273, 0.242, 0.199	(0.003), (0.003),
(0.004)	ND, ND, ND	0.72	0.158	0.30

milk (day 28)	0.609, 0.495, 0.642	0.316, 0.288, 0.283	(0.004), ND,
(0.008)	ND, ND, ND	0.90	0.198	0.30

cream (day 14)	1.866, 2.390, 1.826	0.974, 1.281, 0.933	(0.010), 0.010,
0.011	ND, ND, ND	3.11	0.684	milk fat - 7.5

cream (day 28)	2.964, 4.143, 4.192	1.602, 2.396, 2.132	0.026, 0.019,
0.029	0.011, ND, ND	5.87	1.291	milk fat - 7.5

skim milk (day 14)	0.051, 0.026, 0.051	0.021, 0.011, 0.022	ND, ND, ND
ND, ND, ND	0.08	0.018	0.30

skim milk (day 28)	0.045, 0.026, 0.065	0.020, 0.012, 0.028	ND, ND, ND
ND, ND, ND	0.09	0.020	0.30

1  ND = not detected (<0.003 ppm).  Residue concentration in parenthesis
indicates a value <LOQ (0.01 ppm) but ≥LOD (0.003 ppm). For total
residue calculation, 0.01 ppm was assumed for all residues <LOQ.  Note
that residues in controls were ND for all control samples except for
XDE-175-J and XDE-175-L detect in one kidney control samples at 0.0045
ppm and 0.0031 ppm.

860.1500 Crop Field Trials

47554001.der.doc

merous peaks with each representing ≤3% TRR (PHI = 0-30 days); (3) the
proposed spinetoram application rates were less than or equal to the
application rates used in the spinosad field trial studies; and (4) the
spinosad and spinetoram side-by-side residue data indicated that, in
general, residues of spinetoram (combined XDE-175-J, XDE-175-L, ND-J,
NF-J) were comparable to residues of spinosad (combined spinosyn A and
D) provided the application scenarios were similar.  The following is a
summary petitioner's proposals and HED's conclusions.  

Date:  HED previously concluded that the California spinosad plum/prune
residue data (D249374, M. Doherty, 24-Jun-1999) may be used in support
of the establishment of a spinosad date tolerance (plum - 4 x 0.062-134
lb ai/acre (final two applications at the higher rate); prune - 4 x
0.219-0.468 lb ai/acre (final two applications at the higher rate); RTI
= 7 days; PHI = 7 days).  Spinosad residues (immunochemical method
(Method GRM 96.11); LOQ = 0.018 ppm) were as follows:  plum (n=12) -
<0.018, prune (fresh; n=8) - 0.04-0.08 ppm; and prune (dried; n=8) -
0.03-0.08 ppm.  Based on these data, HED recommended for the
establishment of 0.10 ppm spinosad date tolerance (D358163, T. Bloem,
27-May-2009).  Based on these conclusions, the proposed application rate
and that performed in the spinosad plum/prune field trials
(0.6-4.3x/1.5-5.1x proposed single/seasonal application rates), and
previous conclusions concerning the translation of spinosad residues to
spinetoram (see paragraph at the beginning of this section), HED
concludes that the available data support a date tolerance of 0.10 ppm
for the combined residues of XDE-175-J, XDE-1756-L, ND-J, and NF-J.  J,
and NF-J.  A revised Section F is requested.  

Pomegranate:  HED previously concluded that the avocado spinosad
tolerance may be translated to pomegranate in support of application of
spinosad to pomegranate; as a result, HED recommended for the
establishment of 0.30 ppm spinosad pomegranate tolerance (D358163, T.
Bloem, 27-May-2009).  HED notes that the spinosad avocado tolerance was
translated from the spinosad citrus, stone fruit, and apple residue data
(2.1x the proposed spinetoram pomegranate application rate; RTI = 6-7
days; PHI = 1 day for citrus and 7 days for apple and stone fruit; for
discussion concerning this translation see D252416 (G. Herndon,
23-Feb-1999) and D237752 (G. Herndon, 2-Mar-1998)).  Based on these
conclusions; the proposed application rate and that performed in the
spinosad citrus, apple, and stone fruit field trials; and previous
conclusions concerning the translation of spinosad residues to
spinetoram (see paragraph at the beginning of this section); HED
concludes that the available data support a 0.30 ppm pomegranate
tolerance for the combined residues of XDE-175-J, XDE-1756-L, ND-J, and
NF-J.  A revised Section F is requested.  

Pineapple:  The Agency previously reviewed spinosad pineapple residue
data and recommended for a 0.02 ppm tolerance (LOQ tolerance) for the
combined residues of spinosyn A and D (4-5 x 0.094 lb ai/acre; RTI = 6-8
days; PHI = 3 or 6-7 days; D335084, B. Hanson, 19-Sep-2007).  Based on
this conclusion; the proposed spinetoram application rate and that
performed in the spinosad pineapple field trials (1.5x/1.2-1.5x the
proposed single/seasonal application rate); and previous conclusions
concerning the translation of spinosad residues to spinetoram (see
paragraph at the beginning of this section); HED concludes that the
available data support a 0.04 ppm pineapple tolerance for the combined
residues of XDE-175-J, XDE-1756-L, ND-J, and NF-J; note that the
tolerance was increased from 0.02 ppm to 0.04 ppm to account for the
additional residues in the spinetoram tolerance expression.  A revised
Section F is requested.  

Spice (subgroup 19B; except black pepper):  The Agency previously
reviewed spinosad dill seed residue data and recommended for a 1.7 ppm
spice (subgroup 19B; except black pepper) tolerance for the combined
residues of spinosyn A and D (3-4 x 0.156 lb ai/acre; RTI = 9-11 days;
PHI = 13-15 days; D335084, B. Hanson, 19-Sep-2007).  Based on this
conclusion; the proposed spinetoram application rate and that performed
in the spinosad dill seed field trials (2.5x/1.5-2.1x the proposed
single/seasonal application rate); and previous conclusions concerning
the translation of spinosad residues to spinetoram (see paragraph at the
beginning of this section); HED concludes that the available data
support a 1.7 ppm spice (subgroup 19B, except black pepper) tolerance
for the combined residues of XDE-175-J, XDE-1756-L, ND-J, and NF-J. 

Hops:  HED previously concluded that the spinosad dried basil residue
data (5 x 0.094 lb ai/acre; RTI = 4-6 days; PHI = 1 day) may be used in
support of the establishment of a spinosad hop tolerance; based on these
data, a dried hop tolerance of 22 ppm was established for the combined
residues of spinosyn A and D (D330231, T. Bloem, 19-Jul-2006).  Based on
this conclusion; the proposed spinetoram application rate and that
performed in the spinosad basil field trials (1.5x/1.5x the proposed
single/seasonal application rate); and previous conclusions concerning
the translation of spinosad residues to spinetoram (see paragraph at the
beginning of this section); HED concludes that the available data
support a 22 ppm dried hop tolerance for the combined residues of
XDE-175-J, XDE-1756-L, ND-J, and NF-J.

Pistachio and Tree Nuts:  HED has previously reviewed tree nut residue
data and recommended for a 0.10 ppm, 0.10 ppm, and 19 ppm pistachio,
tree nut (group 14), and almond hull tolerances, respectively, for the
combined residues of spinosyn A and D (4 x 0.154-0.158 lb ai/acre; RTI =
6-7 days; PHI = 1 day; D358163, T. Bloem, 27-May-2009).  Based on this
conclusion; the proposed spinetoram application rate and that performed
in the tree nut field trials (1.4x/1.1x the proposed single/seasonal
application rate); and previous conclusions concerning the translation
of spinosad residues to spinetoram (see paragraph at the beginning of
this section); HED concludes that the available data support the
following tolerance for the combined residues of XDE-175-J, XDE-1756-L,
ND-J, and NF-J:  pistachio - 0.10 ppm; tree nut (group 14) - 0.10 ppm;
and almond, hulls - 19 ppm.  A revised Section F is requested.  

OPPTS 860.1520 Processed Food and Feed

HED concluded that translation of the spinosad residue data and
tolerances to spinetoram for the numerous crops was acceptable. 
However, HED requested orange and grape processing studies to verify
that the spinosad and spinetoram residues of concern were partitioning
in a similar matter during processing.  The petitioner submitted the
requested studies and HED concluded that spinosad and spinetoram
residues of concern were partitioning in a similar matter and the
spinosad processing factors may be translated to spinetoram (D357703, T.
Bloem, 28-Apr-2009).  

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, based on the spinetoram pineapple tolerance of 0.04 ppm, HED
recommends for a pineapple process residue tolerance of 0.15 ppm for the
combined residues of XDE-175-J, XDE-175-L, ND-J, and NF-J.  

rotational crop data and the proposed application rates (≤0.46 lb
ai/acre), HED previously concluded that a 30-day plant-back interval for
all non-labeled crops was appropriate (D325387, T. Bloem, 12-Sep-2007;
D353933, T. Bloem, 28-August-2008).  Since the proposed spice rate is
0.305 lb ai/acre, HED concludes that the spice label should indicate
that a 30-day PBI for all nonlabeled crops.  A revised Section B is
requested.

860.1550 Proposed Tolerances

Table 7 is a summary of the proposed and HED-recommended tolerances for
the combined residues of XDE-175-J, XDE-175-L, ND-J, and NF-J (a revised
Section F is requested).  Codex, Canada, and Mexico do not have
spinetoram MRLs for the requested crops; therefore, harmonization is not
an issue.  

Table 7:  Tolerance Summary.

Proposed	HED-Recommended 

Commodity Definition	Tolerance (ppm)1	Commodity Definition	Tolerance
(ppm)1

almond, hulls	9.0	almond, hulls	19

nut, tree, group 14	0.08	nut, tree, group 14	0.10

pistachio	0.08	pistachio	0.10

date	0.1	date	0.10

pomegranate	0.3	pomegranate	0.30

pineapple

ee	0.02	pineapple	0.04

pineapple, process residue	0.08	pineapple, process residue	0.15

spice, subgroup 19B, except black pepper	1.7	spice, subgroup 19B, except
black pepper	1.7

hog, dried cones	22	hog, dried cones	22

1  Proposed and recommended tolerance expression for the combined
residues of XDE-175-J, XDE-175-L, ND-J, and NF-J.

Attachment 1:  IRLS Sheet.

Attachment 2:  Structures.

  SEQ CHAPTER \h \r 1 RDI:  RAB1 Chemists (13-May-2009)

T. Bloem:S10945:Potomac Yard 1:703-605-0217:7509P:RAB1

Attachment 1:  IRLS Sheet.

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:  XDE-175-J  SEQ CHAPTER \h \r 1 : 

(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-13-{[(2R,5S,6R)-5-(dimethylamino)-
6-methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-14-methyl-7,15-dioxo-2,3,3
a,4,5,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-octadecahydro-1H-as-indaceno
[3,2-d]oxacyclododecin-2-yl
6-deoxy-3-O-ethyl-2,4-di-O-methyl-alpha-L-mannopyranoside; XDE-175-L:

(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-13-{[(2R,5S,6R)-5-(dimethylamino)-
6-methyltetrahydro-2H-pyran-2-yl]oxy}-9-ethyl-4,14-dimethyl-7,15-dioxo-2
,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexadecahydro-1H-as-indaceno
[3,2-d]oxacyclododecin-2-yl
6-deoxy-3-O-ethyl-2,4-di-O-methyl-alpha-L-mannopyranoside; 	Common Name:
 spinetoram

	( Proposed tolerance

( Reevaluated tolerance

X Other:  HED recommended	Date:  11-May-2009

Codex Status (Maximum Residue Limits)	U. S. Tolerances

( No Codex proposal step 6 or above

√ No Codex proposal step 6 or above for the crops requested	Petition
Number:  8E7450

DP Barcode:  

Other Identifier:

Residue definition (step 8/CXL): 

Definition of the residue for compliance with MRLs: Spinetoram

Definition of the residue for estimation of dietary intake: Spinetoram
and N-demethyl and N-formyl metabolites of the major

spinetoram component. 	Reviewer/Branch:  Tom Bloem

	Residue definition:  XDE-175-J, XDE-175-L, ND-J; NF-J

Crop (s)	MRL (mg/kg)	Crop(s) 	Tolerance (ppm)

almond, hulls	19

nut, tree, group 14	0.10

pistachio	0.10

date	0.10

pomegranate	0.30

pineapple	0.04

pineapple, process residue	0.15

spice, subgroup 19B, except black pepper	1.7

hog, dried cones	22

Limits for Canada	Limits for Mexico

( No Limits

√  No Limits for the crops requested	√ No Limits

( No Limits for the crops requested

Residue definition:  XDE-175-J; XDE-175-L; ND-J; and NF-J	Residue
definition:  N/A

Crop(s)	MRL (mg/kg)	Crop(s)	MRL (mg/kg)

	Notes/Special Instructions:  S. Funk, 05/11/2009.

Attachment 2:  Structures.

 

N-demethyl-175-J

N-formyl-175-J

Spinosyn A

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4-methyl-α-L-mannopyranosyl)oxy]-13-[[(2R,5S,6R
)-5-(dimethylamino)tetrahydro-6-methyl-2H-pyran-2-yl]oxy]-9-ethyl-2,3,3a
,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahydro-14-methyl-1H-as-indacen
o[3,2-d]oxacyclododecin-7,15-dione

Spinosyn D

Spinetoram	Summary of Analytical Chemistry and Residue Data	D358160

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