UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

	OFFICE OF CHEMICAL SAFETY

	AND POLLUTION PREVENTION

  SEQ CHAPTER \h \r 1 MEMORANDUM

Date:   July 1, 2015

SUBJECT:	Cyprodinil.  Expansions of Existing Crop Group/Representative
Commodity Uses to Stone Fruit Group 12-12, and Adding New Uses on the
Artichoke, Guava, Pomegranate, Passionfruit, Feijoa,Jaboticaba, Wax
Jambu, Starfuit, and Acerola and Amended Uses on Greenhouse Cucumbers
and Small Tomatoes.   Summary of Analytical Chemistry and Residue Data. 

PC Code:  288202	DP Barcode:  D421157

Decision No.:  490951	Registration Nos.:  100-828, 100-953 and 100-1317

Petition No.:  4E8273	Regulatory Action:  Section 3

Risk Assessment Type:  NA	Case No.: 7025

TXR No.:  NA	CAS No.:  121552-61-2

MRID No.:  49346901 – 05	40 CFR:  180.532

		              									

FROM:		Thurston G. Morton, Chemist

	Risk Assessment Branch 4

	Health Effects Division (7509P)

THROUGH:	Charles Smith, Acting Branch Chief

	Risk Assessment Branch 4

		Health Effects Division (7509P)

		

			And

		Sheila Piper,Senior Chemist

		RAB6/HED, 7509P, Chemistry Science Advisory Council (ChemSAC)

		Sumitra Bose Biswas, Chemist

		RAB6/HED, 7509P, ChemSAC

TO:			Laura Nollen/Barbara Madden, RM20

		Minor Use & Emergency Response Branch

Registration Division (7505P)

	  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 

		

Executive Summary

Cyprodinil is an anilino-pyrimidine fungicide used to control various
plant diseases on a wide variety of fruit, nut, vegetable and herb
crops.  Under PP#4E8273, Interregional Research Project No. 4 (hereafter
referred to as IR-4), on behalf of the Agricultural Experiment Stations,
is requesting the establishment of tolerances for residues of cyprodinil
[4-cyclopropyl-6-methyl-N-phenyl-2-pyrimidinamin] in/on the following
raw agricultural commodities:

Artichoke…..	4.0 ppm

Guava	1.5 ppm

Passionfruit………………..………………….………………
.1.5 ppm

Feijoa………………..………………….………….………
….1.5 ppm
Jaboticaba………………..………………….……………..…
.1.5 ppm 

Wax
Jambu………………..………………….……………….1.5
ppm

Starfruit 	1.5 ppm

Acerola	1.5 ppm

Pomegranate	7.0 ppm

Fruit, stone, group 12-12……………...	2.0 ppm

In addition, IR-4 is requesting the removal of the currently established
tolerance for residues of cyprodinil in/on Fruit, stone, group 12 (2.0
ppm) once the fruit, stone, group 12-12 is established.

In conjunction with PP#4E8273, IR-4 is requesting a Section 3
registration for Vanguard™ WG (EPA Reg. No. 100-828), a 75% water
dispersible granule (WDG) formulation for use on artichoke, acerola,
feijoa, guava, jaboticaba, passionfruit, starfruit, and wax jambu;
Switch® 62.5 WG Fungicide (EPA Reg. No. 100-953), a 37.5% water
dispersible granule (WDG) formulation of cyprodinil for use on guava,
passionfruit, starfruit, and pomegranate (post-harvest); and Inspire
Super ™ Fungicide (EPA Reg. No. 100-1317), a 2.09 lb ai/gallon
emulsion oil in water (EW) formulation to artichoke.  In support of
these new uses, IR-4 has submitted new magnitude of the residue data for
cyprodinil using the WDG formulation of cyprodinil at the proposed use
rate.

In addition, IR-4 is requesting amendments for the Section 3
registrations for Vanguard™ WG (EPA Reg. No. 100-828) and Inspire
Super ™ Fungicide (EPA Reg. No. 100-1317) to expand currently
registered foliar uses for stone fruit group 12 to include the
additional commodities specified under the following new crop group: 
Fruit, stone, group 12-12.  No amendments to the use patterns (i.e.,
maximum use rates, retreatment intervals, preharvest intervals, use of
adjuvants, etc.) on the subject crops have been proposed.  No new
residue chemistry data were submitted to support these uses.  Instead
the petitioner wishes to rely on previously submitted residue chemistry
data which support the currently registered uses of cyprodinil.

In addition, IR-4 is proposing to remove the restriction against using
Vanguard™ WG (EPA Reg. No. 100-828) and Switch® 62.5 WG Fungicide
(EPA Reg. No. 100-953) on small tomatoes along with removing the
restriction against using Inspire Super ™ Fungicide (EPA Reg. No.
100-1317) on greenhouse cucumbers.  IR-4 has submitted new greenhouse
grown cucumber magnitude of the residue data to demonstrate that the
existing tolerance for residues of cyprodinil in/on vegetable, cucurbit,
group 9 (0.70 ppm) is adequate for the proposed use.  IR-4 has also
submitted new small tomato magnitude of the residue data to demonstrate
the existing tolerance for residues of cyprodinil in/on vegetable,
fruiting, group 8-10 (1.5 ppm) is adequate for the proposed use.

One of the products (EPA Reg. No. 100-1317) addressed herein contains a
second active ingredient (difenoconazole) and another product (EPA Reg.
No. 100-953) also contains a second active (fludioxonil). 
Difenoconazole and fludioxonil are addressed under separate reviews. 
The subject review addresses the proposed uses and supporting data for
cyprodinil only.  

The nature of cyprodinil residues in plants is understood based on
adequate metabolism studies on apple, peach, potato, tomato, and wheat. 
Only residues of parent cyprodinil need to be included in the tolerance
expression and considered for risk assessment for plant commodities.

The nature of cyprodinil residues in ruminants is also understood based
on an adequate goat metabolism study.  The residues of concern in
ruminants are cyprodinil and its hydroxylated metabolite CGA-304075
(free and conjugated).  No poultry metabolism study is available, but
HED has concluded that none is required.  There are no new livestock
feed stuffs associated with the proposed new uses of cyprodinil.

Adequate HPLC/UV methods (Methods AG-631 and AG-631B) are available for
enforcing tolerances of cyprodinil in/on plant commodities.  The limits
of quantitation (LOQ) for the plant methods range from 0.01 to 0.065 ppm
depending on the commodity.  An adequate LC/MS method (GRM010.01A) is
also available for enforcing tolerances of cyprodinil residues in
livestock commodities.  The method LOQ for this method is 0.02 ppm for
the combined residues of cyprodinil and its metabolite CGA-304075 (free
and conjugated), expressed as parent. 

In the submitted field trial study, residues of cyprodinil were
determined with a method using high performance liquid chromatography
with a tandem mass spectrometer (LC/MS/MS), which is a modified version
of the HPLC/UV Syngenta Method AG-631B, “Analytical Method for the
Determination of Residues of CGA-219417 in Crops by High Performance
Liquid Chromatography with Column Switching.”  Syngenta Methods AG-631
and AG-631B are the current tolerance enforcement methods for
determining cyprodinil in plant commodities.  

Cucumber, globe artichoke, guava, pomegranate, and tomato samples were
stored frozen (-20°C ± 10°C) for up to 12, 2, 22, 11, and 10 months
before analysis, respectively.  The stability of cyprodinil has been
demonstrated in a variety of other crops, including mustard greens for
20 months and grape, wine, apple, wheat (ear and stalk), strawberry, and
potato for up to 2 years.  Therefore, the submitted field trial data are
supported by acceptable storage stability data.  

Data are adequate to support the proposed uses of cyprodinil.  The HAFT
residue level of cyprodinil in greenhouse cucumber, globe artichoke,
guava, and small greenhouse tomato resulting from four applications for
a seasonal rate of 1.3 lb cyprodinil a.i./A was 0.58,  1.33, 0.522, and
1.12 ppm,  respectively. Maximum residue levels of cyprodinil were 0.62
ppm in greenhouse cucumber, 1.52 ppm in globe artichoke, 0.626 ppm in
guava, and 1.28 ppm in small greenhouse tomato.  The HAFT residue level
and maximum residue level of cyprodinil resulting from post-harvest
treatment of pomegranate were 3.42 and 3.60 ppm, respectively.  There
are an adequate number of field trials from representative geographical
locations.  

The Organization for Economic Cooperation and Development (OECD)
tolerance calculation procedures were used to determine appropriate
tolerance levels.  A tolerance level of 10 ppm for pomegranate, 4.0 ppm
for globe artichoke, and 1.5 ppm for guava is appropriate.  The 1.5 ppm
tolerance for guava was translated to acerola, feijoa, jaboticaba,
passionfruit, starfruit, and wax jambu, in accordance with
“Reviewer’s Guide and Summary of HED ChemSAC Approvals for Amending
Crop Group/Subgroups [40 CFR 180.41] and Commodity Definitions [40 CFR
180.1(h)]” (B. Schneider, 6/14/06).  Note that the recommended
tolerance level for pomegranate is different than that petitioned-for by
the registrant due to the decision that each of the post-harvest
scenarios/techniques represented by the data constitutes separate
datasets for tolerance determination with the OECD tolerance calculation
procedures.

No Codex MRLs are established in/on globe artichoke, acerola, feijoa,
guava, jaboticaba, passionfruit, starfruit, wax jambu, and pomegranate. 
Canadian and Mexican MRLs has not been established for the requested
crops.  The Agency will be harmonized with Codex on the fruit, stone,
group 12-12 MRL of 2.0 ppm.  

  SEQ CHAPTER \h \r 1 Regulatory Recommendations and Residue Chemistry
Deficiencies

HED has examined the residue chemistry database for cyprodinil.  With
regards to cyprodinil for PP#4E8273, pending submission of a revised
Section B (see requirements under Directions for Use) and a revised
Section F (see requirements under Proposed Tolerances), there are no
residue chemistry issues that would preclude granting amended 
registrations for Vanguard™ WG (EPA Reg. No. 100-828), Switch® 62.5
WG Fungicide (EPA Reg. No. 100-953), and Inspire Super ™ Fungicide
(EPA Reg. No. 100-1317) to expand currently registered foliar uses for
globe artichoke, acerola, feijoa, guava, jaboticaba, passionfruit,
starfruit, wax jambu, and pomegranate; along with the expansion of
fruit, stone, group 12-12 or establishment of tolerances for residues of
cyprodinil only in/on the following commodities:

Artichoke, globe…..	4.0 ppm

Guava	1.5 ppm

Passionfruit………………..………………….………………
.1.5 ppm

Feijoa………………..………………….………….………
….1.5 ppm
Jaboticaba………………..………………….……………..…
.1.5 ppm 

Wax
Jambu………………..………………….……………….1.5
ppm

Starfruit 	1.5 ppm

Acerola	1.5 ppm

Pomegranate…………………………………………………...1
0 ppm

Fruit, stone, group 12-12……………...	2.0 ppm

In addition, the restriction on use of Switch® 62.5 WG Fungicide (EPA
Reg. No. 100-953) and Vanguard™ WG (EPA Reg. No. 100-828) on small
size tomato may be removed.  The restriction on use of Inspire Super ™
Fungicide (EPA Reg. No. 100-1317) on greenhouse cucurbits may also be
removed.

The approved amended registrations for Vanguard™ WG (EPA Reg. No.
100-828), Switch® 62.5 WG Fungicide (EPA Reg. No. 100-953), and Inspire
Super ™ Fungicide (EPA Reg. No. 100-1317) are limited to expansions to
add the commodities specified under the new crop groups/subgroups and do
not include substantive changes to currently registered use patterns
(i.e., maximum use rates, retreatment intervals, preharvest intervals,
use of adjuvants, etc.).  

A human health risk assessment is forthcoming.

860.1200 Directions for Use – Pertains to Cyprodinil Only

Section B of petition 4E8273 pertaining to uses on artichoke should be
revised to specify globe artichoke only.  [Note:  IR-4 submitted draft
supplemental labels which are substantially similar to Section B of the
petition and should be amended as well.]  

860.1550 Proposed Tolerances

Section F of petition 4E8273 must be revised as follows.  The
recommended tolerance for residues of cyprodinil in/on pomegranate (10
ppm) is not the same as the petitioned-for tolerance (7.0 ppm) due to
the decision that data reflecting each of the three post-harvest
scenarios/techniques constitute separate datasets for tolerance
determination with the OECD tolerance calculation procedures.  In
addition the commodity definition should be for Artichoke, globe. 

Background

Cyprodinil is an anilino-pyrimidine fungicide used to control various
plant diseases on a wide variety of fruit, nut, vegetable and herb
crops.  Tolerances for residues of cyprodinil have been established
in/on a variety of crop commodities at levels ranging from 0.02-170 ppm
[40 CFR §180.532].  Tolerances have also been established at 0.02 ppm
for cyprodinil residues in meat byproducts of cattle, goats, horses, and
sheep.  No tolerance is established for poultry byproducts.  

The chemical structure, nomenclature, and physicochemical properties of
the technical grade of cyprodinil are presented in Tables 1 and 2.

 

Table 1.	Cyprodinil Nomenclature.

Compound	

Common name	Cyprodinil

Company experimental name	CGA219417

IUPAC name	(4-cyclopropyl-6-methyl –pyrimidin-2-yl)-phenyl-amine

CAS name	2-pyrimidinamine, 4-cyclopropyl-6-methyl-N-phenyl-

CAS registry number	121552-61-2

End-use product (EP)	75% water-dispersible granule formulation
(Vangard® WG Fungicide; EPA Reg. No. 100-828); a multiple active
ingredient (MAI) end-use product (Inspire Super ™ Fungicide; EPA Reg.
No. 100-1317) formulated as an emulsion [oil] in water (EW), containing
8.4% difenoconazole and 24.1% cyprodinil



Table 2.	Physicochemical Properties of Technical Grade of Cyprodinil.

Parameter	Value	Reference

Melting point/range	75.9 0C	DP#s 345970 and 345182, W. Cutchin, 6/4/08

pH	9.5 at 25 0C (1% aqueous dispersion)

	Density	1.21 g/cm3 at 20 0C

	Water solubility (mg/L at 25 C)	pH 7.6		16

  SEQ CHAPTER \h \r 1 pH 5		20

pH 7		13

pH 9		15

	Solvent solubility (g/L at 25 C)	ethanol		160

acetone		610

toluene		460

n-octanol		160

n-hexane		30

	Vapor pressure	3.8 x 10-6 mm Hg at 25 0C

	Dissociation constant, pKa	4.44 at 20 0C

	Octanol/water partition coefficient, Log(KOW) at 25 C	3.9 at pH 5

4.0 at pH 7

4.0 at pH 9

	UV/visible absorption spectrum

(molar absorption coefficients for the absorbance maximum)	29,200
l/mol∙cm at 270.8 nm (neutral)

29,200 l/mol∙cm at 251.6 nm (acidic)

29,200 l/mol∙cm at 316.8 nm (acidic)

28,400 l/mol∙cm at 270.8 nm (basic)

	

860.1200  Directions for Use

Table 3.	Summary of Proposed Directions for Use of Cyprodinil

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Artichoke1

Broadcast foliar

Ground/Aerial/Chemigation	Vangard WG

75% WDG

[100-828]	0.33	4 implied	1.3	3	A minimum retreatment interval (RTI) of
14 days is proposed.  

Broadcast foliar

Ground Only	Inspire Super

2.09 lb/gal EW

[100-1317]	0.33	4 implied	1.3 	3	A minimum retreatment interval (RTI) of
7-10 days is proposed.

Acerola, feijoa, guava, jaboticaba, passionfruit, starfruit, wax jambu

Broadcast foliar

Ground/Aerial/Chemigation	Vangard WG

75% WDG

 [100-828]	0.33	2 by aerial

4 implied	1.3	0	A minimum retreatment interval (RTI) of 7-10 days is
proposed.

Broadcast foliar

Ground Only	Switch 62.5WG

37.5% WDG

 [100-953]	0.33	1 by aerial

4 implied	1.3	0	A minimum retreatment interval (RTI) of 7-10 days is
proposed.  Aerial application in California only.

Pomegranate (Post-harvest dip/drench)

In-Line Dip/Drench	Switch 62.5WG

37.5% WDG

 [100-953]

	0.45 lb ai/100 gal of water, wax/emulsion, or aqueous dilution of
wax/oil emulsion

	1-2

	0.45-0.90 lb ai/100 gal of water, wax/emulsion, or aqueous dilution of
wax/oil emulsion 	0	For maximum decay control, treat fruit once before
storage and once after storage, prior to marketing.



Green House Grown Cucumbers

Broadcast foliar

Ground Only	Inspire Super

2.09 lb/gal EW

[100-1317]	0.0075 lb ai/1000 ft2	NS	NS 	7	A minimum retreatment interval
(RTI) of 7-10 days is proposed.

1 Although not specified in the use directions, the use on artichoke is
intended to be for globe artichoke consistent with the supporting data.

Conclusions.  The proposed use directions are sufficient to allow for
evaluation of the available residue data.  

860.1300 Nature of the Residue - Plants

DP# 219794, G. Kramer, 2/13/96 

DP# 233182, G. Kramer, 2/20/98 

MARC Decision Memo, DP# 243198, G. Kramer, 3/11/98

The nature of the residue in plants is adequately understood based on
acceptable metabolism studies on apple, peach, potato, tomato, and
wheat.  These studies indicated that cyprodinil is metabolized primarily
by hydroxylation followed by sugar conjugation.  Cleavage of the amino
bridge, opening of the pyrimidine ring, opening of the cyclopropyl ring
and formation of thiolactic acid conjugates are minor pathways. 
Incorporation into starch was observed in potato tubers and wheat grain.
 The MARC reviewed these studies and determined that the residue of
concern, for purposes of tolerance enforcement and risk assessment, is
cyprodinil. 

860.1300 Nature of the Residue - Livestock

DP# 233182, G. Kramer, 2/20/98 

MARC Decision Memo, DP# 243198, G. Kramer, 3/11/98

DP# 345970 and 345182, G. Kramer, 6/4/08

DP# 362486, J. Stokes, 9/15/09

The nature of the residue in ruminants is adequately understood based on
acceptable lactating goat metabolism studies using [14C-phenyl] and
[14C-pyrimidinyl] cyprodinil.  The metabolism of cyprodinil in ruminants
proceed predominantly via hydroxylation followed by conjugation with
sulfuric and glucuronic acid.  Breakdown of the pyrimidinyl ring was
seen only in the liver and resulted in Metabolite L1.  Cleavage of the
amino bridge between the phenyl and the pyrimidinyl rings was only a
minor reaction as indicated by the small amounts of CGA 249287 found in
the liver and kidneys of goats dosed with [14C-pyrimidinyl]cyprodinil.

HED originally concluded there were no cyprodinil metabolites of
toxicological or regulatory concern in ruminant milk and tissues based
on the dietary burden associated with the registered cyprodinil uses at
that time (362486, J. Stokes, 09/15/09; 378920, B. Cropp-Kohlligian,
10/27/10).  However, HED noted that if future uses significantly
increase the potential livestock dietary burden, then a new cyprodinil
feeding study would be required in which residues of cyprodinil and CGA
304075 (both free and conjugated) are determined.  ARIA subsequently has
concluded that the residues of concern for both risk assessment and the
tolerance definition should include the combined residues of cyprodinil
and metabolite CGA-304075 (free and conjugated), expressed in parent
equivalents.

A poultry metabolism for cyprodinil has not been submitted and none has
been requested since the potential dietary exposure of poultry to
cyprodinil residues is extremely low (estimated at 0.005 ppm based on
canola meal consumption).  There is no reasonable expectation of finite
residues in poultry and egg.  However, if future crops are added that
substantially increase the poultry dietary burden, then HED may require
a study.

Summary of Metabolites and Degradates to be included in the Risk
Assessment and Tolerance Expression for Cyprodinil 

Matrix	Risk Assessment 	Tolerance Expression

Plants	cyprodinil	cyprodinil

Livestock	cyprodinil and CGA-304075	cyprodinil and CGA-304075

Water	cyprodinil and CGA 249287	NA



860.1340 Residue Analytical Methods

Enforcement methods.  Adequate HPLC/UV methods with column switching
(Syngenta Methods AG-631 and AG-631B) are available for enforcing
tolerances of cyprodinil on plant commodities.  The LOQs for these
methods range from 0.01 to 0.065 ppm depending on the plant commodities.
 Method AG-631B also contains procedures for confirmatory analysis by
GC/NPD.  

An adequate HPLC/MS method (GRM010.01A) is also available for enforcing
tolerances in livestock commodities.  This method determines residues of
both parent and the metabolite CGA-304075 (free and conjugated),
expressed as parent.  The LOQ is 0.01 ppm for each analyte for a
combined LOQ of 0.02 ppm.

Data collection methods.   In the submitted field trial studies,
residues of cyprodinil were determined with a method using high
performance liquid chromatography with a tandem mass spectrometer
(LC/MS/MS), which is a modified version of the HPLC/UV Syngenta Method
AG-631B, “Analytical Method for the Determination of Residues of
CGA-219417 in Crops by High Performance Liquid Chromatography with
Column Switching.”  Syngenta Methods AG-631 and AG-631B are the
current tolerance enforcement methods for determining cyprodinil in
plant commodities

For method AG-631B, residues of cyprodinil were extracted with
methanol:water (8:2, v/v), filtered, and acidified with dilute HCl. 
Residues were then cleaned-up by elution through a SPE column with
ammoniated methanol.  Residues were concentrated, reconstituted with
0.1% ammonium acetate, and analyzed by LC/MS/MS using a Phenomenex
Synergi 4 micron Polar-RP 80A column (75 x 2.00 mm) and a
multi-component mobile phase (Component A was 0.1% ammonium acetate in
water and Component B was 90/10 acetonitrile:water plus 0.1% ammonium
acetate) with gradient elution.  The m/z 226.1→93.1 ion transition was
used for detection and quantitation of cyprodinil.  Residues were
quantified using external standards. The validated LOQ was 0.01 ppm; the
LOD was not reported. 

The method was validated in conjunction with the analysis of field trial
samples.  Control samples of were fortified with cyprodinil at 0.01-2.1
ppm.  Recoveries ranged from 70-109%.  Control samples were fortified
with cyprodinil at 0.02-10 ppm.  Recoveries ranged from 68-112%.  

Conclusions.  Adequate HPLC/UV methods are available for enforcing the
proposed new uses.  

All residues of cyprodinil were determined using an adequate HPLC/UV or
LC/MS/MS method.  

860.1360 Multiresidue Methods

G. Kramer, 11/28/1995

Data are available depicting the recovery of cyprodinil and its
metabolite CGA-232449 through FDA Multiresidue method testing protocols
(C through E).  Acceptable recoveries were obtained for cyprodinil in
apple fortified at 0.50 ppm using Protocol D.  These data were forwarded
to FDA.

860.1380 Storage Stability

D233182, G. Kramer, 02/20/98

D288706, T. Bloem ,7/24/03

Cucumber, globe artichoke, guava, pomegranate, and tomato samples were
stored frozen (-20°C ± 10°C) for up to 12, 2, 22, 10, and 11 months
before analysis, respectively.  The stability of cyprodinil has been
demonstrated in a variety of other crops, including mustard greens for
20 months and grape, wine, apple, wheat (ear and stalk), strawberry, and
potato for up to 2 years.  Therefore, the submitted field trial data are
supported by acceptable storage stability data.  

860.1400 Water, Fish, and Irrigated Crops

The proposed uses are not relevant to this guideline.

860.1460 Food Handling

The proposed uses are not relevant to this guideline.

860.1480 Meat, Milk, Poultry, and Eggs

DP#s 345970 and 345182, W. Cutchin, 6/4/08

DP# 362484, J. Stokes, 9/15/09

DP# 378920, B. Cropp-Kohilligian, 10/27/10

Adequate cattle feeding studies are available for cyprodinil, and
tolerances for cyprodinil residues in livestock commodities were
assessed in conjunction with petitions for tolerances on various plant
commodities.  Using the Agency’s most recent guidance on constructing
reasonably balanced livestock diets the maximum reasonably dietary
burdens (MRDBs) of livestock for cyprodinil residues were calculated to
be 0.88 ppm for beef cattle, 1.2 ppm for dairy cattle, and 0.005 ppm for
poultry and swine.  Based on these MDBs, tolerances for residues of
cyprodinil and free and conjugated CGA-304075, expressed in parent
equivalents, were required on meat byproducts of cattle, goats, horses,
and sheep at 0.02 ppm (LOQ).  

Previously, HED recalculated the dietary burden using almond hull in
place of wet apple pomace.  The dietary contribution from the almond
hulls alone did not increase the total dietary burden.  However, this
proposed amended use on almonds was withdrawn and the increased
tolerance for almond hulls did not occur.

Conclusions.  The proposed new uses do not contain any livestock feed
stuffs, therefore, HED has determined that the currently established
0.02 ppm tolerance levels for meat byproducts of cattle, goats, horses,
and sheep are adequate. 

860.1500 Crop Field Trials

MRID #s 49346901, 49346902, 49346903, 49346904, & 49346905

DP# 354013, 3/20/09, B. Cropp-Kohlligian

  SEQ CHAPTER \h \r 1 The results from the field trials are summarized
below  SEQ CHAPTER \h \r 1 .

Cucumber (Greenhouse) Small and Large Varieties

Following four applications of a 2.09 lb ai/gal EW formulation at a
total application rate of 1.30–1.33 lbs ai/A, individual sample (and
per-trial average) residues of cyprodinil were 0.08–0.62 ppm
(0.11–0.58 ppm) in/on cucumber fruit collected at a PHI of 0 days. 
There were no significant differences between the residues in the large
variety cucumbers vs. the small variety cucumbers.  

Table 4.  Summary of Residues from Cucumber (Greenhouse) Field Trials
with EW Formulation of Cyprodinil.

Crop Matrix	Total Application Rate

(lb ai/A)	PHI (days)	n1	Residues (ppm)





Min.2	Max.2	LAFT3	HAFT3	Median3	Mean3	SD3

Cyprodinil

Cucumber (Large and Small), fruit	1.3030–1.3276	0	5	0.08	0.62	0.11
0.58	0.34	0.32	0.20

1  n = number of field trials.

2  Values based on total number of samples.

3  Values based on per-trial averages.  LAFT = lowest average field
trial, HAFT = highest average field trial, SD = standard deviation.  For
computation of the LAFT, HAFT, median, mean, and standard deviation,
values < LOQ are assumed to be at the LOQ.  The LOQ was 0.015 ppm for
cyprodinil in all matrices.

Artichoke, globe

Following four or five applications of a 2.09 lb ai/gal EW formulation
at a total application rate of 1.300–1.655 lbs ai/A, individual
sample (and per-trial average) residues of cyprodinil were 0.825–1.52
ppm (0.932–1.33 ppm) in/on mature globe artichoke flower buds
collected at a PHI of 3 days.  There were no significant differences
between the residues in the perennial globe artichokes vs. the annual
globe artichokes.  

Table 5.	Summary of Residues from Globe Artichoke Field Trials with EW
Formulation of Cyprodinil.

Crop Matrix	Total Application Rate

(lb ai/A) 4	PHI (days)	n1	Residues (ppm)





Min.2	Max.2	LAFT3	HAFT3	Median3	Mean3	SD3

Cyprodinil

Globe artichoke, mature flower buds	1.300–1.655	3	4	0.825	1.52	0.932
1.33	1.22	1.17	0.18

1  n = number of field trials.

2  Values based on total number of samples.

3  Values based on per-trial averages.  LAFT = lowest average field
trial, HAFT = highest average field trial, SD = standard deviation.  For
computation of the LAFT, HAFT, median, mean, and standard deviation,
values < LOQ are assumed to be at the LOQ.  The LOQ was 0.01 ppm for
cyprodinil in all matrices.

4 Calculated by the reviewer.

Side-by-side field trial data on lettuce, mustard greens and tomatoes
comparing residues of cyprodinil resulting from multiple late season
uses of the EW formulation with a WDG formulation of cyprodinil are
available (DP# 354013, 3/20/09, B. Cropp-Kohlligian).  Cyprodinil
residues were similar for the EW and WDG formulations on all three
crops.  

Guava

Following four applications of Switch 62.5WG at a total application rate
of 1.31–1.43 lbs ai/A, individual sample (and per-trial average)
residues of cyprodinil were 0.345–0.626 ppm (0.353–0.522 ppm) in/on
guava fruit collected at a PHI of 0 days.  

Table 6.	Summary of Residues from Guava Field Trials with WDG
Formulation of Cyprodinil.

Crop Matrix	Total Application Rate

(lb ai/A) 4	PHI (days)	n1	Residues (ppm)





Min.2	Max.2	LAFT3	HAFT3	Median3	Mean3	SD3

Cyprodinil

Guava fruit	1.31–1.43	0	4	0.345	0.626	0.360	0.522	0.487	0.464	0.07

1  n = number of independent field trials.

2  Values based on total number of samples.

3  Values based on per-trial averages.  LAFT = lowest average field
trial, HAFT = highest average field trial, SD = standard deviation.  For
computation of the LAFT, HAFT, median, mean, and standard deviation,
values < LOQ are assumed to be at the LOQ.  The LOQ was 0.01 ppm for
cyprodinil in all matrices.

4 Calculated by the reviewer.

Pomegranate (Post-Harvest)

Data reflect three different post-harvest treatment scenarios/techniques
of 1 or 2 applications using a water dispersible granule (WDG)
formulation of cyprodinil (Switch 62.5WG™).  Each of these
post-harvest scenarios/techniques are considered separate/discrete
datasets for tolerance determination.  Following one application as a
dip with wax at 0.45 lb ai/100 gal, individual sample (and per-trial
average) residues of cyprodinil were 0.24-1.60 ppm (0.93-1.52 ppm) in/on
pomegranate collected on the day of treatment.  Following a total of two
applications, one application as a dip with wax at 0.45 lb ai/100 gal
and a second application as a dip with no wax at 0.45-0.46 lb ai/100
gal, individual sample (and per-trial average) residues of cyprodinil
were 2.22-3.60 ppm (2.56-3.42 ppm) in/on pomegranate treated and
collected on the same day.  Following a total of two applications, one
application as a dip with wax at 0.45-0.46 lb ai/100 gal and then a
drench application with no wax at 0.45-0.46 lb ai/100 gal, individual
sample (and per-trial average) residues of cyprodinil were 0.38-2.69 ppm
(0.53-2.25 ppm) in/on pomegranate treated and collected on the same day.
 

Table 7.  Summary of Residues from Pomegranate Post-Harvest Trials with
WDG Formulation of Cyprodinil.

Crop Matrix	Total Application Rate

(oz ai/100gal)1/

[lb ai/100 gal]1	PHI (days)	n2	Residues (ppm)





Min.3	Max.3	LAFT4	HAFT4	Median4	Mean4	SD4

Cyprodinil

Pomegranate	7.2 / [0.45] 5	0	4	0.24	1.60	0.93	1.52	1.155	1.02	0.576

Pomegranate	14.4-14.6 / [0.9] 6	0	4	2.22	3.60	2.56	3.42	3.260	3.13	0.384

Pomegranate	14.4-14.6 / [0.9] 7	0	4	0.38	2.69	0.53	2.25	1.845	1.55	0.893

1  Calculated by the reviewer.

2  n = number of independent trials.

3  Values based on total number of samples.

4  Values based on per-trial averages.  LAFT = lowest average field
trial, HAFT = highest average field trial, SD = standard deviation.  For
computation of the LAFT, HAFT, median, mean, and standard deviation,
values < LOQ are assumed to be at the LOQ.  The LOQ was 0.01 ppm for
cyprodinil in all matrices.

5  One application as a dip with wax. 

6  Total of two applications.  One application as a dip with wax
(0.45-0.46 lb ai/100 gal) and a second application as a dip with no wax
(0.45-0.46 lb ai/100 gal).  Applications were allowed to dry before the
second application was applied.  Samples were treated and collected on
the same day.

7  Total of two applications.  One application as a dip with wax
(0.45-0.46 lb ai/100 gal) and then a drench application with no wax
(0.45-0.46 lb ai/100 gal).  Applications were allowed to dry before the
second application was applied.  Samples were treated and collected on
the same day.

Tomato (Greenhouse) Small Varieties

Following four applications of a 37.5% water dispersible granule (WDG)
formulation at a total application rate of 1.31-1.33 lb ai/A, individual
sample (and per-trial average) residues of cyprodinil were 0.278–1.28
ppm (0.317–1.12 ppm) in/on tomato fruit collected at a PHI of 0 days. 


Table 8.	Summary of Residues from Tomato (Greenhouse) Small Variety
Field Trials with WDG Formulation of Cyprodinil.

Crop Matrix	Total Application Rate

(lb ai/A)4	PHI (days)	n1	Residues (ppm)





Min.2	Max.2	LAFT3	HAFT3	Median3	Mean3	SD3

Cyprodinil

Tomato fruit	1.31-1.33	0	3	0.278	1.28	0.317	1.12	0.365	0.600	0.45

1  n = number of independent field trials.

2  Values based on total number of samples.

3  Values based on per-trial averages.  LAFT = lowest average field
trial, HAFT = highest average field trial, SD = standard deviation.  For
computation of the LAFT, HAFT, median, mean, and standard deviation,
values < LOQ are assumed to be at the LOQ.  The LOQ was 0.01 ppm for
cyprodinil in all matrices.

4 Calculated by the reviewer.

Conclusion: The data adequately support the requested tolerances and
proposed use patterns. 

860.1520 Processed Food and Feed 

None of the new uses have processed commodities that require a
processing study.

860.1550 Harmonization with Codex

No Codex MRLs are established in/on globe artichoke, acerola, feijoa,
guava, jaboticaba, passionfruit, starfruit, wax jambu, and pomegranate. 
Canadian and Mexican MRLs have not been established for the requested
crops.  The Agency with be harmonized with Codex on the fruit, stone,
group 12-12 MRL of 2.0 ppm.  

  SEQ CHAPTER \h \r 1 860.1650 Submittal of Analytical Reference
Standards

Analytical standards for cyprodinil (expiration date 7/30/2018) and
CGA-304075 (expiration date 8/31/2016) are currently available in the
EPA National Pesticide Standards Repository (email communication with T.
Cole, ACB, 04/08/2015).  

860.1850/1900 Confined and Field Accumulation in Rotational Crops

DP# D257898, S. Levy, 2/8/2000

DP# D326346, W. Wassell, 10/18/2006

Adequate confined and limited field rotational crop studies are
available and were conducted at 2.2x and 1.5x the current maximum use
rate for rotated crops (1.3 lb ai/A).  On the basis of these studies,
the HED requested a field rotational crop study which also monitored for
residues of CGA-232449, NOA-422054, CGA-249287, and CGA-263208.  

In the subsequent field accumulation study, cyprodinil (WDG) was applied
to mustard greens at four test sites in CA (2 tests) and NY (2 tests) as
four broadcast foliar applications at 0.328 lb ai/A/application at 7-day
retreatment intervals for a total of 1.31 lb ai/A (1x rate).  The
primary mustard greens crop was destroyed and removed 7 days after the
final application, and rotational crops of wheat, lettuce and garden
beets were planted at PBIs of 27 to 32 days.  Samples of lettuce, garden
beet roots and tops, and wheat forage, hay, straw and grain were
collected from each test at the appropriate stage of maturity.  All
samples were analyzed for residues of parent and each metabolite
(CGA-232449, NOA-422054, CGA-249287, and CGA-263208) using an adequate
HPLC/MS method (Method 2213-01), which has a validated LOQ of 0.05 ppm
for parent and each metabolite.  

As residues of parent and each metabolite were <LOQ in/on all lettuce,
garden beet and wheat RAC samples, HED concluded that rotational crop
tolerances are not currently required.

860.1550 Proposed Tolerances

The Agency has determined that the residue of concern in plant
commodities for the tolerance expression is only cyprodinil.  
Tolerances have been established for residues of cyprodinil in/on a
variety of crop commodities, at levels ranging from 0.02 ppm in/on
almond to 340 ppm in citrus oil [40 CFR §180.532(a)].  Tolerances have
also been established at 0.02 ppm for cyprodinil and its metabolite
CGA-304075 residues in meat byproducts of cattle, goats, horses and
sheep.  

Table 8. 	Tolerance Summary for Cyprodinil

Commodity	Established/Proposed Tolerance (ppm)	Recommended Tolerance
(ppm)	Comments; Correct Commodity Definition

Tolerances Proposed Under PP#4E8273

Artichoke	4.0	4.0	Artichoke, globe

Guava	1.5	1.5	---

Passionfruit	1.5	1.5	---

Feijoa	1.5	1.5	---

Jaboticaba	1.5	1.5	---

Wax Jambu	1.5	1.5	---

Starfruit	1.5	1.5	---

Acerola	1.5	1.5	---

Pomegranate	7.0	10	---

Fruit, stone, group 12-12	2.0	2.0	---



References

DP Numbers:	378920

Subject:		Cyprodinil.  Cyprodinil.  Amended Use and Amended Tolerance
Petition for Pome Fruit.  Summary of Analytical Chemistry and Residue
Data. 

From:		B. Cropp-Kohlligian

To:		L. Jones

Dated:		10/27/10

MRID(s):	47644301

DP Numbers:	362486

Subject:		Cyprodinil.  Petition for Tolerance on Canola Seed Imported
from Canada.  Summary of Analytical Chemistry and Residue Data.  

From:		J. Stokes

To:		L. Jones

Dated:		09/15/09

MRID(s):	47644301

DP Numbers:	345970 and 345182

Subject:		Cyprodinil.  Section 3 Requests for Uses on Tomato, Avocado,
Herbs, Root Vegetables, Leaves of Root and Tuber Vegetables, Lemon,
Lime, Cucurbits, Kiwifruit, Green and Dry Bulb Onions, and Strawberries.
 Registrant’s Response to Conditional Registration on Carrots and
Brassica Vegetables and Livestock Feeding Study.  Summary of Analytical
Chemistry and Residue Data.  

From:		W. Cutchin

To:		W. Cutchin/B. Madden

Dated:		06/04/08

MRID(s):	47161101-47161107 and 47169305-47169311

DP Number:	326346

Subject:		Registration:  100-953; PP#8E05012; Cyprodinil on Onions. 
Review of Revised Label, Field Accumulation in Rotational Crops, Storage
Stability, and Analytical Methods Data Requested as Conditions of
Registration.

From:	W. Wassell

To:	L. Jones/M. Waller

Dated:	10/18/06

MRID(s):	46078901, 46078903, 46165901

DP Number:	288706, 288708, 288710, and 288773

Subject:		Cyprodinil (PC Code 288202).  Section 3 Registration for
Application of Cyprodinil to Lychee, Longan, Spanish Lime, Rambutan, and
Pulasan (ID# - 2E06447); Brassica Leafy Greens Crop Subgroup, Head and
Stem Brassica Crop Subgroup, and Turnip Greens (ID# - 2E06485); Carrot
(ID# - 2E06461); and Herb Crop Subgroup (ID# - 3E06529).  Summary of
Residue Chemistry Data. 

From:		T. Bloem

To:		R. Forrest

Dated:		07/24/03

MRID(s):	45682401, 45721502, 45726101, 45726102, 45795301, 45795302, and
45839801

DP Number:	257898

Subject:	PP# 8E05012.  Cyprodinil in/on Strawberries and Bulb Vegetables
(Crop Group 3).  Evaluation of Residue Data and Analytical Methods.  

From:	S. Levy

To:	R. Forrest/S. Brothers

Dated:	02/08/00

MRID(s):	44615602, 44615601, 44867312, 44867314

DP Numbers:	243198

Subject:	Cyprodinil.  HED Metabolism Assessment Review Committee Meeting
of 02/10/98.

From:	G. Kramer

To:	HED MARC Members

Dated:	03/11/98

MRID(s):	None

DP Numbers:	233561, 233562, 233928, 233182, 239674, and 236086

Subject:	PP# 6F04656. New Chemical- Cyprodinil (i.e., Vangard®) in/on
Stone Fruit, Pome Fruit, Almonds and Grapes. Evaluation of Residue Data
and Analytical Methods.  

From:	G. Kramer

To:	M. Waller/T. Ellwanger

Dated:	02/20/98

MRID(s):	44186401, 44186404 and 44186410 thru 44186420; 43908402,
43908403 and 43908438 thru 43908445; 44382601; and 44275401 and 44275402

DP Number:	219794

Subject:	PP#s 5G04553.  New Chemical – Cyprodinil and Propiconazole in
or on Stone Fruit.  Evaluation of Residue Data and Analytical Methods.

From:	G. Kramer

To:	C. Welch/ K. Whitby

Dated:	02/13/96

MRID(s):	43709001 through 43709004, 43709048 through 43709055, and
43737603

DP Number:	None

Subject:	Multiresidue Method Testing Data for Cyprodinil and CGA-232449

From:	G. Kramer

To:	B. McMahon, FDA

Dated:	11/28/95

MRID(s):	43709050

  SEQ CHAPTER \h \r 1 Attachments:  

Appendix I - International Tolerances

Appendix II – Tolerance Assessment Calculations

F.	DOCUMENT TRACKING

RDI:  C. Smith 07/01/15

Petition Number: 4E8273

DP#: 421157

PC Code: 288202

Template Version September 2005 

Appendix I.  International Tolerances

Cyprodinil (PC Code 288202; 03/12/15)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: 

US	Canada	Mexico2	Codex

40 CFR 180.532:

Plant: Cyprodinil (4-cyclopropyl-6-methyl-N-phenyl-2-pyrimidinamine).
4-cyclopropyl-6-methyl-N-phenyl-2-pyrimidinamine

Cyprodinil

The residue is fat soluble.

Commodity1	Tolerance (ppm) /Maximum Residue Limit (mg/kg)

	US	Canada	Mexico2	Codex

Artichoke, globe	4.0



	Guava	1.5 



	Passionfruit	1.5



	Feijoa	1.5



	Jaboticaba	1.5



	Wax Jambu	1.5



	Starfruit 	1.5



	Acerola	1.5



	Pomegranate	10



	Fruit, stone, group 12-12	2.0

	2



















Completed: M. Negussie; 03/19/15

1 Includes only commodities of interest for this action.  Tolerance
values should be the HED recommendations and not those proposed by the
applicant.

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

Appendix II.  Tolerance Assessment Calculations.

For each of the crops listed below, the OECD MRL Calculator User Guide
(SOP), along with the tolerance spreadsheet, was used for calculating
recommended tolerances.  As specified in the SOP, the tolerance
calculation is in the region of the 95th percentile of the underlying
residue distribution, and is more likely to overestimate rather than
underestimate the 95th percentile.  The rounding procedures specified in
the SOP were also used.  The OECD tolerance spreadsheet does not require
the use of maximum-likelihood estimation (MLE) procedures for values
<LOQ.

Using the OECD MRL Calculator, the recommended tolerances are 1.5 ppm
for guava, 10 ppm for pomegranate, and 4.0 ppm for globe artichoke.    

Cyprodinil

Guava

US

1.31-1.43 lb ai/A

 	 

Total number of data (n)	4

Percentage of censored data	0%

Number of non-censored data	4

Lowest residue	0.360

Highest residue	0.522

Median residue	0.487

Mean	0.464

Standard deviation (SD)	0.071

Correction factor for censoring (CF)	1.000

 	 

Proposed MRL estimate	 

 	 

- Highest residue	0.522

- Mean + 4 SD	0.749

- CF x 3 Mean	1.392

Unrounded MRL	1.392

 	 

Rounded MRL	1.5

 	 

 High uncertainty of MRL estimate.

[Small dataset]



Residues (mg/kg)	n

0.36	1

0.483	1

0.491	1

0.522	1



Cyprodinil

Pomegranate

US

0.9 lb ai/100 gal1

 	 

Total number of data (n)	4

Percentage of censored data	0%

Number of non-censored data	4

Lowest residue	2.560

Highest residue	3.420

Median residue	3.260

Mean	3.125

Standard deviation (SD)	0.384

Correction factor for censoring (CF)	1.000

 	 

Proposed MRL estimate	 

 	 

- Highest residue	3.420

- Mean + 4 SD	4.662

- CF x 3 Mean	9.375

Unrounded MRL	9.375

 	 

Rounded MRL	10

 	 

 High uncertainty of MRL estimate.

[Small dataset]



Residues (mg/kg)	n

2.56	1

3.26	2

3.42	1



1  Total of two applications.  One application as a dip with wax
(0.45-0.46 lb ai/100 gal) and a second application as a dip with no wax
(0.45-0.46 lb ai/100 gal).  Applications were allowed to dry before the
second application was applied.  Samples were treated and collected on
the same day.

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Standard deviation (SD)	0.180

Correction factor for censoring (CF)	1.000

 	 

Proposed MRL estimate	 

 	 

- Highest residue	1.330

- Mean + 4 SD	1.894

- CF x 3 Mean	3.519

Unrounded MRL	3.519

 	 

Rounded MRL	4

 	 

 High uncertainty of MRL estimate.

[Small dataset]



Residues (mg/kg)	n

0.932	1

1.14	1

1.29	1

1.33	1



Cyprodinil	Summary of Analytical Chemistry and Residue Data	DP#:  421157

Page   PAGE  21  of   NUMPAGES  21 

