Document ID: EPA-HQ-OPP-2014-0373-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-09-05T04:00Z

I

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact:[Tony Kish,703-308-9443]

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide 
petition. In cases where the outline element does not apply,please
insert  11NA-Remove" and maintain the outline.Please do not change the
margins,font,or format in your pesticide

petition.Simply replace the instructions that appear in green,i.e.,
11[insert company  name]," with the information specific to your action.

TEMPLATE:

[Syngenta Crop Protection  LLC),PP# 4F8231]

EPA has received a pesticide petition PP# 4F8231from [Syngenta Crop
Protection LLC., P.O. Box 18300, Greensboro,NC 27419-8300] proposing,
pursuant to section 408(d) of the FederalFood,Drug,and Cosmetic Act
(FFDCA), 21U.S.C. 346a(d), to amend 40 CFR part 180.475.

1 by  estab'ishing tolerance for res(ppm ; [pea,hay] at [40] (ppm);
[Bushberry, subgroup 13-07B) at [3.0] (ppm).

2.  By removing tolerance for chickpeas at [0.08] (ppm).

EPA has determined that the petition contains data or information
regarding the elements set forth in section 408 (d)(2) of 
FDDCA;however,EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of the
petition. Additional data may be needed before EPA rules on the
petition.

A. Residue Chemistry

1. Plant metabolism.  The nature of the residues in plants is understood
for the purpose of the proposed tolerance.  The metabolism of
14C-difenoconazole has been studied using both phenyl and triazole
labels in wheat,tomatoes,potatoes,grapes,and spring rape. The metabolic
pathway was the same in these four separate and distinct

                                        

crops. Therefore,the metabolism  of difenoconazole is considered to be
adequately understood for all crops,per EPA Test Guideline 860.1300.

2. Analytical method. Syngenta Crop Protection,Inc. has submitted a
practical analytical method (AG-5758, master record identification
(MRID) No. 428065-04) for detecting and measuring levels of
difenoconazole in or on food with a limit of quantitation (LOQ) that
allows monitoring of food with residues at or above the levels set in
the proposed tolerances.  EPA has validated this method  and copies have
been provided to FDA for insertion into pesticide analytical manual
(PAM) II. Method REM

147.08 BMRID 46950222) is also available for enforcement method,for the
determination of residues of difenoconazole in crops. Residues are
qualified by liquid chromatography (LC)/mass spectrometry (MS)/(MS) The
method is available to anyone who is interested,and may be obtained from
the Field Operations Division,Office  of Pesticide Programs.

ii. Livestock.  Syngenta Crop Protection,Inc.has submitted a practical
analytical method (AG-544A, MRID-43292401) for detecting and measuring
levels of difenoconazole in or on cattle tissues and milk and poultry
tissues and eggs, with a LOQ that allows monitoring of food with
residues at or above the levels set in the proposed tolerances. EPA has
validated this method and copies have been provided to FDA for insertion
 into PAM II. The method is available to anyone who is interested, and
may be obtained from the Field Operations  Division,Office  of Pesticide
Programs. Tolerances in meat,milk, poultry  or eggs were established for
enforcement purposes.]

3. Magnitude  of residues. Syngenta conducted adequate magnitude  of
residue trials under OPPTS 860.1500 to support the requested uses of
difenoconazole. These residue trials satisfy the requested tolerance on
legumes,subgroup 6C and bushberry subgroup 13-078.

B. Toxicological Profile

EPA has evaluated  the available toxicity  data and considered its
validity, completeness, and reliability as well as the relationship of
the results of the studies to human risk.  EPA has also considered 
available information concerning the variability  of the sensitivities
of major  identifiable subgroups of consumers, including infants  and
children.   Specific information on  the  studies  received  and  the 
nature  of  the  toxic  effects  caused by difenoconazole   as  well  as
 the   no-observed-adverse-effect-level  (NOAEL) from   the toxicity
studies 	can	be 	found 	at 		the 	following 	website:     HYPERLINK
http://edocket.access.gpo/ 
http://edocket.access.gpo.gov/2010/2010-9759.htm	A summary  of  the 
toxicological endpoints  for difenoconazole used for human risk
assessment is discussed in Umt III.A and B. of the final rule published 
in the Federal Register of April 28, 2009 (75 FR pages

22256-22263) (FRL-8817-3D.

1. Acute toxicity   [Insert text.]

2.Genotoxicty. [Insert text.]

3. Reproductive and developmental  toxicity. [Insert text.]

4. Subchronic toxicity. [Insert text.]

5. Chronic toxicity. [Insert text.]

6. Animal metabolism. [Insert text.]

7. Metabolite toxicology. [Insert text.]

8. Endocrine disruption. [Insert text.]

C. Aggregate Exposure

1. Dietary exposure. Tier Ill acute, short-term and chronic dietary
exposure evaluations were performed for
difenoconazole,1-[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-4-methyl-1,3-
dioxolan-2-ylmethyi]-1H-1,2,4-triazole, using the Dietary Exposure
Evaluation Model (DEEM

i Food. Acute exposure.  Acute (food only) risk assessments for
difenoconazole were performed for all population subgroups using an
acute reference dose (aRfD) of 0.25 mg/kgBNOAEL) of 25 mg/kg-bw/day and
an uncertainty factor (UF) of lOOX. The 100X safety factor

includes intra- and inter-species variations;no additional FQPA safety
factor was applied. For the purpose of the aggregate risk assessment,the
exposure value was expressed in terms of margin of exposure 
BMOE),which was calculated by dividing the NOAEL by the exposure for

each population subgroup. In addition,exposure was expressed as a
percent of the acute

                                    

reference dose B%aRfD). At the 99.91

percentile,acute (food only) exposure to the U.S.

population resulted in a MOE of 715 B14.0% of the aRfD of 0.25
mg/kg-bw/day). The most exposed sub-population was children (1-2 years
old) with a MOE of 347 (28.8% of the aRfD of

0.25 mg/kg-bw/day). Since the Benchmark MOE for this assessment was 100
and since the EPA generally has no concern for exposures above the
Benchmark MOE or below 100% of the reference dose,Syngenta believes that
there is a reasonable certainty that no harm will result from acute
dietary (food) exposure to residues arising from all current,pending,
and proposed uses for difenoconazole.

Chronic exposure.  Chronic (food only) risk assessment for
difenoconazole were performed for all population subgroups  using a
chronic reference dose (cRfD) of 0.01mg/kg-bw/day, based on

a combined chronic toxicity/carcinogenicity study in rats with a no
observed adverse effect level

BNOAEL) of 0.96 mg/kg-bw/day and an uncertainly factor of 100X. The
100X safety factor includes intra- and inter-species variations; no
additional FQPA safety factor was applied. For the purpose of the
aggregate risk assessment,the exposure values were expressed in terms of
margin of exposure (MOE),which was calculated by dividing the NOAEL by
the exposure for each population subgroup. In addition, exposure was
expressed as a percent of the chronic

reference dose (%cRfD). Chronic (food only) exposures to the U.S.
population resulted in a MOE

of 1, 305 (7.4% of the cRfD of 0.01mg/kg-bw/day). The most exposed
sub-population was children (1-2 years old) with a MOE of 393 B24.5% of
the cRfD of 0.01mg/kg-bw/day). Since the Benchmark MOE for this
assessment was 100 and since the EPA generally has no concern for
exposures above the Benchmark MOE or below 100% of the reference
dose,Syngenta believes that there is a reasonable certainty that no harm
will result from chronic dietary (food) exposure to residues arising
from all current, pending, and proposed uses for difenoconazole.

Cancer. A cancer dietary assessment was not conducted. Difenoconazole is
classified as a Group C,"possible human carcinogen," with a non-linear
BMOE) approach for human risk characterization BCPRC
Document,7/27/94,Memo,P. V. Shah, March 3,2007,HED Doc. No.

0054532).

ii.  Drinking Water: The Estimated Drinking Water Concentrations (EDWCs)
of difenoconazole

BCGA169374) determined as total toxic residues of difenoconazole and
its degradate (CGA205375) were determined using Tier I models SCI-GROW
BScreening Concentration in Ground Water) to estimate pesticide
concentrations in ground  water and Tier II model PRZM/EXAMS (Pesticide
Root Zone Model/Exposure Analysis Modeling System) to estimate pesticide
concentration in surface water.  All registered and proposed  uses on
artichoke, ginseng,green-house cucumbers and blueberries were assessed.
Based on the SCI-GROW modeling,the currently registered golf course turf
use provided a ground  water acute and

chronic EDWC of 0.0136 ppb.  Based on the PRZM/EXAMS modeling,the
currently registered grape use provided a surface water acute EDWC of
20.0 parts per billion (ppb) and a surface water chronic EDWC of 13.5
ppb. Since the surface water EDWCs exceed the ground water EDWC, the
surface water values were used for risk assessment purposes and will be
considered protective for any ground water exposure concerns.

Acute Exposure from  Drinking Water.  The acute surface water EDWC of
20.0 ppb was input directly  into the DEEM-FCID'M software as "water,
direct  and indirect,all sources" to model the acute drinking water
exposures.  Exposure contributions at the 99th percentile of exposures
were determined by taking the difference between the aggregate (food+
drinking water) exposures and the food (alone) exposures for each
population subgroup. Acute drinking water exposure U.S. population
resulted  in a MOE of 30,084 (0.3% of the aRfD of 0.25 mg/kg-bw/day).
The most exposed sub-population was children 1-2 years old with a MOE of
19,592 (0.5% of the aRfD of 0.25 mg/kgfday). Since the benchmark MOE for
this assessment was 100 and since EPA generally has no concern for
exposures below 100% of the aRfD,Syngenta believes that there is a
reasonable certainty that no harm will result from acute drinking water
exposure to residues arising from all registered and proposed uses for
difenoconazole.

Chronic Exposure from Drinking Water.  The chronic surface water EDWC of
13.5 ppb was input directly  into the DEEM-FCID software as "water,
direct  and indirect, all sources" to model the chronic drinking water
exposures. Chronic drinking water exposure to the U.S. population
resulted in a MOE of 3,396 (2.8% of the cRfD of 0.01mgfkg-bw/day).
Chronic drinking water exposure to the most exposed sub-population (all
infants,<1year old) resulted in a MOE of

1,317 (7.3% of the cRfD of 0.01mg/kg-bw/day). Since the Benchmark MOE
for this assessment was 100 and since EPA generally has no concern for
exposures below 100% of the cRfD, Syngenta believes that there is a
reasonable certainty that no harm will result from chronic drinking
water exposure to residues arising from all registered and proposed 
uses for difenoconazole.

2. Non Dietary Exposure: The use of difenoconazole on ornamentals and
flower gardens (Inspire•, Ready-to-Use spray) and golf courses
(Quadris Top'M, Heritage Top™, Briskway'M) may result in residential
handler  or post-application exposures to selected subgroups.  A
short-term toxicological dermal and inhalation endpoint of 1.25
mg/kg-bw/day was selected based upon the no observed adverse effect 
level (NOAEL) from a 2-generation reproductive study in rats with an
uncertainty factor of lOOX,which includes intra- and interexpressed in
terms of margin of exposure (MOE), which was calculated by dividing the
NOAEL by the exposure for each subgroup.  Adult gardeners 19+ years old
had a short-term residential MOE of 249 and youth gardeners had a
short-term residential MOE of 363;there were no other exposed subgroups.
 Since the Benchmark MOE for this assessment was 100 and since the EPA
generally has no concern  for exposures above the Benchmark MOE,Syngenta
believes that

there is a reasonable  certainty that no harm will result from
short-term residential exposure to

residues arising from  all current, pending, and proposed  uses for
difenoconazole.

D. Cumulative Effects

Cumulative Exposure to Substances with  a Cammon Mechanism of Toxicity. 
Section

408(b)(2)(D)(v)  requires that,when considering whether to
establish,modify, or revoke a tolerance, the Agency consider "available
information" concerning the cumulative effects of a particular
pesticide's residues and "other substances that have a common mechanism
of toxicity". An ongoing  series of studies being conducted  by the U.S.
Triazole Task Force (USTTF) are designed to provide the Agency with more
complete toxicological and residue information for 1,2,4 triazole and
two conjugates,triazolylalanine and triazolyl acetic acid, metabolites
common to most of the triazole fungicides. Upon completion of review  of
those data, EPA will prepare a more sophisticated assessment based on
the revised toxicological and exposure databases. For the purposes of
this tolerance action, the EPA has not assumed that difenoconazole has a
common mechanism of toxicity with other substances.

E. Safety Determination

1.U.S. population. The acute dietary exposure analysis (food plus water)
showed that exposure from all current,pending and proposed uses of
difenoconazole would result in a MOE of 699 (14.3% of the aRfD of 0.25
mg/kg-bw/day) for the general U.S. population, which exceeds the
Benchmark MOE of 100.  For the short-term aggregate exposure analysis
the corresponding food,water and residential MOEs were aggregated using
the inverse MOE approach. The short

2. Infants and children. The acute dietary  exposure analysis (food plus
water) showed that exposure from  all current, pending and proposed uses
of difenoconazole would result in a MOE of 341B29.3% of the aRfD of
0.25 mg/kg-bw/day) for the most sensitive population subgroup, children
1-2 years old,which exceeds the Benchmark MOE of 100.  For the
short-term aggregate exposure  analysis the corresponding food, water
and residential MOEs were aggregated using the inverse MOE approach. The
short-term aggregate (food,drinking water, and residential) MOE was 438
for children (1-2 years),which exceeds the Benchmark MOE of

100.  The chronic  dietary exposure analysis (food plus water)  showed
that exposure from all current, pending, and proposed uses of
difenoconazole resulted in a MOE of 337 B28.6% of the cRfD of
0.01mg/kg-bw/day) for the most sensitive population subgroup, children
1-2 years old, which exceeds the Benchmark MOE of 100.  Based on the
completeness and reliability of the toxicity data supporting these
petitions,Syngenta believes that there is a reasonable certainty that no
harm will result to infants  and children from aggregate exposure to
residues arising from all current,pending, and proposed uses of
difenoconazole, including anticipated dietary

exposure from food, water,and all other types of non-occupational
exposures.

F. International Tolerances

Codex Alimentarius Commission established Maximum Residue Limits (MRLs)
for difenoconazole in various agriculturalcommodities including
asparagus, banana,beans,except broad bean and soya bean,
broccoli,Brussels sprouts, cabbages, head, carrot,cauliflower, celeriac,
celery, cherries, edible offal (mammalian),eggs, garlic, ginseng,
grapes,leek, lettuce, head,lettuce, leaf,mango,meat,
milks,nectarine,olives, papaya, passion fruit,peach, peas

(pods and succulent/immature seeds), plums (including prunes), pome
fruits,potato, poultry

meat,poultry, edible  offal of, rape seed,soya bean (dry),sugar 
beet,sunflower seed,tomato, tree nuts, wheat, and wheat  straw and
fodder, dry.