Document ID: EPA-HQ-OPP-2006-0732-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-01-02T05:00Z

SEQ CHAPTER \h \r 1 

    UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

MEMORANDUM

DATE:		September 25, 2007

SUBJECT:	Trifloxystrobin: Human Health Risk Assessment for Section 3
Uses on Asparagus; Vegetable, Root Except Sugar Beet, Subgroup 1B;
Radish (Tops); and Papaya, Black Sapote, Canistel, Mamey Sapote, Mango,
Sapodilla, and Star Apple (PP#: 6E7088, DP Num: 331914, Decision#:
369020, PC#: 129112); a Petition to Decrease the PHI and Increase the
Tolerances for Citrus Fruits, Crop Group 10; Citrus, Oil; and Citrus,
Dried Pulp (PP#: 6F7123, DP Num: 334851, PC#: 129112); and a Petition
for the Use on Strawberry (PP#: 7F7171, DP Num: 339495, PC#: 129112).

TO:		Shaja Brothers, EPS

		Risk Integration, Minor Use, Emergency Response Branch (RIMUERB)

		Registration Division (RD) (7505P)

		

		AND 

		

		Tony Kish / Janet Whitehurst RM 22

		Fungicide Branch (FB)/RD (7505P)

FROM:	Debra Rate, Ph.D., Biologist/Risk Assessor

		Breann Hanson, Biologist

		Mark Dow, Ph.D., Biologist

Alternative Risk Integration and Assessment (ARIA)

		RIMUERB/RD (7505P)

THRU:	William Cutchin, Acting Senior Branch Scientist

		ARIA

		RIMUERB/RD (7505P)

		AND 

		

		Barry O’Keefe, Senior Biologist  

		Registration Action Branch 3 (RAB3)

		Health Effects Division (HED) (7509P)

ARIA/RIMUER Branch of the Office of Pesticide Programs (OPP) is charged
with estimating the risk to human health from exposure to pesticides. 
RD of OPP has requested that ARIA evaluate hazard and exposure data and
conduct dietary, occupational, residential and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result the from proposed uses on asparagus, Subgroup 1B root vegetable
(except sugar beet), radish (tops), papaya, black sapote, canistel,
mamey sapote, mango, sapodilla, star apple, strawberry, and the proposed
decrease in citrus preharvest interval (PHI), in conjunction with the
currently registered uses of the active ingredient trifloxystrobin.

In this document, ARIA has conducted an assessment of the human exposure
and health risks resulting from these proposed and revised uses and all
currently registered uses.  The overall risk assessment was provided by
Debra Rate, the residue chemistry data review by Debra Rate, the dietary
risk assessment by Breann Hanson, and the non-dietary exposure/risk
assessment by Mark Dow.  

Table of Contents

  TOC \f  1.0	Executive Summary	5

2.0	Ingredient Profile	11

2.1	Summary of Registered/Proposed Uses	12

2.2	Structure and Nomenclature	13

2.3	Physical and Chemical Properties	14

3.0	Hazard Characterization	14

3.1	Hazard Profile	15

3.2	FQPA Considerations	15

3.3	Toxicity Endpoint Selection	16

3.4	Endocrine Disruption	18

4.0	Public Health and Pesticide Epidemiology Data	19

5.0	Dietary Exposure/Risk Characterization	19

5.1  Pesticide Metabolism and Environmental Degradation	19

	5.1.1  Metabolism in Primary Crops	19

	5.1.2  Metabolism in Rotational Crops	19

	5.1.3  Metabolism in Livestock	20

	5.1.4  Analytical Methodology	20	

	5.1.5  Multiresidue Methods	20

	5.1.6  Storage Stability	21

	5.1.7  Magnitude in Plants	21

	5.1.8  Magnitude in Meat, Milk, Poultry, and Eggs	22

	5.1.9  Confined and Field Rotational Crops	22

	5.1.10  Pesticide Metabolites and Degradates of Concern	23

	5.1.11  Drinking Water Residue Profile	23

5.2  Dietary Exposure and Risk	24

	5.2.1  Acute Dietary Exposure/Risk	24

	5.2.2  Chronic Dietary Exposure/Risk	25

	5.2.3  Cancer Dietary Risk	26

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	26

6.1	Residential Postapplication Exposure	26

6.2	Combined Exposure	28

6.3	Other (Spray Drift, etc.)	29

7.0	Aggregate Risk Assessments and Risk Characterization	29

7.1	Acute Aggregate Risk	29

7.2	Short-Term Aggregate Risk	30

7.3	Intermediate-Term Aggregate Risk	31

7.4	Long-Term Aggregate Risk	31

7.5	Cancer Risk	31

8.0	Cumulative Risk Characterization/Assessment	31

9.0	Occupational Exposure/Risk Pathway	31

9.1	Short-/Intermediate-Term Handler Risk	31

9.2	Short-/Intermediate-Term Handler Postapplication Risk	34

9.3	Restricted Entry Interval (REI)	34

10.0	Tolerance Summary	35

11.0	Data Needs and Label Recommendations	36

11.1	Toxicology Data Needs and Label Requirements	36

11.2	Residue Chemistry Data Needs and Label Requirements	36

11.3	Occupational Data Needs and Label Requirements	36

12.0	References	36

13.0	Appendix 	38

 

1.0 EXECUTIVE SUMMARY

This document is an ARIA assessment to support the Section 3 requests
(PP#: 6E7088, 6F7123 and 7F7171) for the establishment of a permanent
trifloxystrobin tolerance in/on asparagus, vegetable, root except sugar
beet, subgroup 1B, radish (tops),and papaya, black sapote, canistel,
mamey sapote, mango, sapodilla, star apple and strawberry from its use
as a broad-spectrum fungicide (i.e., 40 CFR §180.555) and the revised
tolerances for citrus fruits, crop group 10, citrus, oil, and citrus,
dried pulp.  ARIA recently assessed the human exposure and health risks
resulting from the use on grasses grown for seed for a Section 3
registration (PP#: 6F7024, DP Num: 325826, D. Rate, 11/APR/2007).  Also,
other previous Section 3 petitions have resulted in the establishment of
tolerances on crops including almonds, barley, carrots, celery, citrus,
corn seed, field corn, hops, fruiting vegetables, oats, pecans,
potatoes, rice, stone fruits, sweet corn, sugar beets, and wheat.  The
formulated end use products pertinent to the subject petitions are
labeled under the registered trade names Flint® Fungicide (EPA Reg. No.
264-777), Gem Fungicide (EPA Reg. No. 264-781), Gem 500 SC Fungicide
(EPA Reg.No. 264-826) and Distinguish 480 SC Fungicide (EPA Reg. No.
264-RNET).  

 

No new hazard data have been submitted since the issuance of the last
human health risk assessment.  For full details on the hazard assessment
and residential exposure assessment, see the following previous risk
assessments: 1)HED Risk Assessment: Trifloxystrobin: HED Exposure/Risk
Assessment to Support a Section 18 Request (05-FL-10 & 05-TN-10) for New
Uses in/on Specialty Legume Vegetables. (DP Num: 317330; B. O’Keefe,
16/AUG/2006); 2) HED Risk Assessment: Human Health Risk Assessment for
Trifloxystrobin for New Section 3 Use on Soybeans (PP#: 5F6956, DP Num:
318618, B. O’Keefe, 07/AUG/2006) and 3) ARIA Risk Assessment:
Trifloxystrobin: Human Health Risk Assessment for Section 3 Registration
for the Proposed Uses on Grasses Grown for Seed (DP Num: 325826, D.
Rate, 11/APR/2007).  This document includes revised dietary (food and
drinking water), occupational (handler and post-application), and
aggregate assessments as they pertain to the requested new uses.

Proposed Uses

Trifloxystrobin is a broad spectrum fungicide and is classified as an
oximinoacetate fungicide in the strobilurin class.  It acts by
interfering with respiration in plant pathogenic fungi and is a potent
inhibitor of spore germination and mycelial growth.  It provides
protective properties against a variety of pathogens in a variety of
crops.  

The trifloxystrobin product to be applied is Flint®, a wettable granule
(WG) formulation containing the active ingredient (ai) trifloxystrobin. 
Trifloxystrobin is to be applied as a broadcast foliar spray by ground
or aerial equipment.  The proposed use pattern allows for 2, 3, 4, or 6
applications to be made up to a maximum seasonal rate of 0.250 lb ai/A,
0.375 lb ai/A, 0.50 lb ai/A or 0.6 lb ai/A, respectively for root
vegetables, asparagus, the specified tropical fruits, strawberry and
citrus fruits.  There is a re-treatment interval (RTI) of 7 to 14 days
depending on the specific crop.  Applications may not be made within 180
days (90 days in California) of harvest for asparagus, 7 days for root
vegetables and citrus fruits, and there is a 0 day PHI for the tropical
fruit and strawberry.  

Toxicology/Hazard

HIARC met on March 7, 2002 to re-evaluate the toxicology database for
trifloxystrobin (HIARC Trifloxystrobin #3, S. Dapson, 01/APR/2002).  The
endpoint selected for acute dietary risk assessment was based on
increased incidence of fused sternebrae #3 and #4 in fetuses observed in
a developmental toxicity study in rabbits.  The acute
population-adjusted dose (aPAD) is only to be used for females of
childbearing age.  No acute dietary endpoint was identified for the
general population or other population subgroups.  The endpoint for
chronic dietary risk assessment was based on decreases in body weight,
body weight gains, reduced food consumption, and histopathological
lesions in the liver, kidneys and spleen of parental animals in a
multi-generation reproduction study in rats.  A chronic dog study in
which increased incidence of clinical signs, increased mean liver weight
and hepatocellular hypertrophy were observed is considered co-critical. 
The chronic population-adjusted dose (cPAD) is applicable to all
population subgroups.  

Short- and intermediate-term dermal toxicity endpoints were based on
increases in mean absolute and relative liver and kidney weights
observed in a 28-day dermal toxicity study in rats.  No long-term dermal
exposure is expected based on the use pattern.  Because a dermal
toxicity study was used to determine the dermal endpoints, no dermal
absorption adjustment is necessary.  The endpoint chosen for assessment
of short- and intermediate-term incidental oral risks (residential) is
based on decreased pup body weights during lactation observed in a
multi-generation reproductive toxicity study (the same study was chosen
for the chronic dietary risk endpoint).  The short-, intermediate- and
long-term inhalation endpoints were based on reduced body weights, body
weight gains, food consumption and food efficiency observed in parental
animals in a multi-generation reproduction study in rats. 

The toxicological database indicates that technical grade
trifloxystrobin has moderate acute toxicity, falling into Toxicity
Category 3 or 4 for all exposure routes.  However, trifloxystrobin is a
strong dermal sensitizer.  Subchronic and chronic toxicity studies
demonstrated that the target organs of trifloxystrobin are the liver,
kidneys and spleen.  Developmental effects were observed in
developmental studies (fused sternebrae #3 and #4 observed in the
rabbit), but only in the presence of maternal toxicity at the same
lowest observable adverse effects level (LOAEL).  

The cancer classification of trifloxystrobin was made by an ad hoc
subcommittee of the Cancer Assessment Review Committee on May 27, 1999. 
The Committee determined that trifloxystrobin should be classified as a
“Not Likely Human Carcinogen,” based on the lack of evidence for
carcinogenicity in rats and mice.  

The toxicological database is adequate for the purposes of risk
assessment.  HED has a high degree of confidence in the toxicology
database.

The trifloxystrobin toxicology database has been evaluated according to
2002 Food Quality Protection Act (FQPA) policies.  The FQPA safety
factor (SF) was reduced to 1x based on toxicological considerations by
the FQPA Safety Factor Committee (HED Doc. No. 013545, B. Tarplee,
01/JUL/1999), the conservative residue assumptions used in the dietary
and residential exposure risk assessments, and the completeness of the
residue chemistry and environmental fate databases (DP Num: 317330, B.
O’Keefe, 16/AUG/2006; DP Num: 317330, J. Arthur, 16/AUG/2006).

Residue Chemistry

The nature of the residue in plants, rotational crops, and ruminants is
adequately understood.  For the purposes of tolerance establishment and
dietary risk assessment (in food), the residues of concern in plants,
animals, and rotational crops are the parent trifloxystrobin and the
acid metabolite (CGA-321113).  The MARC also determined that for
livestock commodities, the metabolite L7a (taurine conjugate of
trifloxystrobin) in liver should be included in the risk assessment.  A
drinking water assessment for trifloxystrobin uses was conducted by EFED
(DP Num: 296314, 296315, 296316, 296317, 296318, 296319, and 296320, S.
Abel, 30/MAR/2004 and DP Num: 343362, D. Rate, 30/AUG/2007).  The
assessment includes trifloxystrobin and degradates as requested by HED. 
There are no livestock feedstuffs associated with the proposed uses on
asparagus, papaya, strawberry or citrus fruit.  However, carrots and
turnips as a part of crop group 1B (vegetable, root, except sugar beet),
are cattle and swine feed items.  The addition of radish tolerances to
the already established tolerance for the vegetable, root, except sugar
beet, except radish subgroup 1B, and the increase of tolerances on
citrus, dried pulp, will have no impact on the established tolerances of
livestock commodities based on this addition to the respective dietary
burdens.  Accordingly, the current tolerances for livestock commodities
are adequate.  No rotational crop studies were submitted with these
petitions.  The previously submitted field rotational crop studies have
been deemed adequate.  

An adequate gas chromatography with nitrogen phosphorus detector
(GC/NPD) method (Method AG-659A) was used for data collection and
submitted as a tolerance enforcement method for residues of
trifloxystrobin in/on plant commodities.  The lowest limit of method
validation (LLMV) is 0.02 ppm for each analyte in radish, 0.05 ppm and
0.02 ppm for trifloxystrobin and CGA-321113, respectively, for
asparagus, for combined LLMVs of 0.04 ppm in/on all radish matrices and
0.07 ppm in/on all asparagus matrices.  The limits of quantitation (LOQ)
for papaya are 0.008 ppm and 0.20 ppm for trifloxystrobin and
CGA-321113, respectively.  The LOQs for oranges, lemons and grapefruit
are 0.01 ppm for both analytes in oranges and 0.02 ppm for both analytes
in lemons and grapefruit.  The LOQs for strawberry are 0.01 ppm for both
analytes.  Method AG-659A was adequately validated by the petitioner as
well as by the Agency (DP Num: 265003, L. Cheng, 13/APR/2000).  The
method has been forwarded to FDA for inclusion in the Pesticide
Analytical Manual (PAM), Vol. II.  

Although submission of a revised label and a revised Section F are
needed for certain commodities, adequate crop field trial data have been
submitted for: asparagus; radish, the representative commodity of
vegetable, root, except sugar beet, subgroup 1B, and radish, tops;
papaya, the representative crop for the subset of proposed tropical
fruits; strawberry, and citrus fruit, adequate to support the
recommended tolerances for citrus fruits, crop group 10, citrus, oil,
and citrus, dried pulp.  

Dietary Risk (Food and Drinking Water)

The Environmental Fate and Effects Division (EFED) determined estimated
drinking water concentrations (EDWCs) of trifloxystrobin in surface and
ground water.  The highest EDWCs for acute and chronic exposure (140
ppb) were used in the dietary analysis.  These estimates of residues in
drinking water were incorporated directly into the DEEM-FCID model of
the dietary risk assessment; i.e., into the food categories “water,
direct, all sources” and “water, indirect, all sources.”

An acute dietary assessment assuming tolerance-level residues for most
commodities with existing, proposed and reassessed tolerances for meat
byproducts of cattle, goats, horses, and sheep, was conducted for
females 13-49 years old.  For all commodities, 100% crop treated (%CT)
was used.  An acute dietary endpoint for the general population
including infants and children was not identified.  The estimated
dietary exposure (food and drinking water) for females 13-49 years old
occupies less than 1% of the aPAD and does not exceed ARIA’s level of
concern.

A chronic dietary assessment, assuming tolerance-level residues for most
commodities with existing and proposed tolerances, anticipated residue
levels for grape, apple and orange, and reassessed tolerances for meat
byproducts of cattle, goats, horses, and sheep, was conducted for the
general population and all population subgroups.  For all commodities,
100%CT was used.  The mean (i.e., relevant to chronic exposure) drinking
water estimate of 140 ppb, provided by EFED, was directly incorporated
into the chronic assessment.  The chronic dietary risk assessment shows
that for all included commodities, the chronic dietary risk estimates
are below ARIA’s level of concern (i.e. <100% chronic population
adjusted doses (cPAD)).  For the U.S. population the exposure for food
and water utilized 20% of the cPAD.  The chronic dietary risk estimate
for the highest reported exposed population subgroup, all infants (<1
year old), is 52% of the cPAD.

Residential Risk

The existing residential uses of trifloxystrobin include
turfgrass/ornamental disease control (CompassTM).  Because the FQPA
requires consideration of aggregate exposure to all likely
non-occupational uses, this assessment uses residential post-application
contact with trifloxystrobin following CompassTM use on turfgrass as the
most common and worst case contributor to such exposures.  In a previous
HED risk assessment, the margins of exposure (MOEs) for applicable
residential scenarios, i.e., post-application dermal (adult and toddler)
and incidental oral (toddlers only) exposures from pesticide residues on
lawns were calculated.  Additionally, risk estimates from separate
incidental oral exposures to toddlers were combined. 

Risk from short-term incidental ingestion by toddlers is assessed by
comparing these exposures to the 3.8 mg/kg/day no observable adverse
effects level (NOAEL) identified from a two-generation reproduction
study in rats (endpoint: decreases in pup body weight during lactation).
 Dermal exposures were compared to the NOAEL of 100 mg/kg/day from a
28-day dermal toxicity study in rats (endpoint: increases in mean
absolute and relative liver and kidney weights).

The HED Standard Operating Procedures for Residential Exposure
Assessments (Draft, December 18, 1997) were used as a guideline for
performing the residential post-application assessment.  Dermal risks
were calculated for adults and children, while risks from incidental
oral exposure were also calculated for children.  Because the endpoints
identified for dermal and incidental oral risk are based on different
endpoints, exposures from these routes are not added together.  The MOEs
for dermal risk from post-application exposure are 1,300 for adults and
760 for children.  The MOEs for children’s risk from oral exposures
range from 750 to 220,000.  When incidental oral exposure from all
possible residential sources are combined (ingestion of residues on
turfgrass from hand-to-mouth activities, mouthing turfgrass and eating
soil), the result is an MOE of 590.  Therefore, all calculated
residential post-application MOEs are greater than 100 on the day of
application, and do not exceed ARIA's level of concern.

Aggregate Risk

Acute, short-term, and chronic aggregate risk estimates resulting from
aggregate exposure to trifloxystrobin in food and drinking water, and
residential settings are below ARIA’s level of concern. 
Intermediate-term exposure (1 to 6 months) to the parent trifloxystrobin
is not expected to occur in residential settings due to its short
half-life (about two days based on soil and aquatic metabolism studies).
 Therefore, an intermediate-term aggregate risk assessment was not
performed. 

For the acute aggregate risk scenario, food and drinking water exposures
were taken into account in the dietary exposure assessment.  The
estimated dietary exposure (food and water) for females 13-49 years old
occupies less than 1% of the aPAD.  Therefore, acute aggregate risk is
below ARIA’s level of concern. 

For the short-term (1 to 30 days) aggregate risk scenarios, food,
drinking water and residential exposures are taken into account. 
Residential exposure for dermal and oral routes must be assessed
separately, since dermal and oral endpoints were different and cannot be
combined.  The resulting MOEs for all short-term aggregate scenarios for
adults and children are above 100, and therefore, do not exceed ARIA’s
level of concern.

For the chronic aggregate risk scenario, food, drinking water, and
residential exposures were taken into account.  In this case, chronic
exposure in residential settings is not expected and the aggregate
chronic assessment included food and drinking water only.  Since the
dietary exposure assessment already includes the highest chronic
exposure from the drinking water modeling data, no further calculations
are necessary.  The general U.S. population and all population subgroups
have exposure and risk estimates which are below ARIA’s level of
concern (i.e., the percentages of the cPADs are all below 100%).  The
aggregate chronic exposure to the U.S. population was 20% of the cPAD
and the most highly exposed subgroup, all infants (<1 year old), was at
52% of the cPAD.  Therefore, chronic aggregate risk is below ARIA’s
level of concern.

Occupational Exposure and Risk

There is a potential for exposure to trifloxystrobin during mixing,
loading, and application activities.  Based on the proposed use
patterns, ARIA believes the most highly exposed occupational pesticide
handlers would be mixer/loaders using open pour loading of water
dispersible granules, applicators using open-cab ground-boom spray
equipment and applicators using open-cab airblast spray equipment. 
Handler’s exposures and risks were estimated for these three different
use scenarios for short-term durations (1-30 days).  Since treatment
blocks (i.e., areas treated) are relatively small when compared with
typical field crops such as cotton, corn, soybeans or wheat, ARIA
believes that pesticide handlers will not be exposed to
intermediate-term (1-6 months) duration exposures.  Chronic exposures
are not expected for handlers.  Daily dermal and inhalation exposures
were calculated separately.  

All handler MOEs for short-term exposures are above the level of concern
(LOC) MOE (100) with baseline personal protective equipment (PPE)
(long-sleeved shirt, long pants, shoes and socks) and the use of
protective gloves.  The lowest MOE is 3,846 for mixer/loaders for
open-cab airblast applications.  These MOEs do not exceed ARIA’s level
of concern. 

The transfer coefficients (TCs) used in this assessment are from an
interim TC Standard Operating Procedure (SOP) developed by HED’s
ExpoSAC using proprietary data from the ARTF database (SOP # 3.1).  As a
screening level assessment, ARIA herein uses the TC of 1,000 cm2/hr for
a conservative estimate of agricultural worker exposure to
post-application residues of  trifloxystrobin.  Lacking compound
specific dislodgeable foliar residue (DFR) data, ARIA will assume 20% of
the application rate is available as DFR on day zero after application. 
This is adapted from the ExpoSAC SOP No. 003 (07/MAY/1998 – Revised
07/AUG/2000).  When calculations are made, the MOE associated with
post-application agricultural worker exposure is 3,125 (DP Num: 339754,
M. Dow, 31/MAY/2007).  A MOE of 100 is adequate to protect agricultural
workers from post-application exposures. Since the estimated MOE is
>100, the proposed uses do not exceed ARIA’s level of concern.  

The label for Flint® has a 12-hour restricted entry interval (REI). 
Technical-grade trifloxystrobin has a Toxicity Category III for Primary
Eye Irritation (other Toxicity Categories are IV).  Per the Worker
Protection Standard (WPS), a 12-hr REI is required for chemicals
classified under Toxicity Category III.  Therefore, the REI of 12 hours
appearing on the Flint® label is in compliance with the WPS.  However,
it is important to note that trifloxystrobin was found to be a strong
dermal sensitizer.  This warrants a requirement for gloves for
mixers/loaders (even though trifloxystrobin is in Category IV for dermal
toxicity).  Also, double notification (i.e., verbal warnings as well as
signs posted around treated fields) for post-application workers is
recommended.  

Environment Justice

Potential areas of environmental justice concern, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations," (  HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

Review of Human Research

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies (listed in Appendix B) have been determined to
require a review of their ethical conduct, and have received that
review.

Additional Data Needs and Recommendations:

No major deficiencies were noted in the subject petition that would
preclude establishing permanent tolerances for trifloxystrobin in/on
asparagus; vegetable, root subgroup 1B (except sugar beet); radish
(tops); papaya, black sapote, canistel, mamey sapote, mango, sapodilla,
and star apple; and strawberry commodities.  In addition, the submitted
studies are adequate to support revised tolerances on citrus fruit
commodities associated with the requested reduced PHI.  However, the
following minor issues must be resolved prior to establishing
tolerances; 1) the petitioner must submit a revised Section F, using the
proper commodity definitions and matching the proposed tolerances to the
recommended tolerances; 2) the petitioner must submit a revised label to
match the proposed and study use rates; and 3) a double notification
(i.e., verbal warnings as well as signs posted around treated fields)
for post-application workers is recommended.

Provided that these issues are addressed by the petitioner, ARIA
recommends for establishing permanent tolerances for the combined
residues of trifloxystrobin, (benzeneacetic acid,
(E,E)-α-(methoxyimino)-2-[[[[1-[3-(trifluoromethyl)
phenyl]ethylidene]amino]oxy] methyl]-methyl ester) and the free form of
its acid metabolite CGA–321113
((E,E)-methoxyimino-[2-[1-(3-trifluoromethylphenyl)-ethylideneaminooxyme
thyl]-phenyl] acetic acid, expressed as parent, at 0.07 ppm for
asparagus; 0.1 ppm for vegetable, root except sugar beet, subgroup 1B;
10 ppm for radish, tops; 0.70 ppm for papaya, black sapote, canistel,
mamey sapote, mango, sapodilla, and star apple; 1.1 ppm for strawberry;
0.6 ppm for citrus fruits, crop group 10; 38.0 ppm for citrus, oil; and
1.0 for citrus, dried pulp.

2.0	Ingredient Profile:

Trifloxystrobin is a broad spectrum fungicide for the control of a wide
range of diseases in commercially important crops.  Trifloxystrobin is
classified as an oximinoacetate fungicide in the strobilurin class.  It
acts by interfering with respiration in plant pathogenic fungi and is a
potent inhibitor of spore germination and mycelial growth.  It provides
both curative and protective properties against a variety of pathogens
in a variety of crops.  

Trifloxystrobin belongs to the MAEs (β-methoxyacryl esters) class of
fungicides, which are synthetic analogs of strobilurin A ((Fungicide
Resistance Action Committee (FRAC) Group 11).  In the U.S.,
trifloxystrobin is registered to Bayer CropScience and is marketed under
the trade names FLINT®, GEM®, Distinguish® and STRATEGO®.  For uses
on food/feed crops, trifloxystrobin is formulated as a 50% WDG, a   SEQ
CHAPTER \h \r 1 4.17 lb/gal suspension concentrate (SC), and a 1.04
lb/gal emulsifiable concentrate (EC).  

2.1	Summary of Proposed Uses:

Table 2.1.  Summary of Directions for Use of Trifloxystrobin.	

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

Asparagus

Foliar Broadcast / Fern	Flint® Fungicide (WG) 

[264-777]	0.125	3	0.375	180 (All States excluding CA)

90 (CA)	Maintain a minimum of 14 day RTIs.

Radish

Foliar Broadcast / Early maturity, Vegetative	Flint® Fungicide (WG) 

[264-777]	0.125	2	0.250	6-8	Maintain a minimum of 7 day RTIs.

Papaya

Foliar Directed / Fruiting	Flint® Fungicide (WG) 

[264-777]	0.125	4	0.5	0	Maintain a minimum of 7 day RTIs.

Citrus Fruits, Crop Group 10

Foliar Broadcast	Flint® Fungicide (WG) 

[264-777]	0.125	4	0.5	7	Use the higher rates when disease pressure is
severe.  

Foliar Broadcast	Gem (SC)

[264-781]	0.125	4	0.5	7	Use the higher rates when disease pressure is
severe.  

Foliar Broadcast	  HYPERLINK "javascript:viewRiName(468360)"  GEM 500
(SC) 

[264-826]	0.125	4	0.5	7	Use the higher rates when disease pressure is
severe.  

May be applied as a foliar spray with air-assisted sprayers, such as
curtec.

Strawberry

Foliar Broadcast	Flint® Fungicide (WG) 

[264-777]	0.10	6	0.6	0	Use the higher rates and shorter intervals when
disease pressure is severe.  Use sufficient water to obtain thorough
coverage.

Foliar Broadcast	Distinguish 480 (SC)

[264-RNET]	0.20	3	0.6	1	Use the higher rates and shorter intervals when
disease pressure is severe.  

Conclusions:  The use patterns described in Section B are adequate to
allow evaluation of the residue data and are supported by submitted
field trial data relative to the proposed uses for asparagus; vegetable,
root except sugar beet, subgroup 1B; and papaya, black sapote, canistel,
mamey sapote, mango, sapodilla, star apple; strawberry; and citrus
fruits, crop group 10.  The label must be revised to match the proposed
and study use rates.  Also, because the petitioner did not request or
submit data for tolerances in/on leaves and foliage of vegetable, root,
except sugar beet, subgroup 1B, the label must include a restriction for
the grazing and feeding of treated leaves/foliage of treated crops.

2.2	Structure and Nomenclature:

Common name	Trifloxystrobin

Company experimental names	BO17211 or CGA-279202

Molecular weight	408.4

IUPAC name	methyl
(E)-methoxyimino-{(E)-α-[1-(α,α,α-trifluoro-m-tolyl)ethylideneaminoo
xy]-o-tolyl}acetate

CAS name
(E,E)-alpha-(methoxyimino)-2-[[[[1-[3-(trifluoromethyl)phenyl]ethylidene
]amino]oxy] methyl]-benzeneacetic acid methyl ester

CAS #	141517-21-7

End-use products/EP	Flint® Fungicide (50% WDG, EPA Reg. No. 264-777) 

Absolute 500 SC Fungicide (2.08  lb/gal FlC; EPA Reg. No. 264-849),
which also contains 2.08 lb/gal of tebuconazole

Regulated Metabolite	

Common Name	Trifloxystrobin acid

Company Code	CGA-321113

Molecular  weight	394

CAS name
(alpha,E)-alpha-(methoxyimino)-2-[[[[1-[3-(trifluoromethyl)phenyl]ethyli
dene]amino]oxy]methyl]-benzeneacetic acid

CAS #	252913-85-2

2.3	Physical and Chemical Properties:

table 2.3  Physicochemical Properties of Trifloxystrobin Technical Grade
Test Compound.

Parameter	Value	Reference

Melting point	72.90 C	MRID No. 44502801, DP Num: 254920, A. Smith,
23/APR/1999.

pH	7.7 in 1% w/w aqueous dispersion at 250C

	Density	1.36 g/cm2 at 210C

	Water solubility	not available

	Solvent solubility (g/L at 250C)	methanol   76

acetone   >500

ethyl acetate   >500

n-hexane   11	dichloromethane  >500

toluene  500

n-octanol  18

	Vapor pressure  (at 250C)	3.4 x 10-6 Pa

	Dissociation constant, pKa	None at pH of 2-12

	Octanol/water partition coefficient  (at 250C)

[logP (ow)] 	4.5

	UV/visible absorption 

(molecular absorption coefficients)	17,500 at 250.7 µm (neutral)

17,300 at 250.2 µm (acidic)

15,900 at 252.3 µm (basic)

	

3.0  HAZARD CHARACTERIZATION

A detailed hazard characterization is available in the following
reference:

TRIFLOXYSTROBIN- 3rd Report of the Hazard Identification Assessment
Review Committee, S. Dapson, HED Document: TXR # 0050612, 01/APR/2002.

All toxicological data requirements for trifloxystrobin technical have
been satisfied.  HED has a high degree of confidence in the toxicology
database.  Acute data requirements for all end-use products have been
satisfied. 

Hazard Profile

The toxicological database indicates that technical grade
trifloxystrobin has moderate acute toxicity and is a strong dermal
sensitizer.  Trifloxystrobin falls into Toxicity Category IV for acute
oral and dermal toxicity.  All toxicological data requirements, have
been satisfied.  An acute neurotoxicity study was requested by the
HIARC, because the submitted study was unacceptable; however, the study
was never required as a core data requirement.  The acute toxicity of
trifloxystrobin technical is summarized in Table 3.1 below. 

Table 3.1  Acute Toxicity of Trifloxystrobin Technical

Guideline No.	Study Type	MRID #	Results	Toxicity Category

870.1100	Acute Oral	44496622

44496623	LD50 > 5 g/kg	IV

870.1200	Acute Dermal	44496626

44496627	LD50 > 2 g/kg	IV

870.1300	Acute Inhalation	44496630	LC50  > 4.65 mg/L	IV

870.2400	Primary Eye Irritation	44496632	mild irritant	III

870.2500	Primary Skin Irritation	44496635	mild irritant	IV

870.2600

	Dermal Sensitization	44496637

44496638	strong sensitizer	N/A

The cancer classification of trifloxystrobin was made by an ad hoc
subcommittee of the Cancer Assessment Review Committee on May 27, 1999. 
The Committee determined that trifloxystrobin should be classified as a
“Not Likely Human Carcinogen.”  Due to the classification, no cancer
risk assessment was performed.

FQPA Considerations

On March 7, 2002, HED’s HIARC evaluated the potential for increased
susceptibility of infants and children from exposure to trifloxystrobin
according to the February 2002 OPP 10x guidance document.  The HIARC
concluded that the toxicology database was adequate for FQPA purposes
and that there are no residual uncertainties for pre-/post-natal
toxicity (S. Dapson, 01/APR/2002).  Based on the hazard data, the FQPA
Safety Factor Committee (B. Tarplee, 01/JUL/1999) recommended the FQPA
Safety Factor (SF) be reduced to 1x.  The trifloxystrobin risk
assessment team evaluated the quality of the exposure data; and, based
on these data, also recommended that the FQPA SF be reduced to 1x.  The
recommendation is based on the following:

There is no indication of increased susceptibility of rat or rabbits to
trifloxystrobin.  In the prenatal developmental study in rats, there was
no developmental toxicity at the Limit Dose.  In the prenatal
developmental study in rabbits, developmental toxicity was seen at a
dose that was higher than the dose that caused maternal toxicity.  In
the two generation reproduction study, there was no offspring toxicity
at the highest dose tested.

The HIARC determined that a developmental neurotoxicity study in rats is
not required;

Although an acute neurotoxicity study is required (the submitted study
was unacceptable), based on a weight-of-the-evidence review of the
available data, the lack of an acute neurotoxicity study does not impact
HED’s ability to make an FQPA safety factor decision since there was
no evidence of Neurotoxicity in this study at the Limit dose nor in the
other subchronic and chronic studies in the database.  Based on the
weight-of-the-evidence a developmental Neurotoxicity study is not
required for this chemical;

The acute and chronic dietary food exposure assessments utilize existing
and proposed tolerance level residues and 100% crop treated information
for all commodities, expect for apples, oranges, and grapes which
utilized anticipated residue levels (See Section 5.2.2).  By using these
screening-level assessments with minor refinement, actual
exposures/risks will not be underestimated;

The exposure assessments will not underestimate the potential dietary
(food and drinking water) or non-dietary exposures for infants and
children from the use of trifloxystrobin;

The dietary drinking water assessment utilizes water concentration
values generated by model and associated modeling parameters, which are
designed to provide conservative, health protective, high-end estimates
of water concentrations, which are not likely to be exceeded; and

The residential post-application assessment is based upon the
residential SOPs.  The assessment is based upon surrogate study data. 
These data are reliable and are not expected to underestimate risk to
adults or children. The residential SOPs are based upon reasonable
“worst-case” assumptions and are not expected to underestimate risk.

3.3  Toxicity Endpoint Selection

On April 1, 2002, HIARC re-evaluated the toxicology data base for
trifloxystrobin, established RfDs, PADs, and selected the toxicological
endpoints for occupational/residential exposure risk assessments.  The
HIARC also addressed the potential enhanced sensitivity of infants and
children from exposure to trifloxystrobin as required by the FQPA of
1996.  Toxicological endpoints for use in risk assessment are presented
in Table 3.3.1 below. 

Table 3.3.1  Summary of Toxicological Doses and Endpoints for
Trifloxystrobin for Use in Dietary and Non-Occupational Human Health
Risk Assessments

Exposure/

Scenario	Point of Departure 	Uncertainty/FQPA Safety Factors	RfD, PAD,
Level of Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary

Females 13-49 only	NOAEL = 250 mg/kg/day

	UFA=10x

UFH=10x

FQPA SF=1x (UFDB)	Acute RfD = acute NOAEL

                      Safety Factors

= 2.5 mg/kg/day

aPAD = acute NOAEL

              Safety Factors 

= 2.5 mg/kg/day	Developmental Toxicity-Rat

LOAEL = 500 mg/kg/day, based upon increased fetal skeletal anomalies.

Acute Dietary

General Population including infants and children	There were no
appropriate toxicological effects attributable to a single exposure
(dose) observed in oral toxicity studies including maternal effects in
developmental studies in rats and rabbits.  Therefore, a dose and
endpoint were not identified for this risk assessment.

Chronic Dietary

all populations	Parental 

NOAEL= 3.8 mg/kg/day

	UFA=10x

UFH=10x

FQPA SF=1x	Chronic RfD = chronic NOAEL

                           Safety Factors 

= 0.038 mg/kg/day

cPAD = chronic NOAEL

               Safety Factors 

= 0.038 mg/kg/day	Two-Generation reproduction study-Rat

LOAEL = 55.3 mg/kg/day, based upon decreases in body weight, body weight
gains, reduced food consumption and histopathological lesions in the
liver, kidneys and spleen.

Short- (1-30 days) and Intermed-Term (1- 6 months) Oral	Offspring NOAEL=
3.8 mg/kg/day	NA	LOC for MOE = 100 	Two-Generation reproduction
study-Rat

LOAEL = 55.3 mg/kg/day, based upon reduced pup body weights during
lactation.

Short- (1-30 days) and Intermed-Term

(1-6 months) Dermal 	Dermal study NOAEL= 100 mg/kg/day

	NA	LOC for MOE = 100 	28-Day Dermal Toxicity Study-Rat

LOAEL = 1000 mg/kg/day, based upon increases in mean absolute and
relative liver and kidney weights.

Long-Term Dermal

(> 6 months)

	Oral study NOAEL= 3.8 mg/kg/day

(dermal absorption rate = 33%)	NA	LOC for MOE = 100 	Two-Generation
reproduction study-Rat

LOAEL = 55.3 mg/kg/day, based upon decreases in body weight, body weight
gains, reduced food consumption and histopathological lesions in the
liver, kidneys and spleen.

Short- (1-30 days), 

Intermed-(1- 6 months) and Long-Term (> 6 months) Inhalation	Oral study
NOAEL= 3.8 mg/kg/day

(inhalation absorption rate = 100%)	NA	LOC for MOE = 100 

	Two-Generation reproduction study-Rat

LOAEL = 55.3 mg/kg/day, based upon decreases in body weight, body weight
gains, reduced food consumption and histopathological lesions in the
liver, kidneys and spleen.

Cancer

(oral, dermal, inhalation)	Trifloxystrobin is classified as “Not
Likely Human Carcinogen” based on the lack of evidence of
carcinogenicity in mouse and rat cancer studies.		

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key data (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  NA = not applicable.

Table 3.3.2  Summary of Toxicological Doses and Endpoints for
Trifloxystrobin for Use in Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Dermal Short-Term (1-30 days)	NOAEL= 250 mg/kg/day	UF = 100	Occupational
LOC for MOE = 100	28-Day Dermal Toxicity Study in Rats

LOAEL = 1000 mg/kg/day based on increases in liver and kidney weights.

Dermal Intermediate-Term (1-6 months)	NOAEL=100 mg/kg/day	UF = 100
Occupational LOC for MOE = 100	28-Day Dermal Toxicity Study in Rats

LOAEL = 1000 mg/kg/day based on increases in liver and kidney weights.

Dermal Long Term (>6 months) a	NOAEL=3.8 mg/kg/day	UF = 100	Occupational
LOC for MOE = 100	Two-generation reproduction - Rat

LOAEL = 55.3 mg/kg/day based on decreases in pup body weights during
lactation

Inhalation Short-Term (1-30 days) b	NOAEL=3.8 mg/kg/day	UF = 100
Occupational LOC for MOE = 100	Two-generation reproduction - Rat

LOAEL = 55.3 mg/kg/day based on decreases in pup body weights during
lactation

Inhalation Intermediate-term (1-6 months) b	NOAEL=3.8 mg/kg/day	UF = 100
Occupational LOC for MOE = 100	Two-generation reproduction - Rat

LOAEL = 55.3 mg/kg/day based on decreases in pup body weights during
lactation

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” based on the absence of significant tumor
increases in two adequate rodent carcinogenicity studies.

a Since an oral NOAEL was selected, a dermal absorption factor of 33 %
should be used for route-to-route extrapolation

b Since an oral NOAEL was selected, inhalation absorption factor 100 %
should be used for route-to-route extrapolation

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key data (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  NA = not applicable.

3.4  Endocrine Disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) "may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate." 
Following the recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there were
scientific bases for including, as part of the program, the androgen and
thyroid hormone systems, in addition to the estrogen hormone system. 
EPA also adopted EDSTAC’s recommendation that the Program include
evaluations of potential effects in wildlife.  For pesticide chemicals,
EPA will use FIFRA and, to the extent that effects in wildlife may help
determine whether a substance may have an effect in humans, FFDCA
authority to require the wildlife evaluations.  As the science develops
and resources allow, screening of additional hormone systems may be
added to the Endocrine Disruptor Screening Program (EDSP).

When additional appropriate screening and/or testing protocols being
considered under the Agency’s EDSP have been developed,
trifloxystrobin may be subjected to further screening and/or testing to
better characterize effects related to endocrine disruption.

4.0	Public Health and Pesticide Epidemiology Data

There is no new public health or pesticide epidemiology data to report
at this time.

5.0	Dietary Exposure/Risk Characterization

5.1	Pesticide Metabolism and Environmental Degradation

5.1.1	Metabolism in Primary Crops

The qualitative nature of the residue in plants is adequately understood
based on acceptable metabolism studies using the direct application of
trifloxystrobin to apples, cucumbers, and peanuts (PP#8F4955, DP Num:
254208 and 257888, F. Ives, 22/JUL/1999), sugar beets (PP#0F06121, DP
Num: 267787 and 272054, L. Cheng, 17/JAN/2002), and wheat (DP Num:
287242, L. Cheng, 08/OCT/2003).  The HED MARC (DP Num: 257835,
13/JUL/1999) concluded that both trifloxystrobin and the free form of
its acid metabolite CGA-321113 are of concern for both regulatory and
risk assessment purposes for plant commodities.  No new information has
been reviewed (DP Num: 332104, D. Rate, 22/AUG/2007; DP Num: 317330, B.
O’Keefe, 16/AUG/2006).

5.1.2	Metabolism in Rotational Crops

An adequate confined rotational crop study is available (DP Num: 254208,
F. Ives, 22/JUL/1999) reflecting the application of 14C-trifloxystrobin
at 2.0 lb ai/A.    SEQ CHAPTER \h \r 1 The previously submitted confined
rotational crop studies were deemed adequate.  Total radioactive
residues (expressed as trifloxystrobin equivalents) accumulated at
levels greater than 0.01 ppm in/on the following rotational commodities
planted in silt loam soil that has been treated with
[14C]trifloxystrobin (GP or TFMP label) at 2.0 lb ai/A (2x the maximum
proposed seasonal rate):  turnip leaves (0.011-0.064 ppm); turnip roots
(0.005-0.018 ppm); spinach (0.016-0.264 ppm); wheat forage (0.021-0.282
ppm); wheat straw (0.042-0.200 ppm); and wheat grain (0.029-0.069 ppm). 
Total radioactive residues in/on commodities from the TFMP-label
treatment were higher than the GP-label treatment.

  SEQ CHAPTER \h \r 1 The study adequately characterized/identified the
majority of radioactive residues in/on all commodities harvested from
all plantback intervals.  The predominant metabolite identified was
trifluoroacetic acid (20.1-93.6% TRR).  HED does not consider this
residue to be of concern at the 0.2 ppm levels observed.  Intact parent
was identified only as a minor (0.001 ppm) component.  The following
additional metabolites were detected at low concentrations (<0.01 ppm
each):  CGA-279202, CGA-331409, CGA-357261, CGA-357262, CGA-321113,
CGA-373465, CGA-373466, CGA-320299, and phthalic acid.

5.1.3	Metabolism in Livestock

No livestock data were submitted with these petitions.  The qualitative
nature of the residue in livestock is adequately understood based on
acceptable studies conducted on goats and laying hens.  The MARC has
determined that the total toxic residue, both for regulatory and risk
assessment purposes, is trifloxystrobin and the free form of its acid
metabolite CGA-321113.  Additionally, metabolite L7a (taurine conjugate
of trifloxystrobin) in the liver should be included in risk assessment. 

5.1.4	Analytical Methodology

An adequate GC/NPD method (Method AG-659A) is available for enforcing
tolerances for the combined residues of trifloxystrobin and the free
form of its acid metabolite (CGA-321113) in plant and livestock
commodities.  This method was validated by the Agency (DP Num: 265003,
L. Cheng, 13/APR/2000) and forwarded to FDA for inclusion in the
Pesticide Analytical Manual (PAM) Vol. II.  

Analytical method AG-659A, modified to utilize GC/MS detection, was used
for the analysis of trifloxystrobin and the acid metabolite CGA 321113
in each of the current commodities (asparagus, radish and papaya
matrices).  The method was adequately validated in conjunction with the
analysis of field trial samples.  The LLMV for trifloxystrobin and CGA
321113 was determined to be 0.05 ppm and 0.020 ppm, respectively for
asparagus.  The LLMV for each analyte, trifloxystrobin and CGA 321113,
was determined to be 0.02 ppm for radishes.  The LLMV for each analyte,
trifloxystrobin and CGA 321113, was determined to be 0.02 ppm for
papaya.  The LLMV for trifloxystrobin and CGA 321113 was not reported
for citrus fruit matrices or strawberry.  

5.1.5  Multiresidue Methods

The regulated residues were tested in accordance with the PAM, Volume I,
Appendix II.  Trifloxystrobin gave adequate responses through protocol
C, and was completely recovered from fortified apple samples when
analyzed through protocols D and E.  Acid metabolite CGA-321113 was
recoverable through protocol B and residues from apples fortified with
CGA-321113 were completely recovered through Section 402 E2/C1
(extraction with methylene chloride).  These data were forwarded to FDA.

5.1.6  Storage Stability

Samples of asparagus were stored frozen up to 198 days prior to
analysis.  Samples of radish tops and roots were stored frozen up to 311
and 410 days, respectively, prior to analysis.  Samples of papaya were
stored frozen up to 504 days prior to analysis.  Samples of strawberry
were stored frozen up to 347 days prior to analysis.  In addition,
samples of oranges, lemons, and grapefruit were stored frozen 378, 451,
and 512 days, respectively prior to analysis.  Storage stability data
are available indicating that both trifloxystrobin and CGA-321113 are
stable at < -15ºC for at least 24 months in cucumber, potatoes, grapes,
and wheat (forage, grain, and straw) and for at least 18.6 months in
peanut nutmeats, hay, and oil (DP Num: 254221, 254213, 254218, 254217;
L. Cheng; 06/APR/2000).    SEQ CHAPTER \h \r 1 These data are adequate
to support the subject petitions.

5.1.7  Magnitude in Plants

IR-4 and Bayer Crop Science have submitted crop field trials supporting
the use of trifloxystrobin (50% WDG or 2.08 lb ai/gal SC) on asparagus
(MRID No. 46886201), radish (MRID No. 46886202), papaya (MRID No.
46886203), strawberry (MRID No. 47021101), and citrus fruits (MRID No.
46960701).    SEQ CHAPTER \h \r 1 The results from these studies are
discussed below and summarized in Table 5.1.7. 

Table 5.1.7.  Summary of Residue Data for Field Trials using a 50% WDG
Formulation of Trifloxystrobin.

Matrix	

Total Rate

lb ai/A

(kg ai/ha)	

PHI (days)	

Total Trifloxystrobin Residues (ppm) 1

	

n	

Min.	

Max.	

HAFT 2	

Mean 	

Std. Dev.

Asparagus	0.37 – 0.39

(0.41 -0.44)	California

92 – 100

Rest of US

167 - 188	16	<0.07	<0.07	NA	NA	NA

Radish Tops	0.251–0.264

(0.281- 0.296)	6 - 8	12	0.12	7.42	7.18	2.65	2.25

Radish Roots

	12	<0.04	0.11	0.10	0.06	0.02

Radish Tops	0.494–0.527

(0.553-0.59)	6 - 8	12	0.19	17.53	15.00	5.61	5.94

Radish Roots

	12	<0.04	0.21	0.20	0.11	0.03

Papaya	0.506-0.521

(0.567-0.584)	0	8	0.09	0.32	0.31	0.20	0.09

Strawberry	0.598-0.606

(0.670-0.679)	0	16	0.11	0.59	0.56	0.35	0.15

Orange	0.492-0.509

(0.552-0.570)	7	50	0.03	0.33	0.29	0.12	0.06

Lemon	0.497-0.502

(0.557-0.563)	6-7	20	0.07	0.37	0.32	0.19	0.09

Grapefruit	0.493-0.505

(0.553-0.566)	7	24	0.03	0.19	0.19	0.09	0.05

1The combined trifloxystrobin residues are trifloxystrobin + CGA-321113.
 The validated method LOQ for trifloxystrobin and CGA-321113 is 0.01 ppm
in oranges and strawberries; 0.02 ppm for lemons, grapefruit, radish and
papaya; 0.02 ppm and 0.05 ppm for CGA-321113 and trifloxystrobin,
respectively in asparagus.  Residues <LOQ were estimated to be at the
LOQ for calculation of mean and standard deviation.

2HAFT = Highest Average Field Trial.

The database is adequate for asparagus and ARIA recommends for the
requested tolerance of 0.07 ppm.  Radish and papaya are representative
commodities for vegetable, root except sugar beet, subgroup 1B; and the
proposed tropical fruit group which includes papaya; sapote, black;
canistel; sapote, mamey; mango; sapodilla; and star apple, respectively.
 The data are adequate and ARIA recommends for tolerances of 0.10 ppm
for vegetable, root except sugar beet, subgroup 1B (based on rejected
log normality (CA method and harmonization with the Codex maximum
residue limits (MRL) at 0.10 ppm in/on carrot), 10 ppm for radish, tops
(the calculated MRL was based on log normality in the 95th percentile);
0.70 ppm for papaya; sapote,black; canistel; sapote, mamey; ,mango;
sapodilla; and star apple (the calculated MRL of 0.70 ppm was based on
European Union (EU) log normality in the 99th percentile); and 1.1 ppm
for strawberry (the calculated MRL was based on European Union (EU) log
normality in the 99th percentile).  The submitted field trial data and
processing studies are adequate to reduce the PHI for use on citrus and
for setting revised tolerances on citrus, fruit crop group 10, citrus,
oil and citrus, dried pulp.  ARIA recommends revising the current
tolerances to 0.6 ppm for citrus fruits, crop group 10; 38.0 ppm for
citrus, oil; and 1.0 ppm for citrus, dried pulp.  

A new Section F must be submitted to the Agency correcting the commodity
definitions as shown in Table 10 and revising the proposed tolerances to
match the recommended tolerances.  

Magnitude in Meat, Milk, Poultry, and Eggs

There are no livestock feedstuffs associated with the proposed uses on
asparagus, papaya, strawberry, or citrus fruit commodities.  However,
carrots and turnips as a part of crop group 1B (vegetable, root, except
sugar beet), are cattle and swine feed items.  The addition of radish to
the already established tolerance for the vegetable, root, except sugar
beet, subgroup 1B, will have no impact on the established tolerances of
livestock commodities based on this addition to the respective dietary
burdens.  Accordingly, the current tolerances for livestock commodities
are adequate.  The leaves and foliage of vegetable, root commodities are
not significant feed items (B. Schneider, e-mail 08/AUG/2007).

5.1.9  Confined and Field Rotational Crops

Of the submitted data for the requested crops, asparagus, radish,
papaya, strawberry, and citrus, only radish is a crop which is typically
rotated.  No rotational crop studies were submitted with this petition
(PP#6E7088).

However, a confined rotational crop study was submitted earlier.  The
study adequately characterized/identified the majority of radioactive
residues in/on all commodities harvested from all plantback intervals.  

5.1.10  Pesticide Metabolites and Degradates of Concern

Table 5.1.10.  Summary of Metabolites and Degradates to be included in
the Risk Assessment and Tolerance Expression

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop	Trifloxystrobin and CGA-321113	Trifloxystrobin and
CGA-321113

	Rotational Crop	Trifloxystrobin and CGA-321113	Trifloxystrobin and
CGA-321113

Livestock

	Ruminant	Trifloxystrobin; CGA-321113; and Metabolite L7a in liver and
meat byproducts	Trifloxystrobin and CGA-321113

	Swine	Trifloxystrobin and CGA-321113	Trifloxystrobin and CGA-321113

	Poultry	Trifloxystrobin and CGA-321113	Trifloxystrobin and CGA-321113

Drinking Water

	Trifloxystrobin and CGA-321113	Not Applicable

5.1.11  Drinking Water Residue Profile

The proposed use rates of trifloxystrobin on the subject commodities are
less than or equal to the use rates previously used in the screening
models to determine residues of water.  As such, no new EDWCs were
calculated for this risk assessment (personal communication with S.
Syslo).  

The drinking water residues incorporated directly into the dietary risk
assessment were provided by the Environmental Fate and Effects Division
(EFED) and summarized in the following memoranda: “Section 18
Ecological Risk and Drinking Water Exposure Assessment for the Control
of Soybean Rust,” DP Num: 296314, 296315, 296316, 296317, 296318,
296319, and 296320, S. Abel, 30/MAR/2004 and “Note to File:
Trifloxystrobin: Change in EDWC from 92 ppb to 140 ppb for the Acute
Dietary Assessment Results in Negligible Change.”, DP Num: 343362, D.
Rate, 30/AUG/2007.

Water residues were incorporated in the DEEM-FCID into the food
categories “water, direct, all sources” and “water, indirect, all
sources.”  The EDWCs used in the dietary assessment are expected to be
conservative.  

In earlier assessments, the Agency used FIRST and SCI-GROW screening
models to determine the EDWCs of trifloxystrobin in surface and ground
water, respectively.  Trifloxystrobin is immobile in soil.  It degrades
and transforms rapidly in soil and aquatic environments.  The primary
degradate is CGA-321113.  EDWCs were calculated for total
trifloxystrobin residues (parent trifloxystrobin plus the major
degradate CGA-321113) using EFED’s FIRST model for surface water and
the SCI-GROW model for ground water.  EFED’s interim method for
drinking water estimates for pesticides used in rice paddies was also
used to generate EDWCs.

The use site with the highest application rate is turf, with a maximum
label rate of 1.078 lb ai/A/yr (three applications at 0.359 lb ai/A/yr).
 EDWCs were also provided for rice paddies that may be treated with
trifloxystrobin. 

To estimate surface water concentrations for use on rice, an interim
rice paddy model was used.  EFED provided an estimate of total
trifloxystrobin residues (parent plus degradates).  The total parent
plus degradates estimate is 140 ppb.  EFED recommends using the highest
total (parent plus degradates) residue estimate for acute and chronic
risk assessment.  ARIA recognizes that the rice estimates are considered
overestimates due to the nature of the assumptions built into the model;
therefore, these values should be viewed as very conservative.  

The highest EDWC estimates for acute and chronic exposure (140 ppb from
use on rice) were used in the dietary analysis.

Table 5.1.11.  Summary of Estimated Surface Water and Groundwater
Concentrations for Trifloxystrobin.

	Trifloxystrobin

	Surface Water Conc., ppb a	Groundwater Conc., ppb b

Acute	140 (rice)	3.4 (turf)

Chronic (non-cancer)	140 (rice)	3.4 (turf)

Chronic (cancer)	NA	NA

a From FIRST model for surface water.  Input parameters are based on
interim rice paddy model.

b From the SCI-GROW model assuming a maximum seasonal use rate of 1.078
lb ai/A/yr, a Koc of 124.0 mL/g, and a half-life of 282.75 days.

Dietary Exposure and Risk

5.2.1	Acute Dietary Exposure/Risk

An acute dietary assessment assuming tolerance-level residues for most
commodities with existing, proposed and reassessed tolerances for meat
byproducts of cattle, goats, horses, and sheep, was conducted for
females 13-49 years old.  For all commodities, 100% crop treated (%CT)
was used.  The peak (i.e., the highest and therefore relevant to acute
exposure) drinking water estimate of 140 ppb, provided by the EFED, was
directly incorporated into the acute assessment.  The acute dietary risk
assessment for trifloxystrobin shows that for all included commodities,
the acute dietary risk estimates are below ARIA’s level of concern
(i.e. <100% aPAD).  There were no appropriate toxicological effects
attributable to a single exposure (dose) for the general population;
therefore, a dose and endpoint were not identified for this risk
assessment.  The aPAD for females 13-49 years was 2.5 mg/kg/day.  For
food and drinking water, the exposure to females 13-49 yrs old was
0.019559 mg/kg/day, which utilized <1% of the aPAD at the 95th
percentile of exposure distribution.

5.2.2	Chronic Dietary Exposure/Risk

A chronic dietary assessment assuming tolerance-level residues for most
commodities with existing, proposed, anticipated tolerances for grape,
apple and orange and reassessed tolerances for meat byproducts of
cattle, goats, horses, and sheep, was conducted for the general
population and all population subgroups.  Anticipated residues (ARs)
were provided by ARIA (email, 9/11/2007) calculated by averaging the
residue values over the entire field trial and using the LOQ for
non-detect samples.  For all commodities, 100%CT was used.  The mean
(i.e., relevant to chronic exposure) drinking water estimate of 140 ppb,
provided by EFED, was directly incorporated into the chronic assessment.
 The chronic dietary risk assessment shows that for all included
commodities, the chronic dietary risk estimates are below ARIA’s level
of concern (i.e. <100% cPAD.  For the U.S. population the exposure for
food and water utilized 20% of the cPAD.  The chronic dietary risk
estimate for the highest reported exposed population subgroup, all
infants (<1 year old), is 52% of the cPAD.

Table 5.2.2.  Summary of Dietary Exposure Risk for Trifloxystrobin

Population Subgroup	Acute Dietary

(95th Percentile)	Chronic Dietary

	Dietary Exposure (mg/kg/day)	% aPAD*	Dietary Exposure

(mg/kg/day)	% cPAD*

General U.S. Population

0.007771	20

All Infants (< 1 year old)

0.019559	52

Children 1-2 years old

0.019163	50

Children 3-5 years old

0.015316	40

Children 6-12 years old

0.009475	25

Youth 13-19 years old

0.006192	16

Adults 20-49 years old

0.006517	17

Adults 50+ years old

0.006441	17

Females 13-49 years old	0.019706	<1	0.006299	17

	* % PADs are reported to 2 significant figures.

	**The values for the highest exposed population for each type of risk
assessment are bolded.

5.2.3	Cancer Dietary Risk

The HIARC classified trifloxystrobin as a “not likely carcinogen”;
therefore, quantification of human cancer risk was not necessary. 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization

Trifloxystrobin’s residential uses include disease control in
turfgrass and ornamentals (Compass®).  Up to three applications may be
made in a season, with the shortest interval between applications being
5-7 days.  Because FQPA requires consideration of aggregate exposure to
all likely non-occupational uses, this assessment uses non-occupational
postapplication contact with trifloxystrobin following Compass® use on
turfgrass as the most common and worst case contributor to such
exposures.  

6.1	Residential Postapplication Exposure  

There is potential for dermal (adults and children) and incidental oral
exposure (children only) during post-application activities.  The
following post-application exposure scenarios resulting from lawn
treatment were previously assessed (DP Num: 264570, J. Arthur,
06/AUG/2001): (1) dermal exposure from pesticide residues on lawns, (2)
incidental non-dietary ingestion of pesticide residues on lawns from
hand-to-mouth transfer, (3) incidental non-dietary ingestion of residues
from object-to-mouth activities (pesticide-treated turfgrass), and (4)
incidental non-dietary ingestion of soil from pesticide-treated
residential areas.  Post-application exposures from various activities
following lawn treatment are considered to be the most common and
significant in residential settings.  An exposure/risk assessment was
previously performed using applicable toxicological endpoints selected
by the HIARC (01/APR/2002).  The proposed new use does not alter the
previous residential risk assessment, therefore a new residential
assessment was not performed. 

  SEQ CHAPTER \h \r 1 The HED Standard Operating Procedures for
Residential Exposure Assessments (Draft, December 18, 1997) were used as
a guideline for performing the residential postapplication assessment. 
Also used in the assessment were interim changes to these SOPs which
were adopted by the HED Exposure Science Advisory Council regarding
standard values, including, for turf transferable residues, turf
transfer coefficients and hand-to-mouth activities (Policy 11, February
22, 2001).  The exposure and risk estimates for the four residential
exposure scenarios are assessed for the day of application (day “0"),
because it is assumed that adults and toddlers could contact the lawn
immediately after application.  On the day of application, it was
assumed that 5 percent of the application rate is available from the
turfgrass as transferable residue (20 percent for object-to-mouth
activities).   

The NOAEL of 100 mg/kg/day from a 28-day dermal toxicity study in rats
(endpoint: increases in mean absolute and relative liver and kidney
weights) was used for determining short-/intermediate-term dermal risk
to adults and toddlers, and the NOAEL of 3.8 mg/kg/day from a
two-generation reproduction study in rats (endpoint: decreases in pup
body weight during lactation), for determining short-/intermediate-term
incidental ingestion risk to toddlers.  

Adult and children’s dermal exposure and risk from treated lawns is
summarized in Table 6.1.1.  The Short-/Intermediate-Term MOEs for adults
and children are 1300 and 760, respectively.

Children’s risk from oral hand-to-mouth activities on treated lawns is
summarized in Table 6.1.2.  The Short-/Intermediate-Term MOE for
children is 750.

Children’s risk from object-to-mouth (turfgrass) from treated lawns is
summarized in Table 6.1.3.  The Short-/Intermediate-Term MOE for
children is 3000.

Children’s risk from incidental ingestion of soil from treated lawns
is summarized in Table 6.1.4.  The Short-Intermediate-Term MOE for
children is 220,000.

Since the short-/intermediate-term MOEs are above 100, they DO NOT
exceed ARIA’s level of concern.  Chronic or long-term exposure is not
expected.  

Table 6.1.1.  Dermal Exposure and Risk for Adults and Children from
Treated Lawns

Subgroup exposed	Application Rate

 (lb ai/A)	Fraction of ai Available	Turf Transferable Residue1

(ug/cm2)	Dermal Transfer Coefficient

(cm2/hr)	Exposure Time 

(hrs/day)	Absorption Factor	Body Weight

(kg)	 Daily Dose2

(mg/kg/day)	Short- & Intermediate-Term MOE3

Adult	0.34	0.05	0.19	14,500	2	1	70	0.079	     1300

Children	0.34	0.05	0.19	5,200	2	1	15	0.13	      760

1 Turf Transferable Residue (ug/cm2) = Application rate (lb ai/A) x
Fraction of ai Available  x  4.54E+8 ug/lb x 2.47E-8 A/cm2

2 Daily Dose = (Turf Transferable Residue x 1E-3 mg/ug x Dermal Transfer
Coefficient x Exposure Time)/Body weight 

3 Short & Intermediate-Term Dermal MOE = Short & Intermediate-Term
Dermal NOAEL (100 mg/kg/day) /Daily Dose

Table 6.1.2.  Oral Hand-to-Mouth Exposure and Risk for Children from
Treated Lawns

Application Rate

 (lb ai/A)	Fraction of ai Available	Turf Transferable Residue1

(ug/cm2)	Exposure Time 

(hrs/day)	Extraction by saliva	Hand Surface Area (cm2/event)	Frequency

(events/ hr)	Body Weight

(kg)	 Daily Dose2

(mg/kg/day)	Short-Term MOE3

0.34	0.05	0.19	2	0.5	20	20 	15	0.0051 	750

1 Turf Transferable Residue (ug/cm2) = Application rate (lb ai/A) x
Fraction of ai Available  x  4.54E+8 ug/lb x 2.47E-8 A/cm2

2 Daily Dose = (Turf Transferable Residue (ug/cm2) x Extraction by
Saliva x Hand Surface Area (cm2/event) x Frequency (events/hr) x 1E-3
mg/ ug x ET (hrs/day)] / [Body Weight (kg)]

3 Short-Term Oral MOE = Intermediate-Term Oral NOAEL (3.8 mg/kg/day)
/Daily Dose  

Table 6.1.3.  Oral Object-to-Mouth (Turf grass) Exposure and Risk for
Children from Treated Lawns 

Application Rate

 (lb ai/A)	Fraction of ai Available	Grass Residue1 

(ug/cm2)	Surface Area Mouthed 

(cm2/day)	Body Weight

(kg)	 Daily Dose2

(mg/kg/day)	Short- & Intermediate-Term MOE3

0.34	0.2	0.76	25	15	0.0013	3000

1Grass residue (ug/cm2) = [Application Rate (lbs ai/A)  x Fraction of ai
Available x  4.54E+8 ug/lb x 2.47E-8 A/cm2]

2 Daily Dose = [Grass residue (ug/cm2) x Surface Area Mouthed (cm2/day)
x 1E-3 mg/ug] / [Body Weight (kg)]

3 Short & Intermediate-Term Oral MOE = Intermediate-Term Oral NOAEL (3.8
mg/kg/day) /Daily Dose 

Table 6.1.4.  Exposure and Risk for Children from Ingestion of Soil from
Treated Lawns

Application Rate

 (lb ai/A)	Fraction of ai Available	Soil Residue1 

(ug/g)	Ingestion Rate

(g/day)	Body  Weight

(kg)	 Daily Dose2

(mg/kg/day)	Short- & Intermediate-Term MOE3

0.34	1.0	2.6	100	15	0.000017	220,000

1 Soil residue (ug/g) = [Application Rate (lbs ai/A)  x Fraction of ai
Available x  4.54E+8 ug/lb x 2.47E-8 A/cm2 x 0.67 cm3/g soil]

2 Daily Dose = [Soil residue (ug/g) x Ingestion rate (mg/day) x 1E-6
g/ug] / [Body Weight (kg)]

3 Short & Intermediate-Term Oral MOE = Intermediate-Term Oral NOAEL (3.8
mg/kg/day) /Daily Dose  

6.2  Combined Exposure 

No new residential uses were proposed in the subject petitions. 
Therefore, residential exposure information is take from the previous
risk assessment, HED Risk Assessment: Human Health Risk Assessment for
Trifloxystrobin for New Section 3 Use on Soybeans, DP Num: 318618, B.
O’Keefe, 07/AUG/2006.

The FQPA requires residential exposures that could reasonably be
expected to occur on the same day be combined and compared to the
appropriate toxicity endpoint.  Because trifloxystrobin is not applied
by residential handlers, the only multiple-residential exposure
scenarios involve children's exposure from dermal and oral routes
following turfgrass treatment by a pest control operator (PCO).  For
incidental oral exposure to toddlers in residential settings, the three
scenarios that would reasonably be expected to occur on the same day are
toddler's incidental ingestion of residues on turf from hand-to-mouth
activities, mouthing turfgrass and eating soil.  These daily exposures,
when combined, total 0.0064 mg/kg/day.  When the combined exposure is
compared to the short-term incidental oral NOAEL (3.8 mg/kg/day), the
MOE = 590.  Because the toxicity endpoints for dermal and oral exposure
are not the same, the combining of risks for these different routes of
exposure is not done.

Therefore, the combined risk from incidental oral exposures anticipated
for toddlers (i.e., MOE = 590) does not exceed ARIA’s level of
concern.  

6.3	Other (Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for
trifloxystrobin.  The Agency has been working with the Spray Drift Task
Force, EPA Regional Offices and State Lead Agencies for pesticide
regulation and other parties to develop the best spray drift management
practices.  On a chemical by chemical basis, the Agency is now requiring
interim mitigation measures for aerial applications that must be placed
on product labels/labeling.  The Agency has completed its evaluation of
the new database submitted by the Spray Drift Task Force, a membership
of U.S. pesticide registrants, and is developing a policy on how to
appropriately apply the data and the AgDRIFT computer model to its risk
assessments for pesticides applied by air, orchard airblast and ground
hydraulic methods.  After the policy is in place, the Agency may impose
further refinements in spray drift management practices to reduce
off-target drift with specific products with significant risks
associated with drift.

It is noted that the 1.078 lb ai/A application rate for turf was modeled
to estimate postapplication residential exposure of toddlers.  As this
rate is equal to or higher than many of agricultural application rates,
this scenario is protective of any exposure of farm children via spray
drift from agricultural trifloxystrobin applications.

7.0	Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate
trifloxystrobin pesticide exposures and risks from three major sources:
food, drinking water, and residential exposures.  In an aggregate
assessment, exposures from relevant sources are added together and
compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or
the risks themselves can be aggregated.  When aggregating exposures and
risks from various sources, HED and ARIA have considered both the route
and duration of exposure.

7.1	Acute Aggregate Risk

There were no appropriate toxicological effects attributable to a single
exposure (dose) for the general population; therefore, a dose and
endpoint were not identified for this risk assessment.  The aPAD for
females 13-49 years was 2.5 mg/kg/day.  To assess the aggregate acute
risk, EDWCs were incorporated directly into the dietary exposure
analysis.  Refer to section 5.2.1 for this risk estimate.  

7.2	Short-Term Aggregate Risk

The short-term aggregate risk assessment estimates risks likely to
result from 1- to 30-day exposure to trifloxystrobin residues from food,
drinking water, and residential pesticide uses.  High-end estimates of
residential exposure are used in the short-term assessment, while
average values are used for food and drinking water exposure (i.e.
chronic exposures).

Different endpoints were identified by HIARC for short-term incidental
oral and dermal risk assessment (the basis for the oral endpoint is
reduced pup body weights and the dermal endpoint is based on increases
in liver and kidney weights).  Therefore, it is not possible to combine
dietary/incidental oral exposure with dermal exposure. 

Short-term aggregate risk assessments were conducted for the following
scenarios: 1) adults (dermal residential + dietary food and drinking
water exposures); 2) children 1-2 years (dermal residential + dietary
food and drinking water exposures); and 3) children 1-2 years
(incidental oral + dietary food and drinking water exposures).  Adult
and child risk from dermal exposure is summarized in Table 6.1.1 in
Section 6.1.  A short-term aggregate risk assessment is required for
infants and children because there are residential postapplication oral
exposure scenarios.  Toddlers’ incidental oral exposure is assumed to
include hand-to-mouth exposure, object-to-mouth exposure and exposure
through incidental ingestion of soil.  See Tables 6.1.2-6.1.4 in Section
6.1 for short-term exposure and risk estimates from incidental oral
sources for children.  Table 7.2 summarizes short-term aggregate risks. 
All short-term aggregate risk estimates result is MOEs greater than 100.
 Therefore, ARIA does not consider short-term aggregate risk to be a
concern.

  SEQ CHAPTER \h \r 1 Table 7.2.  Short-Term Aggregate Risk (Food, Water
and Incidental Exposure)

Population	Short-Term Scenario

 NOAEL

mg/kg/day	LOC

MOE1	Average

Food + Water Exposure

mg/kg/day	Residential Oral Exposure2

mg/kg/day	Residential Dermal Exposure2

mg/kg/day	Aggregate MOE

 (food and residential)3

US Population	

100	

100	0.007771	NA	0.079	1200

All Infants (< 1 year old)

	0.019559	NA	0.1308	670

All Infants (< 1 year old)	3.8	100	0.019559	0.00642	NA	150

  SEQ CHAPTER \h \r 1 1 The level of concern (LOC) MOE is 100, based on
inter- and intra-species safety factors totaling 100.

2 Residential Exposure = [Incidental exposure from all possible
sources]. No residential oral exposure is expected for adults.

3 Aggregate MOE = [NOAEL (mg/kg/day) ÷ (Avg Food Exposure + Residential
Exposure)].

NA = Not Applicable.  Numbers are rounded to 2 significant figures.

7.3	Intermediate-Term Aggregate Risk

An intermediate-term aggregate risk assessment (1 to 6 months of
exposure to trifloxystrobin residues from food, drinking water, and
residential pesticide uses) is not expected to occur based on the short
soil half-life (about 2 days).  Therefore, an intermediate-term
aggregate risk assessment was not performed.

Long-Term Aggregate Risk

Because there are no long-term (chronic) exposures due to residential
use, long-term aggregate risk is solely due to chronic dietary risk and
risk contributed from drinking water.  Refer to section 5.2.2 for the
long-term aggregate risk (chronic dietary and drinking water) estimates.

7.5	Cancer Risk

In accordance with the EPA Draft Guidelines for Carcinogen Risk
Assessment (July, 1999), the HIARC classified trifloxystrobin as a "not
likely” human carcinogen.  Therefore, trifloxystrobin is not expected
to pose a cancer risk.

8.0	Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to trifloxystrobin and any other
substances and trifloxystrobin does not appear to produce a toxic
metabolite produced by other substances. For the purposes of this
tolerance action, therefore, EPA has not assumed that trifloxystrobin
has a common mechanism of toxicity with other substances. For
information regarding EPA’s efforts to determine which chemicals have
a common mechanism of toxicity and to evaluate the cumulative effects of
such chemicals, see the policy statements released by EPA’s Office of
Pesticide Programs concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism on EPA’s website at   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

9.0	Occupational Exposure/Risk Pathway

9.1	Short-/Intermediate-/Long-Term Handler Risk

Based upon all of the proposed use patterns, ARIA believes the most
highly exposed occupational pesticide handlers would be 1) mixer/loaders
using open pour loading of water dispersible granules; 2) mixer/loaders
using open-pour loading of liquids; 3) applicators using open-cab
ground-boom spray equipment and 4) aerial applicators (aircraft with
enclosed cockpits) to citrus crops.  

ARIA believes pesticide handlers will be exposed to short-term duration
(1-30 days) exposures but not to intermediate-term (1-6 months) duration
exposures.  Although multiple applications are possible, they are
separated by 7-21 day retreatment intervals.  Only 2 sequential
applications may be made.  It is unlikely that pesticide handlers would
be exposed continuously for 30 days or more.  Therefore, only short-term
duration risks were assessed.  

Private (i.e., grower) applicators may perform all functions, that is,
mix, load and apply the material.  The HED ExpoSAC SOP Number 12 (29
March 2000) directs that although the same individual may perform all
those tasks, they shall be assessed separately.  The available exposure
data for combined mixer/loader/applicator scenarios are limited in
comparison to the monitoring of these two activities separately.  These
exposure scenarios are outlined in the Pesticide Handler Exposure
Database (PHED) Surrogate Exposure Guide (August 1998).  HED has adopted
a methodology to present the exposure and risk estimates separately for
the job functions in some scenarios and to present them as combined in
other cases.  Most exposure scenarios for hand-held equipment (such as
hand wands, backpack sprayers, and push-type granular spreaders) are
assessed as a combined job function.  With these types of hand held
operations, all handling activities are assumed to be conducted by the
same individual.  The available monitoring data support this and HED
presents them in this way.  Conversely, for equipment types such as
fixed-wing aircraft, ground-boom tractors, or air-blast sprayers, the
applicator exposures are assessed and presented separately from those of
the mixers and loaders.  By separating the two job functions, HED
determines the most appropriate levels of PPE for each aspect of the job
without requiring an applicator to wear unnecessary PPE that might be
required for a mixer/loader (e.g., chemical resistant gloves may only be
necessary during the pouring of a liquid formulation).  

No chemical specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED (v.
1.1, 1998).  For pesticide handlers, it is HED standard practice to
present estimates of dermal exposure for “baseline” that is, for
workers wearing a single layer of work clothing consisting of a
long-sleeved shirt, long pants, shoes plus socks and no protective
gloves as well as for “baseline” and the use of protective gloves or
other PPE as might be necessary.  The proposed product labels direct
applicators and other handlers must wear a long-sleeved shirt, long
pants, shoes plus socks and chemical-resistant gloves made of any
waterproof material.

The PHED does not contain data for handlers using water dispersible
granules.  However it does contain data regarding dry flowable
formulations.  As a surrogate, ARIA uses the unit exposure data for a
dry flowable formulation which is expected to result in similar
exposures.  

The current risk assessment uses toxicological endpoints cited in the
March 7, 2002 HED HIARC report.  Relative to the assessment herein, the
HIARC identified a short-term duration (1-30 days) dermal toxicological
endpoint from a 28-day dermal toxicity study in the rat.  The toxic
effects seen were increases in mean absolute and relative liver and
kidney weights.  The NOAEL is 100 mg ai/kg bw/day.  Since the dermal
endpoint is identified from a dermal study, there is no adjustment for
dermal absorption.  Although ARIA does not expect intermediate-term
duration (1-6 months) exposures, the short-term and intermediate-term
dermal endpoints are the same.  Therefore, in the event that there might
be intermediate-term exposures, the estimates of risk are adequate to
account for intermediate-term exposures.

The HIARC also identified a short-term inhalation toxicological endpoint
from a 2-generation reproduction study in the rat.  The effects seen
were decreases in body weight, body weight gains, reduced food
consumption and histopathological lesions in the liver, kidneys and
spleen in the dams.  Since the toxic effects are maternal effects (i.e.,
not fetal effects) a 70 kg bw is used to calculate exposure.  

The dermal and inhalation toxicological endpoints are identified from
different studies (dermal versus reproduction) and cite different
toxicological effects.  Therefore, dermal and inhalation exposures are
not combined.  The MOEs are presented separately for dermal and
inhalation exposure.  

Table 9.1 is a summary of exposures and risks to occupational pesticide
handlers based on the proposed citrus use which posed the highest risk.

Table 9.1.  Summary of Exposure & Risk for Occupational Handlers
Applying Trifloxystrobin to

 Citrus

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/unit	Units Treated3	Avg. Daily Dose4

mg ai/kg bw/day	MOE5

Mixer/Loader -  Open-pour Loading of Water Dispersible Granule
supporting aerial operations

Dermal:

SLNoGlove       0.066 LC

SLWithGlove    0.066 HC

Inhal.             0.00077 HC	0.125

lb ai/A	350 A	Dermal:

SLNoGlove      0.0413

SLWithGlove  0.0413

Inhal.           0.000481	

2,400

2,400

7,900

Mixer/Loader - Open-pour Loading Liquids supporting aerial operations

Dermal:

SLNoGlove       2.9 HC

SLWithGlove    0.023 HC

Inhal.             0.0012 HC	0.125

lb ai/A	350 A	Dermal:

SLNoGlove      1.81

SLWithGlove  0.0144

Inhal.            0.00075	

55

6,900

5,100

Applicator -  Airblast -  Open-cab

Dermal:

SLNoGlove        0.36 HC

SLWithGlove     0.24 MC

Inhal.             0.0045 HC	0.125

lb ai/A	40 A	Dermal:

SLNoGlove     0.026

SLWithGlove  0.017

Inhal.           0.00032	

3,800

5,900

12,000

Aerial Applicator

Dermal:

SLNoGlove        0.0050 HC

Inhal.             0.000068 HC	0.125

lb ai/A	350 A	Dermal:

SLNoGlove      0.00313

Inhal.            0.0000425	

32,000

 

89,000

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.   Dermal exposure:  SLNoGlove =
single layer of work clothing (long pants long sleeved shirt, shoes plus
socks) and No protective gloves;  SLWithGlove = single layer of work
clothing AND the use of protective gloves.   Inhal. = Inhalation.  Units
= mg ai/pound of active ingredient handled.  Data Confidence: LC = Low
Confidence, MC = Medium Confidence, HC = High Confidence.

2.  Applic. Rate. = Taken from the proposed amendment to the Flint label
and from the proposed Absolute label

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”; SOP  No. 9.1.   ExpoSAC;  Revised 5 July
2000; 

4.  Average Daily Dose (ADD) = Unit Exposure * Applic. Rate * Units
Treated ( Body Weight (70 kg) 

5.  MOE = Margin of Exposure = NOAEL  ( ADD.   Dermal NOAEL = 100 mg
ai/kg bw/day, Inhalation NOAEL = 3.8 mg ai/kg bw/day.  Numbers are
rounded to 2 significant figures.

A MOE of 100 is adequate to protect occupational pesticide handlers from
exposures to trifloxystrobin.  Except for mixer/loaders without
protective gloves using open-pour loading of liquids in support of
aerial operations, all estimated MOEs are > 100.  Since the product
labels require the use of protective gloves, exposures and risks for the
proposed uses do not exceed ARIA’s level of concern.

9.2	Short-/Intermediate-/Long-Term Postapplication Risk

It is possible for agricultural workers to have post-application
exposure to pesticide residues during the course of typical agricultural
activities.  HED in conjunction with the Agricultural Re-entry Task
Force (ARTF) has identified a number of post-application agricultural
activities that may occur and which may result in post-application
exposures to pesticide residues.  HED has also identified Transfer
Coefficients (TC) (cm²/hr) relative to the various activities which
express the amount of foliar contact over time, during each of the
activities identified.  

The TCs used in this assessment are from an interim TC Standard
Operating Procedure (SOP) developed by HED’s ExpoSAC using proprietary
data from the ARTF database (SOP # 3.1).  It is the intention of HED’s
ExpoSAC that this SOP will be periodically updated to incorporate
additional information about agricultural practices in crops and new
data on transfer coefficients.  Much of this information will originate
from exposure studies currently being conducted by the ARTF, from
further analysis of studies already submitted to the Agency, and from
studies in the published scientific literature.

There are few "early season" activities (i.e., around bloom time) that
require re-entry shortly after application.   Irrigation activities and
scouting are identified as the most likely activities.  The TC for
scouting and irrigation is 1,000 cm2/hr.  

Therefore, as a screening level assessment, ARIA herein uses the TC of
1,000 cm2/hr for a conservative estimate of agricultural worker exposure
to post-application residues of trifloxystrobin.

Lacking compound specific dislodgeable foliar residue (DFR) data, HED
assumes 20% of the application rate is available as dislodgeable foliar
residue on day zero after application.  This is adapted from the ExpoSAC
SOP No. 003 (7 May 1998 - Revised 7 August 2000).  

The estimated post-application exposure results in a MOE of 3,100.  A
MOE of 100 is adequate to protect agricultural workers from
post-application exposures.  Since the estimated MOE is > 100, the
proposed uses do not exceed ARIA’s level of concern.

9.3	Restricted Entry Interval (REI)

Trifloxystrobin is classified in Acute Toxicity Category III for primary
eye irritation.  It is classified in Category IV for acute dermal
toxicity, acute inhalation toxicity, primary skin irritation.  It is a
strong dermal sensitizer.  Based upon the acute toxicity
characteristics, the interim Work Protection Standard (WPS) restricted
entry interval (REI) of 12 hours is adequate to protect agricultural
workers from post-application exposures to trifloxystrobin.  The
proposed labels list an REI of 12 hours, with the exception of the
proposed Absolute label which lists a 24 hour REI due assumedly to its
combination with tebuconazole.

10.0	Tolerance Summary

The tolerance expression for trifloxystrobin in/on plants (40 CFR 180.
555) is the combined residues of trifloxystrobin, (benzeneacetic acid,
(E,E)-α-(methoxyimino)-2-[[[[1-[3-(trifluoromethyl)
phenyl]ethylidene]amino]oxy] methyl]-methyl ester) and the free form of
its acid metabolite CGA–321113
((E,E)-methoxyimino-[2-[1-(3-trifluoromethylphenyl)-ethylideneaminooxyme
thyl]-phenyl] acetic acid.

Table 10.	Tolerance Summary for Trifloxystrobin.

Commodity	

Proposed Tolerance (ppm)	

Recommended Tolerance (ppm)

Asparagus	0.07	0.07

Vegetable, root except sugar beet, Subgroup 1B	0.10	0.10

Radish, tops	10	10

Papaya

Sapote, black

Canistel

Sapote, mamey

Mango

Sapodilla

Star apple	0.70	0.70

Strawberry	1.1	1.1

Citrus Fruits, Crop Group 10	0.4	0.6

Citrus, oil	36.0	38.0

Citrus, dried pulp	1.0	1.0

There are currently no Canadian MRLs for trifloxystrobin.  Codex and
Mexican MRLs have been established for trifloxystrobin in/on various
commodities; however, there are no Mexican MRLs for the commodities
associated with the proposed uses.  Codex MRLs have been established on
carrots (0.1 ppm) and strawberry (0.2 ppm), which differs from the MRL
calculated by the MRL spreadsheet for strawberry (1.1 ppm).  Also, the
residue definition for both Codex and Mexican MRLs includes only parent
compound in plant commodities, but the definition for Codex MRLs in
livestock commodities includes parent and the acid metabolite,
CGA321113.  Therefore, harmonization in plant commodities is not
possible at this time as the current U.S. tolerance definition includes
the combined residues of trifloxystrobin and its free acid metabolite. 
Harmonization of the tolerance level in meat byproducts of cattle,
goats, and sheep is not possible at this time as the U.S. tolerance in
meat byproducts reflects higher potential exposures to various
feedstuffs.

11.0	Data Needs and Label Recommendations

11.1	Toxicology

No additional data is required. 

11.2	Residue Chemistry

1)  The petitioner must submit a revised Section F, using the proper
commodity definitions and matching the proposed tolerances to the
recommended tolerances.

2)  The petitioner must submit revised labels to match the proposed use
rates from the Section Bs of each petition.

11.3	Occupational and Residential Exposure

As mentioned above, because trifloxystrobin was found to be a strong
dermal sensitizer.  This warrants a requirement for gloves for
mixers/loaders (even though trifloxystrobin is in Category IV for dermal
toxicity).  Also, double notification (i.e., verbal warnings as well as
signs posted around treated fields) for postapplication workers was
recommended.  The ARIA team recommends that the labels should be
confirmed or amended as may be appropriate.

12.0	References:

Endpoint Selection Document

HIARC Trifloxystrobin #3, S. Dapson, 01/APR/2002

ID#: 04-MN-05, DP Num: 296307, J. Arthur, 20/APR/2004

FQPA SF Committee, HED Doc. No. 013545, B. Tarplee, 01/JUL/1999.

Dietary Exposure Memorandum

Trifloxystrobin Acute and Chronic Dietary Exposure Assessment for the
Interregional Research Project No. 4 (IR-4) Petition Proposing
Tolerances for Residues of Trifloxystrobin on Asparagus, Papaya, Black
Sapote, Canistel, Mamey Sapote, Mango, Sapodilla, Star Apple, Vegetable
Root (Except Sugar Beet) Subgroup 1B and Radish Tops, DP NUM: 332107, 
B. Hanson, 30/NOV/2006.

Trifloxystrobin Acute and Chronic Dietary Exposure Assessment for the
Interregional Research Project No. 4 (IR-4) Petition Proposing
Tolerances for Residues of Trifloxystrobin on Strawberry; DP Number:
341948; B. Hanson; 13/SEP/2007.

Drinking Water Memorandum

Section 18 Ecological Risk and Drinking Water Exposure Assessment for
the Control of Soybean Rust Using Trifloxystrobin, DP Num: 296318, S.
Abel, et. al., 3/30/2004.

Note to File: Trifloxystrobin: Change in EDWC from 92 ppb to 140 ppb for
the Acute Dietary Assessment Results in Negligible Change, DP Num:
343362, D. Rate, 30/AUG/2007.

Product Chemistry Memorandum

MRID No. 44502801, DP Num: 254920, A. Smith, 23/APR/1999.

Residue Chemistry Data Reviews

Trifloxystrobin.  Section 3 Registration on Asparagus, Vegetable, Root
Except Sugar Beet, Subgroup 1B, Radish (Tops),and Papaya, Black Sapote,
Canistel, Mamey Sapote, Mango, Sapodilla, Star Apple, Citrus Fruits,
Crop Group 10, and Strawberry.  Summary of Analytical Chemistry and
Residue Data.  PP#: 6E7088, 6F7123 and 7F7171, DP Num: 332104, D. Rate,
22/AUG/2007. 

Occupational and Residential Exposure Memorandum

TRIFLOXYSTROBIN - Human Nondietary Exposure/Risk Assessment for the
Proposed Use of Trifloxystrobin on Grasses Grown for Seed, DP Num:
333762, M. Dow, 08/NOV/2006.

TRIFLOXYSTROBIN - Human Nondietary Exposure/Risk Assessment for the
Proposed Use of Trifloxystrobin on Grasses Grown for Seed, DP Num:
341947, M. Dow, 28/AUG/2007.

TRIFLOXYSTROBIN - Human Nondietary Exposure/Risk Assessment for the
Proposed Use of Trifloxystrobin on Citrus, DP Num: 339754, M. Dow,
31/MAY/2007.

Occupational and Residential Risk Assessment to Support Request for a
Section 3 Registration of the Trifloxystrobin, DP Num: 264570, J.
Arthur, 06/AUG/2001.

HED Risk Assessment: Human Health Risk Assessment for Trifloxystrobin
for New Section 3 Use on Soybeans, DP Num: 318618, B. O’Keefe,
07/AUG/2006.

Appendix A.  International Tolerances.

INTERNATIONAL RESIDUE LIMIT STATUS

Methyl
(αE)-α-(mrthoxyimino)-2-[[[[(1E)-1-[3-(trifluoromethyl)phenyl]ethylide
ne]amino]oxy]methyl]benzeneacetate	

Common Name:  Trifloxystrobin	

X  Proposed tolerance

( Reevaluated tolerance

( Other	

Date: 07/12/07

Codex Status 

(Maximum Residue Limits)	

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( No Codex proposal step 6 or above

( No Codex proposal step 6 or above for the crops requested	

Petition Numbers:  PP#6E7088, PP#6F7123 and 7F7171

DP Num:  332104, 334851, 334854 and 339495

Other Identifier:  

Residue definition (step 8/CXL): Trifloxystrobin (for compliance with
MRL)

	

Reviewer/Branch: D. Rate / RIMUER

	

Proposed Residue definition:  Combined residues of trifloxystrobin and
its free acid metabolite CGA-321113

Crop (s)	

MRL (mg/kg)	

Crop(s) 	

Tolerance (ppm)

Strawberry	0.2

Carrot	0.1	Asparagus	0.07

Potato	0.02 (*)

Citrus fruits	0.5

Citrus pulp, dry	1

	

	Vegetable, root except sugar beet, Subgroup 1B	0.1

	

	Radish, tops	10

Papaya; black sapote; canistel; mamey sapote; mango; sapodilla; and
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√  No Limits

(  No Limits for the crops requested	

(  No Limits

√  No Limits for the crops requested

Residue definition: N/A	

Residue definition:  trifloxystrobin

Crop(s)	

MRL (mg/kg)	

Crop(s)	

MRL (mg/kg)

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