    UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

MEMORANDUM

	

	

DATE:	May 17, 2007

SUBJECT:	Amended (2): Human Health Risk Assessment for Cymoxanil for New
Section 3 Uses in/on Grapes (East of the Rocky Mountains), Hops, Dried
Cones, and Caneberry Subgroup 13A.  PC Code: 129106.  DP Num: 340367.  

FROM:	Debra Rate, Ph.D.

Alternative Risk Integration Assessment (ARIA)

Risk Integration Minor Use Emergency Response Branch (RIMUERB)

Registration Division (RD) (7505P)

Robert Mitkus, Ph.D.

		Registration Action Branch 1 (RAB1)

		Health Effects Division (HED) (7509P)

	

		Susan L. Stanton, Environmental Scientist

		Reregistration Branch III

	HED (7509P)

THROUGH:	William Cutchin, Acting Branch Senior Scientist

ARIA/ RIMUERB

RD (7505P)

And

		P.V. Shah, Ph.D., Acting Branch Chief

		RAB1

		HED (7509P)

TO:		Shaja Brothers

		RIMUERB 

RD (7505P)

The following risk assessment document has been amended to expand the
FQPA level of concern analysis.  The rationale behind the choice of the
FQPA safety factor for each exposure scenario was clearly stated in the
original risk assessment; however, in this amendment this rationale has
been repeated and formally localized in its own section (section 3.4
below).  A revised chronic dietary analysis for the new requested uses
of cymoxanil in/on grapes (east of the Rocky Mountains), hops, dried
cones, and caneberry subgroup 13A (DP Num: 338773, S. Stanton,
06/APR/2007) was included in the previous amended risk assessment of
April 24, 2007.

ARIA/RIMUERB 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 use on grapes grown east of the Rocky
Mountains, hops, dried cones, and caneberry subgroup 13A in conjunction
with the currently registered uses of the active ingredient cymoxanil.

Interregional Research Project No. 4 (IR-4) has submitted a petition
(PP#6E7100) to establish a tolerance for cymoxinal in/on grapes grown
east of the Rocky Mountains, hops, dried cones, and caneberry subgroup
13A for its use as a broad-spectrum fungicide.  In this document, ARIA
has conducted an assessment of the human exposure and health risks
resulting from these proposed 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
Eugenia McAndrew (ARIA), the non-dietary exposure/risk assessment by
Mark Dow (ARIA), the drinking water assessment by Dirk Young (EFED) and
the hazard assessment was provided by Robert Mitkus (RAB1).  The
cymoxanil caneberry residue chemistry data (PP#6E7100) were part of a
Joint review Program with California Department of Pesticide Regulation,
USEPA, and the Canadian Pest Management Regulatory Agency (PMRA).

Recommendations for Tolerances and Registration 

  SEQ CHAPTER \h \r 1 ARIA concludes that there are no residue chemistry
data requirements that would preclude IR-4’s amended registration
request for the dry flowable (DF) formulation of Tanos® (EPA Reg. No.
352-604) to add new uses on hops, grapes grown east of the Rocky
Mountains, and caneberries pending the receipt of tolerance adjustments
and label revisions as recommended below.  However, toxicology data
needs and label requirements require that the petitioner submit a 28-Day
inhalation toxicity study.  The details of the required study are
described below.

860.1200 Directions for Use

The directions for use shown on the draft label for use on caneberry are
consistent with the use directions utilized in the submitted field trial
studies.  No label amendments for Tanos® DF (EPA Reg. No. 352-604) are
required for this commodity.

Label amendments are required for Tanos® DF (EPA Reg. No. 352-604) to
reflect the parameters of field trial data for hops and to be consistent
with the HED’s ChemSAC determination regarding translation of residue
data for grapes.  

For hops, the label should be revised to specify a maximum single foliar
application rate of 0.25 lb ai/A with a 6-8 day retreatment interval
(RTI) and a maximum seasonal rate of 1.5 lb ai/A.  

For grapes grown east of the Rocky Mountains, the label should be
revised to be consistent with the ChemSAC’s determination that   SEQ
CHAPTER \h \r 1 residue data generated in Europe (France, Germany,
Greece, and Spain) for use of cymoxanil plus famoxadone on grapes could
be translated to support use on grapes east of the Rockies provided the
use patterns are identical or the use pattern is more restrictive (i.e.,
lower application rates and longer pre-harvest interval (PHI)). 
Therefore, based on the European field trial data, the proposed use on
grapes grown east of the Rocky Mountains should be revised to specify a
maximum single application rate of 0.107-0.125 lb ai/A, a maximum of 9
applications per season (for an implied seasonal rate of 1.125 lb ai/A)
with a 10-day retreatment interval, and a PHI of 30 days.

ARIA defers to TRB for examination of inert ingredients listed on
Tanos® DF.    SEQ CHAPTER \h \r 1 If Tanos® DF contains an inert which
can significantly increase the adherence or stability of the residues,
the residue data generated in Europe for use of cymoxanil plus
famoxadone on grapes could not be translated to support use on grapes
east of the Rockies.

860.1500 Crop Field Trials

The registrant must submit a revised Section F to adjust the proposed
tolerances to the levels of the recommended tolerances.  For caneberry,
the proposed tolerance of 4.0 ppm is acceptable.  However, the proposed
tolerance of 1.0 ppm for grapes (east of the Rocky Mountains) and 5.0
ppm for hops need to be adjusted based on submitted data and residue
calculations.  These tolerances should be resubmitted as 0.10 and 7.0
ppm, respectively.  Also, the commodity definitions must be corrected to
read grape; hop, dried cones; and caneberry, subgroup 13A.

870.3465 90-Day Inhalation Toxicity 

Toxicology data needs and label requirements require that the petitioner
submit a 28-Day inhalation toxicity.  This study was requested by the
HED Hazard Identification Assessment Review Committee (HIARC) in 2003
for further characterization of inhalation risk assessment.  Due to the
potential for inhalation exposure, there is a concern for toxicity by
the inhalation route.  The protocol for the existing 90-day inhalation
toxicity study (OPPTS 870.3465) should be followed with the exposure
(treatment) ending after 28 days, instead of 90 days.

Conclusion

Pending the receipt of the revised labels for use on grapes (east of the
Rocky Mountains) and hops, the revised Section F, and the 28-day
inhalation toxicity study, ARIA recommends establishing permanent
tolerances for cymoxanil on grape at 0.10 ppm; hop, dried cones at 7.0
ppm; and caneberry, subgroup 13A at 4.0 ppm.

TABLE OF CONTENTS

 TOC \f 

1.0	EXECUTIVE SUMMARY	6

2.0	PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION	13

2.1	Identification of Active Ingredient	13

2.2	Physical and Chemical Properties	14

3.0	HAZARD CHARACTERIZATION	14

3.1	Hazard Profile	14

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)	19

3.3	Toxicity Endpoint Selection	19

	3.3.1	aRfD - Females age 13-49	22

	3.3.2	aRfD - General Population	22

	3.3.3 	cRfD	22

	3.3.4	Incidental Oral Exposure (Short-Term)	22

	3.3.5	Incidental Oral Exposure (Intermediate-Term)	22

	3.3.6	Dermal Absorption	22

	3.3.7	Dermal Exposure (Short- and Intermediate-Term)	23

	3.3.8	Dermal Exposure (Long-Term)	23

	3.3.9	Inhalation Exposure (Short- and Intermediate-Term)	23

	3.3.10	Inhalation Exposure (Long-Term)	23

	3.3.11	Level of Concern for Margin of Exposure	24

3.4	FQPA Considerations Including Level of Concern
Analysis….………………………...24

3.5	Endocrine Disruption	25

3.6	Cumulative Risk
Characterization/Assessment………………………………………
….25

3.7	Toxicology Data Needs and Label
Requirements………………………………………..26

 

4.0	EXPOSURE ASSESSMENT AND CHARACTERIZATION	26

4.1	Summary of Proposed Uses	26

4.2	Dietary Exposure/Risk Pathway	28

4.2.1	Residue Profile	28

4.2.2	Dietary-Exposure Analyses	36

4.3	Water Exposure/Risk Pathway	38

4.4	Residential Exposure/Risk Pathway	38

5.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION	39

5.1	Acute Aggregate Risk (food + drinking water)	39

5.2	Chronic Aggregate Risk (food + drinking water)	39

6.0	CUMULATIVE RISK	39

7.0	OCCUPATIONAL EXPOSURE	40

7.1	Handler	40

7.2	Post-Application	41

7.3	Incidents	43

8.0	DATA NEEDS/LABEL REQUIREMENTS	43

8.1	Chemistry	43

8.2	Toxicology	43

8.3	Occupational Exposure	44

9.0	References	44

 1.0	EXECUTIVE SUMMARY

Background

Cymoxanil is a fungicide that has been registered for use in Europe and
Latin America for the control of select plant diseases in crops such as
tomatoes, grapes, and potatoes.  Cymoxanil is used to control downy
mildew, early and late blights.  It has been formulated and sold alone
or in combination with other fungicides.  It is currently registered in
the United States (U.S.) for use on potatoes, hops, lettuce (head),
fruiting vegetables (crop group 9), and cucurbit vegetables (crop group
8), with import tolerances on grape and lychee.  There are currently no
registered or proposed residential uses of cymoxanil.  

Permanent tolerances have been established under 40 CFR §180.503(a) for
residues of cymoxanil per se in/on potatoes at 0.05 ppm ; vegetable,
cucurbit, group 9 at 0.05 ppm; grape (import tolerance) at 0.1 ppm; hop,
dried cones at 1.0 ppm; lettuce, head at 4.0 ppm; lychee (import
tolerance) at 1.0 ppm; and vegetable, fruiting at 0.2 ppm.  

IR-4 has proposed use of Tanos® 50 DF fungicide, which is a formulated
product containing cymoxanil and fenamidone (25% each by weight), on
grapes grown east of the Rocky Mountains, hops, and caneberry.  DuPont
has applied for an amended registration of Cymoxanil Technical (EPA Reg.
No. 352-591) and a Section 3 registration of the 50% DF formulation
[Tanos® 50DF (also known as DPX-KP481 50DF); EPA Reg. No. 352-604] on
grapes grown east of the Rocky Mountains, hops and caneberries.  Tanos®
50DF contains 25% by weight cymoxanil and 25% by weight famoxadone [note
that henceforth, this document will only be concerned with the
application of cymoxanil (the aggregate risk associated with the use of
famoxadone will be handled in a separate document)].  

Proposed Uses

The petitioner submitted an undated draft specimen label for a 50% dry
flowable (DF) multiple active ingredient (MAI) formulation (Tanos®
fungicide; EPA Reg. No. 352-604) containing 25% cymoxanil and 25%
famoxadone.  In addition, the petitioner included the current accepted
registered label for the same formulation (dated 24/JUN/2005) along with
the proposed use pattern for grapes (east of the Rocky Mountains), hops
and caneberries.  ARIA notes that the use pattern from the undated draft
label differs from the use pattern proposed in Section B for the
commodities, hops and grapes.

  SEQ CHAPTER \h \r 1 The following recommendations were made regarding
resistance management.  Do not make more than one application of Tanos®
before alternating with a fungicide that has a different mode of action,
such as maneb, copper, captan, fosetyl-Al, or dimethomorph.  Do not make
more than three applications of Tanos® or other Group 11 fungicides
(all strobilurins or fenamidone) per cropping cycle.  Do not alternate
or tank mix with fungicides to which resistance has developed.  A
restricted entry interval (REI) of 12 hours is proposed.

The following rotational crop restrictions are specified on the undated
draft specimen label.  Crops listed on the label [cucurbits, grapes
(east of the Rocky Mountains), head lettuce, hops, peppers, potatoes,
tomatoes, and canberries] may be planted back at any time and all other
crops may be planted back following a minimum plantback interval of 30
days.

Hazard Assessment

Cymoxanil has low acute toxicity via the oral, dermal, inhalation, and
ocular routes of exposure (Toxicity Categories III and IV).  It is a
mild skin irritant and not a skin sensitizer.  The systemic toxicity
endpoints were based on decreased body weights, body weight gains and
food consumption in subchronic, chronic, developmental, reproductive and
neurotoxicity studies across species.  Dogs appear to be the most
sensitive species for cymoxanil-induced toxicity with the thymus gland
identified as a target organ in this species during chronic exposure. 
No evidence of immunotoxicity was observed following subchronic exposure
of rats or mice up to 108/117 (M/F) or 218/552 (M/F) mg/kg/day,
respectively.  In a 21-day dermal toxicity study in rats, no systemic
toxicity was observed up to 1000 mg/kg/day (Limit Dose).  In a
subchronic neurotoxicity study, systemic toxicity was observed at
102/137 mg/kg/day (M/F); however, no neurotoxicity and/or neuropathology
was observed up to 224/333 mg/kg/day (M/F; highest dose tested (HDT)). 
In addition, no evidence of neurotoxicity was observed in the
developmental toxicity studies in rats or rabbits, the 2-generation
reproductive toxicity study in rats, the subchronic or chronic dog
studies, the 18-month mouse oncogenicity study, or the 90-day
subchronic/neurotoxicity studies in rats.  However, in the chronic
toxicity/carcinogenicity study in rats clinical signs of hyperactivity
and aggressiveness in males (≥30.3 mg/kg/day), and retinal atrophy
were observed in both sexes (≥30.3 mg/kg/day) were observed.  

Increased susceptibility (qualitative and quantitative) of rats and
rabbits was observed following in utero exposure to cymoxanil.  In
acceptable developmental toxicity studies in both of these species,
developmental effects were seen at doses below those that caused
maternal toxicity.  In the rat developmental toxicity study, decreased
fetal body weights and skeletal malformations were observed at 25
mg/kg/day (lowest observed adverse effect level (LOAEL)), which was
below the LOAEL for maternal toxicity (75 mg/kg/day).  In the rabbit
developmental study, increased skeletal malformations were observed at 8
mg/kg/day (LOAEL), which was also below the maternal no observed adverse
effect level (NOAEL) of 32 mg/kg/day.  Cleft palate was also observed in
fetuses at 32 mg/kg/day.  In the first 2-generation reproduction
toxicity study (1993), there was an indication of increased qualitative
susceptibility in the offspring, since decreased pup viability (PND 0-4)
was observed at maternally toxic doses.  In a second 2-generation
reproduction toxicity study (2001), decreased body weight was observed
during lactation in both F1 and F2 offspring at a dose that was lower
than that at which parental toxicity was observed.  The increased
susceptibility of offspring observed in this study was concordant with
the results obtained in the earlier reproduction and developmental
toxicity studies.  In a developmental neurotoxicity study, offspring
toxicity – adverse effects included decreased pup survival, decreased
pup weight and body weight gain during early lactation, increases in
morphometric measurements (anterior/posterior cerebrum for males,
cerebellar height for females) at PND 79-83, and decreased retention in
the water maze task for adult females – was observed at the same dose
as maternal toxicity (slight decreases in body weight, body weight gain
during gestation, and food consumption).  The LOAEL for both maternal
animals and offspring was 100 mg/kg/day.  It should be noted that clear
parental and offspring NOAELs were established in all
acceptable/guideline developmental and reproductive toxicity studies in
the database.  Therefore, no residual uncertainties exist in the
database for pre-/post-natal toxicity.  In addition, the endpoints
selected for risk assessment (section 3.3) are considered protective of
effects observed in offspring in developmental and reproductive toxicity
studies.

The technical compound was readily absorbed and 86 to 94% of the
administered dose was excreted in 96 hours.  The majority of the
administered dose was recovered in the urine (64 - 57%) with smaller
amounts excreted in the feces (16 - 24%) and carcass (< 1%).  There were
no sex-related differences in the absorption, distribution and
metabolism of cymoxanil.  In urine, about 37 - 55% of the dose was free
and/or conjugated [14C]glycine and 2 cyano-2-methoxyiminoacetic acid
(IN-W3595; about 7 to 33% of the dose).  The parent compound was not
isolated in urine.  In feces, intact [14C]cymoxanil (< 1%) and IN W3595
were detected, but the majority of radioactivity was  [14C]glycine
(about 9 - 13%).  Based on the data, the metabolic pathway in rats
involves hydrolysis of cymoxanil to IN W3595, which is then degraded to
glycine, which in turn is incorporated into natural constituents or
further metabolized.

Cymoxanil was not carcinogenic in rats and mice and is classified as
“not likely to be carcinogenic to humans.”  The available studies
indicate that cymoxanil is not mutagenic in bacteria or cultured
mammalian cells.  There is, however, evidence of clastogenic activity
and induction of unscheduled DNA synthesis induction in vitro.  In
contrast, cymoxanil was neither clastogenic nor aneugenic in vivo in
mouse bone marrow cells and did not induce a genotoxic response in rat
somatic or germinal cells.  The negative results from the in vitro mouse
bone marrow micronucleus assay support the lack of a carcinogenic effect
in long-term rat and mouse feeding studies.

Dose Response Assessment

On 02/JAN/2003, HIARC updated the hazard profile of cymoxanil.  Since
then, several studies have been added to the database and have been
included in this review.  The RAB1 toxicologists reviewed the
toxicological database for cymoxanil with regard to the acute and
chronic reference doses (aRfD and cRfD) and the toxicological endpoint
selection for use as appropriate in occupational/residential exposure
risk assessments.  The potential for increased susceptibility of infants
and children from exposure to cymoxanil was also evaluated as required
by the Food Quality Protection Act (FQPA) of 1996, according to the
Health Effects Division (HED) Hot Sheet #30, “Application of the FQPA
Safety Factor and Data Base Uncertainty Factor in HED Risk
Assessments” (effective 10/16/06).

In the developmental and postnatal studies for which there is increased
susceptibility, the effects are well characterized and conservative
NOAELs were established for all developmental and offspring effects. 
The foster parent (treated mothers rearing untreated pups)
dose-range-finding study raises viability issues which may be
attributable to poor health conditions of the maternal animals and
therefore is not of concern.  In addition, the doses selected for risk
assessment are lower than the NOAELs from these studies and are
protective of any potential pre- and post-natal effects.  Therefore,
there are low levels of concern and no residual uncertainties for pre-
and post-natal toxicity.

Based on toxicological considerations by the HIARC (HED Doc. Date
02/JAN/2003) and updated toxicology review by RAB1 toxicologists, recent
studies, conservative residue assumptions used in the dietary risk
assessment (currently no residential exposures), and the completeness of
the residue chemistry and environmental fate databases (evaluated by the
risk assessment team), the FQPA Safety Factor (SF) was reduced from 10X
to 1X for acute exposure, incidental oral exposure ( short- and
intermediate-term), dermal exposure (short- and intermediate-term), and
inhalation exposure (short- and intermediate-term).  All other FQPA SFs
remain at 10X.  Risk assessments were conducted for the specific
exposure scenarios listed below:

The aRfD and cRfD were calculated by dividing the respective NOAELs by
100 (10X for interspecies extrapolation, 10X for intraspecies
variation).  Since the FQPA SF has been reduced to 1X for the acute
exposure, the acute population-adjusted dose (aPAD) is equal to the
aRfD.  For the chronic exposure, the FQPA SF is 10X, and the chronic
population adjusted dose (cPAD) is equal to the cRfD/10.  Since oral
studies were selected for all durations of inhalation and dermal
exposure, a 100% inhalation absorption factor and a 7.5% dermal
absorption factor were used in the route-to-route extrapolation.  The
level of concern for short- and intermediate-term occupational dermal
and inhalation exposures are for margins of exposure (MOEs = NOAEL (
estimated exposure) <100.  

 

Acute dietary (females 13-50 years old)	NOAEL = 4 mg/kg/day	aRfD and
aPAD  = 0.04 mg/kg/day

Chronic dietary	NOAEL = <0.8 mg/kg/day	cRfD = 0.008 mg/kg/day



cPAD = 0.0008 mg/kg/day

Short-term dermal	Oral NOAEL = 4 mg/kg/day	Target MOE = 100
(occupational)

Intermediate-term dermal	Oral NOAEL = 4 mg/kg/day	Target MOE = 100
(occupational)

Short-term inhalation	NOAEL = 4 mg/kg/day	Target MOE = 100
(occupational)

Intermediate-term inhalation	NOAEL = 4 mg/kg/day	Target MOE = 100
(occupational)



Residue Chemistry

There is an adequate enforcement method for each of the requested RACs
(grape, hops, and caneberry).  Samples were analyzed for cymoxanil using
a slightly modified version of a Morse Laboratories and E.I. DuPont
Nemours and Company method entitled Analytical Method for the
Determination of DPX-JE874 and Cymoxanil Residues in Various Matrices. 
This method has been subjected to a successful independent laboratory
validation (ILV) as well as a Petition Method Validation (PMV).  

The data-collection methods used for the analysis of grape, hop and
caneberry samples for cymoxanil are based on the approved/proposed
enforcement methods; these methods are adequate for data collection
based on acceptable method recoveries which were generally within the
acceptable range of 70-120%.

There are adequate storage stability data to support the integrity of
samples collected from field and processing studies.  Residues of
cymoxanil are stable under frozen storage conditions for up to 18 months
in/on grapes and its processed fractions (juice and dry pomace), 8.5
months in/on dried hops, and ~5 months in/on caneberries.  There are no
storage stability issues or corrections that need to be applied to the
various residue studies.

The results from the grape field trials show that residues of cymoxanil
were below the method limit of quantitation (LOQ) (<0.04 ppm) in/on wine
grapes harvested 28 days after the last of ten foliar spray applications
totaling 1.197-1.462 lb cymoxanil/A.  Residue decline data show that
cymoxanil decreases in wine grapes with increasing PHIs.

The results from the hop field trials show that the maximum residues of
cymoxanil were 4.07 ppm in/on dried hop cones harvested 7-8 days after
the last of six directed foliar applications at ~0.25 lb
ai/A/application for a total application rate of ~1.50 lb cymoxanil
(ai)/A.

The results from the caneberry trials show that cymoxanil residues
ranged from 0.24 ppm to 2.2 ppm on/in treated caneberries when the test
substance was applied at the proposed seasonal application rate of 1.125
lb cymoxanil/A using a 0-day PHI.  Caneberries were stored frozen for a
maximum of 154 days at –21ºC.  Submitted storage stability studies
indicate that cymoxanil residues are stable on caneberries for up to 216
days.  A residue decline study was not conducted by the petitioner.

Dietary Exposure Estimates 

Unrefined acute (females 13-49 years old only) and partially refined
chronic dietary risk assessments were conducted using the Dietary
Exposure Evaluation Model (DEEM-FCID™), Version 2.03, which uses food
consumption data from the U.S. Department of Agriculture’s Continuing
Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. 
A cancer dietary exposure analysis was not conducted since cymoxanil was
classified as not a carcinogen.  There is no reasonable expectation of
finding finite cymoxanil residues of concern in eggs, milk, or the meat,
fat, or meat byproducts of poultry or ruminants as a result of the
proposed and registered uses [Category 180.6(a)(3)]; therefore, residues
from these RACs were not included in the acute or chronic analyses.

Drinking water was incorporated directly into the dietary assessment
using the estimated drinking water concentrations (EDWC).  EDWCs were
generated using the FQPA Index Reservoir Screening Tool (FIRST) (version
1.0) model for surface water.  For the acute assessment, a drinking
water concentration of 0.019 ppm was used; for the chronic assessment,
the value of 0.0001 ppm was used.

The unrefined acute analysis (females 13-49 years old only) assumed that
cymoxanil residues are present in all registered food commodities at
tolerance levels and that 100% of all commodities are treated.  DEEM
version 7.81 default processing factors were used for all registered and
proposed commodities except for grape juice and raisins where the
default concentration factors were set to 1 (DP Num: 333189, E.
McAndrew, 05/DEC/2006).  For risk assessment purposes for lettuce and
hops, the metabolite IN-KQ960 was included, along with the parent, based
on the ratio of IN-KQ960 to the parent (3.5) in the lettuce metabolism
study (i.e., the recommended tolerance level was multiplied by 3.5 to
account for IN-KQ960).  Based on these assumptions, the acute dietary
exposure of females 13-49 years old is below ARIA’s level of concern
at the 95th percentile of exposure.  Combined dietary exposure from food
and drinking water is estimated at 0.028791 mg/kg/day, equivalent to 72%
of the aPAD.

™ software, dietary exposure is estimated at 0.000271 mg/kg/day for
the general U.S. population (34% of the chronic Population Adjusted Dose
(cPAD)) and 0.000405 mg/kg/day (51% of the cPAD) for children 1 to 2
years old, the population subgroup with the highest estimated chronic
dietary exposure to cymoxanil..  

Drinking water was incorporated directly into the dietary assessment
using EDWCs.  EDWCs were generated using the FIRST (version 1.0) model
for surface water.  For the acute assessment, a drinking water
concentration of 0.019 ppm was used; for the chronic assessment, the
value of 0.0001 ppm was used.

Residential Exposure and Risk Assessment

Currently, there are no registered/proposed uses of cymoxanil that
result in residential exposures. 

Aggregate Risk Assessment

ARIA conducts aggregate exposure assessments by summing dietary (food
and water) and residential exposures (residential or other
non-occupational exposures).  Since there are no registered/proposed
uses of cymoxanil that result in residential exposures, acute and
chronic aggregate risk assessments were equal to the acute and chronic
dietary estimates (food and water only).

Occupational Exposure Estimates

Based on the proposed use patterns, cymoxanil may be applied aerially or
by ground equipment.  ARIA believes the most highly exposed occupational
pesticide handlers would be mixers/loaders using open-pour loading of
dry flowable granules and applicators using open-cab, air-blast spray
equipment.  Estimates of exposure are presented for a mixer/loader, as
well as for an aerial applicator and an applicator using ground
equipment.  No cymoxanil 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 Pesticide Handler Exposure Database (PHED) Version 1.1
(AUG-1998).  For pesticide handlers, it is ARIA’s 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 the “baseline” and the use of protective gloves or
other personal protective equipment (PPE) as might be necessary.  MOEs
are “combined” for dermal and inhalation exposures and risk since
the toxicological endpoints are the same and were identified from the
same study.  MOEs of 100 are adequate to protect occupational pesticide
handlers.  In this case, all MOEs for pesticide handlers are >100 and,
therefore, are below ARIA’s level of concern.  

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 Taskforce
(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 (TCs) (cm2/hr) relative to the various activities which
express the amount of foliar contact over time, during each of the
activities identified. The TC for hand-harvesting blackberries and
raspberries is 5,000 cm2/hr.  As a “screening” level assessment,
ARIA herein uses the TC of 5,000 cm2/hr.  Lacking compound specific
dislodgeable foliar residue (DFR) data, HED assumes 20% of the
application rate is available as DFR on day zero after application. This
is adapted from the OPP Science Policy Council for Exposure (ExpoSAC)
standard operating procedure (SOP) No. 003 (07/MAY/1998 – Revised
07/AUG/2000).  Estimated MOEs exceed 100; and, therefore, are below
ARIA’s level of concern.

Recommendation for Tolerances and Registration

The HIARC requested a 28-day inhalation toxicity study as a condition of
registration for PP#0F06072.  However, based on the low volatility and
low inhalation toxicity (Category IV) of cymoxanil and the high
extrapolated MOEs, cymoxanil qualified for a waiver of the 28-day
inhalation toxicity study for the proposed uses (SOP 2002.01- HED
Standard Operating Procedure: Guidance: Waiver Criteria for
Multiple-Exposure Inhalation Toxicity Studies, 15/AUG/2002).  The
requirement for the 28-day inhalation toxicity study was waived. 
However, HED stated that if in the future, requests for new uses or
formulations are submitted that may result in a significant change in
either the toxicity profile or exposure scenarios, HED will reconsider
this data requirement.  Due to the potential for inhalation exposure and
changes in end-point selection (R. Mitkas, 20/OCT/2006), there is a
concern for toxicity by the inhalation route.  The requirement for the
28-day inhalation toxicity study will not be waived for this action. 

Residue Chemistry Deficiencies:

Label amendments are required for Tanos® DF (EPA Reg. No. 352-604) to
reflect the parameters of field trial data for hops and to be consistent
with the HED’s ChemSAC determination regarding translation of residue
data for grapes.  

For hops, the label should be revised to specify a maximum single foliar
application rate of 0.25 lb ai/A with a 6-8 day RTI and a maximum
seasonal rate of 1.5 lb ai/A.  

For grapes grown east of the Rocky Mountains, the label should be
revised to be consistent with the ChemSAC’s determination that   SEQ
CHAPTER \h \r 1 residue data generated in Europe (France, Germany,
Greece, and Spain) for use of cymoxanil plus famoxadone on grapes could
be translated to support use on grapes east of the Rockies provided the
use patterns are identical or the use pattern is more restrictive (i.e.,
lower application rates and longer PHI).  Therefore, based on the
European field trial data, the proposed use on grapes grown east of the
Rocky Mountains should be revised to specify a maximum single
application rate of 0.107-0.125 lb ai/A, a maximum of 9 applications per
season (for an implied seasonal rate of 1.125 lb ai/A) with a 10-day
retreatment interval, and a PHI of 30 days.

ARIA defers to TRB for examination of inert ingredients listed on
Tanos® DF.    SEQ CHAPTER \h \r 1 If Tanos® DF contains an inert which
can significantly increase the adherence or stability of the residues,
the residue data generated in Europe for use of cymoxanil plus
famoxadone on grapes could not be translated to support use on grapes
east of the Rockies.

The registrant must submit a revised Section F to adjust the proposed
tolerances to the levels of the recommended tolerances.  For caneberry,
the proposed tolerance of 4.0 ppm is acceptable.  However, the proposed
tolerance of 1.0 ppm for grapes (east of the Rocky Mountains) and 5.0
ppm for hops need to be adjusted based on submitted data and residue
calculations.  These tolerances should be resubmitted as 0.10 and 7.0
ppm, respectively.  

Toxicology Deficiencies:

Toxicology data needs and label requirements require that the petitioner
submit a 28-Day inhalation toxicity.  This study was also requested by
the HIARC in 2003 for further characterization of inhalation risk
assessment.  Due to the potential for inhalation exposure, there is a
concern for toxicity by the inhalation route.  The protocol for the
existing 90-day inhalation toxicity study (OPPTS 870.3465) should be
followed with the exposure (treatment) ending after 28 days, instead of
90 days.

Recommendations:

Pending the receipt of the revised labels for use on grapes (east of the
Rocky Mountains) and hops, the revised Section F, and the 28-day
inhalation toxicity study, ARIA recommends establishing permanent
tolerances for cymoxanil on grape at 0.10 ppm; hop, dried cones at 7.0
ppm; and caneberry, subgroup 13A at 4.0 ppm.

2.0	PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

2.1	Identification of Active Ingredient

nt™ Tanos® Fungicide; EPA Reg. No. 352-604) contains 25% cymoxanil
and 25% famoxadone



2.2	Physical / Chemical Properties

Table 2. Physical / Chemical Properties

Parameter	Value	Reference

Melting range	  SEQ CHAPTER \h \r 1 159-160°C	MRID 45620301 (L.
Croteau, Pest Management Regulatory Agency (PMRA))

pH	  SEQ CHAPTER \h \r 1 4.1

	Density	  SEQ CHAPTER \h \r 1 1.32 g/cm3

	Water solubility	  SEQ CHAPTER \h \r 1 0.9 g/Lin water, pH 5

	Solvent solubility	  SEQ CHAPTER \h \r 1 62.4 g/L in acetone

	Vapor pressure	  SEQ CHAPTER \h \r 1 1.5 x 10-4 Pa at pH 5

	Dissociation constant, pKa	  SEQ CHAPTER \h \r 1 9.7 ± 0.2

	Octanol/water partition coefficient (log Kow)	  SEQ CHAPTER \h \r 1 3.9
at pH 5, 4.7 at pH 7

	UV/visible absorption spectrum	Not reported

	

3.0	HAZARD CHARACTERIZATION

3.1	Hazard Profile 

The following hazard profile was distilled from and updates the 4th
Hazard Identification Assessment Review Committee (HIARC) report for
cymoxanil (TXR# 0051440, 02/JAN/2003). Several studies have been added
to the hazard database since that report and the last risk assessment
for cymoxanil (PP#0F06072, DP Num: 276290, S. Levy, 08/JAN/2003).  These
studies are summarized in tables 3 and 4.  Several other studies are
still being reviewed by the Agency, but these are not expected to affect
endpoint selection for cymoxanil.

≥30.3 mg/kg/day), as well as retinal atrophy in both sexes (≥30.3
mg/kg/day) were observed.

Increased susceptibility (qualitative and quantitative) of rats and
rabbits was observed following in utero exposure to cymoxanil.  In
acceptable developmental toxicity studies in both of these species,
developmental effects were seen at doses below those that caused
maternal toxicity.  In the rat developmental toxicity study, decreased
fetal body weights and skeletal malformations were observed at 25
mg/kg/day (LOAEL), which was below the LOAEL for maternal toxicity (75
mg/kg/day).  In the rabbit developmental study, increased skeletal
malformations were observed at 8 mg/kg/day (LOAEL), which was also below
the maternal NOAEL of 32 mg/kg/day.  Cleft palate was also observed in
fetuses at 32 mg/kg/day.  In the first 2-generation reproduction
toxicity study (1993), there was an indication of increased qualitative
susceptibility in the offspring, since decreased pup viability (PND 0-4)
was observed at maternally toxic doses.  In a second 2-generation
reproduction toxicity study (2001), decreased body weight was observed
during lactation in both F1 and F2 offspring at a dose that was lower
than that at which parental toxicity was observed.  The increased
susceptibility of offspring observed in this study was concordant with
the results obtained in the earlier reproduction and developmental
toxicity studies.  In a developmental neurotoxicity study, offspring
toxicity – adverse effects included decreased pup survival, decreased
pup weight and body weight gain during early lactation, increases in
morphometric measurements (anterior/posterior cerebrum for males,
cerebellar height for females) at PND 79-83, and decreased retention in
the water maze task for adult females – was observed at the same dose
as maternal toxicity (slight decreases in body weight, body weight gain
during gestation, and food consumption).  The LOAEL for both maternal
animals and offspring was 100 mg/kg/day.  No residual uncertainties
exist in the database for pre-/post-natal toxicity, and the endpoints
selected for risk assessment (section 3.3) are considered protective of
effects observed in offspring in developmental and reproduction toxicity
studies.

Cymoxanil was not carcinogenic in rats and mice and is classified as
“not likely to be carcinogenic to humans”.  The available studies
indicate that cymoxanil is not mutagenic in bacteria or cultured
mammalian cells.  There is, however, evidence of clastogenic activity
and induction of unscheduled DNA synthesis in vitro.  In contrast,
cymoxanil was neither clastogenic nor aneugenic in vivo in mouse bone
marrow cells and did not induce a genotoxic response in rat somatic or
germinal cells.  The negative results from the in vivo mouse bone marrow
micronucleus assay support the lack of a carcinogenic effect in
long-term rat and mouse feeding studies.

Table 3. Acute Toxicity of Cymoxanil Technical Grade Active Ingredient
(TGAI).



Guideline No.	

Study Type	

MRID NO.	

Results	

Toxicity Category



81-1	

Acute Oral	

43616512	

LD50 = 960 mg/kg	

III



81-2	

Acute Dermal	

43616513	

LD50 > 2000 mg/kg	

III



81-3	

Acute Inhalation	

42706303	

LC50 = >5.06  mg/L	

IV



81-4	

Primary Eye Irritation	

43616514	

Non- irritant	

IV



81-5	

Primary Skin Irritation	

43616515	

Mild or slight irritant	

IV



81-6	

Dermal sensitization	

43640501	

Non sensitizer	

N/A



Table 4. Toxicity Profile of Cymoxanil 



Guideline No./ Study Type	

MRID No. (year)/ Classification/Doses

	

Results





870.3100

90-Day oral Toxicity rodents (rat) 	

43616516 (1993)

Acceptable/Guideline

0, 100, 750, 1500, or 3000 ppm, 

M: 0, 6.54, 47.6, 102, or 224 mg/kg/day

F: 0, 8, 59.9, 137, or 333 mg/kg/day	

Systemic Toxicity NOAEL = 47.6 mg/kg/day in males and 59.9 mg/kg/day in
females

Systemic Toxicity LOAEL= 102 mg/kg/day in males and 137 mg/kg/day in
females, based on decreases in body weights, body weight gains and food
efficiency in the females, and body weight decreases and testicular and
epididymal changes in males.



870.3100

90-Day oral Toxicity rodents (mouse) 	

43616517 (1992)

Acceptable/Guideline

0, 50, 500, 1750, 3500, or 7000 ppm

M: 0, 8.25, 82.4, 294, 566, or 1306 mg/kg/day

F: 0, 11.3, 121, 433, 846, or 1130 mg/kg/day 	

Systemic Toxicity NOAEL = 8.25 mg/kg/day in males and 121 mg/kg/day in
females

Systemic Toxicity LOAEL= 82.4 mg/kg/day in males  and 433 mg/kg/day in
females, based on statistically significant dose-related decreased body
weights in males and increased absolute liver weights in females. 



870.3150

90-Day oral toxicity in non-rodents (dog)	

43640502 (1992)

Acceptable/Guideline

0, 100, 200 ppm (0, 3, 5 mg/kg/day) for 13 weeks, or 250 ppm (5
mg/kg/day) for 2 weeks followed by 500 ppm (11 mg/kg/day) for 11 weeks.	

Systemic Toxicity NOAEL not established

Systemic Toxicity LOAEL= 3 mg/kg/day, based on decreased body weights
(13%) and food consumption in females.



870.3200

21/28-Day dermal toxicity (rat)	

44180705 (1996)

Acceptable/Guideline

0, 50, 500 or 1000 mg/kg/day	

Systemic and Dermal Toxicity NOAEL = 1000 mg/kg/day (HDT)

Systemic and Dermal Toxicity LOAEL was not established.



870.3700a

Prenatal developmental (rat)	

43616524 (1993)

Acceptable/Guideline

0, 10, 25, 75, or 150 mg/kg/day	

Maternal NOAEL = 25 mg/kg/day

Maternal LOAEL= 75 mg/kg/day, based upon reduced body weight, body
weight change and food consumption

Developmental NOAEL = 10 mg/kg/day

Developmental LOAEL = 25 mg/kg/day, based upon significant increase in
overall malformations, and generalized dose-related delay in skeletal
ossification; at 75 and 150 mg/kg/day significant decrease in fetal body
weights; at 150 mg/kg/day increased early resorptions resulting in
reduced litter size.



870.3700b

Prenatal developmental (rabbit)	

43640503 & 43616523 (1982)

Acceptable/Guideline

0, 1, 4, 8, or 32 mg/kg/day	

Maternal NOAEL (32 mg/kg/day

Maternal LOAEL was not established

Developmental NOAEL = 4 mg/kg/day

Developmental LOAEL = 8 mg/kg/day, based upon an increase in skeletal
anomalies of the cervical and thoracic vertebrae and ribs; at 32
mg/kg/day, cleft palate was also observed.



870.3700b

Prenatal developmental (rabbit)	

43616522 (1981)

Unacceptable/Guideline, however, in conjunction with MRIDs 43616521,
43616523 & 43640503  provides valuable information in selecting the
maternal and developmental end-points.

0, 8, 16, or 32 mg/kg/day	

Maternal NOAEL = 16 mg/kg/day

Maternal LOAEL = 32 mg/kg/day, based upon increased incidence of
clinical signs and body weight loss during first 4 days of treatment.

Developmental NOAEL(8 mg/kg/day (not established)

Developmental LOAEL = 8 mg/kg/day, based upon an increase in skeletal
anomalies of the cervical and thoracic vertebrae and ribs.



870.3700b

Prenatal developmental (rabbit)	

43616521 (1980)

Unacceptable/Guideline, however, in conjunction with MRIDs 43616522,
43616523 & 43640503  provides valuable information in selecting the
maternal and developmental end-points.

0, 4, 8, or 16 mg/kg/day	

Maternal NOAEL = 16 mg/kg/day (HDT)

Maternal LOAEL = not determined.

Developmental NOAEL≥16 mg/kg/day (HDT))

Developmental LOAEL = not determined.



870.3800

2-Generation Reproduction and Fertility Effects (rat; dietary)	

46749810 (2001)

Acceptable/Non-guideline

0, 150, 450, or 350 ppm [equal to 0/0, 10.5/14.9, 31.6/42.8, or 94/116.3
mg/kg bw/day (M/F)]

	

Parental NOAEL = 31.6/42.8 (M/F) mg/kg/day  

Parental LOAEL = 94/116.3 (M/F) mg/kg/day based on decreases in body
weight, body weight gain, and food consumption in F0 and F1 generations

Reproductive NOAEL = 94/42.8 (M/F) mg/kg/day  

Reproductive LOAEL = 116.3 (F) mg/kg/day based on decreased mean number
of corpora lutea and mean number of implantations and increased
post-implantation loss in F1 females (LOAEL not observed in males)

Offspring NOAEL = 10.5/14.9 (M/F) mg/kg/day  

Offspring LOAEL = 31.6/42.8 (M/F) mg/kg/day based on decreased body
weight during lactation in both F1 and F2 generations



870.4100

Chronic Toxicity (dog; dietary)	

46749811 (2003) 

Acceptable/Guideline

0/0, 50/25, 100/50, or 250/100 ppm (equal to 0/0, 1.3/0.8, 2.8/1.4, or
5.6/2.9 mg/kg bw/day) (M/F)	

NOAEL not observed.  

LOAEL = 1.3/0.8 (M/F) mg/kg/day based on decreased absolute and relative
thymus weights and histopathology of the thymus (thymic
atrophy/involution) (M) and decreased thymus weights (F)



870.4200

Carcinogenicity rodents (mouse) 	

43616519 (1994)

Acceptable/Guideline

0, 30, 300, 1500, or 3000 ppm

M: 0, 4.19, 42.0, 216, or 446 mg/kg/day

F: 0, 5.83, 58.1, 298, or 582 mg/kg/day	

Systemic toxicity NOAEL = 4.19 mg/kg/day for males and 5.83 mg/kg/day
for females

Systemic toxicity LOAEL = 42 mg/kg/day for males and 58.1 mg/kg/day for
females (HDT), based upon increased frequency of sperm cyst/cystic
dilation, tubular dilation and lymphoid aggregates in males and
hyperplastic gastropathy in females.  

No evidence of carcinogenicity. 



870.4300

Combined chronic toxicity/carcinogenicity rodents (rat) 	

43616525 (1994)

Acceptable/Guideline

0, 50, 100, 700, or 2000 ppm

M: 0, 1.98, 4.08, 30.3, or 90.1 mg/kg/day

F: 0, 2.71, 5.36, 38.4, or 126 mg/kg/day	

Systemic toxicity NOAEL = 4.08 mg/kg/day for males and 5.36 mg/kg/day
for females

Systemic toxicity LOAEL = 30.3 mg/kg/day for males and 38.4 mg/kg/day
for females, based upon decreased body weight, body weight gain, and
food efficiency, increased incidence of elongate spermatid degeneration
and increased aggressiveness and/or hyperactivity in males and increased
incidence of non-neoplastic lesions of the lungs, liver, sciatic nerve
and retinal atrophy in females.

No evidence of carcinogenicity. 



870.5100

Bacterial gene mutation assay	

43616526 (1992)

Acceptable/Guideline

Salmonella typhimurium strains TA1535, TA97, TA98 and TA100 were exposed
to Cymoxanil Technical (96.5-97.8%) at concentrations of 10-2500
μg/plate with or without S9 activation (both trials). 	

Cytotoxicity in all strains was seen at (750 μg/plate -S9 and (1000
μg/plate +S9.  The positive controls induced the expected mutagenic
responses in the appropriate tester strain.  There was, however, no
evidence that the test material induced a mutagenic effect under any
test condition.



870.5300

In vitro mammalian cell
gen⁥畭慴楴湯愠獳祡⠠䡃⥏ഇ㌴ㄶ㔶㜲⠠㤱㌹ഩ捁散瑰
扡敬䜯極敤楬敮

Chinese hamster ovary (CHO) cells were exposed to Cymoxanil Technical
(96.5-97.8%) in dose ranges of 5-750 μg/mL -S9 (both trials) and
S9-activated doses of 10-1500 μg/mL (Trials 1 and 2) or 250-1500 μg/mL
(Trial 3).	

Severe cytotoxicity was seen at 750 μg/mL -S9 and (1000 μg/mL +S9. 
The positive controls induced the expected mutagenic responses.  There
was, however, no evidence that the test material was mutagenic at the
HGPRT locus at any dose under any assay condition. 





870.5375

In vitro mammalian chromosomal aberration test 	

42706302 (1993)

Acceptable/Guideline

Human lymphocytes were exposed to Cymoxanil Technical (96.5-97.8%) in
dose ranges of 100-1500 μg/mL ± S9 activation.	

Significant and dose-related clastogenic effects were seen at 1250 and
1500 µg/mL -S9 activation and at 850, 1250 and 1500 µg/mL +S9
activation.  Cymoxanil is clastogenic both in the presence and absence
of S9 activation.  



870.5395

Mammalian erythrocyte micronucleus test 	

43616528 (1993)

Acceptable/Guideline

Groups of six male and six female CR1:CD®-1(ICR)BR mice received single
oral gavage administrations of 450 or 350 mg/kg Cymoxanil Technical
(96.5-97.8%), respectively; lower doses (125 or 225 mg/kg) were
administered to groups of five male and five female mice.  High-dose
group were sacrificed at 24, 48 and 72 hours post-administration; mice
in the low- and mid-dose groups were sacrificed 24 hours post-dosing.	

Death occurred in 6/18 high-dose (350 mg/kg) females.  Other signs of
compound toxicity noted in the high-dose males and females included
abnormal gait, lethargy and tremors.  Suggestive evidence of bone marrow
cytotoxicity was seen in the high-dose females at the 48-hour cell
harvest and in the high-dose males at the 24-hour harvest.  The positive
control induced the expected high yield of MPEs in males and females. 
There was, however, no evidence that the test material induced a
clastogenic or aneugenic effect in either sex at any dose or sacrifice
time. 





870.5550

Unscheduled DNA synthesis in mammalian cells in culture	

42706301 (1993)

Acceptable/Guideline

Primary rat hepatocytes were exposed to Cymoxanil Technical (96.5-97.8%)
at dose levels of 5 to 500 µg/mL	

Cytotoxicity was observed at levels (500 µg/mL.  Cymoxanil tested
positive over 5 to 500 µg/mL range.



870.5550

Unscheduled DNA synthesis in mammalian cells in culture	

43616529(1994)

Acceptable/Guideline

Groups of five male CR1:CD®BR rats were administered single oral gavage
doses of 500 or 1000 mg/kg Cymoxanil Technical (96.5-97.8%) in 0.5%
methyl cellulose.  At 2 and 16 hours post-treatment hepatocytes and
spermatocytes were scored for UDS. 	

Clinical signs of toxicity noted in both treatment groups included death
(3 of 10 rats at 1000 mg/kg; 1 of 10 rats at 500 mg/kg), lethargy,
prostrate posture, labored or rapid respiration, tremors, diarrhea and
abnormal gait (both study groups). Cytotoxicity was not observed in
either target tissue.  Positive controls responded appropriately.  There
was, however, no evidence that the test material induced a genotoxic
response in either tissue at any dose or sacrifice time.  





870.6200

Neurotoxicity screening/Subchronic neurotoxicity	

43616516 (1993)

Acceptable/Guideline

0, 100, 750, 1500, or 3000 ppm, 

M: 0, 6.54, 47.6, 102, or 224 mg/kg/day

F: 0, 8, 59.9, 137, or 333 mg/kg/day	

No effects on the functional observation battery, or motor activity were
observed.  No treatment-related gross or microscopic findings in the
nervous system or skeletal muscles of the male and female rats were
observed.

The Neurotoxicity NOAEL (3000 ppm (224 mg/kg/day in males and 333
mg/kg/day in females; HDT).  Neurotoxicity LOAEL was not established.



870.6300

Developmental neurotoxicity (rat)	

45377901 (2001)

Acceptable/Non-guideline

0, 5, 50 or 100 mg/kg/day	

Maternal Toxicity NOAEL = 50 mg/kg/day

Maternal Toxicity LOAEL = 100 mg/kg/day, based on slight decrease body
weight, body weight gains (17%) and food consumption.

Offspring NOAEL = 50 mg/kg/day

Offspring LOAEL = 100 mg/kg/day, based on decreased pup survival,
decreased pup weight and body weight gain during early lactation (less
than 6%), increases in morphometric measurements (anterior/posterior
cerebrum for males, cerebellar height for females) at PND 79-83, and
decreased retention in the water maze task for adult females (latency
158% of control levels) seen at the LOAEL of 100 mg/kg/day.



870.7485

Metabolism and pharmacokinetics (rat)	

43616530 & 43616531 (1994)

Acceptable/Guideline

[2- ADVANCE \u4 14 ADVANCE \d4 C]cymoxanil (98% a.i.) was administered
to male and female Crl:CD/BR rats (3-5 animals/sex/dose) by gavage as a
single dose at levels of 2.5 or 120 mg/kg, or as a single dose  (2.5
mg/kg) following a 14-day pretreatment with unlabeled cymoxanil (2.5
mg/kg/day).	

Cymoxanil was readily absorbed and 86 to 94% of the administered dose
was excreted in 96 hours.  The majority of the administered dose was
recovered in the urine (64 - 57%) with smaller amounts excreted in the
feces (16 - 24%) and carcass (< 1%).  There were no sex-related
differences in the absorption, distribution and metabolism of cymoxanil.
 In urine about 37 - 55% of the dose was free and/or conjugated
[14C]glycine and 2 cyano-2-methoxyiminoacetic acid (IN-W3595; about 7 to
33% of the dose).  Intact cymoxanil was not isolated in urine.  In feces
intact [14C]cymoxanil (< 1%) and IN W3595 was detected, but the majority
of radioactivity was  [14C]glycine (about 9 - 13%).  Based on the data,
the metabolic pathway involves hydrolysis of cymoxanil to IN W3595,
which is then degraded to glycine, which in turn is incorporated into
natural constituents or further metabolized.



870.7800

Immunotoxicity (rat; dietary)	

44944601 (1999)

Acceptable/Guideline

0, 200, 400, 800, or 1600 ppm [equivalent to 0/0, 14/16, 27/31, 54/59,
or 108/117 mg/kg bw/day (M/F)]	

NOAEL = 108/117 (M/F) mg/kg/day 

LOAEL not observed.



870.7800

Immunotoxicity (mouse; dietary)	

44944602 (1999)

Acceptable/Guideline

0/0, 30/30, 300/300, 600/1200, or 1200/2400 ppm (equivalent to 0/0, 5/7,
56/71, 108/269, or 218/552 mg/kg bw/day) (M/F)	

NOAEL = 218/552 (M/F) mg/kg/day 

LOAEL not observed.



3.2	Absorption, Distribution, Metabolism, Excretion (ADME)

Cymoxanil was readily absorbed, and 86-94% of the administered dose was
excreted in 96 hours. The majority of the administered dose was
recovered in the urine (64-57%) and in the feces (16-24%).  There were
no sex-related differences in the absorption, distribution, and
metabolism of cymoxanil.  In urine about 37-55% of the dose was free
and/or conjugated [14C]glycine and 2 cyano-2-methoxyiminoacetic acid
(IN-W3595; 7-33% of the dose).  Parent was not isolated in urine.  In
feces intact [14C]cymoxanil (< 1%) and IN W3595 were detected, but the
majority of radioactivity was [14C]glycine (9- 13%).  Based on the data,
the metabolic pathway involves hydrolysis of cymoxanil to IN- W3595,
which is then degraded to glycine, which in turn is incorporated into
natural constituents or further metabolized.   

3.3	Toxicity Endpoint Selection

A summary of the toxicological endpoints and doses chosen for the
relevant exposure scenarios for human risk assessment is found in Table
5. 

Table 5.  Updated Summary of Toxicological Doses and Endpoints for
Cymoxanil for Use in 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 (General population, including infants and children)	N/A
N/A	N/A	An endpoint of concern (effect) attributable to a single dose
was not identified in the database. Quantification of acute risk to
general population, including infants and children, is not required.

Acute Dietary (Females 13-49 years of age)	NOAEL = 4

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF = 1X	aRfD = 0.04 mg/kg/day

aPAD = 0.04 mg/kg/day	Developmental toxicity (rabbit) Offspring LOAEL =
8 mg/kg/day based on increased skeletal malformations of the cervical
and thoracic vertebrae and ribs

Chronic Dietary (All populations)	NOAEL < 0.8

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF1 = 10X

(includes UFL = 10X)	cRfD = 0.008 mg/kg/day

cPAD = 0.0008 mg/kg/day	Chronic toxicity (dog; 2003) LOAEL = 1.3/0.8
mg/kg/day (M/F), based on decreased absolute and relative thymus weights
and histopathology of the thymus (thymic atrophy/involution) in males
and decreased thymus weights in females

Incidental Oral

Short-Term (1-30 days)	NOAEL = 10.5

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF = 1X	Residential LOC for MOE = 100	2-generation reproduction
(rat; 2001) Offspring LOAEL = 31.6/42.8 mg/kg/day (M/F) based on
decreased body weight during lactation in both F1 and F2 generations

Incidental Oral

Intermediate-Term (1-6 months)	NOAEL = 6.5

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF = 1X	Residential LOC for MOE = 100	2-generation reproduction
(rat; 1993) Parental LOAEL = 32.1 mg/kg/day (M/F) based on reduced
premating body weight, body weight gain, and food consumption for P
males; and decreased gestation and lactation body weights for F1 females

Dermal

Short-Term (1-30 days)	NOAEL = 4

mg/kg/day

(Dermal absorption = 7.5%)2	UFA = 10X

UFH = 10X

FQPA SF = 1X	Residential/ OccupationalLOC for MOE = 100	Developmental
toxicity (rabbit) Offspring LOAEL = 8 mg/kg/day based on increased
skeletal malformations of the cervical and thoracic vertebrae and ribs

Dermal

Intermediate-Term (1-6 months)	NOAEL = 4

mg/kg/day

(Dermal absorption = 7.5%)2	UFA = 10X

UFH = 10X

FQPA SF = 1X	Residential/ OccupationalLOC for MOE = 100	Developmental
toxicity (rabbit) Offspring LOAEL = 8 mg/kg/day based on increased
skeletal malformations of the cervical and thoracic vertebrae and ribs

Dermal

Long-Term (> 6 months)	NOAEL < 0.8

mg/kg/day

(Dermal absorption = 7.5%)2	UFA = 10X

UFH = 10X

FQPA SF1 = 10X

(includes UFL = 10X)	Residential/ OccupationalLOC for MOE = 1000	Chronic
toxicity (dog; 2003) LOAEL = 1.3/0.8 mg/kg/day (M/F), based on decreased
absolute and relative thymus weights and histopathology of the thymus
(thymic atrophy/involution) in males and decreased thymus weights in
females

Inhalation

Short-Term (1-30 days)	NOAEL = 4

mg/kg/day

(100% inhalation absorption assumed)	UFA = 10X

UFH = 10X

FQPA SF = 1X	Residential/ OccupationalLOC for MOE = 100	Developmental
toxicity (rabbit) Offspring LOAEL = 8 mg/kg/day based on increased
skeletal malformations of the cervical and thoracic vertebrae and ribs

Inhalation

Intermediate-Term (1-6 months)	NOAEL = 4

mg/kg/day

(100% inhalation absorption assumed)	UFA = 10X

UFH = 10X

FQPA SF = 1X	Residential/ OccupationalLOC for MOE = 100	Developmental
toxicity (rabbit) Offspring LOAEL = 8 mg/kg/day based on increased
skeletal malformations of the cervical and thoracic vertebrae and ribs

Inhalation

Long-Term (>6 months)	NOAEL < 0.8

mg/kg/day

(100% inhalation absorption assumed)	UFA = 10X

UFH = 10X

FQPA SF1 = 10X

(includes UFL = 10X)	Residential/ OccupationalLOC for MOE = 1000	Chronic
toxicity (dog; 2003) LOAEL = 1.3/0.8 mg/kg/day (M/F), based on decreased
absolute and relative thymus weights and histopathology of the thymus
(thymic atrophy/involution) in males and decreased thymus weights in
females

Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal
to human (interspecies), UFH = potential variation in sensitivity among
members of the human population (intraspecies), FQPA SF = FQPA Safety
Factor, UFL = to account for the use of a LOAEL to extrapolate a NOAEL,
NOAEL = no observed adverse effect level, LOAEL = lowest observed
adverse effect level, RfD = reference dose (a = acute, c = chronic), PAD
= population adjusted dose, MOE = margin of exposure, LOC = level of
concern, N/A = Not Applicable

1The 10X FQPA SF has been retained in the form of a UFL to account for
the use of a LOAEL to extrapolate a NOAEL

2An upper-bound estimate calculated as follows by comparing the maternal
LOAEL from the oral developmental toxicity study (rat) with the NOAEL
from the dermal toxicity study (rat): [(75 mg/kg/day ÷ 1000 mg/kg/day)
x 100%] = 7.5%; the last HIARC report of Jan. 2, 2003 incorrectly
calculated this to be 2.5%

3.3.1	aRfD - Females age 13-49

The acceptable developmental toxicity study in the rabbit was used to
select the endpoint for establishing the acute RfD (aRfD) for females
13-49 years old.  The aRfD is based on increased skeletal anomalies of
the cervical and thoracic vertebrae and ribs observed in fetuses at the
developmental LOAEL of 8 mg/kg/day.  Because a clear NOAEL of 4
mg/kg/day was observed in the study and there are no residual
uncertainties for pre-/post-natal toxicity, the FQPA safety factor (SF)
is 1X.

3.3.2	aRfD - General Population

An acute dietary endpoint for all populations, including infants and
children, was not established since an endpoint of concern attributable
to a single dose was not identified in the database.

3.3.3	cRfD

The chronic toxicity study in the dog (2003) was used to select the
endpoint for establishing the chronic RfD (cRfD). The cRfD is based on
decreased absolute and relative thymus weights and histopathology of the
thymus (thymic atrophy/involution) in males and decreased thymus weights
in females seen at the LOAEL of 1.3/0.8 mg/kg/day (M/F).  A NOAEL was
not observed in this study; therefore, the FQPA SF (10X) was retained
for the use of a LOAEL to extrapolate a NOAEL.

3.3.4	Incidental Oral Exposure (Short-Term)

A short-term incidental oral endpoint was selected from the second
two-generation reproduction toxicity study in rats (2001).  The endpoint
was based on decreased body weight observed during lactation in both F1
and F2 offspring at the offspring LOAEL of 31.6/42.8 mg/kg/day (M/F). 
Because a clear offspring NOAEL of 10.5 mg/kg/day was observed in the
study and there are no residual uncertainties for pre-/post-natal
toxicity, the FQPA SF is 1X.

3.3.5	Incidental Oral Exposure (Intermediate-Term)

An intermediate-term incidental oral endpoint was selected from the
first two-generation reproductive toxicity study in rats (1993).  The
endpoint was based on reduced pre-mating body weight, body weight gain,
and food consumption observed in P-generation males and decreased
gestation and lactation body weight in F1 dams at the parental LOAEL of
32.1/40.6 mg/kg/day (M/F).  Because a clear parental NOAEL of 6.5
mg/kg/day was observed in the study and there are no residual
uncertainties for pre-/post-natal toxicity, the FQPA SF is 1X.

3.3.6	Dermal Absorption

A dermal absorption study is not available.  Dermal absorption can be
estimated by comparing the results of oral and dermal toxicity studies
conducted in the same species and for the same length of time.  Ideally,
LOAELs for similar effects in the same species via oral and dermal
routes may be used in estimating dermal absorption.  However, a LOAEL
was not established in the 21-day dermal toxicity study in rats; the
NOAEL was 1000 mg/kg/day (highest dose tested).  Therefore, an
upper-bound estimate of dermal absorption was calculated by dividing the
maternal LOAEL from the oral developmental toxicity study in rats (75
mg/kg/day) by the NOAEL from the 21-day dermal toxicity study in rats
(1000 mg/kg/day).  The upper-bound estimate of dermal absorption for
cymoxanil was determined to be 7.5%.

3.3.7	Dermal Exposure (Short- and Intermediate-Term)

Short-and intermediate-term dermal endpoints were selected from the
acceptable developmental toxicity study in rabbits.  Increased skeletal
anomalies of the cervical and thoracic vertebrae and ribs were reported
at the LOAEL of 8 mg/kg/day.  These adverse effects observed in the oral
developmental toxicity study in rabbits were considered appropriate for
this exposure scenario, since they were not measured in the 21-day
dermal study in rats.  Because a clear developmental NOAEL of 4
mg/kg/day was observed in the study and there are no residual
uncertainties for pre-/post-natal toxicity, the FQPA SF is 1X.  Since
endpoints from an oral study were selected for this exposure scenario, a
7.5% dermal absorption factor was used for route-to-route extrapolation.

3.3.8	Dermal Exposure (Long-Term)

The chronic toxicity study in the dog (2003) was used to select the
endpoint for the long-term dermal exposure scenario.  Decreased absolute
and relative thymus weights and histopathology of the thymus (thymic
atrophy/involution) in males and decreased thymus weights in females
were observed at the LOAEL of 1.3/0.8 mg/kg/day (M/F).  A NOAEL was not
observed in this study; therefore, the FQPA SF (10X) was retained for
the use of a LOAEL to extrapolate a NOAEL.  Since an oral endpoint was
selected for this exposure scenario, a 7.5% dermal absorption factor was
used for route-to-route extrapolation.

3.3.9	Inhalation Exposure (Short- and Intermediate-Term)

Short-and intermediate-term inhalation endpoints were selected from the
acceptable developmental toxicity study in rabbits.  Increased skeletal
anomalies of the cervical and thoracic vertebrae and ribs were reported
at the LOAEL of 8 mg/kg/day.  Because a clear developmental NOAEL of 4
mg/kg/day was observed in the study and there are no residual
uncertainties for pre-/post-natal toxicity in the database, the FQPA SF
is 1X.  The adverse effects observed in the oral developmental toxicity
study in rabbits were considered appropriate for this exposure scenario
in the absence of route-specific data.  Accordingly, a 100% inhalation
absorption factor was used for route-to-route extrapolation.

3.3.10	Inhalation Exposure (Long-Term)

The chronic toxicity study in the dog (2003) was used to select the
endpoint for the long-term inhalation exposure scenario.  Decreased
absolute and relative thymus weights and histopathology of the thymus
(thymic atrophy/involution) in males and decreased thymus weights in
females were observed at the LOAEL of 1.3/0.8 mg/kg/day (M/F).  A NOAEL
was not observed in this study; therefore, the FQPA SF (10X) was
retained for the use of a LOAEL to extrapolate a NOAEL.  Since an oral
endpoint was selected in the absence of route-specific data, a 100%
inhalation absorption factor was used for route-to-route extrapolation.

3.3.11	Level of Concern for Margin of Exposure 

The target MOEs for occupational and non-dietary residential exposure
risk assessments are as follows:

Table 6.  Target MOEs for occupational and non-dietary exposure

Route

	Duration

	Short-Term

(1-30 days)	Intermediate-Term

(1-6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100	100	1000

Inhalation	100	100	1000

Residential (Non-Dietary) Exposure

Oral	100	100	N/A

Dermal	100	100	1000

Inhalation	100	100	1000



3.4		FQPA Considerations Including Level of Concern Analysis

As stated in section 3.1, increased susceptibility (qualitative or
quantitative) of rats and rabbits was observed following pre- and
post-natal exposure to cymoxanil.  In acceptable developmental toxicity
studies in both of these species, developmental effects were seen at
doses below those that caused maternal toxicity.  In the 2-generation
reproduction toxicity studies, offspring toxicity was observed at doses
less than or equal to those at which parental toxicity was observed.  In
a developmental neurotoxicity study, offspring toxicity was observed at
the same dose as maternal toxicity.  However, clear maternal and
offspring NOAELs were established in all acceptable/guideline
developmental and reproductive toxicity studies in the database. 
Therefore, there are low levels of concern and no residual uncertainties
for pre- and post-natal toxicity.  In addition, the endpoints selected
for risk assessment (section 3.3) are considered protective of the
effects observed in offspring in the developmental and reproductive
toxicity studies.  

Based on toxicological considerations by the HIARC (HED Doc. Date
02/JAN/2003) and updated toxicology review by RAB1 toxicologists, recent
studies, conservative residue assumptions used in the dietary risk
assessment (currently no residential exposures), and the completeness of
the residue chemistry and environmental fate databases (evaluated by the
risk assessment team), the FQPA Safety Factor (SF) was reduced from 10X
to 1X for acute exposure, incidental oral exposure ( short- and
intermediate-term), dermal exposure (short- and intermediate-term), and
inhalation exposure (short- and intermediate-term).  All other FQPA SFs
remain at 10X.

3.5	Endocrine disruption

EPA is required under the Federal Food Drug and Cosmetic Act (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 was a scientific
basis 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 has 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 the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, cymoxanil may be
subjected to additional screening and/or testing to better characterize
effects related to endocrine disruption.  It is noted that the mean
numbers of corpora lutea and implantations were decreased in F1 females
at the highest dose tested (116 mg/kg/day) in the second submitted
two-generation reproduction toxicity study in rats (2001); these results
corresponded with increased post-implantation loss in the same study. 
Testicular and epididymal changes were also observed in males at the
LOAEL (102 mg/kg/day) in the 90-day oral toxicity study in rats. 
Testicular toxicity was also observed at lower doses in males (≥30
mg/kg/day; chronic exposure) in two independent carcinogenicity studies
in mice and rats.

3.6	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 for cymoxanil and any other
substances, and cymoxanil does not appear to produce a toxic metabolite
produced by other substances.  For the purposes of this action,
therefore, EPA has assumed that cymoxanil does not have 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/ .

3.7	Toxicology Data Needs and Label Requirements

	

28-Day inhalation toxicity.  This study was also requested by the HIARC
in 2003 for further characterization of inhalation risk assessment.  Due
to the potential for inhalation exposure, there is a concern for
toxicity by the inhalation route.  The protocol for the existing 90-day
inhalation toxicity study (OPPTS 870.3465) should be followed with the
exposure (treatment) ending after 28 days, instead of 90 days.

4.0	EXPOSURE ASSESSMENT AND CHARACTERIZATION

4.1	Summary of Proposed Uses

The petitioner submitted an undated draft specimen label for a 50% dry
flowable (DF) multiple active ingredient (MAI) formulation (Tanos®
fungicide; EPA Reg. No. 352-604) containing 25% cymoxanil and 25%
famoxadone.  In addition, the petitioner included the current accepted
registered label for the same formulation (dated 24/JUN/2005) along with
the proposed use pattern for grapes (east of the Rocky Mountains), hops
and caneberries.  The properties of the product proposed for amended use
are presented in Tables 1 and 2.  A summary of the proposed uses on
grapes (east of the Rocky Mountains), hops and caneberries is presented
in Table 7.  ARIA notes that the use pattern from the undated draft
label differs from the use pattern proposed in Section B for the
commodities, hops and grapes.

Table 7.  Summary of Directions for Use of Cymoxanil. 

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

Grapes (East of the Rocky Mountains)

Foliar spray

Ground, aerial, or chemigation	Section B	0.25	Not specified (NS)	2.5	30





Tanos® DF Fungicide

 Undated specimen label;

[352-604]	0.094-0.125	3 per crop cycle	0.375 per crop cycle

1.125 per year	30	Applications may be made in a minimum of 20 gal/A
using ground equipment or 5 gal/A using aerial equipment with a 5- to
7-day retreatment interval.

Hops

Foliar spray

Ground, aerial, or chemigation	Section B	0.125-0.25	NS	1.5	7



Tanos® DF Fungicide 

Undated specimen label;

[352-604]	0.125-0.156	3 per crop cycle	0.469 per crop cycle

1.125 per year	7	Applications may be made in a minimum of 20 gal/A using
ground equipment or 10 gal/A using aerial equipment with a 5- to 7-day
retreatment interval.

Caneberry

Foliar spray

Ground, aerial, or chemigation	Sectioin B	0.1875	NS	1.125	0



Tanos® DF Fungicide 

Undated specimen label;

[352-604]	0.177-0.213	6	1.125 per cropping season/year	0	Applications
may be made in a minimum of 20 gal/A using ground equipment or 5 gal/A
using aerial equipment with a 5- to 7-day retreatment interval.



  SEQ CHAPTER \h \r 1 The following general use directions are also
specified for the 50% DF formulation containing 25% cymoxanil and 25%
famoxadone.    SEQ CHAPTER \h \r 1 Famoxadone, one of the active
ingredients, is a Group 11 (Qol-containing) fungicide, which also
includes all strobilurins and fenamidone.  The following recommendations
were made regarding resistance management.  Do not make more than one
application of Tanos® before alternating with a fungicide that has a
different mode of action, such as maneb, copper, captan, fosetyl-Al, or
dimethomorph.  Do not make more than three applications of Tanos® or
other Group 11 fungicides (all strobilurins or fenamidone) per cropping
cycle.  Do not alternate or tank mix with fungicides to which resistance
has developed.  An REI of 12 hours is proposed.

The following rotational crop restrictions are specified on the undated
draft specimen label.  Crops listed on the label [cucurbits, grapes
(east of the Rocky Mountains), head lettuce, hops, peppers, potatoes,
tomatoes, and canberries] may be planted back at any time and all other
crops may be planted back following a minimum plantback interval of 30
days.

Conclusions.  The directions for use shown on the draft label for use on
caneberry are consistent with the use directions utilized in the
submitted field trial studies.  No label amendments for Tanos® DF (EPA
Reg. No. 352-604) are required for this commodity.  The proposed uses of
  SEQ CHAPTER \h \r 1 Tanos® DF on hops and grapes grown east of the
Rockies are inadequately delineated because of discrepancies regarding
the maximum single and seasonal rates listed in Section B and the
submitted specimen label.  For hops, label revision is required to allow
consistency of use pattern with the field trial data; the label must be
revised to specify a maximum single foliar application rate of 0.25 lb
ai/A with a 6- to 8-day RTI and a maximum seasonal rate of 1.5 lb ai/A. 
For grapes, the label must be revised to comply with the HED ChemSAC’s
determination that   SEQ CHAPTER \h \r 1 residue data generated in
Europe (France, Germany, Greece, and Spain) for use of cymoxanil plus
famoxadone on grapes could be translated to support use on grapes grown
east of the Rockies provided the use patterns are identical or the use
pattern is more restrictive (i.e., lower application rates and longer
PHI).  The proposed use on grapes east of the Rockies should be revised
to specify a maximum single application rate of 0.107-0.125 lb ai/A, a
maximum of 9 applications per season (for an implied seasonal rate of
1.125 lb ai/A) with a 10-day RTI, and a PHI of 30 days.

4.2	Dietary Exposure/Risk Pathway

Complete reviews of the residue chemistry data submitted in conjunction
with the current petition can be found in Memoranda DP Number 324447
(PP# 6E7100).  Since there are no livestock feed items associated with
the current petitions, discussions concerning the nature of the residue
in livestock, livestock enforcement methods, and magnitude of the
residue in livestock commodities are not relevant.

4.2.1	Residue Profile

Background

PP#6E7100:  IR-4 has submitted a petition for the establishment and
revision of permanent tolerances for residues of the fungicide cymoxanil
per se in/on the following RACs:

Grape	0.05 ppm

Hop, dried cones	1.0 ppm

Caneberry, subgroup 13A	4.0 ppm

The cymoxanil caneberry residue chemistry data for this petition was
reviewed as part of the Joint Review Program with the USEPA, California
Department of Pesticide Regulation and the Canadian Pest Management
Regulatory Agency (PMRA).

Nature of the Residue 

Plant metabolism studies with cymoxanil have been conducted on grape,
potato, tomato, and lettuce.  The results from each study are summarized
below.

Grape

  SEQ CHAPTER \h \r 1 Labeled cymoxanil was applied to grapes in outdoor
plots at a rate of 210 g ai/ha.  A total of eight applications were
performed at biweekly intervals.  Grape samples were taken 0, 1, 4, 10,
and 18 days after the final application.  The total radioactive residue
(TRR) ranged from 2.1 to 2.5 ppm.  The organic soluble fraction was
found to contain cymoxanil per se (11% of the TRR at day 0 and 2% at day
18) and the metabolite IN-U3204 (at a maximum level of 0.01 ppm or 0.5%
of the TRR).  The aqueous soluble fraction in the 10-day sample was
comprised of natural components such as glycine (23% of the TRR), acetic
acid (9% of the TRR) and sugars (15% of the TRR).

Potato

  SEQ CHAPTER \h \r 1 Labeled cymoxanil was applied to potatoes in
outdoor plots at a rate of 210 g ai/ha.  A total of four applications
were performed at weekly intervals.  Potato samples were taken 10 days
after the final application and the TRR was 2.4 ppm.  The
aqueous-soluble fraction was comprised of natural components such as
glycine (58% of the TRR), other amino acids (11% of the TRR) and sugars
(14% of the TRR).

Tomato

Radiolabeled cymoxanil was applied three times (0.56 lb ai/A) at 15-19
day interval to tomato plants for a total of 1.68 lb ai/A/season (1.5x
the recommended label rate).  Control tomato plants were grown under the
same conditions as the treated plants in a field plot.

Mature tomato fruits were harvested three days after the last
application.  The TRRs were 1.1 ppm in mature tomato fruits (PHI 3
days).  About 11.2% of the TRRs were rinsed off the fruit with an
aqueous buffer (pH 5.0) and 81.7 % of the TRRs were extractable in water
(including protease digestion released radioactivity).  About 7.1% of
the TRRs were unextractable.  Cymoxanil was detected at approximately
0.01 ppm in the fruit.  No other closely related metabolites were found
at greater than 0.05 ppm.  The major component identified in the
extractable radioactivity after acid hydrolysis was glycine (65.2% of
the TRR, 0.72 ppm).  A small percentage of radioactivity was also found
in sugars (glucose and fructose).

Lettuce

Radiolabeled cymoxanil was applied four times (0.75 lb ai/A) at 15-28
day interval to lettuce plants for a total of 2.99 lb ai/A/season (2.6x
the recommended label rate).  Control lettuce plants were grown under
the same conditions as the treated plants.

Mature leaf lettuce was harvested three days after the last application.
 The TRR was 10.78 ppm in mature lettuce.  About 7.5% of the TRRs (0.81
ppm) were rinsed off the lettuce and 64.6% of the TRRs (6.96 ppm) were
extractable in an aqueous buffer.  About 27.9% of the TRR (3.01 ppm) was
bound.  Cymoxanil was detected only in the surface wash of the lettuce
(2.1% of the TRR; 0.23 ppm).  The major component identified in the
extractable radioactivity after acid hydrolysis was glycine (30.6% of
the TRR; 3.30 ppm).  Glucose from both the surface wash and extracted
foliage totaled 21.1% of the TRR (2.28 ppm).  The surface wash and
extract also contained several other polar metabolites, including
IN-KP533 (2.8% TRR) and IN-KQ960 (7.4% TRR).  The bound radioactivity in
the pellet was further characterized via acid hydrolysis, cellulase and
protease enzymatic digestion.  Acid hydrolysis released 15.4% of the TRR
(1.66 ppm), while cellulase and protease enzymatic digestion released
3.4% (0.36 ppm) and 12.7% (1.37 ppm) of the TRR, respectively.  The
major components were sugars with several other polar components.  A
small amount of glycine was identified in the acid hydrolysis and
protease digestion extracts following derivatization and high
performance liquid chromatography (HPLC) analysis.

Conclusions:    SEQ CHAPTER \h \r 1 The nature of the residue in grape,
lettuce, potato, and tomato is adequately understood.  In grapes,
potatoes, and tomatoes, cymoxanil was metabolized primarily into
[14C]glycine, and further incorporated into the sugars fructose and
glucose (DP Num: 241752, 246386, 247216, 247217, and 247210, G.
Kramer/J. Rowell, 19/AUG/1998 and DP Num: 233933, G. Kramer,
19/NOV/1997).  An ad hoc HED Metabolism Assessment Review Committee
(MARC) met on 1/21/98 to discuss the toxicological significance of
potential metabolites.  It was decided that only the parent is of
regulatory concern (DP Num: 242321, G. Kramer/S. Chun, 26/JAN/1998). 
HED, thus, concluded that cymoxanil per se is the only residue of
concern for tomatoes, potatoes, grapes, livestock, rotational crops, and
drinking water.  Subsequently, HED translated these data for a previous
Section 18 emergency exemption action for hops.  Based on the submitted
data and crop similarities, the tolerance expression for cymoxanil on
caneberry is cymoxanil per se.  

  SEQ CHAPTER \h \r 1 Since the previous MARC meeting, the petitioner
submitted a lettuce metabolism study.    SEQ CHAPTER \h \r 1 Metabolites
IN-KQ960 and IN-KP533 were identified in the lettuce metabolism study
but these metabolites were not detected in the tomato, grape, or potato
metabolism studies.  These results were presented to the HED MARC on
07/AUG/2001 to assess the toxicological significance of these
metabolites and to determine which additional residues, if any, to
regulate (DP Num: 276543, S. Levy/G. Kramer, 01/AUG/2001).  The MARC
determined that the nature of the residue is understood in leafy
vegetables (DP Num: 276796, S. Levy, et.al., 30/AUG/2001).  For the
plant metabolism studies conducted to this point, the detection of
metabolites IN-KQ960 and IN-KP533 is unique in lettuce.  The MARC
concluded that for the tolerance expression, the residue of concern
in/on hops is cymoxanil per se.  For risk assessment purposes, the
metabolite IN-KQ960 must be included, along with the parent, based on
the ratio (3.5:1) of IN-KQ960 to the parent in the lettuce 14C
metabolism study.  

Residue Analytical Methods

Enforcement methods  

An adequate HPLC/UV method is available for the enforcement of proposed
grape tolerance.  Method AMR 3060-90 (MRIDs   SEQ CHAPTER \h \r 1
43616541 and 43640504, DP Num: 218035 and 219844, G. Kramer,
25/APR/0996) was submitted in support of the previous tolerance petition
(PP#5E04504) for imported grapes and tomatoes.  Using this method,
residues in/on crop s  SEQ CHAPTER \h \r 1 amples are extracted by
homogenization in ethyl acetate.  Solids are removed by centrifugation,
and the extract is concentrated and exchanged into acetone.  After
clean-up by SAX and silica column chromatography, the hexane/ethyl
acetate eluate is exchanged into methanol.  Cymoxanil is then analyzed
using HPLC on a CN column with UV detection (254 nm).  Column switching
with a C-18 column is used if additional clean-up is required.  The LOQ
was reported to be 0.05 ppm.  Method AMR 3060-90 was successfully
validated by an independent laboratory and had been forwarded to the
analytical chemistry laboratory (ACL) for a PMV (DP Num: 224541, G.
Kramer, 01/APR/1996).  The PMV was successful; however, the analytical
chemistry branch (ACB) recommended (DP Num: 228837, G. Kramer,
05/AUG/1996) two revisions to the method (removal of directions to
subtract the response of control samples and modification of the HPLC
column specifications to indicate that a 25-cm column should be used
instead of a 15-cm column).  In response, the petitioner submitted
Method AMR 3060-90 Revision No. 2 (MRID 44579103), and Agency review (DP
Num: 241752, G. Kramer, 19/AUG/1998) of the re-written method concluded
that it is adequate for enforcement method.

The submitted method (HPLC/mass spectroscopy (MS)) is an adequate
enforcement method for hops.  In a previous hop petition (PP#1E06224),
the petitioner submitted a method (MRID 45226701) derived from
DuPont’s "Method Validation for the Quantitation of Cymoxanil Residue
in Fresh and Dried Hops."  Preliminary HED review (DP Num: 276291, S.
Levy/G. Kramer, 21/NOV/2002) of the method shows that it determines
residues of cymoxanil per se, and acceptable recoveries were obtained
during a method verification trial.  However, the review noted that the
submitted hops method differed from the available grape/tomato method
(and an existing potato method).  After personal communication with ACL
(S. Levy to F. Griffith, 25/JUL/2001), HED requested that ACL review the
proposed enforcement method and decide whether an ILV of this method
should be conducted prior to initiation of the PMV.  Since this request,
a new enforcement method had been submitted using HPLC/MS.  The only
major change between the validated method and the newly submitted method
is the use of MS detection versus UV detection.  This deficiency is
resolved, and the requirements for analytical enforcement methodology
for hops are fulfilled.  

Data-collection methods

Samples of grapes addressed in this document were analyzed for residues
of cymoxanil using a gas chromatography/nitrogen/phosphorus detector
(GC/NPD) method [referenced as a multi-residue enforcement method (DFG S
19 Modified) for the determination of cymoxanil in dry, high water, and
oil crops].  Adequate concurrent method recovery data have been
submitted for this method.  The validated method LOQ is 0.04 ppm, and
the limit of detection (LOD) is not reported.

Samples of dried hop cones addressed in this document were analyzed for
residues of cymoxanil and famoxadone using the enforcement method (AMR
3705-95, Revision No. 2) with modifications.  The petitioner stated that
a major change to the method is that both famoxadone and cymoxanil are
analyzed by liquid chromatography (LC)/MS.  In the original method,
famoxadone was analyzed by GC/NPD and cymoxanil by LC/UV.  Adequate
method validation and concurrent method recovery data have been
submitted for this method.  The lowest limit for method validation
(LLMV) is 0.05 ppm for cymoxanil, and the calculated LOQ and LOD are
0.041 and 0.014 ppm, respectively, for residues of cymoxanil.

Multiresidue Method (MRM)

  SEQ CHAPTER \h \r 1 The petitioner has previously submitted data
pertaining to the FDA Multiresidue Methods testing of cymoxanil in
conjunction with the grape and tomato tolerance petition (G.F. Kramer,
26/MAR/1996).  The data indicate that cymoxanil was recovered using
Protocol D which can, therefore, be used as a confirmatory method (DP
Num: 218035 and 219844, G. Kramer, 25/APR/1996).  The report was
forwarded to FDA.

Crop Field Trials

IR-4 has submitted magnitude of the residue studies for grape, hop,
dried cones, and caneberry, Subgroup 13A in support of proposed
tolerances discussed in this document.  These studies have been
reviewed, and the Executive Summaries of field trial DERs are reproduced
below followed by a crop conclusion.

Grape

Table 8.  Summary of Residue Data from European Grape Field Trials with
Cymoxanil Submitted to

                Support Use of Tanos® DF on Grapes Grown East of the
Rocky Mountains.  

Crop matrix	Total Applic. Rate

(lb ai/A)

[kg ai/ha]	PHI (days)	Residue Levels (ppm) 1



	n	Min.	Max.	HAFT 2	Median	Mean	Std. Dev.

Grape (proposed use = 0.375 lb ai/A/ crop cycle or 1.125 lb ai/A/year
total application rate, 30-day PHI)

Wine grape, fruit	1.20-1.46

[1.34-1.64]	28	12	<0.04	<0.04	<0.04	0.02	0.02	0.0

1  The method LOQs were <0.04 and <0.05 ppm.  The median, mean, and
standard deviation were calculated using half the LOQ (<0.02 and <0.025
ppm) for all residues reported as <0.04 and <0.05 ppm.

2  HAFT = Highest average field trial result.

IR-4 has submitted field trial data depicting the magnitude of the
residue of cymoxanil in/on wine grapes.  A total of 12 field trials were
conducted in Europe on wine grapes during the 1999 growing season in
Greece (2 trials), Italy (2 trials), southern France (4 trials),
northern France (2 trials), and Germany (2 trials).  However, only
samples from four trials conducted in northern France (2 trials) and
Germany (2 trials) were analyzed for residues of cymoxanil.  At each
test location, a total of 10 foliar spray applications of a
water-dispersible granular (WG) formulation (containing 30% cymoxanil
and 22.5% famoxadone) were applied to wine grapes during the growing
season at progressive vine growth stages.  The first seven applications
were made at 0.079-0.142 lb cymoxanil/A/application followed by three
applications made at 0.162-0.173 lb cymoxanil/A/application, for a total
rate of 1.197-1.462 lb cymoxanil/A.  Applications were made with a 6- to
8-day RTI, using ground equipment (knapsack or portable sprayer) in
~88-171 gal/A spray volumes; no adjuvant was added to the spray mixture.

Samples of mature wine grapes were harvested 28 days PHI.  At one
location, additional immature grape samples were collected 0, 1, 7, and
14 PHI to generate residue decline data.    SEQ CHAPTER \h \r 1 We note
that the WG formulation used in the grape field trials also contained
another active ingredient (famoxadone); data for the famoxadone active
ingredient are reviewed in conjunction with a separate petition
(PP#5E7001; DP Num: 323682, W. Cutchin, 29/NOV/2006); only data
pertaining to cymoxanil are presented herein.

The maximum storage interval of crop samples from harvest to analysis
was 78 days (2.6 months) for grapes.  The results of a storage stability
study (MRID 43616538) were submitted in conjunction with a previous
petition (PP#0F06072; DP Num: 261144, S. Levy, 21/NOV/2002) which
indicate that residues of cymoxanil are stable under frozen storage
conditions in/on fortified samples of grapes for up to 18 months.  These
data are adequate to support the storage intervals of samples from the
grape field trials.

  SEQ CHAPTER \h \r 1 Samples of grapes were analyzed for residues of
cymoxanil using a GC/NPD method, referenced as a multi-residue
enforcement method (DFG S 19 Modified) for the determination of
cymoxanil in dry, high water, and oil crops.  The validated LOQ was 0.04
ppm, and the LOD was not reported.  This method is adequate for data
collection based on acceptable concurrent method recovery data.

The results from the grape field trials show that residues of cymoxanil
were below the method LOQ (<0.04 ppm) in/on wine grapes harvested 28
days after the last of ten foliar spray applications at 1.197-1.462 lb
cymoxanil/A.  Residue decline data show that cymoxanil decreases in wine
grapes with increasing PHIs.

Conclusions:  The residue data from the current field trial submission
indicate that residues of cymoxanil were below the LOQ of 0.04 ppm in/on
grapes harvested 28 days after the last of ten foliar spray applications
of Tanos® DF formulation at a total rate of 1.197-1.462 lb cymoxanil/A.
The residue data that were submitted in support of the grape import
tolerance of 0.1 ppm (PP#5E04504 and PP#7F04814, DP Num: 218035 and
219844, G. Kramer, 25/APR/1996; DP Num: 241752, 246386, 247216, 247217,
and 247210, G. Kramer, 19/AUG/1998; and DP Num: 249398, G. Kramer,
18/SEP/1998) were conducted according to a use pattern reflecting 12
applications at 0.107 lb ai/A/application with a 10-day RTI for a total
seasonal rate of 1.28  lb ai/A and a 14-day PHI.  The available data are
adequate to support the proposed use of Tanos® DF on grapes grown East
of the Rocky Mountains pending label revision to conform with the
HED’s ChemSAC (Directions for Use above) determination regarding  SEQ
CHAPTER \h \r 1  data translation.  A tolerance of 0.10 ppm is supported
by study data.

Hops

Table 9.  Summary of Residue Data from Hop Field Trials with
Cymoxanil.ry of Residue Data from Hop Field Trials with Cymoxanil.  

Crop matrix	Total Applic. Rate

(lb ai/A)	PHI (days)	Residue Levels (ppm)



	n	Min.	Max.	HAFT 1	Median	Mean	Std. Dev.

Hops (proposed use = 1.5 lb ai/A total application rate, 7-day PHI)

Hops, dried cones	1.50-1.53	7-8	6	1.13	4.07	3.76	1.36	2.09	1.32

1  HAFT = Highest average field trial result.

IR-4 has submitted field trial data depicting the magnitude of the
residue of cymoxanil in/on dried hops.  A total of three hop field
trials were conducted in the United States in Zones 11 (ID and WA) and
12 (OR) during the 2000 growing season.  At each test location, hop
plants received six directed foliar applications of the test
formulation, Tanos® DF, a dry flowable (DF) formulation containing 25%
ai famoxadone + 25% ai cymoxanil at ~0.25 lb cymoxanil/A/application
with a 6- to 8-day RTI for a total seasonal rate of ~1.5 lb cymoxanil/A.
 [Residue data for the famoxadone ai are reviewed in conjunction with a
separate petition (PP#5E7001; DP Num: 323682, W. Cutchin, 29/NOV/2006);
only data pertaining to cymoxanil are presented herein.]     SEQ CHAPTER
\h \r 1 No adjuvant was included in the spray mixture.  Samples of fresh
hop cones were harvested 7-8 days PHI, and cones were dried for
approximately 3-20 hours after harvest.

The maximum storage interval of dried hop samples from harvest to
analysis was 205 days (6.8 months).  The storage interval is supported
by adequate storage stability data which were generated concurrently
with the field trials.    SEQ CHAPTER \h \r 1 These data indicate that
residues of cymoxanil are stable in/on fortified dried hop samples
stored frozen up to 258 days.

Samples of hops were analyzed for residues of cymoxanil following LC/MS
procedures described in DuPont Report No. AMR 3705-95, Revision No. 2,
“Analytical Method for the Determination of DPX-JE874 and Cymoxanil
Residues in Various Matrices.”  The method was validated prior to
analysis of the field test samples.  The LLMV was 0.05 ppm.  The
calculated LOQ and LOD were 0.041 and 0.014 ppm, respectively, for
residues of cymoxanil.  This method is adequate for data collection
based on acceptable method validation and concurrent method recovery
data.

The results from the hop field trials show that the maximum residues of
cymoxanil were 4.07 ppm in/on dried hop cones harvested 7-8 days after
the last of six directed foliar applications at ~0.25 lb
ai/A/application for a total application rate of ~1.50 lb cymoxanil
(ai)/A.

Conclusions.  The residue data from the current field trial submission
indicate that residues of cymoxanil ranged from 1.13 ppm to 4.07 ppm
in/on dried hops harvested 7-8 days after the last of six directed
foliar applications of Tanos® DF formulation at ~0.25 lb
ai/A/application for a total rate of ~1.50 lb ai/A.  The submitted data
are adequate pending label revision to reflect the parameters of field
trial data.  ARIA is recommending label revisions to specify a maximum
single foliar application rate of 0.25 lb ai/A with a 6-8 day RTI and a
maximum seasonal rate of 1.50 lb ai/A.  The hop data were entered into
the Agency’s tolerance spreadsheet, and statistical analysis of data
show that a tolerance level of 7.0 ppm will be appropriate for hops.

Caneberry (Crop Subgroup 13A)

TABLE 10.  Summary of Residue Data from Caneberry Field Trials with
Cymoxanil.  

Commodity	Total 

Application Rate,

lb ai/A1

(kg ai/ha)	PHI (days)	Residue Levels (ppm)



	n	Min.	Max.	HAFT1	Median	Mean	Std. Dev.

Caneberry (proposed use = 1.125 lb cymoxanil/A total application rate; 0
day PHI)

Caneberries	1.124-1.141 (1.260-1.279)	0	14	0.24	2.2	2.1	0.54	0.889	0.666

1  HAFT = Highest average field trial result.

IR-4 has submitted field trial data for cymoxanil on caneberry.  Four
supervised crop field trials were conducted in CA (two trials, U.S. EPA
Region 10), WA (U.S. EPA Region 12) and OR (U.S. EPA Region 12) during
the 2003 growing season.  In addition, three supervised crop field
trials were conducted in Canada, with one trial in British Columbia
(Canadian Region 12), one trial in Ontario (Canadian Region 5), and one
trial in Quebec (Canadian Region 5B).  Six foliar applications of
DPX-KP481 50WG (25% cymoxanil) were applied at a rate of 0.75 lb
product/A (0.1875 lb cymoxanil/A) at 6-8 day RTIs (4.5 lb
product/A/season, 1.125 lb cymoxanil/A/season).  Samples were collected
on the day of the last application (0-day PHI).  No adjuvants or
additives were added to the spray mixture for any of the above
applications.  The number and locations of field trials are in
accordance with OPPTS Guideline 860.1500.  

The analytical procedure for quantifying residues of cymoxanil was the
Cornell Analytical Laboratory Method Residue Analysis of Cymoxanil on
Caneberry by HPCL/UV.  This method was adapted from a method developed
by Morse Laboratories and E.I. duPont Nemours and Company and entitled
Analytical Method for the Determination of DPX-JE874 and Cymoxanil
Residues in Various Matrices.  Caneberry samples were extracted in
separate steps with acetonitrile/water and hexane and purified via
several solid phase extraction steps.  After addition of a KH2PO4 buffer
solution (pH 2.9) to purified samples, quantitation was accomplished by
HPLC/UV detection.  Samples of control caneberry were fortified at
levels ranging from 0.05 to 5.0 ppm.  The LOQ and the LOD were
calculated to be 0.024 ppm and 0.0072 ppm, respectively for caneberry. 
The percent recovery of cymoxanil from caneberry ranged from 64 -120%. 
The method is adequate for data collection.

The results from these trials show that cymoxanil residues ranged from
0.24 ppm to 2.2 ppm on/in treated caneberry when the test substance was
applied at the proposed seasonal application rate of 1.125 lb
cymoxanil/A using a 0-day PHI.  Caneberry was stored frozen for a
maximum of 154 days at –21ºC.  Submitted storage stability studies
indicate that cymoxanil residues are stable on caneberry for up to 216
days.  A residue decline study was not conducted by the petitioner.

nil in or on caneberry were ≤ 2.2 ppm when applied at the proposed use
rate (1.125 lb ai/A/season) and harvested at the proposed PHI (0 days). 
The studies conducted were consistent with standard agricultural
practices as per proposed experimental designs and no anomalous weather
events were recorded.  The analytical method has been found suitable for
data collection and for enforcement purposes.  A tolerance of 4.0 ppm is
appropriate for caneberry commodities.  

Processed Food/Feed

HED’s ChemSAC (memo dated 19/APR/2004) concluded that European grape
data could be used to support the use in the eastern U.S.  They also
pointed out that a processing study was required to determine whether
cymoxanil residues concentrated in juice.  Data were not required for
raisins for a use limited to east of the Rocky Mountains.

The petitioner previously submitted European grape processing studies
(MRID 43616534) in conjunction with PP#5E04504.  These data were
reviewed by the Agency (DP Num: 218035 and 219844, G. Kramer,
25/APR/1996 and DP Num: 241752, 246386, 247216, 247217, 247210, G.
Kramer, 19/AUG/1998) where it was reported that concentration of
cymoxanil residues was observed only in juice (>1.4x) at one site.  The
highest average field trial (HAFT) residue of cymoxanil in/on grapes
treated according to the maximum use patterns is 0.07 ppm.  When the
processing factor for juice (>1.4x) is multiplied by the HAFT, the
maximum expected residue of cymoxanil in juice is 0.098 ppm.

Conclusions.  The field trials that supplied the grapes for processing
were conducted at 5x the field application rate.  Processing   SEQ
CHAPTER \h \r 1 followed typical commercial practices for grapes and the
residue data are supported by the analytical methods and storage
stability studies.  This study indicates that residues of cymoxanil per
se may concentrate (>1.4x) in grape juice processed from grapes bearing
nondetectable cymoxanil residues.  The HAFT residue of cymoxanil in/on
grapes treated according to the proposed maximum use patterns is 0.07
ppm.  When the processing factor for juice (>1.4x) is multiplied by the
HAFT, the product is below the reassessed tolerance of 0.1 ppm for the
RAC (grape).  Provided the labels are amended to reflect the maximum
seasonal rate (1.5 lb cymoxanil/A) use in the field trials, a cymoxanil
tolerance for grape juice is not needed because the expected residue in
this processed commodity will be covered by the RAC tolerance.

Confined/Field Accumulation in Rotational Crops 

Field Accumulation in Rotational Crops

Grapes, hops and caneberries   SEQ CHAPTER \h \r 1 are crops which are
typically not rotated; therefore, the proposed uses are not relevant to
these topics.

International Harmonization of Tolerances

There are no CODEX, Canadian or Mexican MRL tolerances established for
cymoxanil on grapes, hops or caneberry.  Therefore, no compatibility
problems exist for the proposed tolerances on the requested commodities.

Table 11.  INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name: 
[2-cyano-N-[(ethylamino)carbonylⵝⴲ洨瑥潨祸浩湩⥯捡瑥浡摩
嵥䌇浯潭⁮慎敭ഺ祃潭慸楮ݬ⁘牐灯獯摥琠汯牥湡散堍
删敥慶畬瑡摥琠汯牥湡散

 Other	Date: 10/26/06

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

X  No Codex proposal step 6 or above

 No Codex proposal step 6 or above for the crops requested	Petition
Number:  PP#6E7100

DP Num:  333252

  No Limits

XNo Limits for the crops requested	    No Limits

X   No Limits for the crops requested

Residue definition  2-cyano-N-[(ethylamino)

carbonyl]-2-(methoxyimino) acetamide

	Residue definition:  cymoxanil

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





















S.Funk, 10/30/2006.



4.2.2	Dietary-Exposure Analyses

Acute and chronic dietary-exposure analyses were conducted using the
DEEM-FCID™, Version 2.03, which uses food consumption data from the
U.S. Department of Agriculture’s CSFII from 1994-1996 and 1998 (DP
Num: 333189, E. McAndrew, 05/DEC/2006; DP Num: 338773, S. Stanton,
06/APR/2007).  The 1994-96, 98 CSFII data are based on the reported
consumption of more than 20,000 individuals over two non-consecutive
survey days.  Foods “as consumed” (i.e., apple pie) are linked to
EPA-defined food commodities (i.e., apples, peeled fruit - cooked; fresh
or N/S; baked; or wheat flour - cooked; fresh or N/S, baked) using
publicly available recipe translation files developed jointly by
USDA/ARS and EPA.  Consumption data are averaged for the entire U.S.
population and within population subgroups for chronic exposure
assessment, but are retained as individual consumption events for acute
exposure assessment.

DEEM-FCID( (ver 2.03) estimates the dietary exposure for the U.S.
population and 28 population subgroups.  Based on an analysis of
1994-96, 98 CSFII consumption data which took into account dietary
patterns and number of survey respondents, HED determined that the
following population groupings were appropriate for regulatory purposes
(only the exposure estimates for these populations are reported in this
document):  U.S. Population, all infants (<1 year old), children 1-2
years old, children 3-5 years old, children 6-12 years old, youth 13-19
years old, females 13-49 years old, adults 20-49 years old, and/or
adults 50+ years old.  

Drinking water was incorporated directly into the dietary assessment
using EDWCs.  EDWCs were generated using the FIRST (version 1.0) model
for surface water.  For the acute assessment, a drinking water
concentration of 0.019 ppm was used; for the chronic assessment, the
value of 0.0001 ppm was used.

Acute and Chronic Results

Acute and chronic dietary-exposure analyses were conducted using the
DEEM-FCID(; ver. 2.03 program which incorporates consumption data from
USDA’s CSFII, 1994-1996/1998.  The acute dietary exposure analysis
assumed tolerance level residues, 100% CT, and DEEM( (ver. 7.81) default
processing factors for all registered/proposed commodities.  The
resulting acute food exposure estimate for females 13-49 years old was
less than ARIA's level of concern (72% aPAD).  This is the only
population for which an acute toxicological endpoint has been
determined.  The chronic dietary exposure analysis assumed
tolerance-level residues, partially refined %CT (DP Num: 333189, E.
McAndrew, 05/DEC/2006; DP Num: 338773, S. Stanton, 06/APR/2007), except
average residues from field trials were used for lettuce, hops and
grapes, and DEEM( (ver. 7.81) default processing factors for all
registered/proposed commodities, except grape juice and raisins (1.4x
and 1x, respectively).  The resulting acute and chronic food exposure
estimates were less than ARIA's level of concern for the general U.S.
population and all population subgroups (34% cPAD); children 1-2 years
old were the most highly exposed subpopulation (51% cPAD).

Table 12.  Summary of Results from Acute and Chronic DEEM-FCID( Analyses
of Cymoxanil from the 95th Percentile.  



Population Subgroup	

Acute Dietary	

Chronic Dietary

	aPAD

(mg/kg/day)	Exposure1 (mg/kg/day)	

% aPAD	

cPAD

(mg/kg/day)	

Exposure

(mg/kg/day)	

% cPAD



General U.S. Population	

NA	0.0008	0.000271	34



All Infants (< 1 year old)

0.0008	0.000147	18



Children 1-2 years old

.0008	0.000405	51



Children 3-5 years old

0.0008	0.000389	49



Children 6-12 years old

0.0008	0.000263	33



Youth 13-19 years old

0.0008	0.000202	25



Adults 20-49 years old

0.0008	0.000293	37



Females 13-49 years old	0.04	0.028791	72	0.0008	0.000233	29



Adults 50+ years old	

NA	0.0008	0.000219	27

	1The population subgroup with the highest estimated acute and chronic
dietary (food + drinking water) exposure and risk is indicated by bold
text.

Cancer

In accordance with the EPA Draft Guidelines for Carcinogen Risk
Assessment (July, 1999), the HIARC classified cymoxanil as a "not
likely” human carcinogen.  Therefore, a cancer dietary exposure
analysis was not performed.

4.3	Water Exposure/Risk Pathway

The EFED calculated screening level surface water and ground water
estimates for cymoxanil using FIRST (version 1.0) model and the SCI-GROW
model (Screening Concentration In GROund Water), respectively. The
drinking water models and their descriptions are available at the EPA
internet site:   HYPERLINK "http://www.epa.gov/oppefed1/models/water/" 
http://www.epa.gov/oppefed1/models/water/ .  The newly proposed
application rate for caneberries is less than the rates evaluated for
the new use of cymoxanil on grapes and hops. Therefore no new drinking
water concentrations are needed for the proposed use. The newly proposed
application rates for use on grapes and hops are higher than the rates
evaluated in the previous Section 3 registration for the use of
cymoxanil on potatoes (DP Num: 233366) and for the initial IR-4
tolerance petition for use of cymoxanil (Curzate 60 DF) on hops (DP Num:
271572).  Therefore new drinking water concentrations were determined
for the proposed uses. EDWCs based on the newly proposed application
rate for grapes appear in Table 13 as follows:

Table 13.  Estimated drinking water concentrations for Cymoxanil.  

	Acute  (ppm)	Chronic  (ppm)

Groundwater	0.000003	0.000003

Surface Water	0.019	0.0001

1 Concentrations determined from the grape application (0.25 lbs per
acre, 10 times), which was the highest application rate reported for the
new proposed uses.

For the purpose of these dietary assessments, ARIA used 0.019 ppm for
the acute analysis and 0.0001 ppm for the chronic analysis.  For both
the acute and chronic analyses, the drinking water EDWC was incorporated
directly as a point estimate in the DEEM analysis to assess exposure to
cymoxanil from drinking water.

4.4	Residential Exposure/Risk Pathway

There are no registered or proposed residential uses of cymoxanil;
therefore, there are no residential exposure risks from this chemical.

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 groundboom application methods.  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.  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 and risks associated with aerial as well as other
application types where appropriate.

5.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

Aggregate exposure risk assessments were performed only for the
following: acute aggregate exposure (food + drinking water) and chronic
aggregate exposure (food + drinking water).  Short-, intermediate-, and
long-term and cancer aggregate risk assessments were not performed
because there are no registered or proposed residential non-food uses,
and cymoxanil is not considered to be carcinogenic, respectively.  

5.1	Acute Aggregate Risk (food + drinking water)

The acute analysis assumed tolerance level residues, 100% CT, and DEEM
(ver. 7.81) default processing factors for all registered/proposed
commodities.  The resulting acute food exposure estimate for females
13-49 years old was less than ARIA's level of concern (72% aPAD).  This
is the only population for which an acute toxicological endpoint has
been determined.  The EDWCs were generated by EFED (DP Num: 331978,
D.Young and T. Steeger, 21/SEPT/2006) and included in the acute dietary
analysis.  Thus, acute aggregate risk estimates are below ARIA's level
of concern.  Table 12 summarizes the acute dietary exposure estimates to
cymoxanil residues which are the same as the aggregate risk estimates.

5.2	Chronic Aggregate Risk (food + drinking water)

The chronic dietary exposure analysis assumed tolerance-level residues,
DEEM(  (ver. 7.81) default processing factors, and partially refined %CT
for some of the proposed and registered commodities.  These include
lettuce, head (10%), potato (10%), cucumber (10%), pumpkin (1%), squash
(1%), watermelon (1%), tomatoes (10%), and peppers (10%).  All other
commodities were unrefined at 100% CT (DP Num: 333189, E. McAndrew,
05/DEC/2006; DP Num: 338773, S. Stanton, 06/APR/2007).  The resulting
chronic aggregate risk estimates were less than ARIA's level of concern
for the general U.S. population and all population subgroups (34% cPAD);
children 1-2 years old were the most highly exposed subpopulations (51%
cPAD).  Thus, chronic aggregate risk estimates are below ARIA's level of
concern.  Table 12 summarizes the chronic aggregate exposure estimates
to cymoxanil residues.

6.0	CUMULATIVE RISK

FQPA (1996) stipulates that when determining the safety of a pesticide
chemical, EPA shall base its assessment of the risk posed by the
chemical on, among other things, available information concerning the
cumulative effects to human health that may result from dietary,
residential, or other non-occupational exposure to other substances that
have a common mechanism of toxicity.  The reason for consideration of
other substances is due to the possibility that low-level exposures to
multiple chemical substances that cause a common toxic effect by a
common mechanism could lead to the same adverse health effect as would a
higher level of exposure to any of the other substances individually.  A
person exposed to a pesticide at a level that is considered safe may in
fact experience harm if that person is also exposed to other substances
that cause a common toxic effect by a mechanism common with that of the
subject pesticide, even if the individual exposure levels to the other
substances are also considered safe.

ARIA did not perform a cumulative risk assessment as part of this
tolerance action for cymoxanil because HED has not yet initiated a
review to determine if there are any other chemical substances that have
a mechanism of toxicity common with that of cymoxanil.  For purposes of
this tolerance action, EPA has assumed that cymoxanil does not have a
common mechanism of toxicity with other substances.

On this basis, the petitioner must submit, upon EPA’s request and
according to a schedule determined by the Agency, such information as
the Agency directs to be submitted in order to evaluate issues related
to whether cymoxanil shares a common mechanism of toxicity with any
other substance and, if so, whether any tolerances for cymoxanil need to
be modified or revoked.  If HED identifies other substances that share a
common mechanism of toxicity with cymoxanil, HED will perform aggregate
exposure assessments on each chemical, and will begin to conduct a
cumulative risk assessment.

HED has recently developed a framework that it proposes to use for
conducting cumulative risk assessments on substances that have a common
mechanism of toxicity.  This guidance was issued for public comment on
January 16, 2002 (67 FR 2210-2214) and is available from the OPP Website
at:  http://www.epa.gov/pesticides/trac/science/cumulative_guidance.pdf

In the guidance, it is stated that a cumulative risk assessment of
substances that cause a common toxic effect by a common mechanism will
not be conducted until an aggregate exposure assessment of each
substance has been completed.

Before undertaking a cumulative risk assessment, HED will follow
procedures for identifying chemicals that have a common mechanism of
toxicity as set forth in the “Guidance for Identifying Pesticide
Chemicals and Other Substances that Have a Common Mechanism of
Toxicity” (64 FR 5795-5796, 05/FEB/1999).

7.0	OCCUPATIONAL EXPOSURE

7.1	Handler

On 1 October 2002, the HED HIARC met to discuss the toxicological
database regarding cymoxanil (TXR NO. 0051440, G. Reddy, 02/JAN/2003).

Cymoxanil is classified in Acute Toxicity Category III for acute dermal
toxicity and in Category IV for acute inhalation, primary eye irritation
and primary skin irritation.  It is not a dermal sensitizer.  Relevant
to this assessment, the HIARC identified dermal and inhalation
toxicological endpoints for use in risk assessments.  The short-term (1
-30 days) dermal toxicological endpoint has a NOAEL of 4.0 mg a.i./kg
bw/day.  The endpoint was identified from a developmental toxicity study
in the rabbit.  The effects seen were increased skeletal malformations
of the cervical and thoracic vertebrae and ribs and cleft palate.  A
60-kg body weight is used in risk calculations.  A dermal absorption
factor of 7.5% was identified for use in exposure assessment to convert
oral doses to dermal equivalents.

The short-term inhalation toxicological NOAEL is also 4.0 mg a.i./kg
bw/day and also based on the developmental toxicity study in the rabbit.
 The toxic effects cited are the same as those for the dermal NOAEL.  RD
assumes 100% absorption via the dermal route of exposure.

Cymoxanil is classified as “not likely” to be a human carcinogen. 
Therefore a cancer risk assessment is not necessary.  See Table 14 for a
summary of exposures and risks to occupational pesticide handlers.  See
Table 5 for a summary of toxicological endpoints for use in risk
assessment.

Table 14  Summary of Exposure & Risk to Occupational Handlers From
Cymoxanil.



Unit Exposure1

(mg ai/lb handled)	

Application Rate2

(lb ai handled/A)	

Units

Treated3	

Average Daily

Exposure4 (ADD)

(mg ai/kg bw/day)	

MOE5



Mixer/Loader -Dry Flowable - Open Pour



Dermal:

SLNoGlove     0.066 LC

SLWithGlove  0.066 HC

Inhal.           0.00077 HC	

0.1875	

200 A/day	

Dermal:

SLNoGlove      0.00309

SLWithGlove   0.00309 Inhal.                0.00048	

No Glove      1,295

With Golve    1,295



Applicator - Ground-boom  - Open Cab



Dermal:

SLNoGlove     0.014 LC

SLWithGlove  0.014 HC

Inhal.           0.00074 HC	

0.1875	

200 A/day	

Dermal:

SLNoGlove      0.000656

SLWithGlove   0.000656 Inhal.                0.000463	

No Glove      6,098

With Golve    6,098



Applicator – Air-blast – Open Cab



Dermal:

SLNoGlove     0.36 LC

SLWithGlove  0.24 HC

Inhal.           0.0045 HC	

0.1875	

40 A/day	

Dermal:

SLNoGlove   0.00338 LC

SLWithGlove 0.00225 HC

Inhal.           0.000563 HC	

No Glove      1,014

With Golve       1,421

1  Unit Exposures are taken from PHED Version 1.1; August 1998; Dermal =
Single Layer Work Clothing No Gloves; Single Layer Work Clothing With
Gloves; Inhal. = Inhalation.  Units = mg ai/pound of active ingredient
handled.  Data Confidence: LC = Low Confidence, MC = Medium confidence,
HC = High Confidence.  

2  Application Rate from proposed labels.

3  Units Treated are taken fro “Standard Values for Daily Acres
Treated in Agriculture”; ExpoSAC SOP No. 9.1.  Revised 05/JUL/2000.

4  Average Daily Dose (ADD) = Unit Exposure * Application Rate * Units
Treated * 7.5% dermal absorption ( 60 kg body weight.  

5  MOE = Margin of Exposure = No Adverse Effect Level (NOAEL) NOAEL (
ADD.  The NOAELs for short- and intermediate-term dermal and inhalation
exposure durations are 4.0  mg ai/kg bw/day.  They are identified from
the same developmental toxicity study in the rabbit and cite the same
toxic effects.  Therefore dermal and inhalation exposures are summed
then divided into NOAEL to determine Margin Exposure.  

 

A MOE ( than 100 is adequate to protect workers.  Since the estimated
MOEs are > than 100, they do not exceed ARIA’s level of concern.	

7.2	Post-Application

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 (ATRF) 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 tiem, during each of the
activities identified.  The TC for hand-harvesting blackberries and
raspberries is 5,000 cm2/hr.  As a “screening” level assessment,
ARIA herein uses the TC of 5,000 cm2/hr.  

TCs used in this assessment are from a interim TC 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, form further analysis of studies already
submitted to the Agency, and from studies in the published scientific
literature.  

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m the ExpoSAC SOP No. 003 (07/MAY/1998 – revised 07/AUG/2000).  

The following convention may be used to estimate post-application
exposure.  

Average Daily Dose (ADD) (mg a.i./kg bw/day) = DFR µg/cm2 * TC cm2/hr *
hr/day * 0.001 mg/µg * 1/60 kg bw 

 and where:

Surrogate Dislodgeable Foliar Residue (DFR) = application rate * 20%
available as dislodgeable residue * (1-D)t * 4.54 x 108 µg/lb * 2.47 x
10-8 A/cm2 .  

0.1875 lb a.i./A * 0.20 * (1-0)0 * 4.54 x 108 µg/lb *  2.47 x10-8
A/cm² = 0.42 µg/cm2 , therefore,

0.42 µg/cm2 * 5,000 cm2/hr * 8 hr/day * 0.001 mg/µg * 0.075 (% dermal
absorption) ( 60 kg bw = 

0. 021 mg/kg bw/day.

MOE = NOAEL ( ADD then 4.0 mg/kg bw/day ( 0.021 mg/kg bw/day = 190.

 A MOE of 100 is adequate to protect agricultural workers from
post-application exposures.  Since the estimated MOEs are > 100, the
proposed use does not exceed ARIA’s level of concern.

Restricted Entry Interval (REI)  

The acute toxicities of cymoxanil are all classified in Acute Toxicity
Categories III and IV.  Therefore, the interim Worker Protection
Standard (WPS) REI of 12 hours is adequate to protect agricultural
workers.  The REI listed on the Tanos® label is 12 hours. 

7.3	Incidents

As of 04/SEP/2002, the OPP Incident Data System indicated that there
were three incident reports in 1994 and one report in 1997 of unknown
certainty. 

8.0	DATA NEEDS/LABEL REQUIREMENTS

8.1	Chemistry

The registrant must submit a revised Section F to adjust the proposed
tolerances to the levels of the recommended tolerances.  For caneberry,
the proposed tolerance of 4.0 ppm is acceptable.  However, the proposed
tolerance of 1.0 ppm for grapes (east of the Rocky Mountains) and 5.0
ppm for hops need to be adjusted based on submitted data and residue
calculations.  These tolerances should be resubmitted as 0.10 and 7.0
ppm respectively.  Also, the commodity definitions must be corrected to
read grape; hop, dried cones; and caneberry, subgroup 13A.

Label amendments are required for Tanos® DF (EPA Reg. No. 352-604) to
reflect the parameters of field trial data for hops and to be consistent
with the HED’s ChemSAC determination regarding translation of residue
data for grapes.  

For hops, the label should be revised to specify a maximum single foliar
application rate of 0.25 lb ai/A with a 6-8 day RTI and a maximum
seasonal rate of 1.5 lb ai/A.  

For grapes grown east of the Rocky Mountains, the label should be
revised to be consistent with the ChemSAC’s determination that   SEQ
CHAPTER \h \r 1 residue data generated in Europe (France, Germany,
Greece, and Spain) for use of cymoxanil plus famoxadone on grapes could
be translated to support use on grapes east of the Rockies provided the
use patterns are identical or the use pattern is more restrictive (i.e.,
lower application rates and longer PHI).  Therefore, based on the
European field trial data, the proposed use on grapes grown east of the
Rocky Mountains should be revised to specify a maximum single
application rate of 0.107-0.125 lb ai/A, a maximum of 9 applications per
season (for an implied seasonal rate of 1.125 lb ai/A) with a 10-day
retreatment interval, and a PHI of 30 days.

8.2	Toxicology	

Toxicology data needs and label requirements require that the petitioner
submit a 28-Day inhalation toxicity.  This study was requested by the
HIARC in 2003 for further characterization of inhalation risk
assessment.  Due to the potential for inhalation exposure, there is a
concern for toxicity by the inhalation route.  The protocol for the
existing 90-day inhalation toxicity study (OPPTS 870.3465) should be
followed with the exposure (treatment) ending after 28 days, instead of
90 days.

8.3	Occupational Exposure

None.

9.0	References:

DP Num: 331978, D.Young and T. Steeger, 21/SEP/2006

DP Num: 323681, D. Young and T. Steeger, 20/SEP/2006

HED Doc. No. 012457 and HED Doc. No. 013879

HED Doc. No. 012457

DP Num: 338773, S. Stanton, 06/APR/2007

DP Num: 324447 (PP# 6E7100)

MRID   SEQ CHAPTER \h \r 1 43616532 (DP Num: 218035 and 219844,
25/APR/1996, G. Kramer)

MRID   SEQ CHAPTER \h \r 1 43616532 (DP Num: 218035 and 219844,
25/APR/1996, G. Kramer)

44439601.der.wpd (DP Num: 261144, 21/NOV/2002, S. Levy)

  SEQ CHAPTER \h \r 1 44944605.der.wpd (DP Num: 261144, 21/NOV/2002, S.
Levy) 

46670202.der.doc, D.Rate, 06/NOV/2006

MRID 43616533 (DP Num: 218035 and 219844, G. Kramer, 25/APR/1996)

PP#0F06072; DP Num: 261144, 21/NOV/2002, S. Levy

DP Num: 218035 and 219844, G. Kramer, 25/APR/1996; 

DP Num: 241752, 246386, 247216, 247217, and 247210, G. Kramer, 8/19/98; 

DP Num: 249398, G. Kramer, 18/SEP/1998

46670201.der.doc, D.Rate, 06/NOV/2006

46905901.der.doc, D.Rate, 06/NOV/2006

DP Num: 218035 and 219844, G. Kramer, 25/APR/1996 

DP Num: 241752, 246386, 247216, 247217, 247210, G. Kramer, 19/AUG/1998

RDI: DNR (02/26/07), WC (02/12/07), GK (02/21/07), DNR(04/13/07)

Petition Number(s): 6E7100

DP Num: 331977

PC Code: 129106

Page   PAGE  45  of   NUMPAGES  45 

OFFICE OF

PREVENTION, PESTICIDES, AND

TOXIC SUBSTANCES

