Document ID: EPA-HQ-OPP-2009-0301-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-12-16T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

MEMORANDUM

Date:		01-DEC-2009

SUBJECT:		Esfenvalerate.  Human Health Assessment Scoping Document in
Support of 				Registration Review.  

PC Code:  109303	DP Barcode:  D365049

Decision No.:  409765	Registration No.:  NA

Petition No.: NA	Regulatory Action: Registration Review 

Risk Assessment Type: Scoping	Case No.: 7406

TXR No.: NA	CAS No.: 66230-04-4

MRID No.: NA	40 CFR: 180.533

Ver.Apr.08

FROM:		William H. Donovan, Ph.D., Chemist/Risk Assessor	

			John Doherty, Ph.D., Toxicologist

			Seyed Tadayon, Chemist

			Risk Assessment Branch V

			Health Effects Division (7509P)

			Office of Pesticide Programs

						

THROUGH:	Jack Arthur, Branch Chief

			Risk Assessment Branch V

			Health Effects Division (7509P)

			Office of Pesticide Programs

TO:		Molly Clayton, CRM

			Reregistration Branch 3 (RB3)

			Pesticide Re-evaluation Division (7508P)

			Office of Pesticide Programs

Executive Summary

The Health Effects Division Esfenvalerate Risk Assessment Team has
evaluated the most recent human health assessments and database for the
insecticide esfenvalerate to determine the scope of work necessary to
support the established tolerances.  The risk assessment conducted in
July, 2004, was the primary source for this evaluation (J. Morales et.
al., D274838, 02-JUL-2004).  That assessment identified the following
deficiencies in the toxicity database for esfenvalerate:   1) a 90-day
inhalation toxicity study, and 2) a developmental neurotoxicity study. 
The esfenvalerate risk assessment team still considers these studies to
be data deficiencies.  Additionally, in accordance with the revised 40
CFR Part 158 data requirements, an immunotoxicity study is now required
for all food and non-food use chemicals.

The 2004 risk assessment identified deficiencies in the esfenvalerate
residue chemistry database pertaining to crop field trial data in/on the
following RACs:  soybean and sorghum aspirated grain fractions, cotton
gin byproducts, and pea vines and hay.  Submission of these requested
studies is still required.  In the registration review process, the
dietary burden to ruminants should be reevaluated to account for the
recently reduced estimate of the contribution of cotton gin byproducts
to ruminant diets (Table 1 Feedstuffs, June 2008).  Also during
registration review, the tolerance expression for esfenvalerate as
listed in 40 CFR §180.533(a) should be revised.  

Occupational and residential exposure scenarios for registered uses of
esfenvalerate were assessed in the 2004 risk assessment document. 
Several residential postapplication exposure scenarios were determined
to exceed HED’s level of concern.  In response, the registrant has
recently submitted a method for estimating potential reentry exposure
levels following crack and crevice applications (MRID 47690501).  This
study will be reviewed during the registration review process together
with a full reassessment of all occupational and residential exposure
scenarios that will reflect any relevant changes in the applicable
occupational and residential standard operating procedures (SOPs) that
are now in review.

Past esfenvalerate risk assessments rely in part on data from studies in
which adult human subjects were intentionally exposed to a pesticide to
determine their dermal and inhalation exposure.  Many such studies,
involving exposure to many different pesticides, comprise generic
pesticide exposure databases such as the Outdoor Residential Exposure
Task Force (ORETF) Database.  EPA has reviewed all the studies in these
multi-pesticide generic exposure databases, and on the basis of
available evidence has found them to have been neither fundamentally
unethical nor significantly deficient relative to standards of ethical
research conduct prevailing when they were conducted.  There is no
regulatory barrier to continued reliance on these studies, and all
applicable requirements of EPA’s Rule for the Protection of Human
Subjects of Research (40 CFR Part 26) have been satisfied.

HED will conduct a revised human health risk assessment when the
required toxicity studies have been submitted and reviewed.  

1.  Introduction

Fenvalerate
[cyano(3-phenoxyphenyl)methyl-4-chloro-α-(1-methylethyl)benzeneacetate]
and esfenvalerate
[(S)-cyano(3-phenoxyphenyl)methyl-4-chloro-alpha-(1-methylethyl)
benzeneacetate] are broad spectrum acaricide/insecticides belonging to
the pyrethroid class of pesticides.  Fenvalerate is a racemic mixture of
four stereoisomers (the S,S; R,S; S,R; and R,R isomers), and was first
registered by the basic registrant, E.I. du Pont de Nemours and Company,
for use on agricultural crops under the trade name Pydrin®.  
Esfenvalerate is the S,S-isomer enriched version of fenvalerate which is
sold under the trade name Asana®.  Presently, esfenvalerate is
registered to DuPont for use on several food and feed crops.  McLaughlin
Gormley King Company has also obtained registration for use of
esfenvalerate in food-handling establishments. There are registered
residential uses for esfenvalerate.  When applied on agricultural crops,
the typical use rate for esfenvalerate (Asana®) is four times lower
than that for fenvalerate (Pydrin®) because the concentration of the
S,S-isomer (the most insecticidally active isomer) is about four times
higher in Asana® than in Pydrin®. Tolerances for esfenvalerate are
listed under 40 CFR§180.533.  DuPont has cancelled all fenvalerate
(Pydrin®) uses on food/feed crops, replaced its former uses on
agricultural crops with esfenvalerate (Asana®), and has proposed
conversion of the existing fenvalerate tolerances to esfenvalerate.

Esfenvalerate is an insecticide used on agricultural crops, residential
and commercial lawns, residential gardens, and in and around industrial,
commercial, and residential premises. When applied to agricultural
crops, the typical use rate for esfenvalerate is four times lower than
for fenvalerate because the concentration of the S,S-isomer is higher in
esfenvalerate. Applications are made throughout the season with PHIs
ranging from 3 to 28 days. Esfenvalerate formulations include liquid
concentrates, wettable powders (homeowner-use only) and ready-to-use
aerosols and trigger sprayers.  Esfenvalerate is not registered for use
on agricultural animals.  Esfenvalerate can be used by homeowners on
lawns, vegetable gardens, and in and around residential premises.  
Applications to agricultural crops can be made with aircraft,
chemigation, groundboom, airblast, and mechanical aerosol/fogger
equipment.  Applications at industrial, commercial, and residential
sites can be made using handheld equipment such as low-pressure handwand
sprayers, backpack sprayers, hose-end sprayers, handgun sprayers,
paintbrushes, termiticide injector, in addition to ready-to-use aerosol
cans, foggers and pump-trigger sprayers.

2.  Hazard Identification  

For the purposes of toxicological assessment, fenvalerate and
esfenvalerate are considered equivalent, and the databases for both
chemicals were considered during the endpoint selection process. 
Esfenvalerate and fenvalerate belong to the Type II subclass of
pyrethroids that usually have a cyano group attached to an alpha carbon.
 The type II pyrethroids produce a characteristic toxicity response in
both insects and mammals that is distinct from the type I pyrethroids. 
For example, at higher doses, the Type I pyrethroids produce responses
more closely resembling the fine tremors seen with DDT.  The type II
pyrethroids produce responses that include tremors plus choreoathetosis
writhing in mammals.  It is generally recognized that the sodium
conductance channel is the site of action of both type I and type II
pyrethroids although the kinetics of the interaction between the type I
and type II pyrethroids are not the same, resulting in the observed
different responses.  

Esfenvalerate is considered moderately acutely toxic via the oral route
(Toxicity Category II) but is less toxic by the dermal route (Toxicity
Category III).  Esfenvalerate is mildly irritating to the skin and eye,
but is not a sensitizer.  In the subchronic toxicity study with
esfenvalerate in rats, decreased body weight and signs of neurotoxicity
(jerky leg movements) were evident.  The indications of body weight
decrease and signs of neurotoxicity (decreased motor activity and
hindlimb grip strength) were also apparent in the two subchronic
neurotoxicity studies with esfenvalerate.   In a chronic feeding study,
dogs demonstrated signs of neurotoxicity as indicated by emesis, head
shaking, biting extremities as well as the other systemic effects
including normocytic anemia, increased serum cholesterol, and possible
hepatic microgranulomatosis.  Mice also show weight loss and anemia,
reactive responses in the lymphatic tissue in multiple locations and
hepatic microgranuloma and giant cell formation in the liver and spleen.
 There is no mutagenicity concern for esfenvalerate based on the weight
of evidence of the studies submitted. There was no indication of a
carcinogenic effect in rats and mice.  Fenvalerate/esfenvalerate are
currently classified as a Group “E” carcinogens (no evidence of
carcinogenicity).

Esfenvalerate is a pyrethroid insecticide that results in tremors
following acute oral administration.  The evidence of tremors in the
acute neurotoxicity study demonstrated the lowest NOAEL (1.75 mg/kg) and
LOAEL (1.95 mg/kg) of the available studies regardless of duration and
was selected as the RfD to assess risk from acute and chronic dietary
exposures as well as from incidental oral and inhalation short-,
intermediate- and long-term exposure (no subchronic inhalation study was
available).  This selection is justified because the lowest combination
of NOAEL and LOAEL will protect against toxicity occurring at higher
doses and for longer exposures.  In the case of esfenvalerate, long-term
daily exposures are considered as multiple daily exposures with each
potentially causing tremors on a daily basis.  

A 100 percent inhalation absorption factor was used to convert all
inhalation exposures to an oral equivalent inhalation dose.  This
endpoint is appropriate for all risk assessments, i.e., short-,
intermediate- and long-term exposures. 

The short-, intermediate- and long-term (non-cancer) dermal risk
assessments for esfenvalerate are based on a 21-day dermal toxicity
study in rats (MRID 45275401).  The findings from this dermal toxicity
study initiated a revisit of this active ingredient to the HIARC. 
Previously, HED elected to use the oral endpoint from the acute
neurotoxicity study mentioned above (i.e. 1.75 mg/kg/day).  A dermal
absorption factor of 25 percent was previously selected, based on dermal
absorption data available for structurally-related pyrethroids (HIARC
document, February 10, 2003).  Subsequent to that decision, the dermal
toxicity study was reviewed.   The HIARC met on 8/19/03 to re-evaluate
the dermal endpoints, dermal absorption and the database uncertainty
factor (UF db) for esfenvalerate.  Prior to determining the dermal
endpoints, the HIARC discussed the 21-day dermal study and raised the
NOAEL/LOAEL in the DER to 25/125 mg/kg/day.   With the 21-day dermal
study, a revised dermal absorption factor of 2% was then estimated by
dividing the LOAEL of 2.5 mg/kg/day from the developmental rat study by
the LOAEL of 125 mg/kg/day from the 21-day dermal study.  Similar
effects had been observed in both studies.  This new dermal absorption
factor supersedes the previously estimated factor of 25%.  The HIARC
then determined that all dermal risk assessments (short-, intermediate-,
and long-term) should be based on the 21-day dermal rat study with a
NOAEL of 25 mg/kg/day, supported by the following rationale:  it is a
route-specific study; since the effects are not cumulative, it is
appropriate for all durations; and, based on the new dermal absorption
factor, the HIARC further noted that the oral endpoint from the acute
neurotoxicity study of 1.75 mg/kg/day modified by the dermal absorption
factor of 2% results in an equivalent dermal dose of 87.5 mg/kg/day
which is less conservative than use of the NOAEL of 25 mg/kg/day from
the route-specific dermal study for assessing risks from dermal
exposures.

Esfenvalerate did not result in developmental toxicity in either rats or
rabbits or in parental reproductive effects in the multi-generation
reproduction study.  Overall, the HIARC concluded that there was no
indication of increased offspring susceptibility in these studies. The
F1 generation in the rat reproduction study would not tolerate the same
high dose that the P generation tolerated and developed more frequent
and additional signs of neurotoxicity. However, this was not a concern
for qualitative susceptibility since these findings have no impact on
the regulatory dose selected for risk assessment; the increase in
susceptibility occurs at a higher dose and a similar difference in the
response was not seen at lower doses.  Therefore, the HIARC determined
that the hazard-based FQPA Safety Factor can be removed (reduced to 1X)
because there is no available evidence of quantitative or relevant
qualitative susceptibility following in utero exposure to rats or
rabbits or pre/postnatal exposure to rats.  However, a UFDB 

is required as discussed below.

A developmental neurotoxicity study in rats is required for
esfenvalerate (see Attachment 3). The registrant provided a briefing to
OPP in May 2009 describing the results of a pilot DNT study.   EPA has
recently determined that, as an alternative to the submission of a new
DNT study, registrants may instead choose to cite the six previously
submitted DNT studies for other pyrethroid pesticides.  The Agency will
make a decision regarding the need for an FQPA or other database
uncertainty/safety factor following receipt of the remaining required
toxicity data, and following a final determination of the potential for
increased susceptibility of infants and children to pyrethroid
pesticides based on the results of all available data.  If EPA
determines that a safety factor is needed, it will use this factor in
the esfenvalerate risk assessment during registration review.  

At the present time, the UFDB for the lack of a developmental
neurotoxicity study (DNT) will remain at 10x for all endpoints except
for dermal exposure.  If it is assumed that the NOAEL in the acute
neurotoxicity study becomes a LOAEL for pups in the DNT study, then the
estimated NOAEL for pups will be 1.75/10 or 0.175 mg/kg/day using an
uncertainty factor of 10x for a lack of a NOAEL.  This value is 10 times
lower than the current oral and inhalation endpoints.  Therefore, the
UFDB factor of 10x will remain for the oral and inhalation risk
assessments.  HIARC determined that the UFDB could be reduced from a 10x
to a 3x for dermal risk assessments based on the following rationale: 
assuming that the estimated NOAEL for pups in the DNT study will be
0.175 mg/kg/day, then a dermal equivalent dose would be estimated by
dividing the NOAEL of 0.175 mg/kg/day by 2%, which results in an
equivalent dermal dose of ~ 10 mg/kg/day.  Since use of the dermal
endpoint of 25 mg/kg/day is 2.5x greater (less protective) than 10
mg/kg/day, an additional UFDB of 3x applied to the dermal endpoint of 25
mg/kg/day should be adequate to protect infants and young against dermal
exposures until the results of the DNT study are submitted and reviewed.

To derive both the acute and chronic dietary reference doses, a total
uncertainty factor (UF) of 1000x was applied to the dose selected for
risk assessment (1.75 mg/kg) to account for both interspecies
extrapolation (10x) and intra-species variability (10x), and an
additional database uncertainty factor of 10x was applied until the data
from the DNT study are received and evaluated.  The acute and chronic
population adjusted doses (aPAD and cPAD) are equal to the aRfD (0.0018
mg/kg) and cRfD (0.0018 mg/kg), respectively.

The HED’s level of concern for noncancer risks (i.e., target level for
MOEs or Margins of Exposure) is defined by the uncertainty factors that
are applied to the assessment.  The HED applies a factor of 100x to
account for inter-species extrapolation to humans from the animal data
and to account for intra-species sensitivity.  Based on the requirements
of the 1996 Food Quality Protection Act (FQPA), the Agency must also
consider sensitive populations in its non-occupational risk assessments.
 As mentioned above, the HED is applying a database uncertainty factor
(UFDB) of 10x for non-occupational inhalation and oral exposures, and 3x
for non-occupational dermal exposures to esfenvalerate due to the lack
of a developmental neurotoxicity study with a special protocol for
pyrethroids.  The total uncertainty factors that have been applied to
noncancer risk assessments are 100x for occupational scenarios, 1000x
for nonoccupational inhalation and oral exposure scenarios, and 300x for
dermal exposure scenarios.  Therefore, occupational risk estimates,
expressed as Margins of Exposure (MOEs) that are ( 100 are not of
concern.  Non-occupational risk estimates (MOEs) ( 1000 are not of
concern for non-occupational inhalation and oral exposures.  And,
non-occupational risk estimates (MOEs) ( 300 are not of concern for
non-occupational dermal exposures.

Since the toxicological endpoints of concern are based on neurological
toxic effects, dermal and inhalation exposures and risks must be
aggregated for occupational scenarios and dermal, inhalation, and
incidental oral exposures and risks must be aggregated for
non-occupational scenarios.

An immunotoxicity study is required as a part of new data requirements
in the 40 CFR Part 158 for conventional pesticide registration.  Because
the immune system is highly complex, studies not specifically conducted
to assess immunotoxic endpoints are inadequate to characterize a
pesticide’s potential immunotoxicity.  While data from hematology,
lymphoid organ weights, and histopathology in routine chronic or
subchronic toxicity studies may offer useful information on potential
immunotoxic effects, these endpoints alone are insufficient to predict
immunotoxicity.   In the absence of required studies, EPA may use a
database uncertainty factor of up to 10x.  An immunotoxicity study on
esfenvalerate should be conducted (see Attachment 3).  Once all data
have been received and reviewed, the Esfenvalerate Registration Review
Team recommends that the points of departure and safety factors used for
risk assessment purposes be reexamined and a new risk assessment done,
if necessary.

A summary of the existing toxicology doses and endpoints is provided in
Table 1.  

Table 1.  Summary of Toxicological Doses and Endpoints for Esfenvalerate
Used in Previous Dietary Human Health Risk Assessments

Exposure/

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

Acute Dietary general population	

NOAEL = 1.75 mg/kg

	UFA= 10x

UFH=10x

UFDB=10x

FQPA SF = 1X	Acute RfD = 

0.0018 mg/kg.

Acute PAD = 0.0018 mg/kg.	

Acute neurotoxicity screen.

LOAEL = 1.90 mg/kg based on tremors.

Chronic Dietary 

all populations	

NOAEL = 1.75 mg/kg/day	UFA= 10x

UFH=10x

UFDB=10x

FQPA SF = 1X	Chronic RfD = 0.0018 mg/kg/day

Chronic PAD = 0.0018 mg/kg/day	Acute neurotoxicity screen.

LOAEL = 1.90 mg/kg based on tremors.

Incidental Oral

(All Durations)	

NOAEL = 1.75 mg/kg/day	UFA= 10x

UFH=10x

UFDB=10x

FQPA SF = 1X	

MOE = 1000 (residential)	Acute neurotoxicity screen.

LOAEL = 1.90 mg/kg based on tremors.

Inhalation

(All Durations)	

NOAEL = 1.75 mg/kg/day

(Inhalation absorption rate = 100%)	UFA= 10x

UFH=10x

UFDB=10x

FQPA SF = 1X	

MOE = 1000 (residential)

MOE = 100 (occupational)	

Acute neurotoxicity screen.

LOAEL = 1.90 mg/kg based on tremors.

Dermal 

(All Durations)	NOAEL =  25 mg/kg/day

(dermal absorption rate =2%)	UFA= 10x

UFH=10x

UFDB=3x

FQPA SF = 1X	MOE = 300 (residential)

MOE = 100 (occupational)	

21-day dermal study in rats.

LAOEL = 125 mg/kg based on abnormal hind limb gait

Cancer 	Classification: no evidence of carcinogenicity

Point of Departure (PoD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies). PAD = population adjusted dose (a = acute, c = chronic)
= the NOEL/all appropriate uncertainty and safety factors. RfD =
reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A
= not applicable.

3. Dietary Exposure

A highly refined probabilistic dietary exposure and risk assessment was
conducted for fenvalerate and esfenvalerate (D288464, J. Morales,
30-MAY-2003). Chronic and acute exposure estimates were based on data
from (1) field trial studies, (2) USDA’s Pesticide Data Program (PDP)
monitoring data for fenvalerate and esfenvalerate (for the years 1998 to
2001), and (3) estimates of percent crop treated.  During the
registration review process, updates to the percent crop treated values
will be needed from the Biological and Economic Analysis Division
(BEAD), along with a reevaluation of the anticipated residue levels.

At the 99.9th percentile of exposure in the acute dietary analysis,
children 1-2 years old were found to be the most highly exposed
population subgroup at 67% aPAD.  Similarly, for the chronic dietary
analysis, children 1-2 years old were also found to be the most highly
exposed population subgroup at 66% cPAD.  

The Environmental Fates and Effects Division (EFED) conducted a drinking
water assessment for esfenvalerate on Christmas trees in Oregon and on
cotton in Mississippi (D280680, I. Saheb, 2/4/2002).  Higher residue
levels were obtained from the Christmas tree scenario (8 applications @
0.19 lb ai/A, aerial) and these values were selected for use in the 2004
risk assessment document.   The peak value appropriate for acute dietary
analysis was 7.54 ppb, while the annual mean value appropriate for
chronic dietary analysis was 5.32 ppb, as calculated from the PRIZM and
EXAMS models.  These values were compared to calculated Drinking Water
Levels of Comparison (DWLOCs) in the 2004 assessment.  EFED will conduct
a new drinking water assessment for esfenvalerate as part of the
registration review process.  Once the updated values are available,
they will be incorporated into a new dietary exposure assessment. 
Additionally, any needed changes to toxicity endpoints, safety factors,
or residue levels will also be incorporated.  

4.  Residue Chemistry

-cyano(3-phenoxyphenyl)methyl-(S)-4-chloro-α-(1-methylethyl)
benzeneacetate] and its non-racemic isomer
[(R)-cyano-(3-phenoxyphenyl)methyl-(R)-4-chloro-α-(1-methylethyl)
benzeneacetate] and its diastereoisomers
[(S)-cyano(3-phenoxyphenyl)methyl-(R)-4-chloro-α-(1-methylethyl)
benzeneacetate and
(R)-cyano(3-phenoxyphenyl)methyl-(S)-4-chloro-α-(1-methylethyl)
benzeneacetate].  The tolerances were established based on field trial
residue data performed at maximum label rates and minimum PHIs.

The esfenvalerate risk assessment in 2004 determined that the residue
chemistry database was complete except for crop field trial data for the
following raw agricultural commodities (RACs):  corn, soybean, and
sorghum aspirated grain fractions, cotton gin byproducts, pea (field)
vines and hay.  These data have not yet been received and are still
required. 

For tolerance enforcement, the Pesticide Analytical Manual, Vol. II
lists two similar gas liquid chromatography methods for the
determination of fenvalerate residues.  These methods are also
applicable to esfenvalerate.  Method I (MMS-R-478-1) determines residues
in/on crops, animal tissues, and water.  Method II (MMS-R-447-3)
determines residues in animal tissue, milk, milk fat, cream, and eggs.
The second method differs from the first in that final clean-up
procedures use a capillary column rather than a packed column. 
Fenvalerate and esfenvalerate residues are composed of two pairs of
diastereoisomers (RS, SR and SS, RR) which appear as two GLC peaks in
both methods.  The Limit of Detection (LOD) is approximately 0.01 ppm.

The registrant has submitted an addendum (AMR 717-87: Supplement 1) to
the enforcement methods published in PAM Vol. II.  The incorporation of
these changes into the PAM Vol. II method produced Method AMR 750-87
which was the data-collection method used in more recent esfenvalerate
field trials.  The major changes include improvements in both the liquid
partitioning, the liquid-solid chromatography clean-up steps, and the
use of a capillary column instead of a packed column.  The method
changes do not affect the LOD of fenvalerate or esfenvalerate in crops
or animal tissue, which is 0.01 ppm; the limit of quantitation (LOQ) was
listed as 0.02 to 0.05 ppm, depending on the matrix.  

During the registration review process, the esfenvalerate dietary burden
to livestock will be reassessed in light of the update to livestock
feedstuff (Table 1 Feedstuffs, June 2008).  Several feedstuffs have had
significant reductions in the percent of cattle diet as a result of the
update, thus likely resulting in a lower dietary burden to ruminants.  
This may also indicate a need to lower livestock commodity tolerances.  

HED is also recommending revision to the tolerance expression to
clarify: 1) That, as provided in FFDCA section 408(a)(3), the tolerance
covers metabolites and degradates of esfenvalerate not specifically
mentioned; and 2) That compliance with the specified tolerance levels is
to be determined by measuring only the specific compounds mentioned in
the tolerance expression. This change is recommended for the tolerance
expression for plant and livestock commodities because it clarifies the
existing language.

Accordingly, in order to ensure that the tolerance expression adequately
addresses both coverage and measurement issues, HED recommends that
paragraph (a) of 40 CFR 180.533 be rewritten to read as follows: 
“Tolerances are established for residues of the insecticide
esfenvalerate, including its metabolites and degradates, in or on the
commodities in the table below.  Compliance with the tolerance levels
specified below is to be determined by measuring only the sum of
esfenvalerate
[(S)-cyano(3-phenoxyphenyl)methyl-(S)-4-chloro-α-(1-methylethyl)
benzeneacetate], its non-racemic isomer
[(R)-cyano-(3-phenoxyphenyl)methyl-(R)-4-chloro-α-(1-methylethyl)
benzeneacetate] and its diastereoisomers
[(S)-cyano(3-phenoxyphenyl)methyl-(R)-4-chloro-α-(1-methylethyl)
benzeneacetate and
(R)-cyano(3-phenoxyphenyl)methyl-(S)-4-chloro-α-(1-methylethyl)
benzeneacetate] in or on the following raw agricultural commodities:”

Commodity	Parts Per Million

See Table 2 in Attachment 1  	

See Table 2 in Attachment 1  

5.  Residential Exposure

Handlers

An assessment of residential exposure to esfenvalerate was conducted as
a part of the 2004 risk assessment.  That assessment concluded that
there are no risk concerns for residential handler exposure as it is
used in residential environments.  No key data gaps were identified for
residential handlers.  

Postapplication

The HED considered a number of residential postapplication exposure
scenarios covering different segments of the population, including
toddlers, youth-aged children, and adults.  MOEs are of concern for
several scenarios, because they exceed the HED’s level of concern
(i.e., Oral MOE < 1000; Dermal MOE < 300) for non-cancer risk
assessments in non-occupational settings.  These scenarios include
applications to lawns using the wettable powder formulation and
applications indoors from space, surface broadcast and crack and crevice
sprays.  Exposures of concern include:

	

dermal exposures to adults and children from activities on treated
indoor surfaces from applications by broadcast sprays (MOEs of 97 for
adults and 68 for toddlers) or crack and crevice sprays (MOEs of 200 for
adults and 140 for toddlers),

oral exposures to toddlers (MOE of 620) from hand-to-mouth transfer of
pesticide from lawns following wettable powder applications, 

oral exposures to toddlers from hand-to-mouth transfer of pesticide from
indoor surfaces  from broadcast spray (MOE of 140) and crack and crevice
spray (MOE of 280) applications.

 

The registrant submitted a study (MRID # 47547701, Determination of
Floor Residues of Esfenvalerate Following a Crack and Crevice or
Broadcast Application of EVERCIDE®  Residual Ant and Roach Spray.  This
study was reviewed by HED and found to be adequate (D358808, S. Tadayon,
05-JUN-2009).  Additionally, HED used the data from the submitted
esfenvalerate deposition study in an informal assessment of residential
risks (electronic mail message from J. Arthur to R. Gebken,
26-MAY-2009).  The esfenvalerate broadcast and crack and crevice (C&C)
products used in the study were applied at approximately the same rates
as those covered in the 2004 ORE assessment.  The 2004 assessment used
the application rates and standard values and assumptions in the
residential SOPs for dermal and incidental oral exposures to estimate
exposure and risk.  Deposition values found in the submitted study were
employed in the same standard equations for estimating dermal and oral
risks.  The dermal MOEs for broadcast application were all under 100 and
for C&C application were all under 300.  The LOC for dermal risk is 300,
so these exposures are of concern to HED.   The MOEs for C&C using a
special tip applicator in voids were over 300 for dermal and over the
LOC or 1000 for incidental oral, but when aggregated, produced a total
aggregate risk index of 1, which leaves no room for food and water.  
While these estimates have not been formalized, they are believed to be
accurate.  Data from the deposition study, as well as additional
analyses submitted by the registrant  [Pandian, M.; Driver, J.; Sharp,
J. (2009) Esfenvalerate: Non-Dietary (Residential) Risk Assessment -
Development of a Random Walk Approach to Estimate Potential Child
Incidental Ingestion (Hand-to-Mouth Contact) Exposures Following Indoor
Crack & Crevice Treatment] will be formally considered during the
registration review process.

The residential postapplication scenarios in the 2004 assessment where
risks are not of concern (i.e., Oral and Inhalation MOEs > 1000; Dermal
MOEs > 300) include: 

dermal exposures to adults and children from

high contact activities on treated lawns following liquid concentrate
applications,

dermal exposures to adults and children from high contact activities on
treated lawns following wettable powder applications, 

dermal exposures to adults from mowing lawns, 

dermal exposures to adults and youth from gardening, 

oral exposures to toddlers from incidental soil ingestion, 

oral exposures to toddlers from transfer of pesticides from object to
mouth on treated lawns following liquid concentrate or wettable powder
applications,  

oral exposures to toddlers from transfer of pesticides from hand to
mouth on treated lawns following liquid concentrate applications, 

dermal exposures to adults and children from activities on treated
indoor surfaces from applications by foggers,

oral exposures to toddlers from transfer of pesticides from hand to
mouth from indoor surfaces from fogger applications, and

inhalation exposures to adult or toddlers from indoor air following
fogger application.

Aggregate Residential Risk Estimates

The HED aggregates risk values resulting from separate handler plus
postapplication exposure scenarios when it is likely they can co-occur
based on the use-pattern and the behavior associated with the exposed
population.  These aggregated values are conservative screening level
risk estimates.  For esfenvalerate, the HED aggregated risk values
(i.e., MOEs) for postapplication exposures of toddlers associated with
turf applications by combining risks from dermal exposures to treated
turfgrass with risks from oral exposures via hand-to-mouth transfer of
residues from treated turf.  In a second tier aggregation, HED combined
the above toddler dermal and hand-to-mouth turfgrass risks with risks
from incidental oral exposures via transfer from turf directly to mouth,
and risks from incidental soil ingestion.  Similarly, HED aggregated
risk values for postapplication exposures to toddlers associated with
indoor surface treatments by combining risks from dermal exposure to
carpet or hard surfaces with risks from hand-to-mouth transfer of
residues from treated indoor surfaces.  

For adults, the HED aggregated risks from handler exposures to adults
applying esfenvalerate to turfgrass with risks from postapplication
exposures from mowing treated turfgrass and with risks from
postapplication exposures through high contact activities on turfgrass. 
In addition, HED aggregated risks from handler exposures to adults
applying esfenvalerate to vegetable gardens with risks from
postapplication exposures to adults involved in gardening tasks. 

Since the toxicological endpoints of concern are based on the similar
adverse effects, dermal and inhalation exposures and risks must be
aggregated for occupational scenarios and dermal, inhalation, and
incidental oral exposures and risks must be aggregated for
nonoccupational scenarios.  For non-occupational scenarios, aggregate
risks were estimated using the Aggregate Risk Index (ARI).  The
aggregate risk index (ARI) method is used to calculate total non-dietary
risk estimates, because the uncertainty factors (UFs) are not all the
same for all routes of exposure.   The route-specific MOEs are combined
using the following formula: ARI total = 1/((1/ARI a) + (1/ARI b) +....
(1/ARI n)); where ARIa=  MOE a/UFa, ARIb=  MOE b/UFb, and ARIn= 
MOEn/UFn, which represent MOEs and UFs for each exposure route of
concern.  An ARITotal < 1 exceeds HED’s level of concern, and an
ARITotal > 1 is not of concern.  The exposure scenarios that result in
aggregated residential risk estimates of concern, i.e., ARITotal < 1,
include:

toddlers on turfgrass following applications of the wettable powder
formulation: dermal exposures plus exposures from transfer of pesticides
from turf to hands to mouth 

toddlers on turfgrass following applications of the wettable powder
formulation: dermal exposures plus exposures from transfer of pesticides
from turf to hands to mouth plus exposures from transfer of pesticides
from objects to mouth plus exposures from soil ingestion.

adults who apply indoor broadcast or RTU sprays and perform high contact
activities within those premises within 24 hours after treatments. 

toddlers on indoor surfaces from foggers or sprays, including dermal
exposures plus exposures from transfer of pesticides from surfaces to
hands to mouth.

	The exposure scenarios that result in aggregated residential risk
estimates not of concern, i.e., ARITotal > 1, include: 

toddlers on turfgrass following applications of the liquid concentrate:
dermal exposures plus exposures from transfer of pesticides from turf to
hands to mouth;

toddlers on turfgrass following applications of the liquid concentrate:
dermal exposures plus exposures from transfer of pesticides from turf to
hands to mouth plus exposures from transfer of pesticides from objects
to mouth plus exposures from soil ingestion.

adults who apply the wettable powder formulation with a pump-trigger
sprayer plus either mow the treated lawn or have high contact activities
on treated lawns.

adults who apply the liquid concentrate with a hose-end sprayer plus
either mow the treated lawn or have high contact activities on treated
lawns.

adults who apply with an aerosol can to vegetable gardens plus perform
gardening tasks.

6.  Aggregate Risk Assessment  

The current registered uses for esfenvalerate not only include
agricultural, but non-occupational (residential) use sites, as well. 
Therefore, in addressing aggregate risks, the 2004 assessment considered
contributions from dietary pathways of food and drinking water to
conduct acute and chronic aggregate assessments.  These acute and
chronic aggregate risks were determined not to exceed HED’s level of
concern.  The 2004 assessment also considered contributions from food
and drinking water plus those from residential uses to conduct a
short-/intermediate-term aggregate assessment, where risk estimates for
some residential scenarios exceeded HED’s level of concern.

 The exposure scenarios that resulted in short/intermediate-term
aggregate risks of concern, i.e., ARITotal < 1, include:

toddlers on turfgrass following applications of the wettable powder
formulation: dermal exposures plus exposures from transfer of pesticides
from turf to hands to mouth. 

toddlers on turfgrass following applications of the wettable powder
formulation: dermal exposures plus exposures from transfer of pesticides
from turf to hands to mouth plus exposures from transfer of pesticides
from objects to mouth plus exposures from soil ingestion.

adults who apply indoor broadcast or RTU sprays and perform high contact
activities within those premises within 24 hours after treatments. 

toddlers on indoor surfaces from foggers or sprays, including dermal
exposures plus exposures from transfer of pesticides from surfaces to
hands to mouth.

Because these aggregate residential risk exposures alone exceed HED’s
level of concern, additional exposure to esfenvalerate in drinking water
and food would cause risk estimates to further exceed the levels of
concern. Therefore, HED did not conduct a short- and intermediate-term
aggregate risk assessment for the scenarios mentioned above.

The exposure scenarios that did not result in aggregated residential
risk estimates of concern, i.e., ARITotal ( 1, include:

toddlers on turfgrass following applications of the liquid concentrate:
dermal exposures plus exposures from transfer of pesticides from turf to
hands to mouth;

toddlers on turfgrass following applications of the liquid concentrate:
dermal exposures plus exposures from transfer of pesticides from turf to
hands to mouth plus exposures from transfer of pesticides from objects
to mouth plus exposures from soil ingestion.

adults who apply the wettable powder formulation with a pump-trigger
sprayer plus either mow the treated lawn or have high contact activities
on treated lawns.

adults who apply the liquid concentrate with a hose-end sprayer plus
either mow the treated lawn or have high contact activities on treated
lawns.

adults who apply with an aerosol can to vegetable gardens plus perform
gardening tasks.

Since the above uses do not exceed HED’s level of concern, an
aggregate short- and intermediate-term risk was conducted with food and
water.  Upon aggregation with food and water exposures, the liquid
formulations used on turf result in risk estimates that exceeded HED’s
level of concern.  However, for liquid spray formulations used in
gardens, the risk estimates were below HED’s level of concern.

7.  Occupational Exposures

An assessment of occupational exposure to esfenvalerate was conducted as
a part of the 2004 risk assessment.  Occupational uses of esfenvalerate
include:

Terrestrial Food Crop

	Cucurbits - cucumber, melons, pumpkin and squash

	Grain Crops - field corn and grain sorghum

	Fruiting Vegetables - tomato, eggplant and pepper

Leafy and Stem Vegetables - bok choy, broccoli, Brussels sprouts,
cabbage, Chinese cabbage, cauliflower, collards, kohlrabi, lettuce
(head, crisphead types, leaf types) and mustard

	Miscellaneous Vegetables - artichoke, cardoon and cocoa beans

Nut Crops - almond, filbert (hazelnut), peanuts, pecan, pistachio,
walnut (English/black), Pome Fruits - apple, pear

	Root Crop Vegetables - carrot (including tops), radish and sweet potato

Small Fruits - blackberry, blueberry, boysenberry, caneberries,
dewberry, loganberry, raspberry (black, red), youngberrires, and
varieties of these		

	Stone Fruits - apricot, cherry, nectarine, peach, plum, and prune

Terrestrial Food+Feed Crop

	Crops Grown for Oil - field corn, canola, and sunflower

	Fruiting Vegetables - tomato

	Grain Crops - field corn and grain sorghum

Groups of Agricultural Crops Which Cross  Established Crop Groupings - 
cotton, peanuts, peas, sorghum, soybeans, and vegetables

	Leafy and Stem Vegetables - mustard and turnip

	Nut Crops - almond, filberts, pecans, pistachios and walnuts

	Pome Fruits - apple and pears

	Root Crop Vegetables - potato, sweet potato and turnip

Seed and Pod Vegetables - dried beans, snap beans, lentils, peanuts,
dried peas, green peas, and soybeans (edible)

	Small Fruits - caneberries, blueberries, 

	Specialized Field Crops - popcorn, seed corn, sweet corn and sunflower

	Sugar Crops - sugar beet and sugarcane

Terrestrial non-food crop

Agricultural Uncultivated Areas - Agricultural fallow/idleland and
Agricultural rights-of way/fencerows/hedgerows  

	Commercial/Industrial/Institutional Premises and Equipment         
Commercial/Institutional/Industrial Premises/Equipment (Outdoor) 

	Fiber Crops                                     

Forest Trees - Christmas tree plantations, conifer seed orchards, forest
tree nurseries and conifer plantations

Groups of Agricultural Crops Which Cross Established Crop Groupings -
Fruits (unspecified)

Nonagricultural Uncultivated Areas - Outdoor buildings/structures,
rights-of- way/fencerows/hedgerows, uncultivated areas/soils, and
recreational areas 

Ornamental Lawns and Turf - commercial/industrial lawns, and
recreational area lawns

Terrestrial non-food+outdoor residential

	Nonagricultural Uncultivated Areas - fencerows/hedgerows           

Forestry

Forest Trees - Christmas tree plantations, conifer seed orchards, forest
tree nurseries, and conifer plantations

7.1  Occupational Exposure:  Handlers

Risks to occupational handlers from current uses of esfenvalerate are
below the HED’s level of concern (i.e., MOE > 100) at baseline attire
(i.e., long-sleeve shirt, long pants, shoes, and socks), or, in some
cases, with the addition of personal protective equipment for dermal
protection (i.e., chemical-resistant gloves). 

7.2  Occupational Postapplication

HED assessed occupational postapplication risks to agricultural workers
following treatments to the agricultural crops.  For these agricultural
crop scenarios, HED uses restricted-entry intervals as a risk mitigation
method when risks are of concern at 12 hours following application
(i.e., day 0).  Under the Worker Protection Standard for Agricultural
Pesticides, a restricted-entry interval (REI) is the time period after a
pesticide application when entry into the treated area is limited.  In
general, during a restricted-entry interval, agricultural workers are
prohibited from entering treated areas and contacting treated surfaces. 
Risk estimates for occupational workers are based on persons wearing
long-sleeve shirts, long pants, shoes, and socks.  The postapplication
occupational assessment for esfenvalerate is based on chemical-specific
dislodgeable foliar residue (DFR) studies on apples, broccoli, and sweet
corn (i.e., MRIDs 44852402, 44852401, and 44852403).  For the
agricultural crops treated with esfenvalerate, risks were not a concern
(i.e., MOEs > 100) at 12 hours following application (i.e., day 0). 

8.  Tolerance Assessment and International Harmonization

A summary of US tolerances, Codex Maximum Residue Limits (MRL), Mexican
MRLs, and Canadian MRLs for esfenvalerate is provided in Attachment 1
(Table 2).  The revised tolerance expression used by the US matches that
used by Codex.  Codex MRLs for esfenvalerate are harmonized with US
tolerances for tree nuts, snap beans, berries, cotton seed, sweet corn
cob with husks removed, pepper, squash, watermelon, sweet potato,
cabbage, and Chinese cabbage.  For crops where MRLs are not harmonized,
the differences are usually small.  For livestock commodities, the US
tolerances are consistently higher than the corresponding Codex MRLs. 

9.  Public Health and Pesticide Epidemiology Data.  

A summary report listing reported incidents for esfenvalerate has been
drafted (M. Hawkins and J. Cordova, 04-AUG-2009).  A search of the OPP
Incident Data System (IDS) from 2002-2008 identified 195 case reports
attributed to esfenvalerate.  The most frequently reported symptom
involved dermal effects (approximately 29% of the reports).  Due to the
moderately large number of case reports in IDS, other incident databases
will be consulted for consistency and reproducibility of effects during
the development of the Final Work Plan (FWP) for esfenvalerate.

10. Environmental Justice  

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"   HYPERLINK
"http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pd
f" 
http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf
.  The Office of Pesticide Programs (OPP) typically considers the
highest potential exposures from the legal use of a pesticide when
conducting human health risk assessments, including, but not limited to,
people who obtain drinking water from sources near agricultural areas,
the variability of diets within the U.S. (including different ages,
regions, and ethnicities), and people who may be exposed when harvesting
crops.  Should these highest exposures indicate potential risks of
concern, OPP further refines the risk assessments to ensure that the
risk estimates are based on the best available information.

11. Cumulative

Esfenvalerate is a member of the pyrethroid class of pesticides. This
class also includes permethrin, cypermethrin, cyfluthrin,
tau-fluvalinate, bifenthrin, fenpropathrin, and lambda-cyhalothrin among
others. The pyrethroids, as a group, have been determined to share a
common mechanism of toxicity (Proposed common mechanism grouping for the
pyrethrins and pyrethroids, draft, May 19, 2009;   HYPERLINK
"http://www.regulations.gov/search/Regs/home.html#documentDetail?R=09000
064809a62df" 
http://www.regulations.gov/search/Regs/home.html#documentDetail?R=090000
64809a62df ). However, a cumulative risk assessment has not been
performed as part of this review because the Agency is currently
examining approaches for completing this type of assessment.  EPA’s
Office of Research and Development is currently investigating the
pharmacokinetics and pharmacodynamics of pyrethroids which will provide
a more solid scientific foundation for the cumulative assessment of
these pesticides in the future.  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
http://www.epa.gov/pesticides/cumulative/.

12.  Human Studies

Esfenvalerate risk assessments rely in part on data from studies in
which adult human subjects were intentionally exposed to a pesticide or
other chemical.  These studies, which comprise the Pesticide Handlers
Exposure Database (PHED), have been reviewed by the Agency and found on
the basis of available evidence to have been neither fundamentally
unethical nor significantly deficient relative to standards of ethical
research conduct prevailing when they were conducted.  There is no
barrier in the Agency’s “Protection of Human Subjects” regulation
to reliance on these studies.

13.  Data Needs

Toxicology

The following toxicity studies are required.  

870.3465.  90-day inhalation toxicity study (see Attachment 2). 

870.6300.  Developmental neurotoxcity study (see Attachment 3). 

870.7800.  Immunotoxicity.  This study is required based on the Revised
Part 158 Toxicology Data Requirements for Conventional Pesticides (see
Attachment 4). 

Residue Chemistry

860.1500 Crop Field Trials.  Corn (field), soybean, and sorghum
aspirated grain fractions, cotton gin byproducts, pea (field) vines and
hay (see Attachment 5).  

Occupational Exposure

None

14.  References

Author	Barcode	Date	Title

J. Morales et. al.	D274838	7/2/2004	Esfenvalerate.  Health Effects
Division (HED) Risk Assessment.

M. Hawkins and J. Cordova	--	

8/4/2009	

Updated Review of Esfenvalerate Incident Reports

S. Tadayon	D358808	

6/5/2009	Esfenvalerate:  Review of “Determination of Floor Residues of
Esfenvalerate Following a Crack and Crevice or Broadcast Application of
EVERCIDE Residual Ant and Roach Spray”.

J. Morales	D288464	5/30/2003	Esfenvalerate/Fenvalerate: Anticipated
Residues and Tier 3 Probabilistic Acute and Chronic Dietary Exposure
Assessments.   

J. Morales	D288461	4/20/2006	Esfenvalerate:  Residue Chemistry Chapter
for the HED Risk Assessment.

J. Morales	D259703	4/20/2006	Esfenvalerate.  Petition for a Regional
Tolerance for Residues of Esfenvalerate in/on Brussels Sprouts

J. Morales	D274838	4/20/2006	Esfenvalerate.  Magnitude of the Residue
in/on Peanuts and Peanut Processed Commodities, Cocoa Beans, Almonds,
and Walnuts Stored in Commercial Food Storage Areas.  Summary of
Analytical Chemistry and Residue Data.

B. O’Keefe	D283153	1/29/2004	Esfenvalerate.  Occupational and
Residential Exposure Assessment for New Proposed Uses on Brussels
sprouts, bok choy, canola, sweet potato, cardoon, pistachios, unshelled
peanuts, cocoa beans, and shelled almonds and walnuts.

I. Saheb	D280680	2/4/2002	Esfenvalerate.  Drinking Water Assessment.

Attachment 1.  Maximum Residue Limits (MRL) Table for Esfenvalerate

Table 2.  Summary of US and International Tolerances and Maximum Residue
Limits 

US	Canada	Mexico	Codex

Residue Definition:

40 CFR 180.379

sum of esfenvalerate
[(S)-cyano(3-phenoxyphenyl)methyl-(S)-4-chloro-α-(1-methylethyl)
benzeneacetate], its non-racemic isomer
[(R)-cyano-(3-phenoxyphenyl)methyl-(R)-4-chloro-α-(1-methylethyl)
benzeneacetate] and its diastereoisomers
[(S)-cyano(3-phenoxyphenyl)methyl-(R)-4-chloro-α-(1-methylethyl)
benzeneacetate and
(R)-cyano(3-phenoxyphenyl)methyl-(S)-4-chloro-α-(1-methylethyl)
benzeneacetate]	None	See US residue definition	Sum of fenvalerate
isomers (fat-soluble).

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

Commodity	US	Canada	Mexico	Codex

Almond	

0.2

	0.2 (tree nuts)

Almond, hulls	

5.0

	

Apple	

1.0

1.0	2 (pome fruit)

Artichoke, globe	

1.0

	

Bean, dry, seed	

0.25

0.25	0.1 (shelled SUCCULENT)

Bean, snap, succulent 	

1.0

	1 (succulent with pods)

Beet, sugar, roots	

0.05

	

Beet, sugar, tops	

5.0

	

Blueberry	

1.0

	1 (Berries and other small fruits)

Broccoli	

1.0

1.0	2

Cabbage

(except Chinese cabbage)	

3.0

	3

Cabbage, Chinese	

1.0

	1

Caneberry

(Crop Subgroup 13-A)	

1.0

	

Cantaloupe	

0.5

	

Carrot, roots	

0.5

	

Cattle, fat	

1.5

	1 (fat)

Cattle, meat	

1.5

	

Cattle, meat byproducts	

1.5

	0.02 (edible offal)

Cauliflower	

0.5

0.5

	

Collards	

3.0

	

Corn, field, forage	15

	

Corn, field, grain	

0.02

0.02	2 (cereal grains)

Post harvest use

Corn, field, stover	

15

	

Corn, pop, grain	

0.02

	

Corn, pop, stover	

15

	

Corn, sweet, forage	

15

	

Corn, sweet, K + CWHR	

0.1

	0.1

Corn, sweet, stover	

15

	

Cotton, undelinted seed	

0.2

0.2	0.2

Cucumber	

0.5

0.5	0.2

Egg	

0.03

	

Eggplant	

0.5

0.5

	

Elderberry	

1.0

	1 (Berries and other small fruits)

Fruit, stone, group 12	

3.0

	2 cherry

5 peach

Goat, fat	

1.5

	1 (fat)

Goat, meat 	

1.5

	

Goat, meat byproducts	

1.5

	0.02 (edible offal)

Gooseberry	

1.0

	1 (Berries and other small fruits)

Hazelnut	

0.2

	0.2 (tree nuts)

Hog, fat	

1.5

	1 (fat)

Hog, meat	

1.5

	

Hog, meat byproducts	

1.5

	0.02 (edible offal)

Horse, fat	

1.5

	1 (fat)

Horse, meat	

1.5

	

Horse, meat byproducts	

1.5

	0.02 (edible offal)

Kiwifruit	

0.5

	

Kohlrabi	

2.0

	

Lentil, seed	

0.25

	

Lettuce, head	

5.0

1

	

Melon, honeydew	

0.5

	0.2 (melons, except watermelon)

Milk	

0.3

	0.1

Milk, fat	

7.0

	

Muskmelon	

0.5

0.5	0.2 (melons, except watermelon)

Mustard greens	

5.0

	

Okra	

0.5

	

Pea, dry, seed	

0.25

2

	

Pea, succulent	

0.5

0.5	0.1

Peanut	

0.02

0.02	0.1

Pear	

1.0

1	2 (pome fruits)

Pecan	

0.2

	0.2 (tree nuts)

Pepper	

0.5

1 (chilli pepper)	0.5

Potato	

0.02

0.02	0.05 (root and tuber vegetables)

Poultry, fat	

0.3

	0.01 (fat)

Poultry, liver	

0.03

	0.01 (edible offal)

Poultry, meat	

0.03

	

Poultry, meat byproducts, except liver	

0.3

	0.01 (edible offal)

Pumpkin	

0.5

0.5

	

Radish, roots	

0.3

	0.05 (root and tuber vegetables)

Radish, tops	

3.0

	0.5

Sheep, fat	

1.5

	

Sheep, meat	

1.5

	

Sheep, meat byproducts	

1.5

	0.1

Sorghum, grain, forage	

10

	

Sorghum, grain, grain	

5.0

	1

Sorghum, grain, stover	

10

	

Soybean, hulls	

0.5

	

Soybean, seed	

0.05

0.05	0.1

Squash, summer	

0.5

0.5	0.5

Squash, winter	

0.5

	0.5

Sugarcane, cane	

1.0

	

Sunflower, seed	

0.5

	0.1

Sweet potato, roots	

0.05

	0.05 (root and tuber vegetables)

Tomato	

0.5

0.5	1

Turnip, greens	

7.0

	

Turnip, roots	

0.5

	0.05 (root and tuber vegetables)

Walnut	

0.2

0.2	0.2 (tree nuts)

Watermelon	

0.5

0.5	0.5

Attachment 2.  Rationale for Requiring a 90-Day Inhalation Study

Guideline Number: 870.3465

Study Title:   90-Day Inhalation Toxicity 

Rationale for Requiring the Data

Instead of conducting the inhalation study for 90-days, the Agency only
needs a 28-day inhalation study because only short- and
intermediate-term (but not long-term) exposure to workers is expected
based on esfenvalerate's use pattern.  A longer-term inhalation study is
required in situations in which a specific concern exists for increased
hazard related to exposure via the inhalation route.  The 28-day
inhalation toxicity study evaluates the potential hazard of a pesticide
chemical following repeated inhalation exposures.  This study is
critical for pesticides with use patterns in which there is potential
for repeated human exposures (e.g., professional applicators, green
house use, etc.).  The study design simulates the route of human
exposure (inhalation).  In this study, animals are exposed (nose/whole
body) to aerosol concentrations of the test material for 6 hours/day, 5
days/week for 28 days.  A detailed toxicological examination including
the histopathology of the respiratory system is conducted.  This
route-specific study would provide data for hazard characterization,
dose response assessment, and a dose and endpoint for assessing
potential risks via the inhalation route.  

Practical Utility of the Data

How will the data be used?  

This study will identify hazard (i.e., provide a dose and endpoint)
following repeated inhalation exposures.  The results will be used in
risk assessments as appropriate.

How could the data impact the Agency’s decision-making?  

A subchronic inhalation study provides critical scientific information
needed to characterize potential hazard to the human respiratory system
from pesticide exposure.  In the case of esfenvalerate, there is no
inhalation study available and accordingly, the most recent inhalation
risk assessment is based on use of an oral NOAEL from an acute oral
neurotoxicity study together with an assumption of a 100% inhalation
absorption rate.  A 28-day repeated exposure study that follows the Test
Guidelines (870.3465) will characterize hazard and provide data for a
more refined inhalation risk assessment.

Attachment 3.  Rationale for Requiring a Developmental Neurotoxicity
Study

Guideline Number: 870.6300

Study Title:  Developmental Neurotoxicity Study 

Rationale for Requiring the Data

A developmental neurotoxicity (DNT) study is conditionally required for
all pesticide chemicals to determine if developing mammals are
susceptible to the neurotoxic effects of the test material especially in
relation to effects that may persist into adulthood.  The trigger for
requiring the study is a weight-of-evidence evaluation that considers
the kinds of evidence available, how that evidence fits together in
drawing conclusions, and significant issues/strengths/limitations. 
Specific to the weight of evidence for requiring a DNT is that the
pesticide causes treatment-related neurological effects in adult animal
studies.  The criteria that were developed for determining the need for
a DNT were developed through extensive peer review including the FIFRA
Scientific Advisory Panel.  

As a pyrethroid pesticide, esfenvalerate was found to produce tremors
following acute oral administration to animals.  This study was selected
as the basis for all the toxicology doses and endpoints selected for
esfenvalerate except for the dermal endpoints where a 21-day dermal
toxicity rat study was available.  Because esfenvalerate has been shown
to cause treatment-related neurological effects in adult animal studies,
a DNT study is warranted.   

However, EPA has recently determined that, as an alternative to the
generation and submission of a new DNT study, registrants may instead
choose to cite the six previously submitted DNT studies for pyrethroid
pesticides.  The six chemicals with acceptable DNTs include: bifenthrin,
cyfluthrin, cyhalothrin, cypermethrin (zeta), fenpropathrin, and
deltamethrin.  Given the similarity of certain results across all these
studies, EPA has concluded that, when considered together, these studies
provide sufficient information for EPA to determine that the conclusions
are applicable to all pyrethroids.  EPA will therefore consider citation
of all of the six studies as a substitute for generating a single new
study for a given pyrethroid chemical.  

Practical Utility of the Data for Developmental Neurotoxicity Study

How will the data be used?

The 10X database uncertainty factor may be removed upon submission of
the DNT study, effectively reducing human health risk estimates by an
order of magnitude.  In addition, the point of departure for the risk
assessment may change based on the results of the study.  

How could the data impact the Agency’s future decision-making?

The removal of the 10x database uncertainty factor, along with a
possible change in the point of departure, may change the Agency’s
dietary assessment by impacting the dietary risk cup.  In addition, the
occupational and residential risk assessments may be changed, depending
on the results of the requested study.  

Attachment 4.  Rationale for Requiring An Immunotoxicity Study

Guideline Number: 870.7800

Study Title:  Immunotoxicity

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the
data requirements for registration of a pesticide (food and non-food
uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing and is designed to evaluate the potential of a
repeated chemical exposure to produce adverse effects (i.e.,
suppression) on the immune system. Immunosuppression is a deficit in the
ability of the immune system to respond to a challenge of bacterial or
viral infections such as tuberculosis (TB), Severe Acquired Respiratory
Syndrome (SARS), or neoplasia.  Because the immune system is highly
complex, studies assessing functional immunotoxic endpoints are helpful
in fully characterizing a pesticide’s potential immunotoxicity.  These
data will be used in combination with data from hematology, lymphoid
organ weights, and histopathology in routine chronic or subchronic
toxicity studies to characterize potential immunotoxic effects.  

Practical Utility of the Data

How will the data be used?

These animal studies can be used to select endpoints and doses for use
in risk assessment of all exposure scenarios and are considered a
primary data source for reliable reference dose calculation. For
example, animal studies have demonstrated that immunotoxicity in rodents
is one of the more sensitive manifestations of TCDD
(2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental, reproductive,
and endocrinologic toxicities.  Additionally, the EPA has established an
oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed
immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

If the Agency does not have this data, a 10X database uncertainty factor
may be applied for conducting a risk assessment from the available
studies.

 

Attachment 5.  Rationale for Requiring Crop Field Trial Studies

Guideline Number: 860.1500

Study Title: Crop field trials – (aspirated grain fractions [corn,
sorghum, and soybean], cotton gin byproducts, pea vine and hay)

Rationale for Requiring the Data

Crop field trials are required for each commodity/commodity group
according to guidelines that take into account where and how much of the
crop is grown.  In general, the OPPTS Series 860 Guidelines, Section
1500, provide the recommended distribution and numbers of field trials
for the various crops.  

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਀e begins and seed heads are formed in the following crops: corn,
sorghum, soybean and wheat.  For fenvalerate/esfenvalerate, this data
requirement has not been fulfilled and data are needed for all four
grains except wheat (no registered wheat uses).  As aspirated grain
fractions may be obtained from any or all of the four grains listed
above, the tolerance level is based on the highest residue level found
in the aspirated grain fraction studies.

Cotton gin byproducts consist of burrs, leaves, stems, lint, immature
seeds, and sand and/or dirt resulting from the ginning process.  A
minimum of three field trials are needed for this RAC, depicting residue
levels that may result from stripper harvest of treated cotton samples. 

A minimum of three trials in EPA Growing Zone 11 is required for field
pea forage and hay with Austrian winter pea the preferred cultivar. This
cultivar is grown only for livestock feeding and is the most appropriate
for determining the contribution to the livestock dietary burden
resulting from this use.  

Practical Utility of the Data

How will the data be used?

These data will allow EPA to set enforceable tolerance levels that
farmers and producers will be able to rely upon for trade and commerce. 
The farmers and producers depend upon EPA to set appropriate tolerance
levels in conjunction with label directions (which can include
restrictions on use of additives) that would prevent legal uses from
producing over-tolerance residues, and thereby resulting in crop
seizure.  Once the tolerance levels are determined, dietary risk will be
assessed. 

How could the data impact the Agency's future decision-making? 

As mentioned previously, when new tolerances are established, the
dietary risk will be assessed.  Therefore, these data will allow the
Agency to determine a more accurate livestock dietary burden, and
consequently a more accurate dietary exposure analysis.  

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