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.

Page   PAGE  1  of   NUMPAGES  24


[Federal Register: June 8, 2009 (Volume 74, Number 108)]
[Notices]
[Page 27134-27135]
[DOCID:fr08jn09-39]

-----------------------------------------------------------------------

DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

Combined Notice of Filings 1

May 28, 2009.
    Take notice that the Commission received the following exempt
wholesale generator filings:
    Docket Numbers: EG09-44-000.
    Applicants: Lost Lakes Wind Farm LLC.
    Description: Notice of Self Certification of Exempt Wholesale
Generator, Status of Lost Lakes Wind Farm LLC.
    Filed Date: 05/27/2009.
    Accession Number: 20090527-5107.
    Comment Date: 5 p.m. Eastern Time on Wednesday, June 17, 2009.

    Docket Numbers: EG09-45-000.
    Applicants: Blue Canyon Windpower V LLC.
    Description: Notice of Self Certification of Exempt Wholesale
Generator, Status of Blue Canyon Windpower V LLC.
    Filed Date: 05/27/2009.
    Accession Number: 20090527-5108.
    Comment Date: 5 p.m. Eastern Time on Wednesday, June 17, 2009.

    Docket Numbers: EG09-46-000.
    Applicants: Lost Creek Wind, LLC.
    Description: Notice of Self-Certification of Exempt Wholesale
Generator of Lost Creek Wind, LLC.
    Filed Date: 05/27/2009.
    Accession Number: 20090527-5115.
    Comment Date: 5 p.m. Eastern Time on Wednesday, June 17, 2009.

    Take notice that the Commission received the following electric
rate filings:
    Docket Numbers: ER08-1109-001.
    Applicants: Maine Public Service Company.
    Description: Maine Public Service Company Submits for Filing a
Settlement Agreement.
    Filed Date: 05/20/2009.
    Accession Number: 20090520-5125.
    Comment Date: 5 p.m. Eastern Time on Wednesday, June 10, 2009.

    Docket Numbers: ER09-874-001.
    Applicants: Discount Power, Inc.
    Description: Discount Power, Inc submits the Second Amended
Petition for Acceptance of Initial Rate Schedule, Waivers and Blanket
Authority.
    Filed Date: 05/26/2009.
    Accession Number: 20090527-0046.
    Comment Date: 5 p.m. Eastern Time on Tuesday, June 16, 2009.

    Docket Numbers: ER09-952-001.
    Applicants: Dayton Power and Light Company.
    Description: Duke Energy Corporation submits the Supplemental IA to
incorporate revisions to the headers and footers of the IA as suggested
by Commission Staff, etc.
    Filed Date: 05/27/2009.
    Accession Number: 20090528-0062.
    Comment Date: 5 p.m. Eastern Time on Wednesday, June 17, 2009.

    Docket Numbers: ER09-1097-001.
    Applicants: Public Service Company of New Mexico.
    Description: Public Service Company of New Mexico submits Service
Agreement 334 to its FERC Electric Tariff, Second Revised Volume 6.
    Filed Date: 05/12/2009.
    Accession Number: 20090513-0161.
    Comment Date: 5 p.m. Eastern Time on Tuesday, June 02, 2009.

    Docket Numbers: ER09-1132-000.
    Applicants: Palmco Power NJ, LLC.
    Description: Palmco Power NJ, LLC submits the Amendment for the
Petition for Acceptance of Initial Tariff, Waivers and Blanket
Authority & requesting acceptance of FERC Electric Tariff Original
Volume 1, etc. et al.
    Filed Date: 05/27/2009.
    Accession Number: 20090528-0063.
    Comment Date: 5 p.m. Eastern Time on Wednesday, June 17, 2009.

    Docket Numbers: ER09-1133-000.
    Applicants: Palmco Power PA, LLC.
    Description: Palmco Power PA, LLC submits the Amendment for the
Petition for Acceptance of Initial Tariff, Waivers and Blanket
Authority, etc.
    Filed Date: 05/27/2009.
    Accession Number: 20090528-0060.
    Comment Date: 5 p.m. Eastern Time on Wednesday, June 17, 2009.

    Docket Numbers: ER09-1194-000.
    Applicants: Palmco Power NJ, LLC.
    Description: Palmco Power NJ, LLC submits the Amendment for the
Petition for Acceptance of Initial Tariff, Waivers and Blanket
Authority & requesting acceptance of FERC Electric Tariff Original
Volume 1, etc.
    Filed Date: 05/27/2009.
    Accession Number: 20090528-0063.
    Comment Date: 5 p.m. Eastern Time on Wednesday, June 17, 2009.

    Docket Numbers: ER09-1195-000.
    Applicants: Palmco Power PA, LLC.
    Description: Palmco Power PA, LLC submits the Amendment for the
Petition for Acceptance of Initial Tariff, Waivers and Blanket
Authority, etc.
    Filed Date: 05/27/2009.
    Accession Number: 20090528-0060.
    Comment Date: 5 p.m. Eastern Time on Wednesday, June 17, 2009.

    Docket Numbers: ER09-1196-000.
    Applicants: Lost Creek Wind, LLC.
    Description: Lost Creek Wind, LLC submits application for accepting
initial tariff, waiving regulations, and granting blanket approvals.
    Filed Date: 05/27/2009.
    Accession Number: 20090528-0220.
    Comment Date: 5 p.m. Eastern Time on Wednesday, June 17, 2009.

    Docket Numbers: ER09-1197-000.
    Applicants: American Electric Power Service Corporation.
    Description: American Electric Power Service Corp submits the
seventeenth revised Interconnection and Local Delivery Service
Agreement.
    Filed Date: 05/26/2009.
    Accession Number: 20090527-0047.
    Comment Date: 5 p.m. Eastern Time on Tuesday, June 16, 2009.

    Docket Numbers: ER09-1198-000.
    Applicants: American Electric Power Service Corporation.
    Description: Notice of Annual Update of Formula Rate of American
Electric Power Service Corporation.
    Filed Date: 05/26/2009.
    Accession Number: 20090526-5302.
    Comment Date: 5 p.m. Eastern Time on Tuesday, June 16, 2009.

    Docket Numbers: ER09-1201-000.
    Applicants: Midwest Independent Transmission System Operator, Inc.
    Description: Midwest Independent Transmission System Operator, Inc.

submits an executed Amended and Restates Large Generator
Interconnection Agreement among the Midwest ISO, et al. limited
liability corporation, etc.
    Filed Date: 05/27/2009.
    Accession Number: 20090528-0059.
    Comment Date: 5 p.m. Eastern Time on Wednesday, June 17, 2009.

    Take notice that the Commission received the following open access
transmission tariff filings:
    Docket Numbers: OA09-29-000.
    Applicants: Avista Corporation.
    Description: Avista Corporation's Informational Filing of
Operational Assessments and Distributions as Required by Order Nos. 890
and 890-A.
    Filed Date: 05/26/2009.
    Accession Number: 20090526-5163.
    Comment Date: 5 p.m. Eastern Time on Tuesday, June 16, 2009.

    Take notice that the Commission received the following electric
reliability filings:
    Docket Numbers: RD09-7-000.
    Applicants: North American Electric Reliability Corporation.
    Description: Petition of the North American Electric Reliability
Corporation for Approval of Version 2 Critical Infrastructure
Protection Standards.
    Filed Date: 05/22/2009.
    Accession Number: 20090522-5150.
    Comment Date: 5 p.m. Eastern Time on Monday, June 29, 2009.

    Any person desiring to intervene or to protest in any of the above
proceedings must file in accordance with Rules 211 and 214 of the
Commission's Rules of Practice and Procedure (18 CFR 385.211 and
385.214) on or before 5 p.m. Eastern time on the specified comment
date. It is not necessary to separately intervene again in a subdocket
related to a compliance filing if you have previously intervened in the
same docket. Protests will be considered by the Commission in
determining the appropriate action to be taken, but will not serve to
make protestants parties to the proceeding. Anyone filing a motion to
intervene or protest must serve a copy of that document on the
Applicant. In reference to filings initiating a new proceeding,
interventions or protests submitted on or before the comment deadline
need not be served on persons other than the Applicant.
    The Commission encourages electronic submission of protests and
interventions in lieu of paper, using the FERC Online links at http://
www.ferc.gov. To facilitate electronic service, persons with Internet
access who will eFile a document and/or be listed as a contact for an
intervenor must create and validate an eRegistration account using the
eRegistration link. Select the eFiling link to log on and submit the
intervention or protests.
    Persons unable to file electronically should submit an original and
14 copies of the intervention or protest to the Federal Energy
Regulatory Commission, 888 First St., NE., Washington, DC 20426.
    The filings in the above proceedings are accessible in the
Commission's eLibrary system by clicking on the appropriate link in the
above list. They are also available for review in the Commission's
Public Reference Room in Washington, DC. There is an eSubscription link
on the Web site that enables subscribers to receive e-mail notification
when a document is added to a subscribed dockets(s). For assistance
with any FERC Online service, please e-mail<EMAIL_ADDRESS>or call<PHONE_NUMBER> (toll free). For TTY, call<PHONE_NUMBER>.

Nathaniel J. Davis, Sr.,
Deputy Secretary.
[FR Doc. E9-13330 Filed 6-5-09; 8:45 am]

BILLING CODE 6717-01-P