Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

•**~** 5 

### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, DC 20460



## ., 0 OFFICE OF CHEMICAL SAFETY AND
POLLUTION PREVENTION



### MEMORANDUM

Date: May 30,2014

SUBJECT: Met hox yfenozide. Re vised Human Health Risk Assessment to Support Proposed
New Section 3 Use on Pineapple.

PC Code: 121 027
Decision No.: 478935
Petition No. : 3F8179 Risk Assessment Type: Single Chemical Aggregate
TXRNo.: NA
MRJDNo.: NA DP Barcode: 0420583 Registrat io n No.: 62719-442 Regulatory Action: Section 3 Registration
Case No.: 7431
CAS No.: 161050-58-4
40 CFR: 180.544



### FROM: Elizabeth Holman, Physical Scientist/Risk Assessor

### ~ ).J..-c.__ Margarita Collantes

, Biologist**7'll fM** **~** 

### (U 

## t&n**~':.l.** Linnea J

. Hansen

, Ph

. D.

, Biologist**~~(f--.-** Risk Assessment Branch II (RA BII) Health Effects Division (7509P)



### THROUGH: Michael Doherty

, Ph

. D., Senior Chemist
Christina Swartz, Branch Chief
Risk Assessment Branch II (RA BII) Health Effects Division (7509P)



### TO: Olga Odiott, Risk Manager Deborah McCall, Branch Chief
Insecticide Branch Registration Division, 7505P

The Registration Division (RD) requested that the Health Effects Division (HED) conduct a risk

assessment for the active ingredient methoxyfenozide to estimate the risk to human health that
will result from the proposed new use on pineapple. The attached human health risk assessment addresses exposure and risk associated with the proposed new use on pineapp l e, as well as the existing uses on various agricultural commodities and ornamentals. The exposures assessed
include dietary (food and water), inhalation for occupational workers and residential handlers

, and aggregate exposure and risk for residential handlers resulting from use on ornamentals

. There were no risks of concern identified for any route or duration of exposure. This revised

assessment is being issued to fix a typographical error in the Executive Summary, which resulted in contradictory statements in this section; no other revisions to the assessment were made.

Page 1 of39Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 2 of 39 

### Table of Contents

1.0 Executive Summary ........................................................................................................... 4 2.0 HED Recommendations .................................................................................................... 6 2.1 Data Deficiencies/Conditions of Registration .............................................................. 6 2.2 Tolerance Considerations .............................................................................................. 6 2.2.1 Enforcement Analytical Method ............................................................................... 6

2.2.2 International Harmonization ..................................................................................... 7

2.2.3 Recommended Tolerances ........................................................................................ 7

2.2.4 Revisions to Petitione d-For Tolerances .................................................................... 7

2.3 Label Recommendations From Residue Review ......................................................... 7 3.0 Introduction ........................................................................................................................ 7 3.1 Chemical Identity ........................................................................................................... 7 3.2 Physical/Chemical Characteristics ............................................................................... 8 3.3 Pesticide Use Pattern ...................................................................................................... 8 3.4 Anticipated Exposure Pathways ................................................................................... 9 3.5 Consideration of Environmental Justice .................................................................... 10 4.0 Hazard Characterization and Dose-Response Assessment .......................................... 10 4.1 Toxicology Studies Available for Analysis ................................................................. 10 4.2 Absorption, Distribution, Metab olism, & Elimination (ADME) ............................. 11 4.2.1 Dermal Absorption.................................................................................................. 11

4.3 Toxicological Effects .................................................................................................... 12 4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 13 4.4.2 Evidence of Neurotoxicity ...................................................................................... 13

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 14

4.5 Toxicity Endpoint and Point of Departure Selections .............................................. 14 4.5.1 Dose-Response Assessment .................................................................................... 14

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment ........ 16

4.5.3 Cancer Classification and Risk Assessment Recommendation .............................. 16

5.0 Dietary Exposure and Risk Assessment ......................................................................... 18 5.1 Metabolite/Degradate Residue Profile ....................................................................... 18 5.1.1 Summary of Plant and Animal Metabolism Studies ............................................... 18

5.1.2 Summary of Environmental Degradation ............................................................... 19

5.1.3 Comparison of Metabolic Pathways ....................................................................... 19

5.1.4 Residues of Concern Summary and Rationale ........................................................ 20

5.2 Food Residue Profile .................................................................................................... 21 5.4 Dietary Risk Assessment .............................................................................................. 23 5.4.1 Description of Residue Data Us ed in Dietary Assessment ..................................... 23

5.4.2 Percent Crop Treated Used in Dietary Assessment ................................................ 23

5.4.3 Acute Dietary Risk Assessment .............................................................................. 23Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 3 of 39 5.4.4 Chronic Dietary Risk Assessment .......................................................................... 23

5.4.5 Cancer Dietary Risk Assessment ............................................................................ 24

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 24 6.1 Residential Handler Exposure .................................................................................... 25 6.2 Dermal Post-Application Exposure ............................................................................ 26 6.5 Spray Drift .................................................................................................................... 26 6.6 Residential Bystander Post-Application Inhalation Exposure ................................ 26 7.0 Aggregate Exposure/Risk Characterization .................................................................. 27 7.1 Acute Aggregate Risk ................................................................................................... 27 7.2 Short-Term Aggregate Risk ........................................................................................ 27 7.3 Chronic Aggregate Risk ............................................................................................... 28 8.0 Cumulative Exposure/Risk Characterization ............................................................... 28 9.0 Occupational Exposure/Risk Characterization ............................................................ 28 9.2 Post-Application Risk .................................................................................................. 29 9.2.1 Post-Application Dermal Exposure ........................................................................ 29

9.2.2. Post-Application Inhalation Exposure .................................................................... 30

10.0 References ......................................................................................................................... 31 Appendix A. Toxicology Prof ile and Executive Summaries .................................................. 33 Appendix B. Physical/Chemical Properties. .......................................................................... 39 Appendix C. Review of Human Research ................................................................................ 39Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 4 of 39 1.0 Executive Summary

Dow Agrosciences LLC has submitted a petition requesting the establishment of a permanent tolerance for residues of methoxyfenozide in or on pineapple. Methoxyfenozide (with CAS name 3-methoxy-2-methylbenzoic acid 2-(3,5-d imethylbenzoyl)-2-(1,1-dime thylethyl)hydrazide, and CAS number 161050-58-4) is a diacylhydrazine ins ecticide used on a wide variety of food and feed crops for the control of lepidopterous pest species. Permanent tolerances are established for residues of methoxyfenozide in or on a wide variety of plant commodities, at levels ranging from 0.02 ppm in peanuts and tuberous/corm vegetables (subgroup 1D), to 400 ppm in Herb Subgroup 19A (40CFR §180.544[a][1]). Permanent tolerances are also established for residues of methoxyfenozide in the milk, me at and fat of livestock (40CFR §180.544[a][1]), and for the combined residues of the parent a nd its glucuronide conjuga te (RH-141,518) in eggs and meat byproducts at 0.02-0.40 ppm (40CFR §180.544[a][2]). In addition, tolerances have been established for indirect or inadvertent residues in a number of commodities (40CFR §180.544[d][1 and 2]) ranging from 0.02 ppm (potato; methoxyfenozid e only) to 8.0 ppm (straw of non-grass animal feeds, Group 18; methoxyfenoz ide, its free-phenol metabolite, and glucose and malonylglycosyl conjugates of the free-phenol metabolite).

In developing this human health risk assessment, HED has examined the available hazard and exposure information regarding methoxyfenozide as it relates to its registered and requested uses. The existing use on ornamentals was prev iously reassessed in ac cordance with current policies, based on the potential for residentia l handlers to use produc ts in and around home gardens. The toxicology databa se is considered complete for the purpose of characterizing the hazard associated with methoxyfenozide and for conducting a human health risk assessment.

The main target organs in the rat and dog were the liver, thyroid and red blood cells (RBCs). The most consistent findings acr oss species and studies were d ecreased red blood cell parameters and increased liver, thyroid, adrena l and spleen weights. Many of the available short-term or subchronic toxicity studies showed little or no toxicity. Increase s in thyroid and adrenal weights were observed in the rat chroni c oral study. Thyroid weights were also increased in the dog following chronic exposure, but no acco mpanying histopathology was observed.

Toxicological testing indicates that methoxyfenozide is not neur otoxic or immunotoxic; it has been categorized as “not likely” to be carci nogenic to humans. There is no evidence of qualitative or quantitative suscep tibility of the developing fetus or offspring, based on the developmental and reproductive t oxicity study results. Therefore, based on the completeness of the database, the lack of suscepti bility, the lack of neurotoxicity and the conservative nature of the exposure assessment, HED has reduced the 10X Food Quality Protection Act (FQPA) Safety
Factor to 1X.

Based on the submitted toxicology data and the cu rrent and proposed use patterns, HED selected endpoints for chronic dietary risk assessment, as well as for inhalation risk assessment for residential and occupational handlers. Acute diet ary risk was not evalua ted because there were no toxic effects associated with a single dose, and therefore an appr opriate endpoint was not identified. There was no toxicity observed in the dermal toxicity study, and no concern for potential developmental effects; therefore, a dermal endpoint was not selected, and noMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 5 of 39 quantitative dermal exposure and risk assessments were conducted (i.e., there is no hazard via the dermal route). Furthermore, HED did not se lect an endpoint for incidental oral risk assessment, since the potential fo r post-application oral exposure to children resulting from the existing use of methoxyfenozide on ornamentals is extremely low. Inhalation risks were assessed using the endpoint and dose from an oral study, with the assumption that inhalation toxicity would be equivalent to oral toxicity for the purpose of route-to-route extrapolation. Based on a weight of evidence (WOE) appro ach, the HASPOC concluded, that a 28-day inhalation toxicity study is not requi red for methoxyfenozide at this time ( TXR #: 0053782).

The endpoint selected for chronic dietary risk assessment was based on liver and thyroid effects observed in the chronic/carcinogeni city study in the rat; the blood effects seen in the dog study were considered co-critical. Fo r inhalation risk assessment, th e endpoint selected was based on blood effects seen in a range-finding study in the dog.

HED used modeling to assess ch ronic dietary exposure to met hoxyfenozide. In combination with an extensive database of food consump tion patterns for the U.S. population and population subgroups, this modeling used conservative upper-bound assumptions regarding residues of methoxyfenozide and its breakdown products in food and drinking water. Specifically, the dietary assessment included tolerance-level resi dues from the existing and proposed uses, the assumption of 100% crop treated (CT) for all crops , and high-end residues in drinking water, derived from modeling the maximum application ra te in vulnerable areas. The highest potential drinking water exposure is from ground water so urces. The chronic dietary exposure and risk estimates are below HED’s level of concern (L OC) of 100% of the chronic population adjusted dose (cPAD) for the general U.S. population an d all population subgroups, including those of infants and children. The highest exposed popula tion subgroup was childre n 1-2 years old, with a dietary risk estimate of 83% cPAD; all other population subgroups had lower risk estimates, including the general U.S. population at 30% cPAD.

Residential exposures are those that may occur as a result of activitie s in and around the home, schools and recreational areas. No new residential uses are associated with the new use on pineapple currently under review . Prior to 2012, a residential exposure assessment was not performed in conjunction with registrati on of the existing use of methoxyfenozide on ornamentals. Since then an inhalation endpoi nt was selected and the OPP HED Residential SOPs were finalized and approve d for risk assessment purposes. Therefore, in a previous newuse risk assessment, HED assessed potential inha lation exposure for residential handlers treating ornamentals in and around home gardens (D 388978, M. Collantes et al, 05/23/2012). The resulting risk estimates are margins of exposur e (MOEs) ranging from 76,000 to more than 3 million, which are not of concern.

In accordance with the FQPA, in evaluating huma n health risks from exposure to pesticides, HED aggregates exposure from various routes, i. e., residential exposure is added to dietary exposure from food and drinking water. The residential handler exposure resulting from applying methoxyfenozide to ornamentals using a backpack sprayer was combined with the chronic dietary exposure from the most highl y exposed adult population subgroup (general US adult population) to determine a ggregate exposure and risk. The calculated exposure resulted inMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 6 of 39 an aggregate MOE of 540; this ri sk estimate is not of concern, si nce it is significantly higher than the LOC of 100.

An occupational exposure assessment was also performed for handler and post-application activities, based on standard assumptions with respect to body weight and area treated, in accordance with HED’s standard procedures. Ther e were no chemical-specific data available to assess handlers’ inhalation exposure, so HED reli ed on surrogate data generated by various task forces. The resulting inhalation risk estimates were MOEs ranging from 20,000 to more than 3 million and were not of concern. A quantitativ e post-application exposure assessment was not completed due to the lack of dermal toxicity, an d because the handlers’ MOEs are expected to be protective of post-application expo sure via the inhalation route.

The risk assessment is based, in part, on data fr om studies in which adu lt human subjects were intentionally exposed to a pest icide or other chemical. Thes e studies are compliant with applicable ethical requireme nts (refer to Appendix C).

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assess ment (see Section 3.5).

2.0 HED Recommendations

HED recommends in favor of the proposed regi stration of the new us e of methoxyfenozide on pineapple and establishment of the associated permanent tolerances as summarized in Table 2.2.3

.

Note to RD: Analytical standards for methoxyfenozid e and its 4 metabolites are currently available at EPA’s National Pesticide Standa rds Repository (NPSR). However, the RH1521,055 metabolite standard expire s on 15 July 2014, and the parent methoxyfenozide standard expires on 17 October 2014. The registrant should resubmit new analytical reference standards, or updated certificates of analysis (COAs), for both of these standards before their expiration date (for further details see D413705, E. Holman, 4/4/2014; Section 2.4).

2.1 Data Deficiencies/Conditions of Registration

None

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The FDA multiresidue methods are not suitable for analysis of methoxyfenozide or its regulated metabolites. However, adequate single methods are available for enforcing the current tolerances for methoxyfenozide in primary crops and animal commodities. Depending on the plant commodity, the limits of quantitation (LOQs) for me thoxyfenozide in primary crop commodities are 0.010-0.050 ppm. Th e tolerance enforcement methods include use of high performance liquid chromatogra phy (HPLC), with either tandem mass spectrometric detectionMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 7 of 39 (LC-MS/MS), or ultravio let detection (HPLC-UV). It is also noted that the European Food Safety Authority (EFSA) has concluded that the multiresidue QuEChERS method, combined with an HPLC-MS/MS, is adequate for toleranc e enforcement in plant and animal commodities (EFSA, 2014).

2.2.2 International Harmonization

Neither Codex nor Canada’s PMRA has establishe d MRLs in pineapple. As such, there are no harmonization issues with Codex or PMRA associat ed with this proposed new use on pineapple. Methoxyfenozide has been the subject of a significant amount of discussion with PMRA regarding harmonization of existi ng tolerances on other agricultural commodities. There are currently no pending or proposed uses of methoxyf enozide in pineapple u nder review by PMRA. However, in the interest of avoiding future harmonization i ssues, PMRA was consulted to determine how they would handle this dataset shoul d they receive it in the future (e.g. for an import tolerance MRL). Based on these discussions with PMRA, they would likely set the same tolerance of 0.70 ppm that is being reco mmended by HED (ChemSAC minutes, 02/19/2014; 03/26/2014). HED’s recommended tolerance for th e new use on pineapple was determined using the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures.

2.2.3 Recommended Tolerances

TABLE 2.2.3 Tolerance Summary for Methoxyfenozide. Commodity as Proposed by the Petitioner Proposed Tolerance (ppm) Recommended Tolerance (ppm) Comments; Correct Commodity Definition 180.544[a][1] Pineapple 0.7 0.70 Revise tolerance from 0.7 ppm to 0.70 ppm.

2.2.4 Revisions to Petitioned-For Tolerances

Instead of the proposed tolerance in pineappl e (0.7 ppm), HED recommends establishing the tolerances at 0.70 ppm, in order to avoid the situation where a fi eld sample containing residues significantly above the tole rance (0.74 ppm, for example) woul d be considered non-violative.

2.3 Label Recommendations From Residue Review

None.

3.0 Introduction

3.1 Chemical Identity

Methoxyfenozide is a diacylhydrazi ne insecticide used on a vari ety of crops for control of armyworms and other lepidopterous pe st species. It mimics the action of the molting hormone ofMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 8 of 39 lepidopterous larvae, causing th e larvae to undergo an incomplete and premature molt, which ultimately results in their death.

TABLE 3.1 Methoxyfenozide Nomenclature.
Chemical structure

Common name Methoxyfenozide Company experimental name RH-2485
Molecular formula C 22 H 28 N 2 O 3 Molecular weight 368.47
IUPAC name N- tert -butyl-N ′ -(3-methoxy- o -toluoyl)-3,5-xylohydrazide CAS name 3-methoxy-2-methylbenzoic acid 2-(3,5-dimethylbenzoyl)-2-(1,1- dimethylethyl)hydrazide CAS registry number 161050-58-4 End-use product (EP) 2 lb ai/gal F (Intrepid 2F, EPA Registration #62719-442)

3.2 Physical/Chemical Characteristics

The information regarding physical chemical characteristics of me thoxyfenozide does not indicate that there are any special concerns in terms of bioaccumulation, exposure or other risk assessment considerations. A ta ble of physical and chemical pr operties for methoxyfenozide is included in Appendix B.

Methoxyfenozide has a low dermal absorption factor . Dermal absorption is the process by which chemicals are transported from the outer surface of the skin into bot h the inner layers of the skin and into the body. The dermal absorption factor is a numerical estimate of the percentage of the topical external dose that traverse s the skin layers to the systemic circulation (e.g. the percentage of the topical external dose that is bioavailable). An in vivo dermal absorption study on an 80% wettable powder (WP) formula tion of methoxyfenozide was conducted in the rat. Cumulative absorption of approximately 2% of the applie d dermal dose was observed after a 10 or 24 hour dermal exposure duration. Consis tent with the low level of ab sorption, a 28-day dermal study in the rat showed no toxicity up to the lim it dose (1000 mg/kg/day). Furthermore, methoxyfenozide has a large octanol -water partition coefficient (K ow ) of 10 3.72 which further supports that methoxyfenozide is not easily absorbed by the skin and thus would result in lower dermal exposure.

Although methoxyfenozide is very persistent (t 1/2 = 1 to 3 years in soil and water), it is not significantly volatile, and has a vapor pressure of 1.0 x 10 -7 mm Hg at 25  ̊ C. Therefore, significant inhalation exposure to me thoxyfenozide is no t expected.

3.3 Pesticide Use Pattern CH 3 O N H N

O CH 3

CH 3 C H 3 CH 3

O C H 3 CH 3Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 9 of 39 Methoxyfenozide is currently registered for use on ornamentals and a wide variety of agricultural crops.

Dow AgroSciences LLC is requesting a new use of the insecticide methoxyfenozide be added to the Intrepid 2F (Reg. No. 62719-442) label for use on pineapples. Intr epid 2F is formulated as a flowable concentrate containing 22. 6% active ingredient (ai) or 2 lb ai per gallon. Intrepid 2F may be applied by air, groundboom, airblast a nd hand-held equipment. Methoxyfenozide may not be applied to pineapples by chemigation.

The PPE statement on the proposed label requires applicators and other ha ndlers to wear longsleeved shirt and long pants, socks, s hoes, and chemical-resistant gloves.

The proposed use directions for the new use on pineapple and the existing use on ornamentals are summarized in Table 3.3. As the existing use on ornamentals is the sole component of the residential exposure assessment, it is incl uded here for characterization purposes.

1. PHI = Pre-Harvest Interval.

3.4 Anticipated Exposure Pathways

As a result of the registered and proposed uses of the insecticide met hoxyfenozide, humans may be exposed through food and drinking water, sinc e the chemical may be applied directly to growing crops and may reach surface and ground water sources of drinking water. In an occupational setting, applicators may be expos ed while handling the pesticide prior to application (i.e., mixing/loading), as well as during application. Th ere is also potential for postapplication exposure for workers re-entering treated fields.

Since methoxyfenozide is also registered for use on ornamentals there is lik ely to be exposure in Table 3.3. Summary of Directions for Proposed Uses of Methoxyfen ozide and Registered Residential Use

Method of Application Application
Rate Maximum
No. Applications per Season Maximum Seasonal Application
Rate (lb ai/A) PHI (Days) Use Directions, Application Timing, Type and Limitations

Pineapples

Ground (Airblast), Aerial and hand held equipment 0.06 – 0.10 lb ai/A (4-7 fl oz/A)

.001 lb ai/gal 4 0.44 lb ai/A 3 Apply as a foliar spray. Heavy infestation may require repeat applications.

Ornamentals (Registered Residential Use)

Handheld Equipment 0.25 lb ai/A (4-16 fl oz/A)

0.025 lb

ai/gal 4 0.5 lb ai/A/yr

(32 fl oz/A yr) NA Repeat applications on a 10-14 day interval. When applying with hand sprayers apply until runoff.Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 10 of 39 residential and non-occupational settings as we ll. While the product doe s not appear to be intended for homeowner use, ther e is the potential for homeowners to purchase and apply the product to their own ornamentals. Although there is also potential for dermal exposure, there is no expectation of dermal risk, based on the lack of dermal toxicity for methoxyfenozide. Furthermore, the potential for pos t-application oral exposure to ch ildren is not expected since the extent to which young children engage in oral-ex posure activities associat ed with areas where residential ornamentals are grown or use these areas for prolonged periods of play is low. This risk assessment considers all of the re levant exposure pathways, combining them as appropriate, to estimate overall exposure and risk.

3.5 Consideration of Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, “Federal Actions to Address Environmental Just ice in Minority Populations an d Low-Income Populations,” ( http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf . As a part of every pesticide risk assessment, OPP considers a large variety of c onsumer subgroups according to well-established procedures. In line with O PP policy, HED estimates risks to population subgroups from pesticide exposures that are ba sed on patterns of that subgrou p’s food and water consumption, and activities in and around th e home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture under the National Health and Nutr ition Examination Survey, What We Eat in America, (NHANES/WWEIA). These food consump tion patterns are used in pesticide risk assessments for all registered food uses of a pest icide. These data are analyzed and categorized by subgroups based on age, season of the year , ethnic group, and region of the country. Additionally, OPP is able to assess dietary e xposure to smaller, specialized subgroups and exposure assessments are performed when condi tions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for ch ildren, youths, and adults enteri ng or playing on treated areas post-application are evaluated. Further considera tions are currently in development as OPP has committed resources and expertise to the developm ent of specialized software and models that consider exposure to bystanders and farm worker s as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicological database is considered comple te for methoxyfenozide. The following studies, which use exposure routes (oral and dermal) consis tent with potential hu man exposure scenarios, have been submitted: primary acute toxicity, irritation and dermal sensitization; subchronic oral toxicity in the rat, mouse and dog; rat 28-day dermal toxicity; rat chronic oral toxicity/carcinogenicity; dog chronic oral toxicity; mouse or al carcinogenicity; rat and rabbit oral toxicity; rat oral two- generation reproductive toxicity; ge notoxicity battery; rat acute and subchronic neurotoxicity; rat gene ral metabolism; rat dermal penetration (on formulation); and rat immunotoxicity. Although a 28-day inhalati on toxicity study has not been submitted, HEDMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 11 of 39 has determined that this st udy is not needed (i.e., th e study has been waived) for methoxyfenozide, based on a weight of evidence (WOE) approach that c onsidered all of the available hazard and exposure information, incl uding the use of a conservative oral point of departure (POD) that results in MOEs ranging from 20,000 to 3,100,000 for risk via the inhalation route due to resi dential and occupational expos ures (TXR #0053782, 4/17/12).

4.2 Absorption, Distribution, Metab olism, & Elimination (ADME)

In the rat, 14 C-radiolabeled methoxyfenozide was rapidly absorbed following gavage administration, with maximum peak plasma c oncentrations observed within 15 minutes of dosing. Peak plasma concentrations followi ng dosing at 10 mg/kg ranged from 0.70 to 1.09 ppm in males and 0.5 to 0.59 ppm in females, depending on the ring location of the radiolabel; at the 1000-mg/kg dose, peak levels were 26.11- 35.52 ppm in males and 21.92 to 29.74 ppm in females. Plasma elimination was biphasic, with an α -phase T 1/2 of 0.2 to 0.6 hr and a β -phase
T 1/2 of 15.2-35.6 hr and showed some variation with radiolabel location. The total plasma elimination rate was longer for the high dose compared to the low dose animals, suggesting metabolic pathway saturation, and the effect was mo re prominent in female rats. Radioactivity was extensively distributed among tissues, with the highest concentrations at C max (0.25 hr) observed in the intestinal tract, stomach, liver and resi dual carcass. Enterohepatic circulation was observed. Methoxyfenozide did not show ev idence of bioaccumulation: by 5 days’ posttreatment, the highest levels were observed in the liver and carcass, but tissue radioactivity in all tissues was insignificant by that tim e. Excretion of radiolabel wa s essentially complete by 48 hrs post dosing. Based on the minimal level of radioa ctivity in tissues at 72 hours, absorption was estimated to be at least 62 to 70% of the admini stered dose (biliary plus urinary excretion). The major route of excretion was in the feces (86-97 % of the administered dose), with 5-13% of the dose excreted in the urine. Significant dose- or sex-dependent diffe rences in metabolic disposition were not observed.

Methoxyfenozide was extensively metabolized. The major routes of metabolism involved O

– demethylation and oxidative hydroxylation of th e A-ring phenyl and/or B-ring methyl groups, followed by glucuronic acid or sulfate conjugation. In addition to the parent compound, seven major metabolites were identified in excret a. These included RH-131,157; RH-141,581 and RH117,236; these metabolites were also identified in crops or livestock. Up to 25 metabolites were isolated from urine, but the ma jority represented <1-2% of th e radioactive dose. Up to 16 metabolites were identified in the feces, includi ng the parent compound, with only six containing
≥ 5% of the administered radiolabel. The major fecal metabolites in all groups were products of Phase I O -demethylation and oxidative hydroxylation noted above. Leve ls of excreted parent compound in the feces were greater in animals r eceiving 1000 mg/kg test material (30 to 39% of dose) when compared to the 10 mg/kg groups (14- 26% of dose), consistent with saturation of absorption. In the bile, up to 24 metabolites we re detected, with the pr imary metabolite (13-18% of dose) being derived by glucuronide conj ugation at the 0-demethylated alpha ring.

4.2.1 Dermal Absorption

An in vivo dermal absorption study on an 80% we ttable powder (WP) formulation of methoxyfenozide was conducted in the rat. Cumu lative absorption of approximately 2% of theMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 12 of 39 applied dermal dose was observed after 10 or 24 hour s of dermal exposure. Consistent with this low level of absorption, a 28-day dermal study in the rat showed no toxic ity up to the limit dose (1000 mg/kg/day).

4.3 Toxicological Effects

Many of the available short-term or subchroni c toxicity stud ies on methoxyfenozide showed little or no toxicity. The main ta rget organs were the liver, thyroid and red blood cells. In the rat metabolism study, liver contained 2-9% of the administered radioactivity at C max , but levels decreased and bioaccumulation was not observed. Levels in the blood were negligible. The effects of methoxyfenozide on the blood in mamm als (methemoglobinemia, decreased red blood cell parameters, Heinz body formation) are cons istent with those of other hydrazine compounds.

Hematologic parameters in the rat and dog were affected by exposure to methoxyfenozide. Mild anemia (decreases in RBC count, hematocrit an d hemoglobin) was observed in both species following chronic dietary exposure, along w ith methemoglobinemia and RBC structural abnormalities. Increased platelets were also observ ed. An increase in the cellularity of rib and sternum bone marrow, along with macrophage pigmentation in the liver and spleen, were reported in the dog. No significant hematological changes were seen in the dog or rat subchronic studies, or the rat two week ra nge-finding studies; how ever, hematological effects were observed in the dog two week range-finding study, along with increased spleen weight. The data suggest that a compensatory mechanism for the RBC effects may occur over time, based on the effects observed at two weeks in the dog range-finding studi es that were not observed in the subchronic study, and on more pronounced changes in hematol ogical parameters at Week 14 in the rat and dog chronic studies than were obser ved at evaluations conducted at later times in those studies. No hematological effects were reported in the mouse.

Increased liver weight and pe riportal hypertrophy were observe d in the rat and dog. These findings were observed in the rat following two- week, subchronic or chr onic dietary exposure, and in the dietary reproductive toxicity study, and in the dog follo wing chronic exposure. In the rat two-week study, increased adrenal gland weight and minimal hypertrophy of the zona fasciculata, and increased thyroi d follicular cell hypertrophy/ hyperplasia were also observed; however, these findings were not seen with subchronic exposure. Thyroid hypertrophy and altered colloid and increased adrenal weights were observed in the rat chronic oral study, and the incidence and severity of chronic progressive glomerulonephropathy was increased. Thyroid weights were increased in the dog following chronic exposure, but there was no accompanying histopathology.

In the mouse, effects were limited to decrease d body weights and weight gain in the subchronic study; however, no effects were seen in the ca rcinogenicity study at dietary concentrations exceeding the limit dose. No body weight e ffects were observed in the rat or dog.

Acute and subchronic oral neurot oxicity studies in the rat did not show evidence of potential neurotoxicity. In the acute study, decreased hi ndlimb grip strength on Day 0 was reported in males. This finding was only observed at the limit dose in males and was not observed in theMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 13 of 39 subchronic neurotoxicity study and was therefore not considered ev idence of neurotoxicity. No clinical signs of neurotoxicity or neurohistopathology were observ ed in other guideline studies.

No maternal or developmental effects were observed in either the rat or rabbit oral developmental toxicity studies. In the rat two-generation reproduc tive toxicity study, parental effects were limited to increas ed liver weight and microsc opic periportal hypertrophy. No offspring or reproductive toxicity was observed. In a 28-day dietary immunotoxicity study in the rat, no immunotoxicity was observed. The only observed effect was in creased liver weight.

Dermal effects were not observe d in the rat following a 28-day e xposure period (5 exposure days per week for a total of 20 exposures). This finding is consistent with th e relatively low dermal absorption of 2% of the applied dose, observed in an in vivo dermal absorption study in rats treated with an 80% WP formulation product.

There was no evidence of carcinogenicity in the rat dietary 24-month chronic toxicity/carcinogenicity study or the mouse dietary 18-mont h carcinogenicity study. No mutagenic or clastogenic poten tial was observed in the batte ry of genotoxicity studies on methoxyfenozide. Based on these findings, methoxyfe nozide is classified as “not likely to be carcinogenic to humans” (2005 Agency revised carcinogenicity assessment guidelines).

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The required 10X FQPA safety factor for meth oxyfenozide was reduced to 1X, based on the following considerations: 1) the toxicity data base for methoxyfenozide is complete, including studies addressing potential pre- and post-natal susceptibility; 2) there is no evidence that methoxyfenozide is neurotoxic, and a developmenta l neurotoxicity study is not required; 3) there is no residual uncertainty, and no ev idence of increased quantitative or qualitative susceptibility in the developing or young animal; and 4) the di etary exposure assessments do not underestimate potential exposure from food and dr inking water, and the use pattern indicates a low potential for residential exposure.

4.4.1 Completeness of the Toxicology Database

The database is considered complete with respect to evaluation of potential susceptibility/sensitivity of infants and children. Acceptable developmental toxicity studies in two species (rat and rabbit) a nd a rat two-generation reproducti on study have been submitted, as well as rat acute and subchronic neurotoxicity and immunotoxicity studie s. A developmental neurotoxicity study is not required, based on the l ack of evidence of neur otoxicity in the adult animal and lack of increased sensitivity/s usceptibility in the de veloping or young animal.

4.4.2 Evidence of Neurotoxicity

The available toxicity data, whic h include acute and subchronic ne urotoxicity studies in the rat, do not demonstrate neurotoxic potential. A decr ease in hindlimb grip strength, observed in male rats on Day 0 of the acute neurotoxicity st udy, was not considered to be evidence of neurotoxicity because it was an is olated finding in males, not obs erved in females and seen onlyMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 14 of 39 at the limit dose of 2000 mg/kg. Additionally, no evidence of neurotoxicity was observed in the rat subchronic neurotoxicity or other studies. A developmental neurotoxicity study is therefore not required.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There was no evidence of increased qualitative or quantitative susceptibilit y in the developing or young animal. No developmental toxicity was observ ed in either the rat or rabbit developmental toxicity studies, and there was no evidence of offspring or reproduc tive toxicity in the rat twogeneration reproductive toxic ity study. Dosing in all st udies achieved the limit dose ( ≥ 1000 mg/kg/day).

4.4.4 Residual Uncertainty in the Exposure Database

There is no residual uncertainty with respec t to the exposure assessments conducted for methoxyfenozide. The dietary exposure estimat es incorporate conservative estimates of all residues of concern from the food exposure path ways. There remains an outstanding data requirement for monitoring of surface water and sedi ment in a representative sample of high use areas in proximity to surface water. Thus, the Environmental Fate and Effects Division (EFED) continues to have concerns about the persistenc e of methoxyfenozide and potential uncertainties regarding the long-term drinking water exposure associated with the use of methoxyfenozide, and has used a highly conservative approach in deriving modeled drinking water values for the purpose of risk assessment. The aggregate assess ment for adult handlers only includes exposure from the existing use on ornamentals based on hi gh-end default assumptions, combined with the conservative dietary exposure assessment summarized above.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

A toxicity profile table is pr ovided in Appendix A of this doc ument. For endpoint selection rationale and detailed summaries of the toxicity studies considered in the selection of toxicity endpoints for exposure assessment, please see the recent 2013 detailed risk assessment document (D407285, E. Holman et al, 08/06/2013). The toxi city endpoint selec tions remain unchanged since this 2013 assessment and no new toxicity data have been evaluated as part of this petition for a new use on pineapple.

For acute dietary exposure assessment, the rat acute oral neurotoxicity study was considered for selection of a dose and endpoint. This study wa s not selected because the only finding was decreased grip strength in males on Day 0 (day of dosing) at the limit dose of 2000 mg/kg; no toxicity was observed at 1000 mg/kg in males or in females up to 2000 mg/kg. The developmental oral toxicity studies in the rat a nd rabbit were also considered but not selected because no maternal or developmental toxicity was observed at doses up to the limit dose (1000 mg/kg/day). There were also no clinical effects on the initial day of dosing in any other oral toxicity study.Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 15 of 39 For selection of a chronic diet ary exposure assessment dose and endpoint, the dietary rat chronic toxicity/carcinogenicity, dog chr onic (1 year) and rat reproduc tive toxicity studies were considered. The mouse carcinogenicity study sh owed no effects at di etary concentrations administering methoxyfenozide s lightly above the lim it dose of 1000 mg/kg/day. Increased liver weight at doses exceeding the limit dose was the only effect observed in parental animals in the rat reproductive toxicity study, and there were no offspring or re productive effects. The rat chronic toxicity/carcinogenici ty study with a NOAEL of 10.2 mg/kg/day was selected for determination of the cRfD. The chronic dog study was selected as the co-critical study because these were the most sensitive studies availabl e and the similar NOAELs (10.2 and 9.8 mg/kg/day for the rat and dog, respectively) yielded the same cRfD of 0.10 mg/kg/day. Hematological effects were observed in both studies at the LOAELs of 106 mg/kg/day in the dog and 411 mg/kg/day in the rat. In the rat, periport al liver hypertrophy, thyr oid hypertrophy and altered colloid and increased adrenal weight were also observed at the LOAEL. The selected dose and endpoint is protective for poten tial developmental effects and toxicity to the young, based on lack of developmental effects (rat and rabbit developmental studies) or toxicity to offspring (rat reproductive toxicity study) and lack of evidence of neurotoxicity. It is also protective of hematological and other effects observed in the dog and rat two-week ra nge-finding studies (see below). The NOAELs/LOAELs from all other ava ilable studies were observed at higher dose levels.

Endpoints were not selected for incidental oral expos ure because, based on current and proposed use patterns which specify use on ornamentals a nd not turf, there are no residential uses for methoxyfenozide where significan t post-application oral expo sure to young children is anticipated.

For dermal exposure (all durations , residential and occupational exposure), an endpoint was not selected. The rat 28-day derm al toxicity study demonstrated no toxicity up to the limit dose (1000 mg/kg/day). Several oral toxicity studies with observed LOAELs were also considered, including the subchronic dietary studies in the rat, mouse and dog, two-week range-finding studies in the rat and dog, and th e rat reproductive toxicity study. However, the effects observed in the oral studies, which included liver hypertro phy and hematologic parameters, were evaluated in the 28-day dermal study but showed no effect of treatment. The developmental oral toxicity studies in the rat and rabbit show ed no maternal or developmenta l toxicity and the rat subchronic dietary neurotoxicity showed no t oxicity at doses up to the lim it dose (1000 mg/kg/day). The rat 28-day dermal toxicity study was therefore cons idered protective of sensitive populations, including potential developmental effects.

Although a 28-day inhalation toxici ty study has not been submitted, HED has determined that this study is not needed (i.e., th e study has been waived) for me thoxyfenozide, based on a weight of evidence (WOE) approach th at considered all of the av ailable hazard and exposure information, including the use of a conservative oral point of departure (POD) that results in MOEs ranging from 20,000 to 3,100,000 for risk via th e inhalation route due to residential and occupational exposures (T XR #0053782, 4/17/12).

Therefore, a two week dietary study in the dog wa s selected for both short- and intermediateterm inhalation exposure because it provided th e most sensitive dose and endpoint availableMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 16 of 39 (NOAEL = 16.8 mg/kg/day, based on hematological effects at the LOAEL of 90.8 mg/kg/day) and was of an appropriate dur ation. The NOAEL and LOAEL were selected from the highest individual animal NOAEL and lowest LOAEL becau se only two animals/sex/dose were tested. Effects observed at the LOAEL included mild anemia, methemoglobinemia and abnormal RBC structure, and were consistently observed in in dividual animals. Although these effects were not identified in the dog 90-day dietary study at dose levels up to about 200 mg/kg/day, mild anemia and methemoglobinemia were observed at Week 14 and later in the chroni c dog study at doses of 106 mg/kg/day. Additionally, in the rat two week range-finding study there were effects observed on the thyroid and adrenal gland at a comparable dose (69.3 mg/kg/day), with a NOAEL of 17 mg/kg/day (effects not observed in the subchronic rat study). These findings were not seen in the subchronic studies, suggesting a compensatory mechanis m for the toxicity of methoxyfenozide with prolonged exposure. This dose and endpoint are therefore considered to be very conservative, but protective of all populat ions that may be exposed. In light of the conservative endpoint, low acute i nhalation toxicity of methoxyfenoz ide, low vapor pressure and low application rates for current use patterns, this oral study is considered to be protective for potential inhalation toxicity.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Dermal exposure was not assessed due to a lack of toxicity via the dermal route. Since adults were assessed for potential inhalation exposure while applying methoxyfenozide to ornamentals, this exposure should be combined with backgr ound levels in food a nd water to determine aggregate exposure. For childre n’s residential exposure, oral post-application exposure was not assessed; only exposure from background levels of food and drinking wate r were assessed. For occupational workers, only inhalationexposure and risk were assessed.

4.5.3 Cancer Classification and Ri sk Assessment Recommendation

Methoxyfenozide is classified as “not likely to be carcinogenic to humans,” according to the revised 2005 Agency Guidelines for Carcinogen Ri sk Assessment. The classification is based on lack of evidence of carcinogenicity in long-term dietary studies in the rat and the mouse, and lack of evidence of genotoxicity in the battery of mutagenicity studies.

4.5.4 Summary of Points of Departure and T oxicity Endpoints Used in Human Risk Assessment

Tables 4.5.4.1 and 4.5.4.2 , below, summarize the dose and en dpoint selection for dietary/nonoccupational and occupational exposure:Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 17 of 39 Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Methoxyfenozide for Use in Dietary and Non-Occupational Human Health Risk Assessments

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

Acute Dietary (All Populations, including Infants and Children and Females 13- 49 years of age) No hazard was identified fo r a single oral exposure.

Chronic Dietary (All Populations) NOAEL= 10.2 mg/kg/day UF A = 10X
UF H = 10X FQPA SF= 1 Chronic RfD
= 0.10 mg/kg/day

cPAD = 0.10 mg/kg/day Co-critical studies:
Combined oral chronic toxicity/carcinogenicity-rat LOAEL = 411/491 mg/kg/day [M/F], based on hematological changes (decreased RBC parameters), periportal liver hypertrophy, thyroid hypertrophy and altered colloid; possibly increased adrenal weight.

Chronic oral toxicity-dog NOAEL = 9.8/12.6 mg/kg/day[M/F] LOAEL = 106.1/110.6 mg/kg/day, based on hematological changes (decreased RBC parameters, slight methemoglobinemia) and increased serum bilirubin.
IncidentalOral ShortTerm (1-30 days) There are no residential uses for methoxyfenozide that would result in significant postapplication incidental oral exposure to children.

Dermal ShortTerm (1-30 days) orIntermediateterm (1-6 months) No toxicity, i.e., no hazard, was identified for dermal exposure.

Inhalation Short- Term (1-30 days) andIntermediateTerm (1-6 months) NOAEL = 16.8 mg/kg/day UF A =10X
UF H =10X Residential LOC for MOE ≤ 100 Two-week oral range-finding study-dog

LOAEL = 90.8 mg/kg/day, based on hematological changes (decreased RBC parameters, increased Heinz body count, reticulocyte counts, erythrocyte morphology and methemoglobinemia) and increased spleen weights. Cancer (oral, dermal, inhalation) Classification: not likely to be carcinogenic to humans.Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 18 of 39 Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intra species). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Methoxyfenozide for Use in Occupational Human Health Risk Assessments

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

Dermal ShortTerm (1-30 days) orIntermediateTerm (1-6 months) No toxicity, i.e., no hazard, wa s identified for dermal exposure

Inhalation Short-Term (1- 30 days) andIntermediateTerm (1-6 months) NOAEL = 16.8 mg/kg/day UF A =10X
UF H =10X Occupational LOC for MOE ≤ 100 Two-week oral range-finding study-dog

LOAEL = 90.8 mg/kg/day, based on hematological changes (decreased RBC parameters, increased Heinz body count, reticulocyte counts, erythrocyte morphology and methemoglobinemia) and increased spleen weights. Cancer (oral, dermal, inhalation) Classification: not likely to be carcinogenic to humans.

Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intrasp ecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Acceptable studies are available de picting the metabolic fate of methoxyfenozide in target crops, rotational crops and livestock. The main distinction betwee n study results was that although methoxyfenozide does not undergo extensive metabolism in primary crops, it is highly metabolized in livestock and rotational crops.

The nature of methoxyfenozide residues in pr imary crops is adequately understood, based on acceptable metabolism studies in cotton, apples, gr apes and rice. Methoxyfenozide does not undergo extensive metabolism in primary crops. HED has determined that the residue ofMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 19 of 39 concern for both the tolerance expression and risk assessment in primary crops is the parent compound only, methoxyfenozide.

However, in rotational crops and livestock, ad ditional metabolites are included in both the tolerance expression and the risk assessment. The metabolites identified in the rotational crops were not similar to those found in the prim ary crop metabolism study. In rotational crops, methoxyfenozide was highly metabolized by oxid ation, demethylation and hydroxylation to nonconjugated metabolites, which were then conjug ated with biomolecules, yielding bound residues and precursors in the su gar synthesis pathway. The residues of concern in rotational crops include methoxyfenozide, its free phenol me tabolite (RH-117,236), conjugated forms of the phenol metabolite (RH-151,055 and RH-152,072) , and the metabolites RH-152,067; RH-131,157 and RH-152,071. For enforcement purposes, the to lerance definition for rotated crops includes parent only in high-moisture crops, and the co mbined residues of parent and metabolites RH151,055; RH-152,072 and RH-117,236 in low-moisture crops.

The residue of concern in milk and ruminant ti ssues (other than liver and kidney) is parent compound; in ruminant liver and kidney met hoxyfenozide and its RH -141,518 metabolite are of concern. The residue of concern in poultry meat (muscle) and fat is parent methoxyfenozide; however, in eggs, poultry liver, and poultry m eat byproducts, residues of concern include methoxyfenozide and its metabolite, RH-141,518.

5.1.2 Summary of Environmental Degradation Memo, K. Milians, Ph.D., Chemist, 8/17/2011, D388876

Methoxyfenozide is very persistent (t 1/2 = 1 to 3 years in soil and water) and moderately mobile (K oc = 219 – 922 L/kg oc in various soils). It is stable to photolysis and hydrolysis, is not significantly volatile, and degrades only very slowly by microbial activity. Degradates are predominantly RH-117,236 (3,5-dimethylbenzoic acid N-tert -butyl- N’ -(3-hydroxy-2- methylbenzoyl)hydrazide) and RH-131,154 (3-[ N-tert -butyl- N’ -(3-methoxy-2-methylbenzoyl)- hydrazinocarbonyl]-5-me thylbenzoic acid), but these are only present at low concentrations. Because of its resistance to degradation and its mobility, methoxyfenozide has the potential to accumulate and to move off the site of appli cation by leaching and erosion/runoff resulting in ground- and surface-water contamination.

5.1.3 Comparison of Metabolic Pathways

Methoxyfenozide is rapidly absorbed, distributed, metabolized and almost completely excreted within 48 hours in rats. The major route of ex cretion was feces (86-97%) with lesser amounts in the urine (5-13%). An enterohepatic circul ation was observed. Th e test material was metabolized principally by O-demethylation of the A-ring methoxy group and oxidative hydroxylation of the B-ring methyl groups followed by conjugati on with glucuronic acid. No significant sex-related or dose-dependent differences in metabolic disposition were noted. Seven metabolites and the parent accounted for 74-90% of the administered dose in all groups. These metabolites included RH-131,157; RH-141,518 and RH -117,236, which were also identified in crops or livestock.Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 20 of 39 Metabolism of methoxyfenozide in other animals (poultry and rumina nts) appears to be similar to its metabolism in rats. Although methoxyfen ozide does not undergo extensive metabolism in primary crops, it is highly metabolized in rota tional crops. Methoxyfenozide is metabolized by oxidation, demethylation and hydroxylation to n on-conjugated metabolites, which were then conjugated with biomolecules, yielding bound resi dues and precursors in the sugar synthesis pathway. This is the same basic pathway as observed in the rat. The major drinking water degradates are also formed by ring hydroxyla tion and oxidation of methyl groups. These degradates were also found in th e rat. Therefore, there were no significant residues in food or drinking water that were not seen in the rat.

5.1.4 Residues of Concern Summary and Rationale

The methoxyfenozide glucuronide conjugates are considered to be less toxic than the parent compound because glucuronide conjugation is well known to be a commonly occurring detoxification mechanism in mammalian species si nce it results in the formation of more polar, more water-soluble metabolites which are readily and easily excreted from the body (in this case, in the bile and urine). Further, based on sim ilarities of chemical stru cture, the non-conjugated metabolites would be expected to be no more t oxic than the parent compound. The metabolites were included in risk assessment and the toleran ce expression, based on the potential for toxicity similar to that of the parent, as well as the po tential for significant levels in crops and livestock, as well as the metabolites determined by the enforcement methods.

Primary Crops: Based on acceptable metabolism studies in cotton, apples, grapes and rice, the nature of methoxyfenozide residues in primary crops is adequately understood. HED concluded that the residue of concern for both the toleran ce expression and the risk assessment in primary crops is methoxyfenozide.

Livestock: The qualitative nature of methoxyfenozide re sidues in livestock is also adequately understood, based on available ruminant and poultr y metabolism studies. HED determined that the residue of concern is the parent compound in milk and ruminant tissues (except meat byproducts), and in poultry meat and fat. The re sidues of concern in meat byproducts and eggs are methoxyfenozide and its RH-141,518 metabolite.

Rotational Crops: The nature of methoxyfenozide residu es in rotational crops is adequately understood, based on the adequate confined accumu lation study. For enforcement purposes, the tolerance definition for rotate d crops includes parent only in high-moisture crops, and thecombined residues of parent and metabolites RH-151,055; RH-152,072 and RH-117,236 in lowmoisture crops. Metabolites RH-152,067; RH -131,157 and RH-152,071 are also to be taken into account in risk assessments.

Drinking Water: The residues of concern in drinking water are the parent methoxyfenozide and the following degradates: RH-117,236and RH-131,154, but these are only present at low concentrations.Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 21 of 39 The toxicological and residue ch emistry databases for methoxyfenozide have been examined to determine residue definitions for the purposes of setting tolerances and risk assessments. The residue definitions are summarized in Table 5.1.4

.

Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression. 1

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Primary Crop Parent methoxyfenozide Parent methoxyfenozide

Rotational Crop Parent methoxyfenozide and metabolites, RH 117,236; RH 151,055; RH 152,072; RH-152,067; RH-131,157; and RH-152,071 Parent methoxyfenozide, and metabolitesRH-151,055; RH-152,072; and RH117,236

Livestock Ruminant Parent methoxyfenozide and metabolite RH-141,518 Parent methoxyfenozide and metabolite RH-141,518

Poultry Parent methoxyfenozide and metabolite 141,518 Parent methoxyfenozide and metabolite RH-141,518

Drinking Water Parent methoxyfenozide anddegradates RH-117,236 and RH131,154 Not Applicable

1 Chemical structures for the residues of concern for tolera nce enforcement purposes are provided in HED’s Metabolism Committee memorandum of 7/23/99 (D258034, W. Wassell).

5.2 Food Residue Profile

Memo, E. Holman, 04/4/2014, D413705

Acceptable crop field trial data are availabl e to support the proposed use on pineapple. Quantifiable residues were observed in/on all cr op commodities. The residue decline data indicate that residues of met hoxyfenozide on pineapple were vari able but genera lly decreased with increasing PHIs. The available data ar e adequate for risk assessment and tolerance assessment. The results from these field trials are summarized in Table 5.2

.
The submitted pineapple processing study data are ad equate. Based on the lack of concentration in processed pineapple commodities, no separate tolerances on these commodities are required.

The available storage stability data are ad equate, and support the storage conditions and durations for samples from the submitted pineapple field trial and processing studies.

Adequate livestock feeding studies are availabl e for methoxyfenozide. No livestock feeding studies were submitted with this petition. The only feedstuff associated with the proposed new uses is pineapple process resi due, a minor feed item. As the calculated maximum residue calculated for pineapple process residue (0.17 ppm) is low relative to the previously estimated livestock dietary burden ( D407758; W. Drew; 16 June 2013 ), addition of this feed item to the livestock diets would not have a significant eff ect on the estimated residue levels in livestock commodities. The currently established tolera nces for residues of methoxyfenozide and itsMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 22 of 39 metabolites in livestock commodities are thus adequate to support the proposed new use on pineapple.

TABLE 5.2. Summary of Residue Data from Pi neapple Field Trials with Methoxyfenozide. Commodity Total Rate lb ai/A (g ai/ha) PHI (days) Residue Levels (ppm) 1

n Sample Min. Sample
Max. LAFT 2 HAFT 2 Median Mean Std.
Dev. Pineapple, Fruit 0.431-0.435 (483-488) 3 6 0.0276 0.365 0.0289 0.346 0.143 0.157 0.119

10 6 0.0189 0.374 0.0237 0.355 0.142 0.150 0.126

1 Except for sample min/max, values reflect per trial averages; n = no. of field trials.

2 LAFT = lowest average field trial; HAFT = highest average field trial.

5.3 Water Residue Profile Memo, K. Milians, Ph.D., Chemist, 4/23/2013, D407566 Memo, I. Negrón-Encarnación, 12/19/2013, D416709

The estimated drinking water concentrations (E DWCs) are based on all current methoxyfenozide uses as well as the new proposed uses. Surface water residues were modeled with the Pesticide Root Zone Model and Exposure Analysis Mo deling System (PRZM-EXAMS), using EFED's standard index reservoir which in corporates flow into and out of the reservoir. Groundwater residues were estimated using the Pesticid e Root Zone Model – Ground Water (PRZM-GW) model, which accounts for pesticide fate in the cr op root zone and multiple years of application. The surface water values are based on the exis ting globe artichoke use represented by the CA lettuce scenario with an applic ation rate of 0.25 lbs. a.i./acre/ application and a total of 1.0 lb a.i./acre/season. The estimated drinking water co ncentrations (EDWCs) are listed in Table 2. The EDWC used in this assessment is bolded in the table below, w ith the value of 214 ppb coming from the groundwater residues estima ted by the PRZM-GW model, as recommended by EFED for chronic dietary risk assessments.

There remains an outstanding data requirement for monitoring of surface water and sediment in a representative sample of high use areas in proximity to surface water. Additionally, EFED continues to have concerns about the persistenc e of methoxyfenozide. This persistence makes it plausible that methoxyfenozide may pose a grea ter long-term drinking water exposure concern than what is suggested by the screening-level as sessment. In particular, once introduced into the environment, this compound could travel to key aquatic environmental compartments, such as aquatic sediment, and persist for extended peri ods of time. Thus, there are significant uncertainties regarding the poten tial long-term drinking water e xposure associated with the use of methoxyfenozide. Therefore EFED has used a conservative a pproach to modeling potential residues in ground water sources of drinking water.

Table 5.3. Tier II estimated drinking water concentrations (EDWCs) resulting from applications of meth oxyfenozide (PRZM-EXAMS)

Drinkin g water source Use (modeled rate) 1-in-10 year acute (ppb) 1-in-10 year chronic (ppb) 30- year average (ppb)

Surface water (aerial application) Globe Artichoke (0.25 lb a.i./A x 4 applic.; total of 1.0 lb/A/yr) 77.7 51.6 37.4Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 23 of 39 Table 5.3. Tier II estimated drinking water concentrations (EDWCs) resulting from applications of meth oxyfenozide (PRZM-EXAMS)

Drinkin g water source Use (modeled rate) 1-in-10 year acute (ppb) 1-in-10 year chronic (ppb) 30- year average (ppb)

Surface water (ground application) Globe Artichoke (0.25 lb a.i./A x 4 applic.; total of 1.0 lb/A/yr) 77.4 50.4 35.8

Tier I EDWCs for Groundwater (PRZM-GW)

Crop/Scenario Highest Daily value (μg/L) Post Breakthrou g h Average (μg/L) Average Simulation Breakthrough Time (days)

Fruiting Vegetable/WI corn 251 214 8684.63

5.4 Dietary Risk Assessment Memo, E. Holman, 04/4/2014, D413706

5.4.1 Description of Residue Data Used in Dietary Assessment

For this analysis existing and recommended tole rance levels were used, as well as 100% CT assumptions for all commodities. DEEM (Version 7.81) default processing factors were used for most processed commodities that do not have individual tolerances; the only exception was a processing factor of 0.2X for orange jui ce (D358341, D. Rate, 6/10/2009) from a reviewed processing study. The existing tolerances for li vestock commodities were considered adequate (D413705, E. Holman, 04/4/2014).

Drinking water was incorporated directly into the dietary asse ssment using the maximum chronic concentration for groundwater generated by the Pesticide Root Zone Model – Ground Water (PRZM-GW) at 214 ppb.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The chronic dietary exposure assessment, ba sed on food and drinking water, includes the assumption of 100% CT for all ex isting and proposed uses.

5.4.3 Acute Dietary Risk Assessment

There was no appropriate endpoint identified for assessing acute dietary exposure; therefore, no acute dietary risk assessment was performed.

5.4.4 Chronic Dietary Risk Assessment

An unrefined chronic dietary analysis for me thoxyfenozide was conducted using tolerance-level residues and 100% CT for all exis ting and proposed primary crop us es, and additional residues of concern in livestock commodities and rotational crops. Methoxyfenozide chronic dietary (food + drinking water) exposure estimates using the DEEM -FCIDTM software are below HED’s level of concern for the U.S. population and each of th e population subgroups. Ch ronic dietary exposure was 30% of the cPAD for the U.S. population. The chronic dietary exposure for the highestMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 24 of 39 reported exposed population subgroup, children 1- 2 years old, was 83% of the cPAD. The results of the analysis indicat e that chronic risk from th e dietary (food + drinking water) exposure to methoxyfenozide will not exceed HE D’s LOC for the general U.S. population, nor any other population subgroups. Based on the ve ry conservative assumptions used, actual dietary exposure to methoxyfenozide from f ood and drinking water is expected to be significantly lower than the expos ures presented in Table 5.4.4.

The results of the chronic dietary exposure analysis are reported in the Summary Table 5.4.4

.

Table 5.4.4. Summary of Dietary Exposure and Risk for Methoxyfenozide.

Population Subgroup 1 DEEM Acute Dietary Analysis,

95 th Percentile DEEM Chronic Dietary Analysis

Exposure (mg/kg/day) % aPAD Exposure (mg/kg/day) % cPAD

General U.S. Population

NA 2 0.030864 30

All Infants (< 1 year old) 0.046336 45

Children 1-2 years old 0.084804 83

Children 3-5 years old 0.064506 63

Children 6-12 years old 0.035771 35

Youth 13-19 years old 0.023449 23

Adults 20-49 years old 0.027010 27

Adults 50+ years old 0.026816 26

Females 13-49 years old 0.027616 27

1 Values for the population with the highest ri sk for each type of risk assessment are bolded

. 2 NA = Not Applicable; no acute dietary endpoint was identified for these population subgroups.

5.4.5 Cancer Dietary Risk Assessment

HED classified methoxyfenozide as “not likely to be carcinogene tic to humans” and, therefore, cancer risk is not of c oncern for methoxyfenozide.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization Memo, M. Collantes 2/27/2012; D389739 Memo, M. Collantes 6/07/2013; D411612

There are no new proposed residential uses at th is time; however, there are existing residential ornamental uses that were previously reasse ssed to reflect updates to HED’s 2012 Residential SOPs 1 along with policy changes for body wei ght assumptions (M. Collantes, D389739, 02/27/12). In order to incorpor ate residential exposure into the short-term aggregate risk assessment, a summary of the residential exposure and risk estimates resulting from the use of methoxyfenozide on ornamental s is provided below.

1 Available: http://www.epa.gov/pesticides/scien ce/residential-exposure-sop.htmlMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 25 of 39 6.1 Residential Handler Exposure

The Intrepid 2F label indicates that it is to be used on trees, shrubs, fo liage plants and flowers grown in commercial nurseries and greenhouses, Ch ristmas tree farms, outdoor landscapes areas, parks, recreational areas, institutional grounds and “ residential property .” Since the label does not identify this product as a restricted use, a residential handler exposure assessment was performed to be protective of potential home owner exposure. The following use scenarios and sources of unit exposures were used to assess residential handler exposures:

 Mixing/Loading/Applying for Sprays Us ing Manually Pressurized Handwand

 Mixing/Loading/Applying for Spra ys with Back-Pack Sprayer

 Mixing/Loading/Applying for Spra ys with Hose-end Sprayer

HED’s LOC is a MOE greater than or equal to 100 for residential expos ure. A quantitative dermal assessment for residential handlers was not conducted since there is no systemic toxicity associated with dermal exposure to methoxyfen ozide. Handler inhala tion exposure scenarios resulted in MOEs greater than 100, ranging from 76,000 to greater than 3 million, and these risk estimates are not of concern. Although a point of departure from an oral study was used to assess the handler inhalation risk s, the calculated MOEs are all >76,000, thus providing an ample margin of safety to account for any uncertainties in the route-to-route extrapolation. Handler exposure and risk estimates are summarized in Table 6.1.

Table 6.1.: Residential Ha ndler Exposure and Risk Es timates for Methoxyfenozide Exposure Scenario Application
Rate a (lb ai/gal) Amount
Treated b (gallons) Inhalation Unit Exposure b (mg/lb ai) Inhalation
Dose c (mg/kg/day) Inhalation MOE d

Liquid with

Manually Pressurized Handwand 0.025 5 0.018 0.0000283 590,000

Liquid with Back Pack 5 0.14 0.00022 76,000

Liquid with Hose-end Sprayer 11 0.0014 0.00000484 3,500,000

a. In accordance with Intrepid® 2F (R eg. No.: 62719-442) label: 0.025 lb ai per gallon for treatment of ornamentals (0.25 lb ai/A ÷ 10 gallons/A for mist blowers and air blast sprayers)
b. In accordance with revised Residential (Garden and Trees) SOP

c. Inhalation dose (mg/kg/day) = inhalation unit exposure (mg/lb ai) * application rate * acres treated / body weight (80 kg)
d. Inhalation MOE = NOAEL (16.8 mg/kg/day)/ Inhalation Dose (mg/kg/day)Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 26 of 39 6.2 Dermal Post-Application Exposure

Although there is potential for post-application dermal exposur e as a result of the use on ornamentals, there’s no dermal toxicity associ ated with this exposure, and a dermal postapplication exposure assessment was not conduc ted. Furthermore, post-application oral exposure to children is not expected since the ex tent to which young children engage in activities associated with areas where residential orna mentals are grown or utilize these areas for prolonged periods of play is low. Therefore an inci dental oral endpoint was not selected and an incidental oral post-application e xposure assessment was not conducted.

6.3 Inhalation Post-Application Exposure

Based on the Agency's current practices, a quant itative post-application inhalation exposure assessment was not performed for methoxyfenozide at this time primarily because of the low acute inhalation toxicity (Toxicity Categor y III and IV), vapor pressure (1 x 10 -7 mm Hg at 25oC), and the low proposed use rate (0.31 lb ai/A).

6.5 Spray Drift

Spray drift is a potential source of exposure to those nearby pest icide applications. This is particularly the case with aerial application, but, to a lesser exte nt, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for methoxyfenoz ide. The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call-In issued by EPA), EPA Regional Offi ces and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information). The Agency is also taking means to qualitatively and qualitatively address spray dr ift as a potential source of exposure in risk assessments for pesticides through existing progr ams such as Ag Drift and chemical specific properties of pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process wh ich ensures that all uses for that pesticide will be considered concurrently.

6.6 Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quant itative post-application inhalation exposure assessment was not performed for methoxyfenozide at this time primarily because of the low vapor pressure (1 x 10 -7 mm Hg at 25oC). Howeve r, volatilization of pesticides may be a source of post-application inhalation expo sure to individuals nearby pesticide applications. The Agency sought expert advice and input on is sues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rode nticide Act Scientific Adviso ry Panel (SAP) in December 2009, and received the SAP’s fi nal report on March 2, 2010 2 . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify

2 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 27 of 39 the need for and, subsequently, the way to inco rporate post-application inhalation exposure into the Agency's risk assessments. If new policie s or procedures are developed, the Agency may revisit the need for a quantitative post-a pplication inha lation exposure assessment for methoxyfenozide.

Although a quantitative residential post-applic ation inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for residential handlers. These exposure scenarios are represen tative of worse case inhalati on exposures and should be considered protective of most post-app lication inhalation exposure scenarios.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or th e risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED consider s both the route and duration of exposure. In the case of methoxyfenozide, chronic aggregate risks result from exposure through food and water only. For short-term risk, adult residential handlers’ inhalation exposure was combined with background exposure from food and water. As previously discussed (see Section 6.2) , there are no residential uses for methoxyfenozide that would result in significant post-application exposure to children, base d on ornamental use only

. Therefore, aggregate exposure and risk for children are equiva lent to those from food and water (see Section 5.4).

7.1 Acute Aggregate Risk

There are no single dos e effects associated with methoxyf enozide, and therefore no acute aggregate risk.

7.2 Short-Term Aggregate Risk

The residential handler exposure from a pplying methoxyfenozide using a backpack ( Table 6.1 ) was combined with the chronic dietary exposure from the mostly highly exposed adult (General U.S. Population) sub-population, to determine aggregate exposure and risk as shown in Table 7.2 . The aggregate MOE is above the LOC of 100, and therefore the aggreg ate risk estimate is not of concern.Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 28 of 39 Table 7.2. Short-Term Aggregate Risk Calculations for Methoxyfenozide.

Population NOAEL mg/kg/day LOC 1 Max Allowable Exposure 2 mg/kg/day Average
Food and

Water Exposure mg/kg/day Residential Exposure mg/kg/day 3 Total Exposure mg/kg/day 4 Aggregate MOE (food, water, and residential) 5

Adult (Handler) 16.8 100 0.168 0.030864 0.00022 0.031084 540

1 The LOC is based on the standard inter- and intra- species uncer tainty factors totaling 100. The FQPA Safety Factor has been reduced to 1X.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure (Adul t Handler) = Inhalation Exposure (Table 6.1).

4 Total Exposure = (Avg. Food & Wate r Exposure + Residential Exposure)

5 Aggregate MOE = [NOAEL16.8 mg/ kg/day/Total Exposure mg/kg/day]

7.3 Chronic Aggregate Risk

Chronic aggregate risk is equivalent to chr onic dietary exposure and risk, which is not of concern. Refer to Section 5.4.4.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has fo llowed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to methoxyfenozide and any other substances an d methoxyfenozide does not appear to produce a toxic metabolite produced by other substances. Fo r the purposes of this action, therefore, EPA has not assumed that methoxyfenozide has a common mechanism of to xicity with other substances. For information regarding EPA’s ef forts to determine which chemicals have a common mechanism of toxicity and to evaluate th e cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and proc edures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pestic ides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Memo, M. Collantes 6/07/2013; D411612 Memo, M. Collantes 4/07/2014; D413706

Methoxyfenozide may be applied through a variety of application methods including: aerial, ground equipment (airblast and groundboom), ha nd-held equipment (backpack sprayer, manually-pressurized handwand and hand gun), and hose-end sprayer. Th erefore, there is potential for short- and intermediate-term occ upational handler and post-application exposure; long-term exposures are not expected.

The proposed new use of methoxyfenozide in pinea pples is applied using the same application methods and agricultural practices as the currentl y registered uses assessed in the most recent occupational risk assessment for use on citrus and root vegetables ; however, at a lower application rate (0.1 lb ai/acre or 0.01 lb ai/gal) then th e previously assessed uses (0.25 lb ai/acre or 0.025 lb ai/gal). Short-term handler inhala tion risk estimates for methoxyfenozide use onMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 29 of 39 citrus resulted in MOEs ranging from 28,000 to 2,700,000 at the baseline level of personal protection (i.e., no respirator) and were not of concern (M. Collantes, D389739, February 27, 2012).

The short- and intermediate-term handler e xposure and risk estimates for the use of methoxyfenozide in pineapples resulted in inhalation MOEs ranging from 34,000 to 7,800,000. These risk estimates are not of concern. Therefore, the previous occupational exposure assessment for methoxyfenozide on citrus is expect ed to be protective of the proposed new use on pineapples and a new occupational exposure assessment was not performed. A summary of the occupational handler risk estimates is provided in Table 9.1

.

Table 9.1. Occupational Handler Non-Cancer Expo sure and Risk Estimates for Methoxyfenozide.

Exposure Scenario Crop or Target Baseline Inhalation Unit Exposure ( μ g/lb ai) 1 Maximum Application
Rate 2 Area
Treated or

Amount
Handled

Daily 3 Inhalation

No Respirator Dose (mg/kg/day) 4 MOE 5

Mixer/Loader

Aerial Pineapples 0.219 0.10 lb ai/A 350 A 0.0000959 180,000

Groundboom 80 A 0.0000219 770,000

Airblast 40 A 0.000011 1,500,000
Applicator

Aerial

Pineapples 0.0049 0.10 lb ai/A 350 A 0.00000215 7,800,000
Groundboom 0.34 80 A 0.000034 490,000

Airblast 4.71 40 A 0.000235 71,000
Flagger
Aerial Pineapples 0.35 0.10 lb ai/A 350 A 0.000154 110,000
Mixer/Loader/Applicator

Back Pack Pineapples 2.58

0.01 lb ai/gal 40 gals 0.0000129 1,300,000

Mechanically Pressurized Handgun 3.9 1000 gals 0.000488 34,000

1 Based on the “Occupational Pesticide Handl er Unit Exposure Surrogate Reference Tabl e”; Level of mitigation: Baseline for

mixer/loader/flaggers, Eng. Contro ls for aerial applicator only. 2 Based on proposed label (Reg. No. 62719-442). 3 Exposure Science Advisory Council Policy #9.1. 6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated

or Amount Handled Daily (A/day or gal/day) ÷ BW (80 kg). 7 Inhalation MOE = Inhalation NOAEL (16.8 mg /kg/day) ÷ Inhalati on Dose (mg/kg/day).

9.2 Post-Application Risk

9.2.1 Post-Application Dermal Exposure

Since there’s no dermal toxicity associated with me thoxyfenozide, a dermal post-application exposure and risk assessment was not conducted.Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 30 of 39 9.2.2. Post-Application Inhalation Exposure

Based on the Agency's current practices, a quant itative post-application inhalation exposure assessment was not performed for methoxyfenozide at this time primarily because of the low acute inhalation toxicity (Toxicity Categor y III and IV), vapor pressure (1 x 10 -7 mm Hg), and the low proposed use rate (0.31 lb ai/A). Howe ver, there are multiple po tential sources of postapplication inhalation exposure to individuals performing po st-application activities in previously treated fields. Th ese potential sources include vol atilization of pesticides and resuspension of dusts and/or pa rticulates that contain pesticid es. The Agency sought expert advice and input on issues related to volatilization of pe sticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 3 . The Agency is in the process of evaluating the SAP report as well as available post-applic ation inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to iden tify the need for and, subsequently, the way to incorporate occupational post-application inhala tion exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-applic ation inhalation exposure assessment for methoxfenozide.

Although a quantitative occupational post-applic ation inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resultin g from application of pesticides outdoors is likely to result in higher exposure than post -application exposure. Therefore, it is expect ed that these handler inhalation exposure estimates would be protec tive of most occupatio nal post-application inhalation exposure scenarios.

Restricted Entry Interval The REI specified on the proposed label is base d on the acute toxicity of methoxyfenozide. Methoxyfenozide is classified as Toxicity Cate gory III via the dermal route and Toxicity Category IV for skin-irritation potential. It is not a skin sens itizer. Under 40 CFR 156.208(c)(2)(iii), ai’s classified as Acute III or IV for acute dermal, ey e irritation and primary skin irritation are assigned a 12-hour REI. Th erefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from postapplication exposures to methoxyfenozide.

However, REIs may be further reduced from 12 hours if certain criteri a are met for both the technical material and the different end-us e products in accordance with the Pesticide Registration (PR) Notice 95-3 [Reduction of Worker Protection Standard (WPS) Interim Restricted Entry Intervals (REIs) for Certain Low Risk Pesticides]. 4

The criteria for reducing REIs include the following: (1) The active ingredient is in Toxicity Categor y III or IV based upon data for acute dermal toxicity, acute inhalation t oxicity, primary skin irritati on, and primary eye irritation.

3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

4 Available: http://www.epa.gov/PR_Notices/pr95-3.htmlMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 31 of 39 (2) The active ingredient is not a dermal sensitizer. (3) The active ingredient is not a cholinesterase inhibitor. (4) The active ingredient is not associated with known reproductive, developmental, carcinogenic, or neurotoxic effects. (5) EPA does not possess incident in formation that are “definitely” or “probably” related to the post-application exposures to the active ingredient.

With respect to the active ingr edient, methoxyfenozide is not cl assified as a carcinogen or a neurotoxicant, nor is it associ ated with known reproductive or developmental effects, which classifies it as a reduced-risk candidate. Therefore, the pr oposed 4-hour REI which appears on the proposed supplemental label is consistent with 4-hour REI on the master label and is a candidate for a reduced-risk chemical.

10.0 References

D407285. Methoxyfenozide. Human Health Risk Assessment to Support Proposed New Uses on Herbs, Caneberries, Dates and Sorghum; to Establish Rotational Crop Tolerances in the Rapeseed and Sunflower Oilseed Subgroups; as well as to extend and update Crop Group Tolerances on Multiple Commodities. E. Holman et al. 08/06/2013

D413705. Methoxyfenozide. Petition for the Es tablishment of a Tolerance (Section 3 Registration) on Pineapple. Summary of Analytical Chemistry and Residue Data. E. Holman, 4/4/2014.

D407566. Drinking Water Assessment for the IR-4 New Use Petitions for the Use of Methoxyfenozide on Herb Subgroup 19A (except ch ives), Dates, Sorghum, Fruiting Vegetable Group 8-10, Pome Fruit Group 11-10, Berry Subgr oups 13-07 A, F & G and Tropical Tree Fruits. K. Milians, 4/23/2013.

D416709. Drinking Water Assessment for the IR-4 New Use Petition for the Use of Methoxyfenozide on Pineapple. I. Negrón-Encarnación, 12/19/2013.

D413706. Methoxyfenozide. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Regi stration on Pineapple. E. Holman, 4/4/2014.

D413707. Methoxyfenozide

. Occupational and Residential Exposure Assessment for Proposed Use on Pineapples.Methoxyfenozide. M. Collantes, 04/7/2014.

D394924. Methoxyfenozide

. Occupational and Resident ial Exposure Assessment for a Proposed Use on Dates, Sorghum, Herbs (subg roup 19A except chives) and Caneberries (subgroup 13-07A). M. Collantes, 6/7/13.

D258034. PP#8F5004 & PP#8F5006: Methoxyfenozide. Conclusions of the 7/13/99 Meeting of the Metabolism Assessment Review Committee. W. Wassell, 7/13/99.Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 32 of 39 EFSA (European Food Safety Authority), 2014. Reasoned opinion on the re view of the existing maximum residue levels (MRLs) for methoxyfen ozide according to Article 12 of Regulation (EC) No 396/2005. EFSA Journal 2014;12(1):3509. Available at: http://www.efsa.europa.eu/en/efsajournal/doc/3509.pdf

Methoxyfenozide: Summary of Hazard and Sc ience Policy Council (HASPOC) Meeting of March 29, 2012: Recommendation on the need for a 28-day inhalation study. K. Rury and J. Van Alstine, 03/23/12. TXR #0053782Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 33 of 39 

### Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for food use for methoxyfenozide are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity ....................................................... 870.1200 Acute Dermal Toxicity .................................................. 870.1300 Acute In halation Toxicity .............................................. 870.2400 Primar y Eye Irr itation

.................................................... 870.2500 Primar y Dermal Irr itation

.............................................. 870.2600 Derm al Sensiti zation ..................................................... yes yes
yes
yes yes
yes yes yes
yes
yes yes
yes

870.3100 Oral Su bchronic (rodent) ............................................... 870.3150 Oral Su bchronic (nonr odent) ......................................... 870.3200 21-Day Dermal .............................................................. 870.3250 90-Day Dermal .............................................................. 870.3465 28-or 90-Day Inhalation ................................................ yes
yes yes

no no* yes
yes yes

-

no
870.3700a Developmental Toxicity (rodent) .................................. 870.3700b Developmental Toxicity (nonrodent) ............................
870.3800 Reproduc tion ................................................................. yes yes
yes yes yes
yes

870.4100a Chronic T oxicity (rodent) .............................................. 870.4100b Chronic Toxi city (nonrodent) ........................................ 870.4200a Oncoge nicity (ra t) .......................................................... 870.4200b Oncogenicity (mouse) ................................................... 870.4300 Chroni c/Oncogeni city ................................................... yes yes
yes
yes yes yes yes
yes
yes yes
870.5100 Mutagenicity—G ene Mutation - bacterial ..................... 870.5300 Mutagenicity—Gene Mutation - mammalian ................ 870.5xxx Mutagenicity—Struc tural Chromosomal Aberrations ... 870.5xxx Mutagenicity—O ther Genotoxic Effects ....................... yes
yes
yes yes yes
yes
yes yes
870.6100a Acute Delayed Neurotoxicity (hen) ............................... 870.6100b 90-Day Neurotoxicity (hen) .......................................... 870.6200a Acute Neurotoxicity Screening Battery (rat) ................. 870.6200b 90-Day Neurotoxicity Screening Battery (rat) .............. 870.6300 Develop. Neurotoxicity ................................................. no

no
yes yes

no -

- yes yes

-

870.7485 Gene ral Metabo lism ......................................................
870.7600 Derm al Penetr ation ........................................................ 870.7800 Immunotoxicity ............................................................. yes
yes yes yes
yes

yes
Special Studies for Ocular Effects Acute Oral (rat) ........................................................... Subchronic Oral (rat) .................................................. Six-month Oral (dog) .................................................. no

no

no -

-

- * The required repeated dose inhalation toxicity study has been waived.Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 34 of 39 A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Prof ile – Methoxyfenoz ide technical

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 44144415 LD 50 >5000 mg/kg, both sexes IV

870.1100 Acute oral [mouse] 44144416 LD 50 >5000 mg/kg, both sexes IV

870.1200 Acute dermal [rat] 44144418 LD 50 >2000 mg/kg, both sexes III

870.1300 Acute inhalation [rat] 44144420 LC 50 >4.3 mg/L, both sexes IV

870.2400 Acute eye irritation [rabbit] 44144422 Very mild irritant IV

870.2500 Acute dermal irritation [rabbit] 44144424 Not an irritant IV

870.2600 Skin sensitization [Guinea pig] 44144426 Not a sensitizer N/A

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline
No. Study Type MRID No. (year)/ Classification /Doses Results

Nonguideline 2-week oral range-finding (rat) 44617722 (1995)
Acceptable/nonguideline 0, 50, 250, 1000, 5000, 20,000 ppm in the diet [note: mg/kg/day equivalents not calculated; see 90-day oral rat for mg/kg/day] NOAEL = 250 ppm (approximately 17.0/19.1 mg/kg/day M/F based on main study doses)
LOAEL = 1000 ppm (approximately 69.3/72.4 mg/kg/day M/F based on main study doses), based on thyroid gland hypertrophy/hyperplasia in males and females, and increased adrenal hypertrophy of zona fasciculata in females.

At ≥ 5000 ppm, increased abs/rel liver and adrenal weights, hepatocellular hypertrophy

870.3100 90-Day oral toxicity (rat) 44617722 (1995) Acceptable/guideline

0, 50, 250, 1000, 5000, 20,000 ppm in the diet

M: 0, 3.4, 17.0, 69.3, 353.4, 1368.8 mg/kg/day F: 0, 3.7, 19.1,72.4, 379.3, 1531.2 mg/kg/day NOAEL = 69.3/72.4 mg/kg/day [M/F] LOAEL = 353.4 mg/kg/day [M/F] based on periportal hepatocellular hypertrophy and increased liver weight. At 1368.8/1531.2 mg/kg/day: decreased RBC and Hg in females.Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 35 of 39 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline
No. Study Type MRID No. (year)/ Classification /Doses Results

870.3100 90-Day oral toxicity (mouse) 44617723 (1995)
Acceptable/guideline
0, 70, 700, 2500, 7000 ppm in the diet
M: 0, 11.9, 112.5, 428.2, 1149.3 mg/kg/day;
F: 0, 17.4, 165.1, 589.4, 1742.1 mg/kg/day NOAEL = 428.2/589.4 mg/kg/day [M/F]
LOAEL = 1149.3/1742.1 mg/kg/day [M/F] based on decreased body weight gain.

Nonguideline 2-week rangefinding (dog) 44617724 (1995)
Acceptable/nonguideline
0, 300, 3500, 15,000 or 30,000 ppm in the diet (2 animals/sex/dose)
M: 0, 11.7-14.7, 141.6- 167.6, 264.7-370.4, 571.4- 631.7, 1113.7-1337.0 mg/kg/day;
F: 0, 13.3-16.8, 90.8- 184.8, 285.9-336.8, 582.3- 630.9, 1092.6-1169.1 mg/kg/day NOAEL = 11.7-14.7/13.3-16.8 mg/kg/day [M/F]
LOAEL = 141.6-167.6/90.8-184.8 mg/kg/day [M/F], based on hematological changes (decreased RBC parameters, increased Heinz body count, reticulocyte counts, erythrocyte morphology and methemoglobinemia) and increased spleen weights.

At ≥ 264.7 mg/kg/day, bilirubinemia

870.3150 90-Day oral toxicity (dog) 44617724 (1995)
Acceptable/guideline
0, 15, 50, 500 or 5000 ppm in the diet
M: 0, 0.6, 2.0, 21.4, 197.5 mg/kg/day;
F: 0, 0.6, 1.9, 20.4, 208.8 mg/kg/day NOAEL = 197.5/208.8 mg/kg/day [M/F] LOAEL >197.5/208.8 mg/kg/day [M/F](HDT).

870.3200 28-Day dermal toxicity (rat) 44517725 (1998)
Acceptable/guideline
0, 75, 300, 1000 mg/kg/day Systemic NOAEL = 1000 mg/kg/day Systemic LOAEL > 1000 mg/kg/day (HDT)
Local dermal NOAEL = 1000 mg/kg/day Local dermal LOAEL > 1000 mg/kg/day (HDT)

870.3700a Prenatal developmental in (rat) 44638201 (1994)
Acceptable/guideline
0, 100, 300, 1000 mg/kg/day (gavage) Maternal NOAEL = 1000 mg/kg/day LOAEL >1000 mg/kg/day (HDT) Developmental NOAEL = 1000 mg/kg/day LOAEL >1000 mg/kg/day (HDT)Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 36 of 39 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline
No. Study Type MRID No. (year)/ Classification /Doses Results

870.3700b Prenatal developmental in (rabbit) 44617726 (1997)
Acceptable/guideline
0, 100, 300, 1000 mg/kg/day (gavage) Materna l NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day (HDT) Developmenta l NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day (HDT)

870.3800 Reproduction and fertility effects (rat) 44617727 (1997)
Acceptable/guideline
0, 200, 2000 or 20,000 ppm in diet
P1 males: 0, 15.4, 153.4 or 1551.9 mg/kg/day;
P1 females: 0, 17.9, 180.7, 1820.7 mg/kg/day Parental/Systemic NOAEL = 153.4/180.7 mg/kg/day [M/F]; LOAEL = 1551.9/1820.7 mg/kg/day [M/F] based on increased absolute and relative liver weights and microscopic midzonal to periportal hepatocellular hypertrophy. Reproductive NOAEL = 1551.9/1820.7 mg/kg/day [M/F]; LOAEL > 1551.9/1820.7 mg/kg/day [M/F](HDT) Offspring NOAEL = mg/kg/day LOAEL > 1551.9/1820.7 mg/kg/day [M/F](HDT)

870.4100a Chronic toxicity (rat) See 870.4300

870.4100b Chronic toxicity (dog) 44617728 (1997)
Acceptable/guideline
0, 60, 300, 3000 or 30,000 ppm in diet
M: 0, 2.2, 9.8, 106.1, 1152.4 mg/kg/day
F: 0, 2.2, 12.6, 110.6, 1199.2 mg/kg/day NOAEL = 9.8/12.6 mg/kg/day [M/F] LOAEL = 106.1/110.6 mg/kg/day [M/F] based on mild hematological changes (decreased RBC parameters, slight methemoglobinemia) and increased serum bilirubin. Hematological effects first observed at week 14. At 1152.4/1199.2 mg/kg/day: bilirubinemia in males, increased abs/rel liver and thyroid weights, increased cellularity of sternum and rib marrow, increased pigmented macrophages in liver and spleen.

870.4200 Carcinogenicity (rat) 44617731 (1998)
Acceptable/guideline
0, 200, 8000 or 20,000 ppm in diet
M: 0, 10.2, 411 or 1045 mg/kg/day
F: 0, 11.9, 491 or 1248 mg/kg/day NOAEL = 10.2/11.9 mg/kg/day [M/F] LOAEL = 411/491 mg/kg/day [M/F] based on hematological changes (decreased RBC parameters), periportal liver hypertrophy, thyroid hypertrophy and altered colloid; possibly increased adrenal weight.

At 1045/1248 mg/kg/day: decreased survival in males, decreased body weight in females, increased abs/rel liver weight, chronic progressive glomerulonephropathy, tissue mineralization.

no evidence of carcinogenicityMethoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 37 of 39 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline
No. Study Type MRID No. (year)/ Classification /Doses Results

870.4300 Carcinogenicity (mouse) 44617729 (1998)
Acceptable/guideline
0, 70, 2800, 7000 ppm
M: 0, 10.0, 40.5 or 1020 mg/kg/day
F: 0, 12.8, 529 or 1354 mg/kg/day NOAEL = 1020/1354 mg/kg/day [M/F] LOAEL >1020/1354 mg/kg/day [M/F](HDT)

no evidence of carcinogenicity

Gene Mutation
870. 5100 Bacterial reverse gene mutation - Salmonella 44144428 (1995)
Acceptable/guideline
0, 50, 200, 500, 2000, 5000 μg/plate, initial assay; 0, 160, 300, 500, 900, 1600 μg/plate, repeat

assay No evidence of mutagenicity with or without S9 activation up to solubility limit (precipitation observed at ≥ 900 μg/plate).

Gene Mutation

870.5100 Bacterial reverse gene mutation
- Salmonella 44617733 (1998)
Acceptable/guideline
0, 50, 200, 500, 2000, 5000 μg/plate, test material: RH-117,236 (Metabolite M-B) No evidence of mutagenicity with or without S9 activation up to solubility limit (precipitation observed at 2000 and 5000 μg/plate)

In Vitro Mammalian Gene Mutation

870.5300 HGPRT forward gene mutation assay (Chinese hamster ovary, or CHO, cells) 44617734 (1994)
Acceptable/guideline
0, 0.1, 0.5, 1.0, 5.0, 10, 50, 100, 500, 1000, 1250 μg/mL (range-finding study);
0.5, 1.0, 5.0, 10, 50, 100 μg/mL (definitive study) No evidence of mutagenicity with or without S9 activation up to solubility limit (precipitation
observed at ≥ 100 μg/mL)

.

In Vitro Cytogenetics
870.5375 Chromosomal aberration, CHO cells 44617735 (1994)
Acceptable/guideline
0, 0.21, 0.63, 2.1, 6.3, 21, 63, 108, 625, 1250 μg/mL (range-finding study);
0, 13, 125, 100, 150 μg/mL (definitive study) No evidence of incr eased frequency of chromosomal aberration in the presence or absence of S9 activation up doses causing reduced mitotic indices ( ≥ 50 μg/mL).

Other Effects 870.5395 In vivo mouse micronucleus

assay 44617801 (1995)
Acceptable/nonguideline
0, 500, 2500, 5000 mg/kg single IP dose No evidence of incr eased frequency of micronucleus formation in treated CD-1mice in bone marrow at 24 or 48 hrs postdosing; tested up to the limit dose for this assay.Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 38 of 39 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline
No. Study Type MRID No. (year)/ Classification /Doses Results

870.6200a Acute neurotoxicity screening battery (rat) 44617802 (1996)
Acceptable/guideline
0, 1000, 2000 mg/kg by

gavage NOAEL = 1000 mg/kg (males); 2000 mg/kg (females; HDT) LOAEL = 2000 mg/kg (males) based on decreased hindlimb grip strength on Day 0; >2000 mg/kg females (HDT)

870.6200b Subchronic neurotoxicity screening battery (rat) 44617803 (1996)
Acceptable/guideline
0, 200, 2000 or 20,000 ppm in diet
Males 0, 13, 130, 1318 mg/kg/day
Females 0, 16, 159, 1577 mg/kg/day NOAEL = 1318/1577 mg/kg/day [M/F]; LOAEL > 1318/1577 mg/kg/day [M/F] (HDT)

870.7485 Metabolism and pharmacokinetics (rat) 44617804 (1998)
Acceptable/guideline
Single gavage doses of 10 mg/kg and 1000 mg/kg; 5- day repeated gavage doses of 10 mg/kg Absorption and excretion were rapid (<48 hrs postdosing). Tissue distribution was extensive but bioaccumulation was not observed. Major route of excretion was via feces (86-97%) and to a lesser extent, the urine (5-13%). Enterohepatic circulation was observed. Theprimary routes of metabolism were Odemethylation and oxidative hydroxylation followed by conjugation with glucuronic acid.

870.7600 Dermal penetration (rat) 44638202 (1998)
Acceptable/guideline Mean dermal absorption at 10 and 24 hrs was 2% using an 80WP formulation.

870.7800 Immunotoxicity (female rat) 48592601 (2011)
Acceptable/guideline
0, 76.9, 324 or 1076 mg/kg/day in the diet (ppm not indicated) Immunotoxicity NOAEL = 1076 mg/kg/day
Immunotoxicity LOAEL = not established
Systemic toxicity NOAEL = = 76.9 mg/kg/day
Systemic toxicity LOAEL = 324 mg/kg/day, based on increased liver weights.Methoxyfenozide Human Health Risk Assessment DP Barcode 420583

Page 39 of 39 Appendix B. Physical/Chemical Properties.

TABLE 2 Physicochemical Propert ies of Methoxyfenozide.
Parameter Value Reference Molecular Weight 368.47 D231303; H. Podall; 19 May 1997
Melting point/range (oC) 206.1-208
pH 7.0 Density (g/cm 3 ) 0.740 ± 0.0081 Water solubility (mg/L at 20oC) 3.3 Solvent solubility (g/L at 20oC) N-heptane 1.87 Xylene 3.38 1,2-dichloroethane 36.72 Methanol 192.92 2-Propanol 50.22 Vapor pressure (25oC) 1.33 x 10 -5 Pa (1 x 10 -7 mm Hg) Dissociation constant, pK a None Octanol/water partition coefficient (Log [K OW ]) 3.72 ± 0.04

UV/visible absorption (max) ε 55313 at 203 nm European Commission; SANCO/10384/202

– rev. 4 ; 7 October 2004

Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Thes e data, which include studies from the Pesticide Handlers Exposure Database Vers ion 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; and th e Outdoor Residential Exposure Task Force (ORETF) database; are s ubject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certai n studies that review may have included review by the Human Studies Revi ew Board. Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/ pesticides/science/handlerexposure-data.html and http://www.epa.gov/pest icides/science/post-a pp-exposure-data.html.